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Sample records for sous-type nr2b par

  1. Distinct roles of NR2A and NR2B cytoplasmic tails in long term potentiation

    PubMed Central

    Foster, Kelly A.; McLaughlin, Nathan; Edbauer, Dieter; Phillips, Marnie; Bolton, Andrew; Constantine-Paton, Martha; Sheng, Morgan

    2010-01-01

    NMDA receptors (NMDARs) are critical mediators of activity-dependent synaptic plasticity, but the differential roles of NR2A- versus NR2B-containing NMDARs have been controversial. Here, we investigate the roles of NR2A and NR2B in LTP in organotypic hippocampal slice cultures using RNAi and overexpression, to complement pharmacological approaches. In young slices, when NR2B is the predominant subunit expressed, LTP is blocked by the NR2B-selective antagonist Ro25-6981. As slices mature, and NR2A expression rises, activation of NR2B receptors became no longer necessary for LTP induction. LTP was blocked, however, by RNAi knockdown of NR2B, and this was rescued by coexpression of an RNAi-resistant NR2B (NR2B*) cDNA. Interestingly, a chimeric NR2B subunit in which the C-terminal cytoplasmic tail was replaced by that of NR2A failed to rescue LTP while the reverse chimera, NR2A channel with NR2B tail, was able to restore LTP. Thus expression of NR2B with its intact cytoplasmic tail is required for LTP induction, at an age when channel activity of NR2B-NMDARs is not required for LTP. Overexpression of wildtype NR2A failed to rescue LTP in neurons transfected with NR2B-RNAi construct, despite restoring NMDA-EPSC amplitude to a similar level as NR2B*. Surprisingly, an NR2A construct lacking its entire C-terminal cytoplasmic tail regained its ability to restore LTP. Together these data suggest that the NR2B subunit plays a critical role for LTP, presumably by recruiting relevant molecules important for LTP via its cytoplasmic tail. By contrast, NR2A is not essential for LTP and its cytoplasmic tail seems to carry inhibitory factors for LTP. PMID:20164351

  2. Postsynaptic density protein 95-regulated NR2B tyrosine phosphorylation and interactions of Fyn with NR2B in levodopa-induced dyskinesia rat models

    PubMed Central

    Ba, Maowen; Kong, Min; Ma, Guozhao

    2015-01-01

    Context Abnormality in interactions between N-methyl-d-aspartate (NMDA) receptor and its signaling molecules occurs in the lesioned striatum in Parkinson’s disease (PD) and levodopa-induced dyskinesia (LID). It was reported that Fyn-mediated NR2B tyrosine phosphorylation, can enhance NMDA receptor function. Postsynaptic density protein 95 (PSD-95), one of the synapse-associated proteins, regulates interactions between receptor and downstream-signaling molecules. In light of the relationship between PSD-95, NR2B, and Fyn kinases, does PSD-95 contribute to the overactivity of NMDA receptor function induced by dopaminergic treatment? To further prove the possibility, the effects of regulating the PSD-95 expression on the augmented NR2B tyrosine phosphorylation and on the interactions of Fyn and NR2B in LID rat models were evaluated. Methods In the present study, parkinsonian rat models were established by injecting 6-hydroxydopamine. Subsequently, valid PD rats were treated with levodopa (50 mg/kg/day with benserazide 12.5 mg/kg/day, twice daily) intraperitoneally for 22 days to create LID rat models. Then, the effect of pretreatment with an intrastriatal injection of the PSD-95mRNA antisense oligonucleotides (PSD-95 ASO) on the rotational response to levodopa challenge was assessed. The effects of pretreatment with an intrastriatal injection of PSD-95 ASO on the augmented NR2B tyrosine phosphorylation and interactions of Fyn with NR2B in the LID rat models were detected by immunoblotting and immunoprecipitation. Results Levodopa administration twice daily for 22 days to parkinsonian rats shortened the rotational duration and increased the peak turning responses. The altered rotational responses were attenuated by PSD-95 ASO pretreatment. Meanwhile, PSD-95 ASO pretreatment decreased the level of PSD-95 protein expression and reduced both the augmented NR2B tyrosine phosphorylation and interactions of Fyn with NR2B triggered during the levodopa administration in the

  3. Kynurenic acid amides as novel NR2B selective NMDA receptor antagonists.

    PubMed

    Borza, István; Kolok, Sándor; Galgóczy, Kornél; Gere, Anikó; Horváth, Csilla; Farkas, Sándor; Greiner, István; Domány, György

    2007-01-15

    A novel series of kynurenic acid amides, ring-enlarged derivatives of indole-2-carboxamides, was prepared and identified as in vivo active NR2B subtype selective NMDA receptor antagonists. The synthesis and SAR studies are discussed. PMID:17074483

  4. Cloning, expression, and purification of a recombinant Tat-HA-NR2B9c peptide.

    PubMed

    Zhou, Hai-Hui; Zhang, Ai-Xia; Zhang, Yu; Zhu, Dong-Ya

    2012-10-01

    To design a peptide disrupting the interaction between N-methyl-d-aspartate receptors-2B (NR2B) and postsynaptic density protein-95 (PSD-95), a gene fragment encoding a chimeric peptide was constructed using polymerase chain reaction and ligated into a novel expression vector for recombinant expression in a T7 RNA polymerase-based expression system. The chimeric peptide contained a fragment of the cell membrane transduction domain of the human immunodeficiency virus type1 (HIV-1) Tat, a influenza virus hemagglutinin (HA) epitope-tag, and the C-terminal 9 amino acids of NR2B (NR2B9c). We named the chimeric peptide Tat-HA-NR2B9c. The expression plasmid contained a gene fragment encoding the Tat-HA-NR2B9c was ligated to the C-terminal fragment of l-asparaginase (AnsB-C) via a unique acid labile Asp-Pro linker. The recombinant fusion protein was expressed in inclusion body in Escherichia coli under isopropyl β-d-1-thiogalactopyranoside (IPTG) and purified by washing with 2M urea, solubilizing in 4M urea, and then ethanol precipitation. The target chimeric peptide Tat-HA-NR2B9c was released from the fusion partner following acid hydrolysis and purified by isoelectric point precipitation and ultrafiltration. SDS-PAGE analysis and MALDI-TOF-MS analysis showed that the purified Tat-HA-NR2B9c was highly homogeneous. Furthermore, we investigated the effects of Tat-HA-NR2B9c on ischemia-induced cerebral injury in the rats subjected to middle cerebral artery occlusion (MCAO) and reperfusion, and found that the peptide reduced infarct size and improved neurological functions. PMID:22944204

  5. DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in Stroke

    PubMed Central

    Tu, Weihong; Xu, Xin; Peng, Lisheng; Zhong, Xiaofen; Zhang, Wenfeng; Soundarapandian, Mangala M.; Balel, Cherine; Wang, Manqi; Jia, Nali; Zhang, Wen; Lew, Frank; Chan, Sic Lung; Chen, Yanfang; Lu, Youming

    2010-01-01

    SUMMARY N-methyl-D-aspartate (NMDA) receptors constitute a major subtype of glutamate receptors at extra-synaptic sites that link multiple intracellular catabolic processes responsible for irreversible neuronal death. Here, we report that cerebral ischemia recruits death-associated protein kinase 1 (DAPK1) into the NMDA receptor NR2B protein complex in the cortex of adult mice. DAPK1 directly binds with the NMDA receptor NR2B C-terminal tail consisting of amino acid 1292–1304 (NR2BCT). A constitutively active DAPK1 phosphorylates NR2B subunit at Ser-1303 and in turn enhances the NR1/NR2B receptor channel conductance. Genetic deletion of DAPK1 or administration of NR2BCT that uncouples an activated DAPK1 from an NMDA receptor NR2B subunit in vivo in mice blocks injurious Ca2+ influx through NMDA receptor channels at extrasynaptic sites and protects neurons against cerebral ischemic insults. Thus, DAPK1 physically and functionally interacts with the NMDA receptor NR2B subunit at extra-synaptic sites and this interaction acts as a central mediator for stroke damage. PMID:20141836

  6. SRC Inhibition Reduces NR2B Surface Expression and Synaptic Plasticity in the Amygdala

    ERIC Educational Resources Information Center

    Sinai, Laleh; Duffy, Steven; Roder, John C.

    2010-01-01

    The Src protein tyrosine kinase plays a central role in the regulation of N-methyl-d-aspartate receptor (NMDAR) activity by regulating NMDAR subunit 2B (NR2B) surface expression. In the amygdala, NMDA-dependent synaptic plasticity resulting from convergent somatosensory and auditory inputs contributes to emotional memory; however, the role of Src…

  7. New benzoyl urea derivatives as novel NR2B selective NMDA receptor antagonists.

    PubMed

    Borza, I; Greiner, I; Kolok, S; Galgóczy, K; Ignácz-Szendrei, Gy; Horváth, Cs; Farkas, S; Gáti, T; Háda, V; Domány, Gy

    2006-09-01

    A novel series of benzoyl urea derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of the substitution of the piperidine ring on the biological activity of the compounds was studied. Compound 9 was active in the formalin test in mice. PMID:17020160

  8. Benzimidazole-2-carboxamides as novel NR2B selective NMDA receptor antagonists.

    PubMed

    Borza, István; Kolok, Sándor; Gere, Anikó; Nagy, József; Fodor, László; Galgóczy, Kornél; Fetter, József; Bertha, Ferenc; Agai, Béla; Horváth, Csilla; Farkas, Sándor; Domány, György

    2006-09-01

    A novel series of benzimidazole-2-carboxamide derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of some structural elements, like H-bond donor groups placed on the benzimidazole skeleton and the substitution pattern of the piperidine ring, on the biological activity was studied. Compound 6a showed excellent analgetic activity in the mouse formalin test following po administration. PMID:16782335

  9. Allosteric modulators of NR2B-containing NMDA receptors: molecular mechanisms and therapeutic potential.

    PubMed

    Mony, Laetitia; Kew, James N C; Gunthorpe, Martin J; Paoletti, Pierre

    2009-08-01

    N-methyl-D-aspartate receptors (NMDARs) are ion channels gated by glutamate, the major excitatory neurotransmitter in the mammalian central nervous system (CNS). They are widespread in the CNS and are involved in numerous physiological and pathological processes including synaptic plasticity, chronic pain and psychosis. Aberrant NMDAR activity also plays an important role in the neuronal loss associated with ischaemic insults and major degenerative disorders including Parkinson's and Alzheimer's disease. Agents that target and alter NMDAR function may, thus, have therapeutic benefit. Interestingly, NMDARs are endowed with multiple extracellular regulatory sites that recognize ions or small molecule ligands, some of which are likely to regulate receptor function in vivo. These allosteric sites, which differ from agonist-binding and channel-permeation sites, provide means to modulate, either positively or negatively, NMDAR activity. The present review focuses on allosteric modulation of NMDARs containing the NR2B subunit. Indeed, the NR2B subunit confers a particularly rich pharmacology with distinct recognition sites for exogenous and endogenous allosteric ligands. Moreover, NR2B-containing receptors, compared with other NMDAR subtypes, appear to contribute preferentially to pathological processes linked to overexcitation of glutamatergic pathways. The actions of extracellular H+, Mg2+, Zn2+, of polyamines and neurosteroids, and of the synthetic compounds ifenprodil and derivatives ('prodils') are presented. Particular emphasis is put upon the structural determinants and molecular mechanisms that underlie the effects exerted by these agents. A better understanding of how NR2B-containing NMDARs (and NMDARs in general) operate and how they can be modulated should help define new strategies to counteract the deleterious effects of dysregulated NMDAR activity. PMID:19594762

  10. NR2B-containing NMDA receptors promote neural progenitor cell proliferation through CaMKIV/CREB pathway

    SciTech Connect

    Li, Mei; Zhang, Dong-Qing; Wang, Xiang-Zhen; Xu, Tie-Jun

    2011-08-12

    Highlights: {yields} The NR2B component of the NMDARs is important for the NSPC proliferation. {yields} pCaMKIV and pCREB exist in NSPCs. {yields} The CaMKIV/CREB pathway mediates NSPC proliferation. -- Abstract: Accumulating evidence indicates the involvement of N-methyl-D-aspartate receptors (NMDARs) in regulating neural stem/progenitor cell (NSPC) proliferation. Functional properties of NMDARs can be markedly influenced by incorporating the regulatory subunit NR2B. Here, we aim to analyze the effect of NR2B-containing NMDARs on the proliferation of hippocampal NSPCs and to explore the mechanism responsible for this effect. NSPCs were shown to express NMDAR subunits NR1 and NR2B. The NR2B selective antagonist, Ro 25-6981, prevented the NMDA-induced increase in cell proliferation. Moreover, we demonstrated that the phosphorylation levels of calcium/calmodulin-dependent protein kinase IV (CaMKIV) and cAMP response element binding protein (CREB) were increased by NMDA treatment, whereas Ro 25-6981 decreased them. The role that NR2B-containing NMDARs plays in NSPC proliferation was abolished when CREB phosphorylation was attenuated by CaMKIV silencing. These results suggest that NR2B-containing NMDARs have a positive role in regulating NSPC proliferation, which may be mediated through CaMKIV phosphorylation and subsequent induction of CREB activation.

  11. Role for the NR2B Subunit of the NMDA Receptor in Mediating Light Input to the Circadian System

    PubMed Central

    Wang, LM; Schroeder, A; Loh, D; Smith, D; Lin, K; Han, JH; Michel, S; Hummer, DL; Ehlen, JC; Albers, HE; Colwell, CS

    2008-01-01

    Light information reaches the suprachiasmatic nucleus (SCN) through a subpopulation of retinal ganglion cells that utilize glutamate as a neurotransmitter. A variety of evidence suggests that the release of glutamate then activates N-methyl-Daspartate (NMDA) receptors within the SCN and triggers a signaling cascade that ultimately leads to phase shifts in the circadian system. In this study, we first sought to explore the role of the NR2B subunit in mediating the effects of light on the circadian system. We found that localized microinjection of the NR2B subunit antagonist ifenprodil into the SCN region inhibits the magnitude of light-induced phase shifts of the circadian rhythm in wheel-running activity. Next, we found that the NR2B message and levels of phospho-NR2B levels vary with time of day in SCN tissue using semi-quantitative real-time PCR and Western blot analysis, respectively. Functionally, we found that blocking the NR2B subunit with ifenprodil significantly reduced the magnitude of NMDA currents recorded in SCN neurons. Ifenprodil also significantly reduced the magnitude of NMDA-induced calcium changes in SCN cells. Together, these results demonstrate that the NR2B subunit is an important component of NMDA receptor mediated responses within SCN neurons and that this subunit contributes to light-induced phase shifts of the mammalian circadian system. PMID:18380671

  12. Dissociable Roles for the Ventromedial Prefrontal Cortex and Amygdala in Fear Extinction: NR2B Contribution

    PubMed Central

    Diaz-Mataix, Llorenç; Bush, David E.A.; LeDoux, Joseph E.

    2009-01-01

    Fear extinction, which involves learning to suppress the expression of previously learned fear, requires N-methyl-D-aspartate receptors (NMDARs) and is mediated by the amygdala and ventromedial prefrontal cortex (vmPFC). Like other types of learning, extinction involves acquisition and consolidation phases. We recently demonstrated that NR2B-containing NMDARs (NR2Bs) in the lateral amygdala (LA) are required for extinction acquisition, but whether they are involved in consolidation is not known. Further, although it has been shown that NMDARs in the vmPFC are required for extinction consolidation, whether NR2Bs in vmPFC are involved in consolidation is not known. In this report, we investigated the possible role of LA and vmPFC NR2Bs in the consolidation of fear extinction using the NR2B-selective antagonist ifenprodil. We show that systemic treatment with ifenprodil immediately after extinction training disrupts extinction consolidation. Ifenprodil infusion into vmPFC, but not the LA, immediately after extinction training also disrupts extinction consolidation. In contrast, we also show pre-extinction training infusions into vmPFC has no effect. These results, together with our previous findings showing that LA NR2Bs are required during the acquisition phase in extinction, indicate a double dissociation for the phase-dependent role of NR2Bs in the LA (acquisition, not consolidation) and vmPFC (consolidation, not acquisition). PMID:18562331

  13. Setdb1 histone methyltransferase regulates mood-related behaviors and expression of the NMDA receptor subunit NR2B.

    PubMed

    Jiang, Yan; Jakovcevski, Mira; Bharadwaj, Rahul; Connor, Caroline; Schroeder, Frederick A; Lin, Cong L; Straubhaar, Juerg; Martin, Gilles; Akbarian, Schahram

    2010-05-26

    Histone methyltransferases specific for the histone H3-lysine 9 residue, including Setdb1 (Set domain, bifurcated 1)/Eset/Kmt1e are associated with repressive chromatin remodeling and expressed in adult brain, but potential effects on neuronal function and behavior remain unexplored. Here, we report that transgenic mice with increased Setdb1 expression in adult forebrain neurons show antidepressant-like phenotypes in behavioral paradigms for anhedonia, despair, and learned helplessness. Chromatin immunoprecipitation in conjunction with DNA tiling arrays (ChIP-chip) revealed that genomic occupancies of neuronal Setdb1 are limited to <1% of annotated genes, which include the NMDA receptor subunit NR2B/Grin2B and other ionotropic glutamate receptor genes. Chromatin conformation capture and Setdb1-ChIP revealed a loop formation tethering the NR2B/Grin2b promoter to the Setdb1 target site positioned 30 kb downstream of the transcription start site. In hippocampus and ventral striatum, two key structures in the neuronal circuitry regulating mood-related behaviors, Setdb1-mediated repressive histone methylation at NR2B/Grin2b was associated with decreased NR2B expression and EPSP insensitivity to pharmacological blockade of NR2B, and accelerated NMDA receptor desensitization consistent with a shift in NR2A/B subunit ratios. In wild-type mice, systemic treatment with the NR2B antagonist, Ro25-6981 [R-(R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propranol], and hippocampal small interfering RNA-mediated NR2B/Grin2b knockdown resulted in behavioral changes similar to those elicited by the Setdb1 transgene. Together, these findings point to a role for neuronal Setdb1 in the regulation of affective and motivational behaviors through repressive chromatin remodeling at a select set of target genes, resulting in altered NMDA receptor subunit composition and other molecular adaptations. PMID:20505083

  14. Effects of diazoxide on Aβ1-42-induced expression of the NR2B subunit in cultured cholinergic neurons.

    PubMed

    Zhu, Jin; Fu, Qingxi; Xia, Chunfeng; Ma, Guozhao

    2015-12-01

    The accumulation of amyloid-β protein (Aβ) is significant in the pathogenesis of Alzheimer's disease. Several previous studies indicate that the NR2B‑containing N‑methyl‑D‑aspartate receptors are critically involved in the Aβ mediated disruption of neuronal function. Diazoxide (DZ), a highly selective drug capable of opening mitochondrial ATP‑sensitive potassium channels, has neuroprotective effects against neuronal cell death. However, the mechanism by which DZ protects cholinergic neurons against Aβ‑induced cytotoxicity remains to be elucidated. The present study was designed to investigate the effects of DZ pretreatment against Aβ1‑42‑induced expression of NR2B in order to gain novel insights into the neuroprotective mechanisms. Following exposure to Aβ1‑42 for 24 h, the expression of the NR2B subunit remained unchanged compared with the control group. However, a significant increase in the expression of the NR2B subunit was observed following treatment with Aβ1‑42 for 72 h (P<0.05); and the upregulation of the expression of the NR2B subunit was reversed by pretreatment with DZ (P<0.05). These results suggested that DZ may counteract Aβ1‑42‑mediated cytotoxicity by alleviating the expression of NR2B. PMID:26496862

  15. Co-activation of NR2A and NR2B subunits induces resistance to fear extinction.

    PubMed

    Leaderbrand, Katherine; Corcoran, Kevin A; Radulovic, Jelena

    2014-09-01

    Unpredictable stress is known to profoundly enhance susceptibility to fear and anxiety while reducing the ability to extinguish fear when threat is no longer present. Accordingly, partial aversive reinforcement, via random exposure to footshocks, induces fear that is resistant to extinction. Here we sought to determine the hippocampal mechanisms underlying susceptibility versus resistance to context fear extinction as a result of continuous (CR) and partial (PR) reinforcement, respectively. We focused on N-methyl-D-aspartate receptor (NMDAR) subunits 2A and B (NR2A and NR2B) as well as their downstream signaling effector, extracellular signal-regulated kinase (ERK), based on their critical role in the acquisition and extinction of fear. Pharmacological inactivation of NR2A, but not NR2B, blocked extinction after CR, whereas inactivation of NR2A, NR2B, or both subunits facilitated extinction after PR. The latter finding suggests that co-activation of NR2A and NR2B contributes to persistent fear following PR. In contrast to CR, PR increased membrane levels of ERK and NR2 subunits after the conditioning and extinction sessions, respectively. In parallel, nuclear activation of ERK was significantly reduced after the extinction session. Thus, co-activation and increased surface expression of NR2A and NR2B, possibly mediated by ERK, may cause persistent fear. These findings suggest that patients with post-traumatic stress disorder (PTSD) may benefit from antagonism of specific NR2 subunits. PMID:24055686

  16. Negative Allosteric Modulators Selective for The NR2B Subtype of The NMDA Receptor Impair Cognition in Multiple Domains.

    PubMed

    Weed, Michael R; Bookbinder, Mark; Polino, Joseph; Keavy, Deborah; Cardinal, Rudolf N; Simmermacher-Mayer, Jean; Cometa, Fu-ni L; King, Dalton; Thangathirupathy, Srinivasan; Macor, John E; Bristow, Linda J

    2016-01-01

    Antidepressant activity of N-methyl-D-aspartate (NMDA) receptor antagonists and negative allosteric modulators (NAMs) has led to increased investigation of their behavioral pharmacology. NMDA antagonists, such as ketamine, impair cognition in multiple species and in multiple cognitive domains. However, studies with NR2B subtype-selective NAMs have reported mixed results in rodents including increased impulsivity, no effect on cognition, impairment or even improvement of some cognitive tasks. To date, the effects of NR2B-selective NAMs on cognitive tests have not been reported in nonhuman primates. The current study evaluated two selective NR2B NAMs, CP101,606 and BMT-108908, along with the nonselective NMDA antagonists, ketamine and AZD6765, in the nonhuman primate Cambridge Neuropsychological Test Automated Battery (CANTAB) list-based delayed match to sample (list-DMS) task. Ketamine and the two NMDA NR2B NAMs produced selective impairments in memory in the list-DMS task. AZD6765 impaired performance in a non-specific manner. In a separate cohort, CP101,606 impaired performance of the nonhuman primate CANTAB visuo-spatial Paired Associates Learning (vsPAL) task with a selective impairment at more difficult conditions. The results of these studies clearly show that systemic administration of a selective NR2B NAM can cause transient cognitive impairment in multiple cognitive domains. PMID:26105137

  17. The selectivity of conantokin-G for ion channel inhibition of NR2B subunit-containing NMDA receptors is regulated by amino acid residues in the S2 region of NR2B.

    PubMed

    Sheng, Zhenyu; Liang, Zhong; Geiger, James H; Prorok, Mary; Castellino, Francis J

    2009-08-01

    The conantokins are short, naturally occurring peptides that inhibit ion flow through N-methyl-d-aspartate receptor (NMDAR) channels. One member of this peptide family, conantokin-G (con-G), shows high selectivity for antagonism of NR2B-containing NMDAR channels, whereas other known conantokins are less selective inhibitors with regard to the nature of the NR2 subunit of the NMDAR complex. In order to define the molecular determinants of NR2B that govern con-G selectivity, we evaluated the ability of con-G to inhibit NMDAR ion channels expressed in human embryonic kidney (HEK)293 cells transfected with NR1, in combination with various NR2A/2B chimeras and point mutants, by electrophysiology using cells voltage-clamped in the whole-cell configuration. We found that a variant of the con-G-insensitive subunit, NR2A, in which the 158 residues comprising the S2 peptide segment (E(657)-I(814)) were replaced by the corresponding S2 region of NR2B (E(658)-I(815)), results in receptors that are highly sensitive to inhibition by con-G. Of the 22 amino acids that are different between the NR2A-S2 and the NR2B-S2 regions, exchange of one of these, M(739) of NR2B for the equivalent K(738) of NR2A, was sufficient to completely import the inhibitory activity of con-G into NR1b/NR2A-containing NMDARs. Some reinforcement of this effect was found by substitution of a second amino acid, K(755) of NR2B for Y(754) of NR2A. The discovery of the molecular determinants of NR2B selectivity with con-G has implications for the design of subunit-selective neurobiological probes and drug therapies, in addition to advancing our understanding of NR2B- versus NR2A-mediated neurological processes. PMID:19427876

  18. NR2B subunit in the prefrontal cortex: A double-edged sword for working memory function and psychiatric disorders.

    PubMed

    Monaco, Sarah A; Gulchina, Yelena; Gao, Wen-Jun

    2015-09-01

    The prefrontal cortex (PFC) is a brain region featured with working memory function. The exact mechanism of how working memory operates within the PFC circuitry is unknown, but persistent neuronal firing recorded from prefrontal neurons during a working memory task is proposed to be the neural correlate of this mnemonic encoding. The PFC appears to be specialized for sustaining persistent firing, with N-methyl-D-aspartate (NMDA) receptors, especially slow-decay NR2B subunits, playing an essential role in the maintenance of sustained activity and normal working memory function. However, the NR2B subunit serves as a double-edged sword for PFC function. Because of its slow kinetics, NR2B endows the PFC with not only "neural psychic" properties, but also susceptibilities for neuroexcitotoxicity and psychiatric disorders. This review aims to clarify the interplay among working memory, the PFC, and NMDA receptors; demonstrate the importance of NR2B in the maintenance of persistent activity; understand the risks and vulnerabilities of how NR2B is related to the development of neuropsychiatric disorders; identify gaps that currently exist in our understanding of these processes; and provide insights regarding future directions that may clarify these issues. We conclude that the PFC is a specialized brain region with distinct delayed maturation, unique neuronal circuitry, and characteristic NMDA receptor function. The unique properties and development of NMDA receptors, especially enrichment of NR2B subunits, endow the PFC with not only the capability to generate sustained activity for working memory, but also serves as a major vulnerability to environmental insults and risk factors for psychiatric disorders. PMID:26143512

  19. Novel approach to probe subunit-specific contributions to N-methyl-D-aspartate (NMDA) receptor trafficking reveals a dominant role for NR2B in receptor recycling.

    PubMed

    Tang, Tina Tze-Tsang; Badger, John D; Roche, Paul A; Roche, Katherine W

    2010-07-01

    N-Methyl-d-aspartate (NMDA) receptors are expressed at excitatory synapses throughout the brain and are essential for neuronal development and synaptic plasticity. Functional NMDA receptors are tetramers, typically composed of NR1 and NR2 subunits (NR2A-D). NR2A and NR2B are expressed in the forebrain and are thought to assemble as diheteromers (NR1/NR2A, NR1/NR2B) and triheteromers (NR1/NR2A/NR2B). NR2A and NR2B contain cytosolic domains that regulate distinct postendocytic sorting events, with NR2A sorting predominantly into the degradation pathway, and NR2B preferentially trafficking through the recycling pathway. However, the interplay between these two subunits remains an open question. We have now developed a novel approach based on the dimeric feature of the alpha- and beta-chains of the human major histocompatibility complex class II molecule. We created chimeras of alpha- and beta-chains with the NR2A and NR2B C termini and evaluated endocytosis of dimers. Like chimeric proteins containing only a single NR2A or NR2B C-terminal domain, major histocompatibility complex class II-NR2A homodimers sort predominantly to late endosomes, whereas NR2B homodimers traffic to recycling endosomes. Interestingly, NR2A/NR2B heterodimers traffic preferentially through the recycling pathway, and NR2B is dominant in regulating dimer trafficking in both heterologous cells and neurons. In addition, the recycling of NR2B-containing NMDARs in wild-type neurons is not significantly different from NR2A(-/-) neurons. These data support a dominant role for NR2B in regulating the trafficking of triheteromeric NMDARs in vivo. Furthermore, our molecular approach allows for the direct and selective evaluation of dimeric assemblies and can be used to define dominant trafficking domains in other multisubunit protein complexes. PMID:20427279

  20. Senegenin Attenuates Hepatic Ischemia-Reperfusion Induced Cognitive Dysfunction by Increasing Hippocampal NR2B Expression in Rats

    PubMed Central

    Gu, Xiaoping; Zheng, Yaguo; Sun, Yu-e; Liang, Ying; Bo, Jinhua; Ma, Zhengliang

    2012-01-01

    Background The root of Polygala tenuifolia, a traditional Chinese medicine, has been used to improve memory and intelligence, while the underlying mechanisms remain largely unknown. In this study, we investigated the protective effects of senegenin, an component of Polygala tenuifolia root extracts, on cognitive dysfunction induced by hepatic ischemia-reperfusion. Methodology/Principal Findings Initially, we constructed a rat model of hepatic ischemia-reperfusion (HIR) and found that the memory retention ability of rats in the step-down and Y maze test was impaired after HIR, paralleled by a decrease of N-methyl-D-aspartate (NMDA) receptor NR2B subunit mRNA and protein expressions in hippocampus. Furthermore, we found that administration of senegenin by gavage attenuated HIR-induced cognitive impairment in a dose and time dependent manner, and its mechanisms might partly due to the increasing expression of NR2B in rat hippocampus. Conclusions/Significance Cognitive dysfunction induced by HIR is associated with reduction of NR2B expression. Senegenin plays a neuroprotective role in HIR via increasing NR2B expression in rat hippocampus. These findings suggest that senegenin might be a potential agent for prevention and treatment of postoperative cognitive dysfunction (POCD) or other neurodegenerative diseases. PMID:23029109

  1. Mas-Related Gene (Mrg) C Activation Attenuates Bone Cancer Pain via Modulating Gi and NR2B

    PubMed Central

    Lu, Cui’e; Lei, Yishan; Ma, Zhengliang; Gu, Xiaoping

    2016-01-01

    Objective This study is to investigate the role of Mas-related gene (Mrg) C in the pathogenesis and treatment of bone cancer pain (BCP). Methods BCP mouse model was established by osteosarcoma cell inoculation. Pain-related behaviors were assessed with the spontaneous lifting behavior test and mechanical allodynia test. Expression levels of MrgC, Gi, and NR2B in the spinal cord were detected with Western blot analysis and immunohistochemistry. Results Pain-related behavior tests showed significantly increased spontaneous flinches (NSF) and decreased paw withdrawal mechanical threshold (PWMT) in mouse models of BCP. Western blot analysis showed that, compared with the control group and before modeling, all the expression levels of MrgC, Gi, and NR2B in the spinal cord of BCP mice were dramatically elevated, which were especially increased at day 7 after operation and thereafter, in a time-dependent manner. Moreover, the treatment of MrgC agonist BAM8-22 significantly up-regulated Gi and down-regulated NR2B expression levels, in the spinal cord of BCP mice, in a time-dependent manner. On the other hand, anti-MrgC significantly down-regulated Gi expression, while dramatically up-regulated NR2B expression, in the BCP mice. Similar results were obtained from the immunohistochemical detection. Importantly, BAM8-22 significantly attenuated the nociceptive behaviors in the BCP mice. Conclusion Our results indicated the MrgC-mediated Gi and NR2B expression alterations in the BCP mice, which might contribute to the pain hypersensitivity. These findings may provide a novel strategy for the treatment of BCP in clinic. PMID:27152740

  2. Protective immunity of rAd5/NR2B vaccine against concomitant aversiveness of spontaneous neuropathic pain following spinal nerve ligation injury

    PubMed Central

    Wang, Gong-Ming; Wang, Xiao-Yan; Liu, Guang-Jie; Cheng, Kun; Wang, Hua; Guo, Shou-Gang

    2015-01-01

    Objective: Peripheral nerve injury elicits an aversive state of spontaneous neuropathic pain, and up to now, the modulation of this concomitant aversive state remains a major therapeutic challenge. NMDA receptor subunits NR2B in the rACC are critically involved in the processing of this aversive state and then a strategy targeted at the NR2B subunit might be promising for modulation of the aversive state. Thus, in the present study, using negative reinforcement animal model to reveal spontaneous pain, we investigated the effect of oral immunization with recombinant adenovirus serotype 5-mediated NR2B gene transfer (rAd5/NR2B) on the modulation of the tonic pain. Material and methods: Following oral administration of the rAd5/NR2B vaccine, NR2B-specific antibodies were induced in serum. And the humoral response was involved in the decreased expression of NR2B protein in the rACC. Results: The present study demonstrated that CPP achieved by spinal administration of clonidine in spinal nerve ligation (SNL) rats revealed the presence of aversive state of spontaneous neuropathic pain. Notably, the humoral autoimmune response blocked the CPP by spinal clonidine, suggesting the relief of the concomitant aversive of spontaneous neuropathic pain in the SNL rats. Conclusion: These data proved the feasibility of oral immunization with rAd5/NR2B for modulation of concomitant aversive of spontaneous neuropathic pain due to peripheral nerve injury. PMID:26309509

  3. NR2B-dependent cyclophilin D translocation suppresses the recovery of synaptic transmission after oxygen-glucose deprivation.

    PubMed

    Zhang, Zhihua; Wang, Yongfu; Yan, Shijun; Du, Fang; Yan, Shirley Shidu

    2015-10-01

    N-methyl d-aspartate receptor (NMDA) subunit 2B (NR2B)-containing NMDA receptors and mitochondrial protein cyclophilin D (CypD) are well characterized in mediating neuronal death after ischemia, respectively. However, whether and how NR2B and CypD work together in mediating synaptic injury after ischemia remains elusive. Using an ex vivo ischemia model of oxygen-glucose deprivation (OGD) in hippocampal slices, we identified a NR2B-dependent mechanism for CypD translocation onto the mitochondrial inner membrane. CypD depletion (CypD null mice) prevented OGD-induced impairment in synaptic transmission recovery. Overexpression of neuronal CypD mice (CypD+) exacerbated OGD-induced loss of synaptic transmission. Inhibition of CypD-dependent mitochondrial permeability transition pore (mPTP) opening by cyclosporine A (CSA) attenuated ischemia-induced synaptic perturbation in CypD+ and non-transgenic (non-Tg) mice. The treatment of antioxidant EUK134 to suppress mitochondrial oxidative stress rescued CypD-mediated synaptic dysfunction following OGD in CypD+ slices. Furthermore, OGD provoked the interaction of CypD with P53, which was enhanced in slices overexpressing CypD but was diminished in CypD-null slices. Inhibition of p53 using a specific inhibitor of p53 (pifithrin-μ) attenuated the CypD/p53 interaction following OGD, along with a restored synaptic transmission in both non-Tg and CypD+ hippocampal slices. Our results indicate that OGD-induced CypD translocation potentiates CypD/P53 interaction in a NR2B dependent manner, promoting oxidative stress and loss of synaptic transmission. We also evaluate a new ex vivo chronic OGD-induced ischemia model for studying the effect of oxidative stress on synaptic damage. PMID:26232180

  4. Early auditory enrichment with music enhances auditory discrimination learning and alters NR2B protein expression in rat auditory cortex.

    PubMed

    Xu, Jinghong; Yu, Liping; Cai, Rui; Zhang, Jiping; Sun, Xinde

    2009-01-01

    Previous studies have shown that the functional development of auditory system is substantially influenced by the structure of environmental acoustic inputs in early life. In our present study, we investigated the effects of early auditory enrichment with music on rat auditory discrimination learning. We found that early auditory enrichment with music from postnatal day (PND) 14 enhanced learning ability in auditory signal-detection task and in sound duration-discrimination task. In parallel, a significant increase was noted in NMDA receptor subunit NR2B protein expression in the auditory cortex. Furthermore, we found that auditory enrichment with music starting from PND 28 or 56 did not influence NR2B expression in the auditory cortex. No difference was found in the NR2B expression in the inferior colliculus (IC) between music-exposed and normal rats, regardless of when the auditory enrichment with music was initiated. Our findings suggest that early auditory enrichment with music influences NMDA-mediated neural plasticity, which results in enhanced auditory discrimination learning. PMID:18706452

  5. Phosphorylation of NR2B NMDA subunits by protein kinase C in arcuate nucleus contributes to inflammatory pain in rats

    PubMed Central

    Bu, Fan; Tian, Huiyu; Gong, Shan; Zhu, Qi; Xu, Guang-Yin; Tao, Jin; Jiang, Xinghong

    2015-01-01

    The arcuate nucleus (ARC) of the hypothalamus plays a key role in pain processing. Although it is well known that inhibition of NMDA receptor (NMDAR) in ARC attenuates hyperalgesia induced by peripheral inflammation, the underlying mechanism of NMDAR activation in ARC remains unclear. Protein kinase C (PKC) is involved in several signalling cascades activated in physiological and pathological conditions. Therefore, we hypothesised that upregulation of PKC activates NMDARs in the ARC, thus contributing to inflammatory hyperalgesia. Intra-ARC injection of chelerythrine (CC), a specific PKC inhibitor, attenuated complete Freund’s adjuvant (CFA) induced thermal and mechanical hyperalgesia in a dose-dependent manner. In vivo extracellular recordings showed that microelectrophoresis of CC or MK-801 (a NMDAR antagonist) significantly reduced the enhancement of spontaneous discharges and pain-evoked discharges of ARC neurons. In addition, CFA injection greatly enhanced the expression of total and phosphorylated PKCγ in the ARC. Interestingly, CFA injection also remarkably elevated the level of phosphorylated NR2B (Tyr1472) without affecting the expression of total NR2B. Importantly, intra-ARC injection of CC reversed the upregulation of phosphorylated NR2B subunits in the ARC. Taken together, peripheral inflammation leads to an activation of NMDARs mediated by PKC activation in the ARC, thus producing thermal and mechanical hyperalgesia. PMID:26515544

  6. A Novel Protein Complex in Membrane Rafts Linking the NR2B Glutamate Receptor and Autophagy Is Disrupted following Traumatic Brain Injury

    PubMed Central

    Bigford, Gregory E.; Alonso, Ofelia F.; Dietrich, W. Dalton

    2009-01-01

    Abstract Hyperactivation of N-methyl-d-aspartate receptors (NRs) is associated with neuronal cell death induced by traumatic brain injury (TBI) and many neurodegenerative conditions. NR signaling efficiency is dependent on receptor localization in membrane raft microdomains. Recently, excitotoxicity has been linked to autophagy, but mechanisms governing signal transduction remain unclear. Here we have identified protein interactions between NR2B signaling intermediates and the autophagic protein Beclin-1 in membrane rafts of the normal rat cerebral cortex. Moderate TBI induced rapid recruitment and association of NR2B and pCaMKII to membrane rafts, and translocation of Beclin-1 out of membrane microdomains. Furthermore, TBI caused significant increases in expression of key autophagic proteins and morphological hallmarks of autophagy that were significantly attenuated by treatment with the NR2B antagonist Ro 25-6981. Thus, stimulation of autophagy by NR2B signaling may be regulated by redistribution of Beclin-1 in membrane rafts after TBI. PMID:19335206

  7. The qEEG Signature of Selective NMDA NR2B Negative Allosteric Modulators; A Potential Translational Biomarker for Drug Development

    PubMed Central

    Keavy, Deborah; Bristow, Linda J.; Sivarao, Digavalli V.; Batchelder, Margaret; King, Dalton; Thangathirupathy, Srinivasan; Macor, John E.; Weed, Michael R.

    2016-01-01

    The antidepressant activity of the N-methyl-D-aspartate (NMDA) receptor channel blocker, ketamine, has led to the investigation of negative allosteric modulators (NAMs) selective for the NR2B receptor subtype. The clinical development of NR2B NAMs would benefit from a translational pharmacodynamic biomarker that demonstrates brain penetration and functional inhibition of NR2B receptors in preclinical species and humans. Quantitative electroencephalography (qEEG) is a translational measure that can be used to demonstrate pharmacodynamic effects across species. NMDA receptor channel blockers, such as ketamine and phencyclidine, increase the EEG gamma power band, which has been used as a pharmacodynamic biomarker in the development of NMDA receptor antagonists. However, detailed qEEG studies with ketamine or NR2B NAMs are lacking in nonhuman primates. The aim of the present study was to determine the effects on the qEEG power spectra of the NR2B NAMs traxoprodil (CP-101,606) and BMT-108908 in nonhuman primates, and to compare them to the NMDA receptor channel blockers, ketamine and lanicemine. Cynomolgus monkeys were surgically implanted with EEG radio-telemetry transmitters, and qEEG was measured after vehicle or drug administration. The relative power for a number of frequency bands was determined. Ketamine and lanicemine increased relative gamma power, whereas the NR2B NAMs traxoprodil and BMT-108908 had no effect. Robust decreases in beta power were elicited by ketamine, traxoprodil and BMT-108908; and these agents also produced decreases in alpha power and increases in delta power at the doses tested. These results suggest that measurement of power spectra in the beta and delta bands may represent a translational pharmacodynamic biomarker to demonstrate functional effects of NR2B NAMs. The results of these studies may help guide the selection of qEEG measures that can be incorporated into early clinical evaluation of NR2B NAMs in healthy humans. PMID:27035340

  8. Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation through activating the NR2B subunits of NMDA receptors

    SciTech Connect

    Shi, Wen-Zhu; Miao, Yu-Liang; Guo, Wen-Zhi; Wu, Wei; Li, Bao-Wei; An, Li-Na; Fang, Wei-Wu; Mi, Wei-Dong

    2014-04-25

    Highlights: • Leptin promotes the proliferation of neural stem cells isolated from embryonic mouse hippocampus. • Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation. • The effects of leptin are partially mediated by upregulating NR2B subunits. - Abstract: Corticosterone inhibits the proliferation of hippocampal neural stem cells (NSCs). The removal of corticosterone-induced inhibition of NSCs proliferation has been reported to contribute to neural regeneration. Leptin has been shown to regulate brain development, improve angiogenesis, and promote neural regeneration; however, its effects on corticosterone-induced inhibition of NSCs proliferation remain unclear. Here we reported that leptin significantly promoted the proliferation of hippocampal NSCs in a concentration-dependent pattern. Also, leptin efficiently reversed the inhibition of NSCs proliferation induced by corticosterone. Interestingly, pre-treatment with non-specific NMDA antagonist MK-801, specific NR2B antagonist Ro 25-6981, or small interfering RNA (siRNA) targeting NR2B, significantly blocked the effect of leptin on corticosterone-induced inhibition of NSCs proliferation. Furthermore, corticosterone significantly reduced the protein expression of NR2B, whereas pre-treatment with leptin greatly reversed the attenuation of NR2B expression caused by corticosterone in cultured hippocampal NSCs. Our findings demonstrate that leptin reverses the corticosterone-induced inhibition of NSCs proliferation. This process is, at least partially mediated by increased expression of NR2B subunits of NMDA receptors.

  9. Inhibition of NR2B-Containing N-methyl-D-Aspartate Receptors (NMDARs) in Experimental Autoimmune Encephalomyelitis, a Model of Multiple Sclerosis

    PubMed Central

    Farjam, Mojtaba; Beigi Zarandi, Faegheh Baha'addini; Farjadian, Shirin; Geramizadeh, Bita; Nikseresht, Ali Reza; Panjehshahin, Mohammad Reza

    2014-01-01

    Neurodegeneration is the pathophysiological basis for permanent neurological disabilities in multiple sclerosis (MS); thus neuroprotection is emerging as a therapeutic approach in MS research. Modulation of excitotoxicity by inhibition of NMDARs has been suggested for neuroprotection, but selective antagonisation of the NR2B subtype of these receptors, a subtype believed to play a more pivotal role in neurodegeneration, has not been tested in MS. In this study inhibition of NR2B-containing NMDAR was evaluated on the animal model of MS, experimental autoimmune encephalomyelitis (EAE). EAE induction was done using MOG in C57BL/6 mice. Therapeutic administration of different doses of highly selective NR2B-containing NMDAR inhibitor (RO25-6981) was compared with memantine (non-selective NMDAR antagonist) and vehicle. Neurological deficits in EAE animals were more efficiently decreased by selective inhibition of NR2B-containing NMDARs. Histological studies of the spinal cords also showed decreased inflammation, myelin degradation and neuro-axonal degeneration when RO25-6981was administered with higher doses. The effects were dose dependent. Regarding the role of NR2B-containing NMDARs in excitotoxicity, selective inhibition of these receptor subtypes seems to modulate the neurological disabilities and pathological changes in EAE. Further elucidation of the exact mechanism of action as well as more experimental studies can suggest NR2B-containing NMDAR inhibition as a potentially effective treatment strategy for slowing down the clinical deterioration of disability in MS. PMID:25237366

  10. SNARE Protein Syntaxin-1 Colocalizes Closely with NMDA Receptor Subunit NR2B in Postsynaptic Spines in the Hippocampus

    PubMed Central

    Hussain, Suleman; Ringsevjen, Håvard; Egbenya, Daniel L.; Skjervold, Torstein L.; Davanger, Svend

    2016-01-01

    Syntaxins are a family of membrane-integrated proteins that are instrumental in exocytosis of vesicles. Syntaxin-1 is an essential component of the presynaptic exocytotic fusion machinery in the brain and interacts with several other proteins. Syntaxin-1 forms a four-helical bundle complex with proteins SNAP-25 and VAMP2 that drives fusion of vesicles with the plasma membrane in the active zone (AZ). Little is known, however, about the ultrastructural localization of syntaxin-1 at the synapse. We have analyzed the intrasynaptic expression of syntaxin-1 in glutamatergic hippocampal synapses in detail by using quantitative postembedding immunogold labeling. Syntaxin-1 was present in highest concentrations at the presynaptic AZ, supporting its role in transmitter release. Presynaptic plasma membrane lateral to the AZ, as well as presynaptic cytoplasmic (PreCy) vesicles were also labeled. However, syntaxin-1 was also significantly expressed in postsynaptic spines, where it was localized at the postsynaptic density (PSD), at postsynaptic lateral membranes and in postsynaptic cytoplasm. Postsynaptically, syntaxin-1 colocalized in the nanometer range with the N-methyl-D-aspartate (NMDA) receptor subunit NR2B, but only weakly with the AMPA receptor subunits GluA2/3. This observation points to the possibility that syntaxin-1 may be involved with NR2B vesicular trafficking from cytoplasmic stores to the postsynaptic plasma membrane, thus facilitating synaptic plasticity. Confocal immunofluorescence double labeling with PSD-95 and ultrastructural fractionation of synaptosomes also confirm localization of syntaxin-1 at the PSD. PMID:26903802

  11. Functional contributions of synaptically localized NR2B subunits of the NMDA receptor to synaptic transmission and long-term potentiation in the adult mouse CNS

    PubMed Central

    Miwa, Hideki; Fukaya, Masahiro; Watabe, Ayako M; Watanabe, Masahiko; Manabe, Toshiya

    2008-01-01

    The NMDA-type glutamate receptor is a heteromeric complex composed of the NR1 and at least one of the NR2 subunits. Switching from the NR2B to the NR2A subunit is thought to underlie functional alteration of the NMDA receptor during synaptic maturation, and it is generally believed that it results in preferential localization of NR2A subunits on the synaptic site and that of NR2B subunits on the extracellular site in the mature brain. It has also been proposed that activation of the NR2A and NR2B subunits results in long-term potentiation (LTP) and long-term depression (LTD), respectively. Furthermore, recent reports suggest that synaptic and extrasynaptic receptors may have distinct roles in synaptic plasticity as well as in gene expression associated with neuronal death. Here, we have investigated whether NR2B subunit-containing receptors are present and functional at mature synapses in the lateral nucleus of the amygdala (LA) and the CA1 region of the hippocampus, comparing their properties between the two brain regions. We have found, in contrast to the above hypotheses, that the NR2B subunit significantly contributes to synaptic transmission as well as LTP induction. Furthermore, its contribution is greater in the LA than in the CA1 region, and biophysical properties of NMDA receptors and the NR2B/NR2A ratio are different between the two brain regions. These results indicate that NR2B subunit-containing NMDA receptors accumulate on the synaptic site and are responsible for the unique properties of synaptic function and plasticity in the amygdala. PMID:18372311

  12. Age- and Hormone-Regulation of N-Methyl-d-Aspartate Receptor Subunit NR2b in the Anteroventral Periventricular Nucleus of the Female Rat

    PubMed Central

    Maffucci, J. A.; Noel, M. L.; Gillette, R.; Wu, D.; Gore, A. C.

    2009-01-01

    Glutamate, acting through its N-methyl-d-aspartate (NMDA) and non-NMDA receptors in the hypothalamus, regulates reproductive neuroendocrine functions via direct and indirect actions upon gonadotrophin-releasing hormone (GnRH) neurones. Previous studies indicate that the NMDA receptor subunit NR2b undergoes changes in protein and gene expression in the hypothalamus in general, and on GnRH neurones in particular, during reproductive ageing. In the present study, we examined whether the NR2b-expressing cell population, both alone and in association with the NR1 subunit (i.e. the latter subunit is necessary for a functional NMDA receptor), is altered as a function of age and/or steroid hormone treatment. Studies focused on the anteroventral periventricular (AVPV) nucleus of the hypothalamus, a region critically involved in the control of reproduction. Young (3-5 months), middle-aged (9-12 months), and aged (approximately 22 months) female rats were ovariectomised and, 1 month later, they were treated sequentially with oestradiol plus progesterone, oestradiol plus vehicle, or vehicle plus vehicle, then perfused. Quantitative stereologic analysis of NR2b-immunoreactive cell numbers in the AVPV showed an age-associated decrease in the density of NR2b-immunoreactive cells, but no effect of hormone treatment. In a second study, immunofluorescent double labelling of NR2b and NR1 was analysed by confocal microscopy of fraction volume, a semi-quantitative measure of fluorescence intensity. No effect of ageing was detected for immunofluorescent NR1 or NR2b alone, whereas the NR2b fraction volume increased in the oestradiol plus vehicle group. With ageing, the fraction volume of the NR2b/NR1-colocalised subunits increased. Together with the stereology results, this suggests that, although fewer cells express the NR2b subunit in the ageing AVPV, a greater percentage of these subunits are co-expressed with NR1. Our results suggest that the subunit composition of NMDA receptors in

  13. Structure of the Zinc-Bound Amino-Terminal Domain of the NMDA Receptor NR2B Subunit

    SciTech Connect

    Karakas, E.; Simorowski, N; Furukawa, H

    2009-01-01

    N-methyl-D-aspartate (NMDA) receptors belong to the family of ionotropic glutamate receptors (iGluRs) that mediate the majority of fast excitatory synaptic transmission in the mammalian brain. One of the hallmarks for the function of NMDA receptors is that their ion channel activity is allosterically regulated by binding of modulator compounds to the extracellular amino-terminal domain (ATD) distinct from the L-glutamate-binding domain. The molecular basis for the ATD-mediated allosteric regulation has been enigmatic because of a complete lack of structural information on NMDA receptor ATDs. Here, we report the crystal structures of ATD from the NR2B NMDA receptor subunit in the zinc-free and zinc-bound states. The structures reveal the overall clamshell-like architecture distinct from the non-NMDA receptor ATDs and molecular determinants for the zinc-binding site, ion-binding sites, and the architecture of the putative phenylethanolamine-binding site.

  14. Chronic Administration of Benzo(a)pyrene Induces Memory Impairment and Anxiety-Like Behavior and Increases of NR2B DNA Methylation

    PubMed Central

    Zhang, Wenping; Tian, Fengjie; Zheng, Jinping; Li, Senlin; Qiang, Mei

    2016-01-01

    Background Recently, an increasing number of human and animal studies have reported that exposure to benzo(a)pyrene (BaP) induces neurological abnormalities and is also associated with adverse effects, such as tumor formation, immunosuppression, teratogenicity, and hormonal disorders. However, the exact mechanisms underlying BaP-induced impairment of neurological function remain unclear. The aim of this study was to examine the regulating mechanisms underlying the impact of chronic BaP exposure on neurobehavioral performance. Methods C57BL mice received either BaP in different doses (1.0, 2.5, 6.25 mg/kg) or olive oil twice a week for 90 days. Memory and emotional behaviors were evaluated using Y-maze and open-field tests, respectively. Furthermore, levels of mRNA expression were measured by using qPCR, and DNA methylation of NMDA receptor 2B subunit (NR2B) was examined using bisulfate pyrosequencing in the prefrontal cortex and hippocampus. Results Compared to controls, mice that received BaP (2.5, 6.25 mg/kg) showed deficits in short-term memory and an anxiety-like behavior. These behavioral alterations were associated with a down-regulation of the NR2B gene and a concomitant increase in the level of DNA methylation in the NR2B promoter in the two brain regions. Conclusions Chronic BaP exposure induces an increase in DNA methylation in the NR2B gene promoter and down-regulates NR2B expression, which may contribute to its neurotoxic effects on behavioral performance. The results suggest that NR2B vulnerability represents a target for environmental toxicants in the brain. PMID:26901155

  15. DIFFERENTIAL ROLE OF NR2A AND NR2B NMDA RECEPTORS IN MEDIATING PHENCYCLIDINE-INDUCED PERINATAL NEURONAL APOPTOSIS AND BEHAVIORAL DEFICITS

    PubMed Central

    Anastasio, Noelle C.; Xia, Yan; O’Connor, Zoe R.; Johnson, Kenneth M.

    2009-01-01

    The mechanism underlying PCP-induced apoptosis in perinatal rats and the development of schizophrenic-like behaviors is incompletely understood. We used antagonists for NR2A- and NR2B-containing NMDARs to test the hypothesis that the behavioral and apoptotic effects of PCP are mediated by blockade of NR1/NR2A-containing receptors, rather than NR1/NR2B-containing receptors. Sprague-Dawley rats were treated on PN7, 9, and 11 with PCP (10 mg/kg), PEAQX (NR2A-preferring antagonist, 10, 20, or 40 mg/kg), or ifenprodil (selective NR2B antagonist, 1, 5, or 10 mg/kg) and sacrificed for measurement of caspase-3 activity (an index of apoptosis) or allowed to age and tested for locomotor sensitization to PCP challenge on PN28-35. PCP or PEAQX on PN7, 9, and 11 markedly elevated caspase-3 activity in the cortex; ifenprodil showed no effect. Striatal apoptosis was evident only after sub-chronic treatment with a high dose of PEAQX (20 mg/kg). Animals treated with PCP or PEAQX on PN7, 9 and 11 showed a sensitized locomotor response to PCP challenge on PN28-35. Ifenprodil treatment had no effect on either measure. Therefore, PCP blockade of cortical NR1/NR2A, rather than NR1/NR2B, appears to be responsible for PCP-induced apoptosis and the development of long-lasting behavioral deficits. PMID:19654040

  16. NR2A- and NR2B-Containing NMDA Receptors in the Prelimbic Medial Prefrontal Cortex Differentially Mediate Trace, Delay, and Contextual Fear Conditioning

    ERIC Educational Resources Information Center

    Gilmartin, Marieke R.; Kwapis, Janine L.; Helmstetter, Fred J.

    2013-01-01

    Activation of "N"-methyl-D-aspartate receptors (NMDAR) in the prelimbic medial prefrontal cortex (PL mPFC) is necessary for the acquisition of both trace and contextual fear memories, but it is not known how specific NR2 subunits support each association. The NR2B subunit confers unique properties to the NMDAR and may differentially…

  17. Endogenous ephrinB2 mediates colon-urethra cross-organ sensitization via Src kinase-dependent tyrosine phosphorylation of NR2B.

    PubMed

    Peng, Hsien-Yu; Chen, Gin-Den; Lai, Cheng-Hung; Tung, Kwong-Chung; Chang, Junn-Liang; Lin, Tzer-Bin

    2010-01-01

    Recently, the role of EphB receptor (EphBR) tyrosine kinase and their ephrinB ligands in spinal pain-related neural plasticity has been identified. To test whether Src-family non-receptor tyrosine kinase-dependent glutamatergic N-methyl-d-aspartate receptor (NMDAR) NR2B subunit phosphorylation underlies lumbosacral spinal EphBR activation to mediate cross-organ sensitization between the colon and the urethra, external urethra sphincter electromyogram activity evoked by pelvic nerve stimulation and protein expression in the lumbosacral (L6-S2) dorsal horn were studied before and after intracolonic mustard oil (MO) instillation. We found MO instillation produced colon-urethra reflex sensitization along with an upregulation of endogenous ephrinB2 expression as well as phosphorylation of EphB 1/2, Src-family kinase, and NR2B tyrosine residues. Intrathecal immunoglobulin fusion protein of EphB1 and EphB2 as well as PP2 reversed the reflex sensitization and NR2B phosphorylation caused by MO. All these results suggest that EphBR-ephrinB interactions, which provoke Src-family kinase-dependent NMDAR NR2B phosphorylation at the lumbosacral spinal cord level, are involved in cross-organ sensitization, contributing to the development of viscero-visceral referred pain between the bowel and the urethra. PMID:19864302

  18. Bisphenol-A rapidly promotes dynamic changes in hippocampal dendritic morphology through estrogen receptor-mediated pathway by concomitant phosphorylation of NMDA receptor subunit NR2B

    SciTech Connect

    Xu Xiaohong Ye Yinping; Li Tao; Chen Lei; Tian Dong; Luo Qingqing; Lu Mei

    2010-12-01

    Bisphenol-A (BPA) is known to be a potent endocrine disrupter. Evidence is emerging that estrogen exerts a rapid influence on hippocampal synaptic plasticity and the dendritic spine density, which requires activation of NMDA receptors. In the present study, we investigated the effects of BPA (ranging from 1 to 1000 nM), focusing on the rapid dynamic changes in dendritic filopodia and the expressions of estrogen receptor (ER) {beta} and NMDA receptor, as well as the phosphorylation of NMDA receptor subunit NR2B in the cultured hippocampal neurons. A specific ER antagonist ICI 182,780 was used to examine the potential involvement of ERs. The results demonstrated that exposure to BPA (ranging from 10 to 1000 nM) for 30 min rapidly enhanced the motility and the density of dendritic filopodia in the cultured hippocampal neurons, as well as the phosphorylation of NR2B (pNR2B), though the expressions of NMDA receptor subunits NR1, NR2B, and ER{beta} were not changed. The antagonist of ERs completely inhibited the BPA-induced increases in the filopodial motility and the number of filopodia extending from dendrites. The increased pNR2B induced by BPA (100 nM) was also completely eliminated. Furthermore, BPA attenuated the effects of 17{beta}-estradiol (17{beta}-E{sub 2}) on the dendritic filopodia outgrowth and the expression of pNR2B when BPA was co-treated with 17{beta}-E{sub 2}. The present results suggest that BPA, like 17{beta}-E{sub 2}, rapidly results in the enhanced motility and density of dendritic filopodia in the cultured hippocampal neurons with the concomitant activation of NMDA receptor subunit NR2B via an ER-mediated signaling pathway. Meanwhile, BPA suppressed the enhancement effects of 17{beta}-E{sub 2} when it coexists with 17{beta}-E{sub 2}. These results provided important evidence suggesting the neurotoxicity of the low levels of BPA during the early postnatal development of the brain.

  19. Overactivation of NR2B-containing NMDA receptors through entorhinal-hippocampal connection initiates accumulation of hyperphosphorylated tau in rat hippocampus after transient middle cerebral artery occlusion.

    PubMed

    Xu, Cheng-Shi; Liu, An-Chun; Chen, Juan; Pan, Zhi-Yong; Wan, Qi; Li, Zhi-Qiang; Wang, Ze-Fen

    2015-08-01

    Middle cerebral artery occlusion (MCAO) induces secondary damages in the hippocampus that is remote from primary ischemic regions. Tau hyperphosphorylation is an important risk for neurodegenerative diseases. Increased tau phosphorylation has been identified in ischemic cortex, but little is known regarding the changes in the hippocampus. We showed that unilateral transient MCAO induced accumulation of hyperphosphorylated tau and concurrent dephosphorylation of glycogen synthase kinase-3β at Ser 9 in the ipsilateral hippocampus. These MCAO-induced changes were not reproduced when glutamatergic inputs from the entorhinal cortex to the hippocampus were transected; however, the changes were mimicked by intrahippocampal N-methyl-d-aspartate (NMDA) administration. Inhibition of NMDA receptor (NMDAR) subunit NR2B, but not NR2A activity in the hippocampus attenuated the accumulation of hyperphosphorylated tau and spatial cognitive impairment in MCAO rats. Together, our data suggest that overactivation of NR2B-containing NMDARs through entorhinal-hippocampal connection plays an important role in the accumulation of hyperphosphorylated tau in the hippocampus following MCAO. Glycogen synthase kinase-3β is an important protein kinase involved in NMDARs-mediated tau hyperphosphorylation. This study indicates that early inhibition of NR2B-containing NMDARs may represent a potential strategy to prevent or delay the occurrence of post-stroke dementia. Middle cerebral artery occlusion induces secondary damage in the hippocampus that is remote from primary ischemic regions. We propose that excessive activation of NR2B-containing NMDA receptors through entorhinal-hippocampal connection initiated the accumulation of hyperphosphorylated tau in the hippocampus, which subsequently induced cognitive deficit. This study provides new insights into the prospects of NR2B inhibition in stoke therapy. PMID:25903928

  20. Dual contribution of NR2B subunit of NMDA receptor and SK3 Ca(2+)-activated K+ channel to genetic predisposition to anorexia nervosa.

    PubMed

    Koronyo-Hamaoui, Maya; Frisch, Amos; Stein, Daniel; Denziger, Yardena; Leor, Shani; Michaelovsky, Elena; Laufer, Neil; Carel, Cynthia; Fennig, Silvana; Mimouni, Mark; Ram, Anca; Zubery, Eynat; Jeczmien, Pablo; Apter, Alan; Weizman, Abraham; Gak, Eva

    2007-01-01

    Since identification of the genetic component in anorexia nervosa (AN), genes that partake in serotonergic and dopaminergic systems and in hormonal and weight regulation have been suggested as potential candidates for AN susceptibility. We propose another set of candidate genes. Those are genes that are involved in the signaling pathway using NMDA-R and SK channels and have been suggested as possible effectors of NMDA-R driven signaling. The role of NMDA-R in the etiology of schizophrenia has already been substantiated on various levels. Several studies based on population and family groups have implicated SK3 in schizophrenia and more recently in AN as well. Our study group consisted of 90 AN family trios. We examined the transmission of two potentially functional polymorphisms, 5073T>G polymorphism in the gene encoding the NR2B subunit of NMDA-R and CAG repeats in the coding region of SK3 channel gene. Using HHRR and TDT approaches, we found that both polymorphisms were preferentially transmitted to AN offspring (TDT yielded chi(2)=5.01, p=0.025 for NR2B 5073G alleles and chi(2)=11.75, p<0.001 for SK3 L alleles including >19 repeats). Distribution analysis of the combined NR2B/SK3 genotypes suggests that the contribution of both polymorphisms to AN risk is independent and cumulative (OR=2.44 for NR2B GG genotype and OR=3.01 for SK3 SL and LL genotypes, and OR=6.8 for the combined NR2B/SK3 genotypes including high-risk alleles). These findings point to the contribution of genes associated with the NMDA-R signaling pathway to predisposition and development of AN. PMID:16157352

  1. Vorinostat, a histone deacetylase inhibitor, facilitates fear extinction and enhances expression of the hippocampal NR2B-containing NMDA receptor gene.

    PubMed

    Fujita, Yosuke; Morinobu, Shigeru; Takei, Shiro; Fuchikami, Manabu; Matsumoto, Tomoya; Yamamoto, Shigeto; Yamawaki, Shigeto

    2012-05-01

    Histone acetylation, which alters the compact chromatin structure and changes the accessibility of DNA to regulatory proteins, is emerging as a fundamental mechanism for regulating gene expression. Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance fear extinction. In this study, we examined whether vorinostat, an HDAC inhibitor, facilitates fear extinction, using a contextual fear conditioning (FC) paradigm, in Sprague-Dawley rats. We found that vorinostat facilitated fear extinction. Next, the levels of global acetylated histone H3 and H4 were measured by Western blotting. We also assessed the effect of vorinostat on the hippocampal levels of NMDA receptor mRNA by real-time quantitative PCR (RT-PCR) and protein by Western blotting. 2 h after vorinostat administration, the levels acetylated histones and NR2B mRNA, but not NR1 or NR2A mRNA, were elevated in the hippocampus. The NR2B protein level was elevated 4 h after vorinostat administration. Last, we investigated the levels of acetylated histones and phospho-CREB (p-CREB) binding at the promoter of the NR2B gene using the chromatin immunoprecipitation (ChIP) assay followed by RT-PCR. The ChIP assay revealed increases in the levels of acetylated histones and they were accompanied by enhanced binding of p-CREB to its binding site at the promoter of the NR2B gene 2 h after vorinostat administration. These findings suggest that vorinostat increases the expression of NR2B in the hippocampus by enhancing histone acetylation, and this process may be implicated in fear extinction. PMID:22364833

  2. Conantokins Derived from the Asprella Clade Impart ConRl-B, an NMDA Receptor Antagonist with a Unique Selectivity Profile for NR2B Subunits

    PubMed Central

    Gowd, Konkallu Hanumae; Han, Tiffany S.; Twede, Vernon; Gajewiak, Joanna; Smith, Misty D.; Watkins, Maren; Platt, Randall J.; Toledo, Gabriela; White, H. Steve; Olivera, Baldomero M.; Bulaj, Grzegorz

    2014-01-01

    Using molecular phylogeny has accelerated the discovery of peptidic ligands targeted to ion channels and receptors. One clade of venomous cone snails, Asprella, appears to be significantly enriched in conantokins, antagonists of N-Methyl D-Asparate receptors (NMDARs). Here, we describe the characterization of two novel conantokins from Conus rolani, including conantokin conRl-B that has shown an unprecedented selectivity for blocking NMDARs that contain NR2B subunits. ConRl-B shares only some sequence similarity to the most studied NR2B-selective conantokin, conG. The divergence between conRl-B and conG in the second inter-Gla loop was used to design analogs for structure-activity studies; the presence of Pro10 was found to be key to the high potency of conRl-B for NR2B, whereas the ε-amino group of Lys8 contributed to discrimination in blocking NR2B- and NR2A-containing NMDARs. In contrast to previous findings from Tyr5 substitutions in other conantokins, conRl-B [L5Y] showed potencies on the four NR2 NMDA receptor subtypes that were similar to those of the native conRl-B. When delivered into the brain, conRl-B was active in suppressing seizures in the model of epilepsy in mice, consistent with NR2B-containing NMDA receptors being potential targets for antiepileptic drugs. Circular dichroism experiments confirmed that the helical conformation of conRl-B is stabilized by divalent metal ions. Given the clinical applications of NMDA antagonists, conRl-B provides a potentially important pharmacological tool for understanding the differential roles of NMDA receptor subtypes in the nervous system. This work shows the effectiveness of coupling molecular phylogeny, chemical synthesis and pharmacology for discovering new bioactive natural products. PMID:22594498

  3. Effects of L-3-n-butylphthalide on cognitive dysfunction and NR2B expression in hippocampus of streptozotocin (STZ)-induced diabetic rats.

    PubMed

    Li, Jie; Zhang, Songyun; Zhang, Lihui; Wang, Ruiying; Wang, Mian

    2015-01-01

    Diabetes mellitus is associated with rapid cognitive decline. Currently, there is no effective treatment for cognitive dysfunction induced by diabetes. L-3-n-Butylphthalide (L-NBP) is a nerve protective drug extracted from seeds of celery, which has been proved to improve learning and memory in vascular dementia animal models by improving microcirculation, protecting mitochondria and increasing long-term potentiation (LTP). NR2B, one of the subunits of N-methyl-D-aspartate receptor, has been proved to be an important factor for the formation of LTP. The study aimed to investigate the role of NR2B in cognitive dysfunction in the rats with type 1 diabetes and define the protective effects of L-NBP on cognition. A rat model of type 1 diabetes was established by a single intraperitoneal injection of streptozotocin at 60 mg/kg. Animals were randomly allocated to four groups: normal control (NC); diabetic control (DC); diabetic + low L-NBP (DL, administered L-NBP 60 mg/kg per day for 12 weeks); and diabetic + high L-NBP (DH, administered L-NBP 120 mg/kg per day, for 12 weeks). After 12 weeks, cognitive and memory changes were investigated in the Morris water maze. The expression of NR2B was assessed by real-time polymerase chain reaction, Western blotting, and immunohistochemistry. Our results indicated that the escape latency was significantly increased and the number of crossing platform was significantly decreased in DC group compared to NC group. Also, the expression of NR2B was significantly declined in DC group. However, compared to DC group, the expression of NR2B of the L-NBP-treated groups was significantly increased and the escape latency was shortened with the DH group being the most obvious. Therefore, L-NBP can improve the cognitive function by up-regulating the expression of NR2B in STZ-diabetic rats, which may provide the direction for future diabetic encephalopathy therapy. PMID:25149651

  4. Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression

    PubMed Central

    Feyissa, Anteneh M.; Zyga, Agata; Stockmeier, Craig A.; Karolewicz, Beata

    2009-01-01

    Recent neuroimaging and postmortem studies have demonstrated abnormalities in glutamatergic transmission in major depression. Glutamate NMDA (N-methyl-D-aspartate) receptors are one of the major mediators of excitatory neurotransmission in the central nervous system. At synaptic sites, NMDA receptors are linked with postsynaptic density protein-95 (PSD-95) that plays a key role in mediating trafficking, clustering, and downstream signaling events, following receptor activation. In this study, we examined the expression of NMDA receptor subunits NR1, NR2A, and NR2B as well as PSD-95 in the anterior prefrontal cortex (PFC) using Western blot method. Cortical samples were obtained from age, gender and postmortem interval matched depressed and psychiatrically healthy controls. The results revealed that there was a reduced expression of the NMDA receptor subunits NR2A (−54%) and NR2B (−48%), and PSD-95 protein level (−40%) in the PFC of depressed subjects relative to controls, with no change in the NR1 subunit. The alterations in NMDA receptor subunits, especially the NR2A and NR2B, as well as PSD-95 suggest an abnormality in the NMDA receptor signaling in the PFC in major depression. Our findings in conjunction with recent clinical, cellular, and neuroimaging studies further implicate the involvement of glutamate neurotransmission in the pathophysiology of depression. This study provides additional evidence that NMDA receptor complex is a target for discovery of novel antidepressants. PMID:18992785

  5. Identification of a Novel Rat NR2B Subunit Gene Promoter Region Variant and Its Association with Microwave-Induced Neuron Impairment.

    PubMed

    Wang, Li-Feng; Tian, Da-Wei; Li, Hai-Juan; Gao, Ya-Bing; Wang, Chang-Zhen; Zhao, Li; Zuo, Hong-Yan; Dong, Ji; Qiao, Si-Mo; Zou, Yong; Xiong, Lu; Zhou, Hong-Mei; Yang, Yue-Feng; Peng, Rui-Yun; Hu, Xiang-Jun

    2016-05-01

    Microwave radiation has been implicated in cognitive dysfunction and neuronal injury in animal models and in human investigations; however, the mechanism of these effects is unclear. In this study, single nucleotide polymorphism (SNP) sites in the rat GRIN2B promoter region were screened. The associations of these SNPs with microwave-induced rat brain dysfunction and with rat pheochromocytoma-12 (PC12) cell function were investigated. Wistar rats (n = 160) were exposed to microwave radiation (30 mW/cm(2) for 5 min/day, 5 days/week, over a period of 2 months). Screening of the GRIN2B promoter region revealed a stable C-to-T variant at nucleotide position -217 that was not induced by microwave exposure. The learning and memory ability, amino acid contents in the hippocampus and cerebrospinal fluid, and NR2B expression were then investigated in the different genotypes. Following microwave exposure, NR2B protein expression decreased, while the Glu contents in the hippocampus and CSF increased, and memory impairment was observed in the TT genotype but not the CC and CT genotypes. In PC12 cells, the effects of the T allele were more pronounced than those of the C allele on transcription factor binding ability, transcriptional activity, NR2B mRNA, and protein expression. These effects may be related to the detrimental role of the T allele and the protective role of the C allele in rat brain function and PC12 cells exposed to microwave radiation. PMID:25917873

  6. Acute hypoxia differentially affects the NMDA receptor NR1, NR2A and NR2B subunit mRNA levels in the developing chick optic tectum: stage-dependent plasticity in the 2B-2A ratio.

    PubMed

    Vacotto, Marina; Rapacioli, Melina; Flores, Vladimir; de Plazas, Sara Fiszer

    2010-10-01

    It is known that the NMDA-R NR1 subunit is needed for the receptor activity and that under hypoxia the evolution toward apoptosis or neuronal survival depends on the balance NR2A/NR2B subunits. This paper analyzes the effect of acute hypoxia on the above mentioned subunits mRNAs during development. The mean percentage of NR1+ neurons displayed the higher plasticity during development while the NR2A+ neurons the higher stability. Acute hypoxia increased the mean percentage of NR1+ and NR2B+ neurons at ED12 but only that of NR1+ neurons at ED18. Acute hypoxia increased the levels of expression of NR1 and NR2B mRNAs at ED12 without changes in the NR2A mRNA. During early stages there is a higher sensitivity to change the subunits mRNA levels under a hypoxic treatment. At ED12 acute hypoxia increased the probability of co-expression of the NR1-NR2A and NR1-NR2B subunits combinations, the level of NR1 and NR2B and the ratio NR2B/NR2A. These conditions facilitate the evolution towards apoptosis. PMID:20596770

  7. Inhibiting effects of rhynchophylline on zebrafish methamphetamine dependence are associated with amelioration of neurotransmitters content and down-regulation of TH and NR2B expression.

    PubMed

    Jiang, Mingjin; Chen, Yifei; Li, Chan; Peng, Qiuxian; Fang, Miao; Liu, Wei; Kang, Qunzhao; Lin, Yingbo; Yung, Ken Kin Lam; Mo, Zhixian

    2016-07-01

    Others and we have reported that rhynchophylline reverses amphetamine-induced conditioned place preference (CPP) effect which may be partly mediated by amelioration of central neurotransmitters and N-methyl-d-aspartate receptor 2B (NR2B) levels in the rat brains. The current study investigated the inhibiting effects of rhynchophylline on methamphetamine-induced (METH-induced) CPP in adult zebrafish and METH-induced locomotor activity in tyrosine hydroxylase-green fluorescent protein (TH-GFP) transgenic zebrafish larvae and attempted to confirm the hypothesis that these effects were mediated via regulation of neurotransmitters and dopaminergic and glutamatergic systems. After baseline preference test (on days 1-3), zebrafish were injected intraperitoneally METH (on days 4, 6 and 8) or the same volume of fish physiological saline (on days 5 and 7) and were immediately conditioned. Rhynchophylline was administered at 12h after injection of METH. On day 9, zebrafish were tested for METH-induced CPP. Results revealed that rhynchophylline (100mg/kg) significantly inhibited the acquisition of METH-induced CPP, reduced the content of dopamine and glutamate and down-regulated the expression of TH and NR2B in the CPP zebrafish brains. Furthermore, the influence of rhynchophylline on METH-induced locomotor activity was also observed in TH-GFP transgenic zebrafish larvae. Results showed that rhynchophylline (50mg/L) treatment led to a significant reduction on the locomotor activity and TH expression in TH-GFP transgenic zebrafish larvae. Taken together, these data indicate that the inhibition of the formation of METH dependence by rhynchophylline in zebrafish is associated with amelioration of the neurotransmitters dopamine and glutamate content and down-regulation of TH and NR2B expression. PMID:27009763

  8. Glucocorticoid mediates water avoidance stress-sensitized colon-bladder cross-talk via RSK2/PSD-95/NR2B in rats.

    PubMed

    Peng, Hsien-Yu; Hsieh, Ming-Chun; Lai, Cheng-Yuan; Chen, Gin-Den; Huang, Yi-Ping; Lin, Tzer-Bin

    2012-11-01

    Unexpected environmental and social stimuli could trigger stress. Although coping with stress is essential for survival, long-term stress impacts visceral functions, and therefore, it plays a role in the development and exacerbation of symptoms of gastrointestinal/urogenital disorders. The aim of this study is to characterize the role of corticosterone in stress-sensitized colon-bladder cross-talk, a phenomenon presumed to underlie the comorbidity of functional bowel and bladder disorders. Cystometry and protein/mRNA expression in the lumbosacral dorsal horn (L6-S1) in response to intracolonic mustard oil (MO) instillation were analyzed in female Wistar-Kyoto rats subjected to water avoidance stress (WAS; 1 h/day for 10 days) or sham stress (WAsham). Whereas it had no effect on baseline-voiding function, chronic stress upregulated plasma corticosterone concentration and dorsal horn spinal p90 ribosomal S6 kinase 2 (RSK2) protein/mRNA levels, and RSK2 immunoreactivity colocalized with NeuN-positive neurons. Intracolonic MO dose-dependently decreased intrercontraction intervals and threshold pressure, provoked spinal RSK2 and NR2B phosphorylation, and enhanced PSD-95-RSK2 and PSD-95-NR2B coupling. Intrathecal kaempferol (a RSK2 activation antagonist; 30 min before MO instillation), bilateral adrenalectomy (7 days prior the stress paradigm), and subcutaneous RU-38486 (a glucocorticoid receptor antagonist; 30 min daily before stress sessions), but not RU-28318 (a mineralocorticoid receptor antagonist), attenuated MO-induced bladder hyperactivity, protein phosphorylation, and protein-protein interactions in the WAS group. Our results suggest that stress-associated glucocorticoid release mediates WAS-dependent sensitization of colon-bladder cross-talk via the spinal RSK2/PSD-95/NR2B cascade and offer a possibility for developing pharmacological strategies for the treatment of stress-related pelvic pain. PMID:23125098

  9. Regulation of fear extinction versus other affective behaviors by discrete cortical scaffolding complexes associated with NR2B and PKA signaling

    PubMed Central

    Corcoran, K A; Leaderbrand, K; Jovasevic, V; Guedea, A L; Kassam, F; Radulovic, J

    2015-01-01

    In patients suffering from post-traumatic stress disorder (PTSD), fear evoked by trauma-related memories lasts long past the traumatic event and it is often complicated by general anxiety and depressed mood. This poses a treatment challenge, as drugs beneficial for some symptoms might exacerbate others. For example, in preclinical studies, antagonists of the NR2B subunit of N-methyl-d-aspartate receptors and activators of cAMP-dependent protein kinase (PKA) act as potent antidepressants and anxiolytics, but they block fear extinction. Using mice, we attempted to overcome this problem by interfering with individual NR2B and PKA signaling complexes organized by scaffolding proteins. We infused cell-permeable Tat peptides that displaced either NR2B from receptor for activated C kinase 1 (RACK1), or PKA from A-kinase anchor proteins (AKAPs) or microtubule-associated proteins (MAPs). The infusions were targeted to the retrosplenial cortex, an area involved in both fear extinction of remotely acquired memories and in mood regulation. Tat-RACK1 and Tat-AKAP enhanced fear extinction, all peptides reduced anxiety and none affected baseline depression-like behavior. However, disruption of PKA complexes distinctively interfered with the rapid antidepressant actions of the N-methyl-D-aspartate receptors antagonist MK-801 in that Tat-MAP2 blocked, whereas Tat-AKAP completely inverted the effect of MK-801 from antidepressant to depressant. These effects were unrelated to the MK-801-induced changes of brain-derived neurotrophic factor messenger RNA levels. Together, the findings suggest that NR2B–RACK1 complexes specifically contribute to fear extinction, and may provide a target for the treatment of PTSD. AKAP-PKA, on the other hand, appears to modulate fear extinction and antidepressant responses in opposite directions. PMID:26460481

  10. The Tau/A152T mutation, a risk factor for frontotemporal-spectrum disorders, leads to NR2B receptor-mediated excitotoxicity.

    PubMed

    Decker, Jochen Martin; Krüger, Lars; Sydow, Astrid; Dennissen, Frank Ja; Siskova, Zuzana; Mandelkow, Eckhard; Mandelkow, Eva-Maria

    2016-04-01

    We report on a novel transgenic mouse model expressing human full-length Tau with the Tau mutation A152T (hTau(AT)), a risk factor for FTD-spectrum disorders including PSP and CBD Brain neurons reveal pathological Tau conformation, hyperphosphorylation, mis-sorting, aggregation, neuronal degeneration, and progressive loss, most prominently in area CA3 of the hippocampus. The mossy fiber pathway shows enhanced basal synaptic transmission without changes in short- or long-term plasticity. In organotypic hippocampal slices, extracellular glutamate increases early above control levels, followed by a rise in neurotoxicity. These changes are normalized by inhibiting neurotransmitter release or by blocking voltage-gated sodium channels. CA3 neurons show elevated intracellular calcium during rest and after activity induction which is sensitive to NR2B antagonizing drugs, demonstrating a pivotal role of extrasynaptic NMDA receptors. Slices show pronounced epileptiform activity and axonal sprouting of mossy fibers. Excitotoxic neuronal death is ameliorated by ceftriaxone, which stimulates astrocytic glutamate uptake via the transporter EAAT2/GLT1. In summary, hTau(AT) causes excitotoxicity mediated by NR2B-containing NMDA receptors due to enhanced extracellular glutamate. PMID:26931569

  11. Increased NR2A:NR2B ratio compresses long-term depression range and constrains long-term memory.

    PubMed

    Cui, Zhenzhong; Feng, Ruiben; Jacobs, Stephanie; Duan, Yanhong; Wang, Huimin; Cao, Xiaohua; Tsien, Joe Z

    2013-01-01

    The NR2A:NR2B subunit ratio of the NMDA receptors is widely known to increase in the brain from postnatal development to sexual maturity and to aging, yet its impact on memory function remains speculative. We have generated forebrain-specific NR2A overexpression transgenic mice and show that these mice had normal basic behaviors and short-term memory, but exhibited broad long-term memory deficits as revealed by several behavioral paradigms. Surprisingly, increased NR2A expression did not affect 1-Hz-induced long-term depression (LTD) or 100 Hz-induced long-term potentiation (LTP) in the CA1 region of the hippocampus, but selectively abolished LTD responses in the 3-5 Hz frequency range. Our results demonstrate that the increased NR2A:NR2B ratio is a critical genetic factor in constraining long-term memory in the adult brain. We postulate that LTD-like process underlies post-learning information sculpting, a novel and essential consolidation step in transforming new information into long-term memory. PMID:23301157

  12. Synthesis, structural activity-relationships, and biological evaluation of novel amide-based allosteric binding site antagonists in NR1A/NR2B N-methyl-D-aspartate receptors☆

    PubMed Central

    Mosley, Cara A.; Myers, Scott J.; Murray, Ernest E.; Santangelo, Rose; Tahirovic, Yesim A.; Kurtkaya, Natalie; Mullasseril, Praseeda; Yuan, Hongjie; Lyuboslavsky, Polina; Le, Phuong; Wilson, Lawrence J.; Yepes, Manuel; Dingledine, Ray; Traynelis, Stephen F.; Liotta, Dennis C.

    2010-01-01

    The synthesis and structure–activity relationship analysis of a novel class of amide-based biaryl NR2B-selective NMDA receptor antagonists are presented. Some of the studied compounds are potent, selective, non-competitive, and voltage-independent antagonists of NR2B-containing NMDA receptors. Like the founding member of this class of antagonists (ifenprodil), several interesting compounds of the series bind to the amino terminal domain of the NR2B subunit to inhibit function. Analogue potency is modu-lated by linker length, flexibility, and hydrogen bonding opportunities. However, unlike previously described classes of NR2B-selective NMDA antagonists that exhibit off-target activity at a variety of monoamine receptors, the compounds described herein show much diminished effects against the hERG channel and α1-adrenergic receptors. Selections of the compounds discussed have acceptable half-lives in vivo and are predicted to permeate the blood–brain barrier. These data together suggest that masking charged atoms on the linker region of NR2B-selective antagonists can decrease undesirable side effects while still maintaining on-target potency. PMID:19648014

  13. The R18 Polyarginine Peptide Is More Effective Than the TAT-NR2B9c (NA-1) Peptide When Administered 60 Minutes after Permanent Middle Cerebral Artery Occlusion in the Rat

    PubMed Central

    Milani, D.; Knuckey, N. W.; Anderton, R. S.; Cross, J. L.; Meloni, B. P.

    2016-01-01

    We examined the dose responsiveness of polyarginine R18 (100, 300, and 1000 nmol/kg) when administered 60 minutes after permanent middle cerebral artery occlusion (MCAO). The TAT-NR2B9c peptide, which is known to be neuroprotective in rodent and nonhuman primate stroke models, served as a positive control. At 24 hours after MCAO, there was reduced total infarct volume in R18 treated animals at all doses, but this reduction only reached statistical significance at doses of 100 and 1000 nmol/kg. The TAT-NR2B9c peptide reduced infarct volume at doses of 300 and 1000 nmol/kg, but not to a statistically significant extent, while the 100 nmol/kg dose was ineffective. The reduction in infarct volume with R18 and TAT-NR2B9c peptide treatments was mirrored by improvements in one or more functional outcomes (namely, neurological score, adhesive tape removal, and rota-rod), but not to a statistically significant extent. These findings further confirm the neuroprotective properties of polyarginine peptides and for R18 extend its therapeutic time window and dose range, as well as demonstrating its greater efficacy compared to TAT-NR2B9c in a severe stroke model. The superior neuroprotective efficacy of R18 over TAT-NR2B9c highlights the potential of this polyarginine peptide as a lead candidate for studies in human stroke. PMID:27247825

  14. Unprecedented Therapeutic Potential with a Combination of A2A/NR2B Receptor Antagonists as Observed in the 6-OHDA Lesioned Rat Model of Parkinson's Disease

    PubMed Central

    Michel, Anne; Downey, Patrick; Nicolas, Jean-Marie; Scheller, Dieter

    2014-01-01

    In Parkinson's disease, the long-term use of dopamine replacing agents is associated with the development of motor complications; therefore, there is a need for non-dopaminergic drugs. This study evaluated the potential therapeutic impact of six different NR2B and A2A receptor antagonists given either alone or in combination in unilateral 6-OHDA-lesioned rats without (monotherapy) or with (add-on therapy) the co-administration of L-Dopa: Sch-58261+ Merck 22; Sch-58261+Co-101244; Preladenant + Merck 22; Preladenant + Radiprodil; Tozadenant + Radiprodil; Istradefylline + Co-101244. Animals given monotherapy were assessed on distance traveled and rearing, whereas those given add-on therapy were assessed on contralateral rotations. Three-way mixed ANOVA were conducted to assess the main effect of each drug separately and to determine whether any interaction between two drugs was additive or synergistic. Additional post hoc analyses were conducted to compare the effect of the combination with the effect of the drugs alone. Motor activity improved significantly and was sustained for longer when the drugs were given in combination than when administered separately at the same dose. Similarly, when tested as add-on treatment to L-Dopa, the combinations resulted in higher levels of contralateral rotation in comparison to the single drugs. Of special interest, the activity observed with some combinations could not be described by a simplistic additive effect and involved more subtle synergistic pharmacological interactions. The combined administration of A2A/NR2B-receptor antagonists improved motor behaviour in 6-OHDA rats. Given the proven translatability of this model such a combination may be expected to be effective in improving motor symptoms in patients. PMID:25513815

  15. Activation of spinal MrgC-Gi-NR2B-nNOS signaling pathway by Mas oncogene-related gene C receptor agonist bovine adrenal medulla 8-22 attenuates bone cancer pain in mice

    PubMed Central

    Sun, Yu’e; Zhang, Juan; Lei, Yishan; Lu, Cui’e; Hou, Bailing; Ma, Zhengliang; Gu, Xiaoping

    2016-01-01

    Objectives: In the present study, we investigate the effects of Mas oncogene-related gene (Mrg) C receptors (MrgC) on the expression and activation of spinal Gi protein, N-methyl-D-aspartate receptor subunit 2B (NR2B), and neuronal nitric oxide synthase (nNOS) in mouse model of bone cancer pain. Methods: The number of spontaneous foot lift (NSF) and paw withdrawal mechanical threshold (PWMT) were measured after inoculation of tumor cells and intrathecal injection of MrgC agonist bovine adrenal medulla 8-22 (BAM8-22) or MrgC antagonist anti-MrgC for 14 days after operation. Expression of spinal MrgC, Gi protein, NR2B and nNOS and their phosphorylated forms after inoculation was examined by immunohistochemistry and Western blotting. Double labeling was used to identify the co-localization of NR2B or nNOS with MrgC in spinal cord dorsal horn (SCDH) neurons. The effects of intrathecal injection of BAM8-22 or anti-MrgC on nociceptive behaviors and the corresponding expression of spinal MrgC, Gi protein, NR2B and nNOS were also investigated. Results: The expression of spinal MrgC, Gi protein, NR2B, and nNOS was higher in tumor-bearing mice in comparison to sham mice or normal mice. Intrathecal injection of MrgC agonist BAM8-22 significantly alleviated bone cancer pain, up-regulated MrgC and Gi protein expression, and down-regulated the expression of spinal p-NR2B, t-nNOS and p-nNOS in SCDH on day 14 after operation, whereas administration of anti-MrgC produced the opposite effect. Meanwhile, MrgC-like immunoreactivity (IR) co-localizes with NR2B-IR or nNOS-IR in SCDH neurons. Conclusions: The present study demonstrates that MrgC-activated spinal Gi-NR2B-nNOS signaling pathway plays important roles in the development of bone cancer pain. These findings may provide a novel strategy for the treatment of bone cancer pain. PMID:27158400

  16. Both NR2A and NR2B Subunits of the NMDA Receptor Are Critical for Long-Term Potentiation and Long-Term Depression in the Lateral Amygdala of Horizontal Slices of Adult Mice

    ERIC Educational Resources Information Center

    Muller, Tobias; Albrecht, Doris; Gebhardt, Christine

    2009-01-01

    The lateral nucleus of the amygdala (LA) is implicated in emotional and social behaviors. We recently showed that in horizontal brain slices, activation of NMDA receptors (NMDARs) is a requirement for persistent synaptic alterations in the LA, such as long-term potentiation (LTP) and long-term depression (LTD). In the LA, NR2A- and NR2B-type NMDRs…

  17. Amygdala Infusions of an NR2B-Selective or an NR2A-Preferring NMDA Receptor Antagonist Differentially Influence Fear Conditioning and Expression in the Fear-Potentiated Startle Test

    ERIC Educational Resources Information Center

    Walker, David L.; Davis, Michael

    2008-01-01

    Within the amygdala, most N-methyl-D-aspartic acid (NMDA) receptors consist of NR1 subunits in combination with either NR2A or NR2B subunits. Because the particular subunit composition greatly influences the receptors' properties, we investigated the contribution of both subtypes to fear conditioning and expression. To do so, we infused the…

  18. Intrahippocampal Administration of Ibotenic Acid Induced Cholinergic Dysfunction via NR2A/NR2B Expression: Implications of Resveratrol against Alzheimer Disease Pathophysiology

    PubMed Central

    Karthick, Chennakesavan; Periyasamy, Sabapathy; Jayachandran, Kesavan S.; Anusuyadevi, Muthuswamy

    2016-01-01

    Although several drugs revealed moderate amelioration of symptoms, none of them have sufficient potency to prevent or reverse the progression toward Alzheimer's disease (AD) pathology. Resveratrol (RSV), a polyphenolic compound has shown an outstanding therapeutic effect on a broad spectrum of diseases like age-associated neurodegeneration, inflammation etc. The present study was thus conducted to assess the therapeutic efficacy of RSV in ameliorating the deleterious effects of Ibotenic acid (IBO) in male Wistar rats. Stereotactic intrahippocampal administration of IBO (5 μg/μl) lesioned rats impairs cholinergic transmission, learning and memory performance that is rather related to AD and thus chosen as a suitable model to understand the drug efficacy in preventing AD pathophysiology. Since IBO is an agonist of glutamate, it is expected to exhibit an excitotoxic effect by altering glutamatergic receptors like NMDA receptor. The current study displayed significant alterations in the mRNA expression of NR2A and NR2B subunits of NMDA receptors, and further it is surprising to note that cholinergic receptors decreased in expression particularly α7-nAChR with increased m1AChR. RSV administration (20 mg/kg body weight, i.p.) significantly reduced these changes in IBO induced rats. Glutamatergic and cholinergic receptor alterations were associated with significant changes in the behavioral parameters of rats induced by IBO. While RSV improved spatial learning performance, attenuated immobility, and improvised open field activity in IBO induced rats. NR2B activation in the present study might mediate cell death through oxidative stress that form the basis of abnormal behavioral pattern in IBO induced rats. Interestingly, RSV that could efficiently encounter oxidative stress have significantly decreased stress markers viz., nitrite, PCO, and MDA levels by enhancing antioxidant status. Histopathological analysis displayed significant reduction in the hippocampal

  19. Intrahippocampal Administration of Ibotenic Acid Induced Cholinergic Dysfunction via NR2A/NR2B Expression: Implications of Resveratrol against Alzheimer Disease Pathophysiology.

    PubMed

    Karthick, Chennakesavan; Periyasamy, Sabapathy; Jayachandran, Kesavan S; Anusuyadevi, Muthuswamy

    2016-01-01

    Although several drugs revealed moderate amelioration of symptoms, none of them have sufficient potency to prevent or reverse the progression toward Alzheimer's disease (AD) pathology. Resveratrol (RSV), a polyphenolic compound has shown an outstanding therapeutic effect on a broad spectrum of diseases like age-associated neurodegeneration, inflammation etc. The present study was thus conducted to assess the therapeutic efficacy of RSV in ameliorating the deleterious effects of Ibotenic acid (IBO) in male Wistar rats. Stereotactic intrahippocampal administration of IBO (5 μg/μl) lesioned rats impairs cholinergic transmission, learning and memory performance that is rather related to AD and thus chosen as a suitable model to understand the drug efficacy in preventing AD pathophysiology. Since IBO is an agonist of glutamate, it is expected to exhibit an excitotoxic effect by altering glutamatergic receptors like NMDA receptor. The current study displayed significant alterations in the mRNA expression of NR2A and NR2B subunits of NMDA receptors, and further it is surprising to note that cholinergic receptors decreased in expression particularly α7-nAChR with increased m1AChR. RSV administration (20 mg/kg body weight, i.p.) significantly reduced these changes in IBO induced rats. Glutamatergic and cholinergic receptor alterations were associated with significant changes in the behavioral parameters of rats induced by IBO. While RSV improved spatial learning performance, attenuated immobility, and improvised open field activity in IBO induced rats. NR2B activation in the present study might mediate cell death through oxidative stress that form the basis of abnormal behavioral pattern in IBO induced rats. Interestingly, RSV that could efficiently encounter oxidative stress have significantly decreased stress markers viz., nitrite, PCO, and MDA levels by enhancing antioxidant status. Histopathological analysis displayed significant reduction in the hippocampal

  20. Distinct expression of synaptic NR2A and NR2B in the central nervous system and impaired morphine tolerance and physical dependence in mice deficient in postsynaptic density-93 protein

    PubMed Central

    Liaw, Wen-Jinn; Zhu, Xu-Guang; Yaster, Myron; Johns, Roger A; Gauda, Estelle B; Tao, Yuan-Xiang

    2008-01-01

    Postsynaptic density (PSD)-93, a neuronal scaffolding protein, binds to and clusters N-methyl-D-aspartate receptor (NMDAR) subunits NR2A and NR2B at cellular membranes in vitro. However, the roles of PSD-93 in synaptic NR2A and NR2B targeting in the central nervous system and NMDAR-dependent physiologic and pathologic processes are still unclear. We report here that PSD-93 deficiency significantly decreased the amount of NR2A and NR2B in the synaptosomal membrane fractions derived from spinal cord dorsal horn and forebrain cortex but did not change their levels in the total soluble fraction from either region. However, PSD-93 deficiency did not markedly change the amounts of NR2A and NR2B in either synaptosomal or total soluble fractions from cerebellum. In mice deficient in PSD-93, morphine dose-dependent curve failed to shift significantly rightward as it did in wild type (WT) mice after acute and chronic morphine challenge. Unlike WT mice, PSD-93 knockout mice also showed marked losses of NMDAR-dependent morphine analgesic tolerance and associated abnormal sensitivity in response to mechanical, noxious thermal, and formalin-induced inflammatory stimuli after repeated morphine injection. In addition, PSD-93 knockout mice displayed dramatic loss of jumping activity, a typical NMDAR-mediated morphine withdrawal abstinence behavior. These findings indicate that impaired NMDAR-dependent neuronal plasticity following repeated morphine injection in PSD-93 knockout mice is attributed to PSD-93 deletion-induced alterations of synaptic NR2A and NR2B expression in dorsal horn and forebrain cortex neurons. The selective effect of PSD-93 deletion on synaptic NMDAR expression in these two major pain-related regions might provide the better strategies for the prevention and treatment of opioid tolerance and physical dependence. PMID:18851757

  1. Improving solubility of NR2B amino-terminal domain of N-methyl-d-aspartate receptor expressed in Escherichia coli.

    PubMed

    Ng, Fui-Mee; Soh, Wanqin; Geballe, Matthew T; Low, Chian-Ming

    2007-10-12

    The amino-terminal domains (ATDs) of N-methyl-d-aspartate (NMDA) receptors contain binding sites for modulators and may serve as potential drug targets in neurological diseases. Here, three fusion tags (6xHis-, GST-, and MBP-) were fused to the ATD of NMDA receptor NR2B subunit (ATD2B) and expressed in Escherichia coli. Each tag's ability to confer enhanced solubility to ATD2B was assessed. Soluble ATD2B was successfully obtained as a MBP fusion protein. Dynamic light scattering revealed the protein (1mg/ml) exists as monodispersed species at 25 degrees C. Functional studies using circular dichroism showed that the soluble MBP-ATD2B bound ifenprodil in a dose-dependent manner. The dissociation constants obtained for ifenprodil were similar in the absence (64nM) and presence (116nM) of saturating concentration of maltose. Moreover, the yield of soluble MBP-ATD2B is 18 times higher than the refolded 6xHis-ATD2B. We have reported a systematic comparison of three different affinity tagging strategies and identified a rapid and efficient method to obtain large amount of ATD2B recombinant protein for biochemical and structural studies. PMID:17706601

  2. Okadaic acid induces epileptic seizures and hyperphosphorylation of the NR2B subunit of the NMDA receptor in rat hippocampus in vivo.

    PubMed

    Arias, Clorinda; Montiel, Teresa; Peña, Fernando; Ferrera, Patricia; Tapia, Ricardo

    2002-09-01

    Overactivation of N-methyl-D-aspartate (NMDA) glutamate receptors is closely related to epilepsy and excitotoxicity, and the phosphorylation of these receptors may facilitate glutamate-mediated synaptic transmission. Here we show that in awake rats the microinjection into the hippocampus of okadaic acid, a potent inhibitor of protein phosphatases 1 and 2A, induces in about 20 min intense electroencephalographic and behavioral limbic-type seizures, which are suppressed by the systemic administration of the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine hydrogen maleate and by the intrahippocampal administration of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, an inhibitor of protein kinases. Two hours after okadaic acid, when the EEG seizures were intense, an increased serine phosphorylation of some hippocampal proteins, including an enhancement of the serine phosphorylation of the NMDA receptor subunit NR2B, was detected by immunoblotting. Twenty-four hours after okadaic acid a marked destruction of hippocampal CA1 region was observed, which was not prevented by the receptor antagonists. These findings suggest that hyperphosphorylation of glutamate receptors in vivo may result in an increased sensitivity to the endogenous transmitter and therefore induce neuronal hyperexcitability and epilepsy. PMID:12429230

  3. Fragile X Mental Retardation Protein Interactions with a G quadruplex structure in the 3′-Untranslated Region of NR2B mRNA

    PubMed Central

    Stefanovic, Snezana; DeMarco, Brett A.; Underwood, Ayana; Williams, Kathryn R.; Bassell, Gary J.; Mihailescu, Mihaela Rita

    2015-01-01

    Fragile X syndrome, the most common cause of inherited intellectual disability, is caused by a trinucleotide CGG expansion in the 5′-untranslated region of the FMR1 gene, which leads to the loss of expression of the fragile X mental retardation protein (FMRP). FMRP, an RNA-binding protein that regulates the translation of specific mRNAs, has been shown to bind a subset of its mRNA targets by recognizing G quadruplex structures. It has been suggested that FMRP controls the local protein synthesis of several protein components of the Post Synaptic Density (PSD) in response to specific cellular needs. We have previously shown that the interactions between FMRP and mRNAs of the PSD scaffold proteins PSD-95 and Shank1 are mediated via stable G-quadruplex structures formed within the 3′-untranslated regions of these mRNAs. In this study we used biophysical methods to show that a comparable G quadruplex structure forms in the 3′-untranslated region of the glutamate receptor subunit NR2B mRNA encoding for a subunit of N-methyl-D-aspartate (NMDA) receptors that is recognized specifically by FMRP, suggesting a common theme for FMRP recognition of its dendritic mRNA targets. PMID:26412477

  4. Dopamine receptor D5 deficiency results in a selective reduction of hippocampal NMDA receptor subunit NR2B expression and impaired memory.

    PubMed

    Moraga-Amaro, Rodrigo; González, Hugo; Ugalde, Valentina; Donoso-Ramos, Juan Pablo; Quintana-Donoso, Daisy; Lara, Marcelo; Morales, Bernardo; Rojas, Patricio; Pacheco, Rodrigo; Stehberg, Jimmy

    2016-04-01

    Pharmacological evidence associates type I dopamine receptors, including subtypes D1 and D5, with learning and memory. Analyses using genetic approaches have determined the relative contribution of dopamine receptor D1 (D1R) in cognitive tasks. However, the lack of drugs that can discriminate between D1R and D5R has made the pharmacological distinction between the two receptors difficult. Here, we aimed to determine the role of D5R in learning and memory. In this study we tested D5R knockout mice and wild-type littermates in a battery of behavioral tests, including memory, attention, locomotion, anxiety and motivational evaluations. Our results show that genetic deficiency of D5R significantly impairs performance in the Morris water maze paradigm, object location and object recognition memory, indicating a relevant role for D5R in spatial memory and recognition memory. Moreover, the lack of D5R resulted in decreased exploration and locomotion. In contrast, D5R deficiency had no impact on working memory, anxiety and depressive-like behavior, measured using the spontaneous alternation, open-field, tail suspension test, and forced swimming test. Electrophysiological analyses performed on hippocampal slices showed impairment in long-term-potentiation in mice lacking D5R. Further analyses at the molecular level showed that genetic deficiency of D5R results in a strong and selective reduction in the expression of the NMDA receptor subunit NR2B in the hippocampus. These findings demonstrate the relevant contribution of D5R in memory and suggest a functional interaction of D5R with hippocampal glutamatergic pathways. PMID:26714288

  5. Identification and characterization of 4-methylbenzyl 4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate, an orally bioavailable, brain penetrant NR2B selective N-methyl-D-aspartate receptor antagonist.

    PubMed

    Liverton, Nigel J; Bednar, Rodney A; Bednar, Bohumil; Butcher, John W; Claiborne, Christopher F; Claremon, David A; Cunningham, Michael; DiLella, Anthony G; Gaul, Stanley L; Libby, Brian E; Lyle, Elizabeth A; Lynch, Joseph J; McCauley, John A; Mosser, Scott D; Nguyen, Kevin T; Stump, Gary L; Sun, Hong; Wang, Hao; Yergey, James; Koblan, Kenneth S

    2007-02-22

    The discovery of a novel series of NR2B subtype selective N-methyl-d-aspartate (NMDA) antagonists is reported. Initial optimization of a high-throughput screening lead afforded an aminopyridine derivative 13 with significant NR2B antagonist potency but limited selectivity over hERG-channel and other off-target activities. Further structure-activity studies on the aminoheterocycle moiety and optimization of the carbamate led to the highly potent 2-aminopyrimidine derivative 20j with a significantly improved off-target activity profile and oral bioavailability in multiple species coupled with good brain penetration. Compound 20j demonstrated efficacy in in vivo rodent models of antinociception, allodynia, and Parkinson's disease. PMID:17249648

  6. Dexmedetomidine protects against learning and memory impairments caused by electroconvulsive shock in depressed rats: Involvement of the NMDA receptor subunit 2B (NR2B)-ERK signaling pathway.

    PubMed

    Gao, Xin; Zhuang, Fu-Zhi; Qin, Shou-Jun; Zhou, Li; Wang, Yun; Shen, Qing-Feng; Li, Mei; Villarreal, Michelle; Benefield, Lauren; Gu, Shu-Ling; Ma, Teng-Fei

    2016-09-30

    Cognitive impairment is a common adverse effect of electroconvulsive therapy (ECT) during treatment for severe depression. Dexmedetomidine (DEX), a sedative-anesthetic drug, is used to treat post-ECT agitation. However, it is not known if DEX can protect against ECT-induced cognitive impairments. To address this, we used chronic unpredictable mild stress (CUMS) to establish a model of depression for ECT treatment. Our Morris water maze and sucrose preference test results suggest that DEX alleviates ECT-induced learning and memory impairments without altering the antidepressant efficacy of ECT. To further investigate the underlying mechanisms of DEX, hippocampal expression of NR2B, p-ERK/ERK, p-CREB/CREB, and BDNF were quantified by western blotting. These results show that DEX suppresses over-activation of NR2B and enhances phosphorylation of ERK1/2 in the hippocampus of ECT-treated depressed rats. Furthermore, DEX had no significant effect on ECT-induced increases in p-CREB and BDNF. Overall, our findings suggest that DEX ameliorates ECT-induced learning and memory impairments in depressed rats via the NR2B-ERK signaling cascade. Moreover, CREB/BDNF seems not appear to participate in the cognitive protective mechanisms of DEX during ECT treatment. PMID:27455425

  7. Behavioural Assessment of the A2a/NR2B Combination in the Unilateral 6-OHDA-Lesioned Rat Model: A New Method to Examine the Therapeutic Potential of Non-Dopaminergic Drugs.

    PubMed

    Michel, Anne; Downey, Patrick; Van Damme, Xavier; De Wolf, Catherine; Schwarting, Rainer; Scheller, Dieter

    2015-01-01

    In Parkinson's disease (PD), dopaminergic therapies are often associated with the development of motor complications. Attention has therefore been focused on the use of non-dopaminergic drugs. This study developed a new behavioural method capable of demonstrating the added value of combining adenosinergic and glutamatergic receptor antagonists in unilateral 6-OHDA lesioned rats. Rats were dosed orally with Tozadenant, a selective A2A receptor antagonist, and three different doses of Radiprodil, an NR2B-selective NMDA receptor antagonist. The drugs were given alone or in combination and rats were placed in an open-field for behavioural monitoring. Video recordings were automatically analysed. Five different behaviours were scored: distance traveled, ipsi- and contraversive turns, body position, and space occupancy. The results show that A2A or NR2B receptor antagonists given alone or in combination did not produce enhanced turning as observed with an active dose of L-Dopa/benserazide. Instead the treated rats maintained a straight body position, were able to shift from one direction to the other and occupied a significantly larger space in the arena. The highest "Tozadenant/Radiprodil" dose combination significantly increased all five behavioural parameters recorded compared to rats treated with vehicle or the same doses of the drugs alone. Our data suggest that the A2A/NR2B antagonist combination may be able to stimulate motor activity to a similar level as that achieved by L-Dopa but in the absence of the side-effects that are associated with dopaminergic hyperstimulation. If these results translate into the clinic, this combination could represent an alternative symptomatic treatment option for PD. PMID:26322641

  8. Experimental evidence that overexpression of NR2B glutamate receptor subunit is associated with brain vacuolation in adult glutaryl-CoA dehydrogenase deficient mice: A potential role for glutamatergic-induced excitotoxicity in GA I neuropathology.

    PubMed

    Rodrigues, Marília Danyelle Nunes; Seminotti, Bianca; Amaral, Alexandre Umpierrez; Leipnitz, Guilhian; Goodman, Stephen Irwin; Woontner, Michael; de Souza, Diogo Onofre Gomes; Wajner, Moacir

    2015-12-15

    Glutaric aciduria type I (GA I) is biochemically characterized by accumulation of glutaric and 3-hydroxyglutaric acids in body fluids and tissues, particularly in the brain. Affected patients show progressive cortical leukoencephalopathy and chronic degeneration of the basal ganglia whose pathogenesis is still unclear. In the present work we investigated parameters of bioenergetics and redox homeostasis in various cerebral structures (cerebral cortex, striatum and hippocampus) and heart of adult wild type (Gcdh(+/+)) and glutaryl-CoA dehydrogenase deficient knockout (Gcdh(-/-)) mice fed a baseline chow. Oxidative stress parameters were also measured after acute lysine overload. Finally, mRNA expression of NMDA subunits and GLT1 transporter was determined in cerebral cortex and striatum of these animals fed a baseline or high lysine (4.7%) chow. No significant alterations of bioenergetics or redox status were observed in these mice. In contrast, mRNA expression of the NR2B glutamate receptor subunit and of the GLT1 glutamate transporter was higher in cerebral cortex of Gcdh(-/-) mice. Furthermore, NR2B expression was markedly elevated in striatum of Gcdh(-/-) animals receiving chronic Lys overload. These data indicate higher susceptibility of Gcdh(-/-) mice to excitotoxic damage, implying that this pathomechanism may contribute to the cortical and striatum alterations observed in GA I patients. PMID:26671102

  9. Mild Hypothermia Combined with Hydrogen Sulfide Treatment During Resuscitation Reduces Hippocampal Neuron Apoptosis Via NR2A, NR2B, and PI3K-Akt Signaling in a Rat Model of Cerebral Ischemia-Reperfusion Injury.

    PubMed

    Dai, Hai-Bin; Xu, Miao-Miao; Lv, Jia; Ji, Xiang-Jun; Zhu, Si-Hai; Ma, Ru-Meng; Miao, Xiao-Lei; Duan, Man-Lin

    2016-09-01

    We investigated whether mild hypothermia combined with sodium hydrosulfide treatment during resuscitation improves neuron survival following cerebral ischemia-reperfusion injury beyond that observed for the individual treatments. Male Sprague-Dawley rats were divided into seven groups (n = 20 for each group). All rats underwent Pulsinelli 4-vessel occlusion. Ischemia was induced for 15 min using ligatures around the common carotid arteries, except for the sham group. Immediately after initiating reperfusion, the mild hypothermia (MH), sodium hydrosulfide (NaHS), hydroxylamine (HA), MH + NaHS, MH + HA, and ischemia-reperfusion (I/R) control groups received an intraperitoneal injection of saline, sodium hydrosulfide, hydroxylamine, sodium hydrosulfide, hydroxylamine, and saline, respectively, and mild hypothermia (32 to 33 °C) was induced in the MH, MH + NaHS, and MH + HA groups for 6 h. The levels of NR2A, NR2B, p-Akt, and p-Gsk-3β in the hippocampus of the MH, NaHS, and MH + NaHS groups were higher than those in the I/R control group, with the highest levels observed in the MH + NaHS group (P < 0.05). Treatment with hydroxylamine reduced the levels of these proteins in the HA and MH + HA groups, compared with the I/R control and MH groups, respectively. The apoptotic index of the CA1 region of the hippocampus was 45.2, 66.5, 63.5, and 84.8 % in the MH + NaHS, MH, NaHS, and I/R control groups, respectively (P < 0.05), indicating that the combination treatment shifted the NR2A/NR2B balance in favor of synaptic neuron stimulation and phosphatidylinositol 3'-kinase (PI3K)/Akt signaling. The combination of mild hypothermia and sodium hydrosulfide treatment for resuscitation following ischemia-reperfusion injury was more beneficial for reducing hippocampal apoptosis and pathology than that of mild hypothermia or hydrogen sulfide treatment alone. PMID:26350917

  10. Traxoprodil, a selective antagonist of the NR2B subunit of the NMDA receptor, potentiates the antidepressant-like effects of certain antidepressant drugs in the forced swim test in mice.

    PubMed

    Poleszak, Ewa; Stasiuk, Weronika; Szopa, Aleksandra; Wyska, Elżbieta; Serefko, Anna; Oniszczuk, Anna; Wośko, Sylwia; Świąder, Katarzyna; Wlaź, Piotr

    2016-08-01

    One of the newest substances, whose antidepressant activity was shown is traxoprodil, which is a selective antagonist of the NR2B subunit of the NMDA receptor. The main goal of the present study was to evaluate the effect of traxoprodil on animals' behavior using the forced swim test (FST), as well as the effect of traxoprodil (10 mg/kg) on the activity of antidepressants, such as imipramine (15 mg/kg), fluoxetine (5 mg/kg), escitalopram (2 mg/kg) and reboxetine (2.5 mg/kg). Serotonergic lesion and experiment using the selective agonists of serotonin receptors 5-HT1A and 5-HT2 was conducted to evaluate the role of the serotonergic system in the antidepressant action of traxoprodil. Brain concentrations of tested agents were determined using HPLC. The results showed that traxoprodil at a dose of 20 and 40 mg/kg exhibited antidepressant activity in the FST and it was not related to changes in animals' locomotor activity. Co-administration of traxoprodil with imipramine, fluoxetine or escitalopram, each in subtherapeutic doses, significantly affected the animals' behavior in the FST and, what is important, these changes were not due to the severity of locomotor activity. The observed effect of traxoprodil is only partially associated with serotonergic system and is independent of the effect on the 5-HT1A and 5-HT2 serotonin receptors. The results of an attempt to assess the nature of the interaction between traxoprodil and the tested drugs show that in the case of joint administration of traxoprodil and fluoxetine, imipramine or escitalopram, there were interactions in the pharmacokinetic phase. PMID:26924124

  11. La pelade par plaques

    PubMed Central

    Spano, Frank; Donovan, Jeff C.

    2015-01-01

    Résumé Objectif Présenter aux médecins de famille des renseignements de base pour faire comprendre l’épidémiologie, la pathogenèse, l’histologie et l’approche clinique au diagnostic de la pelade par plaques. Sources des données Une recension a été effectuée dans PubMed pour trouver des articles pertinents concernant la pathogenèse, le diagnostic et le pronostic de la pelade par plaques. Message principal La pelade par plaques est une forme de perte pileuse auto-immune dont la prévalence durant une vie est d’environ 2 %. Des antécédents personnels ou familiaux de troubles auto-immuns concomitants, comme le vitiligo ou une maladie de la thyroïde, peuvent être observés dans un petit sous-groupe de patients. Le diagnostic peut souvent être posé de manière clinique en se fondant sur la perte de cheveux non cicatricielle et circulaire caractéristique, accompagnée de cheveux en « point d’exclamation » en périphérie chez ceux dont le problème en est aux premiers stades. Le diagnostic des cas plus complexes ou des présentations inhabituelles peut être facilité par une biopsie et un examen histologique. Le pronostic varie largement et de mauvais résultats sont associés à une apparition à un âge précoce, une perte importante, la variante ophiasis, des changements aux ongles, des antécédents familiaux ou des troubles auto-immuns concomitants. Conclusion La pelade par plaques est une forme auto-immune de perte de cheveux périodiquement observée en soins primaires. Les médecins de famille sont bien placés pour identifier la pelade par plaques, déterminer la gravité de la maladie et poser le diagnostic différentiel approprié. De plus, ils sont en mesure de renseigner leurs patients à propos de l’évolution clinique de la maladie ainsi que du pronostic général selon le sous-type de patients.

  12. La pelade par plaques

    PubMed Central

    Spano, Frank; Donovan, Jeff C.

    2015-01-01

    Résumé Objectif Présenter aux médecins de famille des renseignements de base pour faire comprendre les schémas thérapeutiques et les résultats des traitements pour la pelade par plaques, de même que les aider à identifier les patients pour qui une demande de consultation en dermatologie pourrait s’imposer. Sources des données Une recension a été effectuée dans PubMed pour trouver des articles pertinents concernant le traitement de la pelade par plaques. Message principal La pelade par plaques est une forme auto-immune de perte pileuse qui touche à la fois les enfants et les adultes. Même s’il n’y a pas de mortalité associée à la maladie, la morbidité découlant des effets psychologiques de la perte des cheveux peut être dévastatrice. Lorsque la pelade par plaques et le sous-type de la maladie sont identifiés, un schéma thérapeutique approprié peut être amorcé pour aider à arrêter la chute des cheveux et possiblement faire commencer la repousse. Les traitements de première intention sont la triamcinolone intralésionnelle avec des corticostéroïdes topiques ou du minoxidil ou les 2. Les médecins de famille peuvent prescrire ces traitements en toute sécurité et amorcer ces thérapies. Les cas plus avancés ou réfractaires pourraient avoir besoin de diphénylcyclopropénone topique ou d’anthraline topique. On peut traiter la perte de cils avec des analogues de la prostaglandine. Les personnes ayant subi une perte de cheveux abondante peuvent recourir à des options de camouflage ou à des prothèses capillaires. Il est important de surveiller les troubles psychiatriques en raison des effets psychologiques profonds de la perte de cheveux. Conclusion Les médecins de famille verront de nombreux patients qui perdent leurs cheveux. La reconnaissance de la pelade par plaques et la compréhension du processus pathologique sous-jacent permettent d’amorcer un schéma thérapeutique approprié. Les cas plus graves ou r

  13. Pars Injuries in Athletes.

    PubMed

    Oren, Jonathan H; Gallina, Jason M

    2016-03-01

    Pars injuries are common causes of low back pain in adolescent athletes. Workup traditionally has included lumbar radiographs with oblique views and single-photon emission computed tomography (SPECT). However, recent literature has demonstrated the accuracy of MRI as a diagnostic modality. Acute injuries may be amenable to bracing with the goal of a healed lesion. Most cases of spondylolysis will result in asymptomatic non-union, though pars repair is an option for symptomatic pars defects without spondylolisthesis. PMID:26977552

  14. Nonconsecutive Pars Interarticularis Defects.

    PubMed

    Elgafy, Hossein; Hart, Ryan C; Tanios, Mina

    2015-12-01

    Lumbar spondylolysis is a well-recognized condition occurring in adolescents because of repetitive overuse in sports. Nonconsecutive spondylolysis involving the lumbar spine is rare. In contrast to single-level pars defects that respond well to conservative treatment, there is no consensus about the management of multiple-level pars fractures; a few reports indicated that conservative management is successful, and the majority acknowledged that surgery is often required. The current study presents a rare case of pars fracture involving nonconsecutive segments and discusses the management options. In this case report, we review the patient's history, clinical examination, radiologic findings, and management, as well as the relevant literature. An 18-year-old man presented to the clinic with worsening lower back pain related to nonconsecutive pars fractures at L2 and L5. After 6 months of conservative management, diagnostic computed tomography-guided pars block was used to localize the symptomatic level at L2, which was treated surgically; the L5 asymptomatic pars fracture did not require surgery. At the last follow-up 2 years after surgery, the patient was playing baseball and basketball, and denied any back pain. This article reports a case of rare nonconsecutive pars fractures. Conservative management for at least 6 months is recommended. Successful management depends on the choice of appropriate treatment for each level. Single-photon emission computed tomography scan, and computed tomography-guided pars block are valuable preoperative tools to identify the symptomatic level in such a case. PMID:26665257

  15. Par Pond water balance

    SciTech Connect

    Hiergesell, R.A.; Dixon, K.L.

    1996-06-01

    A water budget for the Par Pond hydrologic system was established in order to estimate the rate of groundwater influx to Par Pond. This estimate will be used in modeling exercises to predict Par Pond reservoir elevation and spillway discharge in the scenario where Savannah River water is no longer pumped and discharged into Par Pond. The principal of conservation of mass was used to develop the water budget, where water inflow was set equal to water outflow. Components of the water budget were identified, and the flux associated with each was determined. The water budget was considered balanced when inflow and outflow summed to zero. The results of this study suggest that Par Pond gains water from the groundwater system in the upper reaches of the reservoir, but looses water to the groundwater system near the dam. The rate of flux of groundwater from the water table aquifer into Par Pond was determined to be 13 cfs. The rate of flux from Par Pond to the water table aquifer near the dam was determined to be 7 cfs.

  16. uPAR

    PubMed Central

    Uhrin, Pavel; Breuss, Johannes M.

    2013-01-01

    Vascular endothelial growth factor (VEGF)-initiated angiogenesis requires both coordinated proteolytic degradation of extracellular matrix provided by the urokinase plasminogen activator/urokinase receptor (uPA/uPAR) system and regulation of cell-migration provided by integrin–matrix interaction. Previously we have shown that stimulation of pericellular proteolysis induced by VEGF occurs via the VEGF receptor-2 leading to redistribution of uPAR to focal adhesions at the leading edge of endothelial cells. In our recent work published in Cardiovascular Research, we investigated the mechanisms underlying the uPAR-dependent modulation of VEGF-induced endothelial migration. By applying a micropatterning technique we described that VEGF stimulation results in complex formation between uPAR and α5β1-integrin on the cell surface. The subsequent internalization of this complex, important for receptor redistribution, was demonstrated by flow-cytometry and immunohistochemistry. Targeting of the interaction site between uPAR and α5β1 impairs receptor internalization and leads to the inhibition of endothelial cell migration in vitro and in an angiogenesis model in vivo. This proof-of-principle that the interface of uPAR and α5β1-integrin may represent a promising site to therapeutically target tumor angiogenesis raises hope for the development of an anti-angiogenic approach that is limited to only the mobilizing effect of VEGF to endothelial cells, and does not interfere with the inarguably positive effect of VEGF as survival factor. PMID:23076213

  17. THE MEASURES PAR PROJECT

    NASA Astrophysics Data System (ADS)

    Frouin, R. J.; Franz, B.

    2009-12-01

    The solar energy available for photosynthesis, known as PAR, controls the growth of phytoplankton and, therefore, regulates the composition and evolution of marine ecosystems. Knowing the spatial and temporal distribution of PAR over the oceans is critical to understanding biogeochemical cycles of carbon, nutrients, and oxygen, and to address important climate and global change issues such as the fate of anthropogenic atmospheric carbon dioxide. In view of this, a 12-year time series of PAR at the ocean surface, starting in September 1997, is being produced by the NASA Ocean Biology Processing Group from SeaWiFS, MODIS-Terra, and MODIS-Aqua data. The product covers the global oceans, with a spatial resolution of about 9.3x9.3 km (equal area grid) and a temporal resolution of one day. PAR is computed as the difference between the 400-700 nm solar flux incident on the top of the atmosphere (known) and reflected back to space by the atmosphere and surface (derived from satellite radiance), taking into account atmospheric absorption (modeled). Knowledge of pixel composition is not required, eliminating the need for cloud screening and arbitrary assumptions about sub-pixel cloudiness. Combining data from satellite sensors with different equatorial crossing times accounts for the diurnal variability of clouds and, therefore, increases accuracy on a daily time scale. The processing system, including routine check of accuracy and control of quality, is designed to operate during the entire lifetime of SeaWiFS and MODIS, and to accommodate future sensors with ocean-color capabilities. Maps of daily, weekly, and monthly PAR obtained from individual sensors are presented, as well as merged products. Accuracy is quantified in comparisons with other satellite estimates, the National Centers for Environmental Prediction reanalysis product, and in-situ measurements from fixed buoys and platforms. The good statistical performance makes the satellite PAR product suitable for large

  18. Protease-activated receptor (PAR)1, PAR2 and PAR4 expressions in esophageal squamous cell carcinoma

    PubMed Central

    LI, Si-Man; JIANG, Ping; XIANG, Yang; WANG, Wei-Wei; ZHU, Yue-Chun; FENG, Wei-Yang; LI, Shu-De; YU, Guo-Yu

    2014-01-01

    Here, we used reverse transcription-PCR (RT-PCR) and western blot to detect protease-activated receptor (PAR) 1, PAR 2 and PAR 4 expression in cancer tissues and cell lines of esophageal squamous cell carcinoma, and investigated the co-relationship between PAR expression and clinic-pathological data for esophageal cancer. The methylation of PAR4 gene promoter involved in esophageal carcinoma was also analyzed. By comparing the mRNA expressions of normal esophageal tissue and human esophageal epithelial cells (HEEpiC), we found that among the 28 cases of esophageal squamous cell carcinoma, PAR1 (60%) and PAR2 (71%) were elevated in 17 and 20 cases, respectively, and PAR4 (68%) expression was lowered in 19 cases. Whereas, in human esophageal squamous cells (TE-1 and TE-10), PAR1 and PAR2 expression was increased but PAR4 was decreased. Combined with clinical data, the expression of PAR1 in poorly differentiated (P=0.016) and middle and lower parts of the esophagus (P=0.016) was higher; expression of PAR4 in poorly differentiated carcinoma was lower (P=0.049). Regarding TE-1 and TE-10 protein expression, we found that in randomized esophageal carcinoma, PAR1 (P=0.027) and PAR2 (P=0.039) expressions were increased, but lowered for PAR4 (P=0.0001). In HEEpiC, TE-1, TE-10, esophageal and normal esophagus tissue samples (case No. 7), the frequency of methylation at the 19 CpG loci of PAR4 was 35.4%, 95.2%, 83.8%, 62.6% and 48.2%, respectively. Our results indicate that the expression of PAR1 and PAR2 in esophageal squamous cell carcinoma is increased but PAR4 is decreased. Hypermethylation of the promoter of the PAR4 gene may contribute to reduced expression of PAR4 in esophageal squamous cell carcinoma. PMID:25297082

  19. Par Pond vegetation status 1996

    SciTech Connect

    Mackey, H.E. Jr.; Riley, R.S.

    1996-12-01

    The water level of Par Pond was lowered approximately 20 feet in mid-1991 in order to protect downstream residents from possible dam failure suggested by subsidence on the downstream slope of the dam and to repair the dam. This lowering exposed both emergent and nonemergent macrophyte beds to drying conditions resulting in extensive losses. A survey of the newly emergent, shoreline aquatic plant communities of Par Pond began in June 1995, three months after the refilling of Par Pond to approximately 200 feet above mean sea level. These surveys continued in July, September, and late October, 1995, and into the early spring and late summer of 1996. Communities similar to the pre-drawdown, Par Pond aquatic plant communities continue to become re-established. Emergent beds of maidencane, lotus, waterlily, watershield, and Pontederia are extensive and well developed. Measures of percent cover, width of beds, and estimates of area of coverage with satellite data indicate regrowth within two years of from 40 to 60% of levels prior to the draw down. Cattail occurrence continued to increase during the summer of 1996, especially in the former warm arm of Par Pond, but large beds common to Par Pond prior to the draw down still have not formed. Lotus has invaded and occupies many of the areas formerly dominated by cattail beds. To track the continued development of macrophytes in Par Pond, future surveys through the summer and early fall of 1997, along with the evaluation of satellite data to map the extent of the macrophyte beds of Par Pond, are planned.

  20. Immunopathogenic Background of Pars Planitis.

    PubMed

    Przeździecka-Dołyk, Joanna; Węgrzyn, Agnieszka; Turno-Kręcicka, Anna; Misiuk-Hojło, Marta

    2016-04-01

    Pars planitis is defined as an intermediate uveitis of unknown background of systemic disease with characteristic formations such as vitreous snowballs, snowbanks and changes in peripheral retina. The incidence of pars planitis varies 2.4-15.4 % of the uveitis patients. The pathogenesis of the disease is to be determined in future. Clinical and histopathological findings suggest an autoimmune etiology, most likely as a reaction to endogenous antigen of unknown source, with T cells predominant in both vitreous and pars plana infiltrations. T cells subsets play an important role as a memory-effector peripheral cell. Snowbanks are formed as an effect of post inflammatory glial proliferation of fibrous astrocytes. There is also a genetic predisposition for pars planitis by human leukocyte antigen and several other genes. A coexistence of multiple sclerosis and optic neuritis has been described in numerous studies. Epiretinal membrane, cataract, cystoid macular edema, retinal detachment, retinal vasculitis, neovascularization, vitreous peripheral traction, peripheral hole formation, vitreous hemorrhage, disc edema are common complications observed in pars planitis. There is a need to expand the knowledge of the pathogenic and immunologic background of the pars planitis to create an accurate pharmacological treatment. PMID:26438050

  1. Exploration of locomotion in the ParA/ParB system

    NASA Astrophysics Data System (ADS)

    Jindal, Lavisha; Emberly, Eldon

    2015-03-01

    In many bacteria the ParA/ParB system is responsible for actively segregating DNA during replication. ParB precessively moves by hydrolyzing DNA bound ParA-ATP forming a depleted ParA region in its wake. Recent in-vitro experiments have shown that a ParB covered bead can traverse a ParA bound DNA substrate. It has been suggested that the formation of a gradient in ParA leads to diffusion-ratchet like motion of the ParB bead but its origin and potential consequences requires investigation. We have developed a deterministic model for the in-vitro ParA/ParB system and show that any amount of spatial noise in ParA can lead to the spontaneous formation of its gradient. The velocity of the bead is independent of this noise but depends on the scale over which ParA exerts a force on the bead and the scale over which ParB hydrolyzes ParA from the substrate. There is a particular ratio of these scales at which the velocity is a maximum. We also explore the effects of cooperative vs independent rebinding of ParA to the substrate. Our model shows how the driving force for ParB originates and highlights necessary conditions for directed motion in the in-vitro system that may provide insight into the in-vivo behaviour of the ParA/ParB system.

  2. [Physiology of protease-activated receptors (PARs): involvement of PARs in digestive functions].

    PubMed

    Kawabata, A; Kuroda, R; Hollenberg, M D

    1999-10-01

    The protease-activated receptor (PAR), a G protein-coupled receptor present on cell surface, mediates cellular actions of extracellular proteases. Proteases cleave the extracellular N-terminal of PAR molecules at a specific site, unmasking and exposing a novel N-terminal, a tethered ligand, that binds to the body of receptor molecules resulting in receptor activation. Amongst four distinct PARs that have been cloned, PARs 1, 3 and 4 are activated by thrombin, but PAR-2 is activated by trypsin or mast cell tryptase. Human platelets express two distinct thrombin receptors, PAR-1 and PAR-4, while murine platelets express PAR-3 and PAR-4. Apart from roles of PARs in platelet activation, PARs are distributed to a number of organs in various species, predicting their physiological importance. We have been evaluating agonists specific for each PAR, using multiple procedures including a HEK cell calcium signal receptor desensitization assay. Using specific agonists that we developed, we found the following: 1) the salivary glands express PAR-2 mRNA and secret saliva in response to PAR-2 activation; 2) pancreatic juice secretion occurs following in vivo PAR-2 activation; 3) PAR-1 and PAR-2 modulate duodenal motility. Collectively, PAR plays various physiological and/or pathophysiological roles, especially in the digestive systems, and could be a novel target for drug development. PMID:10629876

  3. Par Pond Fish, Water, and Sediment Chemistry

    SciTech Connect

    Paller, M.H.; Wike, L.D.

    1996-06-01

    The objectives of this report are to describe the Par Pond fish community and the impact of the drawdown and refill on the community, describe contaminant levels in Par Pond fish, sediments, and water and indicate how contaminant concentrations and distributions were affected by the drawdown and refill, and predict possible effects of future water level fluctuations in Par Pond.

  4. Directed and persistent movement arises from mechanochemistry of the ParA/ParB system

    NASA Astrophysics Data System (ADS)

    Hu, Longhua; Vecchiarelli, Anthony G.; Mizuuchi, Kiyoshi; Neuman, Keir C.; Liu, Jian

    The segregation of DNA prior to cell division is essential for faithful genetic inheritance. In many bacteria, segregation of the low-copy-number plasmids involves an active partition system composed of ParA ATPase and its stimulator protein ParB. Recent experiments suggest that ParA/ParB system motility is driven by a diffusion-ratchet mechanism in which ParB-coated plasmid both creates and follows a ParA gradient on the nucleoid surface. However, the detailed mechanism of ParA/ParB-mediated directed and persistent movement remains unknown. We develop a theoretical model describing ParA/ParB-mediated motility. We show that the ParA/ParB system can work as a Brownian ratchet, which effectively couples the ATPase-dependent cycling of ParA-nucleoid affinity to the motion of the ParB bound cargo. Paradoxically, the resulting processive motion relies on quenching diffusive plasmid motion through a large number of transient ParA/ParB-mediated tethers to the nucleoid surface. Our work sheds light on a new emergent phenomenon in which non-motor proteins work collectively via mechanochemical coupling to propel cargos -- an ingenious solution shaped by evolution to cope with the lack of processive motor proteins in bacteria.

  5. The ParB-parS Chromosome Segregation System Modulates Competence Development in Streptococcus pneumoniae

    PubMed Central

    Attaiech, Laetitia; Minnen, Anita; Kjos, Morten; Gruber, Stephan

    2015-01-01

    ABSTRACT ParB proteins bind centromere-like DNA sequences called parS sites and are involved in plasmid and chromosome segregation in bacteria. We previously showed that the opportunistic human pathogen Streptococcus pneumoniae contains four parS sequences located close to the origin of replication which are bound by ParB. Using chromatin immunoprecipitation (ChIP), we found here that ParB spreads out from one of these parS sites, parS(−1.6°), for more than 5 kb and occupies the nearby comCDE operon, which drives competence development. Competence allows S. pneumoniae to take up DNA from its environment, thereby mediating horizontal gene transfer, and is also employed as a general stress response. Mutating parS(−1.6°) or deleting parB resulted in transcriptional up-regulation of comCDE and ssbB (a gene belonging to the competence regulon), demonstrating that ParB acts as a repressor of competence. However, genome-wide transcription analysis showed that ParB is not a global transcriptional regulator. Different factors, such as the composition of the growth medium and antibiotic-induced stress, can trigger the sensitive switch driving competence. This work shows that the ParB-parS chromosome segregation machinery also influences this developmental process. PMID:26126852

  6. Parallel Climate Analysis Toolkit (ParCAT)

    Energy Science and Technology Software Center (ESTSC)

    2013-06-30

    The parallel analysis toolkit (ParCAT) provides parallel statistical processing of large climate model simulation datasets. ParCAT provides parallel point-wise average calculations, frequency distributions, sum/differences of two datasets, and difference-of-average and average-of-difference for two datasets for arbitrary subsets of simulation time. ParCAT is a command-line utility that can be easily integrated in scripts or embedded in other application. ParCAT supports CMIP5 post-processed datasets as well as non-CMIP5 post-processed datasets. ParCAT reads and writes standard netCDF files.

  7. Directed and persistent movement arises from mechanochemistry of the ParA/ParB system.

    PubMed

    Hu, Longhua; Vecchiarelli, Anthony G; Mizuuchi, Kiyoshi; Neuman, Keir C; Liu, Jian

    2015-12-22

    The segregation of DNA before cell division is essential for faithful genetic inheritance. In many bacteria, segregation of low-copy number plasmids involves an active partition system composed of a nonspecific DNA-binding ATPase, ParA, and its stimulator protein ParB. The ParA/ParB system drives directed and persistent movement of DNA cargo both in vivo and in vitro. Filament-based models akin to actin/microtubule-driven motility were proposed for plasmid segregation mediated by ParA. Recent experiments challenge this view and suggest that ParA/ParB system motility is driven by a diffusion ratchet mechanism in which ParB-coated plasmid both creates and follows a ParA gradient on the nucleoid surface. However, the detailed mechanism of ParA/ParB-mediated directed and persistent movement remains unknown. Here, we develop a theoretical model describing ParA/ParB-mediated motility. We show that the ParA/ParB system can work as a Brownian ratchet, which effectively couples the ATPase-dependent cycling of ParA-nucleoid affinity to the motion of the ParB-bound cargo. Paradoxically, this resulting processive motion relies on quenching diffusive plasmid motion through a large number of transient ParA/ParB-mediated tethers to the nucleoid surface. Our work thus sheds light on an emergent phenomenon in which nonmotor proteins work collectively via mechanochemical coupling to propel cargos-an ingenious solution shaped by evolution to cope with the lack of processive motor proteins in bacteria. PMID:26647183

  8. Directed and persistent movement arises from mechanochemistry of the ParA/ParB system

    PubMed Central

    Hu, Longhua; Vecchiarelli, Anthony G.; Mizuuchi, Kiyoshi; Neuman, Keir C.; Liu, Jian

    2015-01-01

    The segregation of DNA before cell division is essential for faithful genetic inheritance. In many bacteria, segregation of low-copy number plasmids involves an active partition system composed of a nonspecific DNA-binding ATPase, ParA, and its stimulator protein ParB. The ParA/ParB system drives directed and persistent movement of DNA cargo both in vivo and in vitro. Filament-based models akin to actin/microtubule-driven motility were proposed for plasmid segregation mediated by ParA. Recent experiments challenge this view and suggest that ParA/ParB system motility is driven by a diffusion ratchet mechanism in which ParB-coated plasmid both creates and follows a ParA gradient on the nucleoid surface. However, the detailed mechanism of ParA/ParB-mediated directed and persistent movement remains unknown. Here, we develop a theoretical model describing ParA/ParB-mediated motility. We show that the ParA/ParB system can work as a Brownian ratchet, which effectively couples the ATPase-dependent cycling of ParA–nucleoid affinity to the motion of the ParB-bound cargo. Paradoxically, this resulting processive motion relies on quenching diffusive plasmid motion through a large number of transient ParA/ParB-mediated tethers to the nucleoid surface. Our work thus sheds light on an emergent phenomenon in which nonmotor proteins work collectively via mechanochemical coupling to propel cargos—an ingenious solution shaped by evolution to cope with the lack of processive motor proteins in bacteria. PMID:26647183

  9. Role of PAR-4 in ovarian cancer.

    PubMed

    Meynier, Sonia; Kramer, Marianne; Ribaux, Pascale; Tille, Jean-Christophe; Delie, Florence; Petignat, Patrick; Cohen, Marie

    2015-09-01

    Prostate apoptosis response-4 (PAR-4) is considered as a tumour suppressor due to its ability to selectively induce cell apoptosis in most cancer cells. However little is known about the role of PAR-4 in ovarian cancer. In this study, we investigated for the first time the role of PAR-4 in ovarian carcinogenesis. We showed that PAR-4 mRNA level is not significantly different between healthy and cancer ovarian cells. Immunohistochemistry on ovarian tissue showed that ovarian cancer cells are positive for PAR-4 nuclear and cytoplasmic staining whereas ovarian healthy cells are negative for PAR-4 nuclear staining. We then studied the role of PAR-4 in cell apoptosis. We determined that PAR-4 induces cell apoptosis in response to stimuli, in vitro, but is also involved in the relocation of GRP78 from endoplasmic reticulum to the cell surface of ovarian cancer cell line (SKOV-3 cells). In ovo, PAR-4 decreases ovarian tumour development and increases the response to taxol treatment. These observations suggest that PAR-4 is a very interesting therapeutic target against ovarian carcinogenesis. PMID:26246468

  10. Role of PAR-4 in ovarian cancer

    PubMed Central

    Meynier, Sonia; Kramer, Marianne; Ribaux, Pascale; Tille, Jean-Christophe; Delie, Florence; Petignat, Patrick; Cohen, Marie

    2015-01-01

    Prostate apoptosis response-4 (PAR-4) is considered as a tumour suppressor due to its ability to selectively induce cell apoptosis in most cancer cells. However little is known about the role of PAR-4 in ovarian cancer. In this study, we investigated for the first time the role of PAR-4 in ovarian carcinogenesis. We showed that PAR-4 mRNA level is not significantly different between healthy and cancer ovarian cells. Immunohistochemistry on ovarian tissue showed that ovarian cancer cells are positive for PAR-4 nuclear and cytoplasmic staining whereas ovarian healthy cells are negative for PAR-4 nuclear staining. We then studied the role of PAR-4 in cell apoptosis. We determined that PAR-4 induces cell apoptosis in response to stimuli, in vitro, but is also involved in the relocation of GRP78 from endoplasmic reticulum to the cell surface of ovarian cancer cell line (SKOV-3 cells). In ovo, PAR-4 decreases ovarian tumour development and increases the response to taxol treatment. These observations suggest that PAR-4 is a very interesting therapeutic target against ovarian carcinogenesis. PMID:26246468

  11. Pars triangularis asymmetry and language dominance.

    PubMed Central

    Foundas, A L; Leonard, C M; Gilmore, R L; Fennell, E B; Heilman, K M

    1996-01-01

    The pars triangular is a portion of Broca's area. The convolutions that form the inferior and caudal extent of the pars triangularis include the anterior horizontal and anterior ascending rami of the sylvian fissure, respectively. To learn if there are anatomic asymmetries of the pars triangularis, these convolutions were measured on volumetric magnetic resonance imaging scans of 11 patients who had undergone selective hemispheric anesthesia (Wada testing) to determine hemispheric speech and language lateralization. Of the 10 patients with language lateralized to the left hemisphere, 9 had a leftward asymmetry of the pars triangularis. The 1 patient with language lateralized to the right hemisphere had a significant rightward asymmetry of the pars triangularis. Our data suggest that asymmetries of the pars triangularis may be related to speech-language lateralization. Images Fig. 1 PMID:8570622

  12. PAR for the Course: A Congruent Pedagogical Approach for a PAR Methods Class

    ERIC Educational Resources Information Center

    Hammond, Joyce D.; Hicks, Maria; Kalman, Rowenn; Miller, Jason

    2005-01-01

    In the past two years, three graduate students and a senior faculty member have co-taught a participatory action research (PAR) course to undergraduate and graduate students. In this article the co-teachers advocate a set of pedagogical principles and practices in a PAR-oriented classroom that establishes congruency with community PAR projects in…

  13. Par Pond vegetation status Summer 1995 -- Summary

    SciTech Connect

    Mackey, H.E. Jr.; Riley, R.S.

    1996-01-01

    The water level of Par Pond was lowered approximately 20 feet in mid-1991 in order to protect downstream residents from possible dam failure suggested by subsidence on the downstream slope of the dam and to repair the dam. This lowering exposed both emergent and nonemergent macrophyte beds to drying conditions resulting in extensive losses. A survey of the newly emergent, shoreline aquatic plant communities of Par Pond began in June 1995, three months after the refilling of Par Pond to approximately 200 feet above mean sea level. These surveys continued in July, September, and late October, 1995. Communities similar to the pre-drawdown, Par Pond aquatic plant communities are becoming re-established. Emergent beds of maidencane, lotus, waterlily, and watershield are extensive and well developed. Cattail occurrence continued to increase during the summer, but large beds common to Par Pond prior to the drawdown have not formed. Estimates from SPOT HRV, remote sensing satellite data indicated that as much as 120 hectares of emergent wetlands vegetation may have been present along the Par Pond shoreline by early October, 1995. To track the continued development of macrophytes in Par Pond, future surveys throughout 1996 and 1997, along with the continued evaluation of satellite data to map the areal extent of the macrophyte beds of Par Pond, are planned.

  14. ParAB Partition Dynamics in Firmicutes: Nucleoid Bound ParA Captures and Tethers ParB-Plasmid Complexes

    PubMed Central

    Lioy, Virginia S.; Volante, Andrea; Soberón, Nora E.; Lurz, Rudi; Ayora, Silvia; Alonso, Juan C.

    2015-01-01

    In Firmicutes, small homodimeric ParA-like (δ2) and ParB-like (ω2) proteins, in concert with cis-acting plasmid-borne parS and the host chromosome, secure stable plasmid inheritance in a growing bacterial population. This study shows that (ω:YFP)2 binding to parS facilitates plasmid clustering in the cytosol. (δ:GFP)2 requires ATP binding but not hydrolysis to localize onto the cell’s nucleoid as a fluorescent cloud. The interaction of (δ:CFP)2 or δ2 bound to the nucleoid with (ω:YFP)2 foci facilitates plasmid capture, from a very broad distribution, towards the nucleoid and plasmid pairing. parS-bound ω2 promotes redistribution of (δ:GFP)2, leading to the dynamic release of (δ:GFP)2 from the nucleoid, in a process favored by ATP hydrolysis and protein-protein interaction. (δD60A:GFP)2, which binds but cannot hydrolyze ATP, also forms unstable complexes on the nucleoid. In the presence of ω2, (δD60A:GFP)2 accumulates foci or patched structures on the nucleoid. We propose that (δ:GFP)2 binding to different nucleoid regions and to ω2-parS might generate (δ:GFP)2 gradients that could direct plasmid movement. The iterative pairing and unpairing cycles may tether plasmids equidistantly on the nucleoid to ensure faithful plasmid segregation by a mechanism compatible with the diffusion-ratchet mechanism as proposed from in vitro reconstituted systems. PMID:26161642

  15. Comparative cactus architecture and par interception

    SciTech Connect

    Geller, G.N.; Nobel, P.S. )

    1987-07-01

    Because CO{sup 2} uptake by cacti can be limited by low levels of photosynthetically active radiation (PAR) and because plant form affects PAR interception, various cactus forms were studied using a computer model, field measurements, and laboratory phototropic studies. Model predictions indicated that CO{sub 2} uptake by individual stems at an equinox was greatest when the stem were vertical, but at the summer and the winter solstice CO{sub 2} uptake was greatest for stems titled 30{degree} away from the equator. Stem tilting depended on form and taxonomic group. Not only can the shape of cacti be affected by PAR, but also shape influences PAR interception and hence CO{sub 2} uptake.

  16. Radioecological implications of the Par Pond drawdown

    SciTech Connect

    Hickey, H.; Whicker, F.W.

    1991-12-05

    The drawdown of the Par Pond reservoir created dramatic alterations in this formerly stable lentic ecosystem. In addition, the radiation environment at Par Pond has changed significantly because of the exposure of Cesium 137-contaminated sediments and the appearance of new transport pathways to the terrestrial environment. In response to this situation, SREL was asked to study the radioecological implications of the reservoir drawdown. This report contains the objectives, methods, and results of the SREL study.

  17. Structural analysis of the ParR/parC plasmid partition complex.

    PubMed

    Møller-Jensen, Jakob; Ringgaard, Simon; Mercogliano, Christopher P; Gerdes, Kenn; Löwe, Jan

    2007-10-17

    Accurate DNA partition at cell division is vital to all living organisms. In bacteria, this process can involve partition loci, which are found on both chromosomes and plasmids. The initial step in Escherichia coli plasmid R1 partition involves the formation of a partition complex between the DNA-binding protein ParR and its cognate centromere site parC on the DNA. The partition complex is recognized by a second partition protein, the actin-like ATPase ParM, which forms filaments required for the active bidirectional movement of DNA replicates. Here, we present the 2.8 A crystal structure of ParR from E. coli plasmid pB171. ParR forms a tight dimer resembling a large family of dimeric ribbon-helix-helix (RHH)2 site-specific DNA-binding proteins. Crystallographic and electron microscopic data further indicate that ParR dimers assemble into a helix structure with DNA-binding sites facing outward. Genetic and biochemical experiments support a structural arrangement in which the centromere-like parC DNA is wrapped around a ParR protein scaffold. This structure holds implications for how ParM polymerization drives active DNA transport during plasmid partition. PMID:17898804

  18. Techniques for measuring intercepted and absorbed PAR in corn canopies

    NASA Technical Reports Server (NTRS)

    Gallo, K. P.; Daughtry, C. S. T.

    1984-01-01

    The quantity of radiation potentially available for photosynthesis that is captured by the crop is best described as absorbed photosynthetically active radiation (PAR). Absorbed PAR (APAR) is the difference between descending and ascending fluxes. The four components of APAR were measured above and within two planting densities of corn (Zea mays L.) and several methods of measuring and estimating APAR were examined. A line quantum sensor that spatially averages the photosynthetic photon flux density provided a rapid and portable method of measuring APAR. PAR reflectance from the soil (Typic Argiaquoll) surface decreased from 10% to less than 1% of the incoming PAR as the canopy cover increased. PAR reflectance from the canopy decreased to less than 3% at maximum vegetative cover. Intercepted PAR (1 - transmitted PAR) generally overestimated absorbed PAR by less than 4% throughout most of the growing season. Thus intercepted PAR appears to be a reasonable estimate of absorbed PAR.

  19. ParCAT: Parallel Climate Analysis Toolkit

    SciTech Connect

    Smith, Brian E.; Steed, Chad A.; Shipman, Galen M.; Ricciuto, Daniel M.; Thornton, Peter E.; Wehner, Michael; Williams, Dean N.

    2013-01-01

    Climate science is employing increasingly complex models and simulations to analyze the past and predict the future of Earth s climate. This growth in complexity is creating a widening gap between the data being produced and the ability to analyze the datasets. Parallel computing tools are necessary to analyze, compare, and interpret the simulation data. The Parallel Climate Analysis Toolkit (ParCAT) provides basic tools to efficiently use parallel computing techniques to make analysis of these datasets manageable. The toolkit provides the ability to compute spatio-temporal means, differences between runs or differences between averages of runs, and histograms of the values in a data set. ParCAT is implemented as a command-line utility written in C. This allows for easy integration in other tools and allows for use in scripts. This also makes it possible to run ParCAT on many platforms from laptops to supercomputers. ParCAT outputs NetCDF files so it is compatible with existing utilities such as Panoply and UV-CDAT. This paper describes ParCAT and presents results from some example runs on the Titan system at ORNL.

  20. Estradiol and the Relationship between Dendritic Spines, NR2B Containing NMDA Receptors, and the Magnitude of Long-Term Potentiation at Hippocampal CA3-CA1 Synapses

    PubMed Central

    Smith, Caroline C.; Vedder, Lindsey C.; McMahon, Lori L.

    2009-01-01

    Summary When circulating estrogen levels decline as a natural consequence of menopause and aging in women, there is an increased incidence of deficits in working memory. In many cases, these deficits are rescued by estrogen replacement therapy. These clinical data therefore highlight the importance of defining the biological pathways linking estrogen to the cellular substrates of learning and memory. It has been known for nearly two decades that estrogen enhances dendritic spine density on apical dendrites of CA1 pyramidal cells in hippocampus, a brain region required for learning. Interestingly, at synapses between CA3-CA1 pyramidal cells, estrogen has also been shown to enhance synaptic NMDA receptor current and the magnitude of long term potentiation, a cellular correlate of learning and memory. Given that synapse density, NMDAR function, and long term potentiation at CA3-CA1 synapses in hippocampus are associated with normal learning, it is likely that modulation of these parameters by estrogen facilitates the improvement in learning observed in rats, primates and humans following estrogen replacement. To facilitate the design of clinical strategies to potentially prevent or reverse the age-related decline in learning and memory during menopause, the relationship between the estrogen-induced morphological and functional changes in hippocampus must be defined and the role these changes play in facilitating learning must be elucidated. The aim of this report is to provide a summary of the proposed mechanisms by which this hormone increases synaptic function and in doing so, it briefly addresses potential mechanisms contributing to the estrogen-induced increase in synaptic morphology and plasticity, as well as important future directions. PMID:19596521

  1. ParA and ParB coordinate chromosome segregation with cell elongation and division during Streptomyces sporulation.

    PubMed

    Donczew, Magdalena; Mackiewicz, Paweł; Wróbel, Agnieszka; Flärdh, Klas; Zakrzewska-Czerwińska, Jolanta; Jakimowicz, Dagmara

    2016-04-01

    In unicellular bacteria, the ParA and ParB proteins segregate chromosomes and coordinate this process with cell division and chromosome replication. During sporulation of mycelial Streptomyces, ParA and ParB uniformly distribute multiple chromosomes along the filamentous sporogenic hyphal compartment, which then differentiates into a chain of unigenomic spores. However, chromosome segregation must be coordinated with cell elongation and multiple divisions. Here, we addressed the question of whether ParA and ParB are involved in the synchronization of cell-cycle processes during sporulation in Streptomyces To answer this question, we used time-lapse microscopy, which allows the monitoring of growth and division of single sporogenic hyphae. We showed that sporogenic hyphae stop extending at the time of ParA accumulation and Z-ring formation. We demonstrated that both ParA and ParB affect the rate of hyphal extension. Additionally, we showed that ParA promotes the formation of massive nucleoprotein complexes by ParB. We also showed that FtsZ ring assembly is affected by the ParB protein and/or unsegregated DNA. Our results indicate the existence of a checkpoint between the extension and septation of sporogenic hyphae that involves the ParA and ParB proteins. PMID:27248800

  2. ParA and ParB coordinate chromosome segregation with cell elongation and division during Streptomyces sporulation

    PubMed Central

    Donczew, Magdalena; Mackiewicz, Paweł; Wróbel, Agnieszka; Flärdh, Klas; Zakrzewska-Czerwińska, Jolanta

    2016-01-01

    In unicellular bacteria, the ParA and ParB proteins segregate chromosomes and coordinate this process with cell division and chromosome replication. During sporulation of mycelial Streptomyces, ParA and ParB uniformly distribute multiple chromosomes along the filamentous sporogenic hyphal compartment, which then differentiates into a chain of unigenomic spores. However, chromosome segregation must be coordinated with cell elongation and multiple divisions. Here, we addressed the question of whether ParA and ParB are involved in the synchronization of cell-cycle processes during sporulation in Streptomyces. To answer this question, we used time-lapse microscopy, which allows the monitoring of growth and division of single sporogenic hyphae. We showed that sporogenic hyphae stop extending at the time of ParA accumulation and Z-ring formation. We demonstrated that both ParA and ParB affect the rate of hyphal extension. Additionally, we showed that ParA promotes the formation of massive nucleoprotein complexes by ParB. We also showed that FtsZ ring assembly is affected by the ParB protein and/or unsegregated DNA. Our results indicate the existence of a checkpoint between the extension and septation of sporogenic hyphae that involves the ParA and ParB proteins. PMID:27248800

  3. Par-4: A New Activator of Myosin Phosphatase

    PubMed Central

    Vetterkind, Susanne; Lee, Eunhee; Sundberg, Eric; Poythress, Ransom H.; Tao, Terence C.; Preuss, Ute

    2010-01-01

    Myosin phosphatase (MP) is a key regulator of myosin light chain (LC20) phosphorylation, a process essential for motility, apoptosis, and smooth muscle contractility. Although MP inhibition is well studied, little is known about MP activation. We have recently demonstrated that prostate apoptosis response (Par)-4 modulates vascular smooth muscle contractility. Here, we test the hypothesis that Par-4 regulates MP activity directly. We show, by proximity ligation assays, surface plasmon resonance and coimmunoprecipitation, that Par-4 interacts with the targeting subunit of MP, MYPT1. Binding is mediated by the leucine zippers of MYPT1 and Par-4 and reduced by Par-4 phosphorylation. Overexpression of Par-4 leads to increased phosphatase activity of immunoprecipitated MP, whereas small interfering RNA knockdown of endogenous Par-4 significantly decreases MP activity and increases MYPT1 phosphorylation. LC20 phosphorylation assays demonstrate that overexpression of Par-4 reduces LC20 phosphorylation. In contrast, a phosphorylation site mutant, but not wild-type Par-4, interferes with zipper-interacting protein kinase (ZIPK)-mediated MP inhibition. We conclude from our results Par-4 operates through a “padlock” model in which binding of Par-4 to MYPT1 activates MP by blocking access to the inhibitory phosphorylation sites, and inhibitory phosphorylation of MYPT1 by ZIPK requires “unlocking” of Par-4 by phosphorylation and displacement of Par-4 from the MP complex. PMID:20130087

  4. suPAR and Team Nephrology

    PubMed Central

    2014-01-01

    Primary focal segmental glomerulosclerosis (FSGS) accounts for nearly 10 % of patients who require renal replacement therapy. Elevated circulating levels of soluble urokinase receptor (suPAR) have been identified as a biomarker to discriminate primary FSGS from other glomerulopathies. Subsequent reports have questioned the diagnostic utility of this test. In a study in BMC Medicine, Huang et al. demonstrate that urinary soluble urokinase receptor (suPAR) excretion assists in distinguishing primary FSGS from other glomerular diseases, and that high plasma suPAR concentrations are not directly linked to a decline in glomerular filtration rate (GFR). This observation suggests that further investigation of suPAR is warranted in patients with FSGS. It should be interpreted in light of a recent report that B7-1 is expressed in the podocytes of a subset of patients with FSGS, and that blocking this molecule may represent the first successful targeted intervention for this disease. These advances highlight the rapid pace of scientific progress in the field of nephrology. Nephrologists should work together, share resources, and expedite the design of protocols to evaluate these novel biomarkers in a comprehensive and scientifically valid manner. Please see related article http://www.biomedcentral.com/1741-7015/12/81. PMID:24885021

  5. suPAR and Team Nephrology.

    PubMed

    Trachtman, Howard

    2014-01-01

    Primary focal segmental glomerulosclerosis (FSGS) accounts for nearly 10 % of patients who require renal replacement therapy. Elevated circulating levels of soluble urokinase receptor (suPAR) have been identified as a biomarker to discriminate primary FSGS from other glomerulopathies. Subsequent reports have questioned the diagnostic utility of this test. In a study in BMC Medicine, Huang et al. demonstrate that urinary soluble urokinase receptor (suPAR) excretion assists in distinguishing primary FSGS from other glomerular diseases, and that high plasma suPAR concentrations are not directly linked to a decline in glomerular filtration rate (GFR). This observation suggests that further investigation of suPAR is warranted in patients with FSGS. It should be interpreted in light of a recent report that B7-1 is expressed in the podocytes of a subset of patients with FSGS, and that blocking this molecule may represent the first successful targeted intervention for this disease. These advances highlight the rapid pace of scientific progress in the field of nephrology. Nephrologists should work together, share resources, and expedite the design of protocols to evaluate these novel biomarkers in a comprehensive and scientifically valid manner. PMID:24885021

  6. View from east to west of PAR site storage building; ...

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

    View from east to west of PAR site storage building; formerly PAR dispensary - Stanley R. Mickelsen Safeguard Complex, Storage Building, Across street from Family Housing Units 110 & 111, Nekoma, Cavalier County, ND

  7. View from west to east of PAR site resident engineer's ...

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

    View from west to east of PAR site resident engineer's office building (REOB) - Stanley R. Mickelsen Safeguard Complex, Resident Engineers Office Building, Southeast of intersection of PAR Access Road & Fourth Avenue, Nekoma, Cavalier County, ND

  8. A Combined Global and Local Approach to Elucidate Spatial Organization of the Mycobacterial ParB-parS Partition Assembly

    SciTech Connect

    B Chaudhuri; S Gupta; V Urban; M Chance; R DMello; L Smith; K Lyons; J Gee

    2011-12-31

    Combining diverse sets of data at global (size, shape) and local (residue) scales is an emerging trend for elucidating the organization and function of the cellular assemblies. We used such a strategy, combining data from X-ray and neutron scattering with H/D-contrast variation and X-ray footprinting with mass spectrometry, to elucidate the spatial organization of the ParB-parS assembly from Mycobacterium tuberculosis. The ParB-parS participates in plasmid and chromosome segregation and condensation in predivisional bacterial cells. ParB polymerizes around the parS centromere(s) to form a higher-order assembly that serves to recruit cyto-skeletal ParA ATPases and SMC proteins for chromosome segregation. A hybrid model of the ParB-parS was built by combining and correlating computational models with experiment-derived information about size, shape, position of the symmetry axis within the shape, internal topology, DNA-protein interface, exposed surface patches, and prior knowledge. This first view of the ParB-parS leads us to propose how ParB spread on the chromosome to form a larger assembly.

  9. A Combined Global and Local Approach to Elucidate Spatial Organization of the Mycobacterial ParB-parS Partition

    SciTech Connect

    Chaudhuri, Barnali; Gupta, Sayan; Urban, Volker S; Chance, Mark; D'Mello, Rhijuta; Smith, Lauren; Lyons, Kelly; Gee, Jessica

    2010-01-01

    Combining diverse sets of data at global (size, shape) and local (residue) scales is an emerging trend for elucidating the organization and function of the cellular assemblies. We used such a strategy, combining data from X-ray and neutron scattering with H/D-contrast variation and X-ray footprinting with mass spectrometry, to elucidate the spatial organization of the ParB-parS assembly from Mycobacterium tuberculosis. The ParB-parS participates in plasmid and chromosome segregation and condensation in predivisional bacterial cells. ParB polymerizes around the parS centromere(s) to form a higher-order assembly that serves to recruit cyto-skeletal ParA ATPases and SMC proteins for chromosome segregation. A hybrid model of the ParB-parS was built by combining and correlating computational models with experiment-derived information about size, shape, position of the symmetry axis within the shape, internal topology, DNA-protein interface, exposed surface patches, and prior knowledge. This first view of the ParB-parS leads us to propose how ParB spread on the chromosome to form a larger assembly.

  10. Lens implant surgery in pars planitis.

    PubMed

    Michelson, J B; Friedlaender, M H; Nozik, R A

    1990-08-01

    Intraocular lens (IOL) implantation is usually contraindicated in eyes with active inflammation, but patients with "burned-out" pars planitis also may be considered as candidates. Fifteen of 16 eyes in eight patients underwent extracapsular cataract extraction (ECCE) with posterior chamber IOL (PC IOL) implantation combined with pars plana vitrectomy for both cataracts and chronic cystoid macular edema (CME); 60% achieved visual acuity of 20/40 or better. Even with "low-grade" inflammation in these patients, however, a persistent veil of debris accumulated over the posterior and anterior surface of the IOL. One patient (patient 2) required 27 YAG procedures for two eyes, and another required 11 YAG procedures and eventual removal of the IOL. Another patient required surgical "brushing-off" of the IOL and vitrectomy. Even in eyes with "burned-out" uveitis, a continual low-grade inflammation may complicate the use of IOL implantation. PMID:2402411

  11. Par Pond refill water quality sampling

    SciTech Connect

    Koch, J.W. II; Martin, F.D.; Westbury, H.M.

    1996-08-01

    This study was designed to document anoxia and its cause in the event that the anoxia caused a fish kill. However, no fish kill was observed during this study, and dissolved oxygen and nutrient concentrations generally remained within the range expected for southeastern reservoirs. Par Pond water quality monitoring will continue during the second summer after refill as the aquatic macrophytes become reestablished and nutrients in the sediments are released to the water column.

  12. Combined DSEK and Transconjunctival Pars Plana Vitrectomy

    PubMed Central

    Sane, Mona; Shaikh, Naazli

    2016-01-01

    We report here three patients who underwent combined Descemet's stripping with endothelial keratoplasty and transconjunctival pars plana vitrectomy for bullous keratopathy and posterior segment pathology. A surgical technique and case histories are described. Anatomic and visual outcomes of combined Descemet's stripping with endothelial keratoplasty and vitrectomy were excellent. Our experience provides technical guidelines and limitations. The combined minimally invasive techniques allow for rapid anatomical recovery and return of function and visual acuity in a single sitting. PMID:27413563

  13. Mechanisms of apoptosis by the tumor suppressor Par-4.

    PubMed

    Hebbar, Nikhil; Wang, Chi; Rangnekar, Vivek M

    2012-12-01

    Par-4 is a pro-apoptotic, tumor suppressor protein that induces apoptosis selectively in cancer cells. Endoplasmic reticulum-stress and higher levels of protein kinase A in tumor cells confer the coveted feature of cancer selective response to extracellular and intracellular Par-4, respectively. Recent studies have shown that systemic Par-4 confers resistance to tumor growth in mice, and that tumor-resistance is transferable by bone-marrow transplantation. Moreover, recombinant Par-4 inhibits the growth of tumors in mice. As systemic Par-4 induces apoptosis via cell surface GRP78, strategies that promote GRP78 trafficking to the cell surface are expected sensitize cancer cells to circulating levels of Par-4. This review illustrates the domains and mechanisms by which Par-4 orchestrates the apoptotic process in both cell culture models and in physiological settings. PMID:22552839

  14. A Single parS Sequence from the Cluster of Four Sites Closest to oriC Is Necessary and Sufficient for Proper Chromosome Segregation in Pseudomonas aeruginosa

    PubMed Central

    Jecz, Paulina; Bartosik, Aneta A.; Glabski, Krzysztof; Jagura-Burdzy, Grazyna

    2015-01-01

    Among the mechanisms that control chromosome segregation in bacteria are highly-conserved partitioning systems comprising three components: ParA protein (a deviant Walker-type ATPase), ParB protein (a DNA-binding element) and multiple cis-acting palindromic centromere-like sequences, designated parS. Ten putative parS sites have been identified in the P. aeruginosa PAO1 genome, four localized in close proximity of oriC and six, diverged by more than one nucleotide from a perfect palindromic sequence, dispersed along the chromosome. Here, we constructed and analyzed P. aeruginosa mutants deprived of each single parS sequence and their different combinations. The analysis included evaluation of a set of phenotypic features, chromosome segregation, and ParB localization in the cells. It was found that ParB binds specifically to all ten parS sites, although with different affinities. The P. aeruginosa parS mutant with all ten parS sites modified (parSnull) is viable however it demonstrates the phenotype characteristic for parAnull or parBnull mutants: slightly slower growth rate, high frequency of anucleate cells, and defects in motility. The genomic position and sequence of parS determine its role in P. aeruginosa biology. It transpired that any one of the four parS sites proximal to oriC (parS1 to parS4), which are bound by ParB with the highest affinity, is necessary and sufficient for the parABS role in chromosome partitioning. When all these four sites are mutated simultaneously, the strain shows the parSnull phenotype, which indicates that none of the remaining six parS sites can substitute for these four oriC-proximal sites in this function. A single ectopic parS2 (inserted opposite oriC in the parSnull mutant) facilitates ParB organization into regularly spaced condensed foci and reverses some of the mutant phenotypes but is not sufficient for accurate chromosome segregation. PMID:25794281

  15. Escherichia coli low-copy-number plasmid R1 centromere parC forms a U-shaped complex with its binding protein ParR

    PubMed Central

    Hoischen, C.; Bussiek, M.; Langowski, J.; Diekmann, S.

    2008-01-01

    The Escherichia coli low-copy-number plasmid R1 contains a segregation machinery composed of parC, ParR and parM. The R1 centromere-like site parC contains two separate sets of repeats. By atomic force microscopy (AFM) we show here that ParR molecules bind to each of the 5-fold repeated iterons separately with the intervening sequence unbound by ParR. The two ParR protein complexes on parC do not complex with each other. ParR binds with a stoichiometry of about one ParR dimer per each single iteron. The measured DNA fragment lengths agreed with B-form DNA and each of the two parC 5-fold interon DNA stretches adopts a linear path in its complex with ParR. However, the overall parC/ParR complex with both iteron repeats bound by ParR forms an overall U-shaped structure: the DNA folds back on itself nearly completely, including an angle of ∼150°. Analysing linear DNA fragments, we never observed dimerized ParR complexes on one parC DNA molecule (intramolecular) nor a dimerization between ParR complexes bound to two different parC DNA molecules (intermolecular). This bacterial segrosome is compared to other bacterial segregation complexes. We speculate that partition complexes might have a similar overall structural organization and, at least in part, common functional properties. PMID:18056157

  16. Modelisation par elements finis du muscle strie

    NASA Astrophysics Data System (ADS)

    Leonard, Mathieu

    Ce present projet de recherche a permis. de creer un modele par elements finis du muscle strie humain dans le but d'etudier les mecanismes engendrant les lesions musculaires traumatiques. Ce modele constitue une plate-forme numerique capable de discerner l'influence des proprietes mecaniques des fascias et de la cellule musculaire sur le comportement dynamique du muscle lors d'une contraction excentrique, notamment le module de Young et le module de cisaillement de la couche de tissu conjonctif, l'orientation des fibres de collagene de cette membrane et le coefficient de poisson du muscle. La caracterisation experimentale in vitro de ces parametres pour des vitesses de deformation elevees a partir de muscles stries humains actifs est essentielle pour l'etude de lesions musculaires traumatiques. Le modele numerique developpe est capable de modeliser la contraction musculaire comme une transition de phase de la cellule musculaire par un changement de raideur et de volume a l'aide des lois de comportement de materiau predefinies dans le logiciel LS-DYNA (v971, Livermore Software Technology Corporation, Livermore, CA, USA). Le present projet de recherche introduit donc un phenomene physiologique qui pourrait expliquer des blessures musculaires courantes (crampes, courbatures, claquages, etc.), mais aussi des maladies ou desordres touchant le tissu conjonctif comme les collagenoses et la dystrophie musculaire. La predominance de blessures musculaires lors de contractions excentriques est egalement exposee. Le modele developpe dans ce projet de recherche met ainsi a l'avant-scene le concept de transition de phase ouvrant la porte au developpement de nouvelles technologies pour l'activation musculaire chez les personnes atteintes de paraplegie ou de muscles artificiels compacts pour l'elaboration de protheses ou d'exosquelettes. Mots-cles Muscle strie, lesion musculaire, fascia, contraction excentrique, modele par elements finis, transition de phase

  17. Evaluation of the PAR corneal topography system

    NASA Astrophysics Data System (ADS)

    Jindal, Prateek; Cheung, Susan; Pirouzian, Amir; Keates, Richard H.; Ren, Qiushi

    1995-05-01

    The purpose of this study was to evaluate the raster photogrammetry based Corneal Topography System by determining: inter-operator variability, reproducibility of images, effects of defocused and decentered images, and the precision of data at different optical zones. 4 human cadaver eyes were used to study the inter-operator variability. To study the reproducibility of images, 3 human cadaver eyes and a test surface doped with flourescine (provided by PAR Vision Systems Corporation) were focused and their images taken four successive times. Defocused and decentered images were taken of 4 human cadaver eyes and four times of the test surface mentioned above. The precision of defocused/decentered cadaver eyes was evaluated at the following optical zones: 3 mm, 4 mm, 5 mm, and 6 mm. All human cadaver eyes used in the above experiments had their epithelial layer removed before imaging. Average inter-operator variability was 0.06 D. In reproducibility attempts, there was an average deviation of 0.28 D for the human cadaver eyes and 0.04 D for the test surface. The defocused and decentered test surface gave an average deviation of 0.09 D. Defocused and decentered cadaver eyes resulted in an average deviation of 0.52 D, 0.37 D, 0.24 D, and 0.22 D at optical zones of 3 mm, 4 mm, 5 mm, and 6 mm, respectively. The imaging method employed by PAR Vision Systems Corporation virtually eliminates inter-operator variability. The PAR Corneal Topography System's clinical usefulness, however, could be improved by improving the reproducibility of images, decreasing the sensitivity to spatial alignment, and increasing accuracy over smaller optical zones.

  18. A Conserved Mode of Protein Recognition and Binding in a ParD−ParE Toxin−Antitoxin Complex

    SciTech Connect

    Dalton, Kevin M.; Crosson, Sean

    2010-05-06

    Toxin-antitoxin (TA) systems form a ubiquitous class of prokaryotic proteins with functional roles in plasmid inheritance, environmental stress response, and cell development. ParDE family TA systems are broadly conserved on plasmids and bacterial chromosomes and have been well characterized as genetic elements that promote stable plasmid inheritance. We present a crystal structure of a chromosomally encoded ParD-ParE complex from Caulobacter crescentus at 2.6 {angstrom} resolution. This TA system forms an {alpha}{sub 2}{beta}{sub 2} heterotetramer in the crystal and in solution. The toxin-antitoxin binding interface reveals extensive polar and hydrophobic contacts of ParD antitoxin helices with a conserved recognition and binding groove on the ParE toxin. A cross-species comparison of this complex structure with related toxin structures identified an antitoxin recognition and binding subdomain that is conserved between distantly related members of the RelE/ParE toxin superfamily despite a low level of overall primary sequence identity. We further demonstrate that ParD antitoxin is dimeric, stably folded, and largely helical when not bound to ParE toxin. Thus, the paradigmatic model in which antitoxin undergoes a disorder-to-order transition upon toxin binding does not apply to this chromosomal ParD-ParE TA system.

  19. A conserved mode of protein recognition and binding in a ParD-ParE toxin-antitoxin complex†

    PubMed Central

    Dalton, Kevin M.; Crosson, Sean

    2010-01-01

    Toxin-antitoxin (TA) systems form a ubiquitous class of prokaryotic proteins with functional roles in plasmid inheritance, environmental stress response, and cell development. ParDE-family TA systems are broadly conserved on plasmids and bacterial chromosomes, and have been well characterized as genetic elements that promote stable plasmid inheritance. We present a crystal structure of a chromosomally-encoded ParD-ParE complex from Caulobacter crescentus at 2.6 Å resolution. This TA system forms an α2β2 heterotetramer in the crystal and in solution. The toxin-antitoxin binding interface reveals extensive polar and hydrophobic contacts of ParD antitoxin helices with a conserved recognition and binding groove on the ParE toxin. A cross-species comparison of this complex structure with related toxin structures identified an antitoxin recognition and binding sub-domain that is conserved between distantly-related members of the RelE/ParE toxin superfamily despite low overall primary sequence identity. We further demonstrate that ParD antitoxin is dimeric, stably folded, and largely helical when not bound to ParE toxin. Thus, the paradigmatic model in which antitoxin undergoes a disorder-to-order transition upon toxin binding does not apply to this chromosomal ParD-ParE TA system. PMID:20143871

  20. Historic macrophyte development in Par Pond

    SciTech Connect

    Grace, J.B.

    1985-08-01

    Aerial photographs from 1975, 1980, and 1983 were examined to evaluate the changes that have occurred in the wetland vegetation of Par Pond, a reactor-cooling reservoir. Evaluation of the aerial photographs was based on comparisons with ground-level vegetation maps made during July 1984. Comparisons of photographs from August and December of 1983 revealed the main seasonal change in the aerial coverage of wetland vegetation to be the wintertime loss of non-persistent emergent species such as Nelumbo lutea and Nymphaea odorata. Comparisons between September 1980 and August 1983 revealed that the lakeward extent of non-persistent macrophytes has increased by an average of 8.2 m, though not all sites have changed equally. For persistent macrophytes (principally Typha), the average increase in lakeward extent between December 1975 and August 1983 was 3.48 m. The extensive development of wetland vegetation in Par Pond as well as the substantial spread of vegetation over only a few years time indicates the high suitability of this habitat for the growth of wetland plants.

  1. A Par-1-Par-3-Centrosome Cell Polarity Pathway and Its Tuning for Isotropic Cell Adhesion.

    PubMed

    Jiang, Tao; McKinley, R F Andrew; McGill, Melanie A; Angers, Stephane; Harris, Tony J C

    2015-10-19

    To form regulated barriers between body compartments, epithelial cells polarize into apical and basolateral domains and assemble adherens junctions (AJs). Despite close links with polarity networks that generate single polarized domains, AJs distribute isotropically around the cell circumference for adhesion with all neighboring cells [1-3]. How AJs avoid the influence of polarity networks to maintain their isotropy has been unclear. In established epithelia, trans cadherin interactions could maintain AJ isotropy [4], but AJs are dynamic during epithelial development and remodeling [5, 6], and thus specific mechanisms may control their isotropy. In Drosophila, aPKC prevents hyper-polarization of junctions as epithelia develop from cellularization to gastrulation [7]. Here, we show that aPKC does so by inhibiting a positive feedback loop between Bazooka (Baz)/Par-3, a junctional organizer [5, 8-10], and centrosomes. Without aPKC, Baz and centrosomes lose their isotropic distributions and recruit each other to single plasma membrane (PM) domains. Surprisingly, our loss- and gain-of-function analyses show that the Baz-centrosome positive feedback loop is driven by Par-1, a kinase known to phosphorylate Baz and inhibit its basolateral localization [8, 11, 12]. We find that Par-1 promotes the positive feedback loop through both centrosome microtubule effects and Baz phosphorylation. Normally, aPKC attenuates the circuit by expelling Par-1 from the apical domain at gastrulation. The combination of local activation and global inhibition is a common polarization strategy [13-16]. Par-1 seems to couple both effects for a potent Baz polarization mechanism that is regulated for the isotropy of Baz and AJs around the cell circumference. PMID:26455305

  2. 2. HI PAR (ACQUISITION RADAR) TOWER AND ENLISTED MEN (EM) ...

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

    2. HI PAR (ACQUISITION RADAR) TOWER AND ENLISTED MEN (EM) BARRACKS WITH RADAR ATTACHED. - Nike Hercules Missile Battery Summit Site, Battery Control Administration & Barracks Building, Anchorage, Anchorage, AK

  3. Transcriptome profiling reveals links between ParS/ParR, MexEF-OprN, and quorum sensing in the regulation of adaptation and virulence in Pseudomonas aeruginosa

    PubMed Central

    2013-01-01

    Background The ParS/ParR two component regulatory system plays critical roles for multidrug resistance in Pseudomonas aeruginosa. It was demonstrated that in the presence of antimicrobials, ParR enhances bacterial survival by distinct mechanisms including activation of the mexXY efflux genes, enhancement of lipopolysaccharide modification through the arn operon, and reduction of the expression of oprD porin. Results In this study, we report on transcriptomic analyses of P. aeruginosa PAO1 wild type and parS and parR mutants growing in a defined minimal medium. Our transcriptomic analysis provides the first estimates of transcript abundance for the 5570 coding genes in P. aeruginosa PAO1. Comparative transcriptomics of P. aeruginosa PAO1 and par mutants identified a total of 464 genes regulated by ParS and ParR. Results also showed that mutations in the parS/parR system abolished expression of the mexEF-oprN operon by down-regulating the regulatory gene mexS. In addition to the known effects on drug resistance genes, transcript abundances of the quorum sensing genes (rhlIR and pqsABCDE-phnAB) were higher in both parS and parR mutants. In accordance with these results, a significant portion of the ParS/ParR regulated genes belonged to the MexEF-OprN and quorum sensing regulons. Deletion of the par genes also led to increased phenazine production and swarming motility, consistent with the up-regulation of the phenazine and rhamnolipid biosynthetic genes, respectively. Conclusion Our results link the ParS/ParR two component signal transduction system to MexEF-OprN and quorum sensing systems in P. aeruginosa. These results expand our understanding of the roles of the ParS/ParR system in the regulation of gene expression in P. aeruginosa, especially in the absence of antimicrobials. PMID:24034668

  4. Taare Zameen Par and dyslexic savants.

    PubMed

    Chakravarty, Ambar

    2009-04-01

    The film Taare Zameen Par (Stars upon the Ground) portrays the tormented life at school and at home of a child with dyslexia and his eventual success after his artistic talents are discovered by his art teacher at the boarding school. The film hints at a curious neurocognitive phenomenon of creativity in the midst of language disability, as exemplified in the lives of people like Leonardo da Vinci and Albert Einstein, both of whom demonstrated extraordinary creativity even though they were probably affected with developmental learning disorders. It has been hypothesized that a developmental delay in the dominant hemisphere most likely 'disinhibits' the nondominant parietal lobe, unmasking talents-artistic or otherwise-in some such individuals. It has been suggested that, in remedial training, children with learning disorders be encouraged to develop such hidden talents to full capacity, rather than be subjected to the usual overemphasis on the correction of the disturbed coded symbol operations. PMID:20142854

  5. Taare Zameen Par and dyslexic savants

    PubMed Central

    Chakravarty, Ambar

    2009-01-01

    The film Taare Zameen Par (Stars upon the Ground) portrays the tormented life at school and at home of a child with dyslexia and his eventual success after his artistic talents are discovered by his art teacher at the boarding school. The film hints at a curious neurocognitive phenomenon of creativity in the midst of language disability, as exemplified in the lives of people like Leonardo da Vinci and Albert Einstein, both of whom demonstrated extraordinary creativity even though they were probably affected with developmental learning disorders. It has been hypothesized that a developmental delay in the dominant hemisphere most likely ‘disinhibits’ the nondominant parietal lobe, unmasking talents—artistic or otherwise—in some such individuals. It has been suggested that, in remedial training, children with learning disorders be encouraged to develop such hidden talents to full capacity, rather than be subjected to the usual overemphasis on the correction of the disturbed coded symbol operations. PMID:20142854

  6. Biased signaling: potential agonist and antagonist of PAR2.

    PubMed

    Kakarala, Kavita Kumari; Jamil, Kaiser

    2016-06-01

    Protease activated receptor 2 (PAR2) has emerged as one of the promising therapeutic targets to inhibit rapidly metastasizing breast cancer cells. However, its elusive molecular mechanism of activation and signaling has made it a difficult target for drug development. In this study, in silico methods were used to unfold PAR2 molecular mechanism of signaling based on the concept of GPCR receptor plasticity. Although, there are no conclusive evidences of the presence of specific endogenous ligands for PAR2, the efficacy of synthetic agonist and antagonist in PAR2 signaling has opened up the possibilities of ligand-mediated signaling. Furthermore, it has been proved that ligands specific for one GPCR can induce signaling in GPCRs belonging to other subfamilies. Therefore, the aim of this study was to identify potential agonists and antagonists from the GPCR ligand library (GLL), which may induce biased signaling in PAR2 using the concept of existence of multiple ligand-stabilized receptor conformations. The results of our in silico study suggest that PAR2 may show biased signaling mainly with agonists of serotonin type 1, β-adrenergic type 1,3 and antagonists of substance K (NK1), serotonin type 2, dopamine type 4, and thromboxane receptors. Further, this study also throws light on the putative ligand-specific conformations of PAR2. Thus, the results of this study provide structural insights to putative conformations of PAR2 and also gives initial clues to medicinal chemists for rational drug design targeting this challenging receptor. PMID:26295578

  7. Proteases in agricultural dust induce lung inflammation through PAR-1 and PAR-2 activation.

    PubMed

    Romberger, Debra J; Heires, Art J; Nordgren, Tara M; Souder, Chelsea P; West, William; Liu, Xiang-de; Poole, Jill A; Toews, Myron L; Wyatt, Todd A

    2015-08-15

    Workers exposed to aerosolized dust present in concentrated animal feeding operations (CAFOs) are susceptible to inflammatory lung diseases, such as chronic obstructive pulmonary disease. Extracts of dust collected from hog CAFOs [hog dust extract (HDE)] are potent stimulators of lung inflammatory responses in several model systems. The observation that HDE contains active proteases prompted the present study, which evaluated the role of CAFO dust proteases in lung inflammatory processes and tested whether protease-activated receptors (PARs) are involved in the signaling pathway for these events. We hypothesized that the damaging proinflammatory effect of HDE is due, in part, to the proteolytic activation of PARs, and inhibiting the proteases in HDE or disrupting PAR activation would attenuate HDE-mediated inflammatory indexes in bronchial epithelial cells (BECs), in mouse lung slices in vitro, and in a murine in vivo exposure model. Human BECs and mouse lung slice cultures stimulated with 5% HDE released significantly more of each of the cytokines measured (IL-6, IL-8, TNF-α, keratinocyte-derived chemokine/CXC chemokine ligand 1, and macrophage inflammatory protein-2/CXC chemokine ligand 2) than controls, and these effects were markedly diminished by protease inhibition. Inhibition of PARs also blunted the HDE-induced cytokine release from BECs. In addition, protease depletion inhibited HDE-induced BEC intracellular PKCα and PKCε activation. C57BL/6J mice administered 12.5% HDE intranasally, either once or daily for 3 wk, exhibited increased total cellular and neutrophil influx, bronchial alveolar fluid inflammatory cytokines, lung histopathology, and inflammatory scores compared with mice receiving protease-depleted HDE. These data suggest that proteases in dust from CAFOs are important mediators of lung inflammation, and these proteases and their receptors may provide novel targets for therapeutic intervention in CAFO dust-induced airways disease. PMID

  8. Cancer-selective apoptosis by tumor suppressor par-4.

    PubMed

    Hebbar, Nikhil; Shrestha-Bhattarai, Tripti; Rangnekar, Vivek M

    2014-01-01

    Tumor suppressor genes play an important role in preventing neoplastic transformation and maintaining normal tissue homeostasis. Par-4 is one such tumor suppressor which is unique in its ability to selectively induce apoptosis in cancer cells while leaving the normal cells unaffected. The cancer cell specific activity of Par-4 is elicited through intracellular as well as extracellular mechanisms. Intracellularly Par-4 acts through the inhibition of pro-survival pathways and activation of Fas mediated apoptosis whereas extracellular (secreted Par-4) acts by binding to cell surface GRP78 leading to activation of the extrinsic apoptotic pathway. Many studies have highlighted the importance of Par-4 not only in preventing cancer development/recurrence but also as a promising anticancer therapeutic agent. PMID:25001535

  9. PAR-3 and PAR-1 Inhibit LET-99 Localization to Generate a Cortical Band Important for Spindle Positioning in Caenorhabditis elegans Embryos

    PubMed Central

    Wu, Jui-Ching

    2007-01-01

    The conserved PAR proteins are localized in asymmetric cortical domains and are required for the polarized localization of cell fate determinants in many organisms. In Caenorhabditis elegans embryos, LET-99 and G protein signaling act downstream of the PARs to regulate spindle positioning and ensure asymmetric division. PAR-3 and PAR-2 localize LET-99 to a posterior cortical band through an unknown mechanism. Here we report that LET-99 asymmetry depends on cortically localized PAR-1 and PAR-4 but not on cytoplasmic polarity effectors. In par-1 and par-4 embryos, LET-99 accumulates at the entire posterior cortex, but remains at low levels at the anterior cortex occupied by PAR-3. Further, PAR-3 and PAR-1 have graded cortical distributions with the highest levels at the anterior and posterior poles, respectively, and the lowest levels of these proteins correlate with high LET-99 accumulation. These results suggest that PAR-3 and PAR-1 inhibit the localization of LET-99 to generate a band pattern. In addition, PAR-1 kinase activity is required for the inhibition of LET-99 localization, and PAR-1 associates with LET-99. Finally, examination of par-1 embryos suggests that the banded pattern of LET-99 is critical for normal posterior spindle displacement and to prevent spindle misorientation caused by cell shape constraints. PMID:17761536

  10. Recombination in the Human Pseudoautosomal Region PAR1

    PubMed Central

    Hinch, Anjali G.; Altemose, Nicolas; Noor, Nudrat; Donnelly, Peter; Myers, Simon R.

    2014-01-01

    The pseudoautosomal region (PAR) is a short region of homology between the mammalian X and Y chromosomes, which has undergone rapid evolution. A crossover in the PAR is essential for the proper disjunction of X and Y chromosomes in male meiosis, and PAR deletion results in male sterility. This leads the human PAR with the obligatory crossover, PAR1, to having an exceptionally high male crossover rate, which is 17-fold higher than the genome-wide average. However, the mechanism by which this obligatory crossover occurs remains unknown, as does the fine-scale positioning of crossovers across this region. Recent research in mice has suggested that crossovers in PAR may be mediated independently of the protein PRDM9, which localises virtually all crossovers in the autosomes. To investigate recombination in this region, we construct the most fine-scale genetic map containing directly observed crossovers to date using African-American pedigrees. We leverage recombination rates inferred from the breakdown of linkage disequilibrium in human populations and investigate the signatures of DNA evolution due to recombination. Further, we identify direct PRDM9 binding sites using ChIP-seq in human cells. Using these independent lines of evidence, we show that, in contrast with mouse, PRDM9 does localise peaks of recombination in the human PAR1. We find that recombination is a far more rapid and intense driver of sequence evolution in PAR1 than it is on the autosomes. We also show that PAR1 hotspot activities differ significantly among human populations. Finally, we find evidence that PAR1 hotspot positions have changed between human and chimpanzee, with no evidence of sharing among the hottest hotspots. We anticipate that the genetic maps built and validated in this work will aid research on this vital and fascinating region of the genome. PMID:25033397

  11. Recombination in the human Pseudoautosomal region PAR1.

    PubMed

    Hinch, Anjali G; Altemose, Nicolas; Noor, Nudrat; Donnelly, Peter; Myers, Simon R

    2014-07-01

    The pseudoautosomal region (PAR) is a short region of homology between the mammalian X and Y chromosomes, which has undergone rapid evolution. A crossover in the PAR is essential for the proper disjunction of X and Y chromosomes in male meiosis, and PAR deletion results in male sterility. This leads the human PAR with the obligatory crossover, PAR1, to having an exceptionally high male crossover rate, which is 17-fold higher than the genome-wide average. However, the mechanism by which this obligatory crossover occurs remains unknown, as does the fine-scale positioning of crossovers across this region. Recent research in mice has suggested that crossovers in PAR may be mediated independently of the protein PRDM9, which localises virtually all crossovers in the autosomes. To investigate recombination in this region, we construct the most fine-scale genetic map containing directly observed crossovers to date using African-American pedigrees. We leverage recombination rates inferred from the breakdown of linkage disequilibrium in human populations and investigate the signatures of DNA evolution due to recombination. Further, we identify direct PRDM9 binding sites using ChIP-seq in human cells. Using these independent lines of evidence, we show that, in contrast with mouse, PRDM9 does localise peaks of recombination in the human PAR1. We find that recombination is a far more rapid and intense driver of sequence evolution in PAR1 than it is on the autosomes. We also show that PAR1 hotspot activities differ significantly among human populations. Finally, we find evidence that PAR1 hotspot positions have changed between human and chimpanzee, with no evidence of sharing among the hottest hotspots. We anticipate that the genetic maps built and validated in this work will aid research on this vital and fascinating region of the genome. PMID:25033397

  12. Circulating suPAR in Two Cohorts of Primary FSGS

    PubMed Central

    Wei, Changli; Trachtman, Howard; Li, Jing; Dong, Chuanhui; Friedman, Aaron L.; Gassman, Jennifer J.; McMahan, June L.; Radeva, Milena; Heil, Karsten M.; Trautmann, Agnes; Anarat, Ali; Emre, Sevinc; Ghiggeri, Gian M.; Ozaltin, Fatih; Haffner, Dieter; Gipson, Debbie S.; Kaskel, Frederick; Fischer, Dagmar-Christiane; Schaefer, Franz

    2012-01-01

    Overexpression of soluble urokinase receptor (suPAR) causes pathology in animal models similar to primary FSGS, and one recent study demonstrated elevated levels of serum suPAR in patients with the disease. Here, we analyzed circulating suPAR levels in two cohorts of children and adults with biopsy-proven primary FSGS: 70 patients from the North America–based FSGS clinical trial (CT) and 94 patients from PodoNet, the Europe-based consortium studying steroid-resistant nephrotic syndrome. Circulating suPAR levels were elevated in 84.3% and 55.3% of patients with FSGS patients in the CT and PodoNet cohorts, respectively, compared with 6% of controls (P<0.0001); inflammation did not account for this difference. Multiple regression analysis suggested that lower suPAR levels associated with higher estimated GFR, male sex, and treatment with mycophenolate mofetil. In the CT cohort, there was a positive association between the relative reduction of suPAR after 26 weeks of treatment and reduction of proteinuria, with higher odds for complete remission (P=0.04). In the PodoNet cohort, patients with an NPHS2 mutation had higher suPAR levels than those without a mutation. In conclusion, suPAR levels are elevated in geographically and ethnically diverse patients with FSGS and do not reflect a nonspecific proinflammatory milieu. The associations between a change in circulating suPAR with different therapeutic regimens and with remission support the role of suPAR in the pathogenesis of FSGS. PMID:23138488

  13. Circulating suPAR in two cohorts of primary FSGS.

    PubMed

    Wei, Changli; Trachtman, Howard; Li, Jing; Dong, Chuanhui; Friedman, Aaron L; Gassman, Jennifer J; McMahan, June L; Radeva, Milena; Heil, Karsten M; Trautmann, Agnes; Anarat, Ali; Emre, Sevinc; Ghiggeri, Gian M; Ozaltin, Fatih; Haffner, Dieter; Gipson, Debbie S; Kaskel, Frederick; Fischer, Dagmar-Christiane; Schaefer, Franz; Reiser, Jochen

    2012-12-01

    Overexpression of soluble urokinase receptor (suPAR) causes pathology in animal models similar to primary FSGS, and one recent study demonstrated elevated levels of serum suPAR in patients with the disease. Here, we analyzed circulating suPAR levels in two cohorts of children and adults with biopsy-proven primary FSGS: 70 patients from the North America-based FSGS clinical trial (CT) and 94 patients from PodoNet, the Europe-based consortium studying steroid-resistant nephrotic syndrome. Circulating suPAR levels were elevated in 84.3% and 55.3% of patients with FSGS patients in the CT and PodoNet cohorts, respectively, compared with 6% of controls (P<0.0001); inflammation did not account for this difference. Multiple regression analysis suggested that lower suPAR levels associated with higher estimated GFR, male sex, and treatment with mycophenolate mofetil. In the CT cohort, there was a positive association between the relative reduction of suPAR after 26 weeks of treatment and reduction of proteinuria, with higher odds for complete remission (P=0.04). In the PodoNet cohort, patients with an NPHS2 mutation had higher suPAR levels than those without a mutation. In conclusion, suPAR levels are elevated in geographically and ethnically diverse patients with FSGS and do not reflect a nonspecific proinflammatory milieu. The associations between a change in circulating suPAR with different therapeutic regimens and with remission support the role of suPAR in the pathogenesis of FSGS. PMID:23138488

  14. Condensation and localization of the partitioning protein ParB on the bacterial chromosome.

    PubMed

    Broedersz, Chase P; Wang, Xindan; Meir, Yigal; Loparo, Joseph J; Rudner, David Z; Wingreen, Ned S

    2014-06-17

    The ParABS system mediates chromosome segregation and plasmid partitioning in many bacteria. As part of the partitioning mechanism, ParB proteins form a nucleoprotein complex at parS sites. The biophysical basis underlying ParB-DNA complex formation and localization remains elusive. Specifically, it is unclear whether ParB spreads in 1D along DNA or assembles into a 3D protein-DNA complex. We show that a combination of 1D spreading bonds and a single 3D bridging bond between ParB proteins constitutes a minimal model for a condensed ParB-DNA complex. This model implies a scaling behavior for ParB-mediated silencing of parS-flanking genes, which we confirm to be satisfied by experimental data from P1 plasmids. Furthermore, this model is consistent with experiments on the effects of DNA roadblocks on ParB localization. Finally, we show experimentally that a single parS site is necessary and sufficient for ParB-DNA complex formation in vivo. Together with our model, this suggests that ParB binding to parS triggers a conformational switch in ParB that overcomes a nucleation barrier. Conceptually, the combination of spreading and bridging bonds in our model provides a surface tension ensuring the condensation of the ParB-DNA complex, with analogies to liquid-like compartments such as nucleoli in eukaryotes. PMID:24927534

  15. SPRY1 promotes the degradation of uPAR and inhibits uPAR-mediated cell adhesion and proliferation

    PubMed Central

    Liu, Xiufeng; Lan, Yan; Zhang, Di; Wang, Kai; Wang, Yao; Hua, Zi-Chun

    2014-01-01

    Urokinase plasminogen activator receptor (uPAR) is a GPI anchored cell surface protein that is closely associated with invasion, migration, and metastasis of cancer cells. Many functional extracellular proteins and transmembrane receptors interact with uPAR. However, few studies have examined the association of uPAR with cytoplasm proteins. We previously used yeast two-hybrid screening to isolate several novel uPAR-interacting cytoplasmic proteins, including Sprouty1 (SPRY1), an inhibitor of the (Ras-mitogen-activated protein kinase) MAPK pathway. In this study, we show that SPRY1 interacts with uPAR and directs it toward lysosomal-mediated degradation. Overexpression of SPRY1 decreased the cell surface and cytoplasmic uPAR protein level. Moreover, SPRY1 overexpression augmented uPAR-induced cell adhesion to vitronectin as well as proliferation of cancer cells. Our results also further support the critical role of SPRY1 contribution to tumor growth. In a subcutaneous tumor model, overexpression of SPRY1 in HCT116 or A549 xenograft in athymic nude mice led to great suppression of tumor growth. These results show that SPRY1 may affect tumor cell function through direct interaction with uPAR and promote its lysosomal degradation. PMID:25520860

  16. Traitement des fractures des plateaux externes par vissage percutané assisté par arthroscopie

    PubMed Central

    Abouchane, Merouane; Belmoubarik, Amine; Benameur, Hamza; Haddoun, Ahmed Reda; Nechad, Mohammed

    2015-01-01

    Le but de notre étude est d'évaluer les résultats de fractures des plateaux tibiaux externes traitées par ostéosynthèse percutanée assistée par arthroscopie. Dix patients (8 hommes et 2 femmes) de 32 ans en moyenne ont subi cette intervention afin de réparer des fractures des plateaux tibiaux Schatzker I-III. Après avoir appliqué un garrot pneumatique, nous avons réduit et fixé la fracture au moyen de vis cannelées souschondrales. Lésions associées retrouvent deux lésions partielles du ménisque externe ont été retrouvé, traitées par résection partielle. Une orthèse de genou été de mise à but antalgique et protectrice pendant six semaines avec béquillage et interdiction de l'appui pour une durée de douze semaines avec reprise d'appui partiel au delà. La durée d'hospitalisation été d'une moyenne de cinq jours. La rééducation passive a été commence le lendemain de l'intervention et continuait dans chez un kinésithérapeute à la sortie du patient du service. Le suivi été à J7, J15, 1mois, 3mois, 6 mois puis tous les 6 mois. Neuf de nos patients ont été revu régulièrement sauf un perdu de vue. Le recul moyen de notre série été de 16 mois (10 et 24 mois). Le score de Lysholm a été utilisé pour évaluer les résultats cliniques chez nos neuf patients: excellent chez trois patients bons chez trois moyen chez un seul et mauvais chez deux patients. Tous nos neuf patients ont consolidé (figure 10 contrôle scopique d un article). Aucune gonarthrose n'a été note chez nos neuf patients due essentiellement au recul moyen faible de 16 mois. Le traitement des fractures des plateaux tibiaux externes assisté par arthroscopie produit des résultats satisfaisants et peut être accepté comme solution de rechange efficace au traitement des fractures des plateaux tibiaux causées par un choc de faible énergie. PMID:26587137

  17. Control of cleavage spindle orientation in Caenorhabditis elegans: The role of the genes par-2 and par-3

    SciTech Connect

    Cheng, N.N.; Kirby, C.M.; Kemphues, K.J.

    1995-02-01

    Polarized asymmetric divisions play important roles in the development of plants and animals. The first two embryonic cleavages of Caenorhabditis elegans provide an opportunity to study the mechanisms controlling polarized asymmetric divisions. The first cleavage is unequal, producing daughters with different sizes and fates. The daughter blastomeres divide with different orientations at the second cleavage; the anterior blastomere divides equally across the long axis of the egg, whereas the posterior blastomere divides unequally along the long axis. We report here the results of our analysis of the genes par-2 and par-3 with respect to their contribution to the polarity of these divisions. Strong loss-of-function mutations in both genes lead to an equal first cleavage and an altered second cleavage. Interestingly, the mutations exhibit striking gene-specific differences at the second cleavage. The par-2 mutations lead to transverse spindle orientations in both blastomeres, whereas par-3 mutations lead to longitudinal spindle orientations in both blastomeres. The spindle orientation defects correlate with defects in centrosome movements during both the first and the second cell cycle. Temperature shift experiments with par-2 (it5ts) indicate that the par-2(+) activity is not required after the two-cell stage. Analysis of double mutants shows that par-3 is epistatic to par-2. We propose a model wherein par-2(+) and par-3(+) act in concert during the first cell cycle to affect asymmetric modification of the cytoskeleton. This polar modification leads to different behaviors of centrosomes in the anterior and posterior and leads ultimately to blastomere-specific spindle orientations at the second cleavage. 44 refs., 5 figs., 5 tabs.

  18. Poly(ADP-ribose) (PAR) polymer is a death signal

    PubMed Central

    Andrabi, Shaida A.; Kim, No Soo; Yu, Seong-Woon; Wang, Hongmin; Koh, David W.; Sasaki, Masayuki; Klaus, Judith A.; Otsuka, Takashi; Zhang, Zhizheng; Koehler, Raymond C.; Hurn, Patricia D.; Poirier, Guy G.; Dawson, Valina L.; Dawson, Ted M.

    2006-01-01

    Excessive activation of the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP-1) plays a prominent role in various of models of cellular injury. Here, we identify poly(ADP-ribose) (PAR) polymer, a product of PARP-1 activity, as a previously uncharacterized cell death signal. PAR polymer is directly toxic to neurons, and degradation of PAR polymer by poly(ADP-ribose) glycohydrolase (PARG) or phosphodiesterase 1 prevents PAR polymer-induced cell death. PARP-1-dependent, NMDA excitotoxicity of cortical neurons is reduced by neutralizing antibodies to PAR and by overexpression of PARG. Neuronal cultures with reduced levels of PARG are more sensitive to NMDA excitotoxicity than WT cultures. Transgenic mice overexpressing PARG have significantly reduced infarct volumes after focal ischemia. Conversely, mice with reduced levels of PARG have significantly increased infarct volumes after focal ischemia compared with WT littermate controls. These results reveal PAR polymer as a signaling molecule that induces cell death and suggests that interference with PAR polymer signaling may offer innovative therapeutic approaches for the treatment of cellular injury. PMID:17116882

  19. Multi-scale photoacoustic remote sensing (PARS) (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Haji Reza, Parsin; Bell, Kevan; Shi, W.; Zemp, Roger J.

    2016-03-01

    We introduce a novel multi-scale photoacoustic remote sensing (PARS) imaging system. Our system can provide optical resolution details for superficial structures as well as acoustic resolution for deep-tissue imaging down to 5 cm, in a non-contact setting. PARS system does not require any contact with the sample or ultrasound coupling medium. The optical resolution PARS (OR-OARS) system uses optically focused pulsed excitation with optical detection of photoacoustic signatures using a long-coherence interrogation beam co-focused and co-scanned with the excitation spot. In the OR-PARS initial pressures are sampled right at their subsurface origin where acoustic pressures are largest. The Acoustic resolution PARS (AR-PARS) picks up the surface oscillation of the tissue caused by generated photoacoustic signal using a modified version of Michelson interferometry. By taking advantage of 4-meters polarization maintaining single-mode fiber and a green fiber laser we have generated a multi-wavelength source using stimulated Raman scattering. Remote functional imaging using this multi-wavelength excitation source and PARS detection mechanism has been demonstrated. The oxygen saturation estimations are shown for both phantom and in vivo studies. Images of blood vessel structures for an In vivo chicken embryo model is demonstrated. The Phantom studies indicates ~3µm and ~300µm lateral resolution for OR-PARS and AR-PARS respectively. To the best of our knowledge this is the first dual modality non-contact optical and acoustic resolution system used for in vivo imaging.

  20. Protease-Activated Receptor (PAR)2, but Not PAR1, Is Involved in Collateral Formation and Anti-Inflammatory Monocyte Polarization in a Mouse Hind Limb Ischemia Model

    PubMed Central

    Nossent, Anne Yael; van Oeveren-Rietdijk, Annemarie M.; de Vries, Margreet R.; Spek, C. Arnold; van Zonneveld, Anton Jan; Reitsma, Pieter H.; Hamming, Jaap F.; de Boer, Hetty C.; Versteeg, Henri H.; Quax, Paul H. A.

    2013-01-01

    Aims In collateral development (i.e. arteriogenesis), mononuclear cells are important and exist as a heterogeneous population consisting of pro-inflammatory and anti-inflammatory/repair-associated cells. Protease-activated receptor (PAR)1 and PAR2 are G-protein-coupled receptors that are both expressed by mononuclear cells and are involved in pro-inflammatory reactions, while PAR2 also plays a role in repair-associated responses. Here, we investigated the physiological role of PAR1 and PAR2 in arteriogenesis in a murine hind limb ischemia model. Methods and Results PAR1-deficient (PAR1-/-), PAR2-deficient (PAR2-/-) and wild-type (WT) mice underwent femoral artery ligation. Laser Doppler measurements revealed reduced post-ischemic blood flow recovery in PAR2-/- hind limbs when compared to WT, while PAR1-/- mice were not affected. Upon ischemia, reduced numbers of smooth muscle actin (SMA)-positive collaterals and CD31-positive capillaries were found in PAR2-/- mice when compared to WT mice, whereas these parameters in PAR1-/- mice did not differ from WT mice. The pool of circulating repair-associated (Ly6C-low) monocytes and the number of repair-associated (CD206-positive) macrophages surrounding collaterals in the hind limbs were increased in WT and PAR1-/- mice, but unaffected in PAR2-/- mice. The number of repair-associated macrophages in PAR2-/- hind limbs correlated with CD11b- and CD115-expression on the circulating monocytes in these animals, suggesting that monocyte extravasation and M-CSF-dependent differentiation into repair-associated cells are hampered. Conclusion PAR2, but not PAR1, is involved in arteriogenesis and promotes the repair-associated response in ischemic tissues. Therefore, PAR2 potentially forms a new pro-arteriogenic target in coronary artery disease (CAD) patients. PMID:23637930

  1. Novel Role for Proteinase-activated Receptor 2 (PAR2) in Membrane Trafficking of Proteinase-activated Receptor 4 (PAR4)*

    PubMed Central

    Cunningham, Margaret R.; McIntosh, Kathryn A.; Pediani, John D.; Robben, Joris; Cooke, Alexandra E.; Nilsson, Mary; Gould, Gwyn W.; Mundell, Stuart; Milligan, Graeme; Plevin, Robin

    2012-01-01

    Proteinase-activated receptors 4 (PAR4) is a class A G protein-coupled receptor (GPCR) recognized through the ability of serine proteases such as thrombin and trypsin to mediate receptor activation. Due to the irreversible nature of activation, a fresh supply of receptor is required to be mobilized to the cell surface for responsiveness to agonist to be sustained. Unlike other PAR subtypes, the mechanisms regulating receptor trafficking of PAR4 remain unknown. Here, we report novel features of the intracellular trafficking of PAR4 to the plasma membrane. PAR4 was poorly expressed at the plasma membrane and largely retained in the endoplasmic reticulum (ER) in a complex with the COPI protein subunit β-COP1. Analysis of the PAR4 protein sequence identified an arginine-based (RXR) ER retention sequence located within intracellular loop-2 (R183AR → A183AA), mutation of which allowed efficient membrane delivery of PAR4. Interestingly, co-expression with PAR2 facilitated plasma membrane delivery of PAR4, an effect produced through disruption of β-COP1 binding and facilitation of interaction with the chaperone protein 14-3-3ζ. Intermolecular FRET studies confirmed heterodimerization between PAR2 and PAR4. PAR2 also enhanced glycosylation of PAR4 and activation of PAR4 signaling. Our results identify a novel regulatory role for PAR2 in the anterograde traffic of PAR4. PAR2 was shown to both facilitate and abrogate protein interactions with PAR4, impacting upon receptor localization and cell signal transduction. This work is likely to impact markedly upon the understanding of the receptor pharmacology of PAR4 in normal physiology and disease. PMID:22411985

  2. Novel role for proteinase-activated receptor 2 (PAR2) in membrane trafficking of proteinase-activated receptor 4 (PAR4).

    PubMed

    Cunningham, Margaret R; McIntosh, Kathryn A; Pediani, John D; Robben, Joris; Cooke, Alexandra E; Nilsson, Mary; Gould, Gwyn W; Mundell, Stuart; Milligan, Graeme; Plevin, Robin

    2012-05-11

    Proteinase-activated receptors 4 (PAR(4)) is a class A G protein-coupled receptor (GPCR) recognized through the ability of serine proteases such as thrombin and trypsin to mediate receptor activation. Due to the irreversible nature of activation, a fresh supply of receptor is required to be mobilized to the cell surface for responsiveness to agonist to be sustained. Unlike other PAR subtypes, the mechanisms regulating receptor trafficking of PAR(4) remain unknown. Here, we report novel features of the intracellular trafficking of PAR(4) to the plasma membrane. PAR(4) was poorly expressed at the plasma membrane and largely retained in the endoplasmic reticulum (ER) in a complex with the COPI protein subunit β-COP1. Analysis of the PAR(4) protein sequence identified an arginine-based (RXR) ER retention sequence located within intracellular loop-2 (R(183)AR → A(183)AA), mutation of which allowed efficient membrane delivery of PAR(4). Interestingly, co-expression with PAR(2) facilitated plasma membrane delivery of PAR(4), an effect produced through disruption of β-COP1 binding and facilitation of interaction with the chaperone protein 14-3-3ζ. Intermolecular FRET studies confirmed heterodimerization between PAR(2) and PAR(4). PAR(2) also enhanced glycosylation of PAR(4) and activation of PAR(4) signaling. Our results identify a novel regulatory role for PAR(2) in the anterograde traffic of PAR(4). PAR(2) was shown to both facilitate and abrogate protein interactions with PAR(4), impacting upon receptor localization and cell signal transduction. This work is likely to impact markedly upon the understanding of the receptor pharmacology of PAR(4) in normal physiology and disease. PMID:22411985

  3. Participation of Chromosome Segregation Protein ParAI of Vibrio cholerae in Chromosome Replication▿ †

    PubMed Central

    Kadoya, Ryosuke; Baek, Jong Hwan; Sarker, Arnab; Chattoraj, Dhruba K.

    2011-01-01

    Vibrio cholerae carries homologs of plasmid-borne parA and parB genes on both of its chromosomes. The par genes help to segregate many plasmids and chromosomes. Here we have studied the par genes of V. cholerae chromosome I. Earlier studies suggested that ParBI binds to the centromeric site parSI near the origin of replication (oriI), and parSI-ParBI complexes are placed at the cell poles by ParAI. Deletion of parAI and parSI caused the origin-proximal DNA to be less polar. Here we found that deletion of parBI also resulted in a less polar localization of oriI. However, unlike the deletion of parAI, the deletion of parBI increased the oriI number. Replication was normal when both parAI and parBI were deleted, suggesting that ParBI mediates its action through ParAI. Overexpression of ParAI in a parABI-deleted strain also increased the DNA content. The results are similar to those found for Bacillus subtilis, where ParA (Soj) stimulates replication and this activity is repressed by ParB (SpoOJ). As in B. subtilis, the stimulation of replication most likely involves the replication initiator DnaA. Our results indicate that control of chromosomal DNA replication is an additional function of chromosomal par genes conserved across the Gram-positive/Gram-negative divide. PMID:21257772

  4. Predicted PAR1 inhibitors from multiple computational methods

    NASA Astrophysics Data System (ADS)

    Wang, Ying; Liu, Jinfeng; Zhu, Tong; Zhang, Lujia; He, Xiao; Zhang, John Z. H.

    2016-08-01

    Multiple computational approaches are employed in order to find potentially strong binders of PAR1 from the two molecular databases: the Specs database containing more than 200,000 commercially available molecules and the traditional Chinese medicine (TCM) database. By combining the use of popular docking scoring functions together with detailed molecular dynamics simulation and protein-ligand free energy calculations, a total of fourteen molecules are found to be potentially strong binders of PAR1. The atomic details in protein-ligand interactions of these molecules with PAR1 are analyzed to help understand the binding mechanism which should be very useful in design of new drugs.

  5. View from northeast to southwest of PAR site sentry station; ...

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

    View from northeast to southwest of PAR site sentry station; formerly the bachelor's enlisted men's quarter (BEQ) - Stanley R. Mickelsen Safeguard Complex, Sentry Station, North of Second Avenue & West of Electrical Switch Station No. 2, Nekoma, Cavalier County, ND

  6. View from southwest to northeast of PAR site fresh water ...

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

    View from southwest to northeast of PAR site fresh water pump house - Stanley R. Mickelsen Safeguard Complex, Fresh Water Pump House, In Limited Access Area, on Patrol Road next to Open Storage Reservoir No. 736, Nekoma, Cavalier County, ND

  7. PARS: Programs for Analysis and Resizing of Structures, user manual

    NASA Technical Reports Server (NTRS)

    Haftka, R. T.; Prasad, B.; Tsach, U.

    1979-01-01

    PARS processors and their use, flutter analysis, sensitivity analysis for stresses, and resizing are presented. Design variable definition and interface with finite element model, static constraints and their derivatives, flutter derivatives, and optimization are discussed.

  8. Par-4 secretion: stoichiometry of 3-arylquinoline binding to vimentin.

    PubMed

    Sviripa, Vitaliy M; Burikhanov, Ravshan; Obiero, Josiah M; Yuan, Yaxia; Nickell, Justin R; Dwoskin, Linda P; Zhan, Chang-Guo; Liu, Chunming; Tsodikov, Oleg V; Rangnekar, Vivek M; Watt, David S

    2016-01-01

    Advanced prostate tumors usually metastasize to the lung, bone, and other vital tissues and are resistant to conventional therapy. Prostate apoptosis response-4 protein (Par-4) is a tumor suppressor that causes apoptosis in therapy-resistant prostate cancer cells by binding specifically to a receptor, Glucose-regulated protein-78 (GRP78), found only on the surface of cancer cells. 3-Arylquinolines or "arylquins" induce normal cells to release Par-4 from the intermediate filament protein, vimentin and promote Par-4 secretion that targets cancer cells in a paracrine manner. A structure-activity study identified arylquins that promote Par-4 secretion, and an evaluation of arylquin binding to the hERG potassium ion channel using a [(3)H]-dofetilide binding assay permitted the identification of structural features that separated this undesired activity from the desired Par-4 secretory activity. A binding study that relied on the natural fluorescence of arylquins and that used the purified rod domain of vimentin (residues 99-411) suggested that the mechanism behind Par-4 release involved arylquin binding to multiple sites in the rod domain. PMID:26548370

  9. Croissance epitaxiale de GaAs sur substrats de Ge par epitaxie par faisceaux chimiques

    NASA Astrophysics Data System (ADS)

    Belanger, Simon

    La situation energetique et les enjeux environnementaux auxquels la societe est confrontee entrainent un interet grandissant pour la production d'electricite a partir de l'energie solaire. Parmi les technologies actuellement disponibles, la filiere du photovoltaique a concentrateur solaire (CPV pour concentrator photovoltaics) possede un rendement superieur et mi potentiel interessant a condition que ses couts de production soient competitifs. La methode d'epitaxie par faisceaux chimiques (CBE pour chemical beam epitaxy) possede plusieurs caracteristiques qui la rendent interessante pour la production a grande echelle de cellules photovoltaiques a jonctions multiples a base de semi-conducteurs III-V. Ce type de cellule possede la meilleure efficacite atteinte a ce jour et est utilise sur les satellites et les systemes photovoltaiques a concentrateur solaire (CPV) les plus efficaces. Une des principales forces de la technique CBE se trouve dans son potentiel d'efficacite d'utilisation des materiaux source qui est superieur a celui de la technique d'epitaxie qui est couramment utilisee pour la production a grande echelle de ces cellules. Ce memoire de maitrise presente les travaux effectues dans le but d'evaluer le potentiel de la technique CBE pour realiser la croissance de couches de GaAs sur des substrats de Ge. Cette croissance constitue la premiere etape de fabrication de nombreux modeles de cellules solaires a haute performance decrites plus haut. La realisation de ce projet a necessite le developpement d'un procede de preparation de surface pour les substrats de germanium, la realisation de nombreuses sceances de croissance epitaxiale et la caracterisation des materiaux obtenus par microscopie optique, microscopie a force atomique (AFM), diffraction des rayons-X a haute resolution (HRXRD), microscopie electronique a transmission (TEM), photoluminescence a basse temperature (LTPL) et spectrometrie de masse des ions secondaires (SIMS). Les experiences ont permis

  10. Par Pond vegetation status Summer 1995 -- June survey descriptive summary

    SciTech Connect

    Mackey, H.E. Jr.; Riley, R.S.

    1995-06-01

    The water level of Par Pond was lowered approximately 20 feet in mid-1991 in order to protect downstream residents from possible dam failure suggested by subsidence on the downstream slope of the dam and to repair the dam. This lowering exposed both emergent and nonemergent macrophyte beds to drying conditions resulting in extensive losses. A survey of the shoreline aquatic plant communities in June 1995, three months after the refilling of Par Pond to approximately 200 feet above mean sea level, indicated that much of the original plant communities and the intermediate shoreline communities present on the exposed sediments have been lost. The extensive old-field and emergent marsh communities that were present on the exposed shoreline during the drawdown have been flooded and much of the pre-drawdown Par Pond aquatic plant communities have not had sufficient time for re-establishment. The shoreline does, however, have extensive beds of maidencane which extend from the shoreline margin to areas as deep as 2 and perhaps 3 meters. Scattered individual plants of lotus and watershield are common and may indicate likely directions of future wetland development in Par Pond. In addition, within isolated coves, which apparently received ground water seepage and/or stream surface flows during the period of the Par Pond draw down, extensive beds of waterlilies and spike rush are common. Invasion of willow and red maple occurred along the lake shoreline as well. Although not absent from this survey, evidence of the extensive redevelopment of the large cattail and eel grass beds was not observed in this first survey of Par Pond. Future surveys during the growing seasons of 1995, 1996, and 1997 along with the evaluation of satellite date to map the areal extent of the macrophyte beds of Par Pond are planned.

  11. Pars Planitis: Epidemiology, Clinical Characteristics, Management and Visual Prognosis

    PubMed Central

    Ozdal, Pinar Cakar; Berker, Nilufer; Tugal-Tutkun, Ilknur

    2015-01-01

    Pars planitis is an idiopathic chronic intermediate uveitis which predominantly affects children and adolescents, and accounts for 5-26.7% of pediatric uveitis. Although an autoimmune process with a genetic predisposition has been suggested, its etiology still remains unknown. The most common presenting symptoms are floaters and blurred vision. Diffuse vitreous cells, haze, snowballs and snowbanks are typical findings of pars planitis. Peripheral retinal vasculitis, optic disc edema and anterior segment inflammation are other well-known findings. Although pars planitis is known to be a benign form of uveitis in most cases, it may become a potentially blinding disease due to complications including cataract, cystoid macular edema, vitreous opacities and optic disc edema. Cystoid macular edema is the most common cause of visual morbidity. Band keratopathy, epiretinal membrane formation, vitreous condensation, neovascularizations, vitreous hemorrhage, retinal detachment, cyclitic membranes, glaucoma and amblyopia may develop as a consequence of the chronic course of the disease. Exclusion of infectious and non-infectious causes which may present with intermediate uveitis is of utmost importance before starting treatment. Treatment of pars planitis has been a controversial issue. There is no consensus specifically for treatment of cases with minimal inflammation and relatively good visual acuity. However, current experience shows that pars planitis may cause severe inflammation and needs an aggressive treatment. A stepladder approach including corticosteroids, immunosupressive agents, anti-tumor necrosis factor-alpha and pars plana vitrectomy and/or laser photocoagulation is the most commonly used method for treatment of pars planitis. Adequate control of inflammation and prompt detection of associated complications are crucial in order to improve the overall prognosis of the disease. PMID:27051493

  12. Combined pars plana vitrectomy-scleral buckle versus pars plana vitrectomy for proliferative vitreoretinopathy.

    PubMed

    Lai, Frank H P; Lo, Ernie C F; Chan, Vesta C K; Brelen, Mårten; Lo, Wai Ling; Young, Alvin L

    2016-04-01

    The purpose of the study is to evaluate the surgical outcomes of combined pars plana vitrectomy-scleral buckle (PPV-SB) versus pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment complicated with proliferative vitreoretinopathy (PVR). One thousand one hundred and seventy four patients with rhegmatogenous retinal detachment surgery between January 2002 and December 2013 were retrospectively reviewed. Patients with grade C PVR treated with either combined PPV-SB or PPV alone were included in the study. Study outcomes included single surgery anatomic success rate and postoperative visual outcome at 12 months postoperatively. Seventy-seven patients with grade C PVR were identified for analysis. At the end of 12-month follow-up, 80.5 % eyes (33/41) in the PPV-SB group and 58.3 % eyes (21/36) in the PPV group achieved single surgery anatomical success. In a multiple logistic regression model, none of the baseline variables (age, gender, macula status, grade of PVR, extent of detachment, presence of vitreous hemorrhage, lens status, status of high myopia) nor types of retinal detachment surgery (use of scleral buckle, barrier endolaser, 360 degree endolaser, cryopexy, retinectomy, tamponade agent, phacoemulsification) had significant effect on single surgery anatomical success. The post-treatment mean logMAR visual acuity of the PPV-SB group was 1.58 ± 0.58 and the PPV group was 1.57 ± 0.61. There was no significant difference in the postoperative visual acuity between the two groups (P = 0.849). For patients with grade C PVR, PPV-SB did not demonstrate a superiority over PPV alone in achieving single surgery anatomical success. PMID:26260357

  13. Par Pond vegetation status Summer 1995 -- September survey descriptive summary

    SciTech Connect

    Mackey, H.E. Jr.; Riley, R.S.

    1995-09-01

    The water level of Par Pond was lowered approximately 20 feet in mid-1991 in order to protect downstream residents from possible dam failure suggested by subsidence on the downstream slope of the dam and to repair the dam. This lowering exposed both emergent and nonemergent macrophyte beds to drying conditions resulting in extensive losses. A survey of the emergent shoreline aquatic plant communities began in June 1995, three months after the refilling of Par Pond to approximately 200 feet above mean sea level and continued with this mid-September survey. Communities similar to the pre-drawdown Par Pond aquatic plant communities are becoming re-established; especially, beds of maidencane, lotus, waterlily, and watershield are now extensive and well established. Cattail occurrence continues to increase, but large beds common to Par Pond prior to the drawdown have not formed. Future surveys during the late growing seasons of 1995, and throughout 1996 and 1997, along with the evaluation of satellite data to map the areal extent of the macrophyte beds of Par Pond, are planned.

  14. Par Pond vegetation status Summer 1995 -- October survey descriptive summary

    SciTech Connect

    Mackey, H.E. Jr.; Riley, R.S.

    1995-11-01

    The water level of Par Pond was lowered approximately 20 feet in mid-1991 in order to protect downstream residents from possible dam failure suggested by subsidence on the downstream slope of the dam and to repair the dam. This lowering exposed both emergent and nonemergent macrophyte beds to drying conditions resulting in extensive losses. A survey of the emergent shoreline aquatic plant communities began in June 1995, three months after the refilling of Par Pond to approximately 200 feet above mean sea level and continued with this late October survey. Communities similar to the pre-drawdown Par Pond aquatic plant communities are becoming re-established; especially, beds of maiden cane, lotus, waterlily, and watershield are now extensive and well established. Cattail occurrence continues to increase, but large beds common to Par Pond prior to the drawdown have not formed. Future surveys throughout 1996 and 1997, along with the continued evaluation of satellite data to map the areal extent of the macrophyte beds of Par Pond, are planned.

  15. PAR-1 phosphorylates Mind bomb to promote vertebrate neurogenesis

    PubMed Central

    Ossipova, Olga; Ezan, Jerome; Sokol, Sergei Y.

    2010-01-01

    Summary Generation of neurons in the vertebrate central nervous system requires complex transcriptional regulatory network and signaling processes in polarized neuroepithelial progenitor cells. Here we demonstrate that neurogenesis in the Xenopus neural plate in vivo and mammalian neural progenitors in vitro involves intrinsic antagonistic activities of the polarity proteins PAR-1 and aPKC. Furthermore, we show that Mind bomb (Mib), a ubiquitin ligase that promotes Notch ligand trafficking and activity, is a crucial molecular substrate for PAR-1. The phosphorylation of Mib by PAR-1 results in Mib degradation, repression of Notch signaling and stimulation of neuronal differentiation. These observations suggest a conserved mechanism for neuronal fate determination that might operate during asymmetric divisions of polarized neural progenitor cells. PMID:19686683

  16. Bacterial actin: architecture of the ParMRC plasmid DNA partitioning complex.

    PubMed

    Salje, Jeanne; Löwe, Jan

    2008-08-20

    The R1 plasmid employs ATP-driven polymerisation of the actin-like protein ParM to move newly replicated DNA to opposite poles of a bacterial cell. This process is essential for ensuring accurate segregation of the low-copy number plasmid and is the best characterised example of DNA partitioning in prokaryotes. In vivo, ParM only forms long filaments when capped at both ends by attachment to a centromere-like region parC, through a small DNA-binding protein ParR. Here, we present biochemical and electron microscopy data leading to a model for the mechanism by which ParR-parC complexes bind and stabilise elongating ParM filaments. We propose that the open ring formed by oligomeric ParR dimers with parC DNA wrapped around acts as a rigid clamp, which holds the end of elongating ParM filaments while allowing entry of new ATP-bound monomers. We propose a processive mechanism by which cycles of ATP hydrolysis in polymerising ParM drives movement of ParR-bound parC DNA. Importantly, our model predicts that each pair of plasmids will be driven apart in the cell by just a single double helical ParM filament. PMID:18650930

  17. La projection par plasma : une revue

    NASA Astrophysics Data System (ADS)

    Fauchais, P.; Grimaud, A.; Vardelle, A.; Vardelle, M.

    are presented in the fields of aeronautics and mechanics. La qualité d'un dépôt projete par plasma dépend de nombreux paramètres que l'on commence à mieux appréhender du fait des progrès de la modélisation et de la métrologie tant des écoulements plasmas que des transferts plasma-particules ou que des conditions d'écrasement et de refroidissement des particules lors de leur impact sur le substrat ou les couches déjà déposées. Les techniques de mesure utilisdes et leurs limitations sont d'abord rappelées tant pour les jets de plasma que pour les particules en vol et l'importance des différents phénomènes intervenant dans les transferts plasma-particules est soulignée : gradients de température et de concentration d'espèces chimiques très élevés autour des particules, effets de propagation de la chaleur, notamment pour les particules céramiques, effet d'évaporation, effet de raréfaction sensible dès la pression atmosphérique. Les problèmes de distribution de taille et de vitesse d'injection des particules sont également abordés car ils conditionnent les distributions de trajectoires et donc le traitement des particules dans le jet de plasma. La génération du plasma montre d'une part 1'influence considérable de l'injection du gaz, de sa nature, du dessin de la chambre d'arc et de la tuyère ainsi que du pompage de l'air ambiant sur la longueur des jets de plasma d'arc et d'autre part les problèmes d'injection pour éviter le couplage avec la décharge dans les jets de plasmas R.E Tout ceci est illustré avec des exemples de dépôt d'alumine, de zircone, de cermet carbure et de nickel. L'écrasement des particules est ensuite abordé avec les problèmes de réactions chimiques, de trempe ultra-rapide et donc de structure cristalline des dépôts, d'adhdsion mais aussi de containtes résiduelles et de leur contrôle via les gradients de température dans les dépôts pendant le tir. Enfin quelques applications actuelles sont pr

  18. PH motifs in PAR1&2 endow breast cancer growth

    PubMed Central

    Kancharla, A.; Maoz, M.; Jaber, M.; Agranovich, D.; Peretz, T.; Grisaru-Granovsky, S.; Uziely, B.; Bar-Shavit, R.

    2015-01-01

    Although emerging roles of protease-activated receptor1&2 (PAR1&2) in cancer are recognized, their underlying signalling events are poorly understood. Here we show signal-binding motifs in PAR1&2 that are critical for breast cancer growth. This occurs via the association of the pleckstrin homology (PH) domain with Akt/PKB as a key signalling event of PARs. Other PH-domain signal-proteins such as Etk/Bmx and Vav3 also associate with PAR1 and PAR2 through their PH domains. PAR1 and PAR2 bind with priority to Etk/Bmx. A point mutation in PAR2, H349A, but not in R352A, abrogates PH-protein association and is sufficient to markedly reduce PAR2-instigated breast tumour growth in vivo and placental extravillous trophoblast (EVT) invasion in vitro. Similarly, the PAR1 mutant hPar1-7A, which is unable to bind the PH domain, reduces mammary tumours and EVT invasion, endowing these motifs with physiological significance and underscoring the importance of these previously unknown PAR1 and PAR2 PH-domain-binding motifs in both pathological and physiological invasion processes. PMID:26600192

  19. PH motifs in PAR1&2 endow breast cancer growth.

    PubMed

    Kancharla, A; Maoz, M; Jaber, M; Agranovich, D; Peretz, T; Grisaru-Granovsky, S; Uziely, B; Bar-Shavit, R

    2015-01-01

    Although emerging roles of protease-activated receptor1&2 (PAR1&2) in cancer are recognized, their underlying signalling events are poorly understood. Here we show signal-binding motifs in PAR1&2 that are critical for breast cancer growth. This occurs via the association of the pleckstrin homology (PH) domain with Akt/PKB as a key signalling event of PARs. Other PH-domain signal-proteins such as Etk/Bmx and Vav3 also associate with PAR1 and PAR2 through their PH domains. PAR1 and PAR2 bind with priority to Etk/Bmx. A point mutation in PAR2, H349A, but not in R352A, abrogates PH-protein association and is sufficient to markedly reduce PAR2-instigated breast tumour growth in vivo and placental extravillous trophoblast (EVT) invasion in vitro. Similarly, the PAR1 mutant hPar1-7A, which is unable to bind the PH domain, reduces mammary tumours and EVT invasion, endowing these motifs with physiological significance and underscoring the importance of these previously unknown PAR1 and PAR2 PH-domain-binding motifs in both pathological and physiological invasion processes. PMID:26600192

  20. Aqueous misdirection following pars plana vitrectomy and silicone oil injection

    PubMed Central

    Ghoraba, Hammouda H; Ghali, Ali Ahmed; Mansour, Hosam Othman

    2015-01-01

    Purpose To report a retrospective series of seven phakic eyes of seven patients suffering from a malignant glaucoma-like syndrome following pars plana vitrectomy and silicone oil (SO) injection. Materials and methods Seven eyes with retinal detachment treated with pars plana vitrectomy with or without scleral buckling with SO tamponade. This was followed by cataract extraction to manage the elevated intraocular pressure (IOP). Results This was a retrospective review of seven cases that received pars plana vitrectomy and SO with or without scleral buckling for different causes of retinal detachment (three were rhegmatogenous and four were tractional). After a period ranging from 1 week to 1 month, they presented with malignant glaucoma-like manifestations; high IOP, shallow axial anterior chamber, and remarkable decrease of visual acuity. Atropine eye drops and anti-glaucoma medical treatment (topical and systemic) had been tried but failed to improve the condition. Dramatic decrease of IOP and deepening of the axial anterior chamber was observed in all cases in the first postoperative day after phacoemulsification and posterior chamber foldable intraocular lens implantation with posterior capsulotomy. Conclusion Aqueous misdirection syndrome may be observed following pars plana vitrectomy and SO tamponade. This must be differentiated from other causes of post vitrectomy glaucoma. Cataract extraction with posterior capsulotomy controls the condition. PMID:26056429

  1. The Pars Triangularis in Dyslexia and ADHD: A Comprehensive Approach

    ERIC Educational Resources Information Center

    Kibby, Michelle Y.; Kroese, Judith M.; Krebbs, Hillery; Hill, Crystal E.; Hynd, George W.

    2009-01-01

    Limited research has been conducted on the structure of the pars triangularis (PT) in dyslexia despite functional neuroimaging research finding it may play a role in phonological processing. Furthermore, research to date has not examined PT size in ADHD even though the right inferior frontal region has been implicated in the disorder. Hence, one…

  2. Radiological impact of Par Pond drawdown from liquid effluent pathways

    SciTech Connect

    Carlton, W.H.; Hamby, D.M.

    1991-10-25

    The water level of Par Pond has been lowered over the past several months to reduce the effects in the event of catastrophic dam failure while assessing the condition of the dam and determining if repairs are necessary. In lowering the level of Par Pond, 60 billion liters of water containing low levels of tritium and cesium-137 were discharged to several onsite streams. SRS surface streams flow to the Savannah River. An assessment made to determine the total amount of tritium and Cs-137 discharged and to estimate the consequences to downstream Savannah River users. It is estimated that a total of 160 curies of tritium were displaced from Par Pond to the Savannah River between June 28, 1991 and September 19, 1991. This release could hypothetically result in a maximum individual dose of 3. 2{times}10{sup {minus}4} mrem and a total (80-km and drinking water populations) population dose of 1.4{times}10{sup {minus}2} person-rem. Likewise, a maximum individual dose of 5.0{times}10{sup {minus}2} mrem and a total population dose of 1.7{times}10{sup {minus}1} person- rem are predicted as a result of an estimated 0.21 curies of Cs-137 being discharged from Par Pond to the Savannah River.

  3. Par Pond vegetation status summer 1995 - July survey descriptive summary

    SciTech Connect

    Mackey, H.E. Jr.; Riley, R.S.

    1995-07-01

    A survey of the emergent shoreline aquatic plant, communities began in June 1995, three months after the refilling of Par Pond to approximately 200 feet (61 meters) above mean sea level, and continued with this July survey. Aquatic plant communities, similar to the pre-drawdown Par Pond communities, are becoming reestablished. Beds of maidencane (Panicum hemitomon), lotus (Nelumbo lutea), water lily (Nymphaea odorata), and watershield (Brasenia schreberi) are now extensive and well established. In addition, within isolated coves, extensive beds of water lilies and spike-rush (Eleocharis sp.) are common. Cattail occurrence has increased since refill, but large beds common to Par Pond prior to the drawdown have not formed. Invasion of willow (Salix sp.) and red maple (Acer rubrum) occurred along the lake shoreline during drawdown. The red maples along the present shoreline are beginning to show evidence of stress and mortality from flooding over the past four months. Some of the willows appear to be stressed as well. The loblolly pines (Pinus taeda), which were flooded in all but the shallow shoreline areas, are now dead. Future surveys are planned for the growing seasons of 1995, 1996, and 1997, along with the evaluation of satellite data for mapping the areal extent of the macrophyte beds of Par Pond.

  4. BOREAS RSS-10 TOMS Circumpolar One-Degree PAR Images

    NASA Technical Reports Server (NTRS)

    Dye, Dennis G.; Holben, Brent; Nickeson, Jaime (Editor); Hall, Forrest G. (Editor); Smith, David E. (Technical Monitor)

    2000-01-01

    The Boreal Ecosystem-Atmosphere Study (BOREAS) Remote Sensing Science (RSS)-10 team investigated the magnitude of daily, seasonal, and yearly variations of Photosynthetically Active Radiation (PAR) from ground and satellite observations. This data set contains satellite estimates of surface-incident PAR (400-700 nm, MJ/sq m) at one-degree spatial resolution. The spatial coverage is circumpolar from latitudes of 41 to 66 degrees north. The temporal coverage is from May through September for years 1979 through 1989. Eleven-year statistics are also provided: (1) mean, (2) standard deviation, and (3) coefficient of variation for 1979-89. The PAR estimates were derived from the global gridded ultraviolet reflectivity data product (average of 360, 380 nm) from the Nimbus-7 Total Ozone Mapping Spectrometer (TOMS). Image mask data are provided for identifying the boreal forest zone, and ocean/land and snow/ice-covered areas. The data are available as binary image format data files. The PAR data are available from the Earth Observing System Data and Information System (EOSDIS) Oak Ridge National Laboratory (ORNL) Distributed Active Archive Center (DAAC). The data files are available on a CD-ROM (see document number 20010000884).

  5. Results of peripheral laser photocoagulation in pars planitis.

    PubMed Central

    Pulido, J S; Mieler, W F; Walton, D; Kuhn, E; Postel, E; Hartz, A; Jampol, L M; Weinberg, D V; Logani, S

    1998-01-01

    PURPOSE: To determine the effect of peripheral retinal laser photocoagulation (PLP) on visual acuity, intraocular inflammation, and other ocular findings, including retinal neovascularization in eyes with pars planitis. METHODS: A retrospective chart review of eyes with pars planitis that had undergone PLP. RESULTS: Twenty-two eyes in 17 patients with pars planitis had undergone treatment with PLP at 2 centers. The mean age at the time of treatment was 19.3 years. Following treatment, mean follow-up was 16.3 months (range, 6 to 37 months). Mean visual acuity was 20/60 preoperatively and 20/50 postoperatively. This level of improvement was not statistically significant (P > .10), but there was a statistically significant decrease in the use of corticosteroids between the preoperative examination and the last postoperative examination (86% versus 27%, P < .05). There was also a statistically significant decrease in vitritis at the last follow-up (P = .0008) and a decrease in neovascularization of the vitreous base (P = .03) and in clinically apparent cystoid macular edema (P = .02). Epiretinal membranes were noted in 23% of eyes preoperatively and in 45% of eyes postoperatively. Only one of these epiretinal membranes was considered to be visually significant. One eye developed a tonic dilated pupil, which slowly improved. CONCLUSIONS: Although the long-term natural history of clinical findings in pars planitis is not well documented, PLP appears to decrease the need for corticosteroids while stabilizing visual acuity. It also appears to decrease vitreous inflammation. PLP has few complications and should be considered in patients with pars planitis who are unresponsive or have adverse reactions to corticosteroids. PMID:10360286

  6. The role of pars flaccida in human middle ear sound transmission.

    PubMed

    Aritomo, H; Goode, R L; Gonzalez, J

    1988-04-01

    The role of the pars flaccida in middle ear sound transmission was studied with the use of twelve otoscopically normal, fresh, human temporal bones. Peak-to-peak umbo displacement in response to a constant sound pressure level at the tympanic membrane was measured with a noncontacting video measuring system capable of repeatable measurements down to 0.2 micron. Measurements were made before and after pars flaccida modifications at 18 frequencies between 100 and 4000 Hz. Four pars flaccida modifications were studied: (1) acoustic insulation of the pars flaccida to the ear canal with a silicone rubber baffle, (2) stiffening the pars flaccida with cyanoacrylate cement, (3) decreasing the tension of the pars flaccida with a nonperforating incision, and (4) perforation of the pars flaccida. All of the modifications (except the perforation) had a minimal effect on umbo displacement; this seems to imply that the pars flaccida has a minor acoustic role in human beings. PMID:3132684

  7. The Role of Prostate Apoptosis Response-4 (Par-4) in Mycobacterium tuberculosis Infected Macrophages.

    PubMed

    Han, Ji-Ye; Lim, Yun-Ji; Choi, Ji-Ae; Lee, Jung-Hwan; Jo, Sung-Hee; Oh, Sung-Man; Song, Chang-Hwa

    2016-01-01

    Prostate apoptosis response-4 (Par-4) is a tumor suppressor protein that forms a complex with glucose-regulated protein 78 (GRP78) to induce apoptosis. Previously, we reported that ER stress-induced apoptosis is a critical host defense mechanism against Mycobacterium tuberculosis (Mtb). We sought to understand the role of Par-4 during ER stress-induced apoptosis in response to mycobacterial infection. Par-4 and GRP78 protein levels increased in response Mtb (strain: H37Ra) infection. Furthermore, Par-4 and GRP78 translocate to the surface of Mtb H37Ra-infected macrophages and induce apoptosis via caspase activation. NF-κB activation, Mtb-mediated ER stress, and Par-4 production were significantly diminished in macrophages with inhibited ROS production. To test Par-4 function during mycobacterial infection, we analyzed intracellular survival of Mtb H37Ra in macrophages with Par-4 overexpression or knockdown. Mtb H37Ra growth was significantly reduced in Par-4 overexpressing macrophages and increased in knockdown macrophages. We also observed increased Par-4, GRP78, and caspases activation in Bacillus Calmette-Guérin (BCG)-infected prostate cancer cells. Our data demonstrate that Par-4 is associated with ER stress-induced apoptosis resulting in reduced intracellular survival of mycobacteria. BCG treatment increases Par-4-dependent caspase activation in prostate cancer cells. These results suggest ER stress-induced Par-4 acts as an important defense mechanism against mycobacterial infection and regulates cancer. PMID:27552917

  8. The Role of Prostate Apoptosis Response-4 (Par-4) in Mycobacterium tuberculosis Infected Macrophages

    PubMed Central

    Han, Ji-Ye; Lim, Yun-Ji; Choi, Ji-Ae; Lee, Jung-hwan; Jo, Sung-Hee; Oh, Sung-Man; Song, Chang-Hwa

    2016-01-01

    Prostate apoptosis response-4 (Par-4) is a tumor suppressor protein that forms a complex with glucose-regulated protein 78 (GRP78) to induce apoptosis. Previously, we reported that ER stress-induced apoptosis is a critical host defense mechanism against Mycobacterium tuberculosis (Mtb). We sought to understand the role of Par-4 during ER stress-induced apoptosis in response to mycobacterial infection. Par-4 and GRP78 protein levels increased in response Mtb (strain: H37Ra) infection. Furthermore, Par-4 and GRP78 translocate to the surface of Mtb H37Ra-infected macrophages and induce apoptosis via caspase activation. NF-κB activation, Mtb-mediated ER stress, and Par-4 production were significantly diminished in macrophages with inhibited ROS production. To test Par-4 function during mycobacterial infection, we analyzed intracellular survival of Mtb H37Ra in macrophages with Par-4 overexpression or knockdown. Mtb H37Ra growth was significantly reduced in Par-4 overexpressing macrophages and increased in knockdown macrophages. We also observed increased Par-4, GRP78, and caspases activation in Bacillus Calmette-Guérin (BCG)-infected prostate cancer cells. Our data demonstrate that Par-4 is associated with ER stress-induced apoptosis resulting in reduced intracellular survival of mycobacteria. BCG treatment increases Par-4-dependent caspase activation in prostate cancer cells. These results suggest ER stress-induced Par-4 acts as an important defense mechanism against mycobacterial infection and regulates cancer. PMID:27552917

  9. Is There an "F" in Your PAR? Understanding, Teaching and Doing Action Research

    ERIC Educational Resources Information Center

    Lorenzetti, Liza; Walsh, Christine Ann

    2014-01-01

    Participatory Action Research (PAR) is increasingly recognized within academic research and pedagogy. What are the benefits of including feminism within participatory action research and teaching? In responding to this question, we discuss the similarities and salient differences between PAR and feminist informed PAR (FPAR). There are eight themes…

  10. ParA resolvase catalyzes site-specific excision of DNA from the Arabidopsis genome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The small serine resolvase ParA from bacterial plasmids RK2 and RP4 catalyzes the recombination of two identical 133 bp recombination sites known as MRS. Previously, we reported that ParA is active in the fission yeast Schizosaccharomyces pombe. In this work, the parA recombinase gene was placed un...

  11. Detection of suPAR in the Saliva of Healthy Young Adults: Comparison with Plasma Levels

    PubMed Central

    Gustafsson, Anna; Ajeti, Vjosa; Ljunggren, Lennart

    2011-01-01

    The soluble urokinase plasminogen activator receptor (suPAR) has been detected in blood, plasma, serum, urine, ovarian cystic fluid, and cerebrospinal fluid. Elevated suPAR levels in plasma have been associated with negative outcomes in various diseases, such as bacteremia, sepsis, SIRS, cardiovascular disease, cancer, and tuberculosis. The primary aim of this study was to investigate whether suPAR can be detected in saliva from healthy individuals and thus, if saliva suPAR can be related to plasma suPAR, CRP, BMI, or gender. Blood and unstimulated whole saliva was collected from 20 healthy individuals (10 female and 10 male, median age of 28 years; range 21–41). CRP and suPAR were measured with ELISA in saliva and serum/plasma. suPAR was detected in all saliva samples in the 5.2–28.1 ng/mL range, with a median value of 17.1 ng/mL. Saliva suPAR was significantly higher (P < 0.001) but not correlated to plasma suPAR in healthy young adults with normal plasma suPAR levels. suPAR and CRP levels were correlated in blood but not in saliva. No correlation was found between BMI, age, or gender and suPAR in saliva. PMID:22084570

  12. ParCAT: A Parallel Climate Analysis Toolkit

    NASA Astrophysics Data System (ADS)

    Haugen, B.; Smith, B.; Steed, C.; Ricciuto, D. M.; Thornton, P. E.; Shipman, G.

    2012-12-01

    Climate science has employed increasingly complex models and simulations to analyze the past and predict the future of our climate. The size and dimensionality of climate simulation data has been growing with the complexity of the models. This growth in data is creating a widening gap between the data being produced and the tools necessary to analyze large, high dimensional data sets. With single run data sets increasing into 10's, 100's and even 1000's of gigabytes, parallel computing tools are becoming a necessity in order to analyze and compare climate simulation data. The Parallel Climate Analysis Toolkit (ParCAT) provides basic tools that efficiently use parallel computing techniques to narrow the gap between data set size and analysis tools. ParCAT was created as a collaborative effort between climate scientists and computer scientists in order to provide efficient parallel implementations of the computing tools that are of use to climate scientists. Some of the basic functionalities included in the toolkit are the ability to compute spatio-temporal means and variances, differences between two runs and histograms of the values in a data set. ParCAT is designed to facilitate the "heavy lifting" that is required for large, multidimensional data sets. The toolkit does not focus on performing the final visualizations and presentation of results but rather, reducing large data sets to smaller, more manageable summaries. The output from ParCAT is provided in commonly used file formats (NetCDF, CSV, ASCII) to allow for simple integration with other tools. The toolkit is currently implemented as a command line utility, but will likely also provide a C library for developers interested in tighter software integration. Elements of the toolkit are already being incorporated into projects such as UV-CDAT and CMDX. There is also an effort underway to implement portions of the CCSM Land Model Diagnostics package using ParCAT in conjunction with Python and gnuplot. Par

  13. Minimally invasive pars approach for foraminal disc herniation.

    PubMed

    Hitchon, Patrick W; Awe, Olatilewa O; Close, Liesl; Sukkarieh, Hamdi G

    2015-07-01

    We present a retrospective cohort study on the outcome of patients with foraminal disc herniations (FDH) treated with partial pars resections using minimally invasive surgery (MIS) through a tube. FDH present a challenge due to the more lateral trajectory needed for their excision and thereby more muscle dissection and possibly facet resection. Forty patients, 19 women and 21 men with a mean age ± standard deviation of 58 ± 12 years, underwent MIS for FDH. Data on length of hospital stay, body mass index and outcomes were collected prospectively and reviewed retrospectively. Average length of stay following surgery was 1 ± 1 days. There was one wound infection and four unsatisfactory results. Using the Macnab score, good to excellent results were achieved in 89% of the patients. Based on these results, MIS surgery with partial pars resection is an attractive option in the treatment of FDH with low morbidity and short hospital stays. PMID:25882259

  14. Traumatismes Oculaires par Petards: Bilan sur Trois Annees

    PubMed Central

    Zouaoui-Kesraoui, N.; Derdour, A.

    2009-01-01

    Summary Les accidents dus aux pétards sont des accidents graves. Leur recrudescence ces dernières années en Algérie, essentiellement durant les fêtes du Mawlid Ennabaoui (fête de la naissance du prophète), mérite à notre sens d'entreprendre des bilans exhaustifs dont celui-ci dans le but d'une sensibilisation de toutes les compétences concernées. Nous avons réuni sur trois années consécutives (2002, 2003, 2004) 60 dossiers de malades ayant subi des accidents oculaires par pétards. Nos patients sont répartis en 42 consultations pour blessures légères et 18 hospitalisations pour blessures graves. Parmi ces derniers, neuf ont présenté des complications et séquelles graves (cinq cas de cécité par atrophie du globe oculaire, trois cas de cécité cornéenne et un cas de cécité par trou maculaire). Dans tous ces cas l'incapacité permanente partielle est au minimum de 30%. Au vu de ces données nous proposons des mesures d'éducation sanitaire et une sensibilisation du grand public aux traumatismes oculaires, par le biais de mé dias appropriés: radio, télévision, affiches. PMID:21991157

  15. The Pars Interarticularis Stress Reaction, Spondylolysis, and Spondylolisthesis Progression

    PubMed Central

    Motley, Gina; Nyland, John; Jacobs, Jake; Caborn, David N. M.

    1998-01-01

    Objective: To review the classification, etiology, clinical and radiologic evaluation, and management of the pars interarticularis stress reaction, spondylolysis, and spondylolisthesis progression. Data Sources: Grateful Med was searched from 1980 to 1998 using the terms “spondylolysis,” “spondylolisthesis,” “female athlete” “spondylogenic,” and “pars interarticularis.” Data Synthesis: The progression from pars interarticularis stress reaction through spondylolysis to spondylolisthesis is common in adolescent athletes, and, because of hormonal influences and cheerleading and gymnastic maneuvers, females are particularly at risk. Proper diagnosis and management include a thorough evaluation, radiographs (possibly with technetium bone scan or single-photon emission computed tomography), activity modification, dietary counseling, a therapeutic exercise program focusing on proper trunk and hip muscle strength and extensibility balances, and education regarding proper back postures, positioning, lifting mechanics, and jump landings. Conclusions/Recommendations: The athletic trainer plays an integral part in managing this injury progression, particularly with identifying at-risk individuals and intervening appropriately. ImagesFigure 4. PMID:16558534

  16. ParB Partition Proteins: Complex Formation and Spreading at Bacterial and Plasmid Centromeres

    PubMed Central

    Funnell, Barbara E.

    2016-01-01

    In bacteria, active partition systems contribute to the faithful segregation of both chromosomes and low-copy-number plasmids. Each system depends on a site-specific DNA binding protein to recognize and assemble a partition complex at a centromere-like site, commonly called parS. Many plasmid, and all chromosomal centromere-binding proteins are dimeric helix-turn-helix DNA binding proteins, which are commonly named ParB. Although the overall sequence conservation among ParBs is not high, the proteins share similar domain and functional organization, and they assemble into similar higher-order complexes. In vivo, ParBs “spread,” that is, DNA binding extends away from the parS site into the surrounding non-specific DNA, a feature that reflects higher-order complex assembly. ParBs bridge and pair DNA at parS and non-specific DNA sites. ParB dimers interact with each other via flexible conformations of an N-terminal region. This review will focus on the properties of the HTH centromere-binding protein, in light of recent experimental evidence and models that are adding to our understanding of how these proteins assemble into large and dynamic partition complexes at and around their specific DNA sites. PMID:27622187

  17. Dynamic Filament Formation by a Divergent Bacterial Actin-Like ParM Protein

    PubMed Central

    Brzoska, Anthony J.; Jensen, Slade O.; Barton, Deborah A.; Davies, Danielle S.; Overall, Robyn L.; Skurray, Ronald A.; Firth, Neville

    2016-01-01

    Actin-like proteins (Alps) are a diverse family of proteins whose genes are abundant in the chromosomes and mobile genetic elements of many bacteria. The low-copy-number staphylococcal multiresistance plasmid pSK41 encodes ParM, an Alp involved in efficient plasmid partitioning. pSK41 ParM has previously been shown to form filaments in vitro that are structurally dissimilar to those formed by other bacterial Alps. The mechanistic implications of these differences are not known. In order to gain insights into the properties and behavior of the pSK41 ParM Alp in vivo, we reconstituted the parMRC system in the ectopic rod-shaped host, E. coli, which is larger and more genetically amenable than the native host, Staphylococcus aureus. Fluorescence microscopy showed a functional fusion protein, ParM-YFP, formed straight filaments in vivo when expressed in isolation. Strikingly, however, in the presence of ParR and parC, ParM-YFP adopted a dramatically different structure, instead forming axial curved filaments. Time-lapse imaging and selective photobleaching experiments revealed that, in the presence of all components of the parMRC system, ParM-YFP filaments were dynamic in nature. Finally, molecular dissection of the parMRC operon revealed that all components of the system are essential for the generation of dynamic filaments. PMID:27310470

  18. ParB Partition Proteins: Complex Formation and Spreading at Bacterial and Plasmid Centromeres.

    PubMed

    Funnell, Barbara E

    2016-01-01

    In bacteria, active partition systems contribute to the faithful segregation of both chromosomes and low-copy-number plasmids. Each system depends on a site-specific DNA binding protein to recognize and assemble a partition complex at a centromere-like site, commonly called parS. Many plasmid, and all chromosomal centromere-binding proteins are dimeric helix-turn-helix DNA binding proteins, which are commonly named ParB. Although the overall sequence conservation among ParBs is not high, the proteins share similar domain and functional organization, and they assemble into similar higher-order complexes. In vivo, ParBs "spread," that is, DNA binding extends away from the parS site into the surrounding non-specific DNA, a feature that reflects higher-order complex assembly. ParBs bridge and pair DNA at parS and non-specific DNA sites. ParB dimers interact with each other via flexible conformations of an N-terminal region. This review will focus on the properties of the HTH centromere-binding protein, in light of recent experimental evidence and models that are adding to our understanding of how these proteins assemble into large and dynamic partition complexes at and around their specific DNA sites. PMID:27622187

  19. Structure of the ParM filament at 8.5 Å resolution

    PubMed Central

    Gayathri, Pananghat; Fujii, Takashi; Namba, Keiichi; Löwe, Jan

    2013-01-01

    The actin-like protein ParM forms the cytomotive filament of the ParMRC system, a type II plasmid segregation system encoded by Escherichia coli R1 plasmid. We report an 8.5 Å resolution reconstruction of the ParM filament, obtained using cryo-electron microscopy. Fitting of the 3D density reconstruction with monomeric crystal structures of ParM provides insights into dynamic instability of ParM filaments. The structural analysis suggests that a ParM conformation, corresponding to a metastable state, is held within the filament by intrafilament contacts. This filament conformation of ParM can be attained only from the ATP-bound state, and induces a change in conformation of the bound nucleotide. The structural analysis also provides a rationale for the observed stimulation of hydrolysis upon polymerisation into the filament. PMID:23462100

  20. ParA resolvase catalyzes site-specific excision of DNA from the Arabidopsis genome.

    PubMed

    Thomson, James G; Yau, Yuan-Yeu; Blanvillain, Robert; Nunes, Wylla M; Chiniquy, Dawn; Thilmony, Roger; Ow, David W

    2009-04-01

    The small serine resolvase ParA from bacterial plasmids RK2 and RP4 catalyzes the recombination of two identical 133 bp recombination sites known as MRS. Previously, we reported that ParA is active in the fission yeast Schizosaccharomyces pombe. In this work, the parA recombinase gene was placed under the control of the Arabidopsis OXS3 promoter and introduced into Arabidopsis lines harboring a chromosomally integrated MRS-flanked target. The ParA recombinase excised the MRS-flanked DNA and the excision event was detected in subsequent generations in the absence of ParA, indicating germinal transmission of the excision event. The precise site-specific deletion by the ParA recombination system in planta demonstrates that the ParA recombinase can be used to remove transgenic DNA, such as selectable markers or other introduced transgenes that are no longer desired in the final product. PMID:18704739

  1. Is PAR a Good Investment? Understanding the Costs and Benefits of Teacher Peer Assistance and Review Programs

    ERIC Educational Resources Information Center

    Papay, John P.; Johnson, Susan Moore

    2012-01-01

    Peer Assistance and Review (PAR) is a local labor-management initiative designed to improve teacher quality. In PAR, expert "consulting teachers" mentor, support, and evaluate novice and underperforming veteran teachers. Evaluations under PAR can lead to dismissals. The authors examine the costs and benefits of PAR, both financial and…

  2. Par3 regulates invasion of pancreatic cancer cells via interaction with Tiam1.

    PubMed

    Guo, Xingjun; Wang, Min; Zhao, Yan; Wang, Xin; Shen, Ming; Zhu, Feng; Shi, Chengjian; Xu, Meng; Li, Xu; Peng, Feng; Zhang, Hang; Feng, Yechen; Xie, Yu; Xu, Xiaodong; Jia, Wei; He, Ruizhi; Jiang, Jianxin; Hu, Jun; Tian, Rui; Qin, Renyi

    2016-08-01

    The conserved polarity complex, which comprises partitioning-defective proteins Par3, Par6, and the atypical protein kinase C, affects various cell-polarization events, including assembly of tight junctions. Control of tight junction assembly is closely related to invasion and migration potential. However, as the importance of conserved polarity complexes in regulating pancreatic cancer invasion and metastasis is unclear, we investigated their role and mechanism in pancreatic cancers. We first detect that the key protein of the conserved polarity complex finds that only Par3 is down-regulated in pancreatic cancer tissues while Par6 and aPKC show no difference. What is more, Par3 tissues level was significantly and positively associated with patient overall survival. Knocking-down Par3 promotes pancreatic cancer cells invasion and migration. And Par3 requires interaction with Tiam1 to affect tight junction assembly, and then affect invasion and migration of pancreatic cancer cells. Then, we find that tight junction marker protein ZO-1 and claudin-1 are down-regulated in pancreatic cancer tissues. And the relationship of the expression of Par3 and ZO-1 in pancreatic cancer tissue is linear correlation. We establish liver metastasis model of human pancreatic cancer cells in Balb/c nude mice and find that knocking down Par3 promotes invasion and metastasis and disturbs tight junction assembly in vivo. Taken together, these results suggest that the Par3 regulates invasion and metastasis in pancreatic cancers by controlling tight junction assembly. PMID:26084985

  3. An ELISA method detecting the active form of suPAR.

    PubMed

    Zhou, Xiaolei; Xu, Mingming; Huang, Hailong; Mazar, Andrew; Iqbal, Zafar; Yuan, Cai; Huang, Mingdong

    2016-11-01

    Urokinase plasminogen activator receptor (uPAR) exists in a number of formats in human plasma, including soluble uPAR (suPAR) and uPAR fragments. We developed an ELISA method to detect specifically the active form suPAR, which binds to its natural ligand uPA. The intra CV and inter CV of this ELISA assay is 8.5% and 9.6% respectively, and the assay can recover 99.74% of added recombinant suPAR from 10% plasma. This assay is quite sensitive, capable of detecting down to 15pg/ml of suPAR, and can measure suPAR concentrations in the range of 0.031-8ng/ml with high linear relationship. Plasma samples from pregnant women were also measured for the active form of suPAR with this assay, giving an averaged level of 1.39ng/ml, slightly higher than the level of pooled plasma from healthy donors (0.96ng/ml). This study demonstrates the feasibility to measure the active form of suPAR, which will likely have value in clinical applications. PMID:27591605

  4. PAR1 is selectively over expressed in high grade breast cancer patients: a cohort study

    PubMed Central

    Hernández, Norma A; Correa, Elma; Avila, Esther P; Vela, Teresa A; Pérez, Víctor M

    2009-01-01

    Background The protease-activated receptor (PAR1) expression is correlated with the degree of invasiveness in cell lines. Nevertheless it has never been directed involved in breast cancer patients progression. The aim of this study was to determine whether PAR1 expression could be used as predictor of metastases and mortality. Methods In a cohort of patients with infiltrating ductal carcinoma studied longitudinally since 1996 and until 2007, PAR1 over-expression was assessed by immunoblotting, immunohistochemistry, and flow citometry. Chi-square and log rank tests were used to determine whether there was a statistical association between PAR1 overexpression and metastases, mortality, and survival. Multivariate analysis was performed including HER1, stage, ER and nodes status to evaluate PAR1 as an independent prognostic factor. Results Follow up was 95 months (range: 2–130 months). We assayed PAR1 in a cohort of patients composed of 136 patients; we found PAR1 expression assayed by immunoblotting was selectively associated with high grade patients (50 cases of the study cohort; P = 0.001). Twenty-nine of 50 (58%) patients overexpressed PAR1, and 23 of these (46%) developed metastases. HER1, stage, ER and PAR1 overexpression were robustly correlated (Cox regression, P = 0.002, P = 0.024 and P = 0.002 respectively). Twenty-one of the 50 patients (42%) expressed both receptors (PAR1 and HER1 P = 0.0004). We also found a statistically significant correlation between PAR1 overexpression and increased mortality (P = 0.0001) and development of metastases (P = 0.0009). Conclusion Our data suggest PAR1 overexpression may be involved in the development of metastases in breast cancer patient and is associated with undifferentiated cellular progression of the tumor. Further studies are needed to understand PAR1 mechanism of action and in a near future assay its potential use as risk factor for metastasis development in high grade breast cancer patients. PMID:19538737

  5. Emerging Roles of PAR-1 and PAFR in Melanoma Metastasis

    PubMed Central

    Melnikova, Vladislava O.; Villares, Gabriel J.

    2008-01-01

    Melanoma growth, angiogenesis and metastatic progression are strongly promoted by the inflammatory tumor microenvironment due to high levels of cytokine and chemokine secretion by the recruited inflammatory and stromal cells. In addition, platelets and molecular components of procoagulant pathways have been recently emerging as critical players of tumor growth and metastasis. In particular, thrombin, through the activity of its receptor protease-activated receptor-1 (PAR-1), regulates tumor cell adhesion to platelets and endothelial cells, stimulates tumor angiogenesis, and promotes tumor growth and metastasis. Notably, in many tumor types including melanoma, PAR-1 expression directly correlates with their metastatic phenotype and is directly responsible for the expression of interleukin-8, matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor, platelet-derived growth factor, and integrins. Another proinflammatory receptor–ligand pair, platelet-activating factor (PAF) and its receptor (PAFR), have been shown to act as important modulators of tumor cell adhesion to endothelial cells, angiogenesis, tumor growth and metastasis. PAF is a bioactive lipid produced by a variety of cells from membrane glycerophospholipids in the same reaction that releases arachidonic acid, and can be secreted by platelets, inflammatory cells, keratinocytes and endothelial cells. We have demonstrated that in metastatic melanoma cells, PAF stimulates the phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB) and activating transcription factor 1 (ATF-1), which results in overexpression of MMP-2 and membrane type 1-MMP (membrane type 1-MMP). Since only metastatic melanoma cells overexpress CREB/ATF-1, we propose that metastatic melanoma cells are better equipped than their non-metastatic counterparts to respond to PAF within the tumor microenvironment. The evidence supporting the hypothesis that the two G-protein coupled receptors, PAR-1

  6. Emerging roles of PAR-1 and PAFR in melanoma metastasis.

    PubMed

    Melnikova, Vladislava O; Villares, Gabriel J; Bar-Eli, Menashe

    2008-12-01

    Melanoma growth, angiogenesis and metastatic progression are strongly promoted by the inflammatory tumor microenvironment due to high levels of cytokine and chemokine secretion by the recruited inflammatory and stromal cells. In addition, platelets and molecular components of procoagulant pathways have been recently emerging as critical players of tumor growth and metastasis. In particular, thrombin, through the activity of its receptor protease-activated receptor-1 (PAR-1), regulates tumor cell adhesion to platelets and endothelial cells, stimulates tumor angiogenesis, and promotes tumor growth and metastasis. Notably, in many tumor types including melanoma, PAR-1 expression directly correlates with their metastatic phenotype and is directly responsible for the expression of interleukin-8, matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor, platelet-derived growth factor, and integrins. Another proinflammatory receptor-ligand pair, platelet-activating factor (PAF) and its receptor (PAFR), have been shown to act as important modulators of tumor cell adhesion to endothelial cells, angiogenesis, tumor growth and metastasis. PAF is a bioactive lipid produced by a variety of cells from membrane glycerophospholipids in the same reaction that releases arachidonic acid, and can be secreted by platelets, inflammatory cells, keratinocytes and endothelial cells. We have demonstrated that in metastatic melanoma cells, PAF stimulates the phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB) and activating transcription factor 1 (ATF-1), which results in overexpression of MMP-2 and membrane type 1-MMP (membrane type 1-MMP). Since only metastatic melanoma cells overexpress CREB/ATF-1, we propose that metastatic melanoma cells are better equipped than their non-metastatic counterparts to respond to PAF within the tumor microenvironment. The evidence supporting the hypothesis that the two G-protein coupled receptors, PAR-1

  7. A systematic computation scheme of PAR-WIG cruising performance

    NASA Astrophysics Data System (ADS)

    Ando, Shigenori

    1993-08-01

    A systematic computation scheme is presented for PAR-WIG cruising performance, on a FORTRAN program. It is suitable for implementation on PCs. Effects of many parameters on the transportation efficiency are explored. Two concepts are presented in three views and artist impressions. One is a smallest single-crewman vehicle for experiment, sports, or pleasure. The other is a large vehicle for civil transportation. Both have twin hulls, which are quite suitable for installing a 'SMALL-TAIL-WIG' or 'WIG-let' to establish longitudinal attitude stability.

  8. BOREAS TE-12 Incoming PAR Through the Forest Canopy Data

    NASA Technical Reports Server (NTRS)

    Hall, Forrest G. (Editor); Papagno, Andrea (Editor); Walter-Shea, Elizabeth A.; Mesarch, Mark A.

    2000-01-01

    The Boreal Ecosystem-Atmospheric Study (BOREAS) TE-12 (Terrestrial Ecology) team collected photosynthetically active radiation (PAR) data sets in support of its efforts to characterize and interpret information on shoot geometry, leaf optical properties, leaf water potential, and leaf gas exchange. The data were collected at the Southern Study Area-Old Black Spruce (SSA-OBS) site from 04-Jul-1996 to 25-Jul-1996. The data are stored in tabular ASCII files. The data files are available on a CD-ROM (see document number 20010000884), or from the Oak Ridge National Laboratory (ORNL) Distributed Active Archive Center (DAAC).

  9. Estimating Photosynthetically Available Radiation (PAR) at the Earth's surface from satellite observations

    NASA Technical Reports Server (NTRS)

    Frouin, Robert

    1993-01-01

    Current satellite algorithms to estimate photosynthetically available radiation (PAR) at the earth' s surface are reviewed. PAR is deduced either from an insolation estimate or obtained directly from top-of-atmosphere solar radiances. The characteristics of both approaches are contrasted and typical results are presented. The inaccuracies reported, about 10 percent and 6 percent on daily and monthly time scales, respectively, are useful to model oceanic and terrestrial primary productivity. At those time scales variability due to clouds in the ratio of PAR and insolation is reduced, making it possible to deduce PAR directly from insolation climatologies (satellite or other) that are currently available or being produced. Improvements, however, are needed in conditions of broken cloudiness and over ice/snow. If not addressed properly, calibration/validation issues may prevent quantitative use of the PAR estimates in studies of climatic change. The prospects are good for an accurate, long-term climatology of PAR over the globe.

  10. Fluoroquinolone Resistance Mutations in the parC, parE, and gyrA Genes of Clinical Isolates of Viridans Group Streptococci

    PubMed Central

    González, Irene; Georgiou, Marios; Alcaide, Fernando; Balas, Delia; Liñares, Josefina; de la Campa, Adela G.

    1998-01-01

    The nucleotide sequences of the quinolone resistance-determining regions (QRDRs) of the parC and gyrA genes from seven ciprofloxacin-resistant (Cpr) isolates of viridans group streptococci (two high-level Cpr Streptococcus oralis and five low-level Cpr Streptococcus mitis isolates) were determined and compared with those obtained from susceptible isolates. The nucleotide sequences of the QRDRs of the parE and gyrB genes from the five low-level Cpr S. mitis isolates and from the NCTC 12261 type strain were also analyzed. Four of these low-level Cpr isolates had changes affecting the subunits of DNA topoisomerase IV: three in Ser-79 (to Phe or Ile) of ParC and one in ParE at a position not previously described to be involved in quinolone resistance (Pro-424). One isolate did not show any mutation. The two high-level Cpr S. oralis isolates showed mutations affecting equivalent residue positions of ParC and GyrA, namely, Ser-79 to Phe and Ser-81 to Phe or Tyr, respectively. The parC mutations were able to transform Streptococcus pneumoniae to ciprofloxacin resistance, while the gyrA mutations transformed S. pneumoniae only when mutations in parC were present. These results suggest that DNA topoisomerase IV is a primary target of ciprofloxacin in viridans group streptococci, DNA gyrase being a secondary target. PMID:9797205

  11. PAR2-dependent activation of GSK3β regulates the survival of colon stem/progenitor cells.

    PubMed

    Nasri, Imen; Bonnet, Delphine; Zwarycz, Bailey; d'Aldebert, Emilie; Khou, Sokchea; Mezghani-Jarraya, Raoudha; Quaranta, Muriel; Rolland, Corinne; Bonnart, Chrystelle; Mas, Emmanuel; Ferrand, Audrey; Cenac, Nicolas; Magness, Scott; Van Landeghem, Laurianne; Vergnolle, Nathalie; Racaud-Sultan, Claire

    2016-08-01

    Protease-activated receptors PAR1 and PAR2 play an important role in the control of epithelial cell proliferation and migration. However, the survival of normal and tumor intestinal stem/progenitor cells promoted by proinflammatory mediators may be critical in oncogenesis. The glycogen synthase kinase-3β (GSK3β) pathway is overactivated in colon cancer cells and promotes their survival and drug resistance. We thus aimed to determine PAR1 and PAR2 effects on normal and tumor intestinal stem/progenitor cells and whether they involved GSK3β. First, PAR1 and PAR2 were identified in colon stem/progenitor cells by immunofluorescence. In three-dimensional cultures of murine crypt units or single tumor Caco-2 cells, PAR2 activation decreased numbers and size of normal or cancerous spheroids, and PAR2-deficient spheroids showed increased proliferation, indicating that PAR2 represses proliferation. PAR2-stimulated normal cells were more resistant to stress (serum starvation or spheroid passaging), suggesting prosurvival effects of PAR2 Accordingly, active caspase-3 was strongly increased in PAR2-deficient normal spheroids. PAR2 but not PAR1 triggered GSK3β activation through serine-9 dephosphorylation in normal and tumor cells. The PAR2-triggered GSK3β activation implicates an arrestin/PP2A/GSK3β complex that is dependent on the Rho kinase activity. Loss of PAR2 was associated with high levels of GSK3β nonactive form, strengthening the role of PAR2 in GSK3β activation. GSK3 pharmacological inhibition impaired the survival of PAR2-stimulated spheroids and serum-starved cells. Altogether our data identify PAR2/GSK3β as a novel pathway that plays a critical role in the regulation of stem/progenitor cell survival and proliferation in normal colon crypts and colon cancer. PMID:27313176

  12. Brulure par Foudre. A Propos d’une Observation

    PubMed Central

    Mradmi, W.; Fassi-Fihri, J.; Mehaji, G.; Ezzoubi, M.; Diouri, M.; Bahechar, N.; Boukind, E.H.

    2005-01-01

    Summary Aussi loin que l’on remonte dans la littérature, on retrouve des récits relatant des accidents consécutifs à la fulguration chez l’homme. La foudre était alors associée à la colère des dieux ou à la notion de châtiment. La fulguration correspond à un transfert d’énergie entre un cumulonimbus de charge négative et un objet de charge positive se trouvant au niveau du sol. Les lésions déterminées sont à la fois thermiques et électrothermiques. Bien que l’arrêt cardiorespiratoire soit une cause bien documentée de décès, la plupart des cas rapportés dans la littérature décrivent un éventail très disparate des séquelles qui surviennent suite à cet accident. Les Auteurs rapportent le cas d’un patient atteint par la foudre en insistant particulièrement sur les complications neurologiques qui sont survenues en cours d’évolution. Se basant sur cette observation et sur une revue de la littérature, les Auteurs soulignent que le pronostic des patients atteints par la foudre est plus favorable que généralement rapporté. PMID:21990993

  13. The polarity protein Par3 regulates APP trafficking and processing through the endocytic adaptor protein Numb.

    PubMed

    Sun, Miao; Asghar, Suwaiba Z; Zhang, Huaye

    2016-09-01

    The processing of amyloid precursor protein (APP) into β-amyloid peptide (Aβ) is a key step in the pathogenesis of Alzheimer's disease (AD), and trafficking dysregulations of APP and its secretases contribute significantly to altered APP processing. Here we show that the cell polarity protein Par3 plays an important role in APP processing and trafficking. We found that the expression of full length Par3 is significantly decreased in AD patients. Overexpression of Par3 promotes non-amyloidogenic APP processing, while depletion of Par3 induces intracellular accumulation of Aβ. We further show that Par3 functions by regulating APP trafficking. Loss of Par3 decreases surface expression of APP by targeting APP to the late endosome/lysosome pathway. Finally, we show that the effects of Par3 are mediated through the endocytic adaptor protein Numb, and Par3 functions by interfering with the interaction between Numb and APP. Together, our studies show a novel role for Par3 in regulating APP processing and trafficking. PMID:27072891

  14. Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race

    PubMed Central

    Edelstein, Leonard C.; Simon, Lukas M.; Lindsay, Cory R.; Kong, Xianguo; Teruel-Montoya, Raúl; Tourdot, Benjamin E.; Chen, Edward S.; Ma, Lin; Coughlin, Shaun; Nieman, Marvin; Holinstat, Michael; Shaw, Chad A.

    2014-01-01

    Human platelets express 2 thrombin receptors: protease-activated receptor (PAR)-1 and PAR4. Recently, we reported 3.7-fold increased PAR4-mediated aggregation kinetics in platelets from black subjects compared with white subjects. We now show that platelets from blacks (n = 70) express 14% more PAR4 protein than those from whites (n = 84), but this difference is not associated with platelet PAR4 function. Quantitative trait locus analysis identified 3 common single nucleotide polymorphisms in the PAR4 gene (F2RL3) associated with PAR4-induced platelet aggregation. Among these single nucleotide polymorphisms, rs773902 determines whether residue 120 in transmembrane domain 2 is an alanine (Ala) or threonine (Thr). Compared with the Ala120 variant, Thr120 was more common in black subjects than in white subjects (63% vs 19%), was associated with higher PAR4-induced human platelet aggregation and Ca2+ flux, and generated greater inositol 1,4,5-triphosphate in transfected cells. A second, less frequent F2RL3 variant, Phe296Val, was only observed in blacks and abolished the enhanced PAR4-induced platelet aggregation and 1,4,5-triphosphate generation associated with PAR4-Thr120. PAR4 genotype did not affect vorapaxar inhibition of platelet PAR1 function, but a strong pharmacogenetic effect was observed with the PAR4-specific antagonist YD-3 [1-benzyl-3(ethoxycarbonylphenyl)-indazole]. These findings may have an important pharmacogenetic effect on the development of new PAR antagonists. PMID:25293779

  15. Activation of protease-activated receptors (PARs)-1 and -2 promotes alpha-smooth muscle actin expression and release of cytokines from human lung fibroblasts

    PubMed Central

    Asokananthan, Nithiananthan; Lan, Rommel S; Graham, Peter T; Bakker, Anthony J; Tokanović, Ana; Stewart, Geoffrey A

    2015-01-01

    Previous studies have shown that protease-activated receptors (PARs) play an important role in various physiological processes. In the present investigation, we determined the expression of PARs on human lung fibroblasts (HLF-1) and whether they were involved in cellular differentiation and pro-inflammatory cytokine and prostaglandin (PGE2) secretion. PAR-1, PAR-2, PAR-3, and PAR-4 were detected in fibroblasts using RT-PCR, immunocytochemistry, and flow cytometry. Increased expression of PAR-4, but not other PARs, was observed in fibroblasts stimulated with phorbol myristate acetate. The archetypical activators of PARs, namely, thrombin and trypsin, as well as PAR-1 and PAR-2 agonist peptides, stimulated transient increases in intracellular Ca2+, and promoted increased α-smooth muscle actin expression. The proteolytic and peptidic PAR activators also stimulated the release of IL-6 and IL-8, as well as PGE2, with a rank order of potency of PAR-1 > PAR-2. The combined stimulation of PAR-1 and PAR-2 resulted in an additive release of both IL-6 and IL-8. In contrast, PAR-3 and PAR-4 agonist peptides, as well as all the PAR control peptides examined, were inactive. These results suggest an important role for PARs associated with fibroblasts in the modulation of inflammation and remodeling in the airway. PMID:25663523

  16. Secreted uPAR isoform 2 (uPAR7b) is a novel direct target of miR-221.

    PubMed

    Falkenberg, Natalie; Anastasov, Nataša; Schaub, Annalisa; Radulovic, Vanja; Schmitt, Manfred; Magdolen, Viktor; Aubele, Michaela

    2015-04-10

    miR-221/-222 and components of the urokinase-type plasminogen activator system (uPAS) are associated with metastasis and poor prognosis in breast cancer, including the triple-negative subtype (TNBC). Modification of components of uPAS and involved miRNAs may contribute to targeted therapy for breast cancer patients. miR-221-/-222-overexpressing or miR-221-depleted cells were employed for qRT-PCR and Western blots to show associations of uPAR with miR-221/-222. To substantiate direct targeting of miR-221/-222 within 3' UTR of the uPAR isoform 2, in silico analysesand in vitro assays were conducted. Significant associations between miR-221 and uPAR isoform 2 expressions were observed at the mRNA and protein levels in breast cancer cells representing TNBC. For the first time, the uPAR isoform 2 was demonstrated as direct target for miR-221/-222. Inhibition of miR-221 reduced uPAR protein expression and expression of the tumor cell invasion markers vimentin and RHOC. These results demonstrate a direct and positive regulation of the secreted uPAR isoform 2 by miR-221, increasing its protein expression, a prerequisite for malignancy, while the other uPAR isoforms (1, 3 and 4) are indirectly regulated through miR-10b and miR-221/-222. By targeting uPAR isoforms and/or miRNA-221/-222, the diagnosis and therapy of breast cancer, in particular in TNBC, could be significantly improved. PMID:25797271

  17. Poly (ADP-ribose) (PAR) Binding to Apoptosis-Inducing Factor Is Critical For PAR Polymerase-1-Dependent Cell Death (Parthanatos)

    PubMed Central

    Wang, Yingfei; Kim, No Soo; Haince, Jean-Francois; Kang, HoChul; David, Karen K.; Andrabi, Shaida A.; Poirier, Guy G.; Dawson, Valina L.; Dawson, Ted M.

    2011-01-01

    The mitochondrial protein apoptosis-inducing factor (AIF) plays a pivotal role in poly(ADP-ribose) polymerase-1 (PARP-1)-mediated cell death (parthanatos), during which it is released from the mitochondria and translocates to the nucleus. Here, we show that AIF is a high affinity poly(ADP-ribose) (PAR)–binding protein and that PAR binding to AIF is required for parthanatos both in vitro and in vivo. AIF bound PAR at a site distinct from AIF’s DNA binding site and this interaction triggered AIF release from the cytosolic side of the mitochondrial outer membrane. Mutation of the PAR binding site in AIF did not affect its NADH oxidase activity, its ability to bind FAD or DNA, or its ability to induce nuclear condensation. However, this AIF mutant was not released from mitochondria and did not translocate to the nucleus or mediate cell death following PARP-1 activation. These results suggest a mechanism for PARP-1 to initiate AIF-mediated cell death and indicate that AIF’s bioenergetic cell survival-promoting functions are separate from its effects as a mitochondrially-derived death effector. Interference with the PAR-AIF interaction or PAR signaling may provide unique opportunities for preventing cell death following activation of PARP-1. PMID:21467298

  18. Clinical outcomes of pars plicata anterior vitrectomy: 2-year results

    PubMed Central

    Narang, Priya; Agarwal, Amar

    2015-01-01

    Purpose: To demonstrate the safety and outcome of a surgical approach that uses pars plicata site for anterior vitrectomy during phacoemulsification procedure complicated by posterior capsule rupture and residual cortical matter. Design: Single center, retrospective, interventional, noncomparative study. Materials and Methods: Medical records of a consecutive series of 35 eyes of 35 patients who underwent pars plicata anterior vitrectomy (PPAV) were reviewed. The main outcome measures were corrected and uncorrected distance visual acuity (CDVA, UDVA), early and late postoperative complications and intraocular pressure (IOP). Ultrasound biomicroscopic (UBM) evaluation of sclerotomy site and spectral domain optical coherence tomography analysis for central macular thickness (CMT) was performed. The final visual outcome at 2 years was evaluated. Results: At 2 years follow-up, the mean postoperative UDVA (logarithm of the minimum angle of resolution [logMAR]) and CDVA (logMAR) was 0.49 ± 0.26 and 0.19 ± 0.14, respectively. There was no significant change in the IOP (P = 0.061) and the mean CMT at 2 years was 192.5 ± 5.54 μm. The postoperative UBM image of the sclerotomy site at 8 weeks demonstrated a clear wound without any vitreous adhesion or incarceration. Intraoperative hyphema was seen in 1 (2.8%) case and postoperative uveitis was seen in 2 (5.7%) cases, which resolved with medications. No case of an iatrogenic retinal break or retinal detachment was reported. Conclusions: PPAV enables a closed chamber approach, allows thorough cleanup of vitreous in the pupillary plane and anterior chamber and affords better access to the subincisional and retropupillary cortical remnant with a significant visual outcome and an acceptable complication rate. PMID:26632124

  19. Targeting Melanoma Growth and Metastasis with Systemic Delivery of Liposomal Incorporated PAR-1 siRNA

    PubMed Central

    Villares, Gabriel J.; Zigler, Maya; Wang, Hua; Melnikova, Vladislava O.; Wu, Hong; Friedman, Ran; Leslie, Michael C.; Vivas-Mejia, Pablo E.; Lopez-Berestein, Gabriel; Sood, Anil K.; Bar-Eli, Menashe

    2008-01-01

    The thrombin receptor (PAR-1, Protease-Activated-Receptor-1) is over-expressed in highly metastatic melanoma cell lines and in patients with metastatic lesions. Activation of PAR-1 leads to cell signaling and upregulation of genes involved in adhesion, invasion and angiogenesis. Herein, we stably silence PAR-1 through the use of lentiviral shRNA and found significant decreases in both tumor growth (P<.01) and metastasis (P<.001) of highly metastatic melanoma cell lines in vivo. The use of viruses for therapy is not ideal as it can induce toxic immune responses and possible gene alterations following viral integration. Therefore, we also utilized systemic delivery of PAR-1 siRNA incorporated into neutral liposomes (DOPC) to decrease melanoma growth and metastasis in vivo. Significant decreases in tumor growth, weight and metastatic lung colonies (P<.001 for all) were found in mice treated with PAR-1-siRNA-DOPC. The in vivo effects of PAR-1 on invasion and angiogenesis were analyzed via immunohistochemistry. Concomitant decreases in VEGF, IL-8, and MMP-2 expression levels, as well as decreased blood-vessel density (CD31), were found in tumor samples from PAR-1 siRNA-treated mice, suggesting that PAR-1 is a regulator of melanoma cell growth and metastasis by affecting angiogenic and invasive factors. We propose that siRNA incorporated into DOPC nanoparticles could be delivered systemically and used as a new modality for melanoma treatment. PMID:18974154

  20. 12 CFR 925.19 - Par value and price of stock.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Par value and price of stock. 925.19 Section 925.19 Banks and Banking FEDERAL HOUSING FINANCE BOARD FEDERAL HOME LOAN BANK MEMBERS AND HOUSING ASSOCIATES MEMBERS OF THE BANKS Stock Requirements § 925.19 Par value and price of stock. The capital...

  1. Solar PAR and UVR modify the community composition and photosynthetic activity of sea ice algae.

    PubMed

    Enberg, Sara; Piiparinen, Jonna; Majaneva, Markus; Vähätalo, Anssi V; Autio, Riitta; Rintala, Janne-Markus

    2015-10-01

    The effects of increased photosynthetically active radiation (PAR) and ultraviolet radiation (UVR) on species diversity, biomass and photosynthetic activity were studied in fast ice algal communities. The experimental set-up consisted of nine 1.44 m(2) squares with three treatments: untreated with natural snow cover (UNT), snow-free (PAR + UVR) and snow-free ice covered with a UV screen (PAR). The total algal biomass, dominated by diatoms and dinoflagellates, increased in all treatments during the experiment. However, the smaller biomass growth in the top 10-cm layer of the PAR + UVR treatment compared with the PAR treatment indicated the negative effect of UVR. Scrippsiella complex (mainly Scrippsiella hangoei, Biecheleria baltica and Gymnodinium corollarium) showed UV sensitivity in the top 5-cm layer, whereas Heterocapsa arctica ssp. frigida and green algae showed sensitivity to both PAR and UVR. The photosynthetic activity was highest in the top 5-cm layer of the PAR treatment, where the biomass of the pennate diatom Nitzschia frigida increased, indicating the UV sensitivity of this species. This study shows that UVR is one of the controlling factors of algal communities in Baltic Sea ice, and that increased availability of PAR together with UVR exclusion can cause changes in algal biomass, photosynthetic activity and community composition. PMID:26310455

  2. The parA resolvase performs site-specific genomic excision in Arabidopsis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have designed a site-specific excision detection system in Arabidopsis to study the in planta activity of the small serine recombinase ParA. Using a transient expression assay as well as stable transgenic plant lines, we show that the ParA recombinase is catalytically active and capable of perfo...

  3. The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis.

    PubMed

    Burikhanov, Ravshan; Zhao, Yanming; Goswami, Anindya; Qiu, Shirley; Schwarze, Steven R; Rangnekar, Vivek M

    2009-07-23

    Prostate apoptosis response-4 (Par-4) is a proapoptotic protein with intracellular functions in the cytoplasm and nucleus. Unexpectedly, we noted Par-4 protein is spontaneously secreted by normal and cancer cells in culture, and by Par-4 transgenic mice that are resistant to spontaneous tumors. Short exposure to endoplasmic reticulum (ER) stress-inducing agents further increased cellular secretion of Par-4 by a brefeldin A-sensitive pathway. Secretion occurred independently of caspase activation and apoptosis. Interestingly, extracellular Par-4 induced apoptosis by binding to the stress response protein, glucose-regulated protein-78 (GRP78), expressed at the surface of cancer cells. The interaction of extracellular Par-4 and cell surface GRP78 led to apoptosis via ER stress and activation of the FADD/caspase-8/caspase-3 pathway. Moreover, apoptosis inducible by TRAIL, which also exerts cancer cell-specific effects, is dependent on extracellular Par-4 signaling via cell surface GRP78. Thus, Par-4 activates an extrinsic pathway involving cell surface GRP78 receptor for induction of apoptosis. PMID:19632185

  4. Questioning Our Questions: Assessing Question Asking Practices to Evaluate a yPAR Program

    ERIC Educational Resources Information Center

    Grace, Sarah; Langhout, Regina Day

    2014-01-01

    The purpose of this research was to examine question asking practices in a youth participatory action research (yPAR) after school program housed at an elementary school. The research question was: In which ways did the adult question asking practices in a yPAR setting challenge and/or reproduce conventional models of power in educational…

  5. Participatory Action Research (PAR) cum Action Research (AR) in Teacher Professional Development: A Literature Review

    ERIC Educational Resources Information Center

    Morales, Marie Paz E.

    2016-01-01

    This paper reviews Participatory Action Research as an approach to teacher professional development. It maps the origins of Participatory Action Research (PAR) and discusses the benefits and challenges that have been identified by other researchers in utilizing PAR approaches in conducting research. It draws ideas of combining the features of…

  6. Manual for the Use of the Pupil Activities Record--Revised (PAR-R).

    ERIC Educational Resources Information Center

    Ligon, Glynn; And Others

    A comprehensive guide for observers using the Pupil Activities Record--Revised (PAR-R), this manual covers procedures followed in systematic observation of a student's classroom activities for the period of one instructional day. The manual provides general information about the purpose and design of the PAR and explains the revisions, which were…

  7. Compression Myelopathy due to Proliferative Changes around C2 Pars Defects without Instability.

    PubMed

    Kimura, Tetsuya; Sakai, Toshinori; Tezuka, Fumitake; Abe, Mitsunobu; Yamashita, Kazuta; Takata, Yoichiro; Higashino, Kosaku; Sairyo, Koichi

    2016-06-01

    We report a case with compression myelopathy due to proliferative changes around the C2 pars defects without instability. A 69-year-old man presented with progressive clumsy hands and spastic gait. Plain radiographs showed bilateral spondylolysis (pars defects) at C2 and fusion between C2 and C3 spinous processes. Dynamic views revealed mobility through the pars defects, but there was no apparent instability. Computed tomography showed proliferative changes at the pars defects, which protruded into spinal canal. On magnetic resonance imaging, the spinal cord was compressed and intramedullary high signal change was found. A diagnosis of compression myelopathy due to proliferative changes around the C2 pars defects was made. We performed posterior decompression. Postoperatively, symptoms have been alleviated and images revealed sufficient decompression and no apparent instability. In patients with the cervical spondylolysis, myelopathy caused by instability or slippage have been periodically reported. The present case involving C2 spondylolysis is extremely rare. PMID:27340539

  8. Compression Myelopathy due to Proliferative Changes around C2 Pars Defects without Instability

    PubMed Central

    Kimura, Tetsuya; Tezuka, Fumitake; Abe, Mitsunobu; Yamashita, Kazuta; Takata, Yoichiro; Higashino, Kosaku; Sairyo, Koichi

    2016-01-01

    We report a case with compression myelopathy due to proliferative changes around the C2 pars defects without instability. A 69-year-old man presented with progressive clumsy hands and spastic gait. Plain radiographs showed bilateral spondylolysis (pars defects) at C2 and fusion between C2 and C3 spinous processes. Dynamic views revealed mobility through the pars defects, but there was no apparent instability. Computed tomography showed proliferative changes at the pars defects, which protruded into spinal canal. On magnetic resonance imaging, the spinal cord was compressed and intramedullary high signal change was found. A diagnosis of compression myelopathy due to proliferative changes around the C2 pars defects was made. We performed posterior decompression. Postoperatively, symptoms have been alleviated and images revealed sufficient decompression and no apparent instability. In patients with the cervical spondylolysis, myelopathy caused by instability or slippage have been periodically reported. The present case involving C2 spondylolysis is extremely rare. PMID:27340539

  9. Profiling Gene Expression Induced by Protease-Activated Receptor 2 (PAR2) Activation in Human Kidney Cells

    PubMed Central

    Suen, Jacky Y.; Gardiner, Brooke; Grimmond, Sean; Fairlie, David P.

    2010-01-01

    Protease-Activated Receptor-2 (PAR2) has been implicated through genetic knockout mice with cytokine regulation and arthritis development. Many studies have associated PAR2 with inflammatory conditions (arthritis, airways inflammation, IBD) and key events in tumor progression (angiogenesis, metastasis), but they have relied heavily on the use of single agonists to identify physiological roles for PAR2. However such probes are now known not to be highly selective for PAR2, and thus precisely what PAR2 does and what mechanisms of downstream regulation are truly affected remain obscure. Effects of PAR2 activation on gene expression in Human Embryonic Kidney cells (HEK293), a commonly studied cell line in PAR2 research, were investigated here by comparing 19,000 human genes for intersecting up- or down-regulation by both trypsin (an endogenous protease that activates PAR2) and a PAR2 activating hexapeptide (2f-LIGRLO-NH2). Among 2,500 human genes regulated similarly by both agonists, there were clear associations between PAR2 activation and cellular metabolism (1,000 genes), the cell cycle, the MAPK pathway, HDAC and sirtuin enzymes, inflammatory cytokines, and anti-complement function. PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. This is the first widespread profiling of specific activation of PAR2 and provides a valuable platform for better understanding key mechanistic roles of PAR2 in human physiology. Results clearly support the development of both antagonists and agonists of human PAR2 as potential disease modifying therapeutic agents. PMID:21072196

  10. Facteurs de risque de mortalité par tuberculose pulmonaire

    PubMed Central

    Janah, Hicham; Souhi, Hicham; Kouismi, Hatim; Mark, Karima; Zahraoui, Rachida; Benamor, Jouda; Soualhi, Mona; Bourkadi, Jamal Eddine

    2014-01-01

    La tuberculose est une maladie infectieuse transmissible provoquée par myco-bacterium tuberculosis (bacille de Koch ou BK). Elle représente, selon les estimations del'Organisation Mondiale de la Santé (OMS), l'une des pathologies infectieuses causant le plus de décès au niveau mondial avec plus de 1 million de décès par an. Pour déterminer les facteurs de risque de mortalité au cours de la tuberculose pulmonaire à microscopie positive nous avons mené une étude rétrospective portant sur tous les cas de tuberculose pulmonaire à microscopie positive et qui étaient décédés au cours de leur hospitalisation. Cette étude a colligé 1803 cas de tuberculose sur une période de 2 ans et demi dont 46 sont décédés. La prévalence de décès est de 2,55%. La population se répartit en 32 hommes et 14 femmes. L’âge moyen était de 53ans ± 17 ans. Le tabagisme était retrouvé chez la moitié des cas. Une comorbidité était retrouvée dans 43%, avec 17% de diabète. Le délai de diagnostic avait une médiane de 60 jours avec percentile (30j; 105j). La symptomatologie clinique était dominée par la toux, la dyspnée et les expectorations soit respectivement: 97,8%, 69,6% et 67,4% des cas. Sur le plan radiologique les lésions étaient diffuses et bilatérales dans 76,1% des cas. Tous les patients étaient mis sous SRHZ. 11% avaient présenté une toxicité aux antibacillaires (de type hépatiques dans 3 cas et neurologiques dans 2 cas). Le délai médian de décès était de 8,5 jours (5j; 17j). Les causes de décès retrouvées étaient: Une hépatite fulminante (3 cas), une décompensation acido-cétosique (3 cas), un SDRA (2 cas), des hémoptysies foudroyantes (2 cas), et respectivement un cas secondaire à une décompensation de BPCO, une décompensation cardiaque, une hypoglycémie et un tableau d'anasarque. Cette étude suggère que le terrain, le retard diagnostique et les effets secondaires du traitement sont les principaux facteurs de risque de

  11. The 14-3-3 protein PAR-5 regulates the asymmetric localization of the LET-99 spindle positioning protein.

    PubMed

    Wu, Jui-Ching; Espiritu, Eugenel B; Rose, Lesilee S

    2016-04-15

    PAR proteins play important roles in establishing cytoplasmic polarity as well as regulating spindle positioning during asymmetric division. However, the molecular mechanisms by which the PAR proteins generate asymmetry in different cell types are still being elucidated. Previous studies in Caenorhabditis elegans revealed that PAR-3 and PAR-1 regulate the asymmetric localization of LET-99, which in turn controls spindle positioning by affecting the distribution of the conserved force generating complex. In wild-type embryos, LET-99 is localized in a lateral cortical band pattern, via inhibition at the anterior by PAR-3 and at the posterior by PAR-1. In this report, we show that the 14-3-3 protein PAR-5 is also required for cortical LET-99 asymmetry. PAR-5 associated with LET-99 in pull-down assays, and two PAR-5 binding sites were identified in LET-99 using the yeast two-hybrid assay. Mutation of these sites abolished binding in yeast and altered LET-99 localization in vivo: LET-99 was present at the highest levels at the posterior pole of the embryo instead of a band in par-5 embryos. Together the results indicate that PAR-5 acts in a mechanism with PAR-1 to regulate LET-99 cortical localization. PMID:26921457

  12. Proteinase-activated receptors (PARs) – focus on receptor-receptor-interactions and their physiological and pathophysiological impact

    PubMed Central

    2013-01-01

    Proteinase-activated receptors (PARs) are a subfamily of G protein-coupled receptors (GPCRs) with four members, PAR1, PAR2, PAR3 and PAR4, playing critical functions in hemostasis, thrombosis, embryonic development, wound healing, inflammation and cancer progression. PARs are characterized by a unique activation mechanism involving receptor cleavage by different proteinases at specific sites within the extracellular amino-terminus and the exposure of amino-terminal “tethered ligand“ domains that bind to and activate the cleaved receptors. After activation, the PAR family members are able to stimulate complex intracellular signalling networks via classical G protein-mediated pathways and beta-arrestin signalling. In addition, different receptor crosstalk mechanisms critically contribute to a high diversity of PAR signal transduction and receptor-trafficking processes that result in multiple physiological effects. In this review, we summarize current information about PAR-initiated physical and functional receptor interactions and their physiological and pathological roles. We focus especially on PAR homo- and heterodimerization, transactivation of receptor tyrosine kinases (RTKs) and receptor serine/threonine kinases (RSTKs), communication with other GPCRs, toll-like receptors and NOD-like receptors, ion channel receptors, and on PAR association with cargo receptors. In addition, we discuss the suitability of these receptor interaction mechanisms as targets for modulating PAR signalling in disease. PMID:24215724

  13. CERCLA interim action at the Par Pond unit: A case study

    SciTech Connect

    Hickey, H.M.; Matthews, S.S.; Neal, L.W.; Weiss, W.R.

    1993-11-01

    The Par Pond unit designated under CERCLA consists of sediments within a Savannah River Site (SRS) cooling water reservoir. The sediments are contaminated with radionuclides and nonradioactive constituents from nuclear production reactor operations. The mercury in Par Pond is believed to have originated from the Savannah River. Because of Par Pond Dam safety Issues, the water level of the reservoir was drawn down, exposing more than 1300 acres of contaminated sediments and triggering the need for CERCLA interim remedial action. This paper presents the interim action approach taken with Par Pond as a case study. The approach considered the complexity of the Par Pond ecosystem, the large size of Par Pond, the volume of contaminated sediments, and the institutional controls existing at SRS. The Environmental Protection Agency (EPA) considers units with large volumes of low-concentration wastes, as is the case with Par Pond, to be {open_quotes}special sites.{close_quotes} Accordingly, EPA guidance establishes that the range of alternatives developed focus primarily on containment options and other remedial approaches that mitigate potential risks associated with the {open_quotes}special site.{close_quotes} The remedial alternatives, according to EPA, are not to be prohibitively expensive or difficult to implement. This case study also is representative of the types of issues that will need to be addressed within the Department of Energy (DOE) complex as nuclear facilities are transitioned to inactive status and corrective/remedial actions are warranted.

  14. Improved Satellite-based Photosysnthetically Active Radiation (PAR) for Air Quality Studies

    NASA Astrophysics Data System (ADS)

    Pour Biazar, A.; McNider, R. T.; Cohan, D. S.; White, A.; Zhang, R.; Dornblaser, B.; Doty, K.; Wu, Y.; Estes, M. J.

    2015-12-01

    One of the challenges in understanding the air quality over forested regions has been the uncertainties in estimating the biogenic hydrocarbon emissions. Biogenic volatile organic compounds, BVOCs, play a critical role in atmospheric chemistry, particularly in ozone and particulate matter (PM) formation. In southeastern United States, BVOCs (mostly as isoprene) are the dominant summertime source of reactive hydrocarbon. Despite significant efforts in improving BVOC estimates, the errors in emission inventories remain a concern. Since BVOC emissions are particularly sensitive to the available photosynthetically active radiation (PAR), model errors in PAR result in large errors in emission estimates. Thus, utilization of satellite observations to estimate PAR can help in reducing emission uncertainties. Satellite-based PAR estimates rely on the technique used to derive insolation from satellite visible brightness measurements. In this study we evaluate several insolation products against surface pyranometer observations and offer a bias correction to generate a more accurate PAR product. The improved PAR product is then used in biogenic emission estimates. The improved biogenic emission estimates are compared to the emission inventories over Texas and used in air quality simulation over the period of August-September 2013 (NASA's Discover-AQ field campaign). A series of sensitivity simulations will be performed and evaluated against Discover-AQ observations to test the impact of satellite-derived PAR on air quality simulations.

  15. PAR-1, -4, and the mTOR Pathway Following Germinal Matrix Hemorrhage.

    PubMed

    Lekic, Tim; Krafft, Paul R; Klebe, Damon; Flores, Jerry; Rolland, William B; Tang, Jiping; Zhang, John H

    2016-01-01

    Germinal matrix hemorrhage (GMH) is the most common cause of neurological complications of prematurity and has lasting implications. PAR-1 and PAR-4 receptors are involved with upstream signaling pathways following brain hemorrhage in adult models of stroke, of which the mammalian target of rapamycin (mTOR) is a potential downstream mediator. Therefore, we hypothesized a role for PAR-1, -4/ mTOR signaling following GMH brain injury. Postnatal day 7 Sprague-Dawley rats were subjected to GMH through stereotactic infusion of collagenase into the right ganglionic eminence. Rodents were euthanized at 72 h (short term), or 4 weeks (long term). Short-term mTOR expression was evaluated by Western blot in the context of PAR-1 (SCH-79797) and PAR-4 (P4pal10) inhibition. Pups in the long-term group were administered the selective mTOR inhibitor (rapamycin) with neurobehavioral and brain pathological examinations performed at 4 weeks. Pharmacological PAR-1, -4 antagonism normalized the increased mTOR expression following GMH. Early inhibition of mTOR by rapamycin improved long-term outcomes in rats. Mammalian-TOR signaling plays an important role in brain injury following neonatal GMH, possibly involving upstream PAR-1, -4 mechanisms. PMID:26463951

  16. Cathepsin S Signals via PAR2 and Generates a Novel Tethered Ligand Receptor Agonist

    PubMed Central

    Lerner, Ethan A.

    2014-01-01

    Protease-activated receptor-2 is widely expressed in mammalian epithelial, immune and neural tissues. Cleavage of PAR2 by serine proteases leads to self-activation of the receptor by the tethered ligand SLIGRL. The contribution of other classes of proteases to PAR activation has not been studied in detail. Cathepsin S is a widely expressed cysteine protease that is upregulated in inflammatory conditions. It has been suggested that cathepsin S activates PAR2. However, cathepsin S activation of PAR2 has not been demonstrated directly nor has the potential mechanism of activation been identified. We show that cathepsin S cleaves near the N-terminus of PAR2 to expose a novel tethered ligand, KVDGTS. The hexapeptide KVDGTS generates downstream signaling events specific to PAR2 but is weaker than SLIGRL. Mutation of the cathepsin S cleavage site prevents receptor activation by the protease while KVDGTS retains activity. In conclusion, the range of actions previously ascribed to cysteine cathepsins in general, and cathepsin S in particular, should be expanded to include molecular signaling. Such signaling may link together observations that had been attributed previously to PAR2 or cathepsin S individually. These interactions may contribute to inflammation. PMID:24964046

  17. Quinolone-resistant mutants of escherichia coli DNA topoisomerase IV parC gene.

    PubMed Central

    Kumagai, Y; Kato, J I; Hoshino, K; Akasaka, T; Sato, K; Ikeda, H

    1996-01-01

    Escherichia coli quinolone-resistant strains with mutations of the parC gene, which codes for a subunit of topoisomerase IV, were isolated from a quinolone-resistant gyrA mutant of DNA gyrase. Quinolone-resistant parC mutants were also identified among the quinolone-resistant clinical strains. The parC mutants became susceptible to quinolones by introduction of a parC+ plasmid. Introduction of the multicopy plasmids carrying the quinolone-resistant parC mutant gene resulted in an increase in MICs of quinolones for the parC+ and quinolone-resistant gyrA strain. Nucleotide sequences of the quinolone-resistant parC mutant genes were determined, and missense mutations at position Gly-78, Ser-80, or Glu-84, corresponding to those in the quinolone-resistance-determining region of DNA gyrase, were identified. These results indicate that topoisomerase IV is a target of quinolones in E. coli and suggest that the susceptibility of E. coli cells to quinolones is determined by sensitivity of the targets, DNA gyrase and topoisomerase IV. PMID:8851598

  18. Par-4/NF-κB Mediates the Apoptosis of Islet β Cells Induced by Glucolipotoxicity.

    PubMed

    QiNan, Wu; XiaGuang, Gan; XiaoTian, Lei; WuQuan, Deng; Ling, Zhang; Bing, Chen

    2016-01-01

    Apoptosis of islet β cells is a primary pathogenic feature of type 2 diabetes, and ER stress and mitochondrial dysfunction play important roles in this process. Previous research has shown that prostate apoptosis response-4 (Par-4)/NF-κB induces cancer cell apoptosis through endoplasmic reticulum (ER) stress and mitochondrial dysfunction. However, the mechanism by which Par-4/NF-κB induces islet β cell apoptosis remains unknown. We used a high glucose/palmitate intervention to mimic type 2 diabetes in vitro. We demonstrated that the high glucose/palmitate intervention induced the expression and secretion of Par-4. It also causes increased expression and activation of NF-κB, which induced NIT-1 cell apoptosis and dysfunction. Overexpression of Par-4 potentiates these effects, whereas downregulation of Par-4 attenuates them. Inhibition of NF-κB inhibited the Par-4-induced apoptosis. Furthermore, these effects occurred through the ER stress cell membrane and mitochondrial pathway of apoptosis. Our findings reveal a novel role for Par-4/NF-κB in islet β cell apoptosis and type 2 diabetes. PMID:27340675

  19. Par3A is dispensable for the function of the glomerular filtration barrier of the kidney.

    PubMed

    Koehler, Sybille; Tellkamp, Frederik; Niessen, Carien M; Bloch, Wilhelm; Kerjaschki, Dontscho; Schermer, Bernhard; Benzing, Thomas; Brinkkoetter, Paul T

    2016-07-01

    Polarity signaling through the atypical PKC (aPKC)-Par polarity complex is essential for the development and maintenance of the podocyte architecture and the function of the glomerular filtration barrier of the kidney. To study the contribution of Par3A in this complex, we generated a novel Pard3 podocyte-specific knockout mouse model by targeting exon 6 of the Pard3 gene. Genetic deletion of Pard3a did not impair renal function, neither at birth nor later in life. Even challenging the animals did not result in glomerular disease. Despite its well-established role in aPKC-mediated signaling, Par3A appears to be dispensable for the function of the glomerular filtration barrier. Moreover, its homolog Pard3b, and not Pard3a, is the dominant Par3 gene expressed in podocytes and found at the basis of the slit diaphragm, where it partially colocalizes with podocin. In conclusion, Par3A function is either dispensable for slit diaphragm integrity, or compensatory mechanisms and a high redundancy of the different polarity proteins, including Par3B, Lgl, or PALS1, maintain the function of the glomerular filtration barrier, even in the absence of Par3A. PMID:27122542

  20. Evidence for a DNA-relay mechanism in ParABS-mediated chromosome segregation

    PubMed Central

    Lim, Hoong Chuin; Surovtsev, Ivan Vladimirovich; Beltran, Bruno Gabriel; Huang, Fang; Bewersdorf, Jörg; Jacobs-Wagner, Christine

    2014-01-01

    The widely conserved ParABS system plays a major role in bacterial chromosome segregation. How the components of this system work together to generate translocation force and directional motion remains uncertain. Here, we combine biochemical approaches, quantitative imaging and mathematical modeling to examine the mechanism by which ParA drives the translocation of the ParB/parS partition complex in Caulobacter crescentus. Our experiments, together with simulations grounded on experimentally-determined biochemical and cellular parameters, suggest a novel 'DNA-relay' mechanism in which the chromosome plays a mechanical function. In this model, DNA-bound ParA-ATP dimers serve as transient tethers that harness the elastic dynamics of the chromosome to relay the partition complex from one DNA region to another across a ParA-ATP dimer gradient. Since ParA-like proteins are implicated in the partitioning of various cytoplasmic cargos, the conservation of their DNA-binding activity suggests that the DNA-relay mechanism may be a general form of intracellular transport in bacteria. DOI: http://dx.doi.org/10.7554/eLife.02758.001 PMID:24859756

  1. Par-4/NF-κB Mediates the Apoptosis of Islet β Cells Induced by Glucolipotoxicity

    PubMed Central

    QiNan, Wu; XiaGuang, Gan; XiaoTian, Lei; WuQuan, Deng; Ling, Zhang; Bing, Chen

    2016-01-01

    Apoptosis of islet β cells is a primary pathogenic feature of type 2 diabetes, and ER stress and mitochondrial dysfunction play important roles in this process. Previous research has shown that prostate apoptosis response-4 (Par-4)/NF-κB induces cancer cell apoptosis through endoplasmic reticulum (ER) stress and mitochondrial dysfunction. However, the mechanism by which Par-4/NF-κB induces islet β cell apoptosis remains unknown. We used a high glucose/palmitate intervention to mimic type 2 diabetes in vitro. We demonstrated that the high glucose/palmitate intervention induced the expression and secretion of Par-4. It also causes increased expression and activation of NF-κB, which induced NIT-1 cell apoptosis and dysfunction. Overexpression of Par-4 potentiates these effects, whereas downregulation of Par-4 attenuates them. Inhibition of NF-κB inhibited the Par-4-induced apoptosis. Furthermore, these effects occurred through the ER stress cell membrane and mitochondrial pathway of apoptosis. Our findings reveal a novel role for Par-4/NF-κB in islet β cell apoptosis and type 2 diabetes. PMID:27340675

  2. KSHV-Mediated Regulation of Par3 and SNAIL Contributes to B-Cell Proliferation.

    PubMed

    Jha, Hem C; Sun, Zhiguo; Upadhyay, Santosh K; El-Naccache, Darine W; Singh, Rajnish K; Sahu, Sushil K; Robertson, Erle S

    2016-07-01

    Studies have suggested that Epithelial-Mesenchymal Transition (EMT) and transformation is an important step in progression to cancer. Par3 (partitioning-defective protein) is a crucial factor in regulating epithelial cell polarity. However, the mechanism by which the latency associated nuclear antigen (LANA) encoded by Kaposi's Sarcoma associated herpesvirus (KSHV) regulates Par3 and EMTs markers (Epithelial-Mesenchymal Transition) during viral-mediated B-cell oncogenesis has not been fully explored. Moreover, several studies have demonstrated a crucial role for EMT markers during B-cell malignancies. In this study, we demonstrate that Par3 is significantly up-regulated in KSHV-infected primary B-cells. Further, Par3 interacted with LANA in KSHV positive and LANA expressing cells which led to translocation of Par3 from the cell periphery to a predominantly nuclear signal. Par3 knockdown led to reduced cell proliferation and increased apoptotic induction. Levels of SNAIL was elevated, and E-cadherin was reduced in the presence of LANA or Par3. Interestingly, KSHV infection in primary B-cells led to enhancement of SNAIL and down-regulation of E-cadherin in a temporal manner. Importantly, knockdown of SNAIL, a major EMT regulator, in KSHV cells resulted in reduced expression of LANA, Par3, and enhanced E-cadherin. Also, SNAIL bound to the promoter region of p21 and can regulate its activity. Further a SNAIL inhibitor diminished NF-kB signaling through upregulation of Caspase3 in KSHV positive cells in vitro. This was also supported by upregulation of SNAIL and Par3 in BC-3 transplanted NOD-SCID mice which has potential as a therapeutic target for KSHV-associated B-cell lymphomas. PMID:27463802

  3. KSHV-Mediated Regulation of Par3 and SNAIL Contributes to B-Cell Proliferation

    PubMed Central

    Jha, Hem C.; Sun, Zhiguo; Upadhyay, Santosh K.; El-Naccache, Darine W.; Singh, Rajnish K.; Sahu, Sushil K.; Robertson, Erle S.

    2016-01-01

    Studies have suggested that Epithelial–Mesenchymal Transition (EMT) and transformation is an important step in progression to cancer. Par3 (partitioning-defective protein) is a crucial factor in regulating epithelial cell polarity. However, the mechanism by which the latency associated nuclear antigen (LANA) encoded by Kaposi's Sarcoma associated herpesvirus (KSHV) regulates Par3 and EMTs markers (Epithelial-Mesenchymal Transition) during viral-mediated B-cell oncogenesis has not been fully explored. Moreover, several studies have demonstrated a crucial role for EMT markers during B-cell malignancies. In this study, we demonstrate that Par3 is significantly up-regulated in KSHV-infected primary B-cells. Further, Par3 interacted with LANA in KSHV positive and LANA expressing cells which led to translocation of Par3 from the cell periphery to a predominantly nuclear signal. Par3 knockdown led to reduced cell proliferation and increased apoptotic induction. Levels of SNAIL was elevated, and E-cadherin was reduced in the presence of LANA or Par3. Interestingly, KSHV infection in primary B-cells led to enhancement of SNAIL and down-regulation of E-cadherin in a temporal manner. Importantly, knockdown of SNAIL, a major EMT regulator, in KSHV cells resulted in reduced expression of LANA, Par3, and enhanced E-cadherin. Also, SNAIL bound to the promoter region of p21 and can regulate its activity. Further a SNAIL inhibitor diminished NF-kB signaling through upregulation of Caspase3 in KSHV positive cells in vitro. This was also supported by upregulation of SNAIL and Par3 in BC-3 transplanted NOD-SCID mice which has potential as a therapeutic target for KSHV-associated B-cell lymphomas. PMID:27463802

  4. PAR-2 elicits afferent arteriolar vasodilation by NO-dependent and NO-independent actions.

    PubMed

    Trottier, Greg; Hollenberg, Morley; Wang, Xuemei; Gui, Yu; Loutzenhiser, Kathy; Loutzenhiser, Rodger

    2002-05-01

    Proteinase-activated receptors (PARs) are a novel class of G protein-coupled receptors that respond to signals through endogenous proteinases. PAR activation involves enzymatic cleavage of the extracellular NH(2)-terminal domain and unmasking of a new NH(2) terminus, which serves as an anchored ligand to activate the receptor. At least four PAR subtypes have been identified. In the present study, we used the in vitro perfused hydronephrotic rat kidney to examine the effects of activating PAR-2 on the afferent arteriole. The synthetic peptide SLIGRL-NH(2), which corresponds to the exposed ligand sequence and selectively activates PAR-2, did not alter basal afferent arteriolar diameter but caused a concentration-dependent vasodilation (3-30 microM) of arterioles preconstricted by angiotensin II (0.1 nM). A modified peptide sequence (LSIGRL-NH(2), inactive at PAR-2) had no effect. This vasodilation was characterized by an initial transient component followed by a smaller sustained response. A similar pattern of vasodilation was seen when SLIGRL-NH(2) was administered to isolated perfused normal rat kidney. The sustained component of the PAR-2-induced afferent arteriolar vasodilation was eliminated by nitric oxide (NO) synthase inhibition (100 microM nitro-L-arginine methyl ester). In contrast, the transient vasodilation persisted under these conditions. This transient response was not observed when afferent arterioles were preconstricted with elevated KCl, suggesting involvement of an endothelium-derived hyperpolarizing factor. Finally, RT-PCR revealed the presence of PAR-2 mRNA in isolated afferent arterioles. These findings indicate that PAR-2 is expressed in the afferent arteriole and that its activation elicits afferent arteriolar vasodilation by NO-dependent and NO-independent mechanisms. PMID:11934700

  5. Par-complex aPKC and Par3 cross-talk with innate immunity NF-κB pathway in epithelial cells

    PubMed Central

    Forteza, Radia; Wald, Flavia A.; Mashukova, Anastasia; Kozhekbaeva, Zhanna; Salas, Pedro J.

    2013-01-01

    Summary Components of the Par-complex, atypical PKC and Par3, have been found to be downregulated upon activation of NF-κB in intestinal epithelial cells. To determine their possible role in pro-inflammatory responses we transduced Caco-2 human colon carcinoma cells with constitutively active (ca) PKCι or anti-Par3 shRNA-expressing lentiviral particles. Contrary to previous reports in other cell types, ca-PKCι did not activate, but rather decreased, baseline NF-κB activity in a luminiscence reporter assay. An identical observation applied to a PB1 domain deletion PKCι, which fails to localize to the tight-junction. Conversely, as expected, the same ca-PKCι activated NF-κB in non-polarized HEK293 cells. Likewise, knockdown of Par3 increased NF-κB activity and, surprisingly, greatly enhanced its response to TNFα, as shown by transcription of IL-8, GRO-1, GRO-2 and GRO-3. We conclude that aPKC and Par3 are inhibitors of the canonical NF-κB activation pathway, although perhaps acting through independent pathways, and may be involved in pro-inflammatory responses. PMID:24244864

  6. Aspergillus fumigatus Endophthalmitis with Necrotizing Scleritis following Pars Plana Vitrectomy

    PubMed Central

    Allen, Felicity; Graham, Elizabeth M.

    2016-01-01

    We present a case of Aspergillus fumigatus endophthalmitis complicated by necrotizing scleritis in a 68-year-old man with diet-controlled diabetes, after retinal detachment repair. He was initially treated with systemic steroids for surgically induced necrotizing scleritis following routine pars plana vitrectomy. An additional diagnosis of endophthalmitis was made when the patient developed a hypopyon. Repeat vitreous culture isolated Aspergillus fumigatus. Symptoms improved following antifungal treatment leaving the patient with scleromalacia and an advanced postoperative cataract. Fungal scleritis and endophthalmitis are rare complications of intraocular surgery with sight-threatening consequences, and, as this case demonstrates, may even occur concomitantly. The overlapping features of both conditions can make differentiating one from the other difficult. A fungal aetiology should be considered in cases of postoperative scleritis and endophthalmitis that are protracted and refractory to standard therapy. Even in cases of early diagnosis and treatment, visual outcomes in Aspergillus endophthalmitis and scleritis are variable and often disappointing, not infrequently necessitating enucleation of a painful blind eye. PMID:27379189

  7. Aspergillus fumigatus Endophthalmitis with Necrotizing Scleritis following Pars Plana Vitrectomy.

    PubMed

    Gruener, Anna M; Allen, Felicity; Stanford, Miles R; Graham, Elizabeth M

    2016-01-01

    We present a case of Aspergillus fumigatus endophthalmitis complicated by necrotizing scleritis in a 68-year-old man with diet-controlled diabetes, after retinal detachment repair. He was initially treated with systemic steroids for surgically induced necrotizing scleritis following routine pars plana vitrectomy. An additional diagnosis of endophthalmitis was made when the patient developed a hypopyon. Repeat vitreous culture isolated Aspergillus fumigatus. Symptoms improved following antifungal treatment leaving the patient with scleromalacia and an advanced postoperative cataract. Fungal scleritis and endophthalmitis are rare complications of intraocular surgery with sight-threatening consequences, and, as this case demonstrates, may even occur concomitantly. The overlapping features of both conditions can make differentiating one from the other difficult. A fungal aetiology should be considered in cases of postoperative scleritis and endophthalmitis that are protracted and refractory to standard therapy. Even in cases of early diagnosis and treatment, visual outcomes in Aspergillus endophthalmitis and scleritis are variable and often disappointing, not infrequently necessitating enucleation of a painful blind eye. PMID:27379189

  8. Plaies des membres par agression: analyse de 245 dossiers

    PubMed Central

    Boufettal, Monsef; Mahfoud, Mustapha; Ismael, Farid; Kharmaz, Mohamed; Bardouni, Ahmed El; Berrada, Mohamed Saleh; Yaacoubi, Moradh El

    2015-01-01

    Il s'agit d'une étuderétrospective, analytique, monocentrique rentrant dans le cadre d'une étude épidémiologique s’étalant sur une période de trois années (de 2010 à 2012) durant laquelle nous avons revu les dossiers de 245 patients victimes de violence et d'agression. Nous avons exclu les lésions simples traitées en ambulatoire. Par conséquent, nous nous sommes limités aux cas de blessures ayant nécessité une prise en charge spécialisée au bloc opératoire. Les objectifs de notre travail étaient de connaitre la fréquence des agressions au service de traumatologie du CHU de Rabat, classer les différents types de lésions, évaluer leur gravité, mettre la lumière sur les populations les plus touchées et enfin montrer les différentes modalités de prise en charge thérapeutiques. PMID:26918078

  9. PAR-1 and thrombin: the ties that bind the microenvironment to melanoma metastasis.

    PubMed

    Zigler, Maya; Kamiya, Takafumi; Brantley, Emily C; Villares, Gabriel J; Bar-Eli, Menashe

    2011-11-01

    Progression of melanoma is dependent on cross-talk between tumor cells and the adjacent microenvironment. The thrombin receptor, protease-activated receptor-1 (PAR-1), plays a key role in exerting this function during melanoma progression. PAR-1 and its activating factors, which are expressed on tumor cells and the surrounding stroma, induce not only coagulation but also cell signaling, which promotes the metastatic phenotype. Several adhesion molecules, cytokines, growth factors, and proteases have recently been identified as downstream targets of PAR-1 and have been shown to modulate interactions between tumor cells and the microenvironment in the process of melanoma growth and metastasis. Inhibiting such interactions by targeting PAR-1 could potentially be a useful therapeutic modality for melanoma patients. PMID:22009534

  10. PAR-1 and Thrombin: The Ties that Bind the Microenvironment to Melanoma Metastasis*

    PubMed Central

    Zigler, Maya; Kamiya, Takafumi; Brantley, Emily C.; Villares, Gabriel J.; Bar-Eli, Menashe

    2011-01-01

    Progression of melanoma is dependent on cross-talk between tumor cells and the adjacent microenvironment. The thrombin receptor, Protease Activated Receptor-1 (PAR-1) plays a key role in exerting this function during melanoma progression. PAR-1 and its activating factors, which are expressed on tumor cells and the surrounding stroma, induce not only coagulation, but also cell signaling which promotes the metastatic phenotype. Several adhesion molecules, cytokines, growth factors and proteases have recently been identified as downstream targets of PAR-1 and have been shown to modulate interactions between tumor cells and the microenvironment in the process of melanoma growth and metastasis. Inhibition of these interactions by targeting PAR-1 could be utilized as a potential therapeutic modality for melanoma patients. PMID:22009534

  11. The Emerging Role of the Thrombin Receptor (PAR-1) in Melanoma Metastasis - a Possible Therapeutic Target

    PubMed Central

    Villares, Gabriel J.; Zigler, Maya; Bar-Eli, Menashe

    2011-01-01

    Melanoma remains as the deadliest form of skin cancer with limited and inefficient treatment options available for patients with metastatic disease. Within the last decade, the thrombin receptor, Protease Activated Receptor-1, has been described as an essential gene involved in the progression of human melanoma. PAR-1 is known to activate adhesive, invasive and angiogenic factors to promote melanoma metastasis. It is overexpressed not only in metastatic melanoma cell lines but is also highly expressed in metastatic lesions as compared to primary nevi and normal skin. Recently, PAR-1 has been described to regulate the gap junction protein Connexin 43 and the tumor suppressor gene Maspin to promote the metastatic melanoma phenotype. Herein, we review the role of PAR-1 in the progression of melanoma as well as utilizing PAR-1-regulated genes as potential therapeutic targets for melanoma treatment. PMID:21378407

  12. PAR3 acts as a molecular organizer to define the apical domain of chick neuroepithelial cells.

    PubMed

    Afonso, Cristina; Henrique, Domingos

    2006-10-15

    Neural progenitors in the vertebrate nervous system are fully polarized epithelial cells, with intercellular junctions at the apical region. These progenitor cells remain within the neuroepithelium throughout neurogenesis, and will ultimately give rise to all the neurons in the mature nervous system. We have addressed the role of the PAR polarity complex in vertebrate neuroepithelial polarity and show that PAR3 functions as the initial scaffold to assemble and organize the PAR complex at the apical region of neuroepithelial cells, coordinating also the recruitment of additional polarity complexes and junction-associated proteins to the same region, while restricting other polarity proteins to the basolateral membrane. We propose that PAR3 acts as a molecular organizer to connect the acquisition of apico-basal polarity with the positioning and formation of junctional structures in neuroepithelial cells, a function of upmost importance for the morphogenesis of embryonic neural tissue and the process of neurogenesis. PMID:17003110

  13. Exchange cart and par level supply distribution systems: form follows function.

    PubMed

    Perrin, R A

    1994-02-01

    This article examines the various types of distribution systems, such as exchange cart, par level, and just-in-time, to assist material managers in controlling costs and maximizing patient care. PMID:10131700

  14. Model parameterization to simulate and compare the PAR absorption potential of two competing plant species

    PubMed Central

    Silva, Brenner; Roos, Kristin; Göttlicher, Dietrich Otto; Rollenbeck, Rütger; Nauß, Thomas; Beck, Erwin

    2009-01-01

    Mountain pastures dominated by the pasture grass Setaria sphacelata in the Andes of southern Ecuador are heavily infested by southern bracken (Pteridium arachnoideum), a major problem for pasture management. Field observations suggest that bracken might outcompete the grass due to its competitive strength with regard to the absorption of photosynthetically active radiation (PAR). To understand the PAR absorption potential of both species, the aims of the current paper are to (1) parameterize a radiation scheme of a two-big-leaf model by deriving structural (LAI, leaf angle parameter) and optical (leaf albedo, transmittance) plant traits for average individuals from field surveys, (2) to initialize the properly parameterized radiation scheme with realistic global irradiation conditions of the Rio San Francisco Valley in the Andes of southern Ecuador, and (3) to compare the PAR absorption capabilities of both species under typical local weather conditions. Field data show that bracken reveals a slightly higher average leaf area index (LAI) and more horizontally oriented leaves in comparison to Setaria. Spectrometer measurements reveal that bracken and Setaria are characterized by a similar average leaf absorptance. Simulations with the average diurnal course of incoming solar radiation (1998–2005) and the mean leaf–sun geometry reveal that PAR absorption is fairly equal for both species. However, the comparison of typical clear and overcast days show that two parameters, (1) the relation of incoming diffuse and direct irradiance, and (2) the leaf–sun geometry play a major role for PAR absorption in the two-big-leaf approach: Under cloudy sky conditions (mainly diffuse irradiance), PAR absorption is slightly higher for Setaria while under clear sky conditions (mainly direct irradiance), the average bracken individual is characterized by a higher PAR absorption potential. (∼74 MJ m−2 year−1). The latter situation which occurs if the maximum daily

  15. Model parameterization to simulate and compare the PAR absorption potential of two competing plant species.

    PubMed

    Bendix, Jörg; Silva, Brenner; Roos, Kristin; Göttlicher, Dietrich Otto; Rollenbeck, Rütger; Nauss, Thomas; Beck, Erwin

    2010-05-01

    Mountain pastures dominated by the pasture grass Setaria sphacelata in the Andes of southern Ecuador are heavily infested by southern bracken (Pteridium arachnoideum), a major problem for pasture management. Field observations suggest that bracken might outcompete the grass due to its competitive strength with regard to the absorption of photosynthetically active radiation (PAR). To understand the PAR absorption potential of both species, the aims of the current paper are to (1) parameterize a radiation scheme of a two-big-leaf model by deriving structural (LAI, leaf angle parameter) and optical (leaf albedo, transmittance) plant traits for average individuals from field surveys, (2) to initialize the properly parameterized radiation scheme with realistic global irradiation conditions of the Rio San Francisco Valley in the Andes of southern Ecuador, and (3) to compare the PAR absorption capabilities of both species under typical local weather conditions. Field data show that bracken reveals a slightly higher average leaf area index (LAI) and more horizontally oriented leaves in comparison to Setaria. Spectrometer measurements reveal that bracken and Setaria are characterized by a similar average leaf absorptance. Simulations with the average diurnal course of incoming solar radiation (1998-2005) and the mean leaf-sun geometry reveal that PAR absorption is fairly equal for both species. However, the comparison of typical clear and overcast days show that two parameters, (1) the relation of incoming diffuse and direct irradiance, and (2) the leaf-sun geometry play a major role for PAR absorption in the two-big-leaf approach: Under cloudy sky conditions (mainly diffuse irradiance), PAR absorption is slightly higher for Setaria while under clear sky conditions (mainly direct irradiance), the average bracken individual is characterized by a higher PAR absorption potential. (approximately 74 MJ m(-2) year(-1)). The latter situation which occurs if the maximum daily

  16. Lensectomy using a bimanual microincision cataract surgery technique during pars plana vitrectomy.

    PubMed

    Byeon, Suk Ho; Kwon, Oh W

    2009-01-01

    Lens extraction during vitrectomy is sometimes necessary to obtain an adequate view of the retina. Currently, phacoemulsification through a clear corneal incision with implantation of a foldable intraocular lens has become the preferred technique for cataract extraction during pars plana vitrectomy. The authors described the technique of lensectomy using a bimanual microincisional cataract surgery technique during pars plana vitrectomy and insertion of the intraocular lens at the end of surgery, which has several advantages over conventional coaxial phacoemulsification procedures. PMID:19205506

  17. Psychodopygus complexus, a new vector of Leishmania braziliensis to humans in Pará State, Brazil.

    PubMed

    de Souza, A; Ishikawa, E; Braga, R; Silveira, F; Lainson, R; Shaw, J

    1996-01-01

    This paper reports the finding of 4 specimens of Psychodopygus complexus, captured in the Paragominas region of Pará State, Brazil, naturally infected with trypanosomatids that were positively identified as Leishmania (Viannia) braziliensis. Attention is drawn to the importance of this species as a vector since it is highly anthropophilic and has a very extensive geographical distribution in the lower Amazon region of Pará State south of the Amazon river, including the island of Marajó. PMID:8761563

  18. Molecular mechanism of bundle formation by the bacterial actin ParM

    SciTech Connect

    Popp, David; Narita, Akihiro; Iwasa, Mitsusada; Robinson, Robert C.

    2010-01-22

    The actin homolog ParM plays a microtubule-like role in segregating DNA prior to bacterial cell division. Fluorescence and cryo-electron microscopy have shown that ParM forms filament bundles between separating DNA plasmids in vivo. Given the lack of ParM bundling proteins it remains unknown how ParM bundles form at the molecular level. Here we show using time-lapse TIRF microscopy, under in vitro molecular crowding conditions, that ParM-bundle formation consists of two distinct phases. At the onset of polymerization bundle thickness and shape are determined in the form of nuclei of short helically disordered filaments arranged in a liquid-like lattice. These nuclei then undergo an elongation phase whereby they rapidly increase in length. At steady state, ParM bundles fuse into one single large aggregate. This behavior had been predicted by theory but has not been observed for any other cytomotive biopolymer, including F-actin. We employed electron micrographs of ParM rafts, which are 2-D analogs of 3-D bundles, to identify the main molecular interfilament contacts within these suprastructures. The interface between filaments is similar for both parallel and anti-parallel orientations and the distribution of filament polarity is random within a bundle. We suggest that the interfilament interactions are not due to the interactions of specific residues but rather to long-range, counter ion mediated, electrostatic attractive forces. A randomly oriented bundle ensures that the assembly is rigid and that DNA may be captured with equal efficiency at both ends of the bundle via the ParR binding protein.

  19. Ambroise Paré IV: The early history of artificial limbs (from robotic to prostheses).

    PubMed

    Hernigou, Philippe

    2013-06-01

    One of the earliest written references to prosthetics is found in a book published in France in 1579. That year, French surgeon Ambroise Paré (1510-1590) published his complete works, part of which described some of the artificial limbs he fitted on his amputees. As a military surgeon, Paré had removed many a soldier's shattered arm or leg, and he eventually began designing and building artificial limbs to help the men who had been maimed. PMID:23604214

  20. PAR-WIG performance prediction during acceleration from water-borne to air-borne

    NASA Astrophysics Data System (ADS)

    Ando, Shigenori; Kato, Michiyo

    1991-11-01

    Take-off performance is calculated for PAR-WIG which utilizes propeller-slipstream. For this purpose, a quick automatic computation scheme is developed for performance of 'engine-propeller combination system'. Example calculations are presented, which show that the hump drag is completely removed with PAR effect. It is noted that variable-geometry of wing-end-plates is desirable and variable-camber of main-wing is essential.

  1. Unitary synaptic connections among substantia nigra pars reticulata neurons.

    PubMed

    Higgs, Matthew H; Wilson, Charles J

    2016-06-01

    Neurons in substantia nigra pars reticulata (SNr) are synaptically coupled by local axon collaterals, providing a potential mechanism for local signal processing. Because SNr neurons fire spontaneously, these synapses are constantly active. To investigate their properties, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) from SNr neurons in brain slices, in which afferents from upstream nuclei are severed, and the cells fire rhythmically. The sIPSC trains contained a mixture of periodic and aperiodic events. Autocorrelation analysis of sIPSC trains showed that a majority of cells had one to four active unitary inputs. The properties of the unitary IPSCs (uIPSCs) were analyzed for cells with one unitary input, using a model of periodic presynaptic firing and stochastic synaptic transmission. The inferred presynaptic firing rates and coefficient of variation of interspike intervals (ISIs) corresponded well with direct measurements of spiking in SNr neurons. Methods were developed to estimate the success probability, amplitude distributions, and kinetics of the uIPSCs, while removing the contribution from aperiodic sIPSCs. The sIPSC amplitudes were not increased upon release from halorhodopsin silencing, suggesting that most synapses were not depressed at the spontaneous firing rate. Gramicidin perforated-patch recordings indicated that the average reversal potential of spontaneous inhibitory postsynaptic potentials was -64 mV. Because of the change in driving force across the ISI, the unitary inputs are predicted to have a larger postsynaptic impact when they arrive late in the ISI. Simulations of network activity suggest that this very sparse inhibitory coupling may act to desynchronize the activity of SNr neurons while having only a small effect on firing rate. PMID:26961101

  2. Mesencephalic origin of the rostral Substantia nigra pars reticulata.

    PubMed

    Madrigal, M Pilar; Moreno-Bravo, Juan A; Martínez-López, Jesús E; Martínez, Salvador; Puelles, Eduardo

    2016-04-01

    In embryonic development, the neurons that will constitute a heterogeneous nucleus may have distinct origins. The different components of these populations reach their final location by radial and tangential migrations. The Substantia nigra pars reticulata (SNR) presents a high level of neuronal heterogeneity. It is composed by GABAergic neurons located in the mes-diencephalic basal plate. These inhibitory neurons usually display tangential migrations and it has been already described that the caudal SNR is colonized tangentially from rhombomere 1. Our aim is to unveil the origin of the rostral SNR. We have localized a Nkx6.2 positive ventricular domain located in the alar midbrain. Nkx6.2 derivatives' fate map analysis showed mainly a rostral colonization of this GABAergic neuronal population. We confirmed the mesencephalic origin by the expression of Six3. Both transcription factors are sequentially expressed along the differentiation of these neurons. We demonstrated the origin of the rostral SNR; our data allowed us to postulate that this nucleus is composed by two neuronal populations distributed in opposite gradients with different origins, one from rhombomere 1, caudal to rostral, and the other from the midbrain, rostral to caudal. We can conclude that the SNR has multiple origins and follows complex mechanisms of specification and migration. Our results support vital information for the study of genetic modifications in these extremely complex processes that result in devastating behavioral alterations and predisposition to psychiatric diseases. Understanding the development, molecular identity and functional characteristics of these diverse neuronal populations might lead to better diagnosis and treatment of several forms of neurological and psychiatric disease. PMID:25579066

  3. [Diabetics in population of patients treated by pars plana vitrectomy].

    PubMed

    Bezdésová-Bohunická, N; Skorkovská, S; Synek, S; Kanovský, R; Masková, Z; Synková, M

    2007-11-01

    The purpose of this study is to evaluate visual and anatomic outcomes following pars plana vitrectomy (PPV) for complications of diabetic retinopathy (DR), and to assess risk factors that might influence the visual outcome after successful PPV. The medical records of 35 diabetic patients of both types 1 and 2 of diabetes, who underwent vitrectomy for complications of proliferative diabetic retinopathy (PDR) between 2004 and 2005, were analyzed retrospectively. Certain preoperative systemic and ophthalmic variables, intraoperative variables and postoperative complications with negative influence on visual outcome after PPV were recorded. The postoperative follow-up time was 6 months. The collected data as well as visual outcomes after PPV were statistically analyzed. Statistically significant visual improvement was achieved in 51.4 % of the patients; visual acuity (VA) deteriorated in 25.7% of the patients and remained unchanged in 22.9 % of the patients. Preoperative median of VA was 0.0167, changed to 0.1 postoperatively and remained stable on 0.1 level during the 6 months follow-up. VA > or = 0.1 was achieved in 60 % of the patients 6 months after PPV. Some of the followed variables associated with deteriorated or unchanged postoperative VA can be considered as risk factors of an unfavorable prognosis. Evaluated risk factors include preoperative VA worse than 0.1, presence of systemic complications of DM accompanying ocular complications, postoperative occurrence of iris neovascularization and neovascular glaucoma. In conclusion, anatomically successful PPV in diabetic patients is not always followed by an improvement of VA. The optimal timing of vitrectomy is very important not only in order to obtain good visual acuity but also to maintain good visual function for long time. We suppose that an adequate control of DM, sufficient screening for DR and timely laser intervention of DR might decrease the progression of DR and onset of sight threatening complications

  4. Structural Polymorphism of the ParM Filament and Dynamic Instability

    PubMed Central

    Galkin, Vitold E.; Orlova, Albina; Rivera, Chris; Mullins, R. Dyche; Egelman, Edward H.

    2009-01-01

    Segregation of the R1 plasmid in bacteria relies on ParM, an actin homolog that segregates plasmids by switching between cycles of polymerization and depolymerization. We find similar polymerization kinetics and stability in the presence of either ATP or GTP and a 10-fold affinity preference for ATP over GTP. We used electron cryo-microscopy to evaluate the heterogeneity within ParM filaments. In addition to variable twist ParM has variable axial rise, and both parameters are coupled. Subunits in the same ParM filaments can exist in two different structural states, with the nucleotide-binding cleft closed or open, and the bound nucleotide biases the distribution of states. The interface between protomers is different between these states, and in neither state is it similar to F-actin. Our results suggest that the closed state of the cleft is required but not sufficient for ParM polymerization, and provide a structural basis for the dynamic instability of ParM filaments. PMID:19748346

  5. Breaking the epithelial polarity barrier in cancer: the strange case of LKB1/PAR-4

    PubMed Central

    Partanen, Johanna I.; Tervonen, Topi A.; Klefström, Juha

    2013-01-01

    The PAR clan of polarity regulating genes was initially discovered in a genetic screen searching for genes involved in asymmetric cell divisions in the Caenorhabditis elegans embryo. Today, investigations in worms, flies and mammals have established PAR proteins as conserved and fundamental regulators of animal cell polarization in a broad range of biological phenomena requiring cellular asymmetries. The human homologue of invertebrate PAR-4, a serine–threonine kinase LKB1/STK11, has caught attention as a gene behind Peutz–Jeghers polyposis syndrome and as a bona fide tumour suppressor gene commonly mutated in sporadic cancer. LKB1 functions as a master regulator of AMP-activated protein kinase (AMPK) and 12 other kinases referred to as the AMPK-related kinases, including four human homologues of PAR-1. The role of LKB1 as part of the energy sensing LKB1-AMPK module has been intensively studied, whereas the polarity function of LKB1, in the context of homoeostasis or cancer, has gained less attention. Here, we focus on the PAR-4 identity of LKB1, discussing the weight of evidence indicating a role for LKB1 in regulation of cell polarity and epithelial integrity across species and highlight recent investigations providing new insight into the old question: does the PAR-4 identity of LKB1 matter in cancer? PMID:24062587

  6. PAR3-aPKC regulates Tiam1 by modulating suppressive internal interactions

    PubMed Central

    Matsuzawa, Kenji; Akita, Hiroki; Watanabe, Takashi; Kakeno, Mai; Matsui, Toshinori; Wang, Shujie; Kaibuchi, Kozo

    2016-01-01

    Tiam1 is one of the most extensively analyzed activators of the small GTPase Rac. However, fundamental aspects of its regulation are poorly understood. Here we demonstrate that Tiam1 is functionally suppressed by internal interactions and that the PAR complex participates in its full activation. The N-terminal region of Tiam1 binds to the protein-binding and catalytic domains to inhibit its localization and activation. Atypical PKCs phosphorylate Tiam1 to relieve its intramolecular interactions, and the subsequent stabilization of its interaction with PAR3 allows it to exert localized activity. By analyzing Tiam1 regulation by PAR3-aPKC within the context of PDGF signaling, we also show that PAR3 directly binds PDGF receptor β. Thus we provide the first evidence for the negative regulation of Tiam1 by internal interactions, elucidate the nature of Tiam1 regulation by the PAR complex, and reveal a novel role for the PAR complex in PDGF signaling. PMID:26941335

  7. Organization, evolution and functions of the human and mouse Ly6/uPAR family genes.

    PubMed

    Loughner, Chelsea L; Bruford, Elspeth A; McAndrews, Monica S; Delp, Emili E; Swamynathan, Sudha; Swamynathan, Shivalingappa K

    2016-01-01

    Members of the lymphocyte antigen-6 (Ly6)/urokinase-type plasminogen activator receptor (uPAR) superfamily of proteins are cysteine-rich proteins characterized by a distinct disulfide bridge pattern that creates the three-finger Ly6/uPAR (LU) domain. Although the Ly6/uPAR family proteins share a common structure, their expression patterns and functions vary. To date, 35 human and 61 mouse Ly6/uPAR family members have been identified. Based on their subcellular localization, these proteins are further classified as GPI-anchored on the cell membrane, or secreted. The genes encoding Ly6/uPAR family proteins are conserved across different species and are clustered in syntenic regions on human chromosomes 8, 19, 6 and 11, and mouse Chromosomes 15, 7, 17, and 9, respectively. Here, we review the human and mouse Ly6/uPAR family gene and protein structure and genomic organization, expression, functions, and evolution, and introduce new names for novel family members. PMID:27098205

  8. Control of Smc Coiled Coil Architecture by the ATPase Heads Facilitates Targeting to Chromosomal ParB/parS and Release onto Flanking DNA.

    PubMed

    Minnen, Anita; Bürmann, Frank; Wilhelm, Larissa; Anchimiuk, Anna; Diebold-Durand, Marie-Laure; Gruber, Stephan

    2016-03-01

    Smc/ScpAB promotes chromosome segregation in prokaryotes, presumably by compacting and resolving nascent sister chromosomes. The underlying mechanisms, however, are poorly understood. Here, we investigate the role of the Smc ATPase activity in the recruitment of Smc/ScpAB to the Bacillus subtilis chromosome. We demonstrate that targeting of Smc/ScpAB to ParB/parS loading sites is strictly dependent on engagement of Smc head domains and relies on an open organization of the Smc coiled coils. We find that dimerization of the Smc hinge domain stabilizes closed Smc rods and hinders head engagement as well as chromosomal targeting. Conversely, the ScpAB sub-complex promotes head engagement and Smc rod opening and thereby facilitates recruitment of Smc to parS sites. Upon ATP hydrolysis, Smc/ScpAB is released from loading sites and relocates within the chromosome-presumably through translocation along DNA double helices. Our findings define an intermediate state in the process of chromosome organization by Smc. PMID:26904953

  9. Control of Smc Coiled Coil Architecture by the ATPase Heads Facilitates Targeting to Chromosomal ParB/parS and Release onto Flanking DNA

    PubMed Central

    Minnen, Anita; Bürmann, Frank; Wilhelm, Larissa; Anchimiuk, Anna; Diebold-Durand, Marie-Laure; Gruber, Stephan

    2016-01-01

    Summary Smc/ScpAB promotes chromosome segregation in prokaryotes, presumably by compacting and resolving nascent sister chromosomes. The underlying mechanisms, however, are poorly understood. Here, we investigate the role of the Smc ATPase activity in the recruitment of Smc/ScpAB to the Bacillus subtilis chromosome. We demonstrate that targeting of Smc/ScpAB to ParB/parS loading sites is strictly dependent on engagement of Smc head domains and relies on an open organization of the Smc coiled coils. We find that dimerization of the Smc hinge domain stabilizes closed Smc rods and hinders head engagement as well as chromosomal targeting. Conversely, the ScpAB sub-complex promotes head engagement and Smc rod opening and thereby facilitates recruitment of Smc to parS sites. Upon ATP hydrolysis, Smc/ScpAB is released from loading sites and relocates within the chromosome—presumably through translocation along DNA double helices. Our findings define an intermediate state in the process of chromosome organization by Smc. PMID:26904953

  10. Targeting of peptide conjugated magnetic nanoparticles to urokinase plasminogen activator receptor (uPAR) expressing cells

    NASA Astrophysics Data System (ADS)

    Hansen, Line; Unmack Larsen, Esben Kjær; Nielsen, Erik Holm; Iversen, Frank; Liu, Zhuo; Thomsen, Karen; Pedersen, Michael; Skrydstrup, Troels; Nielsen, Niels Chr.; Ploug, Michael; Kjems, Jørgen

    2013-08-01

    Ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles are currently being used as a magnetic resonance imaging (MRI) contrast agent in vivo, mainly by their passive accumulation in tissues of interest. However, a higher specificity can ideally be achieved when the nanoparticles are targeted towards cell specific receptors and this may also facilitate specific drug delivery by an enhanced target-mediated endocytosis. We report efficient peptide-mediated targeting of magnetic nanoparticles to cells expressing the urokinase plasminogen activator receptor (uPAR), a surface biomarker for poor patient prognosis shared by several cancers including breast, colorectal, and gastric cancers. Conjugation of a uPAR specific targeting peptide onto polyethylene glycol (PEG) coated USPIO nanoparticles by click chemistry resulted in a five times higher uptake in vitro in a uPAR positive cell line compared to nanoparticles carrying a non-binding control peptide. In accordance with specific receptor-mediated recognition, a low uptake was observed in the presence of an excess of ATF, a natural ligand for uPAR. The uPAR specific magnetic nanoparticles can potentially provide a useful supplement for tumor patient management when combined with MRI and drug delivery.Ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles are currently being used as a magnetic resonance imaging (MRI) contrast agent in vivo, mainly by their passive accumulation in tissues of interest. However, a higher specificity can ideally be achieved when the nanoparticles are targeted towards cell specific receptors and this may also facilitate specific drug delivery by an enhanced target-mediated endocytosis. We report efficient peptide-mediated targeting of magnetic nanoparticles to cells expressing the urokinase plasminogen activator receptor (uPAR), a surface biomarker for poor patient prognosis shared by several cancers including breast, colorectal, and gastric cancers. Conjugation of a uPAR specific

  11. Estimation of photosynthetically available radiation (PAR) from OCEANSAT-I OCM using a simple atmospheric radiative transfer model

    NASA Astrophysics Data System (ADS)

    Tripathy, Madhumita; Raman, Mini; Chauhan, Prakash

    2015-10-01

    Photosynthetically available radiation (PAR) is an important variable for radiation budget, marine and terrestrial ecosystem models. OCEANSAT-1 Ocean Color Monitor (OCM) PAR was estimated using two different methods under both clear and cloudy sky conditions. In the first approach, aerosol optical depth (AOD) and cloud optical depth (COD) were estimated from OCEANSAT-1 OCM TOA (top-of-atmosphere) radiance data on a pixel by pixel basis and PAR was estimated from extraterrestrial solar flux for fifteen spectral bands using a radiative transfer model. The second approach used TOA radiances measured by OCM in the PAR spectral range to compute PAR. This approach also included surface albedo and cloud albedo as inputs. Comparison between OCEANSAT-1 OCM PAR at noon with in situ measured PAR shows that root mean square difference was 5.82% for the method I and 7.24% for the method II in daily time scales. Results indicate that methodology adopted to estimate PAR from OCEANSAT-1 OCM can produce reasonably accurate PAR estimates over the tropical Indian Ocean region. This approach can be extended to OCEANSAT-2 OCM and future OCEANSAT-3 OCM data for operational estimation of PAR for regional marine ecosystem applications.

  12. PAR6, A Potential Marker for the Germ Cells Selected to Form Primordial Follicles in Mouse Ovary

    PubMed Central

    Wen, Jing; Zhang, Hua; Li, Ge; Mao, Guanping; Chen, Xiufen; Wang, Jianwei; Guo, Meng; Mu, Xinyi; Ouyang, Hong; Zhang, Meijia; Xia, Guoliang

    2009-01-01

    Partitioning-defective proteins (PAR) are detected to express mainly in the cytoplast, and play an important role in cell polarity. However, we showed here that PAR6, one kind of PAR protein, was localized in the nuclei of mouse oocytes that formed primordial follicles during the perinatal period, suggesting a new role of PAR protein. It is the first time we found that, in mouse fetal ovaries, PAR6 appeared in somatic cell cytoplasm and fell weak when somatic cells invaded germ cell cysts at 17.5 days post coitus (dpc). Meanwhile, the expression of PAR6 was observed in cysts, and became strong in the nuclei of some germ cells at 19.5 dpc and all primordial follicular oocytes at 3 day post parturition (dpp), and then obviously declined when the primordial follicles entered the folliculogenic growth phase. During the primordial follicle pool foundation, the number of PAR6 positive germ cells remained steady and was consistent with that of formed follicles at 3 dpp. There were no TUNEL (apoptosis examination) positive germ cells stained with PAR6 at any time studied. The number of follicles significantly declined when 15.5 dpc ovaries were treated with the anti-PAR6 antibody and PAR6 RNA interference. Carbenoxolone (CBX, a known blocker of gap junctions) inhibited the expression of PAR6 in germ cells and the formation of follicles. Our results suggest that PAR6 could be used as a potential marker of germ cells for the primordial follicle formation, and the expression of PAR6 by a gap junction-dependent process may contribute to the formation of primordial follicles and the maintenance of oocytes at the diplotene stage. PMID:19809506

  13. Ocular trauma treated with pars plana vitrectomy: early outcome report

    PubMed Central

    Mansouri, Mohammad Reza; Tabatabaei, Seyed Ali; Soleimani, Mohammad; Kiarudi, Mohammad Yaser; Molaei, Saber; Rouzbahani, Mehdi; Mireshghi, Meysam; Zaeferani, Mohsen; Ghasempour, Mehrbod

    2016-01-01

    AIM To evaluate demographic variables and visual outcomes, among patients with ocular injuries involving the posterior segment, managed with pars plana vitrectomy. METHODS The records of patients were studied retrospectively from March to September 2010, to determine the age, gender, place of occurrence of trauma, visual acuity, anatomical site, nature of injury, wound length, the presence of an afferent pupillary defect, and the timing of vitrectomy. The Ocular Trauma Score was measured. The minimum follow-up from presentation was 6mo. RESULTS Ninety patients (77 males, 13 females), with a mean age of 32.7±15.8y were included over the 6-month period. The majority of cases occurred in the workplace (47 patients), followed by home (14 patients). The mean visual acuity (logMAR) of patients significantly improved from 2.36±0.72 preoperatively to 1.50±1.14 postoperatively. Twenty-three patients had preoperative vision better than 2.0 logMAR, the postoperative visual acuity was significantly better among these patients than patients with worse than 2.0 logMAR (P<0.001). Visual improvement between groups with early vitrectomy (<7d) and delayed vitrectomy (>7d) was not significantly different (P=0.66). Postoperative visual acuity was not significantly different between patients with injury in Zone I and II (P=0.64), but patients with injury in Zone III had significantly poorer visual acuity (P=0.02). Patients with relative afferent pupillary defect had significantly poorer postoperative visual acuity (P=0.02). Preoperative visual acuity, the difference of preoperative and postoperative visual acuity, and postoperative visual acuity were significantly different between groups with different ocular trauma scores (P<0.001). CONCLUSION Trauma is more likely to occur in men under 40y of age and in the workplace. The favorable final visual outcome is associated with the absence of afferent pupillary defect, ocular trauma score and presenting visual acuity as well as the zone

  14. A method for estimating the diffuse attenuation coefficient (KdPAR)from paired temperature sensors

    USGS Publications Warehouse

    Read, Jordan S.; Rose, Kevin C.; Winslow, Luke A.; Read, Emily Kara

    2015-01-01

    A new method for estimating the diffuse attenuation coefficient for photosynthetically active radiation (KdPAR) from paired temperature sensors was derived. We show that during cases where the attenuation of penetrating shortwave solar radiation is the dominant source of temperature changes, time series measurements of water temperatures at multiple depths (z1 and z2) are related to one another by a linear scaling factor (a). KdPAR can then be estimated by the simple equation KdPAR ln(a)/(z2/z1). A suggested workflow is presented that outlines procedures for calculating KdPAR according to this paired temperature sensor (PTS) method. This method is best suited for conditions when radiative temperature gains are large relative to physical noise. These conditions occur frequently on water bodies with low wind and/or high KdPARs but can be used for other types of lakes during time periods of low wind and/or where spatially redundant measurements of temperatures are available. The optimal vertical placement of temperature sensors according to a priori knowledge of KdPAR is also described. This information can be used to inform the design of future sensor deployments using the PTS method or for campaigns where characterizing sub-daily changes in temperatures is important. The PTS method provides a novel method to characterize light attenuation in aquatic ecosystems without expensive radiometric equipment or the user subjectivity inherent in Secchi depth measurements. This method also can enable the estimation of KdPAR at higher frequencies than many manual monitoring programs allow.

  15. ParsEval: parallel comparison and analysis of gene structure annotations

    PubMed Central

    2012-01-01

    Background Accurate gene structure annotation is a fundamental but somewhat elusive goal of genome projects, as witnessed by the fact that (model) genomes typically undergo several cycles of re-annotation. In many cases, it is not only different versions of annotations that need to be compared but also different sources of annotation of the same genome, derived from distinct gene prediction workflows. Such comparisons are of interest to annotation providers, prediction software developers, and end-users, who all need to assess what is common and what is different among distinct annotation sources. We developed ParsEval, a software application for pairwise comparison of sets of gene structure annotations. ParsEval calculates several statistics that highlight the similarities and differences between the two sets of annotations provided. These statistics are presented in an aggregate summary report, with additional details provided as individual reports specific to non-overlapping, gene-model-centric genomic loci. Genome browser styled graphics embedded in these reports help visualize the genomic context of the annotations. Output from ParsEval is both easily read and parsed, enabling systematic identification of problematic gene models for subsequent focused analysis. Results ParsEval is capable of analyzing annotations for large eukaryotic genomes on typical desktop or laptop hardware. In comparison to existing methods, ParsEval exhibits a considerable performance improvement, both in terms of runtime and memory consumption. Reports from ParsEval can provide relevant biological insights into the gene structure annotations being compared. Conclusions Implemented in C, ParsEval provides the quickest and most feature-rich solution for genome annotation comparison to date. The source code is freely available (under an ISC license) at http://parseval.sourceforge.net/. PMID:22852583

  16. Transcription factor network downstream of protease activated receptors (PARs) modulating mouse bladder inflammation

    PubMed Central

    Saban, Ricardo; Simpson, Cindy; Davis, Carole A; Dozmorov, Igor; Maier, Julie; Fowler, Ben; Ihnat, Michael A; Hurst, Robert E; Wershil, Barry K; Saban, Marcia R

    2007-01-01

    Background All four PARs are present in the urinary bladder, and their expression is altered during inflammation. In order to search for therapeutic targets other than the receptors themselves, we set forth to determine TFs downstream of PAR activation in the C57BL/6 urinary bladders. Methods For this purpose, we used a protein/DNA combo array containing 345 different TF consensus sequences. Next, the TF selected was validated by EMSA and IHC. As mast cells seem to play a fundamental role in bladder inflammation, we determined whether c-kit receptor deficient (Kitw/Kitw-v) mice have an abrogated response to PAR stimulation. Finally, TFEB antibody was used for CHIP/Q-PCR assay and revealed up-regulation of genes known to be downstream of TFEB. Results TFEB, a member of the MiTF family of basic helix-loop-helix leucine zipper, was the only TF commonly up-regulated by all PAR-APs. IHC results confirm a correlation between inflammation and TFEB expression in C57BL/6 mice. In contrast, Kitw/Kitw-v mice did not exhibit inflammation in response to PAR activation. EMSA results confirmed the increased TFEB binding activity in C57BL/6 but not in Kitw/Kitw-v mice. Conclusion This is the first report describing the increased expression of TFEB in bladder inflammation in response to PAR activation. As TFEB belongs to a family of TFs essential for mast cell survival, our findings suggest that this molecule may influence the participation of mast cells in PAR-mediated inflammation and that targeting TFEB/MiTF activity may be a novel approach for the treatment of bladder inflammatory disorders. PMID:17705868

  17. Detecting Plant Photoprotective Response to Water Stress Through Variation In PAR Reflectance

    NASA Astrophysics Data System (ADS)

    Zygielbaum, A. I.; Arkebauer, T. J.; Walter-Shea, E.

    2012-12-01

    Published papers over several decades have shown increasing leaf-level optical reflectance with decreasing leaf water content. Our experimental results using maize and sorghum showed this increase consistently, caused by variation in optical absorption, in the visible (photosynthetically active radiation - PAR) and middle infrared (MIR) spectral regions. Relatively smaller response, driven by variation in optical scatter, was observed in near infrared (NIR). The concomitant increasing reflectance in the PAR and MIR regions is perplexing. PAR reflectance is dominated by chlorophyll absorption while MIR reflectance is dominated by water molecule absorption. However, changes in chlorophyll concentration, determined by chemical extraction, were too small to account for the variation in PAR reflectance. PAR and MIR reflectances were also influenced by the strength of incident light. Hence PAR reflectance appears to be modulated not only by pigment concentration, the classical description, but also by the strength of incident light and the severity of water deficit. We previously reported that these findings were consistent with chloroplast avoidance movement, a plant photoprotective response, which limits light absorption by pigments. We report here our continuing investigation of this phenomenon. In addition to reflectance measurements, time-lapse microscope images of leaves under increasing water deficit conditions were obtained. These show a brightening between veins which strongly supports our assertion that changes in PAR reflectance accompanying water deficit are caused primarily by chloroplast avoidance movement. Our results suggest that leaf, and possibly canopy, reflectance can therefore be used to detect and measure plant stress. These results also indicate that chloroplast avoidance movement may cause poor estimates of leaf chlorophyll content using techniques based on fluoresced, reflected or transmitted light.

  18. Cortical Polarity of the RING Protein PAR-2 Is Maintained by Exchange Rate Kinetics at the Cortical-Cytoplasmic Boundary.

    PubMed

    Arata, Yukinobu; Hiroshima, Michio; Pack, Chan-Gi; Ramanujam, Ravikrishna; Motegi, Fumio; Nakazato, Kenichi; Shindo, Yuki; Wiseman, Paul W; Sawa, Hitoshi; Kobayashi, Tetsuya J; Brandão, Hugo B; Shibata, Tatsuo; Sako, Yasushi

    2016-08-23

    Cell polarity arises through the spatial segregation of polarity regulators. PAR proteins are polarity regulators that localize asymmetrically to two opposing cortical domains. However, it is unclear how the spatially segregated PAR proteins interact to maintain their mutually exclusive partitioning. Here, single-molecule detection analysis in Caenorhabditis elegans embryos reveals that cortical PAR-2 diffuses only short distances, and, as a result, most PAR-2 molecules associate and dissociate from the cortex without crossing into the opposing domain. Our results show that cortical PAR-2 asymmetry is maintained by the local exchange reactions that occur at the cortical-cytoplasmic boundary. Additionally, we demonstrate that local exchange reactions are sufficient to maintain cortical asymmetry in a parameter-free mathematical model. These findings suggest that anterior and posterior PAR proteins primarily interact through the cytoplasmic pool and not via cortical diffusion. PMID:27524610

  19. Towards an Improved LAI Collection Protocol via Simulated and Field-Based PAR Sensing

    PubMed Central

    Yao, Wei; Kelbe, David; van Leeuwen, Martin; Romanczyk, Paul; van Aardt, Jan

    2016-01-01

    In support of NASA’s next-generation spectrometer—the Hyperspectral Infrared Imager (HyspIRI)—we are working towards assessing sub-pixel vegetation structure from imaging spectroscopy data. Of particular interest is Leaf Area Index (LAI), which is an informative, yet notoriously challenging parameter to efficiently measure in situ. While photosynthetically-active radiation (PAR) sensors have been validated for measuring crop LAI, there is limited literature on the efficacy of PAR-based LAI measurement in the forest environment. This study (i) validates PAR-based LAI measurement in forest environments, and (ii) proposes a suitable collection protocol, which balances efficiency with measurement variation, e.g., due to sun flecks and various-sized canopy gaps. A synthetic PAR sensor model was developed in the Digital Imaging and Remote Sensing Image Generation (DIRSIG) model and used to validate LAI measurement based on first-principles and explicitly-known leaf geometry. Simulated collection parameters were adjusted to empirically identify optimal collection protocols. These collection protocols were then validated in the field by correlating PAR-based LAI measurement to the normalized difference vegetation index (NDVI) extracted from the “classic” Airborne Visible Infrared Imaging Spectrometer (AVIRIS-C) data (R2 was 0.61). The results indicate that our proposed collecting protocol is suitable for measuring the LAI of sparse forest (LAI < 3–5 (m2/m2)). PMID:27428969

  20. PAR-1 mediated apoptosis of breast cancer cells by V. cholerae hemagglutinin protease.

    PubMed

    Ray, Tanusree; Pal, Amit

    2016-05-01

    Bacterial toxins have emerged as promising agents in cancer treatment strategy. Hemagglutinin (HAP) protease secreted by Vibrio cholerae induced apoptosis in breast cancer cells and regresses tumor growth in mice model. The success of novel cancer therapies depends on their selectivity for cancer cells with limited toxicity for normal tissues. Increased expression of Protease Activated Receptor-1 (PAR-1) has been reported in different malignant cells. In this study we report that HAP induced activation and over expression of PAR-1 in breast cancer cells (EAC). Immunoprecipitation studies have shown that HAP specifically binds with PAR-1. HAP mediated activation of PAR-1 caused nuclear translocation of p50-p65 and the phosphorylation of p38 which triggered the activation of NFκB and MAP kinase signaling pathways. These signaling pathways enhanced the cellular ROS level in malignant cells that induced the intrinsic pathway of cell apoptosis. PAR-1 mediated apoptosis by HAP of malignant breast cells without effecting normal healthy cells in the same environment makes it a good therapeutic agent for treatment of cancer. PMID:26897170

  1. Novel mechanism of apoptosis resistance in cancer mediated by extracellular PAR-4.

    PubMed

    Burikhanov, Ravshan; Shrestha-Bhattarai, Tripti; Qiu, Shirley; Shukla, Nidhi; Hebbar, Nikhil; Lele, Subodh M; Horbinski, Craig; Rangnekar, Vivek M

    2013-01-15

    Tumor suppressor PAR-4 acts in part by modulating sensitivity to apoptosis, but the basis for its activity is not fully understood. In this study, we describe a novel mechanism of antiapoptosis by NF-κB, revealing that it can block PAR-4-mediated apoptosis by downregulating trafficking of the PAR-4 receptor GRP78 from the endoplasmic reticulum to the cell surface. Mechanistic investigations revealed that NF-κB mediated this antiapoptotic mechanism by upregulating expression of UACA, a proinflammatory protein in certain disease settings. In clinical specimens of cancer, a strong correlation existed between NF-κB activity and UACA expression, relative to normal tissues. UACA bound to intracellular PAR-4 in diverse cancer cells, where it prevented translocation of GRP78 from the endoplasmic reticulum to the cell surface. This pathway of antiapoptosis could be inhibited by suppressing levels of NF-κB or UACA expression, which enhanced endoplasmic reticulum stress and restored GRP78 trafficking to the cell surface, thereby sensitizing cancer cells to apoptosis by extracellular PAR-4 or GRP78 agonistic antibody. In summary, our results identify a novel intracellular pathway of apoptosis mediated by NF-κB through UACA elevation, which by attenuating endoplasmic reticulum stress and GRP78 translocation to the cell surface can blunt the sensitivity of cancer cells to apoptosis. PMID:23204231

  2. Microtubule-like Properties of the Bacterial Actin Homolog ParM-R1*

    PubMed Central

    Popp, David; Narita, Akihiro; Lee, Lin Jie; Larsson, Mårten; Robinson, Robert C.

    2012-01-01

    In preparation for mammalian cell division, microtubules repeatedly probe the cytoplasm to capture chromosomes and assemble the mitotic spindle. Critical features of this microtubule system are the formation of radial arrays centered at the centrosomes and dynamic instability, leading to persistent cycles of polymerization and depolymerization. Here, we show that actin homolog, ParM-R1 that drives segregation of the R1 multidrug resistance plasmid from Escherichia coli, can also self-organize in vitro into asters, which resemble astral microtubules. ParM-R1 asters grow from centrosome-like structures consisting of interconnected nodes related by a pseudo 8-fold symmetry. In addition, we show that ParM-R1 is able to perform persistent microtubule-like oscillations of assembly and disassembly. In vitro, a whole population of ParM-R1 filaments is synchronized between phases of growth and shrinkage, leading to prolonged synchronous oscillations even at physiological ParM-R1 concentrations. These results imply that the selection pressure to reliably segregate DNA during cell division has led to common mechanisms within diverse segregation machineries. PMID:22908230

  3. Mammalian Par3 regulates progenitor cell asymmetric division via Notch signaling in the developing neocortex

    PubMed Central

    Bultje, Ronald S.; Castaneda-Castellanos, David R.; Jan, Lily Yeh; Jan, Yuh-Nung; Kriegstein, Arnold R.; Shi, Song-Hai

    2009-01-01

    Asymmetric cell division of radial glial progenitors produces neurons while allowing self-renewal; however, little is known about the mechanism that generates asymmetry in daughter cell fate specification. Here we found that mammalian partition defective protein 3 (mPar3), a key cell polarity determinant, exhibits dynamic distribution in radial glial progenitors. While it is enriched at the lateral membrane domain in the ventricular endfeet during interphase, mPar3 becomes dispersed and shows asymmetric localization as cell cycle progresses. Either removal or ectopic expression of mPar3 prevents radial glial progenitors from dividing asymmetrically yet generates different outcomes in daughter cell fate specification. Furthermore, the expression level of mPar3 affects Notch signaling, and manipulations of Notch signaling or Numb expression suppress mPar3 regulation of radial glial cell division and daughter cell fate specification. These results reveal a critical molecular pathway underlying asymmetric cell division of radial glial progenitors in the mammalian neocortex. PMID:19640478

  4. Participatory Action Research (PAR) in Middle School: Opportunities, Constraints, and Key Processes

    PubMed Central

    Ritterman, Miranda L.; Wanis, Maggie G.

    2010-01-01

    Late childhood and early adolescence represent a critical transition in the developmental and academic trajectory of youth, a time in which there is an upsurge in academic disengagement and psychopathology. PAR projects that can promote youth’s sense of meaningful engagement in school and a sense of efficacy and mattering can be particularly powerful given the challenges of this developmental stage. In the present study, we draw on data from our own collaborative implementation of PAR projects in secondary schools to consider two central questions: (1) How do features of middle school settings and the developmental characteristics of the youth promote or inhibit the processes, outcomes, and sustainability of the PAR endeavor? and (2) How can the broad principles and concepts of PAR be effectively translated into specific intervention activities in schools, both within and outside of the classroom? In particular, we discuss a participatory research project conducted with 6th and 7th graders at an urban middle school as a means of highlighting the opportunities, constraints, and lessons learned in our efforts to contribute to the high-quality implementation and evaluation of PAR in diverse urban public schools. PMID:20676754

  5. Towards an Improved LAI Collection Protocol via Simulated and Field-Based PAR Sensing.

    PubMed

    Yao, Wei; Kelbe, David; Leeuwen, Martin van; Romanczyk, Paul; Aardt, Jan van

    2016-01-01

    In support of NASA's next-generation spectrometer-the Hyperspectral Infrared Imager (HyspIRI)-we are working towards assessing sub-pixel vegetation structure from imaging spectroscopy data. Of particular interest is Leaf Area Index (LAI), which is an informative, yet notoriously challenging parameter to efficiently measure in situ. While photosynthetically-active radiation (PAR) sensors have been validated for measuring crop LAI, there is limited literature on the efficacy of PAR-based LAI measurement in the forest environment. This study (i) validates PAR-based LAI measurement in forest environments, and (ii) proposes a suitable collection protocol, which balances efficiency with measurement variation, e.g., due to sun flecks and various-sized canopy gaps. A synthetic PAR sensor model was developed in the Digital Imaging and Remote Sensing Image Generation (DIRSIG) model and used to validate LAI measurement based on first-principles and explicitly-known leaf geometry. Simulated collection parameters were adjusted to empirically identify optimal collection protocols. These collection protocols were then validated in the field by correlating PAR-based LAI measurement to the normalized difference vegetation index (NDVI) extracted from the "classic" Airborne Visible Infrared Imaging Spectrometer (AVIRIS-C) data ( R 2 was 0.61). The results indicate that our proposed collecting protocol is suitable for measuring the LAI of sparse forest (LAI < 3-5 ( m 2 / m 2 )). PMID:27428969

  6. uPAR-induced cell adhesion and migration: vitronectin provides the key

    PubMed Central

    Madsen, Chris D.; Ferraris, Gian Maria Sarra; Andolfo, Annapaola; Cunningham, Orla; Sidenius, Nicolai

    2007-01-01

    Expression of the membrane receptor uPAR induces profound changes in cell morphology and migration, and its expression correlates with the malignant phenotype of cancers. To identify the molecular interactions essential for uPAR function in these processes, we carried out a complete functional alanine scan of uPAR in HEK293 cells. Of the 255 mutant receptors characterized, 34 failed to induce changes in cell morphology. Remarkably, the molecular defect of all of these mutants was a specific reduction in integrin-independent cell binding to vitronectin. A membrane-tethered plasminogen activator inhibitor-1, which has the same binding site in vitronectin as uPAR, replicated uPAR-induced changes. A direct uPAR–vitronectin interaction is thus both required and sufficient to initiate downstream changes in cell morphology, migration, and signal transduction. Collectively these data demonstrate a novel mechanism by which a cell adhesion molecule lacking inherent signaling capability evokes complex cellular responses by modulating the contact between the cell and the matrix without the requirement for direct lateral protein–protein interactions. PMID:17548516

  7. Lambeaux autofermants pour le traitement des brulures electriques du scalp par haut voltage

    PubMed Central

    Hafidi, J.; El Mazouz, S.; El Mejatti, H.; Fejjal, N.; Gharib, N.E.; Abbassi, A.; Belmahi, A.M.

    2011-01-01

    Summary Les brûlures électriques par haut voltage sont responsables de gros dégâts tissulaires en immédiat et dans les jours suivant l’accident du fait de la chaleur importante dégagée par effet joule et de la thrombose microvasculaire évolutive. Les pertes de substances du scalp secondaires à ces brûlures nécessitent une couverture par lambeaux vu la destruction du périoste et du calvarium en regard. De juin 1997 à juin 2008, 15 patients ont été traités pour des pertes de substance du scalp secondaires à des brûlures électriques par haut voltage de diamètre allant de 8 à 11 cm et siégeant dans la région tonsurale. Ces patients ont été opérés dans la première semaine suivant l’accident. Les pertes de substance du scalp de taille moyenne secondaires à ces brûlures peuvent être couvertes per primam de façon fiable par des lambeaux locaux axialisés et multiples. Nous relatons l’expérience du Service de Chirurgie Plastique du Centre Hospitalier Universitaire Ibn-Sina, Rabat, Maroc, dans la gestion et la prise en charge de ces brûlures. PMID:22262963

  8. "It was like reading a detective novel": Using PAR to work together for culture change.

    PubMed

    Fortune, Darla; McKeown, Janet; Dupuis, Sherry; de Witt, Lorna

    2015-08-01

    Participatory action research (PAR), with its focus on engagement and collaboration, is uniquely suited to enhancing culture change initiatives in dementia care. Yet, there is limited literature of its application to culture change approaches in care settings, and even less in dementia specific care contexts. To address these gaps in the literature, the purpose of this paper is to examine the complexities of a PAR project aimed at changing the culture of dementia care in two diverse dementia care settings, including a long term care (LTC) and community care setting. Drawing from data gathered throughout the PAR process, we unpack the challenges experienced by participants working together to guide culture change within their respective care settings. These challenges include: overextending selves through culture change participation; fluctuating group membership; feeling uncertainty, confusion and apprehension about the process; frustratingly slow process; and seeking diverse group representation in decision making. We also highlight the potential for appreciative inquiry (AI) to be integrated with PAR to guide a process whereby participants involved in culture change initiatives can develop strategies to mitigate challenges they experience. We view the challenges and strategies shared here as being constructive to would-be culture change agents and hope this paper will move others to consider the use of PAR when engaging in culture change initiatives. PMID:26162724

  9. Towards an improved LAI collection protocol via simulated field-based PAR sensing

    DOE PAGESBeta

    Yao, Wei; Van Leeuwen, Martin; Romanczyk, Paul; van Aardt, Jan; Kelbe, David

    2016-07-14

    In support of NASA’s next-generation spectrometer—the Hyperspectral Infrared Imager (HyspIRI)—we are working towards assessing sub-pixel vegetation structure from imaging spectroscopy data. Of particular interest is Leaf Area Index (LAI), which is an informative, yet notoriously challenging parameter to efficiently measure in situ. While photosynthetically-active radiation (PAR) sensors have been validated for measuring crop LAI, there is limited literature on the efficacy of PAR-based LAI measurement in the forest environment. This study (i) validates PAR-based LAI measurement in forest environments, and (ii) proposes a suitable collection protocol, which balances efficiency with measurement variation, e.g., due to sun flecks and various-sized canopymore » gaps. A synthetic PAR sensor model was developed in the Digital Imaging and Remote Sensing Image Generation (DIRSIG) model and used to validate LAI measurement based on first-principles and explicitly-known leaf geometry. Simulated collection parameters were adjusted to empirically identify optimal collection protocols. Furthermore, these collection protocols were then validated in the field by correlating PAR-based LAI measurement to the normalized difference vegetation index (NDVI) extracted from the “classic” Airborne Visible Infrared Imaging Spectrometer (AVIRIS-C) data (R2 was 0.61). The results indicate that our proposed collecting protocol is suitable for measuring the LAI of sparse forest (LAI < 3–5 ( m2/m2)).« less

  10. Protease-activated receptors (PARs) in cancer: Novel biased signaling and targets for therapy.

    PubMed

    Bar-Shavit, R; Maoz, M; Kancharla, A; Jaber, M; Agranovich, D; Grisaru-Granovsky, S; Uziely, B

    2016-01-01

    Despite the fact that G protein-coupled receptors (GPCRs) mediate numerous physiological processes and represent targets for therapeutics for a vast array of diseases, their role in tumor biology is under appreciated. Protease-activated receptors (PARs) form a family which belongs to GPCR class A. PAR1&2 emerge with a central role in epithelial malignancies. Although the part of PAR1&2 in cancer is on the rise, their underlying signaling events are poorly understood. We review hereby past, present, and future cancer-associated PAR biology. Mainly, their role in physiological (placenta-cytotophobalst) and patho-physiological invasion processes. The identification and characterization of signal pleckstrin homology (PH)-domain-binding motifs established critical sites for breast cancer growth in PAR1&2. Among the proteins found to harbor important PH-domains and are involved in PAR biology are Akt/PKB as also Etk/Bmx and Vav3. A point mutation in PAR2, H349A, but not R352A, abrogated PH-protein association and is sufficient to markedly reduce PAR2-instigated breast tumor growth in vivo as also placental extravillous trophoblast (EVT) invasion in vitro is markedly reduced. Similarly, the PAR1 mutant hPar1-7A, which is unable to bind PH-domain, inhibits mammary tumors and EVT invasion, endowing these motifs with physiological significance and underscoring the importance of these previously unknown PAR1 and PAR2 PH-domain-binding motifs in both pathological and physiological invasion processes. PMID:26928551

  11. Streptococcal SpeB Cleaved PAR-1 Suppresses ERK Phosphorylation and Blunts Thrombin-Induced Platelet Aggregation

    PubMed Central

    Ender, Miriam; Andreoni, Federica; Zinkernagel, Annelies Sophie; Schuepbach, Reto Andreas

    2013-01-01

    Background The family of 4 related protease-activated receptors (PAR-1, 2, 3 & 4) expressed by mammalian cells allow to sense for and react to extracellular proteolytic activity. Since major human bacterial pathogens secret a wide array of protease(-s) we investigated whether they interfere with human PAR function. Methodology/Principal Findings Supernatants from cultures of major human bacterial pathogens were assayed for the presence of protease(-s) capable to cleave overexpressed human PAR-1, 2, 3 and 4 reporter constructs. Group A streptococcus (GAS) was found to secret a PAR-1-cleaving protease. Experiments involving genetical and pharmacological gain and loss of function identified streptococcal pyrogenic exotoxin B SpeB as the protease responsible. On the host’s side analysis of overexpressed PAR-1 carrying alanine substitutions and deletions showed the amino acid residue leucine44 on PAR-1’s extracellular N-terminus to be the only cleavage site. Complementary studies on endogenously expressed PAR-1 using PAR-1 blocking antibodies further supported our conclusion. Through PAR-1 cleavage SpeB efficiently blunted thrombin-induced induction of the ERK-pathway in endothelial cells and prevented platelets aggregation in response to thrombin. Conclusions/Significance Our results identify a novel function of the streptococcal virulence factor SpeB. By cleaving human PAR-1 at the N-terminal amino acid residue leucine44 SpeB rendered endothelial cells unresponsive to thrombin and prevented human platelets from thrombin-induced aggregation. These results suggest that by blunting PAR-1 signaling, SpeB modulates various innate host responses directed against invasive GAS potentially helping the invasive bacteria to escape. This may allow to tailor additional treatments in the future since upon invasion of the blood stream endothelial cells as well as platelets and mononuclear cells respond to PAR-1 agonists aiming to prevent further bacterial dissemination. PMID

  12. Hook2, a microtubule-binding protein, interacts with Par6α and controls centrosome orientation during polarized cell migration.

    PubMed

    Pallesi-Pocachard, Emilie; Bazellieres, Elsa; Viallat-Lieutaud, Annelise; Delgrossi, Marie-Hélène; Barthelemy-Requin, Magali; Le Bivic, André; Massey-Harroche, Dominique

    2016-01-01

    Polarity protein complexes function during polarized cell migration and a subset of these proteins localizes to the reoriented centrosome during this process. Despite these observations, the mechanisms behind the recruitment of these polarity complexes such as the aPKC/PAR6α complex to the centrosome are not well understood. Here we identify Hook2 as an interactor for the aPKC/PAR6α complex that functions to localize this complex at the centrosome. We first demonstrate that Hook2 is essential for the polarized Golgi re-orientation towards the migration front. Depletion of Hook2 results in a decrease of PAR6α at the centrosome during cell migration, while overexpression of Hook2 in cells induced the formation of aggresomes with the recruitment of PAR6α, aPKC and PAR3. In addition, we demonstrate that the interaction between the C-terminal domain of Hook2 and the aPKC-binding domain of PAR6α localizes PAR6α to the centrosome during cell migration. Our data suggests that Hook2, a microtubule binding protein, plays an important role in the regulation of PAR6α recruitment to the centrosome to bridge microtubules and the aPKC/PAR complex. This data reveals how some of the polarity protein complexes are recruited to the centrosome and might regulate pericentriolar and microtubule organization and potentially impact on polarized migration. PMID:27624926

  13. Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: Discovery and SAR of ML354.

    PubMed

    Wen, Wandong; Young, Summer E; Duvernay, Matthew T; Schulte, Michael L; Nance, Kellie D; Melancon, Bruce J; Engers, Julie; Locuson, Charles W; Wood, Michael R; Daniels, J Scott; Wu, Wenjun; Lindsley, Craig W; Hamm, Heidi E; Stauffer, Shaun R

    2014-10-01

    Herein we report the discovery and SAR of an indole-based protease activated receptor-4 (PAR-4) antagonist scaffold derived from a similarity search of the Vanderbilt HTS collection, leading to MLPCN probe ML354 (VU0099704). Using a novel PAC-1 fluorescent αIIbβ3 activation assay this probe molecule antagonist was found to have an IC50 of 140nM for PAR-4 with 71-fold selectivity versus PAR-1 (PAR-1IC50=10μM). PMID:25176330

  14. Potential Ecological Effects of Contaminants in the Exposed Par Pond Sediments

    SciTech Connect

    Paller, M.H.; Wike, L.D.

    1996-08-01

    Sediment and small mammal samples were collected from the exposed sediments of Par Pond in early 1995, shortly before the reservoir was refilled after a 4-year drawdown. Sampling was confined to elevations between 58 and 61 meters (190 and 200 feet) above mean sea level, which includes the sediments likely to be exposed if the Par Pond water level is permitted to fluctuate naturally. Both soil and small mammal samples were analyzed for a number of radionuclides and metals. Some of the soil samples were also analyzed for organic contaminants. The objective of the study was to determine if contaminant levels in the Par Pond sediments were high enough to cause deleterious ecological effects.

  15. Paraplégie compliquant une plaie abdominale antérieure par arme blanche

    PubMed Central

    Elahmadi, Brahim; Awab, Almahdi; El Moussaoui, Rachid; El Hijri, Ahmed; Azzouzi, Abderrahim; Alilou, Mustapha

    2015-01-01

    Les traumatismes médullaires sont des complications rares des plaies abdominales antérieures par arme blanche. Son diagnostic est difficile parfois retardé. L'imagerie par résonance magnétique reste l'examen de choix. Le traitement dépend du tableau clinique et de la gravité de la souffrance médullaire. Le pronostic est corrélé à l’étendue et à la nature de la lésion médullaire. Nous rapportons un cas exceptionnel d'un traumatisme médullaire chez une patiente victime d'une plaie abdominale antérieure par arme blanche. PMID:25995808

  16. Expression of uPAR in human trophoblast and its role in trophoblast invasion

    PubMed Central

    Liu, Shuai; Zheng, Qin; Cui, Xin-Yuan; Dai, Kui-Xing; Yang, Xue-Song; Li, Fa-Sheng; Yan, Qiu

    2015-01-01

    Placental trophoblast cells differentiate into invasive trophoblasts or syncytiotrophoblasts. Abnormal trophoblast invasion results in pregnancy-associated disease and abortion. uPAR is a cell membrane-bound glycosylated protein, involved in physiological and pathological processes. However, uPAR expression in villi during threatened abortion and its role in trophoblast differentiation are unclear. We determined that, uPAR expression in the villi was reduced in threatened abortion patients than that in normal pregnancy. uPARsiRNA inhibited the potential for trophoblast migration and invasion in explants culture and HTR8/SVneo cells. It also enhanced forskolin-induced fusion of HTR8/SVneo cells. Overall, this study provides a possible reason for abortion. PMID:26823748

  17. Stress reaction of the pars interarticularis leading to spondylolysis. A cause of adolescent low back pain.

    PubMed

    Weir, M R; Smith, D S

    1989-11-01

    We report an adolescent with progression from a stress reaction of the pars interarticularis without radiographic findings, to radiographic fracture and spondylolysis, illustrating the evolution of spondylolysis in an athletically active early adolescent. Gymnastics, diving, pole vaulting, or collision/contact sports such as football, soccer, hockey, and la crosse are common sports with a disproportional frequency of spondylolysis. Rotational forces around the long axis of the spine with load bearing hyperextension are important in etiology. Low back pain in the active adolescent or preadolescent, even with normal oblique lumbar radiographs, may have a treatable origin--stress reaction or fracture of a lumbar pars interarticularis. Screening evaluation is the standing one-leg extension maneuver. Liberal use of nuclear studies for minimal back symptoms in athletic adolescents may help exclude this relatively common, potentially treatable condition, spondylolysis of the pars interarticularis. PMID:2532632

  18. Factor Xa stimulates fibroblast procollagen production, proliferation, and calcium signaling via PAR{sub 1} activation

    SciTech Connect

    Blanc-Brude, Olivier P. . E-mail: olivier.blanc-brude@larib.inserm.fr; Archer, Fabienne; Leoni, Patricia; Derian, Claudia; Bolsover, Steven; Laurent, Geoffrey J.; Chambers, Rachel C.

    2005-03-10

    Fibroblast proliferation and procollagen production are central features of tissue repair and fibrosis. In addition to its role in blood clotting, the coagulation cascade proteinase thrombin can contribute to tissue repair by stimulating fibroblasts via proteolytic activation of proteinase-activated receptor-1 (PAR{sub 1}). During hemostasis, the coagulation cascade proteinase factor X is converted into factor Xa. We have previously shown that factor Xa upregulates fibroblast proliferation via production of autocrine PDGF. In this study, we further examined the effects of factor Xa on fibroblast function and aimed to identify its signaling receptor. We showed that factor Xa stimulates procollagen promoter activity and protein production by human and mouse fibroblasts. This effect was independent of PDGF and thrombin production, but dependent on factor Xa proteolytic activity. We also showed that PAR{sub 1}-deficient mouse fibroblasts did not upregulate procollagen production, mobilize cytosolic calcium, or proliferate in response to factor Xa. Desensitization techniques and PAR{sub 1}-specific agonists and inhibitors were used to demonstrate that PAR{sub 1} mediates factor Xa signaling in human fibroblasts. This is the first report that factor Xa stimulates extracellular matrix production. In contrast with endothelial cells and vascular smooth muscle cells, fibroblasts appear to be the only cell type in which the effects of factor Xa are mediated mainly via PAR{sub 1} and not PAR{sub 2}. These findings are critical for our understanding of tissue repair and fibrotic mechanisms, and for the design of novel approaches to inhibit the profibrotic effects of the coagulation cascade without compromising blood hemostasis.

  19. First-in-human uPAR PET: Imaging of Cancer Aggressiveness.

    PubMed

    Persson, Morten; Skovgaard, Dorthe; Brandt-Larsen, Malene; Christensen, Camilla; Madsen, Jacob; Nielsen, Carsten H; Thurison, Tine; Klausen, Thomas Levin; Holm, Søren; Loft, Annika; Berthelsen, Anne Kiil; Ploug, Michael; Pappot, Helle; Brasso, Klaus; Kroman, Niels; Højgaard, Liselotte; Kjaer, Andreas

    2015-01-01

    A first-in-human clinical trial with Positron Emission Tomography (PET) imaging of the urokinase-type plasminogen activator receptor (uPAR) in patients with breast, prostate and bladder cancer, is described. uPAR is expressed in many types of human cancers and the expression is predictive of invasion, metastasis and indicates poor prognosis. uPAR PET imaging therefore holds promise to be a new and innovative method for improved cancer diagnosis, staging and individual risk stratification. The uPAR specific peptide AE105 was conjugated to the macrocyclic chelator DOTA and labeled with (64)Cu for targeted molecular imaging with PET. The safety, pharmacokinetic, biodistribution profile and radiation dosimetry after a single intravenous dose of (64)Cu-DOTA-AE105 were assessed by serial PET and computed tomography (CT) in 4 prostate, 3 breast and 3 bladder cancer patients. Safety assessment with laboratory blood screening tests was performed before and after PET ligand injection. In a subgroup of the patients, the in vivo stability of our targeted PET ligand was determined in collected blood and urine. No adverse or clinically detectable side effects in any of the 10 patients were found. The ligand exhibited good in vivo stability and fast clearance from plasma and tissue compartments by renal excretion. In addition, high uptake in both primary tumor lesions and lymph node metastases was seen and paralleled high uPAR expression in excised tumor tissue. Overall, this first-in-human study therefore provides promising evidence for safe use of (64)Cu-DOTA-AE105 for uPAR PET imaging in cancer patients. PMID:26516369

  20. First-in-human uPAR PET: Imaging of Cancer Aggressiveness

    PubMed Central

    Persson, Morten; Skovgaard, Dorthe; Brandt-Larsen, Malene; Christensen, Camilla; Madsen, Jacob; Nielsen, Carsten H.; Thurison, Tine; Klausen, Thomas Levin; Holm, Søren; Loft, Annika; Berthelsen, Anne Kiil; Ploug, Michael; Pappot, Helle; Brasso, Klaus; Kroman, Niels; Højgaard, Liselotte; Kjaer, Andreas

    2015-01-01

    A first-in-human clinical trial with Positron Emission Tomography (PET) imaging of the urokinase-type plasminogen activator receptor (uPAR) in patients with breast, prostate and bladder cancer, is described. uPAR is expressed in many types of human cancers and the expression is predictive of invasion, metastasis and indicates poor prognosis. uPAR PET imaging therefore holds promise to be a new and innovative method for improved cancer diagnosis, staging and individual risk stratification. The uPAR specific peptide AE105 was conjugated to the macrocyclic chelator DOTA and labeled with 64Cu for targeted molecular imaging with PET. The safety, pharmacokinetic, biodistribution profile and radiation dosimetry after a single intravenous dose of 64Cu-DOTA-AE105 were assessed by serial PET and computed tomography (CT) in 4 prostate, 3 breast and 3 bladder cancer patients. Safety assessment with laboratory blood screening tests was performed before and after PET ligand injection. In a subgroup of the patients, the in vivo stability of our targeted PET ligand was determined in collected blood and urine. No adverse or clinically detectable side effects in any of the 10 patients were found. The ligand exhibited good in vivo stability and fast clearance from plasma and tissue compartments by renal excretion. In addition, high uptake in both primary tumor lesions and lymph node metastases was seen and paralleled high uPAR expression in excised tumor tissue. Overall, this first-in-human study therefore provides promising evidence for safe use of 64Cu-DOTA-AE105 for uPAR PET imaging in cancer patients. PMID:26516369

  1. Parádsasvárite, a new member of the malachite-rosasite group from Parádsasvár, Mátra Mountains, Hungary

    NASA Astrophysics Data System (ADS)

    Fehér, Béla; Szakáll, Sándor; Zajzon, Norbert; Mihály, Judith

    2015-08-01

    Parádsasvárite (IMA No. 2012-077) was found in the Nagy-Lápafő area, Parádsasvár, Mátra Mountains, Hungary. It forms pale beige, globular aggregates up to 0.2 mm in diameter on calcite. Associated secondary minerals are smithsonite, hemimorphite, hydrozincite, aurichalcite and rosasite. The mineral was formed as an alteration product of sphalerite and chalcopyrite in a carbonate-rich environment. Parádsasvárite is translucent with a weakly vitreous, dull or silky lustre and white streak. Its Mohs hardness is about 2-3, cleavage and parting were not observed. It is brittle; the fracture is finely fibrous. Average of nine electron-microprobe analyses gave ZnO 58.08, CuO 12.60, PbO 1.27, CO2 (calc.) 19.50, H2O (calc.) 7.94, total 99.39 wt.%, corresponding to the empirical formula (Zn0.62Cu0.36Pb0.01)Σ0.99Zn1.00(CO3)(OH)2. The seven strongest lines in the X-ray powder diffraction pattern are [dhkl in Å (Iobs %, hkl)] 6.054 (67, 200), 5.085 (100, 210), 3.703 (87, 310 and 220), 3.021 (25, 400 and 130), 2.971 (25, -211 and 001), 2.603 (62, -221) and 2.539 (36, 420). According to its X-ray powder diffraction data and chemical formula, parádsasvárite belongs to the malachite-rosasite group and it is isostructural with rosasite. It is monoclinic, space group P21/ a, a = 12.92(1), b = 9.372(7), c = 3.159(4) Å, β = 110.4(1)°, V = 358.5(5) Å3, Z = 4.

  2. K-Area and Par Pond Sewage Sludge Application Sites groundwater monitoring reports, second quarter 1992

    SciTech Connect

    Not Available

    1992-10-01

    During second quarter 1992, the three wells at the K-Area Sewage Sludge Application Site (KSS wells) and the three wells at the Par Pond Sewage Sludge Application Site (PSS wells) were sampled for analyses required each quarter or annually by South Carolina Department of Health and Environmental Control Construction Permit 13, 173. This report includes the results of those analyses. None of the analyzed constituents exceeded the Primary Drinking Water Standard or the Savannah River Site Flag 2 criteria at either the K-Area Sewage Sludge Application Site or the Par Pond Sewage Sludge Application Site.

  3. PARma: identification of microRNA target sites in AGO-PAR-CLIP data.

    PubMed

    Erhard, Florian; Dölken, Lars; Jaskiewicz, Lukasz; Zimmer, Ralf

    2013-01-01

    PARma is a complete data analysis software for AGO-PAR-CLIP experiments to identify target sites of microRNAs as well as the microRNA binding to these sites. It integrates specific characteristics of the experiments into a generative model. The model and a novel pattern discovery tool are iteratively applied to data to estimate seed activity probabilities, cluster confidence scores and to assign the most probable microRNA. Based on differential PAR-CLIP analysis and comparison to RIP-Chip data, we show that PARma is more accurate than existing approaches. PARma is available from http://www.bio.ifi.lmu.de/PARma. PMID:23895117

  4. PARma: identification of microRNA target sites in AGO-PAR-CLIP data

    PubMed Central

    2013-01-01

    PARma is a complete data analysis software for AGO-PAR-CLIP experiments to identify target sites of microRNAs as well as the microRNA binding to these sites. It integrates specific characteristics of the experiments into a generative model. The model and a novel pattern discovery tool are iteratively applied to data to estimate seed activity probabilities, cluster confidence scores and to assign the most probable microRNA. Based on differential PAR-CLIP analysis and comparison to RIP-Chip data, we show that PARma is more accurate than existing approaches. PARma is available from http://www.bio.ifi.lmu.de/PARma PMID:23895117

  5. Using Photosynthetically Active Radiation (PAR) Observations to Estimate Potential Evaporation with Combination Equations

    NASA Astrophysics Data System (ADS)

    Kim, J.; Freyberg, D. L.

    2011-12-01

    Estimating potential evaporation with combination equations typically depends on observations of solar radiation. In situations where only photosynthetically active radiation (PAR) observations are available, a conversion model is required. We use coincident observations of solar radiation and PAR to build a conversion model for the Santa Cruz Mountains region of California, USA. The model takes advantage of the strong seasonality in cloud cover and albedo, using two seasonal sub-models to improve performance. We examine the uncertainty induced by model error in predictions of potential evaporation and reference crop evaporation using locally calibrated combination equations, and compare with direct observations of pan evaporation and inferred estimates of lake evaporation.

  6. MtPAR MYB transcription factor acts as an on switch for proanthocyanidin biosynthesis in Medicago truncatula.

    PubMed

    Verdier, Jerome; Zhao, Jian; Torres-Jerez, Ivone; Ge, Shujun; Liu, Chenggang; He, Xianzhi; Mysore, Kirankumar S; Dixon, Richard A; Udvardi, Michael K

    2012-01-31

    MtPAR (Medicago truncatula proanthocyanidin regulator) is an MYB family transcription factor that functions as a key regulator of proanthocyanidin (PA) biosynthesis in the model legume Medicago truncatula. MtPAR expression is confined to the seed coat, the site of PA accumulation. Loss-of-function par mutants contained substantially less PA in the seed coat than the wild type, whereas levels of anthocyanin and other specialized metabolites were normal in the mutants. In contrast, massive accumulation of PAs occurred when MtPAR was expressed ectopically in transformed hairy roots of Medicago. Transcriptome analysis of par mutants and MtPAR-expressing hairy roots, coupled with yeast one-hybrid analysis, revealed that MtPAR positively regulates genes encoding enzymes of the flavonoid-PA pathway via a probable activation of WD40-1. Expression of MtPAR in the forage legume alfalfa (Medicago sativa) resulted in detectable levels of PA in shoots, highlighting the potential of this gene for biotechnological strategies to increase PAs in forage legumes for reduction of pasture bloat in ruminant animals. PMID:22307644

  7. The Rac-GAP Bcr is a novel regulator of the Par complex that controls cell polarity

    PubMed Central

    Narayanan, Anjana S.; Reyes, Steve B.; Um, Kyongmi; McCarty, Joseph H.; Tolias, Kimberley F.

    2013-01-01

    Cell polarization is essential for many biological processes, including directed cell migration, and loss of polarity contributes to pathological conditions such as cancer. The Par complex (Par3, Par6, and PKCζ) controls cell polarity in part by recruiting the Rac-specific guanine nucleotide exchange factor T-lymphoma invasion and metastasis 1 (Tiam1) to specialized cellular sites, where Tiam1 promotes local Rac1 activation and cytoskeletal remodeling. However, the mechanisms that restrict Par-Tiam1 complex activity to the leading edge to maintain cell polarity during migration remain unclear. We identify the Rac-specific GTPase-activating protein (GAP) breakpoint cluster region protein (Bcr) as a novel regulator of the Par-Tiam1 complex. We show that Bcr interacts with members of the Par complex and inhibits both Rac1 and PKCζ signaling. Loss of Bcr results in faster, more random migration and striking polarity defects in astrocytes. These polarity defects are rescued by reducing PKCζ activity or by expressing full-length Bcr, but not an N-terminal deletion mutant or the homologous Rac-GAP, Abr, both of which fail to associate with the Par complex. These results demonstrate that Bcr is an integral member of the Par-Tiam1 complex that controls polarized cell migration by locally restricting both Rac1 and PKCζ function. PMID:24152735

  8. aPKC Inhibition by Par3 CR3 Flanking Regions Controls Substrate Access and Underpins Apical-Junctional Polarization.

    PubMed

    Soriano, Erika V; Ivanova, Marina E; Fletcher, Georgina; Riou, Philippe; Knowles, Philip P; Barnouin, Karin; Purkiss, Andrew; Kostelecky, Brenda; Saiu, Peter; Linch, Mark; Elbediwy, Ahmed; Kjær, Svend; O'Reilly, Nicola; Snijders, Ambrosius P; Parker, Peter J; Thompson, Barry J; McDonald, Neil Q

    2016-08-22

    Atypical protein kinase C (aPKC) is a key apical-basal polarity determinant and Par complex component. It is recruited by Par3/Baz (Bazooka in Drosophila) into epithelial apical domains through high-affinity interaction. Paradoxically, aPKC also phosphorylates Par3/Baz, provoking its relocalization to adherens junctions (AJs). We show that Par3 conserved region 3 (CR3) forms a tight inhibitory complex with a primed aPKC kinase domain, blocking substrate access. A CR3 motif flanking its PKC consensus site disrupts the aPKC kinase N lobe, separating P-loop/αB/αC contacts. A second CR3 motif provides a high-affinity anchor. Mutation of either motif switches CR3 to an efficient in vitro substrate by exposing its phospho-acceptor site. In vivo, mutation of either CR3 motif alters Par3/Baz localization from apical to AJs. Our results reveal how Par3/Baz CR3 can antagonize aPKC in stable apical Par complexes and suggests that modulation of CR3 inhibitory arms or opposing aPKC pockets would perturb the interaction, promoting Par3/Baz phosphorylation. PMID:27554858

  9. Loss of Hep Par 1 immunoreactivity in the livers of patients with carbamoyl phosphate synthetase 1 deficiency.

    PubMed

    Yamaguchi, Maki; Kataoka, Tatsuki R; Shibayama, Takahiro; Fukuda, Akinari; Nakazawa, Atsuko; Minamiguchi, Sachiko; Sakurai, Takaki; Miyagawa-Hayashino, Aya; Yorifuji, Toru; Kasahara, Mureo; Uemoto, Shinji; Haga, Hironori

    2016-06-01

    The hepatocyte paraffin 1 (Hep Par 1) antibody is widely used as a hepatocyte marker, recognizing carbamoyl phosphate synthetase 1 (CPS1), an essential component of the urea cycle. Various missense, nonsense, and frameshift mutations occur in the CPS1 gene. In neonatal patients with homozygous CPS1 deficiency (CPS1D), urea cycle defects with resulting severe hyperammonemia can be fatal, though liver transplantation provides a complete cure for CPS1D. We performed Hep Par 1 immunostaining in the explanted livers of 10 liver transplant patients with CPS1D. Seven were negative for Hep Par 1 in the hepatocytes and the other three showed normal diffuse granular cytoplasmic staining. As expected, all three Hep Par 1-positive patients had at least one missense mutation, and all four patients who had only nonsense or frameshift mutations were Hep Par 1-negative. The other three patients were unexpectedly negative for Hep Par 1, even though each had one missense mutation. These results suggest that CPS1D can be related to the loss of Hep Par 1 reactivity due to the loss of protein production, a one amino acid substitution resulting in an abortive protein product, or both. Hep Par 1 immunohistochemistry can be used as a simple method to confirm CPS1D. PMID:27150549

  10. Plant-derived SAC domain of PAR-4 (Prostate Apoptosis Response 4) exhibits growth inhibitory effects in prostate cancer cells

    PubMed Central

    Sarkar, Shayan; Jain, Sumeet; Rai, Vineeta; Sahoo, Dipak K.; Raha, Sumita; Suklabaidya, Sujit; Senapati, Shantibhusan; Rangnekar, Vivek M.; Maiti, Indu B.; Dey, Nrisingha

    2015-01-01

    The gene Par-4 (Prostate Apoptosis Response 4) was originally identified in prostate cancer cells undergoing apoptosis and its product Par-4 showed cancer specific pro-apoptotic activity. Particularly, the SAC domain of Par-4 (SAC-Par-4) selectively kills cancer cells leaving normal cells unaffected. The therapeutic significance of bioactive SAC-Par-4 is enormous in cancer biology; however, its large scale production is still a matter of concern. Here we report the production of SAC-Par-4-GFP fusion protein coupled to translational enhancer sequence (5′ AMV) and apoplast signal peptide (aTP) in transgenic Nicotiana tabacum cv. Samsun NN plants under the control of a unique recombinant promoter M24. Transgene integration was confirmed by genomic DNA PCR, Southern and Northern blotting, Real-time PCR, and Nuclear run-on assays. Results of Western blot analysis and ELISA confirmed expression of recombinant SAC-Par-4-GFP protein and it was as high as 0.15% of total soluble protein. In addition, we found that targeting of plant recombinant SAC-Par-4-GFP to the apoplast and endoplasmic reticulum (ER) was essential for the stability of plant recombinant protein in comparison to the bacterial derived SAC-Par-4. Deglycosylation analysis demonstrated that ER-targeted SAC-Par-4-GFP-SEKDEL undergoes O-linked glycosylation unlike apoplast-targeted SAC-Par-4-GFP. Furthermore, various in vitro studies like mammalian cells proliferation assay (MTT), apoptosis induction assays, and NF-κB suppression suggested the cytotoxic and apoptotic properties of plant-derived SAC-Par-4-GFP against multiple prostate cancer cell lines. Additionally, pre-treatment of MAT-LyLu prostate cancer cells with purified SAC-Par-4-GFP significantly delayed the onset of tumor in a syngeneic rat prostate cancer model. Taken altogether, we proclaim that plant made SAC-Par-4 may become a useful alternate therapy for effectively alleviating cancer in the new era. PMID:26500666

  11. Reemergence of vaccinia virus during Zoonotic outbreak, Pará State, Brazil.

    PubMed

    de Assis, Felipe L; Vinhote, Wagner M; Barbosa, José D; de Oliveira, Cairo H S; de Oliveira, Carlos M G; Campos, Karinny F; Silva, Natália S; Trindade, Giliane de Souza

    2013-12-01

    In 2010, vaccinia virus caused an outbreak of bovine vaccinia that affected dairy cattle and rural workers in Pará State, Brazil. Genetic analyses identified the virus as distinct from BeAn58058 vaccinia virus (identified in 1960s) and from smallpox vaccine virus strains. These findings suggest spread of autochthonous group 1 vaccinia virus in this region. PMID:24274374

  12. Extending from PARs in Caenorhabditis elegans to homologues in Haemonchus contortus and other parasitic nematodes.

    PubMed

    Nikolaou, S; Gasser, R B

    2007-04-01

    Signal transduction molecules play key roles in the regulation of developmental processes, such as morphogenesis, organogenesis and cell differentiation in all organisms. They are organized into 'pathways' that represent a coordinated network of cell-surface receptors and intracellular molecules, being involved in sensing environmental stimuli and transducing signals to regulate or modulate cellular processes, such as gene expression and cytoskeletal dynamics. A particularly important group of molecules implicated in the regulation of the cytoskeleton for the establishment and maintenance of cell polarity is the PAR proteins (derived from partition defective in asymmetric cell division). The present article reviews salient aspects of PAR proteins involved in the early embryonic development and morphogenesis of the free-living nematode Caenorhabditis elegans and some other organisms, with an emphasis on the molecule PAR-1. Recent advances in the knowledge and understanding of PAR-1 homologues from the economically important parasitic nematode, Haemonchus contortus, of small ruminants is summarized and discussed in the context of exploring avenues for future research in this area for parasitic nematodes. PMID:17107637

  13. Crystal Structure of Thrombin Bound to the Uncleaved Extracellular Fragment of PAR1

    SciTech Connect

    Gandhi, Prafull S.; Chen, Zhiwei; Di Cera, Enrico

    2010-05-11

    Abundant structural information exists on how thrombin recognizes ligands at the active site or at exosites separate from the active site region, but remarkably little is known about how thrombin recognizes substrates that bridge both the active site and exosite I. The case of the protease-activated receptor PAR1 is particularly relevant in view of the plethora of biological effects associated with its activation by thrombin. Here, we present the 1.8 {angstrom} resolution structure of thrombin S195A in complex with a 30-residue long uncleaved extracellular fragment of PAR1 that documents for the first time a productive binding mode bridging the active site and exosite I. The structure reveals two unexpected features of the thrombin-PAR1 interaction. The acidic P3 residue of PAR1, Asp{sup 39}, does not hinder binding to the active site and actually makes favorable interactions with Gly{sup 219} of thrombin. The tethered ligand domain shows a considerable degree of disorder even when bound to thrombin. The results fill a significant gap in our understanding of the molecular mechanisms of recognition by thrombin in ways that are relevant to other physiological substrates.

  14. INHIBITION OF PS II PHOTOCHEMISTRY BY PAR AND UV RADIATION IN NATURAL PHYTOPLANKTON COMMUNITIES

    EPA Science Inventory

    The effects of PAR and UV radiation on PS II photochemistry were examined in natural phytoplankton communities from coastal waters off Rhode Island (USA) and the subtropical Pacific. he photochemical energy conversion efficiency, the functional absorption cross section and the ki...

  15. [Attenuation of photosynthetically available radiation (PAR) in Meiliang Bay under different winds and waves].

    PubMed

    Zhang, Yunlin; Qin, Boqiang; Chen, Weimin; Hu, Weiping; Gao, Guang; Zhu, Guangwei; Luo, Liancong

    2005-06-01

    Based on the successive underwater irradiance measurement in situ from Jul. 12 to 17 in 2003, the attenuation of photosynthetically available radiation (PAR) and euphotic depth in Meiliang Bay were analyzed under different winds and waves. The results showed that the downward PAR attenuation coefficients ranged from 2.63 to 4.7 m(-1), with an average of 3.63 +/- 0.47 x m(-1), and the corresponding euphotic depth ranged from 0.98 to 1.75 m, with an average of 1.29 +/- 0.18 m, which demonstrated that phytoplankton and macrophyte could not grow below 1.5 m due to the lack of adequate solar radiation. The total suspended solids resulted from wind and wave increased the attenuation of light, with the downward attenuation coefficients of PAR being 2.63, 3.72 and 4.37 x m(-1) under small, medium and large wind and wave, respectively. Significant linear correlations were found between transparence, PAR attenuation coefficient, euphotic depth and total suspended solid, especially inorganic suspended solid, while chlorophyll a was the most nonsignificant light attenuator. Multiple stepwise linear regressions showed that inorganic suspended solid was the most important light attenuator dominating the light attenuation in wind-exposed Meiliang Bay. PMID:16180769

  16. CALiPER Report 20.3: Robustness of LED PAR38 Lamps

    SciTech Connect

    none,

    2014-12-30

    A small sample of each of the CALiPER Application Summary Report 20 PAR38 lamp types underwent stress testing that included substantial temperature and humidity changes, electrical variation, and vibration. The results do not directly address expected lifetime, but can be compared with one another, as well as with benchmark conventional products, to assess the relative robustness of the product designs.

  17. Bayesian hidden Markov models to identify RNA-protein interaction sites in PAR-CLIP.

    PubMed

    Yun, Jonghyun; Wang, Tao; Xiao, Guanghua

    2014-06-01

    The photoactivatable ribonucleoside enhanced cross-linking immunoprecipitation (PAR-CLIP) has been increasingly used for the global mapping of RNA-protein interaction sites. There are two key features of the PAR-CLIP experiments: The sequence read tags are likely to form an enriched peak around each RNA-protein interaction site; and the cross-linking procedure is likely to introduce a specific mutation in each sequence read tag at the interaction site. Several ad hoc methods have been developed to identify the RNA-protein interaction sites using either sequence read counts or mutation counts alone; however, rigorous statistical methods for analyzing PAR-CLIP are still lacking. In this article, we propose an integrative model to establish a joint distribution of observed read and mutation counts. To pinpoint the interaction sites at single base-pair resolution, we developed a novel modeling approach that adopts non-homogeneous hidden Markov models to incorporate the nucleotide sequence at each genomic location. Both simulation studies and data application showed that our method outperforms the ad hoc methods, and provides reliable inferences for the RNA-protein binding sites from PAR-CLIP data. PMID:24571656

  18. Cortical PAR polarity proteins promote robust cytokinesis during asymmetric cell division.

    PubMed

    Jordan, Shawn N; Davies, Tim; Zhuravlev, Yelena; Dumont, Julien; Shirasu-Hiza, Mimi; Canman, Julie C

    2016-01-01

    Cytokinesis, the physical division of one cell into two, is thought to be fundamentally similar in most animal cell divisions and driven by the constriction of a contractile ring positioned and controlled solely by the mitotic spindle. During asymmetric cell divisions, the core polarity machinery (partitioning defective [PAR] proteins) controls the unequal inheritance of key cell fate determinants. Here, we show that in asymmetrically dividing Caenorhabditis elegans embryos, the cortical PAR proteins (including the small guanosine triphosphatase CDC-42) have an active role in regulating recruitment of a critical component of the contractile ring, filamentous actin (F-actin). We found that the cortical PAR proteins are required for the retention of anillin and septin in the anterior pole, which are cytokinesis proteins that our genetic data suggest act as inhibitors of F-actin at the contractile ring. Collectively, our results suggest that the cortical PAR proteins coordinate the establishment of cell polarity with the physical process of cytokinesis during asymmetric cell division to ensure the fidelity of daughter cell formation. PMID:26728855

  19. Cortical PAR polarity proteins promote robust cytokinesis during asymmetric cell division

    PubMed Central

    Jordan, Shawn N.; Davies, Tim; Zhuravlev, Yelena; Dumont, Julien; Shirasu-Hiza, Mimi

    2016-01-01

    Cytokinesis, the physical division of one cell into two, is thought to be fundamentally similar in most animal cell divisions and driven by the constriction of a contractile ring positioned and controlled solely by the mitotic spindle. During asymmetric cell divisions, the core polarity machinery (partitioning defective [PAR] proteins) controls the unequal inheritance of key cell fate determinants. Here, we show that in asymmetrically dividing Caenorhabditis elegans embryos, the cortical PAR proteins (including the small guanosine triphosphatase CDC-42) have an active role in regulating recruitment of a critical component of the contractile ring, filamentous actin (F-actin). We found that the cortical PAR proteins are required for the retention of anillin and septin in the anterior pole, which are cytokinesis proteins that our genetic data suggest act as inhibitors of F-actin at the contractile ring. Collectively, our results suggest that the cortical PAR proteins coordinate the establishment of cell polarity with the physical process of cytokinesis during asymmetric cell division to ensure the fidelity of daughter cell formation. PMID:26728855

  20. Participation and Participatory Action Research (PAR) in Environmental Education Processes: For What Are People Empowered?

    ERIC Educational Resources Information Center

    Le Grange, Lesley

    2009-01-01

    Participatory action research (PAR) derived from anti-colonial struggles in the third world in the 1960s. Traditionally it has been a method of the margins because of its commitment to linking social justice to research. Because of its counter-hegemonic tendency it has had great appeal among environmental educators advocating a socially critical…

  1. ParCYCLIC: finite element modelling of earthquake liquefaction response on parallel computers

    NASA Astrophysics Data System (ADS)

    Peng, Jun; Lu, Jinchi; Law, Kincho H.; Elgamal, Ahmed

    2004-10-01

    This paper presents the computational procedures and solution strategy employed in ParCYCLIC, a parallel non-linear finite element program developed based on an existing serial code CYCLIC for the analysis of cyclic seismically-induced liquefaction problems. In ParCYCLIC, finite elements are employed within an incremental plasticity, coupled solid-fluid formulation. A constitutive model developed for simulating liquefaction-induced deformations is a main component of this analysis framework. The elements of the computational strategy, designed for distributed-memory message-passing parallel computer systems, include: (a) an automatic domain decomposer to partition the finite element mesh; (b) nodal ordering strategies to minimize storage space for the matrix coefficients; (c) an efficient scheme for the allocation of sparse matrix coefficients among the processors; and (d) a parallel sparse direct solver. Application of ParCYCLIC to simulate 3-D geotechnical experimental models is demonstrated. The computational results show excellent parallel performance and scalability of ParCYCLIC on parallel computers with a large number of processors. Copyright

  2. Leuconychie transversale induite par la manucurie: y a-t-il un apport de la dermoscopie?

    PubMed Central

    Gallouj, Salim; Mernissi, Fatima Zahra

    2014-01-01

    La leuconychie transversale induite par la manucurie est une leuconychie secondaire au microtraumatisme transmis à la matrice unguéale. Nous rapportant une observation où la dermoscopie avait un intérêt considérable pour l'orientation diagnostic. PMID:25368728

  3. The Utility of Clinicians Ratings of Anxiety Using the Pediatric Anxiety Rating Scale (PARS)

    ERIC Educational Resources Information Center

    Ginsburg, Golda S.; Keeton, Courtney P.; Drazdowski, Tess K.; Riddle, Mark A.

    2011-01-01

    Clinician ratings of anxiety hold the promise of clarifying discrepancies often found between child and parent reports of anxiety. The Pediatric Anxiety Rating Scale (PARS) is a clinician-administered instrument that assesses the frequency, severity, and impairment of common pediatric anxiety disorders and has been used as a primary outcome…

  4. Appropriately Targeting Group Interventions for Academic Success Adopting the Clinical Model and PAR Profiles

    ERIC Educational Resources Information Center

    Johnson, Craig W.; Johnson, Ronald; Steigman, Michael; Odo, Chioma; Vijayan, Suvendra; Tata, Devadatta V.

    2016-01-01

    Prevalence of academic risk (PAR) group profiles provide data enabling empirically based group-specialized prescriptions for targeted academic success interventions to increase student retention, completion, and graduation rates, while improving allocation of institutional resources. Postsecondary student attrition engenders student debt,…

  5. Serum uPAR as Biomarker in Breast Cancer Recurrence: A Mathematical Model

    PubMed Central

    Hao, Wenrui; Friedman, Avner

    2016-01-01

    There are currently over 2.5 million breast cancer survivors in the United States and, according to the American Cancer Society, 10 to 20 percent of these women will develop recurrent breast cancer. Early detection of recurrence can avoid unnecessary radical treatment. However, self-examination or mammography screening may not discover a recurring cancer if the number of surviving cancer cells is small, while biopsy is too invasive and cannot be frequently repeated. It is therefore important to identify non-invasive biomarkers that can detect early recurrence. The present paper develops a mathematical model of cancer recurrence. The model, based on a system of partial differential equations, focuses on tissue biomarkers that include the plasminogen system. Among them, only uPAR is known to have significant correlation to its concentration in serum and could therefore be a good candidate for serum biomarker. The model includes uPAR and other associated cytokines and cells. It is assumed that the residual cancer cells that survived primary cancer therapy are concentrated in the same location within a region with a very small diameter. Model simulations establish a quantitative relation between the diameter of the growing cancer and the total uPAR mass in the cancer. This relation is used to identify uPAR as a potential serum biomarker for breast cancer recurrence. PMID:27078836

  6. The interaction between uPAR and vitronectin triggers ligand-independent adhesion signalling by integrins

    PubMed Central

    Ferraris, Gian Maria Sarra; Schulte, Carsten; Buttiglione, Valentina; De Lorenzi, Valentina; Piontini, Andrea; Galluzzi, Massimiliano; Podestà, Alessandro; Madsen, Chris D; Sidenius, Nicolai

    2014-01-01

    The urokinase-type plasminogen activator receptor (uPAR) is a non-integrin vitronectin (VN) cell adhesion receptor linked to the plasma membrane by a glycolipid anchor. Through structure–function analyses of uPAR, VN and integrins, we document that uPAR-mediated cell adhesion to VN triggers a novel type of integrin signalling that is independent of integrin–matrix engagement. The signalling is fully active on VN mutants deficient in integrin binding site and is also efficiently transduced by integrins deficient in ligand binding. Although integrin ligation is dispensable, signalling is crucially dependent upon an active conformation of the integrin and its association with intracellular adaptors such as talin. This non-canonical integrin signalling is not restricted to uPAR as it poses no structural constraints to the receptor mediating cell attachment. In contrast to canonical integrin signalling, where integrins form direct mechanical links between the ECM and the cytoskeleton, the molecular mechanism enabling the crosstalk between non-integrin adhesion receptors and integrins is dependent upon membrane tension. This suggests that for this type of signalling, the membrane represents a critical component of the molecular clutch. PMID:25168639

  7. Protease Activated Receptor-1 (PAR-1) Mediated Platelet Aggregation is Dependant on Clopidogrel Response

    PubMed Central

    Kreutz, Rolf P.; Breall, Jeffrey A.; Kreutz, Yvonne; Owens, Janelle; Lu, Deshun; Bolad, Islam; von der Lohe, Elisabeth; Sinha, Anjan; Flockhart, David A.

    2012-01-01

    Introduction Clopidogrel inhibits ADP mediated platelet aggregation through inhibition of the P2Y12 receptor by its active metabolite. Thrombin induces platelet aggregation by binding to protease activated receptor-1 (PAR-1), and inhibition of PAR-1 has been evaluated in patients treated with clopidogrel to reduce ischemic events after acute coronary syndromes. Residual PAR-1 mediated platelet aggregation may be dependent on extent of clopidogrel response. Material and Methods Platelet aggregation was measured in 55 patients undergoing elective PCI at 16-24 hours after 600mg clopidogrel loading dose by light transmittance aggregometry using ADP 20μM and thrombin receptor agonist peptide (TRAP) at 15 μM and 25 μM as agonists. Genomic DNA was genotyped for common CYP2C19 variants. Results Increasing quartiles of 20 μM ADP induced platelet aggregation after clopidogrel loading were associated with increasing levels of TRAP mediated platelet aggregation. Patients in the highest quartile (clopidogrel non-responders) of post treatment ADP aggregation had significantly higher TRAP mediated aggregation than the patients in the lowest quartile (clopidogrel responders) [TRAP 15 μM: 79.6±5% vs. 69.5±8%, p<0.001]. Conclusions Non-responders to clopidogrel show increased residual platelet aggregation induced by TRAP, whereas clopidogrel responders exhibit attenuated response to TRAP. Addition of PAR-1 antiplatelet drugs may be most effective in patients with reduced clopidogrel response and high residual TRAP mediated platelet aggregation. PMID:22459907

  8. Serum uPAR as Biomarker in Breast Cancer Recurrence: A Mathematical Model.

    PubMed

    Hao, Wenrui; Friedman, Avner

    2016-01-01

    There are currently over 2.5 million breast cancer survivors in the United States and, according to the American Cancer Society, 10 to 20 percent of these women will develop recurrent breast cancer. Early detection of recurrence can avoid unnecessary radical treatment. However, self-examination or mammography screening may not discover a recurring cancer if the number of surviving cancer cells is small, while biopsy is too invasive and cannot be frequently repeated. It is therefore important to identify non-invasive biomarkers that can detect early recurrence. The present paper develops a mathematical model of cancer recurrence. The model, based on a system of partial differential equations, focuses on tissue biomarkers that include the plasminogen system. Among them, only uPAR is known to have significant correlation to its concentration in serum and could therefore be a good candidate for serum biomarker. The model includes uPAR and other associated cytokines and cells. It is assumed that the residual cancer cells that survived primary cancer therapy are concentrated in the same location within a region with a very small diameter. Model simulations establish a quantitative relation between the diameter of the growing cancer and the total uPAR mass in the cancer. This relation is used to identify uPAR as a potential serum biomarker for breast cancer recurrence. PMID:27078836

  9. Participatory Action Research: Reflections on Critical Incidents in a PAR Project.

    ERIC Educational Resources Information Center

    Santelli, Betsy; Singer, George H. S.; DiVenere, Nancy; Ginsberg, Connie; Powers, Laurie E.

    1998-01-01

    This article describes a participatory action research (PAR) project designed to evaluate Parent to Parent programs in five states. The process of developing a shared understanding of the program and of the purpose for evaluating them, along with an on-going willingness of parents and researchers to compromise, led to creative solutions to…

  10. Split Scenes, Converging Visions: The Ethical Terrains where PAR and Borderlands Scholarship Meet

    ERIC Educational Resources Information Center

    Ayala, Jennifer

    2009-01-01

    This paper examines theoretical linkages between Anzaldua's borderland scholarship, in particular the notion of mestiza consciousness, and participatory action research. Two studies with high school and college co-researchers falling along different points of the PAR spectrum are described to illustrate these conceptual linkages. Points in the…

  11. UTILITY OF A WIDE SPECTRUM LIGHT METER AS AN UNDERWATER SENSOR OF PHOTOSYNTHETICALLY ACTIVE RADIATION (PAR)

    EPA Science Inventory

    The strong attenuation of infra red wavelengths (>700 nm) in coastal waters is suggestive that some instruments with broad spectral responses might be useful, inexpensive substitutes for PAR sensors in studies of estuarine plant dynamics. Wide spectrum (350-1100 nm) light intensi...

  12. Serologically Defined Variations in Malaria Endemicity in Pará State, Brazil

    PubMed Central

    Cunha, Maristela G.; Silva, Eliane S.; Sepúlveda, Nuno; Costa, Sheyla P. T.; Saboia, Tiago C.; Guerreiro, João F.; Póvoa, Marinete M.; Corran, Patrick H.; Riley, Eleanor; Drakeley, Chris J.

    2014-01-01

    Background Measurement of malaria endemicity is typically based on vector or parasite measures. A complementary approach is the detection of parasite specific IgG antibodies. We determined the antibody levels and seroconversion rates to both P. vivax and P. falciparum merozoite antigens in individuals living in areas of varying P. vivax endemicity in Pará state, Brazilian Amazon region. Methodology/Principal Findings The prevalence of antibodies to recombinant antigens from P. vivax and P. falciparum was determined in 1,330 individuals. Cross sectional surveys were conducted in the north of Brazil in Anajás, Belém, Goianésia do Pará, Jacareacanga, Itaituba, Trairão, all in the Pará state, and Sucuriju, a free-malaria site in the neighboring state Amapá. Seroprevalence to any P. vivax antigens (MSP1 or AMA-1) was 52.5%, whereas 24.7% of the individuals were seropositive to any P. falciparum antigens (MSP1 or AMA-1). For P. vivax antigens, the seroconversion rates (SCR) ranged from 0.005 (Sucuriju) to 0.201 (Goianésia do Pará), and are strongly correlated to the corresponding Annual Parasite Index (API). We detected two sites with distinct characteristics: Goianésia do Pará where seroprevalence curve does not change with age, and Sucuriju where seroprevalence curve is better described by a model with two SCRs compatible with a decrease in force of infection occurred 14 years ago (from 0.069 to 0.005). For P. falciparum antigens, current SCR estimates varied from 0.002 (Belém) to 0.018 (Goianésia do Pará). We also detected a putative decrease in disease transmission occurred ∼29 years ago in Anajás, Goianésia do Pará, Itaituba, Jacareacanga, and Trairão. Conclusions We observed heterogeneity of serological indices across study sites with different endemicity levels and temporal changes in the force of infection in some of the sites. Our study provides further evidence that serology can be used to measure and monitor transmission of both major

  13. Project Plan 7930 Cell G PaR Remote Handling System Replacement

    SciTech Connect

    Kinney, Kathryn A

    2009-10-01

    For over 40 years the US Department of Energy (DOE) and its predecessors have made Californium-252 ({sup 252}Cf) available for a wide range of industries including medical, nuclear fuels, mining, military and national security. The Radiochemical Engineering Development Center (REDC) located within the Oak Ridge National Laboratory (ORNL) processes irradiated production targets from the High Flux Isotope Reactor (HFIR). Operations in Building 7930, Cell G provide over 70% of the world's demand for {sup 252}Cf. Building 7930 was constructed and equipped in the mid-1960s. Current operations for {sup 252}Cf processing in Building 7930, Cell G require use of through-the-wall manipulators and the PaR Remote Handling System. Maintenance and repairs for the manipulators is readily accomplished by removal of the manipulator and relocation to a repair shop where hands-on work can be performed in glove boxes. Contamination inside cell G does not currently allow manned entry and no provisions were created for a maintenance area inside the cell. There has been no maintenance of the PaR system or upgrades, leaving operations vulnerable should the system have a catastrophic failure. The Cell G PaR system is currently being operated in a run to failure mode. As the manipulator is now 40+ years old there is significant risk in this method of operation. In 2006 an assessment was completed that resulted in recommendations for replacing the manipulator operator control and power centers which are used to control and power the PaR manipulator in Cell G. In mid-2008 the chain for the bridge drive failed and subsequent examinations indicated several damaged links (see Figure 1). To continue operations the PaR manipulator arm is being used to push and pull the bridge as a workaround. A retrieval tool was fabricated, tested and staged inside Cell G that will allow positioning of the bridge and manipulator arm for removal from the cell should the PaR system completely fail. A fully

  14. La structure de l'eau liquide: Une etude thermique par spectroscopie infrarouge

    NASA Astrophysics Data System (ADS)

    Larouche, Pascal

    Le probleme de la structure de l'eau liquide est important car l'eau est le liquide le plus present sur Terre, et complexe, la quete d'un modele precis pour decrire comment fonctionne ce liquide ayant debute des la fin du dix-neuvieme siecle. Cette etude aborde ce probleme en etudiant l'effet de l'augmentation de la temperature sur H2O et D 2O purs a l'aide de la spectroscopie infrarouge. L'intervalle de temperatures scrute est 29--93.1°C. Les spectres enregistres sont des spectres MIR-ATR entre 650 et 6000 cm-1 . L'analyse par facteurs de ces donnees permet de montrer que deux et seulement deux facteurs principaux sont necessaires pour decomposer tous les spectres experimentaux. Ces resultats sont confirmes grace a l'analyse par facteurs de spectres de la region FIR. Par la suite, la transformation en spectres de la partie reelle n et imaginaire k de l'indice de refraction permet de combiner les donnees des regions MIR et FIR. Une fois ce calcul termine, les spectres de transmission complets de H 2O et D2O entre 25 et 90°C sont connus. Ils sont ensuite utilises pour calculer par extrapolation le spectre des especes constituant l'eau liquide, puis leur abondance en fonction de la temperature. L'extrapolation de ces abondances montre que les especes correspondent a des temperatures limites de --18 et 122°C. Par la suite, la decomposition gaussienne des spectres d'especes met en evidence la riche structure de ces objets et permet de demontrer que l'apparent deplacement du massif d'absorption OH (OD) est produit par une variation de l'intensite des bandes et non pas de leur deplacement. L'examen attentif des spectres des especes prouve qu'il n'y a pas de OH libres crees par l'augmentation de la temperature: meme a 93.1°C, chaque molecule possede quatre liens-H. Ces conclusions sont de plus confirmees par une analyse thermodynamique du passage des molecules de la phase solide a la phase gazeuse. Pour diversifier la nature des resultats experimentaux utilises, des

  15. The tyrosine kinase inhibitor bafetinib inhibits PAR2-induced activation of TRPV4 channels in vitro and pain in vivo

    PubMed Central

    Grace, M S; Lieu, T; Darby, B; Abogadie, F C; Veldhuis, N; Bunnett, N W; McIntyre, P

    2014-01-01

    BACKGROUND AND PURPOSE Protease-activated receptor 2 (PAR2) is expressed on nociceptive neurons, and can sensitize transient receptor potential (TRP) ion channels to amplify neurogenic inflammation and pain. The mechanisms by which this occurs are not fully understood. PAR2 causes receptor-operated activation of TRPV4 channels and TRPV4 null mice have attenuated PAR2-stimulated neurogenic inflammation and mechanical hyperalgesia. Here we investigate the intracellular signalling mechanisms underlying PAR2-induced TRPV4 channel activation and pain. EXPERIMENTAL APPROACH Responses of non-transfected and TRPV4-transfected HEK293 cells to agonists of PAR2 (trypsin and SLIGRL) and TRPV4 channels (GSK1016790A) were determined using calcium imaging. Inhibitors of TRPV4 channels (HC067047), sarcoendoplasmic reticulum calcium transport ATPase (thapsigargin), Gαq (UBO-QIC), tyrosine kinases (bafetinib and dasatinib) or PI3 kinases (wortmannin and LY294002) were used to investigate signalling mechanisms. In vivo effects of tyrosine kinase inhibitors on PAR2-induced mechanical hyperalgesia were assessed in mice. KEY RESULTS In non-transfected HEK293 cells, PAR2 activation transiently increased intracellular calcium ([Ca2+]i). Functional expression of TRPV4 channels caused a sustained increase of [Ca2+]i, inhibited by HC067047, bafetinib and wortmannin; but not by thapsigargin, UBO-QIC, dasatinib or LY294002. Bafetinib but not dasatinib inhibited PAR2-induced mechanical hyperalgesia in vivo. CONCLUSIONS AND IMPLICATIONS This study supports a role for tyrosine kinases in PAR2-mediated receptor-operated gating of TRPV4 channels, independent of Gαq stimulation. The ability of a tyrosine kinase inhibitor to diminish PAR2-induced activation of TRPV4 channels and consequent mechanical hyperalgesia identifies bafetinib (which is in development in oncology) as a potential novel analgesic therapy. PMID:24779362

  16. A novel repressor, par-4, modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1.

    PubMed Central

    Johnstone, R W; See, R H; Sells, S F; Wang, J; Muthukkumar, S; Englert, C; Haber, D A; Licht, J D; Sugrue, S P; Roberts, T; Rangnekar, V M; Shi, Y

    1996-01-01

    The tumor suppressor WT1 represses and activates transcription. The loss and/or imbalance of the dual transcriptional activity of WT1 may contribute to Wilms' tumor. In this study, we identified par-4 (for prostate apoptosis response) as a WT1-interacting protein that itself functions as a transcriptional repressor. par-4 contains a putative leucine zipper domain and is specifically upregulated during apoptosis of prostate cells (S. F. Sells, D. P. Wood, Jr., S. S. Joshi-Barve, S. Muthukkumar, R. J. Jacob, S. A. Crist, S. Humphreys, and V. M. Rangnekar, Cell Growth Differ. 5:457-466, 1994). The leucine repeat domain of par-4 was shown to interact with the zinc finger DNA binding domain of WT1. Immunoprecipitation-Western blot (immunoblot) analyses demonstrated in vivo WT1-par-4 interactions. par-4 was ubiquitously expressed, and the protein was found in both the nucleus and the cytoplasm. Functionally, par-4 inhibited transcription activated by WT1, but not by the related protein EGR1. Inhibition of WT1-mediated transcription was dependent on the domain of par-4 that mediates its physical association with WT1. In addition, par-4 augmented WT1-mediated repression, possibly by contributing an additional repression domain. Consistent with these results, par-4 functioned as a transcriptional repressor when brought to a promoter via a heterologous DNA binding domain. Significantly, par-4, but not a mutant unable to interact with WT1, rescued growth suppression caused by WT1. Thus, we identified a novel repressor that modulates transcription as well as growth suppression functions of WT1. PMID:8943350

  17. Etude par spectroscopie de Coulomb de points quantiques lateraux individuels et couples

    NASA Astrophysics Data System (ADS)

    Pioro-Ladriere, Michel

    Des points quantiques contenant un nombre discret et variable d'electrons sont formes dans un gaz bi-dimensionnel d'electrons a l'aide de grilles metalliques. Le transport electrique, le blocage de spin et la detection de charge sont employes comme outils spectroscopiques permettant de sonder les proprietes de ces nanostructures. Ces techniques permettent aussi de controler exactement le nombres d'electrons confines dans des points quantiques individuels et couples en utilisant un patron de grille judicieux. Une technique de refroidissement en tension est developpee afin de minimiser les effets parasites du bruit telegraphique. Ce type de bruit de charge deteriore la stabilite des nanostructures laterales par l'activation d'un minuscule courant de fuite entre les grilles et le gaz bi-dimensionnel. Un modele expliquant le role du refroidissement en tension sur le courant de fuite est presente. L'activation du courant de fuite est confirmee par detection de charge. Les effets des interactions entre les electrons pieges dans un point quantique sont ensuite etudies dans un regime ou il est possible de comparer les resulats experimentaux avec ceux obtenus par diagonalisation exacte. L'etude demontre que la phase associee au facteur de remplissage nu = 2 est instable au-dessus d'un nombre critique d'electrons. Cette instabilite est confirmee experimentalement par blocage de spin. On demontre aussi l'existence d'etats correles dans le regime des renversements de spin, associe au passage de la phase nu = 2 a nu = 1. Les etats correles sont identifies par spectroscopie en transport non lineaire. Cette caracterisation du diagramme de phase de points individuels permet de coupler deux points quantiques configures a nu = 2. Pour ce regime, la nanostructure se comporte comme un systeme a deux niveaux pouvant contenir entre un et quatre electrons de valence et ce, meme si le nombre total d'electrons est plus eleve. Les degres de liberte de charge et de spin des deux points

  18. Impacts of Light Use Efficiency and fPAR Parameterization on Gross Primary Production Modeling

    NASA Technical Reports Server (NTRS)

    Cheng, Yen-Ben; Zhang, Qingyuan; Lyapustin, Alexei I.; Wang, Yujie; Middleton, Elizabeth M.

    2014-01-01

    This study examines the impact of parameterization of two variables, light use efficiency (LUE) and the fraction of absorbed photosynthetically active radiation (fPAR or fAPAR), on gross primary production(GPP) modeling. Carbon sequestration by terrestrial plants is a key factor to a comprehensive under-standing of the carbon budget at global scale. In this context, accurate measurements and estimates of GPP will allow us to achieve improved carbon monitoring and to quantitatively assess impacts from cli-mate changes and human activities. Spaceborne remote sensing observations can provide a variety of land surface parameterizations for modeling photosynthetic activities at various spatial and temporal scales. This study utilizes a simple GPP model based on LUE concept and different land surface parameterizations to evaluate the model and monitor GPP. Two maize-soybean rotation fields in Nebraska, USA and the Bartlett Experimental Forest in New Hampshire, USA were selected for study. Tower-based eddy-covariance carbon exchange and PAR measurements were collected from the FLUXNET Synthesis Dataset. For the model parameterization, we utilized different values of LUE and the fPAR derived from various algorithms. We adapted the approach and parameters from the MODIS MOD17 Biome Properties Look-Up Table (BPLUT) to derive LUE. We also used a site-specific analytic approach with tower-based Net Ecosystem Exchange (NEE) and PAR to estimate maximum potential LUE (LUEmax) to derive LUE. For the fPAR parameter, the MODIS MOD15A2 fPAR product was used. We also utilized fAPAR chl, a parameter accounting for the fAPAR linked to the chlorophyll-containing canopy fraction. fAPAR chl was obtained by inversion of a radiative transfer model, which used the MODIS-based reflectances in bands 1-7 produced by Multi-Angle Implementation of Atmospheric Correction (MAIAC) algorithm. fAPAR chl exhibited seasonal dynamics more similar with the flux tower based GPP than MOD15A2 fPAR, especially

  19. Cross-talk between toll-like receptor 4 (TLR4) and proteinase-activated receptor 2 (PAR2) is involved in vascular function

    PubMed Central

    Bucci, M; Vellecco, V; Harrington, L; Brancaleone, V; Roviezzo, F; Mattace Raso, G; Ianaro, A; Lungarella, G; De Palma, R; Meli, R; Cirino, G

    2013-01-01

    Background and Purpose Proteinase-activated receptors (PARs) and toll-like receptors (TLRs) are involved in innate immune responses. The aim of this study was to evaluate the possible cross-talk between PAR2 and TLR4 in vessels in physiological condition and how it varies following stimulation of TLR4 by using in vivo and ex vivo models. Experimental Approach Thoracic aortas were harvested from both naïve and endotoxaemic rats for in vitro studies. Arterial blood pressure was monitored in anaesthetized rats in vivo. LPS was used as a TLR4 agonist while PAR2 activating peptide (AP) was used as a PAR2 agonist. Aortas harvested from TLR4–/– mice were also used to characterize the PAR2 response. Key Results PAR2, but not TLR4, expression was enhanced in aortas of endotoxaemic rats. PAR2AP-induced vasorelaxation was increased in aortic rings of LPS-treated rats. TLR4 inhibitors, curcumine and resveratrol, reduced PAR2AP-induced vasorelaxation and PAR2AP-induced hypotension in both naïve and endotoxaemic rats. Finally, in aortic rings from TLR4–/– mice, the expression of PAR2 was reduced and the PAR2AP-induced vasodilatation impaired compared with those from wild-type mice and both resveratrol and curcumine were ineffective. Conclusions and Implications Cross-talk between PAR2 and TLR4 contributes to vascular homeostasis. PMID:22957757

  20. Relationship between urokinase plasminogen activator receptor (uPAR) and the invasion of human prenatal hair follicle.

    PubMed

    Gao, Qiangguo; Fu, Gang; Huang, Gang; Lian, Xiaohua; Yu, Jin; Yang, Tian

    2010-08-01

    During the morphogenesis of hair follicles, the invasive migration of basal keratinocytes resembles cell's dissemination of tissue remodeling. The urokinase-type plasminogen activator receptor (uPAR) appears to be a key molecule in the metastasis. In order to elucidate the relationship between uPAR and the invasion of the human hair follicle, immunohistochemistry, RT-PCR, plasmids transfection, and western blot were used. The results showed that uPAR was expressed in the outermost epithelial cells of the hair follicle and the basal keratinocytes of epidermis, and that the expression decreased with the development of the hair follicle. The cells of the outer root sheath (ORS) and interfollicle epidermis, which overexpressed uPAR, acquired increased invasiveness; however, they showed decreased invasion with overexpression of the urokinase-type plasminogen activator amino terminal fragment (uPA ATF), which inhibited the combination of uPAR and uPA competitively, and the cell invasive migration with overexpressed uPAR was required activated extracellular signal-regulated kinases (ERK). These results implied that overexpression of uPAR promote the invasive migration of hair follicle into the dermis in uPA-dependent and independent manner during human prenatal development. PMID:20012874

  1. Characterization of a point mutation in the parC gene of Mycoplasma bovirhinis associated with fluoroquinolone resistance.

    PubMed

    Hirose, K; Kawasaki, Y; Kotani, K; Abiko, K; Sato, H

    2004-05-01

    Quinolone-resistant (QR) mutants of Mycoplasma bovirhinis strain PG43 (type strain) were generated by stepwise selection in increasing concentrations of enrofloxacin (ENR). An alteration was found in the quinolone resistance-determining region (QRDR) of the parC gene coding for the ParC subunit of topoisomerase IV from these mutants, but not in the gyrA, gyrB, and parE gene coding for the GyrA and GyrB subunits of DNA gyrase and the ParE subunit of topoisomerase IV. Similarly, such an alteration in QRDR of parC was found in the field isolates of M. bovirhinis, which possessed various levels of QR. The substitution of leucine (Leu) by serine (Ser) at position 80 of QRDR of ParC was observed in both QR-mutants and QR-isolates. This is the first report of QR based on a point mutation of the parC gene in M. bovirhinis. PMID:15228551

  2. A site for direct integrin αvβ6·uPAR interaction from structural modelling and docking.

    PubMed

    Sowmya, Gopichandran; Khan, Javed Mohammed; Anand, Samyuktha; Ahn, Seong Beom; Baker, Mark S; Ranganathan, Shoba

    2014-03-01

    Integrin αvβ6 is an epithelially-restricted heterodimeric transmembrane glycoprotein, known to interact with the urokinase plasminogen activating receptor (uPAR), playing a critical role in cancer progression. While the X-ray crystallographic structures of segments of other integrin heterodimers are known, there is no structural information for the complete αvβ6 integrin to assess its direct interaction with uPAR. We have performed structural analysis of αvβ6·uPAR interactions using model data with docking simulations to pinpoint their interface, in accord with earlier reports of the β-propeller region of integrin α-chain interacting with uPAR. Interaction of αvβ6·uPAR was demonstrated by our previous study using immunoprecipitation coupled with proteomic analysis by mass spectrometry. Recently this interaction was validated with proximity ligation assays and peptide arrays. The data suggested that two potential peptide regions from domain II and one peptide region from domain III of uPAR, interact with αvβ6 integrin. Only the peptide region from domain III is consistent with the three-dimensional interaction site proposed in this study. The molecular basis of integrin αvβ6·uPAR binding using structural data is discussed for its implications as a potential therapeutic target in cancer management. PMID:24423664

  3. Relationships between high resolution RapidEye based fPAR and MODIS vegetation indices in a heterogeneous agricultural region

    NASA Astrophysics Data System (ADS)

    Fritsch, Sebastian; Machwitz, Miriam; Conrad, Christopher; Dech, Stefan

    2011-11-01

    The Moderate Imaging Spectroradiometer (MODIS) provides operational products of the Normalized Difference Vegetation Index (NDVI), the Enhanced Vegetation Index (EVI), and the fraction of photosynthetic active radiation (fPAR). FPAR can be used in productivity models, but agricultural applications depend on sub-pixel heterogeneity. Examples for heterogeneous areas are the irrigation systems of the inner Aral Sea Basin, where the 1 km fPAR product proved less suited. An alternative can be to upscale fPAR to the 250 m scale, but there are few studies evaluating this approach. In this study, the use of MODIS 250 m NDVI and EVI for this approach was investigated in an irrigation system in western Uzbekistan. The analysis was based on high resolution fPAR maps and a crop map for the growing season 2009, derived from ground measurements and multitemporal RapidEye data. The data was used to explore statistical relationships between RapidEye fPAR and MODIS NDVI/EVI with respect to spatial heterogeneity. The correlations varied between products (daily NDVI, 8-day NDVI, 16-day NDVI/EVI), with results suggesting that 8-day NDVI performed best. The analyses and the compiled fPAR maps show that, compared to 1 km MODIS fPAR, the 250 m scale is more homogeneous, allows for crop-specific analyses, and better captures the spatial patterns in the study region.

  4. Comparative analysis of a plant pseudoautosomal region (PAR) in Silene latifolia with the corresponding S. vulgaris autosome

    PubMed Central

    2012-01-01

    Background The sex chromosomes of Silene latifolia are heteromorphic as in mammals, with females being homogametic (XX) and males heterogametic (XY). While recombination occurs along the entire X chromosome in females, recombination between the X and Y chromosomes in males is restricted to the pseudoautosomal region (PAR). In the few mammals so far studied, PARs are often characterized by elevated recombination and mutation rates and high GC content compared with the rest of the genome. However, PARs have not been studied in plants until now. In this paper we report the construction of a BAC library for S. latifolia and the first analysis of a > 100 kb fragment of a S. latifolia PAR that we compare to the homologous autosomal region in the closely related gynodioecious species S. vulgaris. Results Six new sex-linked genes were identified in the S. latifolia PAR, together with numerous transposable elements. The same genes were found on the S. vulgaris autosomal segment, with no enlargement of the predicted coding sequences in S. latifolia. Intergenic regions were on average 1.6 times longer in S. latifolia than in S. vulgaris, mainly as a consequence of the insertion of transposable elements. The GC content did not differ significantly between the PAR region in S. latifolia and the corresponding autosomal region in S. vulgaris. Conclusions Our results demonstrate the usefulness of the BAC library developed here for the analysis of plant sex chromosomes and indicate that the PAR in the evolutionarily young S. latifolia sex chromosomes has diverged from the corresponding autosomal region in the gynodioecious S. vulgaris mainly with respect to the insertion of transposable elements. Gene order between the PAR and autosomal region investigated is conserved, and the PAR does not have the high GC content observed in evolutionarily much older mammalian sex chromosomes. PMID:22681719

  5. Par-4 dependent modulation of cellular β-catenin by medicinal plant natural product derivative 3-azido Withaferin A.

    PubMed

    Amin, Hina; Nayak, Debasis; Ur Rasool, Reyaz; Chakraborty, Souneek; Kumar, Anmol; Yousuf, Khalid; Sharma, Parduman Raj; Ahmed, Zabeer; Sharma, Neelam; Magotra, Asmita; Mukherjee, Debaraj; Kumar, Lekha Dinesh; Goswami, Anindya

    2016-05-01

    Here, we provide evidences that natural product derivative 3-azido Withaferin A (3-AWA) abrogated EMT and invasion by modulating β-catenin localization and its transcriptional activity in the prostate as well as in breast cancer cells. This study, for the first time, reveals 3-AWA treatment consistently sequestered nuclear β-catenin and augmented its cytoplasmic pool as evidenced by reducing β-catenin transcriptional activity in these cells. Moreover, 3-AWA treatment triggered robust induction of pro-apoptotic intracellular Par-4, attenuated Akt activity and rescued Phospho-GSK3β (by Akt) to promote β-catenin destabilization. Further, our in vitro studies demonstrate that 3-AWA treatment amplified E-cadherin expression along with sharp downregulation of c-Myc and cyclin D1 proteins. Strikingly, endogenous Par-4 knock down by siRNA underscored 3-AWA mediated inhibition of nuclear β-catenin was Par-4 dependent and suppression of Par-4 activity, either by Bcl-2 or by Ras transfection, restored the nuclear β-catenin level suggesting Par-4 mediated β-catenin regulation was not promiscuous. In vivo results further demonstrated that 3-AWA was effective inhibitor of tumor growth and immunohistochemical studies indicated that increased expression of total β-catenin and decreased expression of phospho-β-catenin and Par-4 in breast cancer tissues as compared to normal breast tissue suggesting Par-4 and β-catenin proteins are mutually regulated and inversely co-related in normal as well as cancer condition. Thus, strategic regulation of intracellular Par-4 by 3-AWA in diverse cancers could be an effective tool to control cancer cell metastasis. Conclusively, this report puts forward a novel approach of controlling deregulated β-catenin signaling by 3-AWA induced Par-4 protein. © 2015 Wiley Periodicals, Inc. PMID:25969134

  6. PAR-1 antagonist SCH79797 ameliorates apoptosis following surgical brain injury through inhibition of ASK1-JNK in rats

    PubMed Central

    Manaenko, Anatol; Sun, Xuejun; Kim, Cherine; Yan, Junhao; Ma, Qingyi

    2012-01-01

    Neurosurgical procedures inevitably produce intraoperative hemorrhage. The subsequent entry of blood into the brain parenchyma results in the release of large amounts of thrombin, a known contributor to perihematomal edema formation and apoptosis after brain injury. The present study seeks to test 1) the effect of surgically induced brain injury (SBI) on thrombin activity, expression of thrombin’s receptor PAR-1, and PAR-1 mediated apoptosis; 2) the effect of thrombin inhibition by argatroban and PAR-1 inhibition by SCH79797 on the development of secondary brain injury in the SBI model on rats. A total of 88 Sprague-Dawley male rats were randomly divided into sham, vehicle-, argatroban-, or SCH79797-treated groups. SBI involved partial resection of the right frontal lobe under inhalation isoflurane anesthesia. Sham-operated animals received only craniotomy. Thrombin activity, brain water content, and neurological deficits were measured at 24 hours following SBI. Involvement of the Ask1/JNK pathway in PAR-1-induced post-SBI apoptosis was characterized by using Ask1 or JNK inhibitors. We observed that SBI increased thrombin activity, yet failed to demonstrate any effect on PAR-1 expression. Argatroban and SCH79797 reduced SBI-induced brain edema and neurological deficits in a dose-dependent manner. SBI-induced apoptosis seemed mediated by the PAR-1/Ask1/JNK pathways. Administration of SCH79797 ameliorated the apoptosis following SBI. Our finding indicate that PAR-1 antagonist protects against secondary brain injury after SBI by decreasing both brain edema and apoptosis by inactivating PAR-1/Ask1/JNK pathway. The anti-apoptotic effect of PAR-1 antagonists may provide a promising path for therapy following SBI. PMID:23000356

  7. Stabilizing a flexible interdomain hinge region harboring the SMB binding site drives uPAR into its closed conformation.

    PubMed

    Zhao, Baoyu; Gandhi, Sonu; Yuan, Cai; Luo, Zhipu; Li, Rui; Gårdsvoll, Henrik; de Lorenzi, Valentina; Sidenius, Nicolai; Huang, Mingdong; Ploug, Michael

    2015-03-27

    The urokinase-type plasminogen activator receptor (uPAR) is a multidomain glycolipid-anchored membrane protein, which facilitates extracellular matrix remodeling by focalizing plasminogen activation to cell surfaces via its high-affinity interaction with uPA. The modular assembly of its three LU (Ly6/uPAR-like) domains is inherently flexible and binding of uPA drives uPAR into its closed conformation, which presents the higher-affinity state for vitronectin thus providing an allosteric regulatory mechanism. Using a new class of epitope-mapped anti-uPAR monoclonal antibodies (mAbs), we now demonstrate that the reciprocal stabilization is indeed also possible. By surface plasmon resonance studies, we show that these mAbs and vitronectin have overlapping binding sites on uPAR and that they share Arg91 as hotspot residue in their binding interfaces. The crystal structure solved for one of these uPAR·mAb complexes at 3.0Å clearly shows that this mAb preselects the closed uPAR conformation with an empty but correctly assembled large hydrophobic binding cavity for uPA. Accordingly, these mAbs inhibit the uPAR-dependent lamellipodia formation and migration on vitronectin-coated matrices irrespective of the conformational status of uPAR and its occupancy with uPA. This is the first study to the best of our knowledge, showing that the dynamic assembly of the three LU domains in uPARwt can be driven toward the closed form by an external ligand, which is not engaging the hydrophobic uPA binding cavity. As this binding interface is also exploited by the somatomedin B domain of vitronectin, therefore, this relationship should be taken into consideration when exploring uPAR-dependent cell adhesion and migration in vitronectin-rich environments. PMID:25659907

  8. Secretory prostate apoptosis response (Par)-4 sensitizes multicellular spheroids (MCS) of glioblastoma multiforme cells to tamoxifen-induced cell death

    PubMed Central

    Jagtap, Jayashree C.; Parveen, D.; Shah, Reecha D.; Desai, Aarti; Bhosale, Dipali; Chugh, Ashish; Ranade, Deepak; Karnik, Swapnil; Khedkar, Bhushan; Mathur, Aaishwarya; Natesh, Kumar; Chandrika, Goparaju; Shastry, Padma

    2014-01-01

    Glioblastoma multiforme (GBM) is the most malignant form of brain tumor and is associated with resistance to conventional therapy and poor patient survival. Prostate apoptosis response (Par)-4, a tumor suppressor, is expressed as both an intracellular and secretory/extracellular protein. Though secretory Par-4 induces apoptosis in cancer cells, its potential in drug-resistant tumors remains to be fully explored. Multicellular spheroids (MCS) of cancer cells often acquire multi-drug resistance and serve as ideal experimental models. We investigated the role of Par-4 in Tamoxifen (TAM)-induced cell death in MCS of human cell lines and primary cultures of GBM tumors. TCGA and REMBRANT data analysis revealed that low levels of Par-4 correlated with low survival period (21.85 ± 19.30 days) in GBM but not in astrocytomas (59.13 ± 47.26 days) and oligodendrogliomas (58.04 ± 59.80 days) suggesting low PAWR expression as a predictive risk factor in GBM. Consistently, MCS of human cell lines and primary cultures displayed low Par-4 expression, high level of chemo-resistance genes and were resistant to TAM-induced cytotoxicity. In monolayer cells, TAM-induced cytotoxicity was associated with enhanced expression of Par-4 and was alleviated by silencing of Par-4 using specific siRNA. TAM effectively induced secretory Par-4 in conditioned medium (CM) of cells cultured as monolayer but not in MCS. Moreover, MCS were rendered sensitive to TAM-induced cell death by exposure to conditioned medium (CM)-containing Par-4 (derived from TAM-treated monolayer cells). Also TAM reduced the expression of Akt and PKCζ in GBM cells cultured as monolayer but not in MCS. Importantly, combination of TAM with inhibitors to PI3K inhibitor (LY294002) or PKCζ resulted in secretion of Par-4 and cell death in MCS. Since membrane GRP78 is overexpressed in most cancer cells but not normal cells, and secretory Par-4 induces apoptosis by binding to membrane GRP78, secretory Par-4 is an

  9. Inferring total canopy APAR from PAR bidirectional reflectances and vegetation indices in tallgrass prairie. [Absorbed Photosynthetically Active Radiation

    NASA Technical Reports Server (NTRS)

    Middleton, Elizabeth M.

    1992-01-01

    The fraction of photosynthetically active radiation (PAR) absorbed by a vegetated canopy (APARc) or landscape (APARs) is a critical parameter in climate processes. A grassland study examined: 1) whether APARs can be estimated from PAR bidirectional exitance fractions; and 2) whether APARs is correlated with spectral vegetation indices (SVIs). Data were acquired with a high resolution continuous spectroradiometer at 4 sun angles on grassland sites. APARs was computed from the scattered surface PAR exitance fractions. The nadir APARs value was the most variable diurnally; it provided a good estimate of the average surface APARs at 95 percent. APARc was best represented by exitance factors between 30-60* forward.

  10. Quinolone resistance locus nfxD of Escherichia coli is a mutant allele of the parE gene encoding a subunit of topoisomerase IV.

    PubMed Central

    Breines, D M; Ouabdesselam, S; Ng, E Y; Tankovic, J; Shah, S; Soussy, C J; Hooper, D C

    1997-01-01

    The locus nfxD, which contributes to high-level quinolone resistance in Escherichia coli KF111b (gyrAr nfxB nfxD), is only expressed in the presence of a gyrA mutation, and maps to the region of the parC and parE genes, was outcrossed into strain KF130, creating strain DH161 (gyrAr nfxD). DNA sequence analysis of DH161 revealed no changes in the topoisomerase IV parC quinolone resistance-determining region but did identify a single T-to-A mutation in parE at codon 445, leading to a change from Leu to His. Full-length cloned parE+ partially complemented the resistance phenotype in KF111b and DH161, but did not complement the resistance phenotype in strain KF130 (gyrAr). No complementation was seen with cloned, truncated parE+. To confirm these findings, gyrAr was first outcrossed from KF130 into E. coli W3110parE10 [parE temperature sensitive(Ts)] and KL16. The transduced strains KL16 and W3110parE10 were subsequently transformed with plasmids containing cloned parE from DH161 or KL16. Cloned parE from DH161 increased norfloxacin resistance in the parE(Ts) background twofold at 30 degrees C and fourfold at 42 degrees C compared to those for cloned parE from KL16. The same experiment with a non-Ts background revealed a twofold increase in the norfloxacin MIC at both 30 and 42 degrees C. These data identify the nfxD conditional resistance locus as a mutant allele of parE. This report is the first of a quinolone-resistant parE mutant and confirms the role of topoisomerase IV as a secondary target of norfloxacin in E. coli. PMID:8980775

  11. Manipulation quantique de la lumière par un amplificateur non linéaire

    NASA Astrophysics Data System (ADS)

    Symul, T.; Bencheikh, K.; Levenson, J. A.

    2002-06-01

    Nous proposons un dispositif original, appelé Amplificateur Non Linéaire (ANL), permettant la génération et la manipulation d'états quantiques de la lumière. Ce dispositif permet une compression du bruit quantique de la lumière en dessous de la limite quantique standard plus efficace que celle obtenue par interactions non linéaires du second ordre ou du troisième ordre. Il permet également d'inverser les fluctuations quantiques en intensité de la lumière, et de produire des photons jumeaux ayant des corrélations quantiques plus élevées et plus robustes que ceux produits par un amplificateur paramétrique seul.

  12. Rabies in humans and non-human in the state of Pará, Brazilian Amazon.

    PubMed

    Fernandes, Marcus Emanuel Barroncas; Costa, Lanna Jamile Corrêa da; Andrade, Fernanda Atanaena Gonçalves de; Silva, Lucila Pereira

    2013-01-01

    We evaluate the relationship of positive cases of rabies with the continuing expansion of livestock production, and analyse the trends of this zoonosis in human population in the state of Pará, Brazilian Amazon. The distribution of rabies cases was recorded between 1999 and 2004. Of 148 cases of rabies, 21% were in humans and 79% in non-human mammals. The rapid growth in livestock numbers seems to be associated with the increase of positive cases in bovine livestock transmitted by vampire bats. This idea is supported by positive and significant relationship of both events in time (p<0.01), but failed when spatial distribution among regions of the state was considered. However, rabies cases tend to occur toward the northeastern of the state of Pará, where rabies cases are proportionally five times greater than other mesoregions, suggesting that increased livestock production may influence the increase of this zoonosis. PMID:23477765

  13. Perianesthetic development of diaphragmatic hernia in a horse with equine pituitary pars intermedia dysfunction (PPID)

    PubMed Central

    Shepard, Molly K.; Lee, Wesley L.; Eggleston, Randy B.

    2015-01-01

    A 21-year-old Thoroughbred gelding with a history of equine pituitary pars intermedia dysfunction (PPID) presented with priapism of 2 days’ duration. The horse received a caudal morphine epidural and then underwent corpus cavernosum lavage and phallectomy under general anesthesia. The patient’s recovery featured multiple unsuccessful attempts to stand and his respiratory distress persisted for several hours until he acutely developed severe colic and was euthanized. Necropsy findings revealed a pituitary adenoma of the pars intermedia, bilateral adrenal cortical hyperplasia, and diaphragmatic herniation. This report suggests that horses with PPID may present a greater risk for diaphragmatic hernia under general anesthesia or during procedures placing stress on the diaphragm, including anesthetic recovery. PMID:25565714

  14. Hydraulic and hydrologic evaluation of PAR Pond Dam. Technical evaluation report

    SciTech Connect

    Reich, M.; Wang, P.C.; Khanbilvardi, R.; Bezler, P.

    1993-10-01

    The PAR Pond Dam at Savannah River Plant was constructed in 1958--1959. Seepage, depressions, boils and spring flow were observed in varying locations on the dam in the last few years. Comprehensive geotechnical and hydraulic investigations pertaining to the effects of the above observations on the abilities of the dam to withstand future floods were made in 1991 and early 1993 where dam capacity to survive flooding and seismic events were evaluated. Brookhaven National Laboratory (BNL) was asked by the Department of Energy (EH) to carry out an independent review of the PAR Pond Dam response to future flooding and seismic events. This report addresses the studies made to evaluate the capacity of the dam to survive floods. A companion report will summarize the evaluations performed to assess the seismic capacity of the dam.

  15. BOREAS TE-9 PAR and Leaf Nitrogen Data for NSA Species

    NASA Technical Reports Server (NTRS)

    Hall, Forrest G. (Editor); Curd, Shelaine (Editor); Dang, Qinglai; Margolis, Hank; Coyea, Marie

    2000-01-01

    The Boreal Ecosystem-Atmospheric Study (BOREAS) TE-9 (Terrestrial Ecology) team collected several data sets related to chemical and photosynthetic properties of leaves in boreal forest tree species. This data set describes the relationship between photosynthetically active radiation (PAR) levels and foliage nitrogen in samples from six sites in the BOREAS Northern Study Area (NSA) collected during the three 1994 intensive field campaigns (IFCs). This information is useful for modeling the vertical distribution of carbon fixation for these different forest types in the boreal forest. The data were collected to quantify the relationship between PAR and leaf nitrogen of black spruce, jack pine, and aspen. The data are available in tabular ASCII files. The data files are available on a CD-ROM (see document number 20010000884), or from the Oak Ridge National Laboratory (ORNL) Distributed Active Archive Center (DAAC).

  16. Disrupting the right pars opercularis with electrical stimulation frees the song: case report.

    PubMed

    Herbet, Guillaume; Lafargue, Gilles; Almairac, Fabien; Moritz-Gasser, Sylvie; Bonnetblanc, François; Duffau, Hugues

    2015-12-01

    The authors report the first case of a strikingly unusual speech impairment evoked by intraoperative electrostimulation in a 36-year-old right-handed patient, a well-trained singer, who underwent awake surgery for a right fronto-temporo-insular low-grade glioma. Functionally disrupting the pars opercularis of the right inferior frontal gyrus led the patient to automatically switch from a speaking to a singing mode of language production. Given the central role of the right pars opercularis in the inhibitory control network, the authors propose that this finding may be interpreted as possible evidence for a competitive and independent neurocognitive subnetwork devoted to the melodically intoned articulation of words (normal language-based vs singing-based) in subjects with high expertise. From a more clinical perspective, such data may have implications for awake neurosurgery, especially to preserve the quality of life for singers. PMID:26140496

  17. Estimation of Downstream Cesium Concentrations Following a Postulated PAR Pond Dam Break

    SciTech Connect

    Chen, K.F.

    2002-07-08

    Following a postulated PAR Pond dam break, some of the PAR Pond sediment including the cesium could be eroded and be transported downstream to the Savannah River through the Lower Three Runs Creek. Studies showed that most of the eroded sediment including the cesium would deposit in the Lower Three Runs Creek and the remainder would discharge to the Savannah River from the mouth of Lower Three Runs Creek. A WASP5 model was developed to simulate the eroded sediment and cesium transport from the Lower Three Runs Creek mouth to the Atlantic coast. The dissolved cesium concentrations at the Highway 301 bridge and near the City of Savannah Industrial and Domestic Water Supply Plant are 30 and 27 pCi/l, respectively. The concentrations at both locations are less than the U. S. Environmental Protection Agency drinking water standard of 200 pCi/l.

  18. PARalyzer: definition of RNA binding sites from PAR-CLIP short-read sequence data

    PubMed Central

    2011-01-01

    Crosslinking and immunoprecipitation (CLIP) protocols have made it possible to identify transcriptome-wide RNA-protein interaction sites. In particular, PAR-CLIP utilizes a photoactivatable nucleoside for more efficient crosslinking. We present an approach, centered on the novel PARalyzer tool, for mapping high-confidence sites from PAR-CLIP deep-sequencing data. We show that PARalyzer delineates sites with a high signal-to-noise ratio. Motif finding identifies the sequence preferences of RNA-binding proteins, as well as seed-matches for highly expressed microRNAs when profiling Argonaute proteins. Our study describes tailored analytical methods and provides guidelines for future efforts to utilize high-throughput sequencing in RNA biology. PARalyzer is available at http://www.genome.duke.edu/labs/ohler/research/PARalyzer/. PMID:21851591

  19. K-Area and Par Pond Sewage Sludge Application Sites groundwater monitoring report, Third quarter 1992

    SciTech Connect

    Thompson, C.Y.

    1993-01-01

    During third quarter 1992, the three wells at the K-Area Sewage Sludge Application Site (KSS wells) and the three wells at the Par Pond Sewage Sludge Application Site (PSS wells) were sampled for analyses required each quarter or annually by South Carolina Department of Health and Environmental Control Construction Permit 13,173 and for base-neutral/acid semivolatile constituents. None of the analytical results exceeded standards.

  20. A drug carrier targeting murine uPAR for photodynamic therapy and tumor imaging.

    PubMed

    Zhou, Xiaolei; Zheng, Ke; Li, Rui; Chen, Zhuo; Yuan, Cai; Hu, Ping; Chen, Jincan; Xue, Jinping; Huang, Mingdong

    2015-09-01

    Photodynamic therapy (PDT) has been used as an effective therapeutical modality for tumors. In PDT, a photosensitizer was used to capture the light of specific wavelength, leading to the generation of reactive oxygen species and cytotoxicity surrounding the photosensitizer. Modifications of photosensitizers to enhance tumor specificity are common approaches to increase the efficacy and reduce the side effects of PDT. Previously, we developed a human serum albumin (HSA)-based drug carrier fused with the human amino-terminal fragment (hATF), which binds to a tumor surface marker (urokinase receptor, uPAR). However, hATF-HSA binds to murine uPAR much weaker (79-fold) than to human uPAR, and is not optimal for applications on murine tumor models. In this study, we developed a murine version of the drug carrier (mATF-HSA). A photosensitizer (mono-substituted β-carboxy phthalocyanine zinc, CPZ) was loaded into this carrier, giving a rather stable macromolecule (mATF-HSA:CPZ) that was shown to bind to murine uPAR in vitro. In addition, we evaluated both the photodynamic therapy efficacy and tumor retention capability of the macromolecule (at a dose of 0.05mg CPZ/kg mouse body weight) on murine hepatoma-22 (H22) tumor bearing mouse model. mATF-HSA:CPZ showed more accumulation in tumors compared to its human counterpart (hATF-HSA:CPZ) measured by quantitative fluorescence molecular tomography (FMT). Besides, mATF-HSA:CPZ exhibited a higher tumor killing efficacy than hATF-HSA:CPZ. Together, the macromolecule mATF-HSA is a promising tumor-specific drug carrier on murine tumor models and is an useful tool to study tumor biology on murine tumor models. PMID:26004218

  1. CALiPER Application Summary Report 20. LED PAR38 Lamps

    SciTech Connect

    none,

    2012-11-01

    This report analyzes the independently tested photometric performance of 38 LED PAR38 lamps. The test results indicate substantial improvement versus earlier CALiPER testing of similar products, and performance comparable to recent data from LED Lighting Facts and ENERGY STAR. Additional testing that focuses on performance attributes beyond those covered by LM-79-08 is planned for this group of lamps, and will be presented in subsequent reports.

  2. Magnétométrie à hélium par pompage laser: le bilan

    NASA Astrophysics Data System (ADS)

    Gilles, H.; Hamel, J.; Monfort, Y.

    2002-06-01

    Depuis 1986, l'équipe Physique Atomique et Capteurs du CIRIL-ISMRA de Caen étudie les magnétomètres à hélium par pompage laser. On présente ici le bilan de ces travaux de recherche et les performances des deux prototypes (hélium4 et hélium3) réalisés au Laboratoire.

  3. La fracture de Hahn Steinthal traitée par vissage d'Herbert: 3 cas

    PubMed Central

    Bienvenu, Bouhelo-Pam Kevin Parfait; Amine, El Rhazi; Khalid, Chmali; Mohamed, Azarkane; Mohamed, El Idrissi; Mohamed, Shimi; Abdelhalim, El Ibrahimi; Abdelmajid, El Mrini

    2015-01-01

    Les fractures du capitulum sont rares. Leur prise en charge initiale doit être précoce et efficace en raison des risques engendrés sur le coude: rigidité, instabilité, arthrose. De nombreux traitements ont été proposés. Notre étude décrit le vissage par vis d'Herbert pratiqué chez trois patientes recensées entre 2012 et 2013. Elles ont été inclues selon les critères de traumatisme du coude avec douleur exquise externe avec un trait de fracture radiologique frontal du condyle huméral externe emportant la joue externe de la trochlée. Le diagnostic a été orienté par l'examen clinique et confirmé à la radiographie de face, de profil et des ¾ internes. Les lésions ont été classées selon Bryan et Morrey. Les patients ont été opérés en urgence par abord postéro-latéral de Kocher, réduction à ciel ouvert puis stabilisation par vis de Herbert enfouies. Le recul moyen a été de un an. La récupération fonctionnelle totale moyenne a été de 3,6 mois. L’évaluation fonctionnelle a été jugée excellente selon le score MEPI (Mayo Elbow Performance Index) pour les trois patients. Il n'y a pas eu de démontage de matériel. La consolidation osseuse moyenne a été de 2,6 mois. PMID:26015850

  4. Seismic analysis of the Par Pond Dam: Study of slope failure and liquefaction. Technical evaluation report

    SciTech Connect

    Simos, N.; Reich, M.

    1994-07-01

    Stability concerns of the Par Pond Dam, an embankment structure in the Savannah River Site complex, resulted in a comprehensive evaluation of the state of its integrity. Specifically, excessive seepage through the embankment, slope failure due to an earthquake event as well as liquefaction potential of the embankment and the foundation are addressed and the potential of failure is evaluated. Lastly, remedial benefits of the addition of a berm structure are also assessed.

  5. ViPAR: a software platform for the Virtual Pooling and Analysis of Research Data

    PubMed Central

    Carter, Kim W; Carter, KW; Francis, RW; Bresnahan, M; Gissler, M; Grønborg, TK; Gross, R; Gunnes, N; Hammond, G; Hornig, M; Hultman, CM; Huttunen, J; Langridge, A; Leonard, H; Newman, S; Parner, ET; Petersson, G; Reichenberg, A; Sandin, S; Schendel, DE; Schalkwyk, L; Sourander, A; Steadman, C; Stoltenberg, C; Suominen, A; Surén, P; Susser, E; Sylvester Vethanayagam, A; Yusof, Z

    2016-01-01

    Background: Research studies exploring the determinants of disease require sufficient statistical power to detect meaningful effects. Sample size is often increased through centralized pooling of disparately located datasets, though ethical, privacy and data ownership issues can often hamper this process. Methods that facilitate the sharing of research data that are sympathetic with these issues and which allow flexible and detailed statistical analyses are therefore in critical need. We have created a software platform for the Virtual Pooling and Analysis of Research data (ViPAR), which employs free and open source methods to provide researchers with a web-based platform to analyse datasets housed in disparate locations. Methods: Database federation permits controlled access to remotely located datasets from a central location. The Secure Shell protocol allows data to be securely exchanged between devices over an insecure network. ViPAR combines these free technologies into a solution that facilitates ‘virtual pooling’ where data can be temporarily pooled into computer memory and made available for analysis without the need for permanent central storage. Results: Within the ViPAR infrastructure, remote sites manage their own harmonized research dataset in a database hosted at their site, while a central server hosts the data federation component and a secure analysis portal. When an analysis is initiated, requested data are retrieved from each remote site and virtually pooled at the central site. The data are then analysed by statistical software and, on completion, results of the analysis are returned to the user and the virtually pooled data are removed from memory. Conclusions: ViPAR is a secure, flexible and powerful analysis platform built on open source technology that is currently in use by large international consortia, and is made publicly available at [http://bioinformatics.childhealthresearch.org.au/software/vipar/]. PMID:26452388

  6. uPAR-targeted multimodal tracer for pre- and intraoperative imaging in cancer surgery

    PubMed Central

    van Willigen, Danny M.; Stammes, Marieke A.; Prevoo, Hendrica A.J.M.; Tummers, Quirijn R.J.G.; Mazar, Andrew P.; Beekman, Freek J.; Kuppen, Peter J.K.; van de Velde, Cornelis J.H.; Löwik, Clemens W.G.M.; Frangioni, John V.; van Leeuwen, Fijs W.B.; Sier, Cornelis F.M.; Vahrmeijer, Alexander L.

    2015-01-01

    Pre- and intraoperative diagnostic techniques facilitating tumor staging are of paramount importance in colorectal cancer surgery. The urokinase receptor (uPAR) plays an important role in the development of cancer, tumor invasion, angiogenesis, and metastasis and over-expression is found in the majority of carcinomas. This study aims to develop the first clinically relevant anti-uPAR antibody-based imaging agent that combines nuclear (111In) and real-time near-infrared (NIR) fluorescent imaging (ZW800-1). Conjugation and binding capacities were investigated and validated in vitro using spectrophotometry and cell-based assays. In vivo, three human colorectal xenograft models were used including an orthotopic peritoneal carcinomatosis model to image small tumors. Nuclear and NIR fluorescent signals showed clear tumor delineation between 24h and 72h post-injection, with highest tumor-to-background ratios of 5.0 ± 1.3 at 72h using fluorescence and 4.2 ± 0.1 at 24h with radioactivity. 1-2 mm sized tumors could be clearly recognized by their fluorescent rim. This study showed the feasibility of an uPAR-recognizing multimodal agent to visualize tumors during image-guided resections using NIR fluorescence, whereas its nuclear component assisted in the pre-operative non-invasive recognition of tumors using SPECT imaging. This strategy can assist in surgical planning and subsequent precision surgery to reduce the number of incomplete resections. PMID:25895028

  7. Preliminary Results for the PAR-PRO: A Measure of Home and Community Participation

    PubMed Central

    Ostir, Glenn V.; Granger, Carl V.; Black, Terrie; Roberts, Pamela; Burgos, Laura; Martinkewiz, Paula; Ottenbacher, Kenneth J.

    2007-01-01

    Objective To develop a measure of home and community participation related to the World Health Organization’s International Classification of Functioning, Disability and Health. Design Cross-sectional analysis of survey data. Setting Nine medical inpatient rehabilitation facilities from 6 states. Participants A total of 594 patients of mixed impairment type admitted for inpatient rehabilitation in 2002. Mean age was 74.0 years and 61.4% were women. Interventions Not applicable. Main Outcome Measures Reliability and validity of the participation instrument. Results A 20-item instrument of home and community participation was developed (PAR-PRO). The instrument showed good internal consistency and good Rasch person and item fit statistics. Four subfactors were identified beyond the unidimensional construct of participation including domestic management, socialization, physical vigor, and generative activities. The PAR-PRO total participation score correlated inversely with age (r=−.31, P<.001) but did not differ by sex. Conclusions The 20-item PAR-PRO instrument of home and community participation displayed good psychometric characteristics. The instrument shows promise as a broad measure of home and community involvement for persons with disabilities. Further work is needed to support its application for people without disability. PMID:16876548

  8. MPDZ EXPRESSION IN THE CAUDOLATERAL SUBSTANTIA NIGRA PARS RETICULATA IS CRUCIALLY INVOLVED IN ALCOHOL WITHDRAWAL

    PubMed Central

    Kruse, L.C.; Walter, N.A.R.; Buck, K.J.

    2014-01-01

    Association studies implicate the multiple PDZ domain protein (MUPP1/MPDZ) gene in risk for alcoholism in humans and alcohol withdrawal in mice. Although manipulation of the Mpdz gene by homologous recombination and bacterial artificial chromosome transgenesis has suggested that its expression affects alcohol withdrawal risk, the potential confounding effects of linked genes and developmental compensation currently limit interpretation. Here, using RNA interference, we directly test the impact of Mpdz expression on alcohol withdrawal severity and provide brain regional mechanistic information. Lentiviral-mediated delivery of Mpdz short hairpin RNA (shRNA) to the caudolateral substantia nigra pars reticulata significantly reduces Mpdz expression and exacerbates alcohol withdrawal convulsions compared to control mice delivered a scrambled shRNA. Neither baseline nor pentylenetetrazol enhanced convulsions differed between Mpdz shRNA and control animals, indicating that Mpdz expression in the caudolateral substantia nigra pars reticulata does not generally affect seizure susceptibility. To our knowledge, these represent the first in vivo Mpdz RNA interference analyses, and provide the first direct evidence that Mpdz expression impacts behavior. Our results confirm that Mpdz is a quantitative trait gene for alcohol withdrawal and demonstrate that its expression in the caudolateral substantia nigra pars reticulata is crucially involved in risk for alcohol withdrawal. PMID:25109596

  9. K-Area and Par Pond Sewage Sludge Application Sites groundwater monitoring report: Second quarter 1993

    SciTech Connect

    Not Available

    1993-10-01

    During second quarter 1993, samples from the three monitoring wells at the K-Area site (KSS series) and the three monitoring wells at the Par Pond site (PSS series) were analyzed for constituents required by South Carolina Department of Health and Environmental Control Construction Permit 13,173 and for other constituents as part of the Savannah River Site (SRS) Groundwater Monitoring Program. This report describes monitoring results that exceeded the final Primary Drinking Water Standards (PDWS) or the SRS flagging criteria. During second quarter 1993, no constituents exceeded the final PDWS or any other flagging criteria at the K-Area and Par Pond Sewage Sludge Application Sites. During first quarter 1993, aluminum and iron exceeded the SRS Flag 2 criteria in one or more of the KSS and the PSS wells. These constituents were not analyzed second quarter 1993. In the KSS well series, the field measurement for alkalinity ranged as high as 35 mg/L in well KSS 1D. Alkalinity measurements were zero in the PSS wells, except for a single measurement of 1 mg/L in well PSS 1D. Historical and current water-level elevations at the K-Area Sewage Sludge Application Site indicate that the groundwater flow direction is south to southwest (SRS grid coordinates). The groundwater flow direction at the Par Pond Sewage Sludge Application Site could not be determined second quarter 1993.

  10. K-Area and Par Pond Sewage Sludge Application Sites Groundwater Monitoring Report

    SciTech Connect

    Thompson, C.Y.

    1993-04-01

    During fourth quarter 1992, samples from the three monitoring wells at the K-Area site (KSS series) and the three monitoring wells at the Par Pond site (PSS series) were analyzed for constituents required by South Carolina Department of Health and Environmental Control Construction Permit 13, 173 and for other constituents as part of the Savannah River Site (SRS) Groundwater Monitoring Program. This report describes monitoring results that exceeded the final Primary Drinking Water Standards (PDWS) or the SRS flagging criteria. During fourth quarter 1992, no constituents analyzed exceeded the PDWS or the SRS Flag 2 criteria at the K-Area and Par Pond Sewage Sludge Application Sites. In the KSS well series, the field measurement for alkalinity ranged as high as 26 mg/L in well KSS 1D. Alkalinity measurements were zero in the PSS wells. Historical and current water-level elevations at the K-Area and Par Pond Sewage Sludge Application Site indicate that the groundwater flow directions are south to southwest (SRS grid coordinates).

  11. uPAR-targeted multimodal tracer for pre- and intraoperative imaging in cancer surgery.

    PubMed

    Boonstra, Martin C; van Driel, Pieter B A A; van Willigen, Danny M; Stammes, Marieke A; Prevoo, Hendrica A J M; Tummers, Quirijn R J G; Mazar, Andrew P; Beekman, Freek J; Kuppen, Peter J K; van de Velde, Cornelis J H; Löwik, Clemens W G M; Frangioni, John V; van Leeuwen, Fijs W B; Sier, Cornelis F M; Vahrmeijer, Alexander L

    2015-06-10

    Pre- and intraoperative diagnostic techniques facilitating tumor staging are of paramount importance in colorectal cancer surgery. The urokinase receptor (uPAR) plays an important role in the development of cancer, tumor invasion, angiogenesis, and metastasis and over-expression is found in the majority of carcinomas. This study aims to develop the first clinically relevant anti-uPAR antibody-based imaging agent that combines nuclear (111In) and real-time near-infrared (NIR) fluorescent imaging (ZW800-1). Conjugation and binding capacities were investigated and validated in vitro using spectrophotometry and cell-based assays. In vivo, three human colorectal xenograft models were used including an orthotopic peritoneal carcinomatosis model to image small tumors. Nuclear and NIR fluorescent signals showed clear tumor delineation between 24h and 72h post-injection, with highest tumor-to-background ratios of 5.0 ± 1.3 at 72h using fluorescence and 4.2 ± 0.1 at 24h with radioactivity. 1-2 mm sized tumors could be clearly recognized by their fluorescent rim. This study showed the feasibility of an uPAR-recognizing multimodal agent to visualize tumors during image-guided resections using NIR fluorescence, whereas its nuclear component assisted in the pre-operative non-invasive recognition of tumors using SPECT imaging. This strategy can assist in surgical planning and subsequent precision surgery to reduce the number of incomplete resections. PMID:25895028

  12. Polycystin-1 binds Par3/aPKC and controls convergent extension during renal tubular morphogenesis.

    PubMed

    Castelli, Maddalena; Boca, Manila; Chiaravalli, Marco; Ramalingam, Harini; Rowe, Isaline; Distefano, Gianfranco; Carroll, Thomas; Boletta, Alessandra

    2013-01-01

    Several organs, including the lungs and kidneys, are formed by epithelial tubes whose proper morphogenesis ensures correct function. This is best exemplified by the kidney, where defective establishment or maintenance of tubular diameter results in polycystic kidney disease, a common genetic disorder. Most polycystic kidney disease cases result from loss-of-function mutations in the PKD1 gene, encoding Polycystin-1, a large receptor of unknown function. Here we demonstrate that PC-1 has an essential role in the establishment of correct tubular diameter during nephron development. Polycystin-1 associates with Par3 favouring the assembly of a pro-polarizing Par3/aPKC complex and it regulates a programme of cell polarity important for oriented cell migration and for a convergent extension-like process during tubular morphogenesis. Par3 inactivation in the developing kidney results in defective convergent extension and tubular morphogenesis, and in renal cyst formation. Our data define Polycystin-1 as central to cell polarization and to epithelial tube morphogenesis and homeostasis. PMID:24153433

  13. Polycystin-1 binds Par3/aPKC and controls convergent extension during renal tubular morphogenesis

    NASA Astrophysics Data System (ADS)

    Castelli, Maddalena; Boca, Manila; Chiaravalli, Marco; Ramalingam, Harini; Rowe, Isaline; Distefano, Gianfranco; Carroll, Thomas; Boletta, Alessandra

    2013-10-01

    Several organs, including the lungs and kidneys, are formed by epithelial tubes whose proper morphogenesis ensures correct function. This is best exemplified by the kidney, where defective establishment or maintenance of tubular diameter results in polycystic kidney disease, a common genetic disorder. Most polycystic kidney disease cases result from loss-of-function mutations in the PKD1 gene, encoding Polycystin-1, a large receptor of unknown function. Here we demonstrate that PC-1 has an essential role in the establishment of correct tubular diameter during nephron development. Polycystin-1 associates with Par3 favouring the assembly of a pro-polarizing Par3/aPKC complex and it regulates a programme of cell polarity important for oriented cell migration and for a convergent extension-like process during tubular morphogenesis. Par3 inactivation in the developing kidney results in defective convergent extension and tubular morphogenesis, and in renal cyst formation. Our data define Polycystin-1 as central to cell polarization and to epithelial tube morphogenesis and homeostasis.

  14. Repositioning of glaucoma tubes into the pars plana for refractory malignant glaucoma: a case report

    PubMed Central

    2013-01-01

    Introduction Malignant glaucoma occurs when the intraocular pressure elevates in the setting of a shallow anterior chamber and patent iridectomy. We describe a case in which malignant glaucoma that was refractory to conventional treatment and complete vitrectomy was successfully managed by rerouting the glaucoma tubes into the pars plana. Case presentation A 47-year-old Latino man had a history of neovascular glaucoma and subsequent peripheral anterior synechiae. He was status post-two glaucoma drainage devices. He developed pupillary block. Laser iridotomy was performed without complications. He subsequently developed malignant glaucoma that was refractory to yttrium aluminum garnet capsulohyaloidotomy of the anterior hyaloid. He underwent pars plana vitrectomy with successful control of his intraocular pressure. After 2 weeks, the malignant glaucoma recurred. He underwent repositioning of the tubes into the pars plana with successful control of his intraocular pressure. Conclusion In rare cases of malignant glaucoma refractive to yttrium aluminum garnet hyaloidotomy and vitrectomy, placement of glaucoma drainage devices is a reasonable alternative. PMID:23577950

  15. Allosteric activation of the Par-6 PDZ via a partial unfolding transition

    PubMed Central

    Whitney, Dustin S.; Peterson, Francis C.; Kovrigin, Evgenii L.; Volkman, Brian F.

    2013-01-01

    Proteins exist in a delicate balance between the native and unfolded states, where thermodynamic stability may be sacrificed to attain the flexibility required for efficient catalysis, binding or allosteric control. Par-6 regulates the Par polarity complex by transmitting a GTPase signal through the CRIB-PDZ module that alters PDZ lig-and binding. Allosteric activation of the PDZ is achieved by local rearrangement of the L164 and K165 side chains to stabilize the interdomain CRIB-PDZ interface and reposition a conserved element of the ligand binding pocket. However, microsecond to millisecond dynamics measurements revealed that L164/K165 exchange requires a larger rearrangement than expected. The margin of thermodynamic stability for the PDZ domain is modest (~3 kcal/mol) and further reduced by transient interactions with the disordered CRIB domain. Measurements of local structural stability revealed that tertiary contacts within the PDZ are disrupted by a partial unfolding transition that enables interconversion of the L/K switch. The unexpected participation of partial PDZ unfolding in the allosteric mechanism of Par-6 suggests that native-state unfolding may be essential for the function of other marginally stable proteins. PMID:23705660

  16. Four Possible Itching Pathways Related to the TRPV1 Channel, Histamine, PAR-2 and Serotonin

    PubMed Central

    NAKAGAWA, Hiroshi; HIURA, Akio

    2013-01-01

    The following four possible pathways for itching sensation have been suggested by recent reports. 1) Histaminergic TRPV1-positive pathway: Although histamine-positive nerve fibers cannot strictly be classified as “itch specific” due to their excitation also by pure algogens (making them itch-selective), the existence of a subpopulation of nociceptors responsible for itching is strongly suggested. Moreover, the TRPV1-expressing neurons have been suggested to be the main sensors and mediators of itching. 2) Histaminergic TRPV1-negative pathway: The scratching behavior caused by itching was not different between capsaicin-pre-treated and vehicle-treated (control) mast cell-rich NC mice. This result suggests the existence of a capsaicin-insensitive (TRPV1-negative) histaminergic pathway. 3) Non-histaminergic PAR-2 pathway: Protease-activated receptor 2 (PAR-2) has been shown to play a role in the itching of atopic dermatitis (AD). The itch evoked by cowhage (a non-histaminergic pruritogen that activates PAR-2) is very similar in characteristics to the itch evoked by conditions such as AD. 4) Non-histaminergic serotonin (5-HT) pathway: 5-HT alone applied to the human skin evokes an itching sensation and has been suggested to be involved in the itching associated with pruritic diseases, such as polycythemia vera and cholestasis. PMID:24043991

  17. On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1

    PubMed Central

    Luo, Xin; Kraus, W. Lee

    2012-01-01

    Cellular stress responses are mediated through a series of regulatory processes that occur at the genomic, transcriptional, post-transcriptional, translational, and post-translational levels. These responses require a complex network of sensors and effectors from multiple signaling pathways, including the abundant and ubiquitous nuclear enzyme poly(ADP-ribose) (PAR) polymerase-1 (PARP-1). PARP-1 functions at the center of cellular stress responses, where it processes diverse signals and, in response, directs cells to specific fates (e.g., DNA repair vs. cell death) based on the type and strength of the stress stimulus. Many of PARP-1's functions in stress response pathways are mediated by its regulated synthesis of PAR, a negatively charged polymer, using NAD+ as a donor of ADP-ribose units. Thus, PARP-1's functions are intimately tied to nuclear NAD+ metabolism and the broader metabolic profile of the cell. Recent studies in cell and animal models have highlighted the roles of PARP-1 and PAR in the response to a wide variety of extrinsic and intrinsic stress signals, including those initiated by oxidative, nitrosative, genotoxic, oncogenic, thermal, inflammatory, and metabolic stresses. These responses underlie pathological conditions, including cancer, inflammation-related diseases, and metabolic dysregulation. The development of PARP inhibitors is being pursued as a therapeutic approach to these conditions. In this review, we highlight the newest findings about PARP-1's role in stress responses in the context of the historical data. PMID:22391446

  18. The emerging role of the thrombin receptor (PAR-1) in melanoma metastasis--a possible therapeutic target.

    PubMed

    Villares, Gabriel J; Zigler, Maya; Bar-Eli, Menashe

    2011-01-01

    Melanoma remains as the deadliest form of skin cancer with limited and inefficient treatment options available for patients with metastatic disease. Within the last decade, the thrombin receptor, Protease Activated Receptor-1, has been described as an essential gene involved in the progression of human melanoma. PAR-1 is known to activate adhesive, invasive and angiogenic factors to promote melanoma metastasis. It is overexpressed not only in metastatic melanoma cell lines but is also highly expressed in metastatic lesions as compared to primary nevi and normal skin. Recently, PAR-1 has been described to regulate the gap junction protein Connexin 43 and the tumor suppressor gene Maspin to promote the metastatic melanoma phenotype. Herein, we review the role of PAR-1 in the progression of melanoma as well as utilizing PAR-1-regulated genes as potential therapeutic targets for melanoma treatment. PMID:21378407

  19. Disentangling the confounding effects of PAR and air temperature on net ecosystem exchange in time and scale

    NASA Astrophysics Data System (ADS)

    yang, Z.; Chen, J.; Becker, R.; Chu, H.; Xie, J.; Shao, C.

    2013-12-01

    Net ecosystem exchange of CO2 (NEE) in temperate forests is modulated by microclimatic factors. The effects of those factors differ at different time scales and during different time periods. Some of them are correlated across a number of time scales, so their effects on NEE are confounded by each other. PAR and air temperature (Ta) are among the two most important drivers of NEE in temperate forests, and among the two most correlated microclimatic factors. PAR and Ta have similar daily, seasonal, and annual cycles. Their influence on NEE is confounded by each other and entangled together especially at those scales. In this study, we tried to disentangle the confounding effects of them on NEE at different time scales and during different time periods. To accomplish this objective, we applied the innovative spectral analysis techniques including Continuous Wavelet Transformation (CWT), Cross Wavelet Transformation (XWT), Wavelet Coherent (WTC), and Partial Wavelet Coherence (PWC) on seven years time series (2004-2010) of PAR, Ta and NEE from the Ohio Oak Openings site (N 41.5545°, W 83.8438°), USA for spectral analysis. We found that PAR is the major driver at short time scales (e.g. semidiurnal and daily) and Ta is the major driver at long time scales (e.g. seasonal and annual). At daily scale during growing seasons, PAR is anti-phase with NEE with no time delay while Ta lagged PAR about 2-3 hours, which could be explained by the strong dependence of photosynthesis on PAR and a 2-3 hours lags of the daily course of Ta to PAR. At daily scale during non-growing season, NEE has little variation and thus neither Ta nor PAR has high common wavelet power and significant coherence with NEE. At annual scale, Ta is anti-phase with NEE and PAR leads NEE about 34 days, which could be explained by the strong dependence of LAI dynamics on Ta and the lag between the LAI/biomass development and the progress of sunlight. We also found that NEE distributes most of its variation

  20. Apparent PS II absorption cross-section and estimation of mean PAR in optically thin and dense suspensions of Chlorella.

    PubMed

    Klughammer, Christof; Schreiber, Ulrich

    2015-01-01

    Theoretical prediction of effective mean PAR in optically dense samples is complicated by various optical effects, including light scattering and reflections. Direct information on the mean rate of photon absorption by PS II is provided by the kinetics of the fluorescence rise induced upon onset of strong actinic illumination (O-I1 rise). A recently introduced kinetic multi-color PAM fluorometer was applied to study the relationship between initial slope and cell density in the relatively simple model system of suspensions of Chlorella. Use of a curve fitting routine was made which was originally developed for assessment of the wavelength-dependent absorption cross-section of PS II, σ II(λ), in dilute suspensions. The model underlying analysis of the O-I1 rise kinetics is outlined and data on the relationship between fitted values of σ II(λ) and PAR in dilute samples are presented. With increasing cell density, lowering of apparent cross-section, <σ>(λ), with respect to σ II(λ), relates to a decrease of effective mean PAR, <PAR>(λ), relative to incident PAR(λ). When ML and AL are applied in the same direction, the decline of <σ>(λ)/σ II(λ) with increasing optical density is less steep than that of the theoretically predicted <PAR>(λ)/PAR(λ). It approaches a value of 0.5 when the same colors of ML and AL are used, in agreement with theory. These observations open the way for estimating mean PAR in optically dense samples via measurements of <σ>(λ)/σ II(λ)). PMID:25218266

  1. Peroxynitrite-induced thymocyte apoptosis: the role of caspases and poly (ADP-ribose) synthetase (PARS) activation.

    PubMed Central

    Virág, L; Scott, G S; Cuzzocrea, S; Marmer, D; Salzman, A L; Szabó, C

    1998-01-01

    The mechanisms by which immature thymocyte apoptosis is induced during negative selection are poorly defined. Reports demonstrated that cross-linking of T-cell receptor leads to stromal cell activation, expression of inducible nitric oxide synthase (iNOS) and, subsequently, to thymocyte apoptosis. Therefore we examined, whether NO directly or indirectly, through peroxynitrite formation, causes thymocyte apoptosis. Immuno-histochemical detection of nitrotyrosine revealed in vivo peroxynitrite formation in the thymi of naive mice. Nitrotyrosine, the footprint of peroxynitrite, was predominantly found in the corticomedullary junction and the medulla of naive mice. In the thymi of mice deficient in the inducible isoform of nitric oxide synthase, considerably less nitrotyrosine was found. Exposure of thymocytes in vitro to low concentrations (10 microM) of peroxynitrite led to apoptosis, whereas higher concentrations (50 microM) resulted in intense cell death with the characteristics of necrosis. We also investigated the effect of poly (ADP-ribose) synthetase (PARS) inhibition on thymocyte apoptosis. Using the PARS inhibitor 3-aminobenzamide (3-AB), or thymocytes from PARS-deficient animals, we established that PARS determines the fate of thymocyte death. Suppression of cellular ATP levels, and the cellular necrosis in response to peroxynitrite were prevented by PARS inhibition. Therefore, in the absence of PARS, cells are diverted towards the pathway of apoptotic cell death. Similar results were obtained with H2O2 treatment, while apoptosis induced by non-oxidative stimuli such as dexamethasone or anti-FAS antibody was unaffected by PARS inhibition. In conclusion, we propose that peroxynitrite-induced apoptosis may play a role in the process of thymocyte negative selection. Furthermore, we propose that the physiological role of PARS cleavage by apopain during apoptosis may serve as an energy-conserving step, enabling the cell to complete the process of apoptosis

  2. Factor XII stimulates ERK1/2 and Akt through uPAR, integrins, and the EGFR to initiate angiogenesis

    PubMed Central

    LaRusch, Gretchen A.; Mahdi, Fakhri; Shariat-Madar, Zia; Adams, Gregory; Sitrin, Robert G.; Zhang, Wan Ming; McCrae, Keith R.

    2010-01-01

    Factor XII (FXII) and high molecular weight kininogen (HK) mutually block each other's binding to the urokinase plasminogen activator receptor (uPAR). We investigated if FXII stimulates cells by interacting with uPAR. FXII (3-62nM) with 0.05mM Zn2+ induces extracellular signal-related kinase 1/2 (ERK1/2; mitogen-activated protein kinase 44 [MAPK44] andMAPK42) and Akt (Ser473) phosphorylation in endothelial cells. FXII-induced phosphorylation of ERK1/2 or Akt is a zymogen activity, not an enzymatic event. ERK1/2 or Akt phosphorylation is blocked upstream by PD98059 or Wortmannin or LY294002, respectively. An uPAR signaling region for FXII is on domain 2 adjacent to uPAR's integrin binding site. Cleaved HK or peptides from HK's domain 5 blocks FXII-induced ERK1/2 and Akt phosphorylation. A β1 integrin peptide that binds uPAR, antibody 6S6 to β1 integrin, or the epidermal growth factor receptor (EGFR) inhibitor AG1478 blocks FXII-induced phosphorylation of ERK1/2 and Akt. FXII induces endothelial cell proliferation and 5-bromo-2′deoxy-uridine incorporation. FXII stimulates aortic sprouting in normal but not uPAR-deficient mouse aorta. FXII produces angiogenesis in matrigel plugs in normal but not uPAR-deficient mice. FXII knockout mice have reduced constitutive and wound-induced blood vessel number. In sum, FXII initiates signaling mediated by uPAR, β1 integrin, and the EGFR to induce human umbilical vein endothelial cell proliferation, growth, and angiogenesis. PMID:20228268

  3. Row orientation effect on UV-B, UV-A and PAR solar irradiation components in vineyards at Tuscany, Italy

    NASA Astrophysics Data System (ADS)

    Grifoni, D.; Carreras, G.; Zipoli, G.; Sabatini, F.; Dalla Marta, A.; Orlandini, S.

    2008-11-01

    Besides playing an essential role in plant photosynthesis, solar radiation is also involved in many other important biological processes. In particular, it has been demonstrated that ultraviolet (UV) solar radiation plays a relevant role in grapevines ( Vitis vinifera) in the production of certain important chemical compounds directly responsible for yield and wine quality. Moreover, the exposure to UV-B radiation (280-320 nm) can affect plant-disease interaction by influencing the behaviour of both pathogen and host. The main objective of this research was to characterise the solar radiative regime of a vineyard, in terms of photosynthetically active radiation (PAR) and UV components. In this analysis, solar spectral UV irradiance components, broadband UV (280-400 nm), spectral UV-B and UV-A (320-400 nm), the biological effective UVBE, as well as the PAR (400-700 nm) component, were all considered. The diurnal patterns of these quantities and the UV-B/PAR and UV-B/UV-A ratios were analysed to investigate the effect of row orientation of the vineyard in combination with solar azimuth and elevation angles. The distribution of PAR and UV irradiance at various heights of the vertical sides of the rows was also studied. The results showed that the highest portion of plants received higher levels of daily radiation, especially the UV-B component. Row orientation of the vines had a pronounced effect on the global PAR received by the two sides of the rows and, to a lesser extent, UV-A and UV-B. When only the diffused component was considered, this geometrical effect was greatly attenuated. UV-B/PAR and UV-A/PAR ratios were also affected, with potential consequences on physiological processes. Because of the high diffusive capacity of the UV-B radiation, the UV-B/PAR ratio was significantly lower on the plant portions exposed to full sunlight than on those in the shade.

  4. Effet Hall et Magnetisme des Alliages Amorphes Nickel-Zirconium Fabriques Par Pulverisation

    NASA Astrophysics Data System (ADS)

    Morel, Robert

    Cette these se situe dans le cadre d'une etude des proprietes electroniques et structurales des alliages metalliques amorphes, en cours depuis quelques annees a l'Universite de Montreal. Ce programme nous a entre autres amene a caracteriser la magnetoresistivite et l'effet Hall d'alliages FeZr, CoZr et NiZr, ce qui a permis de mettre en evidence deux caracteristiques de l'effet Hall: Dans les alliages amorphes ferromagnetiques, la resistivite elevee engendre un effet Hall extraordinaire beaucoup plus important que celui enregistre dans les metaux cristallins. La polarisation des spins entrai ne une asymetrie de la diffusion qui, tant dans les phases cristalline et amorphe, est tenue responsable de cette contribution. L'autre particularite du comportement de Hall de ces systemes est le renversement de signe du coefficient de Hall ordinaire, qui passe du negatif au positif dans les echantillons plus riches en zirconium. Dans les metaux cristallins, un modele d'electrons libres predit un signe negatif a moins que la conduction ne soit dominee par les trous. Or, dans un milieu desordonne les memes concepts sont difficilement applicables et de nouvelles theories ont du etre elaborees pour expliquer ce phenomene. Jusqu'a maintenant, l'etude des alliages amorphes nickel-zirconium s'est faite surtout a partir d'echantillons fabriques par trempe sur roue. Malheureusement cette technique ne permet pas la fabrication d'alliages contenant plus de 70% de nickel, a l'exception du seul compose Ni _{90}Zr_{10 }. Pour pallier a cette lacune et etendre nos connaissance a l'ensemble de la gamme de compositions, nous avons fabrique par pulverisation cathodique des echantillons NiZr amorphes--et quelques alliages cristallins tres riches en nickel--couvrant une bonne partie de la gamme interdite par la technique de trempe sur roue. Dans un premier temps, par comparaison avec les resultats connus nous avons mis en evidence les similitudes et les differences entre les alliages obtenus par

  5. Increased Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) Levels in Plasma of Suicide Attempters

    PubMed Central

    Ventorp, Filip; Gustafsson, Anna; Träskman-Bendz, Lil; Westrin, Åsa; Ljunggren, Lennart

    2015-01-01

    The soluble form of the urokinase receptor, suPAR, has been suggested as a novel biomarker of low-grade inflammation. Activation of the immune system has been proposed to contribute to the development of depression and suicidal behavior. In order to identify depressed and suicidal individuals who could benefit from an anti-inflammatory treatment, a reliable biomarker of low-grade inflammation is vital. This study evaluates plasma suPAR levels as a biomarker of low-grade inflammation in patients with major depressive disorder and in patients who recently attempted suicide. The plasma suPAR and an established biomarker, C reactive protein (CRP) of suicide attempters (n = 54), depressed patients (n = 19) and healthy controls (n = 19) was analyzed with enzyme-linked immunosorbent assays. The biomarker attributes of sensitivity and sensibility were evaluated using ROC curve analysis. Both the depressed patients and suicide attempters had increased plasma suPAR. The levels of suPAR discriminated better between controls and suicide attempters than did CRP. In the future, plasma suPAR might be a superior prognosticator regarding outcome of treatment applying conventional antidepressants in conjunction with anti-inflammatory drugs. PMID:26451727

  6. Discovery of 2-aryloxy-4-amino-quinazoline derivatives as novel protease-activated receptor 2 (PAR2) antagonists.

    PubMed

    Cho, Nam-Chul; Cha, Ji Hyoun; Kim, Hyojin; Kwak, Jinsook; Kim, Dohee; Seo, Seung-Hwan; Shin, Ji-Sun; Kim, TaeHun; Park, Ki Duk; Lee, Jiyoun; No, Kyoung Tai; Kim, Yun Kyung; Lee, Kyung-Tae; Pae, Ae Nim

    2015-12-15

    Protease-activated receptor 2 (PAR2) is a member of G protein-coupled receptor and its activation initiates diverse inflammatory responses. Recent studies suggest that antagonists of PAR2 may provide a novel therapeutic strategy for inflammatory diseases. In this study, we have developed a series of 2-aryloxy-4-amino-quinazoline derivatives as PAR2 antagonists and examined their effects against LPS-induced inflammatory responses in RAW 264.7 macrophages. Among these derivatives, compound 2f displayed the greatest antagonistic activity with the IC50 value of 2.8μM. Binding modes of the newly identified PAR2 antagonists were analyzed by molecular docking using IFD/MM-GBSA methods in the putative binding site of PAR2 homology model. Moreover, 2f demonstrated significant inhibitory effects on the LPS-activated pro-inflammatory mediators including nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) through the regulation of various intracellular signaling pathways involving nuclear factor-κB (NF-κB), activator protein 1 (AP-1) and the mitogen-activated protein kinases (MAPK). Furthermore, administration of 2f significantly reduced the mortality of LPS-induced sepsis in mice. These results provide useful insights into the development of novel PAR2 antagonists with anti-inflammatory activity in vitro and in vivo. PMID:26631441

  7. Utility of the Plasma Level of suPAR in Monitoring Risk of Mortality during TB Treatment

    PubMed Central

    Rabna, Paulo; Andersen, Andreas; Wejse, Christian; Oliveira, Ines; Gomes, Victor Francisco; Haaland, Maya Bonde; Aaby, Peter; Eugen-Olsen, Jesper

    2012-01-01

    Objective To investigate whether changes in the plasma level of soluble urokinase plasminogen activator receptor (suPAR) can be used to monitor tuberculosis (TB) treatment efficacy. Design This prospective cohort study included 278 patients diagnosed with active pulmonary TB and followed throughout the 8-month treatment period. Results Mortality during treatment was higher in the highest inclusion quartile of suPAR (23%) compared to the lowest three quartiles (7%), the risk ratio being 3.1 (95% CI 1.65–6.07). No association between early smear conversion and subsequent mortality or inclusion suPAR was observed. After 1 and 2 months of treatment, an increase in suPAR compared to at diagnosis was associated with a Mortality Rate Ratio (MRR) of 4.5 (95%CI: 1.45–14.1) and 2.1 (95%CI 0.62–6.82), respectively, for the remaining treatment period. Conclusions The present study confirmed that elevated suPAR level at time of initiation of TB treatment is associated with increased risk of mortality. Furthermore, increased suPAR levels after one month of treatment was associated with increased risk of mortality during the remaining 7-month treatment period. PMID:22937128

  8. Structure par RMN d'un complexe AlcR(1-60)-ADN: Reconnaissance du petit sillon par la partie N-terminale

    NASA Astrophysics Data System (ADS)

    Cahuzac, B.; Félenbok, B.; Guittet, E.

    1999-10-01

    Aspergillus nidulans is a filamentous fungus able to use ethanol as sole energy source. The activation of the ethanol regulon genes expression is mediated by the AlcR protein. Its DNA-binding domain is located in the N-terminus (residues 1 to 60), and its NMR solution structure shows a global zinc binuclear cluster fold, with two helices in addition to the basic binuclear motif. A small number of crystallographic structures of DNA complexes of binuclear cluster proteins is yet known, and points out the major groove and the first helix as the principal sites of interaction on the DNA and the protein respectively. In this article we show evidences that the N-terminus of the protein is involved in binding to the minor groove. Aspergillus nidulans est un champignon filamenteux capable d'utiliser l'éthanol comme source unique d'énergie. La protéine AlcR est responsable de l'activation de l'expression des gènes du régulon éthanol. Le domaine de liaison à l'ADN est situé dans la partie N-terminale de la protéine (a.a. 1 à 60), et sa structure déterminée par RMN en solution montre un repliement global en bouquet binucléaire à zinc, avec deux hélices supplémentaires par rapport au motif de base. Alors que les structures déjà connues de complexes ADN - bouquets binucléaires permettent de situer dans le grand sillon la quasi-totalité des interactions, nous montrons dans la présente étude l'implication du début de la séquence dans la reconnaissance du petit sillon de l'ADN (a.a. 5 et 6).

  9. Horizontal portion of arcuate fasciculus fibers track to pars opercularis, not pars triangularis, in right and left hemispheres: A DTI study

    PubMed Central

    Kaplan, Elina; Naeser, Margaret A.; Martin, Paula I.; Ho, Michael; Wang, Yunyan; Baker, Errol; Pascual-Leone, Alvaro

    2010-01-01

    The arcuate fasciculus (AF) is a white matter pathway traditionally considered to connect left Broca’s area with posterior language zones. We utilized diffusion tensor imaging (DTI) in eight healthy subjects (5M) to track pathways in the horizontal mid-portion of the AF (hAF) to subregions of Broca’s area - pars triangularis (PTr) and pars opercularis (POp); and to ventral premotor cortex (vPMC) in the right and left hemispheres (RH, LH). These pathways have previously been studied in the LH, but not in the RH. Only 1/8 subjects showed fiber tracts between PTr and hAF in the RH (also, only 1/8 in the LH). In contrast to PTr, 5/8 subjects showed fiber tracts between POp and hAF in the RH (8/8 in the LH). Fiber tracts for vPMC were similar to those of POp, where 7/8 subjects showed fiber tracts between vPMC and hAF in the RH (8/8 in the LH). Our designated hAF could have included some of the superior longitudinal fasciculus (SLF) III, because it is difficult to separate the two fiber bundles. The SLF III has been previously reported to connect supramarginal gyrus with POp and vPMC in the LH. Thus, although the present DTI study showed almost no pathways between PTr and hAF in the RH (and in the LH), robust pathways were observed between POp and/or vPMC with hAF in the RH (and in LH). These results replicate previous studies for the LH, but are new, for the RH. They could contribute to better understanding of recovery in aphasia. PMID:20438853

  10. PAR1 participates in the ability of multidrug resistance and tumorigenesis by controlling Hippo-YAP pathway

    PubMed Central

    Fujimoto, Daisuke; Ueda, Yuki; Hirono, Yasuo; Goi, Takanori; Yamaguchi, Akio

    2015-01-01

    The Hippo pathway significantly correlates with organ size control and tumorigenesis. The activity of YAP/TAZ, a transducer of the Hippo pathway, is required to sustain self-renewal and tumor-initiation capacities in cancer stem cells (CSCs). But, upstream signals that control the mammalian Hippo pathway have not been well understood. Here, we reveal a connection between the Protease-activated receptor 1 (PAR1) signaling pathway and the Hippo-YAP pathway in gastric cancer stem-like cells. The selective PAR1 agonist TFLLR-NH2 induces an increase in the fraction of side population cells which is enriched in CSCs, and promotes tumorigenesis, multi cancer drug resistance, cell morphological change, and cell invasion which are characteristics of CSCs. In addition, PAR1 activation inhibits the Hippo-YAP pathway kinase Lats via Rho GTPase. Lats kinase inhibition in turn results in increased nuclear localization of dephosphorylated YAP. Furthermore, PAR1 activation confers CSCs related traits via the Hippo-YAP pathway, and the Hippo-YAP pathway correlates with epithelial mesenchymal transition which is induced by PAR1 activation. Our research suggests that the PAR1 signaling deeply participates in the ability of multi drug resistance and tumorigenesis through interactions with the Hippo-YAP pathway signaling in gastric cancer stem-like cells. We presume that inhibited YAP is a new therapeutic target in the treatment human gastric cancer invasion and metastasis by dysregulated PAR1 or its agonists. The Hippo pathway significantly correlates with organ size control and tumorigenesis. The activity of YAP/TAZ, a transducer of the Hippo pathway, is required to sustain self-renewal and tumor-initiation capacities in cancer stem cells (CSCs). But, upstream signals that control the mammalian Hippo pathway have not been well understood. Here, we reveal a connection between the Protease-activated receptor 1 (PAR1) signaling pathway and the Hippo-YAP pathway in gastric cancer stem

  11. Peptide-Based Optical uPAR Imaging for Surgery: In Vivo Testing of ICG-Glu-Glu-AE105

    PubMed Central

    Juhl, Karina; Christensen, Anders; Persson, Morten; Ploug, Michael; Kjaer, Andreas

    2016-01-01

    Near infrared intra-operative optical imaging is an emerging technique with clear implications for improved cancer surgery by enabling a more distinct delineation of the tumor margins during resection. This modality has the potential to increase the number of patients having a curative radical tumor resection. In the present study, a new uPAR-targeted fluorescent probe was developed and the in vivo applicability was evaluated in a human xenograft mouse model. Most human carcinomas express high level of uPAR in the tumor-stromal interface of invasive lesions and uPAR is therefore considered an ideal target for intra-operative imaging. Conjugation of the flourophor indocyanine green (ICG) to the uPAR agonist (AE105) provides an optical imaging ligand with sufficiently high receptor affinity to allow for a specific receptor targeting in vivo. For in vivo testing, human glioblastoma xenograft mice were subjected to optical imaging after i.v. injection of ICG-AE105, which provided an optimal contrast in the time window 6–24 h post injection. Specificity of the uPAR-targeting probe ICG-AE105 was demonstrated in vivo by 1) no uptake of unconjugated ICG after 15 hours, 2) inhibition of ICG-AE105 tumor uptake by a bolus injection of the natural uPAR ligand pro-uPA, and finally 3) the histological colocalization of ICG-AE105 fluorescence and immunohistochemical detected human uPAR on resected tumor slides. Taken together, our data supports the potential use of this probe for intra-operative optical guidance in cancer surgery to ensure complete removal of tumors while preserving adjacent, healthy tissue. PMID:26828431

  12. Caenorhabditis elegans PIG-1/MELK acts in a conserved PAR-4/LKB1 polarity pathway to promote asymmetric neuroblast divisions.

    PubMed

    Chien, Shih-Chieh; Brinkmann, Eva-Maria; Teuliere, Jerome; Garriga, Gian

    2013-03-01

    Asymmetric cell divisions produce daughter cells with distinct sizes and fates, a process important for generating cell diversity during development. Many Caenorhabditis elegans neuroblasts, including the posterior daughter of the Q cell (Q.p), divide to produce a larger neuron or neuronal precursor and a smaller cell that dies. These size and fate asymmetries require the gene pig-1, which encodes a protein orthologous to vertebrate MELK and belongs to the AMPK-related family of kinases. Members of this family can be phosphorylated and activated by the tumor suppressor kinase LKB1, a conserved polarity regulator of epithelial cells and neurons. In this study, we present evidence that the C. elegans orthologs of LKB1 (PAR-4) and its partners STRAD (STRD-1) and MO25 (MOP-25.2) regulate the asymmetry of the Q.p neuroblast division. We show that PAR-4 and STRD-1 act in the Q lineage and function genetically in the same pathway as PIG-1. A conserved threonine residue (T169) in the PIG-1 activation loop is essential for PIG-1 activity, consistent with the model that PAR-4 (or another PAR-4-regulated kinase) phosphorylates and activates PIG-1. We also demonstrate that PIG-1 localizes to centrosomes during cell divisions of the Q lineage, but this localization does not depend on T169 or PAR-4. We propose that a PAR-4-STRD-1 complex stimulates PIG-1 kinase activity to promote asymmetric neuroblast divisions and the generation of daughter cells with distinct fates. Changes in cell fate may underlie many of the abnormal behaviors exhibited by cells after loss of PAR-4 or LKB1. PMID:23267054

  13. Improvement of DNA minicircle production by optimization of the secondary structure of the 5'-UTR of ParA resolvase.

    PubMed

    Šimčíková, Michaela; Alves, Cláudia P A; Brito, Liliana; Prather, Kristala L J; Prazeres, Duarte M F; Monteiro, Gabriel A

    2016-08-01

    The use of minicircles in gene therapy applications is dependent on the availability of high-producer cell systems. In order to improve the performance of minicircle production in Escherichia coli by ParA resolvase-mediated in vivo recombination, we focus on the 5' untranslated region (5'-UTR) of parA messenger RNA (mRNA). The arabinose-inducible PBAD/araC promoter controls ParA expression and strains with improved arabinose uptake are used. The 27-nucleotide-long 5'-UTR of parA mRNA was optimized using a predictive thermodynamic model. An analysis of original and optimized mRNA subsequences predicted a decrease of 8.6-14.9 kcal/mol in the change in Gibbs free energy upon assembly of the 30S ribosome complex with the mRNA subsequences, indicating a more stable mRNA-rRNA complex and enabling a higher (48-817-fold) translation initiation rate. No effect of the 5'-UTR was detected when ParA was expressed from a low-copy number plasmid (∼14 copies/cell), with full recombination obtained within 2 h. However, when the parA gene was inserted in the bacterial chromosome, a faster and more effective recombination was obtained with the optimized 5'-UTR. Interestingly, the amount of this transcript was 2.6-3-fold higher when compared with the transcript generated from the original sequence, highlighting that 5'-UTR affects the level of the transcript. A Western blot analysis confirmed that E. coli synthesized higher amounts of ParA with the new 5'-UTR (∼1.8 ± 0.7-fold). Overall, these results show that the improvements made in the 5'-UTR can lead to a more efficient translation and hence to faster and more efficient minicircle generation. PMID:27147534

  14. The microRNA miR-17-3p inhibits mouse cardiac fibroblast senescence by targeting Par4.

    PubMed

    Du, William W; Li, Xianmin; Li, Tianbi; Li, Haoran; Khorshidi, Azam; Liu, Fengqiong; Yang, Burton B

    2015-01-15

    The microRNA miR-17-92 cluster plays a fundamental role in heart development. The aim of this study was to investigate the effect of a member of this cluster, miR-17, on cardiac senescence. We examined the roles of miR-17 in senescence and demonstrated that miR-17-3p attenuates cardiac aging in the myocardium by targeting Par4 (also known as PAWR). This upregulates the downstream proteins CEBPB, FAK, N-cadherin, vimentin, Oct4 and Sca-1 (also known as stem cell antigen-1), and downregulates E-cadherin. Par4 has been reported as a tumor suppressor gene that induces apoptosis in cancer cells, but not in normal cells. Repression of Par4 by miR-17-3p enhances the transcription of CEBPB and FAK, which promotes mouse cardiac fibroblast (MCF) epithelial-to-mesenchymal transition (EMT) and self-renewal, resulting in cellular senescence and apoptosis resistance. We conclude that Par4 can bind to the CEBPB promoter and inhibit its transcription. Decreased Par4 expression increases the amount of CEBPB, which binds to the FAK promoter and enhances FAK transcription. Par4, CEBPB and FAK form a senescence signaling pathway, playing roles in modulating cell survival, growth, apoptosis, EMT and self-renewal. Through this novel senescence signaling axis, miR-17-3p represses Par4 expression, acting pleiotropically as a negative modulator of cardiac aging and cardiac fibroblast cellular senescence. PMID:25472717

  15. An aerial radiological survey of Par Pond and associated drainage pathways of the Savannah River Site, Aiken, South Carolina

    SciTech Connect

    Not Available

    1992-12-01

    The first of a three-phase effort to radiologically monitor the lowering of Par Pond and associated drainage pathways was conducted over three areas of the Savannah River Site (SRS). The areas surveyed during this first phase included Par Pond, the Savannah River swamp from Steel Creek to Little Hell Landing, and Lower Three Runs Creek from the mouth of Lower Three Runs to the Highway 301 Bridge. The first phase was conducted to coincide with the lowering of the water level of Par Pond to an elevation of 190 feet above sea level. Additional surveys were conducted when the water level was at an elevation of 180 feet and prior to refill. The first survey began August 19, 1991, and was completed September 11, 1991. The second survey was conducted in October/November, 1991, during the SRS site-wide survey, and the third survey was conducted in August/September, 1992. Only the Par Pond area itself was surveyed during the third and final phase. The radiation detected over the Creek Plantation portion of the Savannah River swamp and Lower Three Runs areas during the August 1991 survey was consistent with the spatial distribution, quantity, and kinds of radionuclides detected during the 1983 and 1986 surveys. No migration of man-made gamma emitting materials was detected when compared to the prior surveys. The major differences occurred along the Par Pond shoreline where lowered water levels exposed the contaminated pond bed. The activity in the pond bed was attenuated by the water cover prior to the start of the lowering of Par Pond in June 1991. The data collected during each survey were processed in the field and were presented to SRS. A comparison report is being generated after the completion of each survey. A final report will be generated for the three surveys and will include a quantitative comparison of the three surveys in the Par Pond area only.

  16. A prospective study on postoperative discomfort after 20-gauge pars plana vitrectomy

    PubMed Central

    Yu, Ji-guo; Ni, Fang; Xiang, Yi; Feng, Yi-fan; Wang, Jue; Fu, Xun-an

    2015-01-01

    Purpose To evaluate postoperative pain and other irritation symptoms after 20-gauge (20G) pars plana vitrectomy. Materials and methods A total of 110 consecutive patients were enrolled in our studies, and 87 patients who underwent the conventional 20G pars plana vitrectomy were included in the final analysis. All vitrectomies were performed using the same surgical technique by the same surgeon. Patients were examined before surgery and 1 day, 3 days, 7 days, 1 month, and 2 months postoperatively. The main outcome measures include patient age and sex, intraocular pressure (IOP), ocular pain, pain score, pain medication use, and other irritation symptoms comprising itching, foreign body sensation, burning, photophobia, and dryness. The pain was evaluated using the Numerical Rating Scale scored from 0 to 10. Results Postoperative pain was relatively common during the first day after surgery, as it was reported by 43 (49.4%) patients. Then, the prevalence gradually decreased to eleven (12.6%) patients at 2 months. Most patients reported mild or moderate pain, with a pain score of 1–5, but only four patients were given analgesics for ocular pain. A postoperative rise of IOP was noted in 25 patients at day 1. Most of these patients with high IOP reported moderate pain. Other ocular irritation symptoms were varied after surgery. There was still one-quarter of patients that had foreign body sensation and dryness symptoms at month 2 after surgery. Conclusion Mild and moderate ocular pain were relatively common after 20G vitrectomy, which is more often associated with elevated IOP. Other irritation symptoms were also presented after surgery and could affect the life quality of patients. Therefore, the discomforts after 20G pars plana vitrectomy should be of concern, and timely management should be provided as part of routine postoperative care. PMID:26244010

  17. Les Brulures Electriques par Haut Voltage - A Propos de 10 Cas

    PubMed Central

    Belmir, R.; Fejjal, N.; El Omari, M.; El Mazouz, S.; Gharib, N.; Abassi, A.; Belmahi, A.

    2008-01-01

    Summary Les accidents électriques par haute tension (AEHT) provoquent des brûlures profondes par effet Joule le long des axes vasculo-nerveux entre les points d'entrée et de sortie, qui sont le siège de lésions délabrantes. Les Auteurs rapportent une série de dix cas d'AEHT admis au service de chirurgie réparatrice et de brûlés de l'Hôpital Ibn Sina de Rabat à travers laquelle ils étudient les caractéristiques épidémiologiques, cliniques et thérapeutiques. Tous les patients étaient des adultes de sexe masculin dont l'âge moyen était de 31 ans. Dans 70% des cas, ces brûlures étaient secondaires à un contact avec les distributeurs d'électricité avec une surface brûlée inférieure à 20%. Le traitement des lésions électrothermiques a nécessité des interventions itératives avec amputation des segments de membres nécrosés dans 70% des cas, dont les suites étaient marquées par des séquelles fonctionnelles invalidantes. La prévention des AEHT, en particulier pour les accidents du travail au sein des professions exposées, reste fondamentale. PMID:21991124

  18. Vasodilator-Stimulated Phosphoprotein Deficiency Potentiates PAR-1-induced Increase in Endothelial Permeability in Mouse Lungs

    PubMed Central

    Profirovic, Jasmina; Han, Jingyan; Andreeva, Alexandra V.; Neamu, Radu F.; Pavlovic, Sasha; Vogel, Stephen M.; Walter, Ulrich; Voyno-Yasenetskaya, Tatyana A.

    2010-01-01

    Vasodilator-stimulated phosphoprotein (VASP) is implicated in the protection of the endothelial barrier in vitro and in vivo. VASP function in thrombin signaling in the endothelial cells (ECs) is not known. For the first time we studied the effects of VASP deficiency on EC permeability and pulmonary vascular permeability in response to thrombin receptor stimulation. We provided the evidence that VASP deficiency potentiates the increase in endothelial permeability induced by activation of thrombin receptor in cultured human umbilical vein endothelial cells (HUVECs) and isolated mouse lungs. Using transendothelial resistance measurement, we showed that siRNA-mediated VASP downregulation in HUVECs leads to a potentiation of thrombin- and protease-activated receptor 1 (PAR-1) agonist-induced increase in endothelial permeability. Compared to control cells, VASP-deficient HUVECs had delayed endothelial junctional reassembly and abrogated VE-cadherin cytoskeletal anchoring in the recovery phase after thrombin stimulation, as demonstrated by immunofluorescence studies and cell fractionation analysis, respectively. Measurement of the capillary filtration coefficient in isolated mouse lungs demonstrated that VASP−/− mice have increased microvascular permeability in response to infusion with PAR-1 agonist compared to wild type mice. Lack of VASP led to decreased Rac1 activation both in VASP-deficient HUVECs after thrombin stimulation and VASP−/− mouse lungs after PAR-1 agonist infusion, indicating that VASP effects on thrombin signaling may correlated with changes in Rac1 activity. This study demonstrates that VASP may play critical and complex role in the regulation of thrombin-dependent disruption of the endothelial barrier function. PMID:20945373

  19. Clinical efficacy of modified partial pars plana vitrectomy combined with phacoemulsification for malignant glaucoma.

    PubMed

    He, F; Qian, Z; Lu, L; Jiang, J; Fan, X; Wang, Z; Xu, X

    2016-08-01

    ObjectiveThe objective of this study was to evaluate the clinical effects of modified partial pars plana vitrectomy together with phacoemulsification, intraocular lens (IOL) implantation, posterior capsulectomy, and zonulohyaloidectomy for patients with malignant glaucoma after trabeculectomy or cataract surgery.DesignRetrospective, cohort study.ParticipantsThirty consecutive patients (30 eyes) with malignant glaucoma after trabeculectomy surgery or ultrasonic phacoemulsification of cataract between January 2008 and September 2014 were enrolled.MethodsA retrospective analysis of 30 eyes with malignant glaucoma after trabeculectomy surgery for angle-closure glaucoma or ultrasonic phacoemulsification of cataract was performed. All patients underwent modified partial pars plana vitrectomy with zonulohyaloidectomy. Phacoemulsification and IOL implantation was performed in 25 patients with no previous cataract surgery. Pre-operative and post-operative ocular parameters were recorded in detail.Main outcome measuresClinical features, anterior chamber depth, best-corrected visual acuity, and intraocular pressure (IOP).ResultsIn these 30 patients, 25 had undergone trabeculectomy surgery and 5 had undergone cataract surgery. The mean axial length was 21.3±0.8 mm. After surgery, mean IOP decreased from 34±8.3 mm Hg to 10.5±4.1 mm Hg (P<0.001), and mean anterior chamber depth increased from 0.8±0.4 mm to 2.7±0.3 mm (P<0.001). No severe complications occurred.ConclusionsModified partial pars plana vitrectomy combined with phacoemulsification, IOL implantation, posterior capsulectomy, and zonulohyaloidectomy not only simplifies the process of traditional vitrectomy, but effectively resolves the ciliary block and corrects the misdirection of aqueous humor in malignant glaucoma. PMID:27229700

  20. Infection par le virus de l’hépatite E durant la grossesse

    PubMed Central

    Chaudhry, Shahnaz A.; Verma, Natasha; Koren, Gideon

    2015-01-01

    Résumé Question Plusieurs de mes patientes sont originaires de l’Asie du Sud-Est où le virus de l’hépatite E est assez commun. Quelles précautions puis-je leur suggérer de prendre avant de voyager dans cette région et quels sont les risques d’une infection par le VHE durant la grossesse? Réponse L’hépatite E est un pathogène présent dans l’eau qui se transmet par voie oro-fécale. Afin de réduire le risque de contracter le VHE lors de voyages dans des régions endémiques, il est important de maintenir des pratiques d’hygiène telles que se laver les mains avec de l’eau potable, particulièrement avant de manipuler de la nourriture, éviter de boire de l’eau ou d’utiliser des glaçons de pureté inconnue et ne pas manger de fruits ou de légumes non pelés. Actuellement, il n’existe aucun vaccin disponible au Canada pour le VHE. Une infection à l’hépatite E durant la grossesse, surtout durant le troisième trimestre, se caractérise par une infection plus sévère qui se transforme parfois en hépatite fulminante, augmentant ainsi les risques de mortalité et de morbidité maternelles et fœtales.

  1. Senescent Fibroblasts Enhance Early Skin Carcinogenic Events via a Paracrine MMP-PAR-1 Axis

    PubMed Central

    Malaquin, Nicolas; Vercamer, Chantal; Bouali, Fatima; Martien, Sébastien; Deruy, Emeric; Wernert, Nicolas; Chwastyniak, Maggy; Pinet, Florence; Abbadie, Corinne; Pourtier, Albin

    2013-01-01

    The incidence of carcinoma increases greatly with aging, but the cellular and molecular mechanisms underlying this correlation are only partly known. It is established that senescent fibroblasts promote the malignant progression of already-transformed cells through secretion of inflammatory mediators. We investigated here whether the senescent fibroblast secretome might have an impact on the very first stages of carcinogenesis. We chose the cultured normal primary human epidermal keratinocyte model, because after these cells reach the senescence plateau, cells with transformed and tumorigenic properties systematically and spontaneously emerge from the plateau. In the presence of medium conditioned by autologous senescent dermal fibroblasts, a higher frequency of post-senescence emergence was observed and the post-senescence emergent cells showed enhanced migratory properties and a more marked epithelial-mesenchymal transition. Using pharmacological inhibitors, siRNAs, and blocking antibodies, we demonstrated that the MMP-1 and MMP-2 matrix metalloproteinases, known to participate in late stages of cancer invasion and metastasis, are responsible for this enhancement of early migratory capacity. We present evidence that MMPs act by activating the protease-activated receptor 1 (PAR-1), whose expression is specifically increased in post-senescence emergent keratinocytes. The physiopathological relevance of these results was tested by analyzing MMP activity and PAR-1 expression in skin sections. Both were higher in skin sections from aged subjects than in ones from young subjects. Altogether, our results suggest that during aging, the dermal and epidermal skin compartments might be activated coordinately for initiation of skin carcinoma, via a paracrine axis in which MMPs secreted by senescent fibroblasts promote very early epithelial-mesenchymal transition of keratinocytes undergoing transformation and oversynthesizing the MMP-activatable receptor PAR-1. PMID:23675494

  2. Enquete sur les aspects toxicologiques de la phytotherapie utilisee par un herboriste à Fes, Maroc

    PubMed Central

    Zeggwagh, Ali Amine; Lahlou, Younes; Bousliman, Yassir

    2013-01-01

    Introduction Dans le but d'étudier l'aspect toxicologique des plantes médicinales utilisées en médecine traditionnelle, une étude ethnobotanique a été réalisée à la ville de Fès au centre du Maroc. Méthodes Ont été inclus dans l'étude tous les patients ayant bénéficié d'une prescription par l'herboriste de plantes à visée thérapeutique. La discussion de nos résultats s'est faite sur la base d'une revue de la littérature avec identification des principales plantes toxiques utilisées en phytothérapie au Maroc. L'approche bibliographique a permis de compléter les informations. Résultats L'âge moyen des patients traités par des plantes (38 femmes, 32 hommes) était de 35 ± 18 ans. L'enquête ethnobotanique à révélé que la majorité des plantes médicinales étaient utilisées contre les affections urinaires (21%), suivi des maladies de l'appareil digestif (19.6%) et des maladies rhumatologiques (18.2%). Le nombre de plantes prescrits par l'herboriste a été de 53 dont 5 sont potentiellement toxiques. L'identification taxonomique des plantes prescrites a recensé 30 familles dont les plus représentées sont les Lamiaceae (23.33%), les Apiaceae (13,33%) et les Asteraceae (10%). La prescription des plantes considérées comme toxiques a concerné 7,1% des consultants traités par les plantes médicinales. Aucune complication inhérente aux plantes prescrites n'a été déplorée. Conclusion Malgré les résultats encourageants de notre enquête sur le compte de la phytothérapie, la pratique de la phytothérapie est laissée à la vulgarisation et à l'oubli scientifique, législatif et universitaire. PMID:23734270

  3. Mesure de coefficients d'absorption de plasmas créés par laser nanoseconde

    NASA Astrophysics Data System (ADS)

    Thais, F.; Chenais-Popovics, C.; Eidmann, K.; Bastiani, S.; Blenski, T.; Gilleron, F.

    2005-06-01

    La mesure des coefficients d'absorption dans les plasmas chauds est particulièrement utile dans le domaine de la fusion par confinement inertiel ainsi que dans divers contextes en astrophysique. Le développement des calculs de physique atomique qui y sont associés repose sur des hypothèses qu'il est nécessaire de vérifier dans la plus large gamme possible de conditions physiques. Nous présentons ici la méthode de mesure et d'analyse employée en nous appuyant sur l'exemple des cibles multicouches nickel/aluminium.

  4. Atypical presentation of acute-onset endophthalmitis after uncomplicated pars plana vitrectomy.

    PubMed

    Reilly, Gayatri S; Garfinkel, Richard A; Melamud, Alexander

    2015-03-01

    A 70-year-old woman presented with signs of acute-onset endophthalmitis within 24 hours of surgery, with retinal hemorrhages and vascular changes in the absence of pain or significant inflammation. She had undergone uncomplicated 25-gauge pars plana vitrectomy for epiretinal membrane with presenting visual acuity of 20/40- and significant distortion. Vitreous culture revealed Staphylococcus epidermidis. Final visual acuity was no light perception with persistent pain, and the patient ultimately underwent enucleation. Although rarely, acute-onset postoperative endophthalmitis can present as retinal vasculitis with intraretinal hemorrhages and mild inflammation. PMID:25856829

  5. Helicobacter pylori CagA Inhibits PAR1-MARK Family Kinases by Mimicking Host Substrates

    SciTech Connect

    Nesic, D.; Miller, M; Quinkert, Z; Stein, M; Chait, B; Stebbins, C

    2010-01-01

    The CagA protein of Helicobacter pylori interacts with numerous cellular factors and is associated with increased virulence and risk of gastric carcinoma. We present here the cocrystal structure of a subdomain of CagA with the human kinase PAR1b/MARK2, revealing that a CagA peptide mimics substrates of this kinase family, resembling eukaryotic protein kinase inhibitors. Mutagenesis of conserved residues central to this interaction renders CagA inactive as an inhibitor of MARK2.

  6. [Occurrence of Aedes albopictus in the state of Pará, Brazil].

    PubMed

    Segura, Maria de Nazaré de Oliveira; Monteiro, Hamilton Antonio de Oliveira; Lopes, Ernani da Silva; da Silva, Orlando Vaz; Castro, Francisco Corrêa; Vasconcelos, Pedro Fernando da Costa

    2003-06-01

    It is first reported the detection of Aedes (Stg) albopictus mosquitoes in state of Par , Brazil, in the urban area of Medicil ndia, a municipality far 90 km from Altamira, where 42 adult mosquitoes were baited using human attraction. All mosquitoes were pooled and inoculated into C6/36 and suckling mice in attempts for virus isolation. No virus was isolated. The occurrence of Aedes albopictus in urban areas of the Amazon region is of concern since dengue and yellow fever viruses are endemic in the Amazon and thus there is a potential risk for this mosquito species to become infected with both viruses. PMID:12792693

  7. Étude comparative des techniques d'analyse par fluorescence X à dispersion d'énergie (ED-XRF) et à dispersion de longueur d'onde (WD-XRF), et par spectrométrie d'émission atomique à source plasma couplée par induction (ICP-AES)

    NASA Astrophysics Data System (ADS)

    Rahmani, A.; Benyaïch, F.; Bounakhla, M.; Bilal, E.; Moutte, J.; Gruffat, J. J.; Zahry, F.

    2004-11-01

    Dans ce travail, nous présentons une étude comparative des techniques d'analyse par fluorescence X à dispersion d'énergie (ED-XRF) et à dispersion de longueur d'onde (WD-XRF), et par spectrométrie d'émission atomique à source plasma couplée par induction (ICP-AES). Les résultats de la calibration des spectromètres à dispersion d'énergie, à excitation par sources radioactives (55Fe, 109Cd et 241Am) et à excitation secondaire (cible secondaire Mo et Cu) du Centre National pour l'Energie, les Sciences et les Techniques Nucléaires (CNESTEN, Rabat, Maroc) sur des échantillons étalons de références de l'Agence International de l'Energie Atomique (AIEA) et du Community Bureau of Référence (BCR) ont été comparés aux résultats d'analyse des mêmes échantillons étalons par la spectrométrie X à dispersion de longueur d'onde (WD-XRF) et par spectrométrie d'émission atomique à source plasma couplé par induction (ICP-AES) au département GENERIC du centre SPIN à l'Ecole des Mines de Saint-Etienne (France). Les trois techniques d'analyse utilisées donnent des résultats comparables pour le dosage des éléments majeurs, alors que pour les traces on note des déviations importantes à cause des effets de matrice qui sont difficiles à corriger dans le cas de la fluorescence X.

  8. Melanoma cell therapy: Endothelial progenitor cells as shuttle of the MMP12 uPAR-degrading enzyme

    PubMed Central

    Laurenzana, Anna; Biagioni, Alessio; D'Alessio, Silvia; Bianchini, Francesca; Chillà, Anastasia; Margheri, Francesca; Luciani, Cristina; Mazzanti, Benedetta; Pimpinelli, Nicola; Torre, Eugenio; Danese, Silvio; Calorini, Lido; Rosso, Mario Del; Fibbi, Gabriella

    2014-01-01

    The receptor for the urokinase-type plasminogen activator (uPAR) accounts for many features of cancer progression, and is therefore considered a target for anti-tumoral therapy. Only full length uPAR mediates tumor progression. Matrix-metallo-proteinase-12 (MMP12)-dependent uPAR cleavage results into the loss of invasion properties and angiogenesis. MMP12 can be employed in the field of “targeted therapies” as a biological drug to be delivered directly in patient's tumor mass. Endothelial Progenitor Cells (EPCs) are selectively recruited within the tumor and could be used as cellular vehicles for delivering anti-cancer molecules. The aim of our study is to inhibit cancer progression by engeneering ECFCs, a subset of EPC, with a lentivirus encoding the anti-tumor uPAR-degrading enzyme MMP12. Ex vivo manipulated ECFCs lost the capacity to perform capillary morphogenesis and acquired the anti-tumor and anti-angiogenetic activity. In vivo MMP12-engineered ECFCs cleaved uPAR within the tumor mass and strongly inhibited tumor growth, tumor angiogenesis and development of lung metastasis. The possibility to exploit tumor homing and activity of autologous MMP12-engineered ECFCs represents a novel way to combat melanoma by a “personalized therapy”, without rejection risk. The i.v. injection of radiolabelled MMP12-ECFCs can thus provide a new theranostic approach to control melanoma progression and metastasis. PMID:25003596

  9. Melanoma cell therapy: Endothelial progenitor cells as shuttle of the MMP12 uPAR-degrading enzyme.

    PubMed

    Laurenzana, Anna; Biagioni, Alessio; D'Alessio, Silvia; Bianchini, Francesca; Chillà, Anastasia; Margheri, Francesca; Luciani, Cristina; Mazzanti, Benedetta; Pimpinelli, Nicola; Torre, Eugenio; Danese, Silvio; Calorini, Lido; Del Rosso, Mario; Fibbi, Gabriella

    2014-06-15

    The receptor for the urokinase-type plasminogen activator (uPAR) accounts for many features of cancer progression, and is therefore considered a target for anti-tumoral therapy. Only full length uPAR mediates tumor progression. Matrix-metallo-proteinase-12 (MMP12)-dependent uPAR cleavage results into the loss of invasion properties and angiogenesis. MMP12 can be employed in the field of "targeted therapies" as a biological drug to be delivered directly in patient's tumor mass. Endothelial Progenitor Cells (EPCs) are selectively recruited within the tumor and could be used as cellular vehicles for delivering anti-cancer molecules. The aim of our study is to inhibit cancer progression by engeneering ECFCs, a subset of EPC, with a lentivirus encoding the anti-tumor uPAR-degrading enzyme MMP12. Ex vivo manipulated ECFCs lost the capacity to perform capillary morphogenesis and acquired the anti-tumor and anti-angiogenetic activity. In vivo MMP12-engineered ECFCs cleaved uPAR within the tumor mass and strongly inhibited tumor growth, tumor angiogenesis and development of lung metastasis. The possibility to exploit tumor homing and activity of autologous MMP12-engineered ECFCs represents a novel way to combat melanoma by a "personalized therapy", without rejection risk. The i.v. injection of radiolabelled MMP12-ECFCs can thus provide a new theranostic approach to control melanoma progression and metastasis. PMID:25003596

  10. Par2 inactivation inhibits early production of TSLP, but not cutaneous inflammation, in Netherton syndrome adult mouse model.

    PubMed

    Briot, Anaïs; Lacroix, Matthieu; Robin, Aurélie; Steinhoff, Martin; Deraison, Céline; Hovnanian, Alain

    2010-12-01

    Netherton syndrome (NS) is a severe genodermatosis characterized by abnormal scaling and constant atopic manifestations. NS is caused by mutations in SPINK5 (Serine Protease INhibitor Kazal-type 5), which encodes LEKTI (LymphoEpithelial Kazal Type-related Inhibitor). Lack of LEKTI causes stratum corneum detachment secondary to epidermal proteases hyperactivity. Whereas a skin barrier defect is generally regarded as a major cause for atopy, we previously identified a cell-autonomous signaling cascade that triggers pro-Th2 cytokine thymic stromal lymphopoietin (TSLP) production in LEKTI-deficient epidermis. This signaling is initiated by unrestricted kallikrein 5 (KLK5) activity, which directly activates proteinase-activated receptor 2 (PAR2)-mediated expression of TSLP and favors a cutaneous proallergic microenvironment independently of the environment and of the adaptive immune system. To further confirm these results in vivo, we generated Spink5/Par2 double knockout (DKO) mice. At embryonic day 19.5, these mice display a dramatic decrease in TSLP expression, although stratum corneum detachment persists, confirming the role of the KLK5-PAR2 cascade in TSLP-mediated early proallergic signaling. However, deletion of Par2 in adult DKO-grafted skin does not rescue the inflammatory phenotype probably resulting from stratum corneum detachment. We conclude that several mechanisms trigger and maintain the inflammatory phenotype in NS. These include skin barrier impairment, mechanical stress secondary to stratum corneum detachment, as well as protease-induced proinflammatory and proallergic pathways, including PAR2-mediated overexpression of TSLP. PMID:20703245

  11. Comparison between Limbal and Pars Plana Approaches Using Microincision Vitrectomy for Removal of Congenital Cataracts with Primary Intraocular Lens Implantation

    PubMed Central

    Liu, Xin; Zheng, Tianyu; Zhou, Xingtao; Lu, Yi; Zhou, Peng; Fan, Fan; Luo, Yi

    2016-01-01

    Purpose. To compare the surgical outcomes of limbal versus pars plana vitrectomy using the 23-gauge microincision system for removal of congenital cataracts with primary intraocular lens implantation. Methods. We retrospectively reviewed all eyes that underwent cataract removal through limbal or pars plana incision. Main outcome measures included visual outcomes and complications. Results. We included 40 eyes (26 patients) in the limbal group and 41 eyes (30 patients) in the pars plana group. The mean age was 46 months. There was no significant difference in best-corrected visual acuity between the two groups (P = 0.64). Significantly, more eyes had at least one intraoperative complication in the limbal group than in the pars plana group (P = 0.03) that were mainly distributed at 1.5–3 years of age (P = 0.01). The most common intraoperative complications were iris aspiration, iris prolapse, and iris injury. More eyes in the limbal group had postoperative complications and required additional intraocular surgery, but the difference was not significant (P = 0.19). Conclusions. The visual results were encouraging in both approaches. We recommend the pars plana approach for lower incidence of complications. The limbal approach should be reserved for children older than 3 years of age and caution should be exercised to minimize iris disturbance. PMID:27313872

  12. HER2 and uPAR cooperativity contribute to metastatic phenotype of HER2-positive breast cancer

    PubMed Central

    Chandran, Vineesh Indira; Eppenberger-Castori, Serenella; Venkatesh, Thejaswini; Vine, Kara Lea; Ranson, Marie

    2015-01-01

    Human epidermal growth factor receptor type 2 (HER2)-positive breast carcinoma is highly aggressive and mostly metastatic in nature though curable/manageable in part by molecular targeted therapy. Recent evidence suggests a subtype of cells within HER2-positive breast tumors that concomitantly expresses the urokinase plasminogen activator receptor (uPAR) with inherent stem cell/mesenchymal-like properties promoting tumor cell motility and a metastatic phenotype. This HER-positive/uPAR-positive subtype may be partially responsible for the failure of HER2-targeted treatment strategies. Herein we discuss and substantiate the cumulative preclinical and clinical evidence on HER2-uPAR cooperativity in terms of gene co-amplification and/or mRNA/protein co-overexpression. We then propose a regulatory signaling model that we hypothesize to maintain upregulation and cooperativity between HER2 and uPAR in aggressive breast cancer. An improved understanding of the HER2/uPAR interaction in breast cancer will provide critical biomolecular information that may help better predict disease course and response to therapy. PMID:25897424

  13. Comparison between Limbal and Pars Plana Approaches Using Microincision Vitrectomy for Removal of Congenital Cataracts with Primary Intraocular Lens Implantation.

    PubMed

    Liu, Xin; Zheng, Tianyu; Zhou, Xingtao; Lu, Yi; Zhou, Peng; Fan, Fan; Luo, Yi

    2016-01-01

    Purpose. To compare the surgical outcomes of limbal versus pars plana vitrectomy using the 23-gauge microincision system for removal of congenital cataracts with primary intraocular lens implantation. Methods. We retrospectively reviewed all eyes that underwent cataract removal through limbal or pars plana incision. Main outcome measures included visual outcomes and complications. Results. We included 40 eyes (26 patients) in the limbal group and 41 eyes (30 patients) in the pars plana group. The mean age was 46 months. There was no significant difference in best-corrected visual acuity between the two groups (P = 0.64). Significantly, more eyes had at least one intraoperative complication in the limbal group than in the pars plana group (P = 0.03) that were mainly distributed at 1.5-3 years of age (P = 0.01). The most common intraoperative complications were iris aspiration, iris prolapse, and iris injury. More eyes in the limbal group had postoperative complications and required additional intraocular surgery, but the difference was not significant (P = 0.19). Conclusions. The visual results were encouraging in both approaches. We recommend the pars plana approach for lower incidence of complications. The limbal approach should be reserved for children older than 3 years of age and caution should be exercised to minimize iris disturbance. PMID:27313872

  14. Differences in PAR-2 activating potential by king crab (Paralithodes camtschaticus), salmon (Salmo salar), and bovine (Bos taurus) trypsin

    PubMed Central

    2013-01-01

    Background Salmon trypsin is shown to increase secretion of the pro-inflammatory cytokine interleukin (IL)-8 from human airway epithelial cells through activation of PAR-2. Secretion of IL-8 induced by king crab trypsin is observed in a different concentration range compared to salmon trypsin, and seems to be only partially related to PAR-2 activation. This report aim to identify differences in the molecular structure of king crab trypsin (Paralithodes camtschaticus) compared to salmon (Salmo salar) and bovine trypsin (Bos taurus) that might influence the ability to activate protease-activated receptor-2 (PAR-2). Results During purification king crab trypsin displayed stronger binding capacity to the anionic column used in fast protein liquid chromatography compared to fish trypsins, and was identified as a slightly bigger molecule. Measurements of enzymatic activity yielded no obvious differences between the trypsins tested. Molecular modelling showed that king crab trypsin has a large area with strong negative electrostatic potential compared to the smaller negative areas in bovine and salmon trypsins. Bovine and salmon trypsins also displayed areas with strong positive electrostatic potential, a feature lacking in the king crab trypsin. Furthermore we have identified 3 divergent positions (Asp196, Arg244, and Tyr247) located near the substrate binding pocket of king crab trypsin that might affect the binding and cleavage of PAR-2. Conclusion These preliminary results indicate that electrostatic interactions could be of importance in binding, cleavage and subsequent activation of PAR-2. PMID:23870109

  15. Architecture and Assembly of a Divergent Member of the ParM Family of Bacterial Actin-like Proteins

    PubMed Central

    Rivera, Christopher R.; Kollman, Justin M.; Polka, Jessica K.; Agard, David A.; Mullins, R. Dyche

    2011-01-01

    Eubacteria and archaea contain a variety of actin-like proteins (ALPs) that form filaments with surprisingly diverse architectures, assembly dynamics, and cellular functions. Although there is much data supporting differences between ALP families, there is little data regarding conservation of structure and function within these families. We asked whether the filament architecture and biochemical properties of the best-understood prokaryotic actin, ParM from plasmid R1, are conserved in a divergent member of the ParM family from plasmid pB171. Previous work demonstrated that R1 ParM assembles into filaments that are structurally distinct from actin and the other characterized ALPs. They also display three biophysical properties thought to be essential for DNA segregation: 1) rapid spontaneous nucleation, 2) symmetrical elongation, and 3) dynamic instability. We used microscopic and biophysical techniques to compare and contrast the architecture and assembly of these related proteins. Despite being only 41% identical, R1 and pB171 ParMs polymerize into nearly identical filaments with similar assembly dynamics. Conservation of the core assembly properties argues for their importance in ParM-mediated DNA segregation and suggests that divergent DNA-segregating ALPs with different assembly properties operate via different mechanisms. PMID:21339292

  16. Genetic evidence for a role of parC mutations in development of high-level fluoroquinolone resistance in Escherichia coli.

    PubMed

    Heisig, P

    1996-04-01

    Fifteen strains of Escherichia coli with MICs of ciprofloxacin (CIP) between 0.015 and 256 micrograms/ml were examined for the presence of mutations in the quinolone resistance-determining region of the gyrA gene and in an analogous region of the parC gene. No mutation was found in a susceptible isolate (MIC of CIP, 0.015 microgram/ml). Four moderately resistant strains (MIC of CIP 0.06 to 4 micrograms/ml) carried one gyrA mutation affecting serine 83, but in only one strain was an additional parC mutation (Gly-78 to Asp) detected. All ten highly resistant strains examined (MIC of CIP, > 4 micrograms/ml) carried two gyrA mutations affecting residues serine 83 and aspartate 87, and at least one parC mutation. These parC mutations included alterations of serine 80 to arginine or isoleucine and glutamate 84 to glycine or lysine. The parC+ and two mutant alleles (parCI-80 and parCI-80,G-84) were inserted into the mobilizable vector pBP507. Transfer of a plasmid-coded parC+ allele into parC+ strains did not alter the susceptibilities towards ciprofloxacin or nalidixic acid, while a significant increase in susceptibility was detectable for parC mutants. This increase, however, did not restore wild-type susceptibility, whereas transfer of a plasmid-coded gyrA+ allele alone or in combination with parC+ did. These data are in agreement with the view that topoisomerase IV is a secondary, less sensitive target for quinolone action in Escherichia coli and that the development of high-level fluoroquinolone resistance in E. coli requires at least one parC mutation in addition to the gyrA mutation(s). PMID:8849244

  17. Prevalence of Neospora caninum antibodies in cattle from Santarém, Pará, Brazil.

    PubMed

    Minervino, Antonio H H; Ragozo, Alessandra M A; Monteiro, Renata M; Ortolani, Enrico L; Gennari, Solange M

    2008-04-01

    Prevalence of anti-Neospora caninum antibodies was measured in serum samples randomly collected from dairy (40 cows from four farms) and beef cattle (120 animals from 12 farms) from the municipality of Santarém, Pará State, Brazil, calculated by using the Win Episcope 2.0 statistical program. The presence of anti-N. caninum antibodies was determined by indirect immunofluorescence-antibody test with a cut-off value of 1:100. We found that 13 farms (81.25%) showed infection rates above 10%, which indicates widespread distribution of N. caninum in the region. The frequency per animal was 19%. No difference was observed between the prevalence values in dairy and beef animals or between farms, which was probably due to the small number of dairy farms examined. The results confirm, for the first time, the presence of anti-N. caninum antibodies in cattle from Pará State and the necessity to further investigate the epidemiology of N. caninum in the Amazon region. PMID:17619028

  18. Mammalian aPKC/Par polarity complex mediated regulation of epithelial division orientation and cell fate

    SciTech Connect

    Vorhagen, Susanne; Niessen, Carien M.

    2014-11-01

    Oriented cell division is a key regulator of tissue architecture and crucial for morphogenesis and homeostasis. Balanced regulation of proliferation and differentiation is an essential property of tissues not only to drive morphogenesis but also to maintain and restore homeostasis. In many tissues orientation of cell division is coupled to the regulation of differentiation producing daughters with similar (symmetric cell division, SCD) or differential fate (asymmetric cell division, ACD). This allows the organism to generate cell lineage diversity from a small pool of stem and progenitor cells. Division orientation and/or the ratio of ACD/SCD need to be tightly controlled. Loss of orientation or an altered ratio can promote overgrowth, alter tissue architecture and induce aberrant differentiation, and have been linked to morphogenetic diseases, cancer and aging. A key requirement for oriented division is the presence of a polarity axis, which can be established through cell intrinsic and/or extrinsic signals. Polarity proteins translate such internal and external cues to drive polarization. In this review we will focus on the role of the polarity complex aPKC/Par3/Par6 in the regulation of division orientation and cell fate in different mammalian epithelia. We will compare the conserved function of this complex in mitotic spindle orientation and distribution of cell fate determinants and highlight common and differential mechanisms in which this complex is used by tissues to adapt division orientation and cell fate to the specific properties of the epithelium.

  19. Fine structure and photoperiodical seasonal changes in Pars tuberalis of hibernating bats.

    PubMed

    Azzali, Giacomo; Arcari, Maria Luisa; Cacchioli, Antonio; Toni, Roberto

    2003-01-01

    In Pars tuberalis (PT) of pituitary gland of hibernating bats, extending cranially along the ventral face of the hypothalamic median eminence, around the hypophyseal stalk, and caudally continuing in the Pars distalis (PD), pt specific cells, follicular cells and gonadotropic cells were distinguished. Pt specific cells contain peculiar secretory granules positive to lectin WGA and negative to lectins LFA and PNA, positive to S-100 protein labeling and to PD hormones antisera. During hibernation they present a low numerical density of both secretory granules and melatonin binding sites. After light exposure, on the other hand, the latter increase in density and are associated with marked secretion synthetic activity and exocytosis. These aspects result to be more balanced in animals sacrificed during summer. These changes seem to support the hypothesis of marked annual changes even in animal species with seasonal rhythmicity of metabolisms and gonads. Follicular cells, organized in closed follicles, have slightly developed RER and Golgi apparatus during hibernation, whereas they seem to show an increased secretory activity after light exposure and during summer. In perinuclear and supranuclear cytoplasm, glycogen particles clusters (peculiar of hibernation), cilia 9+2 and multivesicular bodies were identified. Concerning FSH cells, a reduced numerical density during hibernation, the secretory granules morphological characteristics and their probable involvement in photoperiod-linked reproductive functions are investigated. PMID:12737515

  20. Parameterization of PAR vertical profile within horizontally uniform forest canopies for use in environmental modeling

    NASA Astrophysics Data System (ADS)

    Lalic, Branislava; Firanj, Ana; Mihailovic, Dragutin T.; Podrascanin, Zorica

    2013-08-01

    radiation transfer within the forest canopy plays crucial role in energy balance and turbulent transfer processes. Objective of this study is to suggest a new relation for vertical profile of photosynthetically active radiation (PAR) in case of horizontally uniform forest canopy. It is based on (i) the Lambert-Beer law relationship and (ii) new parameterization of leaf area density (LAD) profile. We have supposed that absorption coefficient μ varies with height and depends on LAD distribution. To check validity of the relation proposed, we have compared calculated values with the observations using data sets assimilated during Anglo-Brazilian Amazonian Climate Observation Study experiment at two observational sites located in Reserva Jaru and Reserva Ducke (Brazil) with different types of forest. Among all available measurements, 615 profiles observed between 08 and 18 local mean time for 72 days at 2 locations were selected. For comparison study, two more profiles based on constant- and variable-LAD approximation were introduced. Obtained results indicate that suggested relation: (i) well reproduces PAR profile within the forest in comparison with observations and (ii) shows better agreement with observations in comparison with two other profiles used in this study.

  1. Traitement chirurgical des fractures articulaires du calcanéum par plaque vissée

    PubMed Central

    Hammou, Nassreddine; Abid, Hatim; Shimi, Mohammed; El Ibrahimi, Abdelhalim; El Mrini, Abdelmajid

    2015-01-01

    Les fractures du calcanéum sont peu fréquentes mais le plus souvent graves. Le traitement chirurgical par plaque vissée est ardemment défendu. L'objectif de notre travail rétrospectif est d’évaluer les résultats du traitement chirurgical des fractures articulaires du calcanéum à travers une série de 12 patients opérée aux service d'orthopédie du CHU Hassan II de Fès sur une durée de 3 ans, et les comparer aux données de la littérature. L’âge moyen dans notre série était de 34 ans, le geste opératoire était réalisé au 7ème jour. Tous nos patient ont bénéficie d'une réduction à foyer ouvert avec une ostéosynthèse par plaques vissées. Le recul moyen était de 12 mois et les résultats fonctionnels ont été évaluer selon le score de Kitaoka. PMID:26161214

  2. Par@Graph - a parallel toolbox for the construction and analysis of large complex climate networks

    NASA Astrophysics Data System (ADS)

    Ihshaish, H.; Tantet, A.; Dijkzeul, J. C. M.; Dijkstra, H. A.

    2015-01-01

    In this paper, we present Par@Graph, a software toolbox to reconstruct and analyze complex climate networks having a large number of nodes (up to at least O (106)) and of edges (up to at least O (1012)). The key innovation is an efficient set of parallel software tools designed to leverage the inherited hybrid parallelism in distributed-memory clusters of multi-core machines. The performance of the toolbox is illustrated through networks derived from sea surface height (SSH) data of a global high-resolution ocean model. Less than 8 min are needed on 90 Intel Xeon E5-4650 processors to construct a climate network including the preprocessing and the correlation of 3 × 105 SSH time series, resulting in a weighted graph with the same number of vertices and about 3 × 106 edges. In less than 5 min on 30 processors, the resulted graph's degree centrality, strength, connected components, eigenvector centrality, entropy and clustering coefficient metrics were obtained. These results indicate that a complete cycle to construct and analyze a large-scale climate network is available under 13 min. Par@Graph therefore facilitates the application of climate network analysis on high-resolution observations and model results, by enabling fast network construction from the calculation of statistical similarities between climate time series. It also enables network analysis at unprecedented scales on a variety of different sizes of input data sets.

  3. Par@Graph - a parallel toolbox for the construction and analysis of large complex climate networks

    NASA Astrophysics Data System (ADS)

    Ihshaish, H.; Tantet, A.; Dijkzeul, J. C. M.; Dijkstra, H. A.

    2015-10-01

    In this paper, we present Par@Graph, a software toolbox to reconstruct and analyze complex climate networks having a large number of nodes (up to at least 106) and edges (up to at least 1012). The key innovation is an efficient set of parallel software tools designed to leverage the inherited hybrid parallelism in distributed-memory clusters of multi-core machines. The performance of the toolbox is illustrated through networks derived from sea surface height (SSH) data of a global high-resolution ocean model. Less than 8 min are needed on 90 Intel Xeon E5-4650 processors to reconstruct a climate network including the preprocessing and the correlation of 3 × 105 SSH time series, resulting in a weighted graph with the same number of vertices and about 3.2 × 108 edges. In less than 14 min on 30 processors, the resulted graph's degree centrality, strength, connected components, eigenvector centrality, entropy and clustering coefficient metrics were obtained. These results indicate that a complete cycle to construct and analyze a large-scale climate network is available under 22 min Par@Graph therefore facilitates the application of climate network analysis on high-resolution observations and model results, by enabling fast network reconstruct from the calculation of statistical similarities between climate time series. It also enables network analysis at unprecedented scales on a variety of different sizes of input data sets.

  4. Vector analysis of chemical variation in the lavas of Parícutin volcano, Mexico

    USGS Publications Warehouse

    Miesch, A.T.

    1979-01-01

    Compositional variations in the lavas of Parícutin volcano, Mexico, have been examined by an extended method of Q-mode factor analysis. Each sample composition is treated as a vector projected from an original eight-dimensional space into a vector system of three dimensions. The compositions represented by the vectors after projection are closely similar to the original compositions except for Na2Oand Fe2O3.The vectors in the three-dimensional system cluster about three different planes that represent three stages of compositional change in the Parícutin lavas. Because chemical data on the compositions of the minerals in the lavas are presently lacking, interpretations of the mineral phases that may have been involved in fractional crystallization are based on CIPW norm calculations. Changes during the first stage are attributed largely to the fractional crystallization of plagioclase and olivine. Changes during the second stage can be explained by the separation of plagioclase and pyroxene. Changes during the final stage may have resulted mostly from the assimilation of a granitic material, as previously proposed by R. E. Wilcox.

  5. Stress injuries of the pars interarticularis: Radiologic classification and indications for radionuclide imaging

    SciTech Connect

    Pennell, R.; Maurer, A.R.; Bonakdarpour, A.

    1984-01-01

    Lumbar spine radiographs and radionuclide images were compared and correlated with clinical histories of 20 athletes with low back pain. Radiographs were classified as: Normal (Type 0); showing a healing stress fracture (an irregular lucent line) with sclerosis (Type I); as an evolving or healed stress injury with either sclerosis, narrowing, or demineralization (Type II); and as a chronic fracture showing a large lucency with well-defined margins classically referred to as spondylolysis (Type III). Patients were grouped clinically on the basis of their pain: acute onset (Group A, n = 7), acute superimposed on chronic (Group B, n = 9), and chronic pain without an acute event (Group C, n = 4). Radiographic abnormalities were present in 95% (19/20) of the patients and radionuclide studies were positive in 60% (12/20). Scintigraphy was positive most often with Type I pars abnormalities (77%, 10/13) and negative most often with Type III abnormalities (91%, 11/12). Of all positive scintigraphy 12/14 (86%) were in pts in Groups A and B (acute symptoms). The authors' findings support theories that radiographic pars abnormalities exist which correspond to stages in the healing of stress induced fractures. With acute symptoms radionuclide imaging need not be obtained if a Type I radiographic abnormality is seen. Radionuclide imaging is indicated with either Type 0, II or III radiographs to confirm or rule out recent stress injury.

  6. Retrieval of PAR-estimates using remote sensing data and radiation transfer models

    NASA Astrophysics Data System (ADS)

    Fistric, Sascha; Gesell, Gerhard; Guenther, Kurt P.

    2003-04-01

    A new method is proposed for retrieving the photosynthetically active radiation (PAR) using remote sensing data (AVHRR) and a radiation transfer model (libRadtran). The approach applicable for clear and cloudy sky conditions takes into account atmospheric parameters affecting the radiation transfer through the atmosphere, namely, extinction by aerosols and clouds. Due to the high temporal variability of cloud distribution and cloud properties, a geostationary satellite as e.g. the future Meteosat Second Generation (MSG) with SEVIRI on board is proposed to derive inter-daily variation of cloud parameters. The upcoming SEVIRI sensor will deliver spectral information of clouds and atmosphere every 15 minutes. The spectral information content of SEVIRI is simulated by the existing polar orbiting sensor Advanced Very High Resolution Radiometer (AVHRR) on board of the NOAA satellites. Our first results are validated with ground truth data from the European Light Dosimeter Network (ELDONET). Up to 8 stations distributed over Europe are available for validation purposes. It is shown that for heterogeneous atmospheric conditions a good correlation exist between measured and estimated PAR values. Processing more AVHRR data over a longer time period and fine-adjustment of the algorithms combined with extended validation will consolidate our findings in the future.

  7. Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1

    SciTech Connect

    Beaulieu, Lea M.; Church, Frank C. . E-mail: fchurch@email.unc.edu

    2007-02-15

    Activated protein C (APC) is a serine protease that regulates thrombin (IIa) production through inactivation of blood coagulation factors Va and VIIIa. APC also has non-hemostatic functions related to inflammation, proliferation, and apoptosis through various mechanisms. Using two breast cancer cell lines, MDA-MB-231 and MDA-MB-435, we investigated the role of APC in cell chemotaxis and invasion. Treatment of cells with increasing APC concentrations (1-50 {mu}g/ml) increased invasion and chemotaxis in a concentration-dependent manner. Only the active form of APC increased invasion and chemotaxis of the MDA-MB-231 cells when compared to 3 inactive APC derivatives. Using a modified 'checkerboard' analysis, APC was shown to only affect migration when plated with the cells; therefore, APC is not a chemoattractant. Blocking antibodies to endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1) attenuated the effects of APC on chemotaxis in the MDA-MB-231 cells. Finally, treatment of the MDA-MB-231 cells with the proliferation inhibitor, Na butyrate, showed that APC did not increase migration by increasing cell number. Therefore, APC increases invasion and chemotaxis of cells by binding to the cell surface and activating specific signaling pathways through EPCR and PAR-1.

  8. Par-baked Bread Technology: Formulation and Process Studies to Improve Quality.

    PubMed

    Almeida, Eveline Lopes; Steel, Caroline Joy; Chang, Yoon Kil

    2016-01-01

    Extending the shelf-life of bakery products has been an important requirement resulting from the mechanization of this industry and the need to increase the distance for the distribution of final products, caused by the increase in production and consumer demand. Technologies based on the interruption of the breadmaking process represent an alternative to overcome product staling and microbiological deterioration. The production of par-baked breads is one of these technologies. It consists of baking the bread in two stages, and due to the possibility of retarding the second stage, it can be said that the bread can always be offered fresh to the consumer. The technology inserts logistics as part of the production process and creates the "hot point" concept, these being the locations where the bread is finalized, such as in the consumers' homes or sales locations. In this work, a review of the papers published on this subject was carried out, and aspects related to both the formulation and the process were considered. This technology still faces a few challenges, such as solving bread quality problems that appear due to process modifications, and these will also be considered. The market for these breads has grown rapidly and the bakery industry searches innovations related to par-baked bread technology. PMID:25000472

  9. miR-219 regulates neural progenitors by dampening apical Par protein-dependent Hedgehog signaling.

    PubMed

    Hudish, Laura I; Galati, Domenico F; Ravanelli, Andrew M; Pearson, Chad G; Huang, Peng; Appel, Bruce

    2016-07-01

    The transition of dividing neuroepithelial progenitors to differentiated neurons and glia is essential for the formation of a functional nervous system. Sonic hedgehog (Shh) is a mitogen for spinal cord progenitors, but how cells become insensitive to the proliferative effects of Shh is not well understood. Because Shh reception occurs at primary cilia, which are positioned within the apical membrane of neuroepithelial progenitors, we hypothesized that loss of apical characteristics reduces the Shh signaling response, causing cell cycle exit and differentiation. We tested this hypothesis using genetic and pharmacological manipulation, gene expression analysis and time-lapse imaging of zebrafish embryos. Blocking the function of miR-219, a microRNA that downregulates apical Par polarity proteins and promotes progenitor differentiation, elevated Shh signaling. Inhibition of Shh signaling reversed the effects of miR-219 depletion and forced expression of Shh phenocopied miR-219 deficiency. Time-lapse imaging revealed that knockdown of miR-219 function accelerates the growth of primary cilia, revealing a possible mechanistic link between miR-219-mediated regulation of apical Par proteins and Shh signaling. Thus, miR-219 appears to decrease progenitor cell sensitivity to Shh signaling, thereby driving these cells towards differentiation. PMID:27226318

  10. Chronic Rhinosinusitis Patients Show Accumulation of Genetic Variants in PARS2

    PubMed Central

    Henmyr, Viktor; Lind-Halldén, Christina; Halldén, Christer; Säll, Torbjörn; Carlberg, Daniel; Bachert, Claus; Cardell, Lars-Olaf

    2016-01-01

    Genetic studies of chronic rhinosinusitis (CRS) have identified a total of 53 CRS-associated SNPs that were subsequently evaluated for their reproducibility in a recent study. The rs2873551 SNP in linkage disequilibrium with PARS2 showed the strongest association signal. The present study aims to comprehensively screen for rare variants in PARS2 and evaluate for accumulation of such variants in CRS-patients. Sanger sequencing and long-range PCR were used to screen for rare variants in the putative promoter region and coding sequence of 310 CRS-patients and a total of 21 variants were detected. The mutation spectrum was then compared with data from European populations of the 1000Genomes project (EUR) and the Exome Aggregation Consortium (ExAC). The CRS population showed a significant surplus of low-frequency variants compared with ExAC data. Haplotype analysis of the region showed a significant excess of rare haplotypes in the CRS population compared to the EUR population. Two missense mutations were also genotyped in the 310 CRS patients and 372 CRS-negative controls, but no associations with the disease were found. This is the first re-sequencing study in CRS research and also the first study to show an association of rare variants with the disease. PMID:27348859

  11. Multiple IgE recognition on the major allergen of the Parietaria pollen Par j 2.

    PubMed

    Longo, Valeria; Costa, Maria Assunta; Cibella, Fabio; Cuttitta, Giuseppina; La Grutta, Stefania; Colombo, Paolo

    2015-02-01

    The interaction between IgE antibodies and allergens is a key event in triggering an allergic reaction. The characterization of this region provides information of paramount importance for diagnosis and therapy. Par j 2 Lipid Transfer Protein is one of the most important allergens in southern Europe and a well-established marker of sensitization in Parietaria pollen allergy. The main aim of this study was to map the IgE binding regions of this allergen and to study the pattern of reactivity of individual Parietaria-allergic patients. By means of gene fragmentation, six overlapping peptides were expressed in Escherichia coli, and their IgE binding activity was evaluated by immunoblotting in a cohort of 79 Parietaria-allergic patients. Our results showed that Pj-allergic patients display a heterogeneous pattern of IgE binding to the different recombinant fragments, and that patients reacted simultaneously against several protein domains spread all the over the molecule, even in fragments which do not contain structural features resembling the native allergen. Our results reveal the presence of a large number of linear and conformational epitopes on the Par j 2 sequence, which probably explains the high allergenic activity of this allergen. PMID:25284812

  12. Urokinase-type Plasminogen Activator Receptor (uPAR)-mediated Regulation of WNT/β-Catenin Signaling Is Enhanced in Irradiated Medulloblastoma Cells*

    PubMed Central

    Asuthkar, Swapna; Gondi, Christopher S.; Nalla, Arun Kumar; Velpula, Kiran Kumar; Gorantla, Bharathi; Rao, Jasti S.

    2012-01-01

    Urokinase plasminogen activator receptor (uPAR) is known to promote invasion, migration, and metastasis in cancer cells. In this report, we showed that ionizing radiation (IR)-induced uPAR has a role in WNT-β-catenin signaling and mediates induction of cancer stem cell (CSC)-like properties in medulloblastoma cell lines UW228 and D283. We observed that IR induced the expression of uPAR and CSC markers, such as Musashi-1 and CD44, and activated WNT-7a-β-catenin signaling molecules. Overexpression of uPAR alone or with IR treatment led to increased WNT-7a-β-catenin-TCF/LEF-mediated transactivation, thereby promoting cancer stemness. In contrast, treatment with shRNA specific for uPAR (pU) suppressed WNT-7a-β-catenin-TCF/LEF-mediated transactivation both in vitro and in vivo. Quercetin, a potent WNT/β-catenin inhibitor, suppressed uPAR and uPAR-mediated WNT/β-catenin activation, and furthermore, addition of recombinant human WNT-7a protein induced uPAR, indicating the existence of a mutual regulatory relationship between uPAR and WNT/β-catenin signaling. We showed that uPAR was physically associated with the WNT effector molecule β-catenin on the membrane, cytoplasm, and nucleus of IR-treated cells and CSC. Most interestingly, we demonstrated for the first time that localization of uPAR in the nucleus was associated with transcription factors (TF) and their specific response elements. We observed from uPAR-ChIP, TF protein, and protein/DNA array analyses that uPAR associates with activating enhancer-binding protein 2α (AP2a) and mediates β-catenin gene transcription. Moreover, association of uPAR with the β-catenin·TCF/LEF complex and various other TF involved during embryonic development and cancer indicates that uPAR is a potent activator of stemness, and targeting of uPAR in combination with radiation has significant therapeutic implications. PMID:22511755

  13. Urokinase-type plasminogen activator receptor (uPAR)-mediated regulation of WNT/β-catenin signaling is enhanced in irradiated medulloblastoma cells.

    PubMed

    Asuthkar, Swapna; Gondi, Christopher S; Nalla, Arun Kumar; Velpula, Kiran Kumar; Gorantla, Bharathi; Rao, Jasti S

    2012-06-01

    Urokinase plasminogen activator receptor (uPAR) is known to promote invasion, migration, and metastasis in cancer cells. In this report, we showed that ionizing radiation (IR)-induced uPAR has a role in WNT-β-catenin signaling and mediates induction of cancer stem cell (CSC)-like properties in medulloblastoma cell lines UW228 and D283. We observed that IR induced the expression of uPAR and CSC markers, such as Musashi-1 and CD44, and activated WNT-7a-β-catenin signaling molecules. Overexpression of uPAR alone or with IR treatment led to increased WNT-7a-β-catenin-TCF/LEF-mediated transactivation, thereby promoting cancer stemness. In contrast, treatment with shRNA specific for uPAR (pU) suppressed WNT-7a-β-catenin-TCF/LEF-mediated transactivation both in vitro and in vivo. Quercetin, a potent WNT/β-catenin inhibitor, suppressed uPAR and uPAR-mediated WNT/β-catenin activation, and furthermore, addition of recombinant human WNT-7a protein induced uPAR, indicating the existence of a mutual regulatory relationship between uPAR and WNT/β-catenin signaling. We showed that uPAR was physically associated with the WNT effector molecule β-catenin on the membrane, cytoplasm, and nucleus of IR-treated cells and CSC. Most interestingly, we demonstrated for the first time that localization of uPAR in the nucleus was associated with transcription factors (TF) and their specific response elements. We observed from uPAR-ChIP, TF protein, and protein/DNA array analyses that uPAR associates with activating enhancer-binding protein 2α (AP2a) and mediates β-catenin gene transcription. Moreover, association of uPAR with the β-catenin·TCF/LEF complex and various other TF involved during embryonic development and cancer indicates that uPAR is a potent activator of stemness, and targeting of uPAR in combination with radiation has significant therapeutic implications. PMID:22511755

  14. ParC subunit of DNA topoisomerase IV of Streptococcus pneumoniae is a primary target of fluoroquinolones and cooperates with DNA gyrase A subunit in forming resistance phenotype.

    PubMed Central

    Muñoz, R; De La Campa, A G

    1996-01-01

    The genes encoding the ParC and ParE subunits of topoisomerase IV of Streptococcus pneumoniae, together with the region encoding amino acids 46 to 172 (residue numbers are as in Escherichia coli) of the pneumococcal GyrA subunit, were partially characterized. The gyrA gene maps to a physical location distant from the gyrB and parC loci on the chromosome, whereas parC is closely linked to parE. Ciprofloxacin-resistant (Cpr) clinical isolates of S. pneumoniae had mutations affecting amino acid residues of the quinolone resistance-determining region of ParC (low-level Cpr) or in both quinolone resistance-determining regions of ParC and GyrA (high-level Cpr). Mutations were found in residue positions equivalent to the serine at position 83 and the aspartic acid at position 87 of the E. coli GyrA subunit. Transformation experiments suggest that ParC is the primary target of ciprofloxacin. Mutation in parC appears to be a prerequisite before mutations in gyrA can influence resistance levels. PMID:8891124

  15. Mesure du taux de la capture radiative du muon par l'hydrogene liquide

    NASA Astrophysics Data System (ADS)

    Jonkmans, Guy

    À basse énergie, l'interaction faible entre leptons et quarks est décrite par une interaction de la forme courant × courant de type V - A. La présence de l'interaction forte induit des couplages additionnels qui doivent être déterminés expérimentalement. De ceux-ci, le couplage pseudoscalaire induit, gp , est mesuré avec la plus grande incertitude et fait l'objet de la présente recherche. L'hypothèse du Courant Axial Partiellement Conservé (CAPC) et l'usage de la relation de Goldberger-Treiman relie gp au couplage axial ga . Cette relation a été vérifiée traditionnellement par la Capture Ordinaire du Muon (COM) à une valeur fixe du moment de transfert q. La Capture Radiative du Muon (CRM), m- p-->nnmg , est un meilleur outil pour l'étude de gp à cause de sa dépendance variable en q2 qui offre une plus grande sensibilité dans la partie à haute énergie du spectre des photons. Toutefois, le petit rapport d'embranchement (~10-8) de la CRM par rapport à la désintégration du muon a retardé cette mesure jusqu'à ce jour. La théorie et les difficultés expérimentales associées à la détection des photons de CRM sont présentées au deuxième chapitre. On décrit ensuite, au troisième chapitre, les composantes du système de détection. Ce détecteur est un spectromètre à paires de grand angle solide (~3p) et qui permet l'observation des photons par l'analyse des électrons et des positrons de photo-conversion. Ainsi, le bruit de fond important des neutrons de la COM ne constitue pas un problème pour cette mesure. Nous décrivons, au quatrième chapitre, toutes les étapes de l'analyse, nécessaires pour la réduction des multiples bruits de fond. Le cinquième chapitre présente le calcul des efficacités ainsi que l'estimation des erreurs systématiques. Le sixième chapitre démontre comment l'on extrait le rapport d'embranchement pour la CRM ainsi que la valeur ae gp . On insiste sur la dépendance de gp en fonction de la valeur de

  16. Démonstration expérimentale d'une distribution quantique de clé par codage temporel

    NASA Astrophysics Data System (ADS)

    Boucher, W.; Debuisschert, T.

    2006-10-01

    Nous avons démontré expérimentalement la transmission quantique de clé par codage temporel. Alice envoie des impulsions cohérentes atténuées. La clé est codée dans l'instant de détection des photons chez Bob. Une mesure de la durée de cohérence par moyen interférométrique permet d'assurer un fonctionnement en régime quantique. Nous avons mesuré un taux d'erreur quantique de 3.3% et une chute relative de contraste de l'interféromètre de 8.4%. Ces valeurs permettent d'évaluer un avantage d'information de 0.49 bit/impulsion pour Alice et Bob par rapport à un espion éventuel.

  17. Par Pond phytoplankton in association with refilling of the pond: Final Report for sampling from February 1995 -- September 1996

    SciTech Connect

    Wilde, E.W.; Johnson, M.A.; Cody, W.C.

    1996-12-31

    This report describes the results of phytoplankton analyses from Par Pond samples collected between February 1995 and September 1996. The principal objective of the study was to determine the effect of refilling of Par Pond following repair of the dam on the phytoplankton community. Algal blooms are often responsible for fish kills and other detrimental effects in ponds and lakes, and it was postulated that decaying vegetation from formerly exposed sediments might trigger algal blooms that could result in fish kills in Par Pond following the refill. Sporadic algal blooms involving blue-green algae were detected, especially during the summer of 1996. However, the data derived from the study demonstrates that overall, the refilling effort caused no significant negative impact to the pond attributable to phytoplankton dynamics.

  18. RalA and the exocyst complex influence neuronal polarity through PAR-3 and aPKC.

    PubMed

    Lalli, Giovanna

    2009-05-15

    Neuronal polarization requires localized cytoskeletal changes and polarized membrane traffic. Here, I report that the small GTPase RalA, previously shown to control neurite branching, also regulates neuronal polarity. RalA depletion, or ectopic expression of constitutively active RalA in cultured neurons inhibit axon formation. However, expression of a constitutively active RalA mutant that is unable to interact with the exocyst complex has no effect on neuronal polarization. Furthermore, depletion of the Sec6, Sec8 or Exo84 subunits of the exocyst complex also leads to unpolarized neurons. Early stages of neuronal polarization are accompanied by increasing levels of interaction of the exocyst complex with PAR-3 and atypical protein kinase C (aPKC), and by the RalA-dependent association of the exocyst complex with PAR-3. Thus, neuronal polarization involves a RalA-regulated association between mediators of vesicle trafficking (exocyst complex) and cell polarity (PAR-3). PMID:19383721

  19. Cloning, expression, purification, crystallization and preliminary crystallographic analysis of the C-terminal domain of Par-4 (PAWR)

    PubMed Central

    Tiruttani Subhramanyam, Udaya Kumar; Kubicek, Jan; Eidhoff, Ulf B.; Labahn, Joerg

    2014-01-01

    Prostate apoptosis response-4 protein is an intrinsically disordered pro-apoptotic protein with tumour suppressor function. Par-4 is known for its selective induction of apoptosis in cancer cells only and its ability to interact with various apoptotic proteins via its C-terminus. Par-4, with its unique function and various interacting partners, has gained importance as a potential target for cancer therapy. The C-terminus of the rat homologue of Par-4 was crystallized and a 3.7 Å resolution X-ray diffraction data set was collected. Preliminary data analysis shows the space group to be P41212. The unit-cell parameters are a = b = 115.351, c = 123.663 Å, α = β = γ = 90°. PMID:25195896

  20. Results of submerged sediment core sampling and analysis on Par Pond, Pond C, and L Lake: July 1995

    SciTech Connect

    Koch, J.W. II; Martin, F.D.; Friday, G.P.

    1996-06-01

    Sediment cores from shallow and deep water locations in Par Pond, Pond C, and L Lake were collected and analyzed in 1995 for radioactive and nonradioactive constituents. This core analysis was conducted to develop a defensible characterization of contaminants found in the sediments of Par Pond, Pond C, and L Lake. Mercury was the only nonradiological constituent with a nonestimated quantity that was detected above the U.S Environmental Protection Agency Region IV potential contaminants of concern screening criteria. It was detected at a depth of 0.3--0.6 meters (1.0--2.0 feet) at one location in L Lake. Cesium-137, promethium-146, plutonium-238, and zirconium-95 had significantly higher concentrations in Par Pond sediments than in sediments from the reference sites. Cobalt-60, cesium-137, plutonium-238, plutonium-239/240, and strontium-90 had significantly higher concentrations in L-Lake sediments than sediments from the reference sites.

  1. Identification of a Novel Regulatory Mechanism of Nutrient Transport Controlled by TORC1-Npr1-Amu1/Par32.

    PubMed

    Boeckstaens, Mélanie; Merhi, Ahmad; Llinares, Elisa; Van Vooren, Pascale; Springael, Jean-Yves; Wintjens, René; Marini, Anna Maria

    2015-07-01

    Fine-tuning the plasma-membrane permeability to essential nutrients is fundamental to cell growth optimization. Nutritional signals including nitrogen availability are integrated by the TORC1 complex which notably regulates arrestin-mediated endocytosis of amino-acid transporters. Ammonium is a ubiquitous compound playing key physiological roles in many, if not all, organisms. In yeast, it is a preferred nitrogen source transported by three Mep proteins which are orthologues of the mammalian Rhesus factors. By combining genetic, kinetic, biochemical and cell microscopy analyses, the current study reveals a novel mechanism enabling TORC1 to regulate the inherent activity of ammonium transport proteins, independently of arrestin-mediated endocytosis, identifying the still functional orphan Amu1/Par32 as a selective regulator intermediate. We show that, under poor nitrogen supply, the TORC1 effector kinase' Npr1' promotes phosphorylation of Amu1/Par32 which appears mainly cytosolic while ammonium transport proteins are active. Upon preferred nitrogen supplementation, like glutamine or ammonium addition, TORC1 upregulation enables Npr1 inhibition and Amu1/Par32 dephosphorylation. In these conditions, as in Npr1-lacking cells, hypophosphorylated Amu1/Par32 accumulates at the cell surface and mediates the inhibition of specific ammonium transport proteins. We show that the integrity of a conserved repeated motif of Amu1/Par32 is required for the interaction with these transport proteins. This study underscores the diversity of strategies enabling TORC1-Npr1 to selectively monitor cell permeability to nutrients by discriminating between transporters to be degraded or transiently inactivated and kept stable at the plasma membrane. This study further identifies the function of Amu1/Par32 in acute control of ammonium transport in response to variations in nitrogen availability. PMID:26172854

  2. Par4 is required for platelet thrombus propagation but not fibrin generation in a mouse model of thrombosis

    PubMed Central

    Vandendries, Erik R.; Hamilton, Justin R.; Coughlin, Shaun R.; Furie, Bruce; Furie, Barbara C.

    2007-01-01

    Thrombin, a central mediator of hemostasis and thrombosis, converts fibrinogen to fibrin and is a potent platelet activator. Activated platelets provide a surface for assembly of the tenase and prothrombinase complexes required for thrombin generation. The role of thrombin-induced platelet activation in platelet accumulation and its interplay with fibrin deposition during thrombus assembly has not been fully defined. We studied these processes during laser-induced thrombus formation by using real-time digital fluorescence microscopy in mice lacking protease-activated receptor-4 (Par4), which is necessary for thrombin responsiveness in mouse platelets. Juxtamural platelet accumulation immediately after laser injury was not different in wild-type and Par4−/− mice. However, subsequent growth of platelet thrombi was markedly diminished in Par4−/− mice. At the time of maximal thrombus size in wild type, platelet accumulation was more than 10-fold higher in wild type than in Par4−/− mice. P-selectin expression, a marker of platelet activation, was reduced and delayed in Par4−/− thrombi. In contrast to platelet activation and accumulation, the rate and amount of fibrin deposition, predominantly intramural and juxtamural in this model, were indistinguishable in Par4−/− and wild-type mice. These results suggest that platelet activation by thrombin is necessary for normal propagation of a platelet thrombus at a distance from the injured vessel wall and hence for normal thrombus growth. However, platelet activation by thrombin is unnecessary for initial and limited accumulation of platelets at or near the vessel wall, and this limited accumulation of platelets and/or platelet-independent mechanism(s) of thrombin generation are sufficient for normal fibrin deposition in this model. PMID:17190826

  3. In vitro synthesis of ACTH- and beta-endorphin-related substances in the pars distalis of Anolis carolinensis.

    PubMed

    Dores, R M; Surprenant, A

    1984-10-01

    In order to investigate the biosynthesis of ACTH- and beta-endorphin-related substances in the pars distalis of Anolis carolinensis, explants of pars distali were incubated for 24 hr in a complete medium which contained [3H]tyrosine. Acid extracts of the incubates were immunoprecipitated with either an affinity-purified ACTH antiserum or an affinity-purified beta-endorphin antiserum and analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Three distinct peaks of ACTH-related material were detected. The major peak comigrated with human ACTH(1-39), while two minor peaks corresponded in apparent molecular weight to ACTH biosynthetic intermediate and precursor-sized material. Three peaks of beta-endorphin-related material were also detected. The major peak comigrated with beta-endorphin(1-31), while two minor peaks corresponded to beta-lipotropin (LPH) and precursor-sized material. Sequential immunoprecipitation experiments indicated that the precursor-sized material had antigenic determinants for both ACTH and beta-endorphin. In addition this peak was identical in apparent molecular weight to the common precursor for alpha-melanocyte-stimulating hormone (alpha-MSH) and beta-endorphin in the pars intermedia of A. carolinensis (R.M. Dores, Peptides 3, 925-935). Analysis of extracts of reptile pars distalis by gel-filtration chromatography revealed a single peak of naloxone-reversible opiate bioactivity which coeluted with the peak of beta-endorphin-sized immunoreactivity. On a molar basis there is tenfold more opiate bioactivity in the reptile pars distalis than in the reptile pars intermedia. PMID:6092211

  4. Identification of a Novel Regulatory Mechanism of Nutrient Transport Controlled by TORC1-Npr1-Amu1/Par32

    PubMed Central

    Boeckstaens, Mélanie; Merhi, Ahmad; Llinares, Elisa; Van Vooren, Pascale; Springael, Jean-Yves; Wintjens, René; Marini, Anna Maria

    2015-01-01

    Fine-tuning the plasma-membrane permeability to essential nutrients is fundamental to cell growth optimization. Nutritional signals including nitrogen availability are integrated by the TORC1 complex which notably regulates arrestin-mediated endocytosis of amino-acid transporters. Ammonium is a ubiquitous compound playing key physiological roles in many, if not all, organisms. In yeast, it is a preferred nitrogen source transported by three Mep proteins which are orthologues of the mammalian Rhesus factors. By combining genetic, kinetic, biochemical and cell microscopy analyses, the current study reveals a novel mechanism enabling TORC1 to regulate the inherent activity of ammonium transport proteins, independently of arrestin-mediated endocytosis, identifying the still functional orphan Amu1/Par32 as a selective regulator intermediate. We show that, under poor nitrogen supply, the TORC1 effector kinase' Npr1' promotes phosphorylation of Amu1/Par32 which appears mainly cytosolic while ammonium transport proteins are active. Upon preferred nitrogen supplementation, like glutamine or ammonium addition, TORC1 upregulation enables Npr1 inhibition and Amu1/Par32 dephosphorylation. In these conditions, as in Npr1-lacking cells, hypophosphorylated Amu1/Par32 accumulates at the cell surface and mediates the inhibition of specific ammonium transport proteins. We show that the integrity of a conserved repeated motif of Amu1/Par32 is required for the interaction with these transport proteins. This study underscores the diversity of strategies enabling TORC1-Npr1 to selectively monitor cell permeability to nutrients by discriminating between transporters to be degraded or transiently inactivated and kept stable at the plasma membrane. This study further identifies the function of Amu1/Par32 in acute control of ammonium transport in response to variations in nitrogen availability. PMID:26172854

  5. Pharmacological inhibition of PAR2 with the pepducin P2pal-18S protects mice against acute experimental biliary pancreatitis.

    PubMed

    Michael, E S; Kuliopulos, A; Covic, L; Steer, M L; Perides, G

    2013-03-01

    Pancreatic acinar cells express proteinase-activated receptor-2 (PAR2) that is activated by trypsin-like serine proteases and has been shown to exert model-specific effects on the severity of experimental pancreatitis, i.e., PAR2(-/-) mice are protected from experimental acute biliary pancreatitis but develop more severe secretagogue-induced pancreatitis. P2pal-18S is a novel pepducin lipopeptide that targets and inhibits PAR2. In studies monitoring PAR2-stimulated intracellular Ca(2+) concentration changes, we show that P2pal-18S is a full PAR2 inhibitor in acinar cells. Our in vivo studies show that P2pal-18S significantly reduces the severity of experimental biliary pancreatitis induced by retrograde intraductal bile acid infusion, which mimics injury induced by endoscopic retrograde cholangiopancreatography (ERCP). This reduction in pancreatitis severity is observed when the pepducin is given before or 2 h after bile acid infusion but not when it is given 5 h after bile acid infusion. Conversely, P2pal-18S increases the severity of secretagogue-induced pancreatitis. In vitro studies indicate that P2pal-18S protects acinar cells against bile acid-induced injury/death, but it does not alter bile acid-induced intracellular zymogen activation. These studies are the first to report the effects of an effective PAR2 pharmacological inhibitor on pancreatic acinar cells and on the severity of experimental pancreatitis. They raise the possibility that a pepducin such as P2pal-18S might prove useful in the clinical management of patients at risk for developing severe biliary pancreatitis such as occurs following ERCP. PMID:23275617

  6. Protease activated receptor 1 (PAR1) enhances Src-mediated tyrosine phosphorylation of NMDA receptor in intracerebral hemorrhage (ICH)

    PubMed Central

    Duan, Zhen-Zhen; Zhang, Feng; Li, Feng-Ying; Luan, Yi-Fei; Guo, Peng; Li, Yi-Hang; Liu, Yong; Qi, Su-Hua

    2016-01-01

    It has been demonstrated that Src could modulate NMDA receptor, and PAR1 could also affect NMDAR signaling. However, whether PAR1 could regulate NMDAR through Src under ICH has not yet been investigated. In this study, we demonstrated the role of Src-PSD95-GluN2A signaling cascades in rat ICH model and in vitro thrombin challenged model. Using the PAR1 agonist SFLLR, antagonist RLLFS and Src inhibitor PP2, electrophysiological analysis showed that PAR1 regulated NMDA-induced whole-cell currents (INMDA) though Src in primary cultured neurons. Both in vivo and in vitro results showed the elevated phosphorylation of tyrosine in Src and GluN2A and enhanced interaction of the Src-PSD95-GluN2A under model conditions. Treatment with the PAR1 antagonist RLLFS, AS-PSD95 (Antisense oligonucleotide against PSD95) and Src inhibitor PP2 inhibited the interaction among Src-PSD95-GluN2A, and p-Src, p-GluN2A. Co-application of SFLLR and AS-PSD95, PP2, or MK801 (NMDAR inhibitor) abolished the effect of SF. In conclusion, our results demonstrated that activated thrombin receptor PAR1 induced Src activation, enhanced the interaction among Src-PSD95-GluN2A signaling modules, and up-regulated GluN2A phosphorylation after ICH injury. Elucidation of such signaling cascades would possibly provide novel targets for ICH treatment. PMID:27385592

  7. Une alternative au cobalt pour la synthese de nanotubes de carbone monoparoi par plasma inductif thermique

    NASA Astrophysics Data System (ADS)

    Carrier, Jean-Francois

    Les nanotubes de carbone de type monoparoi (C-SWNT) sont une classe recente de nanomateriaux qui ont fait leur apparition en 1991. L'interet qu'on leur accorde provient des nombreuses proprietes d'avant-plan qu'ils possedent. Leur resistance mecanique serait des plus rigide, tout comme ils peuvent conduire l'electricite et la chaleur d'une maniere inegalee. Non moins, les C-SWNT promettent de devenir une nouvelle classe de plateforme moleculaire, en servant de site d'attache pour des groupements reactifs. Les promesses de ce type particulier de nanomateriau sont nombreuses, la question aujourd'hui est de comment les realiser. La technologie de synthese par plasma inductif thermique se situe avantageusement pour la qualite de ses produits, sa productivite et les faibles couts d'operation. Par contre, des recherches recentes ont permis de mettre en lumiere des risques d'expositions reliees a l'utilisation du cobalt, comme catalyseur de synthese; son elimination ou bien son remplacement est devenu une preoccupation importante. Quatre recettes alternatives ont ete mises a l'essai afin de trouver une alternative plus securitaire a la recette de base; un melange catalytique ternaire, compose de nickel, de cobalt et d'oxyde d'yttrium. La premiere consiste essentiellement a remplacer la proportion massique de cobalt par du nickel, qui etait deja present dans la recette de base. Les trois options suivantes contiennent de nouveaux catalyseurs, en remplacement au Co, qui sont apparus dans plusieurs recherches scientifiques au courant des dernieres annees: le dioxyde de zircone (ZrO2), dioxyde de manganese (MnO2) et le molybdene (Mo). La methode utilisee consiste a vaporiser la matiere premiere, sous forme solide, dans un reacteur plasma a haute frequence (3 MHz) a paroi refroidi. Apres le passage dans le plasma, le systeme traverse une section dite de "croissance", isolee thermiquement a l'aide de graphite, afin de maintenir une certaine plage de temperature favorable a la

  8. Early changes in the ultrastructure of the pars intermedia of the pituitary of Xenopus laevis after change of background color.

    PubMed

    Volcanes, B D; Weatherhead, B

    1976-01-01

    Stereological analysis of the secretory cells of the pars intermedia of Xenopus laevis over a period of 3 days following the transfer of animals from a white to a black background has revealed that significant alterations in the ultrastructural appearance of these cells can be detected 8 h after the transfer. In particular, changes in the secretory granules and the rough endoplasmic reticulum were found to correlate well with previous reports concerning the melanocyte-stimulating hormone (MSH) content and the capacity for protein synthesis of the pars intermedia. PMID:1028946

  9. Brulures Profondes des Membres Apres Intoxication au Co Par Usage du Barbecue Traditionnel en Salle de Bain

    PubMed Central

    Chraïbi, R.; Moussaoui, A.; Tourabi, K.; Ennouhi, A.; Ihrai, H.; Hassam, B.

    2007-01-01

    Summary En l'absence des moyens de chauffage moderne à domicile chez une proportion non négligeable des Marocains, le recours au moyen traditionnel est fréquent. A travers six observations de brûlures profondes des membres, particulières par leur mode de survenue et par leur gravité, les Auteurs attirent l'attention sur le danger de l'utilisation du barbecue traditionnel «majmer» pour réchauffement en milieu clos. PMID:21991072

  10. Differential uPAR recruitment in caveolar-lipid rafts by GM1 and GM3 gangliosides regulates endothelial progenitor cells angiogenesis.

    PubMed

    Margheri, Francesca; Papucci, Laura; Schiavone, Nicola; D'Agostino, Riccardo; Trigari, Silvana; Serratì, Simona; Laurenzana, Anna; Biagioni, Alessio; Luciani, Cristina; Chillà, Anastasia; Andreucci, Elena; Del Rosso, Tommaso; Margheri, Giancarlo; Del Rosso, Mario; Fibbi, Gabriella

    2015-01-01

    Gangliosides and the urokinase plasminogen activator receptor (uPAR) tipically partition in specialized membrane microdomains called lipid-rafts. uPAR becomes functionally important in fostering angiogenesis in endothelial progenitor cells (EPCs) upon recruitment in caveolar-lipid rafts. Moreover, cell membrane enrichment with exogenous GM1 ganglioside is pro-angiogenic and opposite to the activity of GM3 ganglioside. On these basis, we first checked the interaction of uPAR with membrane models enriched with GM1 or GM3, relying on the adoption of solid-supported mobile bilayer lipid membranes with raft-like composition formed onto solid hydrophilic surfaces, and evaluated by surface plasmon resonance (SPR) the extent of uPAR recruitment. We estimated the apparent dissociation constants of uPAR-GM1/GM3 complexes. These preliminary observations, indicating that uPAR binds preferentially to GM1-enriched biomimetic membranes, were validated by identifying a pro-angiogenic activity of GM1-enriched EPCs, based on GM1-dependent uPAR recruitment in caveolar rafts. We have observed that addition of GM1 to EPCs culture medium promotes matrigel invasion and capillary morphogenesis, as opposed to the anti-angiogenesis activity of GM3. Moreover, GM1 also stimulates MAPKinases signalling pathways, typically associated with an angiogenesis program. Caveolar-raft isolation and Western blotting of uPAR showed that GM1 promotes caveolar-raft partitioning of uPAR, as opposed to control and GM3-challenged EPCs. By confocal microscopy, we have shown that in EPCs uPAR is present on the surface in at least three compartments, respectively, associated to GM1, GM3 and caveolar rafts. Following GM1 exogenous addition, the GM3 compartment is depleted of uPAR which is recruited within caveolar rafts thereby triggering angiogenesis. PMID:25313007

  11. Differential uPAR recruitment in caveolar-lipid rafts by GM1 and GM3 gangliosides regulates endothelial progenitor cells angiogenesis

    PubMed Central

    Margheri, Francesca; Papucci, Laura; Schiavone, Nicola; D'Agostino, Riccardo; Trigari, Silvana; Serratì, Simona; Laurenzana, Anna; Biagioni, Alessio; Luciani, Cristina; Chillà, Anastasia; Andreucci, Elena; Del Rosso, Tommaso; Margheri, Giancarlo; Del Rosso, Mario; Fibbi, Gabriella

    2015-01-01

    Gangliosides and the urokinase plasminogen activator receptor (uPAR) tipically partition in specialized membrane microdomains called lipid-rafts. uPAR becomes functionally important in fostering angiogenesis in endothelial progenitor cells (EPCs) upon recruitment in caveolar-lipid rafts. Moreover, cell membrane enrichment with exogenous GM1 ganglioside is pro-angiogenic and opposite to the activity of GM3 ganglioside. On these basis, we first checked the interaction of uPAR with membrane models enriched with GM1 or GM3, relying on the adoption of solid-supported mobile bilayer lipid membranes with raft-like composition formed onto solid hydrophilic surfaces, and evaluated by surface plasmon resonance (SPR) the extent of uPAR recruitment. We estimated the apparent dissociation constants of uPAR-GM1/GM3 complexes. These preliminary observations, indicating that uPAR binds preferentially to GM1-enriched biomimetic membranes, were validated by identifying a pro-angiogenic activity of GM1-enriched EPCs, based on GM1-dependent uPAR recruitment in caveolar rafts. We have observed that addition of GM1 to EPCs culture medium promotes matrigel invasion and capillary morphogenesis, as opposed to the anti-angiogenesis activity of GM3. Moreover, GM1 also stimulates MAPKinases signalling pathways, typically associated with an angiogenesis program. Caveolar-raft isolation and Western blotting of uPAR showed that GM1 promotes caveolar-raft partitioning of uPAR, as opposed to control and GM3-challenged EPCs. By confocal microscopy, we have shown that in EPCs uPAR is present on the surface in at least three compartments, respectively, associated to GM1, GM3 and caveolar rafts. Following GM1 exogenous addition, the GM3 compartment is depleted of uPAR which is recruited within caveolar rafts thereby triggering angiogenesis. PMID:25313007

  12. Increased Protease-Activated Receptor-2 (PAR-2) Expression on CD14++CD16+ Peripheral Blood Monocytes of Patients with Severe Asthma

    PubMed Central

    Shrestha Palikhe, Nami; Nahirney, Drew; Laratta, Cheryl; Gandhi, Vivek Dipak; Vethanayagam, Dilini; Bhutani, Mohit; Mayers, Irvin

    2015-01-01

    Background Protease-Activated Receptor-2 (PAR-2), a G protein coupled receptor activated by serine proteases, is widely expressed in humans and is involved in inflammation. PAR-2 activation in the airways plays an important role in the development of allergic airway inflammation. PAR-2 expression is known to be upregulated in the epithelium of asthmatic subjects, but its expression on immune and inflammatory cells in patients with asthma has not been studied. Methods We recruited 12 severe and 24 mild/moderate asthmatics from the University of Alberta Hospital Asthma Clinics and collected baseline demographic information, medication use and parameters of asthma severity. PAR-2 expression on blood inflammatory cells was analyzed by flow cytometry. Results Subjects with severe asthma had higher PAR-2 expression on CD14++CD16+ monocytes (intermediate monocytes) and also higher percentage of CD14++CD16+PAR-2+ monocytes (intermediate monocytes expressing PAR-2) in blood compared to subjects with mild/moderate asthma. Receiver operating characteristics (ROC) curve analysis showed that the percent of CD14++CD16+PAR-2+ in peripheral blood was able to discriminate between patients with severe and those with mild/moderate asthma with high sensitivity and specificity. In addition, among the whole populations, subjects with a history of asthma exacerbations over the last year had higher percent of CD14++CD16+ PAR-2+ cells in peripheral blood compared to subjects without exacerbations. Conclusions PAR-2 expression is increased on CD14++CD16+ monocytes in the peripheral blood of subjects with severe asthma and may be a biomarker of asthma severity. Our data suggest that PAR-2 -mediated activation of CD14++CD16+ monocytes may play a role in the pathogenesis of severe asthma. PMID:26658828

  13. Identification of two distinct structural regions in a human porcine endogenous retrovirus receptor, HuPAR2, contributing to function for viral entry

    PubMed Central

    Marcucci, Katherine T; Argaw, Takele; Wilson, Carolyn A; Salomon, Daniel R

    2009-01-01

    Background Of the three subclasses of Porcine Endogenous Retrovirus (PERV), PERV-A is able to infect human cells via one of two receptors, HuPAR1 or HuPAR2. Characterizing the structure-function relationships of the two HuPAR receptors in PERV-A binding and entry is important in understanding receptor-mediated gammaretroviral entry and contributes to evaluating the risk of zoonosis in xenotransplantation. Results Chimeras of the non-permissive murine PAR and the permissive HuPAR2, which scanned the entire molecule, revealed that the first 135 amino acids of HuPAR2 are critical for PERV-A entry. Within this critical region, eighteen single residue differences exist. Site-directed mutagenesis used to map single residues confirmed the previously identified L109 as a binding and infectivity determinant. In addition, we identified seven residues contributing to the efficiency of PERV-A entry without affecting envelope binding, located in multiple predicted structural motifs (intracellular, extracellular and transmembrane). We also show that expression of HuPAR2 in a non-permissive cell line results in an average 11-fold higher infectivity titer for PERV-A compared to equal expression of HuPAR1, although PERV-A envelope binding is similar. Chimeras between HuPAR-1 and -2 revealed that the region spanning amino acids 152–285 is responsible for the increase of HuPAR2. Fine mapping of this region revealed that the increased receptor function required the full sequence rather than one or more specific residues. Conclusion HuPAR2 has two distinct structural regions. In one region, a single residue determines binding; however, in both regions, multiple residues influence receptor function for PERV-A entry. PMID:19144196

  14. Adaptive and Efficient Computing for Subsurface Simulation within ParFlow

    SciTech Connect

    Tiedeman, H; Woodward, C S

    2010-11-16

    This project is concerned with the PF.WRF model as a means to enable more accurate predictions of wind fluctuations and subsurface storage. As developed at LLNL, PF.WRF couples a groundwater (subsurface) and surface water flow model (ParFlow) to a mesoscale atmospheric model (WRF, Weather Research and Forecasting Model). It was developed as a unique tool to address coupled water balance and wind energy questions that occur across traditionally separated research regimes of the atmosphere, land surface, and subsurface. PF.WRF is capable of simulating fluid, mass, and energy transport processes in groundwater, vadose zone, root zone, and land surface systems, including overland flow, and allows for the WRF model to both directly drive and respond to surface and subsurface hydrologic processes and conditions. The current PF.WRF model is constrained to have uniform spatial gridding below the land surface and matching areal grids with the WRF model at the land surface. There are often cases where it is advantageous for land surface, overland flow and subsurface models to have finer gridding than their atmospheric counterparts. Finer vertical discretization is also advantageous near the land surface (to properly capture feedbacks) yet many applications have a large vertical extent. However, the surface flow is strongly dependent on topography leading to a need for greater lateral resolution in some regions and the subsurface flow is tightly coupled to the atmospheric model near the surface leading to a need for finer vertical resolution. In addition, the interactions (e.g. rain) will be highly variable in space and time across the problem domain so an adaptive scheme is preferred to a static strategy to efficiently use computing and memory resources. As a result, this project focussed on algorithmic research required for development of an adaptive simulation capability in the PF.WRF system and its subsequent use in an application problem in the Central Valley of

  15. LDRD final report on massively-parallel linear programming : the parPCx system.

    SciTech Connect

    Parekh, Ojas; Phillips, Cynthia Ann; Boman, Erik Gunnar

    2005-02-01

    This report summarizes the research and development performed from October 2002 to September 2004 at Sandia National Laboratories under the Laboratory-Directed Research and Development (LDRD) project ''Massively-Parallel Linear Programming''. We developed a linear programming (LP) solver designed to use a large number of processors. LP is the optimization of a linear objective function subject to linear constraints. Companies and universities have expended huge efforts over decades to produce fast, stable serial LP solvers. Previous parallel codes run on shared-memory systems and have little or no distribution of the constraint matrix. We have seen no reports of general LP solver runs on large numbers of processors. Our parallel LP code is based on an efficient serial implementation of Mehrotra's interior-point predictor-corrector algorithm (PCx). The computational core of this algorithm is the assembly and solution of a sparse linear system. We have substantially rewritten the PCx code and based it on Trilinos, the parallel linear algebra library developed at Sandia. Our interior-point method can use either direct or iterative solvers for the linear system. To achieve a good parallel data distribution of the constraint matrix, we use a (pre-release) version of a hypergraph partitioner from the Zoltan partitioning library. We describe the design and implementation of our new LP solver called parPCx and give preliminary computational results. We summarize a number of issues related to efficient parallel solution of LPs with interior-point methods including data distribution, numerical stability, and solving the core linear system using both direct and iterative methods. We describe a number of applications of LP specific to US Department of Energy mission areas and we summarize our efforts to integrate parPCx (and parallel LP solvers in general) into Sandia's massively-parallel integer programming solver PICO (Parallel Interger and Combinatorial Optimizer). We

  16. Latitudinal UVR-PAR measurements in Argentina: extent of the 'ozone hole'

    NASA Astrophysics Data System (ADS)

    Luis Orce, V.; Walter Helbling, E.

    1997-10-01

    The UVR-PAR Argentinean Monitoring Network started its operation in September 1994 recording ultraviolet (UVR) and Photosynthetic Available Radiation (PAR) at a frequency of once per minute, at four sites, throughout the entire year. Four spectroradiometers (GUV-511, Biospherical Instruments, Inc.) were installed at research centers separated by about 8-12 degrees of latitude, extending from the Subantarctic-Fueguian region to the Tropic of Capricorn. The instruments are located in populated areas ranging from 30,000 to 11 million people and with extremely different climate regimes and conditions of tropospheric pollution. Our ground-based data indicated that the irradiance increased steadily from south to north. This increase was also observed in the calculated daily doses of UV-B (280-320 nm); however, daily integrated values for UV-A (320-400 nm) and PAR (400-700 nm) were higher at mid-latitudes (Puerto Madryn, 42°47'S). A similar south-to-north increase was evident in the ratio of the energy at 305 nm and 340 nm wavelengths (with low 305/340 ratios indicating high total ozone column concentration), with low values at Ushuaia (55°01'S) and high values at Jujuy (24°10'S). However, the 305/340 ratios increased significantly over their normal spring values at two sites, Ushuaia and Puerto Madryn, for variable time periods during October-December. Our data suggest that the ozone hole was over South America extending to about 38°S for at least a week during October and about two weeks during November-December of the years of 1994 and 1995. However, it should be noted that the erythemal irradiance, in the area influenced by the ozone hole, was at all times lower than that in Buenos Aires and well below the value at Jujuy (tropical station). This study also indicates that when assessing the impact of solar UVR upon organisms, other variables such as cloud cover, solar zenith angle, day length, latitude, and atmospheric pollution should be considered in addition to

  17. Sources of Uncertainty in the Prediction of LAI / fPAR from MODIS

    NASA Technical Reports Server (NTRS)

    Dungan, Jennifer L.; Ganapol, Barry D.; Brass, James A. (Technical Monitor)

    2002-01-01

    To explicate the sources of uncertainty in the prediction of biophysical variables over space, consider the general equation: where z is a variable with values on some nominal, ordinal, interval or ratio scale; y is a vector of input variables; u is the spatial support of y and z ; x and u are the spatial locations of y and z , respectively; f is a model and B is the vector of the parameters of this model. Any y or z has a value and a spatial extent which is called its support. Viewed in this way, categories of uncertainty are from variable (e.g. measurement), parameter, positional. support and model (e.g. structural) sources. The prediction of Leaf Area Index (LAI) and the fraction of absorbed photosynthetically active radiation (fPAR) are examples of z variables predicted using model(s) as a function of y variables and spatially constant parameters. The MOD15 algorithm is an example of f, called f(sub 1), with parameters including those defined by one of six biome types and solar and view angles. The Leaf Canopy Model (LCM)2, a nested model that combines leaf radiative transfer with a full canopy reflectance model through the phase function, is a simpler though similar radiative transfer approach to f(sub 1). In a previous study, MOD15 and LCM2 gave similar results for the broadleaf forest biome. Differences between these two models can be used to consider the structural uncertainty in prediction results. In an effort to quantify each of the five sources of uncertainty and rank their relative importance for the LAI/fPAR prediction problem, we used recent data for an EOS Core Validation Site in the broadleaf biome with coincident surface reflectance, vegetation index, fPAR and LAI products from the Moderate Resolution Imaging Spectrometer (MODIS). Uncertainty due to support on the input reflectance variable was characterized using Landsat ETM+ data. Input uncertainties were propagated through the LCM2 model and compared with published uncertainties from the MOD15

  18. Conversion du methanol en ethanol par carbonylation suivie d'hydrogenolyse

    NASA Astrophysics Data System (ADS)

    Gaucher, Melissa

    Ce projet de maîtrise s'inscrit dans le cadre des nouvelles filières énergétiques renouvelables et s'effectue au sein de la Chaire de recherche industrielle sur l'éthanol cellulosique créée par trois partenaires industriels (Enerkem, CRB et Ethanol Greenfield) et le gouvernement du Québec en collaboration avec l'Université de Sherbrooke. La stratégie d'un des partenaires, Enerkem, est de convertir par gazéification des résidus de biomasse non homogène en Syngas, ce gaz est ensuite converti en méthanol puis en éthanol. L'objectif principal de ce projet est la conversion catalytique de l'acétate en alcool. Un catalyseur commercial, composé de cuivre et de chrome, a permis l'obtention des conversions de plus de 95 % et une sélectivité pour l'éthanol de plus de 50 % avec l'acétate de méthyle, de 99 % avec l'acétate d'éthyle et de 50 % avec l'acétate de butyle. Les conditions optimales trouvées impliquent une température de 215 °C, une pression de 350 psig, une vitesse spatiale de 1800 h -1 H2 STP et un ratio H2 : Acétate de 7. Un catalyseur alternatif, à base de cuivre et de zinc, a aussi été testé. L'objectif secondaire est la carbonylation du méthanol en acétate. Cette étape a été réalisée en phase gazeuse où des rendements très élevés, soit plus de 2000 kg d'acétate de méthyle par kg de métal précieux à l'heure (kg AM/ kg métal précieux/h), ont été obtenus. Les conditions d'opérations testées impliquent une température variant entre 200-240 °C, une pression entre 250-600 psig, des ratios McOH : CO de 1 à 2,5. Mots clés: Carbonylation, Éthanol, Hydrogénolyse, Catalyse hétérogène.

  19. Protection des ions organiques contre les dommages induits a l'ADN par les electrons de basse energie

    NASA Astrophysics Data System (ADS)

    Dumont, Ariane

    Il a ete demontre que les electrons de basse energie (EBE) peuvent induire des cassures simple brin (CSB) a l'ADN, via la formation d'anions transitoires qui decroissent par attachement dissociatif, ou dans d'autres etats electroniques dissociatifs menant a la fragmentation. Afin d'effectuer une etude complete des effets des electrons de basse energie sur la matiere biologique, il est necessaire de comprendre leur mecanismes d'interaction non seulement avec l'ADN, mais avec les constituants de son environnement. Les histones sont une composante importante de l'environnement moleculaire de l'ADN. Leur charge positive leur permet de s'associer aux groupements phosphate anionique de l'ADN. Le role principal de ces proteines basiques consiste a organiser l'ADN et l'empaqueter afin de former la chromatine. Les cations sont une autre composante importante de la cellule; ils jouent un role dans la stabilisation de la conformation B de l'ADN in vitro par leurs interactions avec les petits et grands sillons de l'ADN, ainsi qu'avec le groupement phosphate charge negativement. Avec les histones, ils participent egalement a la compaction de l'ADN pour former la chromatine. Cette etude a pour but de comprendre comment la presence d'ions organiques (sous forme de Tris et d'EDTA) a proximite de l'ADN modifie le rendement de cassures simple brin induit par les electrons de basse energie. Le Tris et l'EDTA ont-ete choisis comme objet d'etude, puisqu'en solution, ils forment le tampon standard pour solubiliser l'ADN dans les experiences in vitro (10mM Tris, 1mM EDTA). De plus, la molecule Tris possede un groupement amine alors que l'EDTA possede 4 groupements carboxyliques. Ensembles, ils peuvent se comporter comme un modele simple pour les acides amines. Le ratio molaire de 10 :1 de Tris par rapport a l'EDTA a pour but d'imiter le comportement des histones qui sont riches en arginine et lysine, acides amines possedant un groupement amine charge positivement additionnel. Des films d

  20. Localization of amylin-like immunoreactivity in melanocyte-stimulating hormone-containing cells of the pars intermedia but not those of the pars distalis in the axolotl (Ambystoma mexicanum) pituitary.

    PubMed

    Suzuki, Hirohumi; Yamamoto, Toshiharu

    2016-04-01

    Immunohistochemical techniques were employed to investigate the distribution of amylin-like immunoreactivity in the axolotl (Ambystoma mexicanum) pituitary. Amylin-immunoreactive cells were observed in the pars intermedia, and these cells were found to be immunoreactive for α-melanocyte-stimulating hormone (αMSH) as well. In contrast, αMSH-immunoreactive cells in the pars distalis were immuno-negaitive for amylin. These light microscopic findings were confirmed by immunoelectron microscopy. Amylin-immunoreactive signals were located on the haloes of presumable secretory granules in association with αMSH-immunoreactive signals in the amylin-positive cells. However, in the pars distalis, the αMSH-positive cells did not contain amylin-immunoreactive secretory granules. Western blot analysis of axolotl pituitary extracts revealed the labeling of a protein band at approximately 10.5-kDa by the anti-rat amylin serum, which was not labeled by the anti-αMSH antibody. These findings indicate that amylin secreted from MSH-producing cells in the pars intermedia may modulate MSH secretion in an autocrine fashion and may participate in MSH functions such as fatty homeostasis together with MSH. PMID:26797189

  1. Pituitary pars intermedia dysfunction (equine Cushing’s disease) in a Thoroughbred stallion: a single report

    PubMed Central

    HATAZOE, Takashi; KAWAGUCHI, Hiroaki; HOBO, Seiji; MISUMI, Kazuhiro

    2016-01-01

    ABSTRACT Equine pituitary pars intermedia dysfunction (PPID) generally occurs in older horses showing hirsutism, delayed molting, weight loss, polydipsia, polyuria, laminitis, and reproductive disorders (in broodmares), but there have been no reports on stallions. This report presents a case of a 21-year-old Thoroughbred stallion that developed hirsutism and experienced delayed molting. There were no abnormal findings for semen quality or the stallion’s sexual desire. The horse was diagnosed with PPID based on dexamethasone suppression test and plasma levels of adrenocorticotropic hormone. It was then medicated with pergolide mesylate. Since the horse died due to humerus fracture, an autopsy was conducted, and pituitary adenoma was confirmed. No pathological findings were defined in the testicles; therefore, reproductive activity might not have been impaired. PMID:26858577

  2. New species of Hippopleurifera (Bryozoa, Cheilostomata) from the Miocene Pirabas Formation, Pará state, Brazil.

    PubMed

    Ramalho, Laís V; Távora, Vladimir A; Tilbrook, Kevin J; Zágoršek, Kamil

    2015-01-01

    The Pirabas Formation in Brazil has been studied for many years and a great diversity of animal groups (in particular fishes, molluscs and echinoderms) have been described from there, whereas the Bryozoa have scarcely been mentioned. New samples, collected specifically to focus on bryozoans, have shown that the diversity in this formation is higher than previously thought. Here we describe two new species belonging to the cheilostomate genus Hippopleurifera--H. barbosae sp. nov. and H. confusa sp. nov. Both species were collected at Atalaia Beach, northeastern Pará state, which boasts some of the best marine Cenozoic fossil outcrops in Brazil. After accounting for all described species, plus the two new species and four generic reassignments (new combinations) described herein, some 29 Hippopleurifera species are now known. Most of these are fossils from Europe or the USA, but a handful are known from the Recent Mediterranean, Caribbean and Indo-West Pacific. PMID:26250330

  3. Traumatic Ghost Cell Glaucoma with Successful Resolution of Corneal Blood Staining Following Pars Plana Vitrectomy.

    PubMed

    Alamri, Amal; Alkatan, Hind; Aljadaan, Ibrahim

    2016-01-01

    Ghost cell glaucoma (GCG) was first described in 1976. It is a type of a secondary open angle glaucoma, which occurs following long-standing vitreous hemorrhage. The ghost cells are rigid and less pliable than fresh red blood cells; therefore, they may cause direct obstruction of the trabecular meshwork and secondary increase in the intraocular pressure (IOP). This case report presents the diagnosis and management of a rare case of traumatic GCG after vitreous hemorrhage in a phakic child. Pars plana vitrectomy was done after unsuccessful medical therapy and the diagnosis was confirmed by cytopathology. Surprisingly, spontaneous resolution of the corneal blood staining occurred. The outcome in this case was favorable with controlled IOP in the affected eye. PMID:27555716

  4. Traumatic Ghost Cell Glaucoma with Successful Resolution of Corneal Blood Staining Following Pars Plana Vitrectomy

    PubMed Central

    Alamri, Amal; Alkatan, Hind; Aljadaan, Ibrahim

    2016-01-01

    Ghost cell glaucoma (GCG) was first described in 1976. It is a type of a secondary open angle glaucoma, which occurs following long-standing vitreous hemorrhage. The ghost cells are rigid and less pliable than fresh red blood cells; therefore, they may cause direct obstruction of the trabecular meshwork and secondary increase in the intraocular pressure (IOP). This case report presents the diagnosis and management of a rare case of traumatic GCG after vitreous hemorrhage in a phakic child. Pars plana vitrectomy was done after unsuccessful medical therapy and the diagnosis was confirmed by cytopathology. Surprisingly, spontaneous resolution of the corneal blood staining occurred. The outcome in this case was favorable with controlled IOP in the affected eye. PMID:27555716

  5. Surgical management of retraction pockets of the pars tensa with cartilage and perichondrial grafts.

    PubMed

    Spielmann, P; Mills, R

    2006-09-01

    Stable, self-cleansing retraction pockets of the pars tensa are common incidental findings and require no treatment. In other cases, recurrent discharge occurs and there may also be associated conductive hearing loss. In a minority of cases, cholesteatoma may develop. This paper presents the results of surgery using a graft composed of cartilage and perichondrium for retraction pockets involving the posterior half of the tympanic membrane, as well as early results using a larger graft designed to manage retraction of the entire tympanic membrane. Data on 51 patients with posterior retraction pockets are presented. Forty-two (82 per cent) patients had no aural discharge one year following surgery and the tympanic membrane was not retracted in 43 (84 per cent). The larger 'Mercedes-Benz' graft was used in four patients and the results obtained suggested that it may prove a successful technique for extensive retraction pockets. PMID:16740207

  6. Applications of the massively parallel machine, the MasPar MP-1, to Earth sciences

    NASA Technical Reports Server (NTRS)

    Fischer, James R.; Strong, James P.; Dorband, John E.; Tilton, James C.

    1991-01-01

    The computational workload of upcoming NASA science missions, especially the ground data processing for the Earth Observing System, is projected to be quite large (in the 50 to 100 gigaFLOPS range) and corespondingly very expensive to perform using conventional supercomputer systems. High performance, general purpose massively parallel computer systems such as the MasPar MP-1 are being investigated by NASA as a more cost effective alternative. Massively parallel systems are targeted for accelerated development and maturation by NASA's upcoming five-year High Performance Computing and Communications Program. A summary of the broad range of applications currently running on the MP-1 at NASA/Goddard are presented in this paper along with descriptions of the parallel algorithmic techniques employed in five applications that have bearing on Earth sciences.

  7. Ambroise Paré (1510 to 1590): a surgeon centuries ahead of his time.

    PubMed

    Shen, James T; Weinstein, Michael; Beekley, Alec; Yeo, Charles; Cowan, Scott

    2014-06-01

    In their extensive writings, Hippocrates and Celsus counseled physicians to be knowledgeable in both the medical and surgical management of patient recovery. However, their words fell by the wayside because cutting of the body was forbidden by the Roman Catholic Church. Furthermore, the contemporaneous Arabic medical teachings emphasized tradition and authority over observation and personal experience. This created an ever-growing rift between the schools of surgical and pharmacologic medicine with both groups denying their involvement in the other domain. Surgeons had been plagued by postoperative complications including infection, malnutrition, and muscular wasting for centuries. Surgeons were forced to re-examine how diet and exercise affected outcomes before the advent of microbiology and advances in pharmacology. All of this changed when Ambroise Paré, a 16th century surgeon, revolutionized the medical world with his astute observations of postoperative diet and exercise. PMID:24887788

  8. K-Area and Par Pond Sewage Sludge Application Sites Groundwater Monitoring Report. First quarter 1993

    SciTech Connect

    Not Available

    1993-07-01

    Samples from the three wells at the K-Area Sewage Sludge Application Site (KSS wells) and the three wells at the Par Pond Sewage Sludge Application Site (PSS wells) are analyzed quarterly for constituents required by South Carolina Department of Health and Environmental Control Construction Permit 13,173 and, as requested, for other constituents as part of the Savannah River Site Groundwater Monitoring Program. Annual analyses for other constituents, primarily metals, also are required by the permit. During first quarter 1993, no permit-required constituents exceeded standards at the two sites except iron, which was elevated in one KSS well and two PSS wells. Aluminum, not required by the permit, was the only other constituent that exceeded standards. Elevated levels of aluminum and iron at these two sites may be concurrent with a change in analytical methodology. As in previous quarters, chlordane concentrations did not exceed the detection limit in any of the wells.

  9. K-Area and Par Pond Sewage Sludge Application Sites Groundwater Monitoring Report: Third quarter 1993

    SciTech Connect

    Not Available

    1994-01-01

    Samples from the three wells at the K-Area Sewage Sludge Application Site (KSS wells) and the three wells at the Par Pond Sewage Sludge Application Site (PSS wells) are analyzed quarterly for constituents required by South Carolina Department of Health and Environmental Control Construction Permit 13,173 and, as requested, for other constituents as part of the Savannah River Site (SRS) Groundwater Monitoring Program. Annual analyses for other constituents, primarily metals, also are required by the permit. Iron and lead, permit-required constituents, and aluminum presently exceed SRS flagging standards in samples from the two sites. Elevated concentrations of metals at these sites, not reported during 1992, may be the reflection of a recent change in analytical methodology.

  10. Extending the parQ transition matrix method to grand canonical ensembles

    NASA Astrophysics Data System (ADS)

    Haber, René; Hoffmann, Karl Heinz

    2016-06-01

    Phase coexistence properties as well as other thermodynamic features of fluids can be effectively determined from the grand canonical density of states (DOS). We present an extension of the par Q transition matrix method in combination with the efasTM method as a very fast approach for determining the grand canonical DOS from the transition matrix. The efasTM method minimizes the deviation from detailed balance in the transition matrix using a fast Krylov-based equation solver. The method allows a very effective use of state space transition data obtained by different exploration schemes. An application to a Lennard-Jones system produces phase coexistence properties of the same quality as reference data.

  11. Tactile devices to sense touch on a par with a human finger.

    PubMed

    Maheshwari, Vivek; Saraf, Ravi

    2008-01-01

    Our sense of touch enables us to recognize texture and shape and to grasp objects. The challenge in making an electronic skin which can emulate touch for applications such as a humanoid robot or minimally invasive and remote surgery is both in mimicking the (passive) mechanical properties of the dermis and the characteristics of the sensing mechanism, especially the intrinsic digital nature of neurons. Significant progress has been made towards developing an electronic skin by using a variety of materials and physical concepts, but the challenge of emulating the sense of touch remains. Recently, a nanodevice was developed that has achieved the resolution to decipher touch on a par with the human finger; this resolution is over an order of magnitude improvement on previous devices with a sensing area larger than 1 cm(2). With its robust mechanical properties, this new system represents an important step towards the realization of artificial touch. PMID:18816579

  12. Genome-wide identification of miRNA targets by PAR-CLIP

    PubMed Central

    Hafner, Markus; Lianoglou, Steve; Tuschl, Thomas; Betel, Doron

    2012-01-01

    MiRNAs are short (20-23 nt) RNAs that are loaded into proteins of the Argonaute (AGO) family and guide them to partially complementary target sites on mRNAs, resulting in mRNA destabilization and/or translational repression. It is estimated that about 60% of the mammalian genes are potentially regulated by miRNAs, and therefore methods for experimental miRNA target determination have become valuable tools for the characterization of posttranscriptional gene regulation. Here we present a step-by-step protocol and guidelines for the computational analysis for the large-scale identification of miRNA target sites in cultured cells by photoactivatable ribonucleoside enhanced crosslinking and immunoprecipitation (PAR-CLIP) of AGO proteins. PMID:22926237

  13. La prévention des infections par le virus respiratoire syncytial

    PubMed Central

    Robinson, JL

    2011-01-01

    RÉSUMÉ L’infection par le virus respiratoire syncytial (VRS) est la principale cause d’infections des voies respiratoires inférieures chez les jeunes enfants. Le palivizumab, un anticorps monoclonal anti-VRS, réduit le taux d’hospitalisation des enfants à haut risque mais est très coûteux. Le présent document de principes remplace les trois précédents documents de principes de la Société canadienne de pédiatrie sur le sujet et est mis à jour principalement pour traiter des récentes modifications aux lignes directrices de l’American Academy of Pediatrics dans le contexte canadien. Il contient une analyse des publications ainsi que des recommandations au sujet de l’utilisation du palivizumab chez les enfants à haut risque

  14. Pars tensa retraction pockets in children: treatment by excision and ventilation tube insertion.

    PubMed

    Srinivasan, V; Banhegyi, G; O'Sullivan, G; Sherman, I W

    2000-08-01

    Tympanic membrane retraction pockets involving the pars tensa are not uncommon in clinical practice. Recurrent infections, ossicular erosion and cholesteatoma are the recognized sequelae. The management options include surveillance, medical treatment and surgery. The surgical procedures range from grommet insertion to extensive tympanoplasty procedures. We report our experience with simple excision and grommet insertion, performed in 31 ears in 26 patients as day cases. The follow-up ranged from 8 to 34 months with a mean of 16 months. The procedure was successful in 23 ears (success rate of 74%). Recurrence of retraction occurred in seven ears and in one ear there was a persistent perforation. Age, previous grommet insertion and severity of retraction did not have a statistically significant influence on the final outcome. We conclude that excision and grommet insertion is a simple, safe and efficient procedure for the management of tympanic membrane retraction pockets and can be considered in preference to extensive tympanoplasty. PMID:10971530

  15. Extending the parQ transition matrix method to grand canonical ensembles.

    PubMed

    Haber, René; Hoffmann, Karl Heinz

    2016-06-01

    Phase coexistence properties as well as other thermodynamic features of fluids can be effectively determined from the grand canonical density of states (DOS). We present an extension of the parQ transition matrix method in combination with the efasTM method as a very fast approach for determining the grand canonical DOS from the transition matrix. The efasTM method minimizes the deviation from detailed balance in the transition matrix using a fast Krylov-based equation solver. The method allows a very effective use of state space transition data obtained by different exploration schemes. An application to a Lennard-Jones system produces phase coexistence properties of the same quality as reference data. PMID:27415394

  16. Recurrence of aqueous misdirection following pars plana vitrectomy in pseudophakic eyes.

    PubMed

    Dave, Paaraj; Rao, Aparna; Senthil, Sirisha; Choudhari, Nikhil Shreeram

    2015-01-01

    We present a retrospective interventional case series of four patients with pseudophakic eye who developed recurrent aqueous misdirection following pars plana vitrectomy (PPV) for malignant glaucoma (MG). The patients were treated with neodymium: YAG (Yttrium Aluminum Garnet) laser hyaloidotomy/membranotomy through the patent peripheral iridectomy. The main outcome measure was resolution of MG. The intervention resulted in resolution of MG in all four cases. The cause for recurrence was an inflammatory membrane covering the hyaloidotomy opening in three eyes and the haptic of intraocular lens blocking the hyaloidotomy opening in one eye. Recurrence of aqueous misdirection even after vitrectomy may be related to obstruction of aqueous flow through the communication created, either by intraocular lens or fibrin. Treatment of this condition involves restoring aqueous flow to the anterior chamber from the anterior vitreous by treating the cause, and most often the YAG laser hyaloidotomy/membranotomy is successful in relieving the condition. PMID:25899512

  17. Traditional knowledge and artisanal fishing technology on the Xingu River in Pará, Brazil.

    PubMed

    Mesquita, E M C; Isaac-Nahum, V J

    2015-08-01

    In artisanal fishing, the techniques used by a community reflect the characteristics of the natural environment, in particular the distribution and availability of resources, as well as local traditions and customs. However, economic development may result in the loss of these traditions. The present study documents the fishing techniques used by the communities on the Xingu River in the Brazilian state of Pará (Maribel, Altamira, Belo Monte, Vitória do Xingu, Vila Nova, Senador José Porfírio, Porto de Moz, and Gurupá). Interviews were used to investigate traditional local knowledge and the distribution of the different fishing methods within the study area. The local fishers described the use of 12 different types of net, 10 hook and line techniques, and eight kinds of spearfishing. Free diving and scuba diving are also used for the capture of ornamental fish. PMID:26691086

  18. Report: future industrial solid waste management in pars Special Economic Energy Zone (PSEEZ), Iran.

    PubMed

    Mokhtarani, Babak; Moghaddam, Mohammad Reza Alavi; Mokhtarani, Nader; Khaledi, Hossein Jomeh

    2006-06-01

    The Pars Special Economic Energy Zone (PSEEZ) is located in the south of Iran, on the northern coastline of the Persian Gulf. This area was established in 1998 for the utilization of south Pars field oil and gas resources. This field is one of the largest gas resources in the world and contains about 6% of the total fossil fuels known. Petrochemical industries, gas refineries and downstream industries are being constructed in this area. At present there are three gas refineries in operation and five more gas refineries are under construction. In this study, different types of solid waste including municipal solid waste (MSW) and industrial wastes were investigated separately. The aim of the study was to focus on the management of the industrial wastes in order to minimize the environmental impact. In the first stage, the types and amounts of industrial waste in PSEEZ were evaluated by an inventory. The main types of industrial waste are oil products (fuel oil, light oil, lubricating oil), spent catalysts, adsorbents, resins, coke, wax and packaging materials. The waste management of PSEEZ is quite complex because of the different types of industry and the diversity of industrial residues. In some cases recycling/reuse of waste is the best option, but treatment and disposal are also necessary tools. Recently a design has been prepared for a disposal site in PSEEZ for the industrial waste that cannot be reused or recycled. The total surface area of this disposal site where the industrial waste should be tipped for the next 20 years was estimated to be about 42 000 m2. PMID:16784172

  19. Negative regulation of neuromedin U mRNA expression in the rat pars tuberalis by melatonin.

    PubMed

    Aizawa, Sayaka; Sakata, Ichiro; Nagasaka, Mai; Higaki, Yuriko; Sakai, Takafumi

    2013-01-01

    The pars tuberalis (PT) is part of the anterior pituitary gland surrounding the median eminence as a thin cell layer. The characteristics of PT differ from those of the pars distalis (PD), such as cell composition and gene expression, suggesting that the PT has a unique physiological function compared to the PD. Because the PT highly expresses melatonin receptor type 1, it is considered a mediator of seasonal and/or circadian signals of melatonin. Expression of neuromedin U (NMU) that is known to regulate energy balance has been previously reported in the rat PT; however, the regulatory mechanism of NMU mRNA expression and secretion in the PT are still obscure. In this study, we examined both the diurnal change of NMU mRNA expression in the rat PT and the effects of melatonin on NMU in vivo. In situ hybridization and quantitative PCR analysis of laser microdissected PT samples revealed that NMU mRNA expression in the PT has diurnal variation that is high during the light phase and low during the dark phase. Furthermore, melatonin administration significantly suppressed NMU mRNA expression in the PT in vivo. On the other hand, 48 h fasting did not have an effect on PT-NMU mRNA expression, and the diurnal change of NMU mRNA expression was maintained. We also found the highest expression of neuromedin U receptor type 2 (NMUR2) mRNA in the third ventricle ependymal cell layer, followed by the arcuate nucleus and the spinal cord. These results suggest that NMU mRNA expression in the PT is downregulated by melatonin during the dark phase and shows diurnal change. Considering that NMU mRNA in the PT showed the highest expression level in the brain, PT-NMU may act on NMUR2 in the brain, especially in the third ventricle ependymal cell layer, with a circadian rhythm. PMID:23843987

  20. Negative Regulation of Neuromedin U mRNA Expression in the Rat Pars Tuberalis by Melatonin

    PubMed Central

    Aizawa, Sayaka; Sakata, Ichiro; Nagasaka, Mai; Higaki, Yuriko; Sakai, Takafumi

    2013-01-01

    The pars tuberalis (PT) is part of the anterior pituitary gland surrounding the median eminence as a thin cell layer. The characteristics of PT differ from those of the pars distalis (PD), such as cell composition and gene expression, suggesting that the PT has a unique physiological function compared to the PD. Because the PT highly expresses melatonin receptor type 1, it is considered a mediator of seasonal and/or circadian signals of melatonin. Expression of neuromedin U (NMU) that is known to regulate energy balance has been previously reported in the rat PT; however, the regulatory mechanism of NMU mRNA expression and secretion in the PT are still obscure. In this study, we examined both the diurnal change of NMU mRNA expression in the rat PT and the effects of melatonin on NMU in vivo. In situ hybridization and quantitative PCR analysis of laser microdissected PT samples revealed that NMU mRNA expression in the PT has diurnal variation that is high during the light phase and low during the dark phase. Furthermore, melatonin administration significantly suppressed NMU mRNA expression in the PT in vivo. On the other hand, 48 h fasting did not have an effect on PT-NMU mRNA expression, and the diurnal change of NMU mRNA expression was maintained. We also found the highest expression of neuromedin U receptor type 2 (NMUR2) mRNA in the third ventricle ependymal cell layer, followed by the arcuate nucleus and the spinal cord. These results suggest that NMU mRNA expression in the PT is downregulated by melatonin during the dark phase and shows diurnal change. Considering that NMU mRNA in the PT showed the highest expression level in the brain, PT-NMU may act on NMUR2 in the brain, especially in the third ventricle ependymal cell layer, with a circadian rhythm. PMID:23843987

  1. Improving Long-term Post-wildfire hydrologic simulations using ParFlow

    NASA Astrophysics Data System (ADS)

    Lopez, S. R.; Kinoshita, A. M.

    2015-12-01

    Wildfires alter the natural hydrologic processes within a watershed. After vegetation is burned, the combustion of organic material and debris settles into the soil creating a hydrophobic layer beneath the soil surface with varying degree of thickness and depth. Vegetation regrowth rates vary as a function of radiative exposure, burn severity, and precipitation patterns. Hydrologic models used by the Burned Area Emergency Response (BAER) teams use input data and model calibration constraints that are generally either one-dimensional, empirically-based models, or two-dimensional, conceptually-based models with lumped parameter distributions. These models estimate runoff measurements at the watershed outlet; however, do not provide a distributed hydrologic simulation at each point within the watershed. This work uses ParFlow, a three-dimensional, distributed hydrologic model to (1) correlate burn severity with hydrophobicity, (2) evaluate vegetation recovery rate on water components, and (3) improve flood prediction for managers to help with resource allocation and management operations in burned watersheds. ParFlow is applied to Devil Canyon (43 km2) in San Bernardino, California, which was 97% burned in the 2003 Old Fire. The model set-up uses a 30m-cell size resolution over a 6.7 km by 6.4 km lateral extent. The subsurface reaches 30 m and is assigned a variable cell thickness. Variable subsurface thickness allows users to explicitly consider the degree of recovery throughout the stages of regrowth. Burn severity maps from remotely sensed imagery are used to assign initial hydrophobic layer parameters and thickness. Vegetation regrowth is represented with satellite an Enhanced Vegetation Index. Pre and post-fire hydrologic response is evaluated using runoff measurements at the watershed outlet, and using water component (overland flow, lateral flow, baseflow) measurements.

  2. Diagnostic pars plana vitrectomy report of a 21-year retrospective study.

    PubMed Central

    Palexas, G N; Green, W R; Goldberg, M F; Ding, Y

    1995-01-01

    PURPOSE: To review the experience of diagnostic pars plana vitrectomies (PPV). METHODS: The authors reviewed 405 consecutive diagnostic PPV's performed between November 1973 and October 1994. RESULTS: Diagnostic vitrectomy was performed in 215 (53%) of 405 eyes for suspected endophthalmitis. Of those 215 cases, acute inflammation was confirmed in 62 (28.8%), 60 (27.9%) had microbial organisms present and 36 (16.7%) were culture-positive. Microbial organisms were observed microscopically in 31 (20%) of 156 patients suspected of postoperative endophthalmitis. Of those 31 cases, 23 (74%) were gram-positive, eleven (37%) of 30 eyes had organisms associated with glaucoma filtering procedures and 20 (16%) of 126 eyes had organisms with non-filtering procedures. The pooled percentage of eyes that developed postoperative endophthalmitis as a complication during the period July 1990 thru June 1994 is 5 (0.046%) out of a heterogeneous group of 10,898 cases operated on at the Wilmer Eye Institute for cataract, glaucoma, corneal transplant, pars plana vitrectomy and retinal detachment. Bacteria were identified microscopically in 6 (18%) of 34 post-traumatic cases. Microbial organisms were identified in 23 (92%) of 25 cases with an endogenous infection. Patients with endogenous infections had the most fungal infections, and the majority were in males. Neoplasms were diagnosed in 58 (14%) of the 405 cases. The most common neoplasm was ocular lymphoma 42 (72%), 69% of which were in females. Only 42 (48.3%) of 87 patients clinically suspected of having ocular lymphoma, actually had ocular lymphoma. Those negative for lymphoma were significantly older (67.4 +/- 10 years) compared to those with lymphoma (60.4 +/- 14 years) (P = 0.01). CONCLUSION: Diagnostic PPV has proved to be valuable in confirming and establishing various clinical diagnoses. PMID:8719683

  3. Probing the ATP-binding site of P1 ParA: partition and repression have different requirements for ATP binding and hydrolysis

    PubMed Central

    Fung, Emma; Bouet, Jean-Yves; Funnell, Barbara E.

    2001-01-01

    The ParA family of proteins is involved in partition of a variety of plasmid and bacterial chromosomes. P1 ParA plays two roles in partition: it acts as a repressor of the par operon and has an undefined yet indispensable role in P1 plasmid localization. We constructed seven mutations in three putative ATP-binding motifs of ParA. Three classes of phenotypes resulted, each represented by mutations in more than one motif. Three mutations created ‘super-repressors’, in which repressor activity was much stronger than in wild-type ParA, while the remainder damaged repressor activity. All mutations eliminated partition activities, but two showed a plasmid stability defect that was worse than that of a null mutation. Four mutant ParAs, two super-repressors and two weak repressors, were analyzed biochemically, and all exhibited damaged ATPase activity. The super-repressors bound site-specifically to the par operator sequence, and this activity was strongly stimulated by ATP and ADP. These results support the proposal that ATP binding is essential but hydrolysis is inhibitory for ParA’s repressor activity and suggest that ATP hydrolysis is essential for plasmid localization. PMID:11532954

  4. Protease-activated receptor-1 (PAR1) acts via a novel Galpha13-dishevelled axis to stabilize beta-catenin levels.

    PubMed

    Turm, Hagit; Maoz, Myriam; Katz, Vered; Yin, Yong-Jun; Offermanns, Steffan; Bar-Shavit, Rachel

    2010-05-14

    We have previously shown a novel link between hPar-1 (human protease-activated receptor-1) and beta-catenin stabilization. Although it is well recognized that Wnt signaling leads to beta-catenin accumulation, the role of PAR1 in the process is unknown. We provide here evidence that PAR1 induces beta-catenin stabilization independent of Wnt, Fz (Frizzled), and the co-receptor LRP5/6 (low density lipoprotein-related protein 5/6) and identify selective mediators of the PAR1-beta-catenin axis. Immunohistological analyses of hPar1-transgenic (TG) mouse mammary tissues show the expression of both Galpha(12) and Galpha(13) compared with age-matched control counterparts. However, only Galpha(13) was found to be actively involved in PAR1-induced beta-catenin stabilization. Indeed, a dominant negative form of Galpha(13) inhibited both PAR1-induced Matrigel invasion and Lef/Tcf (lymphoid enhancer factor/T cell factor) transcription activity. PAR1-Galpha(13) association is followed by the recruitment of DVL (Dishevelled), an upstream Wnt signaling protein via the DIX domain. Small interfering RNA-Dvl silencing leads to a reduction in PAR1-induced Matrigel invasion, inhibition of Lef/Tcf transcription activity, and decreased beta-catenin accumulation. It is of note that PAR1 also promotes the binding of beta-arrestin-2 to DVL, suggesting a role for beta-arrestin-2 in PAR1-induced DVL phosphorylation dynamics. Although infection of small interfering RNA-LRP5/6 or the use of the Wnt antagonists, SFRP2 (soluble Frizzled-related protein 2) or SFRP5 potently reduced Wnt3A-mediated beta-catenin accumulation, no effect was observed on PAR1-induced beta-catenin stabilization. Collectively, our data show that PAR1 mediates beta-catenin stabilization independent of Wnt. We propose here a novel cascade of PAR1-induced Galpha(13)-DVL axis in cancer and beta-catenin stabilization. PMID:20223821

  5. Tau phosphorylation at Alzheimer's disease-related Ser356 contributes to tau stabilization when PAR-1/MARK activity is elevated.

    PubMed

    Ando, Kanae; Oka, Mikiko; Ohtake, Yosuke; Hayashishita, Motoki; Shimizu, Sawako; Hisanaga, Shin-Ichi; Iijima, Koichi M

    2016-09-16

    Abnormal phosphorylation of the microtubule-associated protein tau is observed in many neurodegenerative diseases, including Alzheimer's disease (AD). AD-related phosphorylation of two tau residues, Ser262 and Ser356, by PAR-1/MARK stabilizes tau in the initial phase of mismetabolism, leading to subsequent phosphorylation events, accumulation, and toxicity. However, the relative contribution of phosphorylation at each of these sites to tau stabilization has not yet been elucidated. In a Drosophila model of human tau toxicity, we found that tau was phosphorylated at Ser262, but not at Ser356, and that blocking Ser262 phosphorylation decreased total tau levels. By contrast, when PAR-1 was co-overexpressed with tau, tau was hyperphosphorylated at both Ser262 and Ser356. Under these conditions, the protein levels of tau were significantly elevated, and prevention of tau phosphorylation at both residues was necessary to completely suppress this elevation. These results suggest that tau phosphorylation at Ser262 plays the predominant role in tau stabilization when PAR-1/MARK activity is normal, whereas Ser356 phosphorylation begins to contribute to this process when PAR-1/MARK activity is abnormally elevated, as in diseased brains. PMID:27520376

  6. Difficultes de Prise en Charge des Brulures Electriques par Haut Voltage: a propos d’un cas

    PubMed Central

    Mejjati, H.; Tourabi, K.; Arrob, A.; Moussaoui, A.; Ihrai, H.

    2010-01-01

    Summary Les brûlures électriques à haut voltage sont caractérisées par leur potentialité évolutive avec une extension en profondeur et une destruction tissulaire étendue dont les conséquences fonctionnelles sont considérables. La prise en charge de ces brûlures électriques se trouve toujours compliquée par un problème essentiel représenté par la difficulté diagnostique qui sous-évalue régulièrement la profondeur et l’étendue de ces lésions: en effet la nécrose cutanée s’étend progressivement jusqu’au quatrième jour à cause des thromboses vasculaires extensives, et par conséquent le diagnostic d’étendue et de profondeur de ces brûlures est difficile avant le quatrième jour. Nous présentons le cas illustré d’un jeune patient admis dans notre formation pour des brûlures à haut voltage ayant bénéficié d’un traitement chirurgical à la phase aiguë et une réparation secondaire. PMID:21991228

  7. Fatal Levofloxacin Failure in Treatment of a Bacteremic Patient Infected with Streptococcus pneumoniae with a Preexisting parC Mutation▿

    PubMed Central

    de Cueto, M.; Rodríguez, J. M.; Soriano, M. J.; López-Cerero, L.; Venero, J.; Pascual, A.

    2008-01-01

    The fatal outcome of levofloxacin treatment in a patient with bacteremic pneumonia caused by Streptococcus pneumoniae with a preexisting parC mutation is reported. Failure was due to the emergence of a gyrA mutation after 4 days of therapy. Problems encountered in detecting first-step mutation isolates are discussed. PMID:18287316

  8. Towards a Political Ecology of Education: The Educational Politics of Scale in Southern Pará, Brazil

    ERIC Educational Resources Information Center

    Meek, David

    2015-01-01

    Social movements have initiated both academic programs and disciplines. I present ethnographic data that I gathered during 17 months of fieldwork with the Brazilian Landless Workers' Movement (MST) in southeastern Pará, Brazil, to explore the MST's role in creating agroecological education opportunities. My analysis highlights three factors in…

  9. PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells

    PubMed Central

    Gur-Cohen, Shiri; Itkin, Tomer; Chakrabarty, Sagarika; Graf, Claudine; Kollet, Orit; Ludin, Aya; Golan, Karin; Kalinkovich, Alexander; Ledergor, Guy; Wong, Eitan; Niemeyer, Elisabeth; Porat, Ziv; Erez, Ayelet; Sagi, Irit; Esmon, Charles T; Ruf, Wolfram; Lapidot, Tsvee

    2016-01-01

    Retention of long-term repopulating hematopoietic stem cells (LT-HSCs) in the bone marrow is essential for hematopoiesis and for protection from myelotoxic injury. We report that signaling cascades that are traditionally viewed as coagulation-related also control retention of EPCR+ LT-HSCs in the bone marrow and their recruitment to the blood via two different protease activated receptor 1 (PAR1)-mediated pathways. Thrombin-PAR1 signaling induces nitric oxide (NO) production, leading to TACE-mediated EPCR shedding, enhanced CXCL12-CXCR4-induced motility, and rapid stem and progenitor cell mobilization. Conversely, bone marrow blood vessels provide a microenvironment enriched with protein C that retain EPCR+ LT-HSCs by limiting NO generation, reducing Cdc42 activity and enhancing VLA4 affinity and adhesion. Inhibition of NO production by activated protein C (aPC)-EPCR-PAR1 signaling reduces progenitor cell egress, increases NOlow bone marrow EPCR+ LT-HSCs retention and protects mice from chemotherapy-induced hematological failure and death. Our study reveals new roles for PAR1 and EPCR that control NO production to balance maintenance and recruitment of bone marrow EPCR+ LT-HSCs with clinical relevance. PMID:26457757

  10. Suppression of ischaemia-induced injuries in rat brain by protease-activated receptor-1 (PAR-1) activating peptide.

    PubMed

    Zhen, Xia; Ng, Ethel Sau Kuen; Lam, Francis Fu Yuen

    2016-09-01

    Ischaemic stroke has become one of the leading causes of death and disability worldwide. The role of protease activated receptor-1 (PAR-1) in this disease is uncertain. In the present study, the actions of a protease activated receptor-1 activating peptide (PAR-1 AP) SFLLRN-NH2 were investigated in an in vivo rat model of ischaemic stroke induced by middle cerebral artery occlusion (MCAO) and in an in vitro model induced by oxygen and glucose deprivation (OGD) in primary cultured rat embryonic cortical neurones. Rats subjected to MCAO exhibited increased brain infarct volume, oedema, and neurological deficit. Rat cortical neurones subjected to OGD showed increased lactate dehydrogenase, caspase-3 activity and TUNEL positive cells, whereas, mitochondrial membrane potential and cell viability were decreased. Furthermore, both models had elevated levels of reactive oxygen species, nitrite, and malondialdehyde, while anti-oxidant enzymes and bcl-2/bax ratio were decreased. These detrimental changes were suppressed by SFLLRN-NH2, and its protective actions were inhibited by a PAR-1 antagonist (BMS-200261). In summary, SFLLRN-NH2 was found to possess anti-oxidant and anti-apoptotic properties, and it produced marked inhibition on the detrimental effects of ischaemia in in vivo and in vitro models of ischaemic stroke. The present findings suggest PAR-1 is a promising target for development of novel treatments of ischaemic brain disease. PMID:27238976

  11. Par for the Course: Students Design Their Miniature Golf Course Sculptures while Considering Functional, Technical, and Communication Elements

    ERIC Educational Resources Information Center

    Vassil, Darlene

    2005-01-01

    Designing an eighteen-hole miniature-golf course is not the typical end-of-the-year art project, but at Winfield School it's "par for the course." Students anxiously count the days to the first day of miniature golf, courtesy of the sixth-grade art classes. The design and production of the miniature gold course serves as a great motivator and…

  12. A moving ParA gradient on the nucleoid directs subcellular cargo transport via a chemophoresis force

    PubMed Central

    Vecchiarelli, Anthony G; Seol, Yeonee; Neuman, Keir C; Mizuuchi, Kiyoshi

    2014-01-01

    DNA segregation is a critical process for all life, and although there is a relatively good understanding of eukaryotic mitosis, the mechanism in bacteria remains unclear. The small size of a bacterial cell and the number of factors involved in its subcellular organization make it difficult to study individual systems under controlled conditions in vivo. We developed a cell-free technique to reconstitute and visualize bacterial ParA-mediated segregation systems. Our studies provide direct evidence for a mode of transport that does not use a classical cytoskeletal filament or motor protein. Instead, we demonstrate that ParA-type DNA segregation systems can establish a propagating ParA ATPase gradient on the nucleoid surface, which generates the force required for the directed movement of spatially confined cargoes, such as plasmids or large organelles, and distributes multiple cargos equidistant to each other inside cells. Here we present the critical principles of our diffusion-ratchet model of ParA-mediated transport and expand on the mathematically derived chemophoresis force using experimentally-determined biochemical and cellular parameters. PMID:25759913

  13. Douleurs induites par les soins: la réalité au Centre Hospitalier Universitaire de Befelatanana Antananarivo, Madagascar

    PubMed Central

    Mahavivola, Ernestho-Ghoud Indretsy; Olivah, Razanaparany Miarisoa Mireille; Mihary, Dodo; Hendriniaina, Rakotoharivelo; Lalao, Randriamboavonjy Rado; Henintsoa, Rakotonirainy Oliva; Fahafahantsoa, Rapelanoro Rabenja

    2014-01-01

    La douleur induite par les soins correspond à la douleur survenant lors des actes à visé diagnostique et/ou thérapeutique. A notre connaissance, nous n'avons pas encore des données disponibles pour les douleurs induites par les soins à l'Hôpital de Befelatanana. Nos objectifs étaient de décrire le profil épidémiologique de la douleur induite par les soins, d'identifier les principaux facteurs influençant sur l'intensité de la douleur et leurs retentissements chez les patients. Il s'agissait d'une étude rétrospective, transversale type un jour donné menée dans les douze services de Médecines au Centre Hospitalier Universitaire de Befelatanana en Novembre 2013. Cent deux patients ont été retenus dans l’étude et trois cent vingt trois actes douloureux étaient enregistrés. La fréquence de la douleur induite par les soins était de 69,86%. Le genre féminin prédominait dans 52% des cas (n = 53) avec un sex-ratio à 0,92. L’âge moyen était de 46 ans. Les ponctions vasculaires étaient l'acte prédominant dans 49,54% (n = 109) des cas. Les infirmiers réalisaient les soins dans 47,05% (n = 48) des cas. L'information verbale était la mesure préventive utilisée dans 57,84% des cas (n = 59). Le transport par marche à pied et au dos représentait 16,67% des cas (n = 17). Les patients naïfs des gestes étaient plus anxieux. Ces patients gardaient de mauvais souvenir dans 64,71% des cas (n = 66). La fréquence de douleur induite par les soins était trop élevée. Un effort important est nécessaire pour réduire la douleur induite par les soins PMID:25932071

  14. Conception et caracterisation d'un magnetoplasma produit par une onde de surface pour la pulverisation d'echantillons solides

    NASA Astrophysics Data System (ADS)

    Masse, Louis Philippe

    Suite a l'extraordinaire explosion de l'informatique de la derniere decennie, la science et la technologie des materiaux ont pris un essor extraordinaire. Par exemple, il est devenu crucial de concevoir des materiaux a haut degre de purete. Ce besoin a fortement motive le developpement de methodes d'analyse de solides. Traditionnellement, la methode adoptee est l'analyse par torche ICP, mais pour de nombreuses raisons, dont la lenteur de cette methode, la communaute scientifique oeuvrant en chimie analytique recherche des techniques d'analyse de solides directes, rapides et plus sensibles. Parmi les voies possibles, on trouve les methodes basees sur la pulverisation par plasma. Dans ce contexte, nous avons etudie la possibilite et la pertinence d'utiliser un magnetoplasma entretenu par une onde de surface pour pulveriser des solides dans le but de les analyser. Nos travaux portent principalement sur l'etude du comportement du plasma lors de la pulverisation. Nous avons montre que la pulverisation affecte la decharge de diverses facons. En premier lieu, la concentration d'especes provenant du materiau pulverise dans le plasma augmente avec la tension de polarisation. De plus, la concentration d'especes pulverisees diminue lorsque la pression croit, possiblement a cause du redepot. Nous avons aussi montre qu'il etait possible de pulveriser des solides isolants en exploitant le phenomene d'autopolarisation du a l'application d'une tension RF. Nous avons aussi etudie l'effet de la pulverisation sur la temperature et la densite electronique. Ainsi, lors de la pulverisation de metaux tels que le cuivre, la temperature electronique diminue lorsque la tension de polarisation augmente. Ceci est attribuable a l'augmentation de la densite d'especes metalliques neutres facilement ionisables par impact electronique. Nous avons aussi note que la densite electronique augmente avec la concentration d'especes metalliques dans le plasma, ce qui resulte d'un meilleur bilan de

  15. A unique hetero-hexadecameric architecture displayed by the Escherichia coli O157 PaaA2-ParE2 antitoxin-toxin complex.

    PubMed

    Sterckx, Yann G-J; Jové, Thomas; Shkumatov, Alexander V; Garcia-Pino, Abel; Geerts, Lieselotte; De Kerpel, Maia; Lah, Jurij; De Greve, Henri; Van Melderen, Laurence; Loris, Remy

    2016-04-24

    Many bacterial pathogens modulate their metabolic activity, virulence and pathogenicity through so-called "toxin-antitoxin" (TA) modules. The genome of the human pathogen Escherichia coli O157 contains two three-component TA modules related to the known parDE module. Here, we show that the toxin EcParE2 maps in a branch of the RelE/ParE toxin superfamily that is distinct from the branches that contain verified gyrase and ribosome inhibitors. The structure of EcParE2 closely resembles that of Caulobacter crescentus ParE but shows a distinct pattern of conserved surface residues, in agreement with its apparent inability to interact with GyrA. The antitoxin EcPaaA2 is characterized by two α-helices (H1 and H2) that serve as molecular recognition elements to wrap itself around EcParE2. Both EcPaaA2 H1 and H2 are required to sustain a high-affinity interaction with EcParE2 and for the inhibition of EcParE2-mediated killing in vivo. Furthermore, evidence demonstrates that EcPaaA2 H2, but not H1, determines specificity for EcParE2. The initially formed EcPaaA2-EcParE2 heterodimer then assembles into a hetero-hexadecamer, which is stable in solution and is formed in a highly cooperative manner. Together these findings provide novel data on quaternary structure, TA interactions and activity of a hitherto poorly characterized family of TA modules. PMID:26996937