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Sample records for sous-type nr2b par

  1. 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

  2. NR2B antagonist CP-101,606 inhibits NR2B phosphorylation at tyrosine-1472 and its interactions with Fyn in levodopa-induced dyskinesia rat model.

    PubMed

    Kong, Min; Ba, Maowen; Liu, Chuanyu; Zhang, Yanxiang; Zhang, Hongli; Qiu, Haiyan

    2015-04-01

    The augmented tyrosine phosphorylation of NR2B subunit of N-methyl-d-aspartate receptors (NMDAR) dependent on Fyn kinase has been associated with levodopa (l-dopa)-induced dyskinesia (LID). CP-101,606, one selective NR2B subunit antagonist, can improve dyskinesia. Yet, the accurate action mechanism is less well understood. In the present study, the evidences were investigated. Valid 6-hydroxydopamine-lesioned parkinsonian rats were treated with l-dopa intraperitoneally for 22 days to induce LID rat model. On day 23, rats received either CP-101,606 (0.5mg/kg) or vehicle with each l-dopa dose. On the day of 1, 8, 15, 22, and 23 during l-dopa treatment, we determined abnormal involuntary movements (AIMs) in rats. The levels of NR2B phosphorylation at tyrosine-1472 (pNR2B-Tyr1472) and interactions of NR2B with Fyn in LID rat model were detected by immunoblotting and immunoprecipitation. Results showed that CP-101,606 attenuated l-dopa-induced AIMs. In agreement with behavioral analysis, CP-101,606 reduced the augmented pNR2B-Tyr1472 and its interactions with Fyn triggered during the l-dopa administration in the lesioned striatum of parkinsonian rats. Moreover, CP-101,606 also decreased the level of Ca(2+)/calmodulin-dependent protein kinase II at threonine-286 hyperphosphorylation (pCaMKII-Thr286), which was the downstream signaling amplification molecule of NMDAR overactivation and closely associated with LID. However, the protein level of NR2B and Fyn had no difference under the above conditions. These data indicate that the inhibition of the interactions of NR2B with Fyn and NR2B tyrosine phosphorylation may contribute to the CP-101,606-induced downregulation of NMDAR function and provide benefit for the therapy of LID.

  3. Tat-NR2B9c prevents excitotoxic neuronal superoxide production

    PubMed Central

    Chen, Yanting; Brennan-Minnella, Angela M; Sheth, Sunil; El-Benna, Jamel; Swanson, Raymond A

    2015-01-01

    The Tat-NR2B9c peptide has shown clinical efficacy as a neuroprotective agent in acute stroke. Tat-NR2B9c is designed to prevent nitric oxide (NO) production by preventing postsynaptic density protein 95 (PSD-95) binding to N-methyl-D-aspartate (NMDA) receptors and neuronal nitric oxide synthase; however, PSD-95 is a scaffolding protein that also couples NMDA receptors to other downstream effects. Here, using neuronal cultures, we show that Tat-NR2B9c also prevents NMDA-induced activation of neuronal NADPH oxidase, thereby blocking superoxide production. Given that both superoxide and NO are required for excitotoxic injury, the neuroprotective effect of Tat-NR2B9c may alternatively be attributable to uncoupling neuronal NADPH oxidase from NMDA receptor activation. PMID:25669908

  4. Differential effects of enrichment on learning and memory function in NR2B transgenic mice.

    PubMed

    Tang, Y P; Wang, H; Feng, R; Kyin, M; Tsien, J Z

    2001-11-01

    It has been known that environmental enrichment leads to better learning and memory in mice. However, the molecular mechanisms are not known. In this study, we used the 10th-12th of the NR2B transgenic (Tg) lines, in which the NMDA receptor function is enhanced via the NR2B subunit transgene in neurons of the forebrain, to test the hypothesis of the involvement of NMDA receptor function in enrichment-induced better learning and memory. Consistent with our previous results, both larger long-term potentiation (LTP) in the hippocampus and superior learning and memory were observed in naive NR2B Tg mice even after the 10th-12th generation of breeding. After enrichment, wild-type mice exhibited overall improvement in their performances in contextual and cued conditioning, fear extinctions, and novel object recognition tasks. Interestingly, the same enrichment procedures could not further increase the performance of NR2B Tg mice in contextual conditioning, cued conditioning, or fear extinction, thereby indicating that enhanced NMDA receptor function can occlude these enrichment effects. However, we found that in the novel object recognition task enriched NR2B Tg mice exhibited much longer recognition memory (up to 1 week), compared to that (up to 3 days) in naive NR2B Tg mice. Furthermore, our biochemical experiments showed that enrichment significantly increased protein levels of GluR1, NR2B, and NR2A subunits of glutamate receptors in both wild-type and NR2B Tg mice. Therefore, our results suggest an interactive nature of molecular pathways involved in both environmental and genetic NMDA receptor manipulations for enhancing learning and memory.

  5. Chronic Kappa opioid receptor activation modulates NR2B: Implication in treatment resistant depression.

    PubMed

    Dogra, Shalini; Kumar, Ajeet; Umrao, Deepmala; Sahasrabuddhe, Amogh A; Yadav, Prem N

    2016-01-01

    Psychotomimetic and prodepressive effect by kappa opioid receptor (KOR) activation in rodents and human is widely known. Significantly, recent clinical investigations demonstrated the salutary effects of KOR antagonists in patients with treatment resistant depression, indicating essential role of KOR signaling in refractory depression. This study was undertaken to reveal the molecular determinant of KOR mediated depression and antidepressant response of KOR antagonist. We observed that chronic KOR activation by U50488, a selective KOR agonist, significantly increased depression like symptoms (behavioral despair, anhedonia and sociability) in C57BL/6J mice, which were blocked by KOR antagonist norBNI and antidepressant imipramine, but not by fluoxetine or citalopram. Further, chronic KOR activation increased phosphorylation of NR2B subunit of NMDA at tyrosine 1472 (pNR2B NMDA) in the hippocampus, but not in the cortex. Similar to behavioral effects norBNI and imipramine, but not SSRIs, blocked NR2B phosphorylation. Moreover, KOR induced depression like behaviors were reversed by NR2B selective inhibitor Ro 25-6981. Mechanistic studies in primary cultured neurons and brain tissues using genetic and pharmacological approaches revealed that stimulation of KOR modulates several molecular correlates of depression. Thus, these findings elucidate molecular mechanism of KOR signaling in treatment resistant depression like behaviors in mice. PMID:27634008

  6. Chronic Kappa opioid receptor activation modulates NR2B: Implication in treatment resistant depression

    PubMed Central

    Dogra, Shalini; Kumar, Ajeet; Umrao, Deepmala; Sahasrabuddhe, Amogh A.; Yadav, Prem N.

    2016-01-01

    Psychotomimetic and prodepressive effect by kappa opioid receptor (KOR) activation in rodents and human is widely known. Significantly, recent clinical investigations demonstrated the salutary effects of KOR antagonists in patients with treatment resistant depression, indicating essential role of KOR signaling in refractory depression. This study was undertaken to reveal the molecular determinant of KOR mediated depression and antidepressant response of KOR antagonist. We observed that chronic KOR activation by U50488, a selective KOR agonist, significantly increased depression like symptoms (behavioral despair, anhedonia and sociability) in C57BL/6J mice, which were blocked by KOR antagonist norBNI and antidepressant imipramine, but not by fluoxetine or citalopram. Further, chronic KOR activation increased phosphorylation of NR2B subunit of NMDA at tyrosine 1472 (pNR2B NMDA) in the hippocampus, but not in the cortex. Similar to behavioral effects norBNI and imipramine, but not SSRIs, blocked NR2B phosphorylation. Moreover, KOR induced depression like behaviors were reversed by NR2B selective inhibitor Ro 25-6981. Mechanistic studies in primary cultured neurons and brain tissues using genetic and pharmacological approaches revealed that stimulation of KOR modulates several molecular correlates of depression. Thus, these findings elucidate molecular mechanism of KOR signaling in treatment resistant depression like behaviors in mice. PMID:27634008

  7. 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…

  8. Identification of a novel NR2B-selective NMDA receptor antagonist using a virtual screening approach.

    PubMed

    Mony, Laetitia; Triballeau, Nicolas; Paoletti, Pierre; Acher, Francine C; Bertrand, Hugues-Olivier

    2010-09-15

    We report the identification of a novel NR2B-selective NMDAR antagonist with an original scaffold, LSP10-0500. This compound was identified by a virtual high-throughput screening approach on the basis of a quantitative pharmacophore model of NR2B-specific NMDAR antagonists. A SAR study around LSP10-0500 is also described.

  9. 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.

  10. Effects of chronic NMDA-NR2b inhibition in the median eminence of the reproductive senescent female rat.

    PubMed

    Kermath, B A; Riha, P D; Sajjad, A; Gore, A C

    2013-10-01

    Gonadotrophin-releasing hormone (GnRH) neurones of the hypothalamic-pituitary-gonadal (HPG) axis drive reproductive function and undergo age-related decreases in activation during the transition to reproductive senescence. Decreased GnRH secretion from the median eminence (ME) partially arises from attenuated glutamatergic signalling via the NMDA receptor (NMDAR) and may be a result of changing NMDAR stoichiometry to favour NR2b over NR2a subunit expression with ageing. We have previously shown that the systemic inhibition of NR2b-containing receptors with ifenprodil, an NR2b-specific antagonist, stimulates parameters of luteinising hormone (used as a proxy for GnRH) release in both young and middle-aged females. In the present study, we chronically administered ifenprodil, an NR2b-specific antagonist, at the site of GnRH terminals in the ME or at GnRH perikarya in the preoptic area, in reproductively senescent middle-aged female rats, aiming to determine whether NR2b antagonism could restore aspects of reproductive functionality. Effects on oestrous cyclicity, serum hormones, and protein expression of GnRH, NR2b and phosphorylated NR2b (Tyr-1472) in the ME were measured. Chronic ifenprodil treatment in the ME (but not the preoptic area) altered oestrous cyclicity by increasing the percentage of days spent in pro-oestrus. This was accompanied by increased GnRH fluorescence intensity in the external ME zone and a greater proportion of GnRH terminals that co-labelled with pNR2b with treatment. We also observed changes in the relationships between protein immunofluorescence, serum hormone levels and other aspects of reproductive physiology in acyclic females, as revealed by bionetwork analysis. Together, these data support the hypothesis that NMDAR-NR2b expression and phosphorylation state play a role in reproductive senescence and highlight the ME as a major player in reproductive ageing.

  11. 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.

  12. Discovery of 3-Substituted Aminocyclopentanes as Potent and Orally Bioavailable NR2B Subtype-Selective NMDA Antagonists

    PubMed Central

    2011-01-01

    A series of 3-substituted aminocyclopentanes has been identified as highly potent and selective NR2B receptor antagonists. Incorporation of a 1,2,4-oxadiazole linker and substitution of the pendant phenyl ring led to the discovery of orally bioavailable analogues that showed efficient NR2B receptor occupancy in rats. Unlike nonselective NMDA antagonists, the NR2B-selective antagonist 22 showed no adverse affects on motor coordination in the rotarod assay at high dose. Compound 22 was efficacious following oral administration in a spinal nerve ligation model of neuropathic pain and in an acute model of Parkinson’s disease in a dose dependent manner. PMID:22816022

  13. 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

  14. SETDB1 HISTONE METHYLTRANSFERASE REGULATES MOOD-RELATED BEHAVIORS AND EXPRESSION OF THE NMDA RECEPTOR SUBUNIT NR2B

    PubMed Central

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

    2010-01-01

    Histone methyltransferases specific for the histone H3-lysine 9 (H3K9) 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 less than 1% of annotated genes, which include the NMDA receptor subunit NR2B/Grin2B and other ionotropic glutamate receptor genes. Chromatin conformation capture (“3C”) and Setdb1-ChIP revealed a loop formation tethering the NR2B/Grin2b promoter to the Setdb1 target site positioned 30Kb 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 wildtype mice, systemic treatment with the NR2B antagonist, Ro-256981, and hippocampal siRNA-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

  15. Antinociceptive activity of CP-101,606, an NMDA receptor NR2B subunit antagonist

    PubMed Central

    Taniguchi, Kana; Shinjo, Katsuhiro; Mizutani, Mayumi; Shimada, Kaoru; Ishikawa, Toshihisa; Menniti, Frank S; Nagahisa, Atsushi

    1997-01-01

    The analgesic activity of CP-101,606, an NR2B subunit-selective N-methyl-D-aspartate (NMDA) receptor antagonist, was examined in carrageenan-induced hyperalgesia, capsaicin- and 4β-phorbol-12-myristate-13-acetate (PMA)-induced nociceptive tests in the rat. CP-101,606 30 mg kg−1, s.c., at 0.5 and 2.5 h after carrageenan challenge suppressed mechanical hyperalgesia without any apparant alternations in motor coordination or behaviour in the rat. CP-101,606 also inhibited capsaicin- and PMA-induced nociceptive responses (licking behaviour) with ED50 values of 7.5 and 5.7 mg kg−1, s.c., respectively. These results suggest that inhibition of the NR2B subunit of the NMDA receptor is effective in vivo at modulating nociception and hyperalgesia responses without causing the behavioural side effects often observed with currently available NMDA receptor antagonists. PMID:9384494

  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.

  17. NMDA receptor NR2B subunits contribute to PTZ-kindling-induced hippocampal astrocytosis and oxidative stress.

    PubMed

    Zhu, Xinjian; Dong, Jingde; Shen, Kai; Bai, Ying; Zhang, Yuan; Lv, Xuan; Chao, Jie; Yao, Honghong

    2015-05-01

    The N-methyl-d-aspartate (NMDA) receptor plays an important role in the pathophysiology of several neurological diseases, including epilepsy. The present study investigated the effect of NMDA receptor NR2B subunits on pentylenetetrazole (PTZ)-kindling-induced pathological and biochemical events in mice. Our results showed that PTZ-kindling up-regulates the expression of NMDA receptor NR2B subunits in the hippocampus and that kindled mice were characterized by significant astrocytosis and neuron loss in the hippocampus. Oxidative stress, including excessive malondialdehyde (MDA) production and decreased enzymatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), were detected in the hippocampus after the mice were fully kindled. Additionally, expression of brain-derived neurotrophic factor (BDNF) in the hippocampus was found to be up-regulated in PTZ-kindled mice. However, selectively blocking NMDA receptor NR2B subunits by ifenprodil significantly suppressed PTZ-kindling-induced hippocampal astrocytosis, oxidative stress and neuron loss. Furthermore, blocking NMDA receptor NR2B subunits also abolished PTZ-kindling-induced BDNF expression. These results indicate that NMDA receptor NR2B subunits contribute to epilepsy-associated pathological and biochemical events, including hippocampal astrocytosis, oxidative stress and neuron loss, and these events might be correlated with up-regulation of BDNF expression.

  18. Modulation of NR2B-regulated contextual fear in the hippocampus by the tissue plasminogen activator system.

    PubMed

    Norris, Erin H; Strickland, Sidney

    2007-08-14

    Contextual fear conditioning is regulated by the hippocampus, and NR2B, a subunit of the NMDA receptor (NR), is involved in this process. We show that acute stress modulates tissue plasminogen activator (tPA) activity in the hippocampus by inducing expression of its inhibitor, plasminogen activator inhibitor-1. Acute stress increases NR2B expression and ERK1/2 phosphorylation, a classical marker of postsynaptic plasticity, in the hippocampus. tPA forms a complex with NR2B and is necessary for binding NR2B to postsynaptic density-95, allowing for NR activation and membrane anchoring. Acute stress increases the interaction between NR2B and RACK-1, which is also dependent on tPA, further suggesting that tPA is an important factor in NMDA signaling and plasticity in the hippocampus. Finally, acutely stressed tPA(-/-) mice show a decrease in contextual fear conditioning compared with stressed WT mice. These results indicate that tPA is a key modulator in stabilizing the NR complex during stress and participates in changes in behavior and synaptic plasticity.

  19. Down-regulation of NR2B receptors partially contributes to analgesic effects of Gentiopicroside in persistent inflammatory pain.

    PubMed

    Chen, Lei; Liu, Jin-cheng; Zhang, Xiao-nan; Guo, Yan-yan; Xu, Zhao-hui; Cao, Wei; Sun, Xiao-li; Sun, Wen-ji; Zhao, Ming-Gao

    2008-06-01

    Gentiopicroside is one of the secoiridoid compound isolated from Gentiana lutea. It exhibits analgesic activities in the mice. The anterior cingulate cortex (ACC) is a forebrain structure known for its roles in pain transmission and modulation. Painful stimuli potentiate the prefrontal synaptic transmission and induce glutamate NMDA NR2B receptor expression in the ACC. But little is known about Gentiopicroside on the persistent inflammatory pain and chronic pain-induced synaptic transmission changes in the ACC. The present study was undertaken to investigate its analgesic activities and central synaptic modulation to the peripheral painful inflammation. Gentiopicroside produced significant analgesic effects against persistent inflammatory pain stimuli in mice. Systemic administration of Gentiopicroside significantly reversed NR2B over-expression during the chronic phases of persistent inflammation caused by hind-paw administration of complete Freunds adjuvant (CFA) in mice. Whole-cell patch clamp recordings revealed that Gentiopicroside significantly reduced NR2B receptors mediated postsynaptic currents in the ACC. Our findings provide strong evidence that analgesic effects of Gentiopicroside involve down-regulation of NR2B receptors in the ACC to persistent inflammatory pain.

  20. 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

  1. NR2B Expression in Rat DRG Is Differentially Regulated Following Peripheral Nerve Injuries That Lead to Transient or Sustained Stimuli-Evoked Hypersensitivity

    PubMed Central

    Norcini, Monica; Sideris, Alexandra; Adler, Samantha M.; Hernandez, Lourdes A. M.; Zhang, Jin; Blanck, Thomas J. J.; Recio-Pinto, Esperanza

    2016-01-01

    Following injury, primary sensory neurons undergo changes that drive central sensitization and contribute to the maintenance of persistent hypersensitivity. NR2B expression in the dorsal root ganglia (DRG) has not been previously examined in neuropathic pain models. Here, we investigated if changes in NR2B expression within the DRG are associated with hypersensitivities that result from peripheral nerve injuries. This was done by comparing the NR2B expression in the DRG derived from two modalities of the spared nerve injury (SNI) model, since each variant produces different neuropathic pain phenotypes. Using the electronic von Frey to stimulate the spared and non-spared regions of the hindpaws, we demonstrated that sural-SNI animals develop sustained neuropathic pain in both regions while the tibial-SNI animals recover. NR2B expression was measured at Day 23 and Day 86 post-injury. At Day 23 and 86 post-injury, sural-SNI animals display strong hypersensitivity, whereas tibial-SNI animals display 50 and 100% recovery from post-injury-induced hypersensitivity, respectively. In tibial-SNI at Day 86, but not at Day 23 the perinuclear region of the neuronal somata displayed an increase in NR2B protein. This retention of NR2B protein within the perinuclear region, which will render them non-functional, correlates with the recovery observed in tibial-SNI. In sural-SNI at Day 86, DRG displayed an increase in NR2B mRNA which correlates with the development of sustained hypersensitivity in this model. The increase in NR2B mRNA was not associated with an increase in NR2B protein within the neuronal somata. The latter may result from a decrease in kinesin Kif17, since Kif17 mediates NR2B transport to the soma’s plasma membrane. In both SNIs, microglia/macrophages showed a transient increase in NR2B protein detected at Day 23 but not at Day 86, which correlates with the initial post-injury induced hypersensitivity in both SNIs. In tibial-SNI at Day 86, but not at Day 23

  2. 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

  3. 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

  4. 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.

  5. An NR2B-Dependent Decrease in the Expression of trkB Receptors Precedes the Disappearance of Dopaminergic Cells in Substantia Nigra in a Rat Model of Presymptomatic Parkinson's Disease

    PubMed Central

    Riquelme, Eduardo; Abarca, Jorge; Campusano, Jorge M.; Bustos, Gonzalo

    2012-01-01

    Compensatory changes occurring during presymptomatic stages of Parkinson's disease (PD) would explain that the clinical symptoms of the disease appear late, when the degenerative process is quite advanced. Several data support the proposition that brain-derived neurotrophic factor (BDNF) could play a role in these plastic changes. In the present study, we evaluated the expression of the specific BDNF receptor, trkB, in a rat model of presymptomatic PD generated by intrastriatal injection of the neurotoxin 6-OHDA. Immunohistochemical studies revealed a decrease in trkB expression in SN pars compacta (SNc) seven days after 6-OHDA injection. At this time point, no change in the number of tyrosine hydroxylase (TH) immunoreactive (TH-IR) cells is detected, although a decrease is evident 14 days after neurotoxin injection. The decrease in TH-positive cells and trkB expression in SNc was significantly prevented by systemic administration of Ifenprodil, a specific antagonist of NR2B-containing NMDA receptors. Therefore, an NR2B-NMDA receptor-dependent decrease in trkB expression precedes the disappearance of TH-IR cells in SNc in response to 6-OHDA injection. These results support the idea that a functional coupling between NMDA receptors and BDNF/trkB signalling may be important for the maintenance of the dopaminergic phenotype in SNc during presymptomatic stages of PD. PMID:22720191

  6. The effect of (+/-)-CP-101,606, an NMDA receptor NR2B subunit selective antagonist, in the Morris watermaze.

    PubMed

    Guscott, Martin R; Clarke, Hannah F; Murray, Fraser; Grimwood, Sarah; Bristow, Linda J; Hutson, Peter H

    2003-08-29

    It is well established that the NMDA receptor antagonists block hippocampal long-term potentiation and impair acquisition in the Morris watermaze task, although the role of individual NMDA receptor subtypes is largely unknown. In the present study, we compared the effects of (+/-)-CP-101,606, an antagonist selective for NMDA receptor NR1/NR2B subunit-containing receptors and the nonselective NMDA receptor antagonist MK-801, on acquisition in the Morris watermaze. Male hooded Lister rats were given 4 trials/day to find a fixed hidden platform submerged beneath the opaque water of the Morris watermaze. Twenty-four hours after the last acquisition trial, a 'probe trial' was conducted to assess the rat's spatial memory for the location of the hidden platform. Those rats treated with MK-801 (0.1 mg/kg, i.p.) 60 min prior to the acquisition and probe trials took significantly longer to find the hidden platform during training and spent significantly less time searching the platform's location during the probe trial than vehicle-treated rats. In contrast, 60-min pretreatment with (+/-)-CP-101,606 (60 mg/kg, p.o.), a dose that fully occupied hippocampal NR1/NR2B subunit-containing receptors, as determined by ex vivo NMDA receptor-specific [3H]ifenprodil binding immediately following watermaze experiments, had no effect on acquisition or the probe trial. These results suggest that antagonists selective for NR1/NR2B subunit-containing receptors may not impair spatial memory in rats in the Morris watermaze.

  7. N-methyl-D-aspartate receptor NR2B subunit involved in depression-like behaviours in lithium chloride-pilocarpine chronic rat epilepsy model.

    PubMed

    Peng, Wei-Feng; Ding, Jing; Li, Xin; Fan, Fan; Zhang, Qian-Qian; Wang, Xin

    2016-01-01

    Depression is a common comorbidity in patients with epilepsy with unclear mechanisms. This study is to explore the role of glutamate N-methyl-D-aspartate (NMDA) receptor NR1, NR2A and NR2B subunits in epilepsy-associated depression. Lithium chloride (Licl)-pilocarpine chronic rat epilepsy model was established and rats were divided into epilepsy with depression (EWD) and epilepsy without depression (EWND) subgroups based on forced swim test. Expression of NMDA receptor NR1, NR2A and NR2B subunits was measured by western blot and immunofluorescence methods. The immobility time (IMT) was significantly greater in Licl-pilocarpine model group than in Control group, which was also greater in EWD group than in EWND group. No differences of spontaneous recurrent seizure (SRS) counts over two weeks and latency were found between EWD and EWND groups. The number of NeuN positive cells was significantly less in Licl-pilocarpine model group than in Control group, but had no difference between EWD and EWND groups. The ratios of phosphorylated NR1 (p-NR1)/NR1 and p-NR2B/NR2B were significantly greater in the hippocampus in EWD group than in EWND group. Moreover, the expression of p-NR1 and p-NR2B in the CA1 subfield of hippocampus were both greater in Licl-pilocarpine model group than Control group. Selective blockage of NR2B subunit with ifenprodil could alleviate depression-like behaviours of Licl-pilocarpine rat epilepsy model. In conclusion, glutamate NMDA receptor NR2B subunit was involved in promoting depression-like behaviours in the Licl-pilocarpine chronic rat epilepsy model and might be a target for treating epilepsy-associated depression.

  8. 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

  9. NR2A- and NR2B-containing NMDA receptors in the prelimbic medial prefrontal cortex differentially mediate trace, delay, and contextual fear conditioning.

    PubMed

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

    2013-05-15

    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 regulate these two fear memories. Here we show that NR2A-containing NMDARs mediate trace, delay, and contextual fear memories, but NR2B-containing NMDARs are required only for trace conditioning, consistent with a role for PL mPFC in working memory.

  10. 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.

  11. 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…

  12. 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.

  13. Selective Regulation of NR2B by Protein Phosphatase-1 for the Control of the NMDA Receptor in Neuroprotection

    PubMed Central

    Grewe, Benjamin F.; Tyagarajan, Shiva K.; Helmchen, Fritjof; Mansuy, Isabelle M.

    2012-01-01

    An imbalance between pro-survival and pro-death pathways in brain cells can lead to neuronal cell death and neurodegeneration. While such imbalance is known to be associated with alterations in glutamatergic and Ca2+ signaling, the underlying mechanisms remain undefined. We identified the protein Ser/Thr phosphatase protein phosphatase-1 (PP1), an enzyme associated with glutamate receptors, as a key trigger of survival pathways that can prevent neuronal death and neurodegeneration in the adult hippocampus. We show that PP1α overexpression in hippocampal neurons limits NMDA receptor overactivation and Ca2+ overload during an excitotoxic event, while PP1 inhibition favors Ca2+ overload and cell death. The protective effect of PP1 is associated with a selective dephosphorylation on a residue phosphorylated by CaMKIIα on the NMDA receptor subunit NR2B, which promotes pro-survival pathways and associated transcriptional programs. These results reveal a novel contributor to the mechanisms of neuroprotection and underscore the importance of PP1-dependent dephosphorylation in these mechanisms. They provide a new target for the development of potential therapeutic treatment of neurodegeneration. PMID:22479519

  14. Perinatal exposure to PTU delays switching from NR2B to NR2A subunits of the NMDA receptor in the rat cerebellum.

    PubMed

    Kobayashi, Kumiko; Tsuji, Ryozo; Yoshioka, Takafumi; Mino, Terumasa; Seki, Takaki

    2006-03-01

    Certain kinds of developmental neurotoxicants are considered to act by affecting the levels of thyroid hormones, which are essential for the brain development of both humans and experimental animals. Hypothyroidism experimentally induced in rats with propylthiouracil (PTU) offers a useful animal model for developmental neurotoxicity. The purpose of the present study was to clarify developmental alterations in gene expression caused by PTU in this model, with the focus on eight genes implicated in neural network formation or synaptic functions, such as the brain-derived neurotrophic factor (BDNF) and NMDA receptors 2A/2B. First, we measured the developmental profile of gene expression in vehicle-dosed rat cerebellum by quantitative RT-PCR and then examined the effects of PTU on mRNA levels on postnatal day (PND) 22, when most of the cerebellar structures in mature animals are already formed. PTU induced up-regulation of NR2B mRNA and down-regulation of NR2A and BDNF mRNAs in the cerebellum on PND 22, but there were no changes in the other genes (growth associated protein-43, L1, neuronal cell adhesion molecule, synaptophysin, post synaptic density-95). Examination of the effects of PTU on maturation of NMDAR subunits (NR2A/NR2B) demonstrated changes in relative expression on PND 14, but not on PND 4, with recovery after maturation. The profile of NMDAR subunits in vehicle-dosed rats showed a shift from NR2B to NR2A during development. These results suggest PTU can delay this switching from NR2B to NR2A subunits in the maturation of NMDA receptors.

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

    PubMed

    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

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

    PubMed

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

    2015-10-13

    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.

  17. Effect of the N-methyl-D-aspartate NR2B subunit antagonist ifenprodil on precursor cell proliferation in the hippocampus.

    PubMed

    Bunk, E C; König, H-G; Prehn, J H M; Kirby, B P

    2014-06-01

    The N-methyl-D-aspartate (NMDA) receptor, one of the ionotropic glutamate receptor, plays important physiological and pathological roles in learning and memory, neuronal development, acute and chronic neurological diseases, and neurogenesis. This work examines the contribution of the NR2B NMDA receptor subunit to adult neurogenesis/cell proliferation under physiological conditions and following an excitotoxic insult. We have previously shown in vitro that a discrete NMDA-induced, excitotoxic injury to the hippocampus results in an increase in neurogenesis within the dentate gyrus. Here we have characterized adult neurogenesis or proliferation, using BrdU, in an in vivo model of excitotoxic injury to the CA1 subfield of the hippocampus. We demonstrate a peak in neural stem cell proliferation/neurogenesis between 6 and 9 days after the excitotoxic insult. Treatment with ifenprodil, an NR2B subunit-specific NMDA receptor antagonist, without prior injury induction, also increased the number of BrdU-positive cells within the DG and posterior periventricle, indicating that ifenprodil itself could modulate the rate of proliferation. Interestingly, though, the increased level of cell proliferation did not change significantly when ifenprodil was administered following an excitotoxic insult. In conclusion, our results suggest and add to the growing evidence that NR2B subunit-containing NMDA receptors play a role in neural stem cell proliferation.

  18. Hydrogen-rich saline prevents remifentanil-induced hyperalgesia and inhibits MnSOD nitration via regulation of NR2B-containing NMDA receptor in rats.

    PubMed

    Zhang, L; Shu, R; Wang, H; Yu, Y; Wang, C; Yang, M; Wang, M; Wang, G

    2014-11-01

    Remifentanil administration may subsequently cause paradoxical hyperalgesia in animals and humans, but mechanisms remain unclear. Manganese superoxide dismutase (MnSOD) nitration and inactivation caused by generation of reactive oxygen species and activation of N-methyl-D-aspartate (NMDA) receptors are involved in the induction and maintenance of central neuropathic pain. Hydrogen which selectively removes superoxide has gained much attention in recent years. In this study, we investigated antinociceptive effects of hydrogen-rich saline (HRS) on remifentanil-induced postsurgical hyperalgesia in a rat model of incisional pain. HRS was injected intraperitoneally 10 min before remifentanil infusion (1 μg kg(-1) min(-1) for 60 min). A selective NR2B antagonist Ro25-6981 was used to investigate whether antihypernociception of HRS is associated with NMDA receptor (NMDAR). Nociception was evaluated by the paw withdrawal mechanical threshold and thermal latency respectively. Then we assessed MnSOD, NR2A and NR2B in spinal cord dorsal horn via Western blot and immunohistochemistry after nociceptive tests. Here, we found that the analgesic effect of remifentanil was followed by long-term hyperalgesia lasting at least postoperative 7 days, which was accompanied with increase in NR2B expression and trafficking from cytoplasm to surface and MnSOD nitration in dorsal horn. Pretreatment with HRS (10 ml/kg) significantly attenuated mechanical and thermal hyperalgesia, blocked NR2B trafficking and MnSOD nitration in dorsal horn after remifentanil infusion. Ro25-6981 not 5 μg but 10 and 50 μg dosage-dependently attenuated hyperalgesia, and inhibited MnSOD nitration. Hyperalgesia and MnSOD nitration were attenuated after the combination of HRS (2.5 ml/kg) and Ro25-6981 (5 μg). In conclusion, HRS (10 ml/kg) might reverse remifentanil-induced hyperalgesia, through regulating NR2B-containing NMDAR trafficking to control MnSOD nitration and enhance MnSOD activity.

  19. 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

  20. 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

  1. Isoflurane/nitrous oxide anesthesia induces increases in NMDA receptor subunit NR2B protein expression in the aged rat brain.

    PubMed

    Mawhinney, Lana J; de Rivero Vaccari, Juan Pablo; Alonso, Ofelia F; Jimenez, Christopher A; Furones, Concepción; Moreno, W Javier; Lewis, Michael C; Dietrich, W Dalton; Bramlett, Helen M

    2012-01-11

    Postoperative cognitive dysfunction, POCD, afflicts a large number of elderly surgical patients following surgery with general anesthesia. Mechanisms of POCD remain unclear. N-methyl-D-aspartate (NMDA) receptors, critical in learning and memory, that display protein expression changes with age are modulated by inhalation anesthetics. The aim of this study was to identify protein expression changes in NMDA receptor subunits and downstream signaling pathways in aged rats that demonstrated anesthesia-induced spatial learning impairments. Three-month-old and 18-month-old male Fischer 344 rats were randomly assigned to receive 1.8% isoflurane/70% nitrous oxide (N(2)O) anesthesia for 4h or no anesthesia. Spatial learning was assessed at 2weeks and 3months post-anesthesia in Morris water maze. Hippocampal and cortical protein lysates of 18-month-old rats were immunoblotted for activated caspase 3, NMDA receptor subunits, and extracellular-signal regulated kinase (ERK) 1/2. In a separate experiment, Ro 25-6981 (0.5mg/kg dose) was administered by I.P. injection before anesthesia to 18-month-old rats. Immunoblotting of NR2B was performed on hippocampal protein lysates. At 3months post-anesthesia, rats treated with anesthesia at 18-months-old demonstrated spatial learning impairment corresponding to acute and long-term increases in NR2B protein expression and a reduction in phospho-ERK1/2 in the hippocampus and cortex. Ro 25-6981 pretreatment attenuated the increase in acute NR2B protein expression. Our findings suggest a role for disruption of NMDA receptor mediated signaling pathways in the hippocampus and cortex of rats treated with isoflurane/ N(2)O anesthesia at 18-months-old, leading to spatial learning deficits in these animals. A potential therapeutic intervention for anesthesia associated cognitive deficits is discussed. PMID:22137658

  2. 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

  3. NMDA-induced ERK signalling is mediated by NR2B subunit in rat cortical neurons and switches from positive to negative depending on stage of development.

    PubMed

    Sava, Anna; Formaggio, Elena; Carignani, Corrado; Andreetta, Filippo; Bettini, Ezio; Griffante, Cristiana

    2012-02-01

    It is known that NMDA receptor stimulation can activate or inhibit the extracellular signal-regulated kinase (ERK) signalling cascade, a key pathway involved in neuronal plasticity and survival. However, the specific subtype(s) of NMDA receptor that exert bi-directional regulation of ERK signalling is under debate. Here we show that in young neurons (7-9 days in vitro, DIV), NMDA activated ERK signalling. In mature neurons (14-16 DIV), NMDA-evoked, in coincidence with a concentration-dependent increase in intracellular Ca(2+) ([Ca(2+)](i)), an increase in ERK phosphorylation at low concentrations (1-30 μM) while an inhibition at high concentrations (30 μM-250 μM). In more mature neurons (21-23 DIV) NMDA inhibited ERK signalling. Both activation and inhibition of ERK signalling were fully reversed by the selective NR2B receptor antagonists Ro 25-6981 and ifenprodil. Thus, the NR2B subunit can be both negatively or positively coupled to ERK signalling in rat cortical neurons, depending on their stage of development. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

  4. 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

  5. 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

  6. 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…

  7. 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…

  8. 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

  9. A role for hippocampal PSA-NCAM and NMDA-NR2B receptor function in flavonoid-induced spatial memory improvements in young rats.

    PubMed

    Rendeiro, Catarina; Foley, Andrew; Lau, Vera C; Ring, Rebecca; Rodriguez-Mateos, Ana; Vauzour, David; Williams, Claire M; Regan, Ciaran; Spencer, Jeremy P E

    2014-04-01

    The increase in incidence and prevalence of neurodegenerative diseases highlights the need for a more comprehensive understanding of how food components may affect neural systems. In particular, flavonoids have been recognized as promising agents capable of influencing different aspects of synaptic plasticity resulting in improvements in memory and learning in both animals and humans. Our previous studies highlight the efficacy of flavonoids in reversing memory impairments in aged rats, yet little is known about the effects of these compounds in healthy animals, particularly with respect to the molecular mechanisms by which flavonoids might alter the underlying synaptic modifications responsible for behavioral changes. We demonstrate that a 3-week intervention with two dietary doses of flavonoids (Dose I: 8.7 mg/day and Dose II: 17.4 mg/day) facilitates spatial memory acquisition and consolidation (24 recall) (p < 0.05) in young healthy rats. We show for the first time that these behavioral improvements are linked to increased levels in the polysialylated form of the neural adhesion molecule (PSA-NCAM) in the dentate gyrus (DG) of the hippocampus, which is known to be required for the establishment of durable memories. We observed parallel increases in hippocampal NMDA receptors containing the NR2B subunit for both 8.7 mg/day (p < 0.05) and 17.4 mg/day (p < 0.001) doses, suggesting an enhancement of glutamate signaling following flavonoid intervention. This is further strengthened by the simultaneous modulation of hippocampal ERK/CREB/BDNF signaling and the activation of the Akt/mTOR/Arc pathway, which are crucial in inducing changes in the strength of hippocampal synaptic connections that underlie learning. Collectively, the present data supports a new role for PSA-NCAM and NMDA-NR2B receptor on flavonoid-induced improvements in learning and memory, contributing further to the growing body of evidence suggesting beneficial effects of flavonoids in

  10. 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

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

    SciTech Connect

    Ng, F.-M.; Soh Wanqin; Geballe, Matthew T.; Low, C.-M.

    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 (1 mg/ml) exists as monodispersed species at 25 {sup o}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 (64 nM) and presence (116 nM) 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.

  12. 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.

  13. A history of corticosterone exposure regulates fear extinction and cortical NR2B, GluR2/3, and BDNF.

    PubMed

    Gourley, Shannon L; Kedves, Alexia T; Olausson, Peter; Taylor, Jane R

    2009-02-01

    A history of exposure to stressors may be a predisposing factor for developing posttraumatic stress disorder (PTSD) after trauma. Extinction of conditioned fear appears to be impaired in PTSD, but the consequences of prior stress or excess glucocorticoid exposure for extinction learning are not known. We report that prior chronic exposure to the stress hormone, corticosterone (CORT), decreases endogenous CORT secretion upon context reexposure and impairs extinction after contextual fear conditioning in rats, while leaving fear memory acquisition and expression intact. Posttraining administration of the glucocorticoid receptor (GR) antagonist, RU38486, partially mimicked prior CORT exposure effects on freezing during fear extinction training. Extinction of conditioned fear is an active learning process thought to involve glutamatergic targets--including specific NMDA and AMPA receptor subunits--in the ventromedial prefrontal cortex (vmPFC), which includes the prelimbic, infralimbic, and medial orbitofrontal cortices. After CORT exposure, decreases in the NMDA receptor NR2B subunit and AMPA receptor subunits, GluR2/3, as well as brain-derived neurotrophic factor, were detected in cortical regions, but not dorsal hippocampus (CA1). Receptor subunit expression levels in the vmPFC correlated with freezing during training. In addition, prior CORT selectively decreased sucrose preference, consistent with established models of anhedonia and with blunted affect in PTSD. Together, these data suggest a cellular mechanism by which chronically elevated glucocorticoid exposure--as may be experienced during repeated exposure to stressors--interferes with the neural systems that modulate behavioral flexibility and may thereby contribute to psychopathological fear states.

  14. The NR2B antagonist, ifenprodil, corrects the l-DOPA-induced deficit of bilateral movement and reduces c-Fos expression in the subthalamic nucleus of hemiparkinsonian rats.

    PubMed

    Igarashi, Masakazu; Habata, Toshiya; Akita, Hisanao; Noda, Kazuko; Ogata, Masanori; Saji, Makoto

    2015-07-01

    The use of NR2B antagonists in Parkinsonism is still controversial. To examine their anti-parkinsonian effects, the NR2B antagonist, ifenprodil, and L-DOPA were administered together and separately in hemiparkinsonian rats (hemi-PD) that were subjected to a cylinder test. Recovery from hypoactivity was achieved by single administration of 3-7 mg/kg of L-DOPA; however, improvement in the deficit of bilateral forelimb use was not observed. When administered alone, ifenprodil had no anti-parkinsonian effects; however, combined administration of ifenprodil and 7 mg/kg of L-DOPA significantly reversed the deficit of bilateral forelimb use without adversely affecting the L-DOPA-induced improvement in motor activity. Next, in order to identify the brain area influenced by L-DOPA and ifenprodil, quantitative analysis of L-DOPA-induced c-Fos immunoreactivity was performed in various brain areas of hemi-PD following administration of L-dopa with and without ifenprodil. Among brain areas with robust c-Fos expression within the motor loop circuit in dopamine-depleted hemispheres, co-administered ifenprodil markedly attenuated L-DOPA-induced c-Fos expression in only the subthalamic nucleus (STN), suggesting that the STN is the primary target for the anti-parkinsonian action of NR2B antagonists.

  15. 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

  16. 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 Central

    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

  17. Effects of sex and chronic neonatal nicotine treatment on NKCC1, KCC2, BDNF, NR2A and NR2B mRNA expression in the postnatal rat hippocampus

    PubMed Central

    Damborsky, Joanne C.; Winzer-Serhan, Ursula H.

    2012-01-01

    Chronic exposure to nicotine during the first postnatal week in rats, a developmental period that corresponds to the third trimester of human gestation, results in sexually dimorphic long-term functional defects in the adult hippocampus. One potential cause could be the sex-specific differences in the maturation of GABAA receptor-mediated responses from excitatory to inhibitory, which depends on the expression of the Na2+/K+/Cl−-co-transporter NKCC1 and the K+/Cl− co-transporter KCC2. In the rat hippocampus, this switch occurs during the first and second postnatal week in females and males, respectively, and is regulated by nicotinic receptor activation. Excitatory GABAergic signaling can increase BDNF expression, which might exacerbate sex differences by impacting synaptogenesis. We hypothesized that chronic neonatal nicotine (CNN) exposure differentially regulates the expression of these co-transporters and BDNF in males and females. We use quantitative isotopic in situ hybridization to examine the expression of mRNAs for NKCC1, KCC2, BDNF, and NMDA receptor subunits NR2A and NR2B in the postnatal day (P) 5 and 8 rat hippocampus in both sexes that were either control-treated or with 6 mg/kg/day nicotine in milk formula (CNN) via gastric intubation starting at P1. In line with prolonged GABAergic excitation, we found that at P5 males had significantly higher mRNA expression of NKCC1 and BDNF than females. CNN treatment resulted in a significant increase in KCC2 and BDNF mRNA expression in male but not female hippocampus (p<0.05). Males also had higher expression of NR2A and lower expression of NR2B at P5 compared to females (p<0.05). At P8, there were neither sex nor treatment effects on mRNA expression, indicating the end of a critical period for sensitivity to nicotine. These results suggest that differential maturation of GABAAR-mediated responses result in sex-specific sensitivity to nicotine during early postnatal development, potentially explaining the

  18. 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

  19. 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.

  20. Effects of prenatal chronic mild stress exposure on hippocampal cell proliferation, expression of GSK-3α, β and NR2B in adult offspring during fear extinction in rats.

    PubMed

    Li, Min; Li, Xiaobai; Zhang, Xinxin; Ren, Jintao; Jiang, Han; Wang, Yan; Ma, Yuchao; Cheng, Wenwen

    2014-06-01

    Stress during pregnancy has been implicated as a risk factor for the development of many mental disorders; however, the influence of prenatal stress on the fear or anxiety-related behaviors, especially the fear extinction in adult offspring has been little investigated. In order to investigate how prenatal stress affects fear extinction, which is regarded as a form of new learning that counteracts the expression of Pavlovian's conditioned fear, a rat model of prenatal chronic mild stress (PNS) was used to evaluate the effects of PNS on fear extinction in adult offspring. The expression of hippocampal glycogen synthase kinase-3s (GSK-3α, β), N-methyl-d-aspartic acid receptors (NMDARs)-2B and the hippocampal cell proliferation in dentate gyrus in the adult offspring during fear extinction were studied. Our results showed that PNS significantly reduced body weight of pups, indicating PNS might induce growth retardation in offspring. Moreover, PNS significantly enhanced the freezing behavior of offspring at the phase of extinction, suggesting PNS impaired the abilities of fear extinction learning. In addition, PNS significantly increased the levels of GSK-3α, β and NR2B, but reduced hippocampal cell proliferation during fear extinction. Taken together, our findings suggest that maternal stress during pregnancy can impair the fear extinction of adult offspring, probably by affecting the neural plasticity of brain.

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. De Par en Par (Wide Open), 1993.

    ERIC Educational Resources Information Center

    De Par en Par, 1993

    1993-01-01

    This document consists of the four issues of the serial "De Par en Par" published during 1993. This serial provides lessons in Spanish for elementary school children. It is written by bilingual education teachers for use in the bilingual classroom. The magazine bases itself on the K-6 curriculum and offers a variety of activities for classroom…

  6. 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

  7. 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

  8. 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.

  9. 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.

  10. 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

  11. 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.

  12. Operational Principles for the Dynamics of the In Vitro ParA-ParB System

    PubMed Central

    Jindal, Lavisha; Emberly, Eldon

    2015-01-01

    In many bacteria the ParA-ParB protein system is responsible for actively segregating DNA during replication. ParB proteins move by interacting with DNA bound ParA-ATP, stimulating their unbinding by catalyzing hydrolysis, that leads to rectified motion due to the creation of a wake of depleted ParA. Recent in vitro experiments have shown that a ParB covered magnetic bead can move with constant speed over a DNA covered substrate that is bound by ParA. It has been suggested that the formation of a gradient in ParA leads to diffusion-ratchet like motion of the ParB bead but how it forms and generates a force is still a matter of exploration. Here we develop a deterministic model for the in vitro ParA-ParB system and show that a ParA gradient can spontaneously form due to any amount of initial spatial noise in bound ParA. The speed of the bead is independent of this noise but depends on the ratio of the range of ParA-ParB force on the bead to that of removal of surface bound ParA by ParB. We find that at a particular ratio the speed attains a maximal value. We also consider ParA rebinding (including cooperativity) and ParA surface diffusion independently as mechanisms for ParA recovery on the surface. Depending on whether the DNA covered surface is undersaturated or saturated with ParA, we find that the bead can accelerate persistently or potentially stall. Our model highlights key requirements of the ParA-ParB driving force that are necessary for directed motion in the in vitro system that may provide insight into the in vivo dynamics of the ParA-ParB system. PMID:26670738

  13. 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.

  14. 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.

  15. Parallel Climate Analysis Toolkit (ParCAT)

    SciTech Connect

    Smith, Brian Edward

    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.

  16. suPAR: The Molecular Crystal Ball

    PubMed Central

    Thunø, Maria; Macho, Betina; Eugen-Olsen, Jesper

    2009-01-01

    soluble urokinase Plasminogen Activator Receptor (suPAR) levels reflect inflammation and elevated suPAR levels are found in several infectious diseases and cancer. suPAR exists in three forms; suPARI-III, suPARII-III and suPARI which show different properties due to structural differences. Studies suggest that full-length suPAR is a regulator of uPAR/uPA by acting as uPA-scavenger, whereas the cleaved suPARII-III act as a chemotactic agent promoting the immune response via the SRSRY sequence in the linker-region. This review focus on the various suPAR fragments and their involvement in inflammation and pathogenic processes. We focus on the molecular mechanisms of the suPAR fragments and the link to the inflammatory process, as this could lead to medical applications in infectious and pathological conditions. PMID:19893210

  17. 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.

  18. 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

  19. Protease-activated receptor-1 (PAR1) and PAR2 but not PAR4 mediate relaxations in lower esophageal sphincter.

    PubMed

    Huang, Shih-Che

    2007-07-01

    Protease-activated receptor-1 (PAR1), PAR2 and PAR4 activation can alter the gastrointestinal motility. To investigate effects mediated by PARs in the lower esophageal sphincter, we measured contraction or relaxation of transverse strips from the guinea-pig lower esophageal sphincter caused by PAR1 (TFLLR-NH2 and SFLLRN-NH2), PAR2 (SLIGKV-NH2 and SLIGRL-NH2) and PAR4 peptide agonists (GYPGKF-NH2, GYPGQV-NH2 and AYPGKF-NH2) as well as PAR protease activators (thrombin and trypsin). In resting lower esophageal sphincter strips, TFLLR-NH2 and SFLLRN-NH2 caused moderate concentration-dependent relaxation whereas thrombin did not cause any relaxation or contraction. Furthermore, in carbachol-contracted strips, TFLLR-NH2 and SFLLRN-NH2 caused marked whereas thrombin caused mild concentration-dependent relaxation. These indicate the existence of PAR1 mediating relaxation. Similarly, in resting lower esophageal sphincter strips, trypsin caused moderate concentration-dependent relaxation whereas SLIGRL-NH2 and SLIGKV-NH2 did not cause any relaxation or contraction. In addition, in carbachol-contracted strips, trypsin caused marked whereas SLIGRL-NH2 and SLIGKV-NH2 caused mild concentration-dependent relaxation. These indicate the existence of PAR2 mediating relaxation. The relaxant response of thrombin, TFLLR-NH2, trypsin and SLIGKV-NH2 was insensitive to atropine or tetrodotoxin, suggesting a direct effect. The relaxant response of trypsin was not affected by apamin, charybdotoxin, indomethacin and capsaicin but was attenuated by NG-nitro-L-arginine methyl ester, indicating involvement of NO. FSLLR-NH2, a PAR1 control peptide, and VKGILS-NH2, a PAR2 control peptide, as well as all three PAR4 peptide agonists, GYPGKF-NH2, GYPGQV-NH2 and AYPGKF-NH2, did not cause any relaxation or contraction. Taken together, these results demonstrate that PAR1 and PAR2 but not PAR4 mediate relaxations in the guinea-pig lower esophageal sphincter. PMID:17335921

  20. 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…

  1. 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.

  2. 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

  3. 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.

  4. Proteinase-activated receptor-1 (PAR(1)) and PAR(2) but not PAR(4) mediate contraction in human and guinea-pig gallbladders.

    PubMed

    Lee, M-C; Huang, S-C

    2008-04-01

    Proteinase-activated receptor-1 (PAR(1)) and PAR(2) mediate contraction in the guinea-pig gallbladder. To investigate and compare the effects mediated by PARs in the human gallbladder with those in the guinea-pig gallbladder, we measured contractions of isolated human and guinea-pig gallbladder strips caused by PAR agonists. Results in human were similar to those in guinea-pig gallbladder. The PAR(1) agonists, thrombin, TFLLR-NH2 and SFLLRN-NH2, as well as the PAR(2) agonists, trypsin, SLIGKV-NH2 and SLIGRL-NH2, caused contraction in both human and guinea-pig gallbladders. These indicate the existence of PAR(1) and PAR(2) mediating gallbladder contraction. Furthermore, the existence of PAR(1) and PAR(2) in the human gallbladder was confirmed by reverse transcription-polymerase chain reaction. In contrast, FSLLR-NH2, a PAR(1) control peptide, and VKGILS-NH2, a PAR(2) control peptide, as well as three PAR(4) agonists, GYPGKF-NH2, GYPGQV-NH2 and AYPGKF-NH2, did not cause any contraction or relaxation. The contractile responses to TFLLR-NH2, SFLLRN-NH2 and trypsin in both human and guinea-pig gallbladders were insensitive to atropine and tetrodotoxin, suggesting direct effects. These results demonstrate that, similar to the guinea-pig gallbladder, both PAR(1) and PAR(2) but not PAR(4) mediate muscle contraction in the human gallbladder. PAR(1) and PAR(2) may play important roles in the control of both human and guinea-pig gallbladder motility. PMID:18179608

  5. Proteinase-activated receptor-1 (PAR1) and PAR2 mediate relaxation of guinea pig internal anal sphincter.

    PubMed

    Huang, Shih-Che

    2014-02-10

    Activation of proteinase-activated receptor-1 (PAR1) and PAR2 stimulates contraction of the rat but relaxation of the guinea pig colon. The aim of the present study was to investigate PAR effects on internal anal sphincter (IAS) motility. We measured relaxation of isolated muscle strips from the guinea pig IAS caused by PAR agonists using isometric transducers. Reverse transcription polymerase chain reaction (RT-PCR) was performed to determine the existence of PAR. In the IAS, thrombin and PAR1 peptide agonists TFLLR-NH2 and SFLLRN-NH2 evoked moderate to marked relaxation in a concentration-dependent manner. In addition, trypsin and PAR2 peptide agonists 2-furoyl-LIGRLO-NH2, SLIGRL-NH2 and SLIGKV-NH2 produced relaxation. In contrast, both PAR1 and PAR2 inactive control peptides did not elicit relaxation. Furthermore, the selective PAR1 antagonist vorapaxar and PAR2 antagonist GB 83 specifically inhibited thrombin and trypsin-induced relaxations, respectively. RT-PCR revealed the presence of PAR1 and PAR2 in the IAS. This indicates that PAR1 and PAR2 mediate the IAS relaxation. The relaxant responses of TFLLR-NH2 and trypsin were attenuated by N(omega)-Nitro-L-arginine (L-NNA), indicating involvement of NO. These responses were not affected by tetrodotoxin, implying that the PAR effects are not neurally mediated. On the other hand, PAR4 agonists GYPGKF-NH2, GYPGQV-NH2 and AYPGKF-NH2 did not cause relaxation or contraction, suggesting that PAR4 is not involved in the sphincter motility. Taken together, these results demonstrate that both PAR1 and PAR2 mediate relaxation of the guinea pig IAS through the NO pathway. PAR1 and PAR2 may regulate IAS tone and might be potential therapeutic targets for anal motility disorders. PMID:24631471

  6. 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.

  7. PAR polarity: from complexity to design principles.

    PubMed

    Goehring, Nathan W

    2014-11-01

    The par-titioning-defective or PAR proteins comprise the core of an essential cell polarity network that underlies polarization in a wide variety of cell types and developmental contexts. The output of this network in nearly every case is the establishment of opposing and complementary membrane domains that define a cell׳s polarity axis. Yet, behind this simple pattern is a complex system of interactions, regulation and dynamic behaviors. How these various parts combine to generate polarized patterns of protein localization in cells is only beginning to become clear. This review, part of the Special Issue on Cell Polarity, aims to highlight several emerging themes and design principles that underlie the process of cell polarization by components of the PAR network. PMID:25128809

  8. Humanizing the Protease-Activated Receptor (PAR) Expression Profile in Mouse Platelets by Knocking PAR1 into the Par3 Locus Reveals PAR1 Expression Is Not Tolerated in Mouse Platelets

    PubMed Central

    French, Shauna L.; Paramitha, Antonia C.; Moon, Mitchell J.; Dickins, Ross A.; Hamilton, Justin R.

    2016-01-01

    Anti-platelet drugs are the mainstay of pharmacotherapy for heart attack and stroke prevention, yet improvements are continually sought. Thrombin is the most potent activator of platelets and targeting platelet thrombin receptors (protease-activated receptors; PARs) is an emerging anti-thrombotic approach. Humans express two PARs on their platelets–PAR1 and PAR4. The first PAR1 antagonist was recently approved for clinical use and PAR4 antagonists are in early clinical development. However, pre-clinical studies examining platelet PAR function are challenging because the platelets of non-primates do not accurately reflect the PAR expression profile of human platelets. Mice, for example, express Par3 and Par4. To address this limitation, we aimed to develop a genetically modified mouse that would express the same repertoire of platelet PARs as humans. Here, human PAR1 preceded by a lox-stop-lox was knocked into the mouse Par3 locus, and then expressed in a platelet-specific manner (hPAR1-KI mice). Despite correct targeting and the predicted loss of Par3 expression and function in platelets from hPAR1-KI mice, no PAR1 expression or function was detected. Specifically, PAR1 was not detected on the platelet surface nor internally by flow cytometry nor in whole cell lysates by Western blot, while a PAR1-activating peptide failed to induce platelet activation assessed by either aggregation or surface P-selectin expression. Platelets from hPAR1-KI mice did display significantly diminished responsiveness to thrombin stimulation in both assays, consistent with a Par3-/- phenotype. In contrast to the observations in hPAR1-KI mouse platelets, the PAR1 construct used here was successfully expressed in HEK293T cells. Together, these data suggest ectopic PAR1 expression is not tolerated in mouse platelets and indicate a different approach is required to develop a small animal model for the purpose of any future preclinical testing of PAR antagonists as anti-platelet drugs. PMID

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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.

  14. A combined global and local approach to elucidate spatial organization of the Mycobacterial ParB-parS partition assembly.

    PubMed

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

    2011-03-22

    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.

  15. 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.

  16. Host response biomarker in sepsis: suPAR detection.

    PubMed

    Giamarellos-Bourboulis, Evangelos J; Georgitsi, Marianna

    2015-01-01

    Recent studies of our group have shown that suPAR may complement APACHE II score for risk assessment in sepsis. suPAR may be measured in serum of patients by an enzyme immunosorbent assay developed by Virogates (suPARnostic™). Production of suPAR from circulating neutrophils and monocytes may be assessed after isolation of neutrophils and monocytes and ex vivo culture. This is followed by measurement of suPAR in culture supernatants.

  17. Proteinase-activated receptors (PARs) as targets for antiplatelet therapy.

    PubMed

    Cunningham, Margaret; McIntosh, Kathryn; Bushell, Trevor; Sloan, Graeme; Plevin, Robin

    2016-04-15

    Since the identification of the proteinase-activated receptor (PAR) family as mediators of serine protease activity in the 1990s, there has been tremendous progress in the elucidation of their pathophysiological roles. The development of drugs that target PARs has been the focus of many laboratories for the potential treatment of thrombosis, cancer and other inflammatory diseases. Understanding the mechanisms of PAR activation and G protein signalling pathways evoked in response to the growing list of endogenous proteases has yielded great insight into receptor regulation at the molecular level. This has led to the development of new selective modulators of PAR activity, particularly PAR1. The mixed success of targeting PARs has been best exemplified in the context of inhibiting PAR1 as a new antiplatelet therapy. The development of the competitive PAR1 antagonist, vorapaxar (Zontivity), has clearly shown the value in targeting PAR1 in acute coronary syndrome (ACS); however the severity of associated bleeding with this drug has limited its use in the clinic. Due to the efficacy of thrombin acting via PAR1, strategies to selectively inhibit specific PAR1-mediated G protein signalling pathways or to target the second thrombin platelet receptor, PAR4, are being devised. The rationale behind these alternative approaches is to bias downstream thrombin activity via PARs to allow for inhibition of pro-thrombotic pathways but maintain other pathways that may preserve haemostatic balance and improve bleeding profiles for widespread clinical use. This review summarizes the structural determinants that regulate PARs and the modulators of PAR activity developed to date.

  18. Les Brulures Chimiques Par Le Laurier Rose

    PubMed Central

    Bakkali, H.; Ababou, M.; Nassim Sabah, T.; Moussaoui, A.; Ennouhi, A.; Fouadi, F.Z.; Siah, S.; Ihrai, H.

    2010-01-01

    Summary Le laurier rose ou Nerium oleander est un arbuste qui pousse naturellement dans les régions méditerranéennes. Au Maroc on le trouve dans les lieux humides. Il est réputé par ses risques de toxicité systémique en cas d'empoisonnement à cause de la présence de deux alcaloïdes, surtout l'oléandrine. La littérature illustre des cas d'utilisation locale des feuilles de cette plante contre la gale, les hémorroïdes et les furoncles. Nous rapportons deux cas de brûlures chimiques par le laurier rose de gravité différente. Cela doit aboutir à une information élargie de la population, ainsi qu'une réglementation stricte de sa commercialisation. PMID:21991211

  19. Discovery of Octahydroindenes as PAR1 Antagonists

    PubMed Central

    2013-01-01

    Octahydroindene was identified as a novel scaffold for protease activated receptor 1 (PAR1) antagonists. Herein, the 2-position (C2) was explored for structure–activity relationship (SAR) studies. Compounds 14, 19, and 23b showed IC50 values of 1.3, 8.6, and 2.7 nM in a PAR1 radioligand binding assay, respectively, and their inhibitory activities on platelet activation were comparable to that of vorapaxar in a platelet rich plasma (PRP) aggregation assay. This series of compounds showed high potency and no significant cytotoxicity; however, the compounds were metabolically unstable in both human and rat liver microsomes. Current research efforts are focused on optimizing the compounds to improve metabolic stability and physicochemical properties as well as potency. PMID:24900604

  20. 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

  1. 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.

  2. 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

  3. 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.

  4. Protease-activated receptor 1 (PAR1) signalling desensitization is counteracted via PAR4 signalling in human platelets.

    PubMed

    Fälker, Knut; Haglund, Linda; Gunnarsson, Peter; Nylander, Martina; Lindahl, Tomas L; Grenegård, Magnus

    2011-06-01

    PARs (protease-activated receptors) 1 and 4 belong to the family of G-protein-coupled receptors which induce both G(α12/13) and G(αq) signalling. By applying the specific PAR1- and PAR4-activating hexapeptides, SFLLRN and AYPGKF respectively, we found that aggregation of isolated human platelets mediated via PAR1, but not via PAR4, is abolished upon homologous receptor activation in a concentration- and time-dependent fashion. This effect was not due to receptor internalization, but to a decrease in Ca²⁺ mobilization, PKC (protein kinase C) signalling and α-granule secretion, as well as to a complete lack of dense granule secretion. Interestingly, subthreshold PAR4 activation rapidly abrogated PAR1 signalling desensitization by differentially reconstituting these affected signalling events and functional responses, which was sufficient to re-establish aggregation. The lack of ADP release and P2Y₁₂ receptor-induced G(αi) signalling accounted for the loss of the aggregation response, as mimicking G(αi/z) signalling with 2-MeS-ADP (2-methylthioadenosine-5'-O-diphosphate) or epinephrine (adrenaline) could substitute for intermediate PAR4 activation. Finally, we found that the re-sensitization of PAR1 signalling-induced aggregation via PAR4 relied on PKC-mediated release of both ADP from dense granules and fibrinogen from α-granules. The present study elucidates further differences in human platelet PAR signalling regulation and provides evidence for a cross-talk in which PAR4 signalling counteracts mechanisms involved in PAR1 signalling down-regulation. PMID:21391917

  5. Apoptosis and Tumor Resistance Conferred by Par-4

    PubMed Central

    Zhao, Yanming; Rangnekar, Vivek M.

    2009-01-01

    Par-4 is a tumor suppressor protein with a pro-apoptotic function. Epigenetic silencing of Par-4 is seen in diverse tumors, and Par-4 knockout mice develop spontaneous tumors in various tissues. Endogenous Par-4 is essential for sensitization of cells to diverse apoptotic stimuli, whereas ectopic expression of Par-4 can selectively induce apoptosis in cancer cells. The cancer-specific pro-apoptotic action of Par-4 resides in its centrally located SAC domain. This chapter reviews a novel mouse model with ubiquitous expression of the SAC domain. These SAC transgenic mice display normal development and life span, and, most importantly, are resistant to spontaneous, as well as oncogene-induced, autochthonous tumors. The tumor resistant phenotype and undetectable toxicity of SAC in vivo suggests the SAC domain possesses tremendous therapeutic potential. PMID:18836307

  6. A new model for estimating boreal forest fPAR

    NASA Astrophysics Data System (ADS)

    Majasalmi, Titta; Rautiainen, Miina; Stenberg, Pauline

    2014-05-01

    Life on Earth is continuously sustained by the extraterrestrial flux of photosynthetically active radiation (PAR, 400-700 nm) from the sun. This flux is converted to biomass by chloroplasts in green vegetation. Thus, the fraction of absorbed PAR (fPAR) is a key parameter used in carbon balance studies, and is listed as one of the Essential Climate Variables (ECV). Temporal courses of fPAR for boreal forests are difficult to measure, because of the complex 3D structures. Thus, they are most often estimated based on models which quantify the dependency of absorbed radiation on canopy structure. In this study, we adapted a physically-based canopy radiation model into a fPAR model, and compared modeled and measured fPAR in structurally different boreal forest stands. The model is based on the spectral invariants theory, and uses leaf area index (LAI), canopy gap fractions and spectra of foliage and understory as input data. The model differs from previously developed more detailed fPAR models in that the complex 3D structure of coniferous forests is described using an aggregated canopy parameter - photon recollision probability p. The strength of the model is that all model inputs are measurable or available through other simple models. First, the model was validated with measurements of instantaneous fPAR obtained with the TRAC instrument in nine Scots pine, Norway spruce and Silver birch stands in a boreal forest in southern Finland. Good agreement was found between modeled and measured fPAR. Next, we applied the model to predict temporal courses of fPAR using data on incoming radiation from a nearby flux tower and sky irradiance models. Application of the model to simulate diurnal and seasonal values of fPAR indicated that the ratio of direct-to-total incident radiation and leaf area index are the key factors behind the magnitude and variation of stand-level fPAR values.

  7. 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

  8. 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

  9. Mechanism of DNA Segregation in Prokaryotes: Replicon Pairing by parC of Plasmid R1

    NASA Astrophysics Data System (ADS)

    Jensen, Rasmus Bugge; Lurz, Rudi; Gerdes, Kenn

    1998-07-01

    Prokaryotic chromosomes and plasmids encode partitioning systems that are required for DNA segregation at cell division. The systems are thought to be functionally analogous to eukaryotic centromeres and to play a general role in DNA segregation. The parA system of plasmid R1 encodes two proteins ParM and ParR, and a cis-acting centromere-like site denoted parC. The ParR protein binds to parC in vivo and in vitro. The ParM protein is an ATPase that interacts with ParR specifically bound to parC. Using electron microscopy, we show here that parC mediates efficient pairing of plasmid molecules. The pairing requires binding of ParR to parC and is stimulated by the ParM ATPase. The ParM mediated stimulation of plasmid pairing is dependent on ATP hydrolysis by ParM. Using a ligation kinetics assay, we find that ParR stimulates ligation of parC-containing DNA fragments. The rate-of-ligation was increased by wild type ParM protein but not by mutant ParM protein deficient in the ATPase activity. Thus, two independent assays show that parC mediates pairing of plasmid molecules in vitro. These results are consistent with the proposal that replicon pairing is part of the mechanism of DNA segregation in prokaryotes.

  10. 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.

  11. 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

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

    PubMed Central

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

    2015-01-01

    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

  13. 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

  14. Megestrol acetate NCD oral suspension--Par Pharmaceutical: megestrol acetate nanocrystal dispersion oral suspension, PAR 100.2, PAR-100.2.

    PubMed

    2007-01-01

    Par Pharmaceutical has developed megestrol acetate (Megace ES) oral suspension for the treatment of anorexia, cachexia and a significant weight loss associated with AIDS. Par Pharmaceutical used Elan Corporation's NanoCrystal Dispersion (NCD) technology to develop an advanced, concentrated formulation of megestrol acetate with improved bioavailability, more rapid onset of action, more convenient dosing and a lower dosing regimen compared with the original marketed formulation of megestrol acetate oral suspension. Patients are administered a teaspoon (5mL) of the new NCD formulation once daily, compared with a daily 20mL dosage cup of the original formulation. The new megestrol acetate NCD formulation represents a line-extension of Par's megestrol acetate oral suspension (800mg/20mL, Megace O/S) that has been marketed for anorexia, cachexia and AIDS-related weight loss since July 2001. Par's megestrol acetate is the generic version of Bristol-Myers Squibb's Megace Oral Suspension. NanoCrystal Dispersion (NCD) is a trademark of Elan Corporation. Par Pharmaceutical will market megestol acetate NCD oral suspension under the Megace brand name. The company licensed the Megace name from Bristol-Myers Squib in August 2003. The US FDA approved megestrol acetate oral suspension (625 mg/mL) in July 2005 for the treatment of anorexia, cachexia or a significant, unexplained weight loss in patients with AIDS. The NDA for the product was accepted for review by the agency in September 2004, following its submission in June of that year.Par Pharmaceutical commenced the first of two phase III clinical trials of megestrol acetate oral suspension (PAR 100.2) in cancer-induced anorexia in the first quarter of 2006. However, this trial was discontinued in September 2006 because of slow patient enrolment. The company intends to discuss future development options in this indication with the FDA.New formulations or dosage forms of megestrol acetate concentrated suspension are also in

  15. Megestrol acetate NCD oral suspension -- Par Pharmaceutical: megestrol acetate nanocrystal dispersion oral suspension, PAR 100.2, PAR-100.2.

    PubMed

    2007-01-01

    Par Pharmaceutical has developed megestrol acetate (Megace ES) oral suspension for the treatment of anorexia, cachexia and a significant weight loss associated with AIDS. Par Pharmaceutical used Elan Corporation's NanoCrystal Dispersion (NCD) technology to develop an advanced, concentrated formulation of megestrol acetate with improved bioavailability, more rapid onset of action, more convenient dosing and a lower dosing regimen compared with the original marketed formulation of megestrol acetate oral suspension. Patients are administered a teaspoon (5mL) of the new NCD formulation once daily, compared with a daily 20mL dosage cup of the original formulation. The new megestrol acetate NCD formulation represents a line-extension of Par's megestrol acetate oral suspension (800mg/20mL, Megace O/S) that has been marketed for anorexia, cachexia and AIDS-related weight loss since July 2001. Par's megestrol acetate is the generic version of Bristol-Myers Squibb's Megace Oral Suspension. NanoCrystal Dispersion (NCD) is a trademark of Elan Corporation. Par Pharmaceutical will market megestol acetate NCD oral suspension under the Megace brand name. The company licensed the Megace name from Bristol-Myers Squib in August 2003. The US FDA approved megestrol acetate oral suspension (625 mg/mL) in July 2005 for the treatment of anorexia, cachexia or a significant, unexplained weight loss in patients with AIDS. The NDA for the product was accepted for review by the agency in September 2004, following its submission in June of that year.Par Pharmaceutical commenced the first of two phase III clinical trials of megestrol acetate oral suspension (PAR 100.2) in cancer-induced anorexia in the first quarter of 2006. However, this trial was discontinued in September 2006 because of slow patient enrolment. The company intends to discuss future development options in this indication with the FDA.New formulations or dosage forms of megestrol acetate concentrated suspension are also in

  16. 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.

  17. Scleral Buckling for Rhegmatogenous Retinal Detachment Associated with Pars Planitis

    PubMed Central

    Ahn, Jae Kyoun

    2016-01-01

    Purpose. To evaluate the surgical outcome of scleral buckling (SB) in rhegmatogenous retinal detachment (RRD) patients associated with pars planitis. Methods. Retrospective review of RRD patients (32 eyes of pars planitis RRD and 180 eyes of primary RRD) who underwent SB. We compared primary and final anatomical success rates and visual outcomes between two groups. Results. Primary and final anatomical success were achieved in 25 (78.1%) and 31 (96.8%) eyes in the pars planitis RRD group and in 167 eyes (92.7%) and 176 eyes (97.7%) in primary RRD group, respectively. Both groups showed significant visual improvement (p < 0.001) and there were no significant differences in final visual acuity. Pars planitis RRD group was associated with higher rate of postoperative proliferative vitreoretinopathy (PVR) development (12.5% versus 2.8%, p = 0.031). Pars planitis and high myopia were significant preoperative risk factors and pseudophakia was borderline risk for primary anatomical failure after adjusting for various clinical factors. Conclusions. Pars planitis associated RRD showed inferior primary anatomical outcome after SB due to postoperative PVR development. However, final anatomical and visual outcomes were favorable. RRD cases associated with pars planitis, high myopia, and pseudophakia might benefit from different surgical approaches, such as combined vitrectomy and SB. PMID:27688907

  18. Scleral Buckling for Rhegmatogenous Retinal Detachment Associated with Pars Planitis.

    PubMed

    Kim, Yong-Kyu; Yoon, Wontae; Ahn, Jae Kyoun; Park, Sung Pyo

    2016-01-01

    Purpose. To evaluate the surgical outcome of scleral buckling (SB) in rhegmatogenous retinal detachment (RRD) patients associated with pars planitis. Methods. Retrospective review of RRD patients (32 eyes of pars planitis RRD and 180 eyes of primary RRD) who underwent SB. We compared primary and final anatomical success rates and visual outcomes between two groups. Results. Primary and final anatomical success were achieved in 25 (78.1%) and 31 (96.8%) eyes in the pars planitis RRD group and in 167 eyes (92.7%) and 176 eyes (97.7%) in primary RRD group, respectively. Both groups showed significant visual improvement (p < 0.001) and there were no significant differences in final visual acuity. Pars planitis RRD group was associated with higher rate of postoperative proliferative vitreoretinopathy (PVR) development (12.5% versus 2.8%, p = 0.031). Pars planitis and high myopia were significant preoperative risk factors and pseudophakia was borderline risk for primary anatomical failure after adjusting for various clinical factors. Conclusions. Pars planitis associated RRD showed inferior primary anatomical outcome after SB due to postoperative PVR development. However, final anatomical and visual outcomes were favorable. RRD cases associated with pars planitis, high myopia, and pseudophakia might benefit from different surgical approaches, such as combined vitrectomy and SB. PMID:27688907

  19. Scleral Buckling for Rhegmatogenous Retinal Detachment Associated with Pars Planitis

    PubMed Central

    Ahn, Jae Kyoun

    2016-01-01

    Purpose. To evaluate the surgical outcome of scleral buckling (SB) in rhegmatogenous retinal detachment (RRD) patients associated with pars planitis. Methods. Retrospective review of RRD patients (32 eyes of pars planitis RRD and 180 eyes of primary RRD) who underwent SB. We compared primary and final anatomical success rates and visual outcomes between two groups. Results. Primary and final anatomical success were achieved in 25 (78.1%) and 31 (96.8%) eyes in the pars planitis RRD group and in 167 eyes (92.7%) and 176 eyes (97.7%) in primary RRD group, respectively. Both groups showed significant visual improvement (p < 0.001) and there were no significant differences in final visual acuity. Pars planitis RRD group was associated with higher rate of postoperative proliferative vitreoretinopathy (PVR) development (12.5% versus 2.8%, p = 0.031). Pars planitis and high myopia were significant preoperative risk factors and pseudophakia was borderline risk for primary anatomical failure after adjusting for various clinical factors. Conclusions. Pars planitis associated RRD showed inferior primary anatomical outcome after SB due to postoperative PVR development. However, final anatomical and visual outcomes were favorable. RRD cases associated with pars planitis, high myopia, and pseudophakia might benefit from different surgical approaches, such as combined vitrectomy and SB.

  20. 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.

  1. Limnological database for Par Pond: 1959 to 1980

    SciTech Connect

    Tilly, L.J.

    1981-03-01

    A limnological database for Par Pond, a cooling reservoir for hot reactor effluent water at the Savannah River Plant, is described. The data are derived from a combination of research and monitoring efforts on Par Pond since 1959. The approximately 24,000-byte database provides water quality, primary productivity, and flow data from a number of different stations, depths, and times during the 22-year history of the Par Pond impoundment. The data have been organized to permit an interpretation of the effects of twenty years of cooling system operations on the structure and function of an aquatic ecosystem.

  2. 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.

  3. An electromagnetic PIC code on the MasPar

    SciTech Connect

    MacNeice, P.

    1993-12-31

    A 3D electromagnetic particle-in-cell code has been rewritten to run on the MasPar. The original code; known as TRISTAN which was written by Oscar Buneman was rewritten in MPL and its data structure altered to suit the MasPar architecture and exploit the fully local property of the algorithm. We discuss the significant issues associated with porting the code and present a comparative analysis of the code run times on the MasPar and on the CRAY YMP and C90. Results of a simulation of the interaction of the solar wind with the earth`s magnetosphere are shown.

  4. 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

  5. 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

  6. 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.

  7. 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.

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

    PubMed

    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

  9. 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

  10. Comparison of the effects of PAR1 antagonists, PAR4 antagonists, and their combinations on thrombin-induced human platelet activation.

    PubMed

    Wu, Chin-Chung; Teng, Che-Ming

    2006-09-28

    Thrombin activates human platelets through proteolytic activation of two protease-activated receptors (PARs), PAR1 and PAR4. In the present study, we show that, RWJ-56110, a potent synthetic PAR1 antagonist, inhibited platelet aggregation caused by a low concentration (0.05 U/ml) of thrombin, but lost its effectiveness when higher concentrations of thrombin were used as stimulators. YD-3, a non-peptide PAR4 antagonist, alone had little or no effect on thrombin-induced platelet aggregation, significantly enhanced the anti-aggregatory activity of PAR1 antagonist. In addition, we demonstrate for the first time that P-selectin expression in thrombin-stimulated platelets can be synergistically prevented by combined treatment of PAR1 antagonist and PAR4 antagonist. These results indicate that thrombin-induced platelet activation cannot be effectively inhibited by just blocking either single thrombin receptor pathway, and suggest a rationale for potential combination therapy in arterial thrombosis. PMID:16890935

  11. Regulation of protease-activated receptor (PAR) 1 and PAR4 signaling in human platelets by compartmentalized cyclic nucleotide actions.

    PubMed

    Bilodeau, Matthew L; Hamm, Heidi E

    2007-08-01

    Thrombin potently regulates human platelets by the G protein-coupled receptors protease-activated receptor (PAR) 1 and PAR4. Platelet activation by thrombin and other agonists is broadly inhibited by prostacyclin and nitric oxide acting through adenylyl and guanylyl cyclases to elevate cAMP and cGMP levels, respectively. Using forskolin and YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole] to selectively activate the adenylyl and guanylyl cyclases, respectively, and the membrane-permeable analogs N(6),2'-O-dibutyryladenosine-3'-5'-cAMP (dibutyryl-cAMP) and 8-(4-parachlorophenylthoi)-cGMP (8-pCPT-cGMP), we sought to identify key antiplatelet steps for cyclic nucleotide actions in blocking platelet activation by PAR1 versus PAR4. Platelet aggregation by PAR1 or PAR4 was inhibited with similar EC(50) of 1.2 to 2.1 microM forskolin, 31 to 33 microM YC-1, 57 to 150 microM dibutyryl-cAMP, and 220 to 410 microM 8-pCPT-cGMP. There was a marked left shift in the inhibitory potencies of forskolin and YC-1 for alpha-granule release and glycoprotein IIbIIIa/integrin alphaIIbbeta3 activation (i.e., EC(50) of 1-60 and 40-1300 nM, respectively) that was not observed for dibutyryl-cAMP and 8-pCPT-cGMP (i.e., EC(50) of 200-600 and 40-140 microM, respectively). This inhibition was essentially instantaneous, and measurements of cyclic nucleotide levels and kinase activities support a model of compartmentation involving the cyclic nucleotide effectors and regulators and the key molecular targets for this platelet inhibition. The different sensitivities of PAR1 and PAR4 to inhibition of calcium mobilization and dense granule release identify key antiplatelet steps for cyclic nucleotide actions and are consistent with the signaling models for these receptors. Specifically, PAR4 inhibition depends on the regulation of both calcium mobilization and dense granule release, and PAR1 inhibition depends predominantly on the regulation of dense granule release. PMID:17525299

  12. Stochastic Self-Assembly of ParB Proteins Builds the Bacterial DNA Segregation Apparatus.

    PubMed

    Sanchez, Aurore; Cattoni, Diego I; Walter, Jean-Charles; Rech, Jérôme; Parmeggiani, Andrea; Nollmann, Marcelo; Bouet, Jean-Yves

    2015-08-26

    Many canonical processes in molecular biology rely on the dynamic assembly of higher-order nucleoprotein complexes. In bacteria, the assembly mechanism of ParABS, the nucleoprotein super-complex that actively segregates the bacterial chromosome and many plasmids, remains elusive. We combined super-resolution microscopy, quantitative genome-wide surveys, biochemistry, and mathematical modeling to investigate the assembly of ParB at the centromere-like sequences parS. We found that nearly all ParB molecules are actively confined around parS by a network of synergistic protein-protein and protein-DNA interactions. Interrogation of the empirically determined, high-resolution ParB genomic distribution with modeling suggests that instead of binding only to specific sequences and subsequently spreading, ParB binds stochastically around parS over long distances. We propose a new model for the formation of the ParABS partition complex based on nucleation and caging: ParB forms a dynamic lattice with the DNA around parS. This assembly model and approach to characterizing large-scale, dynamic interactions between macromolecules may be generalizable to many unrelated machineries that self-assemble in superstructures. PMID:27135801

  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. 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.

  17. 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…

  18. 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

  19. 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.

  20. 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).

  1. Competing ParA structures space bacterial plasmids equally over the nucleoid.

    PubMed

    Ietswaart, Robert; Szardenings, Florian; Gerdes, Kenn; Howard, Martin

    2014-12-01

    Low copy number plasmids in bacteria require segregation for stable inheritance through cell division. This is often achieved by a parABC locus, comprising an ATPase ParA, DNA-binding protein ParB and a parC region, encoding ParB-binding sites. These minimal components space plasmids equally over the nucleoid, yet the underlying mechanism is not understood. Here we investigate a model where ParA-ATP can dynamically associate to the nucleoid and is hydrolyzed by plasmid-associated ParB, thereby creating nucleoid-bound, self-organizing ParA concentration gradients. We show mathematically that differences between competing ParA concentrations on either side of a plasmid can specify regular plasmid positioning. Such positioning can be achieved regardless of the exact mechanism of plasmid movement, including plasmid diffusion with ParA-mediated immobilization or directed plasmid motion induced by ParB/parC-stimulated ParA structure disassembly. However, we find experimentally that parABC from Escherichia coli plasmid pB171 increases plasmid mobility, inconsistent with diffusion/immobilization. Instead our observations favor directed plasmid motion. Our model predicts less oscillatory ParA dynamics than previously believed, a prediction we verify experimentally. We also show that ParA localization and plasmid positioning depend on the underlying nucleoid morphology, indicating that the chromosomal architecture constrains ParA structure formation. Our directed motion model unifies previously contradictory models for plasmid segregation and provides a robust mechanistic basis for self-organized plasmid spacing that may be widely applicable.

  2. ParA-mediated plasmid partition driven by protein pattern self-organization

    PubMed Central

    Hwang, Ling Chin; Vecchiarelli, Anthony G; Han, Yong-Woon; Mizuuchi, Michiyo; Harada, Yoshie; Funnell, Barbara E; Mizuuchi, Kiyoshi

    2013-01-01

    DNA segregation ensures the stable inheritance of genetic material prior to cell division. Many bacterial chromosomes and low-copy plasmids, such as the plasmids P1 and F, employ a three-component system to partition replicated genomes: a partition site on the DNA target, typically called parS, a partition site binding protein, typically called ParB, and a Walker-type ATPase, typically called ParA, which also binds non-specific DNA. In vivo, the ParA family of ATPases forms dynamic patterns over the nucleoid, but how ATP-driven patterning is involved in partition is unknown. We reconstituted and visualized ParA-mediated plasmid partition inside a DNA-carpeted flowcell, which acts as an artificial nucleoid. ParA and ParB transiently bridged plasmid to the DNA carpet. ParB-stimulated ATP hydrolysis by ParA resulted in ParA disassembly from the bridging complex and from the surrounding DNA carpet, which led to plasmid detachment. Our results support a diffusion-ratchet model, where ParB on the plasmid chases and redistributes the ParA gradient on the nucleoid, which in turn mobilizes the plasmid. PMID:23443047

  3. 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

  4. 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

  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. 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…

  8. 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...

  9. 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

  10. Alternative 3' UTR selection controls PAR-5 homeostasis and cell polarity in C. elegans embryos.

    PubMed

    Mikl, Martin; Cowan, Carrie R

    2014-09-11

    Cell polarity in one-cell C. elegans embryos guides asymmetric cell division and cell-fate specification. Shortly after fertilization, embryos establish two antagonistic cortical domains of PAR proteins. Here, we find that the conserved polarity factor PAR-5 regulates PAR domain size in a dose-dependent manner. Using quantitative imaging and controlled genetic manipulation, we find that PAR-5 protein levels reflect the cumulative output of three mRNA isoforms with different translational efficiencies mediated by their 3' UTRs. 3' UTR selection is regulated, influencing PAR-5 protein abundance. Alternative splicing underlies the selection of par-5 3' UTR isoforms. 3' UTR splicing is enhanced by the SR protein kinase SPK-1, and accordingly, SPK-1 is required for wild-type PAR-5 levels and PAR domain size. Precise regulation of par-5 isoform selection is essential for polarization when the posterior PAR network is compromised. Together, strict control of PAR-5 protein levels and feedback from polarity to par-5 3' UTR selection confer robustness to embryo polarization. PMID:25199833

  11. Biased signalling and proteinase-activated receptors (PARs): targeting inflammatory disease.

    PubMed

    Hollenberg, M D; Mihara, K; Polley, D; Suen, J Y; Han, A; Fairlie, D P; Ramachandran, R

    2014-03-01

    Although it has been known since the 1960s that trypsin and chymotrypsin can mimic hormone action in tissues, it took until the 1990s to discover that serine proteinases can regulate cells by cleaving and activating a unique four-member family of GPCRs known as proteinase-activated receptors (PARs). PAR activation involves the proteolytic exposure of its N-terminal receptor sequence that folds back to function as a 'tethered' receptor-activating ligand (TL). A key N-terminal arginine in each of PARs 1 to 4 has been singled out as a target for cleavage by thrombin (PARs 1, 3 and 4), trypsin (PARs 2 and 4) or other proteases to unmask the TL that activates signalling via Gq , Gi or G12 /13 . Similarly, synthetic receptor-activating peptides, corresponding to the exposed 'TL sequences' (e.g. SFLLRN-, for PAR1 or SLIGRL- for PAR2) can, like proteinase activation, also drive signalling via Gq , Gi and G12 /13 , without requiring receptor cleavage. Recent data show, however, that distinct proteinase-revealed 'non-canonical' PAR tethered-ligand sequences and PAR-activating agonist and antagonist peptide analogues can induce 'biased' PAR signalling, for example, via G12 /13 -MAPKinase instead of Gq -calcium. This overview summarizes implications of this 'biased' signalling by PAR agonists and antagonists for the recognized roles the PARs play in inflammatory settings. PMID:24354792

  12. Independent Confirmation of the MODIS LAI/fPAR Algorithm

    NASA Astrophysics Data System (ADS)

    Ganapol, B. D.; Dungan, J. L.

    2001-12-01

    The Leaf Canopy Model (LCM)-2 is a nested model that combines leaf radiative transfer with a full canopy reflectance model through the phase function (Ganapol et al. 1999). The basic components of the model include inversion for a leaf scattering coefficient, construction of a representative absorption coefficient and the determination of canopy reflectance given leaf area index (LAI) values and information on canopy type and structure. It can also be used to calculate the fraction of absorbed photosynthetically active radiation (fPAR) for the canopy. It therefore serves as an independent means of confirming the results of the MOD15 algorithm (Knyazikhin et al. 1998) that produces LAI and fPAR fields from reflectance measured by the Moderate Resolution Imaging Spectrometer (MODIS). In LCM2, relatively simple first principles of radiative transfer are used whereas in the MOD15 algorithm, scene variability is accounted for by specifying distributions and a response surface in a table-lookup procedure. The distributions are generated by various radiative transfer models with a host of underlying assumptions. The attempt to compare results from these two models is a useful means of addressing the structural uncertainty in the Earth Observing System prediction problem. We compared LCM2 results with those from the MOD15 algorithm for fPAR calculation. 100 pixels for an EOS Core Validation Site where there were coincident reflectance, vegetation index, fPAR and LAI products were chosen. The 8-day 500 m reflectance product was spatially degraded to coincide with 8-day 1 km LAI and fPAR products and LAI and land cover products were used to parameterize LCM2. Most fPAR results agreed to within 10 percent, though a bias was observed. Poor agreement was seen with vegetation index products. Ganapol, B.D., L.F. Johnson, C.A. Hlavka, D.L. Peterson, and B. Bond, LCM2: A coupled leaf/canopy radiative transfer model, Remote Sensing of Environment, 70:153-166, 1999. Knyazikhin, Y., J

  13. 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

  14. Cross ambiguity functions on the MasPar MP-2

    SciTech Connect

    Carlson, D.A.; Pryor, D.V.; Frock, C.K.

    1995-12-01

    In a signal processing environment, cross ambiguity functions are often used to detect when one signal is a time and/or frequency shift of another. They consist of multiple cross-correlations, which can be computed efficiently using complex valued FFTs. This paper discusses the implementation of cross ambiguity functions on the MasPar MP-2, a SIMD processor array. Two different implementations are developed. The first computes each cross ambiguity function serially, using FFT code that parallelizes across the complete set of processors. The second uses the MasPar IORAM to realign the data so that the cross ambiguity functions can be computed in parallel. In this case, multiple FFTs are executed in parallel on subsets of the processors, which lowers the overall amount of communication required.

  15. Design, construction, and wire calibration of PAR BPM striplines

    NASA Astrophysics Data System (ADS)

    Sellyey, W.; Barr, D.; Erwin, L.

    1995-05-01

    The Positron Accumulator Ring (PAR) is part of the APS injection system. It received 24 30-ns FWHM bursts of 450-meV positrons, and compresses them into 6-nC, 290-ps rms bunches. Striplines were selected as beam position monitors (BPMs) to assure that good position sensitivity is achieved. This paper will describe the design, construction, and wire calibration of the 16 PAR BPMs. It will be demonstrated that all relevant stripline parameters can be determined by solving the two-dimensional LaPlace equation. This was done numerically using the electrostatic part of the PE2D computer program. The construction of the units will be briefly discussed. Wire calibration data on one of the final units will be compared with theory at four frequencies.

  16. Macroinvertebrates of Par Pond and Pond B: Final report, January 1984-June 1985

    SciTech Connect

    Kondratieff, B.C.; Chimney, M.J.; Painter, W.B.

    1985-08-01

    This document reports on the Par Pond and Pond B macroinvertebrate sampling program from January 1984 through June 1985. It includes data on quantitative and qualitative benthic sampling, quantitative meroplankton sampling and quarterly diel sample. The basic objectives were to: (1) characterize the benthic and meroplankton macroinvertebrate communities of Par Pond and Pond B, with respect to taxonomic composition and diversity, density and relative abundance of functional feeding groups; (2) assess the impact of thermal discharges on the macroinvertebrate community of Par Pond; (3) assess the impact and significance of entrainment losses of macroinvertebrate meroplankton from Par Pond; and (4) compare Par Pond macroninvertebrate communities with those in Pond B.

  17. 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

  18. 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

  19. 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.

  20. Proteinase-Activated Receptor 1 (PAR1) Regulates Leukemic Stem Cell Functions

    PubMed Central

    Bäumer, Nicole; Krause, Annika; Köhler, Gabriele; Lettermann, Stephanie; Evers, Georg; Hascher, Antje; Bäumer, Sebastian; Berdel, Wolfgang E.

    2014-01-01

    External signals that are mediated by specific receptors determine stem cell fate. The thrombin receptor PAR1 plays an important role in haemostasis, thrombosis and vascular biology, but also in tumor biology and angiogenesis. Its expression and function in hematopoietic stem cells is largely unknown. Here, we analyzed expression and function of PAR1 in primary hematopoietic cells and their leukemic counterparts. AML patients' blast cells expressed much lower levels of PAR1 mRNA and protein than CD34+ progenitor cells. Constitutive Par1-deficiency in adult mice did not affect engraftment or stem cell potential of hematopoietic cells. To model an AML with Par1-deficiency, we retrovirally introduced the oncogene MLL-AF9 in wild type and Par1−/− hematopoietic progenitor cells. Par1-deficiency did not alter initial leukemia development. However, the loss of Par1 enhanced leukemic stem cell function in vitro and in vivo. Re-expression of PAR1 in Par1−/− leukemic stem cells delayed leukemogenesis in vivo. These data indicate that Par1 contributes to leukemic stem cell maintenance. PMID:24740120

  1. 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

  2. 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

  3. The physical association of the P2Y12 receptor with PAR4 regulates arrestin-mediated Akt activation.

    PubMed

    Khan, Aasma; Li, Dongjun; Ibrahim, Salam; Smyth, Emer; Woulfe, Donna S

    2014-07-01

    It is now well accepted that protease activated receptor (PAR) 1 and PAR4 have differential roles in platelet activation. PAR4, a low-affinity thrombin receptor in human platelets, participates in sustained platelet activation in a P2Y12-dependent manner; however, the mechanisms are not defined. Our previous studies demonstrated that thrombin induces the association of PAR4 with P2Y12, together with arrestin recruitment to the complex. Here we show that PAR4 and P2Y12 directly interact to coregulate Akt signaling after PAR4 activation. We observed direct and specific interaction of P2Y12 with PAR4 but not PAR1 by bioluminescent resonance energy transfer when the receptors were coexpressed in human embryonic kidney 293T cells. PAR4-P2Y12 dimerization was promoted by PAR4-AP and inhibited by P2Y12 antagonist. By using sequence comparison of the transmembrane domains of PAR1 and PAR4, we designed a mutant form of PAR4, "PAR4SFT," by replacing LGL194-196 at the base of transmembrane domain 4 with the corresponding aligned PAR1 residues SFT 220-222. PAR4SFT supported only 8.74% of PAR4-P2Y12 interaction, abolishing P2Y12-dependent arrestin recruitment to PAR4 and Akt activation. Nonetheless, PAR4SFT still supported homodimerization with PAR4. PAR4SFT failed to induce a calcium flux when expressed independently; however, coexpression of increasing concentrations of PAR4SFT, together with PAR4 potentiated PAR4-mediated calcium flux, suggested that PAR4 act as homodimers to signal to Gq-coupled calcium responses. In conclusion, PAR4 LGL (194-196) governs agonist-dependent association of PAR4 with P2Y12 and contributes to Gq-coupled calcium responses. PAR4-P2Y12 association supports arrestin-mediated sustained signaling to Akt. Hence, PAR4-P2Y12 dimerization is likely to be important for the PAR4-P2Y12 dependent stabilization of platelet thrombi.

  4. The physical association of the P2Y12 receptor with PAR4 regulates arrestin-mediated Akt activation.

    PubMed

    Khan, Aasma; Li, Dongjun; Ibrahim, Salam; Smyth, Emer; Woulfe, Donna S

    2014-07-01

    It is now well accepted that protease activated receptor (PAR) 1 and PAR4 have differential roles in platelet activation. PAR4, a low-affinity thrombin receptor in human platelets, participates in sustained platelet activation in a P2Y12-dependent manner; however, the mechanisms are not defined. Our previous studies demonstrated that thrombin induces the association of PAR4 with P2Y12, together with arrestin recruitment to the complex. Here we show that PAR4 and P2Y12 directly interact to coregulate Akt signaling after PAR4 activation. We observed direct and specific interaction of P2Y12 with PAR4 but not PAR1 by bioluminescent resonance energy transfer when the receptors were coexpressed in human embryonic kidney 293T cells. PAR4-P2Y12 dimerization was promoted by PAR4-AP and inhibited by P2Y12 antagonist. By using sequence comparison of the transmembrane domains of PAR1 and PAR4, we designed a mutant form of PAR4, "PAR4SFT," by replacing LGL194-196 at the base of transmembrane domain 4 with the corresponding aligned PAR1 residues SFT 220-222. PAR4SFT supported only 8.74% of PAR4-P2Y12 interaction, abolishing P2Y12-dependent arrestin recruitment to PAR4 and Akt activation. Nonetheless, PAR4SFT still supported homodimerization with PAR4. PAR4SFT failed to induce a calcium flux when expressed independently; however, coexpression of increasing concentrations of PAR4SFT, together with PAR4 potentiated PAR4-mediated calcium flux, suggested that PAR4 act as homodimers to signal to Gq-coupled calcium responses. In conclusion, PAR4 LGL (194-196) governs agonist-dependent association of PAR4 with P2Y12 and contributes to Gq-coupled calcium responses. PAR4-P2Y12 association supports arrestin-mediated sustained signaling to Akt. Hence, PAR4-P2Y12 dimerization is likely to be important for the PAR4-P2Y12 dependent stabilization of platelet thrombi. PMID:24723492

  5. Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6.

    PubMed

    Hidalgo-Carcedo, Cristina; Hooper, Steven; Chaudhry, Shahid I; Williamson, Peter; Harrington, Kevin; Leitinger, Birgit; Sahai, Erik

    2011-01-01

    Collective cell migration occurs in a range of contexts: cancer cells frequently invade in cohorts while retaining cell-cell junctions. Here we show that collective invasion by cancer cells depends on decreasing actomyosin contractility at sites of cell-cell contact. When actomyosin is not downregulated at cell-cell contacts, migrating cells lose cohesion. We provide a molecular mechanism for this downregulation. Depletion of discoidin domain receptor 1 (DDR1) blocks collective cancer-cell invasion in a range of two-dimensional, three-dimensional and 'organotypic' models. DDR1 coordinates the Par3/Par6 cell-polarity complex through its carboxy terminus, binding PDZ domains in Par3 and Par6. The DDR1-Par3/Par6 complex controls the localization of RhoE to cell-cell contacts, where it antagonizes ROCK-driven actomyosin contractility. Depletion of DDR1, Par3, Par6 or RhoE leads to increased actomyosin contactility at cell-cell contacts, a loss of cell-cell cohesion and defective collective cell invasion.

  6. ParABS Systems of the Four Replicons of Burkholderia cenocepacia: New Chromosome Centromeres Confer Partition Specificity†

    PubMed Central

    Dubarry, Nelly; Pasta, Franck; Lane, David

    2006-01-01

    Most bacterial chromosomes carry an analogue of the parABS systems that govern plasmid partition, but their role in chromosome partition is ambiguous. parABS systems might be particularly important for orderly segregation of multipartite genomes, where their role may thus be easier to evaluate. We have characterized parABS systems in Burkholderia cenocepacia, whose genome comprises three chromosomes and one low-copy-number plasmid. A single parAB locus and a set of ParB-binding (parS) centromere sites are located near the origin of each replicon. ParA and ParB of the longest chromosome are phylogenetically similar to analogues in other multichromosome and monochromosome bacteria but are distinct from those of smaller chromosomes. The latter form subgroups that correspond to the taxa of their hosts, indicating evolution from plasmids. The parS sites on the smaller chromosomes and the plasmid are similar to the “universal” parS of the main chromosome but with a sequence specific to their replicon. In an Escherichia coli plasmid stabilization test, each parAB exhibits partition activity only with the parS of its own replicon. Hence, parABS function is based on the independent partition of individual chromosomes rather than on a single communal system or network of interacting systems. Stabilization by the smaller chromosome and plasmid systems was enhanced by mutation of parS sites and a promoter internal to their parAB operons, suggesting autoregulatory mechanisms. The small chromosome ParBs were found to silence transcription, a property relevant to autoregulation. PMID:16452432

  7. Transcriptional Profiling of ParA and ParB Mutants in Actively Dividing Cells of an Opportunistic Human Pathogen Pseudomonas aeruginosa

    PubMed Central

    Bartosik, Aneta A.; Glabski, Krzysztof; Jecz, Paulina; Mikulska, Sylwia; Fogtman, Anna; Koblowska, Marta; Jagura-Burdzy, Grazyna

    2014-01-01

    Accurate chromosome segregation to progeny cells is a fundamental process ensuring proper inheritance of genetic material. In bacteria with simple cell cycle, chromosome segregation follows replication initiation since duplicated oriC domains start segregating to opposite halves of the cell soon after they are made. ParA and ParB proteins together with specific DNA sequences are parts of the segregation machinery. ParA and ParB proteins in Pseudomonas aeruginosa are important for optimal growth, nucleoid segregation, cell division and motility. Comparative transcriptome analysis of parAnull and parBnull mutants versus parental P. aeruginosa PAO1161 strain demonstrated global changes in gene expression pattern in logarithmically growing planktonic cultures. The set of genes similarly affected in both mutant strains is designated Par regulon and comprises 536 genes. The Par regulon includes genes controlled by two sigma factors (RpoN and PvdS) as well as known and putative transcriptional regulators. In the absence of Par proteins, a large number of genes from RpoS regulon is induced, reflecting the need for slowing down the cell growth rate and decelerating the metabolic processes. Changes in the expression profiles of genes involved in c-di-GMP turnover point out the role of this effector in such signal transmission. Microarray data for chosen genes were confirmed by RT-qPCR analysis. The promoter regions of selected genes were cloned upstream of the promoter-less lacZ gene and analyzed in the heterologous host E. coliΔlac. Regulation by ParA and ParB of P. aeruginosa was confirmed for some of the tested promoters. Our data demonstrate that ParA and ParB besides their role in accurate chromosome segregation may act as modulators of genes expression. Directly or indirectly, Par proteins are part of the wider regulatory network in P. aeruginosa linking the process of chromosome segregation with the cell growth, division and motility. PMID:24498062

  8. 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…

  9. A model for the condensation of the bacterial chromosome by the partitioning protein ParB

    NASA Astrophysics Data System (ADS)

    Broedersz, Chase; Wingreen, Ned

    2013-03-01

    The molecular machinery responsible for faithful segregation of the chromosome in bacteria such as Caulobacter crescentus and Bacillus subtilis includes the ParABS a.k.a. Spo0J/Soj partitioning system. In Caulobacter, prior to division, hundreds of ParB proteins bind to the DNA near the origin of replication, and localize to one pole of the cell. Subsequently, the ParB-DNA complex is translocated to the far pole by the binding and retraction of the ParA spindle-like apparatus. Remarkably, the localization of ParB proteins to specific regions of the chromosome appears to be controlled by only a few centromeric parS binding sites. Although lateral interactions between DNA-bound ParB are likely to be important for their localization, the long-range order of ParB domains on the chromosome appears to be inconsistent with a picture in which protein-protein interactions are limited to neighboring DNA-bound proteins. We developed a coarse-grained Brownian dynamics model that allows for lateral and 3D protein-protein interactions among bound ParB proteins. Our model shows how such interactions can condense and organize the DNA spatially, and can control the localization and the long-range order of the DNA-bound proteins.

  10. 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

  11. Serum suPAR in patients with FSGS: trash or treasure?

    PubMed

    Maas, Rutger J H; Deegens, Jeroen K J; Wetzels, Jack F M

    2013-07-01

    The urokinase-type plasminogen activator receptor (uPAR) has important functions in cell migration. uPAR can be shed from the cell membrane resulting in soluble uPAR (suPAR). Further cleavage gives rise to shorter fragments with largely unknown functions. Recent studies have demonstrated that both overexpression of uPAR on podocytes and the administration of suPAR cause proteinuria in mice. The common pathogenic mechanism involves the activation of podocyte β3-integrin. Increased activation of β3-integrin is also observed in patients with focal and segmental glomerulosclerosis (FSGS). These observations form the basis for the hypothesis that suPAR may be the circulating factor causing FSGS. A recent study fosters this idea by demonstrating increased suPAR levels in the serum of patients with FSGS and reporting an association with recurrence after transplantation and response to plasmapheresis. However, this study was heavily biased, and subsequent studies have given conflicting results. Although the experimental work is very suggestive, at present there is no proof that any known human suPAR fragment causes FSGS in humans. We therefore suggest that the measurement of suPAR using currently available assays has absolutely no value at the present time in decision-making in routine clinical practice.

  12. Décontamination nucléaire par laser UV

    NASA Astrophysics Data System (ADS)

    Delaporte, Ph.; Gastaud, M.; Marine, W.; Sentis, M.; Uteza, O.; Thouvenot, P.; Alcaraz, J. L.; Le Samedy, J. M.; Blin, D.

    2003-06-01

    Le développement et l'utilisation de procédés propres pour le nettoyage ou la préparation de surfaces est l'une des priorités du milieu industriel. Cet intérêt est d'autant plus grand dans le domaine du nucléaire pour lequel la réduction des déchets est un axe de recherche important. Un dispositif de décontamination nucléaire par laser UV impulsionnel a été développé et testé. Il est composé. d'un laser à excimères de 1kW, d'un faisceau de fibres optiques et d'un dispositif de récupération des particules. Les essais réalisés en milieu actif ont démontré sa capacité à nettoyer des surfaces métalliques polluées par différents radioéléments avec des facteurs de décontamination généralement supérieurs à 10. Ce dispositif permet de décontaminer de grandes surfaces de géométrie simple en réduisant fortement la génération de déchets secondaires. Il est, à ce jour et dans ces conditions d'utilisations, le procédé de décontamination par voie sèche le plus efficace.

  13. Inflammation and Macular Oedema after Pars Plana Vitrectomy

    PubMed Central

    Romano, Vito; Angi, Martina; del Grosso, Renata; Romano, Davide; Vinciguerra, Paolo; Romano, Mario R.

    2013-01-01

    Cystoid macular oedema (CMO) is a major cause of reduced vision following intraocular surgery. Although the aetiology of CMO is not completely clarified, intraocular inflammation is known to play a major role in its development. The macula may develop cytotoxic oedema when the primary lesion and fluid accumulation occur in the parenchymatous cells (intracellular oedema) or vasogenic oedema when the primary defect occurs in the blood-retinal barrier and leads to extracellular fluid accumulation (extracellular oedema). We report on the mechanisms of CMO formation after pars plana vitrectomy and associated surgical procedures and discuss possible therapeutic approaches. PMID:24288446

  14. David Kasner, MD, and the Road to Pars Plana Vitrectomy.

    PubMed

    Blodi, Christopher F

    2016-01-01

    David Kasner, MD (1927-2001), used his extensive dissections of eye bank eyes and experiences in teaching cataract surgery to resident physicians to realize that excision of vitreous when present in the anterior chamber of eyes undergoing cataract surgery was preferable to prior intraoperative procedures. Noting that eyes tolerated his maneuvers, he then performed planned subtotal open-sky vitrectomies; first on a traumatized eye in 1961, then on two eyes of patients with amyloidosis (1966-1967). The success of these operations was noted by others, most particularly Robert Machemer, MD. Kasner's work directly led to further surgical developments, including closed pars plana vitrectomy. PMID:27660504

  15. 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).

  16. David Kasner, MD, and the Road to Pars Plana Vitrectomy

    PubMed Central

    Blodi, Christopher F.

    2016-01-01

    David Kasner, MD (1927–2001), used his extensive dissections of eye bank eyes and experiences in teaching cataract surgery to resident physicians to realize that excision of vitreous when present in the anterior chamber of eyes undergoing cataract surgery was preferable to prior intraoperative procedures. Noting that eyes tolerated his maneuvers, he then performed planned subtotal open-sky vitrectomies; first on a traumatized eye in 1961, then on two eyes of patients with amyloidosis (1966–1967). The success of these operations was noted by others, most particularly Robert Machemer, MD. Kasner’s work directly led to further surgical developments, including closed pars plana vitrectomy. PMID:27660504

  17. David Kasner, MD, and the Road to Pars Plana Vitrectomy

    PubMed Central

    Blodi, Christopher F.

    2016-01-01

    David Kasner, MD (1927–2001), used his extensive dissections of eye bank eyes and experiences in teaching cataract surgery to resident physicians to realize that excision of vitreous when present in the anterior chamber of eyes undergoing cataract surgery was preferable to prior intraoperative procedures. Noting that eyes tolerated his maneuvers, he then performed planned subtotal open-sky vitrectomies; first on a traumatized eye in 1961, then on two eyes of patients with amyloidosis (1966–1967). The success of these operations was noted by others, most particularly Robert Machemer, MD. Kasner’s work directly led to further surgical developments, including closed pars plana vitrectomy.

  18. Platelet Specific Promoters Are Insufficient to Express Protease Activated Receptor 1 (PAR1) Transgene in Mouse Platelets

    PubMed Central

    Arachiche, Amal; de la Fuente, María; Nieman, Marvin T.

    2014-01-01

    The in vivo study of protease activated receptors (PARs) in platelets is complicated due to species specific expression profiles. Human platelets express PAR1 and PAR4 whereas mouse platelets express PAR3 and PAR4. Further, PAR subtypes interact with one another to influence activation and signaling. The goal of the current study was to generate mice expressing PAR1 on their platelets using transgenic approaches to mimic PAR expression found in human platelets. This system would allow us to examine specific signaling from PAR1 and the PAR1-PAR4 heterodimer in vivo. Our first approach used the mouse GPIbα promoter to drive expression of mouse PAR1 in platelets (GPIbα-Tg-mPAR1). We obtained the expected frequency of founders carrying the transgene and had the expected Mendelian distribution of the transgene in multiple founders. However, we did not observe expression or a functional response of PAR1. As a second approach, we targeted human PAR1 with the same promoter (GPIbα-Tg-hPAR1). Once again we observed the expected frequency and distributing of the transgene. Human PAR1 expression was detected in platelets from the GPIbα-Tg-hPAR1 mice by flow cytometry, however, at a lower level than for human platelets. Despite a low level of PAR1 expression, platelets from the GPIbα-Tg-hPAR1 mice did not respond to the PAR1 agonist peptide (SFLLRN). In addition, they did not respond to thrombin when crossed to the PAR4−/− mice. Finally, we used an alternative platelet specific promoter, human αIIb, to express human PAR1 (αIIb-Tg-hPAR1). Similar to our previous attempts, we obtained the expected number of founders but did not detect PAR1 expression or response in platelets from αIIb-Tg-hPAR1 mice. Although unsuccessful, the experiments described in this report provide a resource for future efforts in generating mice expressing PAR1 on their platelets. We provide an experimental framework and offer considerations that will save time and research funds. PMID:24830314

  19. Platelet specific promoters are insufficient to express protease activated receptor 1 (PAR1) transgene in mouse platelets.

    PubMed

    Arachiche, Amal; de la Fuente, María; Nieman, Marvin T

    2014-01-01

    The in vivo study of protease activated receptors (PARs) in platelets is complicated due to species specific expression profiles. Human platelets express PAR1 and PAR4 whereas mouse platelets express PAR3 and PAR4. Further, PAR subtypes interact with one another to influence activation and signaling. The goal of the current study was to generate mice expressing PAR1 on their platelets using transgenic approaches to mimic PAR expression found in human platelets. This system would allow us to examine specific signaling from PAR1 and the PAR1-PAR4 heterodimer in vivo. Our first approach used the mouse GPIbα promoter to drive expression of mouse PAR1 in platelets (GPIbα-Tg-mPAR1). We obtained the expected frequency of founders carrying the transgene and had the expected Mendelian distribution of the transgene in multiple founders. However, we did not observe expression or a functional response of PAR1. As a second approach, we targeted human PAR1 with the same promoter (GPIbα-Tg-hPAR1). Once again we observed the expected frequency and distributing of the transgene. Human PAR1 expression was detected in platelets from the GPIbα-Tg-hPAR1 mice by flow cytometry, however, at a lower level than for human platelets. Despite a low level of PAR1 expression, platelets from the GPIbα-Tg-hPAR1 mice did not respond to the PAR1 agonist peptide (SFLLRN). In addition, they did not respond to thrombin when crossed to the PAR4-/- mice. Finally, we used an alternative platelet specific promoter, human αIIb, to express human PAR1 (αIIb-Tg-hPAR1). Similar to our previous attempts, we obtained the expected number of founders but did not detect PAR1 expression or response in platelets from αIIb-Tg-hPAR1 mice. Although unsuccessful, the experiments described in this report provide a resource for future efforts in generating mice expressing PAR1 on their platelets. We provide an experimental framework and offer considerations that will save time and research funds. PMID:24830314

  20. 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.

  1. The PARA-suite: PAR-CLIP specific sequence read simulation and processing

    PubMed Central

    Kloetgen, Andreas; Borkhardt, Arndt; Hoell, Jessica I.

    2016-01-01

    Background Next-generation sequencing technologies have profoundly impacted biology over recent years. Experimental protocols, such as photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation (PAR-CLIP), which identifies protein–RNA interactions on a genome-wide scale, commonly employ deep sequencing. With PAR-CLIP, the incorporation of photoactivatable nucleosides into nascent transcripts leads to high rates of specific nucleotide conversions during reverse transcription. So far, the specific properties of PAR-CLIP-derived sequencing reads have not been assessed in depth. Methods We here compared PAR-CLIP sequencing reads to regular transcriptome sequencing reads (RNA-Seq) to identify distinctive properties that are relevant for reference-based read alignment of PAR-CLIP datasets. We developed a set of freely available tools for PAR-CLIP data analysis, called the PAR-CLIP analyzer suite (PARA-suite). The PARA-suite includes error model inference, PAR-CLIP read simulation based on PAR-CLIP specific properties, a full read alignment pipeline with a modified Burrows–Wheeler Aligner algorithm and CLIP read clustering for binding site detection. Results We show that differences in the error profiles of PAR-CLIP reads relative to regular transcriptome sequencing reads (RNA-Seq) make a distinct processing advantageous. We examine the alignment accuracy of commonly applied read aligners on 10 simulated PAR-CLIP datasets using different parameter settings and identified the most accurate setup among those read aligners. We demonstrate the performance of the PARA-suite in conjunction with different binding site detection algorithms on several real PAR-CLIP and HITS-CLIP datasets. Our processing pipeline allowed the improvement of both alignment and binding site detection accuracy. Availability The PARA-suite toolkit and the PARA-suite aligner are available at https://github.com/akloetgen/PARA-suite and https

  2. Biased signalling and proteinase-activated receptors (PARs): targeting inflammatory disease

    PubMed Central

    Hollenberg, M D; Mihara, K; Polley, D; Suen, J Y; Han, A; Fairlie, D P; Ramachandran, R

    2014-01-01

    Although it has been known since the 1960s that trypsin and chymotrypsin can mimic hormone action in tissues, it took until the 1990s to discover that serine proteinases can regulate cells by cleaving and activating a unique four-member family of GPCRs known as proteinase-activated receptors (PARs). PAR activation involves the proteolytic exposure of its N-terminal receptor sequence that folds back to function as a ‘tethered’ receptor-activating ligand (TL). A key N-terminal arginine in each of PARs 1 to 4 has been singled out as a target for cleavage by thrombin (PARs 1, 3 and 4), trypsin (PARs 2 and 4) or other proteases to unmask the TL that activates signalling via Gq, Gi or G12/13. Similarly, synthetic receptor-activating peptides, corresponding to the exposed ‘TL sequences’ (e.g. SFLLRN—, for PAR1 or SLIGRL— for PAR2) can, like proteinase activation, also drive signalling via Gq, Gi and G12/13, without requiring receptor cleavage. Recent data show, however, that distinct proteinase-revealed ‘non-canonical’ PAR tethered-ligand sequences and PAR-activating agonist and antagonist peptide analogues can induce ‘biased’ PAR signalling, for example, via G12/13-MAPKinase instead of Gq-calcium. This overview summarizes implications of this ‘biased’ signalling by PAR agonists and antagonists for the recognized roles the PARs play in inflammatory settings. Linked ArticlesThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-5 PMID:24354792

  3. PhyloPars: estimation of missing parameter values using phylogeny.

    PubMed

    Bruggeman, Jorn; Heringa, Jaap; Brandt, Bernd W

    2009-07-01

    A wealth of information on metabolic parameters of a species can be inferred from observations on species that are phylogenetically related. Phylogeny-based information can complement direct empirical evidence, and is particularly valuable if experiments on the species of interest are not feasible. The PhyloPars web server provides a statistically consistent method that combines an incomplete set of empirical observations with the species phylogeny to produce a complete set of parameter estimates for all species. It builds upon a state-of-the-art evolutionary model, extended with the ability to handle missing data. The resulting approach makes optimal use of all available information to produce estimates that can be an order of magnitude more accurate than ad-hoc alternatives. Uploading a phylogeny and incomplete feature matrix suffices to obtain estimates of all missing values, along with a measure of certainty. Real-time cross-validation provides further insight in the accuracy and bias expected for estimated values. The server allows for easy, efficient estimation of metabolic parameters, which can benefit a wide range of fields including systems biology and ecology. PhyloPars is available at: http://www.ibi.vu.nl/programs/phylopars/.

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

    PubMed

    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; Bray, Paul F

    2014-11-27

    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.

  5. 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

  6. Noncanonical PAR3 activation by factor Xa identifies a novel pathway for Tie2 activation and stabilization of vascular integrity

    PubMed Central

    Stavenuiter, Fabian

    2014-01-01

    Endothelial barrier protective effects of activated protein C (APC) require the endothelial protein C receptor (EPCR), protease-activated receptor (PAR) 1, and PAR3. In contrast, PAR1 and PAR3 activation by thrombin results in barrier disruption. Noncanonical PAR1 and PAR3 activation by APC vs canonical activation by thrombin provides an explanation for the functional selectivity of these proteases. Here we found that factor Xa (FXa) activated PAR1 at canonical Arg41 similar to thrombin but cleaved PAR3 at noncanonical Arg41 similar to APC. This unique PAR1-PAR3 activation profile permitted the identification of noncanonical PAR3 activation as a novel activation pathway for barrier protective tunica intima endothelial receptor tyrosine kinase 2 (Tie2). APC, FXa, and the noncanonical PAR3 tethered-ligand peptide induced prolonged activation of Tie2, whereas thrombin and the canonical PAR3 tethered-ligand peptide did not. Tie2 activation by FXa required PAR3 and EPCR. FXa and the noncanonical PAR3 tethered-ligand peptide induced Tie2- and PAR3-dependent upregulation of tight-junction-associated protein zona occludens 1 (ZO-1), translocation of ZO-1 to cell-cell borders, and the formation of typical ZO-1 honeycomb patterns that are indicative of tight-junction stabilization. These data provide intriguing novel insights into the diversification of functional selectivity of protease signaling achievable by canonical and noncanonical PAR activation, such as the activation of vascular-protective Tie2 by noncanonical PAR3 activation. PMID:25320242

  7. The polarity protein Par6 is coupled to the microtubule network during molluscan early embryogenesis

    SciTech Connect

    Homma, Taihei; Shimizu, Miho; Kuroda, Reiko

    2011-01-07

    Research highlights: {yields} The cDNAs encoding Par6 and aPKC homologues were cloned from the snail Lymnaea stagnalis. {yields} L. stagnalis Par6 directly interacts with tubulin and microtubules and localizes to the microtubule cytoskeleton during the early embryogenesis. {yields} Identical sequence and localization of LsPar6 for the dextral and the sinistral snails exclude the possibility of the gene being the primary determinant of body handedness. -- Abstract: Cell polarity, which directs the orientation of asymmetric cell division and segregation of fate determinants, is a fundamental feature of development and differentiation. Regulators of polarity have been extensively studied, and the critical importance of the Par (partitioning-defective) complex as the polarity machinery is now recognized in a wide range of eukaryotic systems. The Par polarity module is evolutionarily conserved, but its mechanism and cooperating factors vary among different systems. Here we describe the cloning and characterization of a pond snail Lymnaea stagnalis homologue of partitioning-defective 6 (Lspar6). The protein product LsPar6 shows high affinity for microtubules and localizes to the mitotic apparatus during embryonic cell division. In vitro assays revealed direct binding of LsPar6 to tubulin and microtubules, which is the first evidence of the direct interaction between the two proteins. The interaction is mediated by two distinct regions of LsPar6 both located in the N-terminal half. Atypical PKC, a functional partner of Par6, was also found to localize to the mitotic spindle. These results suggest that the L. stagnalis Par complex employs the microtubule network in cell polarity processes during the early embryogenesis. Identical sequence and localization of LsPar6 for the dextral and the sinistral snails exclude the possibility of the gene being the primary determinant of handedness.

  8. Pars plana vitrectomy through the Boston Keratoprosthesis type 1

    PubMed Central

    Harissi-Dagher, M; Durr, G M; Biernacki, K; Sebag, M; Rhéaume, M-A

    2013-01-01

    Purpose To ascertain the feasibility of pars plana vitrectomy (PPV) through a permanent Boston Keratoprosthesis type 1 (KPro) without the use of a temporary KPro. Methods A retrospective interventional case series. Eyes implanted with Boston KPro type 1 between 2008 and 2011 requiring PPV for vitreoretinal complications were included. Feasibility of PPV through the KPro, its anatomical and functional success were studied. Results Five out of 70 patients required PPV for vitreoretinal complications post-KPro surgery resulting in an incidence of 7%. PPV was feasible through the Boston KPro with no deleterious effects on the corneal carrier or the KPro itself. Repeat PPV was necessary in some cases. Although anatomical repair of the vitreoretinal complications was achieved in most cases, post PPV visual acuity remained poor in the majority. Conclusion Our study suggests that although PPV through the Boston KPro is a viable approach for vitreoretinal disease repair, visual rehabilitation remains poor. PMID:23579405

  9. 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

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

    PubMed

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

    2015-02-01

    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 Ca(2+), 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.

  11. 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

  12. Actin polymerisation regulates thrombin-evoked Ca(2+) signalling after activation of PAR-4 but not PAR-1 in human platelets.

    PubMed

    Harper, Matthew T; Sage, Stewart O

    2006-05-01

    The role of actin polymerisation in regulating thrombin-evoked Ca(2+) signalling was investigated in human platelets. We have previously reported that cytochalasin D (Cyt D) inhibits thapsigargin-evoked store-operated Ca(2+) entry (SOCE), which is believed to contribute a major component of thrombin-evoked Ca(2+) entry in platelets. In contrast, Cyt D increased thrombin-evoked Ca(2+) entry to 147.5 +/- 9.2% and Sr(2+) entry to 134.2 +/- 6.4% of control. Similar results were obtained with latrunculin A. This potentiation was not affected if protein kinase C was inhibited using Ro-31-8220, suggesting that it did not involve PKC-dependent non-capacitative Ca(2+) entry. Ca(2+) entry evoked by the PAR-4 agonist, AYPGKF, was increased to 133.7 +/- 12.8% of control by Cyt D, whereas Ca(2+) signalling evoked by the PAR-1 agonist, SFLLRN, was unaffected. The PAR-4 antagonist, tcY-NH(2), abolished the effect of Cyt D on thrombin-evoked Ca(2+) entry. Biotinylation of cell-surface proteins showed that PAR-4 was internalised after stimulation by thrombin. Cyt D reduced this internalisation. These data suggest that Cyt D prevents the internalisation of PAR-4, which may lead to prolonged signalling from this receptor. This may mask a direct effect of Cyt D on the activation of SOCE after the activation of PAR-4. PMID:16702038

  13. Par3 controls neural crest migration by promoting microtubule catastrophe during contact inhibition of locomotion.

    PubMed

    Moore, Rachel; Theveneau, Eric; Pozzi, Sara; Alexandre, Paula; Richardson, Joanna; Merks, Anne; Parsons, Maddy; Kashef, Jubin; Linker, Claudia; Mayor, Roberto

    2013-12-01

    There is growing evidence that contact inhibition of locomotion (CIL) is essential for morphogenesis and its failure is thought to be responsible for cancer invasion; however, the molecular bases of this phenomenon are poorly understood. Here we investigate the role of the polarity protein Par3 in CIL during migration of the neural crest, a highly migratory mesenchymal cell type. In epithelial cells, Par3 is localised to the cell-cell adhesion complex and is important in the definition of apicobasal polarity, but the localisation and function of Par3 in mesenchymal cells are not well characterised. We show in Xenopus and zebrafish that Par3 is localised to the cell-cell contact in neural crest cells and is essential for CIL. We demonstrate that the dynamics of microtubules are different in different parts of the cell, with an increase in microtubule catastrophe at the collision site during CIL. Par3 loss-of-function affects neural crest migration by reducing microtubule catastrophe at the site of cell-cell contact and abrogating CIL. Furthermore, Par3 promotes microtubule catastrophe by inhibiting the Rac-GEF Trio, as double inhibition of Par3 and Trio restores microtubule catastrophe at the cell contact and rescues CIL and neural crest migration. Our results demonstrate a novel role of Par3 during neural crest migration, which is likely to be conserved in other processes that involve CIL such as cancer invasion or cell dispersion.

  14. 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…

  15. 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.

  16. 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...

  17. 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…

  18. 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

  19. Platelet activation via PAR4 is involved in the initiation of thrombin generation and in clot elasticity development.

    PubMed

    Vretenbrant, Karin; Ramström, Sofia; Bjerke, Maria; Lindahl, Tomas L

    2007-03-01

    Thrombin is a pivotal enzyme formed in the coagulation cascade and an important and potent platelet activator. The two protease-activated thrombin receptors on human platelets are denoted PAR1 and PAR4. The physiological relevance of PAR4 is still unclear, as both aggregation and secretion can be accomplished by PAR1 activation alone. In the present study we have investigated the role of PARs in platelet activation, blood coagulation, clot elasticity and fibrinolysis. Flow cytometry, free oscillation rheometry and thrombin generation measurements were used to analyze blood or platelet-rich plasma from healthy individuals. Maximum PAR1 activation with the peptide SFLLRN gave fewer fibrinogen-binding platelets with lower mean fluorescent intensity than maximum PAR4 activation with AYPGKF. Inhibition of any of the receptors prolonged clotting times. However, PAR1 is more important for fibrinolysis; inhibition of this receptor prolonged all the steps in the fibrinolytic process. Clot elasticity decreased significantly when the PAR4 receptor was inhibited. In the thrombin generation measurements, PAR4 inhibition delayed the thrombin generation start and peak, but did not affect the total amount of thrombin generated. PAR1 inhibition had no significant impact on thrombin generation. We found that PAR4 is most likely activated by low concentrations of thrombin during the initial phase of thrombin generation and is of importance to the clotting time. Furthermore, we suggest that the PAR4 receptor may have a physiological role in the stabilisation of the coagulum. PMID:17334509

  20. 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

  1. 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

  2. The ParA/MinD family puts things in their place.

    PubMed

    Lutkenhaus, Joe

    2012-09-01

    Bacteria must segregate their DNA and position a septum to grow and divide. In many bacteria, MinD is involved in spatial regulation of the cytokinetic Z ring, and ParAs are involved in chromosome and plasmid segregation. The use of the MinD/ParA family to provide positional information for spatial organization continues to expand with the recognition that orphan ParAs are required for segregating cytoplasmic protein clusters and the polar localization of chemotaxis proteins, conjugative transfer machinery, type IV pili, and cellulose synthesis. Also, some bacteria lacking MinD use orphan ParAs to regulate cell division. Positioning of MinD/ParA proteins is either due to self-organization on a surface or reliance on a landmark protein that functions as a molecular beacon.

  3. Cell polarity factor Par3 binds SPTLC1 and modulates monocyte serine palmitoyltransferase activity and chemotaxis.

    PubMed

    Tamehiro, Norimasa; Mujawar, Zahedi; Zhou, Suiping; Zhuang, Debbie Z; Hornemann, Thorsten; von Eckardstein, Arnold; Fitzgerald, Michael L

    2009-09-11

    Elevated sphingolipids have been associated with increased cardiovascular disease. Conversely, atherosclerosis is reduced in mice by blocking de novo synthesis of sphingolipids catalyzed by serine palmitoyltransferase (SPT). The SPT enzyme is composed of the SPTLC1 and -2 subunits, and here we describe a novel protein-protein interaction between SPTLC1 and the PDZ protein Par3 (partitioning defective protein 3). Mammalian SPTLC1 orthologs have a highly conserved C terminus that conforms to a type II PDZ protein interaction motif, and by screening PDZ domain protein arrays with an SPTLC1 C-terminal peptide, we found it bound the third PDZ domain of Par3. Overlay and immunoprecipitation assays confirmed this interaction and indicate Par3 is able to associate with the SPTLC1/2 holoenzyme by binding the C-terminal SPTLC1 PDZ motif. The physiologic existence of the SPTLC1/2-Par3 complex was detected in mouse liver and macrophages, and short interfering RNA inhibition of Par3 in human THP-1 monocytes significantly reduced SPT activity and de novo ceramide synthesis by nearly 40%. Given monocyte recruitment into inflamed vessels is thought to promote atherosclerosis, and because Par3 and sphingolipids have been associated with polarized cell migration, we tested whether the ability of THP-1 monocytes to migrate toward MCP-1 (monocyte chemoattractant protein 1) depended upon Par3 and SPTLC1 expression. Knockdown of Par3 significantly reduced MCP1-induced chemotaxis of THP-1 monocytes, as did knockdown of SPTLC1, and this Par3 effect depended upon SPT activity and was blunted by ceramide treatment. In conclusion, protein arrays were used to identify a novel SPTLC1-Par3 interaction that associates with increased monocyte serine palmitoyltransferase activity and chemotaxis toward inflammatory signals. PMID:19592499

  4. Thrombin enhances the barrier function of rat microvascular endothelium in a PAR-1-dependent manner.

    PubMed

    Troyanovsky, B; Alvarez, D F; King, J A; Schaphorst, K L

    2008-02-01

    Thrombin is a multifunctional coagulation protease with pro- and anti-inflammatory vascular effects. We questioned whether thrombin may have segmentally differentiated effects on pulmonary endothelium. In cultured rat endothelial cells, rat thrombin (10 U/ml) recapitulated the previously reported decrease in transmonolayer electrical resistance (TER), F-actin stress fiber formation, paracellular gap formation, and increased permeability. In contrast, in rat pulmonary microvascular endothelial cells (PMVEC), isolated on the basis of Griffonia simplicifolia lectin recognition, thrombin increased TER, induced fewer stress fibers, and decreased permeability. To assess for differential proteinase-activated receptor (PAR) expression as a basis for the different responses, PAR family expression was analyzed. Both pulmonary artery endothelial cells and PMVEC expressed PAR-1 and PAR-2; however, only PMVEC expressed PAR-3, as shown by both RT-PCR and Western analysis. PAR-1 activating peptides (PAR-APs: SFLLRN-NH(2) and TFLLRN-NH(2)) were used to confirm a role for the PAR-1 receptor. PAR-APs (25-250 muM) also increased TER, formed fewer stress fibers, and did not induce paracellular gaps in PMVEC in contrast to that shown in pulmonary artery endothelial cells. These results were confirmed in isolated perfused rat lung preparations. PAR-APs (100 mug/ml) induced a 60% increase in the filtration coefficient over baseline. However, by transmission electron microscopy, perivascular fluid cuffs were seen only along conduit veins and arteries without evidence of intra-alveolar edema. We conclude that thrombin exerts a segmentally differentiated effect on endothelial barrier function in vitro, which corresponds to a pattern of predominant perivascular fluid cuff formation in situ. This may indicate a distinct role for thrombin in the microcirculation. PMID:18083763

  5. 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

  6. 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

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. Targeting uPAR with Antagonistic Recombinant Human Antibodies in Aggressive Breast Cancer

    PubMed Central

    LeBeau, Aaron M.; Duriseti, Sai; Murphy, Stephanie T.; Pepin, Francois; Hann, Byron; Gray, Joe W.; VanBrocklin, Henry F.; Craik, Charles S.

    2013-01-01

    Components of the plasminogen activation system (PAS) which are overexpressed in aggressive breast cancer subtypes offer appealing targets for development of new diagnostics and therapeutics. By comparing gene expression data in patient populations and cultured cell lines, we identified elevated levels of the urokinase plasminogen activation receptor (uPAR, PLAUR) in highly aggressive breast cancer subtypes and cell lines. Recombinant human anti-uPAR antagonistic antibodies exhibited potent binding in vitro to the surface of cancer cells expressing uPAR. In vivo these antibodies detected uPAR expression in triple negative breast cancer (TNBC) tumor xenografts using near infrared (NIR) imaging and 111In single-photon emission computed tomography (SPECT). Antibody-based uPAR imaging probes accurately detected small disseminated lesions in a tumor metastasis model, complementing the current clinical imaging standard 18F-fluorodeoxyglucose (FDG) at detecting non-glucose-avid metastatic lesions. A monotherapy study using the antagonistic antibodies resulted in a significant decrease in tumor growth in a TNBC xenograft model. Additionally, a radioimmunotherapy (RIT) study, using the anti-uPAR antibodies conjugated to the therapeutic radioisotope 177Lu, found that they were effective at reducing tumor burden in vivo. Taken together, our results offer a preclinical proof of concept for uPAR targeting as a strategy for breast cancer diagnosis and therapy using this novel human antibody technology. PMID:23400595

  12. 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

  13. Characterization and function of human Ly-6/uPAR molecules.

    PubMed

    Kong, Hyun Kyung; Park, Jong Hoon

    2012-11-01

    Human Ly-6/uPAR molecules are a superfamily composed of two subfamilies; one is the membrane bound proteins with a GPI-anchor and the other are secreted proteins without the GPI-anchor. Ly-6/uPAR molecules have remarkable amino acid homology through a distinctive 8-10 cysteine-rich domain that is associated predominantly with O-linked glycans. These molecules are encoded by multiple tightly linked genes located on Chr. 8q23, and have a conserved genomic organization. Ly-6/uPAR molecules have an interesting expression pattern during hematopoiesis and on specific tumors indicating that Ly-6/uPAR molecules are associated with development of the immune system and carcinogenesis. Thus, Ly-6/uPAR molecules are useful antigens for diagnostic and therapeutic targets. This review summarizes our understanding of human Ly-6/ uPAR molecules with regard to molecular structure as well as what is known about their function in normal and malignant tissues and suggest Ly-6/uPAR molecules as target antigens for cancer immunotherapy.

  14. 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

  15. Photometric monitoring of the young star Par 1724 in Orion

    NASA Astrophysics Data System (ADS)

    Neuhäuser, R.; Koeltzsch, A.; Raetz, St.; Schmidt, T. O. B.; Mugrauer, M.; Young, N.; Bertoldi, F.; Roell, T.; Eisenbeiss, T.; Hohle, M. M.; Vaňko, M.; Ginski, C.; Rammo, W.; Moualla, M.; Broeg, C.

    2009-05-01

    We report new photometric observations of the ˜ 200 000 year old naked weak-line run-away T Tauri star Par 1724, located north of the Trapezium cluster in Orion. We observed in the broad band filters B, V, R, and I using the 90 cm Dutch telescope on La Silla, the 80 cm Wendelstein telescope, and a 25 cm telescope of the University Observatory Jena in Großschwabhausen near Jena. The photometric data in V and R are consistent with a ˜ 5.7 day rotation period due to spots, as observed before between 1960ies and 2000. Also, for the first time, we present evidence for a long-term 9 or 17.5 year cycle in photometric data (V band) of such a young star, a cycle similar to that to of the Sun and other active stars. Based on observations obtained with telescopes of the University Observatory Jena, which is operated by the Astrophysical Institute of the Friedrich-Schiller-University; a telescope of the University Observatory Munich on Mount Wendelstein, the 0.9m ESO-Dutch telescope on La Silla, Chile, and with the All Sky Automated Survey (ASAS) project (www.astrouw.edu.pl/asas).

  16. 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.

  17. 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

  18. 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

  19. PAR (photosynthetically active radiation) conversion efficiencies of a tropical rain forest

    SciTech Connect

    Luxmoore, R.J.; Saldarriaga, J.G.

    1988-01-01

    The mean annual quantities of photosynthetically active radiation (PAR) absorbed during various stage of regeneration of a tropical rain forest in the upper Rio Negro region of Colombia and Venezuela were estimated for the intervals between clearcut and 1, 3, 10, 20, 35, 60, 80, and 200 years of growth. The forest phytomass and litterfall at each storage were from previous studies, and the data were used to calculate the mean annual quantity of net dry matter production per unit of absorbed PAR, the PAR conversion efficiency. 7 refs., 2 figs., 1 tab.

  20. Pars plana cicatrization of sewn-in posterior chamber intraocular lens haptics.

    PubMed

    McDermott, M L; Puklin, J E

    1997-03-01

    The authors describe the unexpected finding of cicatrization of posterior chamber lens haptics to the pars plana. This was found during removal of a secondary, transscleral sewn-in pseudophakos during a retinal reattachment procedure. Ophthalmic history and intraoperative photography revealed pars plana cicatrization of haptics. Despite removal of trans-scleral prolene fixation sutures and application of gentle traction, the posterior chamber lens haptics remained firmly adherent to pars plana retina. The haptics were amputated to prevent significant chorioretinal damage. The conventional belief that all sewn-in posterior chamber intraocular lenses cause little or no scarring response around the haptics may be unfounded.

  1. Injection of fluorosilicone oil and pars plana vitrectomy for complex retinal detachment.

    PubMed

    Peyman, G A; Smith, R T; Charles, H

    1987-08-01

    Pars plana vitrectomy can be combined with injection of fluorosilicone oil to treat complex retinal detachments. We describe three cases to illustrate the technique, which is adapted according to the type and location of the retinal breaks.

  2. 78 FR 42584 - Additional Designation of Aluminat, Pars Amayesh Sanaat Kish, Parviz Khaki, Pishro Systems...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-16

    ..., Parcham Street, Arak, Iran PARS Amayesh Sanaat Kish AKA: PASK AKA: Vacuumkaran AKA: Vacuum Karan AKA: Vacuum Karan Co. Address: 3rd Floor, No. 6, East 2nd, North Kheradmand, Karimkhan Street, Tehran,...

  3. 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.

  4. [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

  5. [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

  6. Intrinsic and integrative properties of substantia nigra pars reticulata neurons

    PubMed Central

    Zhou, Fu-Ming; Lee, Christian R.

    2011-01-01

    The GABA projection neurons of the substantia nigra pars reticulata (SNr) are output neurons for the basal ganglia and thus critical for movement control. Their most striking neurophysiological feature is sustained, spontaneous high frequency spike firing. A fundamental question is: what are the key ion channels supporting the remarkable firing capability in these neurons? Recent studies indicate that these neurons express tonically active TRPC3 channels that conduct a Na-dependent inward current even at hyperpolarized membrane potentials. When the membrane potential reaches −60 mV, a voltage-gated persistent sodium current (INaP) starts to activate, further depolarizing the membrane potential. At or slightly below −50 mV, the large transient voltage-activated sodium current (INaT) starts to activate and eventually triggers the rapid rising phase of action potentials. SNr GABA neurons have a higher density of (INaT), contributing to the faster rise and larger amplitude of action potentials, compared with the slow-spiking dopamine neurons. INaT also recovers from inactivation more quickly in SNr GABA neurons than in nigral dopamine neurons. In SNr GABA neurons, the rising phase of the action potential triggers the activation of high-threshold, inactivation-resistant Kv3-like channels that can rapidly repolarize the membrane. These intrinsic ion channels provide SNr GABA neurons with the ability to fire spontaneous and sustained high frequency spikes. Additionally, robust GABA inputs from direct pathway medium spiny neurons in the striatum and GABA neurons in the globus pallidus may inhibit and silence SNr GABA neurons, whereas glutamate synaptic input from the subthalamic nucleus may induce burst firing in SNr GABA neurons. Thus, afferent GABA and glutamate synaptic inputs sculpt the tonic high frequency firing of SNr GABA neurons and the consequent inhibition of their targets into an integrated motor control signal that is further fine-tuned by neuromodulators

  7. 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

  8. Developpement de techniques de diagnostic non intrusif par tomographie optique

    NASA Astrophysics Data System (ADS)

    Dubot, Fabien

    Que ce soit dans les domaines des procedes industriels ou de l'imagerie medicale, on a assiste ces deux dernieres decennies a un developpement croissant des techniques optiques de diagnostic. L'engouement pour ces methodes repose principalement sur le fait qu'elles sont totalement non invasives, qu'elle utilisent des sources de rayonnement non nocives pour l'homme et l'environnement et qu'elles sont relativement peu couteuses et faciles a mettre en oeuvre comparees aux autres techniques d'imagerie. Une de ces techniques est la Tomographie Optique Diffuse (TOD). Cette methode d'imagerie tridimensionnelle consiste a caracteriser les proprietes radiatives d'un Milieu Semi-Transparent (MST) a partir de mesures optiques dans le proche infrarouge obtenues a l'aide d'un ensemble de sources et detecteurs situes sur la frontiere du domaine sonde. Elle repose notamment sur un modele direct de propagation de la lumiere dans le MST, fournissant les predictions, et un algorithme de minimisation d'une fonction de cout integrant les predictions et les mesures, permettant la reconstruction des parametres d'interet. Dans ce travail, le modele direct est l'approximation diffuse de l'equation de transfert radiatif dans le regime frequentiel tandis que les parametres d'interet sont les distributions spatiales des coefficients d'absorption et de diffusion reduit. Cette these est consacree au developpement d'une methode inverse robuste pour la resolution du probleme de TOD dans le domaine frequentiel. Pour repondre a cet objectif, ce travail est structure en trois parties qui constituent les principaux axes de la these. Premierement, une comparaison des algorithmes de Gauss-Newton amorti et de Broyden- Fletcher-Goldfarb-Shanno (BFGS) est proposee dans le cas bidimensionnel. Deux methodes de regularisation sont combinees pour chacun des deux algorithmes, a savoir la reduction de la dimension de l'espace de controle basee sur le maillage et la regularisation par penalisation de Tikhonov

  9. 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.

  10. 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

  11. Examining relational empowerment for elementary school students in a yPAR program.

    PubMed

    Langhout, Regina Day; Collins, Charles; Ellison, Erin Rose

    2014-06-01

    This paper joins relational empowerment, youth empowerment, and Bridging Multiple Worlds frameworks to examine forms of relational empowerment for children in two intermediary institutions-school and a youth participatory action research after-school program (yPAR ASP). Participants were twelve children, most of whom were Latina/o and from im/migrant families, enrolled in a yPAR ASP for 2 years. A mixed-method approach was utilized; we analyzed children's interviews, self-defined goals, and their social networks to examine their experiences of relational empowerment. We conclude that children experienced each of the five relational empowerment factors-collaborative competence, bridging social divisions, facilitating others' empowerment, mobilizing networks, and passing on a legacy-in the yPAR ASP setting, and some factors in school. These experiences, however, were more pronounced in the yPAR ASP setting. Additionally, social network analyses revealed that a small but meaningful percentage of actors bridged worlds, especially home and family, but by year 2, also school and the yPAR ASP. Finally, most helpers for school-based goals came from school, but a sizable number came from family, friends, and home worlds, and by year 2, also came from the yPAR ASP. Implications range from theoretical to methodological development, including the use of social network analysis as a tool to descriptively examine relational power in context.

  12. 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

  13. Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition.

    PubMed

    Zhang, K; Zhao, H; Ji, Z; Zhang, C; Zhou, P; Wang, L; Chen, Q; Wang, J; Zhang, P; Chen, Z; Zhu, H H; Gao, W-Q

    2016-03-10

    Epithelial-to-mesenchymal transition (EMT), marked by the dissolution of cell-cell junctions, loss of cell polarity and increased cell motility, is one of the essential steps for prostate cancer metastasis. However, the underlying mechanism has not been fully explored. We report in this study that Shp2 is upregulated in prostate cancers and is associated with a poor disease outcome, namely tumor metastasis and shortened patient survival. Overexpression of wild-type Shp2 or an oncogenic Shp2 mutant leads to increased prostate cancer cell proliferation, colony and sphere formation, and in vivo tumor formation. Opposite effects are seen in Shp2-knockdown cells. Moreover, Shp2 promotes in vitro migration and in vivo metastasis of prostatic tumor cells. Mechanistically, Shp2 interacts with PAR3 (partitioning-defective 3) via its Src homology-2 domain. Ectopic expression of Shp2 attenuates the phosphorylation of PAR3 and the formation of the PAR3/PAR6/atypical protein kinase C polarity protein complex, resulting in disrupted cell polarity, dysregulated cell-cell junctions and increased EMT. These findings provide a novel mechanism by which oncogenic signal-transduction molecules regulate cell polarity and induction of EMT.

  14. Heat stress-induced disruption of endothelial barrier function is via PAR1 signaling and suppressed by Xuebijing injection.

    PubMed

    Xu, Qiulin; Liu, Jingxian; Wang, Zhenglian; Guo, Xiaohua; Zhou, Gengbiao; Liu, Yanan; Huang, Qiaobing; Su, Lei

    2015-01-01

    Increased vascular permeability leading to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is central to the pathogenesis of heatstroke. Protease-activated receptor 1 (PAR1), the receptor for thrombin, plays a key role in disruption of endothelial barrier function in response to extracellular stimuli. However, the role of PAR1 in heat stress-induced endothelial hyper-permeability is unknown. In this study, we measured PAR1 protein expression in heat-stressed human umbilical venous endothelial cells (HUVECs), investigated the influences of PAR1 on endothelial permeability, F-actin rearrangement, and moesin phosphorylation by inhibiting PAR1 with its siRNA, neutralizing antibody (anti-PAR1), specific inhibitor(RWJ56110), and Xuebijing injection (XBJ), a traditional Chinese medicine used for sepsis treatment, and evaluated the role of PAR1 in heatstroke-related ALI/ARDS in mice by suppressing PAR1 with RWJ56110, anti-PAR1and XBJ. We found that heat stress induced PAR1 protein expression 2h after heat stress in endothelial cells, caused the release of endothelial matrix metalloprotease 1, an activator of PAR1, after 60 or 120 min of heat stimulation, as well as promoted endothelial hyper-permeability and F-actin rearrangement, which were inhibited by suppressing PAR1 with RWJ56110, anti-PAR1 and siRNA. PAR1 mediated moesin phosphorylation, which caused F-actin rearrangement and disruption of endothelial barrier function. To corroborate findings from in vitro experiments, we found that RWJ56110 and the anti-PAR1 significantly decreased lung edema, pulmonary microvascular permeability, protein exudation, and leukocytes infiltrations in heatstroke mice. Additionally, XBJ was found to suppress PAR1-moesin signal pathway and confer protective effects on maintaining endothelial barrier function both in vitro and in vivo heat-stressed model, similar to those observed above with the inhibition of PAR1. These results suggest that PAR1 is a potential

  15. A Novel Function for the PAR Complex in Subcellular Morphogenesis of Tracheal Terminal Cells in Drosophila melanogaster

    PubMed Central

    Jones, Tiffani A.; Metzstein, Mark M.

    2011-01-01

    The processes that generate cellular morphology are not well understood. To investigate this problem, we use Drosophila melanogaster tracheal terminal cells, which undergo two distinct morphogenetic processes: subcellular branching morphogenesis and subcellular apical lumen formation. Here we show these processes are regulated by components of the PAR-polarity complex. This complex, composed of the proteins Par-6, Bazooka (Par-3), aPKC, and Cdc42, is best known for roles in asymmetric cell division and apical/basal polarity. We find Par-6, Bazooka, and aPKC, as well as known interactions between them, are required for subcellular branch initiation, but not for branch outgrowth. By analysis of single and double mutants, and isolation of two novel alleles of Par-6, one of which specifically truncates the Par-6 PDZ domain, we conclude that dynamic interactions between apical PAR-complex members control the branching pattern of terminal cells. These data suggest that canonical apical PAR-complex activity is required for subcellular branching morphogenesis. In addition, we find the PAR proteins are downstream of the FGF pathway that controls terminal cell branching. In contrast, we find that while Par-6 and aPKC are both required for subcellular lumen formation, neither Bazooka nor a direct interaction between Par-6 and aPKC is needed for this process. Thus a novel, noncanonical role for the polarity proteins Par-6 and aPKC is used in formation of this subcellular apical compartment. Our results demonstrate that proteins from the PAR complex can be deployed independently within a single cell to control two different morphogenetic processes. PMID:21750259

  16. ParA2, a Vibrio cholerae chromosome partitioning protein, forms left-handed helical filaments on DNA.

    PubMed

    Hui, Monica P; Galkin, Vitold E; Yu, Xiong; Stasiak, Alicja Z; Stasiak, Andrzej; Waldor, Matthew K; Egelman, Edward H

    2010-03-01

    Most bacterial chromosomes contain homologs of plasmid partitioning (par) loci. These loci encode ATPases called ParA that are thought to contribute to the mechanical force required for chromosome and plasmid segregation. In Vibrio cholerae, the chromosome II (chrII) par locus is essential for chrII segregation. Here, we found that purified ParA2 had ATPase activities comparable to other ParA homologs, but, unlike many other ParA homologs, did not form high molecular weight complexes in the presence of ATP alone. Instead, formation of high molecular weight ParA2 polymers required DNA. Electron microscopy and three-dimensional reconstruction revealed that ParA2 formed bipolar helical filaments on double-stranded DNA in a sequence-independent manner. These filaments had a distinct change in pitch when ParA2 was polymerized in the presence of ATP versus in the absence of a nucleotide cofactor. Fitting a crystal structure of a ParA protein into our filament reconstruction showed how a dimer of ParA2 binds the DNA. The filaments formed with ATP are left-handed, but surprisingly these filaments exert no topological changes on the right-handed B-DNA to which they are bound. The stoichiometry of binding is one dimer for every eight base pairs, and this determines the geometry of the ParA2 filaments with 4.4 dimers per 120 A pitch left-handed turn. Our findings will be critical for understanding how ParA proteins function in plasmid and chromosome segregation.

  17. Evaluation of treatment and posttreatment changes of protraction facemask treatment using the PAR index.

    PubMed

    Ngan, P; Yiu, C

    2000-10-01

    The purpose of this study was to use the Peer Assesment Rating (PAR) index score to evaluate the treatment and posttreatment changes of Class III patients treated by protraction facemask. The sample consisted of 20 Chinese children, 6 to 11 years old, with Class III skeletal malocclusion who had been treated with maxillary expansion and a protraction facemask. The average treatment time was 8.2 months, followed by 1 year of retention with a Class III functional appliance. Study casts were taken pretreatment (T1), posttreatment (T2), 1 year follow-up (T3), and 2 years follow-up (T4). After treatment, PAR scores were calculated for each time period. Differences among the 4 time periods were analyzed with the Wilcoxin matched-pairs test. Significant reductions in PAR scores were found at T2 (56%), T3 (70%), and T4 (63%) compared with T1. Immediately posttreatment (T2), 17 (85%) of 20 patients had improved PAR scores by a reduction of at least 30%. Reductions were caused primarily by correction of the anterior crossbite. One year after treatment (T3), further reductions in PAR score were noted (P <.01) as a result of better alignment of the anterior segment, improvement of the buccal occlusion, and overbite and midline corrections. Two years after treatment (T4), PAR scores were higher than at the previous time period. The increases were due to relapses in overjet (4 of 20 patients), overbite, and centerline corrections. These results indicate that significant reductions in the severity of Class III malocclusion can be achieved with early orthopedic facemask treatment. In most cases, further improvement in the PAR score can be expected 1 and 2 years after treatment. In a few patients, the benefits of early treatment are negated by relapses in overjet, overbite, and centerline corrections during the follow-up period.

  18. 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.

  19. 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.

  20. Early intraplatelet signaling enhances the release of human platelet PAR-1 and -4 amino-terminal peptides in response to thrombin.

    PubMed

    Ofosu, Frederick A; Dewar, Lori; Song, Yingqi; Cedrone, Aisha C; Hortelano, Gonzalo; Craven, Sharon J

    2009-02-24

    Activation of washed human platelets initiated with alpha-thrombin, SFLLRN, or AYPGKF invariably results in the generation of PAR-1-(1-41) and PAR-4-(1-47). PAR-1-(1-41) and PAR-4-(1-47) are amino-terminal peptides generated when PAR-1 and -4 are cleaved in their first extracellular domains after R(41) and R(47), respectively, to expose the tethered ligand domains of PAR-1 and -4. Since soybean trypsin inhibitor decreases generation of PAR-1-(1-41) and PAR-4-(1-47) and other platelet aggregation-related responses to these three agonists, but does not inactivate alpha-thrombin, a platelet trypsin-like proteinase apparently activates PAR-1 and -4 to propagate PAR-dependent platelet responses. This study identified the signaling pathways implicated in the generation of the platelet proteinase that in turn produces PAR-1-(1-41) and PAR-4-(1-47), to thereby drive the subsequent PAR-dependent platelet aggregation-related responses to alpha-thrombin, SFLLRN, or AYPGKF. Only inhibitors of signaling enzymes that prevented ATP release (forskolin, PGE(1), or BIMI-1) prevented or delayed the generation of PAR-1-(1-41) and PAR-4-(1-47) in response to all three agonists. SBTI prevented platelet aggregation initiated by alpha-thrombin, SFLLRN, or AYPGKF but did so less effectively when it was added 10 s after each agonist. Thus, the platelet-derived proteinase acts within 10 s of each agonist addition to generate PAR-1-(1-41) and PAR-4-(1-47). Furthermore, alpha-thrombin may not effectively catalyze PAR-1-(1-41) and PAR-4-(1-47) generation. We propose that unidentified ATP-dependent phosphorylation reactions catalyzed by PKC help to generate the platelet-derived proteinase that propagates human platelet PAR-1 and -4 activation by the three agonists. PMID:19182900

  1. Spatiotemporal Variability of Global and Diffuse PAR in the Amazon Region and its Significance for Tropical Forest Photosynthesis

    NASA Astrophysics Data System (ADS)

    Dye, D. G.

    2003-12-01

    This study examines seasonal and inter-annual variation in surface fluxes of global and diffuse photosynthetically active radiation (PAR, 400-700 nm) in the tropical forest of the Amazon region. Spatial and temporal patterns of global and diffuse PAR are determined from reanalysis data from the National Center for Environmental Prediction (NCEP), and from the SeaWIFS Solar Surface Irradiance (SSI) data set. The PAR data and satellite-derived estimates of leaf area index (LAI) are applied to an existing sun-shade model of forest canopy photosynthesis. The seasonality of atmospheric scattering (quantified as the diffuse fraction of global PAR) as a determining factor for the relative influence of variation and trends in incident PAR on tropical forest photosynthesis is quantitatively evaluated. The results provide insight into the role of the surface PAR regime in the dynamics of ecosystem-atmosphere carbon exchange in the Amazon and other tropical forest regions.

  2. 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

  3. Microtubule-like properties of the bacterial actin homolog ParM-R1.

    PubMed

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

    2012-10-26

    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.

  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. "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

  6. Nanomechanical recognition of prognostic biomarker suPAR with DVD-ROM optical technology

    NASA Astrophysics Data System (ADS)

    Bache, Michael; Bosco, Filippo G.; Brøgger, Anna L.; Frøhling, Kasper B.; Sonne Alstrøm, Tommy; Hwu, En-Te; Chen, Ching-Hsiu; Eugen-Olsen, Jesper; Hwang, Ing-Shouh; Boisen, Anja

    2013-11-01

    In this work the use of a high-throughput nanomechanical detection system based on a DVD-ROM optical drive and cantilever sensors is presented for the detection of urokinase plasminogen activator receptor inflammatory biomarker (uPAR). Several large scale studies have linked elevated levels of soluble uPAR (suPAR) to infectious diseases, such as HIV, and certain types of cancer. Using hundreds of cantilevers and a DVD-based platform, cantilever deflection response from antibody-antigen recognition is investigated as a function of suPAR concentration. The goal is to provide a cheap and portable detection platform which can carry valuable prognostic information. In order to optimize the cantilever response the antibody immobilization and unspecific binding are initially characterized using quartz crystal microbalance technology. Also, the choice of antibody is explored in order to generate the largest surface stress on the cantilevers, thus increasing the signal. Using optimized experimental conditions the lowest detectable suPAR concentration is currently around 5 nM. The results reveal promising research strategies for the implementation of specific biochemical assays in a portable and high-throughput microsensor-based detection platform.

  7. 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

  8. 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

  9. A matrix metalloprotease-PAR1 system regulates vascular integrity, systemic inflammation and death in sepsis

    PubMed Central

    Tressel, Sarah L; Kaneider, Nicole C; Kasuda, Shogo; Foley, Caitlin; Koukos, Georgios; Austin, Karyn; Agarwal, Anika; Covic, Lidija; Opal, Steven M; Kuliopulos, Athan

    2011-01-01

    Sepsis is a deadly disease characterized by the inability to regulate the inflammatory–coagulation response in which the endothelium plays a key role. The cause of this perturbation remains poorly understood and has hampered the development of effective therapeutics. Matrix metalloproteases (MMPs) are involved in the host response to pathogens, but can also cause uncontrolled tissue damage and contribute to mortality. We found that human sepsis patients had markedly elevated plasma proMMP-1 and active MMP-1 levels, which correlated with death at 7 and 28 days after diagnosis. Likewise, septic mice had increased plasma levels of the MMP-1 ortholog, MMP-1a. We identified mouse MMP-1a as an agonist of protease-activated receptor-1 (PAR1) on endothelial cells. MMP-1a was released from endothelial cells in septic mice. Blockade of MMP-1 activity suppressed endothelial barrier disruption, disseminated intravascular coagulation (DIC), lung vascular permeability as well as the cytokine storm and improved survival, which was lost in PAR1-deficient mice. Infusion of human MMP-1 increased lung vascular permeability in normal wild-type mice but not in PAR1-deficient mice. These findings implicate MMP-1 as an important activator of PAR1 in sepsis and suggest that therapeutics that target MMP1-PAR1 may prove beneficial in the treatment of sepsis. PMID:21591259

  10. Two-state conformational equilibrium in the Par-4 leucine zipper domain.

    PubMed

    Schwalbe, Martin; Dutta, Kaushik; Libich, David S; Venugopal, Hariprasad; Claridge, Jolyon K; Gell, David A; Mackay, Joel P; Edwards, Patrick J B; Pascal, Steven M

    2010-08-15

    Prostate apoptosis response factor-4 (Par-4) is a pro-apoptotic and tumor-suppressive protein. A highly conserved heptad repeat sequence at the Par-4 C-terminus suggests the presence of a leucine zipper (LZ). This C-terminal region is essential for Par-4 self-association and interaction with various effector proteins. We have used nuclear magnetic resonance (NMR) spectroscopy to fully assign the chemical shift resonances of a peptide comprising the LZ domain of Par-4 at neutral pH. Further, we have investigated the properties of the Par-4 LZ domain and two point mutants under a variety of conditions using NMR, circular dichroism (CD), light scattering, and bioinformatics. Results indicate an environment-dependent conformational equilibrium between a partially ordered monomer (POM) and a predominantly coiled coil dimer (CCD). The combination of techniques used allows the time scales of the equilibrium to be probed and also helps to identify features of the amino acid sequence that may influence the equilibrium.

  11. 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

  12. 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

  13. 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

  14. Proteolytic Activation of the Protease-activated Receptor (PAR)-2 by the Glycosylphosphatidylinositol-anchored Serine Protease Testisin*

    PubMed Central

    Driesbaugh, Kathryn H.; Buzza, Marguerite S.; Martin, Erik W.; Conway, Gregory D.; Kao, Joseph P. Y.; Antalis, Toni M.

    2015-01-01

    Protease-activated receptors (PARs) are a family of seven-transmembrane, G-protein-coupled receptors that are activated by multiple serine proteases through specific N-terminal proteolytic cleavage and the unmasking of a tethered ligand. The majority of PAR-activating proteases described to date are soluble proteases that are active during injury, coagulation, and inflammation. Less investigation, however, has focused on the potential for membrane-anchored serine proteases to regulate PAR activation. Testisin is a unique trypsin-like serine protease that is tethered to the extracellular membrane of cells through a glycophosphatidylinositol (GPI) anchor. Here, we show that the N-terminal domain of PAR-2 is a substrate for testisin and that proteolytic cleavage of PAR-2 by recombinant testisin activates downstream signaling pathways, including intracellular Ca2+ mobilization and ERK1/2 phosphorylation. When testisin and PAR-2 are co-expressed in HeLa cells, GPI-anchored testisin specifically releases the PAR-2 tethered ligand. Conversely, knockdown of endogenous testisin in NCI/ADR-Res ovarian tumor cells reduces PAR-2 N-terminal proteolytic cleavage. The cleavage of PAR-2 by testisin induces activation of the intracellular serum-response element and NFκB signaling pathways and the induction of IL-8 and IL-6 cytokine gene expression. Furthermore, the activation of PAR-2 by testisin results in the loss and internalization of PAR-2 from the cell surface. This study reveals a new biological substrate for testisin and is the first demonstration of the activation of a PAR by a serine protease GPI-linked to the cell surface. PMID:25519908

  15. Hematopoietic lineage cell-specific protein-1 (HS1) regulates PAR-mediated ERK activation and thromboxane generation in platelets.

    PubMed

    Kahner, Bryan N; Dorsam, Robert T; Kim, Soochong; Shankar, Haripriya; Kitamura, Daisuke; Kunapuli, Satya P

    2008-12-01

    Thrombin-induced platelet activation leads to tyrosine phosphorylation of hematopoietic lineage cell-specific protein-1 (HS1), a 75 kDa adapter protein expressed exclusively in cells of hematopoietic lineage. We have shown HS1 to be a functionally important signaling molecule downstream of PAR-4 and GPVI collagen receptor. We have thus begun to elucidate PAR signaling pathway of HS1 phosphorylation, and its functional implications. PAR-1 and PAR-4 activating peptides (SFLLRN and AYPGKF, respectively) induced HS1 phosphorylation in a Gq-dependent manner as shown by incubation with the Gq inhibitor, YM254890. Consistently, HS1 phosphorylation was abolished in platelets from Gq deficient mice upon AYPGKF stimulation. Treatment with ADP receptor antagonists did not affect HS1 phosphorylation. Pretreatment of platelets with Src kinase inhibitors abolished HS1 phosphorylation. Further Syk activation, as measured by tyrosine phosphorylation of Syk (residues 525/526), in response to PAR activation was abolished in the presence of Src inhibitors. HS1 null mice show inhibition of PAR-mediated thromboxane A2 generation compared to wild type littermates. Phosphorylation of Erk, a key signaling molecule in thromboxane generation, was also diminished in HS1 null mice platelets. Based on these findings, we conclude that tyrosine phosphorylation of HS1 occurs downstream of both PAR-1 and PAR-4. HS1 phosphorylation is a Gq mediated response regulated by Src kinases. Thus, HS1 may mediate PAR-induced thromboxane generation through regulation of Erk phosphorylation. PMID:19012179

  16. Tumour Microenvironments Induce Expression of Urokinase Plasminogen Activator Receptor (uPAR) and Concomitant Activation of Gelatinolytic Enzymes

    PubMed Central

    Magnussen, Synnøve; Hadler-Olsen, Elin; Latysheva, Nadezhda; Pirila, Emma; Steigen, Sonja E.; Hanes, Robert; Salo, Tuula; Winberg, Jan-Olof; Uhlin-Hansen, Lars; Svineng, Gunbjørg

    2014-01-01

    Background The urokinase plasminogen activator receptor (uPAR) is associated with poor prognosis in oral squamous cell carcinoma (OSCC), and increased expression of uPAR is often found at the invasive tumour front. The aim of the current study was to elucidate the role of uPAR in invasion and metastasis of OSCC, and the effects of various tumour microenvironments in these processes. Furthermore, we wanted to study whether the cells’ expression level of uPAR affected the activity of gelatinolytic enzymes. Methods The Plaur gene was both overexpressed and knocked-down in the murine OSCC cell line AT84. Tongue and skin tumours were established in syngeneic mice, and cells were also studied in an ex vivo leiomyoma invasion model. Soluble factors derived from leiomyoma tissue, as well as purified extracellular matrix (ECM) proteins, were assessed for their ability to affect uPAR expression, glycosylation and cleavage. Activity of gelatinolytic enzymes in the tissues were assessed by in situ zymography. Results We found that increased levels of uPAR did not induce tumour invasion or metastasis. However, cells expressing low endogenous levels of uPAR in vitro up-regulated uPAR expression both in tongue, skin and leiomyoma tissue. Various ECM proteins had no effect on uPAR expression, while soluble factors originating from the leiomyoma tissue increased both the expression and glycosylation of uPAR, and possibly also affected the proteolytic processing of uPAR. Tumours with high levels of uPAR, as well as cells invading leiomyoma tissue with up-regulated uPAR expression, all displayed enhanced activity of gelatinolytic enzymes. Conclusions Although high levels of uPAR are not sufficient to induce invasion and metastasis, the activity of gelatinolytic enzymes was increased. Furthermore, several tumour microenvironments have the capacity to induce up-regulation of uPAR expression, and soluble factors in the tumour microenvironment may have an important role in the

  17. 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

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

    PubMed Central

    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

  19. 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

  20. 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.

  1. 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

  2. Highly functionalized 2-oxopiperazine-based peptidomimetics: an approach to PAR1 antagonists.

    PubMed

    Valdivielso, Ángel M; Ventosa-Andrés, Pilar; Tato, Francisco; Fernández-Ibañez, M Ángeles; Pappos, Ioannis; Tsopanoglou, Nikos E; García-López, M Teresa; Gutiérrez-Rodríguez, Marta; Herranz, Rosario

    2013-01-01

    A series of pseudodipeptide-based chiral 1,3,4,5-tetrasubstituted-2-oxopiperazines has been designed and synthesized as potential PAR1 antagonists. These highly functionalized piperazines were synthesized from aromatic and basic amino acid derived Ψ[CH(CN)NH]pseudodipeptides through a four step pathway that involves reduction of the cyano group to build the 2-oxopiperazine ring, followed by selective functionalization at the N₄-, N₁-positions, and at the exocyclic moiety at position C5. This regioselective functionalization required the fine tuning of reaction conditions. All new compounds were screened as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN and as cytotoxic agents in human cancer cell lines. Some of the compounds displayed moderate PAR1 antagonist activity, while, others were cytotoxic at μM concentration. No correlation was observed between both types of activities. PMID:24158013

  3. 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

  4. Linking the fPAR, forest albedo and biomass in the northern biomes of Europe

    NASA Astrophysics Data System (ADS)

    Lukeš, Petr; Stenberg, Pauline; Manninen, Terhikki; Rautiainen, Miina; Mõttus, Matti

    2014-05-01

    Land surface albedo and the fraction of photosynthetically active radiation (fPAR) absorbed by plant canopies are two of the essential climate variables controlling the planetary radiative energy budget. Albedo is directly related to the energy exchange between land and the atmosphere as it is the reflectivity of the surface - the higher the albedo, the more incoming solar radiation is reflected and the less absorbed by the surface. The fPAR is related to plant productivity, quantifying the amount of absorbed light available for photosynthesis. It is a key parameter in the modelling of net primary production (NPP) of terrestrial ecosystems. Global climate scenarios are very sensitive to albedo and fPAR estimates, and thus, the effect of changes in canopy structure and density (biomass) on these two variables needs to be quantified reliably. Both parameters are routinely retrieved from current Earth Observation sensors using specialized algorithms. To date, these satellite products have not been linked to extensive forest inventory data sets due to the lack of ground reference data. Data availability for Finland has significantly improved in December 2012, when National Forest Inventory (NFI) data became freely available to the public. The dataset covers the geographical area of Finland (26.1 million hectares) at a spatial resolution of 20 meters including several forest structural variables. In this study, we use the NFI data to study the links between forest albedo, fPAR and forest structure and density during the green vegetation season. More specifically, we investigated the seasonal trends in fPAR and albedo of different spectral regions of northern forests. Empirical relationships between forest albedo, fPAR and total aboveground biomass were established for selected days within the vegetation growing period and across a latitudinal transect of Finland.

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. The ratio of transmitted near-infrared radiation to photosynthetically active radiation (PAR) increases in proportion to the adsorbed PAR in the canopy.

    PubMed

    Kume, Atsushi; Nasahara, Kenlo N; Nagai, Shin; Muraoka, Hiroyuki

    2011-01-01

    The daily total photosynthetically active radiation (400-700 nm, PAR) and near-infrared radiation (700-1000 nm, NIR) were measured in the understory beneath the canopy (PARt and NIRt) and above the canopy (PARi and NIRi) of a Japanese cool-temperate deciduous broad-leaved forest during the snow-free period (May to November). The integration of spectral radiation for NIR and that for PAR, and the daily integrations of instantaneous NIR and PAR, reduced the noises from the optical difference in spectrum and from canopy structure heterogeneity, sky condition and solar elevation. PARi/PARt was linearly related to NIRt/PARt (R² = 0.96). The effect of cloudiness was negligible, because the fluctuation of NIRi/PARi was quite small regardless of season and weather conditions compared with the range of NIRt/PARt in the forest. The ratio of NIRt/PARt beneath the canopy was log-linearly related to the in situ leaf area index (LAI) with a wide range from 0 to 5.25 (R² = 0.97). We conclude that seasonal changes in fAPAR (= 1 - PARt/PARi) and LAI of a canopy can be estimated with high accuracy by transmitted NIRt and PARt beneath the canopy.

  10. Multi-purpose extraocular forceps for small-gauge pars plana vitrectomy.

    PubMed

    Reichel, Elias; Chun, Dal W; Gurley, Kiersten

    2012-01-01

    A multi-purpose titanium forceps has been developed for small-gauge pars plana vitrectomy surgery. These forceps were designed to provide the vitreoretinal surgeon with a single tool for the extraocular manipulations that are necessary for the placement and removal of 23- and 25-gauge trochars for small-incision, sutureless pars plana vitrectomy surgery. The forceps has been designed to allow for the atraumatic manipulation of the conjunctiva, measurement of distance from the limbus, and a strong purchase of the trochar for both its fixation and removal.

  11. Characterization of the stable maintenance properties of the par region of broad-host-range plasmid RK2.

    PubMed Central

    Sobecky, P A; Easter, C L; Bear, P D; Helinski, D R

    1996-01-01

    A 3.2-kb fragment encoding five genes, parCBA/DE, in two divergently transcribed operons promotes stable maintenance of the replicon of the broad-host-range plasmid RK2 in a vector-independent manner in Escherichia coli. The parDE operon has been shown to contribute to stabilization through the postsegregational killing of plasmid-free daughter cells, while the parCBA operon encodes a resolvase, ParA, that mediates the resolution of plasmid multimers through site-specific recombination. To date, evidence indicates that multimer resolution alone does not play a significant role in RK2 stable maintenance by the parCBA operon in E. coli. It has been proposed, instead, that the parCBA region encodes an additional stability mechanism, a partition system, that ensures that each daughter cell receives a plasmid copy at cell division. However, studies carried out to date have not directly determined the plasmid stabilization activity of the parCBA operon alone. An assessment was made of the relative contributions of postsegregational killing (parDE) and the putative partitioning system (parCBA) to the stabilization of mini-RK2 replicons in E. coli. Mini-RK2 replicons carrying either the entire 3.2-kb (parCBA/DE) fragment or the 2.3-kb parCBA region alone were found to be stably maintained in two E. coli strains tested. The stabilization found is not due to resolution of multimers. The stabilizing effectiveness of parCBA was substantially reduced when the plasmid copy number was lowered, as in the case of E. coli cells carrying a temperature-sensitive mini-RK2 replicon grown at a nonpermissive temperature. The presence of the entire 3.2-kb region effectively stabilized the replicon, however, under both low- and high-copy-number-conditions. In those instances of decreased plasmid copy number, the postsegregational killing activity, encoded by parDE, either as part of the 3.2-kb fragment or alone played the major role in the stabilization of mini-RK2 replicons within the

  12. Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex.

    PubMed

    Roll, Patrice; Vernes, Sonja C; Bruneau, Nadine; Cillario, Jennifer; Ponsole-Lenfant, Magali; Massacrier, Annick; Rudolf, Gabrielle; Khalife, Manal; Hirsch, Edouard; Fisher, Simon E; Szepetowski, Pierre

    2010-12-15

    It is a challenge to identify the molecular networks contributing to the neural basis of human speech. Mutations in transcription factor FOXP2 cause difficulties mastering fluent speech (developmental verbal dyspraxia, DVD), whereas mutations of sushi-repeat protein SRPX2 lead to epilepsy of the rolandic (sylvian) speech areas, with DVD or with bilateral perisylvian polymicrogyria. Pathophysiological mechanisms driven by SRPX2 involve modified interaction with the plasminogen activator receptor (uPAR). Independent chromatin-immunoprecipitation microarray screening has identified the uPAR gene promoter as a potential target site bound by FOXP2. Here, we directly tested for the existence of a transcriptional regulatory network between human FOXP2 and the SRPX2/uPAR complex. In silico searches followed by gel retardation assays identified specific efficient FOXP2-binding sites in each of the promoter regions of SRPX2 and uPAR. In FOXP2-transfected cells, significant decreases were observed in the amounts of both SRPX2 (43.6%) and uPAR (38.6%) native transcripts. Luciferase reporter assays demonstrated that FOXP2 expression yielded a marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity. A mutant FOXP2 that causes DVD (p.R553H) failed to bind to SRPX2 and uPAR target sites and showed impaired down-regulation of SRPX2 and uPAR promoter activity. In a patient with polymicrogyria of the left rolandic operculum, a novel FOXP2 mutation (p.M406T) was found in the leucine-zipper (dimerization) domain. p.M406T partially impaired the FOXP2 regulation of SRPX2 promoter activity, whereas that of the uPAR promoter remained unchanged. Together with recently described FOXP2-CNTNAP2 and SRPX2/uPAR links, the FOXP2-SRPX2/uPAR network provides exciting insights into molecular pathways underlying speech-related disorders.

  13. Interleukin 8 is differently expressed and modulated by PAR-1 activation in early and late endothelial progenitor cells.

    PubMed

    Smadja, David M; Bièche, Ivan; Susen, Sophie; Mauge, Laetitia; Laurendeau, Ingrid; d'Audigier, Clément; Grelac, Françoise; Emmerich, Joseph; Aiach, Martine; Gaussem, Pascale

    2009-08-01

    The proinflammatory chemokine interleukin 8 exerts potent angiogenic effects on endothelial cells by interacting with its receptors CXCR1 and CXCR2. As thrombin is also a potent inflammatory factor, and as endothelial progenitor cells (EPC) express functional PAR-1 thrombin receptor, we examined whether PAR-1 stimulation interferes with the IL-8 pathway in EPC. EPC were obtained from adult blood (AB) and cord blood (CB). The effect of PAR-1 stimulation by the peptide SFLLRN on IL-8, CXCR1 and CXCR2 expression was examined by RTQ-PCR and at the protein level in AB and CB late EPC and in AB early EPC. Specific siRNA was used to knock down PAR-1 expression. The IL-8 gene was expressed strongly in AB early EPC and moderately in late EPC. In contrast, CXCR1 and CXCR2 gene expression was restricted to AB early EPC. The IL-8 level in AB early EPC conditioned medium was high in basal conditions and did not change after PAR-1 activation. By contrast, IL-8 secretion by late EPC was low in basal conditions and strongly up-regulated upon PAR-1 activation. PAR-1 activation induced a number of genes involved in activating protein-1 (AP-1) and nuclear factor (NF)-kappaB pathways. Conditioned medium of PAR-1-activated late EPC enhanced the migratory potential of early EPC, and this effect was abrogated by blocking IL-8. Target-specific siRNA-induced PAR-1 knockdown, and fully inhibited PAR-1-induced IL-8 synthesis. In conclusion, PAR-1 activation induces IL-8 synthesis by late EPC. This could potentially enhance cooperation between late and early EPC during neovascularization, through a paracrine effect. PMID:18657231

  14. Planar Cell Polarity Breaks the Symmetry of PAR Protein Distribution prior to Mitosis in Drosophila Sensory Organ Precursor Cells.

    PubMed

    Besson, Charlotte; Bernard, Fred; Corson, Francis; Rouault, Hervé; Reynaud, Elodie; Keder, Alyona; Mazouni, Khalil; Schweisguth, François

    2015-04-20

    During development, cell-fate diversity can result from the unequal segregation of fate determinants at mitosis. Polarization of the mother cell is essential for asymmetric cell division (ACD). It often involves the formation of a cortical domain containing the PAR complex proteins Par3, Par6, and atypical protein kinase C (aPKC). In the fly notum, sensory organ precursor cells (SOPs) divide asymmetrically within the plane of the epithelium and along the body axis to generate two distinct cells. Fate asymmetry depends on the asymmetric localization of the PAR complex. In the absence of planar cell polarity (PCP), SOPs divide with a random planar orientation but still asymmetrically, showing that PCP is dispensable for PAR asymmetry at mitosis. To study when and how the PAR complex localizes asymmetrically, we have used a quantitative imaging approach to measure the planar polarization of the proteins Bazooka (Baz, fly Par3), Par6, and aPKC in living pupae. By using imaging of functional GFP-tagged proteins with image processing and computational modeling, we find that Baz, Par6, and aPKC become planar polarized prior to mitosis in a manner independent of the AuroraA kinase and that PCP is required for the planar polarization of Baz, Par6, and aPKC during interphase. This indicates that a "mitosis rescue" mechanism establishes asymmetry at mitosis in PCP mutants. This study therefore identifies PCP as the initial symmetry-breaking signal for the planar polarization of PAR proteins in asymmetrically dividing SOPs.

  15. Planar Cell Polarity Breaks the Symmetry of PAR Protein Distribution prior to Mitosis in Drosophila Sensory Organ Precursor Cells.

    PubMed

    Besson, Charlotte; Bernard, Fred; Corson, Francis; Rouault, Hervé; Reynaud, Elodie; Keder, Alyona; Mazouni, Khalil; Schweisguth, François

    2015-04-20

    During development, cell-fate diversity can result from the unequal segregation of fate determinants at mitosis. Polarization of the mother cell is essential for asymmetric cell division (ACD). It often involves the formation of a cortical domain containing the PAR complex proteins Par3, Par6, and atypical protein kinase C (aPKC). In the fly notum, sensory organ precursor cells (SOPs) divide asymmetrically within the plane of the epithelium and along the body axis to generate two distinct cells. Fate asymmetry depends on the asymmetric localization of the PAR complex. In the absence of planar cell polarity (PCP), SOPs divide with a random planar orientation but still asymmetrically, showing that PCP is dispensable for PAR asymmetry at mitosis. To study when and how the PAR complex localizes asymmetrically, we have used a quantitative imaging approach to measure the planar polarization of the proteins Bazooka (Baz, fly Par3), Par6, and aPKC in living pupae. By using imaging of functional GFP-tagged proteins with image processing and computational modeling, we find that Baz, Par6, and aPKC become planar polarized prior to mitosis in a manner independent of the AuroraA kinase and that PCP is required for the planar polarization of Baz, Par6, and aPKC during interphase. This indicates that a "mitosis rescue" mechanism establishes asymmetry at mitosis in PCP mutants. This study therefore identifies PCP as the initial symmetry-breaking signal for the planar polarization of PAR proteins in asymmetrically dividing SOPs. PMID:25843034

  16. Regulation of epithelial cell polarity by PAR-3 depends on Girdin transcription and Girdin-Gαi3 signaling.

    PubMed

    Sasaki, Kazunori; Kakuwa, Taku; Akimoto, Kazunori; Koga, Hisashi; Ohno, Shigeo

    2015-07-01

    Epithelial apicobasal polarity has fundamental roles in epithelial physiology and morphogenesis. The PAR complex, comprising PAR-3, PAR-6 and atypical protein kinase C (aPKC), is involved in determining cell polarity in various biological contexts, including in epithelial cells. However, it is not fully understood how the PAR complex induces apicobasal polarity. In this study, we found that PAR-3 regulates the protein expression of Girdin (also known as GIV or CCDC88A), a guanine-nucleotide-exchange factor (GEF) for heterotrimeric Gαi subunits, at the transcriptional level by cooperating with the AP-2 transcription factor. In addition, we confirmed that PAR-3 physically interacts with Girdin, and show that Girdin, together with the Gαi3 (also known as GNAI3), controls tight junction formation, apical domain development and actin organization downstream of PAR-3. Taken together, our findings suggest that transcriptional upregulation of Girdin expression and Girdin-Gαi3 signaling play crucial roles in regulating epithelial apicobasal polarity through the PAR complex.

  17. 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

  18. 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

  19. Regulation of epithelial cell polarity by PAR-3 depends on Girdin transcription and Girdin-Gαi3 signaling.

    PubMed

    Sasaki, Kazunori; Kakuwa, Taku; Akimoto, Kazunori; Koga, Hisashi; Ohno, Shigeo

    2015-07-01

    Epithelial apicobasal polarity has fundamental roles in epithelial physiology and morphogenesis. The PAR complex, comprising PAR-3, PAR-6 and atypical protein kinase C (aPKC), is involved in determining cell polarity in various biological contexts, including in epithelial cells. However, it is not fully understood how the PAR complex induces apicobasal polarity. In this study, we found that PAR-3 regulates the protein expression of Girdin (also known as GIV or CCDC88A), a guanine-nucleotide-exchange factor (GEF) for heterotrimeric Gαi subunits, at the transcriptional level by cooperating with the AP-2 transcription factor. In addition, we confirmed that PAR-3 physically interacts with Girdin, and show that Girdin, together with the Gαi3 (also known as GNAI3), controls tight junction formation, apical domain development and actin organization downstream of PAR-3. Taken together, our findings suggest that transcriptional upregulation of Girdin expression and Girdin-Gαi3 signaling play crucial roles in regulating epithelial apicobasal polarity through the PAR complex. PMID:25977476

  20. Operative treatment of prolapse of the pars membranacea of the trachea.

    PubMed

    Löhr, B; Jelke, L G; Schroeder, L

    1978-03-01

    A new method of operation for stiffening the tracheal back wall in cases of prolapse of the pars membranacea is reported; it has been applied with success on 22 cases. The advantages of this technically demanding operation starting from the neck over the method using transthoracic access with insertion of bone chips, fascia graft, or plastic prostheses are discussed.

  1. 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…

  2. 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

  3. 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

  4. 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.

  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 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…

  7. 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...

  8. [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.

  9. 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.

  10. Tuberculosis prevalence and risk factors for water buffalo in Pará, Brazil.

    PubMed

    Barbosa, José D; da Silva, Jenevaldo B; Rangel, Charles P; da Fonseca, Adivaldo H; Silva, Natália S; Bomjardim, Henrique A; Freitas, Nayra F Q R

    2014-03-01

    The prevalence of and possible risk factors for tuberculosis were studied in water buffalo from Pará, Brazil. In this study, 3,917 pregnant and nonpregnant female Murrah and Mediterranean buffaloes were studied; 2,089 originated from Marajó Island, and 1,108 were from the mainland. The comparative cervical tuberculin test was used as a diagnostic test for tuberculosis in these animals. The prevalence of positive buffaloes was 3.5 % (100/2,809) on Marajó Island and 7.2 % (80/1,108) on the mainland. The municipalities with the highest tuberculosis prevalence rates in animals were Ipixuna do Pará (10.1 %), Marapanim (9.8 %), Chaves (9.4 %), Paragominas (8.6 %), and Cachoeira do Arari (6.7 %). The tuberculosis prevalence was not significantly different between the Murrah (4.3 %) and Mediterranean (4.8 %) breeds or between pregnant (5 %) and nonpregnant (4.3 %) buffaloes. Tuberculosis was detected in water buffaloes from Pará, Brazil; the mainland buffalo exhibited the highest tuberculosis prevalence. These results indicate that this disease is dangerous to public health and buffalo farming in Pará.

  11. 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.

  12. 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

  13. 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

  14. 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,…

  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. 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…

  17. Tuberculosis prevalence and risk factors for water buffalo in Pará, Brazil.

    PubMed

    Barbosa, José D; da Silva, Jenevaldo B; Rangel, Charles P; da Fonseca, Adivaldo H; Silva, Natália S; Bomjardim, Henrique A; Freitas, Nayra F Q R

    2014-03-01

    The prevalence of and possible risk factors for tuberculosis were studied in water buffalo from Pará, Brazil. In this study, 3,917 pregnant and nonpregnant female Murrah and Mediterranean buffaloes were studied; 2,089 originated from Marajó Island, and 1,108 were from the mainland. The comparative cervical tuberculin test was used as a diagnostic test for tuberculosis in these animals. The prevalence of positive buffaloes was 3.5 % (100/2,809) on Marajó Island and 7.2 % (80/1,108) on the mainland. The municipalities with the highest tuberculosis prevalence rates in animals were Ipixuna do Pará (10.1 %), Marapanim (9.8 %), Chaves (9.4 %), Paragominas (8.6 %), and Cachoeira do Arari (6.7 %). The tuberculosis prevalence was not significantly different between the Murrah (4.3 %) and Mediterranean (4.8 %) breeds or between pregnant (5 %) and nonpregnant (4.3 %) buffaloes. Tuberculosis was detected in water buffaloes from Pará, Brazil; the mainland buffalo exhibited the highest tuberculosis prevalence. These results indicate that this disease is dangerous to public health and buffalo farming in Pará. PMID:24356890

  18. 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

  19. Dengue epidemic in Belém, Pará, Brazil, 1996-97.

    PubMed

    Trravassos da Rosa, A P; Vasconcelos, P F; Travassos Da Rosa, E S; Rodrigues, S G; Mondet, B; Cruz, A C; Sousa, M R; Travassos Da Rosa, J F

    2000-01-01

    We describe clinical and epidemiologic findings during the first epidemic of dengue fever in Belém, Pará State, Brazil, in 1996-97. Of 40,237 serum samples, 17,440 (43%) were positive for dengue by virus isolation or serologic testing. No hemorrhagic cases or deaths were reported. Mycobacterium tuberculosis

  20. 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.

  1. 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

  2. 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

  3. 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

  4. uPAR-targeted Optical Imaging Contrasts as Theranostic Agents for Tumor Margin Detection

    PubMed Central

    Yang, Lily; Sajja, Hari Krishna; Cao, Zehong; Qian, Weiping; Bender, Laura; Marcus, Adam I.; Lipowska, Malgorzata; Wood, William C.; Wang, Y. Andrew

    2014-01-01

    Complete removal of tumors by surgery is the most important prognostic factor for cancer patients with the early stage cancers. The ability to identify invasive tumor edges of the primary tumor, locally invaded small tumor lesions, and drug resistant residual tumors following neoadjuvant therapy during surgery should significantly reduce the incidence of local tumor recurrence and improve survival of cancer patients. In this study, we report that urokinase plasminogen activator (uPA) and its receptor (uPAR) are the ligand/cell surface target pair for the development of targeted optical imaging probes for enhancing imaging contrasts in the tumor border. Recombinant peptides of the amino terminal fragment (ATF) of the receptor binding domain of uPA were labeled with near infrared fluorescence (NIR) dye molecules either as peptide-imaging or peptide-conjugated nanoparticle imaging probes. Systemic delivery of the uPAR-targeted imaging probes in mice bearing orthotopic human breast or pancreatic tumor xenografts or mouse mammary tumors led to the accumulation of the probes in the tumor and stromal cells, resulting in strong signals for optical imaging of tumors and identification of tumor margins. Histological analysis showed that a high level of uPAR-targeted nanoparticles was present in the tumor edge or active tumor stroma immediately adjacent to the tumor cells. Furthermore, following targeted therapy using uPAR-targeted theranostic nanoparticles, residual tumors were detectable by optical imaging through the imaging contrasts produced by NIR-dye-labeled theranostic nanoparticles in drug resistant tumor cells. Therefore, results of our study support the potential of the development of uPAR-targeted imaging and theranostic agents for image-guided surgery. PMID:24396518

  5. 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

  6. 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

  7. Ultrasound biomicroscopy of the peripheral retina and the ciliary body in degenerative retinoschisis associated with pars plana cysts

    PubMed Central

    Mannino, G.; Malagola, R.; Abdolrahimzadeh, S.; Villani, G.; Recupero, S.

    2001-01-01

    AIM—To evaluate the ciliary body and peripheral retina in degenerative retinoschisis associated with pars plana cysts using ultrasound biomicroscopy (UBM).
METHODS—18 eyes of 12 patients with degenerative retinoschisis associated with pars plana cysts were selected through binocular indirect ophthalmoscopy and Goldmann three mirror lens examination, both with scleral depression. These patients were studied in detail with UBM.
RESULTS—Study of the ciliary body with UBM showed pars plana cysts of different size and uneven shape. In cross sections the morphology of pars plana cysts in detail and the close relation of the cysts with the oral region and the peripheral retina, where areas of cystoid degeneration and retinoschisis were present, were observed. In transverse sections three main morphological aspects of pars plana cysts could be differentiated ("isolated," "confluent," and "clustered" cysts). Furthermore, ultrabiomicroscopy allowed differential diagnosis between retinoschisis and associated retinal detachment in six eyes.
CONCLUSIONS—The study of peripheral degenerative retinoschisis and pars plana cysts is possible in vivo by means of UBM, showing the detailed morphology of the lesions (not otherwise evident through ophthalmoscopic examination) and the close relation between pars plana cysts, cystoid degeneration, and peripheral retinoschisis.

 PMID:11466258

  8. Expression of MMP-1/PAR-1 and patterns of invasion in oral squamous cell carcinoma as potential prognostic markers

    PubMed Central

    Fan, Hai-Xia; Chen, Yan; Ni, Bo-Xiong; Wang, Shan; Sun, Miao; Chen, Dong; Zheng, Jin-Hua

    2015-01-01

    Background Matrix metalloproteinase (MMP)-1 degrades type I collagen of the extracellular matrix and also activates protease activated receptor (PAR)-1 to induce angiogenesis. The aims of this study were to evaluate microvessel density (MVD) and the expression of PAR-1 and MMP-1 in oral squamous cell carcinoma (SCC) specimens with different patterns of invasion (POI) and to evaluate their association with clinical outcomes. Methods Seventy-four surgically obtained oral SCC samples were classified by POI according to hematoxylin-eosin staining. MVD and the localization and intensity of PAR-1 and MMP-1 expression were detected by immunohistochemistry. Results Of the 74 oral SCC samples, 18, 5, 34, and 17 showed type I, II, III, and IV POI, respectively. MVD and expression levels of MMP-1 and PAR-1 differed between POI types I–II and POI types III–IV. Patients with low tumor expression of MMP-1 and PAR-1 and low MVD had a longer survival time than those with high tumor expression of MMP-1 and PAR-1. Moreover, the survival time of patients with POI types III–IV was shorter than that of patients with POI types I–II. Conclusion POI combined with expression levels of MMP-1 and PAR-1 may be a valuable tool for assessing the clinical prognosis of patients with oral SCC. PMID:26170698

  9. Tight junction protein Par6 interacts with an evolutionarily conserved region in the amino terminus of PALS1/stardust.

    PubMed

    Wang, Qian; Hurd, Toby W; Margolis, Ben

    2004-07-16

    Tight junctions are the structures in mammalian epithelial cells that separate the apical and basolateral membranes and may also be important in the establishment of cell polarity. Two evolutionarily conserved multiprotein complexes, Crumbs-PALS1 (Stardust)-PATJ and Cdc42-Par6-Par3-atypical protein kinase C, have been implicated in the assembly of tight junctions and in polarization of Drosophila melanogaster epithelia. These two complexes have been linked physically and functionally by an interaction between PALS1 and Par6. Here we identify an evolutionarily conserved region in the amino terminus of PALS1 as the Par6 binding site and identify valine and aspartic acid residues in this region as essential for interacting with the PDZ domain of Par6. We have also characterized, in more detail, the amino terminus of Drosophila Stardust and demonstrate that the interaction mechanism between Stardust and Drosophila Par6 is evolutionarily conserved. Par6 interferes with PATJ in binding PALS1, and these two interactions do not appear to function synergistically. Taken together, these results define the molecular mechanisms linking two conserved polarity complexes.

  10. The Clinical Value of Soluble Urokinase Plasminogen Activator Receptor (suPAR) Levels in Autoimmune Connective Tissue Disorders

    PubMed Central

    Toldi, Gergely; Balog, Attila

    2016-01-01

    The assessment of the general inflammatory condition of patients with autoimmune connective tissue disorders (ACTD) is a major challenge. The use of traditional inflammatory markers including CRP-levels and erythrocyte sedimentation rate (ESR) is limited by several preanalytical factors and their low specificities. Soluble urokinase plasminogen activator receptor (suPAR) is one of the novel candidate markers that is increasingly used in immune mediated disorders. In our studies we compared suPAR levels of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and ankylosing spondylitis with those of healthy controls. suPAR provided valuable clinical information on disease activity in RA, SLE and SSc. We identified a subgroup of remitted RA patients, who presented still clinical symptoms of inflammatory activity which correlated to high plasma suPAR (while ESR and CRP were normal). In SLE we established specific suPAR cut-off values that support the discrimination between patients with high and those with moderate SLE activity. In patients with SSc suPAR correlated with objective measures of lung and other complications. In the majority of ACTDs including SLE, SSc or RA, suPAR is seemingly a good biomarker that would provide valuable clinical information. However, before the introduction of this novel parameter in laboratory repertoire important issues should be elucidated. These include the establishment of appropriate and disease specific cutoff values, clarification of interfering preanalytical values and underlying conditions and declaration of age- and gender-specific reference ranges. PMID:27683525

  11. The Clinical Value of Soluble Urokinase Plasminogen Activator Receptor (suPAR) Levels in Autoimmune Connective Tissue Disorders.

    PubMed

    Vasarhelyi, Barna; Toldi, Gergely; Balog, Attila

    2016-04-01

    The assessment of the general inflammatory condition of patients with autoimmune connective tissue disorders (ACTD) is a major challenge. The use of traditional inflammatory markers including CRP-levels and erythrocyte sedimentation rate (ESR) is limited by several preanalytical factors and their low specificities. Soluble urokinase plasminogen activator receptor (suPAR) is one of the novel candidate markers that is increasingly used in immune mediated disorders. In our studies we compared suPAR levels of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and ankylosing spondylitis with those of healthy controls. suPAR provided valuable clinical information on disease activity in RA, SLE and SSc. We identified a subgroup of remitted RA patients, who presented still clinical symptoms of inflammatory activity which correlated to high plasma suPAR (while ESR and CRP were normal). In SLE we established specific suPAR cut-off values that support the discrimination between patients with high and those with moderate SLE activity. In patients with SSc suPAR correlated with objective measures of lung and other complications. In the majority of ACTDs including SLE, SSc or RA, suPAR is seemingly a good biomarker that would provide valuable clinical information. However, before the introduction of this novel parameter in laboratory repertoire important issues should be elucidated. These include the establishment of appropriate and disease specific cutoff values, clarification of interfering preanalytical values and underlying conditions and declaration of age- and gender-specific reference ranges. PMID:27683525

  12. Neutrophil Elastase and Proteinase-3 Trigger G Protein-biased Signaling through Proteinase-activated Receptor-1 (PAR1)*

    PubMed Central

    Mihara, Koichiro; Ramachandran, Rithwik; Renaux, Bernard; Saifeddine, Mahmoud; Hollenberg, Morley D.

    2013-01-01

    Neutrophil proteinases released at sites of inflammation can affect tissue function by either activating or disarming signal transduction mediated by proteinase-activated receptors (PARs). Because PAR1 is expressed at sites where abundant neutrophil infiltration occurs, we hypothesized that neutrophil-derived enzymes might also regulate PAR1 signaling. We report here that both neutrophil elastase and proteinase-3 cleave the human PAR1 N terminus at sites distinct from the thrombin cleavage site. This cleavage results in a disarming of thrombin-activated calcium signaling through PAR1. However, the distinct non-canonical tethered ligands unmasked by neutrophil elastase and proteinase-3, as well as synthetic peptides with sequences derived from these novel exposed tethered ligands, selectively stimulated PAR1-mediated mitogen-activated protein kinase activation. This signaling was blocked by pertussis toxin, implicating a Gαi-triggered signal pathway. We conclude that neutrophil proteinases trigger biased PAR1 signaling and we describe a novel set of tethered ligands that are distinct from the classical tethered ligand revealed by thrombin. We further demonstrate the function of this biased signaling in regulating endothelial cell barrier integrity. PMID:24052258

  13. Developpement d'algorithmes de reconstruction statistique appliques en tomographie rayons-X assistee par ordinateur

    NASA Astrophysics Data System (ADS)

    Thibaudeau, Christian

    La tomodensitometrie (TDM) permet d'obtenir, et ce de facon non invasive, une image tridimensionnelle de l'anatomie interne d'un sujet. Elle constitue l'evolution logique de la radiographie et permet l'observation d'un volume sous differents plans (sagittal, coronal, axial ou n'importe quel autre plan). La TDM peut avantageusement completer la tomographie d'emission par positrons (TEP), un outil de predilection utilise en recherche biomedicale et pour le diagnostic du cancer. La TEP fournit une information fonctionnelle, physiologique et metabolique, permettant la localisation et la quantification de radiotraceurs a l'interieur du corps humain. Cette derniere possede une sensibilite inegalee, mais peut neanmoins souffrir d'une faible resolution spatiale et d'un manque de repere anatomique selon le radiotraceur utilise. La combinaison, ou fusion, des images TEP et TDM permet d'obtenir cette localisation anatomique de la distribution du radiotraceur. L'image TDM represente une carte de l'attenuation subie par les rayons-X lors de leur passage a travers les tissus. Elle permet donc aussi d'ameliorer la quantification de l'image TEP en offrant la possibilite de corriger pour l'attenuation. L'image TDM s'obtient par la transformation de profils d'attenuation en une image cartesienne pouvant etre interpretee par l'humain. Si la qualite de cette image est fortement influencee par les performances de l'appareil, elle depend aussi grandement de la capacite de l'algorithme de reconstruction a obtenir une representation fidele du milieu image. Les techniques de reconstruction standards, basees sur la retroprojection filtree (FBP, filtered back-projection), reposent sur un modele mathematiquement parfait de la geometrie d'acquisition. Une alternative a cette methode etalon est appelee reconstruction statistique, ou iterative. Elle permet d'obtenir de meilleurs resultats en presence de bruit ou d'une quantite limitee d'information et peut virtuellement s'adapter a toutes formes

  14. 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

  15. Quantitative contributions of blue light and PAR to the photocontrol of plant morphogenesis in Trifolium repens (L.).

    PubMed

    Christophe, Angélique; Moulia, Bruno; Varlet-Grancher, Claude

    2006-01-01

    Shade-avoidance is a major adaptive response of plants, and is usually considered to be controlled by phytochromes through the perception of changes in the red:far red light ratio. However, few studies on the effects of blue light (BL) and of light intensity [photosynthetically active radiation (PAR)] on light-grown plants have been conducted, especially concerning changes in PAR at constant BL. The objective here was to quantify the photocontrol of aerial morphogenesis by BL and PAR. Experiments were conducted varying BL and PAR independently, with three BL levels (4, 38, and 83 micromol m(-2) s(-1)) at constant PAR (300 micromol m(-2) s(-1)) and three PAR levels (338, 705, and 163 micromol m(-2) s(-1)) at constant BL (36 micromol m(-2) s(-1)). Effects on morphogenetic processes were analysed as quantitative modulations of ontogenic trends and response curves were produced. White clover (Trifolium repens L.) was used, as it is a typical shade-avoider displaying the whole syndrome of shade-avoidance in a purely vegetative stage. Morphological responses were strongly controlled by both BL and PAR changes, through antagonist effects on leaf appearance rate and additive effects on petiole elongation. All the other responses appeared to be the indirect consequences of changes in the leaf appearance rates. BL acted as a light signal for plant morphogenesis. However, the PAR control probably implicates two distinct mechanisms, such as a trophic effect and a signal. Both PAR and BL actions involved organ-specific differences, which are central in the control of the shade-avoidance responses.

  16. 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

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. 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).

  2. 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

  3. 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

  4. 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.

  5. 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

  6. 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.

  7. Gliome du nerf optique révélé par un strabisme divergent

    PubMed Central

    Handor, Hanan; Laghmari, Mina; Hafidi, Zouheir; Daoudi, Rajae

    2014-01-01

    Les gliomes des nerfs optiques sont des tumeurs rares qui s'observent essentiellement chez l'enfant. L'exophtalmie et le strabisme sont les principaux signes révélateurs de la maladie. La neuroimagerie et notamment l'imagerie par résonnance magnétique est d'un grand apport dans le diagnostic et le suivi de ces tumeurs. La prise en charge thérapeutique de ces gliomes fait appel à différents moyens: l'exérèse chirurgicale, la chimiothérapie, la radiothérapie ou l'abstention sous surveillance. Les indications doivent être discutées au cas par cas. PMID:25309656

  8. [Slaves in purgatory: the Tucunduba Leprosarium (Pará, nineteenth century)].

    PubMed

    Henrique, Márcio Couto

    2012-12-01

    The article analyzes the experience of the slaves interned at the Tucunduba Leprosarium in Belém, state of Pará during the nineteenth century. The slaves were freed once they showed the marks of their leprosy, and expectations were that they would submit to the segregation policy meant to keep them from contact with the rest of the population. The documentation produced by Santa Casa de Misericórdia hospital in Pará and by the province's political authorities reveals the strategies the slaves devised in response to this policy; they used their numerical predominance at the leprosarium to create a network of solidarity that allowed them to recreate their lives and stand in opposition to the type of nation that the era's hygienist theories envisioned.

  9. Laser Nd:YVO{4} impulsionnel à 914 nm pompé par diode

    NASA Astrophysics Data System (ADS)

    Blandin, P.; Druon, F.; Balembois, F.; Georges, P.; Lévêque-Fort, S.; Fontaine-Aupart, M. P.

    2006-10-01

    Nous présentons ici le premier laser impulsionnel à verrouillage de modes en phase passif directement pompé par diode, utilisant la transition 4F{3 / 2}-4I{9/2} de l'ion néodyme à 914 nm. Le système de pompage utilisé permet d'obtenir un dispositif simple. Le train d'impulsions est obtenu grâce à un miroir à absorbant saturable, l'émission laser à 914 nm étant privilégiée par l'introduction dans la cavité de fortes pertes à 1064 nm. Nous obtenons avec notre dispositif des impulsions à 913.8 nm, de durée 8.8 ps à une cadence de 94 MHz et à une puissance de 86 mW.

  10. 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.

  11. Pars planitis is associated with an increased frequency of effector‐memory CD57+ T cells

    PubMed Central

    Pedroza‐Seres, Miguel; Linares, Marisela; Voorduin, Stephanie; Enrique, Rojas‐Ramos; Lascurain, Ricardo; Garfias, Yonathan; Jimenez‐Martinez, Maria Carmen

    2007-01-01

    Aim To evaluate the frequency, phenotype and the potential function of CD57+ T cell subsets in patients with pars planitis. Methods CD4+CD57+ and CD8+CD57+ T cells were quantitated in peripheral blood from 15 patients with pars planitis and 15 healthy controls. To evaluate the phenotype and potential function of CD57+ T cell subsets CCR7, CD27, CD28, CD45RA, CD45RO, intracellular IFN‐γ, IL‐4, perforin and granzyme‐A expression were assessed by flow cytometry. Results CD57+ T cells subsets were increased in patients with pars planitis (p = 0.002). The majority of CD4+CD57+ T cells were CCR7−CD27−CD28−CD45RO+, while the most CD8+CD57+ T cells were CCR7−CD27−CD28−CD45RA+. The number of cells positive for intracellular IFN‐γ and IL‐4 was higher in the CD57+ T cell populations. A greater number of CD8+CD57+ T cells than CD8+CD57− T cells were positive to perforin (p = 0.006) and granzyme‐A (p = 0.01). Conclusions CD57+ T cells had a phenotype associated with peripheral memory (CCR7−CD27−CD28−). Cytokine production by CD57+ T cells suggests that these cells may play a role in helper cell regulation. High expression of intracellular proteins involved in cytotoxicity suggests that CD8+CD57+ T cells may play an effector role. Taken together, this study proposes that CD57+ T cells function as memory‐effector T cell subsets during pars planitis pathogenesis. PMID:17475702

  12. 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

  13. 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

  14. 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.

  15. L'analyse par activation de neutrons de réacteur

    NASA Astrophysics Data System (ADS)

    Meyer, G.

    2003-02-01

    Quand les neutrons traversent la matière, certains sont transmis sans interaction, les autres interagissent avec le milieu traversé par diffusion et par absorption. Ce phénomène d'absorption est utilisé pour se protéger des neutrons, mais aussi pour les détecter; il peut également être utilisé pour identifier les noyaux “absorbants" et ainsi analyser le milieu traversé. En effet par différentes réactions nucléaires (n,γ), (n,p), (n,α), (n,fission), on obtient des noyaux résiduels qui sont souvent radioactifs; on dit que l'échantillon est “activé". Si l'on connaît le rendement d'activation et donc le pourcentage de noyaux ainsi “transmutés", les mesures de radioactivité induite vont permettre de déterminer la composition de l'échantillon irradié. Cette méthode dite d'analyse par activation neutronique est pratiquée depuis la découverte du neutron. Elle a permis grâce à sa sélectivité et à sa sensibilité d'avoir accès au domaine des traces et des ultra-traces dans des champs d'application très divers comme la métallurgie, l'archéologie, la biologie, la géochimie etc...

  16. Laser picoseconde pompé par diode à basse cadence de récurrence

    NASA Astrophysics Data System (ADS)

    Albert, A.; Couderc, V.; Louradour, F.; Barthélémy, A.

    2002-06-01

    Nous présentons une étude expérimentale d'un laser Nd:YAG picoseconde à faible cadence de récurrence. Nous comparons les performances obtenues avec un laser de cavité métrique utilisant la même source de pompe. Des gains en énergie et en puissance crête par impulsion de 10 et 7 ont été obtenus.

  17. Multiple enzymatic activities of ParB/Srx superfamily mediate sexual conflict among conjugative plasmids

    PubMed Central

    Maindola, Priyank; Raina, Rahul; Goyal, Parveen; Atmakuri, Krishnamohan; Ojha, Abhishek; Gupta, Sourabh; Christie, Peter J.; Iyer, Lakshminarayan M.; Aravind, L.; Arockiasamy, Arulandu

    2014-01-01

    Conjugative plasmids are typically locked in intergenomic and sexual conflicts with coresident rivals, whose translocation they block using fertility inhibition factors (FINs). We describe here the first crystal structure of an enigmatic FIN Osa deployed by the proteobacterial plasmid pSa. Osa contains a catalytically active version of the ParB/Sulfiredoxin fold with both ATPase and DNase activity, the latter being regulated by an ATP-dependent switch. Using the Agrobacterium tumefaciens VirB/D4 type-IV secretion system (T4SS), a relative of the conjugative T4SS, we demonstrate that catalytically active Osa blocks T-DNA transfer into plants. With a partially reconstituted T4SS in vitro, we show that Osa degrades T-DNA in the T-DNA-VirD2 complex prior to its translocation. Further, we present evidence for conservation and interplay between ATPase and DNase activities throughout the ParB/Sulfiredoxin fold, using other members of the family, namely P1 ParB and RK2 KorB, which have general functional implications across diverse biological contexts. PMID:25358815

  18. Monthly ratios of PAR to global solar radiation measured at northern Tibetan Plateau, China

    SciTech Connect

    Li, Ren; Zhao, Lin; Xiao, Yao; Liu, Guangyue; Sun, Linchan; Ding, Yongjian; Wang, Sheng; Ji, Guoliang

    2010-06-15

    Using narrowband and broadband solar radiation measurements collected at Wudaoliang (WDL) site in northern Tibetan Plateau (NTP) from September 1993 to December 1998, the relationship between monthly photosynthetically active radiation (Q{sub P}) and global solar radiation (R{sub S}) values is analyzed. Temporal variability of the ratio (Q{sub P}/R{sub S}) and its further dependence on several meteorological variables are presented. The narrowband ratio exhibited diurnal and seasonal variability with high values during morning and afternoon hours and low values around noon in winter time, whereas during summer period the ratio was decreased from morning to afternoon. The ratio (Q{sub P}/R{sub S}) was correlated positively with several atmospheric parameters such as water vapor pressure and low-level cloud amount; in contrast, the ratio was negatively correlated with clearness index, relative sunshine duration and atmospheric turbidity. It was also found that both the relative sunshine duration and water vapor pressure are the most influential parameters on the estimations of the spectral PAR ratio. Finally, an empirically derived model is proposed for estimating monthly average PAR values over the northern Tibetan Plateau. Verification results further ensured that the proposed model predicts monthly global PAR values accurately. (author)

  19. 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

  20. 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

  1. 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

  2. Cortical geometry may influence placement of interface between Par protein domains in early Caenorhabditis elegans embryos.

    PubMed

    Dawes, Adriana T; Iron, David

    2013-09-21

    During polarization, proteins and other polarity determinants segregate to the opposite ends of the cell (the poles) creating biochemically and dynamically distinct regions. Embryos of the nematode worm Caenorhabditis elegans (C. elegans) polarize shortly after fertilization, creating distinct regions of Par protein family members. These regions are maintained through to first cleavage when the embryo divides along the plane specified by the interface between regions, creating daughter cells with different protein content. In wild type single cell embryos the interface between these Par protein regions is reliably positioned at approximately 60% egg length, however, it is not known what mechanisms are responsible for specifying the position of the interface. In this investigation, we use two mathematical models to investigate the movement and positioning of the interface: a biologically based reaction-diffusion model of Par protein dynamics, and the analytically tractable perturbed Allen-Cahn equation. When we numerically simulate the models on a static 2D domain with constant thickness, both models exhibit a persistently moving interface that specifies the boundary between distinct regions. When we modify the simulation domain geometry, movement halts and the interface is stably positioned where the domain thickness increases. Using asymptotic analysis with the perturbed Allen-Cahn equation, we show that interface movement depends explicitly on domain geometry. Using a combination of analytic and numeric techniques, we demonstrate that domain geometry, a historically overlooked aspect of cellular simulations, may play a significant role in spatial protein patterning during polarization.

  3. Compartmentalized calcium signaling triggers subpopulation formation upon platelet activation through PAR1.

    PubMed

    Sveshnikova, Anastasia N; Ataullakhanov, Fazoil I; Panteleev, Mikhail A

    2015-04-01

    Blood platelets need to undergo activation to carry out their function of stopping bleeding. Different activation degrees lead to a stepped hierarchy of responses: ability to aggregate, granule release, and, in a fraction of platelets, phosphatidylserine (PS) exposure. This suggests the existence of decision-making mechanisms in the platelet intracellular signaling network. To identify and investigate them, we developed a computational model of PAR1-stimulated platelet signal transduction that included a minimal set of major players in the calcium signaling network. The model comprised three intracellular compartments: cytosol, dense tubular system (DTS) and mitochondria and extracellular space. Computer simulations showed that the stable resting state of platelets is maintained via a balance between calcium pumps and leaks through the DTS and plasma membranes. Stimulation of PAR1 induced oscillations in the cytosolic calcium concentrations, in good agreement with experimental observations. Further increase in the agonist level activated the mitochondrial uniporter leading to calcium uptake by mitochondria, which caused the collapse of mitochondrial membrane potential in a fraction of platelets leading to the PS exposure. The formation of this subpopulation was shown to be a stochastic process determined by the small number of activated PAR1 receptors and by heterogeneity in the number of ion pumps. These results demonstrate how a gradual increase of the activation degree can be converted into a stepped response hierarchy ultimately leading to formation of two distinct subpopulations from an initially homogeneous population. PMID:25627921

  4. PAR-2, LGL-1 and the CDC-42 GAP CHIN-1 act in distinct pathways to maintain polarity in the C. elegans embryo.

    PubMed

    Beatty, Alexander; Morton, Diane G; Kemphues, Kenneth

    2013-05-01

    In the one-cell C. elegans embryo, polarity is maintained by mutual antagonism between the anterior cortical proteins PAR-3, PKC-3, PAR-6 and CDC-42, and the posterior cortical proteins PAR-2 and LGL-1 on the posterior cortex. The mechanisms by which these proteins interact to maintain polarity are incompletely understood. In this study, we investigate the interplay among PAR-2, LGL-1, myosin, the anterior PAR proteins and CDC-42. We find that PAR-2 and LGL-1 affect cortical myosin accumulation by different mechanisms. LGL-1 does not directly antagonize the accumulation of cortical myosin and instead plays a role in regulating PAR-6 levels. By contrast, PAR-2 likely has separate roles in regulating cortical myosin accumulation and preventing the expansion of the anterior cortical domain. We also provide evidence that asymmetry of active CDC-42 can be maintained independently of LGL-1 and PAR-2 by a redundant pathway that includes the CDC-42 GAP CHIN-1. Finally, we show that, in addition to its primary role in regulating the size of the anterior cortical domain via its binding to PAR-6, CDC-42 has a secondary role in regulating cortical myosin that is not dependent on PAR-6.

  5. Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4.

    PubMed

    Kaplan, Zane S; Zarpellon, Alessandro; Alwis, Imala; Yuan, Yuping; McFadyen, James; Ghasemzadeh, Mehran; Schoenwaelder, Simone M; Ruggeri, Zaverio M; Jackson, Shaun P

    2015-01-01

    Thrombin is a central regulator of leukocyte recruitment and inflammation at sites of vascular injury, a function thought to involve primarily endothelial PAR cleavage. Here we demonstrate the existence of a distinct leukocyte-trafficking mechanism regulated by components of the haemostatic system, including platelet PAR4, GPIbα and fibrin. Utilizing a mouse endothelial injury model we show that thrombin cleavage of platelet PAR4 promotes leukocyte recruitment to sites of vascular injury. This process is negatively regulated by GPIbα, as seen in mice with abrogated thrombin-platelet GPIbα binding (hGPIbα(D277N)). In addition, we demonstrate that fibrin limits leukocyte trafficking by forming a physical barrier to intravascular leukocyte migration. These studies demonstrate a distinct 'checkpoint' mechanism of leukocyte trafficking involving balanced thrombin interactions with PAR4, GPIbα and fibrin. Dysregulation of this checkpoint mechanism is likely to contribute to the development of thromboinflammatory disorders.

  6. Approaching Long Genomic Regions and Large Recombination Rates with msParSm as an Alternative to MaCS

    PubMed Central

    Montemuiño, Carlos; Espinosa, Antonio; Moure, Juan C.; Vera, Gonzalo; Hernández, Porfidio; Ramos-Onsins, Sebastián

    2016-01-01

    The msParSm application is an evolution of msPar, the parallel version of the coalescent simulation program ms, which removes the limitation for simulating long stretches of DNA sequences with large recombination rates, without compromising the accuracy of the standard coalescence. This work introduces msParSm, describes its significant performance improvements over msPar and its shared memory parallelization details, and shows how it can get better, if not similar, execution times than MaCS. Two case studies with different mutation rates were analyzed, one approximating the human average and the other approximating the Drosophila melanogaster average. Source code is available at https://github.com/cmontemuino/msparsm. PMID:27721650

  7. 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

  8. uPAR targeted radionuclide therapy with (177)Lu-DOTA-AE105 inhibits dissemination of metastatic prostate cancer.

    PubMed

    Persson, Morten; Juhl, Karina; Rasmussen, Palle; Brandt-Larsen, Malene; Madsen, Jacob; Ploug, Michael; Kjaer, Andreas

    2014-08-01

    The urokinase-type plasminogen activator receptor (uPAR) is implicated in cancer invasion and metastatic development in prostate cancer and provides therefore an attractive molecular target for both imaging and therapy. In this study, we provide the first in vivo data on an antimetastatic effect of uPAR radionuclide targeted therapy in such lesions and show the potential of uPAR positron emission tomography (PET) imaging for identifying small foci of metastatic cells in a mouse model of disseminating human prostate cancer. Two radiolabeled ligands were generated in high purity and specific activity: a uPAR-targeting probe ((177)Lu-DOTA-AE105) and a nonbinding control ((177)Lu-DOTA-AE105mut). Both uPAR flow cytometry and ELISA confirmed high expression levels of the target uPAR in PC-3M-LUC2.luc cells, and cell binding studies using (177)Lu-DOTA-AE105 resulted in a specific binding with an IC50 value of 100 nM in a competitive binding experiment. In vivo, uPAR targeted radionuclide therapy significantly reduced the number of metastatic lesions in the disseminated metastatic prostate cancer model, when compared to vehicle and nontargeted (177)Lu groups (p < 0.05) using bioluminescence imaging. Moreover, we found a significantly longer metastatic-free survival, with 65% of all mice without any disseminated metastatic lesions present at 65 days after first treatment dose (p = 0.047). In contrast, only 30% of all mice in the combined control groups treated with (177)Lu-DOTA-AE105mut or vehicle were without metastatic lesions. No treatment-induced toxicity was observed during the study as evaluated by observing animal weight and H&E staining of kidney tissue (dose-limiting organ). Finally, uPAR PET imaging using (64)Cu-DOTA-AE105 detected all small, disseminated metastatic foci when compared with bioluminescence imaging in a cohort of animals during the treatment study. In conclusion, uPAR targeted radiotherapy resulted in a significant reduction in the number of

  9. Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex

    PubMed Central

    Roll, Patrice; Vernes, Sonja C.; Bruneau, Nadine; Cillario, Jennifer; Ponsole-Lenfant, Magali; Massacrier, Annick; Rudolf, Gabrielle; Khalife, Manal; Hirsch, Edouard; Fisher, Simon E.; Szepetowski, Pierre

    2010-01-01

    It is a challenge to identify the molecular networks contributing to the neural basis of human speech. Mutations in transcription factor FOXP2 cause difficulties mastering fluent speech (developmental verbal dyspraxia, DVD), whereas mutations of sushi-repeat protein SRPX2 lead to epilepsy of the rolandic (sylvian) speech areas, with DVD or with bilateral perisylvian polymicrogyria. Pathophysiological mechanisms driven by SRPX2 involve modified interaction with the plasminogen activator receptor (uPAR). Independent chromatin-immunoprecipitation microarray screening has identified the uPAR gene promoter as a potential target site bound by FOXP2. Here, we directly tested for the existence of a transcriptional regulatory network between human FOXP2 and the SRPX2/uPAR complex. In silico searches followed by gel retardation assays identified specific efficient FOXP2-binding sites in each of the promoter regions of SRPX2 and uPAR. In FOXP2-transfected cells, significant decreases were observed in the amounts of both SRPX2 (43.6%) and uPAR (38.6%) native transcripts. Luciferase reporter assays demonstrated that FOXP2 expression yielded a marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity. A mutant FOXP2 that causes DVD (p.R553H) failed to bind to SRPX2 and uPAR target sites and showed impaired down-regulation of SRPX2 and uPAR promoter activity. In a patient with polymicrogyria of the left rolandic operculum, a novel FOXP2 mutation (p.M406T) was found in the leucine-zipper (dimerization) domain. p.M406T partially impaired the FOXP2 regulation of SRPX2 promoter activity, whereas that of the uPAR promoter remained unchanged. Together with recently described FOXP2-CNTNAP2 and SRPX2/uPAR links, the FOXP2-SRPX2/uPAR network provides exciting insights into molecular pathways underlying speech-related disorders. PMID:20858596

  10. Effet getter dans des plaquettes de silicium multicristallin par diffusion de phosphore

    NASA Astrophysics Data System (ADS)

    Perichaud, I.; Martinuzzi, S.

    1992-03-01

    The external gettering effect by phosphorus diffusion is used to improve the electrical properties of multicrystalline silicon wafers. After diffusion at 900 °C for 4 h it was found that the effective diffusion lengths L_n of minority carriers achieve or overpass the thickness of the wafers. After diffusion at 850 °C for 4 h the improvements are less marked and hydrogenation is needed to obtain the same increase of L_n. SIMS analysis indicates that the gettered impurities are essentially iron, copper and nickel. Some restricted regions of the wafers are only poorly improved. It was found after chemical etching that these regions contain a high density of subgrain boundaries. The mechanism of the gettering effect used in this work is proposed, taking in account dissolved impurities in the grains and impurities segregated by dislocations. The additivity of the hydrogenation effect might be understood by the neutralisation of the recombination centers related to oxygen atoms segregated by the dislocations. L'effet getter externe par diffusion de phosphore est utilisé pour améliorer les propriétés électriques de plaquettes de silicium multicristallin. Après 4h à 900°C les longueurs de diffusion des porteurs minoritaires atteignent ou dépassent l'épaisseur des plaquettes. Après 4h à 850°C, les augmentations sont moins spectaculaires et une hydrogénation du matériau est nécessaire pour obtenir un résultat comparable au précédent. Les analyses SIMS indiquent que les impuretés extraites sont surtout du fer, du cuivre et du nickel. Certaines régions du matériau, d'extension limitée, sont toutefois peu améliorées. Elles sont caractérisées par la présence d'un réseau très dense de sous-joints. Une interprétation du mécanisme de l'effet getter observé est proposée faisant intervenir les impuretés métalliques dissoutes et celles ségrégées par les dislocations. L'additivité de l'action de l'hydrogène s'expliquerait par la neutralisation

  11. 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

  12. The Tumor Suppressor Prostate Apoptosis Response-4 (Par-4) is Regulated by Mutant IDH1 and Kills Glioma Stem Cells

    PubMed Central

    Liu, Yinxing; Gilbert, Misty R.; Kyprianou, Natasha; Rangnekar, Vivek M.; Horbinski, Craig

    2014-01-01

    Prostate apoptosis response-4 (Par-4) is an endogenous tumor suppressor that selectively induces apoptosis in a variety of cancers. Although it has been the subject of intensive research in other cancers, less is known about its significance in gliomas, including whether it is regulated by key driver mutations, has therapeutic potential against glioma stem cells (GSCs), and/or is a prognostic marker. We found that patient-derived gliomas with mutant isocitrate dehydrogenase 1 have markedly lower Par-4 expression (P < 0.0001), which was validated by The Cancer Genome Atlas dataset (P = 2.0 E-13). The metabolic product of mutant IDH1, D-2-hydroxyglutarate (2-HG), can suppress Par-4 transcription in vitro via inhibition of promoter activity as well as enhanced mRNA degradation, but interestingly not by direct DNA promoter hypermethylation. The Selective for Apoptosis induction in Cancer cells (SAC) domain within Par-4 is highly active against glioma cells, including orthotopic xenografts of patient-derived primary GSCs (P < 0.0001). Among high-grade gliomas that are IDH1 wild-type, those that express more Par-4 have significantly longer median survival (18.4 versus 8.0 months, P = 0.002), a finding confirmed in two external GBM cohorts. Together, these data suggest that Par-4 is a significant component of the mutant IDH1 phenotype, that the activity of 2-HG is complex and can extend beyond direct DNA hypermethylation, and that Par-4 is a promising therapeutic strategy against GSCs. Furthermore, not every effect of mutant IDH1 necessarily contributes to the overall favorable prognosis seen in such tumors; inhibition of Par-4 may be one such effect. PMID:25135281

  13. 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.

  14. Hypersensitivity Induced by Activation of Spinal Cord PAR2 Receptors Is Partially Mediated by TRPV1 Receptors

    PubMed Central

    Mrozkova, Petra; Spicarova, Diana; Palecek, Jiri

    2016-01-01

    Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) receptors in the peripheral nerve endings are implicated in the development of increased sensitivity to mechanical and thermal stimuli, especially during inflammatory states. Both PAR2 and TRPV1 receptors are co-expressed in nociceptive dorsal root ganglion (DRG) neurons on their peripheral endings and also on presynaptic endings in the spinal cord dorsal horn. However, the modulation of nociceptive synaptic transmission in the superficial dorsal horn after activation of PAR2 and their functional coupling with TRPV1 is not clear. To investigate the role of spinal PAR2 activation on nociceptive modulation, intrathecal drug application was used in behavioural experiments and patch-clamp recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs, eEPSCs) were performed on superficial dorsal horn neurons in acute rat spinal cord slices. Intrathecal application of PAR2 activating peptide SLIGKV-NH2 induced thermal hyperalgesia, which was prevented by pretreatment with TRPV1 antagonist SB 366791 and was reduced by protein kinases inhibitor staurosporine. Patch-clamp experiments revealed robust decrease of mEPSC frequency (62.8 ± 4.9%), increase of sEPSC frequency (127.0 ± 5.9%) and eEPSC amplitude (126.9 ± 12.0%) in dorsal horn neurons after acute SLIGKV-NH2 application. All these EPSC changes, induced by PAR2 activation, were prevented by SB 366791 and staurosporine pretreatment. Our results demonstrate an important role of spinal PAR2 receptors in modulation of nociceptive transmission in the spinal cord dorsal horn at least partially mediated by activation of presynaptic TRPV1 receptors. The functional coupling between the PAR2 and TRPV1 receptors on the central branches of DRG neurons may be important especially during different pathological states when it may enhance pain perception. PMID:27755539

  15. 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)).

  16. Loss of Par-1a/MARK3/C-TAK1 Kinase Leads to Reduced Adiposity, Resistance to Hepatic Steatosis, and Defective Gluconeogenesis ▿

    PubMed Central

    Lennerz, Jochen K.; Hurov, Jonathan B.; White, Lynn S.; Lewandowski, Katherine T.; Prior, Julie L.; Planer, G. James; Gereau, Robert W.; Piwnica-Worms, David; Schmidt, Robert E.; Piwnica-Worms, Helen

    2010-01-01

    Par-1 is an evolutionarily conserved protein kinase required for polarity in worms, flies, frogs, and mammals. The mammalian Par-1 family consists of four members. Knockout studies of mice implicate Par-1b/MARK2/EMK in regulating fertility, immune homeostasis, learning, and memory as well as adiposity, insulin hypersensitivity, and glucose metabolism. Here, we report phenotypes of mice null for a second family member (Par-1a/MARK3/C-TAK1) that exhibit increased energy expenditure, reduced adiposity with unaltered glucose handling, and normal insulin sensitivity. Knockout mice were protected against high-fat diet-induced obesity and displayed attenuated weight gain, complete resistance to hepatic steatosis, and improved glucose handling with decreased insulin secretion. Overnight starvation led to complete hepatic glycogen depletion, associated hypoketotic hypoglycemia, increased hepatocellular autophagy, and increased glycogen synthase levels in Par-1a−/− but not in control or Par-1b−/− mice. The intercrossing of Par-1a−/− with Par-1b−/− mice revealed that at least one of the four alleles is necessary for embryonic survival. The severity of phenotypes followed a rank order, whereby the loss of one Par-1b allele in Par-1a−/− mice conveyed milder phenotypes than the loss of one Par-1a allele in Par-1b−/− mice. Thus, although Par-1a and Par-1b can compensate for one another during embryogenesis, their individual disruption gives rise to distinct metabolic phenotypes in adult mice. PMID:20733003

  17. The PAR complex controls the spatiotemporal dynamics of F-actin and the MTOC in directionally migrating leukocytes

    PubMed Central

    Crespo, Carolina Lage; Vernieri, Claudio; Keller, Philipp J.; Garrè, Massimiliano; Bender, Jeffrey R.; Wittbrodt, Joachim; Pardi, Ruggero

    2014-01-01

    ABSTRACT Inflammatory cells acquire a polarized phenotype to migrate towards sites of infection or injury. A conserved polarity complex comprising PAR-3, PAR-6 and atypical protein kinase C (aPKC) relays extracellular polarizing cues to control cytoskeletal and signaling networks affecting morphological and functional polarization. However, there is no evidence that myeloid cells use PAR signaling to migrate vectorially in three-dimensional (3D) environments in vivo. Using genetically encoded bioprobes and high-resolution live imaging, we reveal the existence of F-actin oscillations in the trailing edge and constant repositioning of the microtubule organizing center (MTOC) to direct leukocyte migration in wounded medaka fish larvae (Oryzias latipes). Genetic manipulation in live myeloid cells demonstrates that the catalytic activity of aPKC and the regulated interaction with PAR-3 and PAR-6 are required for consistent F-actin oscillations, MTOC perinuclear mobility, aPKC repositioning and wound-directed migration upstream of Rho kinase (also known as ROCK or ROK) activation. We propose that the PAR complex coordinately controls cytoskeletal changes affecting both the generation of traction force and the directionality of leukocyte migration to sites of injury. PMID:25179599

  18. Horizontal portion of arcuate fasciculus fibers track to pars opercularis, not pars triangularis, in right and left hemispheres: a DTI study.

    PubMed

    Kaplan, Elina; Naeser, Margaret A; Martin, Paula I; Ho, Michael; Wang, Yunyan; Baker, Errol; Pascual-Leone, Alvaro

    2010-08-15

    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 (5 M) 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

  19. 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).

  20. Bazooka/PAR3 is dispensable for polarity in Drosophila follicular epithelial cells.

    PubMed

    Shahab, Jaffer; Tiwari, Manu D; Honemann-Capito, Mona; Krahn, Michael P; Wodarz, Andreas

    2015-03-13

    Apico-basal polarity is the defining characteristic of epithelial cells. In Drosophila, apical membrane identity is established and regulated through interactions between the highly conserved Par complex (Bazooka/Par3, atypical protein kinase C and Par6), and the Crumbs complex (Crumbs, Stardust and PATJ). It has been proposed that Bazooka operates at the top of a genetic hierarchy in the establishment and maintenance of apico-basal polarity. However, there is still ambiguity over the correct sequence of events and cross-talk with other pathways during this process. In this study, we reassess this issue by comparing the phenotypes of the commonly used baz(4) and baz(815-8) alleles with those of the so far uncharacterized baz(XR11) and baz(EH747) null alleles in different Drosophila epithelia. While all these baz alleles display identical phenotypes during embryonic epithelial development, we observe strong discrepancies in the severity and penetrance of polarity defects in the follicular epithelium: polarity is mostly normal in baz(EH747) and baz(XR11) while baz(4) and baz(815) (-8) show loss of polarity, severe multilayering and loss of epithelial integrity throughout the clones. Further analysis reveals that the chromosomes carrying the baz(4) and baz(815-8) alleles may contain additional mutations that enhance the true baz loss-of-function phenotype in the follicular epithelium. This study clearly shows that Baz is dispensable for the regulation of polarity in the follicular epithelium, and that the requirement for key regulators of cell polarity is highly dependent on developmental context and cell type.

  1. Bazooka/PAR3 is dispensable for polarity in Drosophila follicular epithelial cells

    PubMed Central

    Shahab, Jaffer; Tiwari, Manu D.; Honemann-Capito, Mona; Krahn, Michael P.; Wodarz, Andreas

    2015-01-01

    Apico-basal polarity is the defining characteristic of epithelial cells. In Drosophila, apical membrane identity is established and regulated through interactions between the highly conserved Par complex (Bazooka/Par3, atypical protein kinase C and Par6), and the Crumbs complex (Crumbs, Stardust and PATJ). It has been proposed that Bazooka operates at the top of a genetic hierarchy in the establishment and maintenance of apico-basal polarity. However, there is still ambiguity over the correct sequence of events and cross-talk with other pathways during this process. In this study, we reassess this issue by comparing the phenotypes of the commonly used baz4 and baz815-8 alleles with those of the so far uncharacterized bazXR11 and bazEH747 null alleles in different Drosophila epithelia. While all these baz alleles display identical phenotypes during embryonic epithelial development, we observe strong discrepancies in the severity and penetrance of polarity defects in the follicular epithelium: polarity is mostly normal in bazEH747 and bazXR11 while baz4 and baz815-8 show loss of polarity, severe multilayering and loss of epithelial integrity throughout the clones. Further analysis reveals that the chromosomes carrying the baz4 and baz815-8 alleles may contain additional mutations that enhance the true baz loss-of-function phenotype in the follicular epithelium. This study clearly shows that Baz is dispensable for the regulation of polarity in the follicular epithelium, and that the requirement for key regulators of cell polarity is highly dependent on developmental context and cell type. PMID:25770183

  2. Topography of dyskinesias and torticollis evoked by inhibition of substantia nigra pars reticulata.

    PubMed

    Dybdal, David; Forcelli, Patrick A; Dubach, Mark; Oppedisano, Michael; Holmes, Angela; Malkova, Ludise; Gale, Karen

    2013-04-01

    GABAergic neurons of the substantia nigra pars reticulata (SNpr) and globus pallidus pars interna (GPi) constitute the output pathways of the basal ganglia. In monkeys, choreiform limb dyskinesias have been described after inhibition of the GPi, but not the SNpr. Given the anatomical and functional similarities between these structures, we hypothesized that choreiform dyskinesias could be evoked by inhibition of an appropriate region within the SNpr. The GABAA receptor agonist, muscimol, was infused into various sites within the SNpr and the adjacent STN of freely moving macaques. The effect of the GABAA antagonist, bicuculline (BIC), was also examined. Muscimol (MUS) in SNpr evoked the following: (1) choreiform dyskinesias of the contralateral arm and/or leg from central and lateral sites; (2) contralaterally directed torticollis from central and posterior sites; and (3) contraversive quadrupedal rotation from anterior and lateral sites. MUS infusions into the adjacent SN pars compacta or STN were without effect, ruling out a contribution of drug spread to adjacent structures. BIC in SNpr induced ipsiversive postures without choreiform dyskinesia or torticollis, whereas in the STN, it evoked ballistic movements. This is the first report of choreiform dyskinesia evoked by inhibition of the SNpr. This highly site-specific effect was obtained from a restricted region within the SNpr distinct from that responsible for inducing torticollis. These results suggest that overactivity of different SNpr outputs mediates choreiform dyskinesia and torticollis. These abnormalities are symptoms of dystonia, Huntington's disease, and iatrogenic dyskinesias, suggesting that these conditions may result, in part, from a loss of function in SNpr efferent projections.

  3. 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.

  4. 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

  5. Functional dissection of the ParB homologue (KorB) from IncP-1 plasmid RK2

    PubMed Central

    Lukaszewicz, M.; Kostelidou, K.; Bartosik, A. A.; Cooke, G. D.; Thomas, C. M.; Jagura-Burdzy, G.

    2002-01-01

    Active partitioning of low-copy number plasmids requires two proteins belonging to the ParA and ParB families and a cis-acting site which ParB acts upon. Active separation of clusters of plasmid molecules to the defined locations in the cell before cell division ensures stable inheritance of the plasmids. The central control operon of IncP-1 plasmids codes for regulatory proteins involved in the global transcriptional control of operons for vegetative replication, stable maintenance and conjugative transfer. Two of these proteins, IncC and KorB, also play a role in active partitioning, as the ParA and ParB homologues, respectively. Here we describe mapping the regions in KorB responsible for four of its different functions: dimerisation, DNA binding, repression of transcription and interaction with IncC. For DNA binding, amino acids E151 to T218 are essential, while repression depends not only on DNA binding but, additionally, on the adjacent region amino acids T218 to R255. The C-terminus of KorB is the main dimerisation domain but a secondary oligomerisation region is located centrally in the region from amino acid I174 to T218. Using three different methods (potentiation of transcriptional repression, potentiation of DNA binding and activation in the yeast two-hybrid system) we identify this region as also responsible for interactions with IncC. This IncC–KorB contact differs in location from the ParA–ParB/SopA–SopB interactions in P1/F but is similar to these systems in lying close to a masked oligomerisation determinant. PMID:11842117

  6. 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.

  7. 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

  8. Thrombin-mediated IL-10 up-regulation involves protease-activated receptor (PAR)-1 expression in human mononuclear leukocytes.

    PubMed

    Naldini, Antonella; Bernini, Claudia; Pucci, Annalisa; Carraro, Fabio

    2005-09-01

    Thrombin, the key enzyme of the coagulation cascade, exerts cellular effects through activation of the protease-activated receptors (PARs). Interleukin (IL)-10, besides its anti-inflammatory properties, is considered a major denominator of the immunosuppressive effect during human endotoxemia. We have recently shown that thrombin inhibits IL-12 production in human mononuclear cells and that such inhibition is accompanied by IL-10 up-regulation. To our knowledge, there are no data available to show that thrombin mediates IL-10 production by its interactions with PAR-1. We here report that human alpha-thrombin enhances IL-10 expression in human peripheral blood mononuclear cells and in established monocytic cell lines and that this up-regulation requires PAR-1 expression. The use of proteolytically inactive thrombin reveals that such enhancement requires thrombin proteolytic activity. Addition of PAR-1 agonist peptides, such as SFLLRN, results in a significant increase of IL-10 production. PAR-1 expression is required for thrombin-induced IL-10 production, as shown by experiments performed with antisense or sense PAR-1 oligonucleotides. Treatment with thrombin or SFLLRN of monocytic cell lines, such as U937 and Mono Mac-6, results in an increased IL-10 production. This suggests that the observed IL-10 up-regulation may be the result of a direct interaction with monocytes. The observation that thrombin-mediated up-regulation of IL-10 may require the expression of the PAR-1 receptor identifies a new, functional link between inflammation and coagulation. Our results may also contribute to better design therapeutic strategies to treat several disorders, characterized by the presence of inflammatory as well as coagulant responses. PMID:15961578

  9. 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

  10. The Cdc42/Par6/aPKC polarity complex regulates apoptosis-induced compensatory proliferation in epithelia

    PubMed Central

    Warner, Stephen J.; Yashiro, Hanako; Longmore, Gregory D.

    2010-01-01

    Summary Background In response to stress- or tissue damage-induced apoptosis, unaffected epithelial cells undergo compensatory proliferation to maintain the integrity of the epithelium. Proximal signals regulating this response are not fully appreciated, but JNK activity appears to be critical for both apoptosis and compensatory proliferation. Since disruption of epithelial cell apical-basal polarity, as can occur in early cancer development and is correlated with increased proliferation by means not fully characterized, we considered whether disruption of the various polarity complexes could provide signals identifying damaged epithelial cells, and thus lead to apoptosis-induced compensatory proliferation. Results We identify the Cdc42/Par6/aPKC Par polarity complex as uniquely and specifically regulating apoptosis-induced compensatory proliferation in Drosophila epithelia. Genetic depletion of individual components or disruption of complex formation and localization, but not other polarity complexes, induces JNK-dependent apoptosis and JNK-dependent compensatory proliferation following radiation injury. When apoptosis execution is blocked, by P35 expression, Cdc42/Par6/aPKC depleted tissues uniquely hyperproliferate leading to tissue/organ overgrowth. Disruption of Cdc42/Par6/aPKC leads to activation of JNK through increased Rho1-Rok activity, and Rok’s capacity to activate Myosin, but not F-actin. Conclusions We show that the Cdc42/Par6/aPKC polarity complex influences both a physiologic compensatory proliferation response after irradiation injury as well as a contrived compensatory non-cell autonomous hyperproliferation response when cell autonomous apoptosis, resulting from Cdc42/Par6/aPKC disruption, is inhibited. These results suggest the possibility that in cancer where apoptotic regulation is disrupted, loss of the Cdc42/Par6/aPKC polarity complex organization or localization could contribute to tumor hyperproliferation and explain how polarity

  11. 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

  12. [Pars plana vitrectomy in treatment of ocular toxocariasis complications--case report].

    PubMed

    Oficjalska-Młyńczak, J; Duda, A; Muzyka-Woźniak, M; Zajac-Pytrus, H; Marek, J

    2001-01-01

    Ocular toxocariasis in adults may cause serious diagnostic and therapeutic problems. We describe a case of a 54-year-old farmer who developed peripheral granuloma with dense connective tissue strands joined to the disc. The diagnosis was confirmed by high ELISA titers in the serum and vitreous body. We performed pars plana vitrectomy with epiretinal membrane removal and laser photocoagulation of the inferior retina, obtaining improvement of visual acuity. After a few weeks the patient returned with central retinal detachment and macular hole. After the second vitrectomy with use of silicon oil we obtained reattachment of the retina but without functional improvement.

  13. 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.

  14. Laser UV à semiconducteur nitrure pompé par des micropointes

    NASA Astrophysics Data System (ADS)

    Barjon, J.; Adelmann, C.; Baptist, R.; Brault, J.; Daudin, B.; Dang, Le Si; Molva, E.

    2002-06-01

    Dans un Laser à Semiconducteur Micropointes (LSM), le milieu amplificateur est pompé par un faisceau d'électrons issus de micropointes effet de champ. Ce type de laser est particulièrement adapté aux semi-conducteurs à grands gaps tels que les nitrures GaN et AIN émettant dans l'UltraViolet, pour lesquels le dopage et la prise de contact ohmique deviennent problématiques. Ce papier présente ce dispositif et l'état d'avancement des travaux.

  15. Piqures massives par un essaim d'abeilles chez un enfant

    PubMed Central

    Berdai, Mohamed Adnane; Labib, Smael; El Balbal, Monia; Harandou, Mustapha

    2011-01-01

    Les piqûres multiples d'abeilles sont responsables d'envenimation sévère. Nous rapportons un cas d'une attaque massive par un essaim d'abeilles chez un enfant de sept ans. Sa gravité est liée à la localisation céphalique et au nombre important des piqûres qui était d'environ 270. Ses complications étaient l'insuffisance rénale, l'anémie et une conjonctivite. La prise en charge était symptomatique avec bonne évolution clinique et biologique. PMID:22187598

  16. Role of suPAR and Lactic Acid in Diagnosing Sepsis and Predicting Mortality in Elderly Patients

    PubMed Central

    Khater, Walaa S.; Salah-Eldeen, Noha N.; Khater, Mohamed S.; Saleh, Asghraf N.

    2016-01-01

    This study investigated the diagnostic value of soluble urokinase plasminogen activator receptor (suPAR) and serum lactate in elderly patients with sepsis and evaluated their capacity to predict mortality and their correlation to Sequential Organ Failure Assessment (SOFA) score. The study included 80 participants, divided into two groups: 40 cases (mean age, 68.9 ± 5.9) admitted to the intensive care unit and 40 healthy controls (mean age, 67.1 ± 6.2). Elderly patients with sepsis had significantly higher levels of serum suPAR and lactic acid compared to healthy controls. Receiver operating characteristic (ROC) curve analysis showed that suPAR (cutoff value, ≥4.37 ng/ml) has higher area under the curve (AUC) than lactic acid (cutoff value, ≥1.95 mmol/l) for diagnosing sepsis. Serum lactate has superior prognostic value compared to suPAR with AUC of 0.82 (cutoff value, 2.2 mmol/l) and 0.72 (cutoff value, 6.3 ng/ml), respectively. The diagnostic power of combined usage of suPAR and lactate serum concentrations showed AUC of 0.988 (95% confidence interval 0.934 to 1.0). The combination of both biomarkers either together or with SOFA score may serve as a useful guide to patients who need more intensive resuscitation. PMID:27766166

  17. 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

  18. 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

  19. 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

  20. Ablation de ZnO par laser UV (193 nm) : nano-agrégats en phase gazeuse

    NASA Astrophysics Data System (ADS)

    Ozerov, I.; Bulgakov, A.; Nelson, D.; Castell, R.; Sentis, M.; Marine, W.

    2003-06-01

    La condensation de nano-agrégats d'oxyde de zinc en phase gazeuse est mise en évidence lors de l'ablation de ZnO massif par laser ArF pulsé. Nous comparons l'évolution spatio-temporelle de la forme du panache d'ablation (plume) de ZnO sous vide et sous atmosphère de gaz de couverture (oxygène et/ou hélium) à partir des images CCD et des résultats issus d'analyses spectroscopiques. L'expansion du plasma et la croissance des nano-clusters sont influencées par l'effet du confinement de la plume dû aux collisions entre les particules ablatées et les molécules de gaz ambiant ainsi que par les réactions chimiques dans le cas de l'oxygène. Le spectre de rayonnement du plasma est constitué principalement par l'émission d'atomes excités de Zn neutre. Nous avons observé la photoluminescence des nano-agrégats en suspension dans le gaz ainsi que leur décomposition par laser ArF.

  1. 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

  2. uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues

    PubMed Central

    Meng, Songdong; Tripathy, Debu; Shete, Sanjay; Ashfaq, Raheela; Saboorian, Hossein; Haley, Barbara; Frenkel, Eugene; Euhus, David; Leitch, Marilyn; Osborne, Cynthia; Clifford, Edward; Perkins, Steve; Beitsch, Peter; Khan, Amanullah; Morrison, Larry; Herlyn, Dorothee; Terstappen, Leon W. M. M.; Lane, Nancy; Wang, Jianqiang; Uhr, Jonathan

    2006-01-01

    Overexpression of urokinase plasminogen activator system or HER-2 (erbB-2) in breast cancer is associated with a poor prognosis. HER-2 overexpression is caused by HER-2 gene amplification. The anti-HER-2 antibody trastuzumab significantly improves clinical outcome for HER2-positive breast cancer. Drugs that target the uPA system are in early clinical trials. The aims of this study were to determine whether urokinase plasminogen activator receptor (uPAR) gene amplification occurs and whether analysis of individual tumor cells (TCs) in the blood or tissue can add information to conventional pathological analysis that could help in diagnosis and treatment. Analysis of individual TCs indicates that uPAR amplification occurs in a significant portion of primary breast cancers and also circulating tumor cells (CTCs) from patients with advanced disease. There was complete concordance between touch preps (TPs) and conventional pathological examination of HER-2 and uPAR gene status in primary tumors. There was also excellent concordance of HER-2 gene status between primary tumors and CTCs provided that acquisition of HER-2 gene amplification in CTCs was taken into account. Unexpectedly, gene amplification of HER-2 and uPAR occurred most frequently in the same TC and patient, suggesting a biological bias and potential advantage for coamplification. Expression of HER-2 and uPAR in primary tumors predicted gene status in 100 and 92% of patients, respectively. PMID:17079488

  3. 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.

  4. ParFlow.RT: Development and Verification of a New Reactive Transport Model

    NASA Astrophysics Data System (ADS)

    Beisman, J. J., III

    2015-12-01

    In natural subsurface systems, total elemental fluxes are often heavily influenced by areas of disproportionately high reaction rates. These pockets of high reaction rates tend to occur at interfaces, such as the hyporheic zone, where a hydrologic flowpath converges with either a chemically distinct hydrologic flowpath or a reactive substrate. Understanding the affects that these highly reactive zones have on the behavior of shallow subsurface systems is integral to the accurate quantification of nutrient fluxes and biogeochemical cycling. Numerical simulations of these systems may be able to offer some insight. To that end, we have developed a new reactive transport model, ParFlow.RT, by coupling the parallel flow and transport code ParFlow with the geochemical engines of both PFLOTRAN and CrunchFlow. The coupling was accomplished via the Alquimia biogeochemistry API, which provides a unified interface to several geochemical codes and allows a relatively simple implementation of advanced geochemical functionality in flow and transport codes. This model uses an operator-splitting approach, where the transport and reaction steps are solved separately. Here, we present the details of this new model, and the results of verification simulations and biogeochemical cycling simulations of the DOE's East River field site outside of Gothic, CO.

  5. Identification of dopaminergic neurons of the substantia nigra pars compacta as a target of manganese accumulation.

    PubMed

    Robison, Gregory; Sullivan, Brendan; Cannon, Jason R; Pushkar, Yulia

    2015-05-01

    Manganese serves as a cofactor to a variety of proteins necessary for proper bodily development and function. However, an overabundance of Mn in the brain can result in manganism, a neurological condition resembling Parkinson's disease (PD). Bulk sample measurement techniques have identified the globus pallidus and thalamus as targets of Mn accumulation in the brain, however smaller structures/cells cannot be measured. Here, X-ray fluorescence microscopy determined the metal content and distribution in the substantia nigra (SN) of the rodent brain. In vivo retrograde labeling of dopaminergic cells (via FluoroGold™) of the SN pars compacta (SNc) subsequently allowed for XRF imaging of dopaminergic cells in situ at subcellular resolution. Chronic Mn exposure resulted in a significant Mn increase in both the SN pars reticulata (>163%) and the SNc (>170%) as compared to control; no other metal concentrations were significantly changed. Subcellular imaging of dopaminergic cells demonstrated that Mn is located adjacent to the nucleus. Measured intracellular manganese concentrations range between 40-200 μM; concentrations as low as 100 μM have been observed to cause cell death in cell cultures. Direct observation of Mn accumulation in the SNc could establish a biological basis for movement disorders associated with manganism, specifically Mn caused insult to the SNc. Accumulation of Mn in dopaminergic cells of the SNc may help clarify the relationship between Mn and the loss of motor skills associated with manganism. PMID:25695229

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. Mammalian aPKC/Par polarity complex mediated regulation of epithelial division orientation and cell fate.

    PubMed

    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.

  14. SPECTROMÉTRIE NUCLÉAIBE Par Compteurs Proportionnels EN Coincidence

    NASA Astrophysics Data System (ADS)

    Charpak, G.; Suzor, F.

    Description d'un spectromètre à compteurs proportionnels spécialement adapté à l'étude des radiations de faible énergie (électrons ou photons au-dessous de 20 keV) émis par des atomes radioactifs avec une très faible probabilité. Deux compteurs proportionnels sont en contact, dans un plan qui contient le ports source. La source est en contact direct avec le gaz de l'un des compteurs. Les impulsions de ce compteur en coïncidence avec celles de l'autre sont analysées par un analyseur à canaux multiples. On décrit le montage électronique associé, en insistant sur le fait que lea amplificateurs ont été rendus non saturables. Description of a proportional counter spectrometer specially adapted to the study of low energy radiations (electrons or photons below 20 keV) emitted by radioactive atoms with very small probability. Two proportional counters of 18 cm diameter are in contact along a plane which contains the source holder. The source is in direct contact with the gas of one of the counters. Impulses of this counter in coincidence with impulses of the other are analyzed by a multichannel analyzer. The associated electronics in described with particular emphasis on the problems of non overloading qualities of the amplifiers.

  15. 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.

  16. Identification of dopaminergic neurons of the substantia nigra pars compacta as a target of manganese accumulation

    PubMed Central

    Robison, Gregory; Sullivan, Brendan; Cannon, Jason R.; Pushkar, Yulia

    2015-01-01

    Manganese serves as a cofactor to a variety of proteins necessary for proper bodily development and function. However, an overabundance of Mn in the brain can result in manganism, a neurological condition resembling Parkinson’s disease (PD). Bulk sample measurement techniques have identified the globus pallidus and thalamus as targets of Mn accumulation in the brain, however smaller structures/cells cannot be measured. Here, X-ray fluorescence microscopy determined the metal content and distribution in the substantia nigra (SN) of the rodent brain. In vivo retrograde labeling of dopaminergic cells (via FluoroGold™) of the SN pars compacta (SNc) subsequently allowed for XRF imaging of dopaminergic cells in situ at subcellular resolution. Chronic Mn exposure resulted in a significant Mn increase in both the SN pars reticulata (>163%) and the SNc (>170%) as compared to control; no other metal concentrations were significantly changed. Subcellular imaging of dopaminergic cells demonstrated that Mn is located adjacent to the nucleus. Measured intracellular manganese concentrations range between 40–200 μM; concentrations as low as 100 μM have been observed to cause cell death in cell cultures. Direct observation of Mn accumulation in the SNc could establish a biological basis for movement disorders associated with manganism, specifically Mn caused insult to the SNc. Accumulation of Mn in dopaminergic cells of the SNc may help clarify the relationship between Mn and the loss of motor skills associated with manganism. PMID:25695229

  17. 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

  18. 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

  19. Laser XUV haute cadence pompé par laser Titane : Saphir, vers la station LASERIX

    NASA Astrophysics Data System (ADS)

    Kazamias, S.; Cassou, K.; Ros, D.; Plé, F.; Jamelot, G.; Klisnick, A.; Lundh, O.; Lindau, F.; Persson, A.; Wahlström, C.-G.; de Rossi, S.; Joyeux, D.; Zielbauer, B.; Ursescu, D.

    2006-12-01

    Nous présentons des résultats récents de laserX collisionnel transitoire pompé en incidence rasante à haut taux de répétition. Ils ont été obtenus à partir du laser de pompe Titane:Saphir 30 TW disponible sur l'installation européenne du LLC à Lund (Suède). Nous avons démontré lors de cette expérience qu'il était possible d'obtenir en routine près de 3 microjoule par impulsion à 18,9 nm avec seulement 1 J d'énergie de pompe infrarouge. Nous avons plus particulièrement étudié l'influence de l'angle de rasance sur cible de l'impulsion laser qui vient pomper le plasma, quelques centaines de picosecondes après la première impulsion responsable de sa création. Un système d'imagerie XUV à haute résolution nous a en effet permis d'obtenir des informations précieuses sur la pupille de sortie du laserX, comme l'énergie totale dans la tache mais aussi la distance d'émission par rapport à la cible, et encore les dimensions horizontale et verticale de la source.

  20. 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

  1. The aPKC/Par3/Par6 Polarity Complex and Membrane Order Are Functionally Interdependent in Epithelia During Vertebrate Organogenesis.

    PubMed

    Abu-Siniyeh, Ahmed; Owen, Dylan M; Benzing, Carola; Rinkwitz, Silke; Becker, Thomas S; Majumdar, Arindam; Gaus, Katharina

    2016-01-01

    The differential distribution of lipids between apical and basolateral membranes is necessary for many epithelial cell functions, but how this characteristic membrane organization is integrated within the polarity network during ductal organ development is poorly understood. Here we quantified membrane order in the gut, kidney and liver ductal epithelia in zebrafish larvae at 3-11 days post fertilization (dpf) with Laurdan 2-photon microscopy. We then applied a combination of Laurdan imaging, antisense knock-down and analysis of polarity markers to understand the relationship between membrane order and apical-basal polarity. We found a reciprocal relationship between membrane order and the cell polarity network. Reducing membrane condensation by exogenously added oxysterol or depletion of cholesterol reduced apical targeting of the polarity protein, aPKC. Conversely, using morpholino knock down in zebrafish, we found that membrane order was dependent upon the Crb3 and Par3 polarity protein expression in ductal epithelia. Hence our data suggest that the biophysical property of membrane lipid packing is a regulatory element in apical basal polarity.

  2. Etude par resistivite electrique du comportement d'un alliage amorphe Fe 40Ni 38Mo 4B 18 deforme par traction

    NASA Astrophysics Data System (ADS)

    Hoang, Long Phan; Sacovy, Paulette; Delaplace, Jean

    1983-02-01

    Des rubans d'alliages amorphes Metglas du type Fe 40Ni 38Mo 4B 18 à l'état brut de trempe ont été déformés par traction à la température ambiante et l'on a suivi les variations de la résistance électrique des échantillons au cours de la déformation. Il ressort de ces essais que la déformation plastique qui est de l'ordre de 0.5% avant rupture ne se produit pas de faĉon homogène dans l'échantillon. Les mesures électriques effectuées au cours de la déformation mettent en évidence dans le domaine élastique un effet d'élastorésistance, relativement important ( K ≠ 1); elles montrent que dans le domaine plastique la déformation permanente des échantillons s'accompagne d'une diminution de la résistivité électrique du matériau. Deux hypothèses sont discutées pour expliquer cet effet inattendu, l'un qui fait appel à l'existence de volumes libres, l'autre qui suppose une cristallisation localisée du matériau sous l'effet de la contrainte.

  3. Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain*

    PubMed Central

    Zhao, Peishen; Lieu, TinaMarie; Barlow, Nicholas; Sostegni, Silvia; Haerteis, Silke; Korbmacher, Christoph; Liedtke, Wolfgang; Jimenez-Vargas, Nestor N.; Vanner, Stephen J.; Bunnett, Nigel W.

    2015-01-01

    Proteases that cleave protease-activated receptor-2 (PAR2) at Arg36↓Ser37 reveal a tethered ligand that binds to the cleaved receptor. PAR2 activates transient receptor potential (TRP) channels of nociceptive neurons to induce neurogenic inflammation and pain. Although proteases that cleave PAR2 at non-canonical sites can trigger distinct signaling cascades, the functional importance of the PAR2-biased agonism is uncertain. We investigated whether neutrophil elastase, a biased agonist of PAR2, causes inflammation and pain by activating PAR2 and TRP vanilloid 4 (TRPV4). Elastase cleaved human PAR2 at Ala66↓Ser67 and Ser67↓Val68. Elastase stimulated PAR2-dependent cAMP accumulation and ERK1/2 activation, but not Ca2+ mobilization, in KNRK cells. Elastase induced PAR2 coupling to Gαs but not Gαq in HEK293 cells. Although elastase did not promote recruitment of G protein-coupled receptor kinase-2 (GRK2) or β-arrestin to PAR2, consistent with its inability to promote receptor endocytosis, elastase did stimulate GRK6 recruitment. Elastase caused PAR2-dependent sensitization of TRPV4 currents in Xenopus laevis oocytes by adenylyl cyclase- and protein kinase A (PKA)-dependent mechanisms. Elastase stimulated PAR2-dependent cAMP formation and ERK1/2 phosphorylation, and a PAR2- and TRPV4-mediated influx of extracellular Ca2+ in mouse nociceptors. Adenylyl cyclase and PKA-mediated elastase-induced activation of TRPV4 and hyperexcitability of nociceptors. Intraplantar injection of elastase to mice caused edema and mechanical hyperalgesia by PAR2- and TRPV4-mediated mechanisms. Thus, the elastase-biased agonism of PAR2 causes Gαs-dependent activation of adenylyl cyclase and PKA, which activates TRPV4 and sensitizes nociceptors to cause inflammation and pain. Our results identify a novel mechanism of elastase-induced activation of TRPV4 and expand the role of PAR2 as a mediator of protease-driven inflammation and pain. PMID:25878251

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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

  9. Effet de la composition des materiaux composites sur la caracterisation et detection par ondes de Lamb

    NASA Astrophysics Data System (ADS)

    Ostiguy, Pierre-Claude

    Les matériaux composites sont de plus en plus utilisés en aéronautique. Leurs excellentes propriétés mécaniques et leur faible poids leur procurent un avantage certain par rapport aux matériaux métalliques. Ceux-ci étant soumis à diverses conditions de chargement et environnementales, ils sont suceptibles de subir plusieurs types d'endommagements, compromettant leur intégrité. Des méthodes fiables d'inspection sont donc nécessaires pour évaluer leur intégrité. Néanmoins, peu d'approches non destructives, embarquées et efficaces sont présentement utilisées. Ce travail de recherche se penche sur l'étude de l'effet de la composition des matériaux composites sur la détection et la caractérisation par ondes guidées. L'objectif du projet est de développer une approche de caractérisation mécanique embarquée permettant d'améliorer la performance d'une approche d'imagerie par antenne piézoélectriques sur des structures composite et métalliques. La contribution de ce projet est de proposer une approche embarquée de caractérisation mécanique par ultrasons qui ne requiert pas une mesure sur une multitude d'échantillons et qui est non destructive. Ce mémoire par articles est divisé en quatre parties, dont les parties deux A quatre présentant les articles publiés et soumis. La première partie présente l'état des connaissances dans la matière nécessaires à l'acomplissement de ce projet de maîtrise. Les principaux sujets traités portent sur les matériaux composites, propagation d'ondes, la modélisation des ondes guidées, la caractérisation par ondes guidées et la surveillance embarquée des structures. La deuxième partie présente une étude de l'effet des propriétés mécaniques sur la performance de l'algorithme d'imagerie Excitelet. L'étude est faite sur une structure isotrope. Les résultats ont démontré que l'algorithme est sensible à l'exactitude des propriétés mécaniques utilisées dans le modèle. Cette

  10. 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

  11. 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

  12. Erythroblastopénie induite par la grossesse: à propos d'un cas et revue de la literature

    PubMed Central

    Jihad, Drissi; Jaouad, Kouach; Driss, Moussaoui; Mohamed, Dehayni

    2016-01-01

    L’érythroblastopénie induite par la grossesse est une entité pathologique exceptionnelle dont seuls quelques cas isolés ont été décrits dans la littérature anglaise. L'objectif de ce travail est d'analyser les caractéristiques de cette pathologie extrêmement rare à travers la description d'un nouveau cas d’érythroblastopénie induite par la grossesse, et à travers l’étude des 17 cas antérieurement rapportés. PMID:27642487

  13. 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

  14. 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

  15. 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

  16. Sources of uncertainty in the prediction of LAI/fPAR from MODIS

    NASA Astrophysics Data System (ADS)

    Dungan, J. L.; Ganapol, B. D.

    2002-12-01

    To explicate the sources of uncertainty in the prediction of biophysical variables over space, consider the general equation: \\[ z_{v}(u) = f(y_{v}(x),\\theta) \\] where z is a variable with values on some nominal, ordinal, interval or ratio scale; y is a vector of input variables; v 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 θ 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 (Knyazikhin et al. 1998) is an example of f, called f1, 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 (Ganapol et al. 1999), is a simpler though similar radiative transfer approach to f1. 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

  17. 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.

  18. 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

  19. 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

  20. 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

  1. 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.

  2. 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

  3. The leak channel NALCN controls tonic firing and glycolytic sensitivity of substantia nigra pars reticulata neurons.

    PubMed

    Lutas, Andrew; Lahmann, Carolina; Soumillon, Magali; Yellen, Gary

    2016-01-01

    Certain neuron types fire spontaneously at high rates, an ability that is crucial for their function in brain circuits. The spontaneously active GABAergic neurons of the substantia nigra pars reticulata (SNr), a major output of the basal ganglia, provide tonic inhibition of downstream brain areas. A depolarizing 'leak' current supports this firing pattern, but its molecular basis remains poorly understood. To understand how SNr neurons maintain tonic activity, we used single-cell RNA sequencing to determine the transcriptome of individual mouse SNr neurons. We discovered that SNr neurons express the sodium leak channel, NALCN, and that SNr neurons lacking NALCN have impaired spontaneous firing. In addition, NALCN is involved in the modulation of excitability by changes in glycolysis and by activation of muscarinic acetylcholine receptors. Our findings suggest that disruption of NALCN could impair the basal ganglia circuit, which may underlie the severe motor deficits in humans carrying mutations in NALCN. PMID:27177420

  4. Spectroscopie résolue en temps par continuum femtoseconde Applications en neurobiologie

    NASA Astrophysics Data System (ADS)

    Ramstein, S.; Mottin, S.

    2003-06-01

    La spectroscopie résolue en temps utilisant un laser blanc femtoseconde est appliquée à la mesure in vivo des principaux absorbeurs du cerveau. Après génération adéquate du continuum de lumière blanche femtoseconde (50mW/[580-756nm] à 1Hz), cette source se propage dans la calvaria, les méninges et le cortex chez le rat anesthésié. La transmission est étudiée sur 7mm de distance entre l'impact laser et la fibre optique de collection. Le signal transmis est analysé dans la fenêtre 580-760nm, par un spectromètre couplé à une caméra à balayage de fente permettant la décorrélation de l'absorption et de la diffusion.

  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.

  6. 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

  7. 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

  8. Five early accounts of phantom limb in context: Paré, Descartes, Lemos, Bell, and Mitchell.

    PubMed

    Finger, Stanley; Hustwit, Meredith P

    2003-03-01

    PHANTOM LIMB WAS described long before American physician and surgeon Silas Weir Mitchell coined the term and drew attention to the disorder in the 1860s. The early descriptions of Ambroise Paré, René Descartes, Aaron Lemos, Charles Bell, and then Mitchell of this strange consequence of amputation are presented in historical and cultural context. These five men described phantom limbs for various reasons. They also differed when it came to explaining and dealing with these illusory sensations. The rich history of phantom limbs can begin to be appreciated by viewing the contributions of these individuals in perspective and by realizing that their writings represent only a fraction of what was published about phantom limbs more than 130 years ago.

  9. 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

  10. 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.

  11. 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

    2015-08-07

    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.

  12. Pituitary pars intermedia dysfunction (equine Cushing's disease) in a Thoroughbred stallion: a single report.

    PubMed

    Hatazoe, Takashi; Kawaguchi, Hiroaki; Hobo, Seiji; Misumi, Kazuhiro

    2015-01-01

    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

  13. Management of inferior retinal breaks during pars plana vitrectomy for retinal detachment

    PubMed Central

    Tanner, V; Minihan, M; Williamson, T

    2001-01-01

    AIMS—To determine whether it is necessary to support inferior retinal breaks with a scleral explant during pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RD).
METHODS—A prospective study was carried out on nine eyes of nine consecutive patients undergoing PPV for primary RD with associated inferior retinal breaks and no significant proliferative vitreoretinopathy.
RESULTS—Eight eyes were successfully reattached with a single operation. No cases presented with redetachment because of failed closure of the original inferior breaks.
CONCLUSIONS—It is not necessary to support inferior retinal breaks with a scleral explant during PPV for primary RD repair in selected cases.

 PMID:11264142

  14. 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

  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. 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

  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. 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

  19. 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

  20. 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.

  1. 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.

  2. 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

  3. 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

  4. Dike emplacement near Parícutin volcano, Mexico in 2006

    NASA Astrophysics Data System (ADS)

    Gardine, Matt; West, Michael E.; Cox, Tiffany

    2011-03-01

    A major seismic swarm occurred near Parícutin volcano between the end of May and early July 2006. More than 700 earthquakes with magnitude (M L ) exceeding 2.4 were located. Parícutin, located in the Michoacán-Guanajuato volcanic field in western Mexico, is well known as the site of the 1943 eruption in which a new 400 m cinder cone was constructed in what had been farmland. The 2006 swarm exhibits all of the characteristics typically associated with swarms of volcanic origins. The earthquake rate showed the typical ramp up and ramp down over the course of several days. Magnitudes were evenly distributed in time with a notably high b-value of 2.45. The earthquake locations cluster around a northeast-striking trend extending approximately 6 km. Over the first two weeks, hypocenters migrated steadily a few hundred meters per day, rising from 9 to 5 km depth and moving northeast about 5 km. On approximately June 7, the ascent of hypocenters stalled. For the next three weeks, hypocenters held their depth while migrating laterally back to the southwest. Focal mechanisms during the first part of the swarm reflected the increased stress caused by dike inflation. Following June 7, the stress orientation changed and became more consistent with the inflation of horizontal sill-like structures. Though only limited information is available from the seismic swarm preceding the 1943 eruption, several features, including the swarm duration and magnitude relationships, were comparable to those of the 2006 episode. The strong indicators of a magmatic origin to the 2006 swarm suggest that at this location there are few, if any, traditional seismic discriminants that could be used to distinguish which seismic swarms and dike emplacement events might culminate in eruption.

  5. Etude de la dynamique des porteurs dans des nanofils de silicium par spectroscopie terahertz

    NASA Astrophysics Data System (ADS)

    Beaudoin, Alexandre

    Ce memoire presente une etude des proprietes de conduction electrique et de la dynamique temporelle des porteurs de charges dans des nanofils de silicium sondes par rayonnement terahertz. Les cas de nanofils de silicium non intentionnellement dopes et dopes type n sont compares pour differentes configurations du montage experimental. Les mesures de spectroscopie terahertz en transmission montre qu'il est possible de detecter la presence de dopants dans les nanofils via leur absorption du rayonnement terahertz (˜ 1--12 meV). Les difficultes de modelisation de la transmission d'une impulsion electromagnetique dans un systeme de nanofils sont egalement discutees. La detection differentielle, une modification au systeme de spectroscopie terahertz, est testee et ses performances sont comparees au montage de caracterisation standard. Les instructions et des recommendations pour la mise en place de ce type de mesure sont incluses. Les resultats d'une experience de pompe optique-sonde terahertz sont egalement presentes. Dans cette experience, les porteurs de charge temporairement crees suite a l'absorption de la pompe optique (lambda ˜ 800 nm) dans les nanofils (les photoporteurs) s'ajoutent aux porteurs initialement presents et augmentent done l'absorption du rayonnement terahertz. Premierement, l'anisotropie de l'absorption terahertz et de la pompe optique par les nanofils est demontree. Deuxiemement, le temps de recombinaison des photoporteurs est etudie en fonction du nombre de photoporteurs injectes. Une hypothese expliquant les comportements observes pour les nanofils non-dopes et dopes-n est presentee. Troisiemement, la photoconductivite est extraite pour les nanofils non-dopes et dopes-n sur une plage de 0.5 a 2 THz. Un lissage sur la photoconductivite permet d'estimer le nombre de dopants dans les nanofils dopes-n. Mots-cles: nanofil, silicium, terahertz, conductivite, spectroscopie, photoconductivite.

  6. 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.

  7. 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.

  8. 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

  9. Identification of an antithrombotic allosteric modulator that acts through helix 8 of PAR1.

    PubMed

    Dowal, Louisa; Sim, Derek S; Dilks, James R; Blair, Price; Beaudry, Sarah; Denker, Bradley M; Koukos, Georgios; Kuliopulos, Athan; Flaumenhaft, Robert

    2011-02-15

    G protein-coupled receptors (GPCRs) can assume multiple conformations and possess multiple binding sites. Whereas endogenous agonists acting at the orthosteric binding site stabilize the active receptor conformation, small molecules that act at nonorthosteric sites can stabilize alternative conformations. The large majority of these allosteric modulators associate with extracellular loops of GPCRs. The role of intracellular domains in mediating allosteric modulation is largely unknown. In screening a small-molecule library for inhibitors of platelet activation, we identified a family of compounds that modified PAR1-mediated granule secretion. The most potent inhibitory compound, termed JF5, also demonstrated noncompetitive inhibition of the α(2A)-adrenergic receptor. Aggregation studies using a battery of platelet GPCR agonists demonstrated that sensitivity to JF5 was limited to GPCRs that possessed a constrained eighth helix, as defined by a C-terminal palmitoylation site and interactions with TM7 and the i1 loop. Inhibition by JF5 was overcome in a PAR1 mutant in which the eighth helix was deleted, confirming a role for helix 8 in JF5 activity. Evaluation of downstream signaling showed that JF5 was selective with regard to G protein coupling, blocking signaling mediated by G(αq) but not G(α12). The compound inhibited thrombus formation in vivo following vascular injury with an IC(50) of ∼1 mg/kg. These results indicate a role for helix 8 in conferring sensitivity to small molecules, and show that this sensitivity can be exploited to control platelet activation during thrombus formation. PMID:21282664

  10. Vascularization of the pars distalis of the hypophysis in the toad, Bufo bufo (L.) (Amphibia, Anura). A comparative light microscopical and scanning electron microscopical study. I.

    PubMed

    1977-03-30

    The vascularization of the pars distalis of the hypophysis of the toad, Bufo bufo (L.), was studied by the traditional method of injecting a mixture of India-ink and gelatine into the circulatory system of the head via the arteria coratis communis. Further, methyl-methacrylate corrosion casts of the brains were made; the hypothalamo-adenohypophysial region of these corrosion casts was studied with the scanning electron microscope. The results showed that the portal vessels which arise from the median eminence do not supply distinct areas in the pars distalis as is supposed by the point-to-point-hypothesis. The portal vessels enter the ventro-median region of the pars distalis and branch off into a three-dimensional network of the secondary capillary plexus of the pars distalis. The plexus is made up mostly by four- to six-sided meshes. This angioarchitecture guarantees an optimal supply of the glandular cells of the pars distalis with nutritional factors and releasing hormones, on the one hand, and facilitates the removal of the hormones which are released by these cells, on the other hand. The venous drainage of the pars distalis is exerted mainly by two large veins, which bilaterally leave the dorso-lateral region (venous pole) of the pars distalis and by a few small veins, which drain into the wide, sinus-like vessel, which curves around the dorso-caudal region of the pars distalis and joins bilaterally the vena hypophysea transversa.

  11. 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.

  12. 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…

  13. 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…

  14. 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

  15. 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

  16. 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

  17. 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

  18. Simultaneous inactivation of Par-4 and PTEN in vivo leads to synergistic NF-κB activation and invasive prostate carcinoma

    PubMed Central

    Fernandez-Marcos, Pablo J.; Abu-Baker, Shadi; Joshi, Jayashree; Galvez, Anita; Castilla, Elias A.; Cañamero, Marta; Collado, Manuel; Saez, Carmen; Moreno-Bueno, Gema; Palacios, Jose; Leitges, Michael; Serrano, Manuel; Moscat, Jorge; Diaz-Meco, Maria T.

    2009-01-01

    Prostate cancer is one of the most common neoplasias in men. The tumor suppressor Par-4 is an important negative regulator of the canonical NF-κB pathway and is highly expressed in prostate. Here we show that Par-4 expression is lost in a high percentage of human prostate carcinomas, and this occurs in association with phosphatase and tensin homolog deleted from chromosome 10 (PTEN) loss. Par-4 null mice, similar to PTEN-heterozygous mice, only develop benign prostate lesions, but, importantly, concomitant Par-4 ablation and PTEN-heterozygosity lead to invasive prostate carcinoma in mice. This strong tumorigenic cooperation is anticipated in the preneoplastic prostate epithelium by an additive increase in Akt activation and a synergistic stimulation of NF-κB. These results establish the cooperation between Par-4 and PTEN as relevant for the development of prostate cancer and implicate the NF-κB pathway as a critical event in prostate tumorigenesis. PMID:19470463

  19. 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

  20. 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

  1. PAR-2, IL-4R, TGF-β and TNF-α in bronchoalveolar lavage distinguishes extrinsic allergic alveolitis from sarcoidosis

    PubMed Central

    MATĚJ, RADOSLAV; SMĚTÁKOVÁ, MAGDALENA; VAŠÁKOVÁ, MARTINA; NOVÁKOVÁ, JANA; ŠTERCLOVÁ, MARTINA; KUKAL, JAROMÍR; OLEJÁR, TOMÁŠ

    2014-01-01

    Sarcoidosis (SARC) and extrinsic allergic alveolitis (EAA) share certain markers, making a differential diagnosis difficult even with histopathological investigation. In lung tissue, proteinase-activated receptor-2 (PAR-2) is primarily investigated with regard to epithelial and inflammatory perspectives. Varying levels of certain chemokines can be a useful tool for distinguishing EAA and SARC. Thus, in the present study, differences in the levels of transforming growth factor (TGF)-β1, tumor necrosis factor (TNF)-α, interleukin-4 receptor (IL-4R) and PAR-2 in bronchoalveolar lavage fluid (BALF) were compared, using an ELISA method, between 14 patients with EAA and six patients with SARC. Statistically significant higher levels of IL-4R, PAR-2 and the PAR-2/TGF-β1 and PAR-2/TNF-α ratios were observed in EAA patients as compared with SARC patients. Furthermore, the ratios of TNF-α/total protein, TGF-β1/PAR-2 and TNF-α/PAR-2 were significantly lower in EAA patients than in SARC patients. The results indicated a higher detection of PAR-2 in EAA samples in association with TNF-α and TGF-β levels. As EAA and PAR-2 in parallel belong to the Th2-mediated pathway, the results significantly indicated an association between this receptor and etiology. In addition, the results indicated that SARC is predominantly a granulomatous inflammatory disease, thus, higher levels of TNF-α are observed. Therefore, the detection of PAR-2 and investigated chemokines in BALF may serve as a useful tool in the differential diagnosis between EAA and SARC. PMID:25009615

  2. Mapping the topographic epitope landscape on the urokinase plasminogen activator receptor (uPAR) by surface plasmon resonance and X-ray crystallography.

    PubMed

    Zhao, Baoyu; Gandhi, Sonu; Yuan, Cai; Luo, Zhipu; Li, Rui; Gårdsvoll, Henrik; de Lorenzi, Valentina; Sidenius, Nicolai; Huang, Mingdong; Ploug, Michael

    2015-12-01

    The urokinase-type plasminogen activator receptor (uPAR or CD87) is a glycolipid-anchored membrane protein often expressed in the microenvironment of invasive solid cancers and high levels are generally associated with poor patient prognosis (Kriegbaum et al., 2011 [1]). uPAR is organized as a dynamic modular protein structure composed of three homologous Ly6/uPAR domains (LU).This internally flexible protein structure of uPAR enables an allosteric regulation of the interactions with its two principal ligands: the serine protease urokinase-type plasminogen activator (uPA) and the provisional matrix protein vitronectin (Vn) (Mertens et al., 2012; Gårdsvoll et al., 2011; Madsen et al., 2007 [2-4]). The data presented here relates to the non-covalent trapping of one of these biologically relevant uPAR-conformations by a novel class of monoclonal antibodies (Zhao et al., 2015 [5]) and to the general mapping of the topographic epitope landscape on uPAR. The methods required to achieve these data include: (1) recombinant expression and purification of a uPAR-hybrid protein trapped in the desired conformation [patent; WO 2013/020898 A12013]; (2) developing monoclonal antibodies with unique specificities using this protein as antigen; (3) mapping the functional epitope on uPAR for these mAbs by surface plasmon resonance with a complete library of purified single-site uPAR mutants (Zhao et al., 2015; Gårdsvoll et al., 2006 [5,6]); and finally (4) solving the three-dimensional structures for one of these mAbs by X-ray crystallography alone and in complex with uPAR [deposited in the PDB database as 4QTH and 4QTI, respectively].

  3. 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.

  4. Mapping the topographic epitope landscape on the urokinase plasminogen activator receptor (uPAR) by surface plasmon resonance and X-ray crystallography.

    PubMed

    Zhao, Baoyu; Gandhi, Sonu; Yuan, Cai; Luo, Zhipu; Li, Rui; Gårdsvoll, Henrik; de Lorenzi, Valentina; Sidenius, Nicolai; Huang, Mingdong; Ploug, Michael

    2015-12-01

    The urokinase-type plasminogen activator receptor (uPAR or CD87) is a glycolipid-anchored membrane protein often expressed in the microenvironment of invasive solid cancers and high levels are generally associated with poor patient prognosis (Kriegbaum et al., 2011 [1]). uPAR is organized as a dynamic modular protein structure composed of three homologous Ly6/uPAR domains (LU).This internally flexible protein structure of uPAR enables an allosteric regulation of the interactions with its two principal ligands: the serine protease urokinase-type plasminogen activator (uPA) and the provisional matrix protein vitronectin (Vn) (Mertens et al., 2012; Gårdsvoll et al., 2011; Madsen et al., 2007 [2-4]). The data presented here relates to the non-covalent trapping of one of these biologically relevant uPAR-conformations by a novel class of monoclonal antibodies (Zhao et al., 2015 [5]) and to the general mapping of the topographic epitope landscape on uPAR. The methods required to achieve these data include: (1) recombinant expression and purification of a uPAR-hybrid protein trapped in the desired conformation [patent; WO 2013/020898 A12013]; (2) developing monoclonal antibodies with unique specificities using this protein as antigen; (3) mapping the functional epitope on uPAR for these mAbs by surface plasmon resonance with a complete library of purified single-site uPAR mutants (Zhao et al., 2015; Gårdsvoll et al., 2006 [5,6]); and finally (4) solving the three-dimensional structures for one of these mAbs by X-ray crystallography alone and in complex with uPAR [deposited in the PDB database as 4QTH and 4QTI, respectively]. PMID:26504891

  5. Capteur de CO{2} à fibres optiques par absorption moléculaire à 4,3 μm

    NASA Astrophysics Data System (ADS)

    Bendamardji, S.; Alayli, Y.; Huard, S.

    1996-04-01

    This paper describes a remote optical fibre sensor for the carbon dioxide detection by molecular absorption in the near infrared (4.3 μm) corresponding to fundamental mode ν3. To overcome the problem of the strong attenuation signal of optical fibre in the near infrared, we have used the opto-suppling technique which changes the working wavelength from 4.3 μm to 860 nm and permits the use of standard optical fibre 50/125. The simulation of absorption has been obtained by original modelisation of the absorption spectrum and the establishment of the calibration curves takes to the sensor to detect a partial pressures greater than 100 μbar with a minimal error margin of 100 μbar, which is acceptable considering the future use of the device. The sensor has been designed to monitor the CO{2} rate in enriched greenhouses. Cet article décrit un capteur à fibres optiques de gaz carbonique par absorption moléculaire dans l'infrarouge moyen (4,3 μm) correspondant au mode fondamental ν3. La liaison entre le site de mesure et le site de contrôle est assurée par un fibre optique standard 50/125 après une transposition de longueur d'onde de 4,3 μm à 860 nm par opto-alimentation. La simulation de l'absorption a été obtenue par modélisation originale du spectre d'absorption et l'établissement des courbes d'étalonnage prévoit une marge d'erreur minimale de 100 μbar, ce qui est suffisant pour l'application du dispositif à la régulation de taux CO{2} dans les serres agricoles enrichies par de gaz.

  6. Combining the hok/sok, parDE, and pnd postsegregational killer loci to enhance plasmid stability.

    PubMed

    Pecota, D C; Kim, C S; Wu, K; Gerdes, K; Wood, T K

    1997-05-01

    To enhance plasmid segregational stability in bacterial cells, two pairs of independent postsegregational killing loci (genes which induce host killing upon plasmid loss) isolated from plasmids R1, R483, or RP4 (hok+/sok+ pnd+ or hok+/sok+ parDE+) were cloned into a common site of the beta-galactosidase expression vector pMJR1750 (ptac::lacZ+) to form a series of plasmids in which the effect of one or two stability loci on segregational plasmid stability could be discerned. Adding two antisense killer loci (hok+/sok+ pnd+) decreased the specific growth rate by 50% though they were more effective at reducing segregational instability than hok+/sok+ alone. With the ptac promoter induced fully (2.0 mM isopropyl-beta-D-thiogalactopyranoside) and no antibiotic selection pressure, the combination of a proteic killer locus (parDE+) with antisense killer loci (hok+/sok+) had a negligible impact on specific growth rate, maintained high beta-galactosidase expression, and led to a 30 and 190% increase in segregational stability (based on stable generations) as compared to plasmids containing either hok+/sok+ or parDE+ alone, respectively. Use of hok+/sok+ or parDE+ alone with high cloned-gene expression led to ninefold and fourfold increases in the number of stable generations, respectively. Two convenient cloning cassettes have been constructed to facilitate cloning the dual hok+/sok+ parDE+ and hok+/sok+ pnd+ killer systems. PMID:9143123

  7. Radiation-inducible Silencing of uPA and uPAR in vitro and in vivo in meningioma

    PubMed Central

    Gogineni, Venkateswara Rao; Nalla, Arun Kumar; Gupta, Reshu; Gorantla, Bharathi; Gujrati, Meena; Dinh, Dzung H.; Rao, Jasti S.

    2010-01-01

    Stereospecific radiation treatment offers a distinct opportunity for temporal and spatial regulation of gene expression at tumor sites by means of inducible promoters. To this end, a plasmid, pCArG-U2, was constructed by incorporating nine CArG elements (in tandem) of EGR1 gene upstream to uPA and uPAR siRNA oligonucleotides in a pCi-Neo vector. Radiation-induced siRNA expression was detected in a meningioma cell line (IOMM-Lee). Immunoblotting and RT-PCR analyses confirmed downregulation of uPA and uPAR. A similar effect was observed in transfected cells followed by H2O2 treatment. Moreover, pre-treatment of transfected cells with N-Acetyl L-Cysteine blocked the silencing of uPA and uPAR, which further confirmed the oxidative damage-mediated downregulation. Cell proliferation assays and western blot analysis for apoptotic molecules confirmed cell death in a radiation-inducible fashion. Migration and matrigel invasion assays also revealed a marked decrease in migration and invasion. Immunocytochemistry showed a marked decrease in uPA and uPAR levels in transfected and irradiated cells. H&E staining revealed a decrease in the pre-established tumor volume among the animals treated with pCArG-U2 and radiation. Immunohistochemistry of the brain sections established with intracranial tumors also revealed a marked decrease in uPA and uPAR in a radiation-inducible fashion. Taken together, our data suggest pCArG-U2 as a suitable candidate for radiation-inducible gene therapy. PMID:20198323

  8. Restauration adaptative des contours par une approche inspiree de la prediction des performances

    NASA Astrophysics Data System (ADS)

    Rousseau, Kami

    En teledetection, les cartes de contours peuvent servir, entre autres choses, a la restitution geometrique, a la recherche d'elements lineaires, ainsi qu'a la segmentation. La creation de ces cartes est faite relativement tot dans la chaine de traitements d'une image. Pour assurer la qualite des operations subsequentes, il faut veiller a obtenir une carte de contours precise. Notre problematique est de savoir s'il est possible de diminuer la perte de temps liee au choix d'algorithme et de parametre en corrigeant automatiquement la carte de contours. Nous concentrerons donc nos efforts sur le developpement d'une methode de detection/restauration de contours adaptative. Notre methode s'inspire d'une technique de prediction des performances d'algorithmes de bas niveau. Elle consiste a integrer un traitement par reseau de neurones a une methode " classique " de detection de contours. Plus precisement, nous proposons de combiner la carte de performances avec la carte de gradient pour permettre des decisions plus exactes. La presente etude a permis de developper un logiciel comprenant un reseau de neurones entraine pour predire la presence de contours. Ce reseau de neurones permet d'ameliorer les decisions de detecteurs de contours, en reduisant le nombre de pixels de fausses alarmes et de contours manques. La premiere etape de ce travail consiste en une methode d'evaluation de performance pour les cartes de contours. Une fois ce choix effectue, il devient possible de comparer les cartes entre elles. Il est donc plus aise de determiner, pour chaque image, la meilleure detection de contours. La revue de la litterature realisee simultanement a permis de faire un choix d'un groupe d'indicateurs prometteurs pour la restauration de contours. Ces derniers ont servi a la calibration et a l'entrainement d'un reseau de neurones pour modeliser les contours. Par la suite, l'information fournie par ce reseau a ete combinee par multiplication arithmetique avec les cartes d

  9. Nanoparticules d'or: De l'imagerie par resonance magnetique a la radiosensibilisation

    NASA Astrophysics Data System (ADS)

    Hebert, Etienne M.

    Cette thèse approfondit l'étude de nanoparticules d'or de 5 nm de diamètre recouvertes de diamideéthanethioldiethylènetriaminepentacétate de gadolinium (DTDTPA:Gd), un agent de contraste pour l'imagerie par résonance magnétique (IRM). En guise de ciblage passif, la taille des nanoparticules a été contrôlée afin d'utiliser le réseau de néovaisseaux poreux et perméable des tumeurs. De plus les tumeurs ont un drainage lymphatique déficient qui permet aux nanoparticules de demeurer plus longtemps dans le milieu interstitiel de la tumeur. Les expériences ont été effectuées sur des souris Balb/c femelles portant des tumeurs MC7-L1. La concentration de nanoparticules a pu être mesurée à l'IRM in vivo. La concentration maximale se retrouvait à la fin de l'infusion de 10 min. La concentration s'élevait à 0.3 mM dans la tumeur et de 0.12 mM dans le muscle environnant. Les nanoparticules étaient éliminées avec une demi-vie de 22 min pour les tumeurs et de 20 min pour le muscle environnant. Les nanoparticules ont été fonctionnalisées avec le peptide Tat afin de leur conférer des propriétés de ciblage actif La rétention de ces nanoparticules a ainsi été augmentée de 1600 %, passant d'une demi-vie d'élimination de 22 min à 350 min. La survie des souris a été mesurée à l'aide de courbes Kaplan-Meier et d'un modèle mathématique évalue l'efficacité de traitements. Le modèle nous permet, à l'aide de la vitesse de croissance des tumeurs et de l'efficacité des traitements, de calculer la courbe de survie des spécimens. Un effet antagoniste a été observé au lieu de l'effet synergétique attendu entre une infusion de Au@DTDTPA:Gd et l'irradiation aux rayons X. L'absence d'effet synergétique a été attribuée à l'épaisseur du recouvrement de DTDTPA:Gd qui fait écran aux électrons produits par l'or. De plus, le moyen d'ancrage du recouvrement utilise des thiols qui peuvent s'avérer être des capteurs de radicaux. De plus

  10. Traitement par plasma thermique d'une liqueur caustique pour la destruction des cyanures

    NASA Astrophysics Data System (ADS)

    Fortin, Luc

    L'objectif principal de cette recherche est d'evaluer la possibilite de traiter le lixiviat de brasques usees produit par le procede LCL&L (Lixiviation a bas caustique et chaulage) par contact direct avec un jet de plasma thermique. L'utilisation d'un chalumeau au plasma permet d'eliminer les problemes de reaction avec les produits de combustion relies a l'utilisation de chalumeaux conventionnels (e.g. carbonatation du NaOH en Na2CO3). Le fait de se servir de ce type de chalumeau en mode submerge pour le traitement d'une solution liquide constitue l'originalite du projet. Les essais effectues dans le cadre de ce travail experimental sont realises a l'echelle banc d'essai dans un premier temps. Ils visent a determiner le taux de decomposition des cyanures contenus dans le lixiviat sous des conditions de plasma thermique en fonction de differents parametres et a faire la mise a l'echelle d'un reacteur pilote. La puissance electrique fournie au chalumeau, la temperature et la pression d'operation, le point d'addition d'eau, le volume de lixiviat traite et l'addition de peroxyde d'hydrogene (H2O2) comme co-reactif ont tous un impact sur le taux de destruction des cyanures trouve. Sous toutes les conditions etudiees, le reacteur plasma offre un taux de destruction plus rapide qu'un reacteur agite sous pression pour une meme concentration en cyanures. Ainsi, la comparaison de la constante cinetique obtenue pour le reacteur agite avec une constante similaire pour le reacteur plasma (pente du graphique -ln(C/C0) en fonction du temps) est de 0.04x10-3 s-1 vs 0.59x10-3 s-1 a 100°C et de 1.85x10-3 s-1' vs 3x10 -3 s-1s a 170°C. Ces resultats confirment que le plasma joue un role important sur la decomposition des cyanures et qu'il contribue a en augmenter le taux de destruction. Suite aux connaissances acquises sur le banc d'essai, un reacteur pilote est concu. Un chalumeau au plasma d'une puissance de 60 kW-150 kW et fonctionnant avec l'air comme gaz plasmagene y est

  11. Fabrication de memoire monoelectronique non volatile par une approche de nanogrille flottante

    NASA Astrophysics Data System (ADS)

    Guilmain, Marc

    Les transistors monoelectroniques (SET) sont des dispositifs de tailles nanometriques qui permettent la commande d'un electron a la fois et donc, qui consomment peu d'energie. Une des applications complementaires des SET qui attire l'attention est son utilisation dans des circuits de memoire. Une memoire monoelectronique (SEM) non volatile a le potentiel d'operer a des frequences de l'ordre des gigahertz ce qui lui permettrait de remplacer en meme temps les memoires mortes de type FLASH et les memoires vives de type DRAM. Une puce SEM permettrait donc ultimement la reunification des deux grands types de memoire au sein des ordinateurs. Cette these porte sur la fabrication de memoires monoelectroniques non volatiles. Le procede de fabrication propose repose sur le procede nanodamascene developpe par C. Dubuc et al. a 1'Universite de Sherbrooke. L'un des avantages de ce procede est sa compatibilite avec le back-end-of-line (BEOL) des circuits CMOS. Ce procede a le potentiel de fabriquer plusieurs couches de circuits memoirestres denses au-dessus de tranches CMOS. Ce document presente, entre autres, la realisation d'un simulateur de memoires monoelectroniques ainsi que les resultats de simulations de differentes structures. L'optimisation du procede de fabrication de dispositifs monoelectroniques et la realisation de differentes architectures de SEM simples sont traitees. Les optimisations ont ete faites a plusieurs niveaux : l'electrolithographie, la gravure de l'oxyde, le soulevement du titane, la metallisation et la planarisation CMP. La caracterisation electrique a permis d'etudier en profondeur les dispositifs formes de jonction de Ti/TiO2 et elle a demontre que ces materiaux ne sont pas appropries. Par contre, un SET forme de jonction de TiN/Al2O3 a ete fabrique et caracterise avec succes a basse temperature. Cette demonstration demontre le potentiel du procede de fabrication et de la deposition de couche atomique (ALD) pour la fabrication de memoires

  12. Combined pars plana vitrectomy and Baerveldt glaucoma implant placement for refractory glaucoma

    PubMed Central

    Campagnoli, Thalmon R.; Kim, Sung Soo; Smiddy, William E.; Gedde, Steve J.; Budenz, Donald L.; Parrish, Richard K.; Palmberg, Paul F.; Feuer, William; Shi, Wei

    2015-01-01

    AIM To evaluate outcomes of combined pars plana vitrectomy and Baerveldt glaucoma implant (PPV-BGI) placement for refractory glaucoma. METHODS The medical records of 92 eyes (89 patients) that underwent PPV-BGI were retrospectively reviewed, including 43 eyes with neovascular glaucoma (NVG) and 49 eyes with other types of glaucoma (non-NVG). RESULTS Outcome measures were visual acuity (VA), intraocular pressure (IOP), glaucoma medical therapy, complications, and success [VA>hand motions (HM), IOP≥6 mm Hg and ≤21 mm Hg, no subsequent glaucoma surgery]. Cumulative success rates for the non-NVG group and NVG group were 79% and 40% at 1y, respective