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Sample records for parp inhibitor-induced collapsed

  1. REV7 counteracts DNA double-strand break resection and affects PARP inhibition

    NARCIS (Netherlands)

    Xu, Guotai; Chapman, J. Ross; Brandsma, Inger; Yuan, Jingsong; Mistrik, Martin; Bouwman, Peter; Bartkova, Jirina; Gogola, Ewa; Warmerdam, Daniël; Barazas, Marco; Jaspers, Janneke E.; Watanabe, Kenji; Pieterse, Mark; Kersbergen, Ariena; Sol, Wendy; Celie, Patrick H. N.; Schouten, Philip C.; van den Broek, Bram; Salman, Ahmed; Nieuwland, Marja; de Rink, Iris; de Ronde, Jorma; Jalink, Kees; Boulton, Simon J.; Chen, Junjie; van Gent, Dik C.; Bartek, Jiri; Jonkers, Jos; Borst, Piet; Rottenberg, Sven

    2015-01-01

    Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway(1). In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with

  2. Structural Implications for Selective Targeting of PARPs.

    Science.gov (United States)

    Steffen, Jamin D; Brody, Jonathan R; Armen, Roger S; Pascal, John M

    2013-12-20

    Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that use NAD(+) as a substrate to synthesize polymers of ADP-ribose (PAR) as post-translational modifications of proteins. PARPs have important cellular roles that include preserving genomic integrity, telomere maintenance, transcriptional regulation, and cell fate determination. The diverse biological roles of PARPs have made them attractive therapeutic targets, which have fueled the pursuit of small molecule PARP inhibitors. The design of PARP inhibitors has matured over the past several years resulting in several lead candidates in clinical trials. PARP inhibitors are mainly used in clinical trials to treat cancer, particularly as sensitizing agents in combination with traditional chemotherapy to reduce side effects. An exciting aspect of PARP inhibitors is that they are also used to selectivity kill tumors with deficiencies in DNA repair proteins (e.g., BRCA1/2) through an approach termed "synthetic lethality." In the midst of the tremendous efforts that have brought PARP inhibitors to the forefront of modern chemotherapy, most clinically used PARP inhibitors bind to conserved regions that permits cross-selectivity with other PARPs containing homologous catalytic domains. Thus, the differences between therapeutic effects and adverse effects stemming from pan-PARP inhibition compared to selective inhibition are not well understood. In this review, we discuss current literature that has found ways to gain selectivity for one PARP over another. We furthermore provide insights into targeting other domains that make up PARPs, and how new classes of drugs that target these domains could provide a high degree of selectivity by affecting specific cellular functions. A clear understanding of the inhibition profiles of PARP inhibitors will not only enhance our understanding of the biology of individual PARPs, but may provide improved therapeutic options for patients.

  3. Investigation of PARP-1, PARP-2, and PARG interactomes by affinity-purification mass spectrometry

    Directory of Open Access Journals (Sweden)

    Isabelle Maxim

    2010-04-01

    Full Text Available Abstract Background Poly(ADP-ribose polymerases (PARPs catalyze the formation of poly(ADP-ribose (pADPr, a post-translational modification involved in several important biological processes, namely surveillance of genome integrity, cell cycle progression, initiation of the DNA damage response, apoptosis, and regulation of transcription. Poly(ADP-ribose glycohydrolase (PARG, on the other hand, catabolizes pADPr and thereby accounts for the transient nature of poly(ADP-ribosylation. Our investigation of the interactomes of PARP-1, PARP-2, and PARG by affinity-purification mass spectrometry (AP-MS aimed, on the one hand, to confirm current knowledge on these interactomes and, on the other hand, to discover new protein partners which could offer insights into PARPs and PARG functions. Results PARP-1, PARP-2, and PARG were immunoprecipitated from human cells, and pulled-down proteins were separated by gel electrophoresis prior to in-gel trypsin digestion. Peptides were identified by tandem mass spectrometry. Our AP-MS experiments resulted in the identifications of 179 interactions, 139 of which are novel interactions. Gene Ontology analysis of the identified protein interactors points to five biological processes in which PARP-1, PARP-2 and PARG may be involved: RNA metabolism for PARP-1, PARP-2 and PARG; DNA repair and apoptosis for PARP-1 and PARP-2; and glycolysis and cell cycle for PARP-1. Conclusions This study reveals several novel protein partners for PARP-1, PARP-2 and PARG. It provides a global view of the interactomes of these proteins as well as a roadmap to establish the systems biology of poly(ADP-ribose metabolism.

  4. PARP Inhibitors in Ovarian Cancer.

    Science.gov (United States)

    Mittica, Gloria; Ghisoni, Eleonora; Giannone, Gaia; Genta, Sofia; Aglietta, Massimo; Sapino, Anna; Valabrega, Giorgio

    2018-03-05

    Treatment of Epithelial Ovarian Cancer (EOC), historically based on surgery and platinum doublet chemotherapy, is associated with high risk of relapse and poor prognosis for recurrent disease. In this landscape, the innovative treatment with PARP inhibitors (PARPis) demonstrated an outstanding activity in EOC, and is currently changing clinical practice in BRCA mutant patients. To highlight the mechanism of action, pharmacokinetics, clinical activity, indications and current strategies of development of Olaparib, Niraparib, Rucaparib, Talazoparib and Veliparib, the 5 most relevant PARPis. We performed a review on Pubmed using 'ovarian cancer' and the name of each PARPi (PARP inhibitor) discussed in the review as Medical Subject Headings (MeSH) keywords. The same search was performed on "clinicaltrial.gov" to identify ongoing clinical trials and on "google.com/patents" and "uspto.gov" for recent patents exploring PARPIs in ovarian cancer. Olaparib, Niraparib and Rucaparib are already approved for treatment of recurrent EOC and their indications are partially overlapping. Talazoparib and Veliparib are promising PARPis, but currently under investigation in early phase trials. Several studies are evaluating PARPis in monotherapy or in associations, in a wide range of settings (i.e. first line, neoadjuvant, platinum-sensitive and resistant disease). PARPis are valuable options in patients with recurrent ovarian cancer with promising activity in different stages of this disease. Further studies are required to better define optimal clinical settings, predictors of response beyond BRCA mutations and strategies to overcome secondary resistance of PARPis therapy in EOC. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Radiosensitivity modulating factors: Role of PARP-1, PARP-2 and Cdk5 proteins and chromatin implication

    International Nuclear Information System (INIS)

    Boudra, M.T.

    2011-12-01

    The post-translational modifications of DNA repair proteins and histone remodeling factors by poly(ADP-ribose)ylation and phosphorylation are essential for the maintenance of DNA integrity and chromatin structure, and in particular in response to DNA damaging produced by ionizing radiation (IR). Amongst the proteins implicated in these two processes are the poly(ADP-ribose) polymerase -1 (PARP-1) and PARP-2, and the cyclin-dependent kinase Cdk5: PARP-1 and 2 are involved in DNA single strand break (SSB) repair (SSBR) and Cdk5 depletion has been linked with increased cell sensitivity to PARP inhibition. We have shown by using HeLa cells stably depleted for either CdK5 or PARP-2, that the recruitment profile of PARP-1 and XRCC-1, two proteins involved in the short-patch (SP) SSBR sub-pathway, to DNA damage sites is sub-maximal and that of PCNA, a protein involved in the long-patch (LP) repair pathway, is increased in the absence of Cdk5 and decreased in the absence of PARP-2 suggesting that both Cdk5 and PARP-2 are involved in both SSBR sub-pathways. PARP-2 and Cdk5 also impact on the poly(ADP-ribose) levels in cells as in the absence of Cdk5 a hyper-activation of PARP-1 was found and in the absence of PARP-2 a reduction in poly(ADP-ribose) glyco-hydrolase (PARG) activity was seen. However, in spite of these changes no impact on the repair of SSBs induced by IR was seen in either the Cdk5 or PARP-2 depleted cells (Cdk5 KD or PARP-2 KD cells) but, interestingly, increased radiation sensitivity in terms of cell killing was noted in the Cdk5 depleted cells. We also found that Cdk5, PARP-2 and PARG were all implicated in the regulation of the recruitment and the dissociation of the chromatin-remodeling factor ALC1 from DNA damage sites suggesting a role for these three proteins in changes in chromatin structure after DNA photo-damage. These results, taken together with the observation that PARP-1 recruitment is sub-optimal in both Cdk5 KD and PARP-2 KD cells, show that

  6. Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma.

    Science.gov (United States)

    Gill, Sonja J; Travers, Jon; Pshenichnaya, Irina; Kogera, Fiona A; Barthorpe, Syd; Mironenko, Tatiana; Richardson, Laura; Benes, Cyril H; Stratton, Michael R; McDermott, Ultan; Jackson, Stephen P; Garnett, Mathew J

    2015-01-01

    Ewing's sarcoma is a malignant pediatric bone tumor with a poor prognosis for patients with metastatic or recurrent disease. Ewing's sarcoma cells are acutely hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibition and this is being evaluated in clinical trials, although the mechanism of hypersensitivity has not been directly addressed. PARP inhibitors have efficacy in tumors with BRCA1/2 mutations, which confer deficiency in DNA double-strand break (DSB) repair by homologous recombination (HR). This drives dependence on PARP1/2 due to their function in DNA single-strand break (SSB) repair. PARP inhibitors are also cytotoxic through inhibiting PARP1/2 auto-PARylation, blocking PARP1/2 release from substrate DNA. Here, we show that PARP inhibitor sensitivity in Ewing's sarcoma cells is not through an apparent defect in DNA repair by HR, but through hypersensitivity to trapped PARP1-DNA complexes. This drives accumulation of DNA damage during replication, ultimately leading to apoptosis. We also show that the activity of PARP inhibitors is potentiated by temozolomide in Ewing's sarcoma cells and is associated with enhanced trapping of PARP1-DNA complexes. Furthermore, through mining of large-scale drug sensitivity datasets, we identify a subset of glioma, neuroblastoma and melanoma cell lines as hypersensitive to the combination of temozolomide and PARP inhibition, potentially identifying new avenues for therapeutic intervention. These data provide insights into the anti-cancer activity of PARP inhibitors with implications for the design of treatment for Ewing's sarcoma patients with PARP inhibitors.

  7. PARP-1 Interaction with and Activation by Histones and Nucleosomes.

    Science.gov (United States)

    Thomas, Colin; Kotova, Elena; Tulin, Alexei V

    2017-01-01

    Poly(ADP-ribose) Polymerase 1 (PARP-1) is an abundant chromatin associated protein, typical for most eukaryotic nuclei. The localization of PARP-1 in chromatin and its enzymatic activation involves multiple interactions of PARP-1 with nucleosomal histones, other proteins, and DNA. We report a set of methods designed to reconstitute PARP-1 regulation in vitro. These methods involve the expression of PARP-1 and PARP-1-regulating proteins using bacterial and eukaryotic systems, purification of these proteins using chromatography, testing of individual interactions in vitro, assembly of active complexes, and reconstitution of PARP-1 regulating reactions in vitro.

  8. PARP1 Val762Ala polymorphism reduces enzymatic activity

    International Nuclear Information System (INIS)

    Wang Xiaogan; Wang Zhaoqi; Tong Weimin; Shen Yan

    2007-01-01

    Poly(ADP-ribose) polymerase 1 (PARP1) modifies a variety of nuclear proteins by poly(ADP-ribosyl)ation, and plays diverse roles in molecular and cellular processes. A common PARP1 single nucleotide polymorphism (SNP) at codon 762, resulting in the substitution of alanine (Ala) for valine (Val) in the catalytic domain has been implicated in susceptibility to cancer. To characterize the functional effect of this polymorphism on PARP1, we performed in vitro enzymatic analysis on PARP1-Ala762 and PARP1-Val762. We found that PARP1-Ala762 displayed 57.2% of the activity of PARP1-Val762 for auto-poly(ADP-ribosyl)ation and 61.9% of the activity of PARP1-Val762 for trans-poly(ADP-ribosyl)ation of histone H1. The kinetic characterization revealed that the K m of PARP1-Ala762 was increased to a 1.2-fold of the K m of PARP1-Val762 for trans-poly(ADP-ribosyl)ation. Thus, the PARP1 Val762Ala polymorphism reduces the enzymatic activity of PARP1 by increasing K m . This finding suggests that different levels of poly(ADP-ribosyl)ation by PARP1 might aid in understanding Cancer risk of carriers of the PARP1 Val762Ala polymorphism

  9. PARP-1 como regulador del ciclo celular

    OpenAIRE

    Iglesias Vázquez, Pablo

    2015-01-01

    En el presente estudio hemos querido investigar las implicaciones biológicas de la interacción PARP-1/E2F-1 en escenarios en los que el factor de transcripción E2F-1 resulta de gran importancia como son el desarrollo embrionario y la oncogénesis. En este respecto, hemos demostrado que tanto PJ34, inhibidor de la actividad enzimática de PARP, como gosipol, inhibidor de las interacciones proteína-proteína, son capaces de reducir la actividad transcripcional de E2F-1 y la proli...

  10. PARP inhibition versus PARP-1 silencing: different outcomes in terms of single-strand break repair and radiation susceptibility

    International Nuclear Information System (INIS)

    Godon, C.; Cordelieres, F.P.; Giocanti, N.; Megnin-Chanet, F.; Hall, J.; Favaudon, V.; Godon, C.; Giocanti, N.; Megnin-Chanet, F.; Hall, J.; Favaudon, V.; Cordelieres, F.P.; Cordelieres, F.P.; Biard, D.

    2008-01-01

    The consequences of PARP-1 disruption or inhibition on DNA single-strand break repair (SSBR) and radio-induced lethality were determined in synchronized, iso-genic HeLa cells stably silenced or not for poly(ADP-ribose) polymerase-1 (PARP-1) (PARP-1(KD)) or XRCC1 (XRCC1(KD)). PARP-1 inhibition prevented XRCC1-YFP recruitment at sites of 405 nm laser micro irradiation, slowed SSBR 10-fold and triggered the accumulation of large persistent foci of GFP-PARP-1 and GFP-PCNA at photo damaged sites. These aggregates are presumed to hinder the recruitment of other effectors of the base excision repair (BER) pathway.PARP-1 silencing also prevented XRCC1-YFP recruitment but did not lengthen the lifetime of GFP-PCNA foci. Moreover, PARP-1(KD) and XRCC1(KD) cells in S phase completed SSBR as rapidly as controls, while SSBR was delayed in G1. Taken together, the data demonstrate that a PARP-1- and XRCC1-independent SSBR pathway operates when the short patch repair branch of the BER is deficient. Long patch repair is the likely mechanism, as GFP-PCNA recruitment at photo-damaged sites was normal in PARP-1(KD) cells. PARP-1 silencing elicited hyper-radiosensitivity, while radiosensitization by a PARP inhibitor reportedly occurs only in those cells treated in S phase. PARP-1 inhibition and deletion thus have different outcomes in terms of SSBR and radiosensitivity. (authors)

  11. Texture collapse

    International Nuclear Information System (INIS)

    Prokopec, T.; Sornborger, A.; Brandenberger, R.H.

    1992-01-01

    We study single-texture collapse using a leapfrog discretization method on a 30x30x30 spatial lattice. We investigate the influence of boundary conditions, physical size of the lattice, type of space-time background (flat, i.e., nonexpanding, vs radiation-dominated and matter-dominated universes), and spatial distribution of the initial texture configuration on collapse time and critical winding. For a spherically symmetric initial configuration of size equal to the horizon size on a lattice containing 12 (30) horizon volumes, the critical winding is found to be 0.621±0.001 (0.602±0.003) (flat case), 0.624±0.002 (0.604±0.005) (radiation era), 0.628±0.002 (0.612±0.003) (matter era). The larger the physical size of the lattice (in units of the horizon size), the smaller is the critical winding, and in the limit of an infinite lattice, we argue that the critical winding approaches 0.5. For radially asymmetric cases, contraction of one axis ( /Ipancake case) slightly reduces collapse time and critical winding, and contraction of two axes (d/Icigar case) reduces collapse time and critical winding significantly

  12. PARP-1 and PARP-2 activity in cancer-induced cachexia: potential therapeutic implications.

    Science.gov (United States)

    Barreiro, Esther; Gea, Joaquim

    2018-01-26

    Skeletal muscle dysfunction and mass loss is a characteristic feature in patients with chronic diseases including cancer and acute conditions such as critical illness. Maintenance of an adequate muscle mass is crucial for the patients' prognosis irrespective of the underlying condition. Moreover, aging-related sarcopenia may further aggravate the muscle wasting process associated with chronic diseases and cancer. Poly(adenosine diphosphate-ribose) polymerase (PARP) activation has been demonstrated to contribute to the pathophysiology of muscle mass loss and dysfunction in animal models of cancer-induced cachexia. Genetic inhibition of PARP activity attenuated the deleterious effects seen on depleted muscles in mouse models of oncologic cachexia. In the present minireview the mechanisms whereby PARP activity inhibition may improve muscle mass and performance in models of cancer-induced cachexia are discussed. Specifically, the beneficial effects of inhibition of PARP activity on attenuation of increased oxidative stress, protein catabolism, poor muscle anabolism and mitochondrial content and epigenetic modulation of muscle phenotype are reviewed in this article. Finally, the potential therapeutic strategies of pharmacological PARP activity inhibition for the treatment of cancer-induced cachexia are also being described in this review.

  13. Trial watch – inhibiting PARP enzymes for anticancer therapy

    Science.gov (United States)

    Sistigu, Antonella; Manic, Gwenola; Obrist, Florine; Vitale, Ilio

    2016-01-01

    ABSTRACT Poly(ADP-ribose) polymerases (PARPs) are a members of family of enzymes that catalyze poly(ADP-ribosyl)ation (PARylation) and/or mono(ADP-ribosyl)ation (MARylation), two post-translational protein modifications involved in crucial cellular processes including (but not limited to) the DNA damage response (DDR). PARP1, the most abundant family member, is a nuclear protein that is activated upon sensing distinct types of DNA damage and contributes to their resolution by PARylating multiple DDR players. Recent evidence suggests that, along with DDR, activated PARP1 mediates a series of prosurvival and proapoptotic processes aimed at preserving genomic stability. Despite this potential oncosuppressive role, upregulation and/or overactivation of PARP1 or other PARP enzymes has been reported in a variety of human neoplasms. Over the last few decades, several pharmacologic inhibitors of PARP1 and PARP2 have been assessed in preclinical and clinical studies showing potent antineoplastic activity, particularly against homologous recombination (HR)-deficient ovarian and breast cancers. In this Trial Watch, we describe the impact of PARP enzymes and PARylation in cancer, discuss the mechanism of cancer cell killing by PARP1 inactivation, and summarize the results of recent clinical studies aimed at evaluating the safety and therapeutic profile of PARP inhibitors in cancer patients. PMID:27308587

  14. Six collapses

    International Nuclear Information System (INIS)

    Miller, R.H.; Smith, B.F.

    1979-01-01

    The self-consistent dynamical development of six stellar systems, started from rotating spherical configurations, has been studied by means of a fully three-dimensional n-body integration. The six examples had different initial angular velocities and velocity dispersions. All settled down into prolate bars rotating about a short axis within two initial rotation periods. The bars are long-lived, robust, and stable. Bars are the natural form toward which rapidly rotating stellar dynamical systems develop, instead of the flattened axisymmetric disks that had been expected.The early stages of each collapse are reasonably well described by a theoretical model according to which a collapse passes through a sequence of rigidly rotating, uniform-density spheroids. The first significant departures from spheroidal form were axisymmetric in all cases. Rings formed in some examples, sheets in others, with transition cases between these extremes. Nonaxisymmetry forms developed from these intermediate stages

  15. Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner.

    Science.gov (United States)

    Calvo, Jennifer A; Allocca, Mariacarmela; Fake, Kimberly R; Muthupalani, Sureshkumar; Corrigan, Joshua J; Bronson, Roderick T; Samson, Leona D

    2016-07-19

    Nephrotoxicity is a common toxic side-effect of chemotherapeutic alkylating agents. Although the base excision repair (BER) pathway is essential in repairing DNA alkylation damage, under certain conditions the initiation of BER produces toxic repair intermediates that damage healthy tissues. We have shown that the alkyladenine DNA glycosylase, Aag (a.k.a. Mpg), an enzyme that initiates BER, mediates alkylation-induced whole-animal lethality and cytotoxicity in the pancreas, spleen, retina, and cerebellum, but not in the kidney. Cytotoxicity in both wild-type and Aag-transgenic mice (AagTg) was abrogated in the absence of Poly(ADP-ribose) polymerase-1 (Parp1). Here we report that Parp1-deficient mice expressing increased Aag (AagTg/Parp1-/-) develop sex-dependent kidney failure upon exposure to the alkylating agent, methyl methanesulfonate (MMS), and suffer increased whole-animal lethality compared to AagTg and wild-type mice. Macroscopic, histological, electron microscopic and immunohistochemical analyses revealed morphological kidney damage including dilated tubules, proteinaceous casts, vacuolation, collapse of the glomerular tuft, and deterioration of podocyte structure. Moreover, mice exhibited clinical signs of kidney disease indicating functional damage, including elevated blood nitrogen urea and creatinine, hypoproteinemia and proteinuria. Pharmacological Parp inhibition in AagTg mice also resulted in sensitivity to MMS-induced nephrotoxicity. These findings provide in vivo evidence that Parp1 modulates Aag-dependent MMS-induced nephrotoxicity in a sex-dependent manner and highlight the critical roles that Aag-initiated BER and Parp1 may play in determining the side-effects of chemotherapeutic alkylating agents.

  16. The NAD+/PARP1/SIRT1 Axis in Aging.

    Science.gov (United States)

    Mendelsohn, Andrew R; Larrick, James W

    2017-06-01

    NAD+ levels decline with age in diverse animals from Caenorhabditis elegans to mice. Raising NAD+ levels by dietary supplementation with NAD+ precursors, nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), improves mitochondrial function and muscle and neural and melanocyte stem cell function in mice, as well as increases murine life span. Decreased NAD+ levels with age reduce SIRT1 function and reduce the mitochondrial unfolded protein response, which can be overcome by NR supplementation. Decreased NAD+ levels cause NAD+-binding protein DBC1 to form a complex with PARP1, inhibiting poly(adenosine diphosphate-ribose) polymerase (PARP) catalytic activity. Old mice have increased amounts of DBC1-PARP1 complexes, lower PARP activity, increased DNA damage, and reduced nonhomologous end joining and homologous recombination repair. DBC1-PARP1 complexes in old mice can be broken by increasing NAD+ levels through treatment with NMN, reducing DNA damage and restoring PARP activity to youthful levels. The mechanism of declining NAD+ levels and its fundamental importance to aging are yet to be elucidated. There is a correlation of PARP activity with mammalian life span that suggests that NAD+/SIRT1/PARP1 may be more significant than the modest effects on life span observed for NR supplementation in old mice. The NAD+/PARP1/SIRT1 axis may link NAD+ levels and DNA damage with the apparent epigenomic DNA methylation clocks that have been described.

  17. Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade.

    Directory of Open Access Journals (Sweden)

    Fenqing Shang

    Full Text Available Hyperglycemia and hypertension impair endothelial function in part through oxidative stress-activated poly (ADP-ribose polymerase 1 (PARP1. Biguanides and angiotensin II receptor blockers (ARBs such as metformin and telmisartan have a vascular protective effect. We used cultured vascular endothelial cells (ECs, diabetic and hypertensive rodent models, and AMPKα2-knockout mice to investigate whether metformin and telmisartan have a beneficial effect on the endothelium via AMP-activated protein kinase (AMPK phosphorylation of PARP1 and thus inhibition of PARP1 activity. The results showed that metformin and telmisartan, but not glipizide and metoprolol, activated AMPK, which phosphorylated PARP1 Ser-177 in cultured ECs and the vascular wall of rodent models. Experiments using phosphorylated/de-phosphorylated PARP1 mutants show that AMPK phosphorylation of PARP1 leads to decreased PARP1 activity and attenuated protein poly(ADP-ribosylation (PARylation, but increased endothelial nitric oxide synthase (eNOS activity and silent mating type information regulation 2 homolog 1 (SIRT1 expression. Taken together, the data presented here suggest biguanides and ARBs have a beneficial effect on the vasculature by the cascade of AMPK phosphorylation of PARP1 to inhibit PARP1 activity and protein PARylation in ECs, thereby mitigating endothelial dysfunction.

  18. Parp-1 genetic ablation in Ela-myc mice unveils novel roles for Parp-1 in pancreatic cancer.

    Science.gov (United States)

    Martínez-Bosch, Neus; Iglesias, Mar; Munné-Collado, Jessica; Martínez-Cáceres, Carlos; Moreno, Mireia; Guerra, Carmen; Yélamos, Jose; Navarro, Pilar

    2014-10-01

    Pancreatic cancer has a dismal prognosis and is currently the fourth leading cause of cancer-related death in developed countries. The inhibition of poly(ADP-ribose) polymerase-1 (Parp-1), the major protein responsible for poly(ADP-ribosy)lation in response to DNA damage, has emerged as a promising treatment for several tumour types. Here we aimed to elucidate the involvement of Parp-1 in pancreatic tumour progression. We assessed Parp-1 protein expression in normal, preneoplastic and pancreatic tumour samples from humans and from K-Ras- and c-myc-driven mouse models of pancreatic cancer. Parp-1 was highly expressed in acinar cells in normal and cancer tissues. In contrast, ductal cells expressed very low or undetectable levels of this protein, both in a normal and in a tumour context. The Parp-1 expression pattern was similar in human and mouse samples, thereby validating the use of animal models for further studies. To determine the in vivo effects of Parp-1 depletion on pancreatic cancer progression, Ela-myc-driven pancreatic tumour development was analysed in a Parp-1 knock-out background. Loss of Parp-1 resulted in increased tumour necrosis and decreased proliferation, apoptosis and angiogenesis. Interestingly, Ela-myc:Parp-1(-/-) mice displayed fewer ductal tumours than their Ela-myc:Parp-1(+/+) counterparts, suggesting that Parp-1 participates in promoting acinar-to-ductal metaplasia, a key event in pancreatic cancer initiation. Moreover, impaired macrophage recruitment can be responsible for the ADM blockade found in the Ela-myc:Parp-1(-/-) mice. Finally, molecular analysis revealed that Parp-1 modulates ADM downstream of the Stat3-MMP7 axis and is also involved in transcriptional up-regulation of the MDM2, VEGFR1 and MMP28 cancer-related genes. In conclusion, the expression pattern of Parp-1 in normal and cancer tissue and the in vivo functional effects of Parp-1 depletion point to a novel role for this protein in pancreatic carcinogenesis and shed light

  19. PARP-1 inhibition alleviates diabetic cardiac complications in experimental animals.

    Science.gov (United States)

    Zakaria, Esraa M; El-Bassossy, Hany M; El-Maraghy, Nabila N; Ahmed, Ahmed F; Ali, Abdelmoneim A

    2016-11-15

    Cardiovascular complications are the major causes of mortality among diabetic population. Poly(ADP-ribose) polymerase-1 enzyme (PARP-1) is activated by oxidative stress leading to cellular damage. We investigated the implication of PARP-1 in diabetic cardiac complications. Type 2 diabetes was induced in rats by high fructose-high fat diet and low streptozotocin dose. PARP inhibitor 4-aminobenzamide (4-AB) was administered daily for ten weeks after diabetes induction. At the end of study, surface ECG, blood pressure and vascular reactivity were studied. PARP-1 activity, reduced glutathione (GSH) and nitrite contents were assessed in heart muscle. Fasting glucose, fructosamine, insulin, and tumor necrosis factor alpha (TNF-α) levels were measured in serum. Finally, histological examination and collagen deposition detection in rat ventricular and aortic sections were carried out. Hearts isolated from diabetic animals showed increased PARP-1 enzyme activity compared to control animals while significantly reduced by 4-AB administration. PARP-1 inhibition by 4-AB alleviated cardiac ischemia in diabetic animals as indicated by ECG changes. PARP-1 inhibition also reduced cardiac inflammation in diabetic animals as evidenced by histopathological changes. In addition, 4-AB administration improved the elevated blood pressure and the associated exaggerated vascular contractility, endothelial destruction and vascular inflammation seen in diabetic animals. Moreover, PARP-1 inhibition decreased serum levels of TNF-α and cardiac nitrite but increased cardiac GSH contents in diabetic animals. However, PARP-1 inhibition did not significantly affect the developed hyperglycemia. Our findings prove that PARP-1 enzyme plays an important role in diabetic cardiac complications through combining inflammation, oxidative stress, and fibrosis mechanisms. Copyright © 2016. Published by Elsevier B.V.

  20. Prevention of gravitational collapse

    International Nuclear Information System (INIS)

    Moffat, J.W.; Taylor, J.G.

    1981-01-01

    We apply a new theory of gravitation to the question of gravitational collapse to show that collapse is prevented in this theory under very reasonable conditions. This result also extends to prevent ultimate collapse of the Universe. (orig.)

  1. Mechanistic Links Between PARP, NAD, and Brain Inflammation After TBI

    Science.gov (United States)

    2015-10-01

    1 AWARD NUMBER: W81XWH-13-2-0091 TITLE: Mechanistic Links Between PARP, NAD , and Brain Inflammation After TBI PRINCIPAL INVESTIGATOR...COVERED 25 Sep 2014 - 24 Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Mechanistic Links Between PARP, NAD , and Brain Inflammation After TBI 5b. GRANT...efficacy of veliparib and NAD as agents for suppressing inflammation and improving outcomes after traumatic brain injury. The animal models include

  2. PARP Inhibition Restores Extrinsic Apoptotic Sensitivity in Glioblastoma

    Science.gov (United States)

    Karpel-Massler, Georg; Pareja, Fresia; Aimé, Pascaline; Shu, Chang; Chau, Lily; Westhoff, Mike-Andrew; Halatsch, Marc-Eric; Crary, John F.; Canoll, Peter; Siegelin, Markus D.

    2014-01-01

    Background Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma (GBM). We show that targeting PARP by the small molecule inhibitors, Olaparib (AZD-2281) or PJ34, reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo. Methods The sensitizing effects of PARP inhibition on TRAIL-mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines, low-passage neurospheres and astrocytes in vitro. Molecular analyses included western blots and gene silencing. In vivo, effects on tumor growth were examined in a murine subcutaneous xenograft model. Results The combination treatment of PARP inhibitors and TRAIL led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single-agent treatment. Mechanistically, pharmacological PARP inhibition elicited a nuclear stress response with up-regulation of down-stream DNA-stress response proteins, e.g., CCAAT enhancer binding protein (C/EBP) homology protein (CHOP). Furthermore, Olaparib and PJ34 increased protein levels of DR5 in a concentration and time-dependent manner. In turn, siRNA-mediated suppression of DR5 mitigated the effects of TRAIL/PARP inhibitor-mediated apoptosis. In addition, suppression of PARP-1 levels enhanced TRAIL-mediated apoptosis in malignant glioma cells. Treatment of human astrocytes with the combination of TRAIL/PARP inhibitors did not cause toxicity. Finally, the combination treatment of TRAIL and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone. Conclusions PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM. PMID:25531448

  3. Inhibition of matrix metalloproteinase-2 by PARP inhibitors

    International Nuclear Information System (INIS)

    Nicolescu, Adrian C.; Holt, Andrew; Kandasamy, Arulmozhi D.; Pacher, Pal; Schulz, Richard

    2009-01-01

    Matrix metalloproteinase-2 (MMP-2), a ubiquitously expressed zinc-dependent endopeptidase, and poly(ADP-ribosyl) polymerase (PARP), a nuclear enzyme regulating DNA repair, are activated by nitroxidative stress associated with various pathologies. As MMP-2 plays a detrimental role in heart injuries resulting from enhanced nitroxidative stress, where PARP and MMP inhibitors are beneficial, we hypothesized that PARP inhibitors may affect MMP-2 activity. Using substrate degradation assays to determine MMP-2 activity we found that four PARP inhibitors (3-AB, PJ-34, 5-AIQ, and EB-47) inhibited 64 kDa MMP-2 in a concentration-dependent manner. The IC 50 values of PJ-34 and 5-AIQ were in the high micromolar range and comparable to those of known MMP-2 inhibitors doxycycline, minocycline or o-phenanthroline, whereas those for 3-AB and EB-47 were in the millimolar range. Co-incubation of PARP inhibitors with doxycycline showed an additive inhibition of MMP-2 that was significant for 3-AB alone. These data demonstrate that the protective effects of some PARP inhibitors may include inhibition of MMP-2 activity.

  4. Inhibition of matrix metalloproteinase-2 by PARP inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Nicolescu, Adrian C.; Holt, Andrew; Kandasamy, Arulmozhi D. [Departments of Pharmacology and Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alta., Canada T6G 2S2 (Canada); Pacher, Pal [National Institutes of Health, NIAAA, Laboratory of Physiologic Studies, Bethesda, MD (United States); Schulz, Richard, E-mail: richard.schulz@ualberta.ca [Departments of Pharmacology and Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alta., Canada T6G 2S2 (Canada)

    2009-10-02

    Matrix metalloproteinase-2 (MMP-2), a ubiquitously expressed zinc-dependent endopeptidase, and poly(ADP-ribosyl) polymerase (PARP), a nuclear enzyme regulating DNA repair, are activated by nitroxidative stress associated with various pathologies. As MMP-2 plays a detrimental role in heart injuries resulting from enhanced nitroxidative stress, where PARP and MMP inhibitors are beneficial, we hypothesized that PARP inhibitors may affect MMP-2 activity. Using substrate degradation assays to determine MMP-2 activity we found that four PARP inhibitors (3-AB, PJ-34, 5-AIQ, and EB-47) inhibited 64 kDa MMP-2 in a concentration-dependent manner. The IC{sub 50} values of PJ-34 and 5-AIQ were in the high micromolar range and comparable to those of known MMP-2 inhibitors doxycycline, minocycline or o-phenanthroline, whereas those for 3-AB and EB-47 were in the millimolar range. Co-incubation of PARP inhibitors with doxycycline showed an additive inhibition of MMP-2 that was significant for 3-AB alone. These data demonstrate that the protective effects of some PARP inhibitors may include inhibition of MMP-2 activity.

  5. CT of lobar collapse

    International Nuclear Information System (INIS)

    Suh, D. C.; Im, J. G.; Park, J. H.; Han, M. C.

    1987-01-01

    The computed tomographic (CT) findings of labor collapse are analysed in an attempt to evaluate the patterns of labor collapse and to get the helpful signs in differentiation between benign and malignant causes of collapse. 43 cases of labor collapse with or without endobronchial obstruction were reviewed. In 29 of 43 cases the collapses were caused by lung cancer. Benign causes of labor collapse included tuberculosis(10), broncholith(2), organizing pneumonia(1) and hamartoma(1). The helpful signs favoring malignant cause of the labor collapse were proximal bulging of the collapsed lobe, low density mass within the collapsed lung, and endobronchial lesion. Above described differential findings were especially applicable in cases of upper lobe collapse

  6. Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP

    Directory of Open Access Journals (Sweden)

    Hsueh Chung-Tsen

    2011-04-01

    Full Text Available Abstract We reviewed preclinical data and clinical development of MDM2 (murine double minute 2, ALK (anaplastic lymphoma kinase and PARP (poly [ADP-ribose] polymerase inhibitors. MDM2 binds to p53, and promotes degradation of p53 through ubiquitin-proteasome degradation. JNJ-26854165 and RO5045337 are 2 small-molecule inhibitors of MDM2 in clinical development. ALK is a transmembrane protein and a member of the insulin receptor tyrosine kinases. EML4-ALK fusion gene is identified in approximately 3-13% of non-small cell lung cancer (NSCLC. Early-phase clinical studies with Crizotinib, an ALK inhibitor, in NSCLC harboring EML4-ALK have demonstrated promising activity with high response rate and prolonged progression-free survival. PARPs are a family of nuclear enzymes that regulates the repair of DNA single-strand breaks through the base excision repair pathway. Randomized phase II study has shown adding PARP-1 inhibitor BSI-201 to cytotoxic chemotherapy improves clinical outcome in patients with triple-negative breast cancer. Olaparib, another oral small-molecule PARP inhibitor, demonstrated encouraging single-agent activity in patients with advanced breast or ovarian cancer. There are 5 other PARP inhibitors currently under active clinical investigation.

  7. Cells deficient in PARP-1 show an accelerated accumulation of DNA single strand breaks, but not AP sites, over the PARP-1-proficient cells exposed to MMS

    Energy Technology Data Exchange (ETDEWEB)

    Pachkowski, Brian F. [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC (United States); Tano, Keizo [Research Reactor Institute, Kyoto University, Kumatori (Japan); Afonin, Valeriy [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC (United States); Elder, Rhoderick H. [School of Environment and Life Sciences, University of Salford, Greater Manchester (United Kingdom); Takeda, Shunichi [Department of Radiation Genetics, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto (Japan); Watanabe, Masami [Research Reactor Institute, Kyoto University, Kumatori (Japan); Swenberg, James A. [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC (United States); Nakamura, Jun, E-mail: ynakamur@email.unc.edu [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC (United States)

    2009-12-01

    Poly(ADP-ribose) polymerase-1 (PARP-1) is a base excision repair (BER) protein that binds to DNA single strand breaks (SSBs) and subsequently synthesizes and transfers poly(ADP-ribose) polymers to various nuclear proteins. Numerous biochemical studies have implicated PARP-1 as a modulator of BER; however, the role of PARP-1 in BER in living cells remains unclear partly due to lack of accurate quantitation of BER intermediates existing in cells. Since DT40 cells, chicken B lymphocytes, naturally lack PARP-2, DT40 cells allow for the investigation of the PARP-1 null phenotype without confounding by PARP-2. To test the hypothesis that PARP-1 is necessary for efficient BER during methylmethane sulfonate (MMS) exposure in vertebrate cells, intact DT40 cells and their isogenic PARP-1 null counterparts were challenged with different exposure scenarios for phenotypic characterization. With chronic exposure, PARP-1 null cells exhibited sensitivity to MMS but with an acute exposure did not accumulate base lesions or AP sites to a greater extent than wild-type cells. However, an increase in SSB content in PARP-1 null cell DNA, as indicated by glyoxal gel electrophoresis under neutral conditions, suggested the presence of BER intermediates. These data suggest that during exposure, PARP-1 impacts the stage of BER after excision of the deoxyribosephosphate moiety from the 5' end of DNA strand breaks by polymerase {beta}.

  8. Cells deficient in PARP-1 show an accelerated accumulation of DNA single strand breaks, but not AP sites, over the PARP-1-proficient cells exposed to MMS.

    Science.gov (United States)

    Pachkowski, Brian F; Tano, Keizo; Afonin, Valeriy; Elder, Rhoderick H; Takeda, Shunichi; Watanabe, Masami; Swenberg, James A; Nakamura, Jun

    2009-12-01

    Poly(ADP-ribose) polymerase-1 (PARP-1) is a base excision repair (BER) protein that binds to DNA single strand breaks (SSBs) and subsequently synthesizes and transfers poly(ADP-ribose) polymers to various nuclear proteins. Numerous biochemical studies have implicated PARP-1 as a modulator of BER; however, the role of PARP-1 in BER in living cells remains unclear partly due to lack of accurate quantitation of BER intermediates existing in cells. Since DT40 cells, chicken B lymphocytes, naturally lack PARP-2, DT40 cells allow for the investigation of the PARP-1 null phenotype without confounding by PARP-2. To test the hypothesis that PARP-1 is necessary for efficient BER during methylmethane sulfonate (MMS) exposure in vertebrate cells, intact DT40 cells and their isogenic PARP-1 null counterparts were challenged with different exposure scenarios for phenotypic characterization. With chronic exposure, PARP-1 null cells exhibited sensitivity to MMS but with an acute exposure did not accumulate base lesions or AP sites to a greater extent than wild-type cells. However, an increase in SSB content in PARP-1 null cell DNA, as indicated by glyoxal gel electrophoresis under neutral conditions, suggested the presence of BER intermediates. These data suggest that during exposure, PARP-1 impacts the stage of BER after excision of the deoxyribosephosphate moiety from the 5' end of DNA strand breaks by polymerase beta.

  9. Assessment of 105 Patients with Angiotensin Converting Enzyme-Inhibitor Induced Angioedema

    DEFF Research Database (Denmark)

    Rasmussen, Eva Rye; von Buchwald, Christian; Wadelius, Mia

    2017-01-01

    Objective. To asses a cohort of 105 consecutive patients with angiotensin converting enzyme-inhibitor induced angioedema with regard to demographics, risk factors, family history of angioedema, hospitalization, airway management, outcome, and use of diagnostic codes used for the condition. Study...... gender was associated with a significantly higher risk of angiotensin converting enzyme-inhibitor induced angioedema. 6.7% had a positive family history of angioedema. Diabetes seemed to be a protective factor with regard to angioedema. 95% experienced angioedema of the head and neck. 4.7% needed...... Design. Cohort study. Methods. This was a retrospective cohort study of 105 patients with angiotensin converting enzyme-inhibitor induced angioedema in the period 1995-2014. Results. The cohort consisted of 67 females and 38 males (F : M ratio 1.8), with a mean age of 63 [range 26-86] years. Female...

  10. Analyzing structure–function relationships of artificial and cancer-associated PARP1 variants by reconstituting TALEN-generated HeLa PARP1 knock-out cells

    Science.gov (United States)

    Rank, Lisa; Veith, Sebastian; Gwosch, Eva C.; Demgenski, Janine; Ganz, Magdalena; Jongmans, Marjolijn C.; Vogel, Christopher; Fischbach, Arthur; Buerger, Stefanie; Fischer, Jan M.F.; Zubel, Tabea; Stier, Anna; Renner, Christina; Schmalz, Michael; Beneke, Sascha; Groettrup, Marcus; Kuiper, Roland P.; Bürkle, Alexander; Ferrando-May, Elisa; Mangerich, Aswin

    2016-01-01

    Genotoxic stress activates PARP1, resulting in the post-translational modification of proteins with poly(ADP-ribose) (PAR). We genetically deleted PARP1 in one of the most widely used human cell systems, i.e. HeLa cells, via TALEN-mediated gene targeting. After comprehensive characterization of these cells during genotoxic stress, we analyzed structure–function relationships of PARP1 by reconstituting PARP1 KO cells with a series of PARP1 variants. Firstly, we verified that the PARP1\\E988K mutant exhibits mono-ADP-ribosylation activity and we demonstrate that the PARP1\\L713F mutant is constitutively active in cells. Secondly, both mutants exhibit distinct recruitment kinetics to sites of laser-induced DNA damage, which can potentially be attributed to non-covalent PARP1–PAR interaction via several PAR binding motifs. Thirdly, both mutants had distinct functional consequences in cellular patho-physiology, i.e. PARP1\\L713F expression triggered apoptosis, whereas PARP1\\E988K reconstitution caused a DNA-damage-induced G2 arrest. Importantly, both effects could be rescued by PARP inhibitor treatment, indicating distinct cellular consequences of constitutive PARylation and mono(ADP-ribosyl)ation. Finally, we demonstrate that the cancer-associated PARP1 SNP variant (V762A) as well as a newly identified inherited PARP1 mutation (F304L\\V762A) present in a patient with pediatric colorectal carcinoma exhibit altered biochemical and cellular properties, thereby potentially supporting human carcinogenesis. Together, we establish a novel cellular model for PARylation research, by revealing strong structure–function relationships of natural and artificial PARP1 variants. PMID:27694308

  11. ARTD1/PARP1 Negatively Regulates Glycolysis by Inhibiting Hexokinase 1 Independent of NAD+ Depletion

    Directory of Open Access Journals (Sweden)

    Elise Fouquerel

    2014-09-01

    Full Text Available ARTD1 (PARP1 is a key enzyme involved in DNA repair through the synthesis of poly(ADP-ribose (PAR in response to strand breaks, and it plays an important role in cell death following excessive DNA damage. ARTD1-induced cell death is associated with NAD+ depletion and ATP loss; however, the molecular mechanism of ARTD1-mediated energy collapse remains elusive. Using real-time metabolic measurements, we compared the effects of ARTD1 activation and direct NAD+ depletion. We found that ARTD1-mediated PAR synthesis, but not direct NAD+ depletion, resulted in a block to glycolysis and ATP loss. We then established a proteomics-based PAR interactome after DNA damage and identified hexokinase 1 (HK1 as a PAR binding protein. HK1 activity is suppressed following nuclear ARTD1 activation and binding by PAR. These findings help explain how prolonged activation of ARTD1 triggers energy collapse and cell death, revealing insight into the importance of nucleus-to-mitochondria communication via ARTD1 activation.

  12. Types of collapse calderas

    Energy Technology Data Exchange (ETDEWEB)

    Aguirre-Diaz, Gerardo J [Centro de Geociencias, Universidad Nacional Autonoma de Mexico, Campus Juriquilla, Queretaro, Qro., 76230 (Mexico)], E-mail: ger@geociencias.unam.mx

    2008-10-01

    Three main types of collapse calderas can be defined, 1) summit caldera: those formed at the top of large volcanoes, 2) classic caldera: semi-circular to irregular-shaped large structures, several km in diameter and related to relatively large-volume pyroclastic products, and 3) graben caldera: explosive volcano-tectonic collapse structures from which large-volume, ignimbrite-forming eruptions occurred through several fissural vents along the graben master faults and the intra-graben block faults. These in turn can collapse at least with three styles: 1) Piston: when the collapse occurs as a single crustal block; 2) Trap-door: when collapse occurs unevenly along one side while the opposite side remains with no collapse; 3) Piece-meal: when collapse occurs as broken pieces of the crust on top of the magma chamber.

  13. Bosutinib induced pleural effusions: Case report and review of tyrosine kinase inhibitors induced pulmonary toxicity

    Directory of Open Access Journals (Sweden)

    Natalia I. Moguillansky, MD

    2017-01-01

    Full Text Available Tyrosine kinase inhibitors are known to cause pulmonary complications. We report a case of bosutinib related bilateral pleural effusions in a patient with chronic myeloid leukemia. Characteristics of the pleural fluid are presented. We also discuss other tyrosine kinase inhibitors induced pulmonary toxicities, including pulmonary hypertension and interstitial lung disease.

  14. Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors.

    Science.gov (United States)

    Thorsell, Ann-Gerd; Ekblad, Torun; Karlberg, Tobias; Löw, Mirjam; Pinto, Ana Filipa; Trésaugues, Lionel; Moche, Martin; Cohen, Michael S; Schüler, Herwig

    2017-02-23

    Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.

  15. Arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Xi; Zhou, Xixi [Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Du, Libo [Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 (China); Liu, Wenlan [Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Liu, Yang [Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 (China); Hudson, Laurie G. [Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States); Liu, Ke Jian, E-mail: kliu@salud.unm.edu [Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States)

    2014-01-15

    Inhibition of DNA repair is a recognized mechanism for arsenic enhancement of ultraviolet radiation-induced DNA damage and carcinogenesis. Poly(ADP-ribose) polymerase-1 (PARP-1), a zinc finger DNA repair protein, has been identified as a sensitive molecular target for arsenic. The zinc finger domains of PARP-1 protein function as a critical structure in DNA recognition and binding. Since cellular poly(ADP-ribosyl)ation capacity has been positively correlated with zinc status in cells, we hypothesize that arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair. To test this hypothesis, we compared the effects of arsenite exposure with zinc deficiency, created by using the membrane-permeable zinc chelator TPEN, on 8-OHdG formation, PARP-1 activity and zinc binding to PARP-1 in HaCat cells. Our results show that arsenite exposure and zinc deficiency had similar effects on PARP-1 protein, whereas supplemental zinc reversed these effects. To investigate the molecular mechanism of zinc loss induced by arsenite, ICP-AES, near UV spectroscopy, fluorescence, and circular dichroism spectroscopy were utilized to examine arsenite binding and occupation of a peptide representing the first zinc finger of PARP-1. We found that arsenite binding as well as zinc loss altered the conformation of zinc finger structure which functionally leads to PARP-1 inhibition. These findings suggest that arsenite binding to PARP-1 protein created similar adverse biological effects as zinc deficiency, which establishes the molecular mechanism for zinc supplementation as a potentially effective treatment to reverse the detrimental outcomes of arsenic exposure. - Highlights: • Arsenite binding is equivalent to zinc deficiency in reducing PARP-1 function. • Zinc reverses arsenic inhibition of PARP-1 activity and enhancement of DNA damage. • Arsenite binding and zinc loss alter the conformation of zinc finger

  16. Arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair

    International Nuclear Information System (INIS)

    Sun, Xi; Zhou, Xixi; Du, Libo; Liu, Wenlan; Liu, Yang; Hudson, Laurie G.; Liu, Ke Jian

    2014-01-01

    Inhibition of DNA repair is a recognized mechanism for arsenic enhancement of ultraviolet radiation-induced DNA damage and carcinogenesis. Poly(ADP-ribose) polymerase-1 (PARP-1), a zinc finger DNA repair protein, has been identified as a sensitive molecular target for arsenic. The zinc finger domains of PARP-1 protein function as a critical structure in DNA recognition and binding. Since cellular poly(ADP-ribosyl)ation capacity has been positively correlated with zinc status in cells, we hypothesize that arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair. To test this hypothesis, we compared the effects of arsenite exposure with zinc deficiency, created by using the membrane-permeable zinc chelator TPEN, on 8-OHdG formation, PARP-1 activity and zinc binding to PARP-1 in HaCat cells. Our results show that arsenite exposure and zinc deficiency had similar effects on PARP-1 protein, whereas supplemental zinc reversed these effects. To investigate the molecular mechanism of zinc loss induced by arsenite, ICP-AES, near UV spectroscopy, fluorescence, and circular dichroism spectroscopy were utilized to examine arsenite binding and occupation of a peptide representing the first zinc finger of PARP-1. We found that arsenite binding as well as zinc loss altered the conformation of zinc finger structure which functionally leads to PARP-1 inhibition. These findings suggest that arsenite binding to PARP-1 protein created similar adverse biological effects as zinc deficiency, which establishes the molecular mechanism for zinc supplementation as a potentially effective treatment to reverse the detrimental outcomes of arsenic exposure. - Highlights: • Arsenite binding is equivalent to zinc deficiency in reducing PARP-1 function. • Zinc reverses arsenic inhibition of PARP-1 activity and enhancement of DNA damage. • Arsenite binding and zinc loss alter the conformation of zinc finger

  17. The PARP inhibitor PJ-34 sensitizes cells to UVA-induced phototoxicity by a PARP independent mechanism

    International Nuclear Information System (INIS)

    Lakatos, Petra; Hegedűs, Csaba; Salazar Ayestarán, Nerea; Juarranz, Ángeles; Kövér, Katalin E.; Szabó, Éva; Virág, László

    2016-01-01

    Highlights: • PARP-1 is not a key regulator of photochemotherapy. • The PARP inhibitor PJ-34 sensitizes cells to UVA-induced phototoxicity by a PARP independent mechanism. • Photosensitization by PJ-34 is associated with increased ROS production and DNA damage. • Cells sensitized by PJ-34 undergo caspase-mediated apoptosis. - Abstract: A combination of a photosensitizer with light of matching wavelength is a common treatment modality in various diseases including psoriasis, atopic dermatitis and tumors. DNA damage and production of reactive oxygen intermediates may impact pathological cellular functions and viability. Here we set out to investigate the role of the nuclear DNA nick sensor enzyme poly(ADP-ribose) polymerase 1 in photochemical treatment (PCT)-induced tumor cell killing. We found that silencing PARP-1 or inhibition of its enzymatic activity with Veliparib had no significant effect on the viability of A431 cells exposed to 8-methoxypsoralen (8-MOP) and UVA (2.5 J/cm"2) indicating that PARP-1 is not likely to be a key player in either cell survival or cell death of PCT-exposed cells. Interestingly, however, another commonly used PARP inhibitor PJ-34 proved to be a photosensitizer with potency equal to 8-MOP. Irradiation of PJ-34 with UVA caused changes both in the UV absorption and in the 1H NMR spectra of the compound with the latter suggesting UVA-induced formation of tautomeric forms of the compound. Characterization of the photosensitizing effect revealed that PJ–34 + UVA triggers overproduction of reactive oxygen species, induces DNA damage, activation of caspase 3 and caspase 8 and internucleosomal DNA fragmentation. Cell death in this model could not be prevented by antioxidants (ascorbic acid, trolox, glutathione, gallotannin or cell permeable superoxide dismutase or catalase) but could be suppressed by inhibitors of caspase-3 and −8. In conclusion, PJ-34 is a photosensitizer and PJ–34 + UVA causes DNA damage and caspase

  18. The PARP inhibitor PJ-34 sensitizes cells to UVA-induced phototoxicity by a PARP independent mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Lakatos, Petra; Hegedűs, Csaba [Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen (Hungary); Salazar Ayestarán, Nerea; Juarranz, Ángeles [Department of Biology, Faculty of Sciences, Universidad Autónoma of Madrid, 28049-Madrid (Spain); Kövér, Katalin E. [Department of Inorganic and Analytical Chemistry, Faculty of Sciences, University of Debrecen, Debrecen (Hungary); Szabó, Éva [Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen (Hungary); Virág, László, E-mail: lvirag@med.unideb.hu [Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen (Hungary); MTA-DE Cell Biology and Signaling Research Group, Debrecen (Hungary)

    2016-08-15

    Highlights: • PARP-1 is not a key regulator of photochemotherapy. • The PARP inhibitor PJ-34 sensitizes cells to UVA-induced phototoxicity by a PARP independent mechanism. • Photosensitization by PJ-34 is associated with increased ROS production and DNA damage. • Cells sensitized by PJ-34 undergo caspase-mediated apoptosis. - Abstract: A combination of a photosensitizer with light of matching wavelength is a common treatment modality in various diseases including psoriasis, atopic dermatitis and tumors. DNA damage and production of reactive oxygen intermediates may impact pathological cellular functions and viability. Here we set out to investigate the role of the nuclear DNA nick sensor enzyme poly(ADP-ribose) polymerase 1 in photochemical treatment (PCT)-induced tumor cell killing. We found that silencing PARP-1 or inhibition of its enzymatic activity with Veliparib had no significant effect on the viability of A431 cells exposed to 8-methoxypsoralen (8-MOP) and UVA (2.5 J/cm{sup 2}) indicating that PARP-1 is not likely to be a key player in either cell survival or cell death of PCT-exposed cells. Interestingly, however, another commonly used PARP inhibitor PJ-34 proved to be a photosensitizer with potency equal to 8-MOP. Irradiation of PJ-34 with UVA caused changes both in the UV absorption and in the 1H NMR spectra of the compound with the latter suggesting UVA-induced formation of tautomeric forms of the compound. Characterization of the photosensitizing effect revealed that PJ–34 + UVA triggers overproduction of reactive oxygen species, induces DNA damage, activation of caspase 3 and caspase 8 and internucleosomal DNA fragmentation. Cell death in this model could not be prevented by antioxidants (ascorbic acid, trolox, glutathione, gallotannin or cell permeable superoxide dismutase or catalase) but could be suppressed by inhibitors of caspase-3 and −8. In conclusion, PJ-34 is a photosensitizer and PJ–34 + UVA causes DNA damage and caspase

  19. Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment

    DEFF Research Database (Denmark)

    Oplustilova, L.; Wolanin, K.; Bartkova, J.

    2012-01-01

    combinations with camptothecin or ionizing radiation. Furthermore, monitoring pARsylation and Rad51 foci formation as surrogate markers for PARP activity and HR, respectively, supported their candidacy for biomarkers of PARP-1i responses. As to resistance mechanisms, we confrmed the role of the multidrug......(ADp-ribose) polymerase-1 (PARP-1), an enzyme critical for repair pathways alternative to HR. While promising, treatment with PARP-1 inhibitors (PARP-1i) faces some hurdles, including (1) acquired resistance, (2) search for other sensitizing, non-BRCA1/2 cancer defects and (3) lack of biomarkers to predict response...

  20. Increased oxidative stress mediates the antitumor effect of PARP inhibition in ovarian cancer

    Directory of Open Access Journals (Sweden)

    Dong Hou

    2018-07-01

    Full Text Available PARP inhibitors have been widely tested in clinical trials, especially for the treatment of breast cancer and ovarian cancer, and were shown to be highly successful. Because PARP primarily functions in sensing and repairing DNA strand breaks, the therapeutic effect of PARP inhibition is generally believed to be attributed to impaired DNA repair. We here report that oxidative stress is also increased by PARP inhibition and mediates the antitumor effect. We showed that PARP1 is highly expressed in specimens of high grade serous ovarian carcinoma and its activity is required for unperturbed proliferation of ovarian cancer cells. Inhibition or depletion of PARP leads to not only an increase in DNA damage, but also an elevation in the levels of reactive oxygen species (ROS. Importantly, antioxidant N-acetylcysteine (NAC significantly attenuated the induction of DNA damage and the perturbation of proliferation by PARP inhibition or depletion. We further showed that NADPH oxidases 1 and 4 were significantly upregulated by PARP inhibition and were partially responsible for the induction of oxidative stress. Depletion of NOX1 and NOX4 partially rescued the growth inhibition of PARP1-deficient tumor xenografts. Our findings suggest that in addition to compromising the repair of DNA damage, PARP inhibition or depletion may exert extra antitumor effect by elevating oxidative stress in ovarian cancer cells. Keywords: PARP1, Oxidative stress, NADPH oxidases, Ovarian cancer

  1. PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration

    Directory of Open Access Journals (Sweden)

    Alexander Jonathan S

    2010-12-01

    Full Text Available Abstract The normal function of poly (ADP-ribose polymerase-1 (PARP-1 is the routine repair of DNA damage by adding poly (ADP ribose polymers in response to a variety of cellular stresses. Recently, it has become widely appreciated that PARP-1 also participates in diverse physiological and pathological functions from cell survival to several forms of cell death and has been implicated in gene transcription, immune responses, inflammation, learning, memory, synaptic functions, angiogenesis and aging. In the CNS, PARP inhibition attenuates injury in pathologies like cerebral ischemia, trauma and excitotoxicity demonstrating a central role of PARP-1 in these pathologies. PARP-1 is also a preferred substrate for several 'suicidal' proteases and the proteolytic action of suicidal proteases (caspases, calpains, cathepsins, granzymes and matrix metalloproteinases (MMPs on PARP-1 produces several specific proteolytic cleavage fragments with different molecular weights. These PARP-1 signature fragments are recognized biomarkers for specific patterns of protease activity in unique cell death programs. This review focuses on specific suicidal proteases active towards PARP-1 to generate signature PARP-1 fragments that can identify key proteases and particular forms of cell death involved in pathophysiology. The roles played by some of the PARP-1 fragments and their associated binding partners in the control of different forms of cell death are also discussed.

  2. PARP Inhibition Attenuates Histopathological Lesion in Ischemia/Reperfusion Renal Mouse Model after Cold Prolonged Ischemia

    Directory of Open Access Journals (Sweden)

    Raimundo M. G. del Moral

    2013-01-01

    Full Text Available We test the hypothesis that PARP inhibition can decrease acute tubular necrosis (ATN and other renal lesions related to prolonged cold ischemia/reperfusion (IR in kidneys preserved at 4°C in University of Wisconsin (UW solution. Material and Methods. We used 30 male Parp1+/+ wild-type and 15 male Parp10/0 knockout C57BL/6 mice. Fifteen of these wild-type mice were pretreated with 3,4-dihydro-5-[4-(1-piperidinylbutoxyl]-1(2H-isoquinolinone (DPQ at a concentration of 15 mg/kg body weight, used as PARP inhibitor. Subgroups of mice were established (A: IR 45 min/6 h; B: IR + 48 h in UW solution; and C: IR + 48 h in UW solution plus DPQ. We processed samples for morphological, immunohistochemical, ultrastructural, and western-blotting studies. Results. Prolonged cold ischemia time in UW solution increased PARP-1 expression and kidney injury. Preconditioning with PARP inhibitor DPQ plus DPQ supplementation in UW solution decreased PARP-1 nuclear expression in renal tubules and renal damage. Parp10/0 knockout mice were more resistant to IR-induced renal lesion. In conclusion, PARP inhibition attenuates ATN and other IR-related renal lesions in mouse kidneys under prolonged cold storage in UW solution. If confirmed, these data suggest that pharmacological manipulation of PARP activity may have salutary effects in cold-stored organs at transplantation.

  3. The PARP inhibitor PJ-34 sensitizes cells to UVA-induced phototoxicity by a PARP independent mechanism.

    Science.gov (United States)

    Lakatos, Petra; Hegedűs, Csaba; Salazar Ayestarán, Nerea; Juarranz, Ángeles; Kövér, Katalin E; Szabó, Éva; Virág, László

    2016-08-01

    A combination of a photosensitizer with light of matching wavelength is a common treatment modality in various diseases including psoriasis, atopic dermatitis and tumors. DNA damage and production of reactive oxygen intermediates may impact pathological cellular functions and viability. Here we set out to investigate the role of the nuclear DNA nick sensor enzyme poly(ADP-ribose) polymerase 1 in photochemical treatment (PCT)-induced tumor cell killing. We found that silencing PARP-1 or inhibition of its enzymatic activity with Veliparib had no significant effect on the viability of A431 cells exposed to 8-methoxypsoralen (8-MOP) and UVA (2.5J/cm(2)) indicating that PARP-1 is not likely to be a key player in either cell survival or cell death of PCT-exposed cells. Interestingly, however, another commonly used PARP inhibitor PJ-34 proved to be a photosensitizer with potency equal to 8-MOP. Irradiation of PJ-34 with UVA caused changes both in the UV absorption and in the 1H NMR spectra of the compound with the latter suggesting UVA-induced formation of tautomeric forms of the compound. Characterization of the photosensitizing effect revealed that PJ-34+UVA triggers overproduction of reactive oxygen species, induces DNA damage, activation of caspase 3 and caspase 8 and internucleosomal DNA fragmentation. Cell death in this model could not be prevented by antioxidants (ascorbic acid, trolox, glutathione, gallotannin or cell permeable superoxide dismutase or catalase) but could be suppressed by inhibitors of caspase-3 and -8. In conclusion, PJ-34 is a photosensitizer and PJ-34+UVA causes DNA damage and caspase-mediated cell death independently of PARP-1 inhibition. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Imaging findings in a child with calcineurin inhibitor-induced pain syndrome after bone marrow transplant for beta thalassemia major

    International Nuclear Information System (INIS)

    Ayyala, Rama S.; Arnold, Staci D.; Bhatia, Monica; Dastgir, Jahannaz

    2016-01-01

    Calcineurin inhibitor-induced pain syndrome is an entity recognized in patients on immunosuppressive therapy after transplantation. Diagnosis is characterized by onset of pain beginning in the setting of an elevated calcineurin-inhibitor trough level. Reducing the medication dose relieves symptoms. Imaging findings can be nonspecific, including bone marrow edema and periosteal reaction. We present the unique case of calcineurin inhibitor-induced pain syndrome in a child and review the imaging findings. (orig.)

  5. Imaging findings in a child with calcineurin inhibitor-induced pain syndrome after bone marrow transplant for beta thalassemia major

    Energy Technology Data Exchange (ETDEWEB)

    Ayyala, Rama S.; Arnold, Staci D.; Bhatia, Monica; Dastgir, Jahannaz [Columbia University Medical Center, Morgan Stanley Children' s Hospital, Department of Radiology, New York, NY (United States)

    2016-10-15

    Calcineurin inhibitor-induced pain syndrome is an entity recognized in patients on immunosuppressive therapy after transplantation. Diagnosis is characterized by onset of pain beginning in the setting of an elevated calcineurin-inhibitor trough level. Reducing the medication dose relieves symptoms. Imaging findings can be nonspecific, including bone marrow edema and periosteal reaction. We present the unique case of calcineurin inhibitor-induced pain syndrome in a child and review the imaging findings. (orig.)

  6. Mechanisms of cascade collapse

    International Nuclear Information System (INIS)

    Diaz de la Rubia, T.; Smalinskas, K.; Averback, R.S.; Robertson, I.M.; Hseih, H.; Benedek, R.

    1988-12-01

    The spontaneous collapse of energetic displacement cascades in metals into vacancy dislocation loops has been investigated by molecular dynamics (MD) computer simulation and transmission electron microscopy (TEM). Simulations of 5 keV recoil events in Cu and Ni provide the following scenario of cascade collapse: atoms are ejected from the central region of the cascade by replacement collision sequences; the central region subsequently melts; vacancies are driven to the center of the cascade during resolidification where they may collapse into loops. Whether or not collapse occurs depends critically on the melting temperature of the metal and the energy density and total energy in the cascade. Results of TEM are presented in support of this mechanism. 14 refs., 4 figs., 1 tab

  7. Neutrinos from gravitational collapse

    International Nuclear Information System (INIS)

    Mayle, R.; Wilson, J.R.; Schramm, D.N.

    1986-05-01

    Detailed calculations are made of the neutrino spectra emitted during gravitational collapse events (Type II supernovae). Those aspects of the neutrino signal which are relatively independent of the collapse model and those aspects which are sensitive to model details are discussed. The easier-to-detect high energy tail of the emitted neutrinos has been calculated using the Boltzmann equation which is compared with the result of the traditional multi-group flux limited diffusion calculations. 8 figs., 28 refs

  8. A New Nanobody-Based Biosensor to Study Endogenous PARP1 In Vitro and in Live Human Cells.

    Directory of Open Access Journals (Sweden)

    Andrea Buchfellner

    Full Text Available Poly(ADP-ribose polymerase 1 (PARP1 is a key player in DNA repair, genomic stability and cell survival and it emerges as a highly relevant target for cancer therapies. To deepen our understanding of PARP biology and mechanisms of action of PARP1-targeting anti-cancer compounds, we generated a novel PARP1-affinity reagent, active both in vitro and in live cells. This PARP1-biosensor is based on a PARP1-specific single-domain antibody fragment (~ 15 kDa, termed nanobody, which recognizes the N-terminus of human PARP1 with nanomolar affinity. In proteomic approaches, immobilized PARP1 nanobody facilitates quantitative immunoprecipitation of functional, endogenous PARP1 from cellular lysates. For cellular studies, we engineered an intracellularly functional PARP1 chromobody by combining the nanobody coding sequence with a fluorescent protein sequence. By following the chromobody signal, we were for the first time able to monitor the recruitment of endogenous PARP1 to DNA damage sites in live cells. Moreover, tracing of the sub-nuclear translocation of the chromobody signal upon treatment of human cells with chemical substances enables real-time profiling of active compounds in high content imaging. Due to its ability to perform as a biosensor at the endogenous level of the PARP1 enzyme, the novel PARP1 nanobody is a unique and versatile tool for basic and applied studies of PARP1 biology and DNA repair.

  9. A New Nanobody-Based Biosensor to Study Endogenous PARP1 In Vitro and in Live Human Cells.

    Science.gov (United States)

    Buchfellner, Andrea; Yurlova, Larisa; Nüske, Stefan; Scholz, Armin M; Bogner, Jacqueline; Ruf, Benjamin; Zolghadr, Kourosh; Drexler, Sophie E; Drexler, Guido A; Girst, Stefanie; Greubel, Christoph; Reindl, Judith; Siebenwirth, Christian; Romer, Tina; Friedl, Anna A; Rothbauer, Ulrich

    2016-01-01

    Poly(ADP-ribose) polymerase 1 (PARP1) is a key player in DNA repair, genomic stability and cell survival and it emerges as a highly relevant target for cancer therapies. To deepen our understanding of PARP biology and mechanisms of action of PARP1-targeting anti-cancer compounds, we generated a novel PARP1-affinity reagent, active both in vitro and in live cells. This PARP1-biosensor is based on a PARP1-specific single-domain antibody fragment (~ 15 kDa), termed nanobody, which recognizes the N-terminus of human PARP1 with nanomolar affinity. In proteomic approaches, immobilized PARP1 nanobody facilitates quantitative immunoprecipitation of functional, endogenous PARP1 from cellular lysates. For cellular studies, we engineered an intracellularly functional PARP1 chromobody by combining the nanobody coding sequence with a fluorescent protein sequence. By following the chromobody signal, we were for the first time able to monitor the recruitment of endogenous PARP1 to DNA damage sites in live cells. Moreover, tracing of the sub-nuclear translocation of the chromobody signal upon treatment of human cells with chemical substances enables real-time profiling of active compounds in high content imaging. Due to its ability to perform as a biosensor at the endogenous level of the PARP1 enzyme, the novel PARP1 nanobody is a unique and versatile tool for basic and applied studies of PARP1 biology and DNA repair.

  10. A New Nanobody-Based Biosensor to Study Endogenous PARP1 In Vitro and in Live Human Cells

    Science.gov (United States)

    Nüske, Stefan; Scholz, Armin M.; Bogner, Jacqueline; Ruf, Benjamin; Zolghadr, Kourosh; Drexler, Sophie E.; Drexler, Guido A.; Girst, Stefanie; Greubel, Christoph; Reindl, Judith; Siebenwirth, Christian; Romer, Tina; Friedl, Anna A.; Rothbauer, Ulrich

    2016-01-01

    Poly(ADP-ribose) polymerase 1 (PARP1) is a key player in DNA repair, genomic stability and cell survival and it emerges as a highly relevant target for cancer therapies. To deepen our understanding of PARP biology and mechanisms of action of PARP1-targeting anti-cancer compounds, we generated a novel PARP1-affinity reagent, active both in vitro and in live cells. This PARP1-biosensor is based on a PARP1-specific single-domain antibody fragment (~ 15 kDa), termed nanobody, which recognizes the N-terminus of human PARP1 with nanomolar affinity. In proteomic approaches, immobilized PARP1 nanobody facilitates quantitative immunoprecipitation of functional, endogenous PARP1 from cellular lysates. For cellular studies, we engineered an intracellularly functional PARP1 chromobody by combining the nanobody coding sequence with a fluorescent protein sequence. By following the chromobody signal, we were for the first time able to monitor the recruitment of endogenous PARP1 to DNA damage sites in live cells. Moreover, tracing of the sub-nuclear translocation of the chromobody signal upon treatment of human cells with chemical substances enables real-time profiling of active compounds in high content imaging. Due to its ability to perform as a biosensor at the endogenous level of the PARP1 enzyme, the novel PARP1 nanobody is a unique and versatile tool for basic and applied studies of PARP1 biology and DNA repair. PMID:26950694

  11. Effects of PARP-1 Deficiency on Th1 and Th2 Cell Differentiation

    Directory of Open Access Journals (Sweden)

    M. Sambucci

    2013-01-01

    Full Text Available T cell differentiation to effector Th cells such as Th1 and Th2 requires the integration of multiple synergic and antagonist signals. Poly(ADP-ribosylation is a posttranslational modification of proteins catalyzed by Poly(ADP-ribose polymerases (PARPs. Recently, many reports showed that PARP-1, the prototypical member of the PARP family, plays a role in immune/inflammatory responses. Consistently, its enzymatic inhibition confers protection in several models of immune-mediated diseases, mainly through an inhibitory effect on NF-κB (and NFAT activation. PARP-1 regulates cell functions in many types of immune cells, including dendritic cells, macrophages, and T and B lymphocytes. Our results show that PARP-1KO cells displayed a reduced ability to differentiate in Th2 cells. Under both nonskewing and Th2-polarizing conditions, naïve CD4 cells from PARP-1KO mice generated a reduced frequency of IL-4+ cells, produced less IL-5, and expressed GATA-3 at lower levels compared with cells from wild type mice. Conversely, PARP-1 deficiency did not substantially affect differentiation to Th1 cells. Indeed, the frequency of IFN-γ+ cells as well as IFN-γ production, in nonskewing and Th1-polarizing conditions, was not affected by PARP-1 gene ablation. These findings demonstrate that PARP-1 plays a relevant role in Th2 cell differentiation and it might be a target to be exploited for the modulation of Th2-dependent immune-mediated diseases.

  12. Imidazoquinolinone, imidazopyridine, and isoquinolindione derivatives as novel and potent inhibitors of the poly(ADP-ribose) polymerase (PARP): a comparison with standard PARP inhibitors.

    Science.gov (United States)

    Eltze, Tobias; Boer, Rainer; Wagner, Thomas; Weinbrenner, Steffen; McDonald, Michelle C; Thiemermann, Christoph; Bürkle, Alexander; Klein, Thomas

    2008-12-01

    We have identified three novel structures for inhibitors of the poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA and implicated in DNA repair, apoptosis, organ dysfunction or necrosis. 2-[4-(5-Methyl-1H-imidazol-4-yl)-piperidin-1-yl]-4,5-dihydro-imidazo[4,5,1-i,j]quinolin-6-one (BYK49187), 2-(4-pyridin-2-yl-phenyl)-4,5-dihydro-imidazo[4,5,1-i,j]quinolin-6-one (BYK236864), 6-chloro-8-hydroxy-2,3-dimethyl-imidazo-[1,2-alpha]-pyridine (BYK20370), and 4-(1-methyl-1H-pyrrol-2-ylmethylene)-4H-isoquinolin-1,3-dione (BYK204165) inhibited cell-free recombinant human PARP-1 with pIC(50) values of 8.36, 7.81, 6.40, and 7.35 (pK(i) 7.97, 7.43, 5.90, and 7.05), and murine PARP-2 with pIC(50) values of 7.50, 7.55, 5.71, and 5.38, respectively. BYK49187, BYK236864, and BYK20370 displayed no selectivity for PARP-1/2, whereas BYK204165 displayed 100-fold selectivity for PARP-1. The IC(50) values for inhibition of poly(ADP-ribose) synthesis in human lung epithelial A549 and cervical carcinoma C4I cells as well in rat cardiac myoblast H9c2 cells after PARP activation by H(2)O(2) were highly significantly correlated with those at cell-free PARP-1 (r(2) = 0.89-0.96, P < 0.001) but less with those at PARP-2 (r(2) = 0.78-0.84, P < 0.01). The infarct size caused by coronary artery occlusion and reperfusion in the anesthetized rat was reduced by 22% (P < 0.05) by treatment with BYK49187 (3 mg/kg i.v. bolus and 3 mg/kg/h i.v. during 2-h reperfusion), whereas the weaker PARP inhibitors, BYK236864 and BYK20370, were not cardioprotective. In conclusion, the imidazoquinolinone BYK49187 is a potent inhibitor of human PARP-1 activity in cell-free and cellular assays in vitro and reduces myocardial infarct size in vivo. The isoquinolindione BYK204165 was found to be 100-fold more selective for PARP-1. Thus, both compounds might be novel and valuable tools for investigating PARP-1-mediated effects.

  13. Collapsed Dark Matter Structures.

    Science.gov (United States)

    Buckley, Matthew R; DiFranzo, Anthony

    2018-02-02

    The distributions of dark matter and baryons in the Universe are known to be very different: The dark matter resides in extended halos, while a significant fraction of the baryons have radiated away much of their initial energy and fallen deep into the potential wells. This difference in morphology leads to the widely held conclusion that dark matter cannot cool and collapse on any scale. We revisit this assumption and show that a simple model where dark matter is charged under a "dark electromagnetism" can allow dark matter to form gravitationally collapsed objects with characteristic mass scales much smaller than that of a Milky-Way-type galaxy. Though the majority of the dark matter in spiral galaxies would remain in the halo, such a model opens the possibility that galaxies and their associated dark matter play host to a significant number of collapsed substructures. The observational signatures of such structures are not well explored but potentially interesting.

  14. Collapsed Dark Matter Structures

    Science.gov (United States)

    Buckley, Matthew R.; DiFranzo, Anthony

    2018-02-01

    The distributions of dark matter and baryons in the Universe are known to be very different: The dark matter resides in extended halos, while a significant fraction of the baryons have radiated away much of their initial energy and fallen deep into the potential wells. This difference in morphology leads to the widely held conclusion that dark matter cannot cool and collapse on any scale. We revisit this assumption and show that a simple model where dark matter is charged under a "dark electromagnetism" can allow dark matter to form gravitationally collapsed objects with characteristic mass scales much smaller than that of a Milky-Way-type galaxy. Though the majority of the dark matter in spiral galaxies would remain in the halo, such a model opens the possibility that galaxies and their associated dark matter play host to a significant number of collapsed substructures. The observational signatures of such structures are not well explored but potentially interesting.

  15. PARP2 Is the Predominant Poly(ADP-Ribose Polymerase in Arabidopsis DNA Damage and Immune Responses.

    Directory of Open Access Journals (Sweden)

    Junqi Song

    2015-05-01

    Full Text Available Poly (ADP-ribose polymerases (PARPs catalyze the transfer of multiple poly(ADP-ribose units onto target proteins. Poly(ADP-ribosylation plays a crucial role in a variety of cellular processes including, most prominently, auto-activation of PARP at sites of DNA breaks to activate DNA repair processes. In humans, PARP1 (the founding and most characterized member of the PARP family accounts for more than 90% of overall cellular PARP activity in response to DNA damage. We have found that, in contrast with animals, in Arabidopsis thaliana PARP2 (At4g02390, rather than PARP1 (At2g31320, makes the greatest contribution to PARP activity and organismal viability in response to genotoxic stresses caused by bleomycin, mitomycin C or gamma-radiation. Plant PARP2 proteins carry SAP DNA binding motifs rather than the zinc finger domains common in plant and animal PARP1 proteins. PARP2 also makes stronger contributions than PARP1 to plant immune responses including restriction of pathogenic Pseudomonas syringae pv. tomato growth and reduction of infection-associated DNA double-strand break abundance. For poly(ADP-ribose glycohydrolase (PARG enzymes, we find that Arabidopsis PARG1 and not PARG2 is the major contributor to poly(ADP-ribose removal from acceptor proteins. The activity or abundance of PARP2 is influenced by PARP1 and PARG1. PARP2 and PARP1 physically interact with each other, and with PARG1 and PARG2, suggesting relatively direct regulatory interactions among these mediators of the balance of poly(ADP-ribosylation. As with plant PARP2, plant PARG proteins are also structurally distinct from their animal counterparts. Hence core aspects of plant poly(ADP-ribosylation are mediated by substantially different enzymes than in animals, suggesting the likelihood of substantial differences in regulation.

  16. PARP-1: Friend or Foe of DNA Damage and Repair in Tumorigenesis?

    International Nuclear Information System (INIS)

    Swindall, Amanda F.; Stanley, Jennifer A.; Yang, Eddy S.

    2013-01-01

    Oxidative stress induced by reactive oxygen species can result in DNA damage within cells and subsequently increase risk for carcinogenesis. This may be averted by repair of DNA damage through the base or nucleotide excision repair (BER/NER) pathways. PARP, a BER protein, is known for its role in DNA-repair. However, multiple lesions can occur within a small range of DNA, known as oxidative clustered DNA lesions (OCDLs), which are difficult to repair and may lead to the more severe DNA double-strand break (DSB). Inefficient DSB repair can then result in increased mutagenesis and neoplastic transformation. OCDLs occur more frequently within a variety of tumor tissues. Interestingly, PARP is highly expressed in several human cancers. Additionally, chronic inflammation may contribute to tumorigenesis through ROS-induced DNA damage. Furthermore, PARP can modulate inflammation through interaction with NFκB and regulating the expression of inflammatory signaling molecules. Thus, the upregulation of PARP may present a double-edged sword. PARP is needed to repair ROS-induced DNA lesions, but PARP expression may lead to increased inflammation via upregulation of NFκB signaling. Here, we discuss the role of PARP in the repair of oxidative damage versus the formation of OCDLs and speculate on the feasibility of PARP inhibition for the treatment and prevention of cancers by exploiting its role in inflammation

  17. PARP-1: Friend or Foe of DNA Damage and Repair in Tumorigenesis?

    Energy Technology Data Exchange (ETDEWEB)

    Swindall, Amanda F.; Stanley, Jennifer A. [Department of Radiation Oncology Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, 176F HSROC Suite 2232B, 1700 6th Avenue South, Birmingham, AL 35249 (United States); Yang, Eddy S., E-mail: eyang@uab.edu [Department of Radiation Oncology Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, 176F HSROC Suite 2232B, 1700 6th Avenue South, Birmingham, AL 35249 (United States); Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35249 (United States); Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35249 (United States)

    2013-07-26

    Oxidative stress induced by reactive oxygen species can result in DNA damage within cells and subsequently increase risk for carcinogenesis. This may be averted by repair of DNA damage through the base or nucleotide excision repair (BER/NER) pathways. PARP, a BER protein, is known for its role in DNA-repair. However, multiple lesions can occur within a small range of DNA, known as oxidative clustered DNA lesions (OCDLs), which are difficult to repair and may lead to the more severe DNA double-strand break (DSB). Inefficient DSB repair can then result in increased mutagenesis and neoplastic transformation. OCDLs occur more frequently within a variety of tumor tissues. Interestingly, PARP is highly expressed in several human cancers. Additionally, chronic inflammation may contribute to tumorigenesis through ROS-induced DNA damage. Furthermore, PARP can modulate inflammation through interaction with NFκB and regulating the expression of inflammatory signaling molecules. Thus, the upregulation of PARP may present a double-edged sword. PARP is needed to repair ROS-induced DNA lesions, but PARP expression may lead to increased inflammation via upregulation of NFκB signaling. Here, we discuss the role of PARP in the repair of oxidative damage versus the formation of OCDLs and speculate on the feasibility of PARP inhibition for the treatment and prevention of cancers by exploiting its role in inflammation.

  18. Research progress of PARP-1 inhibitors in antitumor drugs and radionuclide markers

    International Nuclear Information System (INIS)

    Zhao Lingzhou; Zhang Huabei

    2011-01-01

    Poly(ADP-ribose)polymerase (PARP) is a new target in the cancer treatment nowadays. PARP not only can repair DNA damage, regulate and control transcription, maintain the stability of intracellular environment and genome, regulate the process of cell survival and death, but also is the main transcription factor in the development of inflammation and the process of cancer. To inhibit PARP activity can reduce the DNA repair function in tumor cells, and increase the sensibility to DNA damage agents, so as to improve the efficacy of radiation therapy and chemotherapy for tumor. A number of studies have suggested that, whether used alone or combination with other chemotherapy drugs, PARP inhibitors show the potential in the anti-tumor therapeutic areas. In this paper, PARP-1 inhibitors were reviewed in antitumor research progress. According to the stage of development , PARP-1 inhibitors are classified. Several representative PARP-1 inhibitors, in clinical trials, with potential clinical value were introduced. Positron emission tomography (PET), uses the main short half-life elementary in human body as tracer, and at the molecular level, achieve the no wound, quantitative and dynamic observation about the different changes of metabolites or drugs in the body. PET is the most advanced contemporary video diagnostic technology, and this paper simply introduce the research progress of PARP-1 inhibitors labeled with radioactive nuclides. (authors)

  19. Gravitational collapse and supernovae

    International Nuclear Information System (INIS)

    Lattimer, J.M.

    1989-01-01

    The collapse of the core of a massive star and the subsequent birth of a neutron star in a supernova explosion are discussed, and a model of the supernova mechanism is developed. The basic theory is then compared with the particular case of SN1987A, whose emitted neutrinos permitted the first direct test of the model. (author)

  20. Unfolding of core nucleosomes by PARP-1 revealed by spFRET microscopy

    Directory of Open Access Journals (Sweden)

    Daniel Sultanov

    2017-01-01

    Full Text Available DNA accessibility to various protein complexes is essential for various processes in the cell and is affected by nucleosome structure and dynamics. Protein factor PARP-1 (poly(ADP-ribose polymerase 1 increases the accessibility of DNA in chromatin to repair proteins and transcriptional machinery, but the mechanism and extent of this chromatin reorganization are unknown. Here we report on the effects of PARP-1 on single nucleosomes revealed by spFRET (single-particle Förster Resonance Energy Transfer microscopy. PARP-1 binding to a double-strand break in the vicinity of a nucleosome results in a significant increase of the distance between the adjacent gyres of nucleosomal DNA. This partial uncoiling of the entire nucleosomal DNA occurs without apparent loss of histones and is reversed after poly(ADP-ribosylation of PARP-1. Thus PARP-1-nucleosome interactions result in reversible, partial uncoiling of the entire nucleosomal DNA.

  1. Characterization of Novel Cytoplasmic PARP in the Brain of Octopus vulgaris

    Science.gov (United States)

    DE LISA, EMILIA; DE MAIO, ANNA; MOROZ, LEONID L.; MOCCIA, FRANCESCO; MENNELLA, MARIA ROSARIA FARAONE; DI COSMO, ANNA

    2014-01-01

    Recent investigation has focused on the participation of the poly (ADP-ribose) polymerase (PARP) reaction in the invertebrate central nervous system (CNS) during the process of long-term memory (LTM). In this paper, we characterize, localize, and assign a possible role to a cytoplasmic PARP in the brain of Octopus vulgaris. PARP activity was assayed in optic lobes, supraesophageal mass, and optic nerves. The highest levels of enzyme were found in the cytoplasmic fraction. Hyper-activation of the enzyme was detected in Octopus brain after visual discrimination training. Finally, cytoplasmic PARP was found to inhibit Octopus vulgaris actin polymerization. We propose that the cytoplasmic PARP plays a role in vivo to induce the cytoskeletonal reorganization that occurs during learning-induced neuronal plasticity. PMID:22815366

  2. Neutrinos and supernova collapse

    International Nuclear Information System (INIS)

    Colgate, S.A.; Petschek, A.G.

    1980-01-01

    The neutrino emission resulting from stellar collapse and supernova formation is reviewed. The electron capture and consequent neutronization of the collapsing stellar matter at the end of evolution determines both the initial adiabat of core collapse as well as the trapped lepton fraction. The initial lepton fraction, Y/sub l/ = .48 supplies the pressure for neutral support of the star at the Chandrasekhar limit. High trapping values, Y/sub l/ = .4, lead to soft core collapses; low values to harder collapses. The value of Y/sub l/ is presently in dispute. The neutrino emission from initial electron capture is relatively small. A strong core-bounce shock releases both electron neutrino as well as thermal muon and tau neutrinos. Subsequent neutrino emission and cooling can sometimes lead to an unstable buoyancy gradient in the core in which case unstable core overturn is expected. Calculations have already shown the importance of the largest possible eddy or equivalently the lowest mode of overturn. Present models of low lepton trapping ratio lead to high entropy creation by the reflected shock and the stabilization of the core matter against overturn. In such cases the exterior matter must cool below an entropy of approximately s/k approx. = 2 to become unstable. This may require too long a time approximately one second for neutrino cooling from a neutrinosphere at rho approx. = 2 x 10 12 g cm -3 . On the other hand, high values of Y/sub l/ such as .4 lead to softer bounces at lower density and values of the critical stabilizing entropy of 3 or higher. Under such circumstances, core overturn can still occur

  3. Poly(ADP-ribose polymerase (PARP-1 is not involved in DNA double-strand break recovery

    Directory of Open Access Journals (Sweden)

    Fernet Marie

    2003-07-01

    Full Text Available Abstract Background The cytotoxicity and the rejoining of DNA double-strand breaks induced by γ-rays, H2O2 and neocarzinostatin, were investigated in normal and PARP-1 knockout mouse 3T3 fibroblasts to determine the role of poly(ADP-ribose polymerase (PARP-1 in DNA double-strand break repair. Results PARP-1-/- were considerably more sensitive than PARP-1+/+ 3T3s to induced cell kill by γ-rays and H2O2. However, the two cell lines did not show any significant difference in the susceptibility to neocarzinostatin below 1.5 nM drug. Restoration of PARP-1 expression in PARP-1-/- 3T3s by retroviral transfection of the full PARP-1 cDNA did not induce any change in neocarzinostatin response. Moreover the incidence and the rejoining kinetics of neocarzinostatin-induced DNA double-strand breaks were identical in PARP-1+/+ and PARP-1-/- 3T3s. Poly(ADP-ribose synthesis following γ-rays and H2O2 was observed in PARP-1-proficient cells only. In contrast neocarzinostatin, even at supra-lethal concentration, was unable to initiate PARP-1 activation yet it induced H2AX histone phosphorylation in both PARP1+/+ and PARP-1-/- 3T3s as efficiently as γ-rays and H2O2. Conclusions The results show that PARP-1 is not a major determinant of DNA double-strand break recovery with either strand break rejoining or cell survival as an endpoint. Even though both PARP-1 and ATM activation are major determinants of the cell response to γ-rays and H2O2, data suggest that PARP-1-dependent poly(ADP-ribose synthesis and ATM-dependent H2AX phosphorylation, are not inter-related in the repair pathway of neocarzinostatin-induced DNA double-strand breaks.

  4. PARP activity and inhibition in fetal and adult oligodendrocyte precursor cells: Effect on cell survival and differentiation.

    Science.gov (United States)

    Baldassarro, Vito A; Marchesini, Alessandra; Giardino, Luciana; Calzà, Laura

    2017-07-01

    Poly (ADP-ribose) polymerase (PARP) family members are ubiquitously expressed and play a key role in cellular processes, including DNA repair and cell death/survival balance. Accordingly, PARP inhibition is an emerging pharmacological strategy for cancer and neurodegenerative diseases. Consistent evidences support the critical involvement of PARP family members in cell differentiation and phenotype maturation. In this study we used an oligodendrocyte precursor cells (OPCs) enriched system derived from fetal and adult brain to investigate the role of PARP in OPCs proliferation, survival, and differentiation. The PARP inhibitors PJ34, TIQ-A and Olaparib were used as pharmacological tools. The main results of the study are: (i) PARP mRNA expression and PARP activity are much higher in fetal than in adult-derived OPCs; (ii) the culture treatment with PARP inhibitors is cytotoxic for OPCs derived from fetal, but not from adult, brain; (iii) PARP inhibition reduces cell number, according to the inhibitory potency of the compounds; (iv) PARP inhibition effect on fetal OPCs is a slow process; (v) PARP inhibition impairs OPCs maturation into myelinating OL in fetal, but not in adult cultures, according to the inhibitory potency of the compounds. These results have implications for PARP-inhibition therapies for diseases and lesions of the central nervous system, in particular for neonatal hypoxic/ischemic encephalopathy. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  5. ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy

    DEFF Research Database (Denmark)

    Rodríguez-Vargas, José Manuel; Ruiz-Magaña, María José; Ruiz-Ruiz, Carmen

    2012-01-01

    , leading to ATP depletion (an early event after nutrient deprivation). The absence of PARP-1 blunted AMPK activation and prevented the complete loss of mTOR activity, leading to a delay in autophagy. PARP-1 depletion favors apoptosis in starved cells, suggesting a pro-survival role of autophagy and PARP-1...

  6. Spherically symmetric scalar field collapse

    Indian Academy of Sciences (India)

    2013-03-01

    Mar 1, 2013 ... The very recent interest in scalar field collapse stems from a cosmological ... The objective of the present investigation is to explore the collapsing modes of a simple ..... The authors thank the BRNS (DAE) for financial support.

  7. Collapse settlement in compacted soils

    CSIR Research Space (South Africa)

    Booth, AR

    1977-01-01

    Full Text Available Research into collapse settlement in compacted soils is described, with special reference to recent cases in Southern Africa where collapse settlement occurred in road embankments following wetting of the soil. The laboratory work described...

  8. The f electron collapse revisited

    International Nuclear Information System (INIS)

    Bennett, B.I.

    1987-03-01

    A reexamination of the collapse of 4f and 5f electrons in the lanthanide and actinide series is presented. The calculations show the well-known collapse of the f electron density at the thresholds of these series along with an f 2 collapse between thorium and protactinium. The collapse is sensitive to the choice of model for the exchange-correlation potential and the behavior of the potential at large radius

  9. Aromatase Inhibitor-Induced Erythrocytosis in a Patient Undergoing Hormonal Treatment for Breast Cancer

    Directory of Open Access Journals (Sweden)

    Sri Lakshmi Hyndavi Yeruva

    2015-01-01

    Full Text Available Aromatase inhibitors (AIs are most commonly used for breast cancer patients with hormone receptor positive disease. Although the side effect profile of aromatase inhibitors is well known, including common side effects like arthralgia, bone pain, arthritis, hot flashes, and more serious problems like osteoporosis, we present a case of an uncommon side effect of these medications. We report the case of a postmenopausal woman on adjuvant hormonal therapy with anastrozole after completing definitive therapy for stage IIIB estrogen receptor-positive breast cancer, who was referred to hematology service for evaluation of persistent erythrocytosis. Primary and known secondary causes of polycythemia were ruled out. On further evaluation, we found that her erythrocytosis began after initiation of anastrozole and resolved after it was discontinued. We discuss the pathophysiology of aromatase inhibitor-induced erythrocytosis and reference of similar cases reported in the literature.

  10. Cardiopulmonary Collapse during Labour

    Directory of Open Access Journals (Sweden)

    Vasilis Sitras

    2010-01-01

    Full Text Available Cardiopulmonary collapse during labour is a catastrophic event caused by various medical, surgical and obstetrical conditions. It is an emergency that threatens the life of the mother and her unborn child. We present a case of a pregnant woman who suffered from preeclampsia and underwent induction of labour. Severe lung edema occurred early in labour that caused cardiopulmonary collapse. Advanced heart-lung resuscitation was established immediately and continued until an emergency cesarean section was performed few minutes later. The outcome was favourable for both mother and child. We further discuss some aspects of the pathophysiology and appropriate treatment of cardiorespiratory arrest during labour, which involves the coordinated action of the obstetric, pediatric and surgical ward personnel.

  11. Tracheal collapse in two cats

    International Nuclear Information System (INIS)

    Hendricks, J.C.; O'Brien, J.A.

    1985-01-01

    Two cats examined bronchoscopically to discover the cause of tracheal collapse were found to have tracheal obstruction cranial to the collapse. Cats with this unusual sign should be examined bronchoscopically to ascertain whether there is an obstruction, as the cause in these 2 cats was distinct from the diffuse airway abnormality that causes tracheal collapse in dogs

  12. Collapse, environment, and society

    Science.gov (United States)

    2012-01-01

    Historical collapse of ancient states poses intriguing social-ecological questions, as well as potential applications to global change and contemporary strategies for sustainability. Five Old World case studies are developed to identify interactive inputs, triggers, and feedbacks in devolution. Collapse is multicausal and rarely abrupt. Political simplification undermines traditional structures of authority to favor militarization, whereas disintegration is preconditioned or triggered by acute stress (insecurity, environmental or economic crises, famine), with breakdown accompanied or followed by demographic decline. Undue attention to stressors risks underestimating the intricate interplay of environmental, political, and sociocultural resilience in limiting the damages of collapse or in facilitating reconstruction. The conceptual model emphasizes resilience, as well as the historical roles of leaders, elites, and ideology. However, a historical model cannot simply be applied to contemporary problems of sustainability without adjustment for cumulative information and increasing possibilities for popular participation. Between the 14th and 18th centuries, Western Europe responded to environmental crises by innovation and intensification; such modernization was decentralized, protracted, flexible, and broadly based. Much of the current alarmist literature that claims to draw from historical experience is poorly focused, simplistic, and unhelpful. It fails to appreciate that resilience and readaptation depend on identified options, improved understanding, cultural solidarity, enlightened leadership, and opportunities for participation and fresh ideas. PMID:22371579

  13. Regulation of FOXO1-mediated transcription and cell proliferation by PARP-1

    Energy Technology Data Exchange (ETDEWEB)

    Sakamaki, Jun-ichi; Daitoku, Hiroaki; Yoshimochi, Kenji [Center for Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577 (Japan); Miwa, Masanao [Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga 526-0829 (Japan); Fukamizu, Akiyoshi, E-mail: akif@tara.tsukuba.ac.jp [Center for Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577 (Japan)

    2009-05-08

    Forkhead box O (FOXO) transcription factors play an important role in a wide range of biological processes, including cell cycle control, apoptosis, detoxification of reactive oxygen species, and gluconeogenesis through regulation of gene expression. In this study, we demonstrated that PARP-1 functions as a negative regulator of FOXO1. We showed that PARP-1 directly binds to and poly(ADP-ribosyl)ates FOXO1 protein. PARP-1 represses FOXO1-mediated expression of cell cycle inhibitor p27{sup Kip1} gene. Notably, poly(ADP-ribosyl)ation activity was not required for the repressive effect of PARP-1 on FOXO1 function. Furthermore, knockdown of PARP-1 led to a decrease in cell proliferation in a manner dependent on FOXO1 function. Chromatin immunoprecipitation experiments confirmed that PARP-1 is recruited to the p27{sup Kip1} gene promoter through a binding to FOXO1. These results suggest that PARP-1 acts as a corepressor for FOXO1, which could play an important role in proper cell proliferation by regulating p27{sup Kip1} gene expression.

  14. Autoimmune response to PARP and BRCA1/BRCA2 in cancer

    Science.gov (United States)

    Zhu, Qing; Han, Su-Xia; Zhou, Cong-Ya; Cai, Meng-Jiao; Dai, Li-Ping; Zhang, Jian-Ying

    2015-01-01

    Purpose To determine the role of autoantibodies to PARP1 and BRCA1/BRCA2 which were involved in the synthetic lethal interaction in cancer. Methods Enzyme-Linked Immunosorbent Assay (ELISA) was used to detect autoantibodies to PARP1 and BRCA1/BRCA2 in 618 serum samples including 131 from breast cancer, 94 from lung cancer, 34 from ovarian cancer, 107 from prostate cancer, 76 from liver cancer, 41 from pancreatic cancer and 135 from normal individuals. The positive sera with ELISA were confirmed by Western blot. Immunohistochemistry was used to examine the expression of PARP1 and BRCA1/BRCA2 in breast cancer. Results Autoantibody frequency to PARP1, BRCA1, and BRCA2 in cancer varied from 0% to 50%. When the sera from cancer patients were tested for the presence of autoantibodies to PARP1 and BRCA1/BRCA2, the autoantibody responses slightly decreased and the positive autoantibody reactions varied from 0% to 50.0%. This was significantly higher autoantibody responses to PARP1 and BRCA1/BRCA2 (especially to PARP1 and BRCA1) in ovarian cancer and breast cancer compared to normal control sera (P cancer was different (P cancers have different profiles of autoantibodies. The autoantibodies to proteins involving the synthetic lethal interactions would be novel serological biomarker in some selective cancers. PMID:25865228

  15. PARP-1 expression is increased in colon adenoma and carcinoma and correlates with OGG1.

    Directory of Open Access Journals (Sweden)

    Tomasz Dziaman

    Full Text Available The ethiology of colon cancer is largely dependent on inflammation driven oxidative stress. The analysis of 8-oxodeoxyguanosine (8-oxodGuo level in leukocyte DNA of healthy controls (138 individuals, patients with benign adenomas (AD, 137 individuals and with malignant carcinomas (CRC, 169 individuals revealed a significant increase in the level of 8-oxodGuo in leukocyte DNA of AD and CRC patients in comparison to controls. The counteracting mechanism is base excision repair, in which OGG1 and PARP-1 play a key role. We investigated the level of PARP-1 and OGG1 mRNA and protein in diseased and marginal, normal tissues taken from AD and CRC patients and in leukocytes taken from the patients as well as from healthy subjects. In colon tumors the PARP-1 mRNA level was higher than in unaffected colon tissue and in polyp tissues. A high positive correlation was found between PARP-1 and OGG1 mRNA levels in all investigated tissues. This suggests reciprocal influence of PARP-1 and OGG1 on their expression and stability, and may contribute to progression of colon cancer. PARP-1 and OGG1 proteins level was several fold higher in polyps and CRC in comparison to normal colon tissues. Individuals bearing the Cys326Cys genotype of OGG1 were characterized by higher PARP-1 protein level in diseased tissues than the Ser326Cys and Ser326Ser genotypes. Aforementioned result may suggest that the diseased cells with polymorphic OGG1 recruit more PARP protein, which is necessary to remove 8-oxodGuo. Thus, patients with decreased activity of OGG1/polymorphism of the OGG1 gene and higher 8-oxodGuo level may be more susceptible to treatment with PARP-1 inhibitors.

  16. PARP-1 modulation of mTOR signaling in response to a DNA alkylating agent.

    Directory of Open Access Journals (Sweden)

    Chantal Ethier

    Full Text Available Poly(ADP-ribose polymerase-1 (PARP-1 is widely involved in cell death responses. Depending on the degree of injury and on cell type, PARP activation may lead to autophagy, apoptosis or necrosis. In HEK293 cells exposed to the alkylating agent N-methyl-N'-nitro-N'-nitrosoguanine (MNNG, we show that PARP-1 activation triggers a necrotic cell death response. The massive poly(ADP-ribose (PAR synthesis following PARP-1 activation leads to the modulation of mTORC1 pathway. Shortly after MNNG exposure, NAD⁺ and ATP levels decrease, while AMP levels drastically increase. We characterized at the molecular level the consequences of these altered nucleotide levels. First, AMP-activated protein kinase (AMPK is activated and the mTORC1 pathway is inhibited by the phosphorylation of Raptor, in an attempt to preserve cellular energy. Phosphorylation of the mTORC1 target S6 is decreased as well as the phosphorylation of the mTORC2 component Rictor on Thr1135. Finally, Akt phosphorylation on Ser473 is lost and then, cell death by necrosis occurs. Inhibition of PARP-1 with the potent PARP inhibitor AG14361 prevents all of these events. Moreover, the antioxidant N-acetyl-L-cysteine (NAC can also abrogate all the signaling events caused by MNNG exposure suggesting that reactive oxygen species (ROS production is involved in PARP-1 activation and modulation of mTOR signaling. In this study, we show that PARP-1 activation and PAR synthesis affect the energetic status of cells, inhibit the mTORC1 signaling pathway and possibly modulate the mTORC2 complex affecting cell fate. These results provide new evidence that cell death by necrosis is orchestrated by the balance between several signaling pathways, and that PARP-1 and PAR take part in these events.

  17. Differential sensitivities of cellular XPA and PARP-1 to arsenite inhibition and zinc rescue.

    Science.gov (United States)

    Ding, Xiaofeng; Zhou, Xixi; Cooper, Karen L; Huestis, Juliana; Hudson, Laurie G; Liu, Ke Jian

    2017-09-15

    Arsenite directly binds to the zinc finger domains of the DNA repair protein poly (ADP ribose) polymerase (PARP)-1, and inhibits PARP-1 activity in the base excision repair (BER) pathway. PARP inhibition by arsenite enhances ultraviolet radiation (UVR)-induced DNA damage in keratinocytes, and the increase in DNA damage is reduced by zinc supplementation. However, little is known about the effects of arsenite and zinc on the zinc finger nucleotide excision repair (NER) protein xeroderma pigmentosum group A (XPA). In this study, we investigated the difference in response to arsenite exposure between XPA and PARP-1, and the differential effectiveness of zinc supplementation in restoring protein DNA binding and DNA damage repair. Arsenite targeted both XPA and PARP-1 in human keratinocytes, resulting in zinc loss from each protein and a pronounced decrease in XPA and PARP-1 binding to chromatin as demonstrated by Chip-on-Western assays. Zinc effectively restored DNA binding of PARP-1 and XPA to chromatin when zinc concentrations were equal to those of arsenite. In contrast, zinc was more effective in rescuing arsenite-augmented direct UVR-induced DNA damage than oxidative DNA damage. Taken together, our findings indicate that arsenite interferes with PARP-1 and XPA binding to chromatin, and that zinc supplementation fully restores DNA binding activity to both proteins in the cellular context. Interestingly, rescue of arsenite-inhibited DNA damage repair by supplemental zinc was more sensitive for DNA damage repaired by the XPA-associated NER pathway than for the PARP-1-dependent BER pathway. This study expands our understanding of arsenite's role in DNA repair inhibition and co-carcinogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Gravitational waves from gravitational collapse

    Energy Technology Data Exchange (ETDEWEB)

    Fryer, Christopher L [Los Alamos National Laboratory; New, Kimberly C [Los Alamos National Laboratory

    2008-01-01

    Gravitational wave emission from stellar collapse has been studied for nearly four decades. Current state-of-the-art numerical investigations of collapse include those that use progenitors with more realistic angular momentum profiles, properly treat microphysics issues, account for general relativity, and examine non-axisymmetric effects in three dimensions. Such simulations predict that gravitational waves from various phenomena associated with gravitational collapse could be detectable with ground-based and space-based interferometric observatories. This review covers the entire range of stellar collapse sources of gravitational waves: from the accretion induced collapse of a white dwarf through the collapse down to neutron stars or black holes of massive stars to the collapse of supermassive stars.

  19. Gravitational Waves from Gravitational Collapse

    Directory of Open Access Journals (Sweden)

    Chris L. Fryer

    2011-01-01

    Full Text Available Gravitational-wave emission from stellar collapse has been studied for nearly four decades. Current state-of-the-art numerical investigations of collapse include those that use progenitors with more realistic angular momentum profiles, properly treat microphysics issues, account for general relativity, and examine non-axisymmetric effects in three dimensions. Such simulations predict that gravitational waves from various phenomena associated with gravitational collapse could be detectable with ground-based and space-based interferometric observatories. This review covers the entire range of stellar collapse sources of gravitational waves: from the accretion-induced collapse of a white dwarf through the collapse down to neutron stars or black holes of massive stars to the collapse of supermassive stars.

  20. Gravitational Waves from Gravitational Collapse.

    Science.gov (United States)

    Fryer, Chris L; New, Kimberly C B

    2011-01-01

    Gravitational-wave emission from stellar collapse has been studied for nearly four decades. Current state-of-the-art numerical investigations of collapse include those that use progenitors with more realistic angular momentum profiles, properly treat microphysics issues, account for general relativity, and examine non-axisymmetric effects in three dimensions. Such simulations predict that gravitational waves from various phenomena associated with gravitational collapse could be detectable with ground-based and space-based interferometric observatories. This review covers the entire range of stellar collapse sources of gravitational waves: from the accretion-induced collapse of a white dwarf through the collapse down to neutron stars or black holes of massive stars to the collapse of supermassive stars. Supplementary material is available for this article at 10.12942/lrr-2011-1.

  1. PARP-1 serves as a novel molecular marker for hepatocellular carcinoma in a Southern Chinese Zhuang population.

    Science.gov (United States)

    Li, Jiatong; Dou, Dongwei; Li, Ping; Luo, Wenqi; Lv, Wenxin; Zhang, Chengdong; Song, Xiaowei; Yang, Yuan; Zhang, Yuening; Xu, Yanzhen; Xiao, Feifan; Wei, Yan; Qin, Jian; Li, Hongtao; Yang, Xiaoli

    2017-07-01

    PARP-1 (poly(ADP-ribose) polymerase-1) plays an important role in tumorigenesis. Since its effects on different populations are varied, this study investigated the impact of PARP-1 on primary hepatocellular carcinoma in a Southern Chinese Zhuang population. We assessed the global PARP-1 messenger RNA expression in patients with hepatocellular carcinoma using The Cancer Genome Atlas dataset. Increased PARP-1 expression, related to alpha-fetoprotein level, was observed. The area under the receiver operating characteristic curve value was 0.833. Kaplan-Meier survival curves indicated that higher PARP-1 expression was not correlated with poorer overall survival and recurrence-free survival. In a Zhuang population, PARP-1 messenger RNA and protein levels were increased in the hepatocellular carcinoma tissue and its adjacent liver tissues as assessed by quantitative polymerase chain reaction, immunohistochemistry, and western blotting. Higher PARP-1 level was associated with a higher tumor stage (p  0.05). Further analysis suggested that H2AX, a PARP-1 protein interaction partner, was coordinated with PARP-1 in hepatocellular carcinoma tumorigenesis. Overall, some new characteristics of PARP-1 expression were noted in the Zhuang population. PARP-1 is a novel promising diagnostic marker for hepatocellular carcinoma in the Southern Chinese Zhuang population.

  2. PARP-2 regulates cell cycle-related genes through histone deacetylation and methylation independently of poly(ADP-ribosyl)ation

    International Nuclear Information System (INIS)

    Liang, Ya-Chen; Hsu, Chiao-Yu; Yao, Ya-Li; Yang, Wen-Ming

    2013-01-01

    Highlights: ► PARP-2 acts as a transcription co-repressor independently of PARylation activity. ► PARP-2 recruits HDAC5, 7, and G9a and generates repressive chromatin. ► PARP-2 is recruited to the c-MYC promoter by DNA-binding factor YY1. ► PARP-2 represses cell cycle-related genes and alters cell cycle progression. -- Abstract: Poly(ADP-ribose) polymerase-2 (PARP-2) catalyzes poly(ADP-ribosyl)ation (PARylation) and regulates numerous nuclear processes, including transcription. Depletion of PARP-2 alters the activity of transcription factors and global gene expression. However, the molecular action of how PARP-2 controls the transcription of target promoters remains unclear. Here we report that PARP-2 possesses transcriptional repression activity independently of its enzymatic activity. PARP-2 interacts and recruits histone deacetylases HDAC5 and HDAC7, and histone methyltransferase G9a to the promoters of cell cycle-related genes, generating repressive chromatin signatures. Our findings propose a novel mechanism of PARP-2 in transcriptional regulation involving specific protein–protein interactions and highlight the importance of PARP-2 in the regulation of cell cycle progression

  3. Scapholunate advanced collapse

    International Nuclear Information System (INIS)

    Chen, C.; Haller, J.; Resnick, D.

    1989-01-01

    Scapholunate advanced collapse 9SLAC) is a pattern of wrist malalignment (characterized mainly by radiocarpal abnormalities) that has been attributed to osteoarthritis. In order to determine the frequency of SLAC in calcium pyrophosphate dihydrate (CPPD) disease, the authors have reviewed wrist radiographs in 190 cases of this disorder. Forty-two (22%) of these cases reveal wrist abnormalities typical of SLAC. Associated findings include bilateral alterations (63%), abnormal calcification (70%), scapholunate dissociation (70%), and additional compartmental arthropathies. The authors' results confirm that CPPD crystal deposition disease is a major cause of SLAC. They believe, therefore, that this pattern of malalignment is not specific for posttraumatic or spontaneous osteoarthritis of the wrist

  4. A collapsible shelter

    Energy Technology Data Exchange (ETDEWEB)

    Sharafutdinov, I.G.; Asadulin, Kh.F.; Maloiaroslavtsev, D.A.; Prokopov, O.I.; Rastorquev, M.A.

    1980-08-15

    A collapsible shelter is proposed which includes a foundation, a framework with reinforced elements which form a roof, tie bolt elements which are riveted to the reinforced elements, and a railing; it is characterized by an arrangement whereby in order to simplify its construction and improve its reliability, the reinforced elements are detachable and are equipped with rigid connecting rods made of separate sections which are mounted to allow for movement via the reinforced elements; the connecting rod of each reinforcement element is connected to the connecting rod of the adjacent reinforced element using horizontal rods on which the shelter is secured. The shelter is made from separate planks.

  5. Differential expression of PARP1 mRNA in leucocytes of patients ...

    Indian Academy of Sciences (India)

    P. 2011 Differential expression of PARP1 mRNA in leucocytes of patients with Down's syndrome. J. Genet. ... of Alzheimer disease at an earlier age than subjects with- ... family and personal informed consent. .... In effect, they report that.

  6. Theophylline prevents NAD+ depletion via PARP-1 inhibition in human pulmonary epithelial cells

    International Nuclear Information System (INIS)

    Moonen, Harald J.J.; Geraets, Liesbeth; Vaarhorst, Anika; Bast, Aalt; Wouters, Emiel F.M.; Hageman, Geja J.

    2005-01-01

    Oxidative DNA damage, as occurs during exacerbations in chronic obstructive pulmonary disease (COPD), highly activates the nuclear enzyme poly(ADP-ribose)polymerase-1 (PARP-1). This can lead to cellular depletion of its substrate NAD + , resulting in an energy crisis and ultimately in cell death. Inhibition of PARP-1 results in preservation of the intracellular NAD + pool, and of NAD + -dependent cellular processes. In this study, PARP-1 activation by hydrogen peroxide decreased intracellular NAD + levels in human pulmonary epithelial cells, which was found to be prevented in a dose-dependent manner by theophylline, a widely used compound in the treatment of COPD. This enzyme inhibition by theophylline was confirmed in an ELISA using purified human PARP-1 and was found to be competitive by nature. These findings provide new mechanistic insights into the therapeutic effect of theophylline in oxidative stress-induced lung pathologies

  7. Shearfree cylindrical gravitational collapse

    International Nuclear Information System (INIS)

    Di Prisco, A.; Herrera, L.; MacCallum, M. A. H.; Santos, N. O.

    2009-01-01

    We consider diagonal cylindrically symmetric metrics, with an interior representing a general nonrotating fluid with anisotropic pressures. An exterior vacuum Einstein-Rosen spacetime is matched to this using Darmois matching conditions. We show that the matching conditions can be explicitly solved for the boundary values of metric components and their derivatives, either for the interior or exterior. Specializing to shearfree interiors, a static exterior can only be matched to a static interior, and the evolution in the nonstatic case is found to be given in general by an elliptic function of time. For a collapsing shearfree isotropic fluid, only a Robertson-Walker dust interior is possible, and we show that all such cases were included in Cocke's discussion. For these metrics, Nolan and Nolan have shown that the matching breaks down before collapse is complete, and Tod and Mena have shown that the spacetime is not asymptotically flat in the sense of Berger, Chrusciel, and Moncrief. The issues about energy that then arise are revisited, and it is shown that the exterior is not in an intrinsic gravitational or superenergy radiative state at the boundary.

  8. PREFACE: Collapse Calderas Workshop

    Science.gov (United States)

    Gottsmann, Jo; Aguirre-Diaz, Gerardo

    2008-10-01

    Caldera-formation is one of the most awe-inspiring and powerful displays of nature's force. Resultant deposits may cover vast areas and significantly alter the immediate topography. Post-collapse activity may include resurgence, unrest, intra-caldera volcanism and potentially the start of a new magmatic cycle, perhaps eventually leading to renewed collapse. Since volcanoes and their eruptions are the surface manifestation of magmatic processes, calderas provide key insights into the generation and evolution of large-volume silicic magma bodies in the Earth's crust. Despite their potentially ferocious nature, calderas play a crucial role in modern society's life. Collapse calderas host essential economic deposits and supply power for many via the exploitation of geothermal reservoirs, and thus receive considerable scientific, economic and industrial attention. Calderas also attract millions of visitors world-wide with their spectacular scenic displays. To build on the outcomes of the 2005 calderas workshop in Tenerife (Spain) and to assess the most recent advances on caldera research, a follow-up meeting was proposed to be held in Mexico in 2008. This abstract volume presents contributions to the 2nd Calderas Workshop held at Hotel Misión La Muralla, Querétaro, Mexico, 19-25 October 2008. The title of the workshop `Reconstructing the evolution of collapse calderas: Magma storage, mobilisation and eruption' set the theme for five days of presentations and discussions, both at the venue as well as during visits to the surrounding calderas of Amealco, Amazcala and Huichapan. The multi-disciplinary workshop was attended by more than 40 scientist from North, Central and South America, Europe, Australia and Asia. Contributions covered five thematic topics: geology, geochemistry/petrology, structural analysis/modelling, geophysics, and hazards. The workshop was generously supported by the International Association of Volcanology and the Chemistry of The Earth's Interior

  9. Targeted Radiosensitization of ETS Fusion-Positive Prostate Cancer through PARP1 Inhibition

    Directory of Open Access Journals (Sweden)

    Sumin Han

    2013-10-01

    Full Text Available ETS gene fusions, which result in overexpression of an ETS transcription factor, are considered driving mutations in approximately half of all prostate cancers. Dysregulation of ETS transcription factors is also known to exist in Ewing's sarcoma, breast cancer, and acute lymphoblastic leukemia. We previously discovered that ERG, the predominant ETS family member in prostate cancer, interacts with the DNA damage response protein poly (ADP-ribose polymerase 1 (PARP1 in human prostate cancer specimens. Therefore, we hypothesized that the ERG-PARP1 interaction may confer radiation resistance by increasing DNA repair efficiency and that this radio-resistance could be reversed through PARP1 inhibition. Using lentiviral approaches, we established isogenic models of ERG overexpression in PC3 and DU145 prostate cancer cell lines. In both cell lines, ERG overexpression increased clonogenic survival following radiation by 1.25 (±0.07 fold (mean ± SEM and also resulted in increased PARP1 activity. PARP1 inhibition with olaparib preferentially radiosensitized ERG-positive cells by a factor of 1.52 (±0.03 relative to ERG-negative cells (P < .05. Neutral and alkaline COMET assays and immunofluorescence microscopy assessing γ-H2AX foci showed increased short- and long-term efficiencies of DNA repair, respectively, following radiation that was preferentially reversed by PARP1 inhibition. These findings were verified in an in vivo xenograft model. Our findings demonstrate that ERG overexpression confers radiation resistance through increased efficiency of DNA repair following radiation that can be reversed through inhibition of PARP1. These results motivate the use of PARP1 inhibitors as radiosensitizers in patients with localized ETS fusion-positive cancers.

  10. Hyperactivation of PARP triggers nonhomologous end-joining in repair-deficient mouse fibroblasts.

    Directory of Open Access Journals (Sweden)

    Natalie R Gassman

    Full Text Available Regulation of poly(ADP-ribose (PAR synthesis and turnover is critical to determining cell fate after genotoxic stress. Hyperactivation of PAR synthesis by poly(ADP-ribose polymerase-1 (PARP-1 occurs when cells deficient in DNA repair are exposed to genotoxic agents; however, the function of this hyperactivation has not been adequately explained. Here, we examine PAR synthesis in mouse fibroblasts deficient in the base excision repair enzyme DNA polymerase β (pol β. The extent and duration of PARP-1 activation was measured after exposure to either the DNA alkylating agent, methyl methanesulfonate (MMS, or to low energy laser-induced DNA damage. There was strong DNA damage-induced hyperactivation of PARP-1 in pol β nullcells, but not in wild-type cells. In the case of MMS treatment, PAR synthesis did not lead to cell death in the pol β null cells, but instead resulted in increased PARylation of the nonhomologous end-joining (NHEJ protein Ku70 and increased association of Ku70 with PARP-1. Inhibition of the NHEJ factor DNA-PK, under conditions of MMS-induced PARP-1 hyperactivation, enhanced necrotic cell death. These data suggest that PARP-1 hyperactivation is a protective mechanism triggering the classical-NHEJ DNA repair pathway when the primary alkylated base damage repair pathway is compromised.

  11. PARP-1 Inhibition Is Neuroprotective in the R6/2 Mouse Model of Huntington's Disease.

    Directory of Open Access Journals (Sweden)

    Antonella Cardinale

    Full Text Available Poly (ADP-ribose polymerase 1 (PARP-1 is a nuclear enzyme that is involved in physiological processes as DNA repair, genomic stability, and apoptosis. Moreover, published studies demonstrated that PARP-1 mediates necrotic cell death in response to excessive DNA damage under certain pathological conditions. In Huntington's disease brains, PARP immunoreactivity was described in neurons and in glial cells, thereby suggesting the involvement of apoptosis in HD. In this study, we sought to determine if the PARP-1 inhibitor exerts a neuroprotective effect in R6/2 mutant mice, which recapitulates, in many aspects, human HD. Transgenic mice were treated with the PARP-1 inhibitor INO-1001 mg/Kg daily starting from 4 weeks of age. After transcardial perfusion, histological and immunohistochemical studies were performed. We found that INO 1001-treated R6/2 mice survived longer and displayed less severe signs of neurological dysfunction than the vehicle treated ones. Primary outcome measures such as striatal atrophy, morphology of striatal neurons, neuronal intranuclear inclusions and microglial reaction confirmed a neuroprotective effect of the compound. INO-1001 was effective in significantly increasing activated CREB and BDNF in the striatal spiny neurons, which might account for the beneficial effects observed in this model. Our findings show that PARP-1 inhibition could be considered as a valid therapeutic approach for HD.

  12. PARP1 inhibitors: contemporary attempts at their use in anticancer therapy and future perspective

    Directory of Open Access Journals (Sweden)

    Ewelina Wiśnik

    2016-04-01

    Full Text Available Current cancer therapies are based mainly on the use of compounds that cause DNA damage. Unfortunately, even the combination therapies do not give rewarding effects, due to the high efficiency of DNA damage repair mechanisms in tumor cells. Therefore, the present studies should be focused on proteins that are involved in DNA repair systems. Poly(ADP-ribose polymerase-1 is an example of a protein commonly known as an enzyme that plays a role in the detection of DNA damage and repair. Activation of PARP1 in response to DNA damage leads to poly-ADP-ribosylation of proteins contributing to DNA repair systems, therefore facilitating the maintenance of genome stability. On the other hand, inhibition of PARP1 enzyme results in the accumulation of DNA damage, which in turn contributes to cell death. Studies on inhibitors of PARP1 are still ongoing, and some of them are currently in the third phase of clinical trials. To date, only one representative of the PARP1 inhibitors, called olaparib, has been approved for anti-cancer therapy in the EU and the USA. Moreover, a growing body of evidence indicates a role of this protein in various intracellular processes such as bioenergetics, proliferation, regulation of gene expression, cell death as well as immunoregulation. A number of different intracellular processes regulated by PARP1 give rise to potential wider use of PARP1 inhibitors in treatment of other diseases, including immune or autoimmune disorders.

  13. Accelerated Aging during Chronic Oxidative Stress: A Role for PARP-1

    Directory of Open Access Journals (Sweden)

    Daniëlle M. P. H. J. Boesten

    2013-01-01

    Full Text Available Oxidative stress plays a major role in the pathophysiology of chronic inflammatory disease and it has also been linked to accelerated telomere shortening. Telomeres are specialized structures at the ends of linear chromosomes that protect these ends from degradation and fusion. Telomeres shorten with each cell division eventually leading to cellular senescence. Research has shown that poly(ADP-ribose polymerase-1 (PARP-1 and subtelomeric methylation play a role in telomere stability. We hypothesized that PARP-1 plays a role in accelerated aging in chronic inflammatory diseases due to its role as coactivator of NF-κb and AP-1. Therefore we evaluated the effect of chronic PARP-1 inhibition (by fisetin and minocycline in human fibroblasts (HF cultured under normal conditions and under conditions of chronic oxidative stress, induced by tert-butyl hydroperoxide (t-BHP. Results showed that PARP-1 inhibition under normal culturing conditions accelerated the rate of telomere shortening. However, under conditions of chronic oxidative stress, PARP-1 inhibition did not show accelerated telomere shortening. We also observed a strong correlation between telomere length and subtelomeric methylation status of HF cells. We conclude that chronic PARP-1 inhibition appears to be beneficial in conditions of chronic oxidative stress but may be detrimental under relatively normal conditions.

  14. Cylindrical collapse and gravitational waves

    Energy Technology Data Exchange (ETDEWEB)

    Herrera, L [Escuela de FIsica, Faculdad de Ciencias, Universidad Central de Venezuela, Caracas, Venezuela (Venezuela); Santos, N O [Universite Pierre et Marie Curie, CNRS/FRE 2460 LERMA/ERGA, Tour 22-12, 4eme etage, BoIte 142, 4 place Jussieu, 75252 Paris Cedex 05 (France); Laboratorio Nacional de Computacao Cientifica, 25651-070 Petropolis RJ (Brazil); Centro Brasileiro de Pesquisas Fisicas, 22290-180 Rio de Janeiro RJ (Brazil)

    2005-06-21

    We study the matching conditions for a collapsing anisotropic cylindrical perfect fluid, and we show that its radial pressure is non-zero on the surface of the cylinder and proportional to the time-dependent part of the field produced by the collapsing fluid. This result resembles the one that arises for the radiation-though non-gravitational-in the spherically symmetric collapsing dissipative fluid, in the diffusion approximation.

  15. Deficiency in Poly(ADP-ribose Polymerase-1 (PARP-1 Accelerates Aging and Spontaneous Carcinogenesis in Mice

    Directory of Open Access Journals (Sweden)

    Tatiana S. Piskunova

    2008-01-01

    Full Text Available Genetic and biochemical studies have shown that PARP-1 and poly(ADP-ribosylation play an important role in DNA repair, genomic stability, cell death, inflammation, telomere maintenance, and suppressing tumorigenesis, suggesting that the homeostasis of poly(ADP-ribosylation and PARP-1 may also play an important role in aging. Here we show that PARP-1−/− mice exhibit a reduction of life span and a significant increase of population aging rate. Analysis of noninvasive parameters, including body weight gain, body temperature, estrous function, behavior, and a number of biochemical indices suggests the acceleration of biological aging in PARP-1−/− mice. The incidence of spontaneous tumors in both PARP-1−/− and PARP-1+/+ groups is similar; however, malignant tumors including uterine tumors, lung adenocarcinomas and hepatocellular carcinomas, develop at a significantly higher frequency in PARP-1−/− mice than PARP-1+/+ mice (72% and 49%, resp.; < .05. In addition, spontaneous tumors appear earlier in PARP-1−/− mice compared to the wild type group. Histopathological studies revealed a wide spectrum of tumors in uterus, ovaries, liver, lungs, mammary gland, soft tissues, and lymphoid organs in both groups of the mice. These results demonstrate that inactivation of DNA repair gene PARP-1 in mice leads to acceleration of aging, shortened life span, and increased spontaneous carcinogenesis.

  16. ACE Inhibitor-Induced Angioedema of the Intestine: Case Report, Incidence, Pathophysiology, Diagnosis and Management

    Directory of Open Access Journals (Sweden)

    Gavin Oudit

    2001-01-01

    Full Text Available A case report of fosinopril-induced angioedema of the intestine with a chronic course accompanied by multiple acute exacerbations is described. Angiotensin-converting enzyme (ACE inhibitor-induced angioedema of the intestine (AIAI occurs in a minority of patients taking an ACE inhibitor. The clinical presentation encompasses acute abdominal symptoms, pronounced bowel edema and ascites with occasional facial and/or oropharyngeal swelling. AIAI is diagnosed based on the temporal relationship between the symptomatic presentation and drug use, absence of alternative diagnoses including other causes of angioedema, and the prompt resolution of symptoms upon discontinuation of the ACE inhibitor. Prompt radiological investigation (abdominal computerized tomography and/or ultrasound is critical in making an early diagnosis and in preventing unnecessary surgical intervention. There is a female predominance of AIAI, which may reflect the interaction of estradiol with the various pathways involved in the pathophysiology of AIAI. Management of AIAI consists mainly of conservative measures and discontinuation of the ACE inhibitor. Angiotensin II receptor antagonists should not be considered as appropriate alternatives. Awareness and knowledge of AIAI are important because of the increasing use of ACE inhibitors, current delays in making the diagnosis, obvious management strategies once the diagnosis is made and the dysutility of alternative diagnoses, which may lead to considerable morbidity. AIAI must be considered in patients taking ACE inhibitors who develop gastrointestinal complaints irrespective of the duration of the therapy.

  17. Blockade of the ERK pathway markedly sensitizes tumor cells to HDAC inhibitor-induced cell death

    International Nuclear Information System (INIS)

    Ozaki, Kei-ichi; Minoda, Ai; Kishikawa, Futaba; Kohno, Michiaki

    2006-01-01

    Constitutive activation of the extracellular signal-regulated kinase (ERK) pathway is associated with the neoplastic phenotype of a large number of human tumor cells. Although specific blockade of the ERK pathway by treating such tumor cells with potent mitogen-activated protein kinase/ERK kinase (MEK) inhibitors completely suppresses their proliferation, it by itself shows only a modest effect on the induction of apoptotic cell death. However, these MEK inhibitors markedly enhance the efficacy of histone deacetylase (HDAC) inhibitors to induce apoptotic cell death: such an enhanced cell death is observed only in tumor cells in which the ERK pathway is constitutively activated. Co-administration of MEK inhibitor markedly sensitizes tumor cells to HDAC inhibitor-induced generation of reactive oxygen species, which appears to mediate the enhanced cell death induced by the combination of these agents. These results suggest that the combination of MEK inhibitors and HDAC inhibitors provides an efficient chemotherapeutic strategy for the treatment of tumor cells in which the ERK pathway is constitutively activated

  18. A natural product-like JAK2/STAT3 inhibitor induces apoptosis of malignant melanoma cells.

    Directory of Open Access Journals (Sweden)

    Ke-Jia Wu

    Full Text Available The JAK2/STAT3 signaling pathway plays a critical role in tumorigenesis, and has been suggested as a potential molecular target for anti-melanoma therapeutics. However, few JAK2 inhibitors were being tested for melanoma therapy. In this study, eight amentoflavone analogues were evaluated for their activity against human malignant melanoma cells. The most potent analogue, compound 1, inhibited the phosphorylation of JAK2 and STAT3 in human melanoma cells, but had no discernible effect on total JAK2 and STAT3 levels. A cellular thermal shift assay was performed to identify that JAK2 is engaged by 1 in cell lysates. Moreover, compound 1 showed higher antiproliferative activity against human melanoma A375 cells compared to a panel of cancer and normal cell lines. Compound 1 also activated caspase-3 and cleaved PARP, which are markers of apoptosis, and suppressed the anti-apoptotic Bcl-2 level. Finally, compound 1 induced apoptosis in 80% of treated melanoma cells. To our knowledge, compound 1 is the first amentoflavone-based JAK2 inhibitor to be investigated for use as an anti-melanoma agent.

  19. Vasoactivity of rucaparib, a PARP-1 inhibitor, is a complex process that involves myosin light chain kinase, P2 receptors, and PARP itself.

    Directory of Open Access Journals (Sweden)

    Cian M McCrudden

    Full Text Available Therapeutic inhibition of poly(ADP-ribose polymerase (PARP, as monotherapy or to supplement the potencies of other agents, is a promising strategy in cancer treatment. We previously reported that the first PARP inhibitor to enter clinical trial, rucaparib (AG014699, induced vasodilation in vivo in xenografts, potentiating response to temozolomide. We now report that rucaparib inhibits the activity of the muscle contraction mediator myosin light chain kinase (MLCK 10-fold more potently than its commercially available inhibitor ML-9. Moreover, rucaparib produces additive relaxation above the maximal degree achievable with ML-9, suggesting that MLCK inhibition is not solely responsible for dilation. Inhibition of nitric oxide synthesis using L-NMMA also failed to impact rucaparib's activity. Rucaparib contains the nicotinamide pharmacophore, suggesting it may inhibit other NAD+-dependent processes. NAD+ exerts P2 purinergic receptor-dependent inhibition of smooth muscle contraction. Indiscriminate blockade of the P2 purinergic receptors with suramin abrogated rucaparib-induced vasodilation in rat arterial tissue without affecting ML-9-evoked dilation, although the specific receptor subtypes responsible have not been unequivocally identified. Furthermore, dorsal window chamber and real time tumor vessel perfusion analyses in PARP-1-/- mice indicate a potential role for PARP in dilation of tumor-recruited vessels. Finally, rucaparib provoked relaxation in 70% of patient-derived tumor-associated vessels. These data provide tantalising evidence of the complexity of the mechanism underlying rucaparib-mediated vasodilation.

  20. Effect of MRE11 loss on PARP-inhibitor sensitivity in endometrial cancer in vitro.

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    Romana Koppensteiner

    Full Text Available To evaluate the frequency of MRE11/RAD50/NBS1 (MRN-complex loss of protein expression in endometrial cancers (EC and to determine whether loss of MRE11 renders the cancer cells sensitive to Poly(ADP-ribose polymerase (PARP-inhibitory treatment.MRN expression was examined in 521 samples of endometrial carcinomas and in 10 cancer cell lines. A putative mutation hotspot in the form of an intronic poly(T allele in MRE11 was sequenced in selected cases (n = 26. Sensitivity to the PARP-inhibitor, BMN673 was tested in colony formation assays before and after MRE11 silencing using siRNA. Homologous recombination (HR DNA repair was evaluated by RAD51-foci formation assay upon irradiation and drug treatment.Loss of MRE11 protein was found in 30.7% of EC tumours and significantly associated with loss of RAD50, NBS1 and mismatch repair protein expression. One endometrial cell line showed a markedly reduced MRE11 expression due to a homozygous poly(T mutation of MRE11, thereby exhibiting an increased sensitivity to BMN673. MRE11 depletion sensitizes MRE11 expressing EC cell lines to the treatment with BMN673. The increased sensitivity to PARP-inhibition correlates with reduced RAD51 foci formation upon ionizing radiation in MRE11-depleted cells.Loss of the MRE11 protein predicts sensitivity to PARP-inhibitor sensitivity in vitro, defining it as an additional synthetic lethal gene with PARP. The high incidence of MRE11 loss in ECs can be potentially exploited for PARP-inhibitor therapy. Furthermore, MRE11 protein expression using immunohistochemistry could be investigated as a predictive biomarker for PARP-inhibitor treatment.

  1. MicroRNAs Modulate Oxidative Stress in Hypertension through PARP-1 Regulation

    Directory of Open Access Journals (Sweden)

    Douglas F. Dluzen

    2017-01-01

    Full Text Available Oxidative stress is thought to contribute to aging and age-related diseases, such as cardiovascular and neurodegenerative diseases, and is a risk factor for systemic arterial hypertension. Previously, we reported differential mRNA and microRNA (miRNA expression between African American (AA and white women with hypertension. Here, we found that the poly-(ADP-ribose polymerase 1 (PARP-1, a DNA damage sensor protein involved in DNA repair and other cellular processes, is upregulated in AA women with hypertension. To explore this mechanism, we identified two miRNAs, miR-103a-2-5p and miR-585-5p, that are differentially expressed with hypertension and were predicted to target PARP1. Through overexpression of each miRNA-downregulated PARP-1 mRNA and protein levels and using heterologous luciferase reporter assays, we demonstrate that miR-103a-2-5p and miR-585-5p regulate PARP1 through binding within the coding region. Given the important role of PARP-1 in DNA repair, we assessed whether overexpression of miR-103a-2-5p or miR-585-5p affected DNA damage and cell survival. Overexpression of these miRNAs enhanced DNA damage and decreased both cell survival and colony formation. These findings highlight the role for PARP-1 in regulating oxidative DNA damage in hypertension and identify important new miRNA regulators of PARP-1 expression. These insights may provide additional avenues to understand hypertension health disparities.

  2. Hyperthermia and PARP1-inhibition for sensitization of radiation and cisplatin treatment of cervical carcinoma cells

    International Nuclear Information System (INIS)

    Franken, Nicolaas; Oei, Arlene; Leeuwen, Caspar van; Stalpers, Lukas; Rodermond, Hans; Bel, Arjan; Kok, Petra; Crezee, Hans

    2014-01-01

    Ionizing radiation causes single and double strand breaks (SSBs and DSBs). DSBs are among the most critical DNA lesions and can be repaired via either non-homologous end joining (NHEJ) in which PARP1, Ku70 and DNA-PKcs are important, or homologous recombination (HR), where BRCA2 and Rad51 are essential. Hyperthermia disturbs HR by temporary inactivation of BRCA2. Cisplatin disrupts NHEJ and PARP1-inhibitor blocks Poly-(ADP-ribose)polymerase- 1, which is important in SSB repair, NHEJ and backup-NHEJ. Our goal was to investigate the additional effectiveness of hyperthermia and PARP1-inhibition on radiation and/or cisplatin treatment. Cervical carcinoma cells (SiHa) were treated at different temperature levels levels (41.0-43.0℃, PARP1-inhibitor (100 μM; NU1025), gamma-irradiation doses (0-8 Gy) or cisplatin (1'R for 1 h). Clonogenic assays were carried out to measure survival and γH2AX staining was used to visualize DSBs. To elucidate mechanisms of action expression levels of DNA repair proteins BRCA2 and DNA-PKcs were investigated after 42.0℃ (1 h) using western blot. Combined hyperthermia and radiation resulted in an increased number of γH2AX foci as compared to radiation alone. Hyperthermia treatment in combination with cisplatin and PARP1 inhibitor and with radiation and PARP1 inhibitor significantly decreased cell survival. Western blot demonstrated a decreased expression of BRCA2 protein at 30 min after hyperthermia treatment. Adding PARP1-inhibitor significantly improves the effectiveness of combined hyperthermia radiotherapy and combined hyperthermia-cisplatin treatment on cervical carcinoma cells. Hyperthermia affects DNA-DSB repair as is indicated by increased γH2AX foci numbers and decreased BRCA2 expression. (author)

  3. Spherical collapse in chameleon models

    International Nuclear Information System (INIS)

    Brax, Ph.; Rosenfeld, R.; Steer, D.A.

    2010-01-01

    We study the gravitational collapse of an overdensity of nonrelativistic matter under the action of gravity and a chameleon scalar field. We show that the spherical collapse model is modified by the presence of a chameleon field. In particular, we find that even though the chameleon effects can be potentially large at small scales, for a large enough initial size of the inhomogeneity the collapsing region possesses a thin shell that shields the modification of gravity induced by the chameleon field, recovering the standard gravity results. We analyse the behaviour of a collapsing shell in a cosmological setting in the presence of a thin shell and find that, in contrast to the usual case, the critical density for collapse in principle depends on the initial comoving size of the inhomogeneity

  4. Spherical collapse in chameleon models

    Energy Technology Data Exchange (ETDEWEB)

    Brax, Ph. [Institut de Physique Théorique, CEA, IPhT, CNRS, URA 2306, F-91191Gif/Yvette Cedex (France); Rosenfeld, R. [Instituto de Física Teórica, Universidade Estadual Paulista, Rua Dr. Bento T. Ferraz, 271, 01140-070, São Paulo (Brazil); Steer, D.A., E-mail: brax@spht.saclay.cea.fr, E-mail: rosenfel@ift.unesp.br, E-mail: daniele.steer@apc.univ-paris7.fr [APC, UMR 7164, CNRS, Université Paris 7, 10 rue Alice Domon et Léonie Duquet, 75205 Paris Cedex 13 (France)

    2010-08-01

    We study the gravitational collapse of an overdensity of nonrelativistic matter under the action of gravity and a chameleon scalar field. We show that the spherical collapse model is modified by the presence of a chameleon field. In particular, we find that even though the chameleon effects can be potentially large at small scales, for a large enough initial size of the inhomogeneity the collapsing region possesses a thin shell that shields the modification of gravity induced by the chameleon field, recovering the standard gravity results. We analyse the behaviour of a collapsing shell in a cosmological setting in the presence of a thin shell and find that, in contrast to the usual case, the critical density for collapse in principle depends on the initial comoving size of the inhomogeneity.

  5. Spherical Collapse in Chameleon Models

    CERN Document Server

    Brax, Ph; Steer, D A

    2010-01-01

    We study the gravitational collapse of an overdensity of nonrelativistic matter under the action of gravity and a chameleon scalar field. We show that the spherical collapse model is modified by the presence of a chameleon field. In particular, we find that even though the chameleon effects can be potentially large at small scales, for a large enough initial size of the inhomogeneity the collapsing region possesses a thin shell that shields the modification of gravity induced by the chameleon field, recovering the standard gravity results. We analyse the behaviour of a collapsing shell in a cosmological setting in the presence of a thin shell and find that, in contrast to the usual case, the critical density for collapse depends on the initial comoving size of the inhomogeneity.

  6. PARP Inhibition Prevents Ethanol-Induced Neuroinflammatory Signaling and Neurodegeneration in Rat Adult-Age Brain Slice Cultures

    Science.gov (United States)

    Tajuddin, Nuzhath; Kim, Hee-Yong

    2018-01-01

    Using rat adult-age hippocampal-entorhinal cortical (HEC) slice cultures, we examined the role of poly [ADP-ribose] polymerase (PARP) in binge ethanol’s brain inflammatory and neurodegenerative mechanisms. Activated by DNA strand breaks, PARP (principally PARP1 in the brain) promotes DNA repair via poly [ADP-ribose] (PAR) products, but PARP overactivation triggers regulated neuronal necrosis (e.g., parthanatos). Previously, we found that brain PARP1 levels were upregulated by neurotoxic ethanol binges in adult rats and HEC slices, and PARP inhibitor PJ34 abrogated slice neurodegeneration. Binged HEC slices also exhibited increased Ca+2-dependent phospholipase A2 (PLA2) isoenzymes (cPLA2 IVA and sPLA2 IIA) that mobilize proinflammatory ω6 arachidonic acid (ARA). We now find in 4-day–binged HEC slice cultures (100 mM ethanol) that PARP1 elevations after two overnight binges precede PAR, cPLA2, and sPLA2 enhancements by 1 day and high-mobility group box-1 (HMGB1), an ethanol-responsive alarmin that augments proinflammatory cytokines via toll-like receptor-4 (TLR4), by 2 days. After verifying that PJ34 effectively blocks PARP activity (↑PAR), we demonstrated that, like PJ34, three other PARP inhibitors—olaparib, veliparib, and 4-aminobenzamide—provided neuroprotection from ethanol. Importantly, PJ34 and olaparib also prevented ethanol’s amplification of the PLA2 isoenzymes, and two PLA2 inhibitors were neuroprotective—thus coupling PARP to PLA2, with PLA2 activity promoting neurodegeneration. Also, PJ34 and olaparib blocked ethanol-induced HMGB1 elevations, linking brain PARP induction to TLR4 activation. The results provide evidence in adult brains that induction of PARP1 may mediate dual neuroinflammatory pathways (PLA2→phospholipid→ARA and HMGB1→TLR4→proinflammatory cytokines) that are complicit in binge ethanol-induced neurodegeneration. PMID:29339456

  7. Role of PARP activity in lung cancer-induced cachexia: Effects on muscle oxidative stress, proteolysis, anabolic markers, and phenotype.

    Science.gov (United States)

    Chacon-Cabrera, Alba; Mateu-Jimenez, Mercè; Langohr, Klaus; Fermoselle, Clara; García-Arumí, Elena; Andreu, Antoni L; Yelamos, Jose; Barreiro, Esther

    2017-12-01

    Strategies to treat cachexia are still at its infancy. Enhanced muscle protein breakdown and ubiquitin-proteasome system are common features of cachexia associated with chronic conditions including lung cancer (LC). Poly(ADP-ribose) polymerases (PARP), which play a major role in chromatin structure regulation, also underlie maintenance of muscle metabolism and body composition. We hypothesized that protein catabolism, proteolytic markers, muscle fiber phenotype, and muscle anabolism may improve in respiratory and limb muscles of LC-cachectic Parp-1-deficient (Parp-1 -/- ) and Parp-2 -/- mice. In diaphragm and gastrocnemius of LC (LP07 adenocarcinoma) bearing mice (wild type, Parp-1 -/- , and Parp-2 -/- ), PARP activity (ADP-ribose polymers, pADPr), redox balance, muscle fiber phenotype, apoptotic nuclei, tyrosine release, protein ubiquitination, muscle-specific E3 ligases, NF-κB signaling pathway, markers of muscle anabolism (Akt, mTOR, p70S6K, and mitochondrial DNA) were evaluated along with body and muscle weights, and limb muscle force. Compared to wild type cachectic animals, in both respiratory and limb muscles of Parp-1 -/- and Parp-2 -/- cachectic mice: cancer induced-muscle wasting characterized by increased PARP activity, protein oxidation, tyrosine release, and ubiquitin-proteasome system (total protein ubiquitination, atrogin-1, and 20S proteasome C8 subunit) were blunted, the reduction in contractile myosin and atrophy of the fibers was attenuated, while no effects were seen in other structural features (inflammatory cells, internal or apoptotic nuclei), and markers of muscle anabolism partly improved. Activation of either PARP-1 or -2 is likely to play a role in muscle protein catabolism via oxidative stress, NF-κB signaling, and enhanced proteasomal degradation in cancer-induced cachexia. Therapeutic potential of PARP activity inhibition deserves attention. © 2017 Wiley Periodicals, Inc.

  8. Reversal of sodium pump inhibitor induced vascular smooth muscle contraction with digibind. Stoichiometry and its implications.

    Science.gov (United States)

    Krep, H H; Graves, S W; Price, D A; Lazarus, M; Ensign, A; Soszynski, P A; Hollenberg, N K

    1996-01-01

    The possibility that a circulating sodium pump inhibitor contributes to the pathogenesis of volume-dependent hypertension via an action on vascular smooth muscle (VSM) is supported by multiple lines of investigation, but remains controversial. We had two goals in this study. The first was to compare the pattern of contractile response of rabbit aorta induced by two candidates, ouabain and a labile sodium pump inhibitor that we have identified in the peritoneal dialysate of volume-expanded hypertensive patients with chronic renal failure. Our second goal was to examine the ability of Digibind, a Fab fragment of antisera directed against digoxin, to reverse VSM contraction induced by both agents. Ouabain induced a concentration-dependent contraction, which was delayed in onset, was gradual, and reached a stable plateau after many hours. The labile sodium pump inhibitor induced a qualitatively similar series of responses. Digibind rapidly reversed the contractile responses to both sodium pump inhibitors, with a rate of relaxation that matched that induced by physical removal of the pump inhibitor from the bath. For ouabain, the Digibind:ouabain stoichiometry was highly predictable. When Digibind was present in a molar concentration equivalent to that of ouabain, or less, it had no effect. When the Digibind concentration was twice that of ouabain, complete relaxation occurred. Although the concentration:VSM response relationship for ouabain was steep, the concentration:effect interaction with Digibind was even more steep. The molar concentration of Digibind required to reverse the effects of the labile endogenous inhibitor from peritoneal dialysate was consistently lower than that for ouabain, which is compatible with either greater potency of the labile factor in VSM or greater affinity for Digibind. These findings are compatible with a role for one or more endogenous sodium pump inhibitors as the determinant of vascular smooth muscle tone in the volume

  9. BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Sergey Karakashev

    2017-12-01

    Full Text Available PARP inhibition is known to be an effective clinical strategy in BRCA mutant cancers, but PARP inhibition has not been applied to BRCA-proficient tumors. Here, we show the synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers due to mitotic catastrophe. Treatment of BRCA-proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell-cycle checkpoint regulator WEE1 and the DNA-damage response factor TOPBP1. Combining PARP inhibitor Olaparib with the BET inhibitor, we observed a synergistic increase in DNA damage and checkpoint defects, which allowed cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe. Moreover, JQ1 and Olaparib showed synergistic suppression of growth of BRCA-proficient cancer in vivo in a xenograft ovarian cancer mouse model. Our findings indicate that a combination of BET inhibitor and PARP inhibitor represents a potential therapeutic strategy for BRCA-proficient cancers.

  10. Computational models of stellar collapse and core-collapse supernovae

    International Nuclear Information System (INIS)

    Ott, Christian D; O'Connor, Evan; Schnetter, Erik; Loeffler, Frank; Burrows, Adam; Livne, Eli

    2009-01-01

    Core-collapse supernovae are among Nature's most energetic events. They mark the end of massive star evolution and pollute the interstellar medium with the life-enabling ashes of thermonuclear burning. Despite their importance for the evolution of galaxies and life in the universe, the details of the core-collapse supernova explosion mechanism remain in the dark and pose a daunting computational challenge. We outline the multi-dimensional, multi-scale, and multi-physics nature of the core-collapse supernova problem and discuss computational strategies and requirements for its solution. Specifically, we highlight the axisymmetric (2D) radiation-MHD code VULCAN/2D and present results obtained from the first full-2D angle-dependent neutrino radiation-hydrodynamics simulations of the post-core-bounce supernova evolution. We then go on to discuss the new code Zelmani which is based on the open-source HPC Cactus framework and provides a scalable AMR approach for 3D fully general-relativistic modeling of stellar collapse, core-collapse supernovae and black hole formation on current and future massively-parallel HPC systems. We show Zelmani's scaling properties to more than 16,000 compute cores and discuss first 3D general-relativistic core-collapse results.

  11. Computational models of stellar collapse and core-collapse supernovae

    Energy Technology Data Exchange (ETDEWEB)

    Ott, Christian D; O' Connor, Evan [TAPIR, Mailcode 350-17, California Institute of Technology, Pasadena, CA (United States); Schnetter, Erik; Loeffler, Frank [Center for Computation and Technology, Louisiana State University, Baton Rouge, LA (United States); Burrows, Adam [Department of Astrophysical Sciences, Princeton University, Princeton, NJ (United States); Livne, Eli, E-mail: cott@tapir.caltech.ed [Racah Institute of Physics, Hebrew University, Jerusalem (Israel)

    2009-07-01

    Core-collapse supernovae are among Nature's most energetic events. They mark the end of massive star evolution and pollute the interstellar medium with the life-enabling ashes of thermonuclear burning. Despite their importance for the evolution of galaxies and life in the universe, the details of the core-collapse supernova explosion mechanism remain in the dark and pose a daunting computational challenge. We outline the multi-dimensional, multi-scale, and multi-physics nature of the core-collapse supernova problem and discuss computational strategies and requirements for its solution. Specifically, we highlight the axisymmetric (2D) radiation-MHD code VULCAN/2D and present results obtained from the first full-2D angle-dependent neutrino radiation-hydrodynamics simulations of the post-core-bounce supernova evolution. We then go on to discuss the new code Zelmani which is based on the open-source HPC Cactus framework and provides a scalable AMR approach for 3D fully general-relativistic modeling of stellar collapse, core-collapse supernovae and black hole formation on current and future massively-parallel HPC systems. We show Zelmani's scaling properties to more than 16,000 compute cores and discuss first 3D general-relativistic core-collapse results.

  12. Tumor suppressive effect of PARP1 and FOXO3A in gastric cancers and its clinical implications

    Science.gov (United States)

    Yoon, Sarah; Jo, Yuna; Kwon, So Mee; Kim, Kyoung Min; Kwon, Keun Sang; Kim, Chan Young; Woo, Hyun Goo

    2015-01-01

    Poly (ADP-ribose) polymerase1 (PARP1) has been reported as a possible target for chemotherapy in many cancer types. However, its action mechanisms and clinical implications for gastric cancer survival are not yet fully understood. Here, we investigated the effect of PARP1 inhibition in the growth of gastric cancer cells. PARP1 inhibition by Olaparib or PARP1 siRNA could significantly attenuate growth and colony formation of gastric cancer cells, and which were mediated through induction of G2/M cell cycle arrest but not apoptosis. FOXO3A expression was induced by PARP1 inhibition, suggesting that FOXO3A might be one of downstream target of the PARP1 effect on gastric cancer cell growth. In addition, by performing tissue microarrays on the 166 cases of gastric cancer patients, we could observe that the expression status of PARP1 and FOXO3A were significantly associated with overall survival (OS) and relapse-free survival (RFS). Strikingly, combined expression status of PARP1 and FOXO3A showed better prediction for patient's clinical outcomes. The patient group with PARP1+/FOXO3A− expression had the worst prognosis while the patient group with PARP1−/FOXO3A+ had the most favorable prognosis (OS: P = 6.0 × 10−9, RFS: P = 2.2 × 10−8). In conclusion, we suggest that PARP1 and FOXO3A play critical roles in gastric cancer progression, and might have therapeutic and/or diagnostic potential in clinic. PMID:26540566

  13. Pathway-Enriched Gene Signature Associated with 53BP1 Response to PARP Inhibition in Triple-Negative Breast Cancer.

    Science.gov (United States)

    Hassan, Saima; Esch, Amanda; Liby, Tiera; Gray, Joe W; Heiser, Laura M

    2017-12-01

    Effective treatment of patients with triple-negative (ER-negative, PR-negative, HER2-negative) breast cancer remains a challenge. Although PARP inhibitors are being evaluated in clinical trials, biomarkers are needed to identify patients who will most benefit from anti-PARP therapy. We determined the responses of three PARP inhibitors (veliparib, olaparib, and talazoparib) in a panel of eight triple-negative breast cancer cell lines. Therapeutic responses and cellular phenotypes were elucidated using high-content imaging and quantitative immunofluorescence to assess markers of DNA damage (53BP1) and apoptosis (cleaved PARP). We determined the pharmacodynamic changes as percentage of cells positive for 53BP1, mean number of 53BP1 foci per cell, and percentage of cells positive for cleaved PARP. Inspired by traditional dose-response measures of cell viability, an EC 50 value was calculated for each cellular phenotype and each PARP inhibitor. The EC 50 values for both 53BP1 metrics strongly correlated with IC 50 values for each PARP inhibitor. Pathway enrichment analysis identified a set of DNA repair and cell cycle-associated genes that were associated with 53BP1 response following PARP inhibition. The overall accuracy of our 63 gene set in predicting response to olaparib in seven breast cancer patient-derived xenograft tumors was 86%. In triple-negative breast cancer patients who had not received anti-PARP therapy, the predicted response rate of our gene signature was 45%. These results indicate that 53BP1 is a biomarker of response to anti-PARP therapy in the laboratory, and our DNA damage response gene signature may be used to identify patients who are most likely to respond to PARP inhibition. Mol Cancer Ther; 16(12); 2892-901. ©2017 AACR . ©2017 American Association for Cancer Research.

  14. Structure/function analysis of PARP-1 in oxidative and nitrosative stress-induced monomeric ADPR formation.

    Directory of Open Access Journals (Sweden)

    Ben Buelow

    2009-07-01

    Full Text Available Poly adenosine diphosphate-ribose polymerase-1 (PARP-1 is a multifunctional enzyme that is involved in two major cellular responses to oxidative and nitrosative (O/N stress: detection and response to DNA damage via formation of protein-bound poly adenosine diphosphate-ribose (PAR, and formation of the soluble 2(nd messenger monomeric adenosine diphosphate-ribose (mADPR. Previous studies have delineated specific roles for several of PARP-1's structural domains in the context of its involvement in a DNA damage response. However, little is known about the relationship between the mechanisms through which PARP-1 participates in DNA damage detection/response and those involved in the generation of monomeric ADPR. To better understand the relationship between these events, we undertook a structure/function analysis of PARP-1 via reconstitution of PARP-1 deficient DT40 cells with PARP-1 variants deficient in catalysis, DNA binding, auto-PARylation, and PARP-1's BRCT protein interaction domain. Analysis of responses of the respective reconstituted cells to a model O/N stressor indicated that PARP-1 catalytic activity, DNA binding, and auto-PARylation are required for PARP-dependent mADPR formation, but that BRCT-mediated interactions are dispensable. As the BRCT domain is required for PARP-dependent recruitment of XRCC1 to sites of DNA damage, these results suggest that DNA repair and monomeric ADPR 2(nd messenger generation are parallel mechanisms through which PARP-1 modulates cellular responses to O/N stress.

  15. PARPi-FL - a Fluorescent PARP1 Inhibitor for Glioblastoma Imaging

    Directory of Open Access Journals (Sweden)

    Christopher P. Irwin

    2014-05-01

    Full Text Available New intravital optical imaging technologies have revolutionized our understanding of mammalian biology and continue to evolve rapidly. However, there are only a limited number of imaging probes available to date. In this study, we investigated in mouse models of glioblastoma whether a fluorescent small molecule inhibitor of the DNA repair enzyme PARP1, PARPi-FL, can be used as an imaging agent to detect glioblastomas in vivo. We demonstrated that PARPi-FL has appropriate biophysical properties, low toxicity at concentrations used for imaging, high stability in vivo, and accumulates selectively in glioblastomas due to high PARP1 expression. Importantly, subcutaneous and orthotopic glioblastoma xenografts were imaged with high contrast clearly defining tumor tissue from normal surrounding tissue. This research represents a step toward exploring and developing PARPi-FL as an optical intraoperative imaging agent for PARP1 in the clinic.

  16. Proteasome inhibitors induce apoptosis and reduce viral replication in primary effusion lymphoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Saji, Chiaki [Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812 (Japan); Higashi, Chizuka; Niinaka, Yasufumi [Faculty of Medicine, University of Yamanashi, Chuoh-shi 409-3898 (Japan); Yamada, Koji [Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812 (Japan); Noguchi, Kohji [Faculty of Pharmacy, Keio University, 1-5-30 Shiba-koen, Minato-ku, Tokyo 105-8512 (Japan); Fujimuro, Masahiro, E-mail: fuji2@mb.kyoto-phu.ac.jp [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan)

    2011-12-02

    Highlights: Black-Right-Pointing-Pointer Constitutive NF-{kappa}B signaling is essential for the survival and growth of PEL cells. Black-Right-Pointing-Pointer NF-{kappa}B signaling is upregulated by the proteasome-dependent degradation of I{kappa}B{alpha}. Black-Right-Pointing-Pointer Proteasome inhibitors suppress NF-{kappa}B signaling and induce apoptosis in PEL cells through stabilization of I{kappa}B{alpha}. Black-Right-Pointing-Pointer Proteasome inhibitors suppress viral replication in PEL cells during lytic KSHV infection. -- Abstract: Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by Kaposi's sarcoma-associated herpesvirus (KSHV). This study provides evidence that proteasomal activity is required for both survival of PEL cells stably harboring the KSHV genome and viral replication of KSHV. We evaluated the cytotoxic effects of proteasome inhibitors on PEL cells. The proteasome inhibitors MG132, lactacystin, and proteasome inhibitor I dramatically inhibited cell proliferation and induced apoptosis of PEL cells through the accumulation of p21 and p27. Furthermore, proteasome inhibitors induced the stabilization of NF-{kappa}B inhibitory molecule (I{kappa}B{alpha}) and suppressed the transcriptional activity of NF-{kappa}B in PEL cells. The NF-{kappa}B specific inhibitor BAY11-7082 also induced apoptosis in PEL cells. The constitutive activation of NF-{kappa}B signaling is essential for the survival and growth of B cell lymphoma cells, including PEL cells. NF-{kappa}B signaling is upregulated by proteasome-dependent degradation of I{kappa}B{alpha}. The suppression of NF-{kappa}B signaling by proteasome inhibitors may contribute to the induction of apoptosis in PEL cells. In addition, proteasome activity is required for KSHV replication in KSHV latently infected PEL cells. MG132 reduced the production of progeny virus from PEL cells at low concentrations, which do not affect PEL cell growth. These findings suggest that proteasome

  17. Human mass balance study and metabolite profiling of 14C-niraparib, a novel poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor, in patients with advanced cancer

    NARCIS (Netherlands)

    van Andel, Lotte; Zhang, Z; Lu, S.; Kansra, V; Agarwal, S.; Hughes, L.; Tibben, M.; Gebretensae, A.; Lucas, L.; Hillebrand, Michel J X; Rosing, H.; Schellens, J H M|info:eu-repo/dai/nl/073926272; Beijnen, J H|info:eu-repo/dai/nl/071919570

    2017-01-01

    Niraparib is an investigational oral, once daily, selective poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor. In the pivotal Phase 3 NOVA/ENGOT/OV16 study, niraparib met its primary endpoint of improving progression-free survival (PFS) for adult patients with recurrent, platinum sensitive,

  18. The collapsed football pla yer

    African Journals Online (AJOL)

    Football is the most popular sport in the world, played by over 265 ... FIFA Medical Officer and Honorary Part-time Lecturer, Wits Centre for Exercise Science and Sports Medicine, Johannesburg .... Management of a collapsed player does not.

  19. Gravity induced wave function collapse

    Science.gov (United States)

    Gasbarri, G.; Toroš, M.; Donadi, S.; Bassi, A.

    2017-11-01

    Starting from an idea of S. L. Adler [in Quantum Nonlocality and Reality: 50 Years of Bell's Theorem, edited by M. Bell and S. Gao (Cambridge University Press, Cambridge, England 2016)], we develop a novel model of gravity induced spontaneous wave function collapse. The collapse is driven by complex stochastic fluctuations of the spacetime metric. After deriving the fundamental equations, we prove the collapse and amplification mechanism, the two most important features of a consistent collapse model. Under reasonable simplifying assumptions, we constrain the strength ξ of the complex metric fluctuations with available experimental data. We show that ξ ≥10-26 in order for the model to guarantee classicality of macro-objects, and at the same time ξ ≤10-20 in order not to contradict experimental evidence. As a comparison, in the recent discovery of gravitational waves in the frequency range 35 to 250 Hz, the (real) metric fluctuations reach a peak of ξ ˜10-21.

  20. Collapse of large extra dimensions

    International Nuclear Information System (INIS)

    Geddes, James

    2002-01-01

    In models of spacetime that are the product of a four-dimensional spacetime with an 'extra' dimension, there is the possibility that the extra dimension will collapse to zero size, forming a singularity. We ask whether this collapse is likely to destroy the spacetime. We argue, by an appeal to the four-dimensional cosmic censorship conjecture, that--at least in the case when the extra dimension is homogeneous--such a collapse will lead to a singularity hidden within a black string. We also construct explicit initial data for a spacetime in which such a collapse is guaranteed to occur and show how the formation of a naked singularity is likely avoided

  1. PARP inhibitors protect against sex- and AAG-dependent alkylation-induced neural degeneration.

    Science.gov (United States)

    Allocca, Mariacarmela; Corrigan, Joshua J; Fake, Kimberly R; Calvo, Jennifer A; Samson, Leona D

    2017-09-15

    Alkylating agents are commonly used to treat cancer. Although base excision repair (BER) is a major pathway for repairing DNA alkylation damage, under certain conditions, the initiation of BER produces toxic repair intermediates that damage healthy tissues. The initiation of BER by the alkyladenine DNA glycosylase (AAG, a.k.a. MPG) can mediate alkylation-induced cytotoxicity in specific cells in the retina and cerebellum of male mice. Cytotoxicity in both wild-type and Aag -transgenic ( AagTg ) mice is abrogated in the absence of Poly(ADP-ribose) polymerase-1 (PARP1). Here, we tested whether PARP inhibitors can also prevent alkylation-induced retinal and cerebellar degeneration in male and female WT and AagTg mice. Importantly, we found that WT mice display sex-dependent alkylation-induced retinal damage (but not cerebellar damage), with WT males being more sensitive than females. Accordingly, estradiol treatment protects males against alkylation-induced retinal degeneration. In AagTg male and female mice, the alkylation-induced tissue damage in both the retina and cerebellum is exacerbated and the sex difference in the retina is abolished. PARP inhibitors, much like Parp1 gene deletion, protect against alkylation-induced AAG-dependent neuronal degeneration in WT and AagTg mice, regardless of the gender, but their efficacy in preventing alkylation-induced neuronal degeneration depends on PARP inhibitor characteristics and doses. The recent surge in the use of PARP inhibitors in combination with cancer chemotherapeutic alkylating agents might represent a powerful tool for obtaining increased therapeutic efficacy while avoiding the collateral effects of alkylating agents in healthy tissues.

  2. Edaravone abrogates LPS-induced behavioral anomalies, neuroinflammation and PARP-1.

    Science.gov (United States)

    Sriram, Chandra Shaker; Jangra, Ashok; Gurjar, Satendra Singh; Mohan, Pritam; Bezbaruah, Babul Kumar

    2016-02-01

    Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA nick-sensor enzyme that functions at the center of cellular stress response and affects the immune system at several key points, and thus modulates inflammatory diseases. Our previous study demonstrated that lipopolysaccharide (LPS)-induced depressive-like behavior in mice can be ameliorated by 3-aminobenzamide, which is a PARP-1 inhibitor. In the present study we've examined the effect of a free radical scavenger, edaravone pretreatment against LPS-induced anxiety and depressive-like behavior as well as various hippocampal biochemical parameters including PARP-1. Male Swiss albino mice were treated with edaravone (3 & 10mg/kgi.p.) once daily for 14days. On the 14th day 30min after edaravone treatment mice were challenged with LPS (1mg/kgi.p.). After 3h and 24h of LPS administration we've tested mice for anxiety and depressive-like behaviors respectively. Western blotting analysis of PARP-1 in hippocampus was carried out after 12h of LPS administration. Moreover, after 24h of LPS administration serum corticosterone, hippocampal BDNF, oxido-nitrosative stress and pro-inflammatory cytokines were estimated by ELISA. Results showed that pretreatment of edaravone (10mg/kg) ameliorates LPS-induced anxiety and depressive-like behavior. Western blotting analysis showed that LPS-induced anomalous expression of PARP-1 significantly reverses by the pretreatment of edaravone (10mg/kg). Biochemical analyses revealed that LPS significantly diminishes BDNF, increases pro-inflammatory cytokines and oxido-nitrosative stress in the hippocampus. However, pretreatment with edaravone (10mg/kg) prominently reversed all these biochemical alterations. Our study emphasized that edaravone pretreatment prevents LPS-induced anxiety and depressive-like behavior, mainly by impeding the inflammation, oxido-nitrosative stress and PARP-1 overexpression. Copyright © 2015. Published by Elsevier Inc.

  3. Sigma-2 ligands and PARP inhibitors synergistically trigger cell death in breast cancer cells

    International Nuclear Information System (INIS)

    McDonald, Elizabeth S.; Mankoff, Julia; Makvandi, Mehran; Chu, Wenhua; Chu, Yunxiang; Mach, Robert H.; Zeng, Chenbo

    2017-01-01

    The sigma-2 receptor is overexpressed in proliferating cells compared to quiescent cells and has been used as a target for imaging solid tumors by positron emission tomography. Recent work has suggested that the sigma-2 receptor may also be an effective therapeutic target for cancer therapy. Poly (ADP-ribose) polymerase (PARP) is a family of enzymes involved in DNA damage response. In this study, we looked for potential synergy of cytotoxicity between PARP inhibitors and sigma-2 receptor ligands in breast cancer cell lines. We showed that the PARP inhibitor, YUN3-6, sensitized mouse breast cancer cell line, EMT6, to sigma-2 receptor ligand (SV119, WC-26, and RHM-138) induced cell death determined by cell viability assay and colony forming assay. The PARP inhibitor, olaparib, sensitized tumor cells to a different sigma-2 receptor ligand SW43-induced apoptosis and cell death in human triple negative cell line, MDA-MB-231. Olaparib inhibited PARP activity and cell proliferation, and arrested cells in G2/M phase of the cell cycle in MDA-MB-231 cells. Subsequently cells became sensitized to SW43 induced cell death. In conclusion, the combination of sigma-2 receptor ligands and PARP inhibitors appears to hold promise for synergistically triggering cell death in certain types of breast cancer cells and merits further investigation. - Highlights: • PARPi, YUN3-6 and olaparib, and σ2 ligands, SV119 and SW43, were evaluated. • Mouse and human breast cancer cells, EMT6 and MDA-MB-231 respectively, were used. • YUN3-6 and SV119 synergistically triggered cell death in EMT6 cells. • Olaparib and SW43 additively triggered cell death in MDA-MB-231 cells. • Olaparib arrested cells in G2/M in MDA-MB-231 cells.

  4. Rucaparib: a novel PARP inhibitor for BRCA advanced ovarian cancer

    Directory of Open Access Journals (Sweden)

    Colombo I

    2018-03-01

    Full Text Available Ilaria Colombo, Stephanie Lheureux, Amit Manulal Oza Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada Abstract: Rucaparib is a potent small-molecule inhibitor of poly (ADP-ribose polymerase (PARP proteins (PARP-1, PARP-2 and PARP-3 that play an important role in repairing DNA damage and maintaining genomic stability. Tumors with mutations in BRCA1/2 or other homologous recombination deficiency (HRD genes are particularly sensitive to PARP inhibitors because of “synthetic lethality”, whereby a therapeutic agent can take advantage of an intrinsic weakness in DNA repair. Rucaparib has been investigated in several preclinical and clinical studies showing promising activity in BRCA-mutant and BRCA–wild-type epithelial ovarian cancers (EOCs. Dose-escalation Phase I studies have established the recommended Phase II dose to be 600 mg twice a day for oral rucaparib. Phase II and III studies have defined its role as treatment for BRCA-mutant recurrent high-grade EOC and as maintenance treatment for platinum-sensitive relapsed EOC following response to platinum-based chemotherapy. Genomic loss of heterozygosity has also been investigated as a potential signature of HRD and as a potential predictive biomarker of response. Treatment-induced adverse events (AEs have been observed in almost all patients treated with rucaparib, but mainly lower grade; with the most common being nausea, vomiting, asthenia/fatigue, anemia and transient transaminitis. The majority of AEs occurred early in treatment, were transient and have been easily managed with supportive treatment, dose interruption or discontinuation. This review will analyze the results of clinical trials investigating efficacy and safety of rucaparib in patients with ovarian cancer. Keywords: rucaparib, ovarian cancer, BRCA mutations, homologous recombination deficiency, maintenance treatment, PARP inhibitor

  5. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction

    DEFF Research Database (Denmark)

    Fang, Evandro Fei; Scheibye-Knudsen, Morten; Brace, Lear E

    2014-01-01

    with excessive cleavage of PINK1 and increased mitochondrial membrane potential. The mitochondrial abnormalities appear to be caused by decreased activation of the NAD(+)-SIRT1-PGC-1α axis triggered by hyperactivation of the DNA damage sensor PARP-1. This phenotype is rescued by PARP-1 inhibition...... or by supplementation with NAD(+) precursors that also rescue the lifespan defect in xpa-1 nematodes. Importantly, this pathogenesis appears common to ataxia-telangiectasia and Cockayne syndrome, two other DNA repair disorders with neurodegeneration, but absent in XPC, a DNA repair disorder without neurodegeneration...

  6. The Prognostic Value of BRCA1 and PARP Expression in Epithelial Ovarian Carcinoma

    DEFF Research Database (Denmark)

    Hjortkjær, Mette; Waldstrøm, Marianne; Jakobsen, Anders

    2017-01-01

    BRCA1/2 mutation status in epithelial ovarian cancer (EOC) presently relies on genetic testing which is resource consuming. Immunohistochemistry is cheap, fairly reproducible, and may identify gene product alterations due to both germline and somatic mutations and other defects along the BRCA gene...... tissue from 170 patients with EOC was stained immunohistochemically with BRCA1 and PARP antibodies. Semiquantitative analyses were performed to determine loss of, equivocal, and retained BRCA1 and high versus low PARP protein expression. These parameters were analyzed for relation with patient...

  7. A Gene Expression Profile of BRCAness That Predicts for Responsiveness to Platinum and PARP Inhibitors

    Science.gov (United States)

    2017-02-01

    affecting the function of Fanconi Anemia (FA) genes ( FANCA /B/C/D2/E/F/G/I/J/L/M, PALB2) or DNA damage response genes involved in HR 5 (ATM, ATR...Award Number: W81XWH-10-1-0585 TITLE: A Gene Expression Profile of BRCAness That Predicts for Responsiveness to Platinum and PARP Inhibitors...To) 15 July 2010 – 2 Nov.2016 4. TITLE AND SUBTITLE A Gene Expression Profile of BRCAness That Predicts for Responsiveness to Platinum and PARP

  8. Stress evolution during caldera collapse

    Science.gov (United States)

    Holohan, E. P.; Schöpfer, M. P. J.; Walsh, J. J.

    2015-07-01

    The mechanics of caldera collapse are subject of long-running debate. Particular uncertainties concern how stresses around a magma reservoir relate to fracturing as the reservoir roof collapses, and how roof collapse in turn impacts upon the reservoir. We used two-dimensional Distinct Element Method models to characterise the evolution of stress around a depleting sub-surface magma body during gravity-driven collapse of its roof. These models illustrate how principal stress orientations rotate during progressive deformation so that roof fracturing transitions from initial reverse faulting to later normal faulting. They also reveal four end-member stress paths to fracture, each corresponding to a particular location within the roof. Analysis of these paths indicates that fractures associated with ultimate roof failure initiate in compression (i.e. as shear fractures). We also report on how mechanical and geometric conditions in the roof affect pre-failure unloading and post-failure reloading of the reservoir. In particular, the models show how residual friction within a failed roof could, without friction reduction mechanisms or fluid-derived counter-effects, inhibit a return to a lithostatically equilibrated pressure in the magma reservoir. Many of these findings should be transferable to other gravity-driven collapse processes, such as sinkhole formation, mine collapse and subsidence above hydrocarbon reservoirs.

  9. Rev1 contributes to proper mitochondrial function via the PARP-NAD(+)-SIRT1-PGC1 alpha axis

    DEFF Research Database (Denmark)

    Fakouri, Nima Borhan; Durhuus, Jon Ambaek; Regnell, Christine Elisabeth

    2017-01-01

    (ADP) ribose polymerase 1 (PARP1) activity, low endogenous NAD+, low expression of SIRT1 and PGC1α and low adenosine monophosphate (AMP)-activated kinase (AMPK) activity. We conclude that replication stress via Rev1-deficiency contributes to metabolic stress caused by compromized mitochondrial function via...... the PARP-NAD+-SIRT1-PGC1α axis....

  10. The role of hnRPUL1 involved in DNA damage response is related to PARP1.

    Directory of Open Access Journals (Sweden)

    Zehui Hong

    Full Text Available Heterogeneous nuclear ribonucleoprotein U-like 1 (hnRPUL1 -also known as adenovirus early region 1B-associated proteins 5 (E1B-AP5 - plays a role in RNA metabolism. Recently, hnRPUL1 has also been shown to be involved in DNA damage response, but the function of hnRPUL1 in response to DNA damage remains unclear. Here, we have demonstrated that hnRPUL1 is associated with PARP1 and recruited to DNA double-strand breaks (DSBs sites in a PARP1-mediated poly (ADP-ribosyl ation dependent manner. In turn, hnRPUL1 knockdown enhances the recruitment of PARP1 to DSBs sites. Specifically, we showed that hnRPUL1 is also implicated in the transcriptional regulation of PARP1 gene. Thus, we propose hnRPUL1 as a new component related to PARP1 in DNA damage response and repair.

  11. Geophysical observations at cavity collapse

    Science.gov (United States)

    Jousset, Philippe; Bazargan-Sabet, Behrooz; Lebert, François; Bernardie, Séverine; Gourry, Jean-Christophe

    2010-05-01

    In Lorraine region (France) salt layers at about 200 meters depth are exploited by Solvay using solution mining methodology which consists in extracting the salt by dissolution, collapsing the cavern overburden during the exploitation phase and finally reclaiming the landscape by creating a water area. In this process, one of the main challenges for the exploiting company is to control the initial 120-m diameter collapse so as to minimize possible damages. In order to detect potential precursors and understand processes associated with such collapses, a wide series of monitoring techniques including micro seismics, broad-band seismology, hydro-acoustic, electromagnetism, gas probing, automatic leveling, continuous GPS, continuous gravity and borehole extensometry was set-up in the frame of an in-situ study carried out by the "Research Group for the Impact and Safety of Underground Works" (GISOS, France). Equipments were set-up well before the final collapse, giving a unique opportunity to analyze a great deal of information prior to and during the collapse process which has been successfully achieved on February the 13th, 2009 by controlling the cavity internal pressure. In this work, we present the results of data recorded by a network of 3 broadband seismometers, 2 accelerometers, 2 tilt-meters and a continuously gravity meter. We relate the variations of the brine pumping rate with the evolutions of the induced geophysical signals and finally we propose a first mechanical model for describing the controlled collapse. Beyond the studied case, extrapolation of the results obtained might contribute to the understanding of uncontrolled cavity collapses, such as pit-craters or calderas at volcanoes.

  12. ROS-mediated PARP activity undermines mitochondrial function after permeability transition pore opening during myocardial ischemia-reperfusion.

    Science.gov (United States)

    Schriewer, Jacqueline M; Peek, Clara Bien; Bass, Joseph; Schumacker, Paul T

    2013-04-18

    Ischemia-reperfusion (I/R) studies have implicated oxidant stress, the mitochondrial permeability transition pore (mPTP), and poly(ADP-ribose) polymerase (PARP) as contributing factors in myocardial cell death. However, the interdependence of these factors in the intact, blood-perfused heart is not known. We therefore wanted to determine whether oxidant stress, mPTP opening, and PARP activity contribute to the same death pathway after myocardial I/R. A murine left anterior descending coronary artery (LAD) occlusion (30 minutes) and release (1 to 4 hours) model was employed. Experimental groups included controls and antioxidant-treated, mPTP-inhibited, or PARP-inhibited hearts. Antioxidant treatment prevented oxidative damage, mPTP opening, ATP depletion, and PARP activity, placing oxidant stress as the proximal death trigger. Genetic deletion of cyclophilin D (CypD(-/-)) prevented loss of total NAD(+) and PARP activity, and mPTP-mediated loss of mitochondrial function. Control hearts showed progressive mitochondrial depolarization and loss of ATP from 1.5 to 4 hours of reperfusion, but not outer mitochondrial membrane rupture. Neither genetic deletion of PARP-1 nor its pharmacological inhibition prevented the initial mPTP-mediated depolarization or loss of ATP, but PARP ablation did allow mitochondrial recovery by 4 hours of reperfusion. These results indicate that oxidant stress, the mPTP, and PARP activity contribute to a single death pathway after I/R in the heart. PARP activation undermines cell survival by preventing mitochondrial recovery after mPTP opening early in reperfusion. This suggests that PARP-mediated prolongation of mitochondrial depolarization contributes significantly to cell death via an energetic crisis rather than by mitochondrial outer membrane rupture.

  13. PARP inhibitor rucaparib induces changes in NAD levels in cells and liver tissues as assessed by MRS.

    Science.gov (United States)

    Almeida, Gilberto S; Bawn, Carlo M; Galler, Martin; Wilson, Ian; Thomas, Huw D; Kyle, Suzanne; Curtin, Nicola J; Newell, David R; Maxwell, Ross J

    2017-09-01

    Poly(adenosine diphosphate ribose) polymerases (PARPs) are multifunctional proteins which play a role in many cellular processes. Namely, PARP1 and PARP2 have been shown to be involved in DNA repair, and therefore are valid targets in cancer treatment with PARP inhibitors, such as rucaparib, currently in clinical trials. Proton magnetic resonance spectroscopy ( 1 H-MRS) was used to study the impact of rucaparib in vitro and ex vivo in liver tissue from mice, via quantitative analysis of nicotinamide adenosine diphosphate (NAD + ) spectra, to assess the potential of MRS as a biomarker of the PARP inhibitor response. SW620 (colorectal) and A2780 (ovarian) cancer cell lines, and PARP1 wild-type (WT) and PARP1 knock-out (KO) mice, were treated with rucaparib, temozolomide (methylating agent) or a combination of both drugs. 1 H-MRS spectra were obtained from perchloric acid extracts of tumour cells and mouse liver. Both cell lines showed an increase in NAD + levels following PARP inhibitor treatment in comparison with temozolomide treatment. Liver extracts from PARP1 WT mice showed a significant increase in NAD + levels after rucaparib treatment compared with untreated mouse liver, and a significant decrease in NAD + levels in the temozolomide-treated group. The combination of rucaparib and temozolomide did not prevent the NAD + depletion caused by temozolomide treatment. The 1 H-MRS results show that NAD + levels can be used as a biomarker of PARP inhibitor and methylating agent treatments, and suggest that in vivo measurement of NAD + would be valuable. Copyright © 2017 John Wiley & Sons, Ltd.

  14. Aag DNA glycosylase promotes alkylation-induced tissue damage mediated by Parp1.

    Science.gov (United States)

    Calvo, Jennifer A; Moroski-Erkul, Catherine A; Lake, Annabelle; Eichinger, Lindsey W; Shah, Dharini; Jhun, Iny; Limsirichai, Prajit; Bronson, Roderick T; Christiani, David C; Meira, Lisiane B; Samson, Leona D

    2013-04-01

    Alkylating agents comprise a major class of front-line cancer chemotherapeutic compounds, and while these agents effectively kill tumor cells, they also damage healthy tissues. Although base excision repair (BER) is essential in repairing DNA alkylation damage, under certain conditions, initiation of BER can be detrimental. Here we illustrate that the alkyladenine DNA glycosylase (AAG) mediates alkylation-induced tissue damage and whole-animal lethality following exposure to alkylating agents. Aag-dependent tissue damage, as observed in cerebellar granule cells, splenocytes, thymocytes, bone marrow cells, pancreatic β-cells, and retinal photoreceptor cells, was detected in wild-type mice, exacerbated in Aag transgenic mice, and completely suppressed in Aag⁻/⁻ mice. Additional genetic experiments dissected the effects of modulating both BER and Parp1 on alkylation sensitivity in mice and determined that Aag acts upstream of Parp1 in alkylation-induced tissue damage; in fact, cytotoxicity in WT and Aag transgenic mice was abrogated in the absence of Parp1. These results provide in vivo evidence that Aag-initiated BER may play a critical role in determining the side-effects of alkylating agent chemotherapies and that Parp1 plays a crucial role in Aag-mediated tissue damage.

  15. Aag DNA glycosylase promotes alkylation-induced tissue damage mediated by Parp1.

    Directory of Open Access Journals (Sweden)

    Jennifer A Calvo

    2013-04-01

    Full Text Available Alkylating agents comprise a major class of front-line cancer chemotherapeutic compounds, and while these agents effectively kill tumor cells, they also damage healthy tissues. Although base excision repair (BER is essential in repairing DNA alkylation damage, under certain conditions, initiation of BER can be detrimental. Here we illustrate that the alkyladenine DNA glycosylase (AAG mediates alkylation-induced tissue damage and whole-animal lethality following exposure to alkylating agents. Aag-dependent tissue damage, as observed in cerebellar granule cells, splenocytes, thymocytes, bone marrow cells, pancreatic β-cells, and retinal photoreceptor cells, was detected in wild-type mice, exacerbated in Aag transgenic mice, and completely suppressed in Aag⁻/⁻ mice. Additional genetic experiments dissected the effects of modulating both BER and Parp1 on alkylation sensitivity in mice and determined that Aag acts upstream of Parp1 in alkylation-induced tissue damage; in fact, cytotoxicity in WT and Aag transgenic mice was abrogated in the absence of Parp1. These results provide in vivo evidence that Aag-initiated BER may play a critical role in determining the side-effects of alkylating agent chemotherapies and that Parp1 plays a crucial role in Aag-mediated tissue damage.

  16. Telomere shortening is associated to TRF1 and PARP1 overexpression in Duchenne muscular dystrophy.

    Science.gov (United States)

    Aguennouz, M'Hammed; Vita, Gian Luca; Messina, Sonia; Cama, Annamaria; Lanzano, Natalia; Ciranni, Annamaria; Rodolico, Carmelo; Di Giorgio, Rosa Maria; Vita, Giuseppe

    2011-12-01

    Telomere shortening is thought to contribute to premature senescence of satellite cells in Duchenne muscular dystrophy (DMD) muscle. Telomeric repeat binding factor-1 (TRF1) and poly (ADP-ribose) polymerase-1 (PARP1) are proteins known to modulate telomerase reverse transcriptase (TERT) activity, which controls telomere elongation. Here we show that an age-dependent telomere shortening occurs in DMD muscles and is associated to overexpression of mRNA and protein levels of TRF1 and PARP1. TERT expression and activity are detectable in normal control muscles and they slightly increase in DMD. This is the first demonstration of TRF1 and PARP1 overexpression in DMD muscles. They can be directly involved in replicative senescence of satellite cells and/or in the pathogenetic cascade through a cross-talk with oxidative stress and inflammatory response. Modulation of these events by TRF1 or PARP1 inhibition might represent a novel strategy for treatment of DMD and other muscular dystrophies. Copyright © 2010 Elsevier Inc. All rights reserved.

  17. RECOVERY OF amiRNA3-PARP1 TRANSGENIC MAIZE PLANTS ...

    African Journals Online (AJOL)

    ACSS

    Positive plant selectable marker genes are commonly used in plant transformation because they not only enhance the frequency of generation transgenic tissues but are considered biosafe, unlike antibiotic or herbicide resistance genes. In this study, the binary vector pNOV2819-ubiamiRNA3PARP1, harbouring the ...

  18. Effects of niacin restriction on sirtuin and PARP responses to photodamage in human skin.

    Directory of Open Access Journals (Sweden)

    Claudia A Benavente

    Full Text Available Sirtuins (SIRTs and poly(ADP-ribose polymerases (PARPs, NAD(+-dependent enzymes, link cellular energy status with responses to environmental stresses. Skin is frequently exposed to the DNA damaging effects of UV irradiation, a known etiology in skin cancer. Thus, understanding the defense mechanisms in response to UV, including the role of SIRTs and PARPs, may be important in developing skin cancer prevention strategies. Here, we report expression of the seven SIRT family members in human skin. SIRTs gene expressions are progressively upregulated in A431 epidermoid carcinoma cells (SIRTs1 and 3, actinic keratoses (SIRTs 2, 3, 5, 6, and 7 and squamous cell carcinoma (SIRTs 1-7. Photodamage induces dynamic changes in SIRT expression with upregulation of both SIRT1 and SIRT4 mRNAs. Specific losses of SIRT proteins occur early after photodamage followed by accumulation later, especially for SIRT4. Niacin restriction, which decreases NAD(+, the sirtuin substrate, results in an increase in acetylated proteins, upregulation of SIRTs 2 and 4, increased inherent DNA damage, alterations in SIRT responses to photodamage, abrogation of PARP activation following photodamage, and increased sensitivity to photodamage that is completely reversed by repleting niacin. These data support the hypothesis that SIRTs and PARPs play important roles in resistance to photodamage and identify specific SIRTs that respond to photodamage and may be targets for skin cancer prevention.

  19. BZLF1 Expression of EBV is correlated with PARP1 Regulation on Nasopharyngeal Carcinoma Tissues

    Directory of Open Access Journals (Sweden)

    Wahyu nur laili fajri, Ahmad Rofi'i, Fatchiyah Fatchiyah

    2013-04-01

    Full Text Available Nasopharyngeal carcinomas (NPC is a cancer that arises in the epithelial tissue that covers the inside of the nasopharyngeal mucosa and nasopharynx. Infected Epstein Barr Virus (EBV cell in a latent infection associated with the expression of nine latent proteins. Latent Membrane Protein 1 (LMP1 is one of latent proteins, and mayor EBV oncoprotein, with functions including virus growth, and to activate BamHI-Z Leftward Reading Frame 1 (BZLF1-EBV, which can inhibit p53 to induce apoptotic resistance, metastasis, and immune modulation. The body will respond to the expansion of EBV infection with activation of Poly(ADP-ribosePolymerase-1 (PARP1. The objective of study is to observe the expression of BZLF1 and determine PARP1 regulation in nasopharyngeal tissues. NPC-T2, NPC-T3 and polyp tissues slides are from Ulin Hospital, Banjarmasin. To characterize the necrotic cells such as pyknosis, karyorrhexsis, and karyolysis, histological slides were stained by HE that the necrotic cells measured by using a BX-53 microscope (Olympus with CellSens Standard software. Tissues slides were stained by using immunofluorohistochemistry with EBV-BZLF1 antibody-Mouse anti-EBV monoclonal antibody against Goat anti-mouse IgG-FITC and anti-PARP1 antibody (MC-10 against Goat anti-mouse IgG labeled Rhodamin. The expression intensities were measured by Confocal Laser Scanning Microscope (Olympus. The percentage number of necrotic cells and BZLF1 and PARP1 expression intensity were analyzed using SPSS 16.0 by one-way ANOVA test with α = 0.05, beside that we use correlate and regression analyze. The research showed that the amount of karryorhexis higher than pyknosis and karyolysis in both tissues. BZLF1 expression 1.79 INT/sel (in polyp, 2.76 INT/sel (NPC Type 2 and 4.36 INT/sel (NPC Type 3, PARP1 expression 2.25 INT/sel (in polyp, 3.31 INT/sel (NPC Type 2, dan 5.93 INT/sel (NPC Type 3.The high of intensity of expression BZLF1 induced the increasing of PARP1 expression

  20. Inhibitor-induced oxidation of the nucleus and cytosol in Arabidopsis thaliana: implications for organelle to nucleus retrograde signalling.

    Science.gov (United States)

    Karpinska, Barbara; Alomrani, Sarah Owdah; Foyer, Christine H

    2017-09-26

    Concepts of organelle-to-nucleus signalling pathways are largely based on genetic screens involving inhibitors of chloroplast and mitochondrial functions such as norflurazon, lincomycin (LINC), antimycin A (ANT) and salicylhydroxamic acid. These inhibitors favour enhanced cellular oxidation, but their precise effects on the cellular redox state are unknown. Using the in vivo reduction-oxidation (redox) reporter, roGFP2, inhibitor-induced changes in the glutathione redox potentials of the nuclei and cytosol were measured in Arabidopsis thaliana root, epidermal and stomatal guard cells, together with the expression of nuclear-encoded chloroplast and mitochondrial marker genes. All the chloroplast and mitochondrial inhibitors increased the degree of oxidation in the nuclei and cytosol. However, inhibitor-induced oxidation was less marked in stomatal guard cells than in epidermal or root cells. Moreover, LINC and ANT caused a greater oxidation of guard cell nuclei than the cytosol. Chloroplast and mitochondrial inhibitors significantly decreased the abundance of LHCA1 and LHCB1 transcripts. The levels of WHY1 , WHY3 and LEA5 transcripts were increased in the presence of inhibitors. Chloroplast inhibitors decreased AOXA1 mRNA levels, while mitochondrial inhibitors had the opposite effect. Inhibitors that are used to characterize retrograde signalling pathways therefore have similar general effects on cellular redox state and gene expression.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'. © 2017 The Authors.

  1. Magnetic tension and gravitational collapse

    International Nuclear Information System (INIS)

    Tsagas, Christos G

    2006-01-01

    The gravitational collapse of a magnetized medium is investigated by studying qualitatively the convergence of a timelike family of non-geodesic worldlines in the presence of a magnetic field. Focusing on the field's tension, we illustrate how the winding of the magnetic forcelines due to the fluid's rotation assists the collapse, while shear-like distortions in the distribution of the field's gradients resist contraction. We also show that the relativistic coupling between magnetism and geometry, together with the tension properties of the field, lead to a magneto-curvature stress that opposes the collapse. This tension stress grows stronger with increasing curvature distortion, which means that it could potentially dominate over the gravitational pull of the matter. If this happens, a converging family of non-geodesic worldlines can be prevented from focusing without violating the standard energy conditions

  2. Collapse of nonlinear Langmuir waves

    International Nuclear Information System (INIS)

    Malkin, V.M.

    1986-01-01

    The dispersion of sufficiently intensive Langmuir waves is determined by intrinsic (electron) nonlinearity. During Langmuir collapse the wave energy density required for the appearance of electron nonlinearity is attained, generally speaking, prior to the development of dissipative processes. Up to now, the effect of electron nonlinearity on the collapse dynamics and spectrum of strong Langmuir turbulence ( which may be very appreciable ) has not been studied extensively because of the difficulty of describing nonlinear Langmuir waves. In the present paper the positive determinacy of the electron nonlinear hamiltonian is proven, the increment of modulation instability of a nonlinear Langmuir wave cluster localized in a cavity is calculated, and the universal law of their collapse is found

  3. Understanding Core-Collapse Supernovae

    Science.gov (United States)

    Hix, W. R.; Lentz, E. J.; Baird, M.; Messer, O. E. B.; Mezzacappa, A.; Lee, C.-T.; Bruenn, S. W.; Blondin, J. M.; Marronetti, P.

    2010-03-01

    Our understanding of core-collapse supernovae continues to improve as better microphysics is included in increasingly realistic neutrino-radiationhydrodynamic simulations. Recent multi-dimensional models with spectral neutrino transport, which slowly develop successful explosions for a range of progenitors between 12 and 25 solar mass, have motivated changes in our understanding of the neutrino reheating mechanism. In a similar fashion, improvements in nuclear physics, most notably explorations of weak interactions on nuclei and the nuclear equation of state, continue to refine our understanding of how supernovae explode. Recent progresses on both the macroscopic and microscopic effects that affect core-collapse supernovae are discussed.

  4. Electron capture and stellar collapse

    International Nuclear Information System (INIS)

    Chung, K.C.

    1979-01-01

    In order, to investigate the function of electron capture in the phenomenon of pre-supernovae gravitacional collapse, an hydrodynamic caculation was carried out, coupling capture, decay and nuclear reaction equation system. A star simplified model (homogeneous model) was adopted using fermi ideal gas approximation for tthe sea of free electrons and neutrons. The non simplified treatment from quasi-static evolution to collapse is presented. The capture and beta decay rates, as wellas neutron delayed emission, were calculated by beta decay crude theory, while the other reaction rates were determined by usual theories. The preliminary results are presented. (M.C.K.) [pt

  5. Moduli destabilization via gravitational collapse

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, Dong-il [Sogang Univ., Seoul (Korea, Republic of). Center for Quantum Spacetime; Pedro, Francisco G. [Deutsches Elektronen-Synchrotron DESY, Hamburg (Germany). Theory Group; Yeom, Dong-han [Sogang Univ., Seoul (Korea, Republic of). Center for Quantum Spacetime; Kyoto Univ. (Japan). Yukawa Inst. for Theoretical Physics

    2013-06-15

    We examine the interplay between gravitational collapse and moduli stability in the context of black hole formation. We perform numerical simulations of the collapse using the double null formalism and show that the very dense regions one expects to find in the process of black hole formation are able to destabilize the volume modulus. We establish that the effects of the destabilization will be visible to an observer at infinity, opening up a window to a region in spacetime where standard model's couplings and masses can differ significantly from their background values.

  6. P2X7 receptor-mediated PARP1 activity regulates astroglial death in the rat hippocampus following status epilepticus

    Directory of Open Access Journals (Sweden)

    Ji Yang eKim

    2015-09-01

    Full Text Available Poly(ADP-ribose polymerase-1 (PARP1 plays a regulatory role in apoptosis, necrosis, and other cellular processes after injury. Recently, we revealed that PARP1 regulates the differential neuronal/astroglial responses to pilocarpine-induced status epilepticus (SE in the distinct brain regions. In addition, P2X7 receptor (P2X7R, an ATP-gated ion channel, activation accelerates astroglial apoptosis, while it attenuates clasmatodendrosis (lysosome-derived autophagic astroglial death. Therefore, we investigated whether P2X7R regulates regional specific astroglial PARP1 expression/activation in response to SE. In the present study, P2X7R activation exacerbates SE-induced astroglial apoptosis, while P2X7R inhibition attenuates it accompanied by increasing PARP1 activity in the molecular layer of the dentate gyrus following SE. In the CA1 region, however, P2X7R inhibition deteriorates SE-induced clasmatodendrosis via PARP1 activation following SE. Taken together, our findings suggest that P2X7R function may affect SE-induced astroglial death by regulating PARP1 activation/expression in regional-specific manner. Therefore, the selective modulation of P2X7R-mediated PARP1 functions may be a considerable strategy for controls in various types of cell deaths.

  7. PARP-1 and YY1 are important novel regulators of CXCL12 gene transcription in rat pancreatic beta cells.

    Directory of Open Access Journals (Sweden)

    Jelena Marković

    Full Text Available Despite significant progress, the molecular mechanisms responsible for pancreatic beta cell depletion and development of diabetes remain poorly defined. At present, there is no preventive measure against diabetes. The positive impact of CXCL12 expression on the pancreatic beta cell prosurvival phenotype initiated this study. Our aim was to provide novel insight into the regulation of rat CXCL12 gene (Cxcl12 transcription. The roles of poly(ADP-ribose polymerase-1 (PARP-1 and transcription factor Yin Yang 1 (YY1 in Cxcl12 transcription were studied by examining their in vitro and in vivo binding affinities for the Cxcl12 promoter in a pancreatic beta cell line by the electrophoretic mobility shift assay and chromatin immunoprecipitation. The regulatory activities of PARP-1 and YY1 were assessed in transfection experiments using a reporter vector with a Cxcl12 promoter sequence driving luciferase gene expression. Experimental evidence for PARP-1 and YY1 revealed their trans-acting potential, wherein PARP-1 displayed an inhibitory, and YY1 a strong activating effect on Cxcl12 transcription. Streptozotocin (STZ-induced general toxicity in pancreatic beta cells was followed by changes in Cxcl12 promoter regulation. PARP-1 binding to the Cxcl12 promoter during basal and in STZ-compromised conditions led us to conclude that PARP-1 regulates constitutive Cxcl12 expression. During the early stage of oxidative stress, YY1 exhibited less affinity toward the Cxcl12 promoter while PARP-1 displayed strong binding. These interactions were accompanied by Cxcl12 downregulation. In the later stages of oxidative stress and intensive pancreatic beta cell injury, YY1 was highly expressed and firmly bound to Cxcl12 promoter in contrast to PARP-1. These interactions resulted in higher Cxcl12 expression. The observed ability of PARP-1 to downregulate, and of YY1 to upregulate Cxcl12 promoter activity anticipates corresponding effects in the natural context where the

  8. Temperature evolution during dissipative collapse

    Indian Academy of Sciences (India)

    Abstract. We investigate the gravitational collapse of a radiating sphere evolving into a final static configuration described by the interior Schwarzschild solution. The temperature profiles of this par- ticular model are obtained within the framework of causal thermodynamics. The overall temperature evolution is enhanced by ...

  9. Numerical investigations of gravitational collapse

    Energy Technology Data Exchange (ETDEWEB)

    Csizmadia, Peter; Racz, Istvan, E-mail: iracz@rmki.kfki.h [RMKI, Budapest, Konkoly Thege Miklos ut 29-33, H-1121 (Hungary)

    2010-03-01

    Some properties of a new framework for simulating generic 4-dimensional spherically symmetric gravitating systems are discussed. The framework can be used to investigate spacetimes that undergo complete gravitational collapse. The analytic setup is chosen to ensure that our numerical method is capable to follow the time evolution everywhere, including the black hole region.

  10. On the Induced Gravitational Collapse

    Directory of Open Access Journals (Sweden)

    M. Becerra Laura

    2018-01-01

    Full Text Available The induced gravitational collapse (IGC paradigm has been applied to explain the long gamma ray burst (GRB associated with type Ic supernova, and recently the Xray flashes (XRFs. The progenitor is a binary systems of a carbon-oxygen core (CO and a neutron star (NS. The CO core collapses and undergoes a supernova explosion which triggers the hypercritical accretion onto the NS companion (up to 10-2 M⊙s-1. For the binary driven hypernova (BdHNe, the binary system is enough bound, the NS reach its critical mass, and collapse to a black hole (BH with a GRB emission characterized by an isotropic energy Eiso > 1052 erg. Otherwise, for binary systems with larger binary separations, the hypercritical accretion onto the NS is not sufficient to induced its gravitational collapse, a X-ray flash is produced with Eiso < 1052 erg. We’re going to focus in identify the binary parameters that limits the BdHNe systems with the XRFs systems.

  11. Transport in the Sawtooth Collapse

    International Nuclear Information System (INIS)

    Wesson, J.A.; Alper, B.; Edwards, A.W.; Gill, R.D.

    1997-01-01

    The rapid temperature collapse in tokamak sawtooth oscillations having incomplete magnetic reconnection is generally thought to occur through ergodization of the magnetic field. An experiment in JET using injected nickel indicates that this explanation is improbable. copyright 1997 The American Physical Society

  12. Thermal duality and gravitational collapse

    International Nuclear Information System (INIS)

    Hewitt, Michael

    2015-01-01

    Thermal duality is a relationship between the behaviour of heterotic string models of the E(8)×E(8) or SO(32) types at inversely related temperatures, a variant of T duality in the Euclidean regime. This duality would have consequences for the nature of the Hagedorn transition in these string models. We propose that the vacuum admits a family of deformations in situations where there are closed surfaces of constant area but high radial acceleration (a string regularized version of a Penrose trapped surface), such as would be formed in situations of extreme gravitational collapse. This would allow a radical resolution of the firewall paradox by allowing quantum effects to significantly modify the spacetime geometry around a collapsed object. A string bremsstrahlung process would convert the kinetic energy of infalling matter in extreme gravitational collapse to form a region of the deformed vacuum, which would be equivalent to forming a high temperature string phase. A heuristic criterion for the conversion process is presented, relating Newtonian gravity to the string tension, suggesting an upper limit to the strength of the gravitational interaction. This conversion process might have observable consequences for charged particles falling into a rotating collapsed object by producing high energy particles via a variant of the Penrose process. (paper)

  13. Collapse of simple harmonic universe

    International Nuclear Information System (INIS)

    Mithani, Audrey T.; Vilenkin, Alexander

    2012-01-01

    In a recent paper Graham et al constructed oscillating and static universe models which are stable with respect to all classical perturbations. Here we show that such universes are quantum-mechanically unstable and can collapse by quantum tunneling to zero radius. We also present instantons describing nucleation of oscillating and static universes from nothing

  14. Critical Effects in Gravitational Collapse

    International Nuclear Information System (INIS)

    Chmaj, T.

    2000-01-01

    The models of gravitational collapse of a dynamical system are investigated by means of the Einstein equations. Different types conjunctions to gravitational field are analyzed and it is shown that in the case of week scalar field (low energy density) the system evaluated to flat space while in the case of strong field (high energy density) to black hole

  15. Thermal conduction and gravitational collapse

    International Nuclear Information System (INIS)

    Herrera, L.; Jimenez, J.; Esculpi, M.

    1987-01-01

    A method used to study the evolution of radiating spheres, reported some years ago by Herrera, Jimenez, and Ruggeri, is extended to the case in which thermal conduction within the sphere is taken into account. By means of an explicit example it is shown that heat flow, if present, may play an important role, affecting the final outcome of collapse

  16. Activity-based assay for human mono-ADP-ribosyltransferases ARTD7/PARP15 and ARTD10/PARP10 aimed at screening and profiling inhibitors.

    Science.gov (United States)

    Venkannagari, Harikanth; Fallarero, Adyary; Feijs, Karla L H; Lüscher, Bernhard; Lehtiö, Lari

    2013-05-13

    Poly(ADP-ribose) polymerases (PARPs) or diphtheria toxin like ADP-ribosyl transferases (ARTDs) are enzymes that catalyze the covalent modification of proteins by attachment of ADP-ribose units to the target amino acid residues or to the growing chain of ADP-ribose. A subclass of the ARTD superfamily consists of mono-ADP-ribosyl transferases that are thought to modify themselves and other substrate proteins by covalently adding only a single ADP-ribose moiety to the target. Many of the ARTD enzymes are either established or potential drug targets and a functional activity assay for them will be a valuable tool to identify selective inhibitors for each enzyme. Existing assays are not directly applicable for screening of inhibitors due to the different nature of the reaction and different target molecules. We modified and applied a fluorescence-based assay previously described for PARP1/ARTD1 and tankyrase/ARTD5 for screening of PARP10/ARTD10 and PARP15/ARTD7 inhibitors. The assay measures the amount of NAD(+) present after chemically converting it to a fluorescent analog. We demonstrate that by using an excess of a recombinant acceptor protein the performance of the activity-based assay is excellent for screening of compound libraries. The assay is homogenous and cost effective, making it possible to test relatively large compound libraries. This method can be used to screen inhibitors of mono-ARTDs and profile inhibitors of the enzyme class. The assay was optimized for ARTD10 and ARTD7, but it can be directly applied to other mono-ARTDs of the ARTD superfamily. Profiling of known ARTD inhibitors against ARTD10 and ARTD7 in a validatory screening identified the best inhibitors with submicromolar potencies. Only few of the tested ARTD inhibitors were potent, implicating that there is a need to screen new compound scaffolds. This is needed to create small molecules that could serve as biological probes and potential starting points for drug discovery projects against

  17. Studies of the expression of human poly(ADP-ribose) polymerase-1 in Saccharomyces cerevisiae and identification of PARP-1 substrates by yeast proteome microarray screening.

    Science.gov (United States)

    Tao, Zhihua; Gao, Peng; Liu, Hung-Wen

    2009-12-15

    Poly(ADP-ribosyl)ation of various nuclear proteins catalyzed by a family of NAD(+)-dependent enzymes, poly(ADP-ribose) polymerases (PARPs), is an important posttranslational modification reaction. PARP activity has been demonstrated in all types of eukaryotic cells with the exception of yeast, in which the expression of human PARP-1 was shown to lead to retarded cell growth. We investigated the yeast growth inhibition caused by human PARP-1 expression in Saccharomyces cerevisiae. Flow cytometry analysis reveals that PARP-1-expressing yeast cells accumulate in the G(2)/M stage of the cell cycle. Confocal microscopy analysis shows that human PARP-1 is distributed throughout the nucleus of yeast cells but is enriched in the nucleolus. Utilizing yeast proteome microarray screening, we identified 33 putative PARP-1 substrates, six of which are known to be involved in ribosome biogenesis. The poly(ADP-ribosyl)ation of three of these yeast proteins, together with two human homologues, was confirmed by an in vitro PARP-1 assay. Finally, a polysome profile analysis using sucrose gradient ultracentrifugation demonstrated that the ribosome levels in yeast cells expressing PARP-1 are lower than those in control yeast cells. Overall, our data suggest that human PARP-1 may affect ribosome biogenesis by modifying certain nucleolar proteins in yeast. The artificial PARP-1 pathway in yeast may be used as a simple platform to identify substrates and verify function of this important enzyme.

  18. Fem1b, a proapoptotic protein, mediates proteasome inhibitor-induced apoptosis of human colon cancer cells.

    Science.gov (United States)

    Subauste, M Cecilia; Sansom, Owen J; Porecha, Nehal; Raich, Natacha; Du, Liqin; Maher, Joseph F

    2010-02-01

    In the treatment of colon cancer, the development of resistance to apoptosis is a major factor in resistance to therapy. New molecular approaches to overcome apoptosis resistance, such as selectively upregulating proapoptotic proteins, are needed in colon cancer therapy. In a mouse model with inactivation of the adenomatous polyposis coli (Apc) tumor suppressor gene, reflecting the pathogenesis of most human colon cancers, the gene encoding feminization-1 homolog b (Fem1b) is upregulated in intestinal epithelium following Apc inactivation. Fem1b is a proapoptotic protein that interacts with apoptosis-inducing proteins Fas, tumor necrosis factor receptor-1 (TNFR1), and apoptotic protease activating factor-1 (Apaf-1). Increasing Fem1b expression induces apoptosis of cancer cells, but effects on colon cancer cells have not been reported. Fem1b is a homolog of feminization-1 (FEM-1), a protein in Caenorhabditis elegans that is regulated by proteasomal degradation, but whether Fem1b is likewise regulated by proteasomal degradation is unknown. Herein, we found that Fem1b protein is expressed in primary human colon cancer specimens, and in malignant SW620, HCT-116, and DLD-1 colon cancer cells. Increasing Fem1b expression, by transfection of a Fem1b expression construct, induced apoptosis of these cells. We found that proteasome inhibitor treatment of SW620, HCT-116, and DLD-1 cells caused upregulation of Fem1b protein levels, associated with induction of apoptosis. Blockade of Fem1b upregulation with morpholino antisense oligonucleotide suppressed the proteasome inhibitor-induced apoptosis of these cells. In conclusion, the proapoptotic protein Fem1b is downregulated by the proteasome in malignant colon cancer cells and mediates proteasome inhibitor-induced apoptosis of these cells. Therefore, Fem1b could represent a novel molecular target to overcome apoptosis resistance in therapy of colon cancer.

  19. Upregulation of PEDF expression by PARP inhibition contributes to the decrease in hyperglycemia-induced apoptosis in HUVECs

    International Nuclear Information System (INIS)

    Chen Haibing; Jia Weiping; Xu Xun; Fan Ying; Zhu Dongqing; Wu Haixiang; Xie Zhenggao; Zheng Zhi

    2008-01-01

    Poly(ADP-ribose)polymerase (PARP) inhibitors decrease angiogenesis through reducing vascular endothelium growth factor (VEGF) induced proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). In contrast to VEGF, pigment epithelium-derived factor (PEDF) has been demonstrated to act as a strong endogenous inhibitor of angiogenesis. Here, we show that PARP inhibition with a specific inhibitor PJ-34 or specific PARP antisense oligonucleotide upregulates hyperglycemia-induced PEDF expression in HUVECs in a dose-dependent manner. This results in the retard of activation of p38 MAP kinase and the concomitant decrease in cell apoptosis. These results give the first direct demonstration that PEDF might represent a target for PARP inhibition treatment and the effects of PEDF on endothelial cells growth are context dependent

  20. The safety of antiangiogenic agents and PARP inhibitors in platinum-sensitive recurrent ovarian cancer.

    Science.gov (United States)

    Lorusso, Domenica; Fontanella, Caterina; Maltese, Giuseppa; Lepori, Stefano; Tripodi, Elisa; Bogani, Giorgio; Raspagliesi, Francesco

    2017-06-01

    Recurrence is a common event in endothelial ovarian cancer (EOC) patients, and the choice of the most appropriate treatment is driven by the platinum-free interval, molecular characteristics of the disease such as BRCA mutational status, previous treatments and toxicity. Areas covered: This review focuses on the main hematologic and non-hematologic toxicities correlated with the use of licensed antiangiogenic agents and PARP inhibitors in recurrent platinum-sensitive EOC, providing recommendations for their management. Expert opinion: The clinical research over the next years will be focused on a more precise characterization of molecular pathways underlying tumorigenesis of the five ovarian tumors, to improve the decision-making process in these rare diseases. For this purpose, new study designs and international collaborations will become mandatory. Immunotherapy, antiangiogenic agents and PARP inhibitors will be combined to build a treatment strategy algorithm which will allow patients to receive all the available treatment option, in the more appropriate sequence.

  1. Radiosensitization by PARP inhibition to proton beam irradiation in cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Hirai, Takahisa [Department of Radiation Oncology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo (Japan); Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan); Saito, Soichiro; Fujimori, Hiroaki [Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan); Matsushita, Keiichiro; Nishio, Teiji [Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima-shi, Hiroshima (Japan); Okayasu, Ryuichi [International Open Laboratory, National Institute of Radiological Science, Chiba-shi, Chiba (Japan); Masutani, Mitsuko, E-mail: mmasutan@nagasaki-u.ac.jp [Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan); Department of Frontier Life Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (Japan)

    2016-09-09

    The poly(ADP-ribose) polymerase (PARP)-1 regulates DNA damage responses and promotes base excision repair. PARP inhibitors have been shown to enhance the cytotoxicity of ionizing radiation in various cancer cells and animal models. We have demonstrated that the PARP inhibitor (PARPi) AZD2281 is also an effective radiosensitizer for carbon-ion radiation; thus, we speculated that the PARPi could be applied to a wide therapeutic range of linear energy transfer (LET) radiation as a radiosensitizer. Institutes for biological experiments using proton beam are limited worldwide. This study was performed as a cooperative research at heavy ion medical accelerator in Chiba (HIMAC) in National Institute of Radiological Sciences. HIMAC can generate various ion beams; this enabled us to compare the radiosensitization effect of the PARPi on cells subjected to proton and carbon-ion beams from the same beam line. After physical optimization of proton beam irradiation, the radiosensitization effect of the PARPi was assessed in the human lung cancer cell line, A549, and the pancreatic cancer cell line, MIA PaCa-2. The effect of the PARPi, AZD2281, on radiosensitization to Bragg peak was more significant than that to entrance region. The PARPi increased the number of phosphorylated H2AX (γ-H2AX) foci and enhanced G2/M arrest after proton beam irradiation. This result supports our hypothesis that a PARPi could be applied to a wide therapeutic range of LET radiation by blocking the DNA repair response. - Highlights: • Effective radiosensitizers for particle radiation therapy have not been reported. • PARP inhibitor treatment radiosensitized after proton beam irradiation. • The sensitization at Bragg peak was greater than that at entrance region. • DSB induction and G2/M arrest is involved in the sensitization mechanism.

  2. Modelling of cladding creep collapse

    International Nuclear Information System (INIS)

    Koundy, V.; Forgeron, T.; Hivroz, J.

    1993-01-01

    The effects of the initial ovality and pressure level on the collapse time of Zircaloy-4 tubing subjected to uniform external pressure were examined experimentally and analytically. Experiments were performed on end closed tubes with two metallurgical states: stress relieved and recrystallized. Numerical simulations were accomplished with a specific computer program based on an analytical approach and the calculated results were compared with the experimental ones. As a comparison, the finite element method is also partially examined in this analysis. Numerical collapse times are in good agreement with regard to experimental results in the case of stress relieved structure. They seem to be too conservative in the case of a recrystallized metallurgical state and the use of the anisotropic option ameliorates numerical results. Sensibility of numerical solutions to the formulation of primary creep laws are presented

  3. Collapsed Thunderstorm, Southwest Pacific Ocean

    Science.gov (United States)

    1992-01-01

    This collapsed thunderstorm was observed over the open ocean (9.0N, 120.0E) between the Philippine island of Mindoro and Borneo, Malaysia. The cleared area in the center is the result of the clouds being driven from there by the sudden rush of katabatic air spreading downward and outward from the dying thunderstorm. Around the edges of the downdrafted air, new though smaller storms are developing. The two small coral atolls are the Tubbataha Reefs.

  4. Critical behavior of collapsing surfaces

    DEFF Research Database (Denmark)

    Olsen, Kasper; Sourdis, C.

    2009-01-01

    We consider the mean curvature evolution of rotationally symmetric surfaces. Using numerical methods, we detect critical behavior at the threshold of singularity formation resembling that of gravitational collapse. In particular, the mean curvature simulation of a one-parameter family of initial...... data reveals the existence of a critical initial surface that develops a degenerate neckpinch. The limiting flow of the type II singularity is accurately modeled by the rotationally symmetric translating soliton....

  5. Soliton collapse during ionospheric heating

    International Nuclear Information System (INIS)

    Sheerin, J.P.; Nicholson, D.R.; Payne, G.L.; Duncan, L.M.

    1984-01-01

    We present analytical and numerical work which indicates that during ionospheric heating with high-powered hf radio waves, the oscillating two-stream instability may dominate the parametric decay instability. The oscillating two-stream instability saturates nonlinearly through the formation of solitons which undergo a collisionally damped collapse. Using the heater and radar facilities at Arecibo Observatory, we have investigated this phenomenon experimentally. Recent results from our theoretical and experimental investigations are presented

  6. Targeting EGFR induced oxidative stress by PARP1 inhibition in glioblastoma therapy.

    Science.gov (United States)

    Nitta, Masayuki; Kozono, David; Kennedy, Richard; Stommel, Jayne; Ng, Kimberly; Zinn, Pascal O; Kushwaha, Deepa; Kesari, Santosh; Inda, Maria-del-Mar; Wykosky, Jill; Furnari, Frank; Hoadley, Katherine A; Chin, Lynda; DePinho, Ronald A; Cavenee, Webster K; D'Andrea, Alan; Chen, Clark C

    2010-05-24

    Despite the critical role of Epidermal Growth Factor Receptor (EGFR) in glioblastoma pathogenesis, EGFR targeted therapies have achieved limited clinical efficacy. Here we propose an alternate therapeutic strategy based on the conceptual framework of non-oncogene addiction. A directed RNAi screen revealed that glioblastoma cells over-expressing EGFRvIII, an oncogenic variant of EGFR, become hyper-dependent on a variety of DNA repair genes. Among these, there was an enrichment of Base Excision Repair (BER) genes required for the repair of Reactive Oxygen Species (ROS)-induced DNA damage, including poly-ADP ribose polymerase 1 (PARP1). Subsequent studies revealed that EGFRvIII over-expression in glioblastoma cells caused increased levels of ROS, DNA strand break accumulation, and genome instability. In a panel of primary glioblastoma lines, sensitivity to PARP1 inhibition correlated with the levels of EGFR activation and oxidative stress. Gene expression analysis indicated that reduced expression of BER genes in glioblastomas with high EGFR expression correlated with improved patient survival. These observations suggest that oxidative stress secondary to EGFR hyper-activation necessitates increased cellular reliance on PARP1 mediated BER, and offer critical insights into clinical trial design.

  7. Targeting EGFR induced oxidative stress by PARP1 inhibition in glioblastoma therapy.

    Directory of Open Access Journals (Sweden)

    Masayuki Nitta

    Full Text Available Despite the critical role of Epidermal Growth Factor Receptor (EGFR in glioblastoma pathogenesis, EGFR targeted therapies have achieved limited clinical efficacy. Here we propose an alternate therapeutic strategy based on the conceptual framework of non-oncogene addiction. A directed RNAi screen revealed that glioblastoma cells over-expressing EGFRvIII, an oncogenic variant of EGFR, become hyper-dependent on a variety of DNA repair genes. Among these, there was an enrichment of Base Excision Repair (BER genes required for the repair of Reactive Oxygen Species (ROS-induced DNA damage, including poly-ADP ribose polymerase 1 (PARP1. Subsequent studies revealed that EGFRvIII over-expression in glioblastoma cells caused increased levels of ROS, DNA strand break accumulation, and genome instability. In a panel of primary glioblastoma lines, sensitivity to PARP1 inhibition correlated with the levels of EGFR activation and oxidative stress. Gene expression analysis indicated that reduced expression of BER genes in glioblastomas with high EGFR expression correlated with improved patient survival. These observations suggest that oxidative stress secondary to EGFR hyper-activation necessitates increased cellular reliance on PARP1 mediated BER, and offer critical insights into clinical trial design.

  8. ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib.

    Science.gov (United States)

    Wang, Chen; Jette, Nicholas; Moussienko, Daniel; Bebb, D Gwyn; Lees-Miller, Susan P

    2017-04-01

    The ataxia telangiectasia mutated (ATM) protein kinase plays a central role in the cellular response to DNA damage. Loss or inactivation of both copies of the ATM gene (ATM) leads to ataxia telangiectasia, a devastating childhood condition characterized by neurodegeneration, immune deficiencies, and cancer predisposition. ATM is also absent in approximately 40% of mantle cell lymphomas (MCLs), and we previously showed that MCL cell lines with loss of ATM are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Next-generation sequencing of patient tumors has revealed that ATM is altered in many human cancers including colorectal, lung, prostate, and breast. Here, we show that the colorectal cancer cell line SK-CO-1 lacks detectable ATM protein expression and is sensitive to the PARP inhibitor olaparib. Similarly, HCT116 colorectal cancer cells with shRNA depletion of ATM are sensitive to olaparib, and depletion of p53 enhances this sensitivity. Moreover, HCT116 cells are sensitive to olaparib in combination with the ATM inhibitor KU55933, and sensitivity is enhanced by deletion of p53. Together our studies suggest that PARP inhibitors may have potential for treating colorectal cancer with ATM dysfunction and/or colorectal cancer with mutation of p53 when combined with an ATM kinase inhibitor. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Collapse models and perceptual processes

    International Nuclear Information System (INIS)

    Ghirardi, Gian Carlo; Romano, Raffaele

    2014-01-01

    Theories including a collapse mechanism have been presented various years ago. They are based on a modification of standard quantum mechanics in which nonlinear and stochastic terms are added to the evolution equation. Their principal merits derive from the fact that they are mathematically precise schemes accounting, on the basis of a unique universal dynamical principle, both for the quantum behavior of microscopic systems as well as for the reduction associated to measurement processes and for the classical behavior of macroscopic objects. Since such theories qualify themselves not as new interpretations but as modifications of the standard theory they can be, in principle, tested against quantum mechanics. Recently, various investigations identifying possible crucial test have been discussed. In spite of the extreme difficulty to perform such tests it seems that recent technological developments allow at least to put precise limits on the parameters characterizing the modifications of the evolution equation. Here we will simply mention some of the recent investigations in this direction, while we will mainly concentrate our attention to the way in which collapse theories account for definite perceptual process. The differences between the case of reductions induced by perceptions and those related to measurement procedures by means of standard macroscopic devices will be discussed. On this basis, we suggest a precise experimental test of collapse theories involving conscious observers. We make plausible, by discussing in detail a toy model, that the modified dynamics can give rise to quite small but systematic errors in the visual perceptual process.

  10. Feedback-regulated poly(ADP-ribosyl)ation by PARP-1 is required for rapid response to DNA damage in living cells

    Science.gov (United States)

    Mortusewicz, Oliver; Amé, Jean-Christophe; Leonhardt, Heinrich

    2007-01-01

    Genome integrity is constantly threatened by DNA lesions arising from numerous exogenous and endogenous sources. Survival depends on immediate recognition of these lesions and rapid recruitment of repair factors. Using laser microirradiation and live cell microscopy we found that the DNA-damage dependent poly(ADP-ribose) polymerases (PARP) PARP-1 and PARP-2 are recruited to DNA damage sites, however, with different kinetics and roles. With specific PARP inhibitors and mutations, we could show that the initial recruitment of PARP-1 is mediated by the DNA-binding domain. PARP-1 activation and localized poly(ADP-ribose) synthesis then generates binding sites for a second wave of PARP-1 recruitment and for the rapid accumulation of the loading platform XRCC1 at repair sites. Further PARP-1 poly(ADP-ribosyl)ation eventually initiates the release of PARP-1. We conclude that feedback regulated recruitment of PARP-1 and concomitant local poly(ADP-ribosyl)ation at DNA lesions amplifies a signal for rapid recruitment of repair factors enabling efficient restoration of genome integrity. PMID:17982172

  11. Importin alpha binding and nuclear localization of PARP-2 is dependent on lysine 36, which is located within a predicted classical NLS

    Directory of Open Access Journals (Sweden)

    Valovka Taras

    2008-07-01

    Full Text Available Abstract Background The enzymes responsible for the synthesis of poly-ADP-ribose are named poly-ADP-ribose polymerases (PARP. PARP-2 is a nuclear protein, which regulates a variety of cellular functions that are mainly controlled by protein-protein interactions. A previously described non-conventional bipartite nuclear localization sequence (NLS lies in the amino-terminal DNA binding domain of PARP-2 between amino acids 1–69; however, this targeting sequence has not been experimentally examined or validated. Results Using a site-directed mutagenesis approach, we found that lysines 19 and 20, located within a previously described bipartite NLS, are not required for nuclear localization of PARP-2. In contrast, lysine 36, which is located within a predicted classical monopartite NLS, was required for PARP-2 nuclear localization. While wild type PARP-2 interacted with importin α3 and to a very weak extent with importin α1 and importin α5, the mutant PARP-2 (K36R did not interact with importin α3, providing a molecular explanation why PARP-2 (K36R is not targeted to the nucleus. Conclusion Our results provide strong evidence that lysine 36 of PARP-2 is a critical residue for proper nuclear targeting of PARP-2 and consequently for the execution of its biological functions.

  12. Collapse Mechanisms Of Masonry Structures

    International Nuclear Information System (INIS)

    Zuccaro, G.; Rauci, M.

    2008-01-01

    The paper outlines a possible approach to typology recognition, safety check analyses and/or damage measuring taking advantage by a multimedia tool (MEDEA), tracing a guided procedure useful for seismic safety check evaluation and post event macroseismic assessment. A list of the possible collapse mechanisms observed in the post event surveys on masonry structures and a complete abacus of the damages are provided in MEDEA. In this tool a possible combination between a set of damage typologies and each collapse mechanism is supplied in order to improve the homogeneity of the damages interpretation. On the other hand recent researches of one of the author have selected a number of possible typological vulnerability factors of masonry buildings, these are listed in the paper and combined with potential collapse mechanisms to be activated under seismic excitation. The procedure takes place from simple structural behavior models, derived from the Umbria-Marche earthquake observations, and tested after the San Giuliano di Puglia event; it provides the basis either for safety check analyses of the existing buildings or for post-event structural safety assessment and economic damage evaluation. In the paper taking advantage of MEDEA mechanisms analysis, mainly developed for the post event safety check surveyors training, a simple logic path is traced in order to approach the evaluation of the masonry building safety check. The procedure starts from the identification of the typological vulnerability factors to derive the potential collapse mechanisms and their collapse multipliers and finally addresses the simplest and cheapest strengthening techniques to reduce the original vulnerability. The procedure has been introduced in the Guide Lines of the Regione Campania for the professionals in charge of the safety check analyses and the buildings strengthening in application of the national mitigation campaign introduced by the Ordinance of the Central Government n. 3362

  13. Functional characterisation of an Arabidopsis gene strongly induced by ionising radiation: the gene coding the poly(ADP-ribose)polymerase-1 (AthPARP-1)

    International Nuclear Information System (INIS)

    Doucet-Chabeaud, G.

    2000-01-01

    Arabidopsis thaliana, the model-system in plant genetics, has been used to study the responses to DNA damage, experimentally introduced by γ-irradiation. We have characterised a radiation-induced gene coding a 111 kDa protein, AthPARP-1, homologous to the human poly(ADP-ribose)polymerase-1 (hPARP-1). As hPARP-1 is composed by three functional domain with characteristic motifs, AthPARP-1 binds to DNA bearing single-strand breaks and shows DNA damage-dependent poly(ADP-ribosyl)ation. The preferential expression of AthPARP-1 in mitotically active tissues is in agreement with a potential role in the maintenance of genome integrity during DNA replication, as proposed for its human counterpart. Transcriptional gene activation by ionising radiation of AthPARP-1 and AthPARP-2 genes is to date plant specific activation. Our expression analyses after exposure to various stress indicate that 1) AthPARP-1 and AthPARP-2 play an important role in the response to DNA lesions, particularly they are activated by genotoxic agents implicating the BER DNA repair pathway 2) AthPARP-2 gene seems to play an additional role in the signal transduction induced by oxidative stress 3) the observed expression profile of AthPARP-1 is in favour of the regulation of AthPARP-1 gene expression at the level of transcription and translation. This mode of regulation of AthPARP-1 protein biosynthesis, clearly distinct from that observed in animals, needs the implication of a so far unidentified transcription factor that is activated by the presence of DNA lesions. The major outcome of this work resides in the isolation and characterisation of such new transcription factor, which will provide new insight on the regulation of plant gene expression by genotoxic stress. (author) [fr

  14. HIERARCHICAL GRAVITATIONAL FRAGMENTATION. I. COLLAPSING CORES WITHIN COLLAPSING CLOUDS

    Energy Technology Data Exchange (ETDEWEB)

    Naranjo-Romero, Raúl; Vázquez-Semadeni, Enrique; Loughnane, Robert M. [Instituto de Radioastronomía y Astrofísica, Universidad Nacional Autónoma de México, Apdo. Postal 3-72, Morelia, Michoacán, 58089, México (Mexico)

    2015-11-20

    We investigate the Hierarchical Gravitational Fragmentation scenario through numerical simulations of the prestellar stages of the collapse of a marginally gravitationally unstable isothermal sphere immersed in a strongly gravitationally unstable, uniform background medium. The core developes a Bonnor–Ebert (BE)-like density profile, while at the time of singularity (the protostar) formation the envelope approaches a singular-isothermal-sphere (SIS)-like r{sup −2} density profile. However, these structures are never hydrostatic. In this case, the central flat region is characterized by an infall speed, while the envelope is characterized by a uniform speed. This implies that the hydrostatic SIS initial condition leading to Shu's classical inside-out solution is not expected to occur, and therefore neither should the inside-out solution. Instead, the solution collapses from the outside-in, naturally explaining the observation of extended infall velocities. The core, defined by the radius at which it merges with the background, has a time-variable mass, and evolves along the locus of the ensemble of observed prestellar cores in a plot of M/M{sub BE} versus M, where M is the core's mass and M{sub BE} is the critical BE mass, spanning the range from the “stable” to the “unstable” regimes, even though it is collapsing at all times. We conclude that the presence of an unstable background allows a core to evolve dynamically from the time when it first appears, even when it resembles a pressure-confined, stable BE-sphere. The core can be thought of as a ram-pressure confined BE-sphere, with an increasing mass due to the accretion from the unstable background.

  15. Black hole formation in perfect fluid collapse

    International Nuclear Information System (INIS)

    Goswami, Rituparno; Joshi, Pankaj S

    2004-01-01

    We construct here a special class of perfect fluid collapse models which generalizes the homogeneous dust collapse solution in order to include nonzero pressures and inhomogeneities into evolution. It is shown that a black hole is necessarily generated as the end product of continued gravitational collapse, rather than a naked singularity. We examine the nature of the central singularity forming as a result of endless collapse and it is shown that no nonspacelike trajectories can escape from the central singularity. Our results provide some insights into how the dynamical collapse works and into the possible formulations of the cosmic censorship hypothesis, which is as yet a major unsolved problem in black hole physics

  16. Collapsing stage of 'bosonic matter'

    International Nuclear Information System (INIS)

    Manoukian, E.B.; Muthaporn, C.; Sirininlakul, S.

    2006-01-01

    We prove rigorously that for 'bosonic matter', if deflation occurs upon collapse as more and more such matter is put together, then for a non-vanishing probability of having the negatively charged particles, with Coulomb interactions, within a sphere of radius R, the latter necessarily cannot decrease faster than N -1/3 for large N, where N denotes the number of the negatively charged particles. This is in clear distinction with matter (i.e., matter with the exclusion principle) which inflates and R necessarily increases not any slower than N 1/3 for large N

  17. PSI collapse and relativistic covariance

    International Nuclear Information System (INIS)

    Costa de Beauregard, Olivier

    1980-01-01

    We call macrorelativistic a theory invariant under the orthochronous Lorentz group and obeying the 'factlike' principle of retarded causality, and microrelativistic a theory invariant under the full Lorentz group and CPT symmetric. The Einstein correlations either direct (non-separability of measurements issuing from a common preparation) or reversed (non-separability of preparations producing a common measurement) are incompatible with the macro-, but compatible with the microrelativity. We assume that fundamental physics is fully Lorentz and CPT invariant (the transition to macrophysics introducing a 'factlike asymmetry) and consequently define the collapse-and-retrocollapse concept [fr

  18. Geotechnical properties of Egyptian collapsible soils

    Directory of Open Access Journals (Sweden)

    Khaled E. Gaaver

    2012-09-01

    Full Text Available The risk of constructing structures on collapsible soils presents significant challenges to geotechnical engineers due to sudden reduction in volume upon wetting. Identifying collapsible soils when encountered in the field and taking the needed precautions should substantially reduce the risk of such problems usually reported in buildings and highways. Collapsible soils are those unsaturated soils that can withstand relatively high pressure without showing significant change in volume, however upon wetting; they are susceptible to a large and sudden reduction in volume. Collapsible soils cover significant areas around the world. In Egypt, collapsible soils were observed within the northern portion of the western desert including Borg El-Arab region, and around the city of Cairo in Six-of-October plateau, and Tenth-of-Ramadan city. Settlements associated with development on untreated collapsible soils usually lead to expensive repairs. One method for treating collapsible soils is to densify their structure by compaction. The ongoing study presents the effect of compaction on the geotechnical properties of the collapsible soils. Undisturbed block samples were recovered from test pits at four sites in Borg El-Arab district, located at about 20 km west of the city of Alexandria, Egypt. The samples were tested in both unsoaked and soaked conditions. Influence of water inundation on the geotechnical properties of collapsible soils was demonstrated. A comparative study between natural undisturbed and compacted samples of collapsible soils was performed. An attempt was made to relate the collapse potential to the initial moisture content. An empirical correlation between California Bearing Ratio of the compacted collapsible soils and liquid limit was adopted. The presented simple relationships should enable the geotechnical engineers to estimate the complex parameters of collapsible soils using simple laboratory tests with a reasonable accuracy.

  19. Stellar core collapse and supernova

    International Nuclear Information System (INIS)

    Wilson, J.R.; Mayle, R.; Woosley, S.E.; Weaver, T.

    1985-04-01

    Massive stars that end their stable evolution as their iron cores collapse to a neutron star or black hole long been considered good candidates for producing Type II supernovae. For many years the outward propagation of the shock wave produced by the bounce of these iron cores has been studied as a possible mechanism for the explosion. For the most part, the results of these studies have not been particularly encouraging, except, perhaps, in the case of very low mass iron cores or very soft nuclear equations of state. The shock stalls, overwhelmed by photodisintegration and neutrino losses, and the star does not explode. More recently, slow late time heating of the envelope of the incipient neutron star has been found to be capable of rejuvenating the stalled shock and producing an explosion after all. The present paper discusses this late time heating and presents results from numerical calculations of the evolution, core collapse, and subsequent explosion of a number of recent stellar models. For the first time they all, except perhaps the most massive, explode with reasonable choices of input physics. 39 refs., 17 figs., 1 tab

  20. Collapsing stellar cores and supernovae

    Energy Technology Data Exchange (ETDEWEB)

    Epstein, R J [Nordisk Inst. for Teoretisk Atomfysik, Copenhagen (Denmark); Noorgaard, H [Nordisk Inst. for Teoretisk Atomfysik, Copenhagen (Denmark); Chicago Univ., IL (USA). Enrico Fermi Inst.); Bond, J R [Niels Bohr Institutet, Copenhagen (Denmark); California Inst. of Tech., Pasadena (USA). W.K. Kellogg Radiation Lab.)

    1979-05-01

    The evolution of a stellar core is studied during its final quasi-hydrostatic contraction. The core structure and the (poorly known) properties of neutron rich matter are parametrized to include most plausible cases. It is found that the density-temperature trajectory of the material in the central part of the core (the core-center) is insensitive to nearly all reasonable parameter variations. The central density at the onset of the dynamic phase of the collapse (when the core-center begins to fall away from the rest of the star) and the fraction of the emitted neutrinos which are trapped in the collapsing core-center depend quite sensitively on the properties of neutron rich matter. We estimate that the amount of energy Ecm which is imparted to the core-mantle by the neutrinos which escape from the imploded core-center can span a large range of values. For plausible choices of nuclear and model parameters Ecm can be large enough to yield a supernova event.

  1. UPP mediated Diabetic Retinopathy via ROS/PARP and NF-κB inflammatory factor pathways.

    Science.gov (United States)

    Luo, D-W; Zheng, Z; Wang, H; Fan, Y; Chen, F; Sun, Y; Wang, W-J; Sun, T; Xu, X

    2015-01-01

    Diabetic retinopathy (DR) is a leading cause of blindness in adults at working age. Human diabetic retinopathy is characterized by the basement membrane thick, pericytes loss, microaneurysms formation, retina neovascularization and vitreous hemorrhage. To investigate whether UPP activated ROS/PARP and NF-κB inflammatory factor pathways in Diabetic Retinopathy, human retinal endothelial cells (HRECs) and rats with streptozotocin-induced diabetes were used to determine the effect of UPP on ROS generation, cell apoptosis, mitochondrial membrane potential (ΔΨm) and inflammatory factor protein expression, through flow cytometry assay, immunohistochemistry, Real-time PCR, Western blot analysis and ELISA. The levels of ROS and apoptosis and the expressions of UPP (Ub and E3) and inflammatory factor protein were increased in high glucose-induced HRECs and retina of diabetic rats, while ΔΨm was decreased. The UPP inhibitor and UbshRNA could attenuate these effects through inhibiting the pathway of ROS/PARP and the expression of NF-κB inflammatory factors, and the increased UPP was a result of high glucose-induced increase of ROS generation and NF-κBp65 expression, accompanied with the decrease of ΔΨm. Clinical study showed the overexpression of UPP and detachment of epiretinal membranes in proliferative DR (PDR) patients. It has been indicated that the pathogenic effect of UPP on DR was involved in the increase of ROS generation and NF-κB expression, which associated with the ROS/PARP and NF-κB inflammatory factor pathways. Our study supports a new insight for further application of UPP inhibitor in DR treatment.

  2. Collapse models with non-white noises

    International Nuclear Information System (INIS)

    Adler, Stephen L; Bassi, Angelo

    2007-01-01

    We set up a general formalism for models of spontaneous wavefunction collapse with dynamics represented by a stochastic differential equation driven by general Gaussian noises, not necessarily white in time. In particular, we show that the non-Schroedinger terms of the equation induce the collapse of the wavefunction to one of the common eigenstates of the collapsing operators, and that the collapse occurs with the correct quantum probabilities. We also develop a perturbation expansion of the solution of the equation with respect to the parameter which sets the strength of the collapse process; such an approximation allows one to compute the leading-order terms for the deviations of the predictions of collapse models with respect to those of standard quantum mechanics. This analysis shows that to leading order, the 'imaginary noise' trick can be used for non-white Gaussian noise

  3. Poly(ADP-ribose polymerase 1 (PARP1 overexpression in human breast cancer stem cells and resistance to olaparib.

    Directory of Open Access Journals (Sweden)

    Marine Gilabert

    Full Text Available BACKGROUND: Breast cancer stem cells (BCSCs have been recognized as playing a major role in various aspects of breast cancer biology. To identify specific biomarkers of BCSCs, we have performed comparative proteomics of BCSC-enriched and mature cancer cell populations from the human breast cancer cell line (BCL, BrCA-MZ-01. METHODS: ALDEFLUOR assay was used to sort BCSC-enriched (ALDH+ and mature cancer (ALDH- cell populations. Total proteins were extracted from both fractions and subjected to 2-Dimensional Difference In-Gel Electrophoresis (2-D DIGE. Differentially-expressed spots were excised and proteins were gel-extracted, digested and identified using MALDI-TOF MS. RESULTS: 2-D DIGE identified poly(ADP-ribose polymerase 1 (PARP1 as overexpressed in ALDH+ cells from BrCA-MZ-01. This observation was confirmed by western blot and extended to four additional human BCLs. ALDH+ cells from BRCA1-mutated HCC1937, which had the highest level of PARP1 overexpression, displayed resistance to olaparib, a specific PARP1 inhibitor. CONCLUSION: An unbiased proteomic approach identified PARP1 as upregulated in ALDH+, BCSC-enriched cells from various human BCLs, which may contribute to clinical resistance to PARP inhibitors.

  4. The inhibition of PARP but not EGFR results in the radiosensitization of HPV/p16-positive HNSCC cell lines

    International Nuclear Information System (INIS)

    Güster, Julian David; Weissleder, Stephanie Valerie; Busch, Chia-Jung; Kriegs, Malte; Petersen, Cordula; Knecht, Rainald; Dikomey, Ekkehard; Rieckmann, Thorsten

    2014-01-01

    Background and purpose: HPV-negative and HPV-positive HNSCC comprise distinct tumor entities with different biological characteristics. Specific regimens for the comparably well curable HPV-positive entity that reduce side effects without compromising outcome have yet to be established. Therefore, we tested here whether the inhibition of EGFR or PARP may be used to specifically enhance the radiosensitivity of HPV-positive HNSCC cells. Materials and methods: Experiments were performed with five HPV/p16-positive HNSCC cell lines. Inhibitors used were cetuximab, olaparib and PF-00477736. The respective inhibition of EGFR, PARP and Chk1 was evaluated by Western blot, immunofluorescence analysis and assessment of cell cycle distribution. Cell survival was assessed by colony formation assay. Results: Inhibition of EGFR by cetuximab failed to radiosensitize any of the HPV-positive HNSCC cell lines tested. In contrast, PARP-inhibition resulted in a substantial radiosensitization of all strains, with the sensitization being further enhanced by the additional inhibition of Chk1. Conclusions: PARP-inhibition effectively radiosensitizes HPV-positive HNSCC cells and may therefore represent a viable alternative to chemotherapy possibly even allowing for a reduction in radiation dose. For the latter, PARP-inhibition may be combined with the inhibition of Chk1. In contrast, the inhibition of EGFR cannot be expected to radiosensitize HPV-positive HNSCC through the modulation of cellular radiosensitivity

  5. Concurrent targeting of nitrosative stress-PARP pathway corrects functional, behavioral and biochemical deficits in experimental diabetic neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Negi, Geeta; Kumar, Ashutosh [Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab 160062 (India); Sharma, Shyam S., E-mail: sssharma@niper.ac.in [Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab 160062 (India)

    2010-01-01

    Peroxynitrite mediated nitrosative stress, an indisputable initiator of DNA damage and overactivation of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated after sensing DNA damage, are two crucial pathogenetic mechanisms in diabetic neuropathy. The intent of the present study was to investigate the effect of combination of a peroxynitrite decomposition catalyst (PDC), FeTMPyP and a PARP inhibitor, 4-ANI against diabetic peripheral neuropathy. The end points of evaluation of the study included motor nerve conduction velocity (MNCV) and nerve blood flow (NBF) for evaluating nerve functions; thermal hyperalgesia and mechanical allodynia for assessing nociceptive alterations, malondialdehyde and peroxynitrite levels to detect oxidative stress-nitrosative stress; NAD concentration in sciatic nerve to assess overactivation of PARP. Additionally immunohistochemical studies for nitrotyrosine and Poly(ADP-ribose) (PAR) was also performed. Treatment with the combination of FeTMPyP and 4-ANI led to significant improvement in nerve functions and pain parameters and also attenuated the oxidative-nitrosative stress markers. Further, the combination also reduced the overactivation of PARP as evident from increased NAD levels and decreased PAR immunopositivity in sciatic nerve microsections. Thus, it can be concluded that treatment with the combination of a PDC and PARP inhibitor attenuates alteration in peripheral nerves in diabetic neuropathy (DN).

  6. Xeroderma Pigmentosum Group A Promotes Autophagy to Facilitate Cisplatin Resistance in Melanoma Cells through the Activation of PARP1.

    Science.gov (United States)

    Ge, Rui; Liu, Lin; Dai, Wei; Zhang, Weigang; Yang, Yuqi; Wang, Huina; Shi, Qiong; Guo, Sen; Yi, Xiuli; Wang, Gang; Gao, Tianwen; Luan, Qi; Li, Chunying

    2016-06-01

    Xeroderma pigmentosum group A (XPA), a key protein in the nucleotide excision repair pathway, has been shown to promote the resistance of tumor cells to chemotherapeutic drugs by facilitating the DNA repair process. However, the role of XPA in the resistance of melanoma to platinum-based drugs like cisplatin is largely unknown. In this study, we initially found that XPA was expressed at higher levels in cisplatin-resistant melanoma cells than in cisplatin-sensitive ones. Furthermore, the knockdown of XPA not only increased cellular apoptosis but also inhibited cisplatin-induced autophagy, which rendered the melanoma cells more sensitive to cisplatin. Moreover, we discovered that the increased XPA in resistant melanoma cells promoted poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) activation and that the inhibition of PARP1 could attenuate the cisplatin-induced autophagy. Finally, we proved that the inhibition of PARP1 and the autophagy process made resistant melanoma cells more susceptible to cisplatin treatment. Our study shows that XPA can promote cell-protective autophagy in a DNA repair-independent manner by enhancing the activation of PARP1 in melanoma cells resistant to cisplatin and that the XPA-PARP1-mediated autophagy process can be targeted to overcome cisplatin resistance in melanoma chemotherapy. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Completely quantized collapse and consequences

    International Nuclear Information System (INIS)

    Pearle, Philip

    2005-01-01

    Promotion of quantum theory from a theory of measurement to a theory of reality requires an unambiguous specification of the ensemble of realizable states (and each state's probability of realization). Although not yet achieved within the framework of standard quantum theory, it has been achieved within the framework of the continuous spontaneous localization (CSL) wave-function collapse model. In CSL, a classical random field w(x,t) interacts with quantum particles. The state vector corresponding to each w(x,t) is a realizable state. In this paper, I consider a previously presented model, which is predictively equivalent to CSL. In this completely quantized collapse (CQC) model, the classical random field is quantized. It is represented by the operator W(x,t) which satisfies [W(x,t),W(x ' ,t ' )]=0. The ensemble of realizable states is described by a single state vector, the 'ensemble vector'. Each superposed state which comprises the ensemble vector at time t is the direct product of an eigenstate of W(x,t ' ), for all x and for 0≤t ' ≤t, and the CSL state corresponding to that eigenvalue. These states never interfere (they satisfy a superselection rule at any time), they only branch, so the ensemble vector may be considered to be, as Schroedinger put it, a 'catalog' of the realizable states. In this context, many different interpretations (e.g., many worlds, environmental decoherence, consistent histories, modal interpretation) may be satisfactorily applied. Using this description, a long-standing problem is resolved, where the energy comes from the particles gain due to the narrowing of their wave packets by the collapse mechanism. It is shown how to define the energy of the random field and its energy of interaction with particles so that total energy is conserved for the ensemble of realizable states. As a by-product, since the random-field energy spectrum is unbounded, its canonical conjugate, a self-adjoint time operator, can be discussed. Finally, CSL

  8. Spherical dust collapse in higher dimensions

    International Nuclear Information System (INIS)

    Goswami, Rituparno; Joshi, Pankaj S.

    2004-01-01

    We consider here whether it is possible to recover cosmic censorship when a transition is made to higher-dimensional spacetimes, by studying the spherically symmetric dust collapse in an arbitrary higher spacetime dimension. It is pointed out that if only black holes are to result as the end state of a continual gravitational collapse, several conditions must be imposed on the collapsing configuration, some of which may appear to be restrictive, and we need to study carefully if these can be suitably motivated physically in a realistic collapse scenario. It would appear, that, in a generic higher-dimensional dust collapse, both black holes and naked singularities would develop as end states as indicated by the results here. The mathematical approach developed here generalizes and unifies the earlier available results on higher-dimensional dust collapse as we point out. Further, the dependence of black hole or naked singularity end states as collapse outcomes on the nature of the initial data from which the collapse develops is brought out explicitly and in a transparent manner as we show here. Our method also allows us to consider here in some detail the genericity and stability aspects related to the occurrence of naked singularities in gravitational collapse

  9. Geophysical Processes - MO 2013 Collapse Potential (SHP)

    Data.gov (United States)

    NSGIC State | GIS Inventory — Collapse potential correlates with locations of underground mines and sinkholes. Computer-generated hazard calculations include areas in close proximity to mines and...

  10. Spherically symmetric radiation in gravitational collapse

    International Nuclear Information System (INIS)

    Bridy, D.J.

    1983-01-01

    This paper investigates a previously neglected mode by which a star may lose energy in the late stages of gravitational collapse to the black hole state. A model consisting of a Schwarzschild exterior matched to a Friedman interior of collapsing pressureless dust is studied. The matter of the collapsing star is taken as the source of a massive vector boson field and a detailed boundary value problem is carried out. Vector mesons are strongly coupled to all nucleons and will be radiated by ordinary matter during the collapse. The time dependent coupling between interior and exterior modes matched across the moving boundary of the collapsing star and the presence of the gravitational fields and their gradients in the field equations may give rise to a parametric amplification mechanism and permit the gravitational field to pump energy into the boson field, greatly enhancing the amount of boson radiation. The significance of a radiative mechanism driven by collapse is that it can react back upon the collapsing source and deprive it of some of the very mass that drives the collapse via its self gravitation. If the mass loss is great enough, this may provide a mechanism to slow or even halt gravitational collapse in some cases

  11. Understand rotating isothermal collapses yet

    International Nuclear Information System (INIS)

    Tohline, J.E.

    1985-01-01

    A scalar virial equation is used to describe the dynamic properties of equilibrium gas clouds, taking into account the relative effects of surface pressure, rotation, self gravity and internal isothermal pressure. Details concerning the internal structure of the clouds are ignored in order to obtain a globalized analytical expression. The obtained solution to the equation is found to agree with the surface-pressure-dominated model of Stahler (1983), and the rotation-dominated model of Hayashi, Narita, and Miyama (1982). On the basis of the analytical expression of virial equilibrium in the clouds, some of the limiting properties of isothermal clouds are described, and a realistic starting model for cloud collapse is proposed. 18 references

  12. Collapse Analysis of Timber Structures

    DEFF Research Database (Denmark)

    Kirkegaard, Poul Henning; Sørensen, John Dalsgaard

    2008-01-01

    of Structures and a probabilistic modelling of the timber material proposed in the Probabilistic Model Code (PMC) of the Joint Committee on Structural Safety (JCSS). Due to the framework in the Danish Code the timber structure has to be evaluated with respect to the following criteria where at least one shall...... to criteria a) and b) the timber frame structure has one column with a reliability index a bit lower than an assumed target level. By removal three columns one by one no significant extensive failure of the entire structure or significant parts of it are obtained. Therefore the structure can be considered......A probabilistic based collapse analysis has been performed for a glulam frame structure supporting the roof over the main court in a Norwegian sports centre. The robustness analysis is based on the framework for robustness analysis introduced in the Danish Code of Practice for the Safety...

  13. An axisymmetric gravitational collapse code

    Energy Technology Data Exchange (ETDEWEB)

    Choptuik, Matthew W [CIAR Cosmology and Gravity Program, Department of Physics and Astronomy, University of British Columbia, Vancouver BC, V6T 1Z1 (Canada); Hirschmann, Eric W [Department of Physics and Astronomy, Brigham Young University, Provo, UT 84604 (United States); Liebling, Steven L [Southampton College, Long Island University, Southampton, NY 11968 (United States); Pretorius, Frans [Theoretical Astrophysics, California Institute of Technology, Pasadena, CA 91125 (United States)

    2003-05-07

    We present a new numerical code designed to solve the Einstein field equations for axisymmetric spacetimes. The long-term goal of this project is to construct a code that will be capable of studying many problems of interest in axisymmetry, including gravitational collapse, critical phenomena, investigations of cosmic censorship and head-on black-hole collisions. Our objective here is to detail the (2+1)+1 formalism we use to arrive at the corresponding system of equations and the numerical methods we use to solve them. We are able to obtain stable evolution, despite the singular nature of the coordinate system on the axis, by enforcing appropriate regularity conditions on all variables and by adding numerical dissipation to hyperbolic equations.

  14. An axisymmetric gravitational collapse code

    International Nuclear Information System (INIS)

    Choptuik, Matthew W; Hirschmann, Eric W; Liebling, Steven L; Pretorius, Frans

    2003-01-01

    We present a new numerical code designed to solve the Einstein field equations for axisymmetric spacetimes. The long-term goal of this project is to construct a code that will be capable of studying many problems of interest in axisymmetry, including gravitational collapse, critical phenomena, investigations of cosmic censorship and head-on black-hole collisions. Our objective here is to detail the (2+1)+1 formalism we use to arrive at the corresponding system of equations and the numerical methods we use to solve them. We are able to obtain stable evolution, despite the singular nature of the coordinate system on the axis, by enforcing appropriate regularity conditions on all variables and by adding numerical dissipation to hyperbolic equations

  15. PARPs database: A LIMS systems for protein-protein interaction data mining or laboratory information management system

    Directory of Open Access Journals (Sweden)

    Picard-Cloutier Aude

    2007-12-01

    Full Text Available Abstract Background In the "post-genome" era, mass spectrometry (MS has become an important method for the analysis of proteins and the rapid advancement of this technique, in combination with other proteomics methods, results in an increasing amount of proteome data. This data must be archived and analysed using specialized bioinformatics tools. Description We herein describe "PARPs database," a data analysis and management pipeline for liquid chromatography tandem mass spectrometry (LC-MS/MS proteomics. PARPs database is a web-based tool whose features include experiment annotation, protein database searching, protein sequence management, as well as data-mining of the peptides and proteins identified. Conclusion Using this pipeline, we have successfully identified several interactions of biological significance between PARP-1 and other proteins, namely RFC-1, 2, 3, 4 and 5.

  16. Pyrimidine Pool Disequilibrium Induced by a Cytidine Deaminase Deficiency Inhibits PARP-1 Activity, Leading to the Under Replication of DNA.

    Directory of Open Access Journals (Sweden)

    Simon Gemble

    2015-07-01

    Full Text Available Genome stability is jeopardized by imbalances of the dNTP pool; such imbalances affect the rate of fork progression. For example, cytidine deaminase (CDA deficiency leads to an excess of dCTP, slowing the replication fork. We describe here a novel mechanism by which pyrimidine pool disequilibrium compromises the completion of replication and chromosome segregation: the intracellular accumulation of dCTP inhibits PARP-1 activity. CDA deficiency results in incomplete DNA replication when cells enter mitosis, leading to the formation of ultrafine anaphase bridges between sister-chromatids at "difficult-to-replicate" sites such as centromeres and fragile sites. Using molecular combing, electron microscopy and a sensitive assay involving cell imaging to quantify steady-state PAR levels, we found that DNA replication was unsuccessful due to the partial inhibition of basal PARP-1 activity, rather than slower fork speed. The stimulation of PARP-1 activity in CDA-deficient cells restores replication and, thus, chromosome segregation. Moreover, increasing intracellular dCTP levels generates under-replication-induced sister-chromatid bridges as efficiently as PARP-1 knockdown. These results have direct implications for Bloom syndrome (BS, a rare genetic disease combining susceptibility to cancer and genomic instability. BS results from mutation of the BLM gene, encoding BLM, a RecQ 3'-5' DNA helicase, a deficiency of which leads to CDA downregulation. BS cells thus have a CDA defect, resulting in a high frequency of ultrafine anaphase bridges due entirely to dCTP-dependent PARP-1 inhibition and independent of BLM status. Our study describes previously unknown pathological consequences of the distortion of dNTP pools and reveals an unexpected role for PARP-1 in preventing DNA under-replication and chromosome segregation defects.

  17. SU-E-T-245: MR Guided Focused Ultrasound Increased PARP Related Apoptosis On Prostate Cancer in Vivo

    International Nuclear Information System (INIS)

    Chen, L; Chen, X; Cvetkovic, D; Gupta, R; Yang, D; Ma, C

    2014-01-01

    Purpose: Our previous study demonstrated that significant tumor growth delay was observed in the mice treated with pulsed high intensity focused ultrasound (pHIFU). The purpose of this study is to understand the cell killing mechanisms of pHIFU. Methods: Prostate cancer cells (LNCaP), were grown orthotopically in 17 nude mice. Tumor-bearing mice were treated using pHIFU with an acoustic power of 25W, pulse width 100msec and 300 pulses in one sonication under MR guidance. Mutiple sonications were used to cover the whole tumor volume. Temperature (less than 40 degree centigrade in the focal spot) was monitored using MR thermometry. Animals were euthanized at pre-determined time points (n=2) after treatment: 0 hours; 6 hrs; 24 hrs; 48 hrs; 4 days and 7 days. Two tumorbearing mice were used as control. Three tumor-bearing mice were treated with radiation (RT, 2 Gy) using 6 MV photon beams. RT treated mice were euthanized at 0 hr, 6 hrs and 24 hrs. The tumors were processed for immunohistochemical (IHC) staining for PARP (a surrogate of apoptosis). A multispectral imaging analysis system was used to quantify the expression of PARP staining. Cell apoptosis was calculated based on the PARP expression level, which is the intensity of the DAB reaction. Results: Our data showed that PARP related apoptosis peaked at 48 hrs and 7 days in pHIFU treated mice, which is comparable to that for the RT group at 24 hrs. The preliminary results from this study were consistent with our previous study on tumor growth delay using pHIFU. Conclusion: Our results demonstrated that non-thermal pHIFU increased apoptotic tumor cell death through the PARP related pathway. MR guided pHIFU may have a great potential as a safe, noninvasive treatment modality for cancer therapy. This treatment modality might be able to synergize with PARP inhibitors to achieve better result

  18. Melatonin regulates PARP1 to control the senescence-associated secretory phenotype (SASP) in human fetal lung fibroblast cells.

    Science.gov (United States)

    Yu, Songtao; Wang, Xiaojiao; Geng, Peiliang; Tang, Xudong; Xiang, Lisha; Lu, Xin; Li, Jianjun; Ruan, Zhihua; Chen, Jianfang; Xie, Ganfeng; Wang, Zhe; Ou, Juanjuan; Peng, Yuan; Luo, Xi; Zhang, Xuan; Dong, Yan; Pang, Xueli; Miao, Hongming; Chen, Hongshan; Liang, Houjie

    2017-08-01

    Cellular senescence is an important tumor-suppressive mechanism. However, acquisition of a senescence-associated secretory phenotype (SASP) in senescent cells has deleterious effects on the tissue microenvironment and, paradoxically, promotes tumor progression. In a drug screen, we identified melatonin as a novel SASP suppressor in human cells. Strikingly, melatonin blunts global SASP gene expression upon oncogene-induced senescence (OIS). Moreover, poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage, was identified as a new melatonin-dependent regulator of SASP gene induction upon OIS. Here, we report two different but potentially coherent epigenetic strategies for melatonin regulation of SASP. The interaction between the telomeric repeat-containing RNA (TERRA) and PARP-1 stimulates the SASP, which was attenuated by 67.9% (illustrated by the case of IL8) by treatment with melatonin. Through binding to macroH2A1.1, PARP-1 recruits CREB-binding protein (CBP) to mediate acetylation of H2BK120, which positively regulates the expression of target SASP genes, and this process is interrupted by melatonin. Consequently, the findings provide novel insight into melatonin's epigenetic role via modulating PARP-1 in suppression of SASP gene expression in OIS-induced senescent cells. Our studies identify melatonin as a novel anti-SASP molecule, define PARP-1 as a new target by which melatonin regulates SASP, and establish a new epigenetic paradigm for a pharmacological mechanism by which melatonin interrupts PARP-1 interaction with the telomeric long noncoding RNA(lncRNA) or chromatin. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. The Collapse of the 'Celtic Tiger' Narrative

    DEFF Research Database (Denmark)

    Böss, Michael

    2011-01-01

    An account of the factors that led to the collapse of the 'Celtic Tiger' economy in 2008 and an explanation of the political effects and implications for Irish identity.......An account of the factors that led to the collapse of the 'Celtic Tiger' economy in 2008 and an explanation of the political effects and implications for Irish identity....

  20. Non explosive collapse of white dwarfs

    International Nuclear Information System (INIS)

    Canal, R.; Schatzmann, E.

    1976-01-01

    We show that if a sufficiently cold carbon-oxygen white dwarf, close to the critical mass, accretes matter from a companion in a binary system, the time scale of collapse is long enough to allow neutronization before the onset of pycnonuclear reactions. This can possibly lead to the formation of X-ray sources by a non explosive collapse. (orig.) [de

  1. Homoclinic phenomena in the gravitational collapse

    International Nuclear Information System (INIS)

    Koiller, J.; Mello Neto, J.R.T. de; Soares, I.D.

    1984-01-01

    A class of Bianchi IX cosmological models is shown to have chaotic gravitational collapse, due to Poincare's homoclinic phenomena. Such models can be programmed so that for any given positive integer N (N=infinity included) the universe undergoes N non-periodic oscillations (each oscillation requiring a long time) before collapsing. For N=infinity the universe undergoes periodic oscillations. (Author) [pt

  2. On the collapse of iron stellar cores

    International Nuclear Information System (INIS)

    Barkat, Z.; Rakavy, G.; Reiss, Y.; Wilson, J.R.

    1975-01-01

    The collapse of iron stellar cores is investigated to see whether the outward shock produced by the bounce at neutron star density is sufficient to burn appreciable amounts of the envelope around the iron core. Several models were tried, and in all cases no appreciable burn took place; hence no explosion results from the collapse of these models

  3. Plastic collapse load of corroded steel plates

    Indian Academy of Sciences (India)

    Keywords. Corroded steel plate; plastic collapse; FEM; rough surface. ... The main aim of present work is to study plastic collapse load of corroded steel plates with irregular surfaces under tension. Non-linear finite element method ... Department of Ocean Engineering, AmirKabir University of Technology, 15914 Tehran, Iran ...

  4. Collapse of Electrostatic Waves in Magnetoplasmas

    DEFF Research Database (Denmark)

    Shukla, P. K.; Yu, M. Y.; Juul Rasmussen, Jens

    1984-01-01

    The two-fluid model is employed to investigate the collapse of electrostatic waves in magnetized plasmas. It is found that nonlinear interaction of ion cyclotron, upper-, and lower-hybrid waves with adiabatic particle motion along the external magnetic field can cause wave-field collapse....

  5. Sharper criteria for the wave collapse

    DEFF Research Database (Denmark)

    Kuznetsov, E.A.; Juul Rasmussen, J.; Rypdal, K.

    1995-01-01

    Sharper criteria for three-dimensional wave collapse described by the Nonlinear Schrodinger Equation (NLSE) are derived. The collapse threshold corresponds to the ground state soliton which is known to be unstable. Thus, for nonprefocusing distributions this represents the separatrix between...

  6. Contagious cooperation, temptation, and ecosystem collapse

    NARCIS (Netherlands)

    Richter, A.; van Soest, D.P.; Grasman, J.

    2013-01-01

    Real world observations suggest that social norms of cooperation can be effective in overcoming social dilemmas such as the joint management of a common pool resource—but also that they can be subject to slow erosion and sudden collapse. We show that these patterns of erosion and collapse emerge

  7. Recurrent hypoinsulinemic hyperglycemia in neonatal rats increases PARP-1 and NF-κB expression and leads to microglial activation in the cerebral cortex.

    Science.gov (United States)

    Gisslen, Tate; Ennis, Kathleen; Bhandari, Vineet; Rao, Raghavendra

    2015-11-01

    Hyperglycemia is a common metabolic problem in extremely low-birth-weight preterm infants. Neonatal hyperglycemia is associated with increased mortality and brain injury. Glucose-mediated oxidative injury may be responsible. Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in DNA repair and cell survival. However, PARP-1 overactivation leads to cell death. NF-κB is coactivated with PARP-1 and regulates microglial activation. The effects of recurrent hyperglycemia on PARP-1/NF-κB expression and microglial activation are not well understood. Rat pups were subjected to recurrent hypoinsulinemic hyperglycemia of 2 h duration twice daily from postnatal (P) day 3-P12 and killed on P13. mRNA and protein expression of PARP-1/NF-κB and their downstream effectors were determined in the cerebral cortex. Microgliosis was determined using CD11 immunohistochemistry. Recurrent hyperglycemia increased PARP-1 expression confined to the nucleus and without causing PARP-1 overactivation and cell death. NF-κB mRNA expression was increased, while IκB mRNA expression was decreased. inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) mRNA expressions were decreased. Hyperglycemia significantly increased the number of microglia. Recurrent hyperglycemia in neonatal rats is associated with upregulation of PARP-1 and NF-κB expression and subsequent microgliosis but not neuronal cell death in the cerebral cortex.

  8. The nuclear protein Poly(ADP-ribose) polymerase 3 (AtPARP3) is required for seed storability in Arabidopsis thaliana.

    Science.gov (United States)

    Rissel, D; Losch, J; Peiter, E

    2014-11-01

    The deterioration of seeds during prolonged storage results in a reduction of viability and germination rate. DNA damage is one of the major cellular defects associated with seed deterioration. It is provoked by the formation of reactive oxygen species (ROS) even in the quiescent state of the desiccated seed. In contrast to other stages of seed life, DNA repair during storage is hindered through the low seed water content; thereby DNA lesions can accumulate. To allow subsequent seedling development, DNA repair has thus to be initiated immediately upon imbibition. Poly(ADP-ribose) polymerases (PARPs) are important components in the DNA damage response in humans. Arabidopsis thaliana contains three homologues to the human HsPARP1 protein. Of these three, only AtPARP3 was very highly expressed in seeds. Histochemical GUS staining of embryos and endosperm layers revealed strong promoter activity of AtPARP3 during all steps of germination. This coincided with high ROS activity and indicated a role of the nuclear-localised AtPARP3 in DNA repair during germination. Accordingly, stored parp3-1 mutant seeds lacking AtPARP3 expression displayed a delay in germination as compared to Col-0 wild-type seeds. A controlled deterioration test showed that the mutant seeds were hypersensitive to unfavourable storage conditions. The results demonstrate that AtPARP3 is an important component of seed storability and viability. © 2014 German Botanical Society and The Royal Botanical Society of the Netherlands.

  9. PARP-1 is a key player in controlling apoptosis induced by high LET carbon ion beam and low LET gamma radiation in HeLa cells

    International Nuclear Information System (INIS)

    Ghorai, Atanu; Ghosh, Utpal; Bhattacharyya, Nitai P.; Sarma, Asitikantha

    2014-01-01

    PARP-1 inhibitors have long been used as chemo-sensitizer or radio-sensitizer and specific PARP-1 inhibitors are also in clinical trial for the treatment of various cancers. PARP-1 is not only involved in DNA repair but also plays very complex role in induction of apoptosis in postirradiation condition. Our objective is to investigate role of PARP-1 in apoptosis triggered by high LET carbon ion beam (CIB) and low LET gamma. We have treated HeLa and PARP-1 knock down HeLa (Hsil) cells with various doses of CIB and gamma. We measured DNA damage by comet assay and various apoptotic parameters such as nuclear fragmentation, activation of caspase-3,8,9, AIF translocation etc. We observed higher DNA breaks and also higher apoptosis in HsiI cells compared with HeLa cells. Both CIB and gamma treatment results G2/M arrest but unlike gamma CIB makes S-phase delay, implicating that gamma and CIB triggers different pathway after DNA damage. Cell death by CIB or by gamma increased up on knocking down of PARP-1 but increase is higher for high LET CIB compared with low LET gamma. Furthermore, expression level of PARP-1 controls the intensity of overall apoptosis in cells in post-irradiation condition. So, combination of PARP-1 inhibition with high LET CIB could be a promising tool to combat cancer. (author)

  10. Fire-induced collapses of steel structures

    DEFF Research Database (Denmark)

    Dondera, Alexandru; Giuliani, Luisa

    Single-story steel buildings such as car parks and industrial halls are often characterised by stiff beams and flexible columns and may experience an outward (sway) collapse during a fire, endangering people and properties outside the building. It is therefore a current interest of the research...... to investigate the collapse behaviour of single-story steel frames and identify relevant structural characteristics that influence the collapse mode. In this paper, a parametric study on the collapse a steel beam-column assembly with beam hinged connection and fixed column support is carried out under...... on the beam. By means of those tables, a simple method for the assessment and the countermeasure of unsafe collapse mode of single-story steel buildings can be derived....

  11. Granular Silo collapse: an experimental study

    Science.gov (United States)

    Clement, Eric; Gutierriez, Gustavo; Boltenhagen, Philippe; Lanuza, Jose

    2008-03-01

    We present an experimental work that develop some basic insight into the pre-buckling behavior and the buckling transition toward plastic collapse of a granular silo. We study different patterns of deformation generated on thin paper cylindrical shells during granular discharge. We study the collapse threshold for different bed height, flow rates and grain sizes. We compare the patterns that appear during the discharge of spherical beads, with those obtained in the axially compressed cylindrical shells. When the height of the granular column is close to the collapse threshold, we describe a ladder like pattern that rises around the cylinder surface in a spiral path of diamond shaped localizations, and develops into a plastic collapsing fold that grows around the collapsing silo.

  12. Collapse analysis of toroidal shell

    International Nuclear Information System (INIS)

    Pomares, R.J.

    1990-01-01

    This paper describes a study performed to determine the collapse characteristics of a toroidal shell using finite element method (FEM) analysis. The study also included free drop testing of a quarter scale prototype to verify the analytical results. The full sized toroidal shell has a 24-inch toroidal diameter with a 24-inch tubal diameter. The shell material is type 304 strainless steel. The toroidal shell is part of the GE Model 2000 transportation packaging, and acts as an energy absorbing device. The analyses performed were on a full sized and quarter scaled models. The finite element program used in all analyses was the LIBRA code. The analytical procedure used both the elasto-plastic and large displacement options within the code. The loading applied in the analyses corresponded to an impact of an infinite rigid plane oriented normal to the drop direction vector. The application of the loading continued incrementally until the work performed by the deforming structure equalled the kinetic energy developed in the free fall. The comparison of analysis and test results showed a good correlation

  13. The dual action of poly(ADP-ribose polymerase -1 (PARP-1 inhibition in HIV-1 infection: HIV-1 LTR inhibition and diminution in Rho GTPase activity

    Directory of Open Access Journals (Sweden)

    Slava eRom

    2015-08-01

    Full Text Available The transcription of HIV-1 (HIV is regulated by complex mechanisms involving various cellular factors and virus-encoded transactivators. Poly(ADP-ribose polymerase 1 (PARP-1 inhibition has emerged recently as a potent anti-inflammatory tool, since PARP-1 is involved in the regulation of some genes through its interaction with various transcription factors. We propose a novel approach to diminish HIV replication via PARP-1 inhibition using human primary monocyte-derived macrophages (MDM as an in vitro model system. PARP-1 inhibitors were able to reduce HIV replication in MDM by 60-80% after 7 days infection. Long Terminal Repeat (LTR acts as a switch in virus replication and can be triggered by several agents such as: Tat, tumor necrosis factor α (TNFα, and phorbol 12-myristate 13-acetate (PMA. Overexpression of Tat in MDM transfected with an LTR reporter plasmid led to a 4.2-fold increase in LTR activation; PARP inhibition resulted in 70% reduction of LTR activity. LTR activity, which increased 3-fold after PMA or TNFα treatment, was reduced by PARP inhibition (by 85-95%. MDM treated with PARP inhibitors showed 90% reduction in NFκB activity (known to mediate PMA- and TNFα-induced HIV LTR activation. Cytoskeleton rearrangements are important in effective HIV-1 infection. PARP inactivation reduced actin cytoskeleton rearrangements by affecting Rho GTPase machinery. These findings suggest that HIV replication in MDM could be suppressed by PARP inhibition via NFκB suppression, diminution of LTR activation and its effects on the cytoskeleton. PARP appears to be essential for HIV replication and its inhibition may provide a potent approach to treatment of HIV infection.

  14. Alkylation induced cerebellar degeneration dependent on Aag and Parp1 does not occur via previously established cell death mechanisms.

    Directory of Open Access Journals (Sweden)

    Carrie M Margulies

    Full Text Available Alkylating agents are ubiquitous in our internal and external environments, causing DNA damage that contributes to mutations and cell death that can result in aging, tissue degeneration and cancer. Repair of methylated DNA bases occurs primarily through the base excision repair (BER pathway, a multi-enzyme pathway initiated by the alkyladenine DNA glycosylase (Aag, also known as Mpg. Previous work demonstrated that mice treated with the alkylating agent methyl methanesulfonate (MMS undergo cerebellar degeneration in an Aag-dependent manner, whereby increased BER initiation by Aag causes increased tissue damage that is dependent on activation of poly (ADP-ribose polymerase 1 (Parp1. Here, we dissect the molecular mechanism of cerebellar granule neuron (CGN sensitivity to MMS using primary ex vivo neuronal cultures. We first established a high-throughput fluorescent imaging method to assess primary neuron sensitivity to treatment with DNA damaging agents. Next, we verified that the alkylation sensitivity of CGNs is an intrinsic phenotype that accurately recapitulates the in vivo dependency of alkylation-induced CGN cell death on Aag and Parp1 activity. Finally, we show that MMS-induced CGN toxicity is independent of all the cellular events that have previously been associated with Parp-mediated toxicity, including mitochondrial depolarization, AIF translocation, calcium fluxes, and NAD+ consumption. We therefore believe that further investigation is needed to adequately describe all varieties of Parp-mediated cell death.

  15. Alkylation induced cerebellar degeneration dependent on Aag and Parp1 does not occur via previously established cell death mechanisms.

    Science.gov (United States)

    Margulies, Carrie M; Chaim, Isaac Alexander; Mazumder, Aprotim; Criscione, June; Samson, Leona D

    2017-01-01

    Alkylating agents are ubiquitous in our internal and external environments, causing DNA damage that contributes to mutations and cell death that can result in aging, tissue degeneration and cancer. Repair of methylated DNA bases occurs primarily through the base excision repair (BER) pathway, a multi-enzyme pathway initiated by the alkyladenine DNA glycosylase (Aag, also known as Mpg). Previous work demonstrated that mice treated with the alkylating agent methyl methanesulfonate (MMS) undergo cerebellar degeneration in an Aag-dependent manner, whereby increased BER initiation by Aag causes increased tissue damage that is dependent on activation of poly (ADP-ribose) polymerase 1 (Parp1). Here, we dissect the molecular mechanism of cerebellar granule neuron (CGN) sensitivity to MMS using primary ex vivo neuronal cultures. We first established a high-throughput fluorescent imaging method to assess primary neuron sensitivity to treatment with DNA damaging agents. Next, we verified that the alkylation sensitivity of CGNs is an intrinsic phenotype that accurately recapitulates the in vivo dependency of alkylation-induced CGN cell death on Aag and Parp1 activity. Finally, we show that MMS-induced CGN toxicity is independent of all the cellular events that have previously been associated with Parp-mediated toxicity, including mitochondrial depolarization, AIF translocation, calcium fluxes, and NAD+ consumption. We therefore believe that further investigation is needed to adequately describe all varieties of Parp-mediated cell death.

  16. Synergetic Effects of PARP Inhibitor AZD2281 and Cisplatin in Oral Squamous Cell Carcinoma in Vitro and in Vivo

    Directory of Open Access Journals (Sweden)

    Masaaki Yasukawa

    2016-02-01

    Full Text Available Cisplatin is a commonly used chemotherapeutic drug for treatment of oral carcinoma, and combinatorial effects are expected to exert greater therapeutic efficacy compared with monotherapy. Poly(ADP-ribosylation is reported to be involved in a variety of cellular processes, such as DNA repair, cell death, telomere regulation, and genomic stability. Based on these properties, poly(ADP-ribose polymerase (PARP inhibitors are used for treatment of cancers, such as BRCA1/2 mutated breast and ovarian cancers, or certain solid cancers in combination with anti-cancer drugs. However, the effects on oral cancer have not been fully evaluated. In this study, we examined the effects of PARP inhibitor on the survival of human oral cancer cells in vitro and xenografted tumors derived from human oral cancer cells in vivo. In vitro effects were assessed by microculture tetrazolium and survival assays. The PARP inhibitor AZD2281 (olaparib showed synergetic effects with cisplatin in a dose-dependent manner. Combinatorial treatment with cisplatin and AZD2281 significantly inhibited xenografted tumor growth compared with single treatment of cisplatin or AZD2281. Histopathological analysis revealed that cisplatin and AZD2281 increased TUNEL-positive cells and decreased Ki67- and CD31-positive cells. These results suggest that PARP inhibitors have the potential to improve therapeutic strategies for oral cancer.

  17. A Systematic Analysis of Factors Localized to Damaged Chromatin Reveals PARP-Dependent Recruitment of Transcription Factors.

    Science.gov (United States)

    Izhar, Lior; Adamson, Britt; Ciccia, Alberto; Lewis, Jedd; Pontano-Vaites, Laura; Leng, Yumei; Liang, Anthony C; Westbrook, Thomas F; Harper, J Wade; Elledge, Stephen J

    2015-06-09

    Localization to sites of DNA damage is a hallmark of DNA damage response (DDR) proteins. To identify DDR factors, we screened epitope-tagged proteins for localization to sites of chromatin damaged by UV laser microirradiation and found >120 proteins that localize to damaged chromatin. These include the BAF tumor suppressor complex and the amyotrophic lateral sclerosis (ALS) candidate protein TAF15. TAF15 contains multiple domains that bind damaged chromatin in a poly-(ADP-ribose) polymerase (PARP)-dependent manner, suggesting a possible role as glue that tethers multiple PAR chains together. Many positives were transcription factors; > 70% of randomly tested transcription factors localized to sites of DNA damage, and of these, ∼90% were PARP dependent for localization. Mutational analyses showed that localization to damaged chromatin is DNA-binding-domain dependent. By examining Hoechst staining patterns at damage sites, we see evidence of chromatin decompaction that is PARP dependent. We propose that PARP-regulated chromatin remodeling at sites of damage allows transient accessibility of DNA-binding proteins. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  18. A Systematic Analysis of Factors Localized to Damaged Chromatin Reveals PARP-Dependent Recruitment of Transcription Factors

    Directory of Open Access Journals (Sweden)

    Lior Izhar

    2015-06-01

    Full Text Available Localization to sites of DNA damage is a hallmark of DNA damage response (DDR proteins. To identify DDR factors, we screened epitope-tagged proteins for localization to sites of chromatin damaged by UV laser microirradiation and found >120 proteins that localize to damaged chromatin. These include the BAF tumor suppressor complex and the amyotrophic lateral sclerosis (ALS candidate protein TAF15. TAF15 contains multiple domains that bind damaged chromatin in a poly-(ADP-ribose polymerase (PARP-dependent manner, suggesting a possible role as glue that tethers multiple PAR chains together. Many positives were transcription factors; > 70% of randomly tested transcription factors localized to sites of DNA damage, and of these, ∼90% were PARP dependent for localization. Mutational analyses showed that localization to damaged chromatin is DNA-binding-domain dependent. By examining Hoechst staining patterns at damage sites, we see evidence of chromatin decompaction that is PARP dependent. We propose that PARP-regulated chromatin remodeling at sites of damage allows transient accessibility of DNA-binding proteins.

  19. The covariant entropy bound in gravitational collapse

    International Nuclear Information System (INIS)

    Gao, Sijie; Lemos, Jose P. S.

    2004-01-01

    We study the covariant entropy bound in the context of gravitational collapse. First, we discuss critically the heuristic arguments advanced by Bousso. Then we solve the problem through an exact model: a Tolman-Bondi dust shell collapsing into a Schwarzschild black hole. After the collapse, a new black hole with a larger mass is formed. The horizon, L, of the old black hole then terminates at the singularity. We show that the entropy crossing L does not exceed a quarter of the area of the old horizon. Therefore, the covariant entropy bound is satisfied in this process. (author)

  20. On the quantum corrected gravitational collapse

    International Nuclear Information System (INIS)

    Torres, Ramón; Fayos, Francesc

    2015-01-01

    Based on a previously found general class of quantum improved exact solutions composed of non-interacting (dust) particles, we model the gravitational collapse of stars. As the modeled star collapses a closed apparent 3-horizon is generated due to the consideration of quantum effects. The effect of the subsequent emission of Hawking radiation related to this horizon is taken into consideration. Our computations lead us to argue that a total evaporation could be reached. The inferred global picture of the spacetime corresponding to gravitational collapse is devoid of both event horizons and shell-focusing singularities. As a consequence, there is no information paradox and no need of firewalls

  1. On the quantum corrected gravitational collapse

    Directory of Open Access Journals (Sweden)

    Ramón Torres

    2015-07-01

    Full Text Available Based on a previously found general class of quantum improved exact solutions composed of non-interacting (dust particles, we model the gravitational collapse of stars. As the modeled star collapses a closed apparent 3-horizon is generated due to the consideration of quantum effects. The effect of the subsequent emission of Hawking radiation related to this horizon is taken into consideration. Our computations lead us to argue that a total evaporation could be reached. The inferred global picture of the spacetime corresponding to gravitational collapse is devoid of both event horizons and shell-focusing singularities. As a consequence, there is no information paradox and no need of firewalls.

  2. On the quantum corrected gravitational collapse

    Science.gov (United States)

    Torres, Ramón; Fayos, Francesc

    2015-07-01

    Based on a previously found general class of quantum improved exact solutions composed of non-interacting (dust) particles, we model the gravitational collapse of stars. As the modeled star collapses a closed apparent 3-horizon is generated due to the consideration of quantum effects. The effect of the subsequent emission of Hawking radiation related to this horizon is taken into consideration. Our computations lead us to argue that a total evaporation could be reached. The inferred global picture of the spacetime corresponding to gravitational collapse is devoid of both event horizons and shell-focusing singularities. As a consequence, there is no information paradox and no need of firewalls.

  3. Galileon radiation from a spherical collapsing shell

    Energy Technology Data Exchange (ETDEWEB)

    Martín-García, Javier [Instituto de Física Teórica UAM/CSIC,C/ Nicolás Cabrera 15, E-28049 Madrid (Spain); Vázquez-Mozo, Miguel Á. [Instituto Universitario de Física Fundamental y Matemáticas (IUFFyM),Universidad de Salamanca, Plaza de la Merced s/n, E-37008 Salamanca (Spain)

    2017-01-17

    Galileon radiation in the collapse of a thin spherical shell of matter is analyzed. In the framework of a cubic Galileon theory, we compute the field profile produced at large distances by a short collapse, finding that the radiated field has two peaks traveling ahead of light fronts. The total energy radiated during the collapse follows a power law scaling with the shell’s physical width and results from two competing effects: a Vainshtein suppression of the emission and an enhancement due to the thinness of the shell.

  4. Menadione triggers cell death through ROS-dependent mechanisms involving PARP activation without requiring apoptosis.

    Science.gov (United States)

    Loor, Gabriel; Kondapalli, Jyothisri; Schriewer, Jacqueline M; Chandel, Navdeep S; Vanden Hoek, Terry L; Schumacker, Paul T

    2010-12-15

    Low levels of reactive oxygen species (ROS) can function as redox-active signaling messengers, whereas high levels of ROS induce cellular damage. Menadione generates ROS through redox cycling, and high concentrations trigger cell death. Previous work suggests that menadione triggers cytochrome c release from mitochondria, whereas other studies implicate the activation of the mitochondrial permeability transition pore as the mediator of cell death. We investigated menadione-induced cell death in genetically modified cells lacking specific death-associated proteins. In cardiomyocytes, oxidant stress was assessed using the redox sensor RoGFP, expressed in the cytosol or the mitochondrial matrix. Menadione elicited rapid oxidation in both compartments, whereas it decreased mitochondrial potential and triggered cytochrome c redistribution to the cytosol. Cell death was attenuated by N-acetylcysteine and exogenous glutathione or by overexpression of cytosolic or mitochondria-targeted catalase. By contrast, no protection was observed in cells overexpressing Cu,Zn-SOD or Mn-SOD. Overexpression of antiapoptotic Bcl-X(L) protected against staurosporine-induced cell death, but it failed to confer protection against menadione. Genetic deletion of Bax and Bak, cytochrome c, cyclophilin D, or caspase-9 conferred no protection against menadione-induced cell death. However, cells lacking PARP-1 showed a significant decrease in menadione-induced cell death. Thus, menadione induces cell death through the generation of oxidant stress in multiple subcellular compartments, yet cytochrome c, Bax/Bak, caspase-9, and cyclophilin D are dispensable for cell death in this model. These studies suggest that multiple redundant cell death pathways are activated by menadione, but that PARP plays an essential role in mediating each of them. Copyright © 2010 Elsevier Inc. All rights reserved.

  5. Gravitational collapse and the vacuum energy

    International Nuclear Information System (INIS)

    Campos, M

    2014-01-01

    To explain the accelerated expansion of the universe, models with interacting dark components (dark energy and dark matter) have been considered recently in the literature. Generally, the dark energy component is physically interpreted as the vacuum energy of the all fields that fill the universe. As the other side of the same coin, the influence of the vacuum energy on the gravitational collapse is of great interest. We study such collapse adopting different parameterizations for the evolution of the vacuum energy. We discuss the homogeneous collapsing star fluid, that interacts with a vacuum energy component, using the stiff matter case as example. We conclude this work with a discussion of the Cahill-McVittie mass for the collapsed object.

  6. Tetanus with multiple wedge vertebral collapses

    African Journals Online (AJOL)

    owner

    2012-07-06

    Jul 6, 2012 ... associated with traumatic injury, often a penetrating wound inflicted by dirty ... multiple vertebral collapses and the management chal- .... back pains and swelling as in our patient.9 There are usually no ... The cervical and.

  7. The collapse of interstellar gas clouds

    International Nuclear Information System (INIS)

    McNally, D.; Settle, J.J.

    1980-01-01

    The stability of spherically symmetric free-fall collapse to small radial perturbations is examined for non-uniform clouds. It is concluded that fragmentation of the central region of a collapsing gas cloud is possible if: (a) the density distribution is sufficiently smooth; and (b) the collapse is nearly free fall. Generally, perturbations enjoy only finite amplification during the collapse, and the amplification tends to decrease with increasing distance from the centre of the cloud. Unlimited amplification occurs only for uniform density clouds. Fragmentation is therefore unlikely to result from dynamical instability in the outer parts of a non-uniform cloud. Isothermal clouds are also briefly considered and, while it is argued that an earlier suggestion of their instability to fragmentation is unfounded, no general conclusion on the instability of such clouds could be drawn. (author)

  8. Lung lobe collapse: pathophysiology and radiologic significance

    International Nuclear Information System (INIS)

    Lord, P.F.; Gomez, J.A.

    1985-01-01

    The radiographic changes caused by collapse of lung lobes in pulmonary disease, pneumothorax, and pleural effusion depend on the lobar recoiling force and local pleural pressure. Differences in the tendency of normal lung lobes or regions to collapse depend on the relative surface-to-volume ratio, determined by shape and size of the region or lobe. This ratio affects the physiologic parameters of pulmonary interdependence, compliance, and collateral air flow. Pulmonary surfactant increases compliance, particularly at low volumes, maintains alveolar stability, and assists in maintaining capillary patency and preventing pulmonary edema. Its loss due to lung injury increases collapsing forces. In the presence of pneumothorax or pleural effusion, diseases that cause lobar collapse produce localized air or fluid entrapment that is a diagnostic sign of the presence of the underlying pulmonary disease

  9. Cooperation, cheating, and collapse in biological populations

    Science.gov (United States)

    Gore, Jeff

    2014-03-01

    Natural populations can collapse suddenly in response to small changes in environmental conditions, and recovery from such a collapse can be difficult. We have used laboratory microbial ecosystems to directly measure theoretically proposed early warning signals of impending population collapse. Yeast cooperatively break down the sugar sucrose, meaning that below a critical size the population cannot sustain itself. We have demonstrated experimentally that changes in the fluctuations of the population size can serve as an early warning signal that the population is close to collapse. The cooperative nature of yeast growth on sucrose suggests that the population may be susceptible to ``cheater'' cells, which do not contribute to the public good and instead merely take advantage of the cooperative cells. We confirm this possibility experimentally and find that such social parasitism decreases the resilience of the population.

  10. Simple Analytic Models of Gravitational Collapse

    Energy Technology Data Exchange (ETDEWEB)

    Adler, R.

    2005-02-09

    Most general relativity textbooks devote considerable space to the simplest example of a black hole containing a singularity, the Schwarzschild geometry. However only a few discuss the dynamical process of gravitational collapse, by which black holes and singularities form. We present here two types of analytic models for this process, which we believe are the simplest available; the first involves collapsing spherical shells of light, analyzed mainly in Eddington-Finkelstein coordinates; the second involves collapsing spheres filled with a perfect fluid, analyzed mainly in Painleve-Gullstrand coordinates. Our main goal is pedagogical simplicity and algebraic completeness, but we also present some results that we believe are new, such as the collapse of a light shell in Kruskal-Szekeres coordinates.

  11. Collapsed Lung: MedlinePlus Health Topic

    Science.gov (United States)

    ... Spanish Pneumothorax - infants (Medical Encyclopedia) Also in Spanish Topic Image MedlinePlus Email Updates Get Collapsed Lung updates ... Lung surgery Pneumothorax - slideshow Pneumothorax - infants Related Health Topics Chest Injuries and Disorders Lung Diseases Pleural Disorders ...

  12. Creep collapse of TAPS fuel cladding

    International Nuclear Information System (INIS)

    Chaudhry, S.M.; Anand, A.K.

    1975-01-01

    Densification of UO 2 can cause axial gaps between fuel pelets and cladding in unsupported (internally) at these regions. An analysis is carried out regarding the possibility of creep collapse in these regions. The analysis is based on Timoshenko's theory of collapse. At various times during the residence of fuel in reactor following parameters are calculated : (1) inelastic collapse of perfectly circular tubes (2) plastic instability in oval tubes (3) effect of creep on ovality. Creep is considered to be a non-linear combination of the following : (a) thermal creep (b) intresenic creep (c) stress aided radiation enhanced (d) stress free growth (4) Critical pressure ratio. The results obtained are compared with G.E. predictions. The results do not predict collapse of TAPS fuel cladding for five year residence time. (author)

  13. Four tails problems for dynamical collapse theories

    Science.gov (United States)

    McQueen, Kelvin J.

    2015-02-01

    The primary quantum mechanical equation of motion entails that measurements typically do not have determinate outcomes, but result in superpositions of all possible outcomes. Dynamical collapse theories (e.g. GRW) supplement this equation with a stochastic Gaussian collapse function, intended to collapse the superposition of outcomes into one outcome. But the Gaussian collapses are imperfect in a way that leaves the superpositions intact. This is the tails problem. There are several ways of making this problem more precise. But many authors dismiss the problem without considering the more severe formulations. Here I distinguish four distinct tails problems. The first (bare tails problem) and second (structured tails problem) exist in the literature. I argue that while the first is a pseudo-problem, the second has not been adequately addressed. The third (multiverse tails problem) reformulates the second to account for recently discovered dynamical consequences of collapse. Finally the fourth (tails problem dilemma) shows that solving the third by replacing the Gaussian with a non-Gaussian collapse function introduces new conflict with relativity theory.

  14. Nonlinear wave collapse and strong turbulence

    International Nuclear Information System (INIS)

    Robinson, P.A.

    1997-01-01

    The theory and applications of wave self-focusing, collapse, and strongly nonlinear wave turbulence are reviewed. In the last decade, the theory of these phenomena and experimental realizations have progressed rapidly. Various nonlinear wave systems are discussed, but the simplest case of collapse and strong turbulence of Langmuir waves in an unmagnetized plasma is primarily used in explaining the theory and illustrating the main ideas. First, an overview of the basic physics of linear waves and nonlinear wave-wave interactions is given from an introductory perspective. Wave-wave processes are then considered in more detail. Next, an introductory overview of the physics of wave collapse and strong turbulence is provided, followed by a more detailed theoretical treatment. Later sections cover numerical simulations of Langmuir collapse and strong turbulence and experimental applications to space, ionospheric, and laboratory plasmas, including laser-plasma and beam-plasma interactions. Generalizations to self-focusing, collapse, and strong turbulence of waves in other systems are also discussed, including nonlinear optics, solid-state systems, magnetized auroral and astrophysical plasmas, and deep-water waves. The review ends with a summary of the main ideas of wave collapse and strong-turbulence theory, a collection of open questions in the field, and a brief discussion of possible future research directions. copyright 1997 The American Physical Society

  15. Current status of relativistic core collapse simulations

    Energy Technology Data Exchange (ETDEWEB)

    Font, Jose A [Departamento de Astronomia y Astrofisica, Universidad de Valencia, Dr. Moliner 50, 46100 Burjassot (Valencia) (Spain)

    2007-05-15

    With the first generation of ground-based gravitational wave laser interferometers already taking data, the availability of reliable waveform templates from astrophysical sources, which may help extract the signal from the anticipated noisy data, is urgently required. Gravitational stellar core collapse supernova has traditionally been considered among the most important astrophysical sources of potentially detectable gravitational radiation. Only very recently the first multidimensional simulations of relativistic rotational core collapse have been possible (albeit for models with simplified input physics), thanks to the use of conservative formulations of the hydrodynamics equations and advanced numerical methodology, as well as stable formulations of Einstein's equations. In this paper, the current status of relativistic core collapse simulations is discussed, with the emphasis given to the modelling of the collapse dynamics and to the computation of the gravitational radiation in the existing numerical approaches. Work employing the conformally-flat approximation (CFC) of the 3+1 Einstein's equations is reported, as well as extensions of this approximation (CFC+) and investigations within the framework of the so-called BSSN formulation of the 3+1 gravitational field equations (with no approximation for the spacetime dynamics). On the other hand, the incorporation of magnetic fields and the MHD equations in numerical codes to improve the realism of core collapse simulations in general relativity, is currently an emerging field where significant progress is bound to be soon achieved. The paper also contains a brief discussion of magneto-rotational simulations of core collapse, aiming at addressing the effects of magnetic fields on the collapse dynamics and on the gravitational waveforms.

  16. Current status of relativistic core collapse simulations

    International Nuclear Information System (INIS)

    Font, Jose A

    2007-01-01

    With the first generation of ground-based gravitational wave laser interferometers already taking data, the availability of reliable waveform templates from astrophysical sources, which may help extract the signal from the anticipated noisy data, is urgently required. Gravitational stellar core collapse supernova has traditionally been considered among the most important astrophysical sources of potentially detectable gravitational radiation. Only very recently the first multidimensional simulations of relativistic rotational core collapse have been possible (albeit for models with simplified input physics), thanks to the use of conservative formulations of the hydrodynamics equations and advanced numerical methodology, as well as stable formulations of Einstein's equations. In this paper, the current status of relativistic core collapse simulations is discussed, with the emphasis given to the modelling of the collapse dynamics and to the computation of the gravitational radiation in the existing numerical approaches. Work employing the conformally-flat approximation (CFC) of the 3+1 Einstein's equations is reported, as well as extensions of this approximation (CFC+) and investigations within the framework of the so-called BSSN formulation of the 3+1 gravitational field equations (with no approximation for the spacetime dynamics). On the other hand, the incorporation of magnetic fields and the MHD equations in numerical codes to improve the realism of core collapse simulations in general relativity, is currently an emerging field where significant progress is bound to be soon achieved. The paper also contains a brief discussion of magneto-rotational simulations of core collapse, aiming at addressing the effects of magnetic fields on the collapse dynamics and on the gravitational waveforms

  17. Timescales of isotropic and anisotropic cluster collapse

    Science.gov (United States)

    Bartelmann, M.; Ehlers, J.; Schneider, P.

    1993-12-01

    From a simple estimate for the formation time of galaxy clusters, Richstone et al. have recently concluded that the evidence for non-virialized structures in a large fraction of observed clusters points towards a high value for the cosmological density parameter Omega0. This conclusion was based on a study of the spherical collapse of density perturbations, assumed to follow a Gaussian probability distribution. In this paper, we extend their treatment in several respects: first, we argue that the collapse does not start from a comoving motion of the perturbation, but that the continuity equation requires an initial velocity perturbation directly related to the density perturbation. This requirement modifies the initial condition for the evolution equation and has the effect that the collapse proceeds faster than in the case where the initial velocity perturbation is set to zero; the timescale is reduced by a factor of up to approximately equal 0.5. Our results thus strengthens the conclusion of Richstone et al. for a high Omega0. In addition, we study the collapse of density fluctuations in the frame of the Zel'dovich approximation, using as starting condition the analytically known probability distribution of the eigenvalues of the deformation tensor, which depends only on the (Gaussian) width of the perturbation spectrum. Finally, we consider the anisotropic collapse of density perturbations dynamically, again with initial conditions drawn from the probability distribution of the deformation tensor. We find that in both cases of anisotropic collapse, in the Zel'dovich approximation and in the dynamical calculations, the resulting distribution of collapse times agrees remarkably well with the results from spherical collapse. We discuss this agreement and conclude that it is mainly due to the properties of the probability distribution for the eigenvalues of the Zel'dovich deformation tensor. Hence, the conclusions of Richstone et al. on the value of Omega0 can be

  18. Review of collapse triggering mechanism of collapsible soils due to wetting

    Directory of Open Access Journals (Sweden)

    Ping Li

    2016-04-01

    Full Text Available Loess soil deposits are widely distributed in arid and semi-arid regions and constitute about 10% of land area of the world. These soils typically have a loose honeycomb-type meta-stable structure that is susceptible to a large reduction in total volume or collapse upon wetting. Collapse characteristics contribute to various problems to infrastructures that are constructed on loess soils. For this reason, collapse triggering mechanism for loess soils has been of significant interest for researchers and practitioners all over the world. This paper aims at providing a state-of-the-art review on collapse mechanism with special reference to loess soil deposits. The collapse mechanism studies are summarized under three different categories, i.e. traditional approaches, microstructure approach, and soil mechanics-based approaches. The traditional and microstructure approaches for interpreting the collapse behavior are comprehensively summarized and critically reviewed based on the experimental results from the literature. The soil mechanics-based approaches proposed based on the experimental results of both compacted soils and natural loess soils are reviewed highlighting their strengths and limitations for estimating the collapse behavior. Simpler soil mechanics-based approaches with less parameters or parameters that are easy-to-determine from conventional tests are suggested for future research to better understand the collapse behavior of natural loess soils. Such studies would be more valuable for use in conventional geotechnical engineering practice applications.

  19. Progressive Collapse of High-Rise Buildings from Fire

    Directory of Open Access Journals (Sweden)

    Pershakov Valerii

    2016-01-01

    Full Text Available Considers ensuring the stability of structures of high-rise buildings against progressive collapse due to fire, proposed measures to ensure the stability of high-rise buildings due to progressive collapse. The analysis of large fires in high-rise buildings with progressive collapse and review of the literature on the issue of progressive collapse. The analysis of the Ukrainian normative documents on progressive collapse resistance.

  20. Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor

    Directory of Open Access Journals (Sweden)

    d'Avila Joana C

    2012-02-01

    Full Text Available Abstract Background Traumatic brain injury (TBI induces activation of microglia. Activated microglia can in turn increase secondary injury and impair recovery. This innate immune response requires hours to days to become fully manifest, thus providing a clinically relevant window of opportunity for therapeutic intervention. Microglial activation is regulated in part by poly(ADP-ribose polymerase-1 (PARP-1. Inhibition of PARP-1 activity suppresses NF-kB-dependent gene transcription and thereby blocks several aspects of microglial activation. Here we evaluated the efficacy of a PARP inhibitor, INO-1001, in suppressing microglial activation after cortical impact in the rat. Methods Rats were subjected to controlled cortical impact and subsequently treated with 10 mg/kg of INO-1001 (or vehicle alone beginning 20 - 24 hours after the TBI. Brains were harvested at several time points for histological evaluation of inflammation and neuronal survival, using markers for microglial activation (morphology and CD11b expression, astrocyte activation (GFAP, and neuronal survival (NeuN. Rats were also evaluated at 8 weeks after TBI using measures of forelimb dexterity: the sticky tape test, cylinder test, and vermicelli test. Results Peak microglial and astrocyte activation was observed 5 to 7 days after this injury. INO-1001 significantly reduced microglial activation in the peri-lesion cortex and ipsilateral hippocampus. No rebound inflammation was observed in rats that were treated with INO-1001 or vehicle for 12 days followed by 4 days without drug. The reduced inflammation was associated with increased neuronal survival in the peri-lesion cortex and improved performance on tests of forelimb dexterity conducted 8 weeks after TBI. Conclusions Treatment with a PARP inhibitor for 12 days after TBI, with the first dose given as long as 20 hours after injury, can reduce inflammation and improve histological and functional outcomes.

  1. Inflationary gravitational waves in collapse scheme models

    Energy Technology Data Exchange (ETDEWEB)

    Mariani, Mauro, E-mail: mariani@carina.fcaglp.unlp.edu.ar [Facultad de Ciencias Astronómicas y Geofísicas, Universidad Nacional de La Plata, Paseo del Bosque S/N, 1900 La Plata (Argentina); Bengochea, Gabriel R., E-mail: gabriel@iafe.uba.ar [Instituto de Astronomía y Física del Espacio (IAFE), UBA-CONICET, CC 67, Suc. 28, 1428 Buenos Aires (Argentina); León, Gabriel, E-mail: gleon@df.uba.ar [Departamento de Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria – Pab. I, 1428 Buenos Aires (Argentina)

    2016-01-10

    The inflationary paradigm is an important cornerstone of the concordance cosmological model. However, standard inflation cannot fully address the transition from an early homogeneous and isotropic stage, to another one lacking such symmetries corresponding to our present universe. In previous works, a self-induced collapse of the wave function has been suggested as the missing ingredient of inflation. Most of the analysis regarding the collapse hypothesis has been solely focused on the characteristics of the spectrum associated to scalar perturbations, and within a semiclassical gravity framework. In this Letter, working in terms of a joint metric-matter quantization for inflation, we calculate, for the first time, the tensor power spectrum and the tensor-to-scalar ratio corresponding to the amplitude of primordial gravitational waves resulting from considering a generic self-induced collapse.

  2. Noncrossing timelike singularities of irrotational dust collapse

    International Nuclear Information System (INIS)

    Liang, E.P.T.

    1979-01-01

    Known naked singularities in spherical dust collapse are either due to shell-crossing or localized to the central world line. They will probably be destroyed by pressure gradients or blue-shift instabilities. To violate the cosmic censorship hypothesis in a more convincing and general context, collapse solutions with naked singularities that are at least nonshell-crossing and nonlocalized need to be constructed. Some results concerning the probable structure of a class of nonshellcrossing and nonlocalized timelike singularities are reviewed. The cylindrical dust model is considered but this model is not asymptotically flat. To make these noncrossing singularities viable counter examples to the cosmic censorship hypothesis, the occurrence of such singularities in asymptotically flat collapse needs to be demonstrated. (UK)

  3. Did mud contribute to freeway collapse?

    Science.gov (United States)

    Hough, Susan E.; Friberg, Paul A.; Busby, Robert; Field, Edward F.; Jacob, Klaus H.; Borcherdt, Roger D.

    At least 41 people were killed October 17 when the upper tier of the Nimitz Freeway in Oakland, Calif., collapsed during the Ms = 7.1 Loma Prieta earthquake. Seismologists studying aftershocks concluded that soil conditions and resulting ground motion amplification were important in the failure of the structure and should be considered in the reconstruction of the highway.Structural design weaknesses in the two-tiered freeway, known as the Cypress structure, had been identified before the tragedy. The seismologists, from Lamont Doherty Geological Observatory in Palisades, N.Y., and the U.S. Geological Survey in Menlo Park, Calif., found that the collapsed section was built on fill over Bay mud. A southern section of the Cypress structure built on alluvium of Quaternary age did not collapse (see Figure 1).

  4. Effect of 3-aminobenzamide, PARP inhibitor, on matrix metalloproteinase-9 level in plasma and brain of ischemic stroke model

    International Nuclear Information System (INIS)

    Koh, Seong-Ho; Chang, Dae-Il; Kim, Hee-Tae; Kim, Juhan; Kim, Myung-Ho; Kim, Kyung Suk; Bae, Inhee; Kim, Haekwon; Kim, Dong Won; Kim, Seung Hyun

    2005-01-01

    We investigated the effect of poly(ADP-ribose) polymerase (PARP) inhibitor on the levels of plasma and brain matrix metalloproteinase-9 (MMP-9) and the expression of nuclear factor kappa B (NF-κB) during experimental focal cerebral ischemia. The 3-aminobenzamide (3-AB), a PARP inhibitor, and saline were administered to 80 Sprague-Dawley rats [3-AB group; 5 rats for plasma sampling, 35 for brain sampling, and 40 for TTC staining] and to 85 rats (10, 35, and 40, respectively), respectively, 10 min before the occlusion of the left middle cerebral artery (MCAo) for 2 h. Infarct volume was measured by TTC staining, the serial levels of plasma and brain MMP-9 were measured by zymography just before and 2, 4, 8, 24, 48, and 72 h after MCAo, brain NF-κB activity was determined by Western blotting, and neutrophil infiltration was evaluated by assessing myeloperoxidase activity. Compared with control group, the levels of plasma and brain MMP-9, brain NF-κB, and MPO activities were significantly reduced in 3-AB group at each time point (p < 0.05). Plasma MMP-9 increased maximally at 4 h and then decreased rapidly, brain MMP-9 increased maximally at 24 h and persisted until 72 h, and NF-κB increased maximally at 24 h and then decreased slowly in both groups. Therefore, the PARP inhibitor reduces the expression of MMP-9 and NF-κB and the infiltration of neutrophils in ischemic stroke

  5. Risk of severe hematologic toxicities in cancer patients treated with PARP inhibitors: results of monotherapy and combination therapy trials

    Directory of Open Access Journals (Sweden)

    Alecu I

    2018-02-01

    Full Text Available Iulian Alecu, Tsveta Milenkova, Simon R Turner Research and Development, AstraZeneca UK Limited, Cambridge, UKThe tolerability profile of PARP inhibitors often includes hematologic toxicities, and the characterization of these adverse events is important to allow effective management by clinicians. Zhou et al1 recently carried out a meta-analysis of the incidence and relative risks of severe neutropenia, thrombocytopenia, and anemia events in 12 randomized controlled trials of PARP inhibitors, either as monotherapy or in combination with chemotherapy or radiotherapy. The authors concluded that olaparib resulted in a higher incidence of severe (common terminology criteria for adverse events [CTCAE] grade $3 neutropenia when compared with niraparib and veliparib; however, these conclusions are based on inappropriate and incomplete comparisons of hematologic toxicity with olaparib or veliparib in combination with myelotoxic chemotherapy versus niraparib monotherapy. While both monotherapy and combination therapy olaparib studies are discussed in the paper, the neutropenia analysis is based on olaparib data solely from studies in combination with paclitaxel or paclitaxel plus carboplatin. In order to inform the practicing clinician of the relative risk of hematologic toxicity associated with different PARP inhibitors, direct comparison needs to be conducted based on monotherapy, where applicable, as per the approved drug indication, otherwise the reader is given misleading information.View the original paper by Zhou et al.

  6. A phenanthrene derived PARP inhibitor is an extra-centrosomes de-clustering agent exclusively eradicating human cancer cells

    Directory of Open Access Journals (Sweden)

    Izraeli Shai

    2011-09-01

    Full Text Available Abstract Background Cells of most human cancers have supernumerary centrosomes. To enable an accurate chromosome segregation and cell division, these cells developed a yet unresolved molecular mechanism, clustering their extra centrosomes at two poles, thereby mimicking mitosis in normal cells. Failure of this bipolar centrosome clustering causes multipolar spindle structures and aberrant chromosomes segregation that prevent normal cell division and lead to 'mitotic catastrophe cell death'. Methods We used cell biology and biochemical methods, including flow cytometry, immunocytochemistry and live confocal imaging. Results We identified a phenanthrene derived PARP inhibitor, known for its activity in neuroprotection under stress conditions, which exclusively eradicated multi-centrosomal human cancer cells (mammary, colon, lung, pancreas, ovarian while acting as extra-centrosomes de-clustering agent in mitosis. Normal human proliferating cells (endothelial, epithelial and mesenchymal cells were not impaired. Despite acting as PARP inhibitor, the cytotoxic activity of this molecule in cancer cells was not attributed to PARP inhibition alone. Conclusion We identified a water soluble phenanthridine that exclusively targets the unique dependence of most human cancer cells on their supernumerary centrosomes bi-polar clustering for their survival. This paves the way for a new selective cancer-targeting therapy, efficient in a wide range of human cancers.

  7. Sonographic Analysis of the Collapsed Gall Bladder

    International Nuclear Information System (INIS)

    Han, Sang Suk; Choi, Jae Young; Choi, Seok Jin; Eun, Chung Ki; Nam, Kyung Jin; Lee, Jeong Mi

    1996-01-01

    This study was done to find answers for further following questions in cases of the collapsed gallbladder (GB) : What is the probability of the presence of stone when stony echo is visible in GB area? What is the probability of the presence of stone when only acoustic shadow is visible from GB area? What are the associated GB pathologies except stone or cholecystitis in previously mentioned situations and is it possible to differentiate them? What are the underlying pathologies of GB collapse without stony echo or acoustic shadow and is it possible to differentiate them sonographic ally? What are the rate and causes of re-expansion of the collapsed GB on follow-up study? Prospective study was done in 157 cases of collapsed GB with no visible or nearly no visible bile filled lumen in recent 3 years. Sonographic analysis for GB lesions was done in 61 confirmed cases. Changing pattern of GB lumen on follow-up study and their underlying pathologies were analyzed in 28 cases. Initial sonographic examination was done with 3 or 3.5 MHz transducer. No other transducer was used in cases showing stony echo or acoustic shadow in GB area, but additional examination was done with 5 or 7-4 MHz transducer in cases without stony echo or acoustic shadow. Among 31 cases, which showed stony echo, stone was found in 30 cases and milk of calcium bile in one case. Stone was present in all of the 11 cases which showed only acoustic shadow from the collapsed GB without stony echo. GB cancer was accompanied in 2 cases among upper 42 cases, and its possibility could be suspected sonographic ally. Underlying pathologies of the 19cases without stony echo or acoustic shadow were as follows : GB stone (3), cholecystitis (6), GB cancer (1), bile plug syndrome (1), hepatitis (5), and ascites (3). And sonographic differentiation of the underlying causes for the collapse was possible in only 1 case of GB cancer. Among 28 cases of the follow-up study, 20 cases showed re-expansion of the GB lumen and

  8. Relativistic collapse using Regge calculus: Pt. 1

    International Nuclear Information System (INIS)

    Dubal, M.R.; Leicester Univ.

    1989-01-01

    Regge calculus is used to simulate the dynamical collapse of model stars. In this paper we describe the general methodology of including a perfect fluid in dynamical Regge calculus spacetimes. The Regge-Einstein equations for spherical collapse are obtained and are then specialised to mimic a particular continuum gauge. The equivalent continuum problem is also set up. This is to be solved using standard numerical techniques (i.e. the method of finite difference). A subsequent paper will consider the solution of the equations presented here and will use the continuum problem for comparison purposes in order to check the Regge calculus results. (author)

  9. Collapse and equilibrium of rotating, adiabatic clouds

    International Nuclear Information System (INIS)

    Boss, A.P.

    1980-01-01

    A numerical hydrodynamics computer code has been used to follow the collapse and establishment of equilibrium of adiabatic gas clouds restricted to axial symmetry. The clouds are initially uniform in density and rotation, with adiabatic exponents γ=5/3 and 7/5. The numerical technique allows, for the first time, a direct comparison to be made between the dynamic collapse and approach to equilibrium of unconstrained clouds on the one hand, and the results for incompressible, uniformly rotating equilibrium clouds, and the equilibrium structures of differentially rotating polytropes, on the other hand

  10. Static axisymmetric discs and gravitational collapse

    Energy Technology Data Exchange (ETDEWEB)

    Chamorro, A.; Gregory, R.; Stewart, J.M.

    1987-09-08

    Regular static axisymmetric vacuum solutions of Einstein's field equations representing the exterior field of a finite thin disc are found. These are used to describe the slow collapse of a disc-like object. If no conditions are placed on the matter, a naked singularity is formed and the cosmic censorship hypothesis would be violated. Imposition of the weak energy condition, however, prevents slow collapse to a singularity and preserves the validity of this hypothesis. The validity of the hoop conjecture is also discussed.

  11. Suppression of Homologous Recombination by insulin-like growth factor-1 inhibition sensitizes cancer cells to PARP inhibitors

    International Nuclear Information System (INIS)

    Amin, Oreekha; Beauchamp, Marie-Claude; Nader, Paul Abou; Laskov, Ido; Iqbal, Sanaa; Philip, Charles-André; Yasmeen, Amber; Gotlieb, Walter H.

    2015-01-01

    Impairment of homologous recombination (HR) is found in close to 50 % of ovarian and breast cancer. Tumors with BRCA1 mutations show increased expression of the Insulin-like growth factor type 1 receptor (IGF-1R). We previously have shown that inhibition of IGF-1R results in growth inhibition and apoptosis of ovarian tumor cells. In the current study, we aimed to investigate the correlation between HR and sensitivity to IGF-1R inhibition. Further, we hypothesized that IGF-1R inhibition might sensitize HR proficient cancers to Poly ADP ribose polymerase (PARP) inhibitors. Using ovarian and breast cancer cellular models with known BRCA1 status, we evaluated their HR functionality by RAD51 foci formation assay. The 50 % lethal concentration (LC50) of Insulin-like growth factor type 1 receptor kinase inhibitor (IGF-1Rki) in these cells was assessed, and western immunoblotting was performed to determine the expression of proteins involved in the IGF-1R pathway. Moreover, IGF-1R inhibitors were added on HR proficient cell lines to assess mRNA and protein expression of RAD51 by qPCR and western blot. Also, we explored the interaction between RAD51 and Insulin receptor substance 1 (IRS-1) by immunoprecipitation. Next, combination effect of IGF-1R and PARP inhibitors was evaluated by clonogenic assay. Cells with mutated/methylated BRCA1 showed an impaired HR function, and had an overactivation of the IGF-1R pathway. These cells were more sensitive to IGF-1R inhibition compared to HR proficient cells. In addition, the IGF-IR inhibitor reduced RAD51 expression at mRNA and protein levels in HR proficient cells, and sensitized these cells to PARP inhibitor. Targeting IGF-1R might lead to improved personalized therapeutic approaches in cancer patients with HR deficiency. Targeting both PARP and IGF-1R might increase the clinical efficacy in HR deficient patients and increase the population of patients who may benefit from PARP inhibitors

  12. State-of-the-Art-Review of Collapsible Soils

    Directory of Open Access Journals (Sweden)

    A. A. AL-Rawas

    2000-12-01

    Full Text Available Collapsible soils are encountered in arid and semi-arid regions. Such soils cause potential construction problems due to their collapse upon wetting. The collapse phenomenon is primarily related to the open structure of the soil. Several soil collapse classifications based on parameters such as moisture content, dry density, Atterberg limits and clay content have been proposed in the literature as indicators of the soil collapse potential. Direct measurement of the magnitude of collapse, using laboratory and/or field tests, is essential once a soil showed indications of collapse potential. Treatment methods such as soil replacement, compaction control and chemical stabilization showed significant reduction in the settlement of collapsible soils. The design of foundations on collapsible soils depends on the depth of the soil, magnitude of collapse and economics of the design. Strip foundations are commonly used when collapsing soil extends to a shallow depth while piles and drilled piers are recommended in cases where the soil extends to several meters. This paper provides a comprehensive review of collapsible soils. These include the different types of collapsible soils, mechanisms of collapse, identification and classification methods, laboratory and field testing, treatment methods and guidelines for foundation design.

  13. Nonlinear Progressive Collapse Analysis Including Distributed Plasticity

    Directory of Open Access Journals (Sweden)

    Mohamed Osama Ahmed

    2016-01-01

    Full Text Available This paper demonstrates the effect of incorporating distributed plasticity in nonlinear analytical models used to assess the potential for progressive collapse of steel framed regular building structures. Emphasis on this paper is on the deformation response under the notionally removed column, in a typical Alternate Path (AP method. The AP method employed in this paper is based on the provisions of the Unified Facilities Criteria – Design of Buildings to Resist Progressive Collapse, developed and updated by the U.S. Department of Defense [1]. The AP method is often used for to assess the potential for progressive collapse of building structures that fall under Occupancy Category III or IV. A case study steel building is used to examine the effect of incorporating distributed plasticity, where moment frames were used on perimeter as well as the interior of the three dimensional structural system. It is concluded that the use of moment resisting frames within the structural system will enhance resistance to progressive collapse through ductile deformation response and that it is conserative to ignore the effects of distributed plasticity in determining peak displacement response under the notionally removed column.

  14. General relativistic collapse of rotating stars

    International Nuclear Information System (INIS)

    Nakamura, T.

    1984-01-01

    When a rotating star begins to collapse, the gravity becomes so strong that there appears a region from which even a photon cannot escape. After the distortion of space-time is radiated as gravitational waves, a Kerr black hole is formed finally. One of the main goals for numerical relativity is to simulate the collapse of a rotating star under realistic conditions. However, to know both the dynamics of matter and the propagation of gravitational radiation seems to be very difficult. Therefore, in this paper the problem is divided into 4 stages. They are: (1) The time evolution of pure gravitational waves is calculated in a 2-D code. (2) In this stage, the author tries to understand the dynamics of a collapsing, rotating star in 2D code. (3) Combining the techniques from stages 1, 2, the author tries to know both the dynamics of matter and the propagation of gravitational waves generated by the nonspherical motion of matter. (4) The author simulates the gravitational collapse of a rotating star to a black hole in 3D. 25 references, 12 figures, 1 table

  15. Langmuir field structures favored in wave collapse

    International Nuclear Information System (INIS)

    Robinson, P.A.; Wouters, M.J.; Broderick, N.G.

    1996-01-01

    Study of Langmuir collapse thresholds shows that they have little polarization dependence and that moving packets have the lowest thresholds in the undamped case. However, incorporation of damping into the density response inhibits collapse of packets moving at more than a small fraction of the sound speed. Investigation of energy transfer to packets localized in density wells emdash the nucleation process emdash shows that at most a few trapped states can exist and that energy transfer is most effective when there is a single barely-trapped state. Coupled with an argument that closely packed wave packets have lower collapse thresholds, this argument yields an estimate of the number density of localized nucleating states in a turbulent plasma. It also leads to a simple and direct semiquantitative estimate of the collapse threshold. All these results are in accord with previous numerical simulations incorporating ion-sound damping, which show a preponderance of slow-moving or stationary packets with little or no intrinsic polarization dependence of thresholds. Likewise, the number densities obtained are in good agreement with simulation values, and the simple estimate of the threshold is semiquantitatively correct. The extent of the agreement supports the nucleation scenario with close-packed nucleation sites in the turbulent state. copyright 1996 American Institute of Physics

  16. Identification and behavior of collapsible soils.

    Science.gov (United States)

    2011-01-01

    Loess is a soil that can exhibit large deformations upon wetting. Cases of wetting induced collapse in loess have : been documented for natural deposits and man-made fills. These issues are of concern to the Indiana DOT due to the growth : of the sta...

  17. The collapse of turbulence in the evening

    NARCIS (Netherlands)

    Wiel, van de B.J.H.; Moene, A.F.; Jonker, H.J.J.; Baas, P.; Basu, S.; Sun, J.; Holtslag, A.A.M.

    2012-01-01

    A common experience in everyday weather is the fact that near-surface wind speeds tend to weaken in the evening, particularly in fair weather conditions. This cessation of wind usually coincides with the collapse of turbulence which leads to a quiet flow near the ground. As the absence of turbulent

  18. Collapsible structure for an antenna reflector

    Science.gov (United States)

    Trubert, M. R. (Inventor)

    1973-01-01

    A collapsible support for an antenna reflector for use in supporting spacecraft antennas is described. The support has a regid base and a number of struts which are pivoted at the base. The deployment of the struts and their final configuration for supporting the antenna are illustrated.

  19. Hydrogen-Poor Core-Collapse Supernovae

    Science.gov (United States)

    Pian, Elena; Mazzali, Paolo A.

    Hydrogen-poor core-collapse supernovae (SNe) signal the explosive death of stars more massive than the progenitors of hydrogen-rich core-collapse supernovae, i.e., approximately in the range 15-50 M⊙ in main sequence. Since hydrogen-poor core-collapse supernovae include those that accompany gamma-ray bursts (GRBs), which were all rigorously identified with type Ic supernovae, their explosion energies cover almost two decades. The light curves and spectra are consequently very heterogeneous and often bear the signature of an asymmetric, i.e., aspherical, explosion. Asphericity is best traced by early-time (within days of the explosion) optical spectropolarimetry and by late-epoch (more than ˜ 100 days after explosion) low-resolution spectroscopy. While the relationship between hydrogen-poor core-collapse supernovae to hydrogen-poor super-luminous supernovae is not understood, a known case of association between an ultra-long gamma-ray burst and a very luminous hydrogen-poor supernova may help unraveling the connection. This is tantalizingly pointing to a magnetar powering source for both phenomena, although this scenario is still highly speculative. Host galaxies of hydrogen-poor supernovae are always star forming; in those of completely stripped supernovae and gamma-ray burst supernovae, the spatial distribution of the explosions follows the blue/ultraviolet light, with a correlation that is more than linear.

  20. Gravitational collapse with decaying vacuum energy

    Indian Academy of Sciences (India)

    Abstract. The effect of dark energy on the end state of spherical radiation collapse is considered within the context of the cosmic censorship hypothesis. It is found that it is possible to have both black holes as well as naked singularities.

  1. Schuster's law, black holes and gravitational collapse

    International Nuclear Information System (INIS)

    Massa, C.

    1988-01-01

    Consequences of the application of Schuster's law to black holes are investigated. It is shown that Schuster's law can reduce the intrinsic angular momentum of a collapsing body. The possibility is supposed that Schuster's law provides the general mechanism required by the cosmic censorship hypothesis which is taken seriously as a fundamental law of nature

  2. A spherical collapse solution with neutrino outflow

    International Nuclear Information System (INIS)

    Glass, E.N.

    1990-01-01

    A three-parameter family of solutions of Einstein's field equations is given that represents a collapsing perfect fluid with outgoing neutrino flux. Solutions with ''naked'' singularities are exhibited. They can be forbidden by requiring pressure less than or equal to the density as a condition of cosmic censorship

  3. Gravitational wave generation by stellar core collapse

    International Nuclear Information System (INIS)

    Moore, T.A.

    1981-01-01

    Stars which have masses greater than 5 to 8 solar masses are thought to undergo a stage of catastrophic core collapse and subsequent supernova explosion at the end of their lives. If the core is not spherically symmetric, the bounce which halts its collapse at transnuclear densities will generate a pulse of gravitational waves. This thesis presents a fully relativistic model of core collapse which treats deviations from spherical symmetry as small perturbations on a spherical background. This model may be used to predict qualitative and quantitative features of the gravitational radiation emitted by stellar cores with odd-parity, axisymmetric fluid perturbations, and represents a first step in the application of perturbative methods to more general asymmetries. The first chapter reviews the present consensus on the physics of core collapse and outlines the important features, assumptions, and limitations of the model. A series of model runs are presented and discussed. Finally, several proposals for future research are presented. Subsequent chapters explore in detail the mathematical features of the present model and its realization on the computer

  4. The heterogeneity of world trade collapses

    NARCIS (Netherlands)

    P.A.G. van Bergeijk (Peter)

    2015-01-01

    textabstractThis paper analyses drivers of imports during the major world trade collapses of the Great Depression (1930s; 34 countries) and the Great Recession (1930s; 173 countries). The analysis deals with the first year of these episodes and develops a small empirical model that shows a

  5. Increased transcript level of poly(ADP-ribose) polymerase (PARP-1) in human tricuspid compared with bicuspid aortic valves correlates with the stenosis severity

    International Nuclear Information System (INIS)

    Nagy, Edit; Caidahl, Kenneth; Franco-Cereceda, Anders; Bäck, Magnus

    2012-01-01

    Highlights: ► Oxidative stress has been implicated in the pathomechanism of calcific aortic valve stenosis. ► We assessed the transcript levels for PARP-1 (poly(ADP-ribose) polymerase), acts as a DNA damage nick sensor in stenotic valves. ► Early stage of diseased tricuspid valves exhibited higher mRNA levels for PARP-1 compared to bicuspid valves. ► The mRNA levels for PARP-1 inversely correlated with the clinical stenosis severity in tricuspid valves. ► Our data demonstrated that DNA damage pathways might be associated with stenosis severity only in tricuspid valves. -- Abstract: Oxidative stress may contribute to the hemodynamic progression of aortic valve stenosis, and is associated with activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) 1. The aim of the present study was to assess the transcriptional profile and the topological distribution of PARP-1 in human aortic valves, and its relation to the stenosis severity. Human stenotic aortic valves were obtained from 46 patients undergoing aortic valve replacement surgery and used for mRNA extraction followed by quantitative real-time PCR to correlate the PARP-1 expression levels with the non invasive hemodynamic parameters quantifying the stenosis severity. Primary isolated valvular interstitial cells (VICs) were used to explore the effects of cytokines and leukotriene C 4 (LTC 4 ) on valvular PARP-1 expression. The thickened areas of stenotic valves with tricuspid morphology expressed significantly higher levels of PARP-1 mRNA compared with the corresponding part of bicuspid valves (0.501 vs 0.243, P = 0.01). Furthermore, the quantitative gene expression levels of PARP-1 were inversely correlated with the aortic valve area (AVA) (r = −0.46, P = 0.0469) and AVA indexed for body surface area (BSA) (r = −0.498; P = 0.0298) only in tricuspid aortic valves. LTC 4 (1 nM) significantly elevated the mRNA levels of PARP-1 by 2.38-fold in VICs. Taken together, these data suggest that

  6. Defibrotide Stimulates Angiogenesis and Protects Endothelial Cells from Calcineurin Inhibitor-Induced Apoptosis via Upregulation of AKT/Bcl-xL.

    Science.gov (United States)

    Wang, Xiangmin; Pan, Bin; Hashimoto, Yuko; Ohkawara, Hiroshi; Xu, Kailin; Zeng, Lingyu; Ikezoe, Takayuki

    2018-01-01

    Sinusoidal obstruction syndrome is a life-threatening complication that can occur after haematopoietic stem cell transplantation. Defibrotide (DF) has been approved for the treatment of individuals with severe sinusoidal obstruction syndrome following haematopoietic stem cell transplantation in the European Union and the United States. However, the precise mechanisms by which DF protects endothelial cells remain to be elucidated. In this study, we found that DF stimulated angiogenesis in vitro and in vivo as assessed by vascular tube formation, scratch-wound repair and Matrigel plug assays. These effects were associated with an activation of pro-survival signalling pathways, including AKT (protein kinase B), ERK (extracellular signal-regulated kinases) and p38. More importantly, DF alleviated calcineurin inhibitor-induced growth inhibition and apoptosis of human umbilical vein endothelial cells and human hepatic sinusoidal endothelial cells in parallel with upregulation of anti-apoptotic protein B-cell lymphoma-extra-large (Bcl-xL), which was mediated by AKT (protein kinase B). Notably, these effects were abrogated when Bcl-xL was depleted by small interfering RNA (ribonucleic acid). In addition, DF counteracted calcineurin inhibitor-induced activation of nuclear factor-κB and Janus kinase 2 (JAK2)/Signal Transducer and Activator of Transcription 3 (STAT3) signalling and production of cytokines in vascular endothelial cell-derived EA.hy926 cells. Taken together, DF has pro-angiogenic, anti-apoptotic and anti-inflammatory effects on endothelial cells. DF is a potentially useful agent to prevent the development of, and treat individuals with, endothelial cell injury-related complications after haematopoietic stem cell transplantation. Schattauer GmbH Stuttgart.

  7. Overcoming Resistance of Cancer Cells to PARP-1 Inhibitors with Three Different Drug Combinations.

    Directory of Open Access Journals (Sweden)

    Michal Yalon

    Full Text Available Inhibitors of poly[ADP-ribose] polymerase 1 (PARPis show promise for treatment of cancers which lack capacity for homologous recombination repair (HRR. However, new therapeutic strategies are required in order to overcome innate and acquired resistance to these drugs and thus expand the array of cancers that could benefit from them. We show that human cancer cell lines which respond poorly to ABT-888 (a PARPi, become sensitive to it when co-treated with vorinostat (a histone deacetylase inhibitor (HDACi. Vorinostat also sensitized PARPis insensitive cancer cell lines to 6-thioguanine (6-TG-a drug that targets PARPis sensitive cells. The sensitizing effect of vorinostat was associated with increased phosphorylation of eukaryotic initiation factor (eIF 2α which in and of itself increases the sensitivity of cancer cells to ABT-888. Importantly, these drug combinations did not affect survival of normal fibroblasts and breast cells, and significantly increased the inhibition of xenograft tumor growth relative to each drug alone, without affecting the mice weight or their liver and kidney function. Our results show that combination of vorinostat and ABT-888 could potentially prove useful for treatment of cancer with innate resistance to PARPis due to active HRR machinery, while the combination of vorinostat and 6-TG could potentially overcome innate or acquired resistance to PARPis due to secondary or reversal BRCA mutations, to decreased PARP-1 level or to increased expression of multiple drug resistant proteins. Importantly, drugs which increase phosphorylation of eIF2α may mimic the sensitizing effect of vorinostat on cellular response to PARPis or to 6-TG, without activating all of its downstream effectors.

  8. Expression of DNA Damage Response Molecules PARP1, γH2AX, BRCA1, and BRCA2 Predicts Poor Survival of Breast Carcinoma Patients

    Directory of Open Access Journals (Sweden)

    See-Hyoung Park

    2015-08-01

    Full Text Available BACKGROUND: Poly(ADP-ribose polymerase 1 (PARP1, γH2AX, BRCA1, and BRCA2 are conventional molecular indicators of DNA damage in cells and are often overexpressed in various cancers. In this study, we aimed, using immunohistochemical detection, whether the co-expression of PARP1, γH2AX, BRCA1, and BRCA2 in breast carcinoma (BCA tissue can provide more reliable prediction of survival of BCA patients. MATERIALS AND METHODS: We investigated immunohistochemical expression and prognostic significance of the expression of PARP1, γH2AX, BRCA1, and BRCA2 in 192 cases of BCAs. RESULTS: The expression of these four molecules predicted earlier distant metastatic relapse, shorter overall survival (OS, and relapse-free survival (RFS by univariate analysis. Multivariate analysis revealed the expression of PARP1, γH2AX, and BRCA2 as independent poor prognostic indicators of OS and RFS. In addition, the combined expressional pattern of BRCA1, BRCA2, PARP1, and γH2AX (CSbbph was an additional independent prognostic predictor for OS (P < .001 and RFS (P < .001. The 10-year OS rate was 95% in the CSbbph-low (CSbbph scores 0 and 1 subgroup, but that was only 35% in the CSbbph-high (CSbbph score 4 subgroup. CONCLUSION: This study has demonstrated that the individual and combined expression patterns of PARP1, γH2AX, BRCA1, and BRCA2 could be helpful in determining an accurate prognosis for BCA patients and for the selection of BCA patients who could potentially benefit from anti-PARP1 therapy with a combination of genotoxic chemotherapeutic agents.

  9. PARP-1 Variant Rs1136410 Confers Protection against Coronary Artery Disease in a Chinese Han Population: A Two-Stage Case-Control Study Involving 5643 Subjects

    Directory of Open Access Journals (Sweden)

    Xue-bin Wang

    2017-11-01

    Full Text Available Inhibition of poly(ADP-ribose polymerase (PARP may protect against coronary artery disease (CAD in animal models, and rs1136410, a non-synonymous single nucleotide polymorphism (SNP in PARP-1, has a potential impact on PARP activities in vitro. This two-stage case-control study, involving 2803 CAD patients and 2840 controls, aimed to investigate the associations of PARP-1 rs1136410 with CAD development, lipid levels, PARP activities, 8-hydroxy-2′-dexyguanosine (8-OHdG, and interleukin (IL-6 levels in a Chinese Han population. Assuming a recessive model, the variant genotype GG of SNP rs1136410 showed a significantly inverse association with CAD risk (adjusted odds ratio (OR = 0.73, P < 0.001, left main coronary artery (LMCA lesions (P = 0.003, vessel scores (P = 0.003, and modified Gensini scores (P < 0.001. There were significant correlations of SNP rs1136410 with higher levels of total cholesterol (TC and lower levels of high-density lipoprotein cholesterol (HDL-c. In gene-environment interaction analyses, participants with the variant genotype GG, but without smoking habit, type 2 diabetes mellitus, and hyperlipidemia, conferred an 84% (P < 0.001 decreased risk of CAD. The genotype-phenotype correlation analyses further supported the functional roles of SNP rs1136410 in decreasing PARP activities and 8-OHdG levels. Taken together, our data suggest that SNP rs1136410 may confer protection against CAD through modulation of PARP activities and gene-environment interactions in a Chinese Han population.

  10. New approaches of PARP-1 inhibitors in human lung cancer cells and cancer stem-like cells by some selected anthraquinone-derived small molecules.

    Directory of Open Access Journals (Sweden)

    Yu-Ru Lee

    Full Text Available Poly (ADP-ribose polymerase-1 (PARP-1 and telomerase, as well as DNA damage response pathways are targets for anticancer drug development, and specific inhibitors are currently under clinical investigation. The purpose of this work is to evaluate anticancer activities of anthraquinone-derived tricyclic and tetracyclic small molecules and their structure-activity relationships with PARP-1 inhibition in non-small cell lung cancer (NSCLC and NSCLC-overexpressing Oct4 and Nanog clone, which show high-expression of PARP-1 and more resistance to anticancer drug. We applied our library selected compounds to NCI's 60 human cancer cell-lines (NCI-60 in order to generate systematic profiling data. Based on our analysis, it is hypothesized that these drugs might be, directly and indirectly, target components to induce mitochondrial permeability transition and the release of pro-apoptotic factors as potential anti-NSCLC or PARP inhibitor candidates. Altogether, the most active NSC747854 showed its cytotoxicity and dose-dependent PARP inhibitory manner, thus it emerges as a promising structure for anti-cancer therapy with no significant negative influence on normal cells. Our studies present evidence that telomere maintenance should be taken into consideration in efforts not only to overcome drug resistance, but also to optimize the use of telomere-based therapeutics. These findings will be of great value to facilitate structure-based design of selective PARP inhibitors, in general, and telomerase inhibitors, in particular. Together, the data presented here expand our insight into the PARP inhibitors and support the resource-demanding lead optimization of structurally related small molecules for human cancer therapy.

  11. New Approaches of PARP-1 Inhibitors in Human Lung Cancer Cells and Cancer Stem-Like Cells by Some Selected Anthraquinone-Derived Small Molecules

    Science.gov (United States)

    Yu, Dah-Shyong; Huang, Kuo-Feng; Chou, Shih-Jie; Chen, Tsung-Chih; Lee, Chia-Chung; Chen, Chun-Liang; Chiou, Shih-Hwa; Huang, Hsu-Shan

    2013-01-01

    Poly (ADP-ribose) polymerase-1 (PARP-1) and telomerase, as well as DNA damage response pathways are targets for anticancer drug development, and specific inhibitors are currently under clinical investigation. The purpose of this work is to evaluate anticancer activities of anthraquinone-derived tricyclic and tetracyclic small molecules and their structure-activity relationships with PARP-1 inhibition in non-small cell lung cancer (NSCLC) and NSCLC-overexpressing Oct4 and Nanog clone, which show high-expression of PARP-1 and more resistance to anticancer drug. We applied our library selected compounds to NCI's 60 human cancer cell-lines (NCI-60) in order to generate systematic profiling data. Based on our analysis, it is hypothesized that these drugs might be, directly and indirectly, target components to induce mitochondrial permeability transition and the release of pro-apoptotic factors as potential anti-NSCLC or PARP inhibitor candidates. Altogether, the most active NSC747854 showed its cytotoxicity and dose-dependent PARP inhibitory manner, thus it emerges as a promising structure for anti-cancer therapy with no significant negative influence on normal cells. Our studies present evidence that telomere maintenance should be taken into consideration in efforts not only to overcome drug resistance, but also to optimize the use of telomere-based therapeutics. These findings will be of great value to facilitate structure-based design of selective PARP inhibitors, in general, and telomerase inhibitors, in particular. Together, the data presented here expand our insight into the PARP inhibitors and support the resource-demanding lead optimization of structurally related small molecules for human cancer therapy. PMID:23451039

  12. Identification and behavior of collapsible soils : [technical summary].

    Science.gov (United States)

    2011-01-01

    Collapsible soils are susceptible to large volumetric strains when they become saturated. Numerous soil types : fall in the general category of collapsible soils, including : loess, a well-known aeolian deposit, present throughout : most of Indiana. ...

  13. Dynamic Control of Collapse in a Vortex Airy Beam

    Science.gov (United States)

    Chen, Rui-Pin; Chew, Khian-Hooi; He, Sailing

    2013-01-01

    Here we study systematically the self-focusing dynamics and collapse of vortex Airy optical beams in a Kerr medium. The collapse is suppressed compared to a non-vortex Airy beam in a Kerr medium due to the existence of vortex fields. The locations of collapse depend sensitively on the initial power, vortex order, and modulation parameters. The collapse may occur in a position where the initial field is nearly zero, while no collapse appears in the region where the initial field is mainly distributed. Compared with a non-vortex Airy beam, the collapse of a vortex Airy beam can occur at a position away from the area of the initial field distribution. Our study shows the possibility of controlling and manipulating the collapse, especially the precise position of collapse, by purposely choosing appropriate initial power, vortex order or modulation parameters of a vortex Airy beam. PMID:23518858

  14. Unifying Research on Social-Ecological Resilience and Collapse.

    Science.gov (United States)

    Cumming, Graeme S; Peterson, Garry D

    2017-09-01

    Ecosystems influence human societies, leading people to manage ecosystems for human benefit. Poor environmental management can lead to reduced ecological resilience and social-ecological collapse. We review research on resilience and collapse across different systems and propose a unifying social-ecological framework based on (i) a clear definition of system identity; (ii) the use of quantitative thresholds to define collapse; (iii) relating collapse processes to system structure; and (iv) explicit comparison of alternative hypotheses and models of collapse. Analysis of 17 representative cases identified 14 mechanisms, in five classes, that explain social-ecological collapse. System structure influences the kind of collapse a system may experience. Mechanistic theories of collapse that unite structure and process can make fundamental contributions to solving global environmental problems. Copyright © 2017. Published by Elsevier Ltd.

  15. mode of collapse of square single panel reinforced concrete space

    African Journals Online (AJOL)

    The models were loaded directly till collapse. The estimated and actual collapse loads of the five models were compared. The estimated collapse load for the slab was 35 kN/m2. Also, the numerical estimate of the collapse load for the beam was 10.2kN/m (with an equivalent slab load of 40.8kN/m2), while the shear capacity ...

  16. Collapse and revival in holographic quenches

    International Nuclear Information System (INIS)

    Silva, Emilia da; Lopez, Esperanza; Mas, Javier; Serantes, Alexandre

    2015-01-01

    We study holographic models related to global quantum quenches in finite size systems. The holographic set up describes naturally a CFT, which we consider on a circle and a sphere. The enhanced symmetry of the conformal group on the circle motivates us to compare the evolution in both cases. Depending on the initial conditions, the dual geometry exhibits oscillations that we holographically interpret as revivals of the initial field theory state. On the sphere, this only happens when the energy density created by the quench is small compared to the system size. However on the circle considerably larger energy densities are compatible with revivals. Two different timescales emerge in this latter case. A collapse time, when the system appears to have dephased, and the revival time, when after rephasing the initial state is partially recovered. The ratio of these two times depends upon the initial conditions in a similar way to what is observed in some experimental setups exhibiting collapse and revivals.

  17. HII regions in collapsing massive molecular clouds

    International Nuclear Information System (INIS)

    Yorke, H.W.; Bodenheimer, P.; Tenorio-Tagle, G.

    1982-01-01

    Results of two-dimensional numerical calculations of the evolution of HII regions associated with self-gravitating, massive molecular clouds are presented. Depending on the location of the exciting star, a champagne flow can occur concurrently with the central collapse of a nonrotating cloud. Partial evaporation of the cloud at a rate of about 0.005 solar masses/yr results. When 100 O-stars are placed at the center of a freely falling cloud of 3x10 5 solar masses no evaporation takes place. Rotating clouds collapse to disks and the champagne flow can evaporate the cloud at a higher rate (0.01 solar masses/yr). It is concluded that massive clouds containing OB-stars have lifetimes of no more than 10 7 yr. (Auth.)

  18. Collapse and bounce of null fluids

    OpenAIRE

    Creelman, Bradley; Booth, Ivan

    2016-01-01

    Exact solutions describing the spherical collapse of null fluids can contain regions which violate the energy conditions. Physically the violations occur when the infalling matter continues to move inwards even when non-gravitational repulsive forces become stronger than gravity. In 1991 Ori proposed a resolution for these violations: spacetime surgery should be used to replace the energy condition violating region with an outgoing solution. The matter bounces. We revisit and implement this p...

  19. Analysis of power system collapse risk

    International Nuclear Information System (INIS)

    Eleschova, Z.; Belan, A.; Cintula, B.; Smitkova, M.

    2012-01-01

    In this paper are analysed the initialization events with considering different scenarios and their impact on the power system transient stability. As an initialization event is considered a short circuit at various places of power line. In each scenario are considered protection failures (backup protection), circuit-breaker failures (breaker failure relay activation). The individual states are analysed and the power system collapse risk assessed based on the simulation experiments results (Authors)

  20. Distributed Monitoring of Voltage Collapse Sensitivity Indices

    OpenAIRE

    Simpson-Porco, John W.; Bullo, Francesco

    2016-01-01

    The assessment of voltage stability margins is a promising direction for wide-area monitoring systems. Accurate monitoring architectures for long-term voltage instability are typically centralized and lack scalability, while completely decentralized approaches relying on local measurements tend towards inaccuracy. Here we present distributed linear algorithms for the online computation of voltage collapse sensitivity indices. The computations are collectively performed by processors embedded ...

  1. Rate of stellar collapses in the Galaxy

    International Nuclear Information System (INIS)

    Lande, K.; Stephens, W.E.

    1977-01-01

    From an analysis of pulsar spatial and luminosity distributions, the number density of observed pulsars in the local region is determined to be 1.1+-0.4x10 -7 pulsar pc -3 . Multiplication by the detection factor and by the ratio of Galaxy mass to local matter density and division by a mean lifetime of pulsars of 3x10 6 yr suggests a pulsar birth every 4 yr. A stellar collapse might occur even more often. (Auth.)

  2. Asymmetric explosion of core-collapse supernovae

    International Nuclear Information System (INIS)

    Kazeroni, Remi

    2016-01-01

    A core-collapse supernova represents the ultimate stage of the evolution of massive stars.The iron core contraction may be followed by a gigantic explosion which gives birth to a neutron star.The multidimensional dynamics of the innermost region, during the first hundreds milliseconds, plays a decisive role on the explosion success because hydrodynamical instabilities are able to break the spherical symmetry of the collapse. Large scale transverse motions generated by two instabilities, the neutrino-driven convection and the Standing Accretion Shock Instability (SASI),increase the heating efficiency up to the point of launching an asymmetric explosion and influencing the birth properties of the neutron star. In this thesis, hydrodynamical instabilities are studied using numerical simulations of simplified models. These models enable a wide exploration of the parameter space and a better physical understanding of the instabilities, generally inaccessible to realistic models.The non-linear regime of SASI is analysed to characterize the conditions under which a spiral mode prevails and to assess its ability to redistribute angular momentum radially.The influence of rotation on the shock dynamics is also addressed. For fast enough rotation rates, a corotation instability overlaps with SASI and greatly impacts the dynamics. The simulations enable to better constrain the effect of non-axisymmetric modes on the angular momentum budget of the iron core collapsing into a neutron star. SASI may under specific conditions spin up or down the pulsar born during the explosion. Finally, an idealised model of the heating region is studied to characterize the non-linear onset of convection by perturbations such as those produced by SASI or pre-collapse combustion inhomogeneities. The dimensionality issue is examined to stress the beneficial consequences of the three-dimensional dynamics on the onset of the explosion. (author) [fr

  3. Acquisition of Relative Interstrand Crosslinker Resistance and PARP Inhibitor Sensitivity in Fanconi Anemia Head and Neck Cancers.

    Science.gov (United States)

    Lombardi, Anne J; Hoskins, Elizabeth E; Foglesong, Grant D; Wikenheiser-Brokamp, Kathryn A; Wiesmüller, Lisa; Hanenberg, Helmut; Andreassen, Paul R; Jacobs, Allison J; Olson, Susan B; Keeble, Winifred W; Hays, Laura E; Wells, Susanne I

    2015-04-15

    Fanconi anemia is an inherited disorder associated with a constitutional defect in the Fanconi anemia DNA repair machinery that is essential for resolution of DNA interstrand crosslinks. Individuals with Fanconi anemia are predisposed to formation of head and neck squamous cell carcinomas (HNSCC) at a young age. Prognosis is poor, partly due to patient intolerance of chemotherapy and radiation requiring dose reduction, which may lead to early recurrence of disease. Using HNSCC cell lines derived from the tumors of patients with Fanconi anemia, and murine HNSCC cell lines derived from the tumors of wild-type and Fancc(-/-) mice, we sought to define Fanconi anemia-dependent chemosensitivity and DNA repair characteristics. We utilized DNA repair reporter assays to explore the preference of Fanconi anemia HNSCC cells for non-homologous end joining (NHEJ). Surprisingly, interstrand crosslinker (ICL) sensitivity was not necessarily Fanconi anemia-dependent in human or murine cell systems. Our results suggest that the increased Ku-dependent NHEJ that is expected in Fanconi anemia cells did not mediate relative ICL resistance. ICL exposure resulted in increased DNA damage sensing and repair by PARP in Fanconi anemia-deficient cells. Moreover, human and murine Fanconi anemia HNSCC cells were sensitive to PARP inhibition, and sensitivity of human cells was attenuated by Fanconi anemia gene complementation. The observed reliance upon PARP-mediated mechanisms reveals a means by which Fanconi anemia HNSCCs can acquire relative resistance to the ICL-based chemotherapy that is a foundation of HNSCC treatment, as well as a potential target for overcoming chemoresistance in the chemosensitive individual. ©2015 American Association for Cancer Research.

  4. Combination strategy of PARP inhibitor with antioxidant prevent bioenergetic deficits and inflammatory changes in CCI-induced neuropathy.

    Science.gov (United States)

    Komirishetty, Prashanth; Areti, Aparna; Gogoi, Ranadeep; Sistla, Ramakrishna; Kumar, Ashutosh

    2017-02-01

    Neuropathic pain, a debilitating pain condition and the underlying pathogenic mechanisms are complex and interwoven amongst each other and still there is scant information available regarding therapies which promise to treat the condition. Evidence indicate that oxidative/nitrosative stress induced poly (ADP-ribose) polymerase (PARP) overactivation initiate neuroinflammation and bioenergetic crisis culminating into neurodegenerative changes following nerve injury. Hence, we investigated the therapeutic effect of combining an antioxidant, quercetin and a PARP inhibitor, 4-amino 1, 8-naphthalimide (4-ANI) on the hallmark deficits induced by chronic constriction injury (CCI) of sciatic nerve in rats. Quercetin (25 mg/kg, p.o.) and 4-ANI (3 mg/kg, p.o.) were administered either alone or in combination for 14 days to examine sciatic functional index, allodynia and hyperalgesia using walking track analysis, Von Frey, acetone spray and hot plate tests respectively. Malondialdehyde, nitrite and glutathione levels were estimated to detect oxidative/nitrosative stress; mitochondrial membrane potential and cytochrome c oxidase activity to assess mitochondrial function; NAD & ATP levels to examine the bioenergetic status and levels of inflammatory markers were evaluated in ipsilateral sciatic nerve. Quercetin and 4-ANI alone improved the pain behaviour and biochemical alterations but the combination therapy demonstrated an appreciable reversal of CCI-induced changes. Nitrotyrosine and Poly ADP-Ribose (PAR) immunopositivity was decreased and nuclear factor erythroid 2-related factor (Nrf-2) levels were increased significantly in micro-sections of the sciatic nerve and dorsal root ganglion (DRG) of treatment group. These results suggest that simultaneous inhibition of oxidative stress-PARP activation cascade may potentially be useful strategies for management of trauma induced neuropathic pain. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Cooperation, cheating, and collapse in microbial populations

    Science.gov (United States)

    Gore, Jeff

    2012-02-01

    Natural populations can suffer catastrophic collapse in response to small changes in environmental conditions, and recovery after such a collapse can be exceedingly difficult. We have used laboratory yeast populations to study proposed early warning signals of impending extinction. Yeast cooperatively breakdown the sugar sucrose, meaning that there is a minimum number of cells required to sustain the population. We have demonstrated experimentally that the fluctuations in the population size increase in magnitude and become slower as the population approaches collapse. The cooperative nature of yeast growth on sucrose suggests that the population may be susceptible to cheater cells, which do not contribute to the public good and instead merely take advantage of the cooperative cells. We have confirmed this possibility experimentally by using a cheater yeast strain that lacks the gene encoding the cooperative behavior [1]. However, recent results in the lab demonstrate that the presence of a bacterial competitor may drive cooperation within the yeast population.[4pt] [1] Gore et al, Nature 459, 253 -- 256 (2009)

  6. Collapse of experimental capsules under external pressure

    International Nuclear Information System (INIS)

    Simonen, F.A.; Shippell, R.J. Jr.

    1980-01-01

    Stress analyses and developmental tests of capsules fabricated from thick-walled tubing were performed for an external pressure design condition. In the design procedure no credit was taken for the expected margin in pressure between yielding of the capsule wall and catastrophic collapse or flattening. In tests of AISI-1018 low carbon steel capsules, a significant margin was seen between yield and collapse pressure. However, the experimental yield pressures were significantly below predictions, essentially eliminating the safety margin present in the conservative design approach. The differences between predictions and test results are attributed to deficiencies in the plasticity theories commonly in use for engineering stress analyses. The results of this study show that the von Mises yield condition does not accurately describe the yield behavior of the AISI-1018 steel tubing material for the triaxial stress conditions of interest. Finite element stress analyses successfully predicted the transition between uniform inward plastic deformation and ovalization that leads to catastrophic collapse. After adjustments to correct for the unexpected yield behavior of the tube material, the predicted pressure-deflection trends were found to follow the experimental data

  7. Collapse of tall granular columns in fluid

    Science.gov (United States)

    Kumar, Krishna; Soga, Kenichi; Delenne, Jean-Yves

    2017-06-01

    Avalanches, landslides, and debris flows are geophysical hazards, which involve rapid mass movement of granular solids, water, and air as a multi-phase system. In order to describe the mechanism of immersed granular flows, it is important to consider both the dynamics of the solid phase and the role of the ambient fluid. In the present study, the collapse of a granular column in fluid is studied using 2D LBM - DEM. The flow kinematics are compared with the dry and buoyant granular collapse to understand the influence of hydrodynamic forces and lubrication on the run-out. In the case of tall columns, the amount of material destabilised above the failure plane is larger than that of short columns. Therefore, the surface area of the mobilised mass that interacts with the surrounding fluid in tall columns is significantly higher than the short columns. This increase in the area of soil - fluid interaction results in an increase in the formation of turbulent vortices thereby altering the deposit morphology. It is observed that the vortices result in the formation of heaps that significantly affects the distribution of mass in the flow. In order to understand the behaviour of tall columns, the run-out behaviour of a dense granular column with an initial aspect ratio of 6 is studied. The collapse behaviour is analysed for different slope angles: 0°, 2.5°, 5° and 7.5°.

  8. Collapse postulate for observables with continuous area

    International Nuclear Information System (INIS)

    Srinivas, M.D.

    1979-03-01

    In order to provide a mathematical framework for discussing the statistical correlations between the outcomes, when an arbitrary sequence of observables are measured, it is necessary to generalize the conventional von Neumann-Lueders collapse postulate to observables with a continuous spectrum. It is shown that the standard prescription in conventional quantum theory for the joint probabilities of compatible observables is sufficient to characterize, more or less completely, the appropriate ''generalized collapse postulate'' which associates with each observable a unique ''finitely additive expectation valued measure''. An interesting feature of the collapse associated with observables with continuous spectra, which again follows from the basic principles of conventional quantum theory, is that it must be formulated in terms of the so-called non-normal conditional expectations, which implies that the joint probabilities associated with successive observations of such observables are not in general σ-additive. The implications of this non-σ-additivity on the determination of expectation values, correlation functions etc., are also investigated. It is demonstrated that the basic prescriptions introduced in this paper constitute a natural completion of the framework of conventional quantum theory for discussing the statistics of an arbitrary sequence of observations

  9. The Collapse of Ecosystem Engineer Populations

    Directory of Open Access Journals (Sweden)

    José F. Fontanari

    2018-01-01

    Full Text Available Humans are the ultimate ecosystem engineers who have profoundly transformed the world’s landscapes in order to enhance their survival. Somewhat paradoxically, however, sometimes the unforeseen effect of this ecosystem engineering is the very collapse of the population it intended to protect. Here we use a spatial version of a standard population dynamics model of ecosystem engineers to study the colonization of unexplored virgin territories by a small settlement of engineers. We find that during the expansion phase the population density reaches values much higher than those the environment can support in the equilibrium situation. When the colonization front reaches the boundary of the available space, the population density plunges sharply and attains its equilibrium value. The collapse takes place without warning and happens just after the population reaches its peak number. We conclude that overpopulation and the consequent collapse of an expanding population of ecosystem engineers is a natural consequence of the nonlinear feedback between the population and environment variables.

  10. Matter and gravitons in the gravitational collapse

    Directory of Open Access Journals (Sweden)

    Roberto Casadio

    2016-12-01

    Full Text Available We consider the effects of gravitons in the collapse of baryonic matter that forms a black hole. We first note that the effective number of (soft off-shell gravitons that account for the (negative Newtonian potential energy generated by the baryons is conserved and always in agreement with Bekenstein's area law of black holes. Moreover, their (positive interaction energy reproduces the expected post-Newtonian correction and becomes of the order of the total ADM mass of the system when the size of the collapsing object approaches its gravitational radius. This result supports a scenario in which the gravitational collapse of regular baryonic matter produces a corpuscular black hole without central singularity, in which both gravitons and baryons are marginally bound and form a Bose–Einstein condensate at the critical point. The Hawking emission of baryons and gravitons is then described by the quantum depletion of the condensate and we show the two energy fluxes are comparable, albeit negligibly small on astrophysical scales.

  11. Matter and gravitons in the gravitational collapse

    Energy Technology Data Exchange (ETDEWEB)

    Casadio, Roberto, E-mail: casadio@bo.infn.it [Dipartimento di Fisica e Astronomia, Alma Mater Universià di Bologna, via Irnerio 46, 40126 Bologna (Italy); I.N.F.N., Sezione di Bologna, IS FLAG, viale B. Pichat 6/2, I-40127 Bologna (Italy); Giugno, Andrea, E-mail: A.Giugno@physik.uni-muenchen.de [Arnold Sommerfeld Center, Ludwig-Maximilians-Universität, Theresienstraße 37, 80333 München (Germany); Giusti, Andrea, E-mail: andrea.giusti@bo.infn.it [Dipartimento di Fisica e Astronomia, Alma Mater Universià di Bologna, via Irnerio 46, 40126 Bologna (Italy); I.N.F.N., Sezione di Bologna, IS FLAG, viale B. Pichat 6/2, I-40127 Bologna (Italy)

    2016-12-10

    We consider the effects of gravitons in the collapse of baryonic matter that forms a black hole. We first note that the effective number of (soft off-shell) gravitons that account for the (negative) Newtonian potential energy generated by the baryons is conserved and always in agreement with Bekenstein's area law of black holes. Moreover, their (positive) interaction energy reproduces the expected post-Newtonian correction and becomes of the order of the total ADM mass of the system when the size of the collapsing object approaches its gravitational radius. This result supports a scenario in which the gravitational collapse of regular baryonic matter produces a corpuscular black hole without central singularity, in which both gravitons and baryons are marginally bound and form a Bose–Einstein condensate at the critical point. The Hawking emission of baryons and gravitons is then described by the quantum depletion of the condensate and we show the two energy fluxes are comparable, albeit negligibly small on astrophysical scales.

  12. Precombination Cloud Collapse and Baryonic Dark Matter

    Science.gov (United States)

    Hogan, Craig J.

    1993-01-01

    A simple spherical model of dense baryon clouds in the hot big bang 'strongly nonlinear primordial isocurvature baryon fluctuations' is reviewed and used to describe the dependence of cloud behavior on the model parameters, baryon mass, and initial over-density. Gravitational collapse of clouds before and during recombination is considered including radiation diffusion and trapping, remnant type and mass, and effects on linear large-scale fluctuation modes. Sufficiently dense clouds collapse early into black holes with a minimum mass of approx. 1 solar mass, which behave dynamically like collisionless cold dark matter. Clouds below a critical over-density, however, delay collapse until recombination, remaining until then dynamically coupled to the radiation like ordinary diffuse baryons, and possibly producing remnants of other kinds and lower mass. The mean density in either type of baryonic remnant is unconstrained by observed element abundances. However, mixed or unmixed spatial variations in abundance may survive in the diffuse baryon and produce observable departures from standard predictions.

  13. Collapse postulate for observables with continuous spectra

    International Nuclear Information System (INIS)

    Srinivas, M.D.; Madras Univ.

    1980-01-01

    In order to provide a mathematical framework for discussing the statistical correlations between the outcomes, when an arbitrary sequence of observables are measured, it is necessary to generalize the conventional von Neumann-Lueders collapse postulate to observables with a continuous spectrum. It is shown that the standard prescription in conventional quantum theory for the joint probabilities of compatible observables is sufficient to characterize, more or less completely, the appropriate 'generalized collapse postulate' which associates with each observable a unique 'finitely additive expectation valued measure'. An interesting feature of the collapse associated with observables with continuous spectra, which again follows from the basic principles of conventional quantum theory, is that it must be formulated in terms of the so-called non-normal conditional expectations, which implies that the joint probabilities associated with successive observations of such observables are not in general sigma-additive. The implications of this non-sigma-additivity on the determination of expectation values, correlation functions etc., are also investigated. It is demonstrated that the basic prescriptions introduced in this paper constitute a natural completion of the framework of conventional quantum theory for discussing the statistics of an arbitrary sequence of observations. (orig.) 891 HJ/orig. 892 CKA

  14. Regulation of HFE expression by poly(ADP-ribose) polymerase-1 (PARP1) through an inverted repeat DNA sequence in the distal promoter.

    Science.gov (United States)

    Pelham, Christopher; Jimenez, Tamara; Rodova, Marianna; Rudolph, Angela; Chipps, Elizabeth; Islam, M Rafiq

    2013-12-01

    Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron overload among Caucasians of northern European descent. Over 85% of all cases with HH are due to mutations in the hemochromatosis protein (HFE) involved in iron metabolism. Although the importance in iron homeostasis is well recognized, the mechanism of sensing and regulating iron absorption by HFE, especially in the absence of iron response element in its gene, is not fully understood. In this report, we have identified an inverted repeat sequence (ATGGTcttACCTA) within 1700bp (-1675/+35) of the HFE promoter capable to form cruciform structure that binds PARP1 and strongly represses HFE promoter. Knockdown of PARP1 increases HFE mRNA and protein. Similarly, hemin or FeCl3 treatments resulted in increase in HFE expression by reducing nuclear PARP1 pool via its apoptosis induced cleavage, leading to upregulation of the iron regulatory hormone hepcidin mRNA. Thus, PARP1 binding to the inverted repeat sequence on the HFE promoter may serve as a novel iron sensing mechanism as increased iron level can trigger PARP1 cleavage and relief of HFE transcriptional repression. © 2013.

  15. Effect of APE1 T2197G (Asp148Glu Polymorphism on APE1, XRCC1, PARP1 and OGG1 Expression in Patients with Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Juliana C. Santos

    2014-09-01

    Full Text Available It has been hypothesized that genetic variation in base excision repair (BER might modify colorectal adenoma risk. Thus, we evaluated the influence of APE1 T2197G (Asp148Glu polymorphism on APE1, XRCC1, PARP1 and OGG1 expression in normal and tumor samples from patients with colorectal cancer. The results indicate a downregulation of OGG1 and an upregulation of XRCC1 expression in tumor tissue. Regarding the anatomical location of APE1, OGG1 and PARP-1, a decrease in gene expression was observed among patients with cancer in the rectum. In patients with or without some degree of tumor invasion, a significant downregulation in OGG1 was observed in tumor tissue. Interestingly, when taking into account the tumor stage, patients with more advanced grades (III and IV showed a significant repression for APE1, OGG1 and PARP-1. XRCC1 expression levels were significantly enhanced in tumor samples and were correlated with all clinical and histopathological data. Concerning the polymorphism T2197G, GG genotype carriers exhibited a significantly reduced expression of genes of the BER repair system (APE1, XRCC1 and PARP1. In summary, our data show that patients with colorectal cancer present expression changes in several BER genes, suggesting a role for APE1, XRCC1, PARP1 and OGG1 and APE1 polymorphism in colorectal carcinogenesis.

  16. Nicotinamide Inhibits Ethanol-Induced Caspase-3 and PARP-1 Over-activation and Subsequent Neurodegeneration in the Developing Mouse Cerebellum.

    Science.gov (United States)

    Ieraci, Alessandro; Herrera, Daniel G

    2018-06-01

    Fetal alcohol spectrum disorder (FASD) is the principal preventable cause of mental retardation in the western countries resulting from alcohol exposure during pregnancy. Ethanol-induced massive neuronal cell death occurs mainly in immature neurons during the brain growth spurt period. The cerebellum is one of the brain areas that are most sensitive to ethanol neurotoxicity. Currently, there is no effective treatment that targets the causes of these disorders and efficient treatments to counteract or reverse FASD are desirable. In this study, we investigated the effects of nicotinamide on ethanol-induced neuronal cell death in the developing cerebellum. Subcutaneous administration of ethanol in postnatal 4-day-old mice induced an over-activation of caspase-3 and PARP-1 followed by a massive neurodegeneration in the developing cerebellum. Interestingly, treatment with nicotinamide, immediately or 2 h after ethanol exposure, diminished caspase-3 and PARP-1 over-activation and reduced ethanol-induced neurodegeneration. Conversely, treatment with 3-aminobenzadine, a specific PARP-1 inhibitor, was able to completely block PARP-1 activation, but not caspase-3 activation or ethanol-induced neurodegeneration in the developing cerebellum. Our results showed that nicotinamide reduces ethanol-induced neuronal cell death and inhibits both caspase-3 and PARP-1 alcohol-induced activation in the developing cerebellum, suggesting that nicotinamide might be a promising and safe neuroprotective agent for treating FASD and other neurodegenerative disorders in the developing brain that shares similar cell death pathways.

  17. Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity

    Czech Academy of Sciences Publication Activity Database

    Frankum, J.; Moudrý, P.; Brough, R.; Hodný, Zdeněk; Ashworth, A.; Bartek, Jiří; Lord, C.J.

    2015-01-01

    Roč. 6, č. 13 (2015), s. 10746-10758 ISSN 1949-2553 R&D Projects: GA ČR GA13-17555S EU Projects: European Commission HEALTH-F2-2010-259893 Grant - others:Lundbeck Foundation(DK) R93-A8990; Danish Council for Independent Research(DK) DFF-1331-00262 Institutional support: RVO:68378050 Keywords : DNA damage response * ubiquitin-proteasome system * RNA interference screens * PARP inhibitors * CBLC Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.008, year: 2015

  18. Collapse dynamics of ultrasound contrast agent microbubbles

    Science.gov (United States)

    King, Daniel Alan

    Ultrasound contrast agents (UCAs) are micron-sized gas bubbles encapsulated with thin shells on the order of nanometers thick. The damping effects of these viscoelastic coatings are widely known to significantly alter the bubble dynamics for linear and low-amplitude behavior; however, their effects on strongly nonlinear and destruction responses are much less studied. This dissertation examines the behaviors of single collapsing shelled microbubbles using experimental and theoretical methods. The study of their dynamics is particularly relevant for emerging experimental uses of UCAs which seek to leverage localized mechanical forces to create or avoid specialized biomedical effects. The central component in this work is the study of postexcitation rebound and collapse, observed acoustically to identify shell rupture and transient inertial cavitation of single UCA microbubbles. This time-domain analysis of the acoustic response provides a unique method for characterization of UCA destruction dynamics. The research contains a systematic documentation of single bubble postexcitation collapse through experimental measurement with the double passive cavitation detection (PCD) system at frequencies ranging from 0.9 to 7.1 MHz and peak rarefactional pressure amplitudes (PRPA) ranging from 230 kPa to 6.37 MPa. The double PCD setup is shown to improve the quality of collected data over previous setups by allowing symmetric responses from a localized confocal region to be identified. Postexcitation signal percentages are shown to generally follow trends consistent with other similar cavitation metrics such as inertial cavitation, with greater destruction observed at both increased PRPA and lower frequency over the tested ranges. Two different types of commercially available UCAs are characterized and found to have very different collapse thresholds; lipid-shelled Definity exhibits greater postexcitation at lower PRPAs than albumin-shelled Optison. Furthermore, by altering

  19. Collapse of Incoherent Light Beams in Inertial Bulk Kerr Media

    DEFF Research Database (Denmark)

    Bang, Ole; Edmundson, Darran; Królikowski, Wieslaw

    1999-01-01

    We use the coherent density function theory to show that partially coherent beams are unstable and may collapse in inertial bulk Kerr media. The threshold power for collapse, and its dependence on the degree of coherence, is found analytically and checked-numerically. The internal dynamics of the...... of the walk-off modes is illustrated for collapsing and diffracting partially coherent beams.......We use the coherent density function theory to show that partially coherent beams are unstable and may collapse in inertial bulk Kerr media. The threshold power for collapse, and its dependence on the degree of coherence, is found analytically and checked-numerically. The internal dynamics...

  20. Gravitational collapse from smooth initial data with vanishing radial pressure

    International Nuclear Information System (INIS)

    Mahajan, Ashutosh; Goswami, Rituparno; Joshi, Pankaj S

    2005-01-01

    We study here the spherical gravitational collapse assuming initial data to be necessarily smooth, as motivated by requirements based on physical reasonableness. A tangential pressure model is constructed and analysed in order to understand the final fate of collapse explicitly in terms of the density and pressure parameters at the initial epoch from which the collapse develops. It is seen that both black holes and naked singularities are produced as collapse end states even when the initial data are smooth. We show that the outcome is decided entirely in terms of the initial data, as given by density, pressure and velocity profiles at the initial epoch, from which the collapse evolves

  1. Collapse of the wave function models, ontology, origin, and implications

    CERN Document Server

    2018-01-01

    This is the first single volume about the collapse theories of quantum mechanics, which is becoming a very active field of research in both physics and philosophy. In standard quantum mechanics, it is postulated that when the wave function of a quantum system is measured, it no longer follows the Schrödinger equation, but instantaneously and randomly collapses to one of the wave functions that correspond to definite measurement results. However, why and how a definite measurement result appears is unknown. A promising solution to this problem are collapse theories in which the collapse of the wave function is spontaneous and dynamical. Chapters written by distinguished physicists and philosophers of physics discuss the origin and implications of wave-function collapse, the controversies around collapse models and their ontologies, and new arguments for the reality of wave function collapse. This is an invaluable resource for students and researchers interested in the philosophy of physics and foundations of ...

  2. Molecular docking and 3D-QSAR studies on inhibitors of DNA damage signaling enzyme human PARP-1.

    Science.gov (United States)

    Fatima, Sabiha; Bathini, Raju; Sivan, Sree Kanth; Manga, Vijjulatha

    2012-08-01

    Poly (ADP-ribose) polymerase-1 (PARP-1) operates in a DNA damage signaling network. Molecular docking and three dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed on human PARP-1 inhibitors. Docked conformation obtained for each molecule was used as such for 3D-QSAR analysis. Molecules were divided into a training set and a test set randomly in four different ways, partial least square analysis was performed to obtain QSAR models using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Derived models showed good statistical reliability that is evident from their r², q²(loo) and r²(pred) values. To obtain a consensus for predictive ability from all the models, average regression coefficient r²(avg) was calculated. CoMFA and CoMSIA models showed a value of 0.930 and 0.936, respectively. Information obtained from the best 3D-QSAR model was applied for optimization of lead molecule and design of novel potential inhibitors.

  3. Distinct spatio temporal patterns and PARP dependence of XRCC1 recruitment to single-strand break and base excision repair

    International Nuclear Information System (INIS)

    Campalans, Anna; Kortulewski, Thierry; Amouroux, Rachel; Radicella, J. Pablo; Menoni, Herve; Vermeulen, Wim

    2013-01-01

    Single-strand break repair (SSBR) and base excision repair (BER) of modified bases and abasic sites share several players. Among them is XRCC1, an essential scaffold protein with no enzymatic activity, required for the coordination of both pathways. XRCC1 is recruited to SSBR by PARP-1, responsible for the initial recognition of the break. The recruitment of XRCC1 to BER is still poorly understood. Here we show by using both local and global induction of oxidative DNA base damage that XRCC1 participation in BER complexes can be distinguished from that in SSBR by several criteria. We show first that XRCC1 recruitment to BER is independent of PARP. Second, unlike SSBR complexes that are assembled within minutes after global damage induction, XRCC1 is detected later in BER patches, with kinetics consistent with the repair of oxidized bases. Third, while XRCC1-containing foci associated with SSBR are formed both in eu- and heterochromatin domains, BER complexes are assembled in patches that are essentially excluded from heterochromatin and where the oxidized bases are detected. (authors)

  4. vPARP Adjusts MVP Expression in Drug-resistant Cell Lines in Conjunction with MDR Proteins.

    Science.gov (United States)

    Wojtowicz, Karolina; Januchowski, Radoslaw; Nowicki, Michal; Zabel, Maciej

    2017-06-01

    The definition of vault (ribonucleoprotein particles) function remains highly complex. Vaults may cooperate with multidrug resistance (MDR) proteins, supporting their role in drug resistance. This topic is the main theme of this publication. The cell viability was determined by an MTT assay. The protein expression was detected by western blot analysis. The proteins were knocked-down using siRNA. No major vault protein (MVP) in the LoVo/Dx and W1PR cell lines after tunicamycin treatment was shown. In W1PR cells with knocked-down MVP, a statistically significant decrease in cell viability was noted. In LoVo/Dx, W1TR and A2780TR cells were vault poly-ADP-ribose polymerase (vPARP) was knockdown, a decrease in cell viability was shown. Also, MVP silencing induced an increase in glycoprotein P (Pgp) expression in LoVo/Dx cells. MVP is important for the drug resistance of cancer cells, but it probably requires the presence of vPARP for full activation. Some correlations between MDR proteins and vaults exist. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  5. Cediranib, a pan-VEGFR inhibitor, and olaparib, a PARP inhibitor, in combination therapy for high grade serous ovarian cancer.

    Science.gov (United States)

    Ivy, S Percy; Liu, Joyce F; Lee, Jung-Min; Matulonis, Ursula A; Kohn, Elise C

    2016-01-01

    An estimated 22,000 women are diagnosed annually with ovarian cancer in the United States. Initially chemo-sensitive, recurrent disease ultimately becomes chemoresistant and may kill ~14,000 women annually. Molecularly targeted therapy with cediranib (AZD2171), a vascular endothelial growth factor receptor (VEGFR)-1, 2, and 3 signaling blocker, and olaparib (AZD2281), a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, administered orally in combination has shown anti-tumor activity in the treatment of high grade serous ovarian cancer (HGSOC). This combination has the potential to change the treatment of HGSOC. Preclinical and clinical studies of single agent cediranib and olaparib or their combination are reviewed. Data are presented from peer-reviewed published manuscripts, completed and ongoing early phase clinical trials registered in ClinicalTrials.gov, National Cancer Institute-sponsored clinical trials, and related recent abstracts. Advances in the treatment of HGSOC that improve progression-free and overall survival have proven elusive despite examination of molecularly targeted therapy. HGSOC patients with deleterious germline or somatic mutations in BRCA1 or BRCA2 (BRCAm) are most responsive to PARP inhibitors (PARPi). PARPi combined with angiogenesis inhibition improved anti-cancer response and duration in both BRCAm and BRCA wild type HGSOC patients, compared to olaparib single agent treatment, demonstrating therapeutic chemical and contextual synthetic lethality.

  6. IDH1/2 Mutations Sensitize Acute Myeloid Leukemia to PARP Inhibition and This Is Reversed by IDH1/2-Mutant Inhibitors.

    Science.gov (United States)

    Molenaar, Remco J; Radivoyevitch, Tomas; Nagata, Yasunobu; Khurshed, Mohammed; Przychodzen, Bartolomiej; Makishima, Hideki; Xu, Mingjiang; Bleeker, Fonnet E; Wilmink, Johanna W; Carraway, Hetty E; Mukherjee, Sudipto; Sekeres, Mikkael A; van Noorden, Cornelis J F; Maciejewski, Jaroslaw P

    2018-04-01

    Purpose: Somatic mutations in IDH1/2 occur in approximately 20% of patients with myeloid neoplasms, including acute myeloid leukemia (AML). IDH1/2 MUT enzymes produce D -2-hydroxyglutarate ( D 2HG), which associates with increased DNA damage and improved responses to chemo/radiotherapy and PARP inhibitors in solid tumor cells. Whether this also holds true for IDH1/2 MUT AML is not known. Experimental Design: Well-characterized primary IDH1 MUT , IDH2 MUT , and IDH1/2 WT AML cells were analyzed for DNA damage and responses to daunorubicin, ionizing radiation, and PARP inhibitors. Results: IDH1/2 MUT caused increased DNA damage and sensitization to daunorubicin, irradiation, and the PARP inhibitors olaparib and talazoparib in AML cells. IDH1/2 MUT inhibitors protected against these treatments. Combined treatment with a PARP inhibitor and daunorubicin had an additive effect on the killing of IDH1/2 MUT AML cells. We provide evidence that the therapy sensitivity of IDH1/2 MUT cells was caused by D 2HG-mediated downregulation of expression of the DNA damage response gene ATM and not by altered redox responses due to metabolic alterations in IDH1/2 MUT cells. Conclusions: IDH1/2 MUT AML cells are sensitive to PARP inhibitors as monotherapy but especially when combined with a DNA-damaging agent, such as daunorubicin, whereas concomitant administration of IDH1/2 MUT inhibitors during cytotoxic therapy decrease the efficacy of both agents in IDH1/2 MUT AML. These results advocate in favor of clinical trials of PARP inhibitors either or not in combination with daunorubicin in IDH1/2 MUT AML. Clin Cancer Res; 24(7); 1705-15. ©2018 AACR . ©2018 American Association for Cancer Research.

  7. Differential transactivation by orphan nuclear receptor NOR1 and its fusion gene product EWS/NOR1: possible involvement of poly(ADP-ribose) polymerase I, PARP-1.

    Science.gov (United States)

    Ohkura, Naganari; Nagamura, Yuko; Tsukada, Toshihiko

    2008-10-15

    In extraskeletal myxoid chondrosarcoma, a chromosomal translocation creates a gene fusion between EWS and an orphan nuclear receptor, NOR1. The resulting fusion protein EWS/NOR1 has been believed to lead to malignant transformation by functioning as a transactivator for NOR1-target genes. By comparing the gene expression profiles of NOR1- and EWS/NOR1-overexpressing cells, we found that they largely shared up-regulated genes, but no significant correlation was observed with respect to the transactivation levels of each gene. In addition, the proteins associated with NOR1 and EWS/NOR1 were mostly the same in these cells. The results suggest that these proteins differentially transactivate overlapping target genes through a similar transcriptional machinery. To clarify the mechanisms underlying the transcriptional divergence between NOR1 and EWS/NOR1, we searched for alternatively associated proteins, and identified poly(ADP-ribose) polymerase I (PARP-1) as an NOR1-specific binding protein. Consistent with its binding properties, PARP-1 acted as a transcriptional repressor of NOR1, but not EWS/NOR1, in a luciferase reporter assay employing PARP-1(-/-) fibroblasts. Interestingly, suppressive activity of PARP-1 was observed in a DNA response element-specific manner, and in a subtype-specific manner toward the NR4A family (Nur77, Nurr1, and NOR1), suggesting that PARP-1 plays a role in the diversity of transcriptional regulation mediated by the NR4A family in normal cells. Altogether, our findings suggest that NOR1 and EWS/NOR1 regulate overlapping target genes differently by utilizing associated proteins, including PARP-1; and that EWS/NOR1 may acquire oncogenic activities by avoiding (or gaining) transcription factor-specific modulation by the associated proteins. (c) 2008 Wiley-Liss, Inc.

  8. Thermal and Chemical Evolution of Collapsing Filaments

    Energy Technology Data Exchange (ETDEWEB)

    Gray, William J. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Scannapieco, Evan [Arizona State Univ., Mesa, AZ (United States). School of Earth and Space Exploration

    2013-01-15

    Intergalactic filaments form the foundation of the cosmic web that connect galaxies together, and provide an important reservoir of gas for galaxy growth and accretion. Here we present very high resolution two-dimensional simulations of the thermal and chemical evolution of such filaments, making use of a 32 species chemistry network that tracks the evolution of key molecules formed from hydrogen, oxygen, and carbon. We study the evolution of filaments over a wide range of parameters including the initial density, initial temperature, strength of the dissociating UV background, and metallicity. In low-redshift, Z ≈ 0.1Z filaments, the evolution is determined completely by the initial cooling time. If this is sufficiently short, the center of the filament always collapses to form dense, cold core containing a substantial fraction of molecules. In high-redshift, Z = 10-3Z filaments, the collapse proceeds much more slowly. This is due mostly to the lower initial temperatures, which leads to a much more modest increase in density before the atomic cooling limit is reached, making subsequent molecular cooling much less efficient. Finally, we study how the gravitational potential from a nearby dwarf galaxy affects the collapse of the filament and compare this to NGC 5253, a nearby starbusting dwarf galaxy thought to be fueled by the accretion of filament gas. In contrast to our fiducial case, a substantial density peak forms at the center of the potential. This peak evolves faster than the rest of the filament due to the increased rate at which chemical species form and cooling occur. We find that we achieve similar accretion rates as NGC 5253, but our two-dimensional simulations do not recover the formation of the giant molecular clouds that are seen in radio observations.

  9. Holographic probes of collapsing black holes

    International Nuclear Information System (INIS)

    Hubeny, Veronika E.; Maxfield, Henry

    2014-01-01

    We continue the programme of exploring the means of holographically decoding the geometry of spacetime inside a black hole using the gauge/gravity correspondence. To this end, we study the behaviour of certain extremal surfaces (focusing on those relevant for equal-time correlators and entanglement entropy in the dual CFT) in a dynamically evolving asymptotically AdS spacetime, specifically examining how deep such probes reach. To highlight the novel effects of putting the system far out of equilibrium and at finite volume, we consider spherically symmetric Vaidya-AdS, describing black hole formation by gravitational collapse of a null shell, which provides a convenient toy model of a quantum quench in the field theory. Extremal surfaces anchored on the boundary exhibit rather rich behaviour, whose features depend on dimension of both the spacetime and the surface, as well as on the anchoring region. The main common feature is that they reach inside the horizon even in the post-collapse part of the geometry. In 3-dimensional spacetime, we find that for sub-AdS-sized black holes, the entire spacetime is accessible by the restricted class of geodesics whereas in larger black holes a small region near the imploding shell cannot be reached by any boundary-anchored geodesic. In higher dimensions, the deepest reach is attained by geodesics which (despite being asymmetric) connect equal time and antipodal boundary points soon after the collapse; these can attain spacetime regions of arbitrarily high curvature and simultaneously have smallest length. Higher-dimensional surfaces can penetrate the horizon while anchored on the boundary at arbitrarily late times, but are bounded away from the singularity. We also study the details of length or area growth during thermalization. While the area of extremal surfaces increases monotonically, geodesic length is neither monotonic nor continuous

  10. Gravitational collapse of conventional polytropic cylinder

    Science.gov (United States)

    Lou, Yu-Qing; Hu, Xu-Yao

    2017-07-01

    In reference to general polytropic and conventional polytropic hydrodynamic cylinders of infinite length with axial uniformity and axisymmetry under self-gravity, the dynamic evolution of central collapsing mass string in free-fall dynamic accretion phase is re-examined in details. We compare the central mass accretion rate and the envelope mass infall rate at small radii. Among others, we correct mistakes and typos of Kawachi & Hanawa (KH hereafter) and in particular prove that their key asymptotic free-fall solution involving polytropic index γ in the two power exponents is erroneous by analytical analyses and numerical tests. The correct free-fall asymptotic solutions at sufficiently small \\hat{r} (the dimensionless independent self-similar variable) scale as {˜ } -|ln \\hat{r}|^{1/2} in contrast to KH's ˜ -|ln \\hat{r}|^{(2-γ )/2} for the reduced bulk radial flow velocity and as {˜ } \\hat{r}^{-1}|ln \\hat{r}|^{-1/2} in contrast to KH's {˜ } \\hat{r}^{-1} |ln \\hat{r}|^{-(2-γ )/2} for the reduced mass density. We offer consistent scenarios for numerical simulation code testing and theoretical study on dynamic filamentary structure formation and evolution as well as pertinent stability properties. Due to unavoidable Jeans instabilities along the cylinder, such collapsing massive filaments or strings can further break up into clumps and segments of various lengths as well as clumps embedded within segments and evolve into chains of gravitationally collapsed objects (such as gaseous planets, brown dwarfs, protostars, white dwarfs, neutron stars, black holes in a wide mass range, globular clusters, dwarf spheroidals, galaxies, galaxy clusters and even larger mass reservoirs etc.) in various astrophysical and cosmological contexts as articulated by Lou & Hu recently. As an example, we present a model scheme for comparing with observations of molecular filaments for forming protostars, brown dwarfs and gaseous planets and so forth.

  11. PARP-1 depletion in combination with carbon ion exposure significantly reduces MMPs activity and overall increases TIMPs expression in cultured HeLa cells

    International Nuclear Information System (INIS)

    Ghorai, Atanu; Sarma, Asitikantha; Chowdhury, Priyanka; Ghosh, Utpal

    2016-01-01

    Hadron therapy is an innovative technique where cancer cells are precisely killed leaving surrounding healthy cells least affected by high linear energy transfer (LET) radiation like carbon ion beam. Anti-metastatic effect of carbon ion exposure attracts investigators into the field of hadron biology, although details remain poor. Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors are well-known radiosensitizer and several PARP-1 inhibitors are in clinical trial. Our previous studies showed that PARP-1 depletion makes the cells more radiosensitive towards carbon ion than gamma. The purpose of the present study was to investigate combining effects of PARP-1 inhibition with carbon ion exposure to control metastatic properties in HeLa cells. Activities of matrix metalloproteinases-2, 9 (MMP-2, MMP-9) were measured using the gelatin zymography after 85 MeV carbon ion exposure or gamma irradiation (0- 4 Gy) to compare metastatic potential between PARP-1 knock down (HsiI) and control cells (H-vector - HeLa transfected with vector without shRNA construct). Expression of MMP-2, MMP-9, tissue inhibitor of MMPs such as TIMP-1, TIMP-2 and TIMP-3 were checked by immunofluorescence and western blot. Cell death by trypan blue, apoptosis and autophagy induction were studied after carbon ion exposure in each cell-type. The data was analyzed using one way ANOVA and 2-tailed paired-samples T-test. PARP-1 silencing significantly reduced MMP-2 and MMP-9 activities and carbon ion exposure further diminished their activities to less than 3 % of control H-vector. On the contrary, gamma radiation enhanced both MMP-2 and MMP-9 activities in H-vector but not in HsiI cells. The expression of MMP-2 and MMP-9 in H-vector and HsiI showed different pattern after carbon ion exposure. All three TIMPs were increased in HsiI, whereas only TIMP-1 was up-regulated in H-vector after irradiation. Notably, the expressions of all TIMPs were significantly higher in HsiI than H-vector at 4 Gy. Apoptosis was

  12. High-resolution simulations of cylindrical void collapse in energetic materials: Effect of primary and secondary collapse on initiation thresholds

    Science.gov (United States)

    Rai, Nirmal Kumar; Schmidt, Martin J.; Udaykumar, H. S.

    2017-04-01

    Void collapse in energetic materials leads to hot spot formation and enhanced sensitivity. Much recent work has been directed towards simulation of collapse-generated reactive hot spots. The resolution of voids in calculations to date has varied as have the resulting predictions of hot spot intensity. Here we determine the required resolution for reliable cylindrical void collapse calculations leading to initiation of chemical reactions. High-resolution simulations of collapse provide new insights into the mechanism of hot spot generation. It is found that initiation can occur in two different modes depending on the loading intensity: Either the initiation occurs due to jet impact at the first collapse instant or it can occur at secondary lobes at the periphery of the collapsed void. A key observation is that secondary lobe collapse leads to large local temperatures that initiate reactions. This is due to a combination of a strong blast wave from the site of primary void collapse and strong colliding jets and vortical flows generated during the collapse of the secondary lobes. The secondary lobe collapse results in a significant lowering of the predicted threshold for ignition of the energetic material. The results suggest that mesoscale simulations of void fields may suffer from significant uncertainty in threshold predictions because unresolved calculations cannot capture the secondary lobe collapse phenomenon. The implications of this uncertainty for mesoscale simulations are discussed in this paper.

  13. Electromagnetic wave collapse in a radiation background

    International Nuclear Information System (INIS)

    Marklund, Mattias; Brodin, Gert; Stenflo, Lennart

    2003-01-01

    The nonlinear interaction, due to quantum electrodynamical (QED) effects between an electromagnetic pulse and a radiation background, is investigated by combining the methods of radiation hydrodynamics with the QED theory for photon-photon scattering. For the case of a single coherent electromagnetic pulse, we obtain a Zakharov-like system, where the radiation pressure of the pulse acts as a driver of acoustic waves in the photon gas. For a sufficiently intense pulse and/or background energy density, there is focusing and the subsequent collapse of the pulse. The relevance of our results for various astrophysical applications are discussed

  14. Formation and collapse of internal transport barrier

    International Nuclear Information System (INIS)

    Fukuyama, A.; Itoh, K.; Itoh, S.I.; Yagi, M.

    1999-01-01

    A theoretical model of internal transport barrier (ITB) is developed. The transport model based on the self-sustained turbulence theory of the current-diffusive ballooning mode is extended to include the effects of ExB rotation shear. Delayed formation of ITB is observed in transport simulations. The influence of finite gyroradius is also discussed. Simulation of the current ramp-up experiment successfully described the radial profile of density, temperature and safety factor. A model of ITB collapse due to magnetic braiding is proposed. Sudden enhancement of transport triggered by overlapping of magnetic islands terminates ITB. The possibility of destabilizing global low-n modes is also discussed. (author)

  15. Formation and collapse of internal transport barrier

    International Nuclear Information System (INIS)

    Fukuyama, A.; Itoh, K.; Itoh, S.-I.; Yagi, M.

    2001-01-01

    A theoretical model of internal transport barrier (ITB) is developed. The transport model based on the self-sustained turbulence theory of the current-diffusive ballooning mode is extended to include the effects of ExB rotation shear. Delayed formation of ITB is observed in transport simulations. The influence of finite gyroradius is also discussed. Simulation of the current ramp-up experiment successfully described the radial profile of density, temperature and safety factor. A model of ITB collapse due to magnetic braiding is proposed. Sudden enhancement of transport triggered by overlaping of magnetic islands terminates ITB. The possibility of destabilizing global low-n modes is also discussed. (author)

  16. The Efficacy of Bisphosphonates in Preventing Aromatase Inhibitor Induced Bone Loss for Postmenopausal Women with Early Breast Cancer: A Systematic Review and Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Pooleriveetil Padikkal Anagha

    2014-01-01

    Full Text Available Objectives. We aim to determine the efficacy of bisphosphonates in preventing aromatase inhibitor induced bone loss (AIBL in postmenopausal women with early breast cancer. The secondary objective was to determine the safety of bisphosphonates. Materials and Methods. We searched electronic databases in a time period of 1995 January to 2013 June. Random effects meta-analytical models were used; between study heterogeneity and publication bias was assessed. Results. A total of six eligible studies reported the BMD T score of LS at 12 months and from that 3 trials of Zoledronic acid compared the change in BMD in immediate ZOL versus delayed ZOL done with subgroups like patients with normal BMD at baseline (OR = 5.402, 95% CI = 1.329–21.959, P value = 0.018 and osteopenic BMD at baseline (OR = 4.008, 95% CI = 2.249–7.143, P value = 0.0002. Both had a significant decrease in BMD that favoured the delayed ZOL; 3 trials of risedronate and ibandronate also had a significant decrease in BMD in AIs alone group. Immediate ZOL versus delayed ZOL also showed increased risk of getting an ADR in immediate group. Conclusion. Third generation bisphosphonates has an effect on BMD of patients who are on treatment of AIs in breast cancer. Furthermore, the patients treated with immediate ZOL had a significantly high risk of musculoskeletal ADR’s than patients with delayed ZOL.

  17. Karst collapse in cities and mining areas, China

    International Nuclear Information System (INIS)

    Jian Chen

    1988-01-01

    Karst collapse is a dynamic geological phenomenon, in which the rock mass or deposits overlying the karstified zone subsides down along the karst cavity, resulting in a collapse pit or sinkhole. After discussing the typical examples of collapse emerging in the karst cities and mines in provinces and regions of South China, such as Guangdong, Guangxi, Hunan, Hubei, Zhejiang, Yunnan, Guizhou, and Jiangxi, it is considered that human activities of economy and production have become a major effect in causing karst collapse. Man-made collapses make 66.4 percent of the total, whereas natural ones 33.6 percent. Most of the collapses occurred to the area with soil overburden (96.7 percent), only a few in areas of bedrock overburden (3.3 percent). The karst collapses have a close relationship with the extent of karst development, the character and the thickness of overburden, and the dynamic condition of underground water. Collapse usually occurs in those parts of an area that are more intensely karstified, with soil thickness less than 5 m and a high amplitude of water table fluctuation. Many kinds of mechanical effects are caused by pumping or draining on the over-burden and destroying its equilibrium, leading to the collapse. These effects included the support loss and load-added effect, penetrating suffusion, gas explosion, water-hammer, suction pressure erosion, and liquefaction effects. The collapses are the result of varied comprehensive effects, particularly the support loss and load-added, and penetrating suffusion

  18. Anomalous polymer collapse winding angle distributions

    Science.gov (United States)

    Narros, A.; Owczarek, A. L.; Prellberg, T.

    2018-03-01

    In two dimensions polymer collapse has been shown to be complex with multiple low temperature states and multi-critical points. Recently, strong numerical evidence has been provided for a long-standing prediction of universal scaling of winding angle distributions, where simulations of interacting self-avoiding walks show that the winding angle distribution for N-step walks is compatible with the theoretical prediction of a Gaussian with a variance growing asymptotically as Clog N . Here we extend this work by considering interacting self-avoiding trails which are believed to be a model representative of some of the more complex behaviour. We provide robust evidence that, while the high temperature swollen state of this model has a winding angle distribution that is also Gaussian, this breaks down at the polymer collapse point and at low temperatures. Moreover, we provide some evidence that the distributions are well modelled by stretched/compressed exponentials, in contradistinction to the behaviour found in interacting self-avoiding walks. Dedicated to Professor Stu Whittington on the occasion of his 75th birthday.

  19. Design and Analysis of Collapsible Scissor Bridge

    Directory of Open Access Journals (Sweden)

    Biro Mohamad Nabil Aklif

    2018-01-01

    Full Text Available Collapsible scissor bridge is a portable bridge that can be deployed during emergency state to access remote areas that are affected by disaster such as flood. The objective of this research is to design a collapsible scissor bridge which is able to be transported by a 4x4 vehicle and to be deployed to connect remote areas. The design is done by using Solidworks and numerical analysis for structural strength is conducted via ANSYS. The research starts with parameters setting and modelling. Finite element analysis is conducted to analyze the strength by determining the safety factor of the bridge. Kutzbach equation is also analyzed to ensure that the mechanism is able to meet the targeted degree of motion. There are five major components of the scissor structure; pin, deck, cross shaft and deck shaft. The structure is controlled by hydraulic pump driven by a motor for the motions. Material used in simulation is A36 structural steel due to limited library in ANSYS. However, the proposed material is Fiber Reinforced Polymer (FRP composites as they have a high strength to weight ratio. FRP also tends to be corrosion resistance and this characteristic is useful in flooded area.

  20. Non-Spherical Gravitational Collapse of Strange Quark Matter

    Institute of Scientific and Technical Information of China (English)

    Zade S S; Patil K D; Mulkalwar P N

    2008-01-01

    We study the non-spherical gravitational collapse of the strange quark null fluid.The interesting feature which emerges is that the non-spherical collapse of charged strange quark matter leads to a naked singularity whereas the gravitational collapse of neutral quark matter proceeds to form a black hole.We extend the earlier work of Harko and Cheng[Phys.Lett.A 266 (2000) 249]to the non-spherical case.

  1. Collapsing dynamics of attractive Bose-Einstein condensates

    DEFF Research Database (Denmark)

    Bergé, L.; Juul Rasmussen, J.

    2002-01-01

    The self-similar collapse of 3D and quasi-2D atom condensates with negative scattering length is examined. 3D condensates are shown to blow up following the scenario of weak collapse, for which 3-body recombination weakly dissipates the atoms. In contrast, 2D condensates undergo a strong collapse......, that absorbs a significant amount of particles. (C) 2002 Elsevier Science B.V. All rights reserved....

  2. Simulation of weak and strong Langmuir collapse regimes

    International Nuclear Information System (INIS)

    Hadzievski, L.R.; Skoric, M.M.; Kono, M.; Sato, T.

    1998-01-01

    In order to check the validity of the self-similar solutions and the existence of weak and strong collapse regimes, direct two dimensional simulation of the time evolution of a Langmuir soliton instability is performed. Simulation is based on the Zakharov model of strong Langmuir turbulence in a weakly magnetized plasma accounting for the full ion dynamics. For parameters considered, agreement with self-similar dynamics of the weak collapse type is found with no evidence of the strong Langmuir collapse. (author)

  3. The collapse of acoustic waves in dispersive media

    International Nuclear Information System (INIS)

    Kuznetsov, E.A.; Musher, S.L.; Shafarenko, A.V.

    1983-01-01

    The existence of the collapse of acoustic waves with a positive dispersion is demonstrated. A qualitative description of wave collapse, based on the analysis of invariants, is proposed. Through the use of a numerical simulation, it is established that, in the Kadomtsev-Petviashvili three-dimensional equation, collapse is accompanied by the formation of a weakly turbulent background by the wave radiation from the cavity

  4. Radiologic evaluation of right middle lobe collapse

    International Nuclear Information System (INIS)

    Kwun, Dae Young; Kim, Jong Deok; Kim, Jong Chul

    1989-01-01

    There are many pathogenetic factors for collapse of right middle lobe; profuse peribronchial clustering of lymph nodes about the right middle lobe bronchus, poor drainage of the bronchus because of its acute angle of take-off from the intermediate bronchus, and the isolation of this small lobe from the right upper and lower lobes, and thus from the aerating effects of collateral ventilation. Retrospectively we reviewed 36 cases of right of right middle lobe collapse of which causes were confirmed by histopathologic or bronchographic findings during the recent 6 years from March 1983 to February 1988 at Inje College Pusan Paik Hospital, and obtained the following results: 1. Male to female ratio was 1:1:4,and peak incidence (64%) was in the fifth and sixth decades with the mean age of 51.1 years. 2. Bronchiectasis was the most common cause (30.6%), and the others were chronic bronchitis (25.0%), pulmonary tuberculosis (19.4%), lung cancer (16.7%), and non-specific inflammatory disease (8.3%). This suggests benign disease is 5 times more common cause of right middle lobe collapse than lung cancer. 3. Among the plain chest radiolograph findings, obliteration of right cardiac border and triangular radiopaque density were the most frequent findings(77.8% in each) and the next was downward and anterior displacement of minor and major fissures (55.6%) 4. Bronchography was done in 11 cases; bronchiectasis was found in 8 cases and chronic bronchitis in 3 cases. Right middle lobe bronchus was obstructed in 2 cases of chronic bronchitis. 5. Chest CT scan was performed in 4 cases of lung cancer, 2 of non-specific inflammatory disease, and 1 of pulmonary tuberculosis: all of lung cancer revealed hilar mass, budged or lobulated fissures, in homogenous density, and mediastinal lymph node enlargement, and all benign disease showed homogenous density and flat to concave fissures. Right middle lobar bronchus narrowing was seen in 5 cases and its obstruction in 2 cases

  5. miR-520 promotes DNA-damage-induced trophoblast cell apoptosis by targeting PARP1 in recurrent spontaneous abortion (RSA).

    Science.gov (United States)

    Dong, Xiujuan; Yang, Long; Wang, Hui

    2017-04-01

    The establishment and maintenance of successful pregnancy mainly depends on trophoblast cells. Their dysfunction has been implicated in recurrent spontaneous abortion (RSA), a major complication of pregnancy. However, the underlying mechanisms of trophoblasts dysfunction remain unclear. DNA-damage-induced cell apoptosis has been reported to play a vital role in cell death. In this study, we identified a novel microRNA (miR-520) in RSA progression via regulating trophoblast cell apoptosis. Microarray analysis showed that miR-520 was highly expressed in villus of RSA patients. By using flow cytometry analysis, we observed miR-520 expression was correlated with human trophoblast cell apoptosis in vitro, along with decreased poly (ADP-ribose) polymerase-1 (PARP1) expression. With the analysis of clinic samples, we observed that miR-520 level was negatively correlated with PARP1 level in RSA villus. In addition, overexpression of PARP1 restored the miR-520-induced trophoblast cell apoptosis in vitro. The status of chromosome in trophoblast implied that miR-520-promoted DNA-damage-induced cell apoptosis to regulate RSA progression. These results indicated that the level of miR-520 might associate with RSA by prompting trophoblast cell apoptosis via PARP1 dependent DNA-damage pathway.

  6. The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

    DEFF Research Database (Denmark)

    Wang, Yifan; Bernhardy, Andrea J; Cruz, Cristina

    2016-01-01

    Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and...

  7. 17-beta estradiol inhibits oxidative stress-induced accumulation of AIF into nucleolus and PARP1-dependent cell death via estrogen receptor alpha.

    Science.gov (United States)

    Batnasan, Enkhzaya; Wang, Ruoxi; Wen, Jitao; Ke, Yueshuang; Li, Xiaoxue; Bohio, Ameer Ali; Zeng, Xianlu; Huo, Hongliang; Han, Liping; Boldogh, Istvan; Ba, Xueqing

    2015-01-05

    Oxidative stress-induced DNA damage results in over-activation of poly(ADP-ribose) polymerase 1 (PARP1), leading to parthanatos, a newly discovered cell elimination pathway. Inhibition of PARP1-dependent cell death has shown to improve the outcome of diseases, including stroke, heart ischemia, and neurodegenerative diseases. In the present study we aimed to detect whether estrogen plays a protective role in inhibiting parthanatos. We utilized human mammary adenocarcinoma cells (MCF7) that abundantly express the estrogen receptor alpha and beta (ERα and ERβ). Parthanatos was induced by challenging the cells with hydrogen peroxide (H2O2). Microscopic imaging and molecular biological techniques, such as Western blot analysis and RNA interference, were performed. The results showed 17β estradiol (E2) protected MCF7 cells from PARP1-dependent cell death by decreasing protein PARylation, and AIF translocation into nuclei/nucleoli. Down-regulation of ERα expression by siRNA before E2 addition resulted in the failure of the E2-mediated inhibition of H2O2-induced protein PARylation and AIF nucleolar translocation. Together these data suggest that estrogen via its alpha-type receptor inhibits oxidative stress-induced, PARP1-dependent cell death. The present study provided us insight into how to apply hormone therapy in intervention of parthanatos-implicated ischemic and degenerative diseases. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  8. Extent of radiosensitization by the PARP inhibitor olaparib depends on its dose, the radiation dose and the integrity of the homologous recombination pathway of tumor cells

    NARCIS (Netherlands)

    Verhagen, Caroline V. M.; de Haan, Rosemarie; Hageman, Floor; Oostendorp, Tim P. D.; Carli, Annalisa L. E.; O'Connor, Mark J.; Jonkers, Jos; Verheij, Marcel; van den Brekel, Michiel W.; Vens, Conchita

    2015-01-01

    The PARP inhibitor olaparib is currently tested in clinical phase 1 trials to define safe dose levels in combination with RT. However, certain clinically relevant insights are still lacking. Here we test, while comparing to single agent activity, the olaparib dose and genetic background dependence

  9. Extent of radiosensitization by the PARP inhibitor olaparib depends on its dose, the radiation dose and the integrity of the homologous recombination pathway of tumor cells

    NARCIS (Netherlands)

    Verhagen, C.V.M.; Haan, R. den; Hageman, F.; Oostendorp, T.P.; Carli, A.L.; O'Connor, M.J.; Jonkers, J.; Verheij, M.; Brekel, M.W. van den; Vens, C.

    2015-01-01

    BACKGROUND AND PURPOSE: The PARP inhibitor olaparib is currently tested in clinical phase 1 trials to define safe dose levels in combination with RT. However, certain clinically relevant insights are still lacking. Here we test, while comparing to single agent activity, the olaparib dose and genetic

  10. Extent of radiosensitization by the PARP inhibitor olaparib depends on its dose, the radiation dose and the integrity of the homologous recombination pathway of tumor cells

    NARCIS (Netherlands)

    Verhagen, C.V.M.; de Haan, R.; Hageman, F.; Oostendorp, T.P.D.; Carli, A.L.E.; O'Connor, M.J.; Jonkers, J.; Verheij, M.; van den Brekel, M.W.; Vens, C.

    2015-01-01

    Background and purpose The PARP inhibitor olaparib is currently tested in clinical phase 1 trials to define safe dose levels in combination with RT. However, certain clinically relevant insights are still lacking. Here we test, while comparing to single agent activity, the olaparib dose and genetic

  11. Effects of 3-AB on PARP expression of Hela cells and apoptosis and cell cycle progression of Hela cells after X-rays irradiation

    International Nuclear Information System (INIS)

    Du Xiang; Zhao Hongguang; Guo Wei; Gong Shouliang; Wang Wen

    2007-01-01

    Objective: To study the changes of apoptosis and cell cycle progression of Hela cells after the poly (ADP- ribose) polymerase (PARP) was inhibited by its inhibitor 3-aminobenzamid (3-AB) and the mechanisms of PARP interaction with Hela cells damaged by irradiation. Methods: Hela cell line was used. Flow cytometry (FCM) was used to examine the PARP expression of control and 3 AB groups at 0, 2, 4, 8, 12 h alter administration with 5 mmol·L -1 3-AB. The percentage of apoptotic cells and cell cycle progression ol control, irradiation, 3-AB plus irradiation groups were measured with FCM at 2, 8, 12, 24 h after exposure to 2 Gy irradiation following administration with 5 mmol·L -1 3-AB. Results: The percentage of Hela cells with positive expression of PARP protein decreased after administration with 3-AB and there was significant difference between 3-AB plus irradiation group and control group (P 2 cells in the 3-AB plus irradiation group were lower than those in the irradiation group (P 2 arrest induced by irradiation. (authors)

  12. The onset of coherence collapse in DBR lasers

    International Nuclear Information System (INIS)

    Woodward, S.L.; Koch, T.L.; Koren, U.

    1990-01-01

    The authors investigate how the onset of coherence collapse depends on laser output power. The lasers were three-section multiquantum-well distributed-Bragg-reflector (MQW-DBR) lasers. The fraction of light reflected back into the lasing mode was varied, and the point at which the transition to coherence collapse occurred was measured. This feedback level varies approximately linearly with laser output power. For these lasers, when the output power is 1 mW, the transition to coherence collapse beings when the optical feedback into the lasing mode is below - 40 dBm; when the feedback power is - 35 dBm the laser line is completely collapsed

  13. Developing empirical collapse fragility functions for global building types

    Science.gov (United States)

    Jaiswal, K.; Wald, D.; D'Ayala, D.

    2011-01-01

    Building collapse is the dominant cause of casualties during earthquakes. In order to better predict human fatalities, the U.S. Geological Survey’s Prompt Assessment of Global Earthquakes for Response (PAGER) program requires collapse fragility functions for global building types. The collapse fragility is expressed as the probability of collapse at discrete levels of the input hazard defined in terms of macroseismic intensity. This article provides a simple procedure for quantifying collapse fragility using vulnerability criteria based on the European Macroseismic Scale (1998) for selected European building types. In addition, the collapse fragility functions are developed for global building types by fitting the beta distribution to the multiple experts’ estimates for the same building type (obtained from EERI’s World Housing Encyclopedia (WHE)-PAGER survey). Finally, using the collapse probability distributions at each shaking intensity level as a prior and field-based collapse-rate observations as likelihood, it is possible to update the collapse fragility functions for global building types using the Bayesian procedure.

  14. Improvement of group collapsing in TRANSX code

    International Nuclear Information System (INIS)

    Jeong, Hyun Tae; Kim, Young Cheol; Kim, Young In; Kim, Young Kyun

    1996-07-01

    A cross section generating and processing computer code TRANSX version 2.15 in the K-CORE system, being developed by the KAERI LMR core design technology development team produces various cross section input files appropriated for flux calculation options from the cross section library MATXS. In this report, a group collapsing function of TRANSX has been improved to utilize the zone averaged flux file RZFLUX written in double precision as flux weighting functions. As a result, an iterative calculation system using double precision RZFLUX consisting of the cross section data library file MATXS, the effective cross section producing and processing code TRANSX, and the transport theory calculation code TWODANT has been set up and verified through a sample model calculation. 4 refs. (Author)

  15. Magnetorotational Explosions of Core-Collapse Supernovae

    Directory of Open Access Journals (Sweden)

    Gennady S. Bisnovatyi-Kogan

    2014-12-01

    Full Text Available Core-collapse supernovae are accompanied by formation of neutron stars. The gravitation energy is transformed into the energy of the explosion, observed as SN II, SN Ib,c type supernovae. We present results of 2-D MHD simulations, where the source of energy is rotation, and magnetic eld serves as a "transition belt" for the transformation of the rotation energy into the energy of the explosion. The toroidal part of the magnetic energy initially grows linearly with time due to dierential rotation. When the twisted toroidal component strongly exceeds the poloidal eld, magneto-rotational instability develops, leading to a drastic acceleration in the growth of magnetic energy. Finally, a fast MHD shock is formed, producing a supernova explosion. Mildly collimated jet is produced for dipole-like type of the initial field. At very high initial magnetic field no MRI development was found.

  16. Inhomogeneities from quantum collapse scheme without inflation

    Energy Technology Data Exchange (ETDEWEB)

    Bengochea, Gabriel R., E-mail: gabriel@iafe.uba.ar [Instituto de Astronomía y Física del Espacio (IAFE), UBA-CONICET, CC 67, Suc. 28, 1428 Buenos Aires (Argentina); Cañate, Pedro, E-mail: pedro.canate@nucleares.unam.mx [Instituto de Ciencias Nucleares, UNAM, México D.F. 04510, México (Mexico); Sudarsky, Daniel, E-mail: sudarsky@nucleares.unam.mx [Instituto de Ciencias Nucleares, UNAM, México D.F. 04510, México (Mexico)

    2015-04-09

    In this work, we consider the problem of the emergence of seeds of cosmic structure in the framework of the non-inflationary model proposed by Hollands and Wald. In particular, we consider a modification to that proposal designed to account for breaking the symmetries of the initial quantum state, leading to the generation of the primordial inhomogeneities. This new ingredient is described in terms of a spontaneous reduction of the wave function. We investigate under which conditions one can recover an essentially scale free spectrum of primordial inhomogeneities, and which are the dominant deviations that arise in the model as a consequence of the introduction of the collapse of the quantum state into that scenario.

  17. Asymptotic safety, singularities, and gravitational collapse

    International Nuclear Information System (INIS)

    Casadio, Roberto; Hsu, Stephen D.H.; Mirza, Behrouz

    2011-01-01

    Asymptotic safety (an ultraviolet fixed point with finite-dimensional critical surface) offers the possibility that a predictive theory of quantum gravity can be obtained from the quantization of classical general relativity. However, it is unclear what becomes of the singularities of classical general relativity, which, it is hoped, might be resolved by quantum effects. We study dust collapse with a running gravitational coupling and find that a future singularity can be avoided if the coupling becomes exactly zero at some finite energy scale. The singularity can also be avoided (pushed off to infinite proper time) if the coupling approaches zero sufficiently rapidly at high energies. However, the evolution deduced from perturbation theory still implies a singularity at finite proper time.

  18. On spontaneous photon emission in collapse models

    International Nuclear Information System (INIS)

    Adler, Stephen L; Bassi, Angelo; Donadi, Sandro

    2013-01-01

    We reanalyze the problem of spontaneous photon emission in collapse models. We show that the extra term found by Bassi and Dürr is present for non-white (colored) noise, but its coefficient is proportional to the zero frequency Fourier component of the noise. This leads one to suspect that the extra term is an artifact. When the calculation is repeated with the final electron in a wave packet and with the noise confined to a bounded region, the extra term vanishes in the limit of continuum state normalization. The result obtained by Fu and by Adler and Ramazanoğlu from application of the Golden Rule is then recovered. (paper)

  19. Gas and vapor bubble growth and collapse

    International Nuclear Information System (INIS)

    Bonnin, J.; Reali, M.; Sardella, L.

    1976-01-01

    The rate of growth or collapse of a spherical bubble of gas or vapor under the effect of a nonequilibrium with the ambient liquid can be expressed in terms of generalized parameters taking into account either mass or heat diffusion. Diffusion equations have been solved either by numerical computation or under the form of a asymptotical solution, for a growing bubble only and with a constant nonequilibrium. Solutions are compared between them and with already published ones. Experimental results obtained match with a unique nonequilibrium parameter, analogous to a Jacob number. Discrepancies with asymptotical solutions can require in some cases complete numerical computation. But taking into account convection due to bubble lift will require a more sophisticated numerical computation [fr

  20. Large-scale Instability during Gravitational Collapse with Neutrino Transport and a Core-Collapse Supernova

    Science.gov (United States)

    Aksenov, A. G.; Chechetkin, V. M.

    2018-04-01

    Most of the energy released in the gravitational collapse of the cores of massive stars is carried away by neutrinos. Neutrinos play a pivotal role in explaining core-collape supernovae. Currently, mathematical models of the gravitational collapse are based on multi-dimensional gas dynamics and thermonuclear reactions, while neutrino transport is considered in a simplified way. Multidimensional gas dynamics is used with neutrino transport in the flux-limited diffusion approximation to study the role of multi-dimensional effects. The possibility of large-scale convection is discussed, which is interesting both for explaining SN II and for setting up observations to register possible high-energy (≳10MeV) neutrinos from the supernova. A new multi-dimensional, multi-temperature gas dynamics method with neutrino transport is presented.

  1. Can a collapse of global civilization be avoided?

    OpenAIRE

    Ehrlich, Paul R.; Ehrlich, Anne H.

    2013-01-01

    Environmental problems have contributed to numerous collapses of civilizations in the past. Now, for the first time, a global collapse appears likely. Overpopulation, overconsumption by the rich and poor choices of technologies are major drivers; dramatic cultural change provides the main hope of averting calamity.

  2. Can a collapse of global civilization be avoided?

    Science.gov (United States)

    Ehrlich, Paul R; Ehrlich, Anne H

    2013-03-07

    Environmental problems have contributed to numerous collapses of civilizations in the past. Now, for the first time, a global collapse appears likely. Overpopulation, overconsumption by the rich and poor choices of technologies are major drivers; dramatic cultural change provides the main hope of averting calamity.

  3. Collapse in a forced three-dimensional nonlinear Schrodinger equation

    DEFF Research Database (Denmark)

    Lushnikov, P.M.; Saffman, M.

    2000-01-01

    We derive sufficient conditions for the occurrence of collapse in a forced three-dimensional nonlinear Schrodinger equation without dissipation. Numerical studies continue the results to the case of finite dissipation.......We derive sufficient conditions for the occurrence of collapse in a forced three-dimensional nonlinear Schrodinger equation without dissipation. Numerical studies continue the results to the case of finite dissipation....

  4. Collapse arresting in an inhomogeneous quintic nonlinear Schrodinger model

    DEFF Research Database (Denmark)

    Gaididei, Yuri Borisovich; Schjødt-Eriksen, Jens; Christiansen, Peter Leth

    1999-01-01

    Collapse of (1 + 1)-dimensional beams in the inhomogeneous one-dimensional quintic nonlinear Schrodinger equation is analyzed both numerically and analytically. It is shown that in the vicinity of a narrow attractive inhomogeneity, the collapse of beams in which the homogeneous medium would blow up...

  5. Collapse of thin wall tubes with small initial ovality

    International Nuclear Information System (INIS)

    Moreno, A.

    1977-01-01

    A simple model of creep collapse of tubes based on the bending theory of curved beams is developed. The model is compared with more complex models. The main result of this study is the definition of a new model of creep collapse of tubes with a minimum of limited hypothesis. (author) [es

  6. Collapse of thin wall tubes small initial ovality

    International Nuclear Information System (INIS)

    Moreno, A.

    1977-01-01

    In this work a simple model of creep collapse of tubes based on the bending theory of curved beams, is developed. The model is compared with more complex models. The main result of this work is the definition of a new model of creep collapse of tubes with a minimum of limitative hypothesis. (Author) 6 refs

  7. Maternal Postpartum Role Collapse as a Theory of Postpartum Depression

    Science.gov (United States)

    Amankwaa, Linda Clark

    2005-01-01

    The purpose of this paper is to discuss the development of a theory of maternal postpartum role collapse. The influences of traditional role theory and symbolic interactionism are presented. The development of the maternal postpartum role collapse theory emerged from the study of postpartum depression among African-American women (Amankwaa, 2000).…

  8. Dynamin inhibitors induce caspase-mediated apoptosis following cytokinesis failure in human cancer cells and this is blocked by Bcl-2 overexpression

    Directory of Open Access Journals (Sweden)

    Braithwaite Antony W

    2011-06-01

    Full Text Available Abstract Background The aim of both classical (e.g. taxol and targeted anti-mitotic agents (e.g. Aurora kinase inhibitors is to disrupt the mitotic spindle. Such compounds are currently used in the clinic and/or are being tested in clinical trials for cancer treatment. We recently reported a new class of targeted anti-mitotic compounds that do not disrupt the mitotic spindle, but exclusively block completion of cytokinesis. This new class includes MiTMAB and OcTMAB (MiTMABs, which are potent inhibitors of the endocytic protein, dynamin. Like other anti-mitotics, MiTMABs are highly cytotoxic and possess anti-proliferative properties, which appear to be selective for cancer cells. The cellular response following cytokinesis failure and the mechanistic pathway involved is unknown. Results We show that MiTMABs induce cell death specifically following cytokinesis failure via the intrinsic apoptotic pathway. This involves cleavage of caspase-8, -9, -3 and PARP, DNA fragmentation and membrane blebbing. Apoptosis was blocked by the pan-caspase inhibitor, ZVAD, and in HeLa cells stably expressing the anti-apoptotic protein, Bcl-2. This resulted in an accumulation of polyploid cells. Caspases were not cleaved in MiTMAB-treated cells that did not enter mitosis. This is consistent with the model that apoptosis induced by MiTMABs occurs exclusively following cytokinesis failure. Cytokinesis failure induced by cytochalasin B also resulted in apoptosis, suggesting that disruption of this process is generally toxic to cells. Conclusion Collectively, these data indicate that MiTMAB-induced apoptosis is dependent on both polyploidization and specific intracellular signalling components. This suggests that dynamin and potentially other cytokinesis factors are novel targets for development of cancer therapeutics.

  9. Neer Award 2016: reduced muscle degeneration and decreased fatty infiltration after rotator cuff tear in a poly(ADP-ribose) polymerase 1 (PARP-1) knock-out mouse model.

    Science.gov (United States)

    Kuenzler, Michael B; Nuss, Katja; Karol, Agnieszka; Schär, Michael O; Hottiger, Michael; Raniga, Sumit; Kenkel, David; von Rechenberg, Brigitte; Zumstein, Matthias A

    2017-05-01

    Disturbed muscular architecture, atrophy, and fatty infiltration remain irreversible in chronic rotator cuff tears even after repair. Poly (adenosine 5'-diphosphate-ribose) polymerase 1 (PARP-1) is a key regulator of inflammation, apoptosis, muscle atrophy, muscle regeneration, and adipocyte development. We hypothesized that the absence of PARP-1 would lead to a reduction in damage to the muscle subsequent to combined tenotomy and neurectomy in a PARP-1 knockout (KO) mouse model. PARP-1 KO and wild-type C57BL/6 (WT group) mice were analyzed at 1, 6, and 12 weeks (total n = 84). In all mice, the supraspinatus and infraspinatus muscles of the left shoulder were detached and denervated. Macroscopic analysis, magnetic resonance imaging, gene expression analysis, immunohistochemistry, and histology were used to assess the differences in PARP-1 KO and WT mice. The muscles in the PARP-1 KO group had significantly less retraction, atrophy, and fatty infiltration after 12 weeks than in the WT group. Gene expression of inflammatory, apoptotic, adipogenic, and muscular atrophy genes was significantly decreased in PARP-1 KO mice in the first 6 weeks. Absence of PARP-1 leads to a reduction in muscular architectural damage, early inflammation, apoptosis, atrophy, and fatty infiltration after combined tenotomy and neurectomy of the rotator cuff muscle. Although the macroscopic reaction to injury is similar in the first 6 weeks, the ability of the muscles to regenerate was much greater in the PARP-1 KO group, leading to a near-normalization of the muscle after 12 weeks. Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

  10. Nucleosynthesis in Core-Collapse Supernovae

    Science.gov (United States)

    Stevenson, Taylor Shannon; Viktoria Ohstrom, Eva; Harris, James Austin; Hix, William R.

    2018-01-01

    The nucleosynthesis which occurs in core-collapse supernovae (CCSN) is one of the most important sources of elements in the universe. Elements from Oxygen through Iron come predominantly from supernovae, and contributions of heavier elements are also possible through processes like the weak r-process, the gamma process and the light element primary process. The composition of the ejecta depends on the mechanism of the explosion, thus simulations of high physical fidelity are needed to explore what elements and isotopes CCSN can contribute to Galactic Chemical Evolution. We will analyze the nucleosynthesis results from self-consistent CCSN simulations performed with CHIMERA, a multi-dimensional neutrino radiation-hydrodynamics code. Much of our understanding of CCSN nucleosynthesis comes from parameterized models, but unlike CHIMERA these fail to address essential physics, including turbulent flow/instability and neutrino-matter interaction. We will present nucleosynthesis predictions for the explosion of a 9.6 solar mass first generation star, relying both on results of the 160 species nuclear reaction network used in CHIMERA within this model and on post-processing with a more extensive network. The lowest mass iron core-collapse supernovae, like this model, are distinct from their more massive brethren, with their explosion mechanism and nucleosynthesis being more like electron capture supernovae resulting from Oxygen-Neon white dwarves. We will highlight the differences between the nucleosynthesis in this model and more massive supernovae. The inline 160 species network is a feature unique to CHIMERA, making this the most sophisticated model to date for a star of this type. We will discuss the need and mechanism to extrapolate the post-processing to times post-simulation and analyze the uncertainties this introduces for supernova nucleosynthesis. We will also compare the results from the inline 160 species network to the post-processing results to study further

  11. Seepage Model for PA Including Drift Collapse

    International Nuclear Information System (INIS)

    Li, G.; Tsang, C.

    2000-01-01

    The purpose of this Analysis/Model Report (AMR) is to document the predictions and analysis performed using the Seepage Model for Performance Assessment (PA) and the Disturbed Drift Seepage Submodel for both the Topopah Spring middle nonlithophysal and lower lithophysal lithostratigraphic units at Yucca Mountain. These results will be used by PA to develop the probability distribution of water seepage into waste-emplacement drifts at Yucca Mountain, Nevada, as part of the evaluation of the long term performance of the potential repository. This AMR is in accordance with the ''Technical Work Plan for Unsaturated Zone (UZ) Flow and Transport Process Model Report'' (CRWMS M andO 2000 [153447]). This purpose is accomplished by performing numerical simulations with stochastic representations of hydrological properties, using the Seepage Model for PA, and evaluating the effects of an alternative drift geometry representing a partially collapsed drift using the Disturbed Drift Seepage Submodel. Seepage of water into waste-emplacement drifts is considered one of the principal factors having the greatest impact of long-term safety of the repository system (CRWMS M andO 2000 [153225], Table 4-1). This AMR supports the analysis and simulation that are used by PA to develop the probability distribution of water seepage into drift, and is therefore a model of primary (Level 1) importance (AP-3.15Q, ''Managing Technical Product Inputs''). The intended purpose of the Seepage Model for PA is to support: (1) PA; (2) Abstraction of Drift-Scale Seepage; and (3) Unsaturated Zone (UZ) Flow and Transport Process Model Report (PMR). Seepage into drifts is evaluated by applying numerical models with stochastic representations of hydrological properties and performing flow simulations with multiple realizations of the permeability field around the drift. The Seepage Model for PA uses the distribution of permeabilities derived from air injection testing in niches and in the cross drift to

  12. Seepage Model for PA Including Dift Collapse

    Energy Technology Data Exchange (ETDEWEB)

    G. Li; C. Tsang

    2000-12-20

    The purpose of this Analysis/Model Report (AMR) is to document the predictions and analysis performed using the Seepage Model for Performance Assessment (PA) and the Disturbed Drift Seepage Submodel for both the Topopah Spring middle nonlithophysal and lower lithophysal lithostratigraphic units at Yucca Mountain. These results will be used by PA to develop the probability distribution of water seepage into waste-emplacement drifts at Yucca Mountain, Nevada, as part of the evaluation of the long term performance of the potential repository. This AMR is in accordance with the ''Technical Work Plan for Unsaturated Zone (UZ) Flow and Transport Process Model Report'' (CRWMS M&O 2000 [153447]). This purpose is accomplished by performing numerical simulations with stochastic representations of hydrological properties, using the Seepage Model for PA, and evaluating the effects of an alternative drift geometry representing a partially collapsed drift using the Disturbed Drift Seepage Submodel. Seepage of water into waste-emplacement drifts is considered one of the principal factors having the greatest impact of long-term safety of the repository system (CRWMS M&O 2000 [153225], Table 4-1). This AMR supports the analysis and simulation that are used by PA to develop the probability distribution of water seepage into drift, and is therefore a model of primary (Level 1) importance (AP-3.15Q, ''Managing Technical Product Inputs''). The intended purpose of the Seepage Model for PA is to support: (1) PA; (2) Abstraction of Drift-Scale Seepage; and (3) Unsaturated Zone (UZ) Flow and Transport Process Model Report (PMR). Seepage into drifts is evaluated by applying numerical models with stochastic representations of hydrological properties and performing flow simulations with multiple realizations of the permeability field around the drift. The Seepage Model for PA uses the distribution of permeabilities derived from air injection testing in

  13. Oxygen Issue in Core Collapse Supernovae

    Science.gov (United States)

    Elmhamdi, A.

    2011-06-01

    We study the spectroscopic properties of a selected sample of 26 events within Core Collapse Supernovae (CCSNe) family. Special attention is paid to the nebular oxygen forbidden line [OI] 6300, 6364 Å doublet. We analyze the line flux ratio F6300/F6364 and infer information about the optical depth evolution, densities, volume-filling factors in the oxygen emitting zones. The line luminosity is measured for the sample events and its evolution is discussed on the basis of the bolometric light curve properties in type II and in type Ib-c SNe. The luminosities are then translated into oxygen abundances using two different methods. The results are combined with the determined 56Ni masses and compared with theoretical models by means of the [O/Fe] vs. Mms diagram. Two distinguishable and continuous populations, corresponding to Ib-c and type II SNe, are found. The higher mass nature of the ejecta in type II objects is also imprinted in the [CaII] 7291, 7324Å to [OI] 6300, 6364Å luminosity ratios. Our results may be used as input parameters for theoretical models studying the chemical enrichment of galaxies.

  14. Asymmetric explosions of core collapse supernovae

    International Nuclear Information System (INIS)

    Guilet, Jerome

    2010-01-01

    This thesis is devoted to the study of several hydrodynamic and magnetohydrodynamic phenomena that could create an asymmetry in core collapse supernovae. In the first part giving the general context, we first describe the theoretical and observational indications suggesting an important asymmetry. We then present several instabilities that could break the initial spherical symmetry, insisting particularly on the role of the Stationary Accretion Shock Instability (SASI). The second part is dedicated to an hydrodynamic study of the Standing Accretion shock instability. We first give an argument using the frequency of unstable modes that enables us to distinguish between the two mechanisms proposed to explain the linear growth of SASI. As a second step, we study the non-linear dynamics of SASI and propose for the first time a mechanism responsible for its saturation. In this scenario, the saturation occurs when parasitic instabilities are able to grow fast enough on a SASI mode. The semi-analytical prediction of the saturation amplitude is successfully compared with published numerical simulations. The third part studies the effect of a moderate magnetic field. We find that such a magnetic field can have either a stabilizing or a destabilizing effect on SASI depending on its geometry. We then concentrate on the dynamics of the Alfven surface, where the Alfven and the advection speed coincide. We show that the amplification of Alfven waves near this surface creates a pressure feedback, which could affect significantly the dynamics of the shock if the magnetic energy is comparable to the kinetic energy. (author) [fr

  15. Tulsa Oklahoma Oktoberfest Tent Collapse Report

    Directory of Open Access Journals (Sweden)

    Kelly E. Deal

    2012-01-01

    Full Text Available Background. On October 17, 2007, a severe weather event collapsed two large tents and several smaller tents causing 23 injuries requiring evacuation to emergency departments in Tulsa, OK. Methods. This paper is a retrospective analysis of the regional health system’s response to this event. Data from the Tulsa Fire Department, The Emergency Medical Services Authority (EMSA, receiving hospitals and coordinating services were reviewed and analyzed. EMS patient care reports were reviewed and analyzed using triage designators assigned in the field, injury severity scores, and critical mortality. Results. EMT's and paramedics from Tulsa Fire Department and EMSA provided care at the scene under unified incident command. Of the 23 patients transported by EMS, four were hospitalized, one with critical spinal injury and one with critical head injury. One patient is still in ongoing rehabilitation. Discussion. Analysis of the 2007 Tulsa Oktoberfest mass casualty incident revealed rapid police/fire/EMS response despite challenges of operations at dark under severe weather conditions and the need to treat a significant number of injured victims. There were no fatalities. Of the patients transported by EMS, a minority sustained critical injuries, with most sustaining injuries amenable to discharge after emergency department care.

  16. Flux-driven simulations of turbulence collapse

    Energy Technology Data Exchange (ETDEWEB)

    Park, G. Y.; Kim, S. S.; Jhang, Hogun; Rhee, T. [National Fusion Research Institute, Daejeon 305-333 (Korea, Republic of); Diamond, P. H. [National Fusion Research Institute, Daejeon 305-333 (Korea, Republic of); CASS and Department of Physics, University of California, San Diego, La Jolla, California 92093-0429 (United States); Xu, X. Q. [Lawrence Livermore National Laboratory, Livermore, California 94551 (United States)

    2015-03-15

    Using three-dimensional nonlinear simulations of tokamak turbulence, we show that an edge transport barrier (ETB) forms naturally once input power exceeds a threshold value. Profiles, turbulence-driven flows, and neoclassical coefficients are evolved self-consistently. A slow power ramp-up simulation shows that ETB transition is triggered by the turbulence-driven flows via an intermediate phase which involves coherent oscillation of turbulence intensity and E×B flow shear. A novel observation of the evolution is that the turbulence collapses and the ETB transition begins when R{sub T} > 1 at t = t{sub R} (R{sub T}: normalized Reynolds power), while the conventional transition criterion (ω{sub E×B}>γ{sub lin} where ω{sub E×B} denotes mean flow shear) is satisfied only after t = t{sub C} ( >t{sub R}), when the mean flow shear grows due to positive feedback.

  17. Colony collapse disorder: a descriptive study.

    Directory of Open Access Journals (Sweden)

    Dennis Vanengelsdorp

    Full Text Available BACKGROUND: Over the last two winters, there have been large-scale, unexplained losses of managed honey bee (Apis mellifera L. colonies in the United States. In the absence of a known cause, this syndrome was named Colony Collapse Disorder (CCD because the main trait was a rapid loss of adult worker bees. We initiated a descriptive epizootiological study in order to better characterize CCD and compare risk factor exposure between populations afflicted by and not afflicted by CCD. METHODS AND PRINCIPAL FINDINGS: Of 61 quantified variables (including adult bee physiology, pathogen loads, and pesticide levels, no single measure emerged as a most-likely cause of CCD. Bees in CCD colonies had higher pathogen loads and were co-infected with a greater number of pathogens than control populations, suggesting either an increased exposure to pathogens or a reduced resistance of bees toward pathogens. Levels of the synthetic acaricide coumaphos (used by beekeepers to control the parasitic mite Varroa destructor were higher in control colonies than CCD-affected colonies. CONCLUSIONS/SIGNIFICANCE: This is the first comprehensive survey of CCD-affected bee populations that suggests CCD involves an interaction between pathogens and other stress factors. We present evidence that this condition is contagious or the result of exposure to a common risk factor. Potentially important areas for future hypothesis-driven research, including the possible legacy effect of mite parasitism and the role of honey bee resistance to pesticides, are highlighted.

  18. Tourism's collapse puts Gambian women at risk.

    Science.gov (United States)

    Coker, M S

    1995-06-01

    Despite efforts of the Gambian government, which established a ministry in 1981 that would tackle gender issues, improve women's health, and promote empowerment, women are underrepresented in government and business, and 84% are illiterate. Child mortality is among the highest in Africa; 134 children per 1000 die before their fifth birthday. In the mid-1980s austerity measures adopted by the World Bank and IMF left the ministry without funds. Rice and vegetable production, the main source of income for women, fell in the 1990s. In 1994, paddy production dropped 23% from the previous year; this was due to a lack of technical and financial assistance. The collapse of tourism with Capt. Yahya Jammeh's seizure of power has put prostitutes catering to tourists out of work, but women who have lost jobs in the hotel industry may be pushed into local prostitution to survive. The impact of this on the HIV/AIDS epidemic is unclear. Although Gambia is one of the world's most aid-dependent countries (more than a quarter of the GNP before the coup), corruption and mismanagement in the nongovernmental sector is widespread. The director of the Women in Development Programme, a $15m World Bank project, was forced to resign over allegations of fraud. The political process sidelines women; only village chiefs, who are traditionally men, are allowed to vote when new heads are elected.

  19. Collapsing avian community on a Hawaiian island

    Science.gov (United States)

    Paxton, Eben H.; Camp, Richard J.; Gorresen, P. Marcos; Crampton, Lisa H.; Leonard, David L.; VanderWerf, Eric

    2016-01-01

    The viability of many species has been jeopardized by numerous negative factors over the centuries, but climate change is predicted to accelerate and increase the pressure of many of these threats, leading to extinctions. The Hawaiian honeycreepers, famous for their spectacular adaptive radiation, are predicted to experience negative responses to climate change, given their susceptibility to introduced disease, the strong linkage of disease distribution to climatic conditions, and their current distribution. We document the rapid collapse of the native avifauna on the island of Kaua‘i that corresponds to changes in climate and disease prevalence. Although multiple factors may be pressuring the community, we suggest that a tipping point has been crossed in which temperatures in forest habitats at high elevations have reached a threshold that facilitates the development of avian malaria and its vector throughout these species’ ranges. Continued incursion of invasive weeds and non-native avian competitors may be facilitated by climate change and could also contribute to declines. If current rates of decline continue, we predict multiple extinctions in the coming decades. Kaua‘i represents an early warning for the forest bird communities on the Maui and Hawai‘i islands, as well as other species around the world that are trapped within a climatic space that is rapidly disappearing.

  20. A single dose of dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY than in type 2 diabetes mellitus.

    Science.gov (United States)

    Hohendorff, J; Szopa, M; Skupien, J; Kapusta, M; Zapala, B; Platek, T; Mrozinska, S; Parpan, T; Glodzik, W; Ludwig-Galezowska, A; Kiec-Wilk, B; Klupa, T; Malecki, M T

    2017-08-01

    SGLT2 inhibitors are a new class of oral hypoglycemic agents used in type 2 diabetes (T2DM). Their effectiveness in maturity onset diabetes of the young (MODY) is unknown. We aimed to assess the response to a single dose of 10 mg dapagliflozin in patients with Hepatocyte Nuclear Factor 1 Alpha (HNF1A)-MODY, Glucokinase (GCK)-MODY, and type 2 diabetes. We examined 14 HNF1A-MODY, 19 GCK-MODY, and 12 type 2 diabetes patients. All studied individuals received a single morning dose of 10 mg of dapagliflozin added to their current therapy of diabetes. To assess the response to dapagliflozin we analyzed change in urinary glucose to creatinine ratio and serum 1,5-Anhydroglucitol (1,5-AG) level. There were only four patients with positive urine glucose before dapagliflozin administration (one with HNF1A-MODY, two with GCK-MODY, and one with T2DM), whereas after SGLT-2 inhibitor use, glycosuria occurred in all studied participants. Considerable changes in mean glucose to creatinine ratio after dapagliflozin administration were observed in all three groups (20.51 ± 12.08, 23.19 ± 8.10, and 9.84 ± 6.68 mmol/mmol for HNF1A-MODY, GCK-MODY, and T2DM, respectively, p MODY, respectively), but not between the two MODY forms (p = 0.7231). Significant change in serum 1,5-AG was noticed only in T2DM and it was -6.57 ± 7.34 mg/ml (p = 0.04). A single dose of dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY than in T2DM. Whether flozins are a valid therapeutic option in these forms of MODY requires long-term clinical studies.

  1. Predicting mining collapse: Superjerks and the appearance of record-breaking events in coal as collapse precursors

    Science.gov (United States)

    Jiang, Xiang; Liu, Hanlong; Main, Ian G.; Salje, Ekhard K. H.

    2017-08-01

    The quest for predictive indicators for the collapse of coal mines has led to a robust criterion from scale-model tests in the laboratory. Mechanical collapse under uniaxial stress forms avalanches with a power-law probability distribution function of radiated energy P ˜E-ɛ , with exponent ɛ =1.5 . Impending major collapse is preceded by a reduction of the energy exponent to the mean-field value ɛ =1.32 . Concurrently, the crackling noise increases in intensity and the waiting time between avalanches is reduced when the major collapse is approaching. These latter criteria were so-far deemed too unreliable for safety assessments in coal mines. We report a reassessment of previously collected extensive collapse data sets using "record-breaking analysis," based on the statistical appearance of "superjerks" within a smaller spectrum of collapse events. Superjerks are defined as avalanche signals with energies that surpass those of all previous events. The final major collapse is one such superjerk but other "near collapse" events equally qualify. In this way a very large data set of events is reduced to a sparse sequence of superjerks (21 in our coal sample). The main collapse can be anticipated from the sequence of energies and waiting times of superjerks, ignoring all weaker events. Superjerks are excellent indicators for the temporal evolution, and reveal clear nonstationarity of the crackling noise at constant loading rate, as well as self-similarity in the energy distribution of superjerks as a function of the number of events so far in the sequence Es j˜nδ with δ =1.79 . They are less robust in identifying the precise time of the final collapse, however, than the shift of the energy exponents in the whole data set which occurs only over a short time interval just before the major event. Nevertheless, they provide additional diagnostics that may increase the reliability of such forecasts.

  2. Repair of radiation-induced heat-labile sites is independent of DNA-PKcs, XRCC1 or PARP

    Energy Technology Data Exchange (ETDEWEB)

    Stenerl& #246; w, Bo; Karlsson, Karin H.; Radulescu, Irina; Rydberg, Bjorn; Stenerlow, Bo

    2008-04-29

    Ionizing radiation induces a variety of different DNA lesions: in addition to the most critical DNA damage, the DSB, numerous base alterations, SSBs and other modifications of the DNA double-helix are formed. When several non-DSB lesions are clustered within a short distance along DNA, or close to a DSB, they may interfere with the repair of DSBs and affect the measurement of DSB induction and repair. We have previously shown that a substantial fraction of DSBs measured by pulsed-field gel electrophoresis (PFGE) are in fact due to heat-labile sites (HLS) within clustered lesions, thus reflecting an artifact of preparation of genomic DNA at elevated temperature. To further characterize the influence of HLS on DSB induction and repair, four human cell lines (GM5758, GM7166, M059K, U-1810) with apparently normal DSB rejoining were tested for bi-phasic rejoining after gamma irradiation. When heat-released DSBs were excluded from the measurements the fraction of fast rejoining decreased to less than 50% of the total. However, neither the half-times of the fast (t{sub 1/2} = 7-8 min) or slow (t{sub 1/2} = 2.5 h) DSB rejoining were changed significantly. At t=0 the heat-released DSBs accounted for almost 40% of the DSBs, corresponding to 10 extra DSB/cell/Gy in the initial DSB yield. These heat-released DSBs were repaired within 60-90 min in all tested cells, including M059K cells treated with wortmannin or DNA-PKcs defect M059J cells. Furthermore, cells lacking XRCC1 or Poly(ADP-ribose) polymerase-1 (PARP-1) rejoined both total DSBs and heat-released DSBs similar to normal cells. In summary, the presence of heat-labile sites have a substantial impact on DSB induction yields and DSB rejoining rates measured by pulsed-field gel electrophoresis, and HLS repair is independent of DNA-PKcs, XRCC1 and PARP.

  3. Study of film boiling collapse behavior during vapor explosion

    International Nuclear Information System (INIS)

    Yagi, Masahiro; Yamano, Norihiro; Sugimoto, Jun; Abe, Yutaka; Adachi, Hiromichi; Kobayashi, Tomoyoshi.

    1996-06-01

    Possible large scale vapor explosions are safety concern in nuclear power plants during severe accident. In order to identify the occurrence of the vapor explosion and to estimate the magnitude of the induced pressure pulse, it is necessary to investigate the triggering condition for the vapor explosion. As a first step of this study, scooping analysis was conducted with a simulation code based on thermal detonation model. It was found that the pressure at the collapse of film boiling much affects the trigger condition of vapor explosion. Based on this analytical results, basic experiments were conducted to clarify the collapse conditions of film boiling on a high temperature solid ball surface. Film boiling condition was established by flooding water onto a high temperature stainless steel ball heated by a high frequency induction heater. After the film boiling was established, the pressure pulse generated by a shock tube was applied to collapse the steam film on the ball surface. As the experimental boundary conditions, materials and size of the balls, magnitude of pressure pulse and initial temperature of the carbon and stainless steel balls were varied. The transients of pressure and surface temperature were measured. It was found that the surface temperature on the balls sharply decreased when the pressure wave passed through the film on balls. Based on the surface temperature behavior, the film boiling collapse pattern was found to be categorized into several types. Especially, the pattern for stainless steel ball was categorized into three types; no collapse, collapse and reestablishment after collapse. It was thus clarified that the film boiling collapse behavior was identified by initial conditions and that the pressure required to collapse film boiling strongly depended on the initial surface temperature. The present results will provide a useful information for the analysis of vapor explosions based on the thermal detonation model. (J.P.N.)

  4. SEEPAGE MODEL FOR PA INCLUDING DRIFT COLLAPSE

    International Nuclear Information System (INIS)

    C. Tsang

    2004-01-01

    The purpose of this report is to document the predictions and analyses performed using the seepage model for performance assessment (SMPA) for both the Topopah Spring middle nonlithophysal (Tptpmn) and lower lithophysal (Tptpll) lithostratigraphic units at Yucca Mountain, Nevada. Look-up tables of seepage flow rates into a drift (and their uncertainty) are generated by performing numerical simulations with the seepage model for many combinations of the three most important seepage-relevant parameters: the fracture permeability, the capillary-strength parameter 1/a, and the percolation flux. The percolation flux values chosen take into account flow focusing effects, which are evaluated based on a flow-focusing model. Moreover, multiple realizations of the underlying stochastic permeability field are conducted. Selected sensitivity studies are performed, including the effects of an alternative drift geometry representing a partially collapsed drift from an independent drift-degradation analysis (BSC 2004 [DIRS 166107]). The intended purpose of the seepage model is to provide results of drift-scale seepage rates under a series of parameters and scenarios in support of the Total System Performance Assessment for License Application (TSPA-LA). The SMPA is intended for the evaluation of drift-scale seepage rates under the full range of parameter values for three parameters found to be key (fracture permeability, the van Genuchten 1/a parameter, and percolation flux) and drift degradation shape scenarios in support of the TSPA-LA during the period of compliance for postclosure performance [Technical Work Plan for: Performance Assessment Unsaturated Zone (BSC 2002 [DIRS 160819], Section I-4-2-1)]. The flow-focusing model in the Topopah Spring welded (TSw) unit is intended to provide an estimate of flow focusing factors (FFFs) that (1) bridge the gap between the mountain-scale and drift-scale models, and (2) account for variability in local percolation flux due to

  5. Gravitational collapse of charged dust shell and maximal slicing condition

    International Nuclear Information System (INIS)

    Maeda, Keiichi

    1980-01-01

    The maximal slicing condition is a good time coordinate condition qualitatively when pursuing the gravitational collapse by the numerical calculation. The analytic solution of the gravitational collapse under the maximal slicing condition is given in the case of a spherical charged dust shell and the behavior of time slices with this coordinate condition is investigated. It is concluded that under the maximal slicing condition we can pursue the gravitational collapse until the radius of the shell decreases to about 0.7 x (the radius of the event horizon). (author)

  6. Search for stellar gravitational collapses with the MACRO detector

    CERN Document Server

    Ambrosio, M; Baldini, A; Barbarino, G C; Barish, B C; Battistoni, G; Bellotti, R; Bemporad, C; Bernardini, P; Bilokon, H; Bloise, C; Bower, C; Brigida, M; Bussino, S; Cafagna, F; Campana, D; Carboni, M; Cecchini, S; Cei, F; Chiarella, V; Choudhary, B C; Coutu, S; Cozzi, M; De Cataldo, G; De Marzo, C; De Mitri, I; De Vincenzi, M; Dekhissi, H; Derkaoui, J; Di Credico, A; Favuzzi, C; Forti, C; Fusco, P; Giacomelli, G; Giannini, G; Giglietto, N; Giorgini, M; Grassi, M; Grillo, A; Gustavino, C; Habig, A; Hanson, K; Heinz, R; Iarocci, E; Katsavounidis, E; Katsavounidis, I; Kearns, E; Kim, H; Kyriazopoulou, S; Lamanna, E; Lane, C; Levin, D S; Lipari, P; Longley, N P; Longo, M J; Loparco, F; Maaroufi, F; Mancarella, G; Mandrioli, G; Margiotta, A; Marini, A; Martello, D; Marzari-Chiesa, A; Mazziotta, M N; Michael, D G; Monacelli, P; Montaruli, T; Monteno, M; Mufson, S; Musser, J; Nicolò, D; Nolty, R; Orth, C; Osteria, G; Palamara, O; Patera, V; Patrizii, L; Pazzi, R; Peck, C W; Perrone, L; Petrera, S; Popa, V; Raino, J A; Reynoldson, J; Ronga, F; Satriano, C; Scapparone, E; Scholberg, K; Sciubba, A; Sioli, M; Sirri, G; Sitta, M; Spinelli, P; Spinetti, M; Spurio, M; Steinberg, R; Stone, J L; Sulak, L R; Surdo, A; Tarle, G; Togo, V; Vakili, M; Walter, C W; Webb, R; 10.1140/epjc/s2004-01981-3

    2004-01-01

    We present the final results of the search for stellar gravitational collapses obtained by the MACRO experiment. The detector was active for a stellar collapse search for more than 11 years and it was sensitive to collapses occurring all over in our galaxy for 8.6 years. A real time system for a prompt recognition of neutrino bursts was developed and was operating on-line for almost the whole life of the experiment. No signal compatible with a neutrino burst from a galactic supernova was observed.

  7. Recoverable and Programmable Collapse from Folding Pressurized Origami Cellular Solids.

    Science.gov (United States)

    Li, S; Fang, H; Wang, K W

    2016-09-09

    We report a unique collapse mechanism by exploiting the negative stiffness observed in the folding of an origami solid, which consists of pressurized cells made by stacking origami sheets. Such a collapse mechanism is recoverable, since it only involves rigid folding of the origami sheets and it is programmable by pressure control and the custom design of the crease pattern. The collapse mechanism features many attractive characteristics for applications such as energy absorption. The reported results also suggest a new branch of origami study focused on its nonlinear mechanics associated with folding.

  8. Coexistence of collapse and stable spatiotemporal solitons in multimode fibers

    Science.gov (United States)

    Shtyrina, Olga V.; Fedoruk, Mikhail P.; Kivshar, Yuri S.; Turitsyn, Sergei K.

    2018-01-01

    We analyze spatiotemporal solitons in multimode optical fibers and demonstrate the existence of stable solitons, in a sharp contrast to earlier predictions of collapse of multidimensional solitons in three-dimensional media. We discuss the coexistence of blow-up solutions and collapse stabilization by a low-dimensional external potential in graded-index media, and also predict the existence of stable higher-order nonlinear waves such as dipole-mode spatiotemporal solitons. To support the main conclusions of our numerical studies we employ a variational approach and derive analytically the stability criterion for input powers for the collapse stabilization.

  9. Hamiltonian treatment of the gravitational collapse of thin shells

    International Nuclear Information System (INIS)

    Crisostomo, Juan; Olea, Rodrigo

    2004-01-01

    A Hamiltonian treatment of the gravitational collapse of thin shells is presented. The direct integration of the canonical constraints reproduces the standard shell dynamics for a number of known cases. The formalism is applied in detail to three-dimensional spacetime and the properties of the (2+1)-dimensional charged black hole collapse are further elucidated. The procedure is also extended to deal with rotating solutions in three dimensions. The general form of the equations providing the shell dynamics implies the stability of black holes, as they cannot be converted into naked singularities by any shell collapse process

  10. Scalar field collapse in Gauss-Bonnet gravity

    Science.gov (United States)

    Banerjee, Narayan; Paul, Tanmoy

    2018-02-01

    We consider a "scalar-Einstein-Gauss-Bonnet" theory in four dimension, where the scalar field couples non-minimally with the Gauss-Bonnet (GB) term. This coupling with the scalar field ensures the non-topological character of the GB term. In this scenario, we examine the possibility for collapsing of the scalar field. Our result reveals that such a collapse is possible in the presence of Gauss-Bonnet gravity for suitable choices of parametric regions. The singularity formed as a result of the collapse is found to be a curvature singularity which is hidden from the exterior by an apparent horizon.

  11. Scalar field collapse in Gauss-Bonnet gravity

    Energy Technology Data Exchange (ETDEWEB)

    Banerjee, Narayan [Indian Institute of Science Education and Research Kolkata, Department of Physical Sciences, Nadia, West Bengal (India); Paul, Tanmoy [Indian Association for the Cultivation of Science, Department of Theoretical Physics, Kolkata (India)

    2018-02-15

    We consider a ''scalar-Einstein-Gauss-Bonnet'' theory in four dimension, where the scalar field couples non-minimally with the Gauss-Bonnet (GB) term. This coupling with the scalar field ensures the non-topological character of the GB term. In this scenario, we examine the possibility for collapsing of the scalar field. Our result reveals that such a collapse is possible in the presence of Gauss-Bonnet gravity for suitable choices of parametric regions. The singularity formed as a result of the collapse is found to be a curvature singularity which is hidden from the exterior by an apparent horizon. (orig.)

  12. Self-similar Langmuir collapse at critical dimension

    International Nuclear Information System (INIS)

    Berge, L.; Dousseau, Ph.; Pelletier, G.; Pesme, D.

    1991-01-01

    Two spherically symmetric versions of a self-similar collapse are investigated within the framework of the Zakharov equations, namely, one relative to a vectorial electric field and the other corresponding to a scalar modeling of the Langmuir field. Singular solutions of both of them depend on a linear time contraction rate ξ(t) = V(t * -t), where t * and V = -ξ denote, respectively, the collapse time and the constant collapse velocity. It is shown that under certain conditions, only the scalar model admits self-similar solutions, varying regularly as a function of the control parameter V from the subsonic (V >1) regime. (author)

  13. Carbon ion beam triggers both caspase-dependent and caspase-independent pathway of apoptosis in HeLa and status of PARP-1 controls intensity of apoptosis.

    Science.gov (United States)

    Ghorai, Atanu; Sarma, Asitikantha; Bhattacharyya, Nitai P; Ghosh, Utpal

    2015-04-01

    High linear energy transfer (LET) carbon ion beam (CIB) is becoming very promising tool for various cancer treatments and is more efficient than conventional low LET gamma or X-rays to kill malignant or radio-resistant cells, although detailed mechanism of cell death is still unknown. Poly (ADP-ribose) polymerase-1 (PARP-1) is a key player in DNA repair and its inhibitors are well-known as radio-sensitizer for low LET radiation. The objective of our study was to find mechanism(s) of induction of apoptosis by CIB and role of PARP-1 in CIB-induced apoptosis. We observed overall higher apoptosis in PARP-1 knocked down HeLa cells (HsiI) compared with negative control H-vector cells after irradiation with CIB (0-4 Gy). CIB activated both intrinsic and extrinsic pathways of apoptosis via caspase-9 and caspase-8 activation respectively, followed by caspase-3 activation, apoptotic body, nucleosomal ladder formation and sub-G1 accumulation. Apoptosis inducing factor translocation into nucleus in H-vector but not in HsiI cells after CIB irradiation contributed caspase-independent apoptosis. Higher p53 expression was observed in HsiI cells compared with H-vector after exposure with CIB. Notably, we observed about 37 % fall of mitochondrial membrane potential, activation of caspase-9 and caspase-3 and mild activation of caspase-8 without any detectable apoptotic body formation in un-irradiated HsiI cells. We conclude that reduction of PARP-1 expression activates apoptotic signals via intrinsic and extrinsic pathways in un-irradiated cells. CIB irradiation further intensified both intrinsic and extrinsic pathways of apoptosis synergistically along with up-regulation of p53 in HsiI cells resulting overall higher apoptosis in HsiI than H-vector.

  14. Expression profiles of vault components MVP, TEP1 and vPARP and their correlation to other multidrug resistance proteins in ovarian cancer.

    Science.gov (United States)

    Szaflarski, Witold; Sujka-Kordowska, Patrycja; Pula, Bartosz; Jaszczyńska-Nowinka, Karolina; Andrzejewska, Małgorzata; Zawierucha, Piotr; Dziegiel, Piotr; Nowicki, Michał; Ivanov, Pavel; Zabel, Maciej

    2013-08-01

    Vaults are cytoplasmic ribonucleoprotein particles composed of three proteins (MVP, TEP1, vPARP) and vault‑associated RNAs (vRNAs). Although the cellular functions of vaults remain unclear, vaults are strongly linked to the development of multidrug resistance (MDR), the major obstacle to the efficient treatment of cancers. Available published data suggest that vaults and their components are frequently upregulated in broad variety of multidrug-resistant cancer cell lines and tumors of different histological origin. Here, we provide detailed analysis of vault protein expression in post-surgery ovarian cancer samples from patients that were not exposed to chemotherapy. Our analysis suggests that vault proteins are expressed in the ovaries of healthy individuals but their expression in cancer patients is changed. Specifically, MVP, TEP1 and vPARP mRNA levels are significantly decreased in cancer samples with tendency of lower expression in higher-grade tumors. The pattern of vault protein mRNA expression is strongly correlated with the expression of other MDR-associated proteins such as MDR1, MRP1 and BCRP. Surprisingly, the protein levels of MVP, TEP1 and vPARP are actually increased in the higher‑grade tumors suggesting existence of post-transcriptional regulation of vault component production.

  15. Andrographolide Induces Apoptosis of C6 Glioma Cells via the ERK-p53-Caspase 7-PARP Pathway

    Directory of Open Access Journals (Sweden)

    Shih-Hung Yang

    2014-01-01

    Full Text Available Background. Glioma is the most malignant tumor of the central nervous system. Efforts on the development of new chemotherapy are mandatory. Andrographolide (AND, a diterpenoid lactone isolated from the Andrographis paniculata, has been shown to have antitumor activities in several types of cancer cells. Whether AND can exert its antitumor activity in glioblastoma cells remains unknown. This study examined the anticancer effects of AND, both in vitro and in vivo. Methods. Cell apoptosis was assayed by flow cytometry and nuclear staining. The signaling pathway for AND was determined by western blotting. The effects of AND on tumor growth was evaluated in a mouse model. Results and Conclusion. In vitro, with application of specific inhibitors and siRNA, AND-induced apoptosis was proven through ROS-ERK-P53-caspase 7-PARP signaling pathway. In vivo, AND significantly retarded tumor growth and caused regression of well-formed tumors in vivo. Furthermore, AND did not induce apoptosis or activate ERK and p53 in primary cultured astrocyte cells, and it may serve as a potential therapeutic candidate for the treatment of glioma.

  16. Hydrofluoric Acid-Based Derivatization Strategy To Profile PARP-1 ADP-Ribosylation by LC-MS/MS.

    Science.gov (United States)

    Gagné, Jean-Philippe; Langelier, Marie-France; Pascal, John M; Poirier, Guy G

    2018-06-11

    Despite significant advances in the development of mass spectrometry-based methods for the identification of protein ADP-ribosylation, current protocols suffer from several drawbacks that preclude their widespread applicability. Given the intrinsic heterogeneous nature of poly(ADP-ribose), a number of strategies have been developed to generate simple derivatives for effective interrogation of protein databases and site-specific localization of the modified residues. Currently, the generation of spectral signatures indicative of ADP-ribosylation rely on chemical or enzymatic conversion of the modification to a single mass increment. Still, limitations arise from the lability of the poly(ADP-ribose) remnant during tandem mass spectrometry, the varying susceptibilities of different ADP-ribose-protein bonds to chemical hydrolysis, or the context dependence of enzyme-catalyzed reactions. Here, we present a chemical-based derivatization method applicable to the confident identification of site-specific ADP-ribosylation by conventional mass spectrometry on any targeted amino acid residue. Using PARP-1 as a model protein, we report that treatment of ADP-ribosylated peptides with hydrofluoric acid generates a specific +132 Da mass signature that corresponds to the decomposition of mono- and poly(ADP-ribosylated) peptides into ribose adducts as a consequence of the cleavage of the phosphorus-oxygen bonds.

  17. Hydromagnetic instabilities and magnetic field amplification in core collapse supernovae

    Energy Technology Data Exchange (ETDEWEB)

    Cerda-Duran, P; Obergaulinger, M; Mueller, E [Max-Planck-Institut fuer Astrophysik, Karl-Schwarzschild-st. 1, 85748 Garching (Germany); Aloy, M A; Font, J A, E-mail: cerda@mpa-garching.mpg.de [Departamento de Astronomia y Astrofisica, Universidad de Valencia, 46100 Burjassot, Valencia (Spain)

    2011-09-22

    Some of the most violent events in the universe, the gamma ray burst, could be related to the gravitational collapse of massive stellar cores. The recent association of long GRBs to some class of type Ic supernova seems to support this view. In such scenario fast rotation, strong magnetic fields and general relativistic effects are key ingredients. It is thus important to understand the mechanism that amplifies the magnetic field under that conditions. I present global simulations of the magneto-rotational collapse of stellar cores in general relativity and semi-global simulations of hydromagnetic instabilities under core collapse conditions. I discuss effect of the magneto-rotational instability and the magnetic field amplification during the collapse, the uncertainties in this process and the dynamical effects in the supernova explosion.

  18. The role of fluid viscosity in an immersed granular collapse

    Science.gov (United States)

    Yang, Geng Chao; Kwok, Chung Yee; Sobral, Yuri Dumaresq

    2017-06-01

    Instabilities of immersed slopes and cliffs can lead to catastrophic events that involve a sudden release of huge soil mass. The scaled deposit height and runout distance are found to follow simple power laws when a granular column collapses on a horizontal plane. However, if the granular column is submerged in a fluid, the mobility of the granular collapse due to high inertia effects will be reduced by fluid-particle interactions. In this study, the effects of fluid viscosity on granular collapse is investigated qualitatively by adopting a numerical approach based on the coupled lattice Boltzmann method (LBM) and discrete element method (DEM). It is found that the granular collapse can be dramatically slowed down due to the presence of viscous fluids. For the considered granular configuration, when the fluid viscosity increases. the runout distance decreases and the final deposition shows a larger deposit angle.

  19. The role of fluid viscosity in an immersed granular collapse

    Directory of Open Access Journals (Sweden)

    Yang Geng Chao

    2017-01-01

    Full Text Available Instabilities of immersed slopes and cliffs can lead to catastrophic events that involve a sudden release of huge soil mass. The scaled deposit height and runout distance are found to follow simple power laws when a granular column collapses on a horizontal plane. However, if the granular column is submerged in a fluid, the mobility of the granular collapse due to high inertia effects will be reduced by fluid-particle interactions. In this study, the effects of fluid viscosity on granular collapse is investigated qualitatively by adopting a numerical approach based on the coupled lattice Boltzmann method (LBM and discrete element method (DEM. It is found that the granular collapse can be dramatically slowed down due to the presence of viscous fluids. For the considered granular configuration, when the fluid viscosity increases. the runout distance decreases and the final deposition shows a larger deposit angle.

  20. Rotating collapse of stellar iron cores in general relativity

    International Nuclear Information System (INIS)

    Ott, C D; Dimmelmeier, H; Marek, A; Janka, H-T; Zink, B; Hawke, I; Schnetter, E

    2007-01-01

    We present results from the first 2 + 1 and 3 + 1 simulations of the collapse of rotating stellar iron cores in general relativity employing a finite-temperature equation of state and an approximate treatment of deleptonization during collapse. We compare full 3 + 1 and conformally-flat spacetime evolution methods and find that the conformally-flat treatment is sufficiently accurate for the core-collapse supernova problem. We focus on the gravitational wave (GW) emission from rotating collapse, core bounce and early postbounce phases. Our results indicate that the GW signature of these phases is much more generic than previously estimated. In addition, we track the growth of a nonaxisymmetric instability of dominant m = 1 character in two of our models that leads to prolonged narrow-band GW emission at ∼920-930 Hz over several tens of milliseconds

  1. Important Details in Performing and Interpreting the Scratch Collapse Test.

    Science.gov (United States)

    Kahn, Lorna C; Yee, Andrew; Mackinnon, Susan E

    2018-02-01

    The utility of the scratch collapse test has been demonstrated in examination of patients with carpal and cubital tunnel syndromes and long thoracic and peroneal nerve compressions. In the authors' clinic, this lesser known test plays a key role in peripheral nerve examination where localization of the nerve irritation or injury is not fully understood. Test utility and accuracy in patients with more challenging presentations likely correlate with tester understanding and experience. This article offers a clear outline of all stages of the test to improve interrater reliability. The nuances of test performance are described, including a description of situations where the scratch collapse test is deemed inappropriate. Four clinical scenarios where the scratch collapse test may be useful are included. Corresponding video content is provided to improve performance and interpretation of the scratch collapse test. Diagnostic, V.

  2. Probing spontaneous wave-function collapse with entangled levitating nanospheres

    Science.gov (United States)

    Zhang, Jing; Zhang, Tiancai; Li, Jie

    2017-01-01

    Wave-function collapse models are considered to be the modified theories of standard quantum mechanics at the macroscopic level. By introducing nonlinear stochastic terms in the Schrödinger equation, these models (different from standard quantum mechanics) predict that it is fundamentally impossible to prepare macroscopic systems in macroscopic superpositions. The validity of these models can only be examined by experiments, and hence efficient protocols for these kinds of experiments are greatly needed. Here we provide a protocol that is able to probe the postulated collapse effect by means of the entanglement of the center-of-mass motion of two nanospheres optically trapped in a Fabry-Pérot cavity. We show that the collapse noise results in a large reduction of the steady-state entanglement, and the entanglement, with and without the collapse effect, shows distinguishable scalings with certain system parameters, which can be used to determine unambiguously the effect of these models.

  3. Collapse above the world's largest potash mine (Ural, Russia.

    Directory of Open Access Journals (Sweden)

    Andrejchuk Vjacheslav

    2002-01-01

    Full Text Available This paper reports the results of the study of a huge collapse that occurred in June 1986 within the area of the 3rd Berezniki potash mine (the Verkhnekamsky potash deposit, Ural. Processes that took place between the first appearance of a water inflow through the mine roof and the eventual collapse are reconstructed in detail. The origin and development of a cavity that induced the collapse are revealed. Two factors played a major role in the formation of the collapse: the presence of a tectonic fold/rupture zone with in both the salt sequence and the overburden (the zone of crush and enhanced permeability, and the ductile pillars mining system.

  4. Forecasting giant, catastrophic slope collapse: lessons from Vajont, Northern Italy

    Science.gov (United States)

    Kilburn, Christopher R. J.; Petley, David N.

    2003-08-01

    Rapid, giant landslides, or sturzstroms, are among the most powerful natural hazards on Earth. They have minimum volumes of ˜10 6-10 7 m 3 and, normally preceded by prolonged intervals of accelerating creep, are produced by catastrophic and deep-seated slope collapse (loads ˜1-10 MPa). Conventional analyses attribute rapid collapse to unusual mechanisms, such as the vaporization of ground water during sliding. Here, catastrophic collapse is related to self-accelerating rock fracture, common in crustal rocks at loads ˜1-10 MPa and readily catalysed by circulating fluids. Fracturing produces an abrupt drop in resisting stress. Measured stress drops in crustal rock account for minimum sturzstrom volumes and rapid collapse accelerations. Fracturing also provides a physical basis for quantitatively forecasting catastrophic slope failure.

  5. Spherical collapse in quintessence models with zero speed of sound

    International Nuclear Information System (INIS)

    Creminelli, Paolo; D'Amico, Guido; Noreña, Jorge; Senatore, Leonardo; Vernizzi, Filippo

    2010-01-01

    We study the spherical collapse model in the presence of quintessence with negligible speed of sound. This case is particularly motivated for w Q /Ω m . This gives a distinctive modification of the total mass function at low redshift

  6. Modelling the self-organization and collapse of complex networks

    Indian Academy of Sciences (India)

    Modelling the self-organization and collapse of complex networks. Sanjay Jain Department of Physics and Astrophysics, University of Delhi Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore Santa Fe Institute, Santa Fe, New Mexico.

  7. Dynamic Deformation and Collapse of Granular Columns

    Science.gov (United States)

    Uenishi, K.; Tsuji, K.; Doi, S.

    2009-12-01

    Large dynamic deformation of granular materials may be found in nature not only in the failure of slopes and cliffs — due to earthquakes, rock avalanches, debris flows and landslides — but also in earthquake faulting itself. Granular surface flows often consist of solid grains and intergranular fluid, but the effect of the fluid may be usually negligible because the volumetric concentration of grains is in many cases high enough for interparticle forces to dominate momentum transport. Therefore, the investigation of dry granular flow of a mass might assist in further understanding of the above mentioned geophysical events. Here, utilizing a high-speed digital video camera system, we perform a simple yet fully-controlled series of laboratory experiments related to the collapse of granular columns. We record, at an interval of some microseconds, the dynamic transient granular mass flow initiated by abrupt release of a tube that contains dry granular materials. The acrylic tube is partially filled with glass beads and has a cross-section of either a fully- or semi-cylindrical shape. Upon sudden removal of the tube, the granular solid may fragment under the action of its own weight and the particles spread on a rigid horizontal plane. This study is essentially the extension of the previous ones by Lajeunesse et al. (Phys. Fluids 2004) and Uenishi and Tsuji (JPGU 2008), but the striped layers of particles in a semi-cylindrical tube, newly introduced in this contribution, allow us to observe the precise particle movement inside the granular column: The development of slip lines inside the column and the movement of particles against each other can be clearly identified. The major controlling parameters of the spreading dynamics are the initial aspect ratio of the granular (semi-)cylindrical column, the frictional properties of the horizontal plane (substrate) and the size of beads. We show the influence of each parameter on the average flow velocity and final radius

  8. Ocean wave generation by collapsing ice shelves

    Science.gov (United States)

    Macayeal, D. R.; Bassis, J. N.; Okal, E. A.; Aster, R. C.; Cathles, L. M.

    2008-12-01

    The 28-29 February, 2008, break-up of the Wilkins Ice Shelf, Antarctica, exemplifies the now-familiar, yet largely unexplained pattern of explosive ice-shelf break-up. While environmental warming is a likely ultimate cause of explosive break-up, several key aspects of their short-term behavior need to be explained: (1) The abrupt, near-simultaneous onset of iceberg calving across long spans of the ice front margin; (2) High outward drift velocity (about 0.3 m/s) of a leading phalanx of tabular icebergs that originate from the seaward edge of the intact ice shelf prior to break-up; (3) Rapid coverage of the ocean surface in the wake of this leading phalanx by small, capsized and dismembered tabular icebergs; (4) Extremely large gravitational potential energy release rates, e.g., up to 3 × 1010 W; (5) Lack of proximal iceberg-calving triggers that control the timing of break-up onset and that maintain the high break-up calving rates through to the conclusion of the event. Motivated by seismic records obtained from icebergs and the Ross Ice Shelf that show hundreds of micro- tsunamis emanating from near the ice shelf front, we re-examine the basic dynamic features of ice- shelf/ocean-wave interaction and, in particular, examine the possibility that collapsing ice shelves themselves are a source of waves that stimulate the disintegration process. We propose that ice-shelf generated surface-gravity waves associated with initial calving at an arbitrary seed location produce stress perturbations capable of triggering the onset of calving on the entire ice front. Waves generated by parting detachment rifts, iceberg capsize and break-up act next to stimulate an inverted submarine landslide (ice- slide) process, where gravitational potential energy released by upward movement of buoyant ice is radiated as surface gravity waves in the wake of the advancing phalanx of tabular icebergs. We conclude by describing how field research and remote sensing can be used to test the

  9. Growing quasi-modes in dynamics of supersonic collapse

    International Nuclear Information System (INIS)

    Malkin, V.M.; Khudik, V.N.

    1989-01-01

    The hypothesis of globally stable self-similar regimes existence for supersonic Langmuir collapse plays a significant role in the attempts to construct a theory of strong Langmuir turbulence. A possibility for destruction of the stable against infinitely small perturbations self-similar regime of supersonic collapse by growing quasi-modes is demonstrated via the numerical solution of Cauchi problem for Zakharov equations. The quantitative criterion for the destruction of self-similar regimes is formulated. 9 refs.; 5 figs

  10. De Novo Collapsing Glomerulopathy in a Renal Allograft Recipient

    Directory of Open Access Journals (Sweden)

    Kanodia K

    2008-01-01

    Full Text Available Collapsing glomerulopathy (CG, characterized histologically by segmental/global glomerular capillary collapse, podocyte hypertrophy and hypercellularity and tubulo-interstitial injury; is characterized clinically by massive proteinuria and rapid progressive renal failure. CG is known to recur in renal allograft and rarely de novo. We report de novo CG 3 years post-transplant in a patient who received renal allograft from haplo-identical type donor.

  11. Wave function collapse implies divergence of average displacement

    OpenAIRE

    Marchewka, A.; Schuss, Z.

    2005-01-01

    We show that propagating a truncated discontinuous wave function by Schr\\"odinger's equation, as asserted by the collapse axiom, gives rise to non-existence of the average displacement of the particle on the line. It also implies that there is no Zeno effect. On the other hand, if the truncation is done so that the reduced wave function is continuous, the average coordinate is finite and there is a Zeno effect. Therefore the collapse axiom of measurement needs to be revised.

  12. Naked singularities in self-similar spherical gravitational collapse

    International Nuclear Information System (INIS)

    Ori, A.; Piran, T.

    1987-01-01

    We present general-relativistic solutions of self-similar spherical collapse of an adiabatic perfect fluid. We show that if the equation of state is soft enough (Γ-1<<1), a naked singularity forms. The singularity resembles the shell-focusing naked singularities that arise in dust collapse. This solution increases significantly the range of matter fields that should be ruled out in order that the cosmic-censorship hypothesis will hold

  13. Field Experiment on Soaking Characteristics of Collapsible Loess

    Directory of Open Access Journals (Sweden)

    Zhichao Wang

    2017-01-01

    Full Text Available In collapsible loess area, migration of soil moisture often causes the temporal discontinuity and spatial nonuniformity of collapsibility, which leads to great damage for infrastructures. Therefore, the research on water infiltration is the key to solving the problem of collapsibility. The aim of this paper is to investigate the spatiotemporal evolution of infiltration characteristics of collapsible loess. A field soaking experiment was conducted on collapsible loess in western China, in which a soaking pool with diameter of 15 m was built. Time-Domain-Reflectometry (TDR system and soil sampling were employed to measure the water content within the depth of 12 m. Then the saturation isograms were drawn for visualization of the process of infiltration. Also, a pilot tunnel was excavated to investigate how the free face can affect the infiltration behaviors. The experimental results revealed the characteristics of infiltration in both horizontal and vertical directions. Moreover, the response of free face on infiltration behaviors was also found. These findings of research could provide the data for the infiltration laws of unsaturated loess and thereby provide the basis for integrated treatment of collapsible loess.

  14. Newton force from wave function collapse: speculation and test

    International Nuclear Information System (INIS)

    Diósi, Lajos

    2014-01-01

    The Diosi-Penrose model of quantum-classical boundary postulates gravity-related spontaneous wave function collapse of massive degrees of freedom. The decoherence effects of the collapses are in principle detectable if not masked by the overwhelming environmental decoherence. But the DP (or any other, like GRW, CSL) spontaneous collapses are not detectable themselves, they are merely the redundant formalism of spontaneous decoherence. To let DP collapses become testable physics, recently we extended the DP model and proposed that DP collapses are responsible for the emergence of the Newton gravitational force between massive objects. We identified the collapse rate, possibly of the order of 1/ms, with the rate of emergence of the Newton force. A simple heuristic emergence (delay) time was added to the Newton law of gravity. This non-relativistic delay is in peaceful coexistence with Einstein's relativistic theory of gravitation, at least no experimental evidence has so far surfaced against it. We derive new predictions of such a 'lazy' Newton law that will enable decisive laboratory tests with available technologies. The simple equation of 'lazy' Newton law deserves theoretical and experimental studies in itself, independently of the underlying quantum foundational considerations.

  15. Correlated random walks induced by dynamical wavefunction collapse

    Science.gov (United States)

    Bedingham, Daniel

    2015-03-01

    Wavefunction collapse models modify Schrödinger's equation so that it describes the collapse of a superposition of macroscopically distinguishable states as a genuine physical process [PRA 42, 78 (1990)]. This provides a basis for the resolution of the quantum measurement problem. An additional generic consequence of the collapse mechanism is that it causes particles to exhibit a tiny random diffusive motion. Furthermore, the diffusions of two sufficiently nearby particles are positively correlated -- it is more likely that the particles diffuse in the same direction than would happen if they behaved independently [PRA 89, 032713 (2014)]. The use of this effect is proposed as an experimental test of wave function collapse models in which pairs of nanoparticles are simultaneously released from nearby traps and allowed a brief period of free fall. The random displacements of the particles are then measured. The experiment must be carried out at sufficiently low temperature and pressure for the collapse effects to dominate over the ambient environmental noise. It is argued that these constraints can be satisfied by current technologies for a large class of viable wavefunction collapse models. Work supported by the Templeton World Charity Foundation.

  16. Gravitational radiation from stellar collapse: The initial burst

    International Nuclear Information System (INIS)

    Shapiro, S.L.

    1977-01-01

    The burst of gravitational radiation emitted during the initial collapse and rebound of a homogeneous, uniformly rotating spheroid with internal pressure is analyzed numerically. The surface of the collapsing spheroid is assumed to start at rest from infinity with negligible eccentricity (''zero-energy collapse''). The adopted internal pressure function is constant on self-similar spheroidal surfaces, and its central value is described by a polytropic law with index n< or =3. The Newtonian equations of motion are integrated numerically to follow the initial collapse and rebound of the configuration for the special case in which the collapse is time-reversal invariant about the moment of maximum compression, and the total energy and frequency spectrum of the emitted quadrupole radiation are computed. The results are employed to estimate the (approx.minimum) total energy and frequency distribution of the initial burst of gravitational radiation emitted during the formation of low-mass (Mapproximately-less-thanM/sub sun/) neutron stars and during the collapse of supermassive gas clouds

  17. Intracapsular implant rupture: MR findings of incomplete shell collapse.

    Science.gov (United States)

    Soo, M S; Kornguth, P J; Walsh, R; Elenberger, C; Georgiade, G S; DeLong, D; Spritzer, C E

    1997-01-01

    The objective of this study was to determine the frequency and significance of the MR findings of incomplete shell collapse for detecting implant rupture in a series of surgically removed breast prostheses. MR images of 86 breast implants in 44 patients were studied retrospectively and correlated with surgical findings at explantation. MR findings included (a) complete shell collapse (linguine sign), 21 implants; (b) incomplete shell collapse (subcapsular line sign, teardrop sign, and keyhole sign), 33 implants; (c) radial folds, 31 implants; and (d) normal, 1 implant. The subcapsular line sign was seen in 26 implants, the teardrop sign was seen in 27 implants, and the keyhole sign was seen in 23 implants. At surgery, 48 implants were found to be ruptured and 38 were intact. The MR findings of ruptured implants showed signs of incomplete collapse in 52% (n = 25), linguine sign in 44% (n = 21), and radial folds in 4% (n = 2). The linguine sign perfectly predicted implant rupture, but sensitivity was low. Findings of incomplete shell collapse improved sensitivity and negative predictive values, and the subcapsular line sign produced a significant incremental increase in predictive ability. MRI signs of incomplete shell collapse were more common than the linguine sign in ruptured implants and are significant contributors to the high sensitivity and negative predictive values of MRI for evaluating implant integrity.

  18. Vapour and air bubble collapse analysis in viscous compressible water

    Directory of Open Access Journals (Sweden)

    Gil Bazanini

    2001-01-01

    Full Text Available Numerical simulations of the collapse of bubbles (or cavities are shown, using the finite difference method, taking into account the compressibility of the liquid, expected to occur in the final stages of the collapse process. Results are compared with experimental and theoretical data for incompressible liquids, to see the influence of the compressibility of the water in the bubble collapse. Pressure fields values are calculated in an area of 800 x 800 mm, for the case of one bubble under the hypothesis of spherical symmetry. Results are shown as radius versus time curves for the collapse (to compare collapse times, and pressure curves in the plane, for pressure fields. Such calculations are new because of their general point of view, since the existing works do not take into account the existence of vapour in the bubble, neither show the pressure fields seen here. It is also expected to see the influence of the compressibility of the water in the collapse time, and in the pressure field, when comparing pressure values.

  19. Inertial collapse of bubble pairs near a solid surface

    Science.gov (United States)

    Alahyari Beig, Shahaboddin; Johnsen, Eric

    2017-11-01

    Cavitation occurs in a variety of applications ranging from naval structures to biomedical ultrasound. One important consequence is structural damage to neighboring surfaces following repeated inertial collapse of vapor bubbles. Although the mechanical loading produced by the collapse of a single bubble has been widely investigated, less is known about the detailed dynamics of the collapse of multiple bubbles. In such a problem, the bubble-bubble interactions typically affect the dynamics, e.g., by increasing the non-sphericity of the bubbles and amplifying/hindering the collapse intensity depending on the flow parameters. Here, we quantify the effects of bubble-bubble interactions on the bubble dynamics, as well as the pressures/temperatures produced by the collapse of a pair of gas bubbles near a rigid surface. We perform high-resolution simulations of this problem by solving the three-dimensional compressible Navier-Stokes equations for gas/liquid flows. The results are used to investigate the non-spherical bubble dynamics and characterize the pressure and temperature fields based on the relevant parameters entering the problem: stand-off distance, geometrical configuration (angle, relative size, distance), collapse strength. This research was supported in part by ONR Grant N00014-12-1-0751 and NSF Grant CBET 1253157.

  20. Genetic variants in PARP1 (rs3219090) and IRF4 (rs12203592) genes associated with melanoma susceptibility in a Spanish population

    International Nuclear Information System (INIS)

    Peña-Chilet, Maria; Ribas, Gloria; Blanquer-Maceiras, Maite; Ibarrola-Villava, Maider; Martinez-Cadenas, Conrado; Martin-Gonzalez, Manuel; Gomez-Fernandez, Cristina; Mayor, Matias; Aviles, Juan Antonio; Lluch, Ana

    2013-01-01

    Few high penetrance genes are known in Malignant Melanoma (MM), however, the involvement of low-penetrance genes such as MC1R, OCA2, ASIP, SLC45A2 and TYR has been observed. Lately, genome-wide association studies (GWAS) have been the ideal strategy to identify new common, low-penetrance susceptibility loci. In this case–control study, we try to validate in our population nine melanoma associated markers selected from published GWAS in melanoma predisposition. We genotyped the 9 markers corresponding to 8 genes (PARP1, MX2, ATM, CCND1, NADSYN1, CASP8, IRF4 and CYP2R1) in 566 cases and 347 controls from a Spanish population using KASPar probes. Genotypes were analyzed by logistic regression and adjusted by phenotypic characteristics. We confirm the protective role in MM of the rs3219090 located on the PARP1 gene (p-value 0.027). Additionally, this SNP was also associated with eye color (p-value 0.002). A second polymorphism, rs12203592, located on the IRF4 gene was associated with protection to develop MM for the dominant model (p-value 0.037). We have also observed an association of this SNP with both lentigines (p-value 0.014) and light eye color (p-value 3.76 × 10 -4 ). Furthermore, we detected a novel association with rs1485993, located on the CCND1 gene, and dark eye color (p-value 4.96 × 10 -4 ). Finally, rs1801516, located on the ATM gene, showed a trend towards a protective role in MM similar to the one firstly described in a GWAS study. To our knowledge, this is the first time that these SNPs have been associated with MM in a Spanish population. We confirmed the proposed role of rs3219090, located on the PARP1 gene, and rs12203592, located on the IRF4 gene, as protective to MM along the same lines as have previous genome-wide associated works. Finally, we have seen associations between IRF4, PARP1, and CCND1 and phenotypic characteristics, confirming previous results for the IRF4 gene and presenting novel data for the last two, suggesting that

  1. In vivo repair of DNA damage induced by X-rays in the early stages of mouse fertilization, and the influence of maternal PARP1 ablation

    Energy Technology Data Exchange (ETDEWEB)

    Pacchierotti, F., E-mail: francesca.pacchierotti@enea.it [Unit of Radiation Biology and Human Health, ENEA CR Casaccia, Via Anguillarese 301, 00123 Rome (Italy); Ranaldi, R. [Unit of Radiation Biology and Human Health, ENEA CR Casaccia, Via Anguillarese 301, 00123 Rome (Italy); Derijck, A.A.; Heijden, G.W. van der; Boer, P. de [Radboud University Nijmegen Medical Centre, Department of Obstetrics and Gynaecology, P.O. Box 9101, 6500 HB Nijmegen (Netherlands)

    2011-09-01

    Highlights: {yields} We measure {gamma}H2AX and chromosome aberrations in mouse zygotes irradiated in vivo. {yields} We compare effects between zygotes obtained from wild type or Parp1 knockout females. {yields} The rate of chromosome aberrations is as high as that previously induced in vitro. {yields} The rate of radiation-induced {gamma}H2AX foci is lower than that measured in other cells. {yields} Without Parp1 there are more {gamma}H2AX foci but chromosome aberration rate is unaffected. - Abstract: The early pronucleus stage of the mouse zygote has been characterised in vitro as radiosensitive, due to a high rate of induction of chromosome-type chromosome abnormalities (CA). We have investigated the repair of irradiation induced double strand DNA breaks in vivo by {gamma}H2AX foci and first cleavage metaphase analysis. Breaks were induced in sperm and in the early zygote stages comprising sperm chromatin remodelling and early pronucleus expansion. Moreover, the role of PARP1 in the formation and repair of spontaneous and radiation-induced double strand breaks in the zygote was evaluated by comparing observations in C57BL/6J and PARP1 genetically ablated females. The results confirmed in vivo that the rate of chromosome aberration induction by X-rays was approximately 3-fold higher in the zygote than in mouse lymphocytes. This finding was related to a diminished efficiency of double strand break signalling, as shown by a lower rate of {gamma}H2AX radiation-induced foci compared to that measured in most other somatic cell types. The spontaneous frequency of CA in PARP1 depleted zygotes was slightly but significantly higher than in wild type zygotes. Also, these zygotes showed some impairment of the radiation-induced DNA Damage Response when exposed closer to the start of S-phase, revealed by a higher number of {gamma}H2AX foci and a longer cell cycle delay. The rate of chromosome aberrations, however, was not elevated over that of wild type zygotes, possibly

  2. Finite element analysis of the collapse and post-collapse behavior of steel pipes applications to the oil industry

    CERN Document Server

    Dvorkin, Eduardo N

    2013-01-01

    This book presents a detailed discussion of the models that were developed to simulate the collapse and post-collapse behavior of steel pipes. The finite element method offers to engineers the possibility of developing models to simulate the collapse behavior of casings inside oil wells and the collapse behavior of deepwater pipelines. However, if technological decisions are going to be reached from these model results, with implications for the economic success of industrial operations, for the occupational safety and health and for the environment, the engineering models need to be highly reliable. Using these models engineers can quantify the effect of manufacturing tolerances, wear, corrosion, etc. This book describes in great details the experimental programs that are developed to validate the numerical results.

  3. Endograft Collapse After Endovascular Treatment for Thoracic Aortic Disease

    International Nuclear Information System (INIS)

    Bandorski, Dirk; Brueck, Martin; Guenther, Hans-Ulrich; Manke, Christoph

    2010-01-01

    Endovascular treatment is an established therapy for thoracic aortic disease. Collapse of the endograft is a potentially fatal complication. We reviewed 16 patients with a thoracic endograft between 2001 and 2006. Medical records of the treated patients were studied. Data collected include age, gender, diagnosis, indication for endoluminal treatment, type of endograft, and time of follow up. All patients (n = 16; mean age, 61 years; range, 21-82 years) underwent computed tomography (CT) for location of the lesion and planning of the intervention. Time of follow-up with CT scan ranged from 1 to 61 months. Indications for endovascular treatment were degenerative aneurysm (n = 7; 44%), aortic dissection (n = 2; 12%), perforated aortic ulcer (n = 4; 25%), and traumatic aortic injury (n = 3; 19%). Three patients suffered from a collapse of the endograft (one patient distal, two patients proximal) between 3 and 8 days after endovascular treatment. These patients were younger (mean age, 37 ± 25 years vs. 67 ± 16 years; P 0.05]; distal, 45 ± 23.5% vs. 38 ± 21.7% [P > 0.05]). Proximal collapse was corrected by placing a bare stent. In conclusion, risk factors for stent-graft collapse are a small lumen of the aorta and a small radius of the aortic arch curvature (young patients), as well as oversizing, which is an important risk factor and is described for different types of endografts and protheses (Gore TAG and Cook Zenith). Dilatation of the collapsed stent-graft is not sufficient. Following therapy implantation of a second stent or surgery is necessary in patients with a proximal endograft collapse. Distal endograft collapse can possibly be treated conservatively under close follow-up.

  4. Steroid-associated hip joint collapse in bipedal emus.

    Directory of Open Access Journals (Sweden)

    Li-Zhen Zheng

    Full Text Available In this study we established a bipedal animal model of steroid-associated hip joint collapse in emus for testing potential treatment protocols to be developed for prevention of steroid-associated joint collapse in preclinical settings. Five adult male emus were treated with a steroid-associated osteonecrosis (SAON induction protocol using combination of pulsed lipopolysaccharide (LPS and methylprednisolone (MPS. Additional three emus were used as normal control. Post-induction, emu gait was observed, magnetic resonance imaging (MRI was performed, and blood was collected for routine examination, including testing blood coagulation and lipid metabolism. Emus were sacrificed at week 24 post-induction, bilateral femora were collected for micro-computed tomography (micro-CT and histological analysis. Asymmetric limping gait and abnormal MRI signals were found in steroid-treated emus. SAON was found in all emus with a joint collapse incidence of 70%. The percentage of neutrophils (Neut % and parameters on lipid metabolism significantly increased after induction. Micro-CT revealed structure deterioration of subchondral trabecular bone. Histomorphometry showed larger fat cell fraction and size, thinning of subchondral plate and cartilage layer, smaller osteoblast perimeter percentage and less blood vessels distributed at collapsed region in SAON group as compared with the normal controls. Scanning electron microscope (SEM showed poor mineral matrix and more osteo-lacunae outline in the collapsed region in SAON group. The combination of pulsed LPS and MPS developed in the current study was safe and effective to induce SAON and deterioration of subchondral bone in bipedal emus with subsequent femoral head collapse, a typical clinical feature observed in patients under pulsed steroid treatment. In conclusion, bipedal emus could be used as an effective preclinical experimental model to evaluate potential treatment protocols to be developed for prevention of

  5. Shock-induced nanobubble collapse and its applications

    Science.gov (United States)

    Vedadi, Mohammad Hossein

    The shock-induced collapse of nanobubbles in water is investigated using molecular dynamics simulations based on a reactive force field. Monitoring the collapse of a cavitation nanobubble, we observe a focused nanojet at the onset of bubble shrinkage and a water hammer shock wave upon bubble collapse. The nanojet length scales linearly with the nanobubble radius, as observed in experiments on micron-to-millimeter size bubbles. The shock induces dramatic structural changes, including an ice-VII-like structural motif at a particle velocity of approximately 1 km/s. The incipient ice VII formation and the calculated Hugoniot curve are in good agreement with experimental results. Moreover, a substantial number of positive and negative ions appear when the nanojet hits the distal side of the nanobubble and the water hammer shock forms. Furthermore, two promising applications of shock-induced nanobubble collapse have been explored. Our simulations of poration in lipid bilayers due to shock-induced collapse of nanobubbles reveal penetration of nanojets into lipid bilayers. The nanojet impact generates shear flow of water on bilayer leaflets and pressure gradients across them, which transiently enhance the bilayer permeability by creating nanopores through which water molecules translocate across the bilayer. The effects of nanobubble size and temperature on the porosity of lipid bilayers are examined. Finally, the shock-induced collapse of CO2-filled nanobubbles in water is investigated. The energetic nanojet and high-pressure water hammer shock formed during and after collapse of the nanobubble trigger mechano-chemical H2O-CO2 reactions, some of which lead to splitting of water molecules. The dominant pathways through which splitting of water molecules occur are identified.

  6. Constraining quantum collapse inflationary models with CMB data

    Energy Technology Data Exchange (ETDEWEB)

    Benetti, Micol; Alcaniz, Jailson S. [Departamento de Astronomia, Observatório Nacional, 20921-400, Rio de Janeiro, RJ (Brazil); Landau, Susana J., E-mail: micolbenetti@on.br, E-mail: slandau@df.uba.ar, E-mail: alcaniz@on.br [Departamento de Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and IFIBA, CONICET, Ciudad Universitaria, PabI, Buenos Aires 1428 (Argentina)

    2016-12-01

    The hypothesis of the self-induced collapse of the inflaton wave function was proposed as responsible for the emergence of inhomogeneity and anisotropy at all scales. This proposal was studied within an almost de Sitter space-time approximation for the background, which led to a perfect scale-invariant power spectrum, and also for a quasi-de Sitter background, which allows to distinguish departures from the standard approach due to the inclusion of the collapse hypothesis. In this work we perform a Bayesian model comparison for two different choices of the self-induced collapse in a full quasi-de Sitter expansion scenario. In particular, we analyze the possibility of detecting the imprint of these collapse schemes at low multipoles of the anisotropy temperature power spectrum of the Cosmic Microwave Background (CMB) using the most recent data provided by the Planck Collaboration. Our results show that one of the two collapse schemes analyzed provides the same Bayesian evidence of the minimal standard cosmological model ΛCDM, while the other scenario is weakly disfavoured with respect to the standard cosmology.

  7. Can static regular black holes form from gravitational collapse?

    International Nuclear Information System (INIS)

    Zhang, Yiyang; Zhu, Yiwei; Modesto, Leonardo; Bambi, Cosimo

    2015-01-01

    Starting from the Oppenheimer-Snyder model, we know how in classical general relativity the gravitational collapse of matter forms a black hole with a central spacetime singularity. It is widely believed that the singularity must be removed by quantum-gravity effects. Some static quantum-inspired singularity-free black hole solutions have been proposed in the literature, but when one considers simple examples of gravitational collapse the classical singularity is replaced by a bounce, after which the collapsing matter expands for ever. We may expect three possible explanations: (i) the static regular black hole solutions are not physical, in the sense that they cannot be realized in Nature, (ii) the final product of the collapse is not unique, but it depends on the initial conditions, or (iii) boundary effects play an important role and our simple models miss important physics. In the latter case, after proper adjustment, the bouncing solution would approach the static one. We argue that the ''correct answer'' may be related to the appearance of a ghost state in de Sitter spacetimes with super Planckian mass. Our black holes have indeed a de Sitter core and the ghost would make these configurations unstable. Therefore we believe that these black hole static solutions represent the transient phase of a gravitational collapse but never survive as asymptotic states. (orig.)

  8. Classical Collapse to Black Holes and Quantum Bounces: A Review

    Directory of Open Access Journals (Sweden)

    Daniele Malafarina

    2017-05-01

    Full Text Available In the last four decades, different programs have been carried out aiming at understanding the final fate of gravitational collapse of massive bodies once some prescriptions for the behaviour of gravity in the strong field regime are provided. The general picture arising from most of these scenarios is that the classical singularity at the end of collapse is replaced by a bounce. The most striking consequence of the bounce is that the black hole horizon may live for only a finite time. The possible implications for astrophysics are important since, if these models capture the essence of the collapse of a massive star, an observable signature of quantum gravity may be hiding in astrophysical phenomena. One intriguing idea that is implied by these models is the possible existence of exotic compact objects, of high density and finite size, that may not be covered by an horizon. The present article outlines the main features of these collapse models and some of the most relevant open problems. The aim is to provide a comprehensive (as much as possible overview of the current status of the field from the point of view of astrophysics. As a little extra, a new toy model for collapse leading to the formation of a quasi static compact object is presented.

  9. Protostellar formation in rotation interstellar clouds. III. Nonaxisymmetric collapse

    International Nuclear Information System (INIS)

    Boss, A.P.

    1980-01-01

    A full three spatial-dimension gravitational hydrodynamics code has been used to follow the collapse of isothermal rotating clouds subjected to various nonaxialy symmetric perturbations (NAP). An initially axially symmetric cloud collapsed to form a ring which then fragmented into a binary protostellar system. A low thermal energy cloud with a large bar-shaped NAP collapsed and fragmented directly into a binary; higher thermal energy clouds damp out such NAPs while higher rotational rotational energy clouds produce binaries with wider separations. Fragmentation into single and binary systems has been seen. The tidal effects of other nearby protostellar clouds are shown to have an important effect upon the collapse and should not be neglected. The three-dimensional calculations indicate that isothermal interstellar clouds may fragment (with or without passing through a transitory ring phase) into protostellar objects while still in the isothermal regime. The fragments obtained have masses and specific spin angular momenta roughly a 10th that of the original cloud. Interstellar clouds and their fragments may pass through successive collapse phases with fragmentation and reduction of spin angular momentum (by conversion to orbital angular momentum and preferential accretion of low angular momentum matter) terminating in the formation of pre--main-sequence stars with the observed pre--main-sequence rotation rates

  10. Core-Collapse Supernovae, Neutrinos, and Gravitational Waves

    Energy Technology Data Exchange (ETDEWEB)

    Ott, C.D. [TAPIR, California Institute of Technology, Pasadena, California (United States); Kavli Institute for the Physics and Mathematics of the Universe, Kashiwa, Chiba (Japan); O' Connor, E.P. [Canadian Institute for Theoretical Astrophysics, Toronto, Ontario (Canada); Gossan, S.; Abdikamalov, E.; Gamma, U.C.T. [TAPIR, California Institute of Technology, Pasadena, California (United States); Drasco, S. [Grinnell College, Grinnell, Iowa (United States); TAPIR, California Institute of Technology, Pasadena, California (United States)

    2013-02-15

    Core-collapse supernovae are among the most energetic cosmic cataclysms. They are prodigious emitters of neutrinos and quite likely strong galactic sources of gravitational waves. Observation of both neutrinos and gravitational waves from the next galactic or near extragalactic core-collapse supernova will yield a wealth of information on the explosion mechanism, but also on the structure and angular momentum of the progenitor star, and on aspects of fundamental physics such as the equation of state of nuclear matter at high densities and low entropies. In this contribution to the proceedings of the Neutrino 2012 conference, we summarize recent progress made in the theoretical understanding and modeling of core-collapse supernovae. In this, our emphasis is on multi-dimensional processes involved in the explosion mechanism such as neutrino-driven convection and the standing accretion shock instability. As an example of how supernova neutrinos can be used to probe fundamental physics, we discuss how the rise time of the electron antineutrino flux observed in detectors can be used to probe the neutrino mass hierarchy. Finally, we lay out aspects of the neutrino and gravitational-wave signature of core-collapse supernovae and discuss the power of combined analysis of neutrino and gravitational wave data from the next galactic core-collapse supernova.

  11. Self-Gravitating Stellar Collapse: Explicit Geodesics and Path Integration

    International Nuclear Information System (INIS)

    Balakrishna, Jayashree; Bondarescu, Ruxandra; Moran, Christine C.

    2016-01-01

    We extend the work of Oppenheimer and Synder to model the gravitational collapse of a star to a black hole by including quantum mechanical effects. We first derive closed-form solutions for classical paths followed by a particle on the surface of the collapsing star in Schwarzschild and Kruskal coordinates for space-like, time-like, and light-like geodesics. We next present an application of these paths to model the collapse of ultra-light dark matter particles, which necessitates incorporating quantum effects. To do so we treat a particle on the surface of the star as a wavepacket and integrate over all possible paths taken by the particle. The waveform is computed in Schwarzschild coordinates and found to exhibit an ingoing and an outgoing component, where the former contains the probability of collapse, while the latter contains the probability that the star will disperse. These calculations pave the way for investigating the possibility of quantum collapse that does not lead to black hole formation as well as for exploring the nature of the wavefunction inside r = 2M.

  12. Core-Collapse Supernovae, Neutrinos, and Gravitational Waves

    International Nuclear Information System (INIS)

    Ott, C.D.; O'Connor, E.P.; Gossan, S.; Abdikamalov, E.; Gamma, U.C.T.; Drasco, S.

    2013-01-01

    Core-collapse supernovae are among the most energetic cosmic cataclysms. They are prodigious emitters of neutrinos and quite likely strong galactic sources of gravitational waves. Observation of both neutrinos and gravitational waves from the next galactic or near extragalactic core-collapse supernova will yield a wealth of information on the explosion mechanism, but also on the structure and angular momentum of the progenitor star, and on aspects of fundamental physics such as the equation of state of nuclear matter at high densities and low entropies. In this contribution to the proceedings of the Neutrino 2012 conference, we summarize recent progress made in the theoretical understanding and modeling of core-collapse supernovae. In this, our emphasis is on multi-dimensional processes involved in the explosion mechanism such as neutrino-driven convection and the standing accretion shock instability. As an example of how supernova neutrinos can be used to probe fundamental physics, we discuss how the rise time of the electron antineutrino flux observed in detectors can be used to probe the neutrino mass hierarchy. Finally, we lay out aspects of the neutrino and gravitational-wave signature of core-collapse supernovae and discuss the power of combined analysis of neutrino and gravitational wave data from the next galactic core-collapse supernova

  13. Self-Gravitating Stellar Collapse: Explicit Geodesics and Path Integration

    Energy Technology Data Exchange (ETDEWEB)

    Balakrishna, Jayashree [Department of Mathematics and Natural Sciences, College of Arts and Sciences, Harris-Stowe State University, St. Louis, MO (United States); Bondarescu, Ruxandra [Department of Physics, University of Zurich, Zurich (Switzerland); Moran, Christine C., E-mail: corbett@tapir.caltech.edu [TAPIR, Department of Theoretical Astrophysics, California Institute of Technology, Pasadena, CA (United States)

    2016-11-25

    We extend the work of Oppenheimer and Synder to model the gravitational collapse of a star to a black hole by including quantum mechanical effects. We first derive closed-form solutions for classical paths followed by a particle on the surface of the collapsing star in Schwarzschild and Kruskal coordinates for space-like, time-like, and light-like geodesics. We next present an application of these paths to model the collapse of ultra-light dark matter particles, which necessitates incorporating quantum effects. To do so we treat a particle on the surface of the star as a wavepacket and integrate over all possible paths taken by the particle. The waveform is computed in Schwarzschild coordinates and found to exhibit an ingoing and an outgoing component, where the former contains the probability of collapse, while the latter contains the probability that the star will disperse. These calculations pave the way for investigating the possibility of quantum collapse that does not lead to black hole formation as well as for exploring the nature of the wavefunction inside r = 2M.

  14. A novel animal model for hyperdynamic airway collapse.

    Science.gov (United States)

    Tsukada, Hisashi; O'Donnell, Carl R; Garland, Robert; Herth, Felix; Decamp, Malcolm; Ernst, Armin

    2010-12-01

    Tracheobronchomalacia (TBM) is increasingly recognized as a condition associated with significant pulmonary morbidity. However, treatment is invasive and complex, and because there is no appropriate animal model, novel diagnostic and treatment strategies are difficult to evaluate. We endeavored to develop a reliable airway model to simulate hyperdynamic airway collapse in humans. Seven 20-kg male sheep were enrolled in this study. Tracheomalacia was created by submucosal resection of > 50% of the circumference of 10 consecutive cervical tracheal cartilage rings through a midline cervical incision. A silicone stent was placed in the trachea to prevent airway collapse during recovery. Tracheal collapsibility was assessed at protocol-specific time points by bronchoscopy and multidetector CT imaging while temporarily removing the stent. Esophageal pressure and flow data were collected to assess flow limitation during spontaneous breathing. All animals tolerated the surgical procedure well and were stented without complications. One sheep died at 2 weeks because of respiratory failure related to stent migration. In all sheep, near-total forced inspiratory airway collapse was observed up to 3 months postprocedure. Esophageal manometry demonstrated flow limitation associated with large negative pleural pressure swings during rapid spontaneous inhalation. Hyperdynamic airway collapse can reliably be induced with this technique. It may serve as a model for evaluation of novel diagnostic and therapeutic strategies for TBM.

  15. 3-D collapse of rotating stars to Kerr black holes

    International Nuclear Information System (INIS)

    Baiotti, L; Hawke, I; Montero, P J; Loeffler, F L; Rezzolla, L; Stergioulas, N; Font, J A; Seidel, E

    2005-01-01

    We study gravitational collapse of uniformly rotating neutron stars to Kerr black holes, using a new three-dimensional, fully general relativistic hydrodynamics code, which uses high-resolution shock-capturing techniques and a conformal traceless formulation of the Einstein equations. We investigate the gravitational collapse by carefully studying not only the dynamics of the matter, but also that of the trapped surfaces, i.e. of both the apparent and event horizons formed during the collapse. The use of these surfaces, together with the dynamical horizon framework, allows for a precise measurement of the black-hole mass and spin. The ability to successfully perform these simulations for sufficiently long times relies on excising a region of the computational domain which includes the singularity and is within the apparent horizon. The dynamics of the collapsing matter is strongly influenced by the initial amount of angular momentum in the progenitor star and, for initial models with sufficiently high angular velocities, the collapse can lead to the formation of an unstable disc in differential rotation

  16. Indicators of collapse in systems undergoing unsustainable growth.

    Science.gov (United States)

    Ridolfi, Luca; D'Odorico, Paolo; Laio, Francesco

    2015-02-01

    Unsustainable growth is typical of systems that rely on a finite pool of non-renewable resources that are tapped until they are depleted. The decrease in resource availability eventually leads these systems to a decline. Here we investigate the dynamics of systems that exhibit unsustainable growth and are prone to a collapse to an alternative ("degraded") state. For these systems the possible imminent occurrence of a collapse is difficult to avert because they keep growing as they approach the transition point. It is therefore important to identify some early warning signs that can be used to predict whether the system is approaching a critical and likely irreversible transition to an undesired and degraded state. This study evaluates whether existing theories of precursors of phase transitions based on the critical slowing down phenomenon are applicable as leading indicators of state shift in unsustainable growth dynamics. It is found that such indicators fail to serve as reliable early warning signs of the system's collapse.

  17. Flow-induced plastic collapse of stacked fuel plates

    Energy Technology Data Exchange (ETDEWEB)

    Davis, D C; Scarton, H A

    1985-03-01

    Flow-induced plastic collapse of stacked fuel plate assemblies was first noted in experimental reactors such as the ORNL High Flux Reactor Assembly and the Engineering Test Reactor (ETR). The ETR assembly is a stack of 19 thin flat rectangular fuel plates separated by narrow channels through which a coolant flows to remove the heat generated by fission of the fuel within the plates. The uranium alloyed plates have been noted to buckle laterally and plastically collapse at the system design coolant flow rate of 10.7 m/s, thus restricting the coolant flow through adjacent channels. A methodology and criterion are developed for predicting the plastic collapse of ETR fuel plates. The criterion is compared to some experimental results and the Miller critical velocity theory.

  18. Production Potential Of Nchanga Underground Mines Collapsed Blocks

    Directory of Open Access Journals (Sweden)

    Eugie Kabwe

    2015-08-01

    Full Text Available Abstract the main purpose of this study is to recommend modification to block caving at Nchanga ensure that it meets anticipated production levels and address the adverse ground conditions of the intensely fractured orebody. Excavations of current methods are driven close to the incompetent orebody. Determination of the appropriate method based on criteria of selection techniques together with the analysis of operating costs and safety. Reclamation of ore in the collapsed blocks entirely depended on maximizing revenue recovery of the mineral and safe working environment for equipment and personnel. On recommendation of a suitable method extent of the collapsed blocks was another aspect considered. The proposed methods of extraction were variants of block caving further shortlisted based on the extent of collapse. Economic appraisal of both the recommended and current mining methods employed included extraction recovery development reclamation costs revenue estimation and revenue raised from finished copper.

  19. Gravitational collapse of a magnetized fermion gas with finite temperature

    Energy Technology Data Exchange (ETDEWEB)

    Delgado Gaspar, I. [Instituto de Geofisica y Astronomia (IGA), La Habana (Cuba); Perez Martinez, A. [Instituto de Cibernetica, Matematica y Fisica (ICIMAF), La Habana (Cuba); Sussman, Roberto A. [Instituto de Ciencias Nucleares, Universidad Nacional Autonoma de Mexico (ICN-UNAM), Mexico (Mexico); Ulacia Rey, A. [Instituto de Cibernetica, Matematica y Fisica (ICIMAF), La Habana (Cuba); Instituto de Ciencias Nucleares, Universidad Nacional Autonoma de Mexico (ICN-UNAM), Mexico (Mexico)

    2013-07-15

    We examine the dynamics of a self-gravitating magnetized fermion gas at finite temperature near the collapsing singularity of a Bianchi-I spacetime. Considering a general set of appropriate and physically motivated initial conditions, we transform Einstein-Maxwell field equations into a complete and self-consistent dynamical system amenable for numerical work. The resulting numerical solutions reveal the gas collapsing into both, isotropic (''point-like'') and anisotropic (''cigar-like''), singularities, depending on the initial intensity of the magnetic field. We provide a thorough study of the near collapse behavior and interplay of all relevant state and kinematic variables: temperature, expansion scalar, shear scalar, magnetic field, magnetization, and energy density. A significant qualitative difference in the behavior of the gas emerges in the temperature range T/m{sub f} {proportional_to} 10{sup -6} and T/m{sub f} {proportional_to} 10{sup -3}. (orig.)

  20. Localized microjetting in the collapse of surface macrocavities

    Science.gov (United States)

    Olney, K. L.; Chiu, P.-H.; Benson, D. J.; Higgins, A.; Serge, M.; Nesterenko, V. F.

    2015-02-01

    This paper focuses on the multiscale mechanism of collapse of hemicylindrical annular surface macrocavities in steel caused by high-strain, high-strain rate plastic flow of copper. Experiments and simulations revealed that a two-stage process is responsible for the observed microjetting phenomena: the formation of lateral copper microjets from the localized shear flow in copper at the interface during the filling of the cavity, and their subsequent collision at the apex of the macrocavity generating two additional horizontal microjets. The lengths of these microjets were an order of magnitude smaller than the cavity size but linearly scaled with the cavity radius. This process of microjet development is sensitive to the cavity geometry and is unlike the previously observed jetting phenomena in cavitation, impact crater collapse, or shock-induced cavity collapse.

  1. Collapse of a cavitation bubble near a free surface

    International Nuclear Information System (INIS)

    Chahine, G.

    1976-01-01

    The interaction between a collapsing bubble and a free surface is investigated theoretically and experimentally using high speed photography. A limiting value for the distance from the free surface to the center of the bubble reported to its radius is found. Under this limit the free surface is not disturbed during the collapse, in the first approximation. Only in this case, the method of images can be used and the free surface be replaced by an image-source, symmetrical with respect to the free surface to the sink representing the bubble. Above this limit, observations show a singular perturbation in the free surface with the formation of a thin spike directed to the air. In all cases the bubble is repelled from the free surface and the re-entering jet, formed during collapse, is oriented away from it [fr

  2. A Critique: Jared Diamond’s Collapse Put In Perspective

    Directory of Open Access Journals (Sweden)

    Emma Gause

    2014-09-01

    Full Text Available Jared Diamond’s book 'Collapse' captivated readers with its tales of past great civilizations succumbing to dramatic cycles of decline, and among them are the ancient Maya. Diamond’s model of the Maya collapse has become quite popular since its publication, however numerous other divergent theories exist as well, which attempt to explain the phenomenon. Diamond, buoyed by the success of his book and his renown as an author, is the assumed authority, despite academic criticism. By comparing Diamond’s 'Collapse' with current research I hope to critique Diamond and thus elucidate the condition of the Maya decline concerning the roles of the environment, the regional variability of various sociopolitical dynamics, such as those that were played out in the Petexbatun region, and the extent of Post Classic continuation of Maya tradition.

  3. Shock waves from non-spherically collapsing cavitation bubbles

    Science.gov (United States)

    Supponen, Outi; Obreschkow, Danail; Farhat, Mohamed

    2017-11-01

    Combining simultaneous high-speed imaging and hydrophone measurements, we uncover details of the multiple shock wave emission from laser-induced cavitation bubbles collapsing in a non-spherical way. For strongly deformed bubbles collapsing near a free surface, we identify the distinct shock waves caused by the jet impact onto the opposite bubble wall and by the individual collapses of the remaining bubble segments. The energy carried by each of these shocks depends on the level of bubble deformation, quantified by the anisotropy parameter ζ, the dimensionless equivalent of the Kelvin impulse. For jetting bubbles, at ζ water hammer as ph = 0.45 (ρc2 Δp) 1 / 2ζ-1 .

  4. Improved Noninterferometric Test of Collapse Models Using Ultracold Cantilevers

    Science.gov (United States)

    Vinante, A.; Mezzena, R.; Falferi, P.; Carlesso, M.; Bassi, A.

    2017-09-01

    Spontaneous collapse models predict that a weak force noise acts on any mechanical system, as a consequence of the collapse of the wave function. Significant upper limits on the collapse rate have been recently inferred from precision mechanical experiments, such as ultracold cantilevers and the space mission LISA Pathfinder. Here, we report new results from an experiment based on a high-Q cantilever cooled to millikelvin temperatures, which is potentially able to improve the current bounds on the continuous spontaneous localization (CSL) model by 1 order of magnitude. High accuracy measurements of the cantilever thermal fluctuations reveal a nonthermal force noise of unknown origin. This excess noise is compatible with the CSL heating predicted by Adler. Several physical mechanisms able to explain the observed noise have been ruled out.

  5. Fate of accreting white dwarfs: Type I supernovae vs collapse

    International Nuclear Information System (INIS)

    Nomoto, Ken'ichi.

    1986-01-01

    The final fate of accreting C + O white dwarfs is either thermonuclear explosion or collapse, if the white dwarf mass grows to the Chandrasekhar mass. We discuss how the fate depends on the initial mass, age, composition of the white dwarf and the mass accretion rate. Relatively fast accretion leads to a carbon deflagration at low central density that gives rise to a Type Ia supernova. Slower accretion induces a helium detonation that could be observed as a Type Ib supernova. If the initial mass of the C + O white dwarf is larger than 1.2 Msub solar, a carbon deflagration starts at high central density and induces a collapse of the white dwarf to form a neutron star. We examine the critical condition for which a carbon deflagration leads to collapse, not explosion. For the case of explosion, we discuss to what extent the nucleosynthesis models are consistent with spectra of Type Ia and Ib supernovae. 61 refs., 18 figs

  6. How summit calderas collapse on basaltic volcanoes: new insights from the April 2007 caldera collapse of Piton de la Fournaise volcano

    Energy Technology Data Exchange (ETDEWEB)

    Michon, Laurent; Catry, Thibault; Merle, Olivier [Laboratoire GeoSciences Reunion, Universite de la Reunion, Institut de Physique du Globe de Paris, CNRS, UMR 7154 - Geologie des Systemes Volcaniques, 15 avenue Rene Cassin, 97715 Saint Denis (France); Villeneuve, Nicolas [Institut de Recherche pour le Developpement, US 140, BP172, 97492 Sainte-Clotilde cedex (France)], E-mail: laurent.michon@univ-reunion.fr

    2008-10-01

    In April 2007, Piton de la Fournaise volcano experienced a caldera collapse during its largest historical eruption. We present here the resulting deformation and a synthesis of the seismicity recorded during recent caldera collapses. It allows us to propose a unifying mechanism that explains the pulsating collapse dynamics.

  7. Reduced estradiol-induced vasodilation and poly-(ADP-ribose polymerase (PARP activity in the aortas of rats with experimental polycystic ovary syndrome (PCOS.

    Directory of Open Access Journals (Sweden)

    Gabriella Masszi

    Full Text Available Polycystic ovary syndrome (PCOS is a complex endocrine disorder characterized by hyperandrogenism and insulin resistance, both of which have been connected to atherosclerosis. Indeed, an increased risk of clinical manifestations of arterial vascular diseases has been described in PCOS. On the other hand endothelial dysfunction can be detected early on, before atherosclerosis develops. Thus we assumed that vascular dysfunction is also related directly to the hormonal imbalance rather than to its metabolic consequences. To detect early functional changes, we applied a novel rodent model of PCOS: rats were either sham operated or hyperandrogenism was achieved by implanting subcutaneous pellets of dihydrotestosterone (DHT. After ten weeks, myograph measurements were performed on isolated aortic rings. Previously we described an increased contractility to norepinephrine (NE. Here we found a reduced immediate relaxation to estradiol treatment in pre-contracted aortic rings from hyperandrogenic rats. Although the administration of vitamin D3 along with DHT reduced responsiveness to NE, it did not restore relaxation to estradiol. Poly-(ADP-ribose polymerase (PARP activity was assessed by poly-ADP-ribose immunostaining. Increased PAR staining in ovaries and circulating leukocytes from DHT rats showed enhanced DNA damage, which was reduced by concomitant vitamin D3 treatment. Surprisingly, PAR staining was reduced in both the endothelium and vascular smooth muscle cells of the aorta rings from hyperandrogenic rats. Thus in the early phase of PCOS, vascular tone is already shifted towards vasoconstriction, characterized by reduced vasorelaxation and vascular dysfunction is concomitant with altered PARP activity. Based on our findings, PARP inhibitors might have a future perspective in restoring metabolic disorders in PCOS.

  8. Reduced estradiol-induced vasodilation and poly-(ADP-ribose) polymerase (PARP) activity in the aortas of rats with experimental polycystic ovary syndrome (PCOS).

    Science.gov (United States)

    Masszi, Gabriella; Horvath, Eszter Maria; Tarszabo, Robert; Benko, Rita; Novak, Agnes; Buday, Anna; Tokes, Anna-Maria; Nadasy, Gyorgy L; Hamar, Peter; Benyó, Zoltán; Varbiro, Szabolcs

    2013-01-01

    Polycystic ovary syndrome (PCOS) is a complex endocrine disorder characterized by hyperandrogenism and insulin resistance, both of which have been connected to atherosclerosis. Indeed, an increased risk of clinical manifestations of arterial vascular diseases has been described in PCOS. On the other hand endothelial dysfunction can be detected early on, before atherosclerosis develops. Thus we assumed that vascular dysfunction is also related directly to the hormonal imbalance rather than to its metabolic consequences. To detect early functional changes, we applied a novel rodent model of PCOS: rats were either sham operated or hyperandrogenism was achieved by implanting subcutaneous pellets of dihydrotestosterone (DHT). After ten weeks, myograph measurements were performed on isolated aortic rings. Previously we described an increased contractility to norepinephrine (NE). Here we found a reduced immediate relaxation to estradiol treatment in pre-contracted aortic rings from hyperandrogenic rats. Although the administration of vitamin D3 along with DHT reduced responsiveness to NE, it did not restore relaxation to estradiol. Poly-(ADP-ribose) polymerase (PARP) activity was assessed by poly-ADP-ribose immunostaining. Increased PAR staining in ovaries and circulating leukocytes from DHT rats showed enhanced DNA damage, which was reduced by concomitant vitamin D3 treatment. Surprisingly, PAR staining was reduced in both the endothelium and vascular smooth muscle cells of the aorta rings from hyperandrogenic rats. Thus in the early phase of PCOS, vascular tone is already shifted towards vasoconstriction, characterized by reduced vasorelaxation and vascular dysfunction is concomitant with altered PARP activity. Based on our findings, PARP inhibitors might have a future perspective in restoring metabolic disorders in PCOS.

  9. [Expression of PARP/NF-κB and intervention effect of 5-AIQ/PDTC in SAP rats with adrenal damage].

    Science.gov (United States)

    Yang, Bo; Guo, Wen-Yi; Yu, Jia; Zhao, Kai-liang; Shi, Qiao; Zuo, Teng; Wang, Wei-xing

    2013-10-15

    To explore the expression of poly (ADP-ribose) polymerase/nuclear factor-κB (PARP/NF-κB) and intervention effect of 5-aminoisoquinolinone/pyrrolidine dithiocarbamate (5-AIQ/PDTC) in severe acute pancreatitis (SAP) rats with adrenal damage. The primarily cultured adrenocortical cells were quantitatively divided into control group (SO), pancreatitis group (SAP), PDTC drug control group (SO+PDTC), PDTC intervention group (SAP+PDTC), 5-AIQ drug control group (SO+ 5-AIQ) and 5-AIQ intervention group (SAP+5-AIQ). The SAP and 2 intervention groups were stimulated with the sera of SAP rats. Then corresponding drugs were added and culture continued for 12 hours. The corticosterone levels and PARP/NF-κB expression were observed for each group. Adrenal cells in vitro cultured were round or oval, had secretory granules and could be stained by 3β-hydroxysteroid dehydrogenase antibody. The adherence rate was 60% after 48-hour culturing. The corticosterone level of SAP group was significantly lower than that of SO group [ (216.4 ± 15.7) vs (294.8 ± 16.3) µg/L, P SAP group (P SAP and PDTC intervention groups were higher than SO group while 5-AIQ intervention group was significantly lower than SAP and PDTC intervention groups, but higher than SO and drug control groups. The expression of NF-κB in SAP group was higher than that in SO group. Two intervention groups were lower than SAP group, but higher than SO and drug control groups. The pathway of PARP/NF-κB participates in adrenal damage of SAP rats. To a certain extent, the uses of 5-AIQ and PDTC may alleviate adrenal damage.

  10. Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers.

    Science.gov (United States)

    de Bono, Johann; Ramanathan, Ramesh K; Mina, Lida; Chugh, Rashmi; Glaspy, John; Rafii, Saeed; Kaye, Stan; Sachdev, Jasgit; Heymach, John; Smith, David C; Henshaw, Joshua W; Herriott, Ashleigh; Patterson, Miranda; Curtin, Nicola J; Byers, Lauren Averett; Wainberg, Zev A

    2017-06-01

    Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2 -mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation-associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day. Significance: In this clinical trial, we show that talazoparib has single-agent antitumor activity and a tolerable safety profile. At its recommended phase II dose of 1.0 mg/day, confirmed responses were observed in patients with BRCA mutation-associated breast and ovarian cancers and in patients with pancreatic and small cell lung cancer. Cancer Discov; 7(6); 620-9. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 539 . ©2017 American Association for Cancer Research.

  11. Baseline clinical predictors of antitumor response to the PARP inhibitor olaparib in germline BRCA1/2 mutated patients with advanced ovarian cancer.

    Science.gov (United States)

    Rafii, Saeed; Gourley, Charlie; Kumar, Rajiv; Geuna, Elena; Ern Ang, Joo; Rye, Tzyvia; Chen, Lee-May; Shapira-Frommer, Ronnie; Friedlander, Michael; Matulonis, Ursula; De Greve, Jacques; Oza, Amit M; Banerjee, Susana; Molife, L Rhoda; Gore, Martin E; Kaye, Stan B; Yap, Timothy A

    2017-07-18

    The PARP inhibitor olaparib was recently granted Food and Drug Administration (FDA) accelerated approval in patients with advanced BRCA1/2 mutation ovarian cancer. However, antitumor responses are observed in only approximately 40% of patients and the impact of baseline clinical factors on response to treatment remains unclear. Although platinum sensitivity has been suggested as a marker of response to PARP inhibitors, patients with platinum-resistant disease still respond to olaparib. 108 patients with advanced BRCA1/2 mutation ovarian cancers were included. The interval between the end of the most recent platinum chemotherapy and PARPi (PTPI) was used to predict response to olaparib independent of conventional definition of platinum sensitivity. RECIST complete response (CR) and partial response (PR) rates were 35% in patients with platinum-sensitive versus 13% in platinum-resistant (p<0.005). Independent of platinum sensitivity status, the RECIST CR/PR rates were 42% in patients with PTPI greater than 52 weeks and 18% in patients with PTPI less than 52 weeks (p=0.016). No association was found between baseline clinical factors such as FIGO staging, debulking surgery, BRCA1 versus BRCA2 mutations, prior history of breast cancer and prior chemotherapy for breast cancer, and the response to olaparib. We conducted an international multicenter retrospective study to investigate the association between baseline clinical characteristics of patients with advanced BRCA1/2 mutation ovarian cancers from eight different cancer centers and their antitumor response to olaparib. PTPI may be used to refine the prediction of response to PARP inhibition based on the conventional categorization of platinum sensitivity.

  12. Gravitational Collapse of Massless Fields in an Expanding Universe

    Directory of Open Access Journals (Sweden)

    Yoo Chul-Moon

    2018-01-01

    Full Text Available Gravitational collapse of a massless scalar field with the periodic boundary condition in a cubic box is reported. This system can be regarded as a lattice universe model. The initial data is constructed for a Gaussian like profile of the scalar field taking the integrability condition associated with the periodic boundary condition into account. For a large initial amplitude, a black hole is formed after a certain period of time. While the scalar field spreads out in the whole region for a small initial amplitude. The difference of the late time expansion law of the lattice universe depending on the final fate of the gravitational collapse is discussed.

  13. Collapse of triangular channels in a soft elastomer

    Science.gov (United States)

    Tepáyotl-Ramírez, Daniel; Lu, Tong; Park, Yong-Lae; Majidi, Carmel

    2013-01-01

    We extend classical solutions in contact mechanics to examine the collapse of channels in a soft elastomer. These channels have triangular cross-section and collapse when pressure is applied to the surrounding elastomer. Treating the walls of the channel as indenters that penetrate the channel base, we derive an algebraic mapping between pressure and cross-sectional area. These theoretical predictions are in strong agreement with results that we obtain through finite element analysis and experimental measurements. This is accomplished without data fitting and suggests that the theoretical approach may be generalized to a broad range of cross-sectional geometries in soft microfluidics.

  14. Evaluating nuclear physics inputs in core-collapse supernova models

    Science.gov (United States)

    Lentz, E.; Hix, W. R.; Baird, M. L.; Messer, O. E. B.; Mezzacappa, A.

    Core-collapse supernova models depend on the details of the nuclear and weak interaction physics inputs just as they depend on the details of the macroscopic physics (transport, hydrodynamics, etc.), numerical methods, and progenitors. We present preliminary results from our ongoing comparison studies of nuclear and weak interaction physics inputs to core collapse supernova models using the spherically-symmetric, general relativistic, neutrino radiation hydrodynamics code Agile-Boltztran. We focus on comparisons of the effects of the nuclear EoS and the effects of improving the opacities, particularly neutrino--nucleon interactions.

  15. Statistical evidence against simple forms of wavefunction collapse

    International Nuclear Information System (INIS)

    Page, Don N.

    2013-01-01

    If the initial quantum state of the universe is a multiverse superposition over many different sets of values of the effective coupling ‘constants’ of physics, and if this quantum state collapses to an eigenstate of the set of coupling ‘constants’ with a probability purely proportional to the absolute square of the amplitude (with no additional factor for something like life or consciousness), then one should not expect that the coupling ‘constants’ would be so biophilic as they are observed to be. Therefore, the observed biophilic values (apparent fine tuning) of the coupling ‘constants’ is statistical evidence against such simple forms of wavefunction collapse

  16. Collapse mechanisms and strength prediction of reinforced concrete pile caps

    DEFF Research Database (Denmark)

    Jensen, Uffe G.; Hoang, Linh Cao

    2012-01-01

    . Calculations have been compared with nearly 200 test results found in the literature. Satisfactory agreement has been found. The analyses are conducted on concentrically loaded caps supported by four piles. The paper briefly outlines how the approach may be extended to more complicated loadings and geometries......This paper describes an upper bound plasticity approach for strength prediction of reinforced concrete pile caps. A number of collapse mechanisms are identified and analysed. The procedure leads to an estimate of the load-carrying capacity and an identification of the critical collapse mechanism...

  17. Two-dimensional collapse calculations of cylindrical clouds

    International Nuclear Information System (INIS)

    Bastien, P.; Mitalas, R.

    1979-01-01

    A two-dimensional hydrodynamic computer code has been extensively modified and expanded to study the collapse of non-rotating interstellar clouds. The physics and the numerical methods involved are discussed. The results are presented and discussed in terms of the Jeans number. The critical Jeans number for collapse of non-rotating cylindrical clouds whose length is the same as their diameter is 1.00. No evidence for fragmentation has been found for these clouds, but fragmentation seems quite likely for more elongated cylindrical clouds. (author)

  18. Statistical evidence against simple forms of wavefunction collapse

    Energy Technology Data Exchange (ETDEWEB)

    Page, Don N., E-mail: profdonpage@gmail.com [Theoretical Physics Institute, Department of Physics, University of Alberta, Room 238 CEB, 11322-89 Avenue, Edmonton, Alberta, T6G 2G7 (Canada)

    2013-02-26

    If the initial quantum state of the universe is a multiverse superposition over many different sets of values of the effective coupling ‘constants’ of physics, and if this quantum state collapses to an eigenstate of the set of coupling ‘constants’ with a probability purely proportional to the absolute square of the amplitude (with no additional factor for something like life or consciousness), then one should not expect that the coupling ‘constants’ would be so biophilic as they are observed to be. Therefore, the observed biophilic values (apparent fine tuning) of the coupling ‘constants’ is statistical evidence against such simple forms of wavefunction collapse.

  19. Diagnosis of ischemic vertebral collapse using selective spinal angiography

    International Nuclear Information System (INIS)

    Stojanovic, J.; Kovac, V.

    1981-01-01

    During the year of 1980 we observed 3 patients with a vertebral collapse of indistinct origin. As there was no recent trauma in the past history, selective spinal angiography (SSA) was used to clarify the diagnosis. In each of the three cases we found evident rarefaction, in some places even an occlusion of the arteries of the adjacent affected vertebra. On the bases of this finding we concluded that this might be an ischemic vertebral collapse, an entity which had been under discussion long ago but not exactly confirmed so far. (orig.) [de

  20. Gravitational collapse, chaos in CFT correlators and the information paradox

    Energy Technology Data Exchange (ETDEWEB)

    Farahi, Arya, E-mail: aryaf@umich.edu; Pando Zayas, Leopoldo A., E-mail: lpandoz@umich.edu

    2014-06-27

    We consider gravitational collapse of a massless scalar field in asymptotically anti-de Sitter spacetime. Following the AdS/CFT dictionary we further study correlations in the field theory side by way of the Klein–Gordon equation of a probe scalar field in the collapsing background. We present evidence that in a certain regime the probe scalar field behaves chaotically, thus supporting Hawking's argument in the black hole information paradox proposing that although the information can be retrieved in principle, deterministic chaos impairs, in practice, the process of unitary extraction of information from a black hole. We emphasize that quantum chaos will change this picture.

  1. Weak Interaction processes in core-collapse supernova

    International Nuclear Information System (INIS)

    Martinez-Pinedo, Gabriel

    2008-01-01

    In this manuscript we review the role that weak interaction processes play in supernova. This includes electron captures and inelastic neutrino-nucleus scattering (INNS). Electron captures during the collapse occur mainly in heavy nuclei, however the proton contribution is responsible for the convergence of different models to a 'norm' stellar trajectory. Neutrino-nucleus cross sections at supernova neutrino energies can be determined from precise data on the magnetic dipole strength. The results agree well with large-scale shell-model calculations. When incorporated in core-collapse simulations INNS increases the neutrino opacities noticeably and strongly reduces the high-energy part of the supernova spectrum

  2. Gravitational Collapse of Radiating Dyon Solution and Cosmic Censorship Hypothesis

    International Nuclear Information System (INIS)

    Patil, K. D.; Zade, S. S.; Mohod, A. N.

    2008-01-01

    We investigate the possibility of cosmic censorship violation in the gravitational collapse of radiating dyon solution. It is shown that the final outcome of the collapse depends sensitively on the electric and magnetic charge parameters. The graphs of the outer apparent horizon, inner Cauchy horizon for different values of parameters are drawn. It is found that the electric and magnetic components push the apparent horizon towards the retarded time-coordinate axis, which in turn reduces the radius of the apparent horizon in Vaidya spacetime. Also, we extend the earlier work of Chamorro and Virbhadra [Pramana, J. Phys. 45 (1995) 181

  3. The Negativity of Times. Collapsed Futures in Maputo, Mozambique

    DEFF Research Database (Denmark)

    Nielsen, Morten

    2014-01-01

    This article explores how urban temporalities in Maputo, Mozambique’s capital, erupt from collapsed futures, which endure within the present as traces of that which will no longer be. The argument is built on an ethnographic analysis of kuzama utomi (‘trying to make a life’), a temporal trope......, which prefigures the future as a failure on a linear scale. Still, although it is identifyed by its collapse, the future wedges itself within the present as a trace of that which will never be. While manifesting the efforts needed in order to reach a desired objective, it also exposes the powers at work...

  4. Flow and oscillations in collapsible tubes: Physiological applications ...

    Indian Academy of Sciences (India)

    pressure changes associated with fluid flow in the tube may be enough to generate large area changes. Collapsible ... As a very simple model, consider a single, uniform pipe containing viscous fluid flowing steadily at volume ..... (1986). For each mode the instability occurs through a Hopf bifurcation, which is supercritical.

  5. Scanning the parameter space of collapsing rotating thin shells

    Science.gov (United States)

    Rocha, Jorge V.; Santarelli, Raphael

    2018-06-01

    We present results of a comprehensive study of collapsing and bouncing thin shells with rotation, framing it in the context of the weak cosmic censorship conjecture. The analysis is based on a formalism developed specifically for higher odd dimensions that is able to describe the dynamics of collapsing rotating shells exactly. We analyse and classify a plethora of shell trajectories in asymptotically flat spacetimes. The parameters varied include the shell’s mass and angular momentum, its radial velocity at infinity, the (linear) equation-of-state parameter and the spacetime dimensionality. We find that plunges of rotating shells into black holes never produce naked singularities, as long as the matter shell obeys the weak energy condition, and so respects cosmic censorship. This applies to collapses of dust shells starting from rest or with a finite velocity at infinity. Not even shells with a negative isotropic pressure component (i.e. tension) lead to the formation of naked singularities, as long as the weak energy condition is satisfied. Endowing the shells with a positive isotropic pressure component allows for the existence of bouncing trajectories satisfying the dominant energy condition and fully contained outside rotating black holes. Otherwise any turning point occurs always inside the horizon. These results are based on strong numerical evidence from scans of numerous sections in the large parameter space available to these collapsing shells. The generalisation of the radial equation of motion to a polytropic equation-of-state for the matter shell is also included in an appendix.

  6. Acoustical signature of the collapse of a cavitation bubble

    International Nuclear Information System (INIS)

    Chahine, G.L.

    1978-10-01

    The influence of the proximity of a wall on the noise emitted when an isolated cavitation bubble collapses is studied qualitatively by correlation between the noise emitted and the dynamics of the bubble, by amplitude analysis and by time analysis [fr

  7. Excision technique in constrained formulations of Einstein equations: collapse scenario

    International Nuclear Information System (INIS)

    Cordero-Carrión, I; Vasset, N; Novak, J; Jaramillo, J L

    2015-01-01

    We present a new excision technique used in constrained formulations of Einstein equations to deal with black hole in numerical simulations. We show the applicability of this scheme in several scenarios. In particular, we present the dynamical evolution of the collapse of a neutron star to a black hole, using the CoCoNuT code and this excision technique. (paper)

  8. Three-dimensional simulations of void collapse in energetic materials

    Science.gov (United States)

    Rai, Nirmal Kumar; Udaykumar, H. S.

    2018-03-01

    The collapse of voids in porous energetic materials leads to hot-spot formation and reaction initiation. This work advances the current knowledge of the dynamics of void collapse and hot-spot formation using 3D reactive void collapse simulations in HMX. Four different void shapes, i.e., sphere, cylinder, plate, and ellipsoid, are studied. For all four shapes, collapse generates complex three-dimensional (3D) baroclinic vortical structures. The hot spots are collocated with regions of intense vorticity. The differences in the vortical structures for the different void shapes are shown to significantly impact the relative sensitivity of the voids. Voids of high surface area generate hot spots of greater intensity; intricate, highly contorted vortical structures lead to hot spots of corresponding tortuosity and therefore enhanced growth rates of reaction fronts. In addition, all 3D voids are shown to be more sensitive than their two-dimensional (2D) counterparts. The results provide physical insights into hot-spot formation and growth and point to the limitations of 2D analyses of hot-spot formation.

  9. Simulation of the collapse and dissipation of Langmuir wave packets

    International Nuclear Information System (INIS)

    Newman, D.L.; Winglee, R.M.; Robinson, P.A.; Glanz, J.; Goldman, M.V.

    1990-01-01

    The collapse of isolated Langmuir wave packets is studied numerically in two dimensions using both particle-in-cell (PIC) simulations and by integrating the Zakharov partial differential equations (PDE's). The initial state consists of a localized Langmuir wave packet in an ion background that either is uniform or has a profile representative of the density wells in which wave packets form during strong plasma turbulence. Collapse thresholds are determined numerically and compared to analytical estimates. A model in which Langmuir damping is significantly stronger than Landau damping is constructed which, when included in the PDE simulations, yields good agreement with the collapse dynamics observed in PIC simulations for wave packets with initial wave energy densities small compared to the thermal level. For more intense initial Langmuir fields, collapse is arrested in PIC simulations at lower field strengths than in PDE simulations. Neither nonlinear saturation of the density perturbation nor fluid electron nonlinearities can account for the difference between simulation methods in this regime. However, at these wave levels inhomogeneous electron heating and coherent jets of transit-time accelerated electrons in phase space are observed, resulting in further enhancement of wave damping and the consequent reduction of fields in the PIC simulations

  10. Heterogeneous economic resilience and the great recession's world trade collapse

    NARCIS (Netherlands)

    van Bergeijk, Peter A.G.; Brakman, Steven; van Marrewijk, Charles

    2017-01-01

    This special section aims to fill a gap in the regional resilience literature and to stimulate future spatial studies of resilience to include the international dimension in empirical analyses. It demonstrates the do-ability and relevance by the natural experience of the global trade collapse that

  11. An experimental investigation of untriggered film boiling collapse

    International Nuclear Information System (INIS)

    Naylor, P.

    1985-03-01

    Film boiling has been investigated in a stagnant pool, using polished brass or anodised aluminium alloy rods in water. Experimental boiling curves were obtained, and pronounced ripples on the vapour/liquid interface were photographed. A criterion for untriggered film boiling collapse is proposed, consistent with experimental results. Application of the results to molten fuel coolant interaction studies is discussed. (U.K.)

  12. Electron sheath collapse in an applied-B ion diode

    International Nuclear Information System (INIS)

    Grechikha, A.V.

    1996-01-01

    The effect of the electron sheath collapse in an applied-B ion diode due to the presence of the resistive anode plasma layer was found. This effect is more damaging at higher diode voltages and may be responsible for the parasitic load effect observed in the experiments. (author). 4 figs., 2 refs

  13. Modelling Technique for Demonstrating Gravity Collapse Structures in Jointed Rock.

    Science.gov (United States)

    Stimpson, B.

    1979-01-01

    Described is a base-friction modeling technique for studying the development of collapse structures in jointed rocks. A moving belt beneath weak material is designed to simulate gravity. A description is given of the model frame construction. (Author/SA)

  14. On stellar collapse: continual or oscillatory. A short comment

    International Nuclear Information System (INIS)

    Leung, P.T.

    1980-01-01

    We comment on a previously published paper on the oscillatory dynamics of stellar collapse and conclude that the Schwarzschild interior solution applied to the 'inflection points' can never give rise to a 'turning back' motion, in spite of the fact that the geodesic equation really does not always describe an attractive gravitational acceleration

  15. Explosive X-point collapse in relativistic magnetically dominated plasma

    Science.gov (United States)

    Lyutikov, Maxim; Sironi, Lorenzo; Komissarov, Serguei S.; Porth, Oliver

    2017-12-01

    The extreme properties of the gamma-ray flares in the Crab nebula present a clear challenge to our ideas on the nature of particle acceleration in relativistic astrophysical plasma. It seems highly unlikely that standard mechanisms of stochastic type are at work here and hence the attention of theorists has switched to linear acceleration in magnetic reconnection events. In this series of papers, we attempt to develop a theory of explosive magnetic reconnection in highly magnetized relativistic plasma which can explain the extreme parameters of the Crab flares. In the first paper, we focus on the properties of the X-point collapse. Using analytical and numerical methods (fluid and particle-in-cell simulations) we extend Syrovatsky's classical model of such collapse to the relativistic regime. We find that the collapse can lead to the reconnection rate approaching the speed of light on macroscopic scales. During the collapse, the plasma particles are accelerated by charge-starved electric fields, which can reach (and even exceed) values of the local magnetic field. The explosive stage of reconnection produces non-thermal power-law tails with slopes that depend on the average magnetization . For sufficiently high magnetizations and vanishing guide field, the non-thermal particle spectrum consists of two components: a low-energy population with soft spectrum that dominates the number census; and a high-energy population with hard spectrum that possesses all the properties needed to explain the Crab flares.

  16. Review of literature on the asymmetric collapse of vapor bubbles

    International Nuclear Information System (INIS)

    Fremd, R.; Froehlich, G.

    1977-06-01

    This report contains a review of literature on the asymmetric collape of vapor bubbles by cavitation with special consideration to vapor explosions. Two numerical models, which describe the collapse of cavities in the neighbourhood of a solid surface, are presented. Moreover experimental results for this case are provided. Propositions to apply the numerical models to vapor explosions are made. (orig.) [de

  17. Building Failures And Collapses: A Case Study Of Portharcourt ...

    African Journals Online (AJOL)

    The Cases of Building failures and consequent collapse in Nigeria has reached an alarming and lamentable stage. It is a disaster comparable to flood disaster, earthquake and aeroplane clash considering the loss of life and destruction of property. Building failure are mostly observed in big cities where there are multiple ...

  18. Surviving a cluster collapse: risk aversion as a core value

    NARCIS (Netherlands)

    Schiele, Holger; Hospers, Gerrit J.; van der Zee, D.J.

    2012-01-01

    Purpose – This paper analyses firms, which survived in a collapsed regional cluster. The target is to analyze whether the principles for enduring success identified researching success factors of very old firms also apply in such an environment. Design/methodology/approach – The authors conduct a

  19. Averting biodiversity collapse in tropical forest protected areas

    Czech Academy of Sciences Publication Activity Database

    Laurence, W. F.; Novotný, Vojtěch

    2012-01-01

    Roč. 489, č. 7415 (2012), s. 290-294 ISSN 0028-0836 Grant - others:NSF grant(AU) RCN-0741956 Institutional support: RVO:60077344 Keywords : biodiversity * tropical forest * collapse Subject RIV: EH - Ecology, Behaviour Impact factor: 38.597, year: 2012 http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature11318.pdf

  20. Rayleigh-Taylor convective overturn in stellar collapse

    International Nuclear Information System (INIS)

    Bruenn, S.W.; Buchler, J.R.; Livio, M.

    1979-01-01

    Rayleigh--Taylor convective overturn in collapsing stellar cores is modeled with a one-dimensional parametrization. The results of a numerical hydrodynamic study are very encouraging and indicate that such an overturn could well be a dominant feature in the supernova explosion mechanism

  1. The collapse of an anti-de Sitter bubble

    International Nuclear Information System (INIS)

    Abbott, L.F.; Coleman, S.

    1985-01-01

    We prove that the ultimate fate of a bubble of negative energy density which forms in a metastable universe of zero energy density is gravitational collapse. We improve on previous treatments in that we allow departures from O(3,1) symmetry in the initial state, so long as they are not too great. (orig.)

  2. Spherical collapse model in time varying vacuum cosmologies

    International Nuclear Information System (INIS)

    Basilakos, Spyros; Plionis, Manolis; Sola, Joan

    2010-01-01

    We investigate the virialization of cosmic structures in the framework of flat Friedmann-Lemaitre-Robertson-Walker cosmological models, in which the vacuum energy density evolves with time. In particular, our analysis focuses on the study of spherical matter perturbations, as they decouple from the background expansion, 'turn around', and finally collapse. We generalize the spherical collapse model in the case when the vacuum energy is a running function of the Hubble rate, Λ=Λ(H). A particularly well-motivated model of this type is the so-called quantum field vacuum, in which Λ(H) is a quadratic function, Λ(H)=n 0 +n 2 H 2 , with n 0 ≠0. This model was previously studied by our team using the latest high quality cosmological data to constrain its free parameters, as well as the predicted cluster formation rate. It turns out that the corresponding Hubble expansion history resembles that of the traditional ΛCDM cosmology. We use this Λ(t)CDM framework to illustrate the fact that the properties of the spherical collapse model (virial density, collapse factor, etc.) depend on the choice of the considered vacuum energy (homogeneous or clustered). In particular, if the distribution of the vacuum energy is clustered, then, under specific conditions, we can produce more concentrated structures with respect to the homogeneous vacuum energy case.

  3. Collapse arrest and soliton stabilization in nonlocal nonlinear media

    DEFF Research Database (Denmark)

    Bang, Ole; Krolikowski, Wieslaw; Wyller, John

    2002-01-01

    that nonlocality of the nonlinearity prevents collapse in, e.g., Bose-Einstein condensates and optical Kerr media in all physical dimensions. The nonlocal nonlinear response must be symmetric and have a positive definite Fourier spectrum, but can otherwise be of completely arbitrary shape and degree of nonlocality...

  4. Pore collapse and regrowth in silicon electrodes for rechargeable batteries

    Energy Technology Data Exchange (ETDEWEB)

    DeCaluwe, S. C. [Department of Mechanical Engineering; Colorado School of Mines; USA; Center for Neutron Research; National Institute of Standards and Technology; Dhar, B. M. [Institute for Materials Research and Dept. of Mechanical Engineering; State University of New York; Binghamton; USA; Material Measurement Laboratory; Huang, L. [Institute for Materials Research and Dept. of Mechanical Engineering; State University of New York; Binghamton; USA; He, Y. [Institute for Materials Research and Dept. of Mechanical Engineering; State University of New York; Binghamton; USA; Department of Physics and Astronomy; Yang, K. [Institute for Materials Research and Dept. of Mechanical Engineering; State University of New York; Binghamton; USA; Owejan, J. P. [Department of Mechanical and Electrical Engineering Technology; State University of New York; Alfred; USA; Zhao, Y. [Department of Physics and Astronomy; University of Georgia; Athens; USA; Talin, A. A. [Center for Nanoscale Science and Technology; National Institute of Standards and Technology; Gaithersburg; USA; Sandia National Laboratories; Dura, J. A. [Center for Neutron Research; National Institute of Standards and Technology; Gaithersburg; USA; Wang, H. [Department of Materials Science and Engineering; University of Maryland; College Park; USA; Institute for Materials Research and Dept. of Mechanical Engineering

    2015-01-01

    In-operando Neutron Reflectometry establishes the pore collapse and regrowth (PCRG) mechanism in amorphous Si. Upon lithiation, porosity is first consumed by expansion of solid Si domains, with little thickness increase. After, the whole film expands. Porosity returns upon delithiation.

  5. Automatic lung segmentation in the presence of alveolar collapse

    Directory of Open Access Journals (Sweden)

    Noshadi Areg

    2017-09-01

    Full Text Available Lung ventilation and perfusion analyses using chest imaging methods require a correct segmentation of the lung to offer anatomical landmarks for the physiological data. An automatic segmentation approach simplifies and accelerates the analysis. However, the segmentation of the lungs has shown to be difficult if collapsed areas are present that tend to share similar gray values with surrounding non-pulmonary tissue. Our goal was to develop an automatic segmentation algorithm that is able to approximate dorsal lung boundaries even if alveolar collapse is present in the dependent lung areas adjacent to the pleura. Computed tomography data acquired in five supine pigs with injured lungs were used for this purpose. First, healthy lung tissue was segmented using a standard 3D region growing algorithm. Further, the bones in the chest wall surrounding the lungs were segmented to find the contact points of ribs and pleura. Artificial boundaries of the dorsal lung were set by spline interpolation through these contact points. Segmentation masks of the entire lung including the collapsed regions were created by combining the splines with the segmentation masks of the healthy lung tissue through multiple morphological operations. The automatically segmented images were then evaluated by comparing them to manual segmentations and determining the Dice similarity coefficients (DSC as a similarity measure. The developed method was able to accurately segment the lungs including the collapsed regions (DSCs over 0.96.

  6. The final outcome of dissipative collapse in the presence of

    Indian Academy of Sciences (India)

    in the gravitational collapse of conformally flat, radiating spheres. ... Comprehensive studies of static fluid spheres in the presence of a cosmological constant have led .... tions with isotropic pressures in the presence of heat flux and cosmological constant ..... radiation from the stellar surface reaches our observer at infinity.

  7. Influence Of Collapsing Matter On The Enveloping Expanding Universe

    OpenAIRE

    Choudhury, A. Latif

    2005-01-01

    Using a collapsing matter model at the center of an expanding universe as described by Weinberg we assume a special type of generated pressure. This pressure transmits into the surrounding expanding universe. Under certain restriction the ensuing hubble parameter is positive. The deacceleration parameter fluctuates with time, indicating that the universe accelerates for certain time and decelerates for other time intervals.

  8. Cosmic censorship in a Kerr-like collapse scenario

    Energy Technology Data Exchange (ETDEWEB)

    Rudnicki, W. [Institute of Physics, Pedagogical University, Rzeszow (Poland)

    1998-04-01

    In this contribution we discuss a recent result which shows that a gravitational collapse cannot in generic situations lead to the formation of a final state resembling the Kerr solution with a naked singularity. This result supports the validity of the cosmic censorship hypothesis. (author)

  9. Stability of a collapsed scalar field and cosmic censorship

    International Nuclear Information System (INIS)

    Abe, S.

    1988-01-01

    The static and asymptotically flat solution to the Einstein-massless-scalar model with spherical symmetry describes the spacetime with a naked singularity when it has a nonvanishing scalar charge. We show that such a solution is unstable against the spherical scalar monopole perturbation. This suggests the validity of the cosmic censorship hypothesis in the spherical collapse of the scalar field

  10. Cosmic censorship in a Kerr-like collapse scenario

    International Nuclear Information System (INIS)

    Rudnicki, W.

    1998-01-01

    In this contribution we discuss a recent result which shows that a gravitational collapse cannot in generic situations lead to the formation of a final state resembling the Kerr solution with a naked singularity. This result supports the validity of the cosmic censorship hypothesis. (author)

  11. Electron sheath collapse in an applied-B ion diode

    Energy Technology Data Exchange (ETDEWEB)

    Grechikha, A V [Forschungszentrum Karlsruhe (Germany). Institut fuer Neutronenphysik und Reaktortechnik

    1997-12-31

    The effect of the electron sheath collapse in an applied-B ion diode due to the presence of the resistive anode plasma layer was found. This effect is more damaging at higher diode voltages and may be responsible for the parasitic load effect observed in the experiments. (author). 4 figs., 2 refs.

  12. Plastic collapse behavior for thin tube with two parallel cracks

    International Nuclear Information System (INIS)

    Moon, Seong In; Chang, Yoon Suk; Kim, Young Jin; Lee, Jin Ho; Song, Myung Ho; Choi, Young Hwan; Kim, Joung Soo

    2004-01-01

    The current plugging criterion is known to be too conservative for some locations and types of defects. Many defects detected during in-service inspection take on the form of multiple cracks at the top of tube sheet but there is no reliable plugging criterion for the steam generator tubes with multiple cracks. Most of the previous studies on multiple cracks are confined to elastic analyses and only few studies have been done on the steam generator tubes failed by plastic collapse. Therefore, it is necessary to develop models which can be used to estimate the failure behavior of steam generator tubes with multiple cracks. The objective of this study is to verify the applicability of the optimum local failure prediction models proposed in the previous study. For this, plastic collapse tests are performed with the tube specimens containing two parallel through-wall cracks. The plastic collapse load of the steam generator tubes containing two parallel through-wall cracks are also estimated by using the proposed optimum global failure model and the applicability is investigated by comparing the estimated results with the experimental results. Also, the interaction effect between two cracks was evaluated to explain the plastic collapse behavior

  13. Geophysical Assessment of Two Collapsed and Concealed Septic ...

    African Journals Online (AJOL)

    ... m and depth of about 2.9 m. The delineated clayey soils at shallow depths suggest that there could be seasonal soil swelling and shrinkages due to seasonal variation in moisture content of the clay. These most likely led to annual ground movements, cumulative soil creep and the subsequent collapse of the septic tanks.

  14. Dangers of collapsible ventricular drainage systems. Technical note.

    Science.gov (United States)

    Kaye, A H; Wallace, D

    1982-02-01

    Ventricular drainage systems employing a collapsible plastic bag for fluid collection were postulated to cause an increasing back-pressure produced in part by the elasticity of the bag. This postulate was shown to be correct in an experimental situation. There was a logarithmic rise in cerebrospinal fluid pressure as the bag filled. By increasing the size of the bag, the problem was overcome.

  15. Prediction of the wetting-induced collapse behaviour using the soil-water characteristic curve

    Science.gov (United States)

    Xie, Wan-Li; Li, Ping; Vanapalli, Sai K.; Wang, Jia-Ding

    2018-01-01

    Collapsible soils go through three distinct phases in response to matric suction decrease during wetting: pre-collapse phase, collapse phase and post-collapse phase. It is reasonable and conservative to consider a strain path that includes a pre-collapse phase in which constant volume is maintained and a collapse phase that extends to the final matric suction to be experienced by collapsible soils during wetting. Upon this assumption, a method is proposed for predicting the collapse behaviour due to wetting. To use the proposed method, two parameters, critical suction and collapse rate, are required. The former is the suction value below which significant collapse deformations take place in response to matric suction decease, and the later is the rate at which void ratio reduces with matric suction in the collapse phase. The value of critical suction can be estimated from the water-entry value taking account of both the microstructure characteristics and collapse mechanism of fine-grained collapsible soils; the wetting soil-water characteristic curve thus can be used as a tool. Five sets of data of wetting tests on both compacted and natural collapsible soils reported in the literature were used to validate the proposed method. The critical suction values were estimated from the water-entry value with parameter a that is suggested to vary between 0.10 and 0.25 for compacted soils and to be lower for natural collapsible soils. The results of a field permeation test in collapsible loess soils were also used to validate the proposed method. The relatively good agreement between the measured and estimated collapse deformations suggests that the proposed method can provide reasonable prediction of the collapse behaviour due to wetting.

  16. Key variables influencing patterns of lava dome growth and collapse

    Science.gov (United States)

    Husain, T.; Elsworth, D.; Voight, B.; Mattioli, G. S.; Jansma, P. E.

    2013-12-01

    Lava domes are conical structures that grow by the infusion of viscous silicic or intermediate composition magma from a central volcanic conduit. Dome growth can be characterized by repeated cycles of growth punctuated by collapse, as the structure becomes oversized for its composite strength. Within these cycles, deformation ranges from slow long term deformation to sudden deep-seated collapses. Collapses may range from small raveling failures to voluminous and fast-moving pyroclastic flows with rapid and long-downslope-reach from the edifice. Infusion rate and magma rheology together with crystallization temperature and volatile content govern the spatial distribution of strength in the structure. Solidification, driven by degassing-induced crystallization of magma leads to the formation of a continuously evolving frictional talus as a hard outer shell. This shell encapsulates the cohesion-dominated soft ductile core. Here we explore the mechanics of lava dome growth and failure using a two-dimensional particle-dynamics model. This meshless model follows the natural evolution of a brittle carapace formed by loss of volatiles and rheological stiffening and avoids difficulties of hour-glassing and mesh-entangelment typical in meshed models. We test the fidelity of the model against existing experimental and observational models of lava dome growth. The particle-dynamics model follows the natural development of dome growth and collapse which is infeasible using simple analytical models. The model provides insight into the triggers that lead to the transition in collapse mechasnism from shallow flank collapse to deep seated sector collapse. Increase in material stiffness due to decrease in infusion rate results in the transition of growth pattern from endogenous to exogenous. The material stiffness and strength are strongly controlled by the magma infusion rate. Increase in infusion rate decreases the time available for degassing induced crystallization leading to a

  17. Intense electromagnetic outbursts from collapsing hypermassive neutron stars

    Science.gov (United States)

    Lehner, Luis; Palenzuela, Carlos; Liebling, Steven L.; Thompson, Christopher; Hanna, Chad

    2012-11-01

    We study the gravitational collapse of a magnetized neutron star using a novel numerical approach able to capture both the dynamics of the star and the behavior of the surrounding plasma. In this approach, a fully general relativistic magnetohydrodynamics implementation models the collapse of the star and provides appropriate boundary conditions to a force-free model which describes the stellar exterior. We validate this strategy by comparing with known results for the rotating monopole and aligned rotator solutions and then apply it to study both rotating and nonrotating stellar collapse scenarios and contrast the behavior with what is obtained when employing the electrovacuum approximation outside the star. The nonrotating electrovacuum collapse is shown to agree qualitatively with a Newtonian model of the electromagnetic field outside a collapsing star. We illustrate and discuss a fundamental difference between the force-free and electrovacuum solutions, involving the appearance of large zones of electric-dominated field in the vacuum case. This provides a clear demonstration of how dissipative singularities appear generically in the nonlinear time evolution of force-free fluids. In both the rotating and nonrotating cases, our simulations indicate that the collapse induces a strong electromagnetic transient, which leaves behind an uncharged, unmagnetized Kerr black hole. In the case of submillisecond rotation, the magnetic field experiences strong winding, and the transient carries much more energy. This result has important implications for models of gamma-ray bursts. Even when the neutron star is surrounded by an accretion torus (as in binary merger and collapsar scenarios), a magnetosphere may emerge through a dynamo process operating in a surface shear layer. When this rapidly rotating magnetar collapses to a black hole, the electromagnetic energy released can compete with the later output in a Blandford-Znajek jet. Much less electromagnetic energy is

  18. On the possibility of a two-bang supernova collapse

    International Nuclear Information System (INIS)

    Berezinsky, V.S.; Castagnoli, C.; Dokuchaev, V.I.; Galeotti, P.

    1988-01-01

    The possibility of a two-bang stellar collapse originating SN 1987a, and having the characteristics of the events recorded in Mont Blanc and Kamiokande, is discussed here. According to the ''standard'' collapse models of nonrotating stars, which predict the formation of a neutrino-sphere with a nondegenerate neutrino gas inside the star, the Mont Blanc and kamiokande data for the first burst give a too large stellar mass. On the contrary, a degenerate neutrino gas with low temperature T ∼ 0.5 MeV, and chemical potential μ ∼ (12-15), predicts a relatively low total energy outflow W ν ∼ (2-6) x 10 54 erg, and a small number of expected interactions in Kamiokande. A possible scenario is suggested: a massive (M ∼ 20M o ) rotating star is fragmented into two pieces, one light and the other heavy, at the onset of the collapse.The massive component collapses to a black hole, and produces the first burst. Neutrinos are trapped inside the collapsing star because of elastic scattering in the outer core off heavy nuclei, with A ∼ 300. It is shown that neutrinos fill up the quantum states, producing a degenerate neutrino gas. The second burst is explained by coalescence of the light fragment (M ∼ (1-3)M o ) onto the massive black hole. The time delay between the two observed bursts (4.7h) is mostly connected with gravitational braking, when the light fragment falls down onto the black hole, with an accompanying emission of gravitational waves for times of order of hours

  19. The neuroprotective effect of nicotine in Parkinson’s disease models is associated with inhibiting PARP-1 and caspase-3 cleavage

    Directory of Open Access Journals (Sweden)

    Justin Y.D. Lu

    2017-10-01

    Full Text Available Clinical evidence points to neuroprotective effects of smoking in Parkinson’s disease (PD, but the molecular mechanisms remain unclear. We investigated the pharmacological pathways involved in these neuroprotective effects, which could provide novel ideas for developing targeted neuroprotective treatments for PD. We used the ETC complex I inhibitor methylpyridinium ion (MPP+ to induce cell death in SH-SY5Y cells as a cellular model for PD and found that nicotine inhibits cell death. Using choline as a nicotinic acetylcholine receptor (nAChR agonist, we found that nAChR stimulation was sufficient to protect SH-SY5Y cells against cell death from MPP+. Blocking α7 nAChR with methyllycaconitine (MLA prevented the protective effects of nicotine, demonstrating that these receptors are necessary for the neuroprotective effects of nicotine. The neuroprotective effect of nicotine involves other pathways relevant to PD. Cleaved Poly (ADP-ribose polymerase-1 (PARP-1 and cleaved caspase-3 were decreased by nicotine in 6-hydroxydopamine (6-OHDA lesioned mice and in MPP+-treated SH-SY5Y cells. In conclusion, our data indicate that nicotine likely exerts neuroprotective effects in PD through the α7 nAChR and downstream pathways including PARP-1 and caspase-3. This knowledge could be pursued in future research to develop neuroprotective treatments for PD.

  20. Determination of karst collapse intensity indicator in area of nuclear power plant construction using incomplete data

    International Nuclear Information System (INIS)

    Sharapov, R

    2014-01-01

    The paper deals with the definition of karst collapse intensity. The technique for determining the intensity of karst formation and collapse on the basis of calculation and probabilistic method is given. Karst collapse formation is affected by a great variety of natural and anthropogenic factors. Each factor can vary quite widely. The paper describes a technique for determining karst collapse intensity from incomplete data. It uses karst processes monitoring data in the area and monitoring data of areas with similar values of the most significant factors leading to the karst collapses. The method used for determination of karst collapse intensity indicator in area of Nizhny Novgorod nuclear power plant construction

  1. Monte Carlo investigation of collapsed versus rotated IMRT plan verification.

    Science.gov (United States)

    Conneely, Elaine; Alexander, Andrew; Ruo, Russell; Chung, Eunah; Seuntjens, Jan; Foley, Mark J

    2014-05-08

    IMRT QA requires, among other tests, a time-consuming process of measuring the absorbed dose, at least to a point, in a high-dose, low-dose-gradient region. Some clinics use a technique of measuring this dose with all beams delivered at a single gantry angle (collapsed delivery), as opposed to the beams delivered at the planned gantry angle (rotated delivery). We examined, established, and optimized Monte Carlo simulations of the dosimetry for IMRT verification of treatment plans for these two different delivery modes (collapsed versus rotated). The results of the simulations were compared to the treatment planning system dose calculations for the two delivery modes, as well as to measurements taken. This was done in order to investigate the validity of the use of a collapsed delivery technique for IMRT QA. The BEAMnrc, DOSXYZnrc, and egs_chamber codes were utilized for the Monte Carlo simulations along with the MMCTP system. A number of different plan complexity metrics were also used in the analysis of the dose distributions in a bid to qualify why verification in a collapsed delivery may or may not be optimal for IMRT QA. Following the Alfonso et al. formalism, the kfclin,frefQclin,Q correction factor was calculated to correct the deviation of small fields from the reference conditions used for beam calibration. We report on the results obtained for a cohort of 20 patients. The plan complexity was investigated for each plan using the complexity metrics of homogeneity index, conformity index, modulation complexity score, and the fraction of beams from a particular plan that intersect the chamber when performing the QA. Rotated QA gives more consistent results than the collapsed QA technique. The kfclin,frefQclin,Qfactor deviates less from 1 for rotated QA than for collapsed QA. If the homogeneity index is less than 0.05 then the kfclin,frefQclin,Q factor does not deviate from unity by more than 1%. A value this low for the homogeneity index can only be obtained

  2. Distinct Element modeling of geophysical signatures during sinkhole collapse

    Science.gov (United States)

    Al-Halbouni, Djamil; Holohan, Eoghan P.; Taheri, Abbas; Dahm, Torsten

    2017-04-01

    A sinkhole forms due to the collapse of rocks or soil near the Earth's surface into an underground cavity. Such cavities represent large secondary pore spaces derived by dissolution and subrosion in the underground. By changing the stress field in the surrounding material, the growth of cavities can lead to a positive feedback, in which expansion and mechanical instability in the surrounding material increases or generates new secondary pore space (e.g. by fracturing), which in turn increases the cavity size, etc. A sinkhole forms due to the eventual subsidence or collapse of the overburden that becomes destabilized and fails all the way to the Earth's surface. Both natural processes like (sub)surface water movement and earthquakes, and human activities, such as mining, construction and groundwater extraction, intensify such feedbacks. The development of models for the mechanical interaction of a growing cavity and fracturing of its surrounding material, thus capturing related precursory geophysical signatures, has been limited, however. Here we report on the advances of a general, simplified approach to simulating cavity growth and sinkhole formation by using 2D Distinct Element Modeling (DEM) PFC5.0 software and thereby constraining pre-, syn- and post-collapse geophysical and geodetic signatures. This physically realistic approach allows for spontaneous cavity development and dislocation of rock mass to be simulated by bonded particle formulation of DEM. First, we present calibration and validation of our model. Surface subsidence above an instantaneously excavated circular cavity is tracked and compared with an incrementally increasing dissolution zone both for purely elastic and non-elastic material.This validation is important for the optimal choice of model dimensions and particles size with respect to simulation time. Second, a cavity growth approach is presented and compared to a well-documented case study, the deliberately intensified sinkhole collapse at

  3. Efficiency criterion for teleportation via channel matrix, measurement matrix and collapsed matrix

    Directory of Open Access Journals (Sweden)

    Xin-Wei Zha

    Full Text Available In this paper, three kinds of coefficient matrixes (channel matrix, measurement matrix, collapsed matrix associated with the pure state for teleportation are presented, the general relation among channel matrix, measurement matrix and collapsed matrix is obtained. In addition, a criterion for judging whether a state can be teleported successfully is given, depending on the relation between the number of parameter of an unknown state and the rank of the collapsed matrix. Keywords: Channel matrix, Measurement matrix, Collapsed matrix, Teleportation

  4. Coupled dynamics of translation and collapse of acoustically driven microbubbles.

    Science.gov (United States)

    Reddy, Anil J; Szeri, Andrew J

    2002-10-01

    Pressure gradients drive the motion of microbubbles relative to liquids in which they are suspended. Examples include the hydrostatic pressure due to a gravitational field, and the pressure gradients in a sound field, useful for acoustic levitation. In this paper, the equations describing the coupled dynamics of radial oscillation and translation of a microbubble are given. The formulation is based on a recently derived expression for the hydrodynamic force on a bubble of changing size in an incompressible liquid [J. Magnaudet and D. Legendre, Phys. Fluids 10, 550-556 (1998)]. The complex interaction between radial and translation dynamics is best understood by examination of the added momentum associated with the liquid motion caused by the moving bubble. Translation is maximized when the bubble collapses violently. The new theory for coupled collapse and translation dynamics is compared to past experiments and to previous theories for decoupled translation dynamics. Special attention is paid to bubbles of relevance in biomedical applications.

  5. Collapse of Non-Rectangular Channels in a Soft Elastomer

    Science.gov (United States)

    Tepayotl-Ramirez, Daniel; Park, Yong-Lae; Lu, Tong; Majidi, Carmel

    2013-03-01

    We examine the collapse of microchannels in a soft elastomer by treating the sidewalls as in- denters that penetrate the channel base. This approach leads to a closed-form algebraic mapping between applied pressure and cross-sectional deformation that are in strong agreement with ex- perimental measurements and Finite Element Analysis (FEA) simulation. Applications of this new approach to modeling soft microchannel collapse range from lab-on-a-chip microfluidics for pressure-controlled protein filtration to soft-matter pressures sensing. We demonstrate the latter by comparing theoretical predictions with experimental measurements of the pressure-controlled electrical resistance of liquid-phase Gallium alloy microchannels embedded in a soft silicone elas- tomer.

  6. Space shuttle solid rocket booster water entry cavity collapse loads

    Science.gov (United States)

    Keefe, R. T.; Rawls, E. A.; Kross, D. A.

    1982-01-01

    Solid rocket booster cavity collapse flight measurements included external pressures on the motor case and aft skirt, internal motor case pressures, accelerometers located in the forward skirt, mid-body area, and aft skirt, as well as strain gages located on the skin of the motor case. This flight data yielded applied pressure longitudinal and circumferential distributions which compare well with model test predictions. The internal motor case ullage pressure, which is below atmospheric due to the rapid cooling of the hot internal gas, was more severe (lower) than anticipated due to the ullage gas being hotter than predicted. The structural dynamic response characteristics were as expected. Structural ring and wall damage are detailed and are considered to be attributable to the direct application of cavity collapse pressure combined with the structurally destabilizing, low internal motor case pressure.

  7. Quantum gravitational collapse: non-singularity and non-locality

    International Nuclear Information System (INIS)

    Greenwood, Eric; Stojkovic, Dejan

    2008-01-01

    We investigate gravitational collapse in the context of quantum mechanics. We take primary interest in the behavior of the collapse near the horizon and near the origin (classical singularity) from the point of view of an infalling observer. In the absence of radiation, quantum effects near the horizon do not change the classical conclusions for an infalling observer, meaning the horizon is not an obstacle for him. However, quantum effects are able to remove the classical singularity at the origin, since the wave function is non-singular at the origin. Also, near the classical singularity, some non-local effects become important. In the Schrodinger equation describing behavior near the origin, derivatives of the wave function at one point are related to the value of the wave function at some other distant point.

  8. Gravitational perfect fluid collapse in Gauss-Bonnet gravity

    Energy Technology Data Exchange (ETDEWEB)

    Abbas, G.; Tahir, M. [The Islamia University of Bahawalpur, Department of Mathematics, Bahawalpur (Pakistan)

    2017-08-15

    The Einstein Gauss-Bonnet theory of gravity is the low-energy limit of heterotic super-symmetric string theory. This paper deals with gravitational collapse of a perfect fluid in Einstein-Gauss-Bonnet gravity by considering the Lemaitre-Tolman-Bondi metric. For this purpose, the closed form of the exact solution of the equations of motion has been determined by using the conservation of the stress-energy tensor and the condition of marginally bound shells. It has been investigated that the presence of a Gauss-Bonnet coupling term α > 0 and the pressure of the fluid modifies the structure and time formation of singularity. In this analysis a singularity forms earlier than a horizon, so the end state of the collapse is a naked singularity depending on the initial data. But this singularity is weak and timelike, which goes against the investigation of general relativity. (orig.)

  9. Quantum continual measurements and a posteriori collapse on CCR

    International Nuclear Information System (INIS)

    Belavkin, V.P.

    1992-01-01

    A quantum stochastic model for the Markovian dynamics of an open system under the nondemolition unsharp observation which is continuous in time, is given. A stochastic equation for the posterior evolution of a quantum continuously observed system is derived and the spontaneous collapse (stochastically continuous reduction of the wave packet) is described. The quantum Langevin evolution equation is solved for the case of a quasi-free Hamiltonian in the initial CCR algebra with a linear output channel, and the posterior dynamics corresponding to an initial Gaussian state is found. It is shown for an example of the posterior dynamics of a quantum oscillator that any mixed state under a complete nondemolition measurement collapses exponentially to a pure Gaussian one. (orig.)

  10. Heat flow during sawtooth collapse in tokamak plasmas

    International Nuclear Information System (INIS)

    Hanada, Kazuaki

    1994-01-01

    Heat flow during sawtooth collapse was studied on the WT-3 tokamak by using temporal evolution of soft X-ray intensity profile in the poloidal cross section in a lower hybrid current driven plasma as well as an electron cyclotron heated plasma. Two phase in sawtooth collapses were observed. In the first phases, the hottest spot that is the peak of the soft X-ray distribution approaches the inversion surface and heat flows out through a narrow gate on the inversion surface. In the second phase, the hottest spot stays on the inversion surface, and heat flows out through the whole inversion surface. This suggests that magnetic reconnection as predicted by Kadomtsev's model occurs in the first phase, but in the second phase, a different mechanism dominates heat flow. (author)

  11. Collapsing radiating stars with various equations of state

    Science.gov (United States)

    Brassel, Byron P.; Goswami, Rituparno; Maharaj, Sunil D.

    2017-06-01

    We study the gravitational collapse of radiating stars in the context of the cosmic censorship conjecture. We consider a generalized Vaidya spacetime with three concentric regions. The local internal atmosphere is a two-component system consisting of standard pressure-free, null radiation and an additional string fluid with energy density and nonzero pressure obeying all physically realistic energy conditions. The middle region is purely radiative which matches to a third region which is the Schwarzschild exterior. We outline the general mathematical framework to study the conditions on the mass function so that future-directed nonspacelike geodesics can terminate at the singularity in the past. Mass functions for several equations of state are analyzed using this framework and it is shown that the collapse in each case terminates at a locally naked central singularity. We calculate the strength of these singularities to show that they are strong curvature singularities which implies that no extension of spacetime through them is possible.

  12. The Strong Disjoint Blow-Up/Collapse Property

    Directory of Open Access Journals (Sweden)

    Héctor N. Salas

    2013-01-01

    Full Text Available Let be a topological vector space, and let be the algebra of continuous linear operators on . The operators are disjoint hypercyclic if there is such that the orbit is dense in . Bès and Peris have shown that if satisfy the Disjoint Blow-up/Collapse property, then they are disjoint hypercyclic. In a recent paper Bès, Martin, and Sanders, among other things, have characterized disjoint hypercyclic -tuples of weighted shifts in terms of this property. We introduce the Strong Disjoint Blow-up/Collapse property and prove that if satisfy this new property, then they have a dense linear manifold of disjoint hypercyclic vectors. This allows us to give a partial affirmative answer to one of their questions.

  13. Gravitational collapse and evolution of holographic black holes

    Energy Technology Data Exchange (ETDEWEB)

    Casadio, R [Dipartimento di Fisica, Universita di Bologna and I.N.F.N., Sezione di Bologna, via Irnerio 46, 40126 Bologna (Italy); Germani, C [D.A.M.T.P., Centre for Mathematical Sciences, University of Cambridge, Wilberforce road, Cambridge CB3 0WA (United Kingdom)

    2006-03-01

    Gravitational collapse is analyzed in the Brane-World by arguing that regularity of five-dimensional geodesics require that stars on the brane have an atmosphere. For the simple case of a spherically symmetric cloud of non-dissipating dust, conditions are found for which the collapsing star evaporates and approaches the Hawking behavior as the (apparent) horizon is being formed. The effective energy of the star vanishes at a finite radius and the star afterwards re-expands and 'anti-evaporates'. Israel junction conditions across the brane (holographically related to the matter trace anomaly) and the projection of the Weyl tensor on the brane (holographically interpreted as the quantum back-reaction on the brane metric) contribute to the total energy as, respectively, an 'anti-evaporation' and an 'evaporation' term.

  14. Rates of collapse and evaporation of globular clusters

    Science.gov (United States)

    Hut, Piet; Djorgovski, S.

    1992-01-01

    Observational estimates of the dynamical relaxation times of Galactic globular clusters are used here to estimate the present rate at which core collapse and evaporation are occurring in them. A core collapse rate of 2 +/- 1 per Gyr is found, which for a Galactic age of about 12 Gyr agrees well with the fact that 27 clusters have surface brightness profiles with the morphology expected for the postcollapse phase. A destruction and evaporation rate of 5 +/- 3 per Gyr is found, suggesting that a significant fraction of the Galaxy's original complement of globular clusters have perished through the combined effects of mechanisms such as relaxation-driven evaporation and shocking due to interaction with the Galactic disk and bulge.

  15. Fire-induced collapse mechanisms of steel buildings

    DEFF Research Database (Denmark)

    Giuliani, Luisa; Aiuti, Riccardo; Bontempi, Franco

    2013-01-01

    This paper presents a study on the failure modes of steel building in fire, with the aim of identify basic collapse mechanisms and design characteristics that play a role in the development and propagation of failures through the structural system. In particular, the effect of deformations...... and eigen-stresses induced by a restrained thermal expansion are not considered by current design methods and regulations, but are known to have driven the collapse of several steel and composite structures. In this study, the effect of restrained thermal expansions of steel beams exposed to fire...... is investigated with respect to two different structural typologies, i.e. single- and multi-story frames. In single-story buildings, such as car parks or industrial halls, the presence of stiff beams, typically required by large spans and higher service loads due to the different occupancy of the premises, may...

  16. Collapse of white dwarfs in low mass binary systems

    International Nuclear Information System (INIS)

    Isern, J.; Canal, R.; Garcia-Berro, E.; Hernanz, M.; Labay, J.

    1987-01-01

    Low-mass binary X-ray sources and cataclysmic variables are composed of a compact star plus a non-degenerate star with a mass of the order of 1 M sun . In the first case, the degenerate star is a neutron star. In the second case, the star is a white dwarf. The similarities of both systems are so high that it is worthwhile to look for the possibility of obtaining a neutron star from the collapse of a white dwarf that accretes matter. The present work shows that massive, initially cold white dwarfs can collapse non-explosively if they accrete mass at a rate greater than 1.0E-7 M sun per year. (Author)

  17. Kax and kol: Collapse and resilience in lowland Maya civilization

    Science.gov (United States)

    Dunning, Nicholas P.; Beach, Timothy P.; Luzzadder-Beach, Sheryl

    2012-01-01

    Episodes of population loss and cultural change, including the famous Classic Collapse, punctuated the long course of Maya civilization. In many cases, these downturns in the fortunes of individual sites and entire regions included significant environmental components such as droughts or anthropogenic environmental degradation. Some afflicted areas remained depopulated for long periods, whereas others recovered more quickly. We examine the dynamics of growth and decline in several areas in the Maya Lowlands in terms of both environmental and cultural resilience and with a focus on downturns that occurred in the Terminal Preclassic (second century Common Era) and Terminal Classic (9th and 10th centuries CE) periods. This examination of available data indicates that the elevated interior areas of the Yucatán Peninsula were more susceptible to system collapse and less suitable for resilient recovery than adjacent lower-lying areas. PMID:22371571

  18. Fast Radio Bursts from the Collapse of Strange Star Crusts

    Science.gov (United States)

    Zhang, Yue; Geng, Jin-Jun; Huang, Yong-Feng

    2018-05-01

    Fast radio bursts (FRBs) are transient radio sources at cosmological distances. No counterparts in other bands have been observed for non-repeating FRBs. Here we suggest the collapse of strange star (SS) crusts as a possible origin for FRBs. SSs, which are composed of almost equal numbers of u, d, and s quarks, may be encapsulated by a thin crust of normal hadronic matter. When a SS accretes matter from its environment, the crust becomes heavier and heavier. It may finally collapse, leading to the release of a large amount of magnetic energy and plenty of electron/positron pairs on a very short timescale. Electron/positron pairs in the polar cap region of the SS can be accelerated to relativistic velocities, streaming along the magnetic field lines to form a thin shell. FRBs are produced by coherent emission from these electrons when the shell is expanding. Basic characteristics of observed FRBs can be explained in our model.

  19. Gravitational collapse with rotating thin shells and cosmic censorship

    International Nuclear Information System (INIS)

    Delsate, Térence; Rocha, Jorge V; Santarelli, Raphael

    2015-01-01

    The study of gravitational collapse is a subject of great importance, both from an astrophysical and a holographic point of view. In this respect, exact solutions can be very helpful but known solutions are very scarce, especially when considering dynamical processes with rotation. We describe a setup in which gravitational collapse of rotating matter shells can be addressed with analytic tools, at the expense of going to higher dimensions and considering equal angular momenta spacetimes. The framework for an exact treatment of the dynamics, relying on a thin shell approximation, is developed. Our analysis allows the inclusion of a non-vanishing cosmological constant. Finally, we discuss applications of this machinery to the construction of stationary solutions describing matter around rotating black holes and to the cosmic censorship conjecture. (paper)

  20. Scalar field critical collapse in 2+1 dimensions

    OpenAIRE

    Jałmużna, Joanna; Gundlach, Carsten; Chmaj, Tadeusz

    2015-01-01

    We carry out numerical experiments in the critical collapse of a spherically symmetric massless scalar field in 2+1 spacetime dimensions in the presence of a negative cosmological constant and compare them against a new theoretical model. We approximate the true critical solution as the $n=4$ Garfinkle solution, matched at the lightcone to a Vaidya-like solution, and corrected to leading order for the effect of $\\Lambda