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Sample records for camptothecin induces escape

  1. Identification and replication of loci involved in camptothecin-induced cytotoxicity using CEPH pedigrees.

    Directory of Open Access Journals (Sweden)

    Venita Gresham Watson

    2011-05-01

    Full Text Available To date, the Centre d'Etude Polymorphism Humain (CEPH cell line model has only been used as a pharmacogenomic tool to evaluate which genes are responsible for the disparity in response to a single drug. The purpose of this study was demonstrate the model's ability to establish a specific pattern of quantitative trait loci (QTL related to a shared mechanism for multiple structurally related drugs, the camptothecins, which are Topoisomerase 1 inhibitors. A simultaneous screen of six camptothecin analogues for in vitro sensitivity in the CEPH cell lines resulted in cytotoxicity profiles and orders of potency which were in agreement with the literature. For all camptothecins studied, heritability estimates for cytotoxic response averaged 23.1 ± 2.6%. Nonparametric linkage analysis was used to identify a relationship between genetic markers and response to the camptothecins. Ten QTLs on chromosomes 1, 3, 5, 6, 11, 12, 16 and 20 were identified as shared by all six camptothecin analogues. In a separate validation experiment, nine of the ten QTLs were replicated at the significant and suggestive levels using three additional camptothecin analogues. To further refine this list of QTLs, another validation study was undertaken and seven of the nine QTLs were independently replicated for all nine camptothecin analogues. This is the first study using the CEPH cell lines that demonstrates that a specific pattern of QTLs could be established for a class of drugs which share a mechanism of action. Moreover, it is the first study to report replication of linkage results for drug-induced cytotoxicity using this model. The QTLs, which have been identified as shared by all camptothecins and replicated across multiple datasets, are of considerable interest; they harbor genes related to the shared mechanism of action for the camptothecins, which are responsible for variation in response.

  2. Identification and replication of loci involved in camptothecin-induced cytotoxicity using CEPH pedigrees.

    Science.gov (United States)

    Watson, Venita Gresham; Motsinger-Reif, Alison; Hardison, Nicholas E; Peters, Eric J; Havener, Tammy M; Everitt, Lorraine; Auman, James Todd; Comins, Daniel L; McLeod, Howard L

    2011-05-05

    To date, the Centre d'Etude Polymorphism Humain (CEPH) cell line model has only been used as a pharmacogenomic tool to evaluate which genes are responsible for the disparity in response to a single drug. The purpose of this study was demonstrate the model's ability to establish a specific pattern of quantitative trait loci (QTL) related to a shared mechanism for multiple structurally related drugs, the camptothecins, which are Topoisomerase 1 inhibitors. A simultaneous screen of six camptothecin analogues for in vitro sensitivity in the CEPH cell lines resulted in cytotoxicity profiles and orders of potency which were in agreement with the literature. For all camptothecins studied, heritability estimates for cytotoxic response averaged 23.1 ± 2.6%. Nonparametric linkage analysis was used to identify a relationship between genetic markers and response to the camptothecins. Ten QTLs on chromosomes 1, 3, 5, 6, 11, 12, 16 and 20 were identified as shared by all six camptothecin analogues. In a separate validation experiment, nine of the ten QTLs were replicated at the significant and suggestive levels using three additional camptothecin analogues. To further refine this list of QTLs, another validation study was undertaken and seven of the nine QTLs were independently replicated for all nine camptothecin analogues. This is the first study using the CEPH cell lines that demonstrates that a specific pattern of QTLs could be established for a class of drugs which share a mechanism of action. Moreover, it is the first study to report replication of linkage results for drug-induced cytotoxicity using this model. The QTLs, which have been identified as shared by all camptothecins and replicated across multiple datasets, are of considerable interest; they harbor genes related to the shared mechanism of action for the camptothecins, which are responsible for variation in response.

  3. Phenylbutyrate inhibits homologous recombination induced by camptothecin and methyl methanesulfonate

    DEFF Research Database (Denmark)

    Kaiser, Gitte Schalck; Germann, Susanne Manuela; Westergaard, Tine

    2011-01-01

    . Treatment with PBA is accompanied by a dramatic reduction in histone H4 lysine 8 acetylation. Live cell imaging of homologous recombination proteins indicates that repair of CPT-induced DNA damage is redirected to a non-recombinogenic pathway in the presence of PBA without loss in cell viability...

  4. Camptothecin resistance

    DEFF Research Database (Denmark)

    Brangi, M; Litman, Thomas; Ciotti, M

    1999-01-01

    The mitoxantrone resistance (MXR) gene encodes a recently characterized ATP-binding cassette half-transporter that confers multidrug resistance. We studied resistance to the camptothecins in two sublines expressing high levels of MXR: S1-M1-80 cells derived from parental S1 colon cancer cells...... and MCF-7 AdVp3,000 isolated from parental MCF-7 breast cancer cells. Both cell lines were 400- to 1,000-fold more resistant to topotecan, 9-amino-20(S)-camptothecin, and the active metabolite of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), than their parental cell lines. The cell lines...... demonstrated much less resistance to camptothecin and to several camptothecin analogues. Reduced accumulation and energy-dependent efflux of topotecan was demonstrated by confocal microscopy. A significant reduction in cleavable complexes in the resistant cells could be observed after SN-38 treatment...

  5. Noxa/Mcl-1 Balance Regulates Susceptibility of Cells to Camptothecin-Induced Apoptosis

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    Yide Mei

    2007-10-01

    Full Text Available Although camptothecin (CPT has been reported to induce apoptosis in various cancer cells, the molecular details of this regulation remain largely unknown. In this study, we demonstrate that 131-113-only protein Noxa is upregulated during CPT-induced apoptosis, which is independent of p53. In addition, we show that phosphatidylinositol 3-kinase (PI3K/Akt signaling pathway is responsible for Noxa's induction. Luciferase assay, cAMP response element binding protein (CREB knockdown experiments further demonstrate that CREB is involved in the transcriptional upregulation of Noxa. Moreover, blocking Noxa expression using specific small interfering ribonucleic acid (siRNA significantly reduces the apoptosis in response to CPT, indicating that Noxa is an essential mediator for CPT-induced apoptosis. Interestingly, antiapoptotic Mcl-1 was also upregulated through PI3K/Akt signaling pathway upon CPT treatment. Using immunoprecipitation assay, Noxa was found to interact with Mcl-1 in the presence or absence of CPT. Knockdown of Mcl-1 expression by short hairpin ribonucleic acid (shRNA was shown to potentiate CPT-induced apoptosis. Consistently, ectopic overexpression of Mcl-1 rescued cells from apoptosis induced by CPT. Cells coexpressing Noxa, Mcl-1 at different ratio correlates well with the extent of apoptosis, suggesting that the balance between Noxa, Mcl-1 may determine the susceptibility of HeLa cells to CPT-induced apoptosis.

  6. Gene homozygosis and mitotic recombination induced by camptothecin and irinotecan in Aspergillus nidulans diploid cells

    OpenAIRE

    GIOVANA N.M. ESQUISSATO; SANT'ANNA,JULIANE R. DE; CLAUDINÉIA C.S. FRANCO; ROSADA, LÚCIA J.; PAULA A.S.R. DOS SANTOS; Marialba A. A. Castro-Prado

    2014-01-01

    Mitotic recombination is a process involved in carcinogenesis which can lead to genetic loss through the loss of heterozygosity. The recombinogenic potentials of two anticancer drugs topoisomerase I inhibitors, camptothecin (CPT) and irinotecan (CPT-11), were evaluated in the present study. The homozygotization assay, which assess the induction of mitotic recombination and gene homozygosis, as well as the heterozygous A757//UT448 diploid strain of Aspergillus nidulans were employed. The three...

  7. Paclitaxel-induced apoptosis is blocked by camptothecin in human breast and pancreatic cancer cells.

    Science.gov (United States)

    Jeansonne, Duane P; Koh, Gar Yee; Zhang, Fang; Kirk-Ballard, Heather; Wolff, Laura; Liu, Dong; Eilertsen, Kenneth; Liu, Zhijun

    2011-05-01

    The combination of paclitaxel (PTX) and topoisomerase I inhibitors such as camptothecin (CPT) constitutes a therapeutic strategy based on anticipated synergism. However, previous in vitro studies have generated contradictory findings for this strategy. The interaction between these drugs can be synergistic or antagonistic, depending on the cell type examined. To gain additional insight into this promising yet controversial strategy, we investigated the interaction between PTX and CPT in three different cell lines (PANC-1, MDA-MB-231 and HL-60) and explored possible underlying mechanisms of synergy or antagonism. Using a novel solubilizing natural compound, rubusoside, water-insoluble PTX and CPT were solubilized to enable the comparison of the effects of single drugs and their combination on cell viability. Intracellular drug concentrations were quantified to examine the effect of CPT on cellular uptake and accumulation of PTX. Flow cytometry and quantitative real-time PCR gene array analyses were used to explore the mechanisms behind the interaction between PTX and CPT. Our studies confirmed that rubusoside-solubilized PTX or CPT maintained cytotoxicity, causing significant reductions in cell viability. However, the efficacy of the combination of PTX and CPT produced varied results based on the cell line tested. CPT antagonistically reduced the cytotoxic activity of PTX in PANC-1 and MDA-MB-231 cells. The effect of CPT on the cytotoxicity of PTX was less pronounced in HL-60 cells, showing neither synergy nor antagonism. Analysis of apoptosis by flow cytometry revealed that upon co-treatment with CPT, apoptosis induced by PTX was attenuated in PANC-1 and MDA-MB-231 cells. In agreement with our cytotoxicity findings, no synergistic or antagonistic effects on apoptosis were observed in HL-60 cells. The antagonism in PANC-1 and MDA-MB-231 cells was not a result of reduced PTX uptake and accumulation because the amount of intracellular PTX was not altered upon co

  8. Low toxic and high soluble camptothecin derivative 2–47 effectively induces apoptosis of tumor cells in vitro

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    Zhou, Yao; Zhao, Hong-Ye; Jiang, Du; Wang, Lu-Yao; Xiang, Cen; Wen, Shao-Peng [Key Laboratory of Industrial Fermentation Microbiology, Tianjin Key Laboratory of Industrial Microbiology, Sino-French Joint Laboratory of Food Nutrition, Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin 300457 (China); Fan, Zhen-Chuan [Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology, Ministry of Education, Tianjin, 300457 (China); Obesita & Algaegen LLC, College Station, TX 77845 (United States); Zhang, Yong-Min [Université Pierre et Marie Curie-Paris 6, Institut Parisien de Chimie Moléculaire UMR CNRS 8232, 4 place Jussieu, 75005, Paris (France); Guo, Na [Key Laboratory of Industrial Fermentation Microbiology, Tianjin Key Laboratory of Industrial Microbiology, Sino-French Joint Laboratory of Food Nutrition, Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin 300457 (China); Teng, Yu-Ou, E-mail: tyo201485@tust.edu.cn [Key Laboratory of Industrial Fermentation Microbiology, Tianjin Key Laboratory of Industrial Microbiology, Sino-French Joint Laboratory of Food Nutrition, Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin 300457 (China); Yu, Peng, E-mail: yupeng@tust.edu.cn [Key Laboratory of Industrial Fermentation Microbiology, Tianjin Key Laboratory of Industrial Microbiology, Sino-French Joint Laboratory of Food Nutrition, Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin 300457 (China)

    2016-04-08

    The cytotoxic activity of camptothecin derivatives is so high that these compounds need to be further modified before their successful application as anti-cancer agents clinically. In this study, we reported the synthesis and biological evaluation of a novel camptothecin derivative called compound 2–47. The changes in structure did not reduce its activity to inhibit DNA topoisomerase I. Compound 2–47 induced apoptosis of many tumor cells including leukemia cells K562, Jurkat, HL-60, breast cancer cell BT-549, colon cancer cell HT-29 and liver cancer cell HepG2 with a half maximal inhibitory concentration (IC{sub 50}) of 2- to 3-fold lower than HCPT as a control. In particular, 2–47 inhibited the proliferation of Jurkat cells with an IC{sub 50} of as low as 40 nM. By making use of Jurkat cell as a model, following treatment of Jurkat cells, compound 2–47 activated caspase-3 and PARP, resulting in a decreased Bcl-2/Bax ratio. These data showed that compound 2–47 induces Jurkat cell death through the mitochondrial apoptotic pathway. In addition, compound 2–47 showed a decreased cytotoxic activity against normal cells and an improved solubility in low-polar solvent. For example, compound 2–47 solutes in CHCl{sub 3} 130-fold higher than HCPT. Taken together, our data demonstrated that camptothecin derivative 2–47 notably inhibits the tumor cell proliferation through mitochondrial-mediated apoptosis in vitro. - Highlights: • Compound 2–47 showed a wide inhibitory effect on the tested tumor cell lines with an IC{sub 50} of 3 times lower than that of HCPT in general. • Compound 2–47 inhibited the proliferation of the human leukemia cell Jurkat at an IC{sub 50} of as low as 40 nM. • As compared to HCPT, compound 2–47 showed much reduced cytotoxicity on normal human cells. • As compared to others, compound 2–47 showed a hundreds-fold higher solubility in non-polar organic solution.

  9. Protein kinase C{eta} activates NF-{kappa}B in response to camptothecin-induced DNA damage

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    Raveh-Amit, Hadas; Hai, Naama; Rotem-Dai, Noa; Shahaf, Galit [The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, The Cancer Research Center, Ben-Gurion University of the Negev (Israel); Gopas, Jacob [The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, The Cancer Research Center, Ben-Gurion University of the Negev (Israel); The Department of Oncology, Soroka University Medical Center, Beer-Sheva 84105 (Israel); Livneh, Etta, E-mail: etta@bgu.ac.il [The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, The Cancer Research Center, Ben-Gurion University of the Negev (Israel)

    2011-08-26

    Highlights: {yields} Protein kinase C-eta (PKC{eta}) is an upstream regulator of the NF-{kappa}B signaling pathway. {yields} PKC{eta} activates NF-{kappa}B in non-stressed conditions and in response to DNA damage. {yields} PKC{eta} regulates NF-{kappa}B by activating I{kappa}B kinase (IKK) and inducing I{kappa}B degradation. -- Abstract: The nuclear factor {kappa}B (NF-{kappa}B) family of transcription factors participates in the regulation of genes involved in innate- and adaptive-immune responses, cell death and inflammation. The involvement of the Protein kinase C (PKC) family in the regulation of NF-{kappa}B in inflammation and immune-related signaling has been extensively studied. However, not much is known on the role of PKC in NF-{kappa}B regulation in response to DNA damage. Here we demonstrate for the first time that PKC-eta (PKC{eta}) regulates NF-{kappa}B upstream signaling by activating the I{kappa}B kinase (IKK) and the degradation of I{kappa}B. Furthermore, PKC{eta} enhances the nuclear translocation and transactivation of NF-{kappa}B under non-stressed conditions and in response to the anticancer drug camptothecin. We and others have previously shown that PKC{eta} confers protection against DNA damage-induced apoptosis. Our present study suggests that PKC{eta} is involved in NF-{kappa}B signaling leading to drug resistance.

  10. Camptothecin inhibits platelet-derived growth factor-BB-induced proliferation of rat aortic vascular smooth muscle cells through inhibition of PI3K/Akt signaling pathway

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    Park, Eun-Seok [Department of Applied Biochemistry, Division of Life Science, College of Health and Biomedical Science, Konkuk University, Chungju, Chungbuk (Korea, Republic of); Kang, Shin-il [College of Pharmacy Medical Research Center, Chungbuk National University, Cheongju (Korea, Republic of); Yoo, Kyu-dong [Hazardous Substances Analysis Division, Gwangju Regional Food and Drug Administration, Gwangju (Korea, Republic of); Lee, Mi-Yea [Department of Nursing Kyungbok University, Pocheon (Korea, Republic of); Yoo, Hwan-Soo; Hong, Jin-Tae [College of Pharmacy Medical Research Center, Chungbuk National University, Cheongju (Korea, Republic of); Shin, Hwa-Sup [Department of Applied Biochemistry, Division of Life Science, College of Health and Biomedical Science, Konkuk University, Chungju, Chungbuk (Korea, Republic of); Kim, Bokyung [Department of Physiology, Konkuk Medical School, Konkuk University, Chungju, Chungbuk (Korea, Republic of); Yun, Yeo-Pyo, E-mail: ypyun@chungbuk.ac.kr [College of Pharmacy Medical Research Center, Chungbuk National University, Cheongju (Korea, Republic of)

    2013-04-15

    The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial wall is a major cause of vascular disorders such as atherosclerosis and restenosis after angioplasty. In this study, we investigated not only the inhibitory effects of camptothecin (CPT) on PDGF-BB-induced VSMC proliferation, but also its molecular mechanism of this inhibition. CPT significantly inhibited proliferation with IC50 value of 0.58 μM and the DNA synthesis of PDGF-BB-stimulated VSMCs in a dose-dependent manner (0.5–2 μM ) without any cytotoxicity. CPT induced the cell cycle arrest at G0/G1 phase. Also, CPT decreased the expressions of G0/G1-specific regulatory proteins including cyclin-dependent kinase (CDK)2, cyclin D1 and PCNA in PDGF-BB-stimulated VSMCs. Pre-incubation of VSMCs with CPT significantly inhibited PDGF-BB-induced Akt activation, whereas CPT did not affect PDGF-receptor beta phosphorylation, extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and phospholipase C (PLC)-γ1 phosphorylation in PDGF-BB signaling pathway. Our data showed that CPT pre-treatment inhibited VSMC proliferation, and that the inhibitory effect of CPT was enhanced by LY294002, a PI3K inhibitor, on PDGF-BB-induced VSMC proliferation. In addition, inhibiting the PI3K/Akt pathway by LY294002 significantly enhanced the suppression of PCNA expression and Akt activation by CPT. These results suggest that the anti-proliferative activity of CPT is mediated in part by downregulating the PI3K/Akt signaling pathway. - Highlights: ► CPT inhibits proliferation of PDGF-BB-induced VSMC without cytotoxicity. ► CPT arrests the cell cycle in G0/G1 phase by downregulation of cyclin D1 and CDK2. ► CPT significantly attenuates Akt phosphorylation in PDGF-BB signaling pathway. ► LY294002 enhanced the inhibitory effect of CPT on VSMC proliferation. ► Thus, CPT is mediated by downregulating the PI3K/Akt signaling pathway.

  11. Metastatic Tumor Dormancy in Cutaneous Melanoma: Does Surgery Induce Escape?

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    Tseng, William W. [Department of Surgery, University of California at San Francisco, 513 Parnassus Avenue, Room S-321, San Francisco, CA 94143 (United States); Fadaki, Niloofar; Leong, Stanley P., E-mail: leongsx@cpmcri.org [Department of Surgery and Center for Melanoma Research and Treatment, California Pacific Medical Center and Research Institute, 2340 Clay Street, 2nd floor, San Francisco, CA 94115 (United States)

    2011-02-21

    According to the concept of tumor dormancy, tumor cells may exist as single cells or microscopic clusters of cells that are clinically undetectable, but remain viable and have the potential for malignant outgrowth. At metastatic sites, escape from tumor dormancy under more favorable local microenvironmental conditions or through other, yet undefined stimuli, may account for distant recurrence after supposed “cure” following surgical treatment of the primary tumor. The vast majority of evidence to date in support of the concept of tumor dormancy originates from animal studies; however, extensive epidemiologic data from breast cancer strongly suggests that this process does occur in human disease. In this review, we aim to demonstrate that metastatic tumor dormancy does exist in cutaneous melanoma based on evidence from mouse models and clinical observations of late recurrence and occult transmission by organ transplantation. Experimental data underscores the critical role of impaired angiogenesis and immune regulation as major mechanisms for maintenance of tumor dormancy. Finally, we examine evidence for the role of surgery in promoting escape from tumor dormancy at metastatic sites in cutaneous melanoma.

  12. Metastatic Tumor Dormancy in Cutaneous Melanoma: Does Surgery Induce Escape?

    Directory of Open Access Journals (Sweden)

    William W. Tseng

    2011-02-01

    Full Text Available According to the concept of tumor dormancy, tumor cells may exist as single cells or microscopic clusters of cells that are clinically undetectable, but remain viable and have the potential for malignant outgrowth. At metastatic sites, escape from tumor dormancy under more favorable local microenvironmental conditions or through other, yet undefined stimuli, may account for distant recurrence after supposed “cure” following surgical treatment of the primary tumor. The vast majority of evidence to date in support of the concept of tumor dormancy originates from animal studies; however, extensive epidemiologic data from breast cancer strongly suggests that this process does occur in human disease. In this review, we aim to demonstrate that metastatic tumor dormancy does exist in cutaneous melanoma based on evidence from mouse models and clinical observations of late recurrence and occult transmission by organ transplantation. Experimental data underscores the critical role of impaired angiogenesis and immune regulation as major mechanisms for maintenance of tumor dormancy. Finally, we examine evidence for the role of surgery in promoting escape from tumor dormancy at metastatic sites in cutaneous melanoma.

  13. Increased alpha2,3-sialylation and hyperglycosylation of N-glycans in embryonic rat cortical neurons during camptothecin-induced apoptosis.

    Science.gov (United States)

    Kim, Sung-Min; Lee, Jung-Sun; Lee, Yoon-Hee; Kim, Woo-Jung; Do, Su-Il; Choo, Young-Kug; Park, Yong-Il

    2007-12-31

    Alterations in the glycan chains of cell surface glycoconjugates are frequently involved biological processes such as cell-cell interaction, cell migration, differentiation and development. Cultured embryonic (E18) rat cortical neurons underwent apoptosis in response to camptothecin, and lectin histochemistry showed that binding to apoptotic neurons of FITC-conjugated Maackia amurensis agglutinin (MAA), which is specific for terminal alpha2,3-sialic acid residues, increased progressively with increasing concentrations of camptothecin. Analysis of the total proteins of apoptotic neurons by SDS-PAGE, and lectin blotting using HRP-labeled MAA, revealed that the expression of terminal alpha2,3-sialic acid residues on an unknown protein with an apparent molecular mass of 25.6 kDa also increased in apoptotic neurons. NP-HPLC analysis of the total cellular N-glycans of normal and apoptotic neurons demonstrated that the expression of structurally simpler biantennary types of N-glycans fell by 49% during apoptosis whereas the more branched triantennary types of N-glycans with terminal sialic acid residues increased by up to 59%. These results suggest that increased surface expression of alpha2,3-sialic acid residues and hyperglycosylation of N-glycans is a common feature of cellular responses to changes in cell physiology such as tumorigenesis and apoptosis.

  14. PAX3-FKHR sensitizes human alveolar rhabdomyosarcoma cells to camptothecin-mediated growth inhibition and apoptosis

    Science.gov (United States)

    Zeng, Fu-Yue; Cui, Jimmy; Liu, Lingling; Chen, Taosheng

    2009-01-01

    Patients with alveolar rhabdomyosarcoma (ARMS) have poorer response to conventional chemotherapy and lower survival rates than those with embryonal RMS (ERMS). By high-throughput screening, we identified camptothecin as an ARMS-selective inhibitor. Camptothecin more efficiently inhibited proliferation and induced apoptosis in Rh30 (ARMS) than RD (ERMS) cells. Ectopic expression of the PAX3-FKHR (PF) fusion protein in RD cells significantly increased sensitivity, whereas siRNA knockdown of PF decreased sensitivity of Rh30 cells to camptothecin. The sensitization required a transcriptionally active PF, and camptothecin downregulated levels of PF protein. These findings suggest that it is feasible to develop agents that preferentially block the growth of ARMS. PMID:19442434

  15. Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin is p53-independent

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    Funanage Vicky L

    2009-05-01

    Full Text Available Abstract Background Deletion or mutation(s of the survival motor neuron 1 (SMN1 gene causes spinal muscular atrophy (SMA. The SMN protein is known to play a role in RNA metabolism, neurite outgrowth, and cell survival. Yet, it remains unclear how SMN deficiency causes selective motor neuron death and muscle atrophy seen in SMA. Previously, we have shown that skin fibroblasts from SMA patients are more sensitive to the DNA topoisomerase I inhibitor camptothecin, supporting a role for SMN in cell survival. Here, we examine the potential mechanism of camptothecin sensitivity in SMA fibroblasts. Results Camptothecin treatment reduced the DNA relaxation activity of DNA topoisomerase I in human fibroblasts. In contrast, kinase activity of DNA topoisomerase I was not affected by camptothecin, because levels of phosphorylated SR proteins were not decreased. Upon camptothecin treatment, levels of p53 were markedly increased. To determine if p53 plays a role in the increased sensitivity of SMA fibroblasts to camptothecin, we analyzed the sensitivity of SMA fibroblasts to another DNA topoisomerase I inhibitor, β-lapachone. This compound is known to induce death via a p53-independent pathway in several cancer cell lines. We found that β-lapachone did not induce p53 activation in human fibroblasts. In addition, SMA and control fibroblasts showed essentially identical sensitivity to this compound. By immunofluorescence staining, SMN and p53 co-localized in gems within the nucleus, and this co-localization was overall reduced in SMA fibroblasts. However, depletion of p53 by siRNA did not lessen the camptothecin sensitivity in SMA fibroblasts. Conclusion Even though p53 and SMN are associated, the increased sensitivity of SMA fibroblasts to camptothecin does not occur through a p53-dependent mechanism.

  16. Heat-induced symmetry breaking in ant (Hymenoptera: Formicidae escape behavior.

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    Yuan-Kai Chung

    Full Text Available The collective egress of social insects is important in dangerous situations such as natural disasters or enemy attacks. Some studies have described the phenomenon of symmetry breaking in ants, with two exits induced by a repellent. However, whether symmetry breaking occurs under high temperature conditions, which are a common abiotic stress, remains unknown. In our study, we deposited a group of Polyrhachis dives ants on a heated platform and counted the number of escaping ants with two identical exits. We discovered that ants asymmetrically escaped through two exits when the temperature of the heated platform was >32.75°C. The degree of asymmetry increased linearly with the temperature of the platform. Furthermore, the higher the temperature of heated platform was, the more ants escaped from the heated platform. However, the number of escaping ants decreased for 3 min when the temperature was higher than the critical thermal limit (39.46°C, which is the threshold for ants to endure high temperature without a loss of performance. Moreover, the ants tended to form small groups to escape from the thermal stress. A preparatory formation of ant grouping was observed before they reached the exit, indicating that the ants actively clustered rather than accidentally gathered at the exits to escape. We suggest that a combination of individual and grouping ants may help to optimize the likelihood of survival during evacuation.

  17. PEGylated versus non-PEGylated magnetic nanoparticles as camptothecin delivery system

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    Paula M. Castillo

    2014-08-01

    Full Text Available Camptothecin (CPT; (S-(+-4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H-dione is a highly cytotoxic natural alkaloid that has not yet found use as chemotherapeutic agent due to its poor water-solubility and chemical instability and, as a consequence, no effective administration means have been designed. In this work, camptothecin has been successfully loaded into iron oxide superparamagnetic nanoparticles with an average size of 14 nm. It was found that surface modification of the nanoparticles by polyethylene glycol enables loading a large amount of camptothecin. While the unloaded nanoparticles do not induce apoptosis in the H460 lung cancer cell line, the camptothecin-loaded nanoparticle formulations exhibit remarkable pro-apoptotic activity. These results indicate that camptothecin retains its biological activity after loading onto the magnetic nanoparticles. The proposed materials represent novel materials based on naturally occurring bioactive molecules loaded onto nanoparticles to be used as chemotherapeutic formulations. The procedure seems apt to be extended to other active molecules extracted from natural products. In addition, these materials offer the potential of being further implemented for combined imaging and therapeutics, as magnetic nanoparticles are known to be multifunctional tools for biomedicine.

  18. Genomic profiling in CEPH cell lines distinguishes between the camptothecins and indenoisoquinolines.

    Science.gov (United States)

    Watson, Venita Gresham; Hardison, Nicholas E; Harris, Tyndall; Motsinger-Reif, Alison; McLeod, Howard L

    2011-10-01

    We have attempted to use a familial genetics strategy to study mechanisms of topoisomerase 1 (Top1) inhibition. Investigations have steadily been chipping away at the pathways involved in cellular response following Top1 inhibition for more than 20 years. Our system-wide approach, which phenotypes a collection of genotyped human cell lines for sensitivity to compounds and interrogates all genes and molecular pathways simultaneously. Previously, we characterized the in vitro sensitivity of 15 families of Centre d'Etude Polymorphisme Humain (CEPH) cell lines (n = 142) to 9 camptothecin analogues. Linkage analysis revealed a pattern of 7 quantitative trait loci (QTL) shared by all of the camptothecins. To identify which, if any, QTLs are related to the general mechanism of Top1 inhibition or should be considered camptothecin specific, we characterized the in vitro sensitivity of the same panel of CEPH cell lines to the indenisoquinolones, a structurally distinct class of Top1 inhibitors. Four QTLs on chromosomes 1, 5, 11, and 16 were shared by both the camptothecins and the indenoisoquinolines and are considered associated with the general mechanism of Top1 inhibition. The remaining 3 QTLs (chromosomes 6 and 20) are considered specific to camptothecin-induced cytotoxicity. Finally, 8 QTLs were identified, which were unique to the indenoisoquinolines.

  19. Effects of over-expression of allene oxide cyclase on camptothecin ...

    African Journals Online (AJOL)

    Camptothecin (CPT) is an anticancer and antiviral monoterpene-derived indole alkaloid which can be induced by plant hormone, jasmonates. To improve the production of the pharmaceuticals, the jasmonate biosynthesis related gene allene oxide cyclase from Camptotheca acuminate was transferred back into C.

  20. Nanobiohybrids as delivery vehicles for camptothecin.

    Science.gov (United States)

    Tyner, Katherine M; Schiffman, Scott R; Giannelis, Emmanuel P

    2004-03-24

    A novel method of delivering non-ionic, poorly water-soluble drugs such as campthothecin was developed. Camptothecin was first incorporated into micelles derived from negatively charged surfactants. The negatively charged micelles were then encapsulated in nanoparticles of magnesium-aluminum layered double hydroxides (LDHs) by an ion exchange process. The resulting nanobiohybrids released camptothecin rapidly with complete release within 10 min at both pH 4.8 and 7.2. The LDH complex with carmine released carmine within 30 min at pH 4.8, but took over 70 days at pH 7.2. When administered to Glioma cells in vitro, the nanobiohybrid containing camptothecin resulted in significantly lower survival times compared to untreated cells, or to cells incubated with the surfactant, the pristine LDH, or water (delivery medium). The encapsulation method allowed for an approximately threefold increase in solubility of camptothecin. In addition, the modification of the surface of the LDH provided potential site-directing of the nanohybrids. These enhancements to the delivery scheme suggest the potential use of these hybrids for a variety of drug therapies.

  1. Characterization and antitumor activity of camptothecin from ...

    African Journals Online (AJOL)

    Background: Camptothecin (CPT) is a potent drug against cancers, originally from plants. The endophytic fungi could produce the secondary metabolite same as the host and is used as medicine. Objectives: The aim of this paper was to investigate an endophytic fungal CPT with anti-neoplastic activity. Methods: Endophytic ...

  2. Characterization and antitumor activity of camptothecin from ...

    African Journals Online (AJOL)

    Abstract. Background: Camptothecin (CPT) is a potent drug against cancers, originally from plants. The endophytic fungi could produce ... Thus, the endophytic fungi in C. acuminata plant are expected to be a potential source for CPT or new .... amined under short wave ultraviolet rays. A band had the same chromatographic ...

  3. Solar cycle dynamic of the Martian induced magnetosphere. Planetary ions acceleration zones and escape.

    Science.gov (United States)

    Fedorov, Andrey; Modolo, Ronan; Jarvinen, Riku; Barabash, Stas

    2016-10-01

    This work presents a massive statistical analysis of the ion flows in the Martian induced magnetosphere. We performed this analysis using Mars Express ion mass spectrometer data taken during 2008 - 2013 time interval. This data allows to make an enhanced study of the induced magnetosphere variations as a response of the solar activity level. Since Mars Express has no onboard magnetometer, we used the hybrid models of the Martian plasma environment to get a proper frame to make an adequate statistics of the magnetospheric response. In this paper we present a spatial distribution of the planetary plasma properties in the planetary wake as well as the ionosospheric escape as a function of the solar activity.

  4. Mutator suppression and escape from replication error-induced extinction in yeast.

    Directory of Open Access Journals (Sweden)

    Alan J Herr

    2011-10-01

    Full Text Available Cells rely on a network of conserved pathways to govern DNA replication fidelity. Loss of polymerase proofreading or mismatch repair elevates spontaneous mutation and facilitates cellular adaptation. However, double mutants are inviable, suggesting that extreme mutation rates exceed an error threshold. Here we combine alleles that affect DNA polymerase δ (Pol δ proofreading and mismatch repair to define the maximal error rate in haploid yeast and to characterize genetic suppressors of mutator phenotypes. We show that populations tolerate mutation rates 1,000-fold above wild-type levels but collapse when the rate exceeds 10⁻³ inactivating mutations per gene per cell division. Variants that escape this error-induced extinction (eex rapidly emerge from mutator clones. One-third of the escape mutants result from second-site changes in Pol δ that suppress the proofreading-deficient phenotype, while two-thirds are extragenic. The structural locations of the Pol δ changes suggest multiple antimutator mechanisms. Our studies reveal the transient nature of eukaryotic mutators and show that mutator phenotypes are readily suppressed by genetic adaptation. This has implications for the role of mutator phenotypes in cancer.

  5. Heterogeneity in MYC-induced mammary tumors contributes to escape from oncogene dependence.

    Science.gov (United States)

    Leung, J Y; Andrechek, E R; Cardiff, R D; Nevins, J R

    2012-05-17

    A hallmark of human cancer is heterogeneity, reflecting the complex series of changes resulting in the activation of oncogenes coupled with inactivation of tumor suppressor genes. Breast cancer is no exception and indeed, many studies have revealed considerable complexity and heterogeneity in the population of primary breast tumors and substantial changes in a recurrent breast tumor that has acquired metastatic properties and drug resistance. We have made use of a Myc-inducible transgenic mouse model of breast cancer in which elimination of Myc activity following tumor development initially leads to a regression of a subset of tumors generally followed by de novo Myc-independent growth. We have observed that tumors that grow independent of Myc expression have gene profiles that are distinct from the primary tumors with characteristics indicative of an epithelial-mesenchymal transition (EMT) phenotype. Phenotypic analyses of Myc-independent tumors confirm the acquisition of an EMT phenotype suggested to be associated with invasive and migratory properties in human cancer cells. Further genomic analyses reveal mouse mammary tumors growing independent of myc have a higher probability of exhibiting a gene signature similar to that observed for human 'tumor-initiating' cells. Collectively, the data reveal genetic alterations that underlie tumor progression and an escape from Myc-dependent growth in a transgenic mouse model that can provide insights to what occurs in human cancers as they acquire drug resistance and metastatic properties.

  6. DHA but not EPA, enhances sound induced escape behavior and Mauthner cells activity in Sparus aurata.

    Science.gov (United States)

    Benítez-Santana, Tibiábin; Atalah, Eyad; Betancor, Mónica Beatriz; Caballero, María José; Hernández-Cruz, Carmen Mari; Izquierdo, Marisol

    2014-01-30

    Dietary omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have a marked effect on fish behavior. There is limited information on the mechanisms involved in this effect and its relation to neuron development and functioning. Deficiency of n-3 LCPUFA reduces fish escape swimming. Mauthner cells (M-cell) are neurons responsible for initiating an escape response. The aim was to compare the effect of dietary DHA and EPA on escape behavior and neuronal activity of sea bream larvae. We studied burst swimming speed as a measure of behavior. M-cell activity was studied by ChAT immuno-fluorescence. Feeding the lowest n-3 LCPUFA levels a lower burst swimming speed. Increase in dietary EPA did not significantly improve escape response. Elevation of dietary DHA was correlated with a higher burst speed denoting the importance of this nutrient for escape swimming. Incorporation of DHA into larval tissues was proportional to DHA dietary levels and significantly correlated with burst speed. In addition, a higher immunoreactivity to ChAT, associated to a higher neural activity, was found in M-cell of larvae fed higher dietary DHA contents. These results show first evidence of n-3 LCPUFA on fish neuronal activity and their implications in behavior, denoting that DHA boosts escape swimming and this effect is at least partly mediated by the increase in neural activity of M-cell. © 2013.

  7. Noise-induced escape from attractors in one-dimensional maps

    Science.gov (United States)

    Beale, Paul D.

    1989-10-01

    The addition of external noise to a dynamical system described by an iterated map causes the orbit to escape from the attractor. The escape time τ has the behavior τ~=τ0exp(E0/Γ), where Γ is the noise temperature, E0 is the minimum escape energy, and τ0 is the inverse of the attempt rate. We will describe an analytical method for calculating the mean escape time based on the principle of minimum escape energy. Analytical solutions for E0 are presented for values of the mapping control parameter a close to tangent bifurcations and interior crises. The minimum escape energy displays a power-law dependence on the control parameter near tangent bifurcations (E0~||a-at||3/2) and near interior crises (E0~||a-ac||2). Numerical solutions are given for control-parameter values throughout the range of the attractor. The results agree with the results of Monte Carlo simulations of the logistic map and with independent work on the noise stability of rf-driven Josephson junctions.

  8. Fucoidan prevents multiple myeloma cell escape from chemotherapy-induced drug cytotoxicity.

    Science.gov (United States)

    Lv, Jinglong; Xiao, Qing; Wang, Li; Liu, Xin; Wang, Xin; Yang, Zesong; Zhang, Hongbin; Dong, Pujiang

    2013-01-01

    Minimal residual disease (MRD) occurrence with some chemotherapy drugs that promote tumor cell escape is also a key factor in blood malignancy relapse. We observed that cytarabine promotes multiple myeloma (MM) cell escape and that the number of cells in the lower chamber increased with increasing clinical disease stage in in vitro model which was constructed by a Boyden chamber, matrigel glue and serum from MM patients in different disease stages. The mechanism of cytarabine that promotes MM cell escape is closely associated with the up-regulation of CXCR4. SDF-1α can up-regulate the expression of MMP9 and RHoC proteins in MM cells with up-regulated CXCR4, and further promote the cell escape. Fucoidan, a sulfated polysaccharide in the cell wall matrix of brown algae, has attracted much attention for its multiple biological activities, and we further explored the effects and possible underlying mechanisms of fucoidan on MM cell escape from cytarabine cytotoxicity. The results show that fucoidan may decrease MM cell escape from cytarabine cytotoxicity, and that fucoidan can down-regulate CXCR4, MMP9 and RHoC expression. This research provides new direction for investigating MRD occurrence and prevention. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. Increased plasma corticosterone levels after periaqueductal gray stimulation-induced escape reaction or panic attacks in rats.

    Science.gov (United States)

    Lim, Lee Wei; Blokland, Arjan; van Duinen, Marlies; Visser-Vandewalle, Veerle; Tan, Sonny; Vlamings, Rinske; Janssen, Mark; Jahanshahi, Ali; Aziz-Mohammadi, Mujzgan; Steinbusch, Harry W M; Schruers, Koen; Temel, Yasin

    2011-04-15

    The hypothalamo-pituitary-adrenal (HPA) axis is involved in stress, depression and anxiety. Controversy exists on HPA axis activation during panic attacks (PAs). We examined whether the HPA axis is involved in the escape or panic-like response in an animal model of PAs induced by electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) in rats. Additionally, rats were also treated with chronic administration of buspirone (BUSP) and escitalopram (ESCIT), respectively; and they were stimulated in the open-field arena for panic-like reaction. Levels of stress hormone corticosterone were measured following 30 min after escape or panic condition. Our results demonstrated that the levels of plasma corticosterone were significantly increased after the induction of escape or panic-like response in comparison with the sham animals. The levels of corticosterone were significantly decreased in the dlPAG stimulated groups after rats were treated chronically with the ESCIT but not the BUSP as compared to the saline treated animals. Importantly, the increase of corticosterone level after escape or panic-like response was paralleled by an increase of neuronal activation of c-Fos in both the parvocellular and magnocellular paraventricular nucleus of the hypothalamus. Moreover, the c-Fos data also showed a decrease in the number of positive cells particularly for the ESCIT as well as the BUSP in comparison with the saline stimulated animals. In conclusion, the present study clearly demonstrated that PA or escape response activates the HPA axis and it remains difficult to anticipate the mechanism underlying HPA axis during PAs and its relationship with 5-HT drugs. Copyright © 2010 Elsevier B.V. All rights reserved.

  10. Escape Velocity

    Directory of Open Access Journals (Sweden)

    Nikola Vlacic

    2010-01-01

    Full Text Available In this project, we investigated if it is feasible for a single staged rocket with constant thrust to attain escape velocity. We derived an equation for the velocity and position of a single staged rocket that launches vertically. From this equation, we determined if an ideal model of a rocket is able to reach escape velocity.

  11. Safe approaches for camptothecin delivery: Structural analogues and nanomedicines.

    Science.gov (United States)

    Botella, Pablo; Rivero-Buceta, Eva

    2017-02-10

    Twenty-(S)-camptothecin is a strongly cytotoxic molecule with excellent antitumor activity over a wide spectrum of human cancers. However, the direct formulation is limited by its poor water solubility, low plasmatic stability and severe toxicity, which currently limits its clinical use. As a consequence, two strategies have been developed in order to achieve safe and efficient delivery of camptothecin to target cells: structural analogues and nanomedicines. In this review, we summarize recent advances in the design, synthesis and development of camptothecin molecular derivatives and supramolecular vehicles, following a systematic classification according to structure-activity relationships (structural analogues) or chemical nature (nanomedicines). A series of organic, inorganic and hybrid materials are presented as nanoplatforms to overcome camptothecin restrictions in administration, biodistribution, pharmacokinetics and toxicity. Nanocarriers which respond to a variety of stimuli endogenously (e.g., pH, redox potential, enzyme activity) or exogenously (e.g., magnetic field, light, temperature, ultrasound) seem the best positioned therapeutic materials for optimal spatial and temporal control over drug release. The main goal of this review is to be used as a source of relevant literature for others interested in the field of camptothecin-based therapeutics. To this end, final remarks on the most important formulations currently under clinical trial are provided. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Learning and CRF-Induced Indecision during Escape and Submission in Rainbow Trout during Socially Aggressive Interactions in the Stress-Alternatives Model.

    Science.gov (United States)

    Summers, Tangi R; Summers, Torrie L; Carpenter, Russ E; Smith, Justin P; Young, Samuel L; Meyerink, Brandon; Orr, T Zachary; Arendt, David H; Summers, Cliff H

    2017-01-01

    Socially stressful environments induce a phenotypic dichotomy of coping measures for populations in response to a dominant aggressor and given a route of egress. This submission- (Stay) or escape-oriented (Escape) dichotomy represents individual decision-making under the stressful influence of hostile social environments. We utilized the Stress-Alternatives Model (SAM) to explore behavioral factors which might predict behavioral phenotype in rainbow trout. The SAM is a compartmentalized tank, with smaller and larger trout separated by an opaque divider until social interaction, and another divider occluding a safety zone, accessible by way of an escape route only large enough for the smaller fish. We hypothesized that distinctive behavioral responses during the first social interaction would indicate a predisposition for one of the behavioral phenotypes in the subsequent interactions. Surprisingly, increased amount or intensity of aggression received had no significant effect on promoting escape in test fish. In fact, during the first day of interaction, fish that turned toward their larger opponent during attack eventually learned to escape. Escaping fish also learn to monitor the patrolling behavior of aggressors, and eventually escape primarily when they are not being observed. Escape per se, was also predicted in trout exhibiting increased movements directed toward the escape route. By contrast, fish that consistently remained in the tank with the aggressor (Stay) showed significantly higher frequency of swimming in subordinate positions, at the top or the bottom of the water column, as well as sitting at the bottom. In addition, a corticotropin-releasing factor (CRF)-induced behavior, snap-shake, was also displayed in untreated fish during aggressive social interaction, and blocked by a CRF1 receptor antagonist. Especially prevalent among the Stay phenotype, snap-shake indicates indecision regarding escape-related behaviors. Snap-shake was also exhibited by

  13. Simvastatin enhances protection against Listeria monocytogenes infection in mice by counteracting Listeria-induced phagosomal escape.

    Directory of Open Access Journals (Sweden)

    Suraj P Parihar

    Full Text Available Statins are well-known cholesterol lowering drugs targeting HMG-CoA-reductase, reducing the risk of coronary disorders and hypercholesterolemia. Statins are also involved in immunomodulation, which might influence the outcome of bacterial infection. Hence, a possible effect of statin treatment on Listeriosis was explored in mice. Statin treatment prior to subsequent L. monocytogenes infection strikingly reduced bacterial burden in liver and spleen (up to 100-fold and reduced histopathological lesions. Statin-treatment in infected macrophages resulted in increased IL-12p40 and TNF-α and up to 4-fold reduced bacterial burden within 6 hours post infection, demonstrating a direct effect of statins on limiting bacterial growth in macrophages. Bacterial uptake was normal investigated in microbeads and GFP-expressing Listeria experiments by confocal microscopy. However, intracellular membrane-bound cholesterol level was decreased, as analyzed by cholesterol-dependent filipin staining and cellular lipid extraction. Mevalonate supplementation restored statin-inhibited cholesterol biosynthesis and reverted bacterial growth in Listeria monocytogenes but not in listeriolysin O (LLO-deficient Listeria. Together, these results suggest that statin pretreatment increases protection against L. monocytogenes infection by reducing membrane cholesterol in macrophages and thereby preventing effectivity of the cholesterol-dependent LLO-mediated phagosomal escape of bacteria.

  14. Cellular Basis of Antiproliferative and Antitumor Activity of the Novel Camptothecin Derivative, Gimatecan, in Bladder Carcinoma Models

    Directory of Open Access Journals (Sweden)

    Paola Ulivi

    2005-02-01

    Full Text Available To investigate the cellular/molecular basis of the activity of a novel lipophilic camptothecin, gimatecan (ST1481, against slowly proliferating cells, we performed a comparative study of topotecan and gimatecan in human bladder cancer models (HT1376 and MCR. Gimatecan was significantly more effective than topotecan in inhibiting the growth of HT1376 tumor, thus reflecting anti proliferative potency. In both HT1376 and MCR cells, gimatecan caused a persistent S-phase arrest, indicating an efficient DNA damage checkpoint. This response was consistent with a cytostatic effect, because no evidence of apoptosis was detected. In contrast to gimatecan, topotecan at equitoxic concentrations caused an early and persistent downregulation of topoisomerase I. Modulation of protein level could not be solely ascribed to the proteasome-mediated degradation of the enzyme because the proteasome inhibitor PS341 sensitized MCR but not HT1376 cells to camptothecins, suggesting alternative mechanisms of drug-induced topoisomerase I downregulation. Indeed, the two camptothecins caused a differential inhibition of topoisomerase I transcription, which is more marked in topotecan-treated cells. The HT1376 model was more sensitive to this immediate decrease of mRNA level. Our data document a marked antitumor activity of gimatecan against a bladder carcinoma model. A limited downregulation of topoisomerase I by gimatecan provides additional insights into the cellular basis of drug potency.

  15. Induced resistance enzymes in wild plants-do `early birds' escape from pathogen attack?

    Science.gov (United States)

    Heil, Martin; Ploss, Kerstin

    2006-09-01

    Systemic acquired resistance (SAR) of plants to pathogens is a well-defined phenomenon. The underlying signalling pathways and its application in crop protection are intensively studied. However, most studies are conducted on crop plants or on Arabidopsis as a model plant. The taxonomic distribution of this phenomenon and its dependence on life history are thus largely unknown. We quantified activities of three classes of resistance-related enzymes in 18 plant species to investigate whether plants with varying life histories differ in their investment in disease resistance. Enzyme activities were quantified in untreated plants, and in plants induced with BION, a chemical resistance elicitor. All species showed constitutive activities of chitinase, peroxidase, or glucanase. However, constitutive chitinase activities varied by 30 times, and peroxidase by 50 times, among species. Several species did not respond to the induction treatment, while enzyme activities in other species increased more than threefold after BION application. Plant species differ dramatically in the presence and inducibility of resistance enzymes. This variation could be related to life history: While all resistance enzymes were significantly induced in larger perennial plants that flower during summer, spring geophytes hardly showed inducible resistance. These plants grow in an environment that is characterised by a low-pathogen pressure, and thus may simply ‘escape’ from infection. Our study presents the first comparative data set on resistance-related enzymes in noncultivated plants. The current view on SAR—narrowed by the concentration on cultivated crops—is not sufficient to understand the ecological and evolutionary relevance of this widespread plant trait.

  16. Brain targeting effect of camptothecin-loaded solid lipid nanoparticles in rat after intravenous administration

    DEFF Research Database (Denmark)

    Martins, S. M.; Sarmento, B.; Nunes, C.

    2013-01-01

    This study intended to investigate the ability of solid lipid nanoparticles (SLN) to deliver camptothecin into the brain parenchyma after crossing the blood-brain barrier. For that purpose, camptothecin-loaded SLN with mean size below 200 nm, low polydispersity index (94%) were produced...... of intravenous camptothecin-loaded SLN performed in rats proved the positive role of SLN on the brain targeting since significant higher brain accumulation of camptothecin was observed, compared to non-encapsulated drug. Pharmacokinetic studies further demonstrated lower deposition of camptothecin in peripheral...... organs, when encapsulated into SLN, with consequent decrease in potential side toxicological effects. These results confirmed the potential of camptothecin-loaded SLN for antitumour brain treatments....

  17. Escaping superoscillations

    Science.gov (United States)

    Berry, M. V.; Fishman, S.

    2018-01-01

    A detailed classical model supports and elaborates an old prediction that in some circumstances gamma radiation could emerge from a box containing only red light. The ‘red light’, travelling nondispersively in a thin tube, is represented by a superoscillatory function: a band-limited function which in some regions oscillates faster than its fastest Fourier component. A weakly transmitting window opens and closes as the superoscillations pass by, releasing light into a half-plane. Detailed analysis of the spectrum of emerging light shows that the superoscillations escape, and propagate into the far field as ‘gamma radiation’, described precisely by a causal scattering amplitude.

  18. Leaping lizards landing on leaves: escape-induced jumps in the rainforest canopy challenge the adhesive limits of geckos.

    Science.gov (United States)

    Higham, Timothy E; Russell, Anthony P; Niklas, Karl J

    2017-06-01

    The remarkable adhesive capabilities of geckos have garnered attention from scientists and the public for centuries. Geckos are known to have an adhesive load-bearing capacity far in excess (by 100-fold or more) of that required to support their body mass or accommodate the loading imparted during maximal locomotor acceleration. Few studies, however, have investigated the ecological contexts in which geckos use their adhesive system and how this may influence its properties. Here we develop a modelling framework to assess whether their prodigious adhesive capacity ever comes under selective challenge. Our investigation is based upon observations of escape-induced aerial descents of canopy-dwelling arboreal geckos that are rapidly arrested by clinging to leaf surfaces in mid-fall. We integrate ecological observations, adhesive force measurements, and body size and shape measurements of museum specimens to conduct simulations. Using predicted bending mechanics of petioles and leaf midribs, we find that the drag coefficient of the gecko, the size of the gecko and the size of the leaf determine impact forces. Regardless of the landing surface, safety factors for geckos range from a maximum of just over 10 to a minimum of well under one, which would be the point at which the adhesive system fails. In contrast to previous research that intimates that gecko frictional adhesive capacity is excessive relative to body mass, we demonstrate that realistic conditions in nature may result in frictional capacity being pushed to its limit. The rapid arrest of the lizard from its falling velocity likely results in the maximal loading to which the adhesive system is exposed during normal activities. We suggest that such activities might be primary determinants in driving their high frictional adhesive capacity. © 2017 The Author(s).

  19. Genome-wide transcriptional effects of the anti-cancer agent camptothecin.

    Directory of Open Access Journals (Sweden)

    Artur Veloso

    Full Text Available The anti-cancer drug camptothecin inhibits replication and transcription by trapping DNA topoisomerase I (Top1 covalently to DNA in a "cleavable complex". To examine the effects of camptothecin on RNA synthesis genome-wide we used Bru-Seq and show that camptothecin treatment primarily affected transcription elongation. We also observed that camptothecin increased RNA reads past transcription termination sites as well as at enhancer elements. Following removal of camptothecin, transcription spread as a wave from the 5'-end of genes with no recovery of transcription apparent from RNA polymerases stalled in the body of genes. As a result, camptothecin preferentially inhibited the expression of large genes such as proto-oncogenes, and anti-apoptotic genes while smaller ribosomal protein genes, pro-apoptotic genes and p53 target genes showed relative higher expression. Cockayne syndrome group B fibroblasts (CS-B, which are defective in transcription-coupled repair (TCR, showed an RNA synthesis recovery profile similar to normal fibroblasts suggesting that TCR is not involved in the repair of or RNA synthesis recovery from transcription-blocking Top1 lesions. These findings of the effects of camptothecin on transcription have important implications for its anti-cancer activities and may aid in the design of improved combinatorial treatments involving Top1 poisons.

  20. Thymidine selectively enhances growth suppressive effects of camptothecin/irinotecan in MSI+ cells and tumors containing a mutation of MRE11

    DEFF Research Database (Denmark)

    Rodriguez, Rene; Hansen, Lasse Tengbjerg; Phear, Geraldine

    2008-01-01

    -thymidine combinations by measuring colony formation, cell cycle distribution, and senescence. Cell strains defective in p53, p21, or Mre11 were used in these assays to investigate the role of these cell cycle regulators. The in vivo antitumor response of xenografts to irinotecan and thymidine combinations was assessed...... in nude mice. RESULTS: Camptothecin-thymidine combinations suppress colony formation of MMR-deficient tumor cells 10- to 3,000-fold relative to that obtained with camptothecin alone and significantly reduce the concentrations of the agents required to induce late S/G(2) arrest and senescence. Sensitivity......PURPOSE: DNA synthesis inhibitors and damaging agents are widely used in cancer therapy; however, sensitivity of tumors to such agents is highly variable. The response of tumor cells in culture to these agents is strongly influenced by the status of DNA damage response pathways. Here, we attempt...

  1. Antitumor Activity of Peptide Amphiphile Nanofiber-Encapsulated Camptothecin

    Energy Technology Data Exchange (ETDEWEB)

    Soukasene, Stephen; Toft, Daniel J.; Moyer, Tyson J.; Lu, Hsuming; Lee, Hyung-Kun; Standley, Stephany M.; Cryns, Vincent L.; Stupp, Samuel I. (NWU)

    2012-04-02

    Self-assembling peptide amphiphile (PA) nanofibers were used to encapsulate camptothecin (CPT), a naturally occurring hydrophobic chemotherapy agent, using a solvent evaporation technique. Encapsulation by PA nanofibers was found to improve the aqueous solubility of the CPT molecule by more than 50-fold. PAs self-assembled into nanofibers in the presence of CPT as demonstrated by transmission electron microscopy. Small-angle X-ray scattering results suggest a slight increase in diameter of the nanofiber to accommodate the hydrophobic cargo. In vitro studies using human breast cancer cells show an enhancement in antitumor activity of the CPT when encapsulated by the PA nanofibers. In addition, using a mouse orthotopic model of human breast cancer, treatment with PA nanofiber-encapsulated CPT inhibited tumor growth. These results highlight the potential of this model PA system to be adapted for delivery of hydrophobic therapies to treat a variety of diseases including cancer.

  2. Camptothecins inhibit the utilization of hydrogen peroxide in the ligation step of topoisomerase I catalysis

    DEFF Research Database (Denmark)

    Lisby, M; Krogh, B O; Boege, F

    1998-01-01

    The antitumor compounds camptothecin and its derivatives topotecan and irinotecan stabilize topoisomerase I cleavage complexes by inhibiting the religation reaction of the enzyme. Previous studies, using radiolabeled camptothecin or affinity labeling reagents structurally related to camptothecin......, suggest that the agent binds at the topoisomerase I-DNA interface of the cleavage complexes, interacting with both the covalently bound enzyme and with the +1 base. In this study, we have investigated the molecular mechanism of camptothecin action further by taking advantage of the ability...... of topoisomerase I to couple non-DNA nucleophiles to the cleaved strand of the covalent enzyme-DNA complexes. This reaction of topoisomerase I was originally observed at moderate basic pH where active cleavage complexes mediate hydrolysis or alcoholysis by accepting water or polyhydric alcohol compounds...

  3. Characterization of DNA topoisomerase-1 in Spodoptera exigua for toxicity evaluation of camptothecin and hydoxy-camptothecin.

    Directory of Open Access Journals (Sweden)

    Lan Zhang

    Full Text Available Camptothecin (CPT, a plant alkaloid originally isolated from the native Chinese tree, Camptotheca acuminate, exerts the toxic effect by targeting eukaryotic DNA topoisomerase 1 (DNA Topo1. Besides as potent anti-cancer agents, CPT and its derivatives are now being explored as potential pesticides for insect control. In this study, we assessed their toxicity to an insect homolog, the Topo1 protein from beet armyworms (Spodoptera exigua Hübner, a worldwide pest of many important crops. The S. exigua Topo1 gene contains an ORF of 2790 base pairs that is predicted to encode a polypeptide of 930 amino acids. The deduced polypeptide exhibits polymorphism at residue sites V420, L530, A653 and T729 (numbered according to human Topo1 among insect species, which are predicted to confer sensitivity to CPT. The DNA relaxation activity of this protein was subsequently examined using a truncated form that contained the residues 337-930 and was expressed in bacteria BL21 cells. The purified protein retained the ability to relax double-stranded DNA and was susceptible to CPT and its derivative hydroxy-camptothecin (HCPT in a dose-dependent manner. The same inhibitory effect was also found on the native Topo1 extracted from IOZCAS-Spex-II cells, a cell line established from beet armyworms. Additionally, CPT and HCPT treatment reduced the steady accumulation of Topo1 protein despite the increased mRNA expression in response to the treatment. Our studies provide information of the S. exigua Topo1 gene and its amino acid polymorphism in insects and uncover some clues about potential mechanisms of CPT toxicity against insect pests. These results also are useful for development of more effective Topo1-targeted CPT insecticides in the future.

  4. Poly(Amido Amine) Dendrimers as Absorption Enhancers for Oral Delivery of Camptothecin

    Science.gov (United States)

    Sadekar, S.; Thiagarajan, G.; Bartlett, K.; Hubbard, D.; Ray, A.; McGill, L.D.; Ghandehari, H.

    2014-01-01

    Oral delivery of camptothecin has a treatment advantage but is limited by low bioavailability and gastrointestinal toxicity. Poly(amido amine) or PAMAM dendrimers have shown promise as intestinal penetration enhancers, drug solubilizers and drug carriers for oral delivery in vitro and in situ. There have been very limited studies in vivo to evaluate PAMAM dendrimers for oral drug delivery. In this study, camptothecin (5 mg/kg) was formulated and co-delivered with cationic, amine-terminated PAMAM dendrimer generation 4.0 (G4.0) (100 and 300 mg/kg) and anionic, carboxylate-terminated PAMAM generation 3.5 (G3.5) (300 and 1000 mg/kg) in CD-1 mice. Camptothecin associated to a higher extent with G4.0 than G3.5 in the formulation, attributed to an electrostatic interaction on the surface of G4.0. Both PAMAM G4.0 and G3.5 increased camptothecin solubilization in simulated gastric fluid and caused a 2-3 fold increase in oral absorption of camptothecin when delivered at 2 hours. PAMAM G4.0 and G3.5 did not increase mannitol transport suggesting that the oral absorption of camptothecin was not due to tight junction modulation. Histologic observations of the epithelial layer of small intestinal segments of the gastrointestinal tract (GIT) at 4 hours post dosing supported no evidence of toxicity at the evaluated doses of PAMAM dendrimers. This study demonstrates that both cationic (G.4) and anionic (G3.5) PAMAM dendrimers were effective in enhancing the oral absorption of camptothecin. Results suggest that drug inclusion in PAMAM interior controlled solubilization in simulated gastric and intestinal fluids, and increased oral bioavailability. PMID:23933439

  5. Induction of oncogene addiction shift to NF-{kappa}B by camptothecin in solid tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Togano, Tomiteru; Sasaki, Masataka; Watanabe, Mariko; Nakashima, Makoto [Department of Hematology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555 (Japan); Tsuruo, Takashi [Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550 (Japan); Umezawa, Kazuo [Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-0061 (Japan); Higashihara, Masaaki [Department of Hematology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555 (Japan); Watanabe, Toshiki [Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 (Japan); Horie, Ryouichi, E-mail: rhorie@med.kitasato-u.ac.jp [Department of Hematology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555 (Japan)

    2009-12-04

    The biological basis of the resistance of solid tumor cells to chemotherapy is not well understood. While addressing this problem, we found that gastric cancer cell line St-4/CPT, lung cancer cell line A549/CPT, and colon cancer cell line HT-29/CPT, all of which are resistant to camptothecin (CPT), showed strong and constitutive nuclear factor (NF)-{kappa}B activity driven by I{kappa}B kinase compared with their parental cell lines St-4, A549, and HT-29. A new NF-{kappa}B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), reduced viability and induced apoptosis in St-4/CPT, A549/CPT, and HT-29/CPT cell lines, while their parental cell lines were resistant to DHMEQ. The results in this study present an example of the shift in signals that support the survival of solid tumor cells to NF-{kappa}B during the acquisition of resistance to CPT. The results also indicate that solid tumor cells that become resistant to chemotherapy may be more easily treated by NF-{kappa}B inhibitors.

  6. Amphiphilic star PEG-Camptothecin conjugates for intracellular targeting.

    Science.gov (United States)

    Omar, Rawan; Bardoogo, Yael Leichtman; Corem-Salkmon, Enav; Mizrahi, Boaz

    2017-07-10

    Camptothecin (CPT) is a naturally occurring cytotoxic alkaloid having a broad spectrum of antitumor activity. Unfortunately, it has low bioavailability and encapsulation efficiency, limiting its clinical use. We report on our efforts to develop a novel drug delivery prototype composed of a short, star hydrophilic polyethylene glycol (PEG) backbone and hydrophobic CPT (PEG 4 -CPT). The amphiphilic bio-conjugate self-assembles in water into stable spherical nano-particles with a mean diameter of 200nm and CPT substitution percentage of 27%w/w. CPT is released in a sustained release profile without burst effect. In addition, PEG 4 -CPT nano-particles are able to load a co-drug, water soluble or non-water soluble doxorubicin and release them simultaneously with the free CPT. The biological evaluation of PEG 4 -CPT against HeLa cells showed improved cellular uptake and enhanced cytotoxicity compared to free CPT. Thus, in this approach CPT acts in two ways: As the hydrophobic segment that enables self-assembly in water and as a potent anticancer agent. This concept of combining hydrophobic drugs and short star polymers shows great potential for efficient delivery of hydrophobic chemotrophic drugs as well as for drugs with inherent stability and pharmacokinetic barriers. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Enhanced camptothecin production by ethanol addition in the suspension culture of the endophyte, Fusarium solani.

    Science.gov (United States)

    Venugopalan, Aarthi; Srivastava, Smita

    2015-01-01

    Ethanolic extract of a non-camptothecin producing plant, Catharanthus roseus when added in the suspension culture of the endophyte Fusarium solani known to produce camptothecin, resulted in enhanced production of camptothecin by 10.6-fold in comparison to that in control (2.8 μg/L). Interestingly, addition of pure ethanol (up to 5% v/v) in the suspension culture of F. solani resulted in maximum enhancement in camptothecin production (up to 15.5-fold) from that obtained in control. In the presence of ethanol, a reduced glucose uptake (by ∼ 40%) and simultaneous ethanol consumption (up to 9.43 g/L) was observed during the cultivation period (14 days). Also, the total NAD level and the protein content in the biomass increased by 3.7- and 1.9-fold, respectively, in comparison to that in control. The study indicates a dual role of ethanol, presumably as an elicitor and also as a carbon/energy source, leading to enhanced biomass and camptothecin production. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Addition of N-glycosylation sites on the globular head of the H5 hemagglutinin induces the escape of highly pathogenic avian influenza A H5N1 viruses from vaccine-induced immunity.

    Science.gov (United States)

    Hervé, Pierre-Louis; Lorin, Valérie; Jouvion, Grégory; Da Costa, Bruno; Escriou, Nicolas

    2015-12-01

    Highly pathogenic avian influenza A H5N1 viruses remain endemic in poultry in several countries and still constitute a pandemic threat. Since the early 20th century, we experienced four influenza A pandemics. H3N2 and H1N1pdm09 viruses that respectively emerged during 1968 and 2009 pandemics are still responsible for seasonal epidemics. These viruses evolve regularly by substitutions in antigenic sites of the hemagglutinin (HA), which prevent neutralization by antibodies directed against previous strains (antigenic drift). For seasonal H3N2 viruses, an addition of N-glycosylation sites (glycosites) on H3 contributed to this drift. Here, we questioned whether additional glycosites on H5 could induce an escape of H5N1 virus from neutralization, as it was observed for seasonal H3N2 viruses. Seven H5N1 mutants were produced by adding glycosites on H5. The most glycosylated virus escaped from neutralizing antibodies, in vitro and in vivo. Furthermore, a single additional glycosite was responsible for this escape. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Formation of nanoparticles by cooperative inclusion between (S)-camptothecin-modified dextrans and ?-cyclodextrin polymers

    OpenAIRE

    Nielsen, Thorbj?rn Terndrup; Amiel, Catherine; Duroux, Laurent; Larsen, Kim Lambertsen; St?de, Lars Wagner; Wimmer, Reinhard; Wintgens, V?ronique

    2015-01-01

    Novel (S)-camptothecin–dextran polymers were obtained by “click” grafting of azide-modified (S)-camptothecin and alkyne-modified dextrans. Two series based on 10 kDa and 70 kDa dextrans were prepared with a degree of substitution of (S)-camptothecin between 3.1 and 10.2%. The binding properties with β-cyclodextrin and β-cyclodextrin polymers were measured by isothermal titration calorimetry and fluorescence spectroscopy, showing no binding with β-cyclodextrin but high binding with β-cyclodext...

  10. Neutral escape at Mars induced by the precipitation of high-energy protons and hydrogen atoms of the solar wind origin

    Science.gov (United States)

    Shematovich, Valery I.

    2017-04-01

    One of the first surprises of the NASA MAVEN mission was the observation by the SWIA instrument of a tenuous population of protons with solar wind energies travelling anti-sunward near periapsis, at altitudes of 150-250 km (Halekas et al., 2015). While the penetration of solar wind protons to low altitude is not completely unexpected given previous Mars Express results, this population maintains exactly the same velocity as the solar wind observed. From previous studies it was known that some fraction of the solar wind can interact with the extended corona of Mars. By charge exchange with the neutral particles in this corona, some fraction of the incoming solar wind protons can gain an electron and become an energetic neutral hydrogen atom. Once neutral, these particles penetrate through the Martian induced magnetosphere with ease, with free access to the collisional atmosphere/ionosphere. The origin, kinetics and transport of the suprathermal O atoms in the transition region (from thermosphere to exosphere) of the Martian upper atmosphere due to the precipitation of the high-energy protons and hydrogen atoms are discussed. Kinetic energy distribution functions of suprathermal and superthermal (ENA) oxygen atoms formed in the Martian upper atmosphere were calculated using the kinetic Monte Carlo model (Shematovich et al., 2011, Shematovich, 2013) of the high-energy proton and hydrogen atom precipitation into the atmosphere. These functions allowed us: (a) to estimate the non-thermal escape rates of neutral oxygen from the Martian upper atmosphere, and (b) to compare with available MAVEN measurements of oxygen corona. Induced by precipitation the escape of hot oxygen atoms may become dominant under conditions of extreme solar events - solar flares and coronal mass ejections, - as it was shown by recent observations of the NASA MAVEN spacecraft (Jakosky et al., 2015). This work is supported by the RFBR project and by the Basic Research Program of the Praesidium of

  11. Brain delivery of camptothecin by means of solid lipid nanoparticles: Formulation design, in vitro and in vivo studies

    DEFF Research Database (Denmark)

    Martins, S.; Tho, I.; Reimold, I.

    2012-01-01

    For the purpose of brain delivery upon intravenous injection, formulations of camptothecin-loaded solid lipid nanoparticles (SLN), prepared by hot high pressure homogenisation, were designed. Incorporation of camptothecin in the hydrophobic and acidic environment of SLN matrix was chosen to stabi......For the purpose of brain delivery upon intravenous injection, formulations of camptothecin-loaded solid lipid nanoparticles (SLN), prepared by hot high pressure homogenisation, were designed. Incorporation of camptothecin in the hydrophobic and acidic environment of SLN matrix was chosen...... to stabilise the lactone ring, which is essential for its antitumour activity, and for avoiding premature loss of drug on the way to target camptothecin to the brain. A multivariate approach was used to assess the influence of the qualitative and quantitative composition on the physicochemical properties...... affinity of the SLN to the porcine brain capillary endothelial cells (BCEC) was shown in comparison to macrophages. MTT studies in BCEC revealed a moderate decrease in the cell viability of camptothecin, when incorporated in SLN compared to free camptothecin in solution. In vivo studies in rats showed...

  12. Linker-determined drug release mechanism of free camptothecin from self-assembling drug amphiphiles.

    Science.gov (United States)

    Cheetham, Andrew G; Ou, Yu-Chuan; Zhang, Pengcheng; Cui, Honggang

    2014-06-07

    We report here that the release mechanism of free camptothecin from self-assembling drug amphiphiles can be regulated by use of different linker groups. Our results highlight the significance of the linker group of drug amphiphiles on the drug release efficiency and their consequent in vitro efficacy.

  13. Effect of fermentation parameters, elicitors and precursors on camptothecin production from the endophyte Fusarium solani.

    Science.gov (United States)

    Venugopalan, Aarthi; Potunuru, Uma Rani; Dixit, Madhulika; Srivastava, Smita

    2016-04-01

    Volumetric productivity of camptothecin from the suspension culture of the endophyte Fusarium solani was enhanced up to ∼152 fold (from 0.19 μg l(-1) d(-1) to 28.9 μg l(-1) d(-1)) under optimized fermentation conditions including initial pH (6.0), temperature (32 °C) and agitation speed (80 rpm) with (5% (v/v)) ethanol as medium component. Among various elicitors and precursors studied, tryptamine (0.5 mM) as precursor and bovine serum albumin (BSA) (0.075 mM) as an elicitor added on day 6 of the cultivation period resulted in maximum enhancement of camptothecin concentration (up to 4.5 and 3.4-fold, respectively). These leads provide immense scope for further enhancement in camptothecin productivity at bioreactor level. The cytotoxicity analysis of the crude camptothecin extract from the fungal biomass revealed its high effectiveness against colon and mammary gland cancer cell lines. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Targeted gene correction using psoralen, chlorambucil and camptothecin conjugates of triplex forming peptide nucleic acid (PNA)

    DEFF Research Database (Denmark)

    Birkedal, Henrik; Nielsen, Peter E

    2011-01-01

    Gene correction activation effects of a small series of triplex forming peptide nucleic acid (PNA) covalently conjugated to the DNA interacting ligands psoralen, chlorambucil and camptothecin targeted proximal to a stop codon mutation in an EGFP reporter gene were studied. A 15-mer homopyrimidine...

  15. Deep sequencing reveals direct targets of gammaherpesvirus-induced mRNA decay and suggests that multiple mechanisms govern cellular transcript escape.

    Directory of Open Access Journals (Sweden)

    Karen Clyde

    Full Text Available One characteristic of lytic infection with gammaherpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV, Epstein-Barr virus (EBV and murine herpesvirus 68 (MHV68, is the dramatic suppression of cellular gene expression in a process known as host shutoff. The alkaline exonuclease proteins (KSHV SOX, MHV-68 muSOX and EBV BGLF5 have been shown to induce shutoff by destabilizing cellular mRNAs. Here we extend previous analyses of cellular mRNA abundance during lytic infection to characterize the effects of SOX and muSOX, in the absence of other viral genes, utilizing deep sequencing technology (RNA-seq. Consistent with previous observations during lytic infection, the majority of transcripts are downregulated in cells expressing either SOX or muSOX, with muSOX acting as a more potent shutoff factor than SOX. Moreover, most cellular messages fall into the same expression class in both SOX- and muSOX-expressing cells, indicating that both factors target similar pools of mRNAs. More abundant mRNAs are more efficiently downregulated, suggesting a concentration effect in transcript targeting. However, even among highly expressed genes there are mRNAs that escape host shutoff. Further characterization of select escapees reveals multiple mechanisms by which cellular genes can evade downregulation. While some mRNAs are directly refractory to SOX, the steady state levels of others remain unchanged, presumably as a consequence of downstream effects on mRNA biogenesis. Collectively, these studies lay the framework for dissecting the mechanisms underlying the susceptibility of mRNA to destruction during lytic gammaherpesvirus infection.

  16. Deep sequencing reveals direct targets of gammaherpesvirus-induced mRNA decay and suggests that multiple mechanisms govern cellular transcript escape.

    Science.gov (United States)

    Clyde, Karen; Glaunsinger, Britt A

    2011-05-09

    One characteristic of lytic infection with gammaherpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV), Epstein-Barr virus (EBV) and murine herpesvirus 68 (MHV68), is the dramatic suppression of cellular gene expression in a process known as host shutoff. The alkaline exonuclease proteins (KSHV SOX, MHV-68 muSOX and EBV BGLF5) have been shown to induce shutoff by destabilizing cellular mRNAs. Here we extend previous analyses of cellular mRNA abundance during lytic infection to characterize the effects of SOX and muSOX, in the absence of other viral genes, utilizing deep sequencing technology (RNA-seq). Consistent with previous observations during lytic infection, the majority of transcripts are downregulated in cells expressing either SOX or muSOX, with muSOX acting as a more potent shutoff factor than SOX. Moreover, most cellular messages fall into the same expression class in both SOX- and muSOX-expressing cells, indicating that both factors target similar pools of mRNAs. More abundant mRNAs are more efficiently downregulated, suggesting a concentration effect in transcript targeting. However, even among highly expressed genes there are mRNAs that escape host shutoff. Further characterization of select escapees reveals multiple mechanisms by which cellular genes can evade downregulation. While some mRNAs are directly refractory to SOX, the steady state levels of others remain unchanged, presumably as a consequence of downstream effects on mRNA biogenesis. Collectively, these studies lay the framework for dissecting the mechanisms underlying the susceptibility of mRNA to destruction during lytic gammaherpesvirus infection.

  17. Spacecraft crew escape

    Science.gov (United States)

    Miller, B. A.

    Safe crew escape from spacecraft is extremely difficult to engineer and has large cost and vehicle payload penalties. Because of these factors calculated risks have apparently been taken and only the most rudimentary means of crew protecion have been provided for space programs. Although designed for maximum reliability and safety a calculated risk is taken that on-balance it is more acceptable to risk the loss of possibly some or all occupants than introduce the mass, cost and complexity of an escape system. This philosophy was accepted until the Challenger tragedy. It is now clear that the use of this previously acceptable logic is invalid and that provisions must be made for spacecraft crew escape in the event of a catastrophic accident. This paper reviews the funded studies and subsequent proposals undertaken by Martin-Baker for the use of both encapsullated and open ejection seats for the Hermes Spaceplane. The technical difficulties, special innovations and future applications are also discussed.

  18. Tetrac-conjugated polymersomes for integrin-targeted delivery of camptothecin to colon adenocarcinoma in vitro and in vivo.

    Science.gov (United States)

    Alibolandi, Mona; Rezvani, Rouhollah; Farzad, Sara Amel; Taghdisi, Seyed Mohammad; Abnous, Khalil; Ramezani, Mohammad

    2017-10-30

    In this study, we prepared tetraiodothyroacetic acid (tetrac) conjugated PEG-PLGA polymersomes for the targeted delivery of camptothecin to colon adenocarcinoma. Tetrac, which binds to integrin αvβ3 with high affinity and specificity, was covalently conjugated to the surface of the PEGylated polymersomal formulation of camptothecin (CPT). The hydrodynamic and morphological properties of the prepared system were evaluated using TEM (transmission electron microscopy), SEM (scanning electron microscopy) and DLS (dynamic light scattering) experiments. Camptothecin was encapsulated in the polymersomal system with encapsulation efficiency and loading content of 84±10.12 and 4.2±0.82, respectively. The in vitro release profile of camptothecin from the polymersomal formulation revealed the sustained release pattern. In vitro cytotoxicity experiments confirmed that the tetrac-conjugated camptothecin loaded-polymersomes had higher cellular toxicity towards integrin-overexpressed HT29 and C26 colorectal cancer cells than integrin-negative CHO cell line. The in vivo tumor inhibitory effect of tetrac-conjugated camptothecin loaded-polymersomes demonstrated an enhanced therapeutic index of integrin targeted polymersomal formulation over both non-targeted polymersomal formulation and free camptothecin in C26 tumor bearing mice. The obtained results demonstrated that the prepared tetrac-conjugated polymersomes were able to control the release of camptothecin, and significantly increase the therapeutic index of compthotecin. This study demonstrates the versatility of integrin-targeted tetrac-conjugated PEG-PLGA polymersomal formulation as an anti-cancer nano-pharmaceutical platform. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Cell-cycle-dependent three-dimensional redistribution of nuclear proteins, P 120, pKi-67, and SC 35 splicing factor, in the presence of the topoisomerase I inhibitor camptothecin.

    Science.gov (United States)

    Elias, Emmanuel; Lalun, Nathalie; Lorenzato, Marianne; Blache, Laurent; Chelidze, Pavel; O'Donohue, Marie-Françoise; Ploton, Dominique; Bobichon, Hélène

    2003-11-15

    Topoisomerase I (Topo I) is mostly known for its role in DNA relaxation, which is required for duplication and transcription. Topo I acts as a protein kinase mainly directed to the mRNA splicing factor SC35. Camptothecin is one of the specific Topo I inhibitors and is effective on the two functions of the enzyme. In this study we demonstrated that treatment of KB cells with camptothecin for only 30 min induced the 3D reorganization and redistribution of three proteins involved in the nucleus machinery, P 120, pKi-67, and SC 35, and this occurred in a cell cycle-dependent manner. Our data were obtained from confocal microscopic studies after immunolabeling, 3D reconstruction, and measurement of the nuclear components volumes. In the presence of camptothecin, P 120, which occupied the nucleolar volume, lost its reticulation and pKi-67 was redistributed within the nucleoplasm and even into the cytoplasm. Finally, for SC 35 the fusion of its dots into bigger volumes was observed specifically during the G1 phase. Variations of volumes were also observed for the nucleolus and for the nucleus. These results pointed out that, depending on the cell cycle phase, Topo I functions were selective toward the three different proteins.

  20. On ion escape from Venus

    Science.gov (United States)

    Jarvinen, R.

    2011-04-01

    This doctoral thesis is about the solar wind influence on the atmosphere of the planet Venus. A numerical plasma simulation model was developed for the interaction between Venus and the solar wind to study the erosion of charged particles from the Venus upper atmosphere. The developed model is a hybrid simulation where ions are treated as particles and electrons are modelled as a fluid. The simulation was used to study the solar wind induced ion escape from Venus as observed by the European Space Agency's Venus Express and NASA's Pioneer Venus Orbiter spacecraft. Especially, observations made by the ASPERA-4 particle instrument onboard Venus Express were studied. The thesis consists of an introductory part and four peer-reviewed articles published in scientific journals. In the introduction Venus is presented as one of the terrestrial planets in the Solar System and the main findings of the work are discussed within the wider context of planetary physics.Venus is the closest neighbouring planet to the Earth and the most earthlike planet in its size and mass orbiting the Sun. Whereas the atmosphere of the Earth consists mainly of nitrogen and oxygen, Venus has a hot carbon dioxide atmosphere, which is dominated by the greenhouse effect. Venus has all of its water in the atmosphere, which is only a fraction of the Earth's total water supply. Since planets developed presumably in similar conditions in the young Solar System, why Venus and Earth became so different in many respects?One important feature of Venus is that the planet does not have an intrinsic magnetic field. This makes it possible for the solar wind, a continuous stream of charged particles from the Sun, to flow close to Venus and to pick up ions from the planet's upper atmosphere. The strong intrinsic magnetic field of the Earth dominates the terrestrial magnetosphere and deflects the solar wind flow far away from the atmosphere. The region around Venus where the planet's atmosphere interacts with the

  1. Effect of precursors feeding and media manipulation on production of novel anticancer pro-drug camptothecin from endophytic fungus

    Directory of Open Access Journals (Sweden)

    Touseef Amna

    2012-12-01

    Full Text Available We have established methodology for the isolation and characterization of a novel endophytic fungus from the inner bark of medicinal plant Nothapodytes foetida, which produced camptothecin in Sabouraud broth (SB under shake flask conditions. Camptothecin and its related compounds are at present obtained by extraction from intact plants, but fungal endopytes may be an alternative source of production. In present study we have observed the effect of different nutrient combinations and precursors (tryptophan, tryptamine, geraniol, citral, mevalonic acid and leucine on the accumulation of camptothecin by endophytic fungus Entrophospora infrequens. The precursors were fed either alone or in combinations (tryptophan and geraniol, tryptophan and citral, tryptophan and mevalonic acid, tryptophan and leucine. The highest camptothecin content was observed in the range of 503 ± 25µg/100g dry cell mass in Sabouraud medium. Camptothecin content in the medium was increased by 2.5 folds by the presence of tryptophan and leucine whereas the production with trytophan was also significantly different from other treatments. Furthermore, the effect of fungal camptothecin on the morphology of human cancer cell lines was also studied. The treated cells showed reduction in size, condensation of nucleus and the protoplasmic extensions were reduced. All these characteristics are found in apoptotic cells.

  2. Restricting wolves risks escape

    Science.gov (United States)

    Mech, L. David; Ballard, Warren; Bangs, Ed; Ream, Bob

    2010-01-01

    Implementing the proposal set forth by Licht and colleagues (BioScience 60: 147–153) requires restricting wolves to tiny "islands," areas that are magnitudes smaller than the ranges of most wolf populations. Wolves naturally have large ranges; restricting their spatial needs increases the risk of wolves escaping, exacerbating public relations and political and legal problems.

  3. Docking and QSAR Studies of Camptothecin Derivatives as Inhibitor of DNA Topoisomerase-I

    OpenAIRE

    Dharmendra K. Yadav; Feroz Khan; Srivastava, Santosh K.

    2011-01-01

    Camptothecin (CPT) is a cytotoxic quinoline alkaloid which inhibits the DNA enzyme Topoisomerase-I (Topo-I) and has shown remarkable anticancer activity in preliminary clinical trials. The major limitation is its low solubility and high adverse reaction. In the studied work, we performed molecular docking of CPT derivatives against Topo-I and developed the quantitative structure activity relationship (QSAR) model for anticancer activity screening. For QSAR, we used CPT and other anticancer dr...

  4. Smart AS1411-aptamer conjugated pegylated PAMAM dendrimer for the superior delivery of camptothecin to colon adenocarcinoma in vitro and in vivo.

    Science.gov (United States)

    Alibolandi, Mona; Taghdisi, Seyed Mohammad; Ramezani, Pouria; Hosseini Shamili, Fazileh; Farzad, Sara Amel; Abnous, Khalil; Ramezani, Mohammad

    2017-03-15

    In the current study camptothecin-loaded pegylated PAMAM dendrimer were synthesized and were functionalized with AS1411 anti-nucleolin aptamers for site-specific targeting against colorectal cancer cells which over expresses nucleolin receptors. The morphological properties and size dispersity of the prepared nanoparticles were evaluated using transmission electron microscope (TEM) and DLS. The drug-loading content and encapsulation efficiency were obtained 8.1% and 93.67% respectively. The in vitro release of camptothecin from the formulation was provided the sustained release of encapsulated camptothecin during 4days. Comparative in vitro cytotoxicity experiments demonstrated that the targeted camptothecin loaded-pegylated dendrimers had higher antiproliferation activity, towards nucleolin-positive HT29 and C26 colorectal cancer cells than nucleolin-negative CHO cell line. Fluorscence microscopy and flow cytometry also confirmed the enhanced cellular uptake of AS1411 targeted pegylated-dendrimer. In vivo study in C26 tumor-bearing BALB/C mice revealed that the AS1411-functionalized camptothecin loaded pegylated dendrimers improved antitumor activity and survival rate of the encapsulated camptothecin. Conjugation of AS1411 aptamer to the camptothecin loaded-pegylated dendrimer surface provides site-specific delivery of camptothecin, inhibit C26 tumor growth in vivo and significantly decrease systemic toxicity. These results suggested that the new nucleolin-targeted pegylated PAMAM dendrimer as a delivery system for camptothecin have the potential for the treatment of nucleolin-overexpressed colorectal cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. PVA engineered microcapsules for targeted delivery of camptothecin to HeLa cells

    Energy Technology Data Exchange (ETDEWEB)

    Galbiati, Alice; Rocca, Blasco Morozzo della; Tabolacci, Claudio; Beninati, Simone; Desideri, Alessandro [Dipartimento di Biologia, Universita di Roma Tor Vergata, Via della Ricerca Scientifica, 00133 Rome (Italy); Paradossi, Gaio, E-mail: paradossi@stc.uniroma2.it [Dipartimento di Scienze e Tecnologie Chimiche, Universita di Roma Tor Vergata, Via della Ricerca Scientifica, 00133 Rome (Italy)

    2011-12-01

    Capsular microvectors are an important tool in the recent research field of nanomedicine to address a drug cargo for the therapeutic treatment of several pathologies. In this study we describe how the product of the conjugation of the polysaccharide chitosan with folate can be used as a coating of poly (vinyl alcohol), PVA, based microcapsules for an efficient targeting of HeLa cells. The influence of the coating on the bioadhesive properties of the vector and on its cargo capacity was also considered using camptothecin as an anticancer drug model. The coating strategy was finalized to exploit the good chemical versatility of PVA, used to form the shell of the vector. This study is a follow up of an investigation activity aiming to show the potentialities of PVA-shelled microcapsules or microbubbles as injectable microdevices supporting a theranostic approach for different types of tumour. Highlights: {yields}Coating of PVA-shelled microcapsules with chitosan-folate. {yields} Selective bioadhesion of microcapsules to HeLa Cells. {yields} Effective loading and release of camptothecin. {yields} In vitro anti-proliferative action of camptothecin loaded microcapsules.

  6. Effect of drug precursor in cell uptake and cytotoxicity of redox-responsive camptothecin nanomedicines.

    Science.gov (United States)

    Botella, Pablo; Muniesa, Carlos; Vicente, Víctor; Cabrera-García, Alejandro

    2016-01-01

    Novel redox-responsive nanomedicines have been synthesized by conjugating camptothecin prodrugs ((pyridine-2-yldisulfanil)alkyl carbonate derivatives) to hybrid porous silica nanoparticles through disulfide bond. After disulfide reduction, camptothecin may be released by an intramolecular cyclization mechanism or by carbonate bond hydrolysis. Samples have been characterized by physico-chemical techniques, and stability and drug release in PBS and human serum have been determined. Moreover, cell uptake was studied by fluorescence microscopy and flow cytometry, whilst cytotoxic activity was validated by MTT test. Obtained results indicate that prodrug side chain carbon number (n=1,2,3) determines material hydrophobic properties and, as a consequence, its stability in aqueous medium. When n value increases, the negative surface charge decreases dramatically due to a shielding effect provoked by hydrophobic ligands, which promotes particle aggregation and favors cell internalization. Furthermore, the n value determines the type of products released and, subsequently, the cytotoxic activity. Full disulfide bridge reduction takes place in all cases, but quick delivery of the free drug by intramolecular cyclization is only possible with the shortest linker (n=1), whereas other nanomedicines only present slow discharge of camptothecin by carbonate hydrolysis. Overall, the drug precursor incorporated to the inorganic nanoplatform modulates both cell uptake rate and cytotoxicity according to the different functionalization. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Synthesis, biological activities, and quantitative structure-activity relationship (QSAR) study of novel camptothecin analogues.

    Science.gov (United States)

    Wu, Dan; Zhang, Shao-Yong; Liu, Ying-Qian; Wu, Xiao-Bing; Zhu, Gao-Xiang; Zhang, Yan; Wei, Wei; Liu, Huan-Xiang; Chen, An-Liang

    2015-05-13

    In continuation of our program aimed at the development of natural product-based pesticidal agents, three series of novel camptothecin derivatives were designed, synthesized, and evaluated for their biological activities against T. Cinnabarinus, B. brassicae, and B. xylophilus. All of the derivatives showed good-to-excellent activity against three insect species tested, with LC50 values ranging from 0.00761 to 0.35496 mmol/L. Remarkably, all of the compounds were more potent than CPT against T. Cinnabarinus, and compounds 4d and 4c displayed superior activity (LC50 0.00761 mmol/L and 0.00942 mmol/L, respectively) compared with CPT (LC50 0.19719 mmol/L) against T. Cinnabarinus. Based on the observed bioactivities, preliminary structure-activity relationship (SAR) correlations were also discussed. Furthermore, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) was built. The model gave statistically significant results with the cross-validated q2 values of 0.580 and correlation coefficient r2 of 0.991 and  of 0.993. The QSAR analysis indicated that the size of the substituents play an important in the activity of 7-modified camptothecin derivatives. These findings will pave the way for further design, structural optimization, and development of camptothecin-derived compounds as pesticidal agents.

  8. Escape from the Alternative

    Directory of Open Access Journals (Sweden)

    Marin Dinu

    2006-12-01

    Full Text Available This paper sets out to elaborate on Romania’s specific agenda regarding the approach to the integration process in the EU as a project of modernization. The focus is on the functional aspects, the type of strategic solutions destined to consolidate the specific transformations belonging to post-communist transition seen as an internal transition, on the one hand and on the other hand to push convergence as the essence of integration, marked by the vision of EU integration as a continuation of change, which is the stage of external transition. Identifying the prominent factors and the pragmatic priorities of the escape from the peripheries of development by engaging in evolution by way of the second modernization constitutes as well a target for analysis. One particularity of the method of analysis is the review if the value-set of the bobsled effect of path dependency – the path of the peripheries – as well as of the set of values of the escape from the peripheries.

  9. Synthesis and biological evaluation of novel conjugates of camptothecin and 5-flurouracil as cytotoxic agents

    OpenAIRE

    Yang, Liu; Zhao,Chun-Yan; Liu, Ying-Qian

    2011-01-01

    A series of novel conjugates of camptothecin and 5-fluorouracil were first synthesized and their cytotoxic activities against two human tumor cell lines (SGC-7901 and A-549) as well as in vitro pharmacokinetic determination of lactone stability were studied. Among these compounds, most tested conjugates showed comparable or superior cytotoxic activities to 2, but less potent compared with 1. Particularly, conjugates 10b and 10d were highly active against A-549 with IC50 values of 0.45 and 0.3...

  10. Nociception and escape behavior in planarians

    Science.gov (United States)

    Schoetz Collins, Eva-Maria

    2015-03-01

    Planarians are famous and widely studied for their regenerative capabilities. When a moving planarian is cut through the middle, the resulting head and tail pieces instantaneously retract and exhibit a characteristic escape response that differs from normal locomotion. In asexual animals, a similar reaction is observed when the planarian undergoes fission, suggesting that reproduction through self-tearing is a rather traumatic event for the animal. Using a multiscale approach, we unravel the dynamics, mechanics, and functional aspects of the planarian escape response. This musculature-driven gait was found to be a dominating response that supersedes the urge to feed or reproduce and quantitatively differs from other modes of planarian locomotion (gliding, peristalsis). We show that this escape gait constitutes the animal's pain response mediated by TRP like receptors and the neurotransmitter histamine, and that it can be induced through adverse thermal, mechanical, electrical or chemical stimuli. Ultimately, we will examine the neuronal subpopulations involved in mediating escape reflexes in planarians and how they are functionally restored during regeneration, thereby gaining mechanistic insight into the neuronal circuits required for specific behaviors. Supported by BWF CASI and Sloan Foundation.

  11. Reconstructing the Alcatraz escape

    Science.gov (United States)

    Baart, F.; Hoes, O.; Hut, R.; Donchyts, G.; van Leeuwen, E.

    2014-12-01

    In the night of June 12, 1962 three inmates used a raft made of raincoatsto escaped the ultimate maximum security prison island Alcatraz in SanFrancisco, United States. History is unclear about what happened tothe escapees. At what time did they step into the water, did theysurvive, if so, where did they reach land? The fate of the escapees has been the subject of much debate: did theymake landfall on Angel Island, or did the current sweep them out ofthe bay and into the cold pacific ocean? In this presentation, we try to shed light on this historic case using avisualization of a high-resolution hydrodynamic simulation of the San Francisco Bay, combined with historical tidal records. By reconstructing the hydrodynamic conditions and using a particle based simulation of the escapees we show possible scenarios. The interactive model is visualized using both a 3D photorealistic and web based visualization. The "Escape from Alcatraz" scenario demonstrates the capabilities of the 3Di platform. This platform is normally used for overland flooding (1D/2D). The model engine uses a quad tree structure, resulting in an order of magnitude speedup. The subgrid approach takes detailed bathymetry information into account. The inter-model variability is tested by comparing the results with the DFlow Flexible Mesh (DFlowFM) San Francisco Bay model. Interactivity is implemented by converting the models from static programs to interactive libraries, adhering to the Basic ModelInterface (BMI). Interactive models are more suitable for answeringexploratory research questions such as this reconstruction effort. Although these hydrodynamic simulations only provide circumstantialevidence for solving the mystery of what happened during the foggy darknight of June 12, 1962, it can be used as a guidance and provides aninteresting testcase to apply interactive modelling.

  12. Escape driven by α -stable white noises

    Science.gov (United States)

    Dybiec, B.; Gudowska-Nowak, E.; Hänggi, P.

    2007-02-01

    We explore the archetype problem of an escape dynamics occurring in a symmetric double well potential when the Brownian particle is driven by white Lévy noise in a dynamical regime where inertial effects can safely be neglected. The behavior of escaping trajectories from one well to another is investigated by pointing to the special character that underpins the noise-induced discontinuity which is caused by the generalized Brownian paths that jump beyond the barrier location without actually hitting it. This fact implies that the boundary conditions for the mean first passage time (MFPT) are no longer determined by the well-known local boundary conditions that characterize the case with normal diffusion. By numerically implementing properly the set up boundary conditions, we investigate the survival probability and the average escape time as a function of the corresponding Lévy white noise parameters. Depending on the value of the skewness β of the Lévy noise, the escape can either become enhanced or suppressed: a negative asymmetry parameter β typically yields a decrease for the escape rate while the rate itself depicts a non-monotonic behavior as a function of the stability index α that characterizes the jump length distribution of Lévy noise, exhibiting a marked discontinuity at α=1 . We find that the typical factor of 2 that characterizes for normal diffusion the ratio between the MFPT for well-bottom-to-well-bottom and well-bottom-to-barrier-top no longer holds true. For sufficiently high barriers the survival probabilities assume an exponential behavior versus time. Distinct non-exponential deviations occur, however, for low barrier heights.

  13. Escape from Vela X

    Energy Technology Data Exchange (ETDEWEB)

    Hinton, J.; /Leicester U.; Funk, S.; /KIPAC, Menlo Park; Parsons, R.D.; /Leeds U.; Ohm, S.; /Leicester U. /Leeds U.

    2012-02-15

    While the Vela pulsar and its associated nebula are often considered as the archetype of a system powered by a {approx} 10{sup 4} year old isolated neutron star, many features of the spectral energy distribution of this pulsar wind nebula are both puzzling and unusual. Here we develop a model that for the first time relates the main structures in the system, the extended radio nebula (ERN) and the X-ray cocoon through continuous injection of particles with a fixed spectral shape. We argue that diffusive escape of particles from the ERN can explain the steep Fermi-LAT spectrum. In this scenario Vela X should produce a distinct feature in the locally-measured cosmic ray electron spectrum at very high energies. This prediction can be tested in the future using the Cherenkov Telescope Array (CTA). If particles are indeed released early in the evolution of PWNe and can avoid severe adiabatic losses, PWN provide a natural explanation for the rising positron fraction in the local CR spectrum.

  14. Clinical developments of chemotherapeutic nanomedicines: Polymers and liposomes for delivery of camptothecins and platinum (II) drugs

    KAUST Repository

    Kieler-Ferguson, Heidi M.

    2013-01-17

    For the past 40 years, liposomal and polymeric delivery vehicles have been studied as systems capable of modulating the cytotoxicity of small molecule chemotherapeutics, increasing tumor bearing animal survival times, and improving drug targeting. Although a number of macromolecular-drug conjugates have progressed to clinical trials, tuning drug release to maintain efficacy in conjunction with controlling drug toxicity has prevented the clinical adoption of many vehicles. In this article, we review the motivations for and approaches to polymer and liposomal delivery with regard to camptothecin and cisplatin delivery. WIREs Nanomed Nanobiotechnol 2013, 5:130-138. doi: 10.1002/wnan.1209 For further resources related to this article, please visit the WIREs website. Conflict of interest: Drs Kieler-Ferguson and Fréchet declare no conflicts of interest. Dr Szoka is the founder of a liposome drug delivery company that is not working on any of the compounds mentioned in this article. © 2013 Wiley Periodicals, Inc.

  15. Replacement of the human topoisomerase linker domain with the plasmodial counterpart renders the enzyme camptothecin resistant

    DEFF Research Database (Denmark)

    Arnò, Barbara; D'Annessa, Ilda; Tesauro, Cinzia

    2013-01-01

    a conformational space much larger than the corresponding domain in the human enzyme. The large linker conformational variability is then linked to important functional properties such as an increased religation rate and a low drug reactivity, demonstrating that the linker domain has a crucial role......A human/plasmodial hybrid enzyme, generated by swapping the human topoisomerase IB linker domain with the corresponding domain of the Plasmodium falciparum enzyme, has been produced and characterized. The hybrid enzyme displays a relaxation activity comparable to the human enzyme......, but it is characterized by a much faster religation rate. The hybrid enzyme is also camptothecin resistant. A 3D structure of the hybrid enzyme has been built and its structural-dynamical properties have been analyzed by molecular dynamics simulation. The analysis indicates that the swapped plasmodial linker samples...

  16. Inhibition of calpain blocks the phagosomal escape of Listeria monocytogenes.

    Directory of Open Access Journals (Sweden)

    Gloria Lopez-Castejon

    Full Text Available Listeria monocytogenes is a gram-positive facultative intracellular bacterium responsible for the food borne infection listeriosis, affecting principally the immunocompromised, the old, neonates and pregnant women. Following invasion L. monocytogenes escapes the phagosome and replicates in the cytoplasm. Phagosome escape is central to L. monocytogenes virulence and is required for initiating innate host-defence responses such as the secretion of the cytokine interleukin-1. Phagosome escape of L. monocytogenes is reported to depend upon host proteins such as γ-interferon-inducible lysosomal thiol reductase and the cystic fibrosis transmembrane conductance regulator. The host cytosolic cysteine protease calpain is required in the life cycle of numerous pathogens, and previous research reports an activation of calpain by L. monocytogenes infection. Thus we sought to determine whether host calpain was required for the virulence of L. monocytogenes. Treatment of macrophages with calpain inhibitors blocked escape of L. monocytogenes from the phagosome and consequently its proliferation within the cytosol. This was independent of any direct effect on the production of bacterial virulence factors or of a bactericidal effect. Furthermore, the secretion of interleukin-1β, a host cytokine whose secretion induced by L. monocytogenes depends upon phagosome escape, was also blocked by calpain inhibition. These data indicate that L. monocytogenes co-opts host calpain to facilitate its escape from the phagosome, and more generally, that calpain may represent a cellular Achilles heel exploited by pathogens.

  17. Inhibition of calpain blocks the phagosomal escape of Listeria monocytogenes.

    Science.gov (United States)

    Lopez-Castejon, Gloria; Corbett, David; Goldrick, Marie; Roberts, Ian S; Brough, David

    2012-01-01

    Listeria monocytogenes is a gram-positive facultative intracellular bacterium responsible for the food borne infection listeriosis, affecting principally the immunocompromised, the old, neonates and pregnant women. Following invasion L. monocytogenes escapes the phagosome and replicates in the cytoplasm. Phagosome escape is central to L. monocytogenes virulence and is required for initiating innate host-defence responses such as the secretion of the cytokine interleukin-1. Phagosome escape of L. monocytogenes is reported to depend upon host proteins such as γ-interferon-inducible lysosomal thiol reductase and the cystic fibrosis transmembrane conductance regulator. The host cytosolic cysteine protease calpain is required in the life cycle of numerous pathogens, and previous research reports an activation of calpain by L. monocytogenes infection. Thus we sought to determine whether host calpain was required for the virulence of L. monocytogenes. Treatment of macrophages with calpain inhibitors blocked escape of L. monocytogenes from the phagosome and consequently its proliferation within the cytosol. This was independent of any direct effect on the production of bacterial virulence factors or of a bactericidal effect. Furthermore, the secretion of interleukin-1β, a host cytokine whose secretion induced by L. monocytogenes depends upon phagosome escape, was also blocked by calpain inhibition. These data indicate that L. monocytogenes co-opts host calpain to facilitate its escape from the phagosome, and more generally, that calpain may represent a cellular Achilles heel exploited by pathogens.

  18. Scrunching: a novel escape gait in planarians

    Science.gov (United States)

    Cochet-Escartin, Olivier; Mickolajczyk, Keith J.; Collins, Eva-Maria S.

    2015-10-01

    The ability to escape a predator or other life-threatening situations is central to animal survival. Different species have evolved unique strategies under anatomical and environmental constraints. In this study, we describe a novel musculature-driven escape gait in planarians, ‘scrunching’, which is quantitatively different from other planarian gaits, such as gliding and peristalsis. We show that scrunching is a conserved gait among different flatworm species, underlying its importance as an escape mechanism. We further demonstrate that it can be induced by a variety of physical stimuli, including amputation, high temperature, electric shock and low pH. We discuss the functional basis for scrunching as the preferential gait when gliding is impaired due to a disruption of mucus production. Finally, we show that the key mechanical features of scrunching are adequately captured by a simple biomechanical model that is solely based on experimental data from traction force microscopy and tissue rheology without fit parameters. Together, our results form a complete description of this novel form of planarian locomotion. Because scrunching has distinct dynamics, this gait can serve as a robust behavioral readout for studies of motor neuron and muscular functions in planarians and in particular the restoration of these functions during regeneration.

  19. Recombinant Receptor-Binding Domains of Multiple Middle East Respiratory Syndrome Coronaviruses (MERS-CoVs) Induce Cross-Neutralizing Antibodies against Divergent Human and Camel MERS-CoVs and Antibody Escape Mutants.

    Science.gov (United States)

    Tai, Wanbo; Wang, Yufei; Fett, Craig A; Zhao, Guangyu; Li, Fang; Perlman, Stanley; Jiang, Shibo; Zhou, Yusen; Du, Lanying

    2017-01-01

    Middle East respiratory syndrome coronavirus (MERS-CoV) binds to cellular receptor dipeptidyl peptidase 4 (DPP4) via the spike (S) protein receptor-binding domain (RBD). The RBD contains critical neutralizing epitopes and serves as an important vaccine target. Since RBD mutations occur in different MERS-CoV isolates and antibody escape mutants, cross-neutralization of divergent MERS-CoV strains by RBD-induced antibodies remains unknown. Here, we constructed four recombinant RBD (rRBD) proteins with single or multiple mutations detected in representative human MERS-CoV strains from the 2012, 2013, 2014, and 2015 outbreaks, respectively, and one rRBD protein with multiple changes derived from camel MERS-CoV strains. Like the RBD of prototype EMC2012 (EMC-RBD), all five RBDs maintained good antigenicity and functionality, the ability to bind RBD-specific neutralizing monoclonal antibodies (MAbs) and the DPP4 receptor, and high immunogenicity, able to elicit S-specific antibodies. They induced potent neutralizing antibodies cross-neutralizing 17 MERS pseudoviruses expressing S proteins of representative human and camel MERS-CoV strains identified during the 2012-2015 outbreaks, 5 MAb escape MERS-CoV mutants, and 2 live human MERS-CoV strains. We then constructed two RBDs mutated in multiple key residues in the receptor-binding motif (RBM) of RBD and demonstrated their strong cross-reactivity with anti-EMC-RBD antibodies. These RBD mutants with diminished DPP4 binding also led to virus attenuation, suggesting that immunoevasion after RBD immunization is accompanied by loss of viral fitness. Therefore, this study demonstrates that MERS-CoV RBD is an important vaccine target able to induce highly potent and broad-spectrum neutralizing antibodies against infection by divergent circulating human and camel MERS-CoV strains. MERS-CoV was first identified in June 2012 and has since spread in humans and camels. Mutations in its spike (S) protein receptor-binding domain (RBD), a

  20. Formation of nanoparticles by cooperative inclusion between (S-camptothecin-modified dextrans and β-cyclodextrin polymers

    Directory of Open Access Journals (Sweden)

    Thorbjørn Terndrup Nielsen

    2015-01-01

    Full Text Available Novel (S-camptothecin–dextran polymers were obtained by “click” grafting of azide-modified (S-camptothecin and alkyne-modified dextrans. Two series based on 10 kDa and 70 kDa dextrans were prepared with a degree of substitution of (S-camptothecin between 3.1 and 10.2%. The binding properties with β-cyclodextrin and β-cyclodextrin polymers were measured by isothermal titration calorimetry and fluorescence spectroscopy, showing no binding with β-cyclodextrin but high binding with β-cyclodextrin polymers. In aqueous solution nanoparticles were formed from association between the (S-camptothecin–dextran polymers and the β-cyclodextrin polymers.

  1. Automated Escape Guidance Algorithms for An Escape Vehicle

    Science.gov (United States)

    Flanary, Ronald; Hammen, David; Ito, Daigoro; Rabalais, Bruce; Rishikof, Brian; Siebold, Karl

    2002-01-01

    An escape vehicle was designed to provide an emergency evacuation for crew members living on a space station. For maximum escape capability, the escape vehicle needs to have the ability to safely evacuate a station in a contingency scenario such as an uncontrolled (e.g., tumbling) station. This emergency escape sequence will typically be divided into three events: The fust separation event (SEP1), the navigation reconstruction event, and the second separation event (SEP2). SEP1 is responsible for taking the spacecraft from its docking port to a distance greater than the maximum radius of the rotating station. The navigation reconstruction event takes place prior to the SEP2 event and establishes the orbital state to within the tolerance limits necessary for SEP2. The SEP2 event calculates and performs an avoidance burn to prevent station recontact during the next several orbits. This paper presents the tools and results for the whole separation sequence with an emphasis on the two separation events. The fust challenge includes collision avoidance during the escape sequence while the station is in an uncontrolled rotational state, with rotation rates of up to 2 degrees per second. The task of avoiding a collision may require the use of the Vehicle's de-orbit propulsion system for maximum thrust and minimum dwell time within the vicinity of the station vicinity. The thrust of the propulsion system is in a single direction, and can be controlled only by the attitude of the spacecraft. Escape algorithms based on a look-up table or analytical guidance can be implemented since the rotation rate and the angular momentum vector can be sensed onboard and a-priori knowledge of the position and relative orientation are available. In addition, crew intervention has been provided for in the event of unforeseen obstacles in the escape path. The purpose of the SEP2 burn is to avoid re-contact with the station over an extended period of time. Performing this maneuver properly

  2. New insights on the collisional escape of light neutrals from Mars

    Science.gov (United States)

    Gacesa, Marko; Zahnle, Kevin

    2017-04-01

    Photodissociative recombination (PDR) of atmospheric molecules on Mars is a major mechanism of production of hot (suprathermal) atoms with sufficient kinetic energy to either directly escape to space or to eject other atmospheric species. This collisional ejection mechanism is important for evaluating the escape rates of all light neutrals that are too heavy to escape via Jeans escape. In particular, it plays a role in estimating the total volume of escaped water constituents (i.e., O and H) from Mars, as well as influences evolution of the atmospheric [D]/[H] ratio1. We present revised estimates of total collisional escape rates of neutral light elements including H, He, and H2, based on recent (years 2015-2016) atmospheric density profiles obtained from the NASA Mars Atmosphere and Volatile Evolution (MAVEN) mission. We also estimate the contribution to the collisional escape from Energetic Neutral Atoms (ENAs) produced in charge-exchange of solar wind H+ and He+ ions with atmospheric gases2,3. Scattering of hot oxygen and atmospheric species of interest is modeled using fully-quantum reactive scattering formalism1,3. The escape rates are evaluated using a 1D model of the atmosphere supplemented with MAVEN measurements of the neutrals. Finally, new estimates of contributions of these non-thermal mechanisms to the estimated PDR escape rates from young Mars4 are presented. [1] M. Gacesa and V. Kharchenko, "Non-thermal escape of molecular hydrogen from Mars", Geophys. Res. Lett., 39, L10203 (2012). [2] N. Lewkow and V. Kharchenko, "Precipitation of Energetic Neutral Atoms and Escape Fluxes induced from the Mars Atmosphere", Astroph. J., 790, 98 (2014). [3] M. Gacesa, N. Lewkow, and V. Kharchenko, "Non-thermal production and escape of OH from the upper atmosphere of Mars", Icarus 284, 90 (2017). [4] J. Zhao, F. Tian, Y. Ni, and X. Huang, "DR-induced escape of O and C from early Mars", Icarus 284, 305 (2017).

  3. Sharks modulate their escape behavior in response to predator size, speed and approach orientation.

    Science.gov (United States)

    Seamone, Scott; Blaine, Tristan; Higham, Timothy E

    2014-12-01

    Escape responses are often critical for surviving predator-prey interactions. Nevertheless, little is known about how predator size, speed and approach orientation impact escape performance, especially in larger prey that are primarily viewed as predators. We used realistic shark models to examine how altering predatory behavior and morphology (size, speed and approach orientation) influences escape behavior and performance in Squalus acanthias, a shark that is preyed upon by apex marine predators. Predator models induced C-start escape responses, and increasing the size and speed of the models triggered a more intense response (increased escape turning rate and acceleration). In addition, increased predator size resulted in greater responsiveness from the sharks. Among the responses, predator approach orientation had the most significant impact on escapes, such that the head-on approach, as compared to the tail-on approach, induced greater reaction distances and increased escape turning rate, speed and acceleration. Thus, the anterior binocular vision in sharks renders them less effective at detecting predators approaching from behind. However, it appears that sharks compensate by performing high-intensity escapes, likely induced by the lateral line system, or by a sudden visual flash of the predator entering their field of view. Our study reveals key aspects of escape behavior in sharks, highlighting the modulation of performance in response to predator approach. Copyright © 2014 Elsevier GmbH. All rights reserved.

  4. Lise Meitner's escape from Germany

    Science.gov (United States)

    Sime, Ruth Lewin

    1990-03-01

    Lise Meitner (1878-1968) achieved prominence as a nuclear physicist in Germany; although of Jewish origin, her Austrian citizenship exempted her from Nazi racial laws until the annexation of Austria in 1938 precipitated her dismissal. Forbidden to emigrate, she narrowly escaped to the Netherlands with the help of concerned friends in the international physics community.

  5. Controlled release of silyl ether camptothecin from thiol-ene click chemistry-functionalized mesoporous silica nanoparticles.

    Science.gov (United States)

    Yan, Yue; Fu, Jie; Wang, Tianfu; Lu, Xiuyang

    2017-03-15

    As efficient drug carriers, stimuli-responsive mesoporous silica nanoparticles are at the forefront of research on drug delivery systems. An acid-responsive system based on silyl ether has been applied to deliver a hybrid prodrug. Thiol-ene click chemistry has been successfully utilized for tethering this prodrug to mesoporous silica nanoparticles. Here, by altering the steric bulk of the substituent on the silicon atom, the release rate of a model drug, camptothecin, was controlled. The synthesized drug delivery system was investigated by analytical methods to confirm the functionalization and conjugation of the mesoporous silica nanoparticles. Herein, trimethyl silyl ether and triethyl silyl ether were selected to regulate the release rate. Under normal plasma conditions (pH 7.4), both types of camptothecin-loaded mesoporous silica nanoparticles (i.e., MSN-Me-CPT and MSN-Et-CPT) did not release the model drug. However, under in vitro acidic conditions (pH 4.0), based on a comparison of the release rates, camptothecin was released from MSN-Me-CPT more rapidly than from MSN-Et-CPT. To determine the biocompatibility of the modified mesoporous silica nanoparticles and the in vivo camptothecin uptake behavior, MTT assays with cancer cells and confocal microscopy observations were conducted, with positive results. These functionalized nanoparticles could be useful in clinical treatments requiring controlled drug release. As the release rate of drug from drug-carrier plays important role in therapy effects, trimethyl silyl ether (TMS) and triethyl silyl ether (TES) were selected as acid-sensitive silanes to control the release rates of model drugs conjugated from MSNs by thiol-ene click chemistry. The kinetic profiles of TMS and TES materials have been studied. At pH 4.0, the release of camptothecin from MSN-Et-CPT occurred after 2h, whereas MSN-Me-CPT showed immediate drug release. The results showed that silyl ether could be used to control release rates of drugs from

  6. Liposome Model Systems to Study the Endosomal Escape of Cell-Penetrating Peptides: Transport across Phospholipid Membranes Induced by a Proton Gradient

    Directory of Open Access Journals (Sweden)

    Fatemeh Madani

    2011-01-01

    Full Text Available Detergent-mediated reconstitution of bacteriorhodopsin (BR into large unilamellar vesicles (LUVs was investigated, and the effects were carefully characterized for every step of the procedure. LUVs were prepared by the extrusion method, and their size and stability were examined by dynamic light scattering. BR was incorporated into the LUVs using the detergent-mediated reconstitution method and octyl glucoside (OG as detergent. The result of measuring pH outside the LUVs suggested that in the presence of light, BR pumps protons from the outside to the inside of the LUVs, creating acidic pH inside the vesicles. LUVs with 20% negatively charged headgroups were used to model endosomes with BR incorporated into the membrane. The fluorescein-labeled cell-penetrating peptide penetratin was entrapped inside these BR-containing LUVs. The light-induced proton pumping activity of BR has allowed us to observe the translocation of fluorescein-labeled penetratin across the vesicle membrane.

  7. Camptothecin and its analog SN-38, the active metabolite of irinotecan, inhibit binding of the transcriptional regulator and oncoprotein FUBP1 to its DNA target sequence FUSE.

    Science.gov (United States)

    Khageh Hosseini, Sabrina; Kolterer, Stefanie; Steiner, Marlene; von Manstein, Viktoria; Gerlach, Katharina; Trojan, Jörg; Waidmann, Oliver; Zeuzem, Stefan; Schulze, Jörg O; Hahn, Steffen; Steinhilber, Dieter; Gatterdam, Volker; Tampé, Robert; Biondi, Ricardo M; Proschak, Ewgenij; Zörnig, Martin

    2017-12-15

    The transcriptional regulator FUSE Binding Protein 1 (FUBP1) is overexpressed in more than 80% of all human hepatocellular carcinomas (HCCs) and other solid tumor entities including prostate and colorectal carcinoma. FUBP1 expression is required for HCC tumor cell expansion, and it functions as an important pro-proliferative and anti-apoptotic oncoprotein that binds to the single-stranded DNA sequence FUSE to regulate the transcription of a variety of target genes. In this study, we screened an FDA-approved drug library and discovered that the Topoisomerase I (TOP1) inhibitor camptothecin (CPT) and its derivative 7-ethyl-10-hydroxycamptothecin (SN-38), the active irinotecan metabolite that is used in the clinics in combination with other chemotherapeutics to treat carcinoma, inhibit FUBP1 activity. Both molecules prevent in vitro the binding of FUBP1 to its single-stranded target DNA FUSE, and they induce deregulation of FUBP1 target genes in HCC cells. Our results suggest the interference with the FUBP1/FUSE interaction as a further molecular mechanism that, in addition to the inactivation of TOP1, may contribute to the therapeutic potential of CPT/SN-38. Targeting of FUBP1 in HCC therapy with SN-38/irinotecan could be a particularly interesting option because of the high FUBP1 levels in HCC cells and their dependency on FUBP1 expression. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Porphyromonas gingivalis Stimulates TLR2-PI3K Signaling to Escape Immune Clearance and Induce Bone Resorption Independently of MyD88

    Directory of Open Access Journals (Sweden)

    Hasnaa Makkawi

    2017-08-01

    Full Text Available Porphyromonas gingivalis is a gram-negative anaerobic periodontal pathogen that persists in dysbiotic mixed-species biofilms alongside a dense inflammatory infiltrate of neutrophils and other leukocytes in the subgingival areas of the periodontium. Toll-like receptor 2 (TLR2 mediates the inflammatory response to P. gingivalis and TLR2-deficient mice resist alveolar bone resorption following oral challenge with this organism. Although, MyD88 is an adaptor protein considered necessary for TLR2-induced inflammation, we now report for the first time that oral challenge with P. gingivalis leads to alveolar bone resorption in the absence of MyD88. Indeed, in contrast to prototypical TLR2 agonists, such as the lipopeptide Pam3CSK4 that activates TLR2 in a strictly MyD88-dependent manner, P. gingivalis strikingly induced TLR2 signaling in neutrophils and macrophages regardless of the presence or absence of MyD88. Moreover, genetic or antibody-mediated inactivation of TLR2 completely reduced cytokine production in P. gingivalis-stimulated neutrophils or macrophages, suggesting that TLR2 plays a non-redundant role in the host response to P. gingivalis. In the absence of MyD88, inflammatory TLR2 signaling in P. gingivalis-stimulated neutrophils or macrophages depended upon PI3K. Intriguingly, TLR2-PI3K signaling was also critical to P. gingivalis evasion of killing by macrophages, since their ability to phagocytose this pathogen was reduced in a TLR2 and PI3K-dependent manner. Moreover, within those cells that did phagocytose bacteria, TLR2-PI3K signaling blocked phago-lysosomal maturation, thereby revealing a novel mechanism whereby P. gingivalis can enhance its intracellular survival. Therefore, P. gingivalis uncouples inflammation from bactericidal activity by substituting TLR2-PI3K in place of TLR2-MyD88 signaling. These findings further support the role of P. gingivalis as a keystone pathogen, which manipulates the host inflammatory response in a way

  9. Intranasal Delivery of Camptothecin-Loaded Tat-Modified Nanomicells for Treatment of Intracranial Brain Tumors

    Directory of Open Access Journals (Sweden)

    Yuuki Takashima

    2012-10-01

    Full Text Available The blood-brain barrier is a substantial obstacle for delivering anticancer agents to brain tumors, and new strategies for bypassing it are sorely needed for brain tumor therapy. Intranasal delivery provides a practical, noninvasive method for delivering therapeutic agents to the brain. Intranasal application of nano-sized micelles that have been modified with Tat peptide facilitates brain delivery of fluorescent model materials. In this study, we evaluated a nose-to-brain delivery system for brain tumor therapy. We nasally administered the anti-tumor drug camptothecin (CPT in solution and in methoxy poly(ethylene glycol (MPEG/poly(e-caprolactone (PCL amphiphilic block copolymers (MPEG-PCL and cell penetrating peptide, Tat analog-modified MPEG-PCL (MPEG-PCL-Tat MPEG-PCL-Tat to rats bearing intracranial glioma tumors and quantified the cytotoxicity against glioma cells, and the therapeutic effects. CPT-loaded MPEG-PCL-Tat micelles showed higher cytotoxicity than CPT-loaded MPEG-PCL. CPT-free MPEG-PCL-Tat didn’t show any cytotoxicity, even at high concentrations (2 mmol/mL. CPT-loaded MPEG-PCL-Tat micelles significantly prolonged the median survival of rats. These results indicate that intranasal delivery of anti-cancer drugs with cell penetrating peptide-modified nanomicelles might be an effective therapy for brain tumors.

  10. Structural and Affinity Analyses of G-Quadruplex DNA Aptamers for Camptothecin Derivatives

    Directory of Open Access Journals (Sweden)

    Naoki Sugimoto

    2013-08-01

    Full Text Available We recently selected DNA aptamers that bind to camptothecin (CPT and CPT derivatives from a 70-mer oligodeoxyribonucleotide (ODN library using the Systematic Evolution of Ligands by EXponential enrichment (SELEX method. The target-binding activity of the obtained 70-mer CPT-binding DNA aptamer, termed CA-70, which contains a 16-mer guanine (G-core motif (G3TG3TG3T2G3 that forms a three-tiered G-quadruplex, was determined using fluorescence titration. In this study, truncated fragments of CA-70 that all have the G-core motif, CA-40, -20, -19, -18A, -18B, -17, and -16, were carefully analyzed. We found that CA-40 retained the target-binding activity, whereas CA-20, -19, and -18B exhibited little or no binding activities. Further, not only CA-18A but also the shorter length fragments CA-17 and -16 clearly retained the binding activity, indicating that tail strands of the G-quadruplex structure can significantly affect the target binding of G-quadruplex DNA aptamers. Further analyses using circular dichroism (CD spectroscopy and fluorescence polarization (FP assay were conducted to investigate the structure and affinity of G-quadruplex DNA aptamers.

  11. Molecular design and synthesis of self-assembling camptothecin drug amphiphiles.

    Science.gov (United States)

    Cheetham, Andrew G; Lin, Yi-An; Lin, Ran; Cui, Honggang

    2017-06-01

    The conjugation of small molecular hydrophobic anticancer drugs onto a short peptide with overall hydrophilicity to create self-assembling drug amphiphiles offers a new prodrug strategy, producing well-defined, discrete nanostructures with a high and quantitative drug loading. Here we show the detailed synthesis procedure and how the molecular structure can influence the synthesis of the self-assembling prodrugs and the physicochemical properties of their assemblies. A series of camptothecin-based drug amphiphiles were synthesized via combined solid- and solution-phase synthetic techniques, and the physicochemical properties of their self-assembled nanostructures were probed using a number of imaging and spectroscopic techniques. We found that the number of incorporated drug molecules strongly influences the rate at which the drug amphiphiles are formed, exerting a steric hindrance toward any additional drugs to be conjugated and necessitating extended reaction time. The choice of peptide sequence was found to affect the solubility of the conjugates and, by extension, the critical aggregation concentration and contour length of the filamentous nanostructures formed. In the design of self-assembling drug amphiphiles, the number of conjugated drug molecules and the choice of peptide sequence have significant effects on the nanostructures formed. These observations may allow the fine-tuning of the physicochemical properties for specific drug delivery applications, ie systemic vs local delivery.

  12. Synthesis and biological evaluation of novel conjugates of camptothecin and 5-Flurouracil as cytotoxic agents

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Liu, E-mail: yqliu@lzu.edu.c [Lanzhou Jiaotong University (China). Environmental and Municipal Engineering School; Chun-Yan Zhaob; Ying-Qian Liu [Lanzhou University (China). School of Pharmacy

    2011-07-01

    A series of novel conjugates of camptothecin and 5-fluorouracil were first synthesized and their cytotoxic activities against two human tumor cell lines (SGC-7901 and A-549) as well as in vitro pharmacokinetic determination of lactone stability were studied. Among these compounds, most tested conjugates showed comparable or superior cytotoxic activities to 2, but less potent compared with 1. Particularly, conjugates 10b and 10d were highly active against A-549 with IC{sub 50} values of 0.45 and 0.38 {mu}mol L{sup -1}, respectively. Also, the in vitro pharmacokinetic determination of lactone levels of representative compound 10b showed that the biological life span of their lactone forms in human and mouse plasma significantly increased compared with their mother compound 1. Quantitative structure-activity relationship (QSAR) method was then applied for developing linear models to predict the cytotoxic activities of these derivatives that have not yet been synthesized or experimentally tested. In addition, molecular docking was used to clarify the binding mode of these derivatives to human DNA topoisomerase I. The important hydrogen-bonding interactions were observed between these derivatives and their receptor. The results from molecular modeling and QSAR study can guide the design of novel conjugates with higher antitumor activity. (author)

  13. Effects of camptothecin or TOP1 overexpression on genetic stability in Saccharomyces cerevisiae.

    Science.gov (United States)

    Sloan, Roketa; Huang, Shar-Yin Naomi; Pommier, Yves; Jinks-Robertson, Sue

    2017-11-01

    Topoisomerase I (Top1) removes DNA torsional stress by nicking and resealing one strand of DNA, and is essential in higher eukaryotes. The enzyme is frequently overproduced in tumors and is the sole target of the chemotherapeutic drug camptothecin (CPT) and its clinical derivatives. CPT stabilizes the covalent Top1-DNA cleavage intermediate, which leads to toxic double-strand breaks (DSBs) when encountered by a replication fork. In the current study, we examined genetic instability associated with CPT treatment or with Top1 overexpression in the yeast Saccharomyces cerevisiae. Two types of instability were monitored: Top1-dependent deletions in haploid strains, which do not require processing into a DSB, and instability at the repetitive ribosomal DNA (rDNA) locus in diploid strains, which reflects DSB formation. Three 2-bp deletion hotspots were examined and mutations at each were elevated either when a wild-type strain was treated with CPT or when TOP1 was overexpressed, with the mutation frequency correlating with the level of TOP1 overexpression. Under both conditions, deletions at novel positions were enriched. rDNA stability was examined by measuring loss-of-heterozygosity and as was observed previously upon CPT treatment of a wild-type strain, Top1 overexpression destabilized rDNA. We conclude that too much, as well as too little of Top1 is detrimental to eukaryotic genomes, and that CPT has destabilizing effects that extend beyond those associated with DSB formation. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Sirt1 attenuates camptothecin-induced apoptosis through caspase-3 pathway in porcine preadipocytes

    Science.gov (United States)

    Adipose tissue is an important energy reservoir, and its over-development results in obesity in humans or body fat over-deposition in livestock. Loss of preadipocytes through apoptosis has been proposed as an alternative way to reduce adipose tissue mass. At present, the effect and regulatory mechan...

  15. Molecular Dications in Planetary Atmospheric Escape

    Directory of Open Access Journals (Sweden)

    Stefano Falcinelli

    2016-08-01

    Full Text Available Fundamental properties of multiply charged molecular ions, such as energetics, structure, stability, lifetime and fragmentation dynamics, are relevant to understand and model the behavior of gaseous plasmas as well as ionosphere and astrophysical environments. Experimental determinations of the Kinetic Energy Released (KER for ions originating from dissociations reactions, induced by Coulomb explosion of doubly charged molecular ions (molecular dications produced by double photoionization of CO2, N2O and C2H2 molecules of interest in planetary atmospheres, are reported. The KER measurement as a function of the ultraviolet (UV photon energy in the range of 28–65 eV was extracted from the electron-ion-ion coincidence spectra obtained by using tunable synchrotron radiation coupled with ion imaging techniques at the ELETTRA Synchrotron Light Laboratory Trieste, Italy. These experiments, coupled with a computational analysis based on a Monte Carlo trajectory simulation, allow assessing the probability of escape for simple ionic species in the upper atmosphere of Mars, Venus and Titan. The measured KER in the case of H+, C+, CH+, CH2+, N+, O+, CO+, N2+ and NO+ fragment ions range between 1.0 and 5.5 eV, being large enough to allow these ionic species to participate in the atmospheric escape from such planets into space. In the case of Mars, we suggest a possible explanation for the observed behavior of the O+ and CO22+ ion density profiles.

  16. EscapED: A Framework for Creating Educational Escape Rooms and Interactive Games to For Higher/Further Education.

    Directory of Open Access Journals (Sweden)

    Samantha Jane Clarke

    2017-09-01

    Full Text Available Game-based learning (GBL is often found to be technologically driven and more often than not, serious games for instance, are conceptualised and designed solely for digital platforms and state of the art technologies. To encourage a greater discussion on the potential benefits and challenges of a more holistic approach to developing GBL that promote human centered interactions and play for learning, the authors present the escapED programme. The escapED programme was conceived following the recent entertainment trend of escape rooms and is used for developing non-digital GBL approaches within education. escapED aids the design and creation of educational Escape Rooms and Interactive Gaming Experiences for staff and students in further/higher education settings. The paper first presents a pilot study that was used to assess the feasibility and acceptance of University teaching staff of embedding interactive GBL into a higher education environment. The authors then present the escapED theoretical framework that was used to create the prototype game for the pilot study as a tool to aid future design and development of on-site interactive experiences. The paper also presents an external developer report of using the escapED framework to develop a prototype game for teaching research methods to Southampton University students. Finally, the authors present a discussion on the use of the escapED framework so far and plans for future work and evaluation in order to provide engaging alternatives for learning and soft skills development amongst higher education staff andstudents.

  17. Sequential targeted delivery of paclitaxel and camptothecin using a cross-linked "nanosponge" network for lung cancer chemotherapy.

    Science.gov (United States)

    Hariri, Ghazal; Edwards, Aaron D; Merrill, Tyler B; Greenbaum, Joshua M; van der Ende, Alice E; Harth, Eva

    2014-01-06

    The applicability of a HVGGSSV peptide targeted "nanosponge" drug delivery system for sequential administration of a microtubule inhibitor (paclitaxel) and topoisomerase I inhibitor (camptothecin) was investigated in a lung cancer model. Schedule-dependent combination treatment with nanoparticle paclitaxel (NP PTX) and camptothecin (NP CPT) was studied in vitro using flow cytometry and confocal imaging to analyze changes in cell cycle, microtubule morphology, apoptosis, and cell proliferation. Results showed significant G2/M phase cell cycle arrest, changes in microtubule dynamics that produced increased apoptotic cell death and decreased proliferation with initial exposure to NP PTX, followed by NP CPT in lung cancer cells. In vivo molecular imaging and TEM studies validated HVGGSSV-NP tumor binding at 24 h and confirmed the presence of Nanogold labeled HVGGSSV-NPs in tumor microvascular endothelial cells. Therapeutic efficacy studies conducted with sequential HVGGSSV targeted NP PTX and NP CPT showed 2-fold greater tumor growth delay in combination versus monotherapy treated groups, and 4-fold greater delay compared to untargeted and systemic drug controls. Analytical HPLC/MS methods were used to quantify drug content in tumor tissues at various time points, with significant paclitaxel and camptothecin levels in tumors 2 days postinjection and continued presence of both drugs up to 23 days postinjection. The efficacy of the NP delivery system in sequential treatments was corroborated in both in vitro and in vivo lung cancer models showing increased G2/M phase arrest and microtubule disruption, resulting in enhanced apoptotic cell death, decreased cell proliferation and vascular density.

  18. The Anti-HIV Actions of 7- and 10-Substituted Camptothecins

    Directory of Open Access Journals (Sweden)

    Yu-Ye Li

    2009-12-01

    Full Text Available Camptothecin (CPT, a traditional anti-tumor drug, has been shown to possess anti-HIV-1 activity. To increase the antiviral potency, the anti-HIV activities of two CPT derivatives, 10-hydroxy-CPT and 7-hydroxymethyl-CPT, were evaluated in vitro. The therapy index (TI of CPT, 10-hydroxy-CPT and 7-hydroxymethyl-CPT against HIV-1IIIB in C8166 were 24.2, 4.2 and 198.1, and against clinical isolated strain HIV-1KM018 in PBMC were 10.3, 3.5 and 66.0, respectively. While the TI of CPT, 10-hydroxy-CPT and 7-hydroxymethyl-CPT against HIV-2CBL-20 were 34.5, 10.7 and 317.0, respectively, and the TI of the three compounds against HIV-2ROD showed the similar values. However, when the antiviral mechanisms were considered, we found there was no inhibition of 7-hydroxymethyl-CPT on viral cell-to-cell transmission, and was no inhibition on reverse transcriptase, protease or integrase in cell-free systems. 7-Hydroxymethyl-CPT showed no selective killing of chronically infected cells after 3 days of incubation. In conclusion, 7-hydroxymethyl-CPT showed more potent anti-HIV activity, while 10-hydroxy-CPT had less efficient activity, compared with the parent CPT. Though the antiviral mechanisms remain to be further elucidated; the modification of -OH residues at C-7 of CPT could enhance the antiviral activity, while of -OH residues at C-10 of CPT had decreased the antiviral activity, which provides the preliminary modification strategy for anti-viral activities enhancement of this compound.

  19. Malaria parasites: the great escape

    Directory of Open Access Journals (Sweden)

    Laurent Rénia

    2016-11-01

    Full Text Available Parasites of the genus Plasmodium have a complex life cycle. They alternate between their final mosquito host and their intermediate hosts. The parasite can be either extra- or intracellular, depending on the stage of development. By modifying their shape, motility, and metabolic requirements, the parasite adapts to the different environments in their different hosts. The parasite has evolved to escape the multiple immune mechanisms in the host that try to block parasite development at the different stages of their development. In this article, we describe the mechanisms reported thus far that allow the Plasmodium parasite to evade innate and adaptive immune responses.

  20. Optimal escape theory predicts escape behaviors beyond flight initiation distance: risk assessment and escape by striped plateau lizards Sceloporus virgatus

    Directory of Open Access Journals (Sweden)

    William E. COOPER Jr.

    2009-04-01

    Full Text Available Escape theory predicts that flight initiation distance (FID = distance between predator and prey when escape begins is longer when risk is greater and shorter when escape is more costly. A few tests suggest that escape theory applies to distance fled. Escape models have not addressed stochastic variables, such as probability of fleeing and of entering refuge, but their economic logic might be applicable. Experiments on several risk factors in the lizard Sceloporus virgatus confirmed all predictions for the above escape variables. FID was greater when approach was faster and more direct, for lizards on ground than on trees, for lizards rarely exposed to humans, for the second of two approaches, and when the predator turned toward lizards rather than away. Lizards fled further during rapid and second consecutive approaches. They were more likely to flee when approached directly, when a predator turned toward them, and during second approaches. They were more likely to enter refuge when approached rapidly. A novel finding is that perch height in trees was unrelated to FID because lizards escaped by moving out of sight, then moving up or down unpredictably. These findings add to a growing body of evidence supporting predictions of escape theory for FID and distance fled. They show that two probabilistic aspects of escape are predictable based on relative predation risk levels. Because individuals differ in boldness, the assessed optimal FID and threshold risks for fleeing and entering refuge are exceeded for an increasing proportion of individuals as risk increases.

  1. Pyrosequencing of the Camptotheca acuminata transcriptome reveals putative genes involved in camptothecin biosynthesis and transport

    Directory of Open Access Journals (Sweden)

    Sun Yongzhen

    2011-10-01

    Full Text Available Abstract Background Camptotheca acuminata is a Nyssaceae plant, often called the "happy tree", which is indigenous in Southern China. C. acuminata produces the terpenoid indole alkaloid, camptothecin (CPT, which exhibits clinical effects in various cancer treatments. Despite its importance, little is known about the transcriptome of C. acuminata and the mechanism of CPT biosynthesis, as only few nucleotide sequences are included in the GenBank database. Results From a constructed cDNA library of young C. acuminata leaves, a total of 30,358 unigenes, with an average length of 403 bp, were obtained after assembly of 74,858 high quality reads using GS De Novo assembler software. Through functional annotation, a total of 21,213 unigenes were annotated at least once against the NCBI nucleotide (Nt, non-redundant protein (Nr, Uniprot/SwissProt, Kyoto Encyclopedia of Genes and Genomes (KEGG, and Arabidopsis thaliana proteome (TAIR databases. Further analysis identified 521 ESTs representing 20 enzyme genes that are involved in the backbone of the CPT biosynthetic pathway in the library. Three putative genes in the upstream pathway, including genes for geraniol-10-hydroxylase (CaPG10H, secologanin synthase (CaPSCS, and strictosidine synthase (CaPSTR were cloned and analyzed. The expression level of the three genes was also detected using qRT-PCR in C. acuminata. With respect to the branch pathway of CPT synthesis, six cytochrome P450s transcripts were selected as candidate transcripts by detection of transcript expression in different tissues using qRT-PCR. In addition, one glucosidase gene was identified that might participate in CPT biosynthesis. For CPT transport, three of 21 transcripts for multidrug resistance protein (MDR transporters were also screened from the dataset by their annotation result and gene expression analysis. Conclusion This study produced a large amount of transcriptome data from C. acuminata by 454 pyrosequencing. According to

  2. Bcmfs1, a novel major facilitator superfamily transporter from Botrytis cinerea, provides tolerance towards the natural toxic compounds camptothecin and cercosporin and towards fungicides

    NARCIS (Netherlands)

    Hayashi, K.; Schoonbeek, H.; Waard, De M.A.

    2002-01-01

    Bcmfs1, a novel major facilitator superfamily gene from Botrytis cinerea, was cloned, and replacement and overexpression mutants were constructed to study its function. Replacement mutants showed increased sensitivity to the natural toxic compounds camptothecin and cercosporin, produced by the plant

  3. Polysaccharopeptides derived from Coriolus versicolor potentiate the S-phase specific cytotoxicity of Camptothecin (CPT on human leukemia HL-60 cells

    Directory of Open Access Journals (Sweden)

    Jiang Pingping

    2010-04-01

    Full Text Available Abstract Background Polysaccharopeptide (PSP from Coriolus versicolor (Yunzhi is used as a supplementary cancer treatment in Asia. The present study aims to investigate whether PSP pre-treatment can increase the response of the human leukemia HL-60 cells to apoptosis induction by Camptothecin (CPT. Methods We used bivariate bromodeoxyuridine/propidium iodide (BrdUrd/PI flow cytometry analysis to measure the relative movement (RM of the BrdUrd positively labeled cells and DNA synthesis time (Ts on the HL-60 cell line. We used annexin V/PI flow cytometry analysis to quantify the viable, necrotic and apoptotic cells. The expression of cyclin E and cyclin B1 was determined with annexin V/PI flow cytometry and western blotting. Human peripheral blood mononuclear cells were used to test the cytotoxicity of PSP and CPT. Results PSP reduced cellular proliferation; inhibited cells progression through both S and G2 phase, reduced 3H-thymidine uptake and prolonged DNA synthesis time (Ts in HL-60 cells. PSP-pretreated cells enhanced the cytotoxicity of CPT. The sensitivity of cells to the cytotoxic effects of CPT was seen to be the highest in the S-phase and to a small extent of the G2 phase of the cell cycle. On the other hand, no cell death (measured by annexin V/PI was evident with the normal human peripheral blood mononuclear cells with treatment of either PSP or CPT. Conclusion The present study shows that PSP increases the sensitization of the HL-60 cells to undergo effective apoptotic cell death induced by CPT. The pattern of sensitivity of cancer cells is similar to that of HL-60 cells. PSP rapidly arrests and/or kills cells in S-phase and did not interfere with the anticancer action of CPT. PSP is a potential adjuvant to treat human leukemia as rapidly proliferating tumors is characterized by a high proportion of S-phase cells.

  4. Camptothecin conjugated with DNA minor-groove binder netropsin: enhanced lactone stability, inhibition of human DNA topoisomerase I and antiproliferative activity.

    Science.gov (United States)

    Sukhanova, Alyona; Grokhovsky, Sergei; Zhuze, Alexei; Devy, Jerome; Pluot, Michel; Oleinikov, Vladimir; Nabiev, Igor

    2003-01-01

    The conjugates of camptothecin (CPT) with ligands possessing different DNA selectivity could be promising agents in cancer therapy affecting expression of specific genes by trapping DNA topoisomerase I (top I)-DNA complexes in a sequence-selective manner. Our recent data show that minor-groove binder netropsin (Nt) and its derivatives modulate the CPT-induced pattern of top I-mediated DNA cleavage. In an effort to develop a new molecule with good biological activity we have linked CPT with Nt and report here the first results of in vitro examination of the new compound. CPT-Nt conjugate linked with flexible spacer through position 7 of CPT chromophore was synthesized and analyzed for lactone stability, the ability to modulate a top I-mediated DNA cleavage and antiproliferative activity within a panel of six tumor cell lines. CPT-Nt conjugate demonstrates enhanced lactone stability and concentration-dependent top I poisoning or suppression in vitro. The rate of conjugate hydrolysis in a water solution displays a 20-fold enhancement of stability compared with CPT. The cytotoxicity of the conjugate against acute promyelocytic leukaemia (HL60), chronic myelogenous leukaemia (K562), breast adenocarcinoma (MCF7), colorectal adenocarcinoma (HT29), lung carcinoma(A549) and ovarian adenocarcinoma (CaOV3) tumor cell lines was evaluated. The lowest IC50 value (0.08 microM) indicated its selective toxicity towards the ovarian adenocarcinoma cell line. The enhanced stability of CPT-Nt conjugate and its selective toxicity against the CaOV3 cell line may indicate its utility as an antitumor agent against ovarian adenocarcinoma.

  5. Thermosensitive mPEG-b-PA-g-PNIPAM comb block copolymer micelles: effect of hydrophilic chain length and camptothecin release behavior.

    Science.gov (United States)

    Yang, Xiao-Li; Luo, Yan-Ling; Xu, Feng; Chen, Ya-Shao

    2014-02-01

    Block copolymer micelles are extensively used as drug controlled release carriers, showing promising application prospects. The comb or brush copolymers are especially of great interest, whose densely-grafted side chains may be important for tuning the physicochemical properties and conformation in selective solvents, even in vitro drug release. The purpose of this work was to synthesize novel block copolymer combs via atom transfer radical polymerization, to evaluate its physicochemical features in solution, to improve drug release behavior and to enhance the bioavailablity, and to decrease cytotoxicity. The physicochemical properties of the copolymer micelles were examined by modulating the composition and the molecular weights of the building blocks. A dialysis method was used to load hydrophobic camptothecin (CPT), and the CPT release and stability were detected by UV-vis spectroscopy and high-performance liquid chromatography, and the cytotoxicity was evaluated by MTT assays. The copolymers could self-assemble into well-defined spherical core-shell micelle aggregates in aqueous solution, and showed thermo-induced micellization behavior, and the critical micelle concentration was 2.96-27.64 mg L(-1). The micelles were narrow-size-distribution, with hydrodynamic diameters about 128-193 nm, depending on the chain length of methoxy polyethylene glycol (mPEG) blocks and poly(N-isopropylacrylamide) (PNIPAM) graft chains or/and compositional ratios of mPEG to PNIPAM. The copolymer micelles could stably and effectively load CPT but avoid toxicity and side-effects, and exhibited thermo-dependent controlled and targeted drug release behavior. The copolymer micelles were safe, stable and effective, and could potentially be employed as CPT controlled release carriers.

  6. Electronic Escape Trails for Firefighters

    Science.gov (United States)

    Jorgensen, Charles; Schipper, John; Betts, Bradley

    2008-01-01

    A proposed wireless-communication and data-processing system would exploit recent advances in radio-frequency identification devices (RFIDs) and software to establish information lifelines between firefighters in a burning building and a fire chief at a control station near but outside the building. The system would enable identification of trails that firefighters and others could follow to escape from the building, including identification of new trails should previously established trails become blocked. The system would include a transceiver unit and a computer at the control station, portable transceiver units carried by the firefighters in the building, and RFID tags that the firefighters would place at multiple locations as they move into and through the building (see figure). Each RFID tag, having a size of the order of a few centimeters, would include at least standard RFID circuitry and possibly sensors for measuring such other relevant environmental parameters as temperature, levels of light and sound, concentration of oxygen, concentrations of hazardous chemicals in smoke, and/or levels of nuclear radiation. The RFID tags would be activated and interrogated by the firefighters and control-station transceivers. Preferably, RFID tags would be configured to communicate with each other and with the firefighters units and the control station in an ordered sequence, with built-in redundancy. In a typical scenario, as firefighters moved through a building, they would scatter many RFID tags into smoke-obscured areas by use of a compressed-air gun. Alternatively or in addition, they would mark escape trails by dropping RFID tags at such points of interest as mantraps, hot spots, and trail waypoints. The RFID tags could be of different types, operating at different frequencies to identify their functions, and possibly responding by emitting audible beeps when activated by signals transmitted by transceiver units carried by nearby firefighters.

  7. Escape as Reinforcement and Escape Extinction in the Treatment of Feeding Problems

    Science.gov (United States)

    LaRue, Robert H.; Stewart, Victoria; Piazza, Cathleen C.; Volkert, Valerie M.; Patel, Meeta R.; Zeleny, Jason

    2011-01-01

    Given the effectiveness of putative escape extinction as treatment for feeding problems, it is surprising that little is known about the effects of escape as reinforcement for appropriate eating during treatment. In the current investigation, we examined the effectiveness of escape as reinforcement for mouth clean (a product measure of…

  8. Learning from escaped prescribed fire reviews [Abstract

    Science.gov (United States)

    Anne Black; Dave Thomas; James Saveland

    2011-01-01

    Over the past decade, the wildland fire community has developed a number of innovative methods for conducting a review following escape of a prescribed fire. The stated purpose been to identify methods that not only meet policy requirements, but to reduce future escapes. Implicit is the assumption that a review leads to learning. Yet, as organizational learning expert...

  9. Escape of atmospheric gases from the Moon

    Indian Academy of Sciences (India)

    The escape rate of atmospheric molecules on the Moon is calculated.Based on the assumption that the rates of emission and escape of gases attain equilibrium, the ratio of molecular number densities during day and night, 0/0, can be explained. The plausible emission rate of helium and radioactive elements present ...

  10. Compound Specific Extraction of Camptothecin from Nothapodytes nimmoniana and Piperine from Piper nigrum Using Accelerated Solvent Extractor.

    Science.gov (United States)

    Upadhya, Vinayak; Pai, Sandeep R; Sharma, Ajay K; Hegde, Harsha V; Kholkute, Sanjiva D; Joshi, Rajesh K

    2014-01-01

    Effects of varying temperatures with constant pressure of solvent on extraction efficiency of two chemically different alkaloids were studied. Camptothecin (CPT) from stem of Nothapodytes nimmoniana (Grah.) Mabb. and piperine from the fruits of Piper nigrum L. were extracted using Accelerated Solvent Extractor (ASE). Three cycles of extraction for a particular sample cell at a given temperature assured complete extraction. CPT and piperine were determined and quantified by using a simple and efficient UFLC-PDA (245 and 343 nm) method. Temperature increased efficiency of extraction to yield higher amount of CPT, whereas temperature had diminutive effect on yield of piperine. Maximum yield for CPT was achieved at 80°C and for piperine at 40°C. Thus, the study determines compound specific extraction of CPT from N. nimmoniana and piperine from P. nigrum using ASE method. The present study indicates the use of this method for simple, fast, and accurate extraction of the compound of interest.

  11. ESCAP migration study gathers momentum.

    Science.gov (United States)

    1980-01-01

    A comparative study is being conducted in the ESCAP (Economic and Social Commission for Asia and the Pacific) region on the relationships of migration and urbanization to development. The 1st stage of the study will entail the preparation of country reports on the census analysis of migration, urbanization and development. The 2nd stage will involve preparation of a series of national migration surveys. The 3rd phase will involve assisting member governments to formulate a comprehensive population redistribution policy as part of their national development planning. 1st-phase country reports have been completed in Sri Lanka, South Korea, the Philippines, and Indonesia. Migration in Sri Lanka has largely been rural-to-rural with little urbanization so far. The picture in South Korea has been the opposite, with rapid urbanization in the 1960s and 1970s; the government is hoping to divert some population to smaller cities away from Seoul. The pattern in the Philippines is 1 of urban primacy with the metropolis of Manila accounting for over 1/3 of the country's total population. Indonesia is characterized by a dense heartland in the Java-Bali regions. However, the rate of urbanization here has been slower. Migrants in all the countries studied are preponderantly young. The sex differential varies from country to country. The influence of migration on subsequent fertility is unknown.

  12. Physics escape room as an educational tool

    Science.gov (United States)

    Vörös, Alpár István Vita; Sárközi, Zsuzsa

    2017-12-01

    Escape rooms have flourished in the last decade. These are adventure games in which players work together to solve puzzles using hints, clues and a strategy to escape from a locked room. In many cases they use different phenomena related to physics. Hence the idea of using escape rooms in science centers or even in classroom activities. Escape rooms are designed for one single team of players, the method is more suitable for activities in a science centre. In our paper, we show that escape rooms' puzzle solving methods could be used in physics classroom activities as well, taking into account that several teams have to work together in the same room/place. We have developed an educational escape game for physics of fluids, as this topic is left out from the Romanian high-school curriculum. We have tried out our game during the project week called "Şcoala altfel" ("school in a different way") and in a physics camp for gifted students. We present the designed physics escape game and the results.

  13. Escapes in Hamiltonian systems with multiple exit channels: Part II

    OpenAIRE

    Zotos, Euaggelos E.

    2015-01-01

    We explore the escape dynamics in open Hamiltonian systems with multiple channels of escape continuing the work initiated in Part I. A thorough numerical investigation is conducted distinguishing between trapped (ordered and chaotic) and escaping orbits. The determination of the location of the basins of escape towards the different escape channels and their correlations with the corresponding escape periods of the orbits is undoubtedly an issue of paramount importance. We consider four diffe...

  14. A Model for SEP Escape

    Science.gov (United States)

    Antiochos, S. K.; Masson, S.; DeVore, C. R.

    2012-01-01

    Magnetic reconnection in the solar atmosphere is believed to be the driver of most solar explosive phenomena. Therefore, the topology of the coronal magnetic field is central to understanding the solar drivers of space weather. Of particular importance to space weather are the impulsive Solar Energetic particles that are associated with some CME/eruptive flare events. Observationally, the magnetic configuration of active regions where solar eruptions originate appears to agree with the standard eruptive flare model. According to this model, particles accelerated at the flare reconnection site should remain trapped in the corona and the ejected plasmoid. However, flare-accelerated particles frequently reach the Earth long before the CME does. We present a model that may account for the injection of energetic particles onto open magnetic flux tubes connecting to the Earth. Our model is based on the well-known 2.5D breakout topology, which has a coronal null point (null line) and a four-flux system. A key new addition, however, is that we include an isothermal solar wind with open-flux regions. Depending on the location of the open flux with respect to the null point, we find that the flare reconnection can consist of two distinct phases. At first, the flare reconnection involves only closed field, but if the eruption occurs close to the open field, we find a second phase involving interchange reconnection between open and closed. We argue that this second reconnection episode is responsible for the injection of flare-accelerated particles into the interplanetary medium. We will report on our recent work toward understanding how flare particles escape to the heliosphere. This work uses high-resolution 2.5D MHD numerical simulations performed with the Adaptively Refined MHD Solver (ARMS).

  15. Escape response of the crab Neohelice to computer generated looming and translational visual danger stimuli.

    Science.gov (United States)

    Scarano, Florencia; Tomsic, Daniel

    2014-01-01

    Historically, arthropod behavior has been considered to be a collection of simple, automaton-like routines commanded by domain-specific brain modules working independently. Nowadays, it is evident that the extensive behavioral repertoire of these animals and its flexibility necessarily imply far more complex abilities than originally assumed. For example, even what was thought to be a straightforward behavior of crabs, the escape response to visual danger stimuli, proved to involve a number of sequential stages, each of which implying decisions made on the bases of stimulus and contextual information. Inspired in previous observations on how the stimulus trajectory can affect the escape response of crabs in the field, we investigated the escape response to images of objects approaching directly toward the crab (looming stimuli: LS) or moving parallel to it (translational stimuli: TS) in the laboratory. Computer simulations of moving objects were effective to elicit escapes. LS evoked escapes with higher probability and intensity (speed and distance of escape) than TS, but responses started later. In addition to the escape run, TS also evoked a defensive response of the animal with its claws. Repeated presentations of TS or LS were both capable of inducing habituation. Results are discussed in connection with the possibilities offered by crabs to investigate the neural bases of behaviors occurring in the natural environment. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Can You Escape the Silent Killer?

    Science.gov (United States)

    ... Peripheral Artery Disease Venous Thromboembolism Aortic Aneurysm More Can You Escape the Silent Killer? Updated:Feb 2, ... Numbers • Understand Symptoms and Risks • Learn How HBP Can Harm Your Health • Commit To A Plan • Make ...

  17. Escape of atmospheric gases from the Moon

    Indian Academy of Sciences (India)

    that the rates of emission and escape of gases attain equilibrium, the ratio of molecular number densities during day and night, n0d/n0n, can ... with a number density of n0d = 3 × 10. 9 m. −3 during day and n0n = 6 × 10. 10 m ..... y, much greater than tM and only a small fraction of mole- cules would escape. Therefore, the ...

  18. Mutation of Gly717Phe in human topoisomerase 1B has an effect on enzymatic function, reactivity to the camptothecin anticancer drug and on the linker domain orientation

    DEFF Research Database (Denmark)

    Wang, Zhenxing; D'Annessa, Ilda; Tesauro, Cinzia

    2015-01-01

    Human topoisomerase 1B controls the topological state of supercoiled DNA allowing the progression of fundamental cellular processes. The enzyme, which is the unique molecular target of the natural anticancer compound camptothecin, acts by cleaving one DNA strand and forming a transient protein......–DNA covalent adduct. In this work the role of the Gly717 residue, located in a α-helix structure bridging the active site and the linker domain, has been investigated mutating it in Phe. The mutation gives rise to drug resistance in vivo as observed through a viability assay of yeast cells. In vitro activity...... interaction with the DNA substrate, likely affecting the strand rotation and religation rate. The mutation also causes a slight rearrangement of the active site and of the drug binding site, providing an additional explanation for the lowered effect of camptothecin toward the mutant....

  19. Coupling Deep Transcriptome Analysis with Untargeted Metabolic Profiling in Ophiorrhiza pumila to Further the Understanding of the Biosynthesis of the Anti-Cancer Alkaloid Camptothecin and Anthraquinones

    Science.gov (United States)

    Yamazaki, Mami; Mochida, Keiichi; Asano, Takashi; Nakabayashi, Ryo; Chiba, Motoaki; Udomson, Nirin; Yamazaki, Yasuyo; Goodenowe, Dayan B.; Sankawa, Ushio; Yoshida, Takuhiro; Toyoda, Atsushi; Totoki, Yasushi; Sakaki, Yoshiyuki; Góngora-Castillo, Elsa; Buell, C. Robin; Sakurai, Tetsuya; Saito, Kazuki

    2013-01-01

    The Rubiaceae species, Ophiorrhiza pumila, accumulates camptothecin, an anti-cancer alkaloid with a potent DNA topoisomerase I inhibitory activity, as well as anthraquinones that are derived from the combination of the isochorismate and hemiterpenoid pathways. The biosynthesis of these secondary products is active in O. pumila hairy roots yet very low in cell suspension culture. Deep transcriptome analysis was conducted in O. pumila hairy roots and cell suspension cultures using the Illumina platform, yielding a total of 2 Gb of sequence for each sample. We generated a hybrid transcriptome assembly of O. pumila using the Illumina-derived short read sequences and conventional Sanger-derived expressed sequence tag clones derived from a full-length cDNA library constructed using RNA from hairy roots. Among 35,608 non-redundant unigenes, 3,649 were preferentially expressed in hairy roots compared with cell suspension culture. Candidate genes involved in the biosynthetic pathway for the monoterpenoid indole alkaloid camptothecin were identified; specifically, genes involved in post-strictosamide biosynthetic events and genes involved in the biosynthesis of anthraquinones and chlorogenic acid. Untargeted metabolomic analysis by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) indicated that most of the proposed intermediates in the camptothecin biosynthetic pathway accumulated in hairy roots in a preferential manner compared with cell suspension culture. In addition, a number of anthraquinones and chlorogenic acid preferentially accumulated in hairy roots compared with cell suspension culture. These results suggest that deep transcriptome and metabolome data sets can facilitate the identification of genes and intermediates involved in the biosynthesis of secondary products including camptothecin in O. pumila. PMID:23503598

  20. Pyrolaser development for aircrew escape systems

    Science.gov (United States)

    Paul, Ben E.; Cobbett, John A.

    A Laser Ordnance Initiation System (LOIS) has been developed for use in military aircraft emergency escape/egress systems. Applying LOIS to a single-seat and a two-seat F-16 aircraft escape system has proven both cost and weight effective. In both cases, system redundancy is supplied. The large weight reduction is attributed to the elimination of certain initiators, the small size of the logic components and the low weight of the fiber-optic lines (0.037 lb/ft). The required components for a laser operated escape systems are described, with emphasis on the mechanically actuated pyrolaser, which supplies the required energy to activate the various seat devices; the optical AND gate, which provides the logic to ensure proper event sequencing; and the optical mode selector, which establishes aircrew control of the ejection sequence in multiseat aircraft only.

  1. Thermal escape from extrasolar giant planets.

    Science.gov (United States)

    Koskinen, Tommi T; Lavvas, Panayotis; Harris, Matthew J; Yelle, Roger V

    2014-04-28

    The detection of hot atomic hydrogen and heavy atoms and ions at high altitudes around close-in extrasolar giant planets (EGPs) such as HD209458b implies that these planets have hot and rapidly escaping atmospheres that extend to several planetary radii. These characteristics, however, cannot be generalized to all close-in EGPs. The thermal escape mechanism and mass loss rate from EGPs depend on a complex interplay between photochemistry and radiative transfer driven by the stellar UV radiation. In this study, we explore how these processes change under different levels of irradiation on giant planets with different characteristics. We confirm that there are two distinct regimes of thermal escape from EGPs, and that the transition between these regimes is relatively sharp. Our results have implications for thermal mass loss rates from different EGPs that we discuss in the context of currently known planets and the detectability of their upper atmospheres.

  2. Lesser Toxicities of Belotecan in Patients with Small Cell Lung Cancer: A Retrospective Single-Center Study of Camptothecin Analogs

    Directory of Open Access Journals (Sweden)

    Yeon Hee Park

    2016-01-01

    Full Text Available Purpose. Topotecan and belotecan are camptothecin derivatives that are used to treat small cell lung cancer (SCLC. This study compared the toxicities and efficacies of belotecan and topotecan monotherapies in patients with SCLC. Methods. We retrospectively reviewed data from 94 patients with SCLC (with or without prior chemotherapy who were treated using belotecan monotherapy (n=59, 188 cycles or topotecan monotherapy (n=35, 65 cycles between September 2003 and December 2011. Results. Thrombocytopenia occurred during 42% and 61.5% of the belotecan and topotecan cycles, respectively (p=0.007. Significant differences between belotecan and topotecan were also observed for grade 4/5 lung infection (3.2% versus 10.8%, resp.; p=0.003, all-grade headache (3.2% versus 10.8%, resp.; p=0.017, and grade 4/5 increased liver enzymes (0.5% versus 4.6%, resp.; p=0.023. The median TTPDs, CSSs, and OSs were 14 months and 11.6 months (p=0.646, 10 months and 7 months (p=0.179, and 34.5 months and 21.4 months (p=0.914 after belotecan and topotecan monotherapy, respectively. Conclusions. Belotecan monotherapy may be safer than topotecan monotherapy in SCLC patients. And in terms of efficacy, belotecan could be comparable to topotecan monotherapy.

  3. Dysoxylum binectariferum bark as a new source of anticancer drug camptothecin: bioactivity-guided isolation and LCMS-based quantification.

    Science.gov (United States)

    Jain, Shreyans K; Meena, Samdarshi; Gupta, Ajai P; Kushwaha, Manoj; Uma Shaanker, R; Jaglan, Sundeep; Bharate, Sandip B; Vishwakarma, Ram A

    2014-07-15

    Camptothecin (CPT, 1) is a potent anticancer natural product which led to the discovery of two clinically used anticancer drugs topotecan and irinotecan. These two drugs are semisynthetic analogs of CPT, and thus the commercial production of CPT as a raw material from various plant sources and tissue culture methods is highly demanding. In the present study, the Dysoxylum binectariferum bark, was identified as an alternative source of CPT, through bioassay-guided isolation. The barks showed presence of CPT (1) and its 9-methoxy analog 2, whereas CPT alkaloids were not present in seeds and leaves. This is the first report on isolation of CPT alkaloids from Meliaceae family. An efficient chromatography-free protocol for enrichment and isolation of CPT from D. binectariferum has been established, which was able to enrich CPT up to 21% in the crude extract. The LCMS (MRM)-based quantification method revealed the presence of 0.105% of CPT in dry barks of D. binectariferum. The discovery of CPT from D. binectariferum bark will certainly create a global interest in cultivation of this plant as a new crop for commercial production of CPT. Isolation of anticancer drug CPT from this plant, indicates that along with rohitukine, CPT and 9-methoxy CPT also contributes significantly to the cytotoxicity of D. binectariferum. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Compound Specific Extraction of Camptothecin from Nothapodytes nimmoniana and Piperine from Piper nigrum Using Accelerated Solvent Extractor

    Directory of Open Access Journals (Sweden)

    Vinayak Upadhya

    2014-01-01

    Full Text Available Effects of varying temperatures with constant pressure of solvent on extraction efficiency of two chemically different alkaloids were studied. Camptothecin (CPT from stem of Nothapodytes nimmoniana (Grah. Mabb. and piperine from the fruits of Piper nigrum L. were extracted using Accelerated Solvent Extractor (ASE. Three cycles of extraction for a particular sample cell at a given temperature assured complete extraction. CPT and piperine were determined and quantified by using a simple and efficient UFLC-PDA (245 and 343 nm method. Temperature increased efficiency of extraction to yield higher amount of CPT, whereas temperature had diminutive effect on yield of piperine. Maximum yield for CPT was achieved at 80∘C and for piperine at 40∘C. Thus, the study determines compound specific extraction of CPT from N. nimmoniana and piperine from P. nigrum using ASE method. The present study indicates the use of this method for simple, fast, and accurate extraction of the compound of interest.

  5. Fractionation and characterization of a conjugate between a polymeric drug-carrier and the antitumor drug camptothecin.

    Science.gov (United States)

    Mendichi, R; Rizzo, V; Gigli, M; Schieroni, A Giacometti

    2002-01-01

    A conjugate between the antitumor drug camptothecin and the polymeric drug-carrier poly[N-(2-hydroxypropyl)methacrylamide] was synthesized and fractionated. The conjugate samples, both fractionated and unfractionated, were characterized with a multi-detector SEC system using three on-line detectors: a multi-angle light scattering photometer, a viscometer, and a refractometer. The used mobile phase (DMF + 0.01 M LiBr + 0.05 M CH(3)COOH) derives from previous experience with similar conjugates. Narrow molar mass distribution fractions of the conjugate obtained by means of a semipreparative LC system were used to derive the coefficients of the Mark-Houwink-Sakurada relationship and to check the universal calibration of the SEC system. This study has demonstrated that the conjugate elutes according to the hydrodynamic volume. Thus, a conventional SEC method that uses only an on-line refractometer detector, commercially available narrow standards, and the universal calibration is adequate for the characterization of the molar mass distribution. Also the size and the conformation of the conjugate were studied by means of the gyration radius-molar mass power law.

  6. Escape of asteroids from the main belt

    Science.gov (United States)

    Granvik, Mikael; Morbidelli, Alessandro; Vokrouhlický, David; Bottke, William F.; Nesvorný, David; Jedicke, Robert

    2017-02-01

    Aims: We locate escape routes from the main asteroid belt, particularly into the near-Earth-object (NEO) region, and estimate the relative fluxes for different escape routes as a function of object size under the influence of the Yarkovsky semimajor-axis drift. Methods: We integrated the orbits of 78 355 known and 14 094 cloned main-belt objects and Cybele and Hilda asteroids (hereafter collectively called MBOs) for 100 Myr and recorded the characteristics of the escaping objects. The selected sample of MBOs with perihelion distance q > 1.3 au and semimajor axis a random spin obliquities (either 0 deg or 180 deg) for each test asteroid. Results: We find more than ten obvious escape routes from the asteroid belt to the NEO region, and they typically coincide with low-order mean-motion resonances with Jupiter and secular resonances. The locations of the escape routes are independent of the semimajor-axis drift rate and thus are also independent of the asteroid diameter. The locations of the escape routes are likewise unaffected when we added a model for Yarkovsky-O'Keefe-Radzievskii-Paddack (YORP) cycles coupled with secular evolution of the rotation pole as a result of the solar gravitational torque. A Yarkovsky-only model predicts a flux of asteroids entering the NEO region that is too high compared to the observationally constrained flux, and the discrepancy grows larger for smaller asteroids. A combined Yarkovsky and YORP model predicts a flux of small NEOs that is approximately a factor of 5 too low compared to an observationally constrained estimate. This suggests that the characteristic timescale of the YORP cycle is longer than our canonical YORP model predicts.

  7. Effects of Serotonergic and Opioidergic Drugs on Escape Behaviors and Social Status of Male Crickets

    Science.gov (United States)

    Dyakonova, V. E.; Schürmann, F.-W.; Sakharov, D. A.

    We examined the effects of selective serotonin depletion and opioid ligands on social rank and related escape behavior of the cricket Gryllus bimaculatus. Establishment of social rank in a pair of males affected their escape reactions. Losers showed a lower and dominants a higher percentage of jumps in response to tactile cercal stimulation than before a fight. The serotonin-depleting drug α-methyltryptophan (AMTP) caused an activation of the escape reactivity in socially naive crickets. AMTP-treated animals also showed a lower ability to become dominants. With an initial 51.6+/-3.6% of wins in the AMTP group, the percentage decreased to 26+/-1.6% on day 5 after injection. The opiate receptor antagonist naloxone affected fight and escape similarly as AMTP. In contrast to naloxone, the opioid agonist [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin decreased escape responsiveness to cercal stimulation in naive and subordinate crickets. We suggest that serotonergic and opioid systems are involved in the dominance induced depression of escape behavior.

  8. An alternative theoretical approach to escape decision-making: the role of visual cues.

    Directory of Open Access Journals (Sweden)

    Veronika Javůrková

    Full Text Available Escape enables prey to avoid an approaching predator. The escape decision-making process has traditionally been interpreted using theoretical models that consider ultimate explanations based on the cost/benefit paradigm. Ultimate approaches, however, suffer from inseparable extra-assumptions due to an inability to accurately parameterize the model's variables and their interactive relationships. In this study, we propose a mathematical model that uses intensity of predator-mediated visual stimuli as a basic cue for the escape response. We consider looming stimuli (i.e. expanding retinal image of the moving predator as a cue to flight initiation distance (FID; distance at which escape begins of incubating Mallards (Anas platyrhynchos. We then examine the relationship between FID, vegetation cover and directness of predator trajectory, and fit the resultant model to experimental data. As predicted by the model, vegetation concealment and directness of predator trajectory interact, with FID decreasing with increased concealment during a direct approach toward prey, but not during a tangential approach. Thus, we show that a simple proximate expectation, which involves only visual processing of a moving predator, may explain interactive effects of environmental and predator-induced variables on an escape response. We assume that our proximate approach, which offers a plausible and parsimonious explanation for variation in FID, may serve as an evolutionary background for traditional, ultimate explanations and should be incorporated into interpretation of escape behavior.

  9. Do the visual conditions at the point of escape affect European sea bass escape behavior?

    Directory of Open Access Journals (Sweden)

    I.E. PAPADAKIS

    2013-03-01

    Full Text Available European sea bass (Dicentrarchus labrax, an important species for the Mediterranean aquaculture industry, has been reported to escape from sea cage installations. Fish escapes are caused mainly by operational and technical failures that eventually result into a creation of a tear. Escapees may interact with wild stocks through interbreeding, transfer of pathogens and competition for food. The aim of this study was to examine at which extent the presence of a visible obstacle close to a tear on the net have an influence on sea bass propensity to escape. Fish were initially confined into small sea cages, with a tear at one side. The escape behavior was tested under experimental conditions. It is clearly demonstrated that sea bass was able to locate a tear on the net pen, immediately after its appearance. Crossings occurred in all cages, in singles or in a series of up to seven individuals. The presence of an obstacle close to the net tear altered the escape behavior of D. labrax resulting in a delay that eventually reduced the escape rate. Concluding, it is highly recommended that sea bass cages should be kept internally the culture array. Furthermore, the placement of artificial obstacles close to the sea cages could be an efficient practice that mitigates the escape risk after severe environmental conditions.

  10. Developing the E-Scape Software System

    Science.gov (United States)

    Derrick, Karim

    2012-01-01

    Most innovations have contextual pre-cursors that prompt new ways of thinking and in their turn help to give form to the new reality. This was the case with the e-scape software development process. The origins of the system existed in software components and ideas that we had developed through previous projects, but the ultimate direction we took…

  11. Learning from escaped prescribed fire reviews

    Science.gov (United States)

    Anne E. Black; Dave Thomas; James Saveland; Jennifer D. Ziegler

    2011-01-01

    The U.S. wildland fire community has developed a number of innovative methods for conducting a review following escape of a prescribed fire (expanding on the typical regional or local reviews, to include more of a learning focus - expanded After Action Reviews, reviews that incorporate High Reliability Organizing, Facilitated Learning Analyses, etc). The stated purpose...

  12. Net escapement of Antartic krill in trawls

    DEFF Research Database (Denmark)

    Krafft, B.A.; Krag, Ludvig Ahm; Herrmann, Bent

    This document describes the aims and methodology of a three year project (commenced in 2012) entitled Net Escapement of Antarctic krill in Trawls (NEAT). The study will include a morphology based mathematical modeling (FISHSELECT) of different sex and maturity groups of Antarctic krill (Euphausia...

  13. Centrifugally Stimulated Exospheric Ion Escape at Mercury

    Science.gov (United States)

    Delcourt, Dominique; Seki, K.; Terada, N.; Moore, Thomas E.

    2012-01-01

    We investigate the transport of ions in the low-altitude magnetosphere magnetosphere of Mercury. We show that, because of small spatial scales, the centrifugal effect due to curvature of the E B drift paths can lead to significant particle energization in the parallel direction. We demonstrate that because of this effect, ions with initial speed smaller than the escape speed such as those produced via thermal desorption can overcome gravity and escape into the magnetosphere. The escape route of this low-energy exosphere originating material is largely controlled by the magnetospheric convection rate. This escape route spreads over a narrower range of altitudes when the convection rate increases. Bulk transport of low-energy planetary material thus occurs within a limited region of space once moderate magnetospheric convection is established. These results suggest that, via release of material otherwise gravitationally trapped, the E B related centrifugal acceleration is an important mechanism for the net supply of plasma to the magnetosphere of Mercury.

  14. The Fastest Saccadic Responses Escape Visual Masking

    DEFF Research Database (Denmark)

    M. Crouzet, Sébastien; Overgaard, Morten; Busch, Niko A.

    2014-01-01

    visual processing while the initial feedforward processing is thought to be left intact. We tested a prediction derived from this hypothesis: the fastest responses, being triggered before the beginning of reentrant processing, should escape the OSM interference. In a saccadic choice reaction time task...

  15. Core–shell hybrid nanocapsules for oral delivery of camptothecin: formulation development, in vitro and in vivo evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Ünal, Hale, E-mail: unalhale@gmail.com [Hacettepe University, Division of Nanotechnology and Nanomedicine, Institute of Pure and Applied Science (Turkey); D’Angelo, Ivana [Second University of Napoli, Di.S.T.A.Bi.F. (Italy); Pagano, Ester; Borrelli, Francesca; Izzo, Angelo; Ungaro, Francesca; Quaglia, Fabiana [University of Naples Federico II, Department of Pharmacy (Italy); Bilensoy, Erem [Hacettepe University, Division of Nanotechnology and Nanomedicine, Institute of Pure and Applied Science (Turkey)

    2015-01-15

    The objective of this study was to design and in vitro–in vivo evaluate oral nanocapsules prepared from amphiphilic cyclodextrins (CDs) or poly-ε-caprolactone (PCL) for the effective oral delivery of an anticancer agent, camptothecin (CPT). CPT-loaded anionic and Chitosan (CS)-coated cationic nanocapsules were prepared and characterized in vitro. Morphological analysis was performed by scanning electron microscope (SEM). CPT release profile was evaluated using dialysis method under sink conditions. To determine the protective effect and drug stability provided by nanocapsules, all the formulations were incubated in simulated gastrointestinal media. Measurement of mucoadhesive tendency of CPT-loaded nanocapsules was realized by turbidimetric method. Penetration of nanocapsules was performed through an artificial mucus model. The permeability of CPT in solution form and bound to nanocapsule formulations were demonstrated across Caco-2 cell line. Finally, the intestinal uptake of nanocapsules was evaluated in vivo, in a mouse model. Both anionic and cationic formulations were in the range of 180–220 nm with a narrow size distribution and desired zeta potential values. CPT-loaded nanocapsules were found to be stable in simulated gastrointestinal media. Turbidimetric measurements confirmed the interaction between nanoparticles and mucin. Penetration of CPT through an artificial mucus gel layer was higher with CS-coated nanocapsules in accordance with the results obtained from permeability studies across Caco-2 cell line. In vivo animal studies confirmed that the intestinal uptake of nanocapsules was significantly higher with cationic nanocapsules. CPT-loaded positively charged CD nanocapsules might be an attractive and promising treatment for oral chemotherapy.

  16. Cell line selection combined with jasmonic acid elicitation enhance camptothecin production in cell suspension cultures of Ophiorrhiza mungos L.

    Science.gov (United States)

    Deepthi, S; Satheeshkumar, K

    2017-01-01

    Ophiorrhiza mungos is a herbaceous medicinal plant which contains a quinoline alkaloid, camptothecin (CPT), an anticancer compound. A high-yielding cell line, O. mungos cell line-3 (OMC3) was selected from cell suspension cultures of O. mungos using cell aggregate cloning method and established cell suspension culture. OMC3 cell suspension produced significantly high biomass (9.25 ± 1.3 g/flask fresh weight (FW)) and CPT yield (0.095 ± 0.002 mg g(-1) dry weight (DW)) compared with the original cell suspension. Inoculum size of OMC3 cell suspension culture was optimised as 14 g L(-1). Media optimisation has shown that 5 % (w/v) sucrose and an increased ammonium/nitrate concentration of 40/20 mM favoured CPT production, whereas 3 % (w/v) sucrose, an ammonium/nitrate concentration of 20/40 mM and 1.25 mM of phosphate favoured biomass accumulation. Jasmonic acid, chitin and salicylic acid was used to elicit CPT production in the original cell suspension culture and achieved significantly high CPT production with jasmonic acid (JA) elicitation. Further, OMC3 cell suspension culture was elicited with JA (50 μM) and obtained 1.12 ± 0.08 mg g(-1) DW CPT and 9.52 ± 1.4 g/flask FW (190.4 g L(-1) FW). The combination of cell line selection and elicitation has produced 18.66-fold increases in CPT production together with significantly high biomass yield. The study is helpful in the scale-up studies of O. mungos cell suspension culture in suitable bioreactor systems for the production of CPT.

  17. Pituitary sensitizing effect of GnRH antagonists: a mechanism explaining LH escape during IVF?

    NARCIS (Netherlands)

    Banga, F.R.; Huirne, J.A.F.; Korsen, T.; Homburg, R.R.; Hompes, P.G.A.; Lambalk, C.B.

    2010-01-01

    Background GnRH antagonists have been introduced to induce persistent LH suppression. Many studies show a gradual increase of LH levels after several days of GnRH antagonist administration, the so-called escape or rebound effect. We hypothesize that, under chronic GnRH antagonist administration, a

  18. Escape routes, weak links, and desynchronization in fluctuation-driven networks

    DEFF Research Database (Denmark)

    Schäfer, Benjamin; Matthiae, Moritz; Zhang, Xiaozhu

    2017-01-01

    on fundamental noise models, we derive analytic insights into which factors limit the dynamic robustness and how fluctuations may induce a system escape from an operating state. Moreover, we identify weak links in the grid that make it particularly vulnerable to fluctuations. These results thereby not only...

  19. The Mask We Wear: Consumer Escapism Through Cosplay

    National Research Council Canada - National Science Library

    Jacob Hiler; Andrew Kuo

    2014-01-01

      This research explores the antecedents, process, and outcomes of consumer escapism in the context of cosplay and discusses escapism's place alongside other related constructs such as flow & fantasy...

  20. Recent Mumps Outbreaks in Vaccinated Populations: No Evidence of Immune Escape

    Science.gov (United States)

    Link, Malen A.; Sauder, Christian J.; Zhang, Cheryl; Ngo, Laurie; Rima, Bert K.; Duprex, W. Paul

    2012-01-01

    Recently, numerous large-scale mumps outbreaks have occurred in vaccinated populations. Clinical isolates sequenced from these outbreaks have invariably been of genotypes distinct from those of vaccine viruses, raising concern that certain mumps virus strains may escape vaccine-induced immunity. To investigate this concern, sera obtained from children 6 weeks after receipt of measles, mumps, and rubella (MMR) vaccine were tested for the ability to neutralize a carefully selected group of genetically diverse mumps virus strains. Although the geometric mean neutralizing antibody titer of the sera was lower against some virus strains than others, all viruses were readily neutralized, arguing against immune escape. PMID:22072778

  1. Escape of atmospheres and loss of water

    Science.gov (United States)

    Hunten, D. M.; Donahue, T. M.; Walker, J. C. G.; Kasting, J. F.

    1989-01-01

    The properties and limitations of several loss processes for atmospheric gases are presented and discussed. They include thermal loss (Jeans and hydrodynamic); nonthermal loss (all processes involve charged particles); and impact erosion, including thermal escape from a molten body heated by rapid accretion. Hydrodynamic escape, or 'blowoff', is of particular interest because it offers the prospect of processing large quantities of gas and enriching the remainder in heavy elements and isotopes. In a second part, the water budgets and likely evolutionary histories of Venus, Earth and Mars are assessed. Although it is tempting to associate the great D/H enrichment on Venus with loss of a large initial endowment, a steady state with juvenile water (perhaps from comets) is equally probable.

  2. The escape problem for mortal walkers

    CERN Document Server

    Grebenkov, D S

    2016-01-01

    We introduce and investigate the escape problem for random walkers that may eventually die, decay, bleach, or lose activity during their diffusion towards an escape or reactive region on the boundary of a confining domain. In the case of a first-order kinetics (i.e., exponentially distributed lifetimes), we study the effect of the associated death rate onto the survival probability, the exit probability, and the mean first passage time. We derive the upper and lower bounds and some approximations for these quantities. We reveal three asymptotic regimes of small, intermediate and large death rates. General estimates and asymptotics are compared to several explicit solutions for simple domains, and to numerical simulations. These results allow one to account for stochastic photobleaching of fluorescent tracers in bio-imaging, degradation of mRNA molecules in genetic translation mechanisms, or high mortality rates of spermatozoa in the fertilization process. This is also a mathematical ground for optimizing stor...

  3. Preequilibrium escape widths of giant resonances

    Science.gov (United States)

    Roos, M. O.; Dias, H.; Rodriguez, O.; Teruya, N.; Hussein, M. S.

    2002-08-01

    In this work we present a calculation of the 2p-2h preequilibrium escape width of giant resonances for the nuclei 40Ca, 90Zr, and 208Pb. The problem studied here involves an excited nucleus in the 1p-1h configuration, evolving to the 2p-2h configuration with the 1p in the continuum. The theoretical approach used for our calculations is based on the statistical multistep compound theory of Feshbach, Kerman, and Koonin (FKK) and on the particle-hole state densities given by Obložinský. Our calculations show that although different state densities supply a similar result for the damping width, the escape width is strongly dependent on the nuclei, on the binding energy of the emitted nucleon, and the excitation energy of the giant resonance.

  4. How does ionizing radiation escape from galaxies?

    Science.gov (United States)

    Orlitova, Ivana

    2016-10-01

    Search for sources that reionized the Universe from z 15 to z 6 is one of the main drivers of present-day astronomy. Low-mass star-forming galaxies are the most favoured sources of ionizing photons, but the searches of escaping Lyman continuum (LyC) have not been extremely successful. Our team has recently detected prominent LyC escape from five Green Pea galaxies at redshift 0.3, using the HST/COS spectrograph, which represents a significant breakthrough. We propose here to study the LyC escape of the strongest among these leakers, J1152, with spatial resolution. From the comparison of the ionizing and non-ionizing radiation maps, and surface brightness profiles, we will infer the major mode in which LyC is escaping: from the strongest starburst, from the galaxy edge, through a hole along our line-of-sight, through clumpy medium, or directly from all the production sites due to highly ionized medium in the entire galaxy. In parallel, we will test the predictive power of two highly debated indirect indicators of LyC leakage: the [OIII]5007/[OII]3727 ratio, and Lyman-alpha. We predict that their spatial distribution should closely follow that of the ionizing continuum if column densities of the neutral gas are low. This combined study, which relies on the HST unique capabilities, will bring crucial information on the structure of the leaking galaxies, provide constraints for hydrodynamic simulations, and will lead to efficient future searches for LyC leakers across a large range of redshifts.

  5. Dynamic Escape Routes for Naval Ships

    Science.gov (United States)

    2005-09-01

    on the contingency. For instance, if an enemy weapon is expected to hit a particular section of the ship, routes can be configured to avoid that...used to access fan rooms, storerooms, and spaces where interior bulkheads are required to be airtight. These doors prevent the spread of fire, toxic ...NAVAL POSTGRADUATE SCHOOL MONTEREY, CALIFORNIA THESIS Approved for public release; distribution is unlimited. DYNAMIC ESCAPE ROUTES

  6. Mars Planetary Ion Escape: Assessing Transitional Trajectories

    Science.gov (United States)

    Johnson, B. C.

    2016-12-01

    The availability of in situ observations of ions escaping from Mars' atmosphere is vital to descriptions of atmospheric loss, but such point measurements taken by orbiting spacecraft cannot easily differentiate between spatial changes along the spacecraft trajectory and temporal changes, nor can they directly provide information about atmospheric loss rates during Mars' long history. Numerical models are therefore crucial to crystalizing understanding of ion escape processes. One such category are test particle models that release non-interacting ions into background electric and magnetic fields and then calculate ion trajectories and loss rates. To date, such models have focused on the collisionless regime. Another approach is to include collisions between the particles, the Direct Simulation Monte Carlo (DSMC) approach. We present the results of the first fully three dimensional collisional Mars ion DSMC model capable of peering deep into the collionsional atmosphere, beneath the ionospheric peak, i.e., the ion version of the Adaptive Mesh Particle Simulator (AMPS) configured for Mars. Multiple model runs are performed, each with a different cutoff altitude below which collisions are included. Escape rates of O+ are calculated for each run, providing both the asymptotic escape rate as the cutoff altitude extends into the exosphere and also an idea of the altitude range for which collisions must be included for the results to reasonably converge to this value. In other words, how low can a collisionless model go? Furthermore, these results can be used to interpret satellite data of planetary ions, helping to determine if the spacecraft is in the upflow or outflow regime. In other words, how low can observations be used for measuring the loss of planetary ions to deep space? This entire process is repeated a second time, with the first set of runs corresponding to solar minimum input parameters, and the second set of runs corresponding to solar maximum parameters.

  7. Paradoxical escape responses by narwhals (Monodon monoceros)

    DEFF Research Database (Denmark)

    Williams, Terrie M.; Blackwell, Susanna B.; Richter, Beau

    2017-01-01

    Until recent declines in Arctic sea ice levels, narwhals (Monodon monoceros) have lived in relative isolation from human perturbation and sustained predation pressures. The resulting naïvety has made this cryptic, deep-diving cetacean highly susceptible to disturbance, although quantifiable effects...... have been lacking. We deployed a submersible, animal-borne electrocardiograph-accelerometer-depth recorder to monitor physiological and behavioral responses of East Greenland narwhals after release from net entanglement and stranding. Escaping narwhals displayed a paradoxical cardiovascular down...

  8. Xenon Fractionation and Archean Hydrogen Escape

    Science.gov (United States)

    Zahnle, K. J.

    2015-01-01

    Xenon is the heaviest gas found in significant quantities in natural planetary atmospheres. It would seem the least likely to escape. Yet there is more evidence for xenon escape from Earth than for any element other than helium and perhaps neon. The most straightforward evidence is that most of the radiogenic Xe from the decay of (129)I (half-life 15.7 Myr) and (244)Pu (half-life 81 Myr) that is Earth's birthright is missing. The missing xenon is often attributed to the impact erosion of early atmospheres of Earth and its ancestors. It is obvious that if most of the radiogenic xenon were driven off by impacts, most of the rest of the atmophiles fared the same fate. The other line of evidence is in the nonradiogenic isotopes of xenon and its silent partner, krypton. Atmospheric xenon is strongly mass fractionated (at about 4% per amu) compared to any known solar system source (Figure 1). This is in stark contrast to krypton, which may not be fractionated at all: atmospheric Kr is slightly heavier than solar Kr (at about 0.5% per amu), but it is the same as in carbonaceous chondrites. Nonradiogenic xenon is also under abundant relative to krypton (the so-called "missing xenon" problem). Together these observations imply that xenon has been subject to fractionating escape and krypton not.

  9. A Visual Pathway for Looming-Evoked Escape in Larval Zebrafish.

    Science.gov (United States)

    Temizer, Incinur; Donovan, Joseph C; Baier, Herwig; Semmelhack, Julia L

    2015-07-20

    Avoiding the strike of an approaching predator requires rapid visual detection of a looming object, followed by a directed escape maneuver. While looming-sensitive neurons have been discovered in various animal species, the relative importance of stimulus features that are extracted by the visual system is still unclear. Furthermore, the neural mechanisms that compute object approach are largely unknown. We found that a virtual looming stimulus, i.e., a dark expanding disk on a bright background, reliably evoked rapid escape movements. Related stimuli, such as dimming, receding, or bright looming objects, were substantially less effective, and angular size was a critical determinant of escape initiation. Two-photon calcium imaging in retinal ganglion cell (RGC) axons revealed three retinorecipient areas that responded robustly to looming stimuli. One of these areas, the optic tectum, is innervated by a subset of RGC axons that respond selectively to looming stimuli. Laser-induced lesions of the tectal neuropil impaired the behavior. Our findings demonstrate a visually mediated escape behavior in zebrafish larvae exposed to objects approaching on a collision course. This response is sensitive to spatiotemporal parameters of the looming stimulus. Our data indicate that a subset of RGC axons within the tectum responds selectively to features of looming stimuli and that this input is necessary for visually evoked escape. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Platelet Activation by Streptococcus pyogenes Leads to Entrapment in Platelet Aggregates, from Which Bacteria Subsequently Escape

    Science.gov (United States)

    Svensson, Lisbeth; Baumgarten, Maria; Mörgelin, Matthias

    2014-01-01

    Platelet activation and aggregation have been reported to occur in response to a number of Gram-positive pathogens. Here, we show that platelet aggregates induced by Streptococcus pyogenes were unstable and that viable bacteria escaped from the aggregates over time. This was not due to differential activation in response to the bacteria compared with physiological activators. All the bacterial isolates induced significant platelet activation, including integrin activation and alpha and dense-granule release, at levels equivalent to those induced by potent physiological platelet activators that induced stable aggregates. The ability to escape the aggregates and to resist the antibacterial effects of platelets was dependent on active protein synthesis by the bacteria within the aggregate. We conclude that S. pyogenes bacteria can temporarily cover themselves with activated platelets, and we propose that this may facilitate survival of the bacteria in the presence of platelets. PMID:25069984

  11. Autologous HIV-1 neutralizing antibodies: emergence of neutralization-resistant escape virus and subsequent development of escape virus neutralizing antibodies

    DEFF Research Database (Denmark)

    Arendrup, M; Nielsen, C; Hansen, J E

    1992-01-01

    of neutralizing antibodies to the primary virus isolates was detected 13-45 weeks after seroconversion. Emergence of escape virus with reduced sensitivity to neutralization by autologous sera was demonstrated. The patients subsequently developed neutralizing antibodies against the escape virus but after a delay...... escape virus may be part of the explanation of the apparent failure of the immune system to control HIV infection....

  12. Risks incurred by hydrogen escaping from containers and conduits

    Energy Technology Data Exchange (ETDEWEB)

    Swain, M.R.; Grilliot, E.S. [Univ. of Miami, Coral Gables, FL (United States); Swain, M.N. [Analytical Technologies, Inc., Miami, FL (United States)

    1998-08-01

    This paper is a discussion of a method for hydrogen leak classification. Leaks are classified as; gas escapes into enclosed spaces, gas escapes into partially enclosed spaces (vented), and gas escapes into unenclosed spaces. Each of the three enclosure classifications is further divided into two subclasses; total volume of hydrogen escaped and flow rate of escaping hydrogen. A method to aid in risk assessment determination in partially enclosed spaces is proposed and verified for several enclosure geometries. Examples are discussed for additional enclosure geometries.

  13. The cost of the sword: escape performance in male swordtails.

    Directory of Open Access Journals (Sweden)

    Alex Baumgartner

    2011-01-01

    Full Text Available The handicap theory of sexual selection posits that male display traits that are favored in mate choice come at a significant cost to performance. We tested one facet of this hypothesis in the green swordtail (Xiphophorus helleri. In this species, the lower ray of male caudal fin is extended into a 'sword', which serves to attract potential mates. However, bearing a long sword may increase drag and thus compromise a male's ability to swim effectively. We tested escape performance in this species by eliciting C-start escape responses, an instinctive escape behavior, in males with various sword lengths. We then removed males' swords and retested escape performance. We found no relationship between escape performance and sword length and no effect of sword removal on escape performance. While having a large sword may attract a predator's attention, our results suggest that sword size does not compromise a male's escape performance.

  14. The cost of the sword: escape performance in male swordtails.

    Science.gov (United States)

    Baumgartner, Alex; Coleman, Seth; Swanson, Brook

    2011-01-06

    The handicap theory of sexual selection posits that male display traits that are favored in mate choice come at a significant cost to performance. We tested one facet of this hypothesis in the green swordtail (Xiphophorus helleri). In this species, the lower ray of male caudal fin is extended into a 'sword', which serves to attract potential mates. However, bearing a long sword may increase drag and thus compromise a male's ability to swim effectively. We tested escape performance in this species by eliciting C-start escape responses, an instinctive escape behavior, in males with various sword lengths. We then removed males' swords and retested escape performance. We found no relationship between escape performance and sword length and no effect of sword removal on escape performance. While having a large sword may attract a predator's attention, our results suggest that sword size does not compromise a male's escape performance.

  15. Geometry of escaping dynamics in nonlinear ship motion

    Science.gov (United States)

    Naik, Shibabrat; Ross, Shane D.

    2017-06-01

    Escape from a potential well is a paradigm to understand critical events in chemical physics, celestial mechanics, structural mechanics, and ship dynamics, to name but a few. The consequences of escape could be desirable or undesirable depending on the specific problem at hand, however, the general question is how escape occurs and the effects of environmental noise on the escape. In this article, we answer the first question by discovering the phase space structures that lead to escape and the second question by investigating the effects of random forcing on these structures in the context of ship dynamics and capsize. The phase space structures that lead to escape are the tube manifolds associated to the rank-1 saddles in the conservative system. They are also robust in the sense of predicting high probability regions of escape even in the presence of random forcing.

  16. Short communication: HIV type 1 escapes inactivation by saliva via rapid escape into oral epithelial cells.

    Science.gov (United States)

    Dietrich, Elizabeth A; Gebhard, Kristin H; Fasching, Claudine E; Giacaman, Rodrigo A; Kappes, John C; Ross, Karen F; Herzberg, Mark C

    2012-12-01

    Saliva contains anti-HIV-1 factors, which show unclear efficacy in thwarting mucosal infection. When incubated in fresh, unfractionated whole saliva, infectious HIV-1 IIIb and BaL (X4- and R5-tropic, respectively) persisted from 4 to at least 30 min in a saliva concentration-dependent manner. In salivary supernatant for up to 6 h, both infectious HIV-1 strains "escaped" into immortalized oral epithelial cells; infectious BaL showed selectively enhanced escape in the presence of saliva. Fluorescently labeled HIV-1 virus-like particles entered oral epithelial cells within minutes of exposure. Using a previously unrecognized mechanism, therefore, strains of HIV-1 escape inactivation by saliva via rapid uptake into oral epithelial cells.

  17. Formulation development, stability and anticancer efficacy of core-shell cyclodextrin nanocapsules for oral chemotherapy with camptothecin.

    Science.gov (United States)

    Ünal, Hale; Öztürk, Naile; Bilensoy, Erem

    2015-01-01

    The aim of this study was to design and evaluate hybrid cyclodextrin (CD) nanocapsules intended for the oral delivery of the anticancer agent camptothecin (CPT) in order to maintain drug stability in the body and to improve its eventual bioavailability. For this reason, an amphiphilic cyclodextrin (CD) derivative per-modified on the primary face 6OCAPRO was used as core molecule to form nanocapsules with the nanoprecipitation technique. Nanocapsules were further coated with the cationic polymer chitosan to improve the cellular uptake and interaction with biological membranes through positive surface charge. Nanocapsules were evaluated for their in vitro characteristics such as particle size, zeta potential, drug loading and release profiles followed by cell culture studies with the MCF-7 and Caco-2 cell line evaluating their anticancer efficacy and permeability. The CD nanocapsules were imaged by scanning electron microscopy (SEM). The concentration of CPT entrapped in nanocapsules was determined by reversed phase HPLC. The in vitro release study of CPT was performed with a dialysis bag method under sink conditions mimicking the gastric and intestinal pH. The hydrolytic stability of CPT in nanocapsules was investigated in simulated gastric and intestinal fluids (SGF, SIF). The mean particle sizes of both anionic and cationic CPT-loaded nanocapsules were in the range of 180-200 nm with polydispersity indices lower than 0.400 indicating monodisperse size distribution of nanocapsules with favourable potential for intracellular drug delivery to tumour cells. Surface charges of anionic and cationic nanocapsules were demonstrated as -21 mV and +18 mV, respectively. The stability of CPT in simulated release media, SGF and SIF were maintained suggesting the improved protection of the drug molecule from rapid hydrolysis degradation or gastrointestinal pH in nanocapsule oily core. Furthermore CD nanocapsules showed higher anticancer efficacy than CPT solution against the MCF

  18. Nucleation theory, the escaping processes, and nonlinear stability

    Science.gov (United States)

    Gonzalez, J. A.; Oliveira, F. A.

    1999-03-01

    We study the solutions describing the critical ``germs'' in nucleation theory, escaping processes, and fractures. We present systems with exact solutions in D=1,2,3 dimensions. We show that when there exist connections between the particles in more than one dimension, the stability is much more increased. In systems where the potential well is a degenerate point, the critical germ solution has a power-law behavior. For D=3 there can exist a continuum of stationary states where all the points of the order parameter take values that are out of the stability zone (i.e., the potential well) leading to effective marginal stability. We discuss the relevance of these results for different physical systems and its connections with recently intensively studied phenomena like sand-pile dynamics, self-organized criticality, noise-induced synchronization in extended systems, and quantum tunneling in the framework of field theory.

  19. Room escape at class: Escape games activities to facilitate the motivation and learning in computer science

    Directory of Open Access Journals (Sweden)

    Carlos Borrego

    2017-06-01

    Full Text Available Real-life room-escape games are ludic activities in which participants enter a room in order to get out of it only after solving some riddles. In this paper, we explain a Room Escape teaching experience developed in the Engineering School at Universitat Autònoma de Barcelona. The goal of this activity is to increase student’s motivation and to improve their learning on two courses of the second year in the Computer Engineering degree: Computer Networksand Information and Security.

  20. Cellular Inhibition of Checkpoint Kinase 2 (Chk2) and Potentiation of Camptothecins and Radiation by the Novel Chk2 Inhibitor PV1019 [7-Nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide

    Energy Technology Data Exchange (ETDEWEB)

    Jobson, Andrew G.; Lountos, George T.; Lorenzi, Philip L.; Llamas, Jenny; Connelly, John; Cerna, David; Tropea, Joseph E.; Onda, Akikazu; Zoppoli, Gabriele; Kondapaka, Sudhir; Zhang, Guangtao; Caplen, Natasha J.; Cardellina, II, John H.; Yoo, Stephen S.; Monks, Anne; Self, Christopher; Waugh, David S.; Shoemaker, Robert H.; Pommier, Yves; (NIH)

    2010-04-05

    Chk2 is a checkpoint kinase involved in the ataxia telangiectasia mutated pathway, which is activated by genomic instability and DNA damage, leading to either cell death (apoptosis) or cell cycle arrest. Chk2 provides an unexplored therapeutic target against cancer cells. We recently reported 4,4'-diacetyldiphenylurea-bis(guanylhydrazone) (NSC 109555) as a novel chemotype Chk2 inhibitor. We have now synthesized a derivative of NSC 109555, PV1019 (NSC 744039) [7-nitro-1H-indole-2-carboxylic acid {l_brace}4-[1-(guanidinohydrazone)-ethyl]-phenyl{r_brace}-amide], which is a selective submicromolar inhibitor of Chk2 in vitro. The cocrystal structure of PV1019 bound in the ATP binding pocket of Chk2 confirmed enzymatic/biochemical observations that PV1019 acts as a competitive inhibitor of Chk2 with respect to ATP. PV1019 was found to inhibit Chk2 in cells. It inhibits Chk2 autophosphorylation (which represents the cellular kinase activation of Chk2), Cdc25C phosphorylation, and HDMX degradation in response to DNA damage. PV1019 also protects normal mouse thymocytes against ionizing radiation-induced apoptosis, and it shows synergistic antiproliferative activity with topotecan, camptothecin, and radiation in human tumor cell lines. We also show that PV1019 and Chk2 small interfering RNAs can exert antiproliferative activity themselves in the cancer cells with high Chk2 expression in the NCI-60 screen. These data indicate that PV1019 is a potent and selective inhibitor of Chk2 with chemotherapeutic and radiosensitization potential.

  1. Arduino adventures escape from Gemini station

    CERN Document Server

    Kelly, James Floyd

    2013-01-01

    Arduino Adventures: Escape from Gemini Station provides a fun introduction to the Arduino microcontroller by putting you (the reader) into the action of a science fiction adventure story.  You'll find yourself following along as Cade and Elle explore Gemini Station-an orbiting museum dedicated to preserving and sharing technology throughout the centuries. Trouble ensues. The station is evacuated, including Cade and Elle's class that was visiting the station on a field trip. Cade and Elle don't make it aboard their shuttle and are trapped on the station along with a friendly artificial intellig

  2. Suicide as escape from psychotic panic.

    Science.gov (United States)

    Goldblatt, Mark J; Ronningstam, Elsa; Schechter, Mark; Herbstman, Benjamin; Maltsberger, John T

    2016-01-01

    Suicides of patients in states of acute persecutory panic may be provoked by a subjective experience of helpless terror threatening imminent annihilation or dismemberment. These patients are literally scared to death and try to run away. They imagine suicide is survivable and desperately attempt to escape from imaginary enemies. These states of terror occur in a wide range of psychotic illnesses and are often associated with command hallucinations and delusions. In this article, the authors consider the subjective experience of persecutory panic and the suicide response as an attempt to flee from danger.

  3. Early low-titer neutralizing antibodies impede HIV-1 replication and select for virus escape.

    Directory of Open Access Journals (Sweden)

    Katharine J Bar

    Full Text Available Single genome sequencing of early HIV-1 genomes provides a sensitive, dynamic assessment of virus evolution and insight into the earliest anti-viral immune responses in vivo. By using this approach, together with deep sequencing, site-directed mutagenesis, antibody adsorptions and virus-entry assays, we found evidence in three subjects of neutralizing antibody (Nab responses as early as 2 weeks post-seroconversion, with Nab titers as low as 1∶20 to 1∶50 (IC(50 selecting for virus escape. In each of the subjects, Nabs targeted different regions of the HIV-1 envelope (Env in a strain-specific, conformationally sensitive manner. In subject CH40, virus escape was first mediated by mutations in the V1 region of the Env, followed by V3. HIV-1 specific monoclonal antibodies from this subject mapped to an immunodominant region at the base of V3 and exhibited neutralizing patterns indistinguishable from polyclonal antibody responses, indicating V1-V3 interactions within the Env trimer. In subject CH77, escape mutations mapped to the V2 region of Env, several of which selected for alterations of glycosylation. And in subject CH58, escape mutations mapped to the Env outer domain. In all three subjects, initial Nab recognition was followed by sequential rounds of virus escape and Nab elicitation, with Nab escape variants exhibiting variable costs to replication fitness. Although delayed in comparison with autologous CD8 T-cell responses, our findings show that Nabs appear earlier in HIV-1 infection than previously recognized, target diverse sites on HIV-1 Env, and impede virus replication at surprisingly low titers. The unexpected in vivo sensitivity of early transmitted/founder virus to Nabs raises the possibility that similarly low concentrations of vaccine-induced Nabs could impair virus acquisition in natural HIV-1 transmission, where the risk of infection is low and the number of viruses responsible for transmission and productive clinical

  4. Escape from viscosity : the kinematics and hydrodynamics of copepod foraging and escape swimming

    NARCIS (Netherlands)

    van Duren, LA; Videler, JJ

    Feeding and escape swimming in adult females of the calanoid copepod. Temora lopgicornis Muller were investigated and compared. Swimming velocities were calculated using a 3-D filming setup., Foraging velocities ranged between 2 and 6 min s(-1), while maximum velocities of up to 80 mm s(-1) were

  5. UNESCO TO BLAME: Reality or Easy Escape?

    Directory of Open Access Journals (Sweden)

    Anna Pereira Roders

    2015-03-01

    Full Text Available “UNESCO to blame” is a trend often observed in scholarly works. In those studies UNESCO is accused to privilege Eurocentric standards on heritage conservation. Is this reality or an easy escape? Can this trend be noted in other UNESCO reference texts? This article seeks to answer this question by studying the two main inscription-based conventions and their contribution to heritage management, while performing a data analysis on the countries behind these conventions, and their roles over time. The 1972 World Heritage Convention and the 2003 Convention for the Safeguarding of the Intangible Cultural Heritage are, therefore, taken as case studies. Based on the results, this paper elaborates on a critical analysis, distinguishing what UNESCO, as well as, Europe can eventually be blamed for and what may be used by the countries as an easy escape. This paper ends setting a research agenda to raise awareness and generate factual knowledge on the role of supranational governance in setting standards in global ethics, in particular, to guideline heritage conservation.

  6. The escape problem for mortal walkers

    Science.gov (United States)

    Grebenkov, D. S.; Rupprecht, J.-F.

    2017-02-01

    We introduce and investigate the escape problem for random walkers that may eventually die, decay, bleach, or lose activity during their diffusion towards an escape or reactive region on the boundary of a confining domain. In the case of a first-order kinetics (i.e., exponentially distributed lifetimes), we study the effect of the associated death rate onto the survival probability, the exit probability, and the mean first passage time. We derive the upper and lower bounds and some approximations for these quantities. We reveal three asymptotic regimes of small, intermediate, and large death rates. General estimates and asymptotics are compared to several explicit solutions for simple domains and to numerical simulations. These results allow one to account for stochastic photobleaching of fluorescent tracers in bio-imaging, degradation of mRNA molecules in genetic translation mechanisms, or high mortality rates of spermatozoa in the fertilization process. Our findings provide a mathematical ground for optimizing storage containers and materials to reduce the risk of leakage of dangerous chemicals or nuclear wastes.

  7. Escape trajectories of the brown shrimp crangon crangon, and a theoretical consideration of initial escape angles from predators

    Science.gov (United States)

    Arnott; Neil; Ansell

    1999-01-01

    Tail-flip escape trajectories of the brown shrimp Crangon crangon have been investigated in response to a natural predator, the cod Gadus morhua, and an artificial stimulus. Shrimps escaped by rolling to their left or right during the initial tail-flip of a response, and thereafter swam on their side. As a result of the laterally directed first tail-flip, initial escape angles always lay between 75 degrees and 156 degrees with respect to the (pre-escape) longitudinal axis (anterior=0 degrees) of the shrimp. Symmetrical attacks from either head-on or tail-on produced escapes to the shrimp's left or right in equal proportions, although a contralateral bias did occur if the shrimp experienced a looming object from one side before a symmetrical attack was applied. Lateral attacks produced a significantly greater proportion of contralateral responses than ipsilateral ones. Empirical and theoretical analyses indicate that the initial escape direction is influenced by an interaction between the range of first tail-flip escape angles that the shrimp is capable of performing and the risk of being intercepted by a predator during the initial stage of an escape. Thus, the unpredictability ('protean behaviour') of the response may be affected by the conditions of the interaction. Subsequent tail-flips of an escape usually directed the response away from the stimulus, but sometimes escapes were instead steered to the side of the stimulus and then behind it. The probability of each type of escape occurring changed with attack direction. The elements of protean behaviour that have been identified in both the initial and subsequent stages of the escape may prevent predators from learning a fixed pattern of response, but a trade-off occurs when escape trajectories infringe upon zones of high capture risk.

  8. Some Possible Cases of Escape Mimicry in Neotropical Butterflies.

    Science.gov (United States)

    Pinheiro, C E G; Freitas, A V L

    2014-10-01

    The possibility that escape or evasive mimicry evolved in butterflies and other prey insects in a similar fashion to classical Batesian and Müllerian mimicry has long been advanced in the literature. However, there is a general disagreement among lepidopterists and evolutionary biologists on whether or not escape mimicry exists, as well as in which mimicry rings this form of mimicry has evolved. Here, we review some purported cases of escape mimicry in Neotropical butterflies and suggest new mimicry rings involving several species of Archaeoprepona, Prepona, and Doxocopa (the "bright blue bands" ring) and species of Colobura and Hypna (the "creamy bands" ring) where the palatability of butterflies, their ability to escape predator attacks, geographic distribution, relative abundance, and co-occurrence in the same habitats strongly suggest that escape mimicry is involved. In addition, we also indicate other butterfly taxa whose similarities of coloration patterns could be due to escape mimicry and would constitute important case studies for future investigation.

  9. RpoS controls the Vibrio cholerae mucosal escape response.

    Directory of Open Access Journals (Sweden)

    Alex Toftgaard Nielsen

    2006-10-01

    Full Text Available Vibrio cholerae causes a severe diarrhoeal disease by secreting a toxin during colonization of the epithelium in the small intestine. Whereas the initial steps of the infectious process have been intensively studied, the last phases have received little attention. Confocal microscopy of V. cholerae O1-infected rabbit ileal loops captured a distinctive stage in the infectious process: 12 h post-inoculation, bacteria detach from the epithelial surface and move into the fluid-filled lumen. Designated the "mucosal escape response," this phenomenon requires RpoS, the stationary phase alternative sigma factor. Quantitative in vivo localization assays corroborated the rpoS phenotype and showed that it also requires HapR. Expression profiling of bacteria isolated from ileal loop fluid and mucus demonstrated a significant RpoS-dependent upregulation of many chemotaxis and motility genes coincident with the emigration of bacteria from the epithelial surface. In stationary phase cultures, RpoS was also required for upregulation of chemotaxis and motility genes, for production of flagella, and for movement of bacteria across low nutrient swarm plates. The hapR mutant produced near-normal numbers of flagellated cells, but was significantly less motile than the wild-type parent. During in vitro growth under virulence-inducing conditions, the rpoS mutant produced 10- to 100-fold more cholera toxin than the wild-type parent. Although the rpoS mutant caused only a small over-expression of the genes encoding cholera toxin in the ileal loop, it resulted in a 30% increase in fluid accumulation compared to the wild-type. Together, these results show that the mucosal escape response is orchestrated by an RpoS-dependent genetic program that activates chemotaxis and motility functions. This may furthermore coincide with reduced virulence gene expression, thus preparing the organism for the next stage in its life cycle.

  10. Balancing reversion of cytotoxic T-lymphocyte and neutralizing antibody escape mutations within human immunodeficiency virus type 1 Env upon transmission.

    Science.gov (United States)

    Peut, Viv; Campbell, Shahan; Gaeguta, Adriana; Center, Rob J; Wilson, Kim; Alcantara, Sheilajen; Fernandez, Caroline S; Purcell, Damian F J; Kent, Stephen J

    2009-09-01

    Human immunodeficiency virus type 1 (HIV-1) envelope protein (Env) is subject to both neutralizing antibody (NAb) and CD8 T-cell (cytotoxic T-lymphocyte [CTL]) immune pressure. We studied the reversion of the Env CTL escape mutant virus to the wild type and the relationship between the reversion of CTL mutations with N-linked glycosylation site (NLGS)-driven NAb escape in pigtailed macaques. Env CTL mutations either did not revert to the wild type or only transiently reverted 5 to 7 weeks after infection. The CTL escape mutant reversion was coincident, for the same viral clones, with the loss of NLGS mutations. At one site studied, both CTL and NLGS mutations were needed to confer NAb escape. We conclude that CTL and NAb escape within Env can be tightly linked, suggesting opportunities to induce effective multicomponent anti-Env immunity.

  11. Conjugates of a novel 7-substituted camptothecin with RGD-peptides as α(v)β₃ integrin ligands: An approach to tumor-targeted therapy.

    Science.gov (United States)

    Dal Pozzo, Alma; Esposito, Emiliano; Ni, Minghong; Muzi, Laura; Pisano, Claudio; Bucci, Federica; Vesci, Loredana; Castorina, Massimo; Penco, Sergio

    2010-11-17

    Eight conjugates of a novel camptothecin derivative (Namitecan, NMT) with RGD peptides have been synthesized and biologically evaluated. This study focused on factors that optimize the drug linkage to the transport vector. The different linkages investigated consist of heterofunctional glycol fragments and a lysosomally cleavable peptide. The linkage length and conformation were systematically modified with the purpose to understand their effect on receptor affinity, systemic stability, cytotoxicity, and solubility of the corresponding conjugates. Among the new conjugates prepared, C6 and C7 showed high receptor affinity and tumor cell adhesion, acceptable stability in murine blood, and high cytotoxic activity (IC₅₀ = 8 nM). The rationale, synthetic strategy, and preliminary biological results will be presented.

  12. Quantitative evaluation of ABC transporter-mediated drug resistance based on the determination of the anticancer activity of camptothecin against breast cancer stem cells using TIRF.

    Science.gov (United States)

    Arumugam, Parthasarathy; Song, Joon Myong

    2016-06-13

    Elevated expression of drug efflux pumps such as multidrug resistant protein-1 (MDR1/ABCB1) and multidrug resistance associated protein-1 (MRP1/ABCC1) in cancer stem cells (CSCs) among a bulky tumor cell population was attributed to drug resistance. For the first time, we have quantitatively evaluated the cytotoxic profile of camptothecin (CPT) against the CSC. In the present study, a Qdot based total internal reflection fluorescence (TIRF) detection system effectively interpreted that drug resistance to CPT was reduced in the CSC under ABCB1 inhibited conditions. This study revealed that quantitative finding of the EC50 value for apoptosis and necrosis in correlation with the ABC inhibitor and CSC population using TIRF could provide more details of the anti-cancer efficacy of chemotherapeutic agents.

  13. Escape Burrowing of Modern Freshwater Bivalves as a Paradigm for Escape Behavior in the Devonian Bivalve Archanodon catskillensis

    Directory of Open Access Journals (Sweden)

    Katja Knoll

    2017-10-01

    Full Text Available Many freshwater bivalves restore themselves to the sediment water interface after burial by upward escape burrowing. We studied the escape burrowing capacity of two modern unionoids, Elliptio complanata and Pyganodon cataracta and the invasive freshwater venerid Corbicula fluminea, in a controlled laboratory setting varying sediment grain size and burial depth. We found that the relatively streamlined E. complanata is a better escape burrower than the more obese P. cataracta. E. complanata is more likely to escape burial in both fine and coarse sand, and at faster rates than P. cataracta. However, successful escape from 10 cm burial, especially in fine sand, is unlikely for both unionoids. The comparatively small and obese C. fluminea outperforms both unionoids in terms of escape probability and escape time, especially when body size is taken into consideration. C. fluminea can escape burial depths many times its own size, while the two unionoids rarely escape from burial equivalent to the length of their shells. E. complanata, and particularly P. cataracta, are morphological paradigms for the extinct Devonian unionoid bivalve Archanodon catskillensis, common in riverine facies of the Devonian Catskill Delta Complex of the eastern United States. Our observations suggest that the escape burrowing capability of A. catskillensis was no better than that of P. cataracta. Archanodon catskillensis was likely unable to escape burial of more than a few centimeters of anastrophically deposited sediment. The long (up to 1 meter, vertical burrows that are associated with A. catskillensis, and interpreted to be its escape burrows, represent a response to episodic, small-scale sedimentation events due to patterns of repetitive hydrologic or weather-related phenomena. They are not a response to a single anastrophic event involving the influx of massive volumes of sediment.

  14. The humanitarians' tragedy: escapable and inescapable cruelties.

    Science.gov (United States)

    de Waal, Alex

    2010-04-01

    Paradoxically, elements of cruelty are intrinsic to the humanitarian enterprise.(1) This paper focuses on some of these. Escapable cruelties arise from technical failings, but the gradual professionalisation of the field and improvements in relief technologies mean that they have been significantly reduced in comparison to earlier eras. Other cruelties arise from clashes among rights, and the tensions inherent in trying to promote humanity amid the horrors of war. These are inescapable and constitute the 'humanitarians' tragedy'. Among them is the individual cruelty of failing to do good at the margin: a clash between the individual's impulses and ideals and the constraints of operating in constrained circumstances. This is a version of triage. In addition, there is the cruelty of compromising dearly-held principles when faced with other competing or overriding demands. There is also the cruelty whereby humanitarians feed victims' dreams that there is an alternative reality, which in fact cannot be attained.

  15. Meteorite impact ejecta - Dependence of mass and energy lost on planetary escape velocity

    Science.gov (United States)

    Okeefe, J. D.; Ahrens, T. J.

    1977-01-01

    The amounts of material and energy which escape a planet in a meteorite impact event is calculated as functions of impact and escape velocities. Results are obtained from the computed flow induced by the impact of iron and gabbroic anorthosite spheres onto a half-space of anorthosite at impact velocities of 5 to 45 km/sec. The impact-induced flows were determined by a numerical method using the mass, momentum, and energy conservation relations in finite-difference approximation, within an Eulerian computational grid. The impact velocities at which ejecta losses equal meteorite mass gains are found to be approximately 20, 35, and 45 km/sec for anorthosite objects and approximately 25, 35, and 40 km/sec for iron objects striking anorthosite surfaces for the gravity fields of the moon, Mercury and Mars.

  16. Managing Pacific salmon escapements: The gaps between theory and reality

    Science.gov (United States)

    Knudsen, E. Eric; Knudsen, E. Eric; Steward, Cleveland R.; MacDonald, Donald D.; Williams, Jack E.; Reiser, Dudley W.

    1999-01-01

    There are myriad challenges to estimating intrinsic production capacity for Pacific salmon populations that are heavily exploited and/or suffering from habitat alteration. Likewise, it is difficult to determine whether perceived decreases in production are due to harvest, habitat, or hatchery influences, natural variation, or some combination of all four. There are dramatic gaps between the true nature of the salmon spawner/recruit relationship and the theoretical basis for describing and understanding the relationship. Importantly, there are also extensive practical difficulties associated with gathering and interpreting accurate escapement and run-size information and applying it to population management. Paradoxically, certain aspects of salmon management may well be contributing to losses in abundance and biodiversity, including harvesting salmon in mixed population fisheries, grouping populations into management units subject to a common harvest rate, and fully exploiting all available hatchery fish at the expense of wild fish escapements. Information on U.S. Pacific salmon escapement goal-setting methods, escapement data collection methods and estimation types, and the degree to which stocks are subjected to mixed stock fisheries was summarized and categorized for 1,025 known management units consisting of 9,430 known populations. Using criteria developed in this study, only 1% of U.S. escapement goals are by methods rated as excellent. Escapement goals for 16% of management units were rated as good. Over 60% of escapement goals have been set by methods rated as either fair or poor and 22% of management units have no escapement goals at all. Of the 9,430 populations for which any information was available, 6,614 (70%) had sufficient information to categorize the method by which escapement data are collected. Of those, data collection methods were rated as excellent for 1%, good for 1%, fair for 2%, and poor for 52%. Escapement estimates are not made for 44

  17. Oxygen ion escape from Venus in a global hybrid simulation: role of the ionospheric O+ ions

    Directory of Open Access Journals (Sweden)

    T. L. Zhang

    2009-11-01

    Full Text Available We study the solar wind induced oxygen ion escape from Venus' upper atmosphere and the Venus Express observations of the Venus-solar wind interaction by the HYB-Venus hybrid simulation code. We compare the simulation to the magnetic field and ion observations during an orbit of nominal upstream conditions. Further, we study the response of the induced magnetosphere to the emission of planetary ions. The hybrid simulation is found to be able to reproduce the main observed regions of the Venusian plasma environment: the bow shock (both perpendicular and parallel regions, the magnetic barrier, the central tail current sheet, the magnetic tail lobes, the magnetosheath and the planetary wake. The simulation is found to best fit the observations when the planetary oxy~escape rate is in the range from 3×1024 s−1 to 1.5×1025 s−1. This range was also found to be a limit for a test particle-like behaviour of the planetary ions: the higher escape rates manifest themselves in a different global configuration of the Venusian induced magnetosphere.

  18. Escape response of planktonic protists to fluid mechanical signals

    DEFF Research Database (Denmark)

    Jakobsen, Hans Henrik

    2001-01-01

    The escape response to fluid mechanical signals was examined in 6 protists, 4 ciliates and 2 dinoflagellates. When exposed to a siphon flow. 3 species of ciliates, Balanion comatum, Strobilidium sp., and Mesodinium pulex, responded with escape jumps. The threshold deformation rates required...

  19. Determination of forage escape protein value with in situ and ...

    African Journals Online (AJOL)

    Windows

    2012-01-12

    Jan 12, 2012 ... This study was carried out to compare in situ and in vitro enzyme techniques for determining estimates of forage escape ... enzyme method had similar escape protein values for vetch hay, wheat hay, grass hay, triticale hay and .... the bags was determined by the macro-Kjeldahl procedure (AOAC,. 1990).

  20. Teachers Offering Healthy Escape Options for Teenagers in Pain

    Science.gov (United States)

    Kaywell, Joan F.

    2005-01-01

    "[T]wenty-five percent of today's teenagers have inordinate emotional baggage beyond the normal angst of adolescence." This burden can lead to unhealthy escapes, including substance abuse, sexual activity, violence, eating disorders, and suicide. One healthy escape, however, lies in books, where students can read about teenagers living in painful…

  1. The Origins and Underpinning Principles of E-Scape

    Science.gov (United States)

    Kimbell, Richard

    2012-01-01

    In this article I describe the context within which we developed project e-scape and the early work that laid the foundations of the project. E-scape (e-solutions for creative assessment in portfolio environments) is centred on two innovations. The first concerns a web-based approach to portfolio building; allowing learners to build their…

  2. Recoiling supermassive black hole escape velocities from dark matter haloes

    Science.gov (United States)

    Choksi, Nick; Behroozi, Peter; Volonteri, Marta; Schneider, Raffaella; Ma, Chung-Pei; Silk, Joseph; Moster, Benjamin

    2017-12-01

    We simulate recoiling black hole trajectories from z = 20 to z = 0 in dark matter haloes, quantifying how parameter choices affect escape velocities. These choices include the strength of dynamical friction, the presence of stars and gas, the accelerating expansion of the Universe (Hubble acceleration), host halo accretion and motion, and seed black hole mass. Lambda cold dark matter halo accretion increases escape velocities by up to 0.6 dex and significantly shortens return time-scales compared to non-accreting cases. Other parameters change orbit damping rates but have subdominant effects on escape velocities; dynamical friction is weak at halo escape velocities, even for extreme parameter values. We present formulae for black hole escape velocities as a function of host halo mass and redshift. Finally, we discuss how these findings affect black hole mass assembly as well as minimum stellar and halo masses necessary to retain supermassive black holes.

  3. Entrapment and escape of liquid lubricant in metal forming

    DEFF Research Database (Denmark)

    Bech, Jakob Ilsted; Bay, Niels; Eriksen, Morten

    1999-01-01

    Using a transparent tool entrapment, compression and eventual escape of liquid lubricant in surface pockets is observed in plane strip drawing. The two mechanisms of lubricant escape. Micro Plasto HydroDynamic and Hydrostatic Lubrication (MPHDL and MPHSL), are observed and quantified experimentally...... with Varying viscosity, speed, reduction, workpiece material, back tension and friction. The mechanisms are influenced by all these parameters in an explicable way. Theoretical models of the escape mechanisms are established combining continuum mechanic analyses of the die pressure distribution with a fluid...... mechanic analysis of the lubricant escape. Oscillations in the drawing force are caused by the local escape of lubricant. (C) 1999 Elsevier Science S.A. All rights reserved....

  4. CTL Escape and Viral Fitness in HIV/SIV Infection.

    Science.gov (United States)

    Seki, Sayuri; Matano, Tetsuro

    2011-01-01

    Cytotoxic T lymphocyte (CTL) responses exert a suppressive effect on HIV and simian immunodeficiency virus (SIV) replication. Under the CTL pressure, viral CTL escape mutations are frequently selected with viral fitness costs. Viruses with such CTL escape mutations often need additional viral genome mutations for recovery of viral fitness. Persistent HIV/SIV infection sometimes shows replacement of a CTL escape mutation with an alternative escape mutation toward higher viral fitness. Thus, multiple viral genome changes under CTL pressure are observed in the chronic phase of HIV/SIV infection. HIV/SIV transmission to HLA/MHC-mismatched hosts drives further viral genome changes including additional CTL escape mutations and reversions under different CTL pressure. Understanding of viral structure/function and host CTL responses would contribute to prediction of HIV evolution and control of HIV prevalence.

  5. Escape for the Slow Solar Wind

    Science.gov (United States)

    Kohler, Susanna

    2017-05-01

    Plasma from the Sun known as the slow solar wind has been observed far away from where scientists thought it was produced. Now new simulations may have resolved the puzzle of where the slow solar wind comes from and how it escapes the Sun to travel through our solar system.An Origin PuzzleA full view of a coronal hole (dark portion) from SDO. The edges of the coronal hole mark the boundary between open and closed magnetic field lines. [SDO; adapted from Higginson et al. 2017]The Suns atmosphere, known as the corona, is divided into two types of regions based on the behavior of magnetic field lines. In closed-field regions, the magnetic field is firmly anchored in the photosphere at both ends of field lines, so traveling plasma is confined to coronal loops and must return to the Suns surface. In open-field regions, only one end of each magnetic field line is anchored in the photosphere, so plasma is able to stream from the Suns surface out into the solar system.This second type of region known as a coronal hole is thought to be the origin of fast-moving plasma measured in our solar system and known as the fast solar wind. But we also observe a slow solar wind: plasma that moves at speeds of less than 500 km/s.The slow solar wind presents a conundrum. Its observational properties strongly suggest it originates in the hot, closed corona rather than the cooler, open regions. But if the slow solar wind plasma originates in closed-field regions of the Suns atmosphere, then how does it escape from the Sun?Slow Wind from Closed FieldsA team of scientists led by Aleida Higginson (University of Michigan) has now used high-resolution, three-dimensional magnetohydrodynamic simulations to show how the slow solar wind can be generated from plasma that starts outin closed-field parts of the Sun.A simulated heliospheric arc, composed of open magnetic field lines. [Higginson et al. 2017]Motions on the Suns surface near the boundary between open and closed-field regions the boundary

  6. Kinematics of aquatic and terrestrial escape responses in mudskippers.

    Science.gov (United States)

    Swanson, Brook O; Gibb, Alice C

    2004-11-01

    Escape responses in fishes are rapid behaviors that are critical for survival. The barred mudskipper (Periophthalmus argentilineatus) is an amphibious fish that must avoid predators in two environments. We compared mudskipper terrestrial and aquatic escapes to address two questions. First, how does an amphibious fish perform an escape response in a terrestrial environment? Second, how similar is a terrestrial escape response to an aquatic escape response? Because a mudskipper on land does not have to contend with the high viscosity of water, we predicted that, if the same behavior is employed across environments, terrestrial escape responses should have 'better' performance (higher velocity and more rapid completion of movements) when compared with aquatic escape responses. By contrast, we predicted that intervertebral bending would be similar across environments because previous studies of escape response behaviors in fishes have proposed that vertebral morphology constrains intervertebral bending. High-speed digital imaging was used to record mudskipper escapes in water and on land, and the resulting images were used to calculate intervertebral bending during the preparatory phase, peak velocity and acceleration of the center of mass during the propulsive phase, and relative timing of movements. Although similar maximum velocities are achieved across environments, terrestrial responses are distinct from aquatic responses. During terrestrial escapes, mudskippers produce greater axial bending in the preparatory phase, but only in the posterior region of the body and over a much longer time period. Mudskippers also occasionally produced the 'wrong' behavior for a given environment. Thus, it appears that the same locomotor morphology is recruited differently by the central nervous system to produce a distinct behavior appropriate for each environment.

  7. The HIV-1 V3 domain on field isolates: participation in generation of escape virus in vivo and accessibility to neutralizing antibodies

    DEFF Research Database (Denmark)

    Arendrup, M; Akerblom, L; Heegaard, P M

    1995-01-01

    patterns against V3 peptides corresponding to sequential primary and escape field isolates, with the strongest reactivity against late isolated escape virus. These observations suggest that the neutralization epitope was influenced by the appearance of mutations. When used as immunogen in rabbits, V3......The V3 domain is highly variable and induces HIV neutralizing antibodies (NA). Here we addressed the issues of 1) the participation of mutations in V3 in generation of neutralization resistant escape virus in vivo and 2) the applicability of synthetic V3 peptides corresponding to field isolates...... to induce neutralizing immune sera. Seven peptides corresponding to the V3 region of primary and escape virus from 3 HIV-1 infected patients were synthesized and used for antibody (Abs) studies and immunizations. The anti-V3 Abs titre in patient serum was generally low against peptides corresponding...

  8. Escape route simulator utilizing augmented reality

    Energy Technology Data Exchange (ETDEWEB)

    Mattos, Karen Salazar Ribeiro de; Mó, Antônio Carlos de A.; Santo, André Cotelli do E.; Silva, Marcio Henrique, E-mail: karensalazar.1190@gmail.com [Instituto de Engenharia Nuclear (IEN/CNEN-RJ), Rio de Janeiro, RJ (Brazil); Centro Universitário Carioca (UniCarioca), Rio de Janeiro, RJ (Brazil)

    2017-07-01

    Due to increasing demand and interest in the interaction of technology platforms and integration of different types of systems and technologies, some tools are already providing practical ways to develop integrated applications. The tools explored by this article are Unity, a platform for game development, and Vuforia, an SDK, software development kit, for augmented reality creation. The coalition proposal of these resources is to create an intuitive escape route that can be used for the evacuation of buildings or open spaces in view of imminent danger, such as radiation leakage, and that can be accessed from a target available at the institution. It has also the intention of simulating situations that involve training of personnel in order to obtain methods that allow to save financial resources, and even to avoid that those who are involved are exposed to risks unnecessarily. The simulator is expected to help design, test, and improve ways to maintain the physical integrity of the facility and provide end users with a better sense of immersion and attractiveness. (author)

  9. Immune escape strategies of malaria parasites

    Directory of Open Access Journals (Sweden)

    Pollyanna Stephanie Gomes

    2016-10-01

    Full Text Available Malaria is one of the most life-threatening infectious diseases worldwide. Immunity to malaria is slow and short-lived despite the repeated parasite exposure in endemic areas. Malaria parasites have evolved refined machinery to evade the immune system based on a range of genetic changes that include allelic variation, biomolecular exposure of proteins and intracellular replication. All of these features increase the probability of survival in both mosquitoes and the vertebrate host. Plasmodium species escape from the first immunological trap in its invertebrate vector host, the Anopheles mosquitoes. The parasites have to pass through various immunological barriers within the mosquito such as anti-microbial molecules and the mosquito microbiota in order to achieve successful transmission to the vertebrate host. Within these hosts, Plasmodium species employ various immune evasion strategies during different life cycle stages. Parasite persistence against the vertebrate immune response depends on the balance among virulence factors, pathology, metabolic cost of the host immune response, and the parasites ability to evade the immune response. In this review we discuss the strategies that Plasmodium parasites use to avoid the vertebrate host immune system and how they promote successful infection and transmission.

  10. Immune Escape Strategies of Malaria Parasites.

    Science.gov (United States)

    Gomes, Pollyanna S; Bhardwaj, Jyoti; Rivera-Correa, Juan; Freire-De-Lima, Celio G; Morrot, Alexandre

    2016-01-01

    Malaria is one of the most life-threatening infectious diseases worldwide. Immunity to malaria is slow and short-lived despite the repeated parasite exposure in endemic areas. Malaria parasites have evolved refined machinery to evade the immune system based on a range of genetic changes that include allelic variation, biomolecular exposure of proteins, and intracellular replication. All of these features increase the probability of survival in both mosquitoes and the vertebrate host. Plasmodium species escape from the first immunological trap in its invertebrate vector host, the Anopheles mosquitoes. The parasites have to pass through various immunological barriers within the mosquito such as anti-microbial molecules and the mosquito microbiota in order to achieve successful transmission to the vertebrate host. Within these hosts, Plasmodium species employ various immune evasion strategies during different life cycle stages. Parasite persistence against the vertebrate immune response depends on the balance among virulence factors, pathology, metabolic cost of the host immune response, and the parasites ability to evade the immune response. In this review we discuss the strategies that Plasmodium parasites use to avoid the vertebrate host immune system and how they promote successful infection and transmission.

  11. Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases.

    Science.gov (United States)

    Muller, Mandy; Glaunsinger, Britt A

    2017-08-01

    During lytic Kaposi's sarcoma-associated herpesvirus (KSHV) infection, the viral endonu- clease SOX promotes widespread degradation of cytoplasmic messenger RNA (mRNA). However, select mRNAs, including the transcript encoding interleukin-6 (IL-6), escape SOX-induced cleavage. IL-6 escape is mediated through a 3' UTR RNA regulatory element that overrides the SOX targeting mechanism. Here, we reveal that this protective RNA element functions to broadly restrict cleavage by a range of homologous and non-homologous viral endonucleases. However, it does not impede cleavage by cellular endonucleases. The IL-6 protective sequence may be representative of a larger class of nuclease escape elements, as we identified a similar protective element in the GADD45B mRNA. The IL-6 and GADD45B-derived elements display similarities in their sequence, putative structure, and several associated RNA binding proteins. However, the overall composition of their ribonucleoprotein complexes appears distinct, leading to differences in the breadth of nucleases restricted. These findings highlight how RNA elements can selectively control transcript abundance in the background of widespread virus-induced mRNA degradation.

  12. The Impacts of Orbital Distance on Exoplanetary Atmospheric Escape

    Science.gov (United States)

    Yang, M.; Guo, J. H.

    2016-11-01

    Driven by the high energy radiation of host stars, atmospheric escape is very important for planet evolution. While the flux drops dramatically with the increase of orbital distance, it is essential to study the impacts of orbital distance on atmospheric escape. We consider the hydrodynamic escape of exoplanets driven by the XUV (X-ray and extreme-ultraviolet) radiation of their host stars. We aim to study the mass-loss rate, the transition of escape mechanism, the structures of temperature and velocity, based on a one-dimensional hydrodynamic model which includes radiative transfer processes and photochemical reactions. As the stellar XUV emission varies with the stellar evolution, we use XSPEC (X-Ray Spectral Fitting Package) to construct the XUV spectra of solar-type stars at different ages. We find that with the increase of orbital distance, the mass-loss rates drop significantly, and when the stellar XUV flux is too small to preserve the hydrodynamic escape, it will turn to Jeans escape. This transition occurs in larger distance for younger and smaller planets. For young planets, hydrodynamic escape can occur in 1-2 au. For very young and close-in planets, the relation between mass-loss rate and stellar flux is not as significant as planets that are not close to their host stars, and the energy-limited equation can lead to large overestimate.

  13. High Resolution Observations of Escaping Ions in the Martian Magnetotail

    Science.gov (United States)

    Halekas, J. S.; Raman, C.; Brain, D.; DiBraccio, G. A.; Harada, Y.; McFadden, J. P.; Mitchell, D. L.; Connerney, J. E. P.; Jakosky, B. M.

    2016-12-01

    Ions escape from the Martian upper atmosphere via a number of channels, including the central plasmasheet of the magnetotail. Mars Express observations show that the heavy ions O+ and O2+ escaping through the central tail often have approximately the same energy, suggesting acceleration in a quasi-static electric field, which has been interpreted as a Hall electric field. The Solar Wind Ion Analyzer (SWIA) on MAVEN was designed to measure the upstream solar wind. However, during orbit segments with appropriate spacecraft attitude, SWIA can also make high resolution measurements of escaping ions in the tail. During the prime mission, these observations were only returned sporadically, during periods of intense escaping fluxes that fortuitously triggered a mode switch. Now, in the extended mission, we return high resolution observations from SWIA routinely. Some of these high resolution measurements reveal slight differences in both the direction and energy of escaping O+ and O2+ ions, which may help determine the acceleration process(es). We investigate the location and solar wind conditions for which the escaping ions separate in energy and angle and the systematics of their energies and flow vectors, and discuss the implications for ion acceleration and the overall picture of Martian atmospheric escape.

  14. Modelling the evolution and spread of HIV immune escape mutants.

    Science.gov (United States)

    Fryer, Helen R; Frater, John; Duda, Anna; Roberts, Mick G; Phillips, Rodney E; McLean, Angela R

    2010-11-18

    During infection with human immunodeficiency virus (HIV), immune pressure from cytotoxic T-lymphocytes (CTLs) selects for viral mutants that confer escape from CTL recognition. These escape variants can be transmitted between individuals where, depending upon their cost to viral fitness and the CTL responses made by the recipient, they may revert. The rates of within-host evolution and their concordant impact upon the rate of spread of escape mutants at the population level are uncertain. Here we present a mathematical model of within-host evolution of escape mutants, transmission of these variants between hosts and subsequent reversion in new hosts. The model is an extension of the well-known SI model of disease transmission and includes three further parameters that describe host immunogenetic heterogeneity and rates of within host viral evolution. We use the model to explain why some escape mutants appear to have stable prevalence whilst others are spreading through the population. Further, we use it to compare diverse datasets on CTL escape, highlighting where different sources agree or disagree on within-host evolutionary rates. The several dozen CTL epitopes we survey from HIV-1 gag, RT and nef reveal a relatively sedate rate of evolution with average rates of escape measured in years and reversion in decades. For many epitopes in HIV, occasional rapid within-host evolution is not reflected in fast evolution at the population level.

  15. Escape to infinity under the action of a potential and a constant electromagnetic field

    CERN Document Server

    Gascon, F G

    2003-01-01

    Escape to infinity is proved for a great variety of potentials, including the potential created by an infinite number of sources. Relativistic escape is studied. Escape in the presence of a constant electromagnetic field and a potential is also considered.

  16. Escape angles in bulk chi((2)) soliton interactions

    DEFF Research Database (Denmark)

    Johansen, Steffen Kjær; Bang, Ole; Sørensen, Mads Peter

    2002-01-01

    We develop a theory for nonplanar interaction between two identical type I spatial solitons propagating at opposite, but arbitrary transverse angles in quadratic nonlinear (or so-called chi((2))) bulk, media. We predict quantitatively the outwards escape angle, below which the solitons turn around...... and collide, and above which they continue to move-away from each other. For in-plane interaction, the theory allows prediction of the Outcome of a collision through the inwards escape angle, i.e., whether the solitons fuse or cross. We find an analytical expression determining the inwards escape angle using...

  17. Exobase properties of hydrodynamic and kinetic models of thermal escape from planetary atmospheres and notion of slow hydrodynamic escape

    Science.gov (United States)

    Volkov, Alexey N.

    2017-12-01

    Exobase parameters obtained based on one-dimensional spherically symmetric hydrodynamic Parker's and kinetic models of thermal escape are studied parametrically for monatomic and diatomic gases. For source parameters, when Parker's and kinetic models predict similar escape rates and atmospheric structures well below the exobase, the exobase parameters obtained based on the both models are different. Parker's model systematically underestimates the exobase distance and overestimates the exobase Jeans parameter. The assumption that the escape rate is equal to the Jeans escape rate at the exobase is not satisfied in both kinetic and hydrodynamic simulations. The ratio of the escape rate to the Jeans rate at the exobase predicted by the hydrodynamics model can be either a few times higher or orders of magnitude smaller than unity. The kinetic model predicts systematic enhancement of the escape rate compared to the Jeans rate at the exobase. This enhancement can be attributed to the bulk velocity only if the exobase Jeans parameter is smaller than 5. This is the domain of slow hydrodynamic escape. At larger exobase Jeans parameters, the enhancement of the escape rate is attributed to non-equilibrium distribution of molecular velocities. In the kinetic solutions obtained for the Maxwell gas, the escape rate is about 2-2.5 of the Jeans rate when the ratio of the mean free path of gas molecules to the atmospheric scale height is ˜0.2. This finding can be used to set up boundary conditions in the hydrodynamic model in order to bring it into agreement with the kinetic model.

  18. Autologous HIV-1 neutralizing antibodies: emergence of neutralization-resistant escape virus and subsequent development of escape virus neutralizing antibodies

    DEFF Research Database (Denmark)

    Arendrup, M; Nielsen, C; Hansen, J E

    1992-01-01

    The capacity of consecutive human sera to neutralize sequentially obtained autologous virus isolates was studied. HIV-1 was isolated three times over a 48-164-week period from three individuals immediately after seroconversion and from two individuals in later stages of infection. Development...... escape virus may be part of the explanation of the apparent failure of the immune system to control HIV infection....... of neutralizing antibodies to the primary virus isolates was detected 13-45 weeks after seroconversion. Emergence of escape virus with reduced sensitivity to neutralization by autologous sera was demonstrated. The patients subsequently developed neutralizing antibodies against the escape virus but after a delay...

  19. Pilot Fullerton dons ejection escape suit (EES) on middeck

    Science.gov (United States)

    1982-01-01

    Pilot Fullerton dons ejection escape suit (EES) (high altitude pressure garment) life preserver unit (LPU) on forward port side of middeck above potable water tank. Fullerton also adjusts lapbelt fitting and helmet holddown strap.

  20. Escape of protists in predator-generated feeding currents

    DEFF Research Database (Denmark)

    Jakobsen, Hans Henrik

    2002-01-01

    The ciliate Strobilidium sp. and 2 flagellates, Chrysochromulina simplex and Gymnodinium sp., were exposed to predator-generated feeding currents, and their escape responses were quantified using 2- and 3-dimensional video techniques. All 3 studied organisms responded by escaping at a defined...... distance to their predators. A critical threshold fluid deformation rate of escape of 3.6 s(-1) was estimated in a quantifiable siphon suction flow field for the ciliate Strobilidium sp. Using previous published models and the critical deformation rate estimated here, I predicted the reaction distance...... to the ciliate, the critical deformation for escape for both the flagellates was estimated to range between 6.9 and 14.5 s(-1). The critical deformation rate of flagellates proved to be slightly higher than that of ciliates. I speculate that this reflects that ciliates are the main predator on flagellates while...

  1. Estimation of coho salmon escapement in the Ugashik lakes

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — From 26 July to 24 September 2002, hourly counts were conducted from counting towers to estimate the escapement of coho salmon Oncorhynchus kisutch into the Ugashik...

  2. The influence of panic on the efficiency of escape

    Science.gov (United States)

    Shen, Jia-Quan; Wang, Xu-Wen; Jiang, Luo-Luo

    2018-02-01

    Whenever we (such as pedestrians) perceive a high density or imminent danger in a confined space, we tend to be panic, which can lead to severe injuries even in the absence of real dangers. Although it is difficult to measure panics in real conditions, we introduced a simple model to study the collective behaviors in condition of fire with dense smoke. Owing to blocking the sight with dense smoke, pedestrians in this condition have two strategies to escape: random-walking or walking along the wall. When the pedestrians are in moderate panic that mean the two types of behaviors are mixed(random-walking and walking along the wall). Our simulation results show that moderate panic, meaning that two escape strategies are mixed, reduces the escape time. In addition, the results indicate that moderate panic can improve the efficiency of escape, this theory also can be useful in a real escape situation. We hope that our research provides the theoretical understanding of underlying mechanisms of panic escape in the condition of poor sight.

  3. Trade-offs between performance and variability in the escape responses of bluegill sunfish (Lepomis macrochirus

    Directory of Open Access Journals (Sweden)

    Amanda C. Hitchcock

    2015-07-01

    Full Text Available Successful predator evasion is essential to the fitness of many animals. Variation in escape behaviour may be adaptive as it reduces predictability, enhancing escape success. High escape velocities and accelerations also increase escape success, but biomechanical factors likely constrain the behavioural range over which performance can be maximized. There may therefore be a trade-off between variation and performance during escape responses. We have used bluegill sunfish (Lepomis macrochirus escape responses to examine this potential trade-off, determining the full repertoire of escape behaviour for individual bluegill sunfish and linking this to performance as indicated by escape velocity and acceleration. Fish escapes involve an initial C-bend of the body axis, followed by variable steering movements. These generate thrust and establish the escape direction. Directional changes during the initial C-bend were less variable than the final escape angle, and the most frequent directions were associated with high escape velocity. Significant inter-individual differences in escape angles magnified the overall variation, maintaining unpredictability from a predator perspective. Steering in the latter stages of the escape to establish the final escape trajectory also affected performance, with turns away from the stimulus associated with reduced velocity. This suggests that modulation of escape behaviour by steering may also have an associated performance cost. This has important implications for understanding the scope and control of intra- and inter-individual variation in escape behaviour and the associated costs and benefits.

  4. Sensitive determination of four camptothecins by solid-phase microextraction-HPLC based on a boronic acid contained polymer monolithic layer.

    Science.gov (United States)

    Chen, Jishun; Min, Xinwen; Li, Peng; Chen, Wu; Tian, Dawei; Chen, Qinhua

    2015-06-16

    Camptothecin (CPT) and its derivative have been revealed to possess special anti-cancer activity, extraction methods are necessary for trace determination of CPTs in complex samples. In this work, we prepared a high efficient boronic acid-based polymer monolithic layer for microextraction of CPTs. A disposable membrane filter-based extraction device was developed, and boronic acid groups were co-polymerized into a polyporous polymer skeleton and served as the monolithic sorbent. The prepared poly(4-VB-MA-TRIM) showed good stability and great extraction efficiency toward four CPTs. After optimization of extraction conditions, poly(4-VB-MA-TRIM)-based solid-phase microextraction was coupled HPLC for determination of CPTs in biological samples. The method exhibited low limits of detection of 0.05-0.2 ng mL(-1), which is significantly more sensitive than reported HPLC methods. The method also showed wide linear range (0.1-100 and 0.5-200 ng mL(-1)), good linearity (R(2)≥0.9981) and good reproducibility (RSD ≤3.76%). The method has been applied in plasma samples, with good selectivity and good recoveries ranging from 85.1 to 104.7%. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Telomerase activity is sufficient to allow transformed cells to escape from crisis.

    Science.gov (United States)

    Halvorsen, T L; Leibowitz, G; Levine, F

    1999-03-01

    The introduction of simian virus 40 large T antigen (SVLT) into human primary cells enables them to proliferate beyond their normal replicative life span. In most cases, this temporary escape from senescence eventually ends in a second proliferative block known as "crisis," during which the cells cease growing or die. Rare immortalization events in which cells escape crisis are frequently correlated with the presence of telomerase activity. We tested the hypothesis that telomerase activation is the critical step in the immortalization process by studying the effects of telomerase activity in two mortal SVLT-Rasval12-transformed human pancreatic cell lines, TRM-6 and betalox5. The telomerase catalytic subunit, hTRT, was introduced into late-passage cells via retroviral gene transfer. Telomerase activity was successfully induced in infected cells, as demonstrated by a telomerase repeat amplification protocol assay. In each of nine independent infections, telomerase-positive cells formed rapidly dividing cell lines while control cells entered crisis. Telomere lengths initially increased, but telomeres were then maintained at their new lengths for at least 20 population doublings. These results demonstrate that telomerase activity is sufficient to enable transformed cells to escape crisis and that telomere elongation in these cells occurs in a tightly regulated manner.

  6. Neural Circuitry that Evokes Escape Behavior upon Activation of Nociceptive Sensory Neurons in Drosophila Larvae.

    Science.gov (United States)

    Yoshino, Jiro; Morikawa, Rei K; Hasegawa, Eri; Emoto, Kazuo

    2017-08-21

    Noxious stimuli trigger a stereotyped escape response in animals. In Drosophila larvae, class IV dendrite arborization (C4 da) sensory neurons in the peripheral nervous system are responsible for perception of multiple nociceptive modalities, including noxious heat and harsh mechanical stimulation, through distinct receptors [1-9]. Silencing or ablation of C4 da neurons largely eliminates larval responses to noxious stimuli [10-12], whereas optogenetic activation of C4 da neurons is sufficient to provoke corkscrew-like rolling behavior similar to what is observed when larvae receive noxious stimuli, such as high temperature or harsh mechanical stimulation [10-12]. The receptors and the regulatory mechanisms for C4 da activation in response to a variety of noxious stimuli have been well studied [13-23], yet how C4 da activation triggers the escape behavior in the circuit level is still incompletely understood. Here we identify segmentally arrayed local interneurons (medial clusters of C4 da second-order interneurons [mCSIs]) in the ventral nerve cord that are necessary and sufficient to trigger rolling behavior. GFP reconstitution across synaptic partners (GRASP) analysis indicates that C4 da axons form synapses with mCSI dendrites. Optogenetic activation of mCSIs induces the rolling behavior, whereas silencing mCSIs reduces the probability of rolling behavior upon C4 da activation. Further anatomical and functional studies suggest that the C4 da-mCSI nociceptive circuit evokes rolling behavior at least in part through segmental nerve a (SNa) motor neurons. Our findings thus uncover a local circuit that promotes escape behavior upon noxious stimuli in Drosophila larvae and provide mechanistic insights into how noxious stimuli are transduced into the stereotyped escape behavior in the circuit level. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Compartmented neuronal cultures reveal two distinct mechanisms for alpha herpesvirus escape from genome silencing.

    Science.gov (United States)

    Koyuncu, Orkide O; MacGibeny, Margaret A; Hogue, Ian B; Enquist, Lynn W

    2017-10-01

    Alpha herpesvirus genomes encode the capacity to establish quiescent infections (i.e. latency) in the peripheral nervous system for the life of their hosts. Multiple times during latency, viral genomes can reactivate to start a productive infection, enabling spread of progeny virions to other hosts. Replication of alpha herpesviruses is well studied in cultured cells and many aspects of productive replication have been identified. However, many questions remain concerning how a productive or a quiescent infection is established. While infections in vivo often result in latency, infections of dissociated neuronal cultures in vitro result in a productive infection unless lytic viral replication is suppressed by DNA polymerase inhibitors or interferon. Using primary peripheral nervous system neurons cultured in modified Campenot tri-chambers, we previously reported that reactivateable, quiescent infections by pseudorabies virus (PRV) can be established in the absence of any inhibitor. Such infections were established in cell bodies only when physically isolated axons were infected at a very low multiplicity of infection (MOI). In this report, we developed a complementation assay in compartmented neuronal cultures to investigate host and viral factors in cell bodies that prevent establishment of quiescent infection and promote productive replication of axonally delivered genomes (i.e. escape from silencing). Stimulating protein kinase A (PKA) signaling pathways in isolated cell bodies, or superinfecting cell bodies with either UV-inactivated PRV or viral light particles (LP) promoted escape from genome silencing and prevented establishment of quiescent infection but with different molecular mechanisms. Activation of PKA in cell bodies triggers a slow escape from silencing in a cJun N-terminal kinase (JNK) dependent manner. However, escape from silencing is induced rapidly by infection with UVPRV or LP in a PKA- and JNK-independent manner. We suggest that viral tegument

  8. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape.

    Science.gov (United States)

    Hegde, Meenakshi; Mukherjee, Malini; Grada, Zakaria; Pignata, Antonella; Landi, Daniel; Navai, Shoba A; Wakefield, Amanda; Fousek, Kristen; Bielamowicz, Kevin; Chow, Kevin K H; Brawley, Vita S; Byrd, Tiara T; Krebs, Simone; Gottschalk, Stephen; Wels, Winfried S; Baker, Matthew L; Dotti, Gianpietro; Mamonkin, Maksim; Brenner, Malcolm K; Orange, Jordan S; Ahmed, Nabil

    2016-08-01

    In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.

  9. To run or hide?: escape behaviour in a cryptic African snake | Maritz ...

    African Journals Online (AJOL)

    Optimal escape theory predicts that escape behaviour of an organism is best understood in terms of costs and benefits of escaping relative to risk of predation. However, risk of predation facing an organism is dependent on various biotic and abiotic factors. In order to better understand escape behaviour of an African snake, ...

  10. The Effect of Solar Wind Variations on the Escape of Oxygen Ions From Mars Through Different Channels: MAVEN Observations

    Science.gov (United States)

    Dubinin, E.; Fraenz, M.; Pätzold, M.; McFadden, J.; Halekas, J. S.; DiBraccio, G. A.; Connerney, J. E. P.; Eparvier, F.; Brain, D.; Jakosky, B. M.; Vaisberg, O.; Zelenyi, L.

    2017-11-01

    We present multi-instrument observations of the effects of solar wind on ion escape fluxes on Mars based on the Mars Atmosphere and Volatile EvolutioN (MAVEN) data from 1 November 2014 to 15 May 2016. Losses of oxygen ions through different channels (plasma sheet, magnetic lobes, boundary layer, and ion plume) as a function of the solar wind and the interplanetary magnetic field variations were studied. We have utilized the modified Mars Solar Electric (MSE) coordinate system for separation of the different escape routes. Fluxes of the low-energy (≤30 eV) and high-energy (≥30 eV) ions reveal different trends with changes in the solar wind dynamic pressure, the solar wind flux, and the motional electric field. Major oxygen fluxes occur through the tail of the induced magnetosphere. The solar wind motional electric field produces an asymmetry in the ion fluxes and leads to different relations between ion fluxes supplying the tail from the different hemispheres and the solar wind dynamic pressure (or flux) and the motional electric field. The main driver for escape of the high-energy oxygen ions is the solar wind flux (or dynamic pressure). On the other hand, the low-energy ion component shows the opposite trend: ion flux decreases with increasing solar wind flux. As a result, the averaged total oxygen ion fluxes reveal a low variability with the solar wind strength. The large standard deviations from the averages values of the escape fluxes indicate the existence of mechanisms which can enhance or suppress the efficiency of the ion escape. It is shown that the Martian magnetosphere possesses the properties of a combined magnetosphere which contains different classes of field lines. The existence of the closed magnetic field lines in the near-Mars tail might be responsible for suppression of the ion escape fluxes.

  11. Loss of water from Venus. I - Hydrodynamic escape of hydrogen

    Science.gov (United States)

    Kasting, J. F.; Pollack, J. B.

    1983-01-01

    A one-dimensional photochemical-dynamic model is used to study hydrodynamic loss of hydrogen from a primitive, water-rich atmosphere on Venus. The escape flux is calculated as a function of the H2O mixing ratio at the atmospheric cold trap. The cold trap mixing ratio is then related in an approximate fashion to the H2O concentration in the lower atmosphere. Hydrodynamic escape should have been the dominant loss process for hydroogen when the H2O mass mixing ratio in the lower atmosphere exceeded approximately 0.1. The escape rate would have depended upon the magnitude of the solar ultraviolet flux and the atmospheric EUV heating efficiency and, to a lesser extent, on the O2 content of the atmosphere. The time required for Venus to have lost the bulk of a terrestrial ocean of water is on the order of a billion years. Deuterium would have been swept away along with hydrogen if the escape rate was high enough, but some D/H enrichment should have occurred as the escape rate slowed down.

  12. Enhancing endosomal escape for nanoparticle mediated siRNA delivery

    Science.gov (United States)

    Ma, Da

    2014-05-01

    Gene therapy with siRNA is a promising biotechnology to treat cancer and other diseases. To realize siRNA-based gene therapy, a safe and efficient delivery method is essential. Nanoparticle mediated siRNA delivery is of great importance to overcome biological barriers for systemic delivery in vivo. Based on recent discoveries, endosomal escape is a critical biological barrier to be overcome for siRNA delivery. This feature article focuses on endosomal escape strategies used for nanoparticle mediated siRNA delivery, including cationic polymers, pH sensitive polymers, calcium phosphate, and cell penetrating peptides. Work has been done to develop different endosomal escape strategies based on nanoparticle types, administration routes, and target organ/cell types. Also, enhancement of endosomal escape has been considered along with other aspects of siRNA delivery to ensure target specific accumulation, high cell uptake, and low toxicity. By enhancing endosomal escape and overcoming other biological barriers, great progress has been achieved in nanoparticle mediated siRNA delivery.

  13. Inferring HIV escape rates from multi-locus genotype data

    Directory of Open Access Journals (Sweden)

    Taylor A Kessinger

    2013-09-01

    Full Text Available Cytotoxic T-lymphocytes (CTLs recognize viral protein fragments displayed by major histocompatibility complex (MHC molecules on the surface of virally infected cells and generate an anti-viral response that can kill the infected cells. Virus variants whose protein fragments are not efficiently presented on infected cells or whose fragments are presented but not recognized by CTLs therefore have a competitive advantage and spread rapidly through the population. We present a method that allows a more robust estimation of these escape rates from serially sampled sequence data. The proposed method accounts for competition between multiple escapes by explicitly modeling the accumulation of escape mutations and the stochastic effects of rare multiple mutants. Applying our method to serially sampled HIV sequence data, we estimate rates of HIV escape that are substantially larger than those previously reported. The method can be extended to complex escapes that require compensatory mutations. We expect our method to be applicable in other contexts such as cancer evolution where time series data is also available.

  14. Escape routes, weak links, and desynchronization in fluctuation-driven networks.

    Science.gov (United States)

    Schäfer, Benjamin; Matthiae, Moritz; Zhang, Xiaozhu; Rohden, Martin; Timme, Marc; Witthaut, Dirk

    2017-06-01

    Shifting our electricity generation from fossil fuel to renewable energy sources introduces large fluctuations to the power system. Here, we demonstrate how increased fluctuations, reduced damping, and reduced intertia may undermine the dynamical robustness of power grid networks. Focusing on fundamental noise models, we derive analytic insights into which factors limit the dynamic robustness and how fluctuations may induce a system escape from an operating state. Moreover, we identify weak links in the grid that make it particularly vulnerable to fluctuations. These results thereby not only contribute to a theoretical understanding of how fluctuations act on distributed network dynamics, they may also help designing future renewable energy systems to be more robust.

  15. Passive Facebook use, Facebook addiction, and associations with escapism: an experimental vignette study

    OpenAIRE

    Young, LN; Kuss, D; Griffiths, M.; Howard, CJ

    2017-01-01

    There is relatively little research considering motivations of passive Facebook use. However, research regarding motivations of general Facebook use indicates that people use Facebook to escape – and that escapism may motivate passive Facebook use. Research also suggests that using Facebook to escape is associated with Facebook addiction. Using an experimental vignette design, the present research investigated whether passive Facebook use is motivated by escapism and whether this escape motiv...

  16. Group nightmares about escape from ex-homeland.

    Science.gov (United States)

    Cernovsky, Z

    1990-09-01

    Escape nightmares (recurrent nightmares about re-escaping ex-homeland) were studied via a 79-item questionnaire administered to 83 Czechoslovak refugees who were living in Switzerland. The key features of the nightmare were not related significantly to the refugees' age, gender, occupation, or educational level. Further analyses dealt with mutual relationships of the various reported aspects of the escape nightmares. The reports of dreaming about arrival in the ex-homeland by a "mistake," such as boarding a wrong airplane (i.e., a Freudian parapraxis), were associated with higher levels of (subsequent) dream anxiety, with waking up due to mounting dream tension, and with the dreamer not knowing at first upon awakening whether he was now in the free world or elsewhere.

  17. Behavior of Ants Escaping from a Single-Exit Room.

    Science.gov (United States)

    Wang, Shujie; Lv, Wei; Song, Weiguo

    2015-01-01

    To study the rules of ant behavior and group-formation phenomena, we examined the behaviors of Camponotus japonicus, a species of large ant, in a range of situations. For these experiments, ants were placed inside a rectangular chamber with a single exit that also contained a filter paper soaked in citronella oil, a powerful repellent. The ants formed several groups as they moved toward the exit to escape. We measured the time intervals between individual escapes in six versions of the experiment, each containing an exit of a different width, to quantify the movement of the groups. As the ants exited the chamber, the time intervals between individual escapes changed and the frequency distribution of the time intervals exhibited exponential decay. We also investigated the relationship between the number of ants in a group and the group flow rate.

  18. Escaping and Falling into Poverty in India Today.

    Science.gov (United States)

    Thorat, Amit; Vanneman, Reeve; Desai, Sonalde; Dubey, Amaresh

    2017-05-01

    The study examines the dynamic nature of movements into and out of poverty over a period when poverty has fallen substantially in India. The analysis identifies people who escaped poverty and those who fell into it over the period 2005 to 2012. The analysis identifies people who escaped poverty and those who fell into it over the period 2005 to 2012. Using panel data from the India Human Development Survey for 2005 and 2012, we find that the risks of marginalized communities such as Dalits and Adivasis of falling into or remaining in poverty were higher than those for more privileged groups. Some, but not all of these higher risks are explained by educational, financial, and social disadvantages of these groups in 2005. Results from a logistic regression show that some factors that help people escape poverty differ from those that push people into it and that the strength of their effects varies.

  19. An anticipative escape system for vehicles in water crashes

    Science.gov (United States)

    Shen, Chuanliang; Wang, Jiawei; Yin, Qi; Zhu, Yantao; Yang, Jiawei; Liao, Mengdi; Yang, Liming

    2017-07-01

    In this article, it designs an escape system for vehicles in water crashes. The structure mainly contains sensors, control organs and actuating mechanism for both doors and windows. Sensors judge whether the vehicle falls into water or is in the falling process. The actuating mechanism accepts the signal delivered by the control organs, then open the electronic central lock on doors and meanwhile lower the window. The water escape system is able to anticipate drowning situations for vehicles and controls both doors and windows in such an emergency. Under the premise of doors staying in an undamaged state, it is for sure that people in the vehicle can open the door while drowning in the water and safely escape.

  20. Behavior of Ants Escaping from a Single-Exit Room.

    Directory of Open Access Journals (Sweden)

    Shujie Wang

    Full Text Available To study the rules of ant behavior and group-formation phenomena, we examined the behaviors of Camponotus japonicus, a species of large ant, in a range of situations. For these experiments, ants were placed inside a rectangular chamber with a single exit that also contained a filter paper soaked in citronella oil, a powerful repellent. The ants formed several groups as they moved toward the exit to escape. We measured the time intervals between individual escapes in six versions of the experiment, each containing an exit of a different width, to quantify the movement of the groups. As the ants exited the chamber, the time intervals between individual escapes changed and the frequency distribution of the time intervals exhibited exponential decay. We also investigated the relationship between the number of ants in a group and the group flow rate.

  1. Lyman-Werner escape fractions from the first galaxies

    Science.gov (United States)

    Schauer, Anna T. P.; Agarwal, Bhaskar; Glover, Simon C. O.; Klessen, Ralf S.; Latif, Muhammad A.; Mas-Ribas, Lluís; Rydberg, Claes-Erik; Whalen, Daniel J.; Zackrisson, Erik

    2017-05-01

    Direct collapse black holes forming in pristine, atomically cooling haloes at z ≈ 10-20 may act as the seeds of supermassive black holes (BHs) at high redshifts. In order to create a massive BH seed, the host halo needs to be prevented from forming stars. H2 therefore needs to be irradiated by a large flux of Lyman-Werner (LW) UV photons in order to suppress H2 cooling. A key uncertainty in this scenario is the escape fraction of LW radiation from first galaxies, which is the dominant source of UV photons at this epoch. To better constrain this escape fraction, we have performed radiation-hydrodynamical simulations of the growth of H II regions and their associated photodissociation regions in the first galaxies using the zeus-mp code. We find that the LW escape fraction crucially depends on the propagation of the ionization front (I-front). For an R-type I-front overrunning the halo, the LW escape fraction is always larger than 95 per cent. If the halo recombines later from the outside-in, due to a softened and weakened spectrum, the LW escape fraction in the rest frame of the halo (the near-field) drops to zero. A detailed and careful analysis is required to analyse slowly moving, D-type I-fronts, where the escape fraction depends on the microphysics and can be as small as 3 per cent in the near-field and 61 per cent in the far-field or as large as 100 per cent in both the near-field and the far-field.

  2. The escaping "pneuma" - gas of ancient earthquake concepts in relation to animal, atmospheric and thermal precursors

    Science.gov (United States)

    Helmut, Tributsch

    2013-04-01

    anomalies matches that of reported unusual animal behaviour. It may indeed be caused by the same geophysical phenomenon, a pressure-change induced liberation of "pneuma" -gas. The latter may simply be understood as the consequence of pressure dependent changes of the chemical equilibrium constants within the condensed phases of the underground. They will be proportional to the reaction molar volume of interfacial and bulk geochemical mechanisms and may lead to the desorption and emission of chemical species, which finally reach the earth surface. The nature of reported animal behaviour is supporting such conclusion. Straightforward experimental strategies will be required for characterization of the escaping gas in terms of chemical and nano- and micro- particle composition. Non-linear irreversible thermodynamic models may be invoked for understanding energy turnover during the geophysical precursor activity.

  3. Cell-specific expression of tryptophan decarboxylase and 10-hydroxygeraniol oxidoreductase, key genes involved in camptothecin biosynthesis in Camptotheca acuminata Decne (Nyssaceae

    Directory of Open Access Journals (Sweden)

    Santamaria Anna

    2010-04-01

    Full Text Available Abstract Background Camptotheca acuminata is a major natural source of the terpenoid indole alkaloid camptothecin (CPT. At present, little is known about the cellular distribution of the biosynthesis of CPT, which would be useful knowledge for developing new strategies and technologies for improving alkaloid production. Results The pattern of CPT accumulation was compared with the expression pattern of some genes involved in CPT biosynthesis in C. acuminata [i.e., Ca-TDC1 and Ca-TDC2 (encoding for tryptophan decarboxylase and Ca-HGO (encoding for 10-hydroxygeraniol oxidoreductase]. Both CPT accumulation and gene expression were investigated in plants at different degrees of development and in plantlets subjected to drought-stress. In all organs, CPT accumulation was detected in epidermal idioblasts, in some glandular trichomes, and in groups of idioblast cells localized in parenchyma tissues. Drought-stress caused an increase in CPT accumulation and in the number of glandular trichomes containing CPT, whereas no increase in epidermal or parenchymatous idioblasts was observed. In the leaf, Ca-TDC1 expression was detected in some epidermal cells and in groups of mesophyll cells but not in glandular trichomes; in the stem, it was observed in parenchyma cells of the vascular tissue; in the root, no expression was detected. Ca-TDC2 expression was observed exclusively in leaves of plantlets subjected to drought-stress, in the same sites described for Ca-TDC1. In the leaf, Ca-HGO was detected in all chlorenchyma cells; in the stem, it was observed in the same sites described for Ca-TDC1; in the root, no expression was detected. Conclusions The finding that the sites of CPT accumulation are not consistently the same as those in which the studied genes are expressed demonstrates an organ-to-organ and cell-to-cell translocation of CPT or its precursors.

  4. Mycoplasma bovis escapes bovine neutrophil extracellular traps.

    Science.gov (United States)

    Gondaira, Satoshi; Higuchi, Hidetoshi; Nishi, Koji; Iwano, Hidetomo; Nagahata, Hajime

    2017-02-01

    Mycoplasma bovis is a significant pathogen in bovine infections including mastitis, pneumonia, arthritis and otitis media, and is the cause of large economic losses in beef and dairy farms. During infection with M. bovis, recruited neutrophils are not sufficient to eradicate M. bovis from the infection site. The release of neutrophil extracellular traps (NETs) is one of the innate immune responses of neutrophils but the effect of M. bovis on NET formation by bovine neutrophils has not yet been clarified. The objective of our research was to examine the effect of M. bovis on NET formation and the killing activity of bovine neutrophils. We showed that NETs were not detected following stimulation of neutrophils by M. bovis alone or with Phorbol 12-myristate 13-acetat (PMA). Reactive oxygen species production is essential for NET formation but the levels in neutrophils stimulated with M. bovis at multiplicity of infections of 10, 100, and 1000 were similar to those of unstimulated cells. NET formation induced by PMA stimulated neutrophils disappeared following the addition of M. bovis but this phenomenon was not observed when ethylenediaminetetraacetic acid (EDTA) was added. M. bovis colony forming units were significantly decreased by the addition of EDTA in the presence of NETs. Our results suggested that M. bovis infection alone did not induce NETs and that M. bovis nucleases, as hypothesis-based, contributed to resistance against the killing activity of NETs. Copyright © 2016. Published by Elsevier B.V.

  5. Case of escape in cassava, Manihot esculenta Crantz.

    Science.gov (United States)

    Nassar, N M A; Mendonza, M

    2017-02-08

    Two cassava escapes where collected from cultivated fields near natural habitat in Bolivia. They are described morphologically and analyzed cytogenetically in this study. It is suggested that they are the product of backcrosses of cassava interspecific hybrids with the cultigen itself, and that selective conditions have developed in which certain forms of cassava segregates have adapted to grow wildly in natural habitats near cassava fields. These segregates may hybridize with cultivated cassava upon coming in contact with such varieties. Because these escapes have incorporated useful genes from the wild into their genetic structure, they could be used for cassava improvement since their genetic barriers with other forms of cassava are very weak.

  6. [Research Advance in Light Chain Escape of Multiple Myeloma -Review].

    Science.gov (United States)

    Huang, Qian-Chuan; Ding, Jin-Ya

    2017-12-01

    More than 80% of patients with MM is present as intact monoclonal immunoglobulin (Ig). Usually, the patients with intact immunoglobulin MM (IIMM) show parallel fluctuations of their intact Ig and FLCs or BJP. In the era of novel agents, including thalidomide, lenalidomide and bortezomib, the natural disease development and classic relapse patterns have been changed, the relapse was characterized by an increase in sFLC or BJP without a corresponding increase in paraprotein level, a phenomenon termed "light chain escape", indicates a worse outcome in patients with MM. This review focuses on the mechanism, clinical significance and early diagnosis of light chain escape.

  7. Development of Guanidine-Bisurea Bifunctional Organocatalyst Bearing Chirality at the Inner and Outer Sides of the Urea Groups, and Application to Enantioselective α-Hydroxylation of Pyranoindolizine Intermediate for Camptothecin Synthesis

    Directory of Open Access Journals (Sweden)

    Minami Odagi

    2015-01-01

    Full Text Available Pyranoindolizine is a tricyclic structure found in various biologically active compounds, such as camptothecin (CPT and its derivatives. In the case of CPTs, the chirality at the α-position in the α-hydroxyl lactone moiety of pyranoindolizine is important for the antitumor activity. This paper deals with enantioselective oxidation of the α-position in pyranoindolizine lactone, which corresponds at C20 in CPT, with cumene hydroperoxide (CHP in the presence of newly synthesized guanidine-bisurea bifunctional organocatalysts bearing chirality on both the inner and outer sides of the urea groups.

  8. Predictability of escape for a stochastic saddle-node bifurcation: When rare events are typical

    Science.gov (United States)

    Herbert, Corentin; Bouchet, Freddy

    2017-09-01

    Transitions between multiple stable states of nonlinear systems are ubiquitous in physics, chemistry, and beyond. Two types of behaviors are usually seen as mutually exclusive: unpredictable noise-induced transitions and predictable bifurcations of the underlying vector field. Here, we report a different situation, corresponding to a fluctuating system approaching a bifurcation, where both effects collaborate. We show that the problem can be reduced to a single control parameter governing the competition between deterministic and stochastic effects. Two asymptotic regimes are identified: When the control parameter is small (e.g., small noise), deviations from the deterministic case are well described by the Freidlin-Wentzell theory. In particular, escapes over the potential barrier are very rare events. When the parameter is large (e.g., large noise), such events become typical. Unlike pure noise-induced transitions, the distribution of the escape time is peaked around a value which is asymptotically predicted by an adiabatic approximation. We show that the two regimes are characterized by qualitatively different reacting trajectories with algebraic and exponential divergences, respectively.

  9. The RAVE survey : constraining the local Galactic escape speed

    NARCIS (Netherlands)

    Smith, Martin C.; Ruchti, Gregory R.; Helmi, Amina; Wyse, Rosemary F. G.; Fulbright, J. P.; Freeman, K. C.; Navarro, J. F.; Seabroke, G. M.; Steinmetz, M.; Williams, M.; Bienayme, O.; Binney, J.; Bland-Hawthorn, J.; Dehnen, W.; Gibson, B. K.; Gilmore, G.; Grebel, E. K.; Munari, U.; Parker, Q. A.; Scholz, R.-D.; Siebert, A.; Watson, F. G.; Zwitter, T.

    2007-01-01

    We report new constraints on the local escape speed of our Galaxy. Our analysis is based on a sample of high-velocity stars from the RAVE survey and two previously published data sets. We use cosmological simulations of disc galaxy formation to motivate our assumptions on the shape of the velocity

  10. Dallas zoo hunts for escaped vulture | Alanis | Vulture News

    African Journals Online (AJOL)

    Vulture News. Journal Home · ABOUT · Advanced Search · Current Issue · Archives · Journal Home > Vol 56 (2007) >. Log in or Register to get access to full text downloads. Username, Password, Remember me, or Register. Dallas zoo hunts for escaped vulture. M Alanis. Abstract. No Abstract. Vulture News Vol. 56 () 2007: ...

  11. Determination of forage escape protein value with in situ and ...

    African Journals Online (AJOL)

    This study was carried out to compare in situ and in vitro enzyme techniques for determining estimates of forage escape proteins. Eight forages (vetch hay, wheat silage, corn silage, wheat hay, grass hay, lentil straw, triticale hay and alfalfa hay) were used as feed materials. During 70 h, incubation with enzyme method had ...

  12. Emergency escape system protects personnel from explosion and fire

    Science.gov (United States)

    Offik, W. G.

    1966-01-01

    Elevator-type emergency escape system evacuates personnel from tall structures, especially when the possibility of explosion or fire exists. The system consists of a spike shaped rescue cabin which descends along a vertical guide cable, penetrates the dome shaped roof of an underground blast shelter and stops in a deceleration bed of granular material.

  13. A Structural Soundness Proof for Shivers's Escape Technique

    DEFF Research Database (Denmark)

    Midtgaard, Jan; Adams, Michael D.; Matthew, Might

    2012-01-01

    Shivers’s escape technique enables one to analyse the control flow of higher-order program fragments. It is widely used, but its soundness has never been proven. In this paper, we present the first soundness proof for the technique. Our proof is structured as a composition of Galois connections...

  14. Enuresis Control through Fading, Escape, and Avoidance Training.

    Science.gov (United States)

    Hansen, Gordon D.

    1979-01-01

    A twin signal device that provides both escape and avoidance conditioning in enuresis control was documented with case studies of two enuretic children (eight and nine years old). In addition, a technique of fading as an adjunct to the process was utilized with one subject. (Author/SBH)

  15. Molecular strategies to design an escape-proof antiviral therapy

    NARCIS (Netherlands)

    Berkhout, Ben; Sanders, Rogier W.

    2011-01-01

    Two antiviral approaches against the human immunodeficiency virus type 1 (HIV-1) were presented at the Antivirals Congress in Amsterdam. The common theme among these two separate therapeutic research lines is the wish to develop a durable therapy that prevents viral escape. We will present a brief

  16. Dissociated neural effects of cortisol depending on threat escapability

    NARCIS (Netherlands)

    Montoya, Estrella R; van Honk, Jack; Bos, Peter A; Terburg, David

    2015-01-01

    Evolution has provided us with a highly flexible neuroendocrine threat system which, depending on threat imminence, switches between active escape and passive freezing. Cortisol, the "stress-hormone", is thought to play an important role in both fear behaviors, but the exact mechanisms are not

  17. Jurisprudential Escapism, Horizontal Anxiety and the Right to

    African Journals Online (AJOL)

    NWUuser

    RACE AS/AND THE TRACE OF THE GHOST: JURISPRUDENTIAL ESCAPISM,. HORIZONTAL ANXIETY AND ... other being a critique of its 'race politics' (its background racial ideology). I shall also examine the ..... Property Control Act provided the judge with ample space to vary the terms of the trust provisions in order to ...

  18. 46 CFR 169.313 - Means of escape.

    Science.gov (United States)

    2010-10-01

    ... 46 Shipping 7 2010-10-01 2010-10-01 false Means of escape. 169.313 Section 169.313 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) NAUTICAL SCHOOLS SAILING SCHOOL VESSELS Construction... apart, uniform for the length of the ladder; (3) At least 3 inches from the nearest permanent object in...

  19. 46 CFR 127.240 - Means of escape.

    Science.gov (United States)

    2010-10-01

    ... GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OFFSHORE SUPPLY VESSELS CONSTRUCTION AND ARRANGEMENTS Particular Construction and Arrangements § 127.240 Means of escape. (a) Except as provided by paragraphs (l... horizontal, greater than 70 degrees but not more than 90 degrees. (g) No means may be provided for locking...

  20. Danger detection and escape behaviour in wood crickets.

    Science.gov (United States)

    Dupuy, Fabienne; Casas, Jérôme; Body, Mélanie; Lazzari, Claudio R

    2011-07-01

    The wind-sensitive cercal system of Orthopteroid insects that mediates the detection of the approach of a predator is a very sensitive sensory system. It has been intensively analysed from a behavioural and neurobiological point of view, and constitutes a classical model system in neuroethology. The escape behaviour is triggered in orthopteroids by the detection of air-currents produced by approaching objects, allowing these insects to keep away from potential dangers. Nevertheless, escape behaviour has not been studied in terms of success. Moreover, an attacking predator is more than "air movement", it is also a visible moving entity. The sensory basis of predator detection is thus probably more complex than the perception of air movement by the cerci. We have used a piston mimicking an attacking running predator for a quantitative evaluation of the escape behaviour of wood crickets Nemobius sylvestris. The movement of the piston not only generates air movement, but it can be seen by the insect and can touch it as a natural predator. This procedure allowed us to study the escape behaviour in terms of detection and also in terms of success. Our results showed that 5-52% of crickets that detected the piston thrust were indeed touched. Crickets escaped to stimulation from behind better than to a stimulation from the front, even though they detected the approaching object similarly in both cases. After cerci ablation, 48% crickets were still able to detect a piston approaching from behind (compared with 79% of detection in intact insects) and 24% crickets escaped successfully (compared with 62% in the case of intact insects). So, cerci play a major role in the detection of an approaching object but other mechanoreceptors or sensory modalities are implicated in this detection. It is not possible to assure that other sensory modalities participate (in the case of intact animals) in the behaviour; rather, than in the absence of cerci other sensory modalities can

  1. Formulation of a Cooperative-Confinement-Escape problem of multiple cooperative defenders against an evader escaping from a circular region

    Science.gov (United States)

    Li, Wei

    2016-10-01

    In this paper, we propose and formulate the Cooperative-Confinement-Escape (CCE) problem of multiple cooperative defenders against an evader escaping from a circular region, in which the defenders are moving on the circle with attempt to prevent possible escape of a single evader who is initially located inside the circle. The main contributions are summarized as follows: (1) we first provide an effective formulation of the CCE problem, which is an emphasis of this paper, with design of two nonlinear control strategies for the cooperative defenders and the adversarial evader, respectively. Particularly, we consider to include a proper interaction between each pair of the nearest-neighbor defenders, and an adaptive trajectory prediction mechanism in the strategies of the defenders to increase the chance of successful confinement. (2) For the first attempt on analyzing the CCE dynamics which is unavoidably strongly nonlinear, we analyze the minimum energy of the evader for possible escape. (3) For understanding of the behaviors of the system under different parameters, (i) we illustrate the effectiveness of the confinement strategy using the adaptive trajectory prediction mechanism, and (ii) the physical roles of the system parameters with respect to the system dynamics, some of which may be unexpected or not straightforward. A separate paper will be presented for systematic analysis of the agents' behaviors with respect to the large intervals of the parameter settings.

  2. Gene regulation network behind drought escape, avoidance and tolerance strategies in black poplar (Populus nigra L.).

    Science.gov (United States)

    Yıldırım, Kubilay; Kaya, Zeki

    2017-06-01

    Drought is the major environmental problem limiting the productivity and survival of plant species. Here, previously identified three black poplar genotypes having contrasting response to drought were subjected to gradual soil water depletion in a pot trial to identify their physiological, morphological and antioxidation related adaptations. We also performed a microarray based transcriptome analyses on the leaves of genotypes by using Affymetrix poplar Genome Array containing 56,000 transcripts. Phenotypic analyses of each genotype confirmed their differential adaptations to drought that could be classified as drought escape, avoidance and tolerance. Comparative transcriptomic analysis indicated highly divergent gene expression patterns among the genotypes in response to drought and post drought re-watering (PDR). We identified 10641, 3824 and 9411 transcripts exclusively regulated in drought escape, avoidance and tolerant genotypes, respectively. The key genes involved in metabolic pathways, such as carbohydrate metabolism, photosynthesis, lipid metabolism, generation of precursor metabolites/energy, protein folding, redox homeostasis, secondary metabolic process and cell wall component biogenesis, were affected by drought stresses in the leaves of these genotypes. Transcript isoforms showed increased expression specificity in the genes coding for bark storage proteins and small heat shock proteins in drought tolerant genotype. On the other hand, drought-avoiding genotype specifically induced the transcripts annotated to the genes functional in secondary metabolite production that linked to enhanced leaf water content and growth performance under drought stress. Transcriptome profiling of drought escape genotype indicated specific regulation of the genes functional in programmed cell death and leaf senescence. Specific upregulation of GTP cyclohydrolase II and transcription factors (WRKY and ERFs) in only this genotype were associated to ROS dependent signalling

  3. Towards an understanding of escape rate and state dependent diffusion for a quantum dissipative system

    Energy Technology Data Exchange (ETDEWEB)

    Shit, Anindita [Department of Chemistry, Bengal Engineering and Science University, Shibpur, Howrah 711 103 (India); Chattopadhyay, Sudip, E-mail: sudip_chattopadhyay@rediffmail.com [Department of Chemistry, Bengal Engineering and Science University, Shibpur, Howrah 711 103 (India); Ray Chaudhuri, Jyotipratim, E-mail: jprc_8@yahoo.com [Department of Physics, Katwa College, Katwa, Burdwan 713 130 (India)

    2011-07-28

    Graphical abstract: The present work demonstrates that the temperature dependence of the escape rate is not only embedded in the so-called Arrhenius type factor, the second exponential factor also includes the temperature dependence which has a purely quantum origin that is entangled with dissipation. Display Omitted Highlights: {yields} We explore the noise-induced barrier crossing dynamics of an open quantum system. {yields} The bath coupled with the system is driven out of equilibrium by an external noise. {yields} Nonlinear system-bath coupling and modulation of the bath affect the escape rate. {yields} An additional exponential factor, other than Arrhenius is also temperature dependent. {yields} This temperature dependence is purely quantum in origin. - Abstract: We address the stochastic dynamics of an open quantum system coupled to a heat reservoir that is driven out of thermal equilibrium by an external noise. By constructing Langevin and Fokker-Planck equations, we obtain the rate of decay from a metastable state of the system when the dissipation is state dependent. We discuss the effects and consequences of the non-linear interaction(s) stemming out of the system-bath coupling alongside the modulation of the bath by an external noise on the rate expression. We demonstrate that the temperature dependence of the escape rate is not only embedded in the so-called Arrhenius type factor, the second exponential factor also includes the temperature dependence. The last effect has a purely quantum origin. Interestingly, we also envisage that this quantum effect is entangled with dissipation. The results offer a basis for clarifying the relationship between the dissipation and exponential factor of the obtained rate expression.

  4. Infrasound initiates directional fast-start escape responses in juvenile roach Rutilus rutilus.

    Science.gov (United States)

    Karlsen, Hans E; Piddington, Robert W; Enger, Per S; Sand, Olav

    2004-11-01

    Acoustic stimuli within the sonic range are effective triggers of C-type escape behaviours in fish. We have previously shown that fish have an acute sensitivity to infrasound also, with acceleration thresholds in the range of 10(-5) m s(-2). In addition, infrasound at high intensities around 10(-2) m s(-2) elicits strong and sustained avoidance responses in several fish species. In the present study, the possible triggering of C-escapes by infrasonic single-cycle vibrations was examined in juvenile roach Rutilus rutilus. The fish were accelerated in a controlled and quantifiable manner using a swing system. The applied stimuli simulated essential components of the accelerations that a small fish would encounter in the hydrodynamic flow field produced by a predatory fish. Typical C- and S-type escape responses were induced by accelerations within the infrasonic range with a threshold of 0.023 m s(-2) for an initial acceleration at 6.7 Hz. Response trajectories were on average in the same direction as the initial acceleration. Unexpectedly, startle behaviours mainly occurred in the trailing half of the test chamber, in which the fish were subjected to linear acceleration in combination with compression, i.e. the expected stimuli produced by an approaching predator. Very few responses were observed in the leading half of the test chamber, where the fish were subjected to acceleration and rarefaction, i.e. the stimuli expected from a suction type of predator. We conclude that particle acceleration is essential for the directionality of the startle response to infrasound, and that the response is triggered by the synergistic effects of acceleration and compression.

  5. DX-8951f, a hexacyclic camptothecin analog, on a daily-times-five schedule: a phase I and pharmacokinetic study in patients with advanced solid malignancies.

    Science.gov (United States)

    Rowinsky, E K; Johnson, T R; Geyer, C E; Hammond, L A; Eckhardt, S G; Drengler, R; Smetzer, L; Coyle, J; Rizzo, J; Schwartz, G; Tolcher, A; Von Hoff, D D; De Jager, R L

    2000-09-01

    To assess the feasibility of administering DX-8951f (exatecan mesylate), a water-soluble, camptothecin analog, as a 30-minute intravenous infusion daily for 5 days every 3 weeks, determine the maximum-tolerated dose (MTD) and pharmacokinetic (PK) behavior of DX-8951f, and seek preliminary evidence of anticancer activity. Patients with advanced solid malignancies were treated with escalating doses of DX-8951f. After three patients were treated at the first dose level, doses were to be escalated in increments of 100%, using a single patient at each dose level unless moderate toxicity was observed. The MTD, defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%, was calculated separately for minimally pretreated (MP) and heavily pretreated (HP) patients. The PK and excretory profiles of DX-8951, the anhydrous form of DX-8951f, were also characterized. Thirty-six patients were treated with 130 courses of DX-8951f at six dose levels ranging from 0.1 to 0.6 mg/m(2)/d. Brief, noncumulative neutropenia was the most common toxicity observed. Severe myelosuppression (neutropenia that was protracted and/or associated with fever and/or severe thrombocytopenia) was consistently experienced by HP and MP patients at doses exceeding 0.3 and 0.5 mg/m(2)/d, respectively. Nonhematologic toxicities (nausea, vomiting, and diarrhea) were also observed, but these effects were rarely severe. Objective antitumor activity included partial responses in one patient each with platinum-resistant extrapulmonary small-cell and fluoropyrimidine- and irinotecan-resistant colorectal carcinoma, and minor responses in patients with prostate, hepatocellular, thymic, primary peritoneal, and irinotecan-resistant colorectal carcinomas. The PKs of total DX-8951 were linear and well fit by a three-compartment model. The recommended doses for phase II studies of DX-8951f as a 30-minute infusion daily for 5 days every 3 weeks are 0.5 and 0.3 mg/m(2)/d for MP and

  6. Anatomy of an escape tectonic zone: Western Irian Jaya (Indonesia)

    Science.gov (United States)

    Pubellier, Manuel; Ego, Frédéric

    2002-07-01

    The western fold-and-thrust belt of New Guinea in Irian Jaya is presently a complex boundary, dominated by the Bird's Head block escape from the collision between the Australian plate and the remnants of volcanic belts carried by the Pacific plate. The escape rate given by geodetic measurements is of the order of 7 cm/yr, and movement is accommodated by a broad shear zone. We analyze this shear pattern using fault slip analyses performed in the field from 1992 to 1996, combined with focal mechanism inversions, moment tensors summations, and surface trace of structures inferred from radar and multispectral satellite images. Time control of the deformation is attained by isotope dating of the recent syntectonic intrusives. The geometry of the macro and microstructures occurred in two stages from the early Pliocene to the Present. The first stage (5 to 2 Ma) is marked by flat-and-ramps structures guided by N60°E lateral ramps associated with a N60°E cleavage, affecting the whole of western Irian Jaya. The second stage (2 Ma to Present) shows the collapse of the western fold-and-thrust belt and the escape of the Bird's Head and the Lengguru belts along N60°E transtensile faults. In the latter stage, the strike-slip offset is distributed on the N60°E schistosity zone along which some fracture planes are reactivated as left-lateral transtensile faults. Shallow earthquakes moment tensors have been inverted for stress and summed to get strain rates to define contrasting structural provinces. The spatial variations in both stress and strain fields from earthquakes and microtectonics show that (1) they are consistent and are assumed to be coeval, (2) they reveal that oblique convergence is partitioned, and (3) they are influenced by the existence of a free boundary. We see no significant rotation of stress axes laterally along the escape zone. Instead, stresses change according to the different orientations of basement structures and thus undergo rapid spatial variations

  7. On the Relative Contributions of Noncontingent Reinforcement and Escape Extinction in the Treatment of Food Refusal

    Science.gov (United States)

    Reed, Gregory K.; Piazza, Cathleen C.; Patel, Meeta R.; Layer, Stacy A.; Bachmeyer, Melanie H.; Bethke, Stephanie D.; Gutshall, Katharine A.

    2004-01-01

    In the current investigation, we evaluated the relative effects of noncontingent reinforcement (NCR), escape extinction, and a combination of NCR and escape extinction as treatment for the feeding problems exhibited by 4 children. For each participant, consumption increased only when escape extinction was implemented, independent of whether NCR…

  8. Unsteady motion: escape jumps in planktonic copepods, their kinematics and energetics

    DEFF Research Database (Denmark)

    Kiørboe, Thomas; Andersen, Anders Peter; Langlois, Vincent J.

    2010-01-01

    We describe the kinematics of escape jumps in three species of 0.3–3.0 mm-sized planktonic copepods. We find similar kinematics between species with periodically alternating power strokes and passive coasting and a resulting highly fluctuating escape velocity. By direct numerical simulations, we ...... propulsion efficiency, again suggesting that copepods are optimally designed for rapid escape jumps....

  9. Library Lockdown: An escape room by kids for the community

    Directory of Open Access Journals (Sweden)

    Jennifer Thoegersen

    2016-11-01

    Full Text Available In Brief Hoping to bring the unexpected to Nebraska City, the Morton-James Public Library applied for an ALA Association for Library Service to Children Curiosity Creates grant to undertake an ambitious project: build an escape room. In a library storage room. With children. The hope was  by trying something completely different, we could increase interest in the library throughout the community and build a sense of ownership in the participants, while encouraging creativity and having a lot of fun. Library Lockdown was a four-month program that brought several dozen kids together—age 8 to 13—to build a fully-functioning escape room. Their creation, the Lab of Dr. Morton McBrains, is now open for business.

  10. Quantum and thermal phase escape in extended Josephson systems

    Energy Technology Data Exchange (ETDEWEB)

    Kemp, A.

    2006-07-12

    In this work I examine phase escape in long annular Josephson tunnel junctions. The sine-Gordon equation governs the dynamics of the phase variable along the junction. This equation supports topological soliton solutions, which correspond to quanta of magnetic flux trapped in the junction barrier. For such Josephson vortices an effective potential is formed by an external magnetic field, while a bias current acts as a driving force. Both together form a metastable potential well, which the vortex is trapped in. When the driving force exceeds the pinning force of the potential, the vortex escapes and the junction switches to the voltage state. At a finite temperature the driving force fluctuates. If the junction's energy scale is small, the phase variable can undergo a macroscopic quantum tunneling (MQT) process at temperatures below the crossover temperature. Without a vortex trapped, the metastable state is not a potential minimum in space, but a potential minimum at zero phase difference. (orig.)

  11. Bacillus anthracis Factors for Phagosomal Escape

    Directory of Open Access Journals (Sweden)

    Irene Zornetta

    2012-07-01

    Full Text Available The mechanism of phagosome escape by intracellular pathogens is an important step in the infectious cycle. During the establishment of anthrax, Bacillus anthracis undergoes a transient intracellular phase in which spores are engulfed by local phagocytes. Spores germinate inside phagosomes and grow to vegetative bacilli, which emerge from their resident intracellular compartments, replicate and eventually exit from the plasma membrane. During germination, B. anthracis secretes multiple factors that can help its resistance to the phagocytes. Here the possible role of B. anthracis toxins, phospholipases, antioxidant enzymes and capsules in the phagosomal escape and survival, is analyzed and compared with that of factors of other microbial pathogens involved in the same type of process.

  12. Partial control of chaotic transients using escape times

    Energy Technology Data Exchange (ETDEWEB)

    Sabuco, Juan; Zambrano, Samuel; Sanjuan, Miguel A F, E-mail: juan.sabuco@urjc.e [Departamento de Fisica, Universidad Rey Juan Carlos, Tulipan s/n, 28933 Mostoles, Madrid (Spain)

    2010-11-15

    The partial control technique allows one to keep the trajectories of a dynamical system inside a region where there is a chaotic saddle and from which nearly all the trajectories diverge. Its main advantage is that this goal is achieved even if the corrections applied to the trajectories are smaller than the action of environmental noise on the dynamics, a counterintuitive result that is obtained by using certain safe sets. Using the Henon map as a paradigm, we show here the deep relationship between the safe sets and the sets of points with different escape times, the escape time sets. Furthermore, we show that it is possible to find certain extended safe sets that can be used instead of the safe sets in the partial control technique. Numerical simulations confirm our findings and show that in some situations, the use of extended safe sets can be more advantageous.

  13. Symmetry associated with symmetry break: Revisiting ants and humans escaping from multiple-exit rooms

    Science.gov (United States)

    Ji, Q.; Xin, C.; Tang, S. X.; Huang, J. P.

    2018-02-01

    Crowd panic has incurred massive injuries or deaths throughout the world, and thus understanding it is particularly important. It is now a common knowledge that crowd panic induces "symmetry break" in which some exits are jammed while others are underutilized. Amazingly, here we show, by experiment, simulation and theory, that a class of symmetry patterns come to appear for ants and humans escaping from multiple-exit rooms while the symmetry break exists. Our symmetry pattern is described by the fact that the ratio between the ensemble-averaging numbers of ants or humans escaping from different exits is equal to the ratio between the widths of the exits. The mechanism lies in the effect of heterogeneous preferences of agents with limited information for achieving the Nash equilibrium. This work offers new insights into how to improve public safety because large public areas are always equipped with multiple exits, and it also brings an ensemble-averaging method for seeking symmetry associated with symmetry breaking.

  14. Augmenting the Efficacy of Immunotoxins and Other Targeted Protein Toxins by Endosomal Escape Enhancers

    Directory of Open Access Journals (Sweden)

    Hendrik Fuchs

    2016-07-01

    Full Text Available The toxic moiety of almost all protein-based targeted toxins must enter the cytosol of the target cell to mediate its fatal effect. Although more than 500 targeted toxins have been investigated in the past decades, no antibody-targeted protein toxin has been approved for tumor therapeutic applications by the authorities to date. Missing efficacy can be attributed in many cases to insufficient endosomal escape and therefore subsequent lysosomal degradation of the endocytosed toxins. To overcome this drawback, many strategies have been described to weaken the membrane integrity of endosomes. This comprises the use of lysosomotropic amines, carboxylic ionophores, calcium channel antagonists, various cell-penetrating peptides of viral, bacterial, plant, animal, human and synthetic origin, other organic molecules and light-induced techniques. Although the efficacy of the targeted toxins was typically augmented in cell culture hundred or thousand fold, in exceptional cases more than million fold, the combination of several substances harbors new problems including additional side effects, loss of target specificity, difficulties to determine the therapeutic window and cell type-dependent variations. This review critically scrutinizes the chances and challenges of endosomal escape enhancers and their potential role in future developments.

  15. [Contribution to tumor escape and chemotherapy response: A choice between senescence and apoptosis in heterogeneous tumors].

    Science.gov (United States)

    Jonchère, Barbara; Vétillard, Alexandra; Toutain, Bertrand; Guette, Catherine; Coqueret, Olivier

    2016-01-01

    Understanding adaptive signaling pathways in response to chemotherapy is one of the main challenges of cancer treatment. Activated in response to DNA damage, cell cycle and mitotic checkpoints activate the p53-p21 and p16-Rb pathways and induce apoptosis or senescence. Since senescent cells survive and produce a secretome that influences neighbouring cells, it is not particularly clear whether these responses are equivalent and if tumor cells escape these two suppressive pathways to the same extent. Predicting escape is also complicated by the fact that cancer cells adapt to treatments by activating the epithelial-mesenchymal transition and by producing clones with cancer-initiating cells features. Dedifferentiation pathways used in stressful conditions reconstitute dividing and sometimes more aggressive populations in response to chemotherapy. These observations illustrate the importance of tumor heterogeneity and the adaptation capacities of different intra-tumoral subclones. Depending on their oncogenic profile, on their localisation within the tumor and on their interaction with stromal cells, these subclones are expected to have different responses and adaptation capacities to chemotherapy. A complete eradication will certainly rely on combination therapies that can kill at the same time the bulk of the sensitive tumor but can also prevent plasticity and the generation of persistent clones. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  16. A Nuclease from Streptococcus mutans Facilitates Biofilm Dispersal and Escape from Killing by Neutrophil Extracellular Traps.

    Science.gov (United States)

    Liu, Jia; Sun, Luping; Liu, Wei; Guo, Lihong; Liu, Zhaohui; Wei, Xi; Ling, Junqi

    2017-01-01

    Streptococcus mutans is the primary etiologic agent of dental caries and occasionally infective endocarditis, with the ability to form biofilms and disperse cells into distal sites to exacerbate and spread infection. In this study, we identified a nuclease (DeoC) as a S. mutans biofilm dispersal modulating factor through microarray analysis. In vitro assays revealed a dispersal defect of a deoC deletion mutant, and functional studies with purified protein were indicative of the biofilm dispersal activity of DeoC. Neutrophils are a key host response factor restraining bacterial spreading through the formation of neutrophil extracellular traps (NETs), which consist of a nuclear DNA backbone associated with antimicrobial peptides. Therefore, we hypothesized that the dispersed S. mutans might utilize DeoC to degrade NETs and escape killing by the immune system. It was found that S. mutans induced NET formation upon contact with neutrophils, while the presence of NETs in turn enhanced the deoC expression of S. mutans. Fluorescence microscopy inspection showed that deoC deletion resulted in a decreased NET degradation ability of S. mutans and enhanced susceptibility to neutrophil killing. Data obtained from this study assigned two important roles for DeoC in S. mutans: contributing to the spread of infection through mediating biofilm dispersal, and facilitating the escape of S. mutans from neutrophil killing through NET degradation.

  17. Augmenting the Efficacy of Immunotoxins and Other Targeted Protein Toxins by Endosomal Escape Enhancers

    Science.gov (United States)

    Fuchs, Hendrik; Weng, Alexander; Gilabert-Oriol, Roger

    2016-01-01

    The toxic moiety of almost all protein-based targeted toxins must enter the cytosol of the target cell to mediate its fatal effect. Although more than 500 targeted toxins have been investigated in the past decades, no antibody-targeted protein toxin has been approved for tumor therapeutic applications by the authorities to date. Missing efficacy can be attributed in many cases to insufficient endosomal escape and therefore subsequent lysosomal degradation of the endocytosed toxins. To overcome this drawback, many strategies have been described to weaken the membrane integrity of endosomes. This comprises the use of lysosomotropic amines, carboxylic ionophores, calcium channel antagonists, various cell-penetrating peptides of viral, bacterial, plant, animal, human and synthetic origin, other organic molecules and light-induced techniques. Although the efficacy of the targeted toxins was typically augmented in cell culture hundred or thousand fold, in exceptional cases more than million fold, the combination of several substances harbors new problems including additional side effects, loss of target specificity, difficulties to determine the therapeutic window and cell type-dependent variations. This review critically scrutinizes the chances and challenges of endosomal escape enhancers and their potential role in future developments. PMID:27376327

  18. Can high-inequality developing countries escape absolute poverty?

    OpenAIRE

    Ravallion, Martin

    1997-01-01

    Do the poor face the same prospects for escaping poverty in high-inequality developing countries as in low-inequality countries? Is it possible for inequality to be so great as to stifle prospects of reducing absolute poverty, even when other initial conditions and policies are favorable to growth? Household survey data for developing countries suggest that initial distribution does affect how much the poor share in rising average incomes. Higher initial inequality tends to reduce growth's im...

  19. Behavioral momentum in the treatment of escape-motivated stereotypy.

    OpenAIRE

    Mace, F C; Belfiore, P

    1990-01-01

    Descriptive and experimental analyses of stereotypy by a woman with severe mental retardation showed that the behavior was maintained by escape from demands. A sequence of high-probability requests issued immediately prior to a task-related request established a momentum of compliance that increased compliance with task-related demands. Increases in compliance were accompanied by collateral reductions in stereotypic behavior. A mechanism of response covariation, called functional incompatibil...

  20. Escape panels in trawls – a consistent management tool?

    DEFF Research Database (Denmark)

    Krag, Ludvig Ahm; Herrmann, Bent; Feekings, Jordan P.

    2016-01-01

    gears are often developed in collaboration between scientists and fishers. Part of the development is a controlled scientific test documenting the selectivity effect. In this study, we compared two versions of a mandatory escape panel that were introduced into the mixed species fishery in the Skagerrak...... to what extent catch quotas instead of the former landings quotas could provide the economic incentives for fishers to actively use selective gear designs more optimally and thereby play an active role in the management of fisheries....

  1. Escape problem under stochastic volatility: the Heston model.

    Science.gov (United States)

    Masoliver, Jaume; Perelló, Josep

    2008-11-01

    We solve the escape problem for the Heston random diffusion model from a finite interval of span L . We obtain exact expressions for the survival probability (which amounts to solving the complete escape problem) as well as for the mean exit time. We also average the volatility in order to work out the problem for the return alone regardless of volatility. We consider these results in terms of the dimensionless normal level of volatility-a ratio of the three parameters that appear in the Heston model-and analyze their form in several asymptotic limits. Thus, for instance, we show that the mean exit time grows quadratically with large spans while for small spans the growth is systematically slower, depending on the value of the normal level. We compare our results with those of the Wiener process and show that the assumption of stochastic volatility, in an apparently paradoxical way, increases survival and prolongs the escape time. We finally observe that the model is able to describe the main exit-time statistics of the Dow-Jones daily index.

  2. Anomalous barrier escape: The roles of noise distribution and correlation

    Science.gov (United States)

    Hu, Meng; Zhang, Jia-Ming; Bao, Jing-Dong

    2017-05-01

    We study numerically and analytically the barrier escape dynamics of a particle driven by an underlying correlated Lévy noise for a smooth metastable potential. A "quasi-monochrome-color" Lévy noise, i.e., the first-order derivative variable of a linear second-order differential equation subjected to a symmetric α-stable white Lévy noise, also called the harmonic velocity Lévy noise, is proposed. Note that the time-integral of the noise Green function of this kind is equal to zero. This leads to the existence of underlying negative time correlation and implies that a step in one direction is likely followed by a step in the other direction. By using the noise of this kind as a driving source, we discuss the competition between long flights and underlying negative correlations in the metastable dynamics. The quite rich behaviors in the parameter space including an optimum α for the stationary escape rate have been found. Remarkably, slow diffusion does not decrease the stationary rate while a negative correlation increases net escape. An approximate expression for the Lévy-Kramers rate is obtained to support the numerically observed dependencies.

  3. ESCAPE FROM SD ASSOCIATED WITH FIXED-RATIO REINFORCEMENT.

    Science.gov (United States)

    THOMPSON, D M

    1964-01-01

    Throughout ascending and descending fixed-ratio (FR) sequences, rats were allowed to terminate the FR stimulus control by pressing a time-out (TO) lever. To minimize chance or accidental responses on this second lever, three presses were required to produce the 30-sec S(Delta) period. As FR performance became more "strained," there was an increased predisposition to escape from the time-in stimulus complex. The generality of this finding was extended by obtaining recoverability (independent of the direction of stimulus change) of the FR-TO function in the descending series. Typically, escapes were produced only during the post-reinforcement pause; however, under a mixed FR FR schedule, their occurrence shifted to a point within the inter-reinforcement interval corresponding to the unreinforced completion of the lower ratio component. It appears that the point where the rat can discriminate the size of the ratio requirement will be the place where TOs are imposed. This inference was supported by a substantial increase in TO frequency accompanying a shift from CRF to extinction on the FR lever. Finally, the escape lever was placed on a progressively increasing FR schedule and later extinguished to demonstrate that the TO condition was in fact reinforcing.

  4. Crew Escape Technologies (CREST) Mission Area Requirements Study Current and Future Crew Escape Requirements

    Science.gov (United States)

    1992-02-01

    anthropometry and the type and location of the equipment worn by the test suboect. Based upon the data taken In the early nineteen sixties it was...3.1.1 of the CREST Specification describes the system as having -Flow stagnation fence to reduce windblast Induced loads on the head, torso and upper

  5. Clonal Plasticity of Aquatic Plant Species Submitted to Mechanical Stress: Escape versus Resistance Strategy

    Science.gov (United States)

    Puijalon, Sara; Bouma, Tjeerd J.; Van Groenendael, Jan; Bornette, Gudrun

    2008-01-01

    Background and Aims The plastic alterations of clonal architecture are likely to have functional consequences, as they affect the spatial distribution of ramets over patchy environments. However, little is known about the effect of mechanical stresses on the clonal growth. The aim of the present study was to investigate the clonal plasticity induced by mechanical stress consisting of continuous water current encountered by aquatic plants. More particularly, the aim was to test the capacity of the plants to escape this stress through clonal plastic responses. Methods The transplantation of ramets of the same clone in two contrasting flow velocity conditions was carried out for two species (Potamogeton coloratus and Mentha aquatica) which have contrasting clonal growth forms. Relative allocation to clonal growth, to creeping stems in the clonal biomass, number and total length of creeping stems, spacer length and main creeping stem direction were measured. Key Results For P. coloratus, plants exposed to water current displayed increased total length of creeping stems, increased relative allocation to creeping stems within the clonal dry mass and increased spacer length. For M. aquatica, plants exposed to current displayed increased number and total length of creeping stems. Exposure to current induced for both species a significant increase of the proportion of creeping stems in the downstream direction to the detriment of creeping stems perpendicular to flow. Conclusions This study demonstrates that mechanical stress from current flow induced plastic variation in clonal traits for both species. The responses of P. coloratus could lead to an escape strategy, with low benefits with respect to sheltering and anchorage. The responses of M. aquatica that may result in a denser canopy and enhancement of anchorage efficiency could lead to a resistance strategy. PMID:18854376

  6. Broad CTL Response in Early HIV Infection Drives Multiple Concurrent CTL Escapes.

    Science.gov (United States)

    Leviyang, Sivan; Ganusov, Vitaly V

    2015-10-01

    Recent studies have highlighted the ability of HIV to escape from cytotoxic T lymphocyte (CTL) responses that concurrently target multiple viral epitopes. Yet, the viral dynamics involved in such escape are incompletely understood. Previous analyses have made several strong assumptions regarding HIV escape from CTL responses such as independent or non-concurrent escape from individual CTL responses. Using experimental data from evolution of HIV half genomes in four patients we observe concurrent viral escape from multiple CTL responses during early infection (first 100 days of infection), providing confirmation of a recent result found in a study of one HIV-infected patient. We show that current methods of estimating CTL escape rates, based on the assumption of independent escapes, are biased and perform poorly when CTL escape proceeds concurrently at multiple epitopes. We propose a new method for analyzing longitudinal sequence data to estimate the rate of CTL escape across multiple epitopes; this method involves few parameters and performs well in simulation studies. By applying our novel method to experimental data, we find that concurrent multiple escapes occur at rates between 0.03 and 0.4 day(-1), a relatively broad range that reflects uncertainty due to sparse sampling and wide ranges of parameter values. However, we show that concurrent escape at rates 0.1-0.2 day(-1) across multiple epitopes is consistent with our patient datasets.

  7. Broad CTL Response in Early HIV Infection Drives Multiple Concurrent CTL Escapes.

    Directory of Open Access Journals (Sweden)

    Sivan Leviyang

    2015-10-01

    Full Text Available Recent studies have highlighted the ability of HIV to escape from cytotoxic T lymphocyte (CTL responses that concurrently target multiple viral epitopes. Yet, the viral dynamics involved in such escape are incompletely understood. Previous analyses have made several strong assumptions regarding HIV escape from CTL responses such as independent or non-concurrent escape from individual CTL responses. Using experimental data from evolution of HIV half genomes in four patients we observe concurrent viral escape from multiple CTL responses during early infection (first 100 days of infection, providing confirmation of a recent result found in a study of one HIV-infected patient. We show that current methods of estimating CTL escape rates, based on the assumption of independent escapes, are biased and perform poorly when CTL escape proceeds concurrently at multiple epitopes. We propose a new method for analyzing longitudinal sequence data to estimate the rate of CTL escape across multiple epitopes; this method involves few parameters and performs well in simulation studies. By applying our novel method to experimental data, we find that concurrent multiple escapes occur at rates between 0.03 and 0.4 day(-1, a relatively broad range that reflects uncertainty due to sparse sampling and wide ranges of parameter values. However, we show that concurrent escape at rates 0.1-0.2 day(-1 across multiple epitopes is consistent with our patient datasets.

  8. The Effect of Interference on the CD8(+) T Cell Escape Rates in HIV.

    Science.gov (United States)

    Garcia, Victor; Regoes, Roland Robert

    2014-01-01

    In early human immunodeficiency virus (HIV) infection, the virus population escapes from multiple CD8(+) cell responses. The later an escape mutation emerges, the slower it outgrows its competition, i.e., the escape rate is lower. This pattern could indicate that the strength of the CD8(+) cell responses is waning, or that later viral escape mutants carry a larger fitness cost. In this paper, we investigate whether the pattern of decreasing escape rates could also be caused by genetic interference among different escape strains. To this end, we developed a mathematical multi-epitope model of HIV dynamics, which incorporates stochastic effects, recombination, and mutation. We used cumulative linkage disequilibrium measures to quantify the amount of interference. We found that nearly synchronous, similarly strong immune responses in two-locus systems enhance the generation of genetic interference. This effect, combined with a scheme of densely spaced sampling times at the beginning of infection and sparse sampling times later, leads to decreasing successive escape rate estimates, even when there were no selection differences among alleles. These predictions are supported by empirical data from one HIV-infected patient. Thus, interference could explain why later escapes are slower. Considering escape mutations in isolation, neglecting their genetic linkage, conceals the underlying haplotype dynamics and can affect the estimation of the selective pressure exerted by CD8(+) cells. In systems in which multiple escape mutations appear, the occurrence of interference dynamics should be assessed by measuring the linkage between different escape mutations.

  9. The rate of immune escape vanishes when multiple immune responses control an HIV infection.

    Science.gov (United States)

    van Deutekom, Hanneke W M; Wijnker, Gilles; de Boer, Rob J

    2013-09-15

    During the first months of HIV infection, the virus typically evolves several immune escape mutations. These mutations are found in epitopes in viral proteins and reduce the impact of the CD8⁺ T cells specific for these epitopes. Recent data show that only a subset of the epitopes escapes, that most of these escapes evolve early, and that the rate of immune escape slows down considerably. To investigate why the evolution of immune escape slows down over the time of infection, we have extended a consensus mathematical model to allow several immune responses to control the virus together. In the extended model, most escapes also occur early, and the immune escape rate becomes small later, and typically only a minority of the epitopes escape. We show that escaping one of the many immune responses provides little advantage after viral setpoint has been approached because the total killing rate hardly depends on the breadth of the immune response. If the breadth of the immune response slowly wanes during disease progression, the model predicts an increase in the rate of immune escape at late stages of infection. Overall, the most striking prediction of the model is that HIV evolves a small number of immune escapes, in both relative and absolute terms, when the CTL immune response is broad.

  10. Seasonal variability of Martian ion escape through the plume and tail from MAVEN observations

    Science.gov (United States)

    Dong, Y.; Fang, X.; Brain, D. A.; McFadden, J. P.; Halekas, J. S.; Connerney, J. E. P.; Eparvier, F.; Andersson, L.; Mitchell, D.; Jakosky, B. M.

    2017-04-01

    We study the Mars Atmosphere and Volatile Evolution spacecraft observations of Martian planetary ion escape during two time periods: 11 November 2014 to 19 March 2015 and 4 June 2015 to 24 October 2015, with the focus on understanding the seasonal variability of Martian ion escape in response to the solar extreme ultraviolet (EUV) flux. We organize the >6 eV O+ ion data by the upstream electric field direction to estimate the escape rates through the plume and tail. To investigate the ion escape dependence on the solar EUV flux, we constrain the solar wind dynamic pressure and interplanetary magnetic filed strength and compare the ion escape rates through the plume and tail in different energy ranges under high and low EUV conditions. We found that the total >6 eV O+ escape rate increases from 2 to 3 × 1024 s-1 as the EUV irradiance increases by almost the same factor, mostly on the <1 keV tailward escape. The plume escape rate does not vary significantly with EUV. The relative contribution from the plume to the total escape varies between 30% and 20% from low to high EUV. Our results suggest that the Martian ion escape is sensitive to the seasonal EUV variation, and the contribution from plume escape becomes more important under low EUV conditions.

  11. The effects of escape from self and interpersonal relationship on the pathological use of Internet games.

    Science.gov (United States)

    Kwon, Jung-Hye; Chung, Chung-Suk; Lee, Jung

    2011-02-01

    The purpose of the present study was to examine whether Baumeister's escape from self theory may account for the pathological use of Internet games among Korean adolescents. A sample of 1,136 junior high school students completed measures assessing Internet game addiction (IGA), real-ideal self discrepancy, escape from self, current mood, peer relationships, perceived parent-child relationship, and parental supervision. IGA was significantly correlated with all of these variables. Multiple regression analysis showed that escape from self best explained the adolescents' IGA. A path model yielded significant paths from self-discrepancy to negative mood, from negative mood to escape from self, and from escape from self to IGA. These results support the validity of using the escape from self theory to explain the adolescents' IGA, thereby suggesting that adolescents become addicted to Internet games in an attempt to escape from self and reality.

  12. Escape erosion and relaxation of craters on Pluto

    Science.gov (United States)

    Porter, S.; Zangari, A.; Stern, A.

    2014-07-01

    Pluto and its major satellite Charon will be the most distant objects ever visited when NASA's New Horizons spacecraft flies past them in mid-2015. Both bodies should have suffered impacts from other transneptunian objects, though those impacts are of much lower velocity than typical on giant-planet satellites. New Horizons will image the illuminated hemispheres of Pluto and Charon seen at closest approach at better than 0.5 km/pix and 1.0 km/pix, respectively. We compare new different predictions of the impactor population on Pluto and Charon, including the effects of escape erosion from Pluto, and examine the crater size distributions those impactors would produce over the range observable to the imagers on New Horizons. The impact distribution models diverge the most for craters smaller than 10 km. We expect the crater size distribution on Charon to be determined by the impactor distribution and the rheology of the surface. Inverting the Charon size distribution seen by New Horizons will then constrain the overall size frequency distribution in the Kuiper belt, and the location of any break in that size frequency distribution. However, owing to escape erosion, craters on Pluto may be much more modified than on Charon. To constrain this modification, we present a range of possible Pluto crater distributions, as a function of impactor distribution, atmospheric escape rate, and surface ice viscosity. Pluto's atmosphere is primarily made of molecular nitrogen and is currently escaping at between 10^{27} and 10^{28} N_2/s according to model estimates. To sustain these escape rates for 3.5 billion years, a global layer of N_2 ice 0.3 to 3 km thick would need to have sublimated from the surface. We show that this gradual mass loss could have erased many of the smaller craters on Pluto, especially craters with diameters smaller than 10 km. This sublimation erosion process does not occur on Charon, which has a water ice surface and no observed atmosphere. We also show

  13. Escaping the Self: Identity, Group Identification and Violence

    Directory of Open Access Journals (Sweden)

    James Hardie-Bick

    2016-12-01

    Full Text Available This article draws on the early work of Erich Fromm. In Escape from Freedom Fromm (1969 [1941] directly addressed the psychological mechanisms of escape modern individuals employ to protect themselves from feelings of ontological insecurity and existential estrangement. The article builds on Fromm’s analysis by discussing the significance of his escape mechanisms for understanding the dynamic psychological attractions of identifying with entitative groups. Fromm’s work will be discussed in relation to Hogg’s recent work on uncertainty-identity theory. The aim of the article is to examine the advantages of combining Fromm’s psychoanalytic analysis with Hogg’s uncertainty-identity theory and to highlight the potential this approach has for understanding why groups engage in violent and destructive behaviour. Este artículo se inspira en las primeras obras de Erich Fromm. En El miedo a la libertad, Fromm (1969 [1941] abordó directamente los mecanismos psicológicos de evasión que los individuos modernos emplean para protegerse de los sentimientos de inseguridad ontológica y distanciamiento existencial. Este artículo se basa en el análisis de Fromm exponiendo el significado de sus mecanismos de evasión para entender las atracciones psicológicas dinámicas de identificación con grupos entitativos. Se analizará la obra de Fromm en relación con la obra reciente de Hogg sobre la teoría de incertidumbre identitaria. El objetivo del artículo es examinar las ventajas de combinar el análisis psicoanalítico de Fromm con la teoría de incertidumbre identitaria de Hogg, y destacar el potencial que tiene esta aproximación para comprender por qué los grupos adoptan un comportamiento violento y destructivo. DOWNLOAD THIS PAPER FROM SSRN: https://ssrn.com/abstract=2875737

  14. Sequential evolution and escape from neutralization of simian immunodeficiency virus SIVsmE660 clones in rhesus macaques.

    Science.gov (United States)

    Wu, Fan; Ourmanov, Ilnour; Kuwata, Takeo; Goeken, Robert; Brown, Charles R; Buckler-White, Alicia; Iyengar, Ranjini; Plishka, Ronald; Aoki, Scott T; Hirsch, Vanessa M

    2012-08-01

    Simian immunodeficiency virus (SIV) infection of rhesus macaques has become an important surrogate model for evaluating HIV vaccine strategies. The extreme resistance to neutralizing antibody (NAb) of many commonly used strains, such as SIVmac251/239 and SIVsmE543-3, limits their potential relevance for evaluating the role of NAb in vaccine protection. In contrast, SIVsmE660 is an uncloned virus that appears to be more sensitive to neutralizing antibody. To evaluate the role of NAb in this model, we generated full-length neutralization-sensitive molecular clones of SIVsmE660 and evaluated two of these by intravenous inoculation of rhesus macaques. All animals became infected and maintained persistent viremia that was accompanied by a decline in memory CD4(+) T cells in blood and bronchoalveolar lavage fluid. High titers of autologous NAb developed by 4 weeks postinoculation but were not associated with control of viremia, and neutralization escape variants were detected concurrently with the generation of NAb. Neutralization escape was associated with substitutions and insertion/deletion polymorphisms in the V1 and V4 domains of envelope. Analysis of representative variants revealed that escape variants also induced NAbs within a few weeks of their appearance in plasma, in a pattern that is reminiscent of the escape of human immunodeficiency virus type 1 (HIV-1) isolates in humans. Although early variants maintained a neutralization-sensitive phenotype, viruses obtained later in infection were significantly less sensitive to neutralization than the parental viruses. These results indicate that NAbs exert selective pressure that drives the evolution of the SIV envelope and that this model will be useful for evaluating the role of NAb in vaccine-mediated protection.

  15. Chases and escapes the mathematics of pursuit and evasion

    CERN Document Server

    Nahin, Paul J

    2012-01-01

    We all played tag when we were kids. What most of us don't realize is that this simple chase game is in fact an application of pursuit theory, and that the same principles of games like tag, dodgeball, and hide-and-seek are also at play in military strategy, high-seas chases by the Coast Guard, and even romantic pursuits. In Chases and Escapes, Paul Nahin gives us the first complete history of this fascinating area of mathematics, from its classical analytical beginnings to the present day. Drawing on game theory, geometry, linear algebra, target-tracking algorithms, and much

  16. Crew Escape Concepts for Advanced High Performance Aircraft.

    Science.gov (United States)

    1978-08-01

    8217AIRCRAFT . IGH / . Final technical Report. \\ 1 Sep 77 - 1 Mar 78, \\°T DC^fe ./swans on (iy\\ Beciiu/pH V 2^ S. LONIRAji’Jfc...nose section for high speed or high altitude escape. Normal ejection occurs^Cover) . ’ >h £ v *— DO , j°" 71 1473 EDITION OF I NOV tS IS... Gowin , Don Fisher, Christopher L. West, Leonard Witonsky, Teresa K. Laird, Sheri K. Bard, and Jeanne M. Owens. Henry Horn of the Boeing Wichita

  17. Dynamics of Periodic Impulsive Collision in Escapement Mechanism

    Directory of Open Access Journals (Sweden)

    Jian Mao

    2013-01-01

    Full Text Available Among various non-smooth dynamic systems, the periodically forced oscillation system with impact is perhaps the most common in engineering applications. The dynamical study becomes complicated due to the impact. This paper presents a systematic study on the periodically forced oscillation system with impact. A simplified model of the escapement mechanism is introduced. Impulsive differential equation and Poincare map are applied to describe the model and study the stability of the system. Numerical examples are given and the results show that the model is highly accurate in describing/predicting their dynamics.

  18. Mechanisms of Pulmonary Escape and Dissemination by Cryptococcus neoformans

    Directory of Open Access Journals (Sweden)

    Steven T. Denham

    2018-02-01

    Full Text Available Cryptococcus neoformans is a common environmental saprophyte and human fungal pathogen that primarily causes disease in immunocompromised individuals. Similar to many environmentally acquired human fungal pathogens, C. neoformans initiates infection in the lungs. However, the main driver of mortality is invasive cryptococcosis leading to fungal meningitis. After C. neoformans gains a foothold in the lungs, a critical early step in invasion is transversal of the respiratory epithelium. In this review, we summarize current knowledge relating to pulmonary escape. We focus on fungal factors that allow C. neoformans to disseminate from the lungs via intracellular and extracellular routes.

  19. The zonal satellite problem - II: Near-escape flow

    Directory of Open Access Journals (Sweden)

    Mioc V.

    1998-01-01

    Full Text Available The study of the zonal satellite problem is continued by tackling the situation r→∞. New equations of motion (for which the infinite distance is a singularity and the corresponding first integrals of energy and angular momentum are set up. The infinity singularity is blown up via McGehee-type transformations, and the infinity manifold is pasted on the phase space. The fictitious flow on this manifold is described. Then, resorting to the rotational symmetry of the problem and to the angular momentum integral, the near-escape local flow is depicted. The corresponding phase curves are interpreted as physical motions.

  20. The route of HIV escape from immune response targeting multiple sites is determined by the cost-benefit tradeoff of escape mutations.

    Science.gov (United States)

    Batorsky, Rebecca; Sergeev, Rinat A; Rouzine, Igor M

    2014-10-01

    Cytotoxic T lymphocytes (CTL) are a major factor in the control of HIV replication. CTL arise in acute infection, causing escape mutations to spread rapidly through the population of infected cells. As a result, the virus develops partial resistance to the immune response. The factors controlling the order of mutating epitope sites are currently unknown and would provide a valuable tool for predicting conserved epitopes. In this work, we adapt a well-established mathematical model of HIV evolution under dynamical selection pressure from multiple CTL clones to include partial impairment of CTL recognition, [Formula: see text], as well as cost to viral replication, [Formula: see text]. The process of escape is described in terms of the cost-benefit tradeoff of escape mutations and predicts a trajectory in the cost-benefit plane connecting sequentially escaped sites, which moves from high recognition loss/low fitness cost to low recognition loss/high fitness cost and has a larger slope for early escapes than for late escapes. The slope of the trajectory offers an interpretation of positive correlation between fitness costs and HLA binding impairment to HLA-A molecules and a protective subset of HLA-B molecules that was observed for clinically relevant escape mutations in the Pol gene. We estimate the value of [Formula: see text] from published experimental studies to be in the range (0.01-0.86) and show that the assumption of complete recognition loss ([Formula: see text]) leads to an overestimate of mutation cost. Our analysis offers a consistent interpretation of the commonly observed pattern of escape, in which several escape mutations are observed transiently in an epitope. This non-nested pattern is a combined effect of temporal changes in selection pressure and partial recognition loss. We conclude that partial recognition loss is as important as fitness loss for predicting the order of escapes and, ultimately, for predicting conserved epitopes that can be

  1. Ultra-fast Escape of a Octopus-inspired Rocket

    Science.gov (United States)

    Weymouth, Gabriel; Triantafyllou, Michael

    2013-11-01

    The octopus, squid, and other cephalopods inflate with water and then release a jet to accelerate in the opposite direction. This escape mechanism is particularly interesting in the octopus because they become initially quite bluff, yet this does not hinder them in achieving impressive bursts of speed. We examine this somewhat paradoxical maneuver using a simple deflating spheroid model in both potential and viscous flow. We demonstrate that the dynamic reduction of the width of the body completely changes the flow and forces acting on the escaping rocket in three ways. First, a body which reduces in size can generate an added mass thrust which counteracts the added mass inertia. Second, the motion of the shrinking wall acts similar to suction on a static wall, reducing separation and drag forces in a viscous fluid, but that this effects depends on the rate of size change. Third, using a combination of these two features it is possible to initially load the fluid with kinetic energy when heavy and bluff and then recover that energy when streamlined and light, enabling ultra-fast accelerations. As a notable example, these mechanisms allow a shrinking spheroid rocket in a heavy inviscid fluid to achieve speeds greater than an identical rocket in the vacuum of space. Southampton Marine and Maritime Institute.

  2. Quantification of Nociceptive Escape Response in C.elegans

    Science.gov (United States)

    Leung, Kawai; Mohammadi, Aylia; Ryu, William; Nemenman, Ilya

    2013-03-01

    Animals cannot rank and communicate their pain consciously. Thus in pain studies on animal models, one must infer the pain level from high precision experimental characterization of behavior. This is not trivial since behaviors are very complex and multidimensional. Here we explore the feasibility of C.elegans as a model for pain transduction. The nematode has a robust neurally mediated noxious escape response, which we show to be partially decoupled from other sensory behaviors. We develop a nociceptive behavioral response assay that allows us to apply controlled levels of pain by locally heating worms with an IR laser. The worms' motions are captured by machine vision programming with high spatiotemporal resolution. The resulting behavioral quantification allows us to build a statistical model for inference of the experienced pain level from the behavioral response. Based on the measured nociceptive escape of over 400 worms, we conclude that none of the simple characteristics of the response are reliable indicators of the laser pulse strength. Nonetheless, a more reliable statistical inference of the pain stimulus level from the measured behavior is possible based on a complexity-controlled regression model that takes into account the entire worm behavioral output. This work was partially supported by NSF grant No. IOS/1208126 and HFSP grant No. RGY0084/2011.

  3. Random fluctuation leads to forbidden escape of particles.

    Science.gov (United States)

    Rodrigues, Christian S; de Moura, Alessandro P S; Grebogi, Celso

    2010-08-01

    A great number of physical processes are described within the context of Hamiltonian scattering. Previous studies have rather been focused on trajectories starting outside invariant structures, since the ones starting inside are expected to stay trapped there forever. This is true though only for the deterministic case. We show however that, under finitely small random fluctuations of the field, trajectories starting inside Kolmogorov-Arnold-Moser (KAM) islands escape within finite time. The nonhyperbolic dynamics gains then hyperbolic characteristics due to the effect of the random perturbed field. As a consequence, trajectories which are started inside KAM curves escape with hyperboliclike time decay distribution, and the fractal dimension of a set of particles that remain in the scattering region approaches that for hyperbolic systems. We show a universal quadratic power law relating the exponential decay to the amplitude of noise. We present a random walk model to relate this distribution to the amplitude of noise, and investigate these phenomena with a numerical study applying random maps.

  4. Lionfish misidentification circumvents an optimized escape response by prey.

    Science.gov (United States)

    McCormick, Mark I; Allan, Bridie J M

    2016-01-01

    Invasive lionfish represent an unprecedented problem in the Caribbean basin, where they are causing major changes to foodwebs and habitats through their generalized predation on fishes and invertebrates. To ascertain what makes the red lionfish (Pterois volitans) such a formidable predator, we examined the reaction of a native damselfish prey, the whitetail damsel (Pomacentrus chrysurus), to a repeatable startle stimulus once they had been forewarned of the sight or smell of lionfish. Fast-start responses were compared with prey forewarned of a predatory rockcod (Cephalopholis microprion), a corallivorous butterflyfish (Chaetodon trifasctiatus) and experimental controls. Forewarning of the sight, smell or a combination of the two cues from a rockcod led to reduced escape latencies and higher response distances, speed and maximal speed compared with controls, suggesting that forewarning primed the prey and enabled a more effective escape response. In contrast, forewarning of lionfish did not affect the fast-start kinematics measured, which were the same as in the control and non-predatory butterflyfish treatments. Lionfish appear to be able to circumvent mechanisms commonly used by prey to identify predators and were misclassified as non-predatory, and this is likely to contribute to their success as predators.

  5. Integrating geographical information and augmented reality techniques for mobile escape guidelines on nuclear accident sites.

    Science.gov (United States)

    Tsai, Ming-Kuan; Lee, Yung-Ching; Lu, Chung-Hsin; Chen, Mei-Hsin; Chou, Tien-Yin; Yau, Nie-Jia

    2012-07-01

    During nuclear accidents, when radioactive materials spread into the environment, the people in the affected areas should evacuate immediately. However, few information systems are available regarding escape guidelines for nuclear accidents. Therefore, this study constructs escape guidelines on mobile phones. This application is called Mobile Escape Guidelines (MEG) and adopts two techniques. One technique is the geographical information that offers multiple representations; the other is the augmented reality that provides semi-realistic information services. When this study tested the mobile escape guidelines, the results showed that this application was capable of identifying the correct locations of users, showing the escape routes, filtering geographical layers, and rapidly generating the relief reports. Users could evacuate from nuclear accident sites easily, even without relief personnel, since using slim devices to access the mobile escape guidelines is convenient. Overall, this study is a useful reference for a nuclear accident emergency response. Copyright © 2012 Elsevier Ltd. All rights reserved.

  6. The role of endosomal escape and mitogen-activated protein kinases in adenoviral activation of the innate immune response.

    Directory of Open Access Journals (Sweden)

    Jeffrey S Smith

    Full Text Available Adenoviral vectors (AdV activate multiple signaling pathways associated with innate immune responses, including mitogen-activated protein kinases (MAPKs. In this study, we investigated how systemically-injected AdVs activate two MAPK pathways (p38 and ERK and the contribution of these kinases to AdV-induced cytokine and chemokine responses in mice. Mice were injected intravenously either with a helper-dependent Ad2 vector that does not express viral genes or transgenes, or with the Ad2 mutant ts1, which is defective in endosomal escape. We found that AdV induced rapid phosphorylation of p38 and ERK as well as a significant cytokine response, but ts1 failed to activate p38 or ERK and induced only a limited cytokine response. These results demonstrate that endosomal escape of virions is a critical step in the induction of these innate pathways and responses. We then examined the roles of p38 and ERK pathways in the innate cytokine response by administering specific kinase inhibitors to mice prior to AdV. The cytokine and chemokine response to AdV was only modestly suppressed by a p38 inhibitor, while an ERK inhibitor has mixed effects, lowering some cytokines and elevating others. Thus, even though p38 and ERK are rapidly activated after i.v. injection of AdV, cytokine and chemokine responses are mostly independent of these kinases.

  7. Vaccination and timing influence SIV immune escape viral dynamics in vivo.

    Directory of Open Access Journals (Sweden)

    Liyen Loh

    2008-01-01

    Full Text Available CD8+ cytotoxic T lymphocytes (CTL can be effective at controlling HIV-1 in humans and SIV in macaques, but their utility is partly offset by mutational escape. The kinetics of CTL escape and reversion of escape mutant viruses upon transmission to MHC-mismatched hosts can help us understand CTL-mediated viral control and the fitness cost extracted by immune escape mutation. Traditional methods for following CTL escape and reversion are, however, insensitive to minor viral quasispecies. We developed sensitive quantitative real-time PCR assays to track the viral load of SIV Gag164-172 KP9 wild-type (WT and escape mutant (EM variants in pigtail macaques. Rapid outgrowth of EM virus occurs during the first few weeks of infection. However, the rate of escape plateaued soon after, revealing a prolonged persistence of WT viremia not detectable by standard cloning and sequencing methods. The rate of escape of KP9 correlated with levels of vaccine-primed KP9-specific CD8+ T cells present at that time. Similarly, when non-KP9 responder (lacking the restricting Mane-A*10 allele macaques were infected with SHIVmn229 stock containing a mixture of EM and WT virus, rapid reversion to WT was observed over the first 2 weeks following infection. However, the rate of reversion to WT slowed dramatically over the first month of infection. The serial quantitation of escape mutant viruses evolving during SIV infection shows that rapid dynamics of immune escape and reversion can be observed in early infection, particularly when CD8 T cells are primed by vaccination. However, these early rapid rates of escape and reversion are transient and followed by a significant slowing in these rates later during infection, highlighting that the rate of escape is significantly influenced by the timing of its occurrence.

  8. Operant Conditioning of Escape Behavior in the Pond Snail, Lymnaea stagnalis(Physiology)

    OpenAIRE

    Suguru, Kobayashi; Satoshi, Kojima; Mari, Yamanaka; Hisayo, Sadamoto; Hiroshi, Nakamura; Yutaka, Fujito; Ryo, Kawai; Manabu, Sakakibara; Etsuro, Ito; Laboratory of Animal Behavior and Intelligence, Division of Biological Sciences, Graduate School of Science, Hokkaido University; Laboratory of Animal Behavior and Intelligence, Division of Biological Sciences, Graduate School of Science, Hokkaido University; Laboratory of Animal Behavior and Intelligence, Division of Biological Sciences, Graduate School of Science, Hokkaido University; Laboratory of Animal Behavior and Intelligence, Division of Biological Sciences, Graduate School of Science, Hokkaido University; Laboratory of Animal Behavior and Intelligence, Division of Biological Sciences, Graduate School of Science, Hokkaido University; Department of Physiology, School of Medicine, Sapporo Medical University

    1998-01-01

    Operant conditioning that the pond snail, Lymnaea stagnalis, suppressed its naturally occurring behavior of escape from a water tank was examined by using a negative reinforcement (I.e. an aversive stimulus) prepared outside the tank. During the training period, the number of escapes from a tank was strongly suppressed. One of behavioral factors for this suppression was confirmed as the elongation of latency to the first escape after training. The effects on the memory retention were examined...

  9. Dentist-implemented contingent escape for management of disruptive child behavior.

    OpenAIRE

    Allen, K.D.; Loiben, T; Allen, S. J., Jr.; Stanley, R T

    1992-01-01

    We evaluated the effectiveness of a dentist-implemented intervention in which brief escape from dental treatment was provided to manage disruptive child behavior during restorative dental treatment. Within a multiple baseline design across subjects, 4 children, aged 3 to 7 years, were provided temporary escape from dental treatment contingent upon brief periods of cooperative behavior. Disruptive behavior decreased when the appropriate escape contingency was used at least 80% of the time. The...

  10. Temporal and ontogenetic variation in the escape response of Ameiva festiva (Squamata, Teiidae)

    OpenAIRE

    Lattanzio

    2014-01-01

    Several factors have been shown to affect lizard escape behavior (flight initiation distance or FID, the distance between predator and prey when the prey initiates escape). Patterns of daily activity, such as foraging or movement behavior, vary with respect to time of day, supporting that escape responses may vary temporally as well. However, there remains scant information regarding the effects of time of day on FID. During peak activity, FID may decrease due to increased cost of giving up r...

  11. Antibody escape kinetics of equine infectious anemia virus infection of horses.

    Science.gov (United States)

    Schwartz, Elissa J; Nanda, Seema; Mealey, Robert H

    2015-07-01

    Lentivirus escape from neutralizing antibodies (NAbs) is not well understood. In this work, we quantified antibody escape of a lentivirus, using antibody escape data from horses infected with equine infectious anemia virus. We calculated antibody blocking rates of wild-type virus, fitness costs of mutant virus, and growth rates of both viruses. These quantitative kinetic estimates of antibody escape are important for understanding lentiviral control by antibody neutralization and in developing NAb-eliciting vaccine strategies. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  12. Improving escape panel selectivity in Nephrops directed fisheries by actively stimulating fish behaviour

    DEFF Research Database (Denmark)

    Krag, Ludvig Ahm; Herrmann, Bent; Feekings, Jordan P.

    2017-01-01

    with it. To increase the efficiency of such panels, the contact probability needs to be improved. In this study, we investigate to what extent the efficiency of escape panels can be improved by actively stimulating the escape behaviour of fish. The performance of two identical panel sections was compared...... in a twin-trawl system, one with and one without a stimulation device. A new coupled analysis method was used to explicitly quantify the improvements in contact probability and release efficiency for the escape panel. The results demonstrate that by actively stimulating escape behaviour, the contact...

  13. 75 FR 79034 - Proposed Extension of Existing Information Collection; Escape and Evacuation Plans (Pertains to...

    Science.gov (United States)

    2010-12-17

    ... information is required with each escape and evacuation plan submission: (1) Mine maps or diagrams showing...) A statement of the availability of emergency communication and transportation facilities, emergency...

  14. Ancient village fire escape path planning based on improved ant colony algorithm

    Science.gov (United States)

    Xia, Wei; Cao, Kang; Hu, QianChuan

    2017-06-01

    The roadways are narrow and perplexing in ancient villages, it brings challenges and difficulties for people to choose route to escape when a fire occurs. In this paper, a fire escape path planning method based on ant colony algorithm is presented according to the problem. The factors in the fire environment which influence the escape speed is introduced to improve the heuristic function of the algorithm, optimal transfer strategy, and adjustment pheromone volatile factor to improve pheromone update strategy adaptively, improve its dynamic search ability and search speed. Through simulation, the dynamic adjustment of the optimal escape path is obtained, and the method is proved to be feasible.

  15. Neuroethological validation of an experimental apparatus to evaluate oriented and non-oriented escape behaviours: Comparison between the polygonal arena with a burrow and the circular enclosure of an open-field test.

    Science.gov (United States)

    Biagioni, Audrey Francisco; dos Anjos-Garcia, Tayllon; Ullah, Farhad; Fisher, Isaac René; Falconi-Sobrinho, Luiz Luciano; de Freitas, Renato Leonardo; Felippotti, Tatiana Tocchini; Coimbra, Norberto Cysne

    2016-02-01

    Inhibition of GABAergic neural inputs to dorsal columns of the periaqueductal grey matter (dPAG), posterior (PH) and dorsomedial (DMH) hypothalamic nuclei elicits distinct types of escape behavioural reactions. To differentiate between the variety and intensity of panic-related behaviours, the pattern of defensive behaviours evoked by blockade of GABAA receptors in the DMH, PH and dPAG were compared in a circular open-field test and in a recently designed polygonal arena. In the circular open-field, the defensive behaviours induced by microinjection of bicuculline into DMH and PH were characterised by defensive alertness behaviour and vertical jumps preceded by rearing exploratory behaviour. On the other hand, explosive escape responses interspersed with horizontal jumps and freezing were observed after the blockade of GABAA receptors on dPAG neurons. In the polygonal arena apparatus, the escape response produced by GABAergic inhibition of DMH and PH neurons was directed towards the burrow. In contrast, the blockade of GABAA receptors in dPAG evoked non-oriented escape behaviour characterised by vigorous running and horizontal jumps in the arena. Our findings support the hypothesis that the hypothalamic nuclei organise oriented escape behavioural responses whereas non-oriented escape is elaborated by dPAG neurons. Additionally, the polygonal arena with a burrow made it easy to discriminate and characterise these two different patterns of escape behavioural responses. In this sense, the polygonal arena with a burrow can be considered a good methodological tool to discriminate between these two different patterns of escape behavioural responses and is very useful as a new experimental animal model of panic attacks. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Biomechanics and Thermodynamics of Nanoparticle Interactions with Plasma and Endosomal Membrane Lipids in Cellular Uptake and Endosomal Escape

    Science.gov (United States)

    2015-01-01

    To be effective for cytoplasmic delivery of therapeutics, nanoparticles (NPs) taken up via endocytic pathways must efficiently transport across the cell membrane and subsequently escape from the secondary endosomes. We hypothesized that the biomechanical and thermodynamic interactions of NPs with plasma and endosomal membrane lipids are involved in these processes. Using model plasma and endosomal lipid membranes, we compared the interactions of cationic NPs composed of poly(d,l-lactide-co-glycolide) modified with the dichain surfactant didodecyldimethylammonium bromide (DMAB) or the single-chain surfactant cetyltrimethylammonium bromide (CTAB) vs anionic unmodified NPs of similar size. We validated our hypothesis in doxorubicin-sensitive (MCF-7, with relatively fluid membranes) and resistant breast cancer cells (MCF-7/ADR, with rigid membranes). Despite their cationic surface charges, DMAB- and CTAB-modified NPs showed different patterns of biophysical interaction: DMAB-modified NPs induced bending of the model plasma membrane, whereas CTAB-modified NPs condensed the membrane, thereby resisted bending. Unmodified NPs showed no effects on bending. DMAB-modified NPs also induced thermodynamic instability of the model endosomal membrane, whereas CTAB-modified and unmodified NPs had no effect. Since bending of the plasma membrane and destabilization of the endosomal membrane are critical biophysical processes in NP cellular uptake and endosomal escape, respectively, we tested these NPs for cellular uptake and drug efficacy. Confocal imaging showed that in both sensitive and resistant cells DMAB-modified NPs exhibited greater cellular uptake and escape from endosomes than CTAB-modified or unmodified NPs. Further, paclitaxel-loaded DMAB-modified NPs induced greater cytotoxicity even in resistant cells than CTAB-modified or unmodified NPs or drug in solution, demonstrating the potential of DMAB-modified NPs to overcome the transport barrier in resistant cells. In

  17. Will 3552 Don Quixote escape from the Solar System?

    Directory of Open Access Journals (Sweden)

    Suryadi Siregar

    2011-05-01

    Full Text Available Asteroid 1983 SA, well known as 3552 Don Quixote, is one of Near Earth Asteroids (NEAs which is the most probable candidate for the cometary origin, or otherwise as Jupiter-Family-Comets (JFCs. The aim of this study is to investigate the possibility of 3552 Don Quixote to be ejected from the Solar System. This paper presents an orbital evolution of 100 hypothetical asteroids generated by cloning 3552 Don Quixote. Investigation of its orbital evolution is conducted by using the SWIFT subroutine package, where the gravitational perturbations of eight major planets in the Solar System are considered. Over very short time scales (220 kyr relative to the Solar System life time (10 Gyr, the asteroid 3552 Don Quixote gave an example of chaotic motion that can cause asteroid to move outward and may be followed by escaping from the Solar System. Probability of ejection within the 220 kyr time scale is 50%.

  18. Velocity of escape from the Galaxy in the solar neighbourhood

    Energy Technology Data Exchange (ETDEWEB)

    Alexander, J.B. (Royal Greenwich Observatory, Hailsham (UK))

    1982-11-01

    The expected properties of stars moving with extremely high velocities relative to the centre of the Galaxy are discussed. Although the kinematic behaviour of the fastest known subdwarfs is consistent with unbound orbits, observational upper limits on the numbers of faint giant stars in the general field strongly suggest that these subdwarfs are bound to the Galaxy. If this is the case, only a lower limit to the value of the velocity of escape in the solar neighbourhood can be obtained. After allowance for observational error, this lower limit is about 400 km s/sup -1/. Although all known subdwarfs are probably in bound orbits, there is evidence that the mode of origin of the peculiar velocities of subdwarfs with extremely large galactocentric velocities is different from that of other high-velocity stars.

  19. Escaping Antiangiogenic Therapy: Strategies Employed by Cancer Cells

    Directory of Open Access Journals (Sweden)

    Mauricio P. Pinto

    2016-09-01

    Full Text Available Tumor angiogenesis is widely recognized as one of the “hallmarks of cancer”. Consequently, during the last decades the development and testing of commercial angiogenic inhibitors has been a central focus for both basic and clinical cancer research. While antiangiogenic drugs are now incorporated into standard clinical practice, as with all cancer therapies, tumors can eventually become resistant by employing a variety of strategies to receive nutrients and oxygen in the event of therapeutic assault. Herein, we concentrate and review in detail three of the principal mechanisms of antiangiogenic therapy escape: (1 upregulation of compensatory/alternative pathways for angiogenesis; (2 vasculogenic mimicry; and (3 vessel co-option. We suggest that an understanding of how a cancer cell adapts to antiangiogenic therapy may also parallel the mechanisms employed in the bourgeoning tumor and isolated metastatic cells delivering responsible for residual disease. Finally, we speculate on strategies to adapt antiangiogenic therapy for future clinical uses.

  20. Novel Anti-Melanoma Immunotherapies: Disarming Tumor Escape Mechanisms

    Directory of Open Access Journals (Sweden)

    Sivan Sapoznik

    2012-01-01

    Full Text Available The immune system fights cancer and sometimes temporarily eliminates it or reaches an equilibrium stage of tumor growth. However, continuous immunological pressure also selects poorly immunogenic tumor variants that eventually escape the immune control system. Here, we focus on metastatic melanoma, a highly immunogenic tumor, and on anti-melanoma immunotherapies, which recently, especially following the FDA approval of Ipilimumab, gained interest from drug development companies. We describe new immunomodulatory approaches currently in the development pipeline, focus on the novel CEACAM1 immune checkpoint, and compare its potential to the extensively described targets, CTLA4 and PD1. This paper combines multi-disciplinary approaches and describes anti-melanoma immunotherapies from molecular, medical, and business angles.

  1. Experimental test of escape theory: accessibility to implicit suicidal mind.

    Science.gov (United States)

    Tang, Junhua; Wu, Shengjun; Miao, Danmin

    2013-08-01

    This study tested the Escape Theory prediction that individuals blaming themselves for failure experience increased accessibility to implicit suicidal mind. One hundred and thirty-eight undergraduate medical students were randomly assigned to three groups: failure-related priming, success-related priming, and control. Following experimental conditions, participants completed a death/suicide Implicit Association Test. Results revealed significant differences between groups in accessibility to implicit suicidal mind. Furthermore, priming manipulation interacted with individual differences in locus of control (LOC). Significant differences in accessibility to implicit suicidal mind were observed in individuals with internal LOC, while effects of priming manipulation were eliminated in individuals with external LOC. © 2013 The American Association of Suicidology.

  2. Escape and avoidance learning in the earthworm Eisenia hortensis

    Directory of Open Access Journals (Sweden)

    W. Jeffrey Wilson

    2014-01-01

    Full Text Available Interest in instrumental learning in earthworms dates back to 1912 when Yerkes concluded that they can learn a spatial discrimination in a T-maze. Rosenkoetter and Boice determined in the 1970s that the “learning” that Yerkes observed was probably chemotaxis and not learning at all. We examined a different form of instrumental learning: the ability to learn both to escape and to avoid an aversive stimulus. Freely moving “master” worms could turn off an aversive white light by increasing their movement; the behavior of yoked controls had no effect on the light. We demonstrate that in as few as 12 trials the behavior of the master worms comes under the control of this contingency.

  3. Convergent evolution of escape from hepaciviral antagonism in primates.

    Directory of Open Access Journals (Sweden)

    Maulik R Patel

    Full Text Available The ability to mount an interferon response on sensing viral infection is a critical component of mammalian innate immunity. Several viruses directly antagonize viral sensing pathways to block activation of the host immune response. Here, we show that recurrent viral antagonism has shaped the evolution of the host protein MAVS--a crucial component of the viral-sensing pathway in primates. From sequencing and phylogenetic analyses of MAVS from 21 simian primates, we found that MAVS has evolved under strong positive selection. We focused on how this positive selection has shaped MAVS' susceptibility to Hepatitis C virus (HCV. We functionally tested MAVS proteins from diverse primate species for their ability to resist antagonism by HCV, which uses its protease NS3/4A to cleave human MAVS. We found that MAVS from multiple primates are resistant to inhibition by the HCV protease. This resistance maps to single changes within the protease cleavage site in MAVS, which protect MAVS from getting cleaved by the HCV protease. Remarkably, most of these changes have been independently acquired at a single residue 506 that evolved under positive selection. We show that "escape" mutations lower affinity of the NS3 protease for MAVS and allow it to better restrict HCV replication. We further show that NS3 proteases from all other primate hepaciviruses, including the highly divergent GBV-A and GBV-C viruses, are functionally similar to HCV. We conclude that convergent evolution at residue 506 in multiple primates has resulted in escape from antagonism by hepaciviruses. Our study provides a model whereby insights into the ancient history of viral infections in primates can be gained using extant host and virus genes. Our analyses also provide a means by which primates might clear infections by extant hepaciviruses like HCV.

  4. Initiating a watch list for Ebola virus antibody escape mutations.

    Science.gov (United States)

    Miller, Craig R; Johnson, Erin L; Burke, Aran Z; Martin, Kyle P; Miura, Tanya A; Wichman, Holly A; Brown, Celeste J; Ytreberg, F Marty

    2016-01-01

    The 2014 Ebola virus (EBOV) outbreak in West Africa is the largest in recorded history and resulted in over 11,000 deaths. It is essential that strategies for treatment and containment be developed to avoid future epidemics of this magnitude. With the development of vaccines and antibody-based therapies using the envelope glycoprotein (GP) of the 1976 Mayinga strain, one important strategy is to anticipate how the evolution of EBOV might compromise these efforts. In this study we have initiated a watch list of potential antibody escape mutations of EBOV by modeling interactions between GP and the antibody KZ52. The watch list was generated using molecular modeling to estimate stability changes due to mutation. Every possible mutation of GP was considered and the list was generated from those that are predicted to disrupt GP-KZ52 binding but not to disrupt the ability of GP to fold and to form trimers. The resulting watch list contains 34 mutations (one of which has already been seen in humans) at six sites in the GP2 subunit. Should mutations from the watch list appear and spread during an epidemic, it warrants attention as these mutations may reflect an evolutionary response from the virus that could reduce the effectiveness of interventions such as vaccination. However, this watch list is incomplete and emphasizes the need for more experimental structures of EBOV interacting with antibodies in order to expand the watch list to other epitopes. We hope that this work provokes experimental research on evolutionary escape in both Ebola and other viral pathogens.

  5. Initiating a watch list for Ebola virus antibody escape mutations

    Directory of Open Access Journals (Sweden)

    Craig R. Miller

    2016-02-01

    Full Text Available The 2014 Ebola virus (EBOV outbreak in West Africa is the largest in recorded history and resulted in over 11,000 deaths. It is essential that strategies for treatment and containment be developed to avoid future epidemics of this magnitude. With the development of vaccines and antibody-based therapies using the envelope glycoprotein (GP of the 1976 Mayinga strain, one important strategy is to anticipate how the evolution of EBOV might compromise these efforts. In this study we have initiated a watch list of potential antibody escape mutations of EBOV by modeling interactions between GP and the antibody KZ52. The watch list was generated using molecular modeling to estimate stability changes due to mutation. Every possible mutation of GP was considered and the list was generated from those that are predicted to disrupt GP-KZ52 binding but not to disrupt the ability of GP to fold and to form trimers. The resulting watch list contains 34 mutations (one of which has already been seen in humans at six sites in the GP2 subunit. Should mutations from the watch list appear and spread during an epidemic, it warrants attention as these mutations may reflect an evolutionary response from the virus that could reduce the effectiveness of interventions such as vaccination. However, this watch list is incomplete and emphasizes the need for more experimental structures of EBOV interacting with antibodies in order to expand the watch list to other epitopes. We hope that this work provokes experimental research on evolutionary escape in both Ebola and other viral pathogens.

  6. Phenotypic mismatches reveal escape from arms-race coevolution.

    Directory of Open Access Journals (Sweden)

    Charles T Hanifin

    2008-03-01

    Full Text Available Because coevolution takes place across a broad scale of time and space, it is virtually impossible to understand its dynamics and trajectories by studying a single pair of interacting populations at one time. Comparing populations across a range of an interaction, especially for long-lived species, can provide insight into these features of coevolution by sampling across a diverse set of conditions and histories. We used measures of prey traits (tetrodotoxin toxicity in newts and predator traits (tetrodotoxin resistance of snakes to assess the degree of phenotypic mismatch across the range of their coevolutionary interaction. Geographic patterns of phenotypic exaggeration were similar in prey and predators, with most phenotypically elevated localities occurring along the central Oregon coast and central California. Contrary to expectations, however, these areas of elevated traits did not coincide with the most intense coevolutionary selection. Measures of functional trait mismatch revealed that over one-third of sampled localities were so mismatched that reciprocal selection could not occur given current trait distributions. Estimates of current locality-specific interaction selection gradients confirmed this interpretation. In every case of mismatch, predators were "ahead" of prey in the arms race; the converse escape of prey was never observed. The emergent pattern suggests a dynamic in which interacting species experience reciprocal selection that drives arms-race escalation of both prey and predator phenotypes at a subset of localities across the interaction. This coadaptation proceeds until the evolution of extreme phenotypes by predators, through genes of large effect, allows snakes to, at least temporarily, escape the arms race.

  7. Convergent evolution of escape from hepaciviral antagonism in primates.

    Science.gov (United States)

    Patel, Maulik R; Loo, Yueh-Ming; Horner, Stacy M; Gale, Michael; Malik, Harmit S

    2012-01-01

    The ability to mount an interferon response on sensing viral infection is a critical component of mammalian innate immunity. Several viruses directly antagonize viral sensing pathways to block activation of the host immune response. Here, we show that recurrent viral antagonism has shaped the evolution of the host protein MAVS--a crucial component of the viral-sensing pathway in primates. From sequencing and phylogenetic analyses of MAVS from 21 simian primates, we found that MAVS has evolved under strong positive selection. We focused on how this positive selection has shaped MAVS' susceptibility to Hepatitis C virus (HCV). We functionally tested MAVS proteins from diverse primate species for their ability to resist antagonism by HCV, which uses its protease NS3/4A to cleave human MAVS. We found that MAVS from multiple primates are resistant to inhibition by the HCV protease. This resistance maps to single changes within the protease cleavage site in MAVS, which protect MAVS from getting cleaved by the HCV protease. Remarkably, most of these changes have been independently acquired at a single residue 506 that evolved under positive selection. We show that "escape" mutations lower affinity of the NS3 protease for MAVS and allow it to better restrict HCV replication. We further show that NS3 proteases from all other primate hepaciviruses, including the highly divergent GBV-A and GBV-C viruses, are functionally similar to HCV. We conclude that convergent evolution at residue 506 in multiple primates has resulted in escape from antagonism by hepaciviruses. Our study provides a model whereby insights into the ancient history of viral infections in primates can be gained using extant host and virus genes. Our analyses also provide a means by which primates might clear infections by extant hepaciviruses like HCV.

  8. Hybrid fluid/kinetic modeling of Pluto’s escaping atmosphere

    Science.gov (United States)

    Erwin, Justin; Tucker, O. J.; Johnson, Robert E.

    2013-09-01

    Predicting the rate of escape and thermal structure of Pluto’s upper atmosphere in preparation for the New Horizons Spacecraft encounter in 2015 is important for planning and interpreting the expected measurements. Having a moderate Jeans parameter Pluto’s atmosphere does not fit the classic definition of Jeans escape for light species escaping from the terrestrial planets, nor does it fit the hydrodynamic outflow from comets and certain exoplanets. It has been proposed for some time that Pluto lies in the region of slow hydrodynamic escape. Using a hybrid fluid/molecular-kinetic model, we previously demonstrated the typical implementation of this model fails to correctly describe the appropriate temperature structure for the upper atmosphere for solar minimum conditions. Here we use a time-dependent solver to allow us to extend those simulations to higher heating rates and we examine fluid models in which Jeans-like escape expressions are used for the upper boundary conditions. We compare these to hybrid simulations of the atmosphere under heating conditions roughly representative of solar minimum and mean conditions as these bracket conditions expected during the New Horizon encounter. Although we find escape rates comparable to those previously estimated by the slow hydrodynamic escape model, and roughly consistent with energy limited escape, our model produces a much more extended atmosphere with higher temperatures roughly consistent with recent observations of CO. Such an extended atmosphere will be affected by Charon and will affect Pluto’s interaction with the solar wind at the New Horizon encounter. For the parameter space covered, we also find an inverse relationship between exobase temperature and altitude and the Jeans escape rate that is consistent with the energy limited escape rate. Since we have previously shown that such models can be scaled, these results have implications for modeling exoplanet atmospheres for which the energy limited

  9. Light-Triggerable Liposomes for Enhanced Endolysosomal Escape and Gene Silencing in PC12 Cells

    Directory of Open Access Journals (Sweden)

    Wenjie Chen

    2017-06-01

    Full Text Available Liposomes are an effective gene and/or drug delivery system, widely used in biomedical applications including gene therapy and chemotherapy. Here, we designed a photo-responsive liposome (lipVP loaded with a photosensitizer verteporfin (VP. This photosensitizer is clinically approved for photodynamic therapy (PDT. LipVP was employed as a DNA carrier for pituitary adenylyl cyclase-activating polypeptide (PACAP receptor 1 (PAC1R gene knockdown in PC12 cells. This has been done by incorporating PAC1R antisense oligonucleotides inside the lipVP cavity. Cells that have taken up the lipVP were exposed to light from a UV light source. As a result of this exposure, reactive oxygen species (ROS were generated from VP, destabilizing the endolysosomal membranes and enhancing the liposomal release of antisense DNA into the cytoplasm. Endolysosomal escape of DNA was documented at different time points based on quantitative analysis of colocalization between fluorescently labeled DNA and endosomes and lysosomes. The released antisense oligonucleotides were found to silence PAC1R mRNA. The efficiency of this photo-induced gene silencing was demonstrated by a 74% ± 5% decrease in PAC1R fluorescence intensity. Following the light-induced DNA transfer into cells, cell differentiation with exposure to two kinds of PACAP peptides was observed to determine the cell phenotypic change after PAC1R gene knockdown.

  10. Loss of runt-related transcription factor 3 expression leads hepatocellular carcinoma cells to escape apoptosis

    Directory of Open Access Journals (Sweden)

    Nakamura Shinichiro

    2011-01-01

    Full Text Available Abstract Background Runt-related transcription factor 3 (RUNX3 is known as a tumor suppressor gene for gastric cancer and other cancers, this gene may be involved in the development of hepatocellular carcinoma (HCC. Methods RUNX3 expression was analyzed by immunoblot and immunohistochemistry in HCC cells and tissues, respectively. Hep3B cells, lacking endogenous RUNX3, were introduced with RUNX3 constructs. Cell proliferation was measured using the MTT assay and apoptosis was evaluated using DAPI staining. Apoptosis signaling was assessed by immunoblot analysis. Results RUNX3 protein expression was frequently inactivated in the HCC cell lines (91% and tissues (90%. RUNX3 expression inhibited 90 ± 8% of cell growth at 72 h in serum starved Hep3B cells. Forty-eight hour serum starvation-induced apoptosis and the percentage of apoptotic cells reached 31 ± 4% and 4 ± 1% in RUNX3-expressing Hep3B and control cells, respectively. Apoptotic activity was increased by Bim expression and caspase-3 and caspase-9 activation. Conclusion RUNX3 expression enhanced serum starvation-induced apoptosis in HCC cell lines. RUNX3 is deleted or weakly expressed in HCC, which leads to tumorigenesis by escaping apoptosis.

  11. Clinical relevance of the tumor microenvironment and immune escape of oral squamous cell carcinoma.

    Science.gov (United States)

    Eckert, Alexander W; Wickenhauser, Claudia; Salins, Paul C; Kappler, Matthias; Bukur, Juergen; Seliger, Barbara

    2016-04-05

    Changes in the tumor microenvironment and immune surveillance represent crucial hallmarks of various kinds of cancer, including oral squamous cell carcinoma (OSCC), and a close crosstalk of hypoxia regulating genes, an activation of chemokines and immune cells has been described. A review about the pivotal role of HIF-1, its crosstalk to various cornerstones in OSCC tumorigenesis is presented. Hypoxia is a frequent event in OSCC and leads to a reprogramming of the cellular metabolism in order to prevent cell death. Hypoxic OSCC cells induce different adaptive changes such as anaerobic glycolysis, pH stabilisation and alterations of the gene and protein expression profile. This complex metabolic program is orchestrated by the hypoxia inducible factor (HIF)-1, the master regulator of early tumor progression. Hypoxia-dependent and -independent alterations in immune surveillance lead to different immune evasion strategies, which are partially mediated by alterations of the tumor cells, changes in the frequency, activity and repertoire of immune cell infiltrates and of soluble and environmental factors of the tumor micromilieu with consecutive generation of an immune escape phenotype, progression of disease and poor clinical outcome of OSCC patients. This review focusses on the importance of HIF-1 in the adaption and reprogramming of the metabolic system to reduced oxygen values as well as on the role of the tumor microenvironment for evasion of OSCC from immune recognition and destruction.

  12. European SpaceCraft for the study of Atmospheric Particle Escape (ESCAPE): a mission proposed in response to the ESA M5-call

    Science.gov (United States)

    Dandouras, Iannis; Yamauchi, Masatoshi; Rème, Henri; De Keyser, Johan; Marghitu, Octav; Fazakerley, Andrew; Grison, Benjamin; Kistler, Lynn; Milillo, Anna; Nakamura, Rumi; Paschalidis, Nikolaos; Paschalis, Antonis; Pinçon, Jean-Louis; Sakanoi, Takeshi; Wieser, Martin; Wurz, Peter; Yoshikawa, Ichiro; Häggström, Ingemar; Liemohn, Mike; Tian, Feng

    2017-04-01

    ESCAPE is a mission proposed in response to the ESA-M5 call that will quantitatively estimate the amount of escaping particles of the major atmospheric components (nitrogen and oxygen), as neutral and ionised species, escaping from the Earth as a magnetised planet. The spatial distribution and temporal variability of the flux of these species and their isotopic composition will be for the first time systematically investigated in an extended altitude range, from the exobase/upper ionosphere (500 km altitude) up to the magnetosphere. The goal is to understand the importance of each escape mechanism, its dependence on solar and geomagnetic activity, and to infer the history of the Earth's atmosphere over a long (geological scale) time period. Since the solar EUV and solar wind conditions during solar maximum at present are comparable to the solar minimum conditions 1-2 billion years ago, the escaping amount and the isotope and N/O ratios should be obtained as a function of external forcing (solar and geomagnetic conditions) to allow a scaling to the past. The result will be used as a reference to understand the atmospheric/ionospheric evolution of magnetised planets. To achieve this goal, a slowly spinning spacecraft is proposed equipped with a suite of instruments developed and supplied by an international consortium. These instruments will detect the upper atmosphere and magnetosphere escaping populations by a combination of in-situ measurements and of remote-sensing observations.

  13. Computer Self-Efficacy, Competitive Anxiety and Flow State: Escaping from Firing Online Game

    Science.gov (United States)

    Hong, Jon-Chao; Pei-Yu, Chiu; Shih, Hsiao-Feng; Lin, Pei-Shin; Hong, Jon-Chao

    2012-01-01

    Flow state in game playing affected by computer self-efficacy and game competitive anxiety was studied. In order to examine the effect of those constructs with high competition, this study select "Escaping from firing online game" which require college students to escape from fire and rescue people and eliminate the fire damage along the way of…

  14. Spoon Distance Fading with and without Escape Extinction as Treatment for Food Refusal

    Science.gov (United States)

    Rivas, Kristi D.; Piazza, Cathleen C.; Patel, Meeta R.; Bachmeyer, Melanie H.

    2010-01-01

    Little is known about the characteristics of meals that serve as motivating operations (MOs) for escape behavior. In the current investigation, we showed that the distance at which a therapist held a spoon from a child's lips served as an MO for escape behavior. Based on these results, we implemented spoon distance fading, compared fading with and…

  15. Treatment of Escape-Maintained Behavior with Positive Reinforcement: The Role of Reinforcement Contingency and Density

    Science.gov (United States)

    Ingvarsson, Einar T.; Hanley, Gregory P.; Welter, Katherine M.

    2009-01-01

    Functional analyses suggested that the disruptive behavior of three preschool children was maintained by escape from demands. While keeping the escape contingency intact, we conducted (a) a density analysis in which the children earned preferred items for task completion according to two schedules that varied in reinforcement density, and (b) a…

  16. A trouser bag experiment that quantify by-catch species escaping ...

    African Journals Online (AJOL)

    Thirty replicate landings showed that; Drepane africana have the highest escape rate of SO.76% followed by Pseudotolithus elongatus (46.83%), while flat fishes like Dasyatis margarita and shell fishes like Callinectes amnicola have low escape rates of zero and 17.62% respectively. Among the five fish groups of pelagic, ...

  17. Assessment of the Relative Effects of Attention and Escape on Noncompliance

    Science.gov (United States)

    Rodriguez, Nicole M.; Thompson, Rachel H.; Baynham, Tanya Y.

    2010-01-01

    The current study presents a method for assessing the relative effects of attention and escape on noncompliance in preschoolers. Attention and escape conditions were alternated in a multielement design, and a contingency reversal procedure, in which one test condition served as a control for the other, was used to demonstrate control. For all 3…

  18. Reducing Escape Behavior and Increasing Task Completion with Functional Communication Training, Extinction, and Response Chaining.

    Science.gov (United States)

    Lalli, Joseph S.; And Others

    1995-01-01

    Functional communication training, extinction, and response chaining decreased escape-maintained aberrant behavior and increased task participation of 3 youth, ages 10 through 15, with moderate mental retardation, 2 of whom also had autism. Task escape was contingent on verbally responding and completing task steps. Behavior chaining also…

  19. The rate of immune escape vanishes when multiple immune responses control an HIV infection

    NARCIS (Netherlands)

    van Deutekom, Hanneke W. M.; Wijnker, Gilles; de Boer, Rob J.

    2013-01-01

    During the first months of HIV infection, the virus typically evolves several immune escape mutations. These mutations are found in epitopes in viral proteins and reduce the impact of the CD8⁺ T cells specific for these epitopes. Recent data show that only a subset of the epitopes escapes, that most

  20. 3D, Multi-fluid, MHD Calculations Of Plasma Escape From Mars

    Science.gov (United States)

    Najib, D.; Toth, G.; Nagy, A.; Ma, Y.

    2008-12-01

    We use our new multi-fluid, MHD model to calculate plasma escape from Mars. Our lower boundary is set at 100 km and we have a radial grid resolution of about 10 km in the ionosphere. We consider both photo and electron impact ionization, as well as charge exchange processes in calculating the escape fluxes, using a variety of solar and upstream conditions.

  1. Mass fractionation during transonic escape and implications for loss of water from Mars and Venus

    Science.gov (United States)

    Zahnle, Kevin J.; Kasting, James F.

    1986-01-01

    Hydrodynamic escape of hydrogen from a planetary atmosphere can remove heavier gases as well as hydrogen, provided that the escape rate is sufficiently large. Analytic approximations for the degree of mass fractionation of a trace species during hydrodynamic escape are compared with accurate numerical solutions for the case of transonic outflow. The analytic approximations are most accurate when the ratio of molecular weights of the heavier and lighter constituents is large so that nonlinear terms in the momentum equation for the heavy constituent become small. The simplest analytic formula is readily generalized to the case where a heavy constituent is also a major species. Application of the generalized formula to hypothetical episodes of hydrodynamic escape from Venus and Mars suggests that both hydrogen and oxygen could have escaped; thus, substantial quantities of water may have been lost without the need to oxidize large amounts of the crust.

  2. Recombination-mediated escape from primary CD8+ T cells in acute HIV-1 infection.

    Science.gov (United States)

    Ritchie, Adam John; Cai, Fangping; Smith, Nicola M G; Chen, Sheri; Song, Hongshuo; Brackenridge, Simon; Abdool Karim, Salim S; Korber, Bette T; McMichael, Andrew J; Gao, Feng; Goonetilleke, Nilu

    2014-09-12

    A major immune evasion mechanism of HIV-1 is the accumulation of non-synonymous mutations in and around T cell epitopes, resulting in loss of T cell recognition and virus escape. Here we analyze primary CD8+ T cell responses and virus escape in a HLA B*81 expressing subject who was infected with two T/F viruses from a single donor. In addition to classic escape through non-synonymous mutation/s, we also observed rapid selection of multiple recombinant viruses that conferred escape from T cells specific for two epitopes in Nef. Our study shows that recombination between multiple T/F viruses provide greater options for acute escape from CD8+ T cell responses than seen in cases of single T/F virus infection. This process may contribute to the rapid disease progression in patients infected by multiple T/F viruses.

  3. Improving the effectiveness of escape windows in directed Norway lobster Nephrops norvegicus trawl fisheries

    DEFF Research Database (Denmark)

    Madsen, Niels; Holst, René; Frandsen, Rikke

    2012-01-01

    A substantial improvement in the bycatch selectivity of Norway lobster Nephrops norvegicus trawls is required, particularly with respect to cod Gadus morhua , whose stocks are at low levels in several areas. Conventional escape windows are not adequate to properly release cod and other bycatch...... species caught in the trawls. To address this issue, we developed a novel sorting box concept consisting of a four-panel section with a window on the top in order to improve the escape of cod and other bycatch species through an escape window while retaining the target catch of Norway lobster. The concept....... The reduction in bycatch decreased with decreasing mesh size and increasing height of the sorting box. Escape of Norway lobster through the escape window was limited. A modified version of the sorting box concept was implemented in the Kattegat fishery from 2009 onwards...

  4. H Escape in 3D: MAVEN IUVS observations of the Mars corona

    Science.gov (United States)

    Chaffin, M.; Chaufray, J. Y.; Deighan, J.; Schneider, N. M.; McClintock, W. E.; Stewart, I. F.; Thiemann, E.; Clarke, J. T.; Holsclaw, G.; Jain, S.; Crismani, M. M. J.; Stiepen, A.; Montmessin, F.; Eparvier, F. G.; Chamberlin, P. C.; Jakosky, B. M.

    2015-12-01

    Mars has lost a significant fraction of its initial water inventory to space, as evidenced by surface morphology and an enrichment of the heavy isotope deuterium relative to hydrogen. This loss continues today via thermal Jeans escape of neutral hydrogen from the extended H corona. The Mars Atmosphere and Volatile EvolutioN mission's Imaging Ultraviolet Spectrometer IUVS constrains this escape with high cadence, spatially resolved measurements of the corona in scattered sunlight in the Lyman alpha line of neutral H at 121.6 nm. These measurements indicate spatial variability in the corona never before recognized, with potential effects on reconstructing the escape history of water and on retrieved escape rates from previous spatially unresolved observations. I will present our current progress in retrieving escape rates and density distributions from the IUVS observations, including the degree to which observations of the H corona can constrain the thermospheric general circulation at Mars.

  5. Fast-starting after a breath: air-breathing motions are kinematically similar to escape responses in the catfish Hoplosternum littorale

    Directory of Open Access Journals (Sweden)

    Paolo Domenici

    2014-12-01

    Full Text Available Fast-starts are brief accelerations commonly observed in fish within the context of predator–prey interactions. In typical C-start escape responses, fish react to a threatening stimulus by bending their body into a C-shape during the first muscle contraction (i.e. stage 1 which provides a sudden acceleration away from the stimulus. Recently, similar C-starts have been recorded in fish aiming at a prey. Little is known about C-starts outside the context of predator–prey interactions, though recent work has shown that escape response can also be induced by high temperature. Here, we test the hypothesis that air-breathing fish may use C-starts in the context of gulping air at the surface. Hoplosternum littorale is an air-breathing freshwater catfish found in South America. Field video observations reveal that their air-breathing behaviour consists of air-gulping at the surface, followed by a fast turn which re-directs the fish towards the bottom. Using high-speed video in the laboratory, we compared the kinematics of the turn immediately following air-gulping performed by H. littorale in normoxia with those of mechanically-triggered C-start escape responses and with routine (i.e. spontaneous turns. Our results show that air-breathing events overlap considerably with escape responses with a large stage 1 angle in terms of turning rates, distance covered and the relationship between these rates. Therefore, these two behaviours can be considered kinematically comparable, suggesting that air-breathing in this species is followed by escape-like C-start motions, presumably to minimise time at the surface and exposure to avian predators. These findings show that C-starts can occur in a variety of contexts in which fish may need to get away from areas of potential danger.

  6. The return of international labour migrants in the ESCAP Region.

    Science.gov (United States)

    1986-03-01

    The social phenomenon of massive temporary international labor migration from the ESCAP region has emerged extremely rapidly. Within 10 years, the number of persons from ESCAP countries grew from a negligible one to 3.5 million. Related research and government policies have lagged behind this latest surge in migration. Most research conducted has been small-scale and lacks an analytical or theoretical framework. Policy formulation for temporary labor migration is difficult because most of the rapid growth in the industry has occurred as a result of private efforts, with a minimum of government intervention. It is now difficult, for the government to provide effective regulations or measures to stimulate and assist the process. Regulations on compulsory remittances or overseas minimum wages have proved to be unrealistic and, if not rescinded, are routinely circumvented. The most effective policies to assist return migrants may not be those which are intended to do so, but those which control the earlier stages of the migration process, such as recruitment, working conditions, and banking arrangements. The most valuable policies may also include those affecting education, training, employment, and general socioeconomic growth. Governments are recommended to provide social services for migrants and their families who are experiencing problems, and to institute community programs in areas with a large number of labor migrants. Governmental efforts to promote forms of labor migration beneficial to the workers would be valuable and should include measures to identify overseas labor markets for employing its nationals, government ot government labor contracts, and government participation in joint-venture projects. International migration should be analyzed in the context of theories and social change in order for governments to formulate effective measures for the reintegration of returning workers. Labor migration on the current scale has many social implications for

  7. 'Light-chain escape-multiple myeloma'-an escape phenomenon from plateau phase: report of the largest patient series using LC-monitoring.

    Science.gov (United States)

    Kühnemund, A; Liebisch, P; Bauchmüller, K; zur Hausen, A; Veelken, H; Wäsch, R; Engelhardt, M

    2009-03-01

    More intensive and novel therapy options in multiple myeloma (MM) hold the promise to improve treatment outcome. However, disease evolution, induced with long disease duration and extensive pretreatment, has resulted in changes in the biological behaviour of MM and unusual relapse emergence, such as of extramedullary (EM) disease or a shift in secretion from intact immunoglobulin (Ig) to free-light chains (FLCs) only. We studied ten patients since 2004, thoroughly assessed relevant patient characteristics, prominent similarities, SFLC-changes, therapy response, mode and speed of progression, and the incidence of light-chain escape (LCE)-MM within our entire myeloma patient cohort. Serum FLCs (SFLCs) were determined via Freelite-assay (Dade-Behringer Nephelometer). This report summarizes the to date largest series of ten patients, whose MM appeared stable, as judged by conventional monitoring of intact Ig levels, but developed severe organ dysfunction as a consequence of initially undetected LC-progression. Median number of anti-MM cycles before LCE occurrence was six, including autologous and/or allogeneic stem cell transplants and novel drugs, predominantly thalidomide, in 4/10. Classic diagnostics, such as electrophoresis and quantitative Ig measurement proved futile to detect LC-progression, whereas SFLCs were reliable markers. The LCE-MM prevalence within 407 MM patients treated in our institution between 2004 and 2007 was 2.46%. Our report suggests that early detection of LCE-MM by means of serial SFLC measurements may prevent unnecessary complications, allows to detect unusual relapse manifestations in the era of intensive and biological therapy options and possibly also permits to improve treatment results in LCE-MM.

  8. Nosema Tolerant Honeybees (Apis mellifera) Escape Parasitic Manipulation of Apoptosis.

    Science.gov (United States)

    Kurze, Christoph; Le Conte, Yves; Dussaubat, Claudia; Erler, Silvio; Kryger, Per; Lewkowski, Oleg; Müller, Thomas; Widder, Miriam; Moritz, Robin F A

    2015-01-01

    Apoptosis is not only pivotal for development, but also for pathogen defence in multicellular organisms. Although numerous intracellular pathogens are known to interfere with the host's apoptotic machinery to overcome this defence, its importance for host-parasite coevolution has been neglected. We conducted three inoculation experiments to investigate in the apoptotic respond during infection with the intracellular gut pathogen Nosema ceranae, which is considered as potential global threat to the honeybee (Apis mellifera) and other bee pollinators, in sensitive and tolerant honeybees. To explore apoptotic processes in the gut epithelium, we visualised apoptotic cells using TUNEL assays and measured the relative expression levels of subset of candidate genes involved in the apoptotic machinery using qPCR. Our results suggest that N. ceranae reduces apoptosis in sensitive honeybees by enhancing inhibitor of apoptosis protein-(iap)-2 gene transcription. Interestingly, this seems not be the case in Nosema tolerant honeybees. We propose that these tolerant honeybees are able to escape the manipulation of apoptosis by N. ceranae, which may have evolved a mechanism to regulate an anti-apoptotic gene as key adaptation for improved host invasion.

  9. Intertextuality in Novel: An Escape from Patriarchal Soliloquy

    Directory of Open Access Journals (Sweden)

    Nargess Bagheri

    2015-12-01

    Full Text Available Hypertextuality is one of the intertextual relationships introduced by Gerard Genette. According to him, hypertextuality includes all the relationships which the hypertext has with the previous text, i.e. the hypotext. However, he does not consider the relationship between these two texts to be in such a way that the hypertext is the interpretation of the hypotext. On the other hand, other theorizers including Bakhtin, regard the conversation between texts a way to escape a one-voiced and dominant discourse. From this viewpoint, the intertextual relationships of Sadegh Hedayat’s The Blind Owl, with Shahrnoush Parsipour’s The Blue Mind and Abbas Maroufi’s The Body of Farhad are in such a way that The Blind Owl can be regarded as a hypotext for the other 2 novels but these two novels interpret the text differently. The present study aims to examine the intertextual relationships between these 3 novels and explore how a multiple-voiced conversation is formed between them.

  10. Evolutionary invasion and escape in the presence of deleterious mutations.

    Directory of Open Access Journals (Sweden)

    Claude Loverdo

    Full Text Available Replicators such as parasites invading a new host species, species invading a new ecological niche, or cancer cells invading a new tissue often must mutate to adapt to a new environment. It is often argued that a higher mutation rate will favor evolutionary invasion and escape from extinction. However, most mutations are deleterious, and even lethal. We study the probability that the lineage will survive and invade successfully as a function of the mutation rate when both the initial strain and an adaptive mutant strain are threatened by lethal mutations. We show that mutations are beneficial, i.e. a non-zero mutation rate increases survival compared to the limit of no mutations, if in the no-mutation limit the survival probability of the initial strain is smaller than the average survival probability of the strains which are one mutation away. The mutation rate that maximizes survival depends on the characteristics of both the initial strain and the adaptive mutant, but if one strain is closer to the threshold governing survival then its properties will have greater influence. These conclusions are robust for more realistic or mechanistic depictions of the fitness landscapes such as a more detailed viral life history, or non-lethal deleterious mutations.

  11. Escape, evacuation, and rescue research project : phase 2

    Energy Technology Data Exchange (ETDEWEB)

    Bercha, F.G. [Bercha Engineering Ltd., Calgary, AB (Canada)

    2003-04-01

    This report describes the work from the Escape, Evacuation and Rescue (EER) research project conducted between April 2001 and March 2003. The objectives were to develop EER performance-based standards (PBS) for offshore oil and gas installations in Canadian waters. It included studies of human performance under extreme conditions, reliability analysis of a specific evacuation system, and the incorporation of research findings into a computer simulation program called the Risk and Performance Tool (RPT). The newest version of the RPT was applied to make use of three major improvements and modifications. This report also discussed the application of RPT to generate information in support of the PBS development program. Methods of quantifying psychological and physiological stressors into the RPT were developed. The RPT was applied to the reliability analysis of the preferred orientation and displacement system. The results indicate the contributions of human and mechanical factors in evacuation performance. Results showed that for evacuations in calm conditions, human error and mechanical failure made the same contribution. Under moderate and severe conditions, human error contributed about twice as much to failure as mechanical failure. Under extreme conditions, both human error and mechanical failure were at the limit. A series of recommendations were proposed to improve performance-based standards. refs., tabs., figs.

  12. Parasite escape through trophic specialization in a species flock.

    Science.gov (United States)

    Hablützel, P I; Vanhove, M P M; Deschepper, P; Grégoir, A F; Roose, A K; Volckaert, F A M; Raeymaekers, J A M

    2017-07-01

    Adaptive radiation occurs when species diversify rapidly to occupy an array of ecological niches. As opportunities for parasite infection and transmission may greatly vary among these niches, adaptive radiation is expected to be associated with a turnover of the parasite community. As major agents of natural and sexual selection, parasites may play a central role in host diversification. The study of parasite turnover may thus be of general relevance and could significantly improve our understanding of adaptive radiation. In this study, we examined the parasite faunas of eleven species belonging to the tribe Tropheini, one of several adaptive radiations of cichlid fishes in Lake Tanganyika. The most parsimonious ancestral foraging strategy among the Tropheini is relatively unselective substrate browsing of aufwuchs. Several lineages evolved more specialized foraging strategies, such as selective combing of microscopic diatoms or picking of macro-invertebrates. We found that representatives of these specialized lineages bear reduced infection with food-web-transmitted acanthocephalan helminths, but not with parasites with a direct life cycle. Possibly, the evolution of selective foraging strategies entailed reduced ingestion of intermediate invertebrate hosts of acanthocephalans. We conclude that some species belonging to the Tropheini virtually escape acanthocephalan infection as a by-product of trophic specialization. © 2017 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2017 European Society For Evolutionary Biology.

  13. Global survey of escape from X inactivation by RNA-sequencing in mouse.

    Science.gov (United States)

    Yang, Fan; Babak, Tomas; Shendure, Jay; Disteche, Christine M

    2010-05-01

    X inactivation equalizes the dosage of gene expression between the sexes, but some genes escape silencing and are thus expressed from both alleles in females. To survey X inactivation and escape in mouse, we performed RNA sequencing in Mus musculus x Mus spretus cells with complete skewing of X inactivation, relying on expression of single nucleotide polymorphisms to discriminate allelic origin. Thirteen of 393 (3.3%) mouse genes had significant expression from the inactive X, including eight novel escape genes. We estimate that mice have significantly fewer escape genes compared with humans. Furthermore, escape genes did not cluster in mouse, unlike the large escape domains in human, suggesting that expression is controlled at the level of individual genes. Our findings are consistent with the striking differences in phenotypes between female mice and women with a single X chromosome--a near normal phenotype in mice versus Turner syndrome and multiple abnormalities in humans. We found that escape genes are marked by the absence of trimethylation at lysine 27 of histone H3, a chromatin modification associated with genes subject to X inactivation. Furthermore, this epigenetic mark is developmentally regulated for some mouse genes.

  14. Reporter Assay for Endo/Lysosomal Escape of Toxin-Based Therapeutics

    Directory of Open Access Journals (Sweden)

    Roger Gilabert-Oriol

    2014-05-01

    Full Text Available Protein-based therapeutics with cytosolic targets are capable of exhibiting their therapeutic effect once they have escaped from the endosomes or lysosomes. In this study, the reporters—horseradish peroxidase (HRP, Alexa Fluor 488 (Alexa and ricin A-chain (RTA—were investigated for their capacity to monitor the endo/lysosomal escape of the ribosome-inactivating protein, saporin. The conjugates—saporin-HRP, Alexasaporin and saporin-KQ-RTA—were constructed, and the endo/lysosomal escape of these conjugates alone (lack of endo/lysosomal release or in combination with certain structurally-specific triterpenoidal saponins (efficient endo/lysosomal escape was characterized. HRP failed in reporting the endo/lysosomal escape of saporin. Contrastingly, Alexa Fluor 488 successfully allowed the report of the process at a toxin concentration of 1000 nM. In addition, single endo/lysosome analysis facilitated the determination of the amount of Alexasaporin released from each vesicle. RTA was also successful in reporting the endo/lysosomal escape of the enzymatically inactive mutant, saporin-KQ, but in this case, the sensitivity of the method reached a toxin concentration of 10 nM. In conclusion, the simultaneous usage of Alexa Fluor 488 and RTA as reporters may provide the possibility of monitoring the endo/lysosomal escape of protein-based therapeutics in the concentration range of 10–1000 nM.

  15. Means of escape provisions and evacuation simulation of public building in Malaysia and Singapore

    Science.gov (United States)

    Samad, Muna Hanim Abdul; Taib, Nooriati; Ying, Choo Siew

    2017-10-01

    The Uniform Building By-law 1984 of Malaysia is the legal document governing fire safety requirements in buildings. Its prescriptive nature has made the requirements out dated from the viewpoint of current performance based approach in most developed countries. The means of escape provisions is a critical requirement to safeguard occupants' safety in fire especially in public buildings. As stipulated in the UBBL 1984, the means of escape provisions includes sufficient escape routes, travel distance, protection of escape routes, etc. designated as means to allow occupants to escape within a safe period of time. This research aims at investigating the effectiveness of those provisions in public buildings during evacuation process involving massive crowd during emergencies. This research includes a scenario-based study on evacuation processes using two software i.e. PyroSim, a crowd modelling software to conduct smoke study and Pathfinder to stimulate evacuation model of building in Malaysia and Singapore as comparative study. The results show that the buildings used as case study were designed according to Malaysian UBBL 1984 and Singapore Firecode, 2013 respectively provide relative safe means of escape. The simulations of fire and smoke and coupled with simulation of evacuation have demonstrated that although there are adequate exits designated according to fire requirements, the impact of the geometry of atriums on the behavior of fire and smoke have significant effect on escape time especially for unfamiliar user of the premises.

  16. The impact of escaped farmed Atlantic salmon (Salmo salar L.) on catch statistics in Scotland.

    Science.gov (United States)

    Green, Darren M; Penman, David J; Migaud, Herve; Bron, James E; Taggart, John B; McAndrew, Brendan J

    2012-01-01

    In Scotland and elsewhere, there are concerns that escaped farmed Atlantic salmon (Salmo salar L.) may impact on wild salmon stocks. Potential detrimental effects could arise through disease spread, competition, or inter-breeding. We investigated whether there is evidence of a direct effect of recorded salmon escape events on wild stocks in Scotland using anglers' counts of caught salmon (classified as wild or farmed) and sea trout (Salmo trutta L.). This tests specifically whether documented escape events can be associated with reduced or elevated escapes detected in the catch over a five-year time window, after accounting for overall variation between areas and years. Alternate model frameworks were somewhat inconsistent, however no robust association was found between documented escape events and higher proportion of farm-origin salmon in anglers' catch, nor with overall catch size. A weak positive correlation was found between local escapes and subsequent sea trout catch. This is in the opposite direction to what would be expected if salmon escapes negatively affected wild fish numbers. Our approach specifically investigated documented escape events, contrasting with earlier studies examining potentially wider effects of salmon farming on wild catch size. This approach is more conservative, but alleviates some potential sources of confounding, which are always of concern in observational studies. Successful analysis of anglers' reports of escaped farmed salmon requires high data quality, particularly since reports of farmed salmon are a relatively rare event in the Scottish data. Therefore, as part of our analysis, we reviewed studies of potential sensitivity and specificity of determination of farmed origin. Specificity estimates are generally high in the literature, making an analysis of the form we have performed feasible.

  17. The impact of escaped farmed Atlantic salmon (Salmo salar L. on catch statistics in Scotland.

    Directory of Open Access Journals (Sweden)

    Darren M Green

    Full Text Available In Scotland and elsewhere, there are concerns that escaped farmed Atlantic salmon (Salmo salar L. may impact on wild salmon stocks. Potential detrimental effects could arise through disease spread, competition, or inter-breeding. We investigated whether there is evidence of a direct effect of recorded salmon escape events on wild stocks in Scotland using anglers' counts of caught salmon (classified as wild or farmed and sea trout (Salmo trutta L.. This tests specifically whether documented escape events can be associated with reduced or elevated escapes detected in the catch over a five-year time window, after accounting for overall variation between areas and years. Alternate model frameworks were somewhat inconsistent, however no robust association was found between documented escape events and higher proportion of farm-origin salmon in anglers' catch, nor with overall catch size. A weak positive correlation was found between local escapes and subsequent sea trout catch. This is in the opposite direction to what would be expected if salmon escapes negatively affected wild fish numbers. Our approach specifically investigated documented escape events, contrasting with earlier studies examining potentially wider effects of salmon farming on wild catch size. This approach is more conservative, but alleviates some potential sources of confounding, which are always of concern in observational studies. Successful analysis of anglers' reports of escaped farmed salmon requires high data quality, particularly since reports of farmed salmon are a relatively rare event in the Scottish data. Therefore, as part of our analysis, we reviewed studies of potential sensitivity and specificity of determination of farmed origin. Specificity estimates are generally high in the literature, making an analysis of the form we have performed feasible.

  18. Fast-starting after a breath: air-breathing motions are kinematically similar to escape responses in the catfish Hoplosternum littorale

    DEFF Research Database (Denmark)

    Domenici, Paolo; Norin, Tommy; Bushnell, Peter G.

    2015-01-01

    Fast-starts are brief accelerations commonly observed in fish within the context of predator–prey interactions. In typical C-start escape responses, fish react to a threatening stimulus by bending their body into a C-shape during the first muscle contraction (i.e. stage 1) which provides a sudden...... acceleration away from the stimulus. Recently, similar C-starts have been recorded in fish aiming at a prey. Little is known about C-starts outside the context of predator–prey interactions, though recent work has shown that escape response can also be induced by high temperature. Here, we test the hypothesis...... that air-breathing fish may use C-starts in the context of gulping air at the surface. Hoplosternum littorale is an air-breathing freshwater catfish found in South America. Field video observations reveal that their air-breathing behaviour consists of air-gulping at the surface, followed by a fast turn...

  19. Type 1 Interferons and NK Cells Limit Murine Cytomegalovirus Escape from the Lymph Node Subcapsular Sinus

    Science.gov (United States)

    Bruce, Kimberley; Lawler, Clara; Cardin, Rhonda D.

    2016-01-01

    Cytomegaloviruses (CMVs) establish chronic, systemic infections. Peripheral infection spreads via lymph nodes, which are also a focus of host defence. Thus, this is a point at which systemic infection spread might be restricted. Subcapsular sinus macrophages (SSM) captured murine CMV (MCMV) from the afferent lymph and poorly supported its replication. Blocking the type I interferon (IFN-I) receptor (IFNAR) increased MCMV infection of SSM and of the fibroblastic reticular cells (FRC) lining the subcapsular sinus, and accelerated viral spread to the spleen. Little splenic virus derived from SSM, arguing that they mainly induce an anti-viral state in the otherwise susceptible FRC. NK cells also limited infection, killing infected FRC and causing tissue damage. They acted independently of IFN-I, as IFNAR blockade increased NK cell recruitment, and NK cell depletion increased infection in IFNAR-blocked mice. Thus SSM restricted MCMV infection primarily though IFN-I, with NK cells providing a second line of defence. The capacity of innate immunity to restrict MCMV escape from the subcapsular sinus suggested that enhancing its recruitment might improve infection control. PMID:27926941

  20. Phenolic Glycolipid Facilitates Mycobacterial Escape from Microbicidal Tissue-Resident Macrophages.

    Science.gov (United States)

    Cambier, C J; O'Leary, Seónadh M; O'Sullivan, Mary P; Keane, Joseph; Ramakrishnan, Lalita

    2017-09-19

    Mycobacterium tuberculosis (Mtb) enters the host in aerosol droplets deposited in lung alveoli, where the bacteria first encounter lung-resident alveolar macrophages. We studied the earliest mycobacterium-macrophage interactions in the optically transparent zebrafish. First-responding resident macrophages phagocytosed and eradicated infecting mycobacteria, suggesting that to establish a successful infection, mycobacteria must escape out of the initially infected resident macrophage into growth-permissive monocytes. We defined a critical role for mycobacterial membrane phenolic glycolipid (PGL) in engineering this transition. PGL activated the STING cytosolic sensing pathway in resident macrophages, inducing the production of the chemokine CCL2, which in turn recruited circulating CCR2(+) monocytes toward infection. Transient fusion of infected macrophages with CCR2(+) monocytes enabled bacterial transfer and subsequent dissemination, and interrupting this transfer so as to prolong mycobacterial sojourn in resident macrophages promoted clearing of infection. Human alveolar macrophages produced CCL2 in a PGL-dependent fashion following infection, arguing for the potential of PGL-blocking interventions or PGL-targeting vaccine strategies in the prevention of tuberculosis. VIDEO ABSTRACT. Copyright © 2017. Published by Elsevier Inc.

  1. An RNA element in human interleukin 6 confers escape from degradation by the gammaherpesvirus SOX protein.

    Science.gov (United States)

    Hutin, Stephanie; Lee, Yeon; Glaunsinger, Britt A

    2013-04-01

    Several viruses express factors to silence host gene expression via widespread mRNA degradation. This phenotype is the result of the coordinated activity of the viral endonuclease SOX and the cellular RNA degradation enzyme Xrn1 during lytic Kaposi's sarcoma-associated herpesvirus (KSHV) infection. While most cellular transcripts are highly downregulated, a subset of host mRNA escapes turnover via unknown mechanisms. One of the most prominent escapees is the interleukin 6 (IL-6) mRNA, which accumulates robustly during KSHV lytic infection and is not subjected to SOX-induced degradation. Here we reveal that the IL-6 mRNA contains a dominant, cis-acting ∼100-nucleotide element within its 3' untranslated region (UTR) that renders it directly refractory to cleavage by SOX. This element specifically interacts with a cellular protein complex both in SOX-transfected cells and in KSHV-infected B cells. Using a directed RNA pulldown approach, we identified two components of this complex to be the AU-rich element (ARE) binding proteins AUF1 and HuR. Depletion of these proteins significantly reduced the protective capacity of the IL-6 RNA element in SOX-expressing cells. These findings suggest that SOX activity may be directly counteracted by select RNA regulatory complexes and reveal a novel mechanism contributing to the robust expression of IL-6 during KSHV replication.

  2. Self-Assembly of Porphyrin-Paclitaxel Conjugates Into Nanomedicines: Enhanced Cytotoxicity due to Endosomal Escape.

    Science.gov (United States)

    Zheng, Xiaohua; Li, Zhensheng; Chen, Li; Xie, Zhigang; Jing, Xiabin

    2016-06-21

    Nanomedicines assembled directly from drug molecules possess several advantages, including precise molecular structure and high content of drugs. Herein, porphyrin-paclitaxel conjugates (Py-s-s-PTX) were synthesized by using a disulfide bond as a linker. The Py-s-s-PTX could self-assemble into nanoparticles (Py-s-s-PTX NPs) with a size of about 100 nm via disulfide-induced assembly. Py-s-s-PTX NPs are highly stable under biological conditions and could be destroyed in the presence of reducing agents as revealed by dynamic light scattering. The obtained Py-s-s-PTX NPs could be internalized by cancer cells via endocytosis and disassociated in the reducing cytoplasm, thus releasing PTX in cancer cells. Endosomal escape triggered upon irradiation could enhance the cytotoxicity of paclitaxel, and Py-s-s-PTX NPs possess cytotoxicity comparable to that of free PTX. We believe that this disulfide-assembled nanomedicine represents a new and important development for chemotherapy in cancer therapy. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Rapid Endolysosomal Escape and Controlled Intracellular Trafficking of Cell Surface Mimetic Quantum-Dots-Anchored Peptides and Glycopeptides.

    Science.gov (United States)

    Tan, Roger S; Naruchi, Kentaro; Amano, Maho; Hinou, Hiroshi; Nishimura, Shin-Ichiro

    2015-09-18

    A novel strategy for the development of a high performance nanoparticules platform was established by means of cell surface mimetic quantum-dots (QDs)-anchored peptides/glycopeptides, which was developed as a model system for nanoparticle-based drug delivery (NDD) vehicles with defined functions helping the specific intracellular trafficking after initial endocytosis. In this paper, we proposed a standardized protocol for the preparation of multifunctional QDs that allows for efficient cellular uptake and rapid escaping from the endolysosomal system and subsequent cytoplasmic molecular delivery to the target cellular compartment. Chemoselective ligation of the ketone-functionalized hexahistidine derivative facilitated both efficient endocytic entry and rapid endolysosomal escape of the aminooxy/phosphorylcholine self-assembled monolayer-coated QDs (AO/PCSAM-QDs) to the cytosol in various cell lines such as human normal and cancer cells, while modifications of these QDs with cell-penetrating arginine-rich peptides showed poor cellular uptake and induced self-aggregation of AO/PCSAM-QDs. Combined use of hexahistidylated AO/PCSAM-QDs with serglycine-like glycopeptides, namely synthetic proteoglycan initiators (PGIs), elicited the entry and controlled intracellular trafficking, Golgi localization, and also excretion of these nanoparticles, which suggested that the present approach would provide an ideal platform for the design of high performance NDD systems.

  4. Crew escape system (CES) testing with Astronaut Bagian in JSC WETF Bldg 29

    Science.gov (United States)

    1988-01-01

    Crew escape system (CES) testing and emergency escape training is conducted with Astronaut James P. Bagian in JSC Weightless Environment Training Facility (WETF) Bldg 29 pool. Bagian, wearing the newly designed (navy blue) launch and entry suit (LES), 'flips' off a pole protruding from a Space Shuttle side egress hatch mockup. The move was part of a rehearsal/ evaluation of the CES pole mode of emergency escape from the Space Shuttle. SCUBA-equipped divers, already in the pool, were on hand to assist with the exercise. In the background, technicians monitor test activity. Bagian wore gear like that to be supplied to each STS-26 crewmember and subsequent crews.

  5. CTL escape mediated by proteasomal destruction of an HIV-1 cryptic epitope.

    Directory of Open Access Journals (Sweden)

    Sylvain Cardinaud

    2011-05-01

    Full Text Available Cytotoxic CD8+ T cells (CTLs play a critical role in controlling viral infections. HIV-infected individuals develop CTL responses against epitopes derived from viral proteins, but also against cryptic epitopes encoded by viral alternative reading frames (ARF. We studied here the mechanisms of HIV-1 escape from CTLs targeting one such cryptic epitope, Q9VF, encoded by an HIVgag ARF and presented by HLA-B*07. Using PBMCs of HIV-infected patients, we first cloned and sequenced proviral DNA encoding for Q9VF. We identified several polymorphisms with a minority of proviruses encoding at position 5 an aspartic acid (Q9VF/5D and a majority encoding an asparagine (Q9VF/5N. We compared the prevalence of each variant in PBMCs of HLA-B*07+ and HLA-B*07- patients. Proviruses encoding Q9VF/5D were significantly less represented in HLA-B*07+ than in HLA-B*07- patients, suggesting that Q9FV/5D encoding viruses might be under selective pressure in HLA-B*07+ individuals. We thus analyzed ex vivo CTL responses directed against Q9VF/5D and Q9VF/5N. Around 16% of HLA-B*07+ patients exhibited CTL responses targeting Q9VF epitopes. The frequency and the magnitude of CTL responses induced with Q9VF/5D or Q9VF/5N peptides were almost equal indicating a possible cross-reactivity of the same CTLs on the two peptides. We then dissected the cellular mechanisms involved in the presentation of Q9VF variants. As expected, cells infected with HIV strains encoding for Q9VF/5D were recognized by Q9VF/5D-specific CTLs. In contrast, Q9VF/5N-encoding strains were neither recognized by Q9VF/5N- nor by Q9VF/5D-specific CTLs. Using in vitro proteasomal digestions and MS/MS analysis, we demonstrate that the 5N variation introduces a strong proteasomal cleavage site within the epitope, leading to a dramatic reduction of Q9VF epitope production. Our results strongly suggest that HIV-1 escapes CTL surveillance by introducing mutations leading to HIV ARF-epitope destruction by proteasomes.

  6. Salmonella enterica induces and subverts the plant immune system

    National Research Council Canada - National Science Library

    García, Ana V; Hirt, Heribert

    2014-01-01

    .... Recent reports shed light into the molecular interaction between plants and Salmonella, highlighting the defense pathways induced and the means used by the bacteria to escape the plant immune system...

  7. Plasma clouds and snowplows: Bulk plasma escape from Mars observed by MAVEN

    National Research Council Canada - National Science Library

    Halekas, J. S; Brain, D. A; Ruhunusiri, S; McFadden, J. P; Mitchell, D. L; Mazelle, C; Connerney, J. E. P; Harada, Y; Hara, T; Espley, J. R; DiBraccio, G.A; Jakosky, B. M

    2016-01-01

    ....” The ions in these clouds are unmagnetized or weakly magnetized, have velocities well above the escape speed, and lie directly downstream from magnetic field amplifications, suggesting a “snowplow” effect...

  8. Escaping the poverty trap: modeling the interplay between economic growth and the ecology of infectious disease

    CERN Document Server

    Goerg, Georg M; Hébert-Dufresne, Laurent; Althouse, Benjamin M

    2013-01-01

    The dynamics of economies and infectious disease are inexorably linked: economic well-being influences health (sanitation, nutrition, treatment capacity, etc.) and health influences economic well-being (labor productivity lost to sickness and disease). Often societies are locked into ``poverty traps'' of poor health and poor economy. Here, using a simplified coupled disease-economic model with endogenous capital growth we demonstrate the formation of poverty traps, as well as ways to escape them. We suggest two possible mechanisms of escape both motivated by empirical data: one, through an influx of capital (development aid), and another through changing the percentage of GDP spent on healthcare. We find that a large influx of capital is successful in escaping the poverty trap, but increasing health spending alone is not. Our results demonstrate that escape from a poverty trap may be possible, and carry important policy implications in the world-wide distribution of aid and within-country healthcare spending.

  9. Effect Of Feedback On The Escape Of Ionizing Radiation From High-Z Galaxies

    Science.gov (United States)

    Trebitsch, Maxime; Blaizot, Jérémy; Rosdahl, Joakim; Devriendt, Julien; Slyz, Adrianne

    2017-06-01

    Quantifying how much of the ionizing radiation produced in high-redshift galaxies escapes in the IGM is one of the main challenges in understanding the sources of reionization. We investigate the radiative properties of simulated low mass galaxies (halos of a few 109 Msun at z=6), where radiation is modelled on-the-fly, and different sources of feedback (from stars and AGN) are included. Using radiation-hydrodynamic simulations performed with Ramses-RT we study how the energy and momentum input from supernovae and black hole activity modulates the properties of the interstellar medium and therefore how, and how many, photons can escape from the galaxy. I will present simulations showing (Trebitsch et al. 2017, https://arxiv.org/abs/1705.00941) that stellar feedback has a pivotal role in regulating the escape fraction in dwarf galaxies. Supernovae carve holes in the gas distribution, through which ionizing photons can escape.

  10. Simple control laws for continuous-thrust escape or capture and their use in optimisation

    Science.gov (United States)

    Petropoulos, A. E.; Whiffen, G. J.; Sims, J. A.

    2002-01-01

    Interplanetary missions which use low-thrust, high specific impulse propulsion can further capitalise on the capabilities of the propulsion system by using it to effect escape from the launch body or capture at a target body.

  11. Effectiveness of using noncontingent escape for general behavior management in a pediatric dental clinic

    National Research Council Canada - National Science Library

    Allen, Keith D; Wallace, Dustin P

    2013-01-01

    ... (noncontingent escape) from ongoing dental treatment. Results demonstrated that the routine delivery of scheduled breaks from treatment significantly reduced the vocal and physical disruptive behavior and the need for restraint in a nonclinical sample...

  12. Escape windows to improve the size selectivity in the Baltic cod trawl fishery

    DEFF Research Database (Denmark)

    Madsen, Niels; Holst, René; Foldager, L.

    2002-01-01

    A rapid decrease of the stock of Baltic cod (Gadus morhua) has provided the incentive to improve the size selectivity in the trawl fishery. Use of escape windows is permitted in the legislation to give means of improving the size selectivity of cod as an alternative to a traditional standard codend....... The history of the use of escape windows in the Baltic Sea cod fishery is reviewed. The present escape windows do not function optimally. The objective of this new experiment was to compare an improved design of escape window, which is placed in the upper panel, with that of standard codend. Three standard...... tool to improve the size selectivity in the Baltic cod fishery is discussed. (C) 2002 Elsevier Science B.V. All rights reserved....

  13. Estimation of coho salmon escapement in the Ugashik lakes, Alaska Peninsula National Wildlife Refuge

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — From 26 July to 24 September 2002, hourly counts were conducted from counting towers to estimate the escapement of coho salmon Oncorhynchus kisutch into the Ugashik...

  14. Task as Reinforcer: a Reactive Alternative to Traditional Forms of Escape Extinction.

    Science.gov (United States)

    Ward, Steve; Parker, Amanda; Perdikaris, Angelina

    2017-03-01

    Inappropriate behaviors, ranging from passive resistance to physical aggression, property destruction, or self-injurious behavior frequently function for escape from or avoidance of non-preferred activities. Proactive procedures have been shown to be only moderately effective without the use of escape extinction, but escape extinction can produce negative side effects, and efforts have been made to find alternatives. The current study tested the efficacy of a reactive procedure that may serve as an alternative to traditional forms of escape extinction. In a multiple baseline across behavioral excesses, non-preferred activities, and participants, a timeout from the opportunity to work effectively reduced behavioral excesses and increased compliance with non-preferred activities. With one participant, a multiple baseline was implemented across instructional targets, resulting in an increased rate of skill acquisition after "wait outs" were introduced to each program.

  15. Escape and surveillance asymmetries in locusts exposed to a Guinea fowl-mimicking robot predator

    National Research Council Canada - National Science Library

    Donato Romano; Giovanni Benelli; Cesare Stefanini

    2017-01-01

    .... In this study, we investigated the lateralization of escape and surveillance responses in young instars and adults of Locusta migratoria during biomimetic interactions with a robot-predator inspired...

  16. Escape probability and mean residence time in random flows with unsteady drift

    Directory of Open Access Journals (Sweden)

    Brannan James R.

    2001-01-01

    Full Text Available We investigate fluid transport in random velocity fields with unsteady drift. First, we propose to quantify fluid transport between flow regimes of different characteristic motion, by escape probability and mean residence time. We then develop numerical algorithms to solve for escape probability and mean residence time, which are described by backward Fokker-Planck type partial differential equations. A few computational issues are also discussed. Finally, we apply these ideas and numerical algorithms to a tidal flow model.

  17. Escape factors for thermionic cathodes in atomic gases in a wide electric field range

    Science.gov (United States)

    Benilov, M. S.; Naidis, G. V.; Petrovic, Z. Lj; Radmilovic-Radjenovic, M.; Stojkovic, A.

    2006-07-01

    An approximate analytical expression is obtained for the escape factors for thermionically emitting cathodes in atomic gases that is uniformly valid at all values of the reduced electric field. This expression is used for evaluation of the escape factors in neon, helium and mercury. An independent evaluation is performed by means of Monte Carlo simulations. The analytical results are in good agreement with the results of Monte Carlo simulations, both for reflecting and non-reflecting cathodes.

  18. Escape factors for thermionic cathodes in atomic gases in a wide electric field range

    Energy Technology Data Exchange (ETDEWEB)

    Benilov, M S [Departamento de Fisica, Universidade da Madeira, Largo do MunicIpio, 9000 Funchal (Portugal); Naidis, G V [Institute for High Temperatures of the Russian Academy of Sciences, Izhorskaya 13/19, Moscow 125412 (Russian Federation); Petrovic, Z Lj [Institute of Physics, POB 68, 11080 Zemun, Belgrade (Serbia); Radmilovic-Radjenovic, M [Institute of Physics, POB 68, 11080 Zemun, Belgrade (Serbia); Stojkovic, A [Institute of Physics, POB 68, 11080 Zemun, Belgrade (Serbia)

    2006-07-21

    An approximate analytical expression is obtained for the escape factors for thermionically emitting cathodes in atomic gases that is uniformly valid at all values of the reduced electric field. This expression is used for evaluation of the escape factors in neon, helium and mercury. An independent evaluation is performed by means of Monte Carlo simulations. The analytical results are in good agreement with the results of Monte Carlo simulations, both for reflecting and non-reflecting cathodes.

  19. Influence of throat configuration and fish density on escapement of channel catfish from hoop nets

    Science.gov (United States)

    Porath, Mark T.; Pape, Larry D.; Richters, Lindsey K.

    2011-01-01

    In recent years, several state agencies have adopted the use of baited, tandemset hoop nets to assess lentic channel catfish Ictalurus punctatus populations. Some level of escapement from the net is expected because an opening exists in each throat of the net, although factors influencing rates of escapement from hoop nets have not been quantified. We conducted experiments to quantify rates of escapement and to determine the influence of throat configuration and fish density within the net on escapement rates. An initial experiment to determine the rate of escapement from each net compartment utilized individually tagged channel catfish placed within the entrance (between the two throats) and cod (within the second throat) compartments of a single hoop net for overnight sets. From this experiment, the mean rate (±SE) of channel catfish escaping was 4.2% (±1.5) from the cod (cod throat was additionally restricted from the traditionally manufactured product), and 74% (±4.2) from the entrance compartments. In a subsequent experiment, channel catfish were placed only in the cod compartment with different throat configurations (restricted or unrestricted) and at two densities (low [6 fish per net] and high [60 fish per net]) for overnight sets to determine the influence of fish density and throat configuration on escapement rates. Escapement rates between throat configurations were doubled at low fish density (13.3 ± 5.4% restricted versus 26.7 ± 5.6% unrestricted) and tripled at high fish density (14.3 ± 4.9% restricted versus 51.9 ± 5.0% unrestricted). These results suggest that retention efficiency is high from cod compartments with restricted throat entrances. However, managers and researchers need to be aware that modification to the cod throats (restrictions) is needed for hoop nets ordered from manufacturers. Managers need to be consistent in their use and reporting of cod end throat configurations when using this gear.

  20. Sesquinary Catenae on the Martian Satellite Phobos from Reaccretion of Escaping Ejecta

    Science.gov (United States)

    2016-08-30

    12591 | DOI: 10.1038/ncomms12591 | www.nature.com/naturecommunications 1 E jecta escaping from an impact on a natural satellite often goes into orbit ...impacts, but faster than the satellite escape velocity. Because they spend time in orbit they do not simply radiate from their primary crater as secondary...intermediate between vesc and the orbital velocity vorb. When the satellite is far from the planet, sesquinaries can produce primary- like crater morphology

  1. Telomerase Activity Is Sufficient To Allow Transformed Cells To Escape from Crisis

    OpenAIRE

    Halvorsen, Tanya L.; Leibowitz, Gil; Levine, Fred

    1999-01-01

    The introduction of simian virus 40 large T antigen (SVLT) into human primary cells enables them to proliferate beyond their normal replicative life span. In most cases, this temporary escape from senescence eventually ends in a second proliferative block known as “crisis,” during which the cells cease growing or die. Rare immortalization events in which cells escape crisis are frequently correlated with the presence of telomerase activity. We tested the hypothesis that telomerase activation ...

  2. Inhibition of chaotic escape from a potential well using small parametric modulations

    Energy Technology Data Exchange (ETDEWEB)

    Chacon, R. [Departamento de Electronica e Ingenieria Electromecanica, Escuela de Ingenierias Industriales, Universidad de Extremadura, 06071 Badajoz (Spain); Balibrea, F. [Departamento de Matematicas, Universidad de Murcia, Murcia (Spain); Lopez, M.A. [Departamento de Matematica Aplicada, Escuela Universitaria de Arquitectura Tecnica, Universidad de Castilla-La Mancha, 16002 Cuenca (Spain)

    1996-11-01

    It is shown theoretically for the first time that, depending on its period, amplitude, and initial phase, a periodic parametric modulation can suppress a chaotic escape from a potential well. The instance of the Helmholtz oscillator is used to demonstrate, by means of Melnikov{close_quote}s method, that parametric modulations of the linear or quadratic potential terms inhibit chaotic escape when certain resonance conditions are met. {copyright} {ital 1996 American Institute of Physics.}

  3. Hot oxygen escape from Mars: Simple scaling with solar EUV irradiance

    Science.gov (United States)

    Cravens, T. E.; Rahmati, A.; Fox, Jane L.; Lillis, R.; Bougher, S.; Luhmann, J.; Sakai, S.; Deighan, J.; Lee, Yuni; Combi, M.; Jakosky, B.

    2017-01-01

    The evolution of the atmosphere of Mars and the loss of volatiles over the lifetime of the solar system is a key topic in planetary science. An important loss process for atomic species, such as oxygen, is ionospheric photochemical escape. Dissociative recombination of O2+ ions (the major ion species) produces fast oxygen atoms, some of which can escape from the planet. Many theoretical hot O models have been constructed over the years, although a number of uncertainties are present in these models, particularly concerning the elastic cross sections of O atoms with CO2. Recently, the Mars Atmosphere and Volatile Evolution mission has been rapidly improving our understanding of the upper atmosphere and ionosphere of Mars and its interaction with the external environment (e.g., solar wind), allowing a new assessment of this important loss process. The purpose of the current paper is to take a simple analytical approach to the oxygen escape problem in order to (1) study the role that variations in solar radiation or solar wind fluxes could have on escape in a transparent fashion and (2) isolate the effects of uncertainties in oxygen cross sections on the derived oxygen escape rates. In agreement with several more elaborate numerical models, we find that the escape flux is directly proportional to the incident solar extreme ultraviolet irradiance and is inversely proportional to the backscatter elastic cross section. The amount of O lost due to ion transport in the topside ionosphere is found to be about 5-10% of the total.

  4. Scaling invariance for the escape of particles from a periodically corrugated waveguide

    Energy Technology Data Exchange (ETDEWEB)

    Leonel, Edson D., E-mail: edleonel@rc.unesp.br [Departamento de Estatística, Matemática Aplicada e Computação, UNESP – Univ Estadual Paulista, Av. 24A, 1515, CEP 13506-900, Rio Claro, SP (Brazil); Costa, Diogo R. da [Departamento de Estatística, Matemática Aplicada e Computação, UNESP – Univ Estadual Paulista, Av. 24A, 1515, CEP 13506-900, Rio Claro, SP (Brazil); Instituto de Física, Univ São Paulo, Rua do Matão, Cidade Universitária, CEP 05314-970, São Paulo, SP (Brazil); Dettmann, Carl P. [School of Mathematics, University of Bristol, Bristol BS8 1TW (United Kingdom)

    2012-01-09

    The escape dynamics of a classical light ray inside a corrugated waveguide is characterised by the use of scaling arguments. The model is described via a two-dimensional nonlinear and area preserving mapping. The phase space of the mapping contains a set of periodic islands surrounded by a large chaotic sea that is confined by a set of invariant tori. When a hole is introduced in the chaotic sea, letting the ray escape, the histogram of frequency of the number of escaping particles exhibits rapid growth, reaching a maximum value at n{sub p} and later decaying asymptotically to zero. The behaviour of the histogram of escape frequency is characterised using scaling arguments. The scaling formalism is widely applicable to critical phenomena and useful in characterisation of phase transitions, including transitions from limited to unlimited energy growth in two-dimensional time varying billiard problems. -- Highlights: ► Escape of light ray inside a corrugated waveguide ► Two-dimensional nonlinear and area preserving mapping ► Scaling for escaping particles.

  5. Multiple HIV-1 infection of cells and the evolutionary dynamics of cytotoxic T lymphocyte escape mutants.

    Science.gov (United States)

    Wodarz, Dominik; Levy, David N

    2009-09-01

    Cytotoxic T lymphocytes (CTL) are an important branch of the immune system, killing virus-infected cells. Many viruses can mutate so that infected cells are not killed by CTL anymore. This escape can contribute to virus persistence and disease. A prominent example is HIV-1. The evolutionary dynamics of CTL escape mutants in vivo have been studied experimentally and mathematically, assuming that a cell can only be infected with one HIV particle at a time. However, according to data, multiple virus particles frequently infect the same cell, a process called coinfection. Here, we study the evolutionary dynamics of CTL escape mutants in the context of coinfection. A mathematical model suggests that an intermediate strength of the CTL response against the wild-type is most detrimental for an escape mutant, minimizing overall virus load and even leading to its extinction. A weaker or, paradoxically, stronger CTL response against the wild-type both lead to the persistence of the escape mutant and higher virus load. It is hypothesized that an intermediate strength of the CTL response, and thus the suboptimal virus suppression observed in HIV-1 infection, might be adaptive to minimize the impact of existing CTL escape mutants on overall virus load.

  6. Lobelia siphilitica Plants That Escape Herbivory in Time Also Have Reduced Latex Production

    Science.gov (United States)

    Parachnowitsch, Amy L.; Caruso, Christina M.; Campbell, Stuart A.; Kessler, André

    2012-01-01

    Flowering phenology is an important determinant of a plant’s reproductive success. Both assortative mating and niche construction can result in the evolution of correlations between phenology and other reproductive, functional, and life history traits. Correlations between phenology and herbivore defence traits are particularly likely because the timing of flowering can allow a plant to escape herbivory. To test whether herbivore escape and defence are correlated, we estimated phenotypic and genetic correlations between flowering phenology and latex production in greenhouse-grown Lobelia siphilitica L. (Lobeliaceae). Lobelia siphilitica plants that flower later escape herbivory by a specialist pre-dispersal seed predator, and thus should invest fewer resources in defence. Consistent with this prediction, we found that later flowering was phenotypically and genetically correlated with reduced latex production. To test whether herbivore escape and latex production were costly, we also measured four fitness correlates. Flowering phenology was negatively genetically correlated with three out of four fitness estimates, suggesting that herbivore escape can be costly. In contrast, we did not find evidence for costs of latex production. Generally, our results suggest that herbivore escape and defence traits will not evolve independently in L. siphilitica. PMID:22662205

  7. Resveratrol-3-O-glucuronide and resveratrol-4’-O-glucuronide reduce DNA strand breakage but not apoptosis in Jurkat T cells treated with camptothecin

    Science.gov (United States)

    Resveratrol has been reported to inhibit or induce DNA damage depending upon the type of cell and experimental conditions. Dietary resveratrol is present in the body mostly as metabolites and little is known about the activities of these metabolic products. We evaluated physiologically obtainable ...

  8. The relationship between migration and development in the ESCAP region.

    Science.gov (United States)

    Skeldon, R

    1991-01-01

    The relationship between migration and development in the ESCAP region including southeast and south Asian countries and the Pacific island of Fiji, Papua New Guinea, Vanuatu, Kiribati, Samoa, and the Solomon Islands is discussed in terms of mobility transition and origin and destination factors. The changing patterns of mobility in Asia are further delineated in the discussion of internal movements and international movement. Emigration in the smaller countries of the Pacific are treated separately. Future predictions are that the Asia Pacific region will experience continued fertility decline and stabilization of low rates over the next 20 years. The declines will result in slow labor force growth, and increased demand for labor in traditional core and neocore countries as defined and presented in table form by Friedman will be heightened. International movements are likely to increase in large urban areas within destination countries. Tokyo and Singapore are the principal cities in Asia. Tokyo by restrictive government policy has limited immigration, but future labor shortages of unskilled labor from southeast Asia and China are expected. Singapore is already dependent on foreign labor by 10%. Current labor shortages have led to the creation of a growth triangle between Singapore, Indonesia, and Malaysia. Other cities expected to emerge as primary cities in international regional complexes with spillover into the hinterlands include the Hong Kong, Guangzhou, and Macau triangle in the Pearl River delta, Taipei and Seoul, and possibly Kuala Lumpur. Internal migration is expected to increase in the capital cities of Bangkok, Manila,j and centers such as Shanghai, Beijing, and other large cities of southeast Asia. These cities will be linked through the flows of skilled international migrants, which began in the 1960s and is expected to become a future major flow. Recreational and resource niches will be left in much of the Pacific, the Himalayan Kingdoms, and

  9. Multiple transmissions of a stable human leucocyte antigen-B27 cytotoxic T-cell-escape strain of HIV-1 in The Netherlands.

    Science.gov (United States)

    Cornelissen, Marion; Hoogland, Frederik M; Back, Nicole K T; Jurriaans, Suzanne; Zorgdrager, Fokla; Bakker, Margreet; Brinkman, Kees; Prins, Maria; van der Kuyl, Antoinette C

    2009-07-31

    The evolution of HIV-1 is largely shaped by the cytotoxic T-cell (CTL) response of the host as encoded by the human leucocyte antigen (HLA) genes. Certain HLA-B alleles can delay disease progression, but it is uncertain whether this protection will sustain or whether the virus is in the process of adaptation. In The Netherlands, HLA-B27 is moderately prevalent (approximately 8-16% of HLA-B alleles). If adaptation to HLA-B alleles is in progress, virus strains carrying escape mutations to HLA-B27 should appear in the epidemic by now. A subtype B HIV-1 strain carrying a HLA-B27 CTL-escape mutation in the main Gag-p24 KK10 epitope, R264G, together with a compensatory mutation outside this epitope, E260D, was detected in four patients from Amsterdam, The Netherlands, by sequence analysis of the gag gene. The patients were a drug user and three men who have sex with men, and were infected with HIV-1 between 2002 and 2008. Characterization and evolutionary analysis of the HIV-1 CTL-escape strain was done by sequence analysis of serial blood plasma samples. The mutations involved were stable during follow-up and after transmission, also in two individuals lacking HLA-B27. The finding that a stable HLA-B27 CTL-escape strain is circulating in The Netherlands has important implications for the understanding of virus-host interactions and vaccine design alike. Vaccines targeted at inducing a CTL response might easily be circumvented by the virus. Also, patients carrying protective HLA alleles might not be protected anymore from disease progression in the future.

  10. Applying antibody-sensitive hypervariable region 1-deleted hepatitis C virus to the study of escape pathways of neutralizing human monoclonal antibody AR5A

    Science.gov (United States)

    Velázquez-Moctezuma, Rodrigo; Bukh, Jens

    2017-01-01

    Hepatitis C virus (HCV) is a major cause of end-stage liver diseases. With 3–4 million new HCV infections yearly, a vaccine is urgently needed. A better understanding of virus escape from neutralizing antibodies and their corresponding epitopes are important for this effort. However, for viral isolates with high antibody resistance, or antibodies with moderate potency, it remains challenging to induce escape mutations in vitro. Here, as proof-of-concept, we used antibody-sensitive HVR1-deleted (ΔHVR1) viruses to generate escape mutants for a human monoclonal antibody, AR5A, targeting a rare cross-genotype conserved epitope. By analyzing the genotype 1a envelope proteins (E1/E2) of recovered Core-NS2 recombinant H77/JFH1ΔHVR1 and performing reverse genetic studies we found that resistance to AR5A was caused by substitution L665W, also conferring resistance to the parental H77/JFH1. The mutation did not induce viral fitness loss, but abrogated AR5A binding to HCV particles and intracellular E1/E2 complexes. Culturing J6/JFH1ΔHVR1 (genotype 2a), for which fitness was decreased by L665W, with AR5A generated AR5A-resistant viruses with the substitutions I345V, L665S, and S680T, which we introduced into J6/JFH1 and J6/JFH1ΔHVR1. I345V increased fitness but had no effect on AR5A resistance. L665S impaired fitness and decreased AR5A sensitivity, while S680T combined with L665S compensated for fitness loss and decreased AR5A sensitivity even further. Interestingly, S680T alone had no fitness effect but sensitized the virus to AR5A. Of note, H77/JFH1L665S was non-viable. The resistance mutations did not affect cell-to-cell spread or E1/E2 interactions. Finally, introducing L665W, identified in genotype 1, into genotypes 2–6 parental and HVR1-deleted variants (not available for genotype 4a) we observed diverse effects on viral fitness and a universally pronounced reduction in AR5A sensitivity. Thus, we were able to take advantage of the neutralization-sensitive HVR1

  11. Escaping Lyman Continuum in Strongly Lensed Galaxies at z=2.0-2.5

    Science.gov (United States)

    Fan, Xiaohui

    2013-10-01

    We propose to obtain deep WFC3 UVIS channel near ultraviolet {NUV} images of a sample of 6 bright lensed galaxies at z = 2.0 - 2.5 to detect the escaping Lyman continuum {LyC} radiation in order to study the physical properties of the LyC emitting region and the evolution of ionizing photon escape fraction with redshift. The LyC escape fraction is a key parameter in determining the contribution of star-forming galaxies to UV ionization background and to the cosmic reionization. It is, however, poorly constrained with conflicting results. In this proposal, we will use the observations of the brightest lensed galaxies {r<21.0} to provide accurate measurement of escape fraction in high-redshift galaxies, sensitive to the flux ratio between intergalactic medium corrected LyC and 1500A of as low as 0.5-3% in individual galaxies, and 0.2% when stacking all galaxies. In addition, lensing effect will allow us to probe a wide range of intrinsic luminosity {-20.5escape geometry. We will correlate LyC properties with physical properties of the lensed galaxies provided by existing deep HST imaging and ground-based near-IR spectroscopy to constrain physical models of LyC escape mechanism. Our sample will also fill the gap of the redshift range between 2.0 - 2.5 that has not been probed in previous works, allowing study of the evolution of escape fraction in the redshift range of z = 1 to 3.5.

  12. Temporal and ontogenetic variation in the escape response of Ameiva festiva (Squamata, Teiidae

    Directory of Open Access Journals (Sweden)

    Lattanzio

    2014-08-01

    Full Text Available Several factors have been shown to affect lizard escape behavior (flight initiation distance or FID, the distance between predator and prey when the prey initiates escape. Patterns of daily activity, such as foraging or movement behavior, vary with respect to time of day, supporting that escape responses may vary temporally as well. However, there remains scant information regarding the effects of time of day on FID. During peak activity, FID may decrease due to increased cost of giving up resources (e.g., prey or potential mates. An alternative hypothesis is that FID may increase because lizard activity in general may serve to alert a predator in advance of its approach. A lizard in this scenario may be favored to flee sooner rather than later. Moreover, juvenile and adult lizards of multiple species may differ in behavioral, ecological, and morphological traits that could influence escape decisions. I tested the effects of time of day (in 30-min intervals and age (juvenile or adult on the FID of a tropical whiptail lizard, Ameiva festiva in Costa Rica. I found that A. festiva escape responses varied with time of day such that in general, their FID decreased throughout the day. In addition, I observed a peak in FID from mid to late-morning that matches published estimates of peak activity times for A. festiva. Overall, juvenile A. festiva initiated an escape response sooner than adults, which may be related to differences in perceived risk associated with differences in size and predator experience between the two age groups. I conclude that escape responses may be contingent on both the activity level of the animal at the time of approach and its age.

  13. Unsteady motion: escape jumps in planktonic copepods, their kinematics and energetics

    Science.gov (United States)

    Kiørboe, Thomas; Andersen, Anders; Langlois, Vincent J.; Jakobsen, Hans H.

    2010-01-01

    We describe the kinematics of escape jumps in three species of 0.3–3.0 mm-sized planktonic copepods. We find similar kinematics between species with periodically alternating power strokes and passive coasting and a resulting highly fluctuating escape velocity. By direct numerical simulations, we estimate the force and power output needed to accelerate and overcome drag. Both are very high compared with those of other organisms, as are the escape velocities in comparison to startle velocities of other aquatic animals. Thus, the maximum weight-specific force, which for muscle motors of other animals has been found to be near constant at 57 N (kg muscle)−1, is more than an order of magnitude higher for the escaping copepods. We argue that this is feasible because most copepods have different systems for steady propulsion (feeding appendages) and intensive escapes (swimming legs), with the muscular arrangement of the latter probably adapted for high force production during short-lasting bursts. The resulting escape velocities scale with body length to power 0.65, different from the size-scaling of both similar sized and larger animals moving at constant velocity, but similar to that found for startle velocities in other aquatic organisms. The relative duration of the pauses between power strokes was observed to increase with organism size. We demonstrate that this is an inherent property of swimming by alternating power strokes and pauses. We finally show that the Strouhal number is in the range of peak propulsion efficiency, again suggesting that copepods are optimally designed for rapid escape jumps. PMID:20462876

  14. Escape Excel: A tool for preventing gene symbol and accession conversion errors.

    Science.gov (United States)

    Welsh, Eric A; Stewart, Paul A; Kuenzi, Brent M; Eschrich, James A

    2017-01-01

    Microsoft Excel automatically converts certain gene symbols, database accessions, and other alphanumeric text into dates, scientific notation, and other numerical representations. These conversions lead to subsequent, irreversible, corruption of the imported text. A recent survey of popular genomic literature estimates that one-fifth of all papers with supplementary gene lists suffer from this issue. Here, we present an open-source tool, Escape Excel, which prevents these erroneous conversions by generating an escaped text file that can be safely imported into Excel. Escape Excel is implemented in a variety of formats (http://www.github.com/pstew/escape_excel), including a command line based Perl script, a Windows-only Excel Add-In, an OS X drag-and-drop application, a simple web-server, and as a Galaxy web environment interface. Test server implementations are accessible as a Galaxy interface (http://apostl.moffitt.org) and simple non-Galaxy web server (http://apostl.moffitt.org:8000/). Escape Excel detects and escapes a wide variety of problematic text strings so that they are not erroneously converted into other representations upon importation into Excel. Examples of problematic strings include date-like strings, time-like strings, leading zeroes in front of numbers, and long numeric and alphanumeric identifiers that should not be automatically converted into scientific notation. It is hoped that greater awareness of these potential data corruption issues, together with diligent escaping of text files prior to importation into Excel, will help to reduce the amount of Excel-corrupted data in scientific analyses and publications.

  15. Escape Excel: A tool for preventing gene symbol and accession conversion errors.

    Directory of Open Access Journals (Sweden)

    Eric A Welsh

    Full Text Available Microsoft Excel automatically converts certain gene symbols, database accessions, and other alphanumeric text into dates, scientific notation, and other numerical representations. These conversions lead to subsequent, irreversible, corruption of the imported text. A recent survey of popular genomic literature estimates that one-fifth of all papers with supplementary gene lists suffer from this issue.Here, we present an open-source tool, Escape Excel, which prevents these erroneous conversions by generating an escaped text file that can be safely imported into Excel. Escape Excel is implemented in a variety of formats (http://www.github.com/pstew/escape_excel, including a command line based Perl script, a Windows-only Excel Add-In, an OS X drag-and-drop application, a simple web-server, and as a Galaxy web environment interface. Test server implementations are accessible as a Galaxy interface (http://apostl.moffitt.org and simple non-Galaxy web server (http://apostl.moffitt.org:8000/.Escape Excel detects and escapes a wide variety of problematic text strings so that they are not erroneously converted into other representations upon importation into Excel. Examples of problematic strings include date-like strings, time-like strings, leading zeroes in front of numbers, and long numeric and alphanumeric identifiers that should not be automatically converted into scientific notation. It is hoped that greater awareness of these potential data corruption issues, together with diligent escaping of text files prior to importation into Excel, will help to reduce the amount of Excel-corrupted data in scientific analyses and publications.

  16. MAVEN Imaging UV Spectrograph Results on the Mars Atmosphere and Atmospheric Escape

    Science.gov (United States)

    Chaffin, Michael; Schneider, Nick; McClintock, Bill; Stewart, Ian; Deighan, Justin; Jain, Sonal; Clarke, John; Holsclaw, Greg; Montmessin, Franck; Lefevre, Franck; Chaufray, Jean-Yves; Stiepen, Arnaud; Crismani, Matteo; Mayyasi, Majd; Evans, Scott; Stevens, Mike; Yelle, Roger; Jakosky, Bruce

    2016-04-01

    The Imaging Ultraviolet Spectrograph (IUVS) is one of nine science instruments aboard the Mars Atmosphere and Volatile and EvolutioN (MAVEN) spacecraft, whose payload is dedicated to exploring the upper atmosphere of Mars and understanding the magnitude and drivers of Mars' atmospheric escape rate. IUVS uses ultraviolet light to investigate the lower and upper atmosphere and ionosphere of Mars. The instrument is among the most powerful spectrographs sent to another planet, with several key capabilities: (1) separate Far-UV & Mid-UV channels for stray light control, (2) a high resolution echelle mode to resolve deuterium and hydrogen emission, (3) internal instrument pointing and scanning capabilities to allow complete mapping and nearly continuous operation, and (4) optimization for airglow studies. IUVS, along with other MAVEN instruments, obtains a comprehensive picture of the current state of the Mars upper atmosphere and ionosphere and the processes that control atmospheric escape. We present an overview of selected IUVS results, including (1) the discovery of diffuse aurora at Mars, and its contrast with previously detected discrete aurora localized near crustal magnetic fields; (2) widespread detection of mesospheric clouds; (3) Significant seasonal and short-timescale variability in thermospheric composition; (4) Global ozone maps spanning six months of seasonal evolution; and (5) mapping of the Mars H and O coronas, deriving the escape rates of H and O and their variability. This last is of particular importance for understanding the long term evolution of Mars and its atmosphere, with the observed preset escape of H potentially capable of removing a large fraction of Mars' initial water inventory, and the differential escape of O relative to H potentially providing a net source of oxidizing power to the atmosphere and planet at present, in contrast with a photochemical theory that predicts stoichiometrically balanced escape. The atmospheric and escape

  17. Role of AmiA in the morphological transition of Helicobacter pylori and in immune escape.

    Directory of Open Access Journals (Sweden)

    Catherine Chaput

    2006-09-01

    Full Text Available The human gastric pathogen Helicobacter pylori is responsible for peptic ulcers and neoplasia. Both in vitro and in the human stomach it can be found in two forms, the bacillary and coccoid forms. The molecular mechanisms of the morphological transition between these two forms and the role of coccoids remain largely unknown. The peptidoglycan (PG layer is a major determinant of bacterial cell shape, and therefore we studied H. pylori PG structure during the morphological transition. The transition correlated with an accumulation of the N-acetyl-D-glucosaminyl-beta(1,4-N-acetylmuramyl-L-Ala-D-Glu (GM-dipeptide motif. We investigated the molecular mechanisms responsible for the GM-dipeptide motif accumulation, and studied the role of various putative PG hydrolases in this process. Interestingly, a mutant strain with a mutation in the amiA gene, encoding a putative PG hydrolase, was impaired in accumulating the GM-dipeptide motif and transforming into coccoids. We investigated the role of the morphological transition and the PG modification in the biology of H. pylori. PG modification and transformation of H. pylori was accompanied by an escape from detection by human Nod1 and the absence of NF-kappaB activation in epithelial cells. Accordingly, coccoids were unable to induce IL-8 secretion by AGS gastric epithelial cells. amiA is, to our knowledge, the first genetic determinant discovered to be required for this morphological transition into the coccoid forms, and therefore contributes to modulation of the host response and participates in the chronicity of H. pylori infection.

  18. Hydrogen escape from Mars enhanced by deep convection in dust storms

    Science.gov (United States)

    Heavens, Nicholas G.; Kleinböhl, Armin; Chaffin, Michael S.; Halekas, Jasper S.; Kass, David M.; Hayne, Paul O.; McCleese, Daniel J.; Piqueux, Sylvain; Shirley, James H.; Schofield, John T.

    2018-02-01

    Present-day water loss from Mars provides insight into Mars's past habitability1-3. Its main mechanism is thought to be Jeans escape of a steady hydrogen reservoir sourced from odd-oxygen reactions with near-surface water vapour2, 4,5. The observed escape rate, however, is strongly variable and correlates poorly with solar extreme-ultraviolet radiation flux6-8, which was predicted to modulate escape9. This variability has recently been attributed to hydrogen sourced from photolysed middle atmospheric water vapour10, whose vertical and seasonal distribution is only partly characterized and understood11-13. Here, we report multi-annual observational estimates of water content and dust and water transport to the middle atmosphere from Mars Climate Sounder data. We provide strong evidence that the transport of water vapour and ice to the middle atmosphere by deep convection in Martian dust storms can enhance hydrogen escape. Planet-encircling dust storms can raise the effective hygropause (where water content rapidly decreases to effectively zero) from 50 to 80 km above the areoid (the reference equipotential surface). Smaller dust storms contribute to an annual mode in water content at 40-50 km that may explain seasonal variability in escape. Our results imply that Martian atmospheric chemistry and evolution can be strongly affected by the meteorology of the lower and middle atmosphere of Mars.

  19. Escape and surveillance asymmetries in locusts exposed to a Guinea fowl-mimicking robot predator.

    Science.gov (United States)

    Romano, Donato; Benelli, Giovanni; Stefanini, Cesare

    2017-10-09

    Escape and surveillance responses to predators are lateralized in several vertebrate species. However, little is known on the laterality of escapes and predator surveillance in arthropods. In this study, we investigated the lateralization of escape and surveillance responses in young instars and adults of Locusta migratoria during biomimetic interactions with a robot-predator inspired to the Guinea fowl, Numida meleagris. Results showed individual-level lateralization in the jumping escape of locusts exposed to the robot-predator attack. The laterality of this response was higher in L. migratoria adults over young instars. Furthermore, population-level lateralization of predator surveillance was found testing both L. migratoria adults and young instars; locusts used the right compound eye to oversee the robot-predator. Right-biased individuals were more stationary over left-biased ones during surveillance of the robot-predator. Individual-level lateralization could avoid predictability during the jumping escape. Population-level lateralization may improve coordination in the swarm during specific group tasks such as predator surveillance. To the best of our knowledge, this is the first report of lateralized predator-prey interactions in insects. Our findings outline the possibility of using biomimetic robots to study predator-prey interaction, avoiding the use of real predators, thus achieving standardized experimental conditions to investigate complex and flexible behaviours.

  20. How Hospitable Are Space Weather Affected Habitable Zones? The Role of Ion Escape

    Science.gov (United States)

    Airapetian, Vladimir S.; Glocer, Alex; Khazanov, George V.; Loyd, R. O. P.; France, Kevin; Sojka, Jan; Danchi, William C.; Liemohn, Michael W.

    2017-02-01

    Atmospheres of exoplanets in the habitable zones around active young G-K-M stars are subject to extreme X-ray and EUV (XUV) fluxes from their host stars that can initiate atmospheric erosion. Atmospheric loss affects exoplanetary habitability in terms of surface water inventory, atmospheric pressure, the efficiency of greenhouse warming, and the dosage of the UV surface irradiation. Thermal escape models suggest that exoplanetary atmospheres around active K-M stars should undergo massive hydrogen escape, while heavier species including oxygen will accumulate forming an oxidizing atmosphere. Here, we show that non-thermal oxygen ion escape could be as important as thermal, hydrodynamic H escape in removing the constituents of water from exoplanetary atmospheres under supersolar XUV irradiation. Our models suggest that the atmospheres of a significant fraction of Earth-like exoplanets around M dwarfs and active K stars exposed to high XUV fluxes will incur a significant atmospheric loss rate of oxygen and nitrogen, which will make them uninhabitable within a few tens to hundreds of Myr, given a low replenishment rate from volcanism or cometary bombardment. Our non-thermal escape models have important implications for the habitability of the Proxima Centauri’s terrestrial planet.

  1. Enhanced Endosomal Escape by Light-Fueled Liquid-Metal Transformer.

    Science.gov (United States)

    Lu, Yue; Lin, Yiliang; Chen, Zhaowei; Hu, Quanyin; Liu, Yang; Yu, Shuangjiang; Gao, Wei; Dickey, Michael D; Gu, Zhen

    2017-04-12

    Effective endosomal escape remains as the "holy grail" for endocytosis-based intracellular drug delivery. To date, most of the endosomal escape strategies rely on small molecules, cationic polymers, or pore-forming proteins, which are often limited by the systemic toxicity and lack of specificity. We describe here a light-fueled liquid-metal transformer for effective endosomal escape-facilitated cargo delivery via a chemical-mechanical process. The nanoscale transformer can be prepared by a simple approach of sonicating a low-toxicity liquid-metal. When coated with graphene quantum dots (GQDs), the resulting nanospheres demonstrate the ability to absorb and convert photoenergy to drive the simultaneous phase separation and morphological transformation of the inner liquid-metal core. The morphological transformation from nanospheres to hollow nanorods with a remarkable change of aspect ratio can physically disrupt the endosomal membrane to promote endosomal escape of payloads. This metal-based nanotransformer equipped with GQDs provides a new strategy for facilitating effective endosomal escape to achieve spatiotemporally controlled drug delivery with enhanced efficacy.

  2. The escape velocity curve of the Milky Way in modified Newtonian dynamics

    Science.gov (United States)

    Banik, Indranil; Zhao, Hongsheng

    2018-01-01

    We determine the escape velocity from the Milky Way (MW) at a range of Galactocentric radii in the context of modified Newtonian dynamics (MOND). Due to its non-linear nature, escape is possible if the MW is considered embedded in a constant external gravitational field (EF) from distant objects. We model this situation using a fully self-consistent method based on a direct solution of the governing equations out to several thousand disc scalelengths. We try out a range of EF strengths and mass models for the MW in an attempt to match the escape velocity measurements of Williams et al. (2017). A reasonable match is found if the EF on the MW is {˜} 0.03 a_{_0}, towards the higher end of the range considered. Our models include a hot gas corona surrounding the MW, but our results suggest that this should have a very low mass of ˜2 × 1010 M⊙ to avoid pushing the escape velocity too high. Our analysis favours a slightly lower baryonic disc mass than the ˜7 × 1010 M⊙ required to explain its rotation curve in MOND. However, given the uncertainties, MOND is consistent with both the locally measured amplitude of the MW rotation curve and its escape velocity over Galactocentric distances of 8-50 kpc.

  3. Fractionation of terrestrial neon by hydrodynamic hydrogen escape from ancient steam atmospheres

    Science.gov (United States)

    Zahnle, K.

    Atmospheric neon is isotopically heavier than mantle neon. By contrast, nonradiogenic mantle Ar, Kr, and Xe are not known to differ from the atmosphere. These observations are most easily explained by selective neon loss to space; however, neon is much too massive to escape from the modern atmosphere. Steam atmospheres are a likely, if intermittent, feature of the accreting Earth. They occur because, on average, the energy liberated during accretion places Earth above the runaway greenhouse threshold, so that liquid water is not stable at the surface. It is found that steam atmospheres should have lasted some ten to fifty million years. Hydrogen escape would have been vigorous, but abundant heavy constituents would have been retained. There is no lack of plausible candidates; CO2, N2, or CO could all suffice. Neon can escape because it is less massive than any of the likely pollutants. Neon fractionation would have been a natural byproduct. Assuming that the initial Ne-20/Ne-22 ratio was solar, it was found that it would have taken some ten million years to effect the observed neon fractionation in a 30 bar steam atmosphere fouled with 10 bars of CO. Thicker atmospheres would have taken longer; less CO, shorter. This mechanism for fractionating neon has about the right level of efficiency. Because the lighter isotope escapes much more readily, total neon loss is pretty minimal; less than half of the initial neon endowment escapes.

  4. Hypoxia promotes tumor growth in linking angiogenesis to immune escape

    Directory of Open Access Journals (Sweden)

    Salem eCHOUAIB

    2012-02-01

    Full Text Available Despite the impressive progress over the past decade, in the field of tumor immunology, such as the identification of tumor antigens and antigenic peptides as potential targets, there are still many obstacles in eliciting an effective immune response to eradicate cancer. It has become increasingly clear that tumor microenvironment plays a crucial role in the control of immune protection and contains many overlapping mechanisms to evade antigen specific immunotherapy. Obviously, tumors have evolved to utilize hypoxic stress to their own advantage by activating key biochemical and cellular pathways that are important in progression, survival and metastasis. Among the hypoxia-induced genes, hypoxia-inducible factor (HIF-1 and vascular endothelial growth factor (VEGF play a determinant role in promoting tumor cell growth and survival. In this regard, hypoxia is emerging as an attractive target for cancer therapy. How the microenvironmental hypoxia poses both obstacles and opportunities for new therapeutic immune interventions will be discussed.

  5. Inter- vs intra-individual variation and temporal repeatability of escape responses in the coral reef fish Amblyglyphidodon curacao

    Directory of Open Access Journals (Sweden)

    Maïwenn Jornod

    2015-11-01

    Full Text Available Fast-start escape responses are critical behaviours used by fishes during predator-prey encounters and some interactions with hetero- and conspecifics. In experimental studies, escape responses are often measured once per individual and considered representative of maximum performance. However, few studies have compared variability and repeatability in escape performances within and among individuals. Using the tropical damselfish Amblyglyphidodon curacao, we quantified inter- and intra-individual variation in behavioural and kinematic components of escape performance during repeated presentations of a stimulus at 15 min intervals. Individual maximum escape performance was repeatable through time, but there was considerable variation in the magnitude of responses both among and within fish. We found no evidence of habituation or fatigue due to repeated stimulations, suggesting that fish can be stimulated multiple times to ensure that an accurate estimate of maximum escape performance is obtained.

  6. Double Plant Homeodomain Fingers 2 (DPF2) Promotes the Immune Escape of Influenza Virus by Suppressing Beta Interferon Production.

    Science.gov (United States)

    Shin, Dongjo; Lee, Jihye; Park, Ji Hoon; Min, Ji-Young

    2017-06-15

    The high mutation rates of the influenza virus genome facilitate the generation of viral escape mutants, rendering vaccines and drugs against influenza virus-encoded targets potentially ineffective. Therefore, we identified host cell determinants dispensable for the host but crucial for virus replication, with the goal of preventing viral escape and finding effective antivirals. To identify these host factors, we screened 2,732 human genes using RNA interference and focused on one of the identified host factors, the double plant homeodomain fingers 2 (DPF2/REQ) gene, for this study. We found that knockdown of DPF2 in cells infected with influenza virus resulted in decreased expression of viral proteins and RNA. Furthermore, production of progeny virus was reduced by two logs in the multiple-cycle growth kinetics assay. We also found that DPF2 was involved in the replication of seasonal influenza A and B viruses. Because DPF2 plays a crucial role in the noncanonical NF-κB pathway, which negatively regulates type I interferon (IFN) induction, we examined the relationship between DPF2 and IFN responses during viral infection. The results showed that knockdown of DPF2 resulted in increased expression of IFN-β and induced phosphorylation of STAT1 in infected cells. In addition, high levels of several cytokines/chemokines (interleukin-8 [IL-8], IP-10, and IL-6) and antiviral proteins (MxA and ISG56) were produced by DPF2 knockdown cells. In conclusion, we identified a novel host factor, DPF2, that is required for influenza virus to evade the host immune response and that may serve as a potential antiviral target.IMPORTANCE Influenza virus is responsible for seasonal epidemics and occasional pandemics and is an ongoing threat to public health worldwide. Influenza virus relies heavily on cellular factors to complete its life cycle. Here we identified a novel host factor, DPF2, which is involved in influenza virus infection. Our results showed that DPF2 plays a crucial

  7. Inter- vs intra-individual variation and temporal repeatability of escape responses in the coral reef fish Amblyglyphidodon curacao

    OpenAIRE

    Maïwenn Jornod; Roche, Dominique G.

    2015-01-01

    ABSTRACT Fast-start escape responses are critical behaviours used by fishes during predator-prey encounters and some interactions with hetero- and conspecifics. In experimental studies, escape responses are often measured once per individual and considered representative of maximum performance. However, few studies have compared variability and repeatability in escape performances within and among individuals. Using the tropical damselfish Amblyglyphidodon curacao, we quantified inter- and in...

  8. Multi-stress resistance in Lactococcus lactis is actually escape from purine-induced stress sensitivity

    DEFF Research Database (Denmark)

    Ryssel, Mia; Hviid, Anne-Mette Meisner; Dawish, Mohamed S.

    2014-01-01

    Multi-stress resistance is a widely documented and fascinating phenotype of lactococci where single mutations, preferentially in genes involved in nucleotide metabolism and phosphate uptake, result in elevated tolerance to multiple stresses simultaneously. In this report, we have analysed...

  9. Expression of Fas ligand by human gastric adenocarcinomas: a potential mechanism of immune escape in stomach cancer.

    LENUS (Irish Health Repository)

    Bennett, M W

    2012-02-03

    BACKGROUND: Despite being immunogenic, gastric cancers overcome antitumour immune responses by mechanisms that have yet to be fully elucidated. Fas ligand (FasL) is a molecule that induces Fas receptor mediated apoptosis of activated immunocytes, thereby mediating normal immune downregulatory roles including immune response termination, tolerance acquisition, and immune privilege. Colon cancer cell lines have previously been shown to express FasL and kill lymphoid cells by Fas mediated apoptosis in vitro. Many diverse tumours have since been found to express FasL suggesting that a "Fas counterattack" against antitumour immune effector cells may contribute to tumour immune escape. AIM: To ascertain if human gastric tumours express FasL in vivo, as a potential mediator of immune escape in stomach cancer. SPECIMENS: Thirty paraffin wax embedded human gastric adenocarcinomas. METHODS: FasL protein was detected in gastric tumours using immunohistochemistry; FasL mRNA was detected in the tumours using in situ hybridisation. Cell death was detected in situ in tumour infiltrating lymphocytes using terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL). RESULTS: Prevalent expression of FasL was detected in all 30 resected gastric adenocarcinomas examined. In the tumours, FasL protein and mRNA were co-localised to neoplastic gastric epithelial cells, confirming expression by the tumour cells. FasL expression was independent of tumour stage, suggesting that it may be expressed throughout gastric cancer progression. TUNEL staining disclosed a high level of cell death among lymphocytes infiltrating FasL positive areas of tumour. CONCLUSIONS: Human gastric adenocarcinomas express the immune downregulatory molecule, FasL. The results suggest that FasL is a prevalent mediator of immune privilege in stomach cancer.

  10. Increased transcapillary escape rate of albumin in type 1 (insulin-dependent) diabetic patients with microalbuminuria

    DEFF Research Database (Denmark)

    Feldt-Rasmussen, B

    1986-01-01

    The transcapillary escape rate, intravascular mass and outflux of albumin were measured in 75 Type 1 (insulin-dependent) diabetic patients. The groups were defined as: group 1: normal urinary albumin excretion, less than 30 mg/24 h (n = 21); group 2: microalbuminuria, 30-300 mg/24 h (n = 36); group...... 3: diabetic nephropathy, less than 300 mg/24 h (n = 18). Fifteen sex- and age-matched non-diabetic persons served as control subjects. The diabetes duration was: group 1: 20 +/- 9 years, group 2: 17 +/- 5 years, group 3: 19 +/- 7 years. The transcapillary escape rate of albumin was similar...... vascular leakage of albumin is an early event in the development of diabetic nephropathy, with the leakage of albumin being fully developed in the microalbuminuric patient. In contrast, long-term diabetic patients with normal urinary albumin excretion have a normal transcapillary escape rate of albumin....

  11. HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment.

    Science.gov (United States)

    Edén, Arvid; Fuchs, Dietmar; Hagberg, Lars; Nilsson, Staffan; Spudich, Serena; Svennerholm, Bo; Price, Richard W; Gisslén, Magnus

    2010-12-15

    Occasional cases of viral escape in cerebrospinal fluid (CSF) despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA have been reported. We investigated CSF viral escape in subjects treated with commonly used antiretroviral therapy regimens in relation to intrathecal immune activation and central nervous system penetration effectiveness (CPE) rank. Sixty-nine neurologically asymptomatic subjects treated with antiretroviral therapy >6 months and plasma HIV-1 RNA penetration effectiveness rank was not a significant predictor of detectable CSF virus or CSF neopterin levels. Viral escape in CSF is more common than previously reported, suggesting that low-grade central nervous system infection may continue in treated patients. Although these findings need extension in longitudinal studies, they suggest the utility of monitoring CSF responses, as new treatment combinations and strategies modify clinical practice.

  12. Quantifying the escape mortality of trawl caught Antarctic krill (Euphausia superba)

    DEFF Research Database (Denmark)

    Krafft, Bjørn A; Krag, Ludvig Ahm; Engås, Arill

    2016-01-01

    Antarctic krill (Euphausia superba) is an abundant fishery resource, the harvest levels of which are expected to increase. However, many of the length classes of krill can escape through commonly used commercial trawl mesh sizes. A vital component of the overall management of a fishery is to esti......Antarctic krill (Euphausia superba) is an abundant fishery resource, the harvest levels of which are expected to increase. However, many of the length classes of krill can escape through commonly used commercial trawl mesh sizes. A vital component of the overall management of a fishery...... is to estimate the total fishing mortality and quantify the mortality rate of individuals that escape from fishing gear. The methods for determining fishing mortality in krill are still poorly developed. We used a covered codend sampling technique followed by onboard observations made in holding tanks to monitor...

  13. European policymaking on the tobacco advertising ban: the importance of escape routes.

    Science.gov (United States)

    Adamini, Sandra; Versluis, Esther; Maarse, Hans

    2011-01-01

    This article analyses the European Union policymaking process regarding tobacco advertising. While others already highlighted the importance of intergovernmental bargaining between member states to explain the outcome of the tobacco advertising case, the main aim of this article is to identify the use of escape routes by the Commission, the European Parliament, the Council and interest groups that played an important role in overcoming the deadlock. When looking at the different institutions that structure policymaking, we argue that indeed focusing on escape routes provides a clear insight in the process and in what strategies were necessary to 'make Europe work'. In the end, it appears to be a combination of escape routes that resulted in the final decision.

  14. Thermoresponsive pegylated bubble liposome nanovectors for efficient siRNA delivery via endosomal escape

    KAUST Repository

    Alamoudi, Kholod

    2017-05-19

    Improving the delivery of siRNA into cancer cells via bubble liposomes. Designing a thermoresponsive pegylated liposome through the introduction of ammonium bicarbonate salt into liposomes so as to control their endosomal escape for gene therapy.A sub-200 nm nanovector was fully characterized and examined for cellular uptake, cytotoxicity, endosomal escape and gene silencing.The siRNA-liposomes were internalized into cancer cells within 5 min and then released siRNAs in the cytosol prior to lysosomal degradation upon external temperature elevation. This was confirmed by confocal bioimaging and gene silencing reaching up to 90% and further demonstrated by the protein inhibition of both target genes.The thermoresponsiveness of ammonium bicarbonate containing liposomes enabled the rapid endosomal escape of the particles and resulted in an efficient gene silencing.

  15. Modelling the spread of HIV immune escape mutants in a vaccinated population.

    Science.gov (United States)

    Fryer, Helen R; McLean, Angela R

    2011-12-01

    Because cytotoxic T-lymphocytes (CTLs) have been shown to play a role in controlling human immunodeficiency virus (HIV) infection and because CTL-based simian immunodeficiency virus (SIV) vaccines have proved effective in non-human primates, one goal of HIV vaccine design is to elicit effective CTL responses in humans. Such a vaccine could improve viral control in patients who later become infected, thereby reducing onwards transmission and enhancing life expectancy in the absence of treatment. The ability of HIV to evolve mutations that evade CTLs and the ability of these 'escape mutants' to spread amongst the population poses a challenge to the development of an effective and robust vaccine. We present a mathematical model of within-host evolution and between-host transmission of CTL escape mutants amongst a population receiving a vaccine that elicits CTL responses to multiple epitopes. Within-host evolution at each epitope is represented by the outgrowth of escape mutants in hosts who restrict the epitope and their reversion in hosts who do not restrict the epitope. We use this model to investigate how the evolution and spread of escape mutants could affect the impact of a vaccine. We show that in the absence of escape, such a vaccine could markedly reduce the prevalence of both infection and disease in the population. However the impact of such a vaccine could be significantly abated by CTL escape mutants, especially if their selection in hosts who restrict the epitope is rapid and their reversion in hosts who do not restrict the epitope is slow. We also use the model to address whether a vaccine should span a broad or narrow range of CTL epitopes and target epitopes restricted by rare or common HLA types. We discuss the implications and limitations of our findings. © 2011 Fryer, McLean.

  16. Escape of O(3P), O(1D), and O(1S) from the Martian atmosphere

    Science.gov (United States)

    Fox, Jane L.; Hać, Aleksander B.

    2018-01-01

    We have computed here the escape probabilities, fluxes and rates for hot O atoms that are initially produced in the ground state and the first two excited metastable states, O(1D)and O(1S), in the Martian thermosphere by dissociative recombination of O2+. In order to compare our results with those of our previous calculations and with those of others, we have employed here the pre-MAVEN models that we have used previously. To compute the escape probabilities, we have employed the Monte Carlo escape code that has been described previously, but we here use for the first time energy-dependent elastic cross sections for collisions of the energetic O atoms with each of the twelve background species in our model. We also incorporate three mechanisms that interchange identities of the O(3P) and O(1D) atoms, including collisional excitation of O(3P) to O(1D), quenching of O(1D) to O(3P), and excitation exchange of O(1D) with O(3P). We find that the escape probabilities of O atoms that are produced initially as O(1D) are reduced compared to those in which these processes are not included, but the escape probabilities of O atoms that are initially produced as O(3P) are not significantly reduced. As a guide for our future research and those of other investigators, we review here what is known about the interactions of O atoms with other species in which the energies of the O atoms are altered, and several other sources of hot and escaping O, many of which have been suggested by other investigators. We will incorporate these data in a future MAVEN-like model.

  17. Generalized Jeans' Escape of Pick-Up Ions in Quasi-Linear Relaxation

    Science.gov (United States)

    Moore, T. E.; Khazanov, G. V.

    2011-01-01

    Jeans escape is a well-validated formulation of upper atmospheric escape that we have generalized to estimate plasma escape from ionospheres. It involves the computation of the parts of particle velocity space that are unbound by the gravitational potential at the exobase, followed by a calculation of the flux carried by such unbound particles as they escape from the potential well. To generalize this approach for ions, we superposed an electrostatic ambipolar potential and a centrifugal potential, for motions across and along a divergent magnetic field. We then considered how the presence of superthermal electrons, produced by precipitating auroral primary electrons, controls the ambipolar potential. We also showed that the centrifugal potential plays a small role in controlling the mass escape flux from the terrestrial ionosphere. We then applied the transverse ion velocity distribution produced when ions, picked up by supersonic (i.e., auroral) ionospheric convection, relax via quasi-linear diffusion, as estimated for cometary comas [1]. The results provide a theoretical basis for observed ion escape response to electromagnetic and kinetic energy sources. They also suggest that super-sonic but sub-Alfvenic flow, with ion pick-up, is a unique and important regime of ion-neutral coupling, in which plasma wave-particle interactions are driven by ion-neutral collisions at densities for which the collision frequency falls near or below the gyro-frequency. As another possible illustration of this process, the heliopause ribbon discovered by the IBEX mission involves interactions between the solar wind ions and the interstellar neutral gas, in a regime that may be analogous [2].

  18. Increased transcapillary escape rate of albumin and IgG in essential hypertension

    DEFF Research Database (Denmark)

    Parving, H H; Jensen, H A; Westrup, M

    1977-01-01

    Transcapillary escape rates of albumin and IgG (fractions of intravascular mass of albumin and IgG that pass to the extravascular space per unit time) were determined simultaneously from the initial disappearance of intravenously injected 131I human albumin and 125I human IgG in seven untreated...... subjects suffering from essential hypertension. The average mean arterial blood pressure of these subjects 193/119 mmHg; four subjects had grade I-III funduscopic changes. Transcapillary escape rates of albumin (TERalb) and IgG (TERIgG) were found significantly increased in the hypertensive subjects...

  19. The Shigella flexneri type 3 secretion system is required for tyrosine kinase-dependent protrusion resolution, and vacuole escape during bacterial dissemination.

    Science.gov (United States)

    Kuehl, Carole J; Dragoi, Ana-Maria; Agaisse, Hervé

    2014-01-01

    Shigella flexneri is a human pathogen that triggers its own entry into intestinal cells and escapes primary vacuoles to gain access to the cytosolic compartment. As cytosolic and motile bacteria encounter the cell cortex, they spread from cell to cell through formation of membrane protrusions that resolve into secondary vacuoles in adjacent cells. Here, we examined the roles of the Type 3 Secretion System (T3SS) in S. flexneri dissemination in HT-29 intestinal cells infected with the serotype 2a strain 2457T. We generated a 2457T strain defective in the expression of MxiG, a central component of the T3SS needle apparatus. As expected, the ΔmxiG strain was severely affected in its ability to invade HT-29 cells, and expression of mxiG under the control of an arabinose inducible expression system (ΔmxiG/pmxiG) restored full infectivity. In this experimental system, removal of the inducer after the invasion steps (ΔmxiG/pmxiG (Ara withdrawal)) led to normal actin-based motility in the cytosol of HT-29 cells. However, the time spent in protrusions until vacuole formation was significantly increased. Moreover, the number of formed protrusions that failed to resolve into vacuoles was also increased. Accordingly, the ΔmxiG/pmxiG (Ara withdrawal) strain failed to trigger tyrosine phosphorylation in membrane protrusions, a signaling event that is required for the resolution of protrusions into vacuoles. Finally, the ΔmxiG/pmxiG (Ara withdrawal) strain failed to escape from the formed secondary vacuoles, as previously reported in non-intestinal cells. Thus, the T3SS system displays multiple roles in S. flexneri dissemination in intestinal cells, including the tyrosine kinase signaling-dependent resolution of membrane protrusions into secondary vacuoles, and the escape from the formed secondary vacuoles.

  20. The Shigella flexneri type 3 secretion system is required for tyrosine kinase-dependent protrusion resolution, and vacuole escape during bacterial dissemination.

    Directory of Open Access Journals (Sweden)

    Carole J Kuehl

    Full Text Available Shigella flexneri is a human pathogen that triggers its own entry into intestinal cells and escapes primary vacuoles to gain access to the cytosolic compartment. As cytosolic and motile bacteria encounter the cell cortex, they spread from cell to cell through formation of membrane protrusions that resolve into secondary vacuoles in adjacent cells. Here, we examined the roles of the Type 3 Secretion System (T3SS in S. flexneri dissemination in HT-29 intestinal cells infected with the serotype 2a strain 2457T. We generated a 2457T strain defective in the expression of MxiG, a central component of the T3SS needle apparatus. As expected, the ΔmxiG strain was severely affected in its ability to invade HT-29 cells, and expression of mxiG under the control of an arabinose inducible expression system (ΔmxiG/pmxiG restored full infectivity. In this experimental system, removal of the inducer after the invasion steps (ΔmxiG/pmxiG (Ara withdrawal led to normal actin-based motility in the cytosol of HT-29 cells. However, the time spent in protrusions until vacuole formation was significantly increased. Moreover, the number of formed protrusions that failed to resolve into vacuoles was also increased. Accordingly, the ΔmxiG/pmxiG (Ara withdrawal strain failed to trigger tyrosine phosphorylation in membrane protrusions, a signaling event that is required for the resolution of protrusions into vacuoles. Finally, the ΔmxiG/pmxiG (Ara withdrawal strain failed to escape from the formed secondary vacuoles, as previously reported in non-intestinal cells. Thus, the T3SS system displays multiple roles in S. flexneri dissemination in intestinal cells, including the tyrosine kinase signaling-dependent resolution of membrane protrusions into secondary vacuoles, and the escape from the formed secondary vacuoles.

  1. Development of an Ionic Liquid-Based Ultrasonic/Microwave-Assisted Simultaneous Distillation and Extraction Method for Separation of Camptothecin, 10-Hydroxycamptothecin, Vincoside-Lactam, and Essential Oils from the Fruits of Camptotheca acuminata Decne

    Directory of Open Access Journals (Sweden)

    Chunjian Zhao

    2016-10-01

    Full Text Available An ionic liquid-based ultrasonic/microwave-assisted simultaneous distillation and extraction (IL-UMASDE method for isolating camptothecin (CPT, 10-hydroxycamptothecin (HCPT, vincoside-lactam (VCS-LT, and essential oils (EOs from Camptotheca acuminata Decne fruits was developed. The important parameters were optimized using single-factor and central composite design experiments. The optimum conditions were 0.75 M 1-octyl-3-methylimidazolium ([C8mim]Br as the extraction solvent, a liquid–solid ratio of 13.7 mL/g, an extraction time of 33.2 min, a microwave power of 582 W, and a fixed ultrasonic power of 50 W. The yields of CPT, HCPT, and VCS-LT obtained under the optimum conditions were 2.463, 0.164, and 0.297 mg/g, respectively; these are 1.08-, 1.12-, and 1.04-fold higher, respectively, than those obtained by conventional 55% ethanol heat reflux extraction (HRE. The extraction time for the equilibrium yields of CPT, HCPT and VCS-LT using IL-UMASDE was 33.6%, 58.5%, 63.1%, and 66.8%, respectively, less than the corresponding times using IL-MASDE, IL-ultrasonic-assisted extraction (IL-UAE, 55% ethanol UAE and 55% ethanol HRE. The yield of EOs obtained using IL-UMASDE was 0.793 mg/g, i.e., 1.31-fold higher than that obtained by conventional hydrodistillation extraction (HDE. The components of the EOs obtained using IL-UMASDE and HDE were similar. The extraction time for the equilibrium yields of EOs using IL-UMASDE is 33.6%, 58.5%, 52.6%, and 72.3% lower than those for IL-MASDE, water-UMASDE, water-MASDE, and HDE, respectively. Compared with other extraction methods, IL-UMASDE gave the highest yields of CPT, HCPT, VCS-LT, and EOs and also had the shortest extraction time. IL-UMASDE is a potential green and highly efficient technique for the extraction of CPT, HCPT, VCS-LT, and EOs from Camptotheca acuminata Decne fruits.

  2. Loss of MYC confers resistance to doxorubicin-induced apoptosis by preventing the activation of multiple serine protease- and caspase-mediated pathways

    DEFF Research Database (Denmark)

    Grassilli, Emanuela; Ballabeni, Andrea; Maellaro, Emilia

    2004-01-01

    -MYC null cells we confirm and extend recent reports showing a c-Myc requirement for the induction of apoptosis by a number of anticancer agents. In particular, we show that c-Myc is required for the induction of apoptosis by doxorubicin and etoposide, whereas it is not required for camptothecin......-induced cell death. We have investigated the molecular mechanisms involved in executing doxorubicin-induced apoptosis and show caspase-3 activation by both mitochondria-dependent and -independent pathways. Moreover, serine proteases participate in doxorubicin-induced apoptosis partly by contributing to caspase......-3 activation. Finally, a complete rescue from doxorubicin-induced apoptosis is obtained only when serine proteases, caspase-3, and mitochondrial activation are inhibited simultaneously. Interestingly, doxorubicin requires c-Myc for the activation of all of these pathways. Our findings therefore...

  3. The schedule-dependent enhanced cytotoxic activity of 7-ethyl-10-hydroxy-camptothecin (SN-38) in combination with Gefitinib (Iressa, ZD1839).

    Science.gov (United States)

    Azzariti, Amalia; Xu, Jian-Ming; Porcelli, Letizia; Paradiso, Angelo

    2004-07-01

    The combination of the topoisomerase I (Topo I) inhibitor CPT-11 with the anti-epidermal growth factor receptor (EGFR) agent Gefitinib (Iressa, ZD1839) represents a promising medical approach for colorectal cancer patients. In this report, we provide pre-clinical evidences for their optimal combination schedule in HT-29 and LoVo human colon cancer cell lines. We analyzed the different effects that three different combination schedules of SN-38 (the active CPT-11 metabolite) and Gefitinib (Gefitinib before; Gefitinib simultaneously; Gefitinib after SN-38) have on cell growth, cell cycle, apoptosis, and expression/phosphorylation of EGFR, Topo I and some steps of the signal transduction pathway. We first determined the IC(50) of each drug choosing the 5 days exposure for Gefitinib (0.6 and 3.8 microM for LoVo and HT-29 cells, respectively) and 1 day exposure for SN-38 (0.31 and 0.5 microM for LoVo and HT-29 cells, respectively). The different drug combination schedules were tested in various concentrations by using equiactive concentrations of the two drugs. The cytotoxicity of Gefitinib and SN-38 combination was schedule- and concentration-dependent but not cell line-specific. The most synergistic schedule was Gefitinib given after SN-38, with combination indexes (CI) of 0.007 and 0.454 in HT-29 and LoVo, respectively. Analysis of bio-molecular targets showed that Gefitinib was able to modulate SN-38 ability to inhibit Topo I, to accumulate cells in S-phase, and to induce apoptosis. Interestingly, SN-38 was able to activate EGFR and its signal transduction pathway. Confirming preliminary clinical experience of Gefitinib with other cytotoxic drugs, it seems that Gefitinib after SN-38 represents the best cytotoxic combination schedule but the biomolecular basis for this synergism remain to be completely elucidated.

  4. Quantifying factors determining the rate of CTL escape and reversion during acute and chronic phases of HIV infection

    Energy Technology Data Exchange (ETDEWEB)

    Ganusov, Vitaly V [Los Alamos National Laboratory; Korber, Bette M [Los Alamos National Laboratory; Perelson, Alan S [Los Alamos National Laboratory

    2009-01-01

    Human immunodeficiency virus (HIV) often evades cytotoxic T cell (CTL) responses by generating variants that are not recognized by CTLs. However, the importance and quantitative details of CTL escape in humans are poorly understood. In part, this is because most studies looking at escape of HIV from CTL responses are cross-sectional and are limited to early or chronic phases of the infection. We use a novel technique of single genome amplification (SGA) to identify longitudinal changes in the transmitted/founder virus from the establishment of infection to the viral set point at 1 year after the infection. We find that HIV escapes from virus-specific CTL responses as early as 30-50 days since the infection, and the rates of viral escapes during acute phase of the infection are much higher than was estimated in previous studies. However, even though with time virus acquires additional escape mutations, these late mutations accumulate at a slower rate. A poor correlation between the rate of CTL escape in a particular epitope and the magnitude of the epitope-specific CTL response suggests that the lower rate of late escapes is unlikely due to a low efficacy of the HIV-specific CTL responses in the chronic phase of the infection. Instead, our results suggest that late and slow escapes are likely to arise because of high fitness cost to the viral replication associated with such CTL escapes. Targeting epitopes in which virus escapes slowly or does not escape at all by CTL responses may, therefore, be a promising direction for the development of T cell based HIV vaccines.

  5. CD8+ T cells from HLA-B*57 elite suppressors effectively suppress replication of HIV-1 escape mutants.

    Science.gov (United States)

    Pohlmeyer, Christopher W; Buckheit, Robert W; Siliciano, Robert F; Blankson, Joel N

    2013-12-12

    Elite Controllers or Suppressors (ES) are HIV-1 positive individuals who maintain plasma viral loads below the limit of detection of standard clinical assays without antiretroviral therapy. Multiple lines of evidence suggest that the control of viral replication in these patients is due to a strong and specific cytotoxic T lymphocyte (CTL) response. The ability of CD8+ T cells to control HIV-1 replication is believed to be impaired by the development of escape mutations. Surprisingly, viruses amplified from the plasma of ES have been shown to contain multiple escape mutations, and it is not clear how immunologic control is maintained in the face of virologic escape. We investigated the effect of escape mutations within HLA*B-57-restricted Gag epitopes on the CD8+ T cell mediated suppression of HIV-1 replication. Using site directed mutagenesis, we constructed six NL4-3 based viruses with canonical escape mutations in one to three HLA*B-57-restricted Gag epitopes. Interestingly, similar levels of CTL-mediated suppression of replication in autologous primary CD4+ T cells were observed for all of the escape mutants. Intracellular cytokine staining was performed in order to determine the mechanisms involved in the suppression of the escape variants. While low baseline CD8+ T cells responses to wild type and escape variant peptides were seen, stimulation of PBMC with either wild type or escape variant peptides resulted in increased IFN-γ and perforin expression. These data presented demonstrate that CD8+ T cells from ES are capable of suppressing replication of virus harboring escape mutations in HLA-B*57-restricted Gag epitopes. Additionally, our data suggest that ES CD8+ T cells are capable of generating effective de novo responses to escape mutants.

  6. Exposure to Melan-A/MART-126-35 tumor epitope specific CD8(+)T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS).

    Science.gov (United States)

    Ebstein, Frédéric; Keller, Martin; Paschen, Annette; Walden, Peter; Seeger, Michael; Bürger, Elke; Krüger, Elke; Schadendorf, Dirk; Kloetzel, Peter-M; Seifert, Ulrike

    2016-05-04

    Efficient processing of target antigens by the ubiquitin-proteasome-system (UPS) is essential for treatment of cancers by T cell therapies. However, immune escape due to altered expression of IFN-γ-inducible components of the antigen presentation machinery and consequent inefficient processing of HLA-dependent tumor epitopes can be one important reason for failure of such therapies. Here, we show that short-term co-culture of Melan-A/MART-1 tumor antigen-expressing melanoma cells with Melan-A/MART-126-35-specific cytotoxic T lymphocytes (CTL) led to resistance against CTL-induced lysis because of impaired Melan-A/MART-126-35 epitope processing. Interestingly, deregulation of p97/VCP expression, which is an IFN-γ-independent component of the UPS and part of the ER-dependent protein degradation pathway (ERAD), was found to be essentially involved in the observed immune escape. In support, our data demonstrate that re-expression of p97/VCP in Melan-A/MART-126-35 CTL-resistant melanoma cells completely restored immune recognition by Melan-A/MART-126-35 CTL. In conclusion, our experiments show that impaired expression of IFN-γ-independent components of the UPS can exert rapid immune evasion of tumor cells and suggest that tumor antigens processed by distinct UPS degradation pathways should be simultaneously targeted in T cell therapies to restrict the likelihood of immune evasion due to impaired antigen processing.

  7. Applying antibody-sensitive hypervariable region 1-deleted hepatitis C virus to the study of escape pathways of neutralizing human monoclonal antibody AR5A

    DEFF Research Database (Denmark)

    Velazquez-Moctezuma, Rodrigo; Law, Mansun; Bukh, Jens

    2017-01-01

    isolates with high antibody resistance, or antibodies with moderate potency, it remains challenging to induce escape mutations in vitro. Here, as proof-of-concept, we used antibody-sensitive HVR1-deleted (ΔHVR1) viruses to generate escape mutants for a human monoclonal antibody, AR5A, targeting a rare....... The mutation did not induce viral fitness loss, but abrogated AR5A binding to HCV particles and intracellular E1/E2 complexes. Culturing J6/JFH1ΔHVR1 (genotype 2a), for which fitness was decreased by L665W, with AR5A generated AR5A-resistant viruses with the substitutions I345V, L665S, and S680T, which we...... effect but sensitized the virus to AR5A. Of note, H77/JFH1L665S was non-viable. The resistance mutations did not affect cell-to-cell spread or E1/E2 interactions. Finally, introducing L665W, identified in genotype 1, into genotypes 2–6 parental and HVR1-deleted variants (not available for genotype 4a) we...

  8. Exposure to Melan-A/MART-126-35 tumor epitope specific CD8+T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS)

    Science.gov (United States)

    Ebstein, Frédéric; Keller, Martin; Paschen, Annette; Walden, Peter; Seeger, Michael; Bürger, Elke; Krüger, Elke; Schadendorf, Dirk; Kloetzel, Peter-M.; Seifert, Ulrike

    2016-01-01

    Efficient processing of target antigens by the ubiquitin-proteasome-system (UPS) is essential for treatment of cancers by T cell therapies. However, immune escape due to altered expression of IFN-γ-inducible components of the antigen presentation machinery and consequent inefficient processing of HLA-dependent tumor epitopes can be one important reason for failure of such therapies. Here, we show that short-term co-culture of Melan-A/MART-1 tumor antigen-expressing melanoma cells with Melan-A/MART-126-35-specific cytotoxic T lymphocytes (CTL) led to resistance against CTL-induced lysis because of impaired Melan-A/MART-126-35 epitope processing. Interestingly, deregulation of p97/VCP expression, which is an IFN-γ-independent component of the UPS and part of the ER-dependent protein degradation pathway (ERAD), was found to be essentially involved in the observed immune escape. In support, our data demonstrate that re-expression of p97/VCP in Melan-A/MART-126-35 CTL-resistant melanoma cells completely restored immune recognition by Melan-A/MART-126-35 CTL. In conclusion, our experiments show that impaired expression of IFN-γ-independent components of the UPS can exert rapid immune evasion of tumor cells and suggest that tumor antigens processed by distinct UPS degradation pathways should be simultaneously targeted in T cell therapies to restrict the likelihood of immune evasion due to impaired antigen processing. PMID:27143649

  9. Low-energy gamma-ray spectroscopy using an X-ray-escape gated proportional counter

    DEFF Research Database (Denmark)

    Gregers Hansen, P.; Nielsen, H.L.; Williams, E.T.

    1965-01-01

    The utility of a gas-filled proportional counter in low-energy γ spectroscopy is greatly increased if it is operated in coincidence with an escaping fluorescent X-ray. An apparatus, having an efficiency greater than 10% of singles, is described and several examples are given. An efficiency curve...

  10. Race as/and the Trace of the Ghost: Jurisprudential Escapism ...

    African Journals Online (AJOL)

    Secondly, how the escape from those legal texts evinces, or perhaps even facilitated, a certain evasion of, or anxiety towards the horizontal application of the Bill of Rights which explicitly proscribes overt (racial) discrimination by private non-state actors. And thirdly, how by following a formalist legal approach, one in which ...

  11. Enhanced escape rate for Hg 254 nm resonance radiation in fluorescent lamps

    Science.gov (United States)

    Lawler, James E.; Raizen, Mark G.

    2013-10-01

    The potential of the low-cost MAGIS isotopic separation method to improve fluorescent lamp efficacy is explored using resonance radiation transport simulations. New Hg isotopic mixes are discovered that yield escape rates for 254 nm Hg I resonance radiation equal to 117% to 122% of the rate for a natural isotopic mix under the same lamp conditions.

  12. The RAVE survey: the Galactic escape speed and the mass of the Milky Way

    NARCIS (Netherlands)

    Piffl, T.; Scannapieco, C.; Binney, J.; Steinmetz, M.; Scholz, R.-D.; Williams, M. E. K.; de Jong, R. S.; Kordopatis, G.; Matijevič, G.; Bienaymé, O.; Bland-Hawthorn, J.; Boeche, C.; Freeman, K.; Gibson, B.; Gilmore, G.; Grebel, E. K.; Helmi, A.; Munari, U.; Navarro, J. F.; Parker, Q.; Reid, W. A.; Seabroke, G.; Watson, F.; Wyse, R. F. G.; Zwitter, T.

    We made new estimates of the Galactic escape speed at various Galactocentric radii using the latest data release of the RAdial Velocity Experiment (RAVE DR4). Compared to previous studies we have a database that is larger by a factor of 10, as well as reliable distance estimates for almost all

  13. The Applicability of the Beall-Panton MMPI Escape Index to Female Felons.

    Science.gov (United States)

    Scott, Norman A.

    1980-01-01

    Tested the discrimination of the MMPI Beall-Panton escape index by applying it to a sample of minimum security incarcerated female felons. The index did not differentiate significantly between escapees and nonescapees. Differentiation between the groups did occur when MMPI clinical and validity scales were considered separately. (Author)

  14. Extended exposure to elevated temperature affects escape response behaviour in coral reef fishes

    Directory of Open Access Journals (Sweden)

    Donald T. Warren

    2017-08-01

    Full Text Available The threat of predation, and the prey’s response, are important drivers of community dynamics. Yet environmental temperature can have a significant effect on predation avoidance techniques such as fast-start performance observed in marine fishes. While it is known that temperature increases can influence performance and behaviour in the short-term, little is known about how species respond to extended exposure during development. We produced a startle response in two species of damselfish, the lemon damsel Pomacentrus moluccensis, and the Ambon damselfish Pomacentrus amboinensis, by the repeated use of a drop stimulus. We show that the length of thermal exposure of juveniles to elevated temperature significantly affects this escape responses. Short-term (4d exposure to warmer temperature affected directionality and responsiveness for both species. After long-term (90d exposure, only P. moluccensis showed beneficial plasticity, with directionality returning to control levels. Responsiveness also decreased in both species, possibly to compensate for higher temperatures. There was no effect of temperature or length of exposure on latency to react, maximum swimming speed, or escape distance suggesting that the physical ability to escape was maintained. Evidence suggests that elevated temperature may impact some fish species through its effect on the behavioural responses while under threat rather than having a direct influence on their physical ability to perform an effective escape response.

  15. Self-consciousness and binge eating in college women : an escape from rumination?

    NARCIS (Netherlands)

    Dalley, Simon; Donofrio, Stacey

    2014-01-01

    Background: Binge-eating is a highly distressing symptom that has been found to co-occur with other symptoms of eating disorders such as bulimia nervosa. One perspective of binge eating is that it is an attempt to escape high levels of aversive self-consciousness. A primary aim of this study is to

  16. Identification of a peptide-pheromone that enhances Listeria monocytogenes escape from host cell vacuoles.

    Science.gov (United States)

    Xayarath, Bobbi; Alonzo, Francis; Freitag, Nancy E

    2015-03-01

    Listeria monocytogenes is a Gram-positive facultative intracellular bacterial pathogen that invades mammalian cells and escapes from membrane-bound vacuoles to replicate within the host cell cytosol. Gene products required for intracellular bacterial growth and bacterial spread to adjacent cells are regulated by a transcriptional activator known as PrfA. PrfA becomes activated following L. monocytogenes entry into host cells, however the signal that stimulates PrfA activation has not yet been defined. Here we provide evidence for L. monocytogenes secretion of a small peptide pheromone, pPplA, which enhances the escape of L. monocytogenes from host cell vacuoles and may facilitate PrfA activation. The pPplA pheromone is generated via the proteolytic processing of the PplA lipoprotein secretion signal peptide. While the PplA lipoprotein is dispensable for pathogenesis, bacteria lacking the pPplA pheromone are significantly attenuated for virulence in mice and have a reduced efficiency of bacterial escape from the vacuoles of nonprofessional phagocytic cells. Mutational activation of PrfA restores virulence and eliminates the need for pPplA-dependent signaling. Experimental evidence suggests that the pPplA peptide may help signal to L. monocytogenes its presence within the confines of the host cell vacuole, stimulating the expression of gene products that contribute to vacuole escape and facilitating PrfA activation to promote bacterial growth within the cytosol.

  17. Tips, techniques, and suggestions for improving learning from escaped prescribed fire reviews (Poster Abstract)

    Science.gov (United States)

    Anne Black; Dave Thomas; Jennifer Ziegler; Jim Saveland

    2012-01-01

    In 2011, we held five 2-day workshops at various locations around the US as part of a Joint Fire Science Program project to understand 'learning from escaped prescribed fire reviews'. Each workshop drew an interagency audience with representation from all facets of fire management, from ground personnel to local line officers, regional, and national positions...

  18. Tips, techniques and suggestions for improving learning from escaped prescribed fire reviews

    Science.gov (United States)

    Anne Black; Dave Thomas; Jennifer Ziegler; Jim Saveland

    2012-01-01

    In 2011, we held five 2-day workshops at various locations around the US as part of a Joint Fire Science Program project to understand 'learning from escaped prescribed fire reviews'. Each workshop drew an interagency audience with representation from all facets of fire management, from ground personnel to local line officers, regional, and national positions...

  19. Queer(y)ing and Recrafting Agency: Moving Away from a Model of Coercion versus Escape

    Science.gov (United States)

    Gowlett, Christina

    2014-01-01

    This paper applies a Butlerian-inspired "queer(y)ing" methodology to disrupt the utility of agency being framed within the binary of escape and coercion. In particular, it uses Butler's concept of performative resignification to analyse how Simon, a 16-year-old white male student, maneouvres his way through the social conventions of…

  20. HIV-1 can escape from RNA interference by evolving an alternative structure in its RNA genome

    NARCIS (Netherlands)

    Westerhout, Ellen M.; Ooms, Marcel; Vink, Monique; Das, Atze T.; Berkhout, Ben

    2005-01-01

    HIV-1 replication can be efficiently inhibited by intracellular expression of an siRNA targeting the viral RNA. However, HIV-1 escape variants emerged after prolonged culturing. These RNAi-resistant viruses contain nucleotide substitutions or deletions in or near the targeted sequence. We observed

  1. Effect of Brief Clinic-Based Training on the Ability of Caregivers to Implement Escape Extinction

    Science.gov (United States)

    McCartney, Ellen J.; Anderson, Cynthia M.; English, Carie L.

    2005-01-01

    Escape extinction has been demonstrated to be an effective treatment for children exhibiting food refusal. To date, most studies have been conducted in inpatient treatment settings by trained clinicians. Few studies have evaluated the extent to which caregivers are able to implement efficacious interventions in their home for their food-selective…

  2. Educational Gaming for Pharmacy Students - Design and Evaluation of a Diabetes-themed Escape Room.

    Science.gov (United States)

    Eukel, Heidi N; Frenzel, Jeanne E; Cernusca, Dan

    2017-09-01

    Objective. To design an educational game that will increase third-year professional pharmacy students' knowledge of diabetes mellitus disease management and to evaluate their perceived value of the game. Methods. Faculty members created an innovative educational game, the diabetes escape room. An authentic escape room gaming environment was established through the use of a locked room, an escape time limit, and game rules within which student teams completed complex puzzles focused on diabetes disease management. To evaluate the impact, students completed a pre-test and post-test to measure the knowledge they've gained and a perception survey to identify moderating factors that could help instructors improve the game's effectiveness and utility. Results. Students showed statistically significant increases in knowledge after completion of the game. A one-sample t-test indicated that students' mean perception was statistically significantly higher than the mean value of the evaluation scale. This statically significant result proved that this gaming act offers a potential instructional benefit beyond its novelty. Conclusion. The diabetes escape room proved to be a valuable educational game that increased students' knowledge of diabetes mellitus disease management and showed a positive perceived overall value by student participants.

  3. Escaping Poverty: Rural Low-Income Mothers' Opportunity to Pursue Post-Secondary Education

    Science.gov (United States)

    Woodford, Michelle; Mammen, Sheila

    2010-01-01

    Using human capital theory, this paper identifies the factors that may affect the opportunity for rural low-income mothers to pursue post-secondary education or training in order to escape poverty. Dependent variables used in the logistic regression model included micro-level household variables as well as the effects of state-wide welfare…

  4. Entrepreneurship for Women: "Escape from the Pink Collar Ghetto." Occasional Paper No. 121.

    Science.gov (United States)

    Taylor, Charlotte

    The role of small business and entrepreneurship in today's economy is well documented. Entrepreneurship and small business ownership are an especially attractive option for women. Women have been seeking an escape from traditional, low-paying, dead-end jobs by choosing entrepreneurship at a rate five times faster than that of men. Women now own…

  5. Distribution and escape of the major neutral species from Titan's atmosphere

    Science.gov (United States)

    Tenishev, Valeriy; Tucker, Orenthal; Borovikov, Dmitry; Combi, Michael R.

    2016-10-01

    Titan possesses the most significant atmosphere among all satellites in the Solar system, and is an important source of material for the Saturn's magnetosphere. Understanding of the neutral species distribution and escape is important for further understanding of the Titan's atmosphere evolution and loss.The first in situ observations of the Titan's atmosphere were performed by Voyager and continued by Cassini, which measured the atmospheric composition, velocity and temperature, as well as the energy spectra of neutral species, ions and electrons. Analysis and interpretation of the acquired data involves coupled modeling of the Saturn magnetosphere and Titan's atmosphere.Having that in mind we have undertaken numerical modeling of the major neutral species (N2 and CH4) in Titan's upper atmosphere to investigate the effect of the solar EUV and magnetospheric ion energy deposition on the neutral species atmospheric distribution and escape. This modeling combines MHD simulation of the Saturn's magnetosphere plasma interacting with Titan's atmosphere, fluid type simulation of the neutral species in Titan's lower atmosphere, and kinetic modeling of the upper atmosphere and exosphere. Here we present estimations of the neutral species escape rate, and discuss the effect of the magnetospheric ion energy deposition on the atmospheric escape concluded from the results of our modeling.This work was supported by NASA Outer Planet Research grant NNX13AL04G.

  6. Identification of a Peptide-Pheromone that Enhances Listeria monocytogenes Escape from Host Cell Vacuoles

    Science.gov (United States)

    Xayarath, Bobbi; Alonzo, Francis; Freitag, Nancy E.

    2015-01-01

    Listeria monocytogenes is a Gram-positive facultative intracellular bacterial pathogen that invades mammalian cells and escapes from membrane-bound vacuoles to replicate within the host cell cytosol. Gene products required for intracellular bacterial growth and bacterial spread to adjacent cells are regulated by a transcriptional activator known as PrfA. PrfA becomes activated following L. monocytogenes entry into host cells, however the signal that stimulates PrfA activation has not yet been defined. Here we provide evidence for L. monocytogenes secretion of a small peptide pheromone, pPplA, which enhances the escape of L. monocytogenes from host cell vacuoles and may facilitate PrfA activation. The pPplA pheromone is generated via the proteolytic processing of the PplA lipoprotein secretion signal peptide. While the PplA lipoprotein is dispensable for pathogenesis, bacteria lacking the pPplA pheromone are significantly attenuated for virulence in mice and have a reduced efficiency of bacterial escape from the vacuoles of nonprofessional phagocytic cells. Mutational activation of PrfA restores virulence and eliminates the need for pPplA-dependent signaling. Experimental evidence suggests that the pPplA peptide may help signal to L. monocytogenes its presence within the confines of the host cell vacuole, stimulating the expression of gene products that contribute to vacuole escape and facilitating PrfA activation to promote bacterial growth within the cytosol. PMID:25822753

  7. Oleoresin characteristics of progeny of loblolly pines that escaped attack by southern pine beetle

    Science.gov (United States)

    B.L. Strom; R.A. Goyer; L.L. Ingram; G.D.L. Boyd; L.H. Lott

    2002-01-01

    Oleoresin characteristics of first-generation (F1) progeny of loblolly pines (Pinus taeda L.) that escaped mortality from the southern pine beetle, Dendroctonus frontalis Zimmermann (Coleoptera: Scolytidae), despite heavy mortality of neighbors, were evaluated and compared to trees from a general (i.e., trees...

  8. Functional Assessment of the Effects of Escape and Attention on Students' Compliance during Instruction.

    Science.gov (United States)

    Noell, George H.; VanDerHeyden, Amanda M.; Gatti, Susan L.; Whitmarsh, Ernest L.

    2001-01-01

    Examined three strategies for assessing compliance in students whose speech and language development were delayed. The effects of attention versus escape from instruction following compliance were examined through a descriptive assessment in the classroom, an out-of-class experimental analysis conducted by a consultant, and an in-class…

  9. Constraints on the Lyman continuum escape fraction for faint star-forming galaxies

    Science.gov (United States)

    Japelj, J.; Vanzella, E.; Fontanot, F.; Cristiani, S.; Caminha, G. B.; Tozzi, P.; Balestra, I.; Rosati, P.; Meneghetti, M.

    2017-06-01

    Star-forming galaxies have long been considered the dominant sources of the cosmic ultraviolet background radiation at early epochs. However, observing and characterizing the galaxy population with significant ionizing emission have proven to be challenging. In particular, the fraction of ionizing radiation that escapes the local environment to the intergalactic medium is poorly known. We investigate the relation between the escape fraction and galaxy luminosity. We combine deep ultraviolet observations of Hubble Ultra Deep Field (UVUDF) with deep Multi Unit Spectroscopic Explorer (MUSE) observations of the same field, collecting a sample of 165 faint star-forming galaxies in the 3 radiation. We bin the galaxies in various redshift and brightness intervals and stack their images. From stacked images, we estimate the relative escape fraction upper limits as a function of the luminosity. Thanks to the depth of the sample, we measure meaningful 1σ upper limits of fesc, rel ionizing background with different prescriptions of fesc(MUV). We show that the understanding of the luminosity dependence hinges on the ability to constrain the escape fraction down to MUV ˜ -18 mag in the future.

  10. Escape from Management Hell: 12 Tales of Horror, Humor, and Heroism.

    Science.gov (United States)

    Gilbreath, Robert D.

    This book offers a set of stories in which corporate executives demonstrate the folly and futility of their own business practices. In the stories, 12 executives are trying to escape from a hell of their own making. The tales provide insights into the management woes with which people at all levels deal on a daily basis. Topics include: the…

  11. A fatal attraction: Mycobacterium tuberculosis and HIV-1 target DC-SIGN to escape immune surveillance

    NARCIS (Netherlands)

    van Kooyk, Yvette; Appelmelk, Ben; Geijtenbeek, Teunis B. H.

    2003-01-01

    Dendritic cells (DCs) are vital in the defense against pathogens. However, it is becoming increasingly clear that some pathogens subvert DC functions to escape immune surveillance. For example, HIV-1 targets the DC-specific C-type lectin DC-SIGN (DC-specific

  12. Atmospheric Athena: 3D Atmospheric escape model with ionizing radiative transfer

    Science.gov (United States)

    Tripathi, Anjali; Krumholz, Mark R.

    2017-03-01

    Atmospheric Athena simulates hydrodynamic escape from close-in giant planets in 3D. It uses the Athena hydrodynamics code (ascl:1010.014) with a new ionizing radiative transfer implementation to self-consistently model photoionization driven winds from the planet. The code is fully compatible with static mesh refinement and MPI parallelization and can handle arbitrary planet potentials and stellar initial conditions.

  13. Autonomous Soft Robotic Fish Capable of Escape Maneuvers Using Fluidic Elastomer Actuators

    Science.gov (United States)

    Onal, Cagdas D.; Rus, Daniela

    2014-01-01

    Abstract In this work we describe an autonomous soft-bodied robot that is both self-contained and capable of rapid, continuum-body motion. We detail the design, modeling, fabrication, and control of the soft fish, focusing on enabling the robot to perform rapid escape responses. The robot employs a compliant body with embedded actuators emulating the slender anatomical form of a fish. In addition, the robot has a novel fluidic actuation system that drives body motion and has all the subsystems of a traditional robot onboard: power, actuation, processing, and control. At the core of the fish's soft body is an array of fluidic elastomer actuators. We design the fish to emulate escape responses in addition to forward swimming because such maneuvers require rapid body accelerations and continuum-body motion. These maneuvers showcase the performance capabilities of this self-contained robot. The kinematics and controllability of the robot during simulated escape response maneuvers are analyzed and compared with studies on biological fish. We show that during escape responses, the soft-bodied robot has similar input–output relationships to those observed in biological fish. The major implication of this work is that we show soft robots can be both self-contained and capable of rapid body motion. PMID:27625912

  14. The disclosure of a metaphysical horizon, or how to escape dialectics

    African Journals Online (AJOL)

    In a footnote to The Inoperative Community French philosopher Jean-Luc Nancy wonders how to escape Hegelian dialectics. Because Nancy in his later work often returns to this attempt of a 'disclosure of our metaphysical horizon', we not only consider this note as a crucial one in his attempt to 'disclose' our metaphysical ...

  15. Computing The No-Escape Envelope Of A Short-Range Missile

    Science.gov (United States)

    Neuman, Frank

    1991-01-01

    Method for computing no-escape envelope of short-range air-to-air missile devised. Useful for analysis of both strategies for avoidance and strategies for attack. With modifications, also useful in analysis of control strategies for one-on-one air-to-air combat, or wherever multiple control strategies considered.

  16. Investigation of Minimum Sized Low-Profile Cockpits (MSLPC) and Crew Escape System Integration.

    Science.gov (United States)

    1979-09-17

    successfully achieve three goals to be of real value: e Significantly reduce the enemy’s attack envelope (i.e., have fewer losses) * Significantly increase its...2ND STAGE MAIN PARACHUTE DIA 26 PT ESCAPE WVENT ICSIEDLIL avw~l EAPSED lUE055w ESAT -AJCSEARATMO 0 DROGUE INITIATION (V > no KEa"E OR ALT > (ALT< l

  17. Escape path complexity and its context dependency in Pacific blue-eyes (Pseudomugil signifer).

    Science.gov (United States)

    Herbert-Read, J E; Ward, A J W; Sumpter, D J T; Mann, R P

    2017-06-01

    The escape paths prey animals take following a predatory attack appear to be highly unpredictable - a property that has been described as 'protean behaviour'. Here, we present a method of quantifying the escape paths of individual animals using a path complexity approach. When individual fish (Pseudomugil signifer) were attacked, we found that a fish's movement path rapidly increased in complexity following the attack. This path complexity remained elevated (indicating a more unpredictable path) for a sustained period (at least 10 s) after the attack. The complexity of the path was context dependent: paths were more complex when attacks were made closer to the fish, suggesting that these responses are tailored to the perceived level of threat. We separated out the components of speed and turning rate changes to determine which of these components contributed to the overall increase in path complexity following an attack. We found that both speed and turning rate measures contributed similarly to an individual's path complexity in absolute terms. Overall, our work highlights the context-dependent escape responses that animals use to avoid predators, and also provides a method for quantifying the escape paths of animals. © 2017. Published by The Company of Biologists Ltd.

  18. Avian Bornaviruses Escape Recognition by the Innate Immune System

    Directory of Open Access Journals (Sweden)

    Antje Reuter

    2010-04-01

    Full Text Available Like other pathogens that readily persist in animal hosts, members of the Bornaviridae family have evolved effective mechanisms to evade the innate immune response. The prototype of this virus family, Borna disease virus employs an unusual replication strategy that removes the triphosphates from the 5’ termini of the viral RNA genome. This strategy allows the virus to avoid activation of RIG-I and other innate immune response receptors in infected cells. Here we determined whether the newly discovered avian bornaviruses (ABV might use a similar strategy to evade the interferon response. We found that de novo infection of QM7 and CEC32 quail cells with two different ABV strains was efficiently inhibited by exogenous chicken IFN-α. IFN-α also reduced the viral load in QM7 and CEC32 cells persistently infected with both ABV strains, suggesting that ABV is highly sensitive to type I IFN. Although quail cells persistently infected with ABV contained high levels of viral RNA, the supernatants of infected cultures did not contain detectable levels of biologically active type I IFN. RNA from cells infected with ABV failed to induce IFN-β synthesis if transfected into human cells. Furthermore, genomic RNA of ABV was susceptible to 5’-monophosphate-specific RNase, suggesting that it lacks 5’-triphospates like BDV. These results indicate that bornaviruses of mammals and birds use similar strategies to evade the host immune response.

  19. Avian Bornaviruses Escape Recognition by the Innate Immune System

    Science.gov (United States)

    Reuter, Antje; Ackermann, Andreas; Kothlow, Sonja; Rinder, Monika; Kaspers, Bernd; Staeheli, Peter

    2010-01-01

    Like other pathogens that readily persist in animal hosts, members of the Bornaviridae family have evolved effective mechanisms to evade the innate immune response. The prototype of this virus family, Borna disease virus employs an unusual replication strategy that removes the triphosphates from the 5′ termini of the viral RNA genome. This strategy allows the virus to avoid activation of RIG-I and other innate immune response receptors in infected cells. Here we determined whether the newly discovered avian bornaviruses (ABV) might use a similar strategy to evade the interferon response. We found that de novo infection of QM7 and CEC32 quail cells with two different ABV strains was efficiently inhibited by exogenous chicken IFN-α. IFN-α also reduced the viral load in QM7 and CEC32 cells persistently infected with both ABV strains, suggesting that ABV is highly sensitive to type I IFN. Although quail cells persistently infected with ABV contained high levels of viral RNA, the supernatants of infected cultures did not contain detectable levels of biologically active type I IFN. RNA from cells infected with ABV failed to induce IFN-β synthesis if transfected into human cells. Furthermore, genomic RNA of ABV was susceptible to 5′-monophosphate-specific RNase, suggesting that it lacks 5′-triphospates like BDV. These results indicate that bornaviruses of mammals and birds use similar strategies to evade the host immune response. PMID:21994661

  20. Spiders do not escape reproductive manipulations by Wolbachia

    Directory of Open Access Journals (Sweden)

    Hendrickx Frederik

    2011-01-01

    Full Text Available Abstract Background Maternally inherited bacteria that reside obligatorily or facultatively in arthropods can increase their prevalence in the population by altering their hosts' reproduction. Such reproductive manipulations have been reported from the major arthropod groups such as insects (in particular hymenopterans, butterflies, dipterans and beetles, crustaceans (isopods and mites. Despite the observation that endosymbiont bacteria are frequently encountered in spiders and that the sex ratio of particular spider species is strongly female biased, a direct relationship between bacterial infection and sex ratio variation has not yet been demonstrated for this arthropod order. Results Females of the dwarf spider Oedothorax gibbosus exhibit considerable variation in the sex ratio of their clutches and were infected with at least three different endosymbiont bacteria capable of altering host reproduction i.e. Wolbachia, Rickettsia and Cardinium. Breeding experiments show that sex ratio variation in this species is primarily maternally inherited and that removal of the bacteria by antibiotics restores an unbiased sex ratio. Moreover, clutches of females infected with Wolbachia were significantly female biased while uninfected females showed an even sex ratio. As female biased clutches were of significantly smaller size compared to non-distorted clutches, killing of male embryos appears to be the most likely manipulative effect. Conclusions This represents to our knowledge the first direct evidence that endosymbiont bacteria, and in particular Wolbachia, might induce sex ratio variation in spiders. These findings are pivotal to further understand the diversity of reproductive phenotypes observed in this arthropod order.

  1. Spiders do not escape reproductive manipulations by Wolbachia.

    Science.gov (United States)

    Vanthournout, Bram; Swaegers, Janne; Hendrickx, Frederik

    2011-01-14

    Maternally inherited bacteria that reside obligatorily or facultatively in arthropods can increase their prevalence in the population by altering their hosts' reproduction. Such reproductive manipulations have been reported from the major arthropod groups such as insects (in particular hymenopterans, butterflies, dipterans and beetles), crustaceans (isopods) and mites. Despite the observation that endosymbiont bacteria are frequently encountered in spiders and that the sex ratio of particular spider species is strongly female biased, a direct relationship between bacterial infection and sex ratio variation has not yet been demonstrated for this arthropod order. Females of the dwarf spider Oedothorax gibbosus exhibit considerable variation in the sex ratio of their clutches and were infected with at least three different endosymbiont bacteria capable of altering host reproduction i.e. Wolbachia, Rickettsia and Cardinium. Breeding experiments show that sex ratio variation in this species is primarily maternally inherited and that removal of the bacteria by antibiotics restores an unbiased sex ratio. Moreover, clutches of females infected with Wolbachia were significantly female biased while uninfected females showed an even sex ratio. As female biased clutches were of significantly smaller size compared to non-distorted clutches, killing of male embryos appears to be the most likely manipulative effect. This represents to our knowledge the first direct evidence that endosymbiont bacteria, and in particular Wolbachia, might induce sex ratio variation in spiders. These findings are pivotal to further understand the diversity of reproductive phenotypes observed in this arthropod order.

  2. Escapism among players of MMORPGs--conceptual clarification, its relation to mental health factors, and development of a new measure.

    Science.gov (United States)

    Hagström, David; Kaldo, Viktor

    2014-01-01

    Previous studies show that the concept of escapism needs to be clarified and that its relation to problematic online gaming and other factors needs further examination. This study uses well-established, basic learning theory to clarify the concept of escapism, and examines its relation to problematic gaming, psychological distress, and satisfaction with life among players of massively multiplayer online role-playing games (MMORPGs). MMORPG players (n=201) answered an online questionnaire where these factors were measured and correlated with a previously developed scale on motivation to play (MTPI), including extra items to cover positive and negative aspects of escapism. Factor analysis and construct validation show that positive aspects of escapism are theoretically and empirically unstable and that escapism is best clarified as purely "negative escapism," corresponding to playing being negatively reinforced as a way of avoiding everyday hassles and distress. Negative escapism had a stronger relationship to symptoms of Internet addiction, psychological distress, and life satisfaction than other variables and other more positive motivations to play. Future studies should use the revised subscale for escapism (in the MTPI-R) presented in the present study, for example when screening for Internet addiction.

  3. Determinants of Human Immunodeficiency Virus Type 1 Escape from the Primary CD8+ Cytotoxic T Lymphocyte Response

    Science.gov (United States)

    Jones, Nicola A.; Wei, Xiping; Flower, Darren R.; Wong, MaiLee; Michor, Franziska; Saag, Michael S.; Hahn, Beatrice H.; Nowak, Martin A.; Shaw, George M.; Borrow, Persephone

    2004-01-01

    CD8+ cytotoxic T lymphocytes (CTLs) play an important role in containment of virus replication in primary human immunodeficiency virus (HIV) infection. HIV's ability to mutate to escape from CTL pressure is increasingly recognized; but comprehensive studies of escape from the CD8 T cell response in primary HIV infection are currently lacking. Here, we have fully characterized the primary CTL response to autologous virus Env, Gag, and Tat proteins in three patients, and investigated the extent, kinetics, and mechanisms of viral escape from epitope-specific components of the response. In all three individuals, we observed variation beginning within weeks of infection at epitope-containing sites in the viral quasispecies, which conferred escape by mechanisms including altered peptide presentation/recognition and altered antigen processing. The number of epitope-containing regions exhibiting evidence of early CTL escape ranged from 1 out of 21 in a subject who controlled viral replication effectively to 5 out of 7 in a subject who did not. Evaluation of the extent and kinetics of HIV-1 escape from >40 different epitope-specific CD8 T cell responses enabled analysis of factors determining escape and suggested that escape is restricted by costs to intrinsic viral fitness and by broad, codominant distribution of CTL-mediated pressure on viral replication. PMID:15545352

  4. Mandible-Powered Escape Jumps in Trap-Jaw Ants Increase Survival Rates during Predator-Prey Encounters.

    Directory of Open Access Journals (Sweden)

    Fredrick J Larabee

    Full Text Available Animals use a variety of escape mechanisms to increase the probability of surviving predatory attacks. Antipredator defenses can be elaborate, making their evolutionary origin unclear. Trap-jaw ants are known for their rapid and powerful predatory mandible strikes, and some species have been observed to direct those strikes at the substrate, thereby launching themselves into the air away from a potential threat. This potential escape mechanism has never been examined in a natural context. We studied the use of mandible-powered jumping in Odontomachus brunneus during their interactions with a common ant predator: pit-building antlions. We observed that while trap-jaw ant workers escaped from antlion pits by running in about half of interactions, in 15% of interactions they escaped by mandible-powered jumping. To test whether escape jumps improved individual survival, we experimentally prevented workers from jumping and measured their escape rate. Workers with unrestrained mandibles escaped from antlion pits significantly more frequently than workers with restrained mandibles. Our results indicate that some trap-jaw ant species can use mandible-powered jumps to escape from common predators. These results also provide a charismatic example of evolutionary co-option, where a trait that evolved for one function (predation has been co-opted for another (defense.

  5. Mandible-Powered Escape Jumps in Trap-Jaw Ants Increase Survival Rates during Predator-Prey Encounters.

    Science.gov (United States)

    Larabee, Fredrick J; Suarez, Andrew V

    2015-01-01

    Animals use a variety of escape mechanisms to increase the probability of surviving predatory attacks. Antipredator defenses can be elaborate, making their evolutionary origin unclear. Trap-jaw ants are known for their rapid and powerful predatory mandible strikes, and some species have been observed to direct those strikes at the substrate, thereby launching themselves into the air away from a potential threat. This potential escape mechanism has never been examined in a natural context. We studied the use of mandible-powered jumping in Odontomachus brunneus during their interactions with a common ant predator: pit-building antlions. We observed that while trap-jaw ant workers escaped from antlion pits by running in about half of interactions, in 15% of interactions they escaped by mandible-powered jumping. To test whether escape jumps improved individual survival, we experimentally prevented workers from jumping and measured their escape rate. Workers with unrestrained mandibles escaped from antlion pits significantly more frequently than workers with restrained mandibles. Our results indicate that some trap-jaw ant species can use mandible-powered jumps to escape from common predators. These results also provide a charismatic example of evolutionary co-option, where a trait that evolved for one function (predation) has been co-opted for another (defense).

  6. Centering Single Cells in Microgels via Delayed Crosslinking Supports Long-Term 3D Culture by Preventing Cell Escape

    NARCIS (Netherlands)

    Kamperman, Tom; Henke, Sieger; Visser, Claas Willem; Karperien, Marcel; Leijten, Jeroen

    2017-01-01

    Single-cell-laden microgels support physiological 3D culture conditions while enabling straightforward handling and high-resolution readouts of individual cells. However, their widespread adoption for long-term cultures is limited by cell escape. In this work, it is demonstrated that cell escape is

  7. Efficacy of NS5A Inhibitors Against Hepatitis C Virus Genotypes 1-7 and Escape Variants

    DEFF Research Database (Denmark)

    Gottwein, Judith M; Pham, Long V; Mikkelsen, Lotte S

    2018-01-01

    NS5A inhibitors against HCV genotype 1-7 prototype isolates and resistant escape variants, and investigated the effects of pre-existing resistance-associated substitutions (RAS) on HCV escape from treatment. METHODS: We measured the efficacy of different concentrations of daclatasvir, ledipasvir...

  8. Comparison of heavy metal levels of farmed and escaped farmed rainbow trout and health risk assessment associated with their consumption.

    Science.gov (United States)

    Varol, Memet; Sünbül, Muhammet Raşit

    2017-10-01

    In this study, levels of ten metals (arsenic, cadmium, cobalt, chromium, copper, iron, manganese, nickel, lead, and zinc) in muscles of farmed and escaped farmed rainbow trout (Oncorhynchus mykiss) in the Keban Dam Reservoir (Turkey) were determined. Also, human health risks associated with their consumption were assessed. Of ten metals, only Co and Fe levels in escaped rainbow trout were significantly higher than those in farmed rainbow trout. The metal levels in farmed and escaped rainbow trout were below the maximum permissible limits. The estimated daily intake (EDI) of each metal in both farmed and escaped farmed rainbow trout was much lower than the respective tolerable daily intake (TDI). The target hazard quotient (THQ) values for individual metal and the total THQ values for combined metals were lower than 1 in both farmed and escaped rainbow trout, indicating no health risk for humans. The cancer risk (CR) values estimated for inorganic As in both farmed and escaped rainbow trout indicated low carcinogenic risk to the consumers. According to the maximum allowable monthly consumption limits (CRmm), adults may safely consume 24 meals of farmed rainbow trout per month or 39 meals of escaped rainbow trout per month, with minimal adverse carcinogenic and non-carcinogenic health effects. This study revealed that the risk from consuming farmed and escaped farmed rainbow trout in the Keban Dam Reservoir due to these trace elements is minimal.

  9. Escape and lipodystrophy in acromegaly during pegvisomant therapy, a retrospective multicentre Spanish study.

    Science.gov (United States)

    Sesmilo, Gemma; Resmini, Eugenia; Bernabeu, Ignacio; Aller, Javier; Soto, Alfonso; Mora, Mireia; Picó, Antonio; Fajardo, Carmen; Torres, Elena; Alvarez-Escolá, Cristina; García, Rogelio; Blanco, Concepción; Cámara, Rosa; Gaztambide, Sonia; Salinas, Isabel; Pozo, Carlos Del; Castells, Ignasi; Villabona, Carles; Biagetti, Betina; Webb, Susan M

    2014-12-01

    Pegvisomant is an effective treatment for acromegaly. To investigate escape (loss of biochemical control in patients previously controlled) and lipodystrophy in acromegalic patients treated with pegvisomant and to evaluate possible associations with clinical features. Multicentre retrospective study involving 19 Spanish centres. Ninety-seven patients were included (59% women, mean age at diagnosis 42 ± 13 years, 80% macroadenomas); mean follow-up on pegvisomant was 5 ± 2·5 years, and 89 (92%) achieved normal IGF-1. Escape was reported in 30/89 (34%) of responders, after a mean treatment duration of 25 ± 21 months. The mean initial dose of pegvisomant was 11 ± 5 mg/day, and mean dose at escape was 14 ± 7 mg/day. Most patients (26/30, 87%) achieved control with dose increase (57%), additional medical treatment (3%) or both (27%). Mean new dose that controlled IGF-1 after escape was 20 ± 7 mg/day. Treatments associated were somatostatin analogues (SSA in 47%), cabergoline (CAB in 47%) and both (6%). Lipodystrophy was observed in 15 patients (13 females), mild in six, moderate in six, severe in three and persistent in four. Among patients with lipodystrophy, three escaped and three were nonresponders to pegvisomant. Four patients discontinued the drug, and four had dose reductions because of lipodystrophy. It tended to be more frequent in females (P = 0·06) and in patients treated with triple association SSA+CAB+PEG (P = 0·018). No relationship between escape and clinical variables was found, except prior CAB (P = 0·04) and metformin treatment (0·02) and grade of lipodystrophy (P = 0·02). A significant proportion of patients treated with pegvisomant escaped (34%); however, the majority (87%) was easily controlled with either dose increase, further medical treatment or both. Lipodystrophy developed in 15%, mostly females, and influenced the response to treatment. © 2014 John Wiley & Sons Ltd.

  10. Can non-lytic CD8+ T cells drive HIV-1 escape?

    Directory of Open Access Journals (Sweden)

    Nafisa-Katrin Seich Al Basatena

    Full Text Available The CD8+ T cell effector mechanisms that mediate control of HIV-1 and SIV infections remain poorly understood. Recent work suggests that the mechanism may be primarily non-lytic. This is in apparent conflict with the observation that SIV and HIV-1 variants that escape CD8+ T cell surveillance are frequently selected. Whilst it is clear that a variant that has escaped a lytic response can have a fitness advantage compared to the wild-type, it is less obvious that this holds in the face of non-lytic control where both wild-type and variant infected cells would be affected by soluble factors. In particular, the high motility of T cells in lymphoid tissue would be expected to rapidly destroy local effects making selection of escape variants by non-lytic responses unlikely. The observation of frequent HIV-1 and SIV escape poses a number of questions. Most importantly, is the consistent observation of viral escape proof that HIV-1- and SIV-specific CD8+ T cells lyse infected cells or can this also be the result of non-lytic control? Additionally, the rate at which a variant strain escapes a lytic CD8+ T cell response is related to the strength of the response. Is the same relationship true for a non-lytic response? Finally, the potential anti-viral control mediated by non-lytic mechanisms compared to lytic mechanisms is unknown. These questions cannot be addressed with current experimental techniques nor with the standard mathematical models. Instead we have developed a 3D cellular automaton model of HIV-1 which captures spatial and temporal dynamics. The model reproduces in vivo HIV-1 dynamics at the cellular and population level. Using this model we demonstrate that non-lytic effector mechanisms can select for escape variants but that outgrowth of the variant is slower and less frequent than from a lytic response so that non-lytic responses can potentially offer more durable control.

  11. Structural Basis for Escape of Human Astrovirus from Antibody Neutralization: Broad Implications for Rational Vaccine Design

    Energy Technology Data Exchange (ETDEWEB)

    Bogdanoff, Walter A.; Perez, Edmundo I.; López, Tomás; Arias, Carlos F.; DuBois, Rebecca M.; Schultz-Cherry, Stacey

    2017-10-25

    a single amino acid mutation induces a structural change in a loop that is responsible for antibody binding. Our findings reveal how viruses can escape antibody neutralization and provide insight for the rational design of vaccines to elicit diverse antibodies that provide broader protection from infection.

  12. Space Weathering of Super-Earths: Model Simulations of Exospheric Sodium Escape from 61 Virgo b

    Energy Technology Data Exchange (ETDEWEB)

    Yoneda, M.; Berdyugina, S.; Kuhn, J. [Kiepenheuer Institute for Solar Physics, Schöneckstraße 6, 79104 Freiburg im Breisgau (Germany)

    2017-10-01

    Rocky exoplanets are expected to be eroded by space weather in a similar way as in the solar system. In particular, Mercury is one of the dramatically eroded planets whose material continuously escapes into its exosphere and further into space. This escape is well traced by sodium atoms scattering sunlight. Due to solar wind impact, micrometeorite impacts, photo-stimulated desorption and thermal desorption, sodium atoms are released from surface regolith. Some of these released sodium atoms are escaping from Mercury’s gravitational-sphere. They are dragged anti-Sun-ward and form a tail structure. We expect similar phenomena on exoplanets. The hot super-Earth 61 Vir b orbiting a G3V star at only 0.05 au may show a similar structure. Because of its small separation from the star, the sodium release mechanisms may be working more efficiently on hot super-Earths than on Mercury, although the strong gravitational force of Earth-sized or even more massive planets may be keeping sodium atoms from escaping from the planet. Here, we performed model simulations for Mercury (to verify our model) and 61 Vir b as a representative super-Earth. We have found that sodium atoms can escape from this exoplanet due to stellar wind sputtering and micrometeorite impacts, to form a sodium tail. However, in contrast to Mercury, the tail on this hot super-Earth is strongly aligned with the anti-starward direction because of higher light pressure. Our model suggests that 61 Vir b seems to have an exo-base atmosphere like that of Mercury.

  13. Role of hepatitis B virus genetic barrier in drug-resistance and immune-escape development.

    Science.gov (United States)

    Svicher, Valentina; Cento, Valeria; Salpini, Romina; Mercurio, Fabio; Fraune, Maria; Beggel, Bastian; Han, Yue; Gori, Caterina; Wittkop, Linda; Bertoli, Ada; Micheli, Valeria; Gubertini, Guido; Longo, Roberta; Romano, Sara; Visca, Michela; Gallinaro, Valentina; Marino, Nicoletta; Mazzotta, Francesco; De Sanctis, Giuseppe Maria; Fleury, Hervè; Trimoulet, Pascale; Angelico, Mario; Cappiello, Giuseppina; Zhang, Xin Xin; Verheyen, Jens; Ceccherini-Silberstein, Francesca; Perno, Carlo Federico

    2011-12-01

    Impact of hepatitis B virus genetic barrier, defined as the number and type of nucleotide substitutions required to overcome drug/immune selective pressure, on drug-resistance/immune-escape development is unknown. Genetic barrier was calculated according to Van de Vijver (2006) in 3482 hepatitis B virus-reverse transcriptase/HBV surface antigen sequences from 555 drug-naïve patients and 2927 antiviral-treated patients infected with hepatitis B virus genotypes A-G. Despite high natural variability, genetic barrier for drug-resistance development is identical amongst hepatitis B virus genotypes, but varies according to drug-resistance mutation type. Highest genetic barrier is found for secondary/compensatory mutations (e.g. rtL80I/V-rtL180M-rtV173L), whilst most primary mutations (including rtM204V-rtA181T/V-rtI169T-rtA194T) are associated with low genetic barrier. An exception is rtM204I, which can derive from a transition or a transversion. Genotypes A and G are more prone to develop immune/diagnostic-escape mutations sT114R and sG130N. Vaccine-escape associated sT131N-mutation is a natural polymorphism in both A and G genotypes. Genetic barrier and reverse transcriptase/HBV surface antigen overlapping can synergistically influence hepatitis B virus drug-resistance/immune-escape development. The different immune-escape potential of specific hepatitis B virus genotypes could have important clinical consequences in terms of disease progression, vaccine strategies and correct HBV surface antigen detection. Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  14. Vaccine escape recombinants emerge after pneumococcal vaccination in the United States.

    Directory of Open Access Journals (Sweden)

    Angela B Brueggemann

    2007-11-01

    Full Text Available The heptavalent pneumococcal conjugate vaccine (PCV7 was introduced in the United States (US in 2000 and has significantly reduced invasive pneumococcal disease; however, the incidence of nonvaccine serotype invasive disease, particularly due to serotype 19A, has increased. The serotype 19A increase can be explained in part by expansion of a genotype that has been circulating in the US prior to vaccine implementation (and other countries since at least 1990, but also by the emergence of a novel "vaccine escape recombinant" pneumococcal strain. This strain has a genotype that previously was only associated with vaccine serotype 4, but now expresses a nonvaccine serotype 19A capsule. Based on prior evidence for capsular switching by recombination at the capsular locus, the genetic event that resulted in this novel serotype/genotype combination might be identifiable from the DNA sequence of individual pneumococcal strains. Therefore, the aim of this study was to characterise the putative recombinational event(s at the capsular locus that resulted in the change from a vaccine to a nonvaccine capsular type. Sequencing the capsular locus flanking regions of 51 vaccine escape (progeny, recipient, and putative donor pneumococci revealed a 39 kb recombinational fragment, which included the capsular locus, flanking regions, and two adjacent penicillin-binding proteins, and thus resulted in a capsular switch and penicillin nonsusceptibility in a single genetic event. Since 2003, 37 such vaccine escape strains have been detected, some of which had evolved further. Furthermore, two new types of serotype 19A vaccine escape strains emerged in 2005. To our knowledge, this is the first time a single recombinational event has been documented in vivo that resulted in both a change of serotype and penicillin nonsusceptibility. Vaccine escape by genetic recombination at the capsular locus has the potential to reduce PCV7 effectiveness in the longer term.

  15. Mapping a region of hepatitis C virus E2 that is responsible for escape from neutralizing antibodies and a core CD81-binding region that does not tolerate neutralization escape mutations.

    Science.gov (United States)

    Keck, Zhen-Yong; Saha, Anasuya; Xia, Jinming; Wang, Yong; Lau, Patrick; Krey, Thomas; Rey, Felix A; Foung, Steven K H

    2011-10-01

    Understanding the interaction between broadly neutralizing antibodies and their epitopes provides a basis for the rational design of a preventive hepatitis C virus (HCV) vaccine. CBH-2, HC-11, and HC-1 are representatives of antibodies to overlapping epitopes on E2 that mediate neutralization by blocking virus binding to CD81. To obtain insights into escape mechanisms, infectious cell culture virus, 2a HCVcc, was propagated under increasing concentrations of a neutralizing antibody to isolate escape mutants. Three escape patterns were observed with these antibodies. First, CBH-2 escape mutants that contained mutations at D431G or A439E, which did not compromise viral fitness, were isolated. Second, under the selective pressure of HC-11, escape mutations progressed from a single L438F substitution at a low antibody concentration to double substitutions, L438F and N434D or L438F and T435A, at higher antibody concentrations. Escape from HC-11 was associated with a loss of viral fitness. An HCV pseudoparticle (HCVpp) containing the L438F mutation bound to CD81 half as efficiently as did wild-type (wt) HCVpp. Third, for HC-1, the antibody at a critical concentration completely suppressed viral replication and generated no escape mutants. Epitope mapping revealed contact residues for CBH-2 and HC-11 in two regions of the E2 glycoprotein, amino acids (aa) 425 to 443 and aa 529 to 535. Interestingly, contact residues for HC-1 were identified only in the region encompassing aa 529 to 535 and not in aa 425 to 443. Taken together, these findings point to a region of variability, aa 425 to 443, that is responsible primarily for viral escape from neutralization, with or without compromising viral fitness. Moreover, the region aa 529 to 535 is a core CD81 binding region that does not tolerate neutralization escape mutations.

  16. Modelling rip current flow and bather escape strategies across a transverse bar and rip channel morphology

    Science.gov (United States)

    McCarroll, R. Jak; Castelle, Bruno; Brander, Robert W.; Scott, Timothy

    2015-10-01

    Rip currents are a hazard to bathers on surf beaches worldwide, yet due to logistical and ethical concerns there has been minimal examination of how bathers caught in them should attempt to escape. This study presents the first numerical model of simulated bathers escaping from a rip current. An understanding of the underlying coastal geomorphology and hydrodynamics form a critical basis for the model, with the intention that outcomes of the model should be evaluated from a physical science perspective. Field observations of a transverse bar rip channel were used as model inputs. Escape simulations were performed with moderate energy (Hs ≈ 1 m), oblique offshore wave forcing, used to generate two non-stationary, asymmetric flow fields (dominant surfzone exits and dominant recirculation). The model treats bathers as particles that move with the underlying flow, with an additional swimming velocity added, iterating until a safety condition, based on depth and current speed, is satisfied or until a maximum time limit is reached. Simulations compared the strategies of ;stay afloat; and various fixed swim directions, using two bather heights and four swim speeds (up to 0.4 m/s). The overall optimal escape strategy was to swim parallel in the direction of alongshore flow. Time to safety was less for: (i) recirculating flow; (ii) taller bathers; and (iii) greater swim speeds. Across all simulations, 44% of ;floaters; reached safety within 10 min, while 80% of slow swimmers (0.2 m/s) succeeded in the same time interval. This suggests that slow sustainable swimming may be a preferable escape action to floating. Optimal swim direction varied with start location, from onshore (near the shoreline), parallel to shore (mid-rip channel) and diagonally onshore (outer rip channel). At lower swim speeds, the optimal swim direction had greater dependence on the underlying flow field, as opposed to distance to safety, therefore choice of direction is more complex for slower swimmers

  17. The escape of Lyman photons from a young starburst: the case of Haro11†

    Science.gov (United States)

    Hayes, Matthew; Östlin, Göran; Atek, Hakim; Kunth, Daniel; Mas-Hesse, J. Miguel; Leitherer, Claus; Jiménez-Bailón, Elena; Adamo, Angela

    2007-12-01

    Lyman α (Lyα) is one of the dominant tools used to probe the star-forming galaxy population at high redshift (z). However, astrophysical interpretations of data drawn from Lyα alone hinge on the Lyα escape fraction which, due to the complex radiative transport, may vary greatly. Here, we map the Lyα emission from the local luminous blue compact galaxy Haro11, a known emitter of Lyα and the only known candidate for low-z Lyman continuum emission. To aid in the interpretation, we perform a detailed ultraviolet and optical multiwavelength analysis and model the stellar population, dust distribution, ionizing photon budget, and star-cluster population. We use archival X-ray observations to further constrain properties of the starburst and estimate the neutral hydrogen column density. The Lyα morphology is found to be largely symmetric around a single young star-forming knot and is strongly decoupled from other wavelengths. From general surface photometry, only very slight correlation is found between Lyα and Hα, E(B - V), and the age of the stellar population. Only around the central Lyα bright cluster do we find the Lyα/Hα ratio at values predicted by the recombination theory. The total Lyα escape fraction is found to be just 3 per cent. We compute that ~90 per cent of the Lyα photons that escape do so after undergoing multiple resonance scattering events, masking their point of origin. This leads to a largely symmetric distribution and, by increasing the distance that photons must travel to escape, decreases the escape probability significantly. While dust must ultimately be responsible for the destruction of Lyα, it plays a little role in governing the observed morphology, which is regulated more by interstellar medium kinematics and geometry. We find tentative evidence for local Lyα equivalent width in the immediate vicinity of star clusters being a function of cluster age, consistent with hydrodynamic studies. We estimate the intrinsic production

  18. Energy conversion through mass loading of escaping ionospheric ions for different Kp values

    Science.gov (United States)

    Yamauchi, Masatoshi; Slapak, Rikard

    2018-01-01

    By conserving momentum during the mixing of fast solar wind flow and slow planetary ion flow in an inelastic way, mass loading converts kinetic energy to other forms - e.g. first to electrical energy through charge separation and then to thermal energy (randomness) through gyromotion of the newly born cold ions for the comet and Mars cases. Here, we consider the Earth's exterior cusp and plasma mantle, where the ionospheric origin escaping ions with finite temperatures are loaded into the decelerated solar wind flow. Due to direct connectivity to the ionosphere through the geomagnetic field, a large part of this electrical energy is consumed to maintain field-aligned currents (FACs) toward the ionosphere, in a similar manner as the solar wind-driven ionospheric convection in the open geomagnetic field region. We show that the energy extraction rate by the mass loading of escaping ions (ΔK) is sufficient to explain the cusp FACs, and that ΔK depends only on the solar wind velocity accessing the mass-loading region (usw) and the total mass flux of the escaping ions into this region (mloadFload), as ΔK ˜ -mloadFloadu2sw/4. The expected distribution of the separated charges by this process also predicts the observed flowing directions of the cusp FACs for different interplanetary magnetic field (IMF) orientations if we include the deflection of the solar wind flow directions in the exterior cusp. Using empirical relations of u0 ∝ Kp + 1.2 and Fload ∝ exp(0.45Kp) for Kp = 1-7, where u0 is the solar wind velocity upstream of the bow shock, ΔK becomes a simple function of Kp as log10(ΔK) = 0.2 ṡ Kp + 2 ṡ log10(Kp + 1.2) + constant. The major contribution of this nearly linear increase is the Fload term, i.e. positive feedback between the increase of ion escaping rate Fload through the increased energy consumption in the ionosphere for high Kp, and subsequent extraction of more kinetic energy ΔK from the solar wind to the current system by the increased

  19. Visuo-motor transformations involved in the escape response to looming stimuli in the crab Neohelice (=Chasmagnathus) granulata.

    Science.gov (United States)

    Oliva, Damián; Tomsic, Daniel

    2012-10-01

    Escape responses to directly approaching predators represent one instance of an animal's ability to avoid collision. Usually, such responses can be easily evoked in the laboratory using two-dimensional computer simulations of approaching objects, known as looming stimuli. Therefore, escape behaviors are considered useful models for the study of computations performed by the brain to efficiently transform visual information into organized motor patterns. The escape response of the crab Neohelice (previously Chasmagnathus) granulata offers an opportunity to investigate the processing of looming stimuli and its transformation into complex motor patterns. Here we studied the escape performance of this crab to a variety of different looming stimuli. The response always consisted of a vigorous run away from the stimulus. However, the moment at which it was initiated, as well as the developed speed, closely matched the expansion dynamics of each particular stimulus. Thus, we analyzed the response events as a function of several variables that could theoretically be used by the crab (angular size, angular velocity, etc.). Our main findings were that: (1) the decision to initiate the escape run is made when the stimulus angular size increases by 7 deg; (2) the escape run is not a ballistic kind of response, as its speed is adjusted concurrently with changes in the optical stimulus variables; and (3) the speed of the escape run can be faithfully described by a phenomenological input-output relationship based on the stimulus angular increment and the angular velocity of the stimulus.

  20. Prior individual training and self-organized queuing during group emergency escape of mice from water pool.

    Directory of Open Access Journals (Sweden)

    Caesar Saloma

    Full Text Available We study the impact of prior individual training during group emergency evacuation using mice that escape from an enclosed water pool to a dry platform via any of two possible exits. Experimenting with mice avoids serious ethical and legal issues that arise when dealing with unwitting human participants while minimizing concerns regarding the reliability of results obtained from simulated experiments using 'actors'. First, mice were trained separately and their individual escape times measured over several trials. Mice learned quickly to swim towards an exit-they achieved their fastest escape times within the first four trials. The trained mice were then placed together in the pool and allowed to escape. No two mice were permitted in the pool beforehand and only one could pass through an exit opening at any given time. At first trial, groups of trained mice escaped seven and five times faster than their corresponding control groups of untrained mice at pool occupancy rate ρ of 11.9% and 4%, respectively. Faster evacuation happened because trained mice: (a had better recognition of the available pool space and took shorter escape routes to an exit, (b were less likely to form arches that blocked an exit opening, and (c utilized the two exits efficiently without preference. Trained groups achieved continuous egress without an apparent leader-coordinator (self-organized queuing-a collective behavior not experienced during individual training. Queuing was unobserved in untrained groups where mice were prone to wall seeking, aimless swimming and/or blind copying that produced circuitous escape routes, biased exit use and clogging. The experiments also reveal that faster and less costly group training at ρ = 4%, yielded an average individual escape time that is comparable with individualized training. However, group training in a more crowded pool (ρ = 11.9% produced a longer average individual escape time.

  1. Escape from autologous neutralizing antibodies in acute/early subtype C HIV-1 infection requires multiple pathways.

    Science.gov (United States)

    Rong, Rong; Li, Bing; Lynch, Rebecca M; Haaland, Richard E; Murphy, Megan K; Mulenga, Joseph; Allen, Susan A; Pinter, Abraham; Shaw, George M; Hunter, Eric; Robinson, James E; Gnanakaran, S; Derdeyn, Cynthia A

    2009-09-01

    One aim for an HIV vaccine is to elicit neutralizing antibodies (Nab) that can limit replication of genetically diverse viruses and prevent establishment of a new infection. Thus, identifying the strengths and weaknesses of Nab during the early stages of natural infection could prove useful in achieving this goal. Here we demonstrate that viral escape readily occurred despite the development of high titer autologous Nab in two subjects with acute/early subtype C infection. To provide a detailed portrayal of the escape pathways, Nab resistant variants identified at multiple time points were used to create a series of envelope (Env) glycoprotein chimeras and mutants within the background of a corresponding newly transmitted Env. In one subject, Nab escape was driven predominantly by changes in the region of gp120 that extends from the beginning of the V3 domain to the end of the V5 domain (V3V5). However, Nab escape pathways in this subject oscillated and at times required cooperation between V1V2 and the gp41 ectodomain. In the second subject, escape was driven by changes in V1V2. This V1V2-dependent escape pathway was retained over time, and its utility was reflected in the virus's ability to escape from two distinct monoclonal antibodies (Mabs) derived from this same patient via introduction of a single potential N-linked glycosylation site in V2. Spatial representation of the sequence changes in gp120 suggested that selective pressure acted upon the same regions of Env in these two subjects, even though the Env domains that drove escape were different. Together the findings argue that a single mutational pathway is not sufficient to confer escape in early subtype C HIV-1 infection, and support a model in which multiple strategies, including potential glycan shifts, direct alteration of an epitope sequence, and cooperative Env domain conformational masking, are used to evade neutralization.

  2. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor–positive human breast cancer

    Science.gov (United States)

    Miller, Todd W.; Hennessy, Bryan T.; González-Angulo, Ana M.; Fox, Emily M.; Mills, Gordon B.; Chen, Heidi; Higham, Catherine; García-Echeverría, Carlos; Shyr, Yu; Arteaga, Carlos L.

    2010-01-01

    Many breast cancers exhibit a degree of dependence on estrogen for tumor growth. Although several therapies have been developed to treat individuals with estrogen-dependent breast cancers, some tumors show de novo or acquired resistance, rendering them particularly elusive to current therapeutic strategies. Understanding the mechanisms by which these cancers develop resistance would enable the development of new and effective therapeutics. In order to determine mechanisms of escape from hormone dependence in estrogen receptor–positive (ER-positive) breast cancer, we established 4 human breast cancer cell lines after long-term estrogen deprivation (LTED). LTED cells showed variable changes in ER levels and sensitivity to 17β-estradiol. Proteomic profiling of LTED cells revealed increased phosphorylation of the mammalian target of rapamycin (mTOR) substrates p70S6 kinase and p85S6 kinase as well as the PI3K substrate AKT. Inhibition of PI3K and mTOR induced LTED cell apoptosis and prevented the emergence of hormone-independent cells. Using reverse-phase protein microarrays, we identified a breast tumor protein signature of PI3K pathway activation that predicted poor outcome after adjuvant endocrine therapy in patients. Our data suggest that upon adaptation to hormone deprivation, breast cancer cells rely heavily on PI3K signaling. Our findings also imply that acquired resistance to endocrine therapy in breast cancer may be abrogated by combination therapies targeting both ER and PI3K pathways. PMID:20530877

  3. Damage escape and repair in dried Chroococcidiopsis spp. from hot and cold deserts exposed to simulated space and martian conditions.

    Science.gov (United States)

    Billi, Daniela; Viaggiu, Emanuela; Cockell, Charles S; Rabbow, Elke; Horneck, Gerda; Onofri, Silvano

    2011-01-01

    The cyanobacterium Chroococcidiopsis, overlain by 3 mm of Antarctic sandstone, was exposed as dried multilayers to simulated space and martian conditions. Ground-based experiments were conducted in the context of Lichens and Fungi Experiments (EXPOSE-E mission, European Space Agency), which were performed to evaluate, after 1.5 years on the International Space Station, the survival of cyanobacteria (Chroococcidiopsis), lichens, and fungi colonized on Antarctic rock. The survival potential and the role played by protection and repair mechanisms in the response of dried Chroococcidiopsis cells to ground-based experiments were both investigated. Different methods were employed, including evaluation of the colony-forming ability, single-cell analysis of subcellular integrities based on membrane integrity molecular and redox probes, evaluation of the photosynthetic pigment autofluorescence, and assessment of the genomic DNA integrity with a PCR-based assay. Desiccation survivors of strain CCMEE 123 (coastal desert, Chile) were better suited than CCMEE 134 (Beacon Valley, Antarctica) to withstand cellular damage imposed by simulated space and martian conditions. Exposed dried cells of strain CCMEE 123 formed colonies, maintained subcellular integrities, and, depending on the exposure conditions, also escaped DNA damage or repaired the induced damage upon rewetting.

  4. EGFR signaling enhances aerobic glycolysis in triple negative breast cancer cells to promote tumor growth and immune escape

    Science.gov (United States)

    Lim, Seung-Oe; Li, Chia-Wei; Xia, Weiya; Lee, Heng-Huan; Chang, Shih-Shin; Shen, Jia; Hsu, Jennifer L.; Raftery, Dan; Djukovic, Danijel; Gu, Haiwei; Chang, Wei-Chao; Wang, Hung-Ling; Chen, Mong-Liang; Huo, Longfei; Chen, Chung-Hsuan; Wu, Yun; Sahin, Aysegul; Hanash, Samir M.; Hortobagyi, Gabriel N.; Hung, Mien-Chie

    2016-01-01

    Oncogenic signaling reprograms cancer cell metabolism to augment the production of glycolytic metabolites in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. Epidermal growth factor (EGF) signaling, frequently dysregulated in triple-negative breast cancer (TNBC), is also associated with increased glycolysis. Here, we demonstrated in TNBC cells that EGF signaling activates the first step in glycolysis, but impedes the last step, leading to an accumulation of metabolic intermediates in this pathway. Furthermore, we showed that one of these intermediates, fructose 1,6 bisphosphate (F1,6BP), directly binds to and enhances the activity of the EGF receptor (EGFR), thereby increasing lactate excretion which leads to inhibition of local cytotoxic T cell activity. Notably, combining the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) with the EGFR inhibitor gefitinib effectively suppressed TNBC cell proliferation and tumor growth. Our results illustrate how jointly targeting the EGFR/F1,6BP signaling axis may offer an immediately applicable therapeutic strategy to treat TNBC. PMID:26759242

  5. EGFR Signaling Enhances Aerobic Glycolysis in Triple-Negative Breast Cancer Cells to Promote Tumor Growth and Immune Escape.

    Science.gov (United States)

    Lim, Seung-Oe; Li, Chia-Wei; Xia, Weiya; Lee, Heng-Huan; Chang, Shih-Shin; Shen, Jia; Hsu, Jennifer L; Raftery, Daniel; Djukovic, Danijel; Gu, Haiwei; Chang, Wei-Chao; Wang, Hung-Ling; Chen, Mong-Liang; Huo, Longfei; Chen, Chung-Hsuan; Wu, Yun; Sahin, Aysegul; Hanash, Samir M; Hortobagyi, Gabriel N; Hung, Mien-Chie

    2016-03-01

    Oncogenic signaling reprograms cancer cell metabolism to augment the production of glycolytic metabolites in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T-cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. EGF signaling, frequently dysregulated in triple-negative breast cancer (TNBC), is also associated with increased glycolysis. Here, we demonstrated in TNBC cells that EGF signaling activates the first step in glycolysis, but impedes the last step, leading to an accumulation of metabolic intermediates in this pathway. Furthermore, we showed that one of these intermediates, fructose 1,6 bisphosphate (F1,6BP), directly binds to and enhances the activity of the EGFR, thereby increasing lactate excretion, which leads to inhibition of local cytotoxic T-cell activity. Notably, combining the glycolysis inhibitor 2-deoxy-d-glucose with the EGFR inhibitor gefitinib effectively suppressed TNBC cell proliferation and tumor growth. Our results illustrate how jointly targeting the EGFR/F1,6BP signaling axis may offer an immediately applicable therapeutic strategy to treat TNBC. ©2016 American Association for Cancer Research.

  6. Nonthermal escape of hydrogen and deuterium from Venus and implications for loss of water

    Science.gov (United States)

    Kumar, S.; Hunten, D. M.; Pollack, J. B.

    1983-01-01

    As the dominant nonthermal mechanism for the escape of hydrogen in past Venus atmospheres, the charge exchange of H(+) with H would have provided an escape flux close to the diffusion-limiting value for H-mixing ratios up to 0.002 at the homopause, which also marks the onset of hydrodynamic flow. Charge exchange therefore represents a viable mechanism through which Venus could have lost up to an earth-equivalent ocean of water from its atmosphere over geologic time. Present Venus atmosphere estimates are based on in situ Pioneer Venus mission measurements, and assumptions in the course of extrapolation to past atmospheres have been with respect to the nature of the bulge, circulation pattern, and ion temperature.

  7. Estimating escapement of fish and invertebrates in a Danish anchor seine

    DEFF Research Database (Denmark)

    Noack, Thomas; Madsen, Niels; Mieske, Bernd

    2017-01-01

    The codend is generally presumed to be the place where the main selectivity of fish occurs in towed fishing gears, but other parts of the net have been found to contribute to the selectivity process of several invertebrate species. This means that conventional selectivity or survival studies may......) invertebrates from the forward parts of the seine net. For seven species of demersal fish, most fish escaped through the lower panel close to the codend. All invertebrate species were found in higher numbers in the collecting bags than in the codend where many organisms escaped in the lower panel of the wings...... or the belly. Mean levels of visible damage ranged from 1.00 to 3.25 for collected invertebrates and were similar for all gear parts. Common starfish (Asterias rubens), however, showed highest damage in the extension part of the net....

  8. Obstacle optimization for panic flow--reducing the tangential momentum increases the escape speed.

    Science.gov (United States)

    Jiang, Li; Li, Jingyu; Shen, Chao; Yang, Sicong; Han, Zhangang

    2014-01-01

    A disastrous form of pedestrian behavior is a stampede occurring in an event involving a large crowd in a panic situation. To deal with such stampedes, the possibility to increase the outflow by suitably placing a pillar or some other shaped obstacles in front of the exit has been demonstrated. We present a social force based genetic algorithm to optimize the best design of architectural entities to deal with large crowds. Unlike existing literature, our simulation results indicate that appropriately placing two pillars on both sides but not in front of the door can maximize the escape efficiency. Human experiments using 80 participants correspond well with the simulations. We observed a peculiar property named tangential momentum, the escape speed and the tangential momentum are found to be negatively correlated. The idea to reduce the tangential momentum has practical implications in crowd architectural design.

  9. Lung Cancer: A Classic Example of Tumor Escape and Progression While Providing Opportunities for Immunological Intervention

    Science.gov (United States)

    Jadus, Martin R.; Natividad, Josephine; Mai, Anthony; Ouyang, Yi; Lambrecht, Nils; Szabo, Sandor; Ge, Lisheng; Hoa, Neil; Dacosta-Iyer, Maria G.

    2012-01-01

    Lung cancers remain one of the most common and deadly cancers in the world today (12.5% of newly diagnosed cancers) despite current advances in chemo- and radiation therapies. Often, by the time these tumors are diagnosed, they have already metastasized. These tumors demonstrate the classic hallmarks of cancer in that they have advanced defensive strategies allowing them to escape various standard oncological treatments. Immunotherapy is making inroads towards effectively treating other fatal cancers, such as melanoma, glioblastoma multiforme, and castrate-resistant prostate cancers. This paper will cover the escape mechanisms of bronchogenic lung cancer that must be overcome before they can be successfully treated. We also review the history of immunotherapy directed towards lung cancers. PMID:22899945

  10. Mechanisms of equine infectious anemia virus escape from neutralizing antibody responses define epitope specificity.

    Science.gov (United States)

    Sponseller, Brett A; Clark, Sandra K; Friedrich, Rachel A

    2012-08-01

    Determining mechanisms of viral escape to particular epitopes recognized by virus-neutralizing antibody can facilitate characterization of host-neutralizing antibody responses as type- versus group-specific, and provides necessary information for vaccine development. Our study reveals that a single N-glycan located in the 5' region of the Wyoming wild-type equine infectious anemia virus (EIAV) principal neutralizing domain (PND) accounts for the differences in neutralization phenotype observed between PND variants, while variations in charged amino acids within the PND do not appear to play a key role in viral escape. Site-directed mutagenesis and peptide mapping of a conserved epitope to neutralizing antibody in the 3' region of the PND showed rapid selective pressure for acquisition of a 5' PND N-glycan responsible for defining the specificity of the neutralizing-antibody response.

  11. Atmospheric escape from the TRAPPIST-1 planets and implications for habitability.

    Science.gov (United States)

    Dong, Chuanfei; Jin, Meng; Lingam, Manasvi; Airapetian, Vladimir S; Ma, Yingjuan; van der Holst, Bart

    2018-01-09

    The presence of an atmosphere over sufficiently long timescales is widely perceived as one of the most prominent criteria associated with planetary surface habitability. We address the crucial question of whether the seven Earth-sized planets transiting the recently discovered ultracool dwarf star TRAPPIST-1 are capable of retaining their atmospheres. To this effect, we carry out numerical simulations to characterize the stellar wind of TRAPPIST-1 and the atmospheric ion escape rates for all of the seven planets. We also estimate the escape rates analytically and demonstrate that they are in good agreement with the numerical results. We conclude that the outer planets of the TRAPPIST-1 system are capable of retaining their atmospheres over billion-year timescales. The consequences arising from our results are also explored in the context of abiogenesis, biodiversity, and searches for future exoplanets. In light of the many unknowns and assumptions involved, we recommend that these conclusions must be interpreted with due caution.

  12. Asymptotic analysis of the narrow escape problem in dendritic spine shaped domain: three dimensions

    Science.gov (United States)

    Li, Xiaofei; Lee, Hyundae; Wang, Yuliang

    2017-08-01

    This paper deals with the three-dimensional narrow escape problem in a dendritic spine shaped domain, which is composed of a relatively big head and a thin neck. The narrow escape problem is to compute the mean first passage time of Brownian particles traveling from inside the head to the end of the neck. The original model is to solve a mixed Dirichlet-Neumann boundary value problem for the Poisson equation in the composite domain, and is computationally challenging. In this paper we seek to transfer the original problem to a mixed Robin-Neumann boundary value problem by dropping the thin neck part, and rigorously derive the asymptotic expansion of the mean first passage time with high order terms. This study is a nontrivial three-dimensional generalization of the work in Li (2014 J. Phys. A: Math. Theor. 47 505202), where a two-dimensional analogue domain is considered.

  13. Transcapillary escape rate of albumin in hypertensive patients with type 1 (insulin-dependent) diabetes mellitus

    DEFF Research Database (Denmark)

    Nørgaard, K; Jensen, T; Feldt-Rasmussen, B

    1993-01-01

    . The systemic blood pressure and the transcapillary escape rate of albumin were measured in the following groups after 4 weeks without antihypertensive treatment: Group 1--eleven healthy control subjects. Group 2--ten Type 1 (insulin-dependent) diabetic patients with incipient nephropathy (urinary albumin...... excretion rate: 30-300 mg/24 h) and normal blood pressure. Group 3--eleven non-diabetic patients with essential hypertension. Group 4--nine Type 1 diabetic patients with hypertension but normal urinary albumin excretion (Type 1 diabetic patients with nephropathy (urinary......Diabetic patients with elevated urinary albumin excretion rate (incipient or clinical nephropathy) also have an increased transcapillary escape rate of albumin. This study was designed to clarify whether this is caused by a general vascular dysfunction or by elevated systemic blood pressure...

  14. Escape time from potential wells of strongly nonlinear oscillators with slowly varying parameters

    Directory of Open Access Journals (Sweden)

    Cai Jianping

    2005-01-01

    Full Text Available The effect of negative damping to an oscillatory system is to force the amplitude to increase gradually and the motion will be out of the potential well of the oscillatory system eventually. In order to deduce the escape time from the potential well of quadratic or cubic nonlinear oscillator, the multiple scales method is firstly used to obtain the asymptotic solutions of strongly nonlinear oscillators with slowly varying parameters, and secondly the character of modulus of Jacobian elliptic function is applied to derive the equations governing the escape time. The approximate potential method, instead of Taylor series expansion, is used to approximate the potential of an oscillation system such that the asymptotic solution can be expressed in terms of Jacobian elliptic function. Numerical examples verify the efficiency of the present method.

  15. MINING SECURITY PIPE© (TSM© WITH UNDERGROUND GPS GLOBAL© (RSPG© ESCAPE SECURITY DEVICE IN UNDERGROUND MINING

    Directory of Open Access Journals (Sweden)

    Rafael Barrionuevo GIMÉNEZ

    2016-04-01

    Full Text Available TSM is escape pipe in case of collapse of terrain. The TSM is a passive security tool placed underground to connect the work area with secure area (mining gallery mainly. TSM is light and hand able pipe made with aramid (Kevlar, carbon fibre, or other kind of new material. The TSM will be placed as a pipe line network with many in/out entrances/exits to rich and connect problem work areas with another parts in a safe mode. Different levels of instrumentation could be added inside such as micro-led escape way suggested, temperature, humidity, level of oxygen, etc.. The open hardware and software like Arduino will be the heart of control and automation system.

  16. Stochastic narrow escape in molecular and cellular biology analysis and applications

    CERN Document Server

    Holcman, David

    2015-01-01

    This book covers recent developments in the non-standard asymptotics of the mathematical narrow escape problem in stochastic theory, as well as applications of the narrow escape problem in cell biology. The first part of the book concentrates on mathematical methods, including advanced asymptotic methods in partial equations, and is aimed primarily at applied mathematicians and theoretical physicists who are interested in biological applications. The second part of the book is intended for computational biologists, theoretical chemists, biochemists, biophysicists, and physiologists. It includes a summary of output formulas from the mathematical portion of the book and concentrates on their applications in modeling specific problems in theoretical molecular and cellular biology. Critical biological processes, such as synaptic plasticity and transmission, activation of genes by transcription factors, or double-strained DNA break repair, are controlled by diffusion in structures that have both large and small sp...

  17. The Great Escape: The Role of Self-esteem and Self-related Cognition in\\ud Terror Management

    OpenAIRE

    Wisman, Arnaud; Heflick, Nathan A; Goldenberg, Jamie L

    2015-01-01

    Integrating terror management theory and objective self-awareness theory, we propose the\\ud existential escape hypothesis, which states that people with low self-esteem should be\\ud especially prone to escaping self-awareness as a distal response to thoughts of death. This is\\ud because they lack the means to bolster the self as a defense, and the propensity to bolster the\\ud self reduces the motivation to escape from self-awareness. Five studies supported this\\ud hypothesis. Individuals low,...

  18. Minimal sufficient balance randomization for sequential randomized controlled trial designs: results from the ESCAPE trial.

    Science.gov (United States)

    Sajobi, Tolulope T; Singh, Gurbakhshash; Lowerison, Mark W; Engbers, Jordan; Menon, Bijoy K; Demchuk, Andrew M; Goyal, Mayank; Hill, Michael D

    2017-11-02

    We describe the implementation of minimal sufficient balance randomization, a covariate-adaptive randomization technique, used for the "Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing CT to recanalization times" (ESCAPE) trial. The ESCAPE trial is a prospective, multicenter, randomized clinical trial that enrolled subjects with the following main inclusion criteria: less than 12 h from symptom onset, age 18 years or older, baseline NIHSS score > 5, ASPECTS score > 5 and computed tomography angiography (CTA) evidence of carotid T/L or M1-segment middle cerebral artery (MCA) occlusion, and at least moderate collaterals by CTA. Patients were randomized using a real-time, dynamic, Internet-based, minimal sufficient balance randomization method that balanced the study arms with respect to baseline covariates including age, sex, baseline NIHSS score, site of arterial occlusion, baseline ASPECTS score and treatment with intravenously administered alteplase. Permutation-based tests of group differences confirmed group balance across several baseline covariates including sex (p = 1.00), baseline NIHSS score (p = 0.95), site of arterial occlusion (p = 1.00), baseline ASPECTS score (p = 0.28), treatment with intravenously administered alteplase (p = 0.31), and age (p = 0.67). Results from the ESCAPE trial demonstrate the feasibility and the benefit of this covariate adaptive randomization scheme in small-sample trials and for data monitoring endeavors. ESCAPE trial - NCT01778335 - at www.clinicaltrials.gov . Registered on 29 January 2013.

  19. Escape of X-linked miRNA genes from meiotic sex chromosome inactivation.

    Science.gov (United States)

    Sosa, Enrique; Flores, Luis; Yan, Wei; McCarrey, John R

    2015-11-01

    Past studies have indicated that transcription of all X-linked genes is repressed by meiotic sex chromosome inactivation (MSCI) during the meiotic phase of spermatogenesis in mammals. However, more recent studies have shown an increase in steady-state levels of certain X-linked miRNAs in pachytene spermatocytes, suggesting that either synthesis of these miRNAs increases or that degradation of these miRNAs decreases dramatically in these cells. To distinguish between these possibilities, we performed RNA-FISH to detect nascent transcripts from multiple miRNA genes in various spermatogenic cell types. Our results show definitively that Type I X-linked miRNA genes are subject to MSCI, as are all or most X-linked mRNA genes, whereas Type II and III X-linked miRNA genes escape MSCI by continuing ongoing, active transcription in primary spermatocytes. We corroborated these results by co-localization of RNA-FISH signals with both a corresponding DNA-FISH signal and an immunofluorescence signal for RNA polymerase II. We also found that X-linked miRNA genes that escape MSCI locate non-randomly to the periphery of the XY body, whereas genes that are subject to MSCI remain located within the XY body in pachytene spermatocytes, suggesting that the mechanism of escape of X-linked miRNA genes from MSCI involves their relocation to a position outside of the repressive chromatin domain associated with the XY body. The fact that Type II and III X-linked miRNA genes escape MSCI suggests an immediacy of function of the encoded miRNAs specifically required during the meiotic stages of spermatogenesis. © 2015. Published by The Company of Biologists Ltd.

  20. Impact of ocean acidification on the early development and escape behavior of marine medaka (Oryzias melastigma).

    Science.gov (United States)

    Wang, Xiaojie; Song, Lulu; Chen, Yi; Ran, Haoyu; Song, Jiakun

    2017-10-01

    Ocean acidification is predicted to affect a wide diversity of marine organisms. However, no studies have reported the effects of ocean acidification on Indian Ocean fish. We have used the Indian Ocean medaka (Oryzias melastigma) as a model species for a marine fish that lives in coastal waters. We investigated the impact of ocean acidification on the embryonic development and the stereotyped escape behavior (mediated by the Mauthner cell) in newly hatched larvae. Newly fertilized eggs of medaka were reared in seawater at three different partial pressures of carbon dioxide (pCO 2 ): control at 450 μatm, moderate at 1160 μatm, and high at 1783 μatm. Hatch rates, embryonic duration, and larval malformation rates were compared and were not significantly different between the treatments and the control. In the high pCO 2 group, however, the yolks of larvae were significantly smaller than in the control group, and the newly hatched larvae were significantly longer than the larvae in the control. In the moderate pCO 2 group, the eye distance decreased significantly. No significantly negative growth effects were observed in the larvae when exposed to pCO 2 levels that are predicted as a result of ocean acidification in the next 100-200 years. Larvae reared under control conditions readily produced C-start escape behavior to mechanosensory stimuli; however, in the moderate and high pCO 2 experimental groups, the probabilities of C-start were significantly lower than those of the control group. Therefore, the sensory integration needed for the C-start escape behavior appears to be vulnerable to ocean acidification. Altered behavior in marine larval fish, particularly behaviors involved in escape from predation, could have potentially negative implications to fish populations, and, further, to the marine ecosystems at the levels of CO 2 projected for the future. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Anomalous reaction-diffusion as a model of nonexponential DNA escape kinetics.

    Science.gov (United States)

    Chatterjee, Debarati; Cherayil, Binny J

    2010-01-14

    We show that data from recent experiments carried out on the kinetics of DNA escape from alpha-hemolysin nanopores [M. Wiggin, C. Tropini, C. T. Cossa, N. N. Jetha, and A. Marziali, Biophys. J. 95, 5317 (2008)] may be rationalized by a model of chain dynamics based on the anomalous diffusion of a particle moving in a harmonic well in the presence of a delta function sink. The experiments of Wiggin et al. found, among other things, that the occasional occurrence of unusually long escape times in the distribution of chain trapping events led to nonexponential decays in the survival probability, S(t), of the DNA molecules within the nanopore. Wiggin et al. ascribed this nonexponentiality to the existence of a distribution of trapping potentials, which they suggested was the result of stochastic interactions between the bases of the DNA and the amino acids located on the surface of the nanopore. Based on this idea, they showed that the experimentally determined S(t) could be well fit in both the short and long time regimes by a function of the form (1+t/tau)(-alpha) (the so called Becquerel function). In our model, S(t) is found to be given by a Mittag-Leffler function at short times and by a generalized Mittag-Leffler function at long times. By suitable choice of certain parameter values, these functions are found to fit the experimental S(t) even better than the Becquerel function. Anomalous diffusion of DNA within the trap prior to escape over a barrier of fixed height may therefore provide a second, plausible explanation of the data, and may offer fresh perspectives on similar trapping and escape problems.

  2. Rural-Urban Differences in Escape Behavior of European Birds across a Latitudinal Gradient

    OpenAIRE

    Samia, Diogo S. M.; Blumstein, Daniel T.; Díaz, Mario; Grim, Tomas; Ibáñez-Álamo, Juan Diego; Jokimäki, Jukka; Tätte, Kunter; Markó, Gábor; Tryjanowski, Piotr; Møller, Anders Pape

    2017-01-01

    Behavioral adjustment is a key factor that facilitates species’ coexistence with humans in a rapidly urbanizing world. Because urban animals often experience reduced predation risk compared to their rural counterparts, and because escape behavior is energetically costly, we expect that urban environments will select for increased tolerance to humans. Many studies have supported this expectation by demonstrating that urban birds have reduced flight initiation distance (FID = pre...

  3. Escaping Dante’s hell with an informed virtual environment for interactive bodies in movement

    Directory of Open Access Journals (Sweden)

    Rousseaux Francis

    2011-12-01

    Full Text Available The paper addresses the question of Informed Virtual Environments from the point of view of some philosophical and ethical key-issues. By browsing some eclectic experiences like dancing, serving Asturian cider, trying to escape Dante’s Hell or manufacturing a tyre, important questions are raised, and some answers are sketched about some possible ways of designing our future environments: but gestures have then to be considered as cultural objects too, being not reducible to their physical traces.

  4. Limited Neutralizing Antibody Specificities Drive Neutralization Escape in Early HIV-1 Subtype C Infection

    OpenAIRE

    Rong Rong; Bing Li; Lynch, Rebecca M.; Haaland, Richard E.; Murphy, Megan K.; Joseph Mulenga; Allen, Susan A.; Abraham Pinter; Shaw, George M.; Eric Hunter; Robinson, James E.; Gnanakaran, S.; Derdeyn, Cynthia A.

    2009-01-01

    One aim for an HIV vaccine is to elicit neutralizing antibodies (Nab) that can limit replication of genetically diverse viruses and prevent establishment of a new infection. Thus, identifying the strengths and weaknesses of Nab during the early stages of natural infection could prove useful in achieving this goal. Here we demonstrate that viral escape readily occurred despite the development of high titer autologous Nab in two subjects with acute/early subtype C infection. To provide a detail...

  5. Species-specific escape of Plasmodium sporozoites from oocysts of avian, rodent, and human malarial parasites.

    Science.gov (United States)

    Orfano, Alessandra S; Nacif-Pimenta, Rafael; Duarte, Ana P M; Villegas, Luis M; Rodrigues, Nilton B; Pinto, Luciana C; Campos, Keillen M M; Pinilla, Yudi T; Chaves, Bárbara; Barbosa Guerra, Maria G V; Monteiro, Wuelton M; Smith, Ryan C; Molina-Cruz, Alvaro; Lacerda, Marcus V G; Secundino, Nágila F C; Jacobs-Lorena, Marcelo; Barillas-Mury, Carolina; Pimenta, Paulo F P

    2016-08-02

    Malaria is transmitted when an infected mosquito delivers Plasmodium sporozoites into a vertebrate host. There are many species of Plasmodium and, in general, the infection is host-specific. For example, Plasmodium gallinaceum is an avian parasite, while Plasmodium berghei infects mice. These two parasites have been extensively used as experimental models of malaria transmission. Plasmodium falciparum and Plasmodium vivax are the most important agents of human malaria, a life-threatening disease of global importance. To complete their life cycle, Plasmodium parasites must traverse the mosquito midgut and form an oocyst that will divide continuously. Mature oocysts release thousands of sporozoites into the mosquito haemolymph that must reach the salivary gland to infect a new vertebrate host. The current understanding of the biology of oocyst formation and sporozoite release is mostly based on experimental infections with P. berghei, and the conclusions are generalized to other Plasmodium species that infect humans without further morphological analyses. Here, it is described the microanatomy of sporozoite escape from oocysts of four Plasmodium species: the two laboratory models, P. gallinaceum and P. berghei, and the two main species that cause malaria in humans, P. vivax and P. falciparum. It was found that sporozoites have species-specific mechanisms of escape from the oocyst. The two model species of Plasmodium had a common mechanism, in which the oocyst wall breaks down before sporozoites emerge. In contrast, P. vivax and P. falciparum sporozoites show a dynamic escape mechanism from the oocyst via polarized propulsion. This study demonstrated that Plasmodium species do not share a common mechanism of sporozoite escape, as previously thought, but show complex and species-specific mechanisms. In addition, the knowledge of this phenomenon in human Plasmodium can facilitate transmission-blocking studies and not those ones only based on the murine and avian models.

  6. New constraints on the escape of ionizing photons from starburst galaxies using ionization-parameter mapping

    Energy Technology Data Exchange (ETDEWEB)

    Zastrow, Jordan; Oey, M. S. [Department of Astronomy, University of Michigan, 500 Church Street, 830 Dennison, Ann Arbor, MI 48109-1042 (United States); Veilleux, Sylvain [Department of Astronomy, University of Maryland, College Park, MD 20742 (United States); McDonald, Michael, E-mail: jazast@umich.edu [Kavli Institute for Astrophysics and Space Research, MIT, Cambridge, MA 02139 (United States)

    2013-12-10

    The fate of ionizing radiation in starburst galaxies is key to understanding cosmic reionization. However, the galactic parameters on which the escape fraction of ionizing radiation depend are not well understood. Ionization-parameter mapping provides a simple, yet effective, way to study the radiative transfer in starburst galaxies. We obtain emission-line ratio maps of [S III]/[S II] for six, nearby, dwarf starbursts: NGC 178, NGC 1482, NGC 1705, NGC 3125, NGC 7126, and He 2-10. The narrowband images are obtained with the Maryland-Magellan Tunable Filter at Las Campanas Observatory. Using these data, we previously reported the discovery of an optically thin ionization cone in NGC 5253, and here we also discover a similar ionization cone in NGC 3125. This latter cone has an opening angle of 40° ± 5° (0.4 sr), indicating that the passageways through which ionizing radiation may travel correspond to a small solid angle. Additionally, there are three sample galaxies that have winds and/or superbubble activity, which should be conducive to escaping radiation, yet they are optically thick. These results support the scenario that an orientation bias limits our ability to directly detect escaping Lyman continuum in many starburst galaxies. A comparison of the star formation properties and histories of the optically thin and thick galaxies is consistent with the model that high escape fractions are limited to galaxies that are old enough (≳3 Myr) for mechanical feedback to have cleared optically thin passageways in the interstellar medium, but young enough (≲5 Myr) that the ionizing stars are still present.

  7. A new insight into diffusional escape from a biased cylindrical trap

    Science.gov (United States)

    Berezhkovskii, Alexander M.; Dagdug, Leonardo; Bezrukov, Sergey M.

    2017-09-01

    Recent experiments with single biological nanopores, as well as single-molecule fluorescence spectroscopy and pulling studies of protein and nucleic acid folding raised a number of questions that stimulated theoretical and computational investigations of barrier crossing dynamics. The present paper addresses a closely related problem focusing on trajectories of Brownian particles that escape from a cylindrical trap in the presence of a force F parallel to the cylinder axis. To gain new insights into the escape dynamics, we analyze the "fine structure" of these trajectories. Specifically, we divide trajectories into two segments: a looping segment, when a particle unsuccessfully tries to escape returning to the trap bottom again and again, and a direct-transit segment, when it finally escapes moving without touching the bottom. Analytical expressions are derived for the Laplace transforms of the probability densities of the durations of the two segments. These expressions are used to find the mean looping and direct-transit times as functions of the biasing force F. It turns out that the force-dependences of the two mean times are qualitatively different. The mean looping time monotonically increases as F decreases, approaching exponential F-dependence at large negative forces pushing the particle towards the trap bottom. In contrast to this intuitively appealing behavior, the mean direct-transit time shows rather counterintuitive behavior: it decreases as the force magnitude, |F|, increases independently of whether the force pushes the particles to the trap bottom or to the exit from the trap, having a maximum at F = 0.

  8. Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation.

    Science.gov (United States)

    Liu, Donglai; Zuo, Tao; Hora, Bhavna; Song, Hongshuo; Kong, Wei; Yu, Xianghui; Goonetilleke, Nilu; Bhattacharya, Tanmoy; Perelson, Alan S; Haynes, Barton F; McMichael, Andrew J; Gao, Feng

    2014-11-19

    Fitness costs and slower disease progression are associated with a cytolytic T lymphocyte (CTL) escape mutation T242N in Gag in HIV-1-infected individuals carrying HLA-B*57/5801 alleles. However, the impact of different context in diverse HIV-1 strains on the fitness costs due to the T242N mutation has not been well characterized. To better understand the extent of fitness costs of the T242N mutation and the repair of fitness loss through compensatory amino acids, we investigated its fitness impact in different transmitted/founder (T/F) viruses. The T242N mutation resulted in various levels of fitness loss in four different T/F viruses. However, the fitness costs were significantly compromised by preexisting compensatory amino acids in (Isoleucine at position 247) or outside (glutamine at position 219) the CTL epitope. Moreover, the transmitted T242N escape mutant in subject CH131 was as fit as the revertant N242T mutant and the elimination of the compensatory amino acid I247 in the T/F viral genome resulted in significant fitness cost, suggesting the fitness loss caused by the T242N mutation had been fully repaired in the donor at transmission. Analysis of the global circulating HIV-1 sequences in the Los Alamos HIV Sequence Database showed a high prevalence of compensatory amino acids for the T242N mutation and other T cell escape mutations. Our results show that the preexisting compensatory amino acids in the majority of circulating HIV-1 strains could significantly compromise the fitness loss due to CTL escape mutations and thus increase challenges for T cell based vaccines.

  9. Gravitational and radiative effects on the escape of helium from the moon

    Science.gov (United States)

    Hodges, R. R., Jr.

    1978-01-01

    On the moon, and probably on Mercury and other similar regolith-covered bodies with tenuous atmosphere, the dominant gas is He-4. It arises as the radiogenic product of the decay of uranium and thorium within any planet, but its major source appears to be the alpha particle flux of the solar wind. The moon intercepts solar wind helium at an average rate of 1.1 times 10 to the 24th atom/sec, and loses it at the same rate. Some helium may escape directly as the result of the process of solar wind soil bombardment which may release previously trapped helium at superthermal speeds. Atmospheric models have been calculated with the total helium influx as source. Subsequent comparison of model and measured helium concentrations indicates that the fraction of helium escaping via the atmosphere may range from 20% to 100% of the solar wind influx. Of the escaping atmosphere, most of the helium (about 93%) becomes trapped in earth orbit, while about 5% gets trapped in satellite orbits about the moon. Owing to a 6 month lifetime for helium in solar radiation, the satellite atoms form a lunar corona that exceeds the lunar atmosphere in total abundance by a factor of 4 to 5.

  10. Papers of the Canadian Association of Petroleum Producers helicopter underwater escape breathing systems workshop : summary report

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2006-03-01

    This workshop evaluated training and medical issues regarding operational escape breathing systems (EBS). The workshop enabled members of the Canadian Association of Petroleum Producers (CAPP) to choose the most appropriate EBS for use on the east coast of Canada. The principles of EBS for helicopter underwater escape were reviewed. Demonstrations of a hybrid re-breather and a compressed gas system were presented. An overview of work conducted to date by the Helicopter Underwater Escape Breathing Apparatus (HUEBA) taskforce was provided. An outline of the Survival at Sea project was presented, as well as background information on the development of the Shark Air Pocket. Training requirements associated with the use of re-breathers and compressed air devices were reviewed with reference to their current usage by the United Kingdom (UK) military. Risks associated with barotraumas were examined, as well as current training practices among the UK offshore oil industry and military. Data on water impact accidents and fatalities were presented. EBS effects on buoyancy were considered. A summary of the risks associated with using a hybrid re-breather in an emergency was provided. Issues including the development of a technical standard for EBS were discussed. It was concluded that there is a need to clarify the medical screening requirements for training with compressed gas. Six presentations were given at the workshop, followed by panel discussions. 2 tabs.

  11. [Effect of modified crushing-cercariae escaping method on detection of infected Oncomelania snails in field].

    Science.gov (United States)

    He, Liang-Cai; Wang, Jia-Song; Li, Hua-Zhong; Rong, Xian-Bing; Yuan, Mei-Zhi; Peng, Xiao-Wu; Zhu, Shao-Liang; Wang, Lu; He, Zheng-Wen; Yang, Zhi-Qiang; Hong, Min; Su, Wen; Li, Jun

    2012-02-01

    To evaluate the effect of a modified crushing-cercariae escaping method on the detection of infected Oncomelania snails in the field. A snail survey was carried out in Jingzhou City in the spring of 2011, and the villages were randomly divided into several groups, the coincidence rates, detection rates and the labour cost of the modified crushing-cercariae escaping method and crushing method were compared. A total of 14 snail spots were surveyed, and the coincidence rate of the two methods was 100%. In the spring snail survey, 539 villages and 3 536 spots with snails were detected by the modified crushing-cercariae escaping method, and 671 villages and 11 375 spots with snails were detected by the crushing method. The detection rates of villages with infected snails of the two methods were 25.79% and 28.46%, respectively, the difference between them was not statistically significant (chi2 = 1.079 5, P > 0.05); and those of spots with infected snails were 5.57% and 3.66%, respectively, which had no significant difference between them (chi2 = 95.464 1, P snails quickly and accurately with less labour cost, therefore, it is suitable for detecting environments with infected snails in batch in endemic areas.

  12. Modelling pollen-mediated gene flow in rice: risk assessment and management of transgene escape.

    Science.gov (United States)

    Rong, Jun; Song, Zhiping; de Jong, Tom J; Zhang, Xinsheng; Sun, Shuguang; Xu, Xian; Xia, Hui; Liu, Bo; Lu, Bao-Rong

    2010-05-01

    Fast development and commercialization of genetically modified plants have aroused concerns of transgene escape and its environmental consequences. A model that can effectively predict pollen-mediated gene flow (PMGF) is essential for assessing and managing risks from transgene escape. A pollen-trap method was used to measure the wind-borne pollen dispersal in cultivated rice and common wild rice, and effects of relative humidity, temperature and wind speed on pollen dispersal were estimated. A PMGF model was constructed based on the pollen dispersal pattern in rice, taking outcrossing rates of recipients and cross-compatibility between rice and its wild relatives into consideration. Published rice gene flow data were used to validate the model. Pollen density decreased in a simple exponential pattern with distances to the rice field. High relative humidity reduced pollen dispersal distances. Model simulation showed an increased PMGF frequency with the increase of pollen source size (the area of a rice field), but this effect levelled off with a large pollen-source size. Cross-compatibility is essential when modelling PMGF from rice to its wild relatives. The model fits the data well, including PMGF from rice to its wild relatives. Therefore, it can be used to predict PMGF in rice under diverse conditions (e.g. different outcrossing rates and cross-compatibilities), facilitating the determination of isolation distances to minimize transgene escape. The PMGF model may be extended to other wind-pollinated plant species such as wheat and barley.

  13. Symmetry breaking on density in escaping ants: experiment and alarm pheromone model.

    Science.gov (United States)

    Li, Geng; Huan, Di; Roehner, Bertrand; Xu, Yijuan; Zeng, Ling; Di, Zengru; Han, Zhangang

    2014-01-01

    The symmetry breaking observed in nature is fascinating. This symmetry breaking is observed in both human crowds and ant colonies. In such cases, when escaping from a closed space with two symmetrically located exits, one exit is used more often than the other. Group size and density have been reported as having no significant impact on symmetry breaking, and the alignment rule has been used to model symmetry breaking. Density usually plays important roles in collective behavior. However, density is not well-studied in symmetry breaking, which forms the major basis of this paper. The experiment described in this paper on an ant colony displays an increase then decrease of symmetry breaking versus ant density. This result suggests that a Vicsek-like model with an alignment rule may not be the correct model for escaping ants. Based on biological facts that ants use pheromones to communicate, rather than seeing how other individuals move, we propose a simple yet effective alarm pheromone model. The model results agree well with the experimental outcomes. As a measure, this paper redefines symmetry breaking as the collective asymmetry by deducing the random fluctuations. This research indicates that ants deposit and respond to the alarm pheromone, and the accumulation of this biased information sharing leads to symmetry breaking, which suggests true fundamental rules of collective escape behavior in ants.

  14. Investigating Possible Effects of Ethnicity and Age on Gambling as an Escape.

    Science.gov (United States)

    Cookman, Matthew L; Weatherly, Jeffrey N

    2016-06-01

    Previous research has shown that there are a number of risk factors for disordered and problem gambling, including an individual's ethnicity and age. Endorsing gambling as an escape has also been shown to contribute to and maintain disordered gambling. The present study examined potential interactions between ethnicity and age as they relate to disordered gambling, as well as if ethnicity and age would be predictors of endorsing gambling as an escape. Three hundred fifteen adults from the United States completed measures relating to gambling. Participants were grouped into ethnic categories of Caucasian and non-Caucasian, and age groups of 18-25, 26-35, 36-55, and 56 years old and above. Non-Caucasians reported more gambling problems than Caucasians. A significant interaction was found between ethnicity and age for 36-55 year olds. Overall, participants were more likely to gamble for positive than negative reinforcement. However, only gambling as an escape was a significant predictor of disordered gambling. Implications and limitations are discussed with the thought that these results are informative to practitioners treating disordered gambling.

  15. Reflection principles for biased random walks and application to escape time distributions

    Science.gov (United States)

    Khantha, M.; Balakrishnan, V.

    1985-12-01

    We present a reflection principle for an arbitrary biased continuous time random walk (comprising both Markovian and non-Markovian processes) in the presence of a reflecting barrier on semi-infinite and finite chains. For biased walks in the presence of a reflecting barrier this principle (which cannot be derived from combinatorics) is completely different from its familiar form in the presence of an absorbing barrier. The result enables us to obtain closed-form solutions for the Laplace transform of the conditional probability for biased walks on finite chains for all three combinations of absorbing and reflecting barriers at the two ends. An important application of these solutions is the calculation of various first-passage-time and escape-time distributions. We obtain exact results for the characteristic functions of various kinds of escape time distributions for biased random walks on finite chains. For processes governed by a long-tailed event-time distribution we show that the mean time of escape from bounded regions diverges even in the presence of a bias—suggesting, in a sense, the absence of true long-range diffusion in such "frozen" processes.

  16. Crossover of the Thermal Escape Problem in Annular Spatially Distributed Systems

    Science.gov (United States)

    Fedorov, Kirill G.; Pankratov, Andrey L.

    2009-12-01

    The computer simulations of fluctuational dynamics of an annular system governed by the sine-Gordon model with a white noise source are performed. It is demonstrated that the mean escape time (MET) of a phase string for an annular structure can be much larger than for a linear one and has a strongly pronounced maximum as a function of system’s length. The location of the MET maximum roughly equals the size of the kink-antikink pair, which leads to evidence of a spatial crossover between two dynamical regimes: when the phase string escapes over the potential barrier as a whole and when the creation of kink-antikink pairs is the main mechanism of the escape process. For large lengths and in the limit of small noise intensity γ, for both MET and inverse concentration of kinks, we observe the same dependence versus the kink energy Ek: ˜exp⁡(2Ek/γ) for the annular structure and ˜exp⁡(Ek/γ) for the linear one.

  17. Broad Targeting Specificity during Bacterial Type III CRISPR-Cas Immunity Constrains Viral Escape.

    Science.gov (United States)

    Pyenson, Nora C; Gayvert, Kaitlyn; Varble, Andrew; Elemento, Olivier; Marraffini, Luciano A

    2017-09-13

    CRISPR loci are a cluster of repeats separated by short "spacer" sequences derived from prokaryotic viruses and plasmids that determine the targets of the host's CRISPR-Cas immune response against its invaders. For type I and II CRISPR-Cas systems, single-nucleotide mutations in the seed or protospacer adjacent motif (PAM) of the target sequence cause immune failure and allow viral escape. This is overcome by the acquisition of multiple spacers that target the same invader. Here we show that targeting by the Staphylococcus epidermidis type III-A CRISPR-Cas system does not require PAM or seed sequences, and thus prevents viral escape via single-nucleotide substitutions. Instead, viral escapers can only arise through complete target deletion. Our work shows that, as opposed to type I and II systems, the relaxed specificity of type III CRISPR-Cas targeting provides robust immune responses that can lead to viral extinction with a single spacer targeting an essential phage sequence. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Spared nerve injury rats exhibit thermal hyperalgesia on an automated operant dynamic thermal escape Task

    Directory of Open Access Journals (Sweden)

    Chialvo Dante R

    2005-05-01

    Full Text Available Abstract Well-established methods are available to measure thermal and mechanical sensitivity in awake behaving rats. However, they require experimenter manipulations and tend to emphasize reflexive behaviors. Here we introduce a new behavioral test, with which we examine thermal sensitivity of rats with neuropathic injury. We contrast thermal hyperalgesia between spared nerve injury and chronic constriction injury rats. This device is a fully automated thermal sensitivity assessment tool designed to emphasize integrated learned responses to thermal painful and non-painful stimuli that are applied dynamically to a surface on which the animal is standing. It documents escape behavior in awake, unrestrained animals to innocuous and noxious heating of the floor where the animal is located. Animals learn to minimize pain by escaping to the opposite non-heated side; escape latency is recorded. On this device, thermal stimulus-response curves showed > 6°C leftward shift in both groups of neuropathic rats. In contrast, when these animals were tested on hotplate the stimulus-response shift was

  19. A novel category of antigens enabling CTL immunity to tumor escape variants: Cinderella antigens.

    Science.gov (United States)

    Seidel, Ursula J E; Oliveira, Claudia C; Lampen, Margit H; Hall, Thorbald van

    2012-01-01

    Deficiencies in MHC class I antigen presentation are a common feature of tumors and allows escape from cytotoxic T lymphocyte (CTL)-mediated killing. It is crucial to take this capacity of tumors into account for the development of T-cell-based immunotherapy, as it may strongly impair their effectiveness. A variety of escape mechanisms has been described thus far, but progress in counteracting them is poor. Here we review a novel strategy to target malignancies with defects in the antigenic processing machinery (APM). The concept is based on a unique category of CD8+ T-cell epitopes that is associated with impaired peptide processing, which we named TEIPP. We characterized this alternative peptide repertoire emerging in MHC-I on tumors lacking classical antigen processing due to defects in the peptide transporter TAP (transporter associated with peptide processing). These TEIPPs exemplify interesting parallels with the folktale figure Cinderella: they are oppressed and neglected by a stepmother (like functional TAP prevents TEIPP presentation), until the suppression is released and Cinderella/TEIPP achieves unexpected recognition. TEIPP-specific CTLs and their cognate peptide-epitopes provide a new strategy to counteract immune evasion by APM defects and bear potential to targeting escape variants observed in a wide range of cancers.

  20. Therapeutics targeting tumor immune escape: towards the development of new generation anticancer vaccines.

    Science.gov (United States)

    Mocellin, Simone; Nitti, Donato

    2008-05-01

    Despite the evidence that immune effectors can play a significant role in controlling tumor growth under natural conditions or in response to therapeutic manipulation, it is clear that malignant cells evade immune surveillance in most cases. Considering that anticancer vaccination has reached a plateau of results and currently no vaccination regimen is indicated as a standard anticancer therapy, the dissection of the molecular events underlying tumor immune escape is the necessary condition to make anticancer vaccines a therapeutic weapon effective enough to be implemented in the routine clinical setting. Recent years have witnessed significant advances in our understanding of the molecular mechanisms underlying tumor immune escape. These mechanistic insights are fostering the development of rationally designed therapeutics aimed at reverting the immunosuppressive circuits that undermine an effective antitumor immune response. In this review, the best characterized mechanisms that allow cancer cells to evade immune surveillance are overviewed and the most debated controversies constellating this complex field are highlighted. In addition, the latest therapeutic strategies devised to overcome tumor immune escape are described, with special regard to those entering clinical phase investigation. Copyright (c) 2007 Wiley-Periodicals, Inc.