Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia.

PubMed

Grembecka, Jolanta; He, Shihan; Shi, Aibin; Purohit, Trupta; Muntean, Andrew G; Sorenson, Roderick J; Showalter, Hollis D; Murai, Marcelo J; Belcher, Amalia M; Hartley, Thomas; Hess, Jay L; Cierpicki, Tomasz

2012-01-29

Translocations involving the mixed lineage leukemia (MLL) gene result in human acute leukemias with very poor prognosis. The leukemogenic activity of MLL fusion proteins is critically dependent on their direct interaction with menin, a product of the multiple endocrine neoplasia (MEN1) gene. Here we present what are to our knowledge the first small-molecule inhibitors of the menin-MLL fusion protein interaction that specifically bind menin with nanomolar affinities. These compounds effectively reverse MLL fusion protein-mediated leukemic transformation by downregulating the expression of target genes required for MLL fusion protein oncogenic activity. They also selectively block proliferation and induce both apoptosis and differentiation of leukemia cells harboring MLL translocations. Identification of these compounds provides a new tool for better understanding MLL-mediated leukemogenesis and represents a new approach for studying the role of menin as an oncogenic cofactor of MLL fusion proteins. Our findings also highlight a new therapeutic strategy for aggressive leukemias with MLL rearrangements.

Escape from R-peptide deletion in a {gamma}-retrovirus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schneider, Irene C.; Eckhardt, Manon; Brynza, Julia

2011-09-30

The R peptide in the cytoplasmic tail (C-tail) of {gamma}-retroviral envelope proteins (Env) prevents membrane fusion before budding. To analyse its role in the formation of replication competent, infectious particles, we developed chimeric murine leukaemia viruses (MLV) with unmodified or R-peptide deleted Env proteins of the gibbon ape leukaemia virus (GaLV). While titres of these viruses were unaffected, R-peptide deficiency led to strongly impaired spreading. Most remarkably, we isolated an escape mutant which had restored an open reading frame for a C-terminal extension of the truncated C-tail. A reconstituted virus encoding this escape C-tail replicated in cell culture. In contrastmore » to R-peptide deficient Env, particle incorporation of the escape Env was effective due to an enhanced protein expression and restored intracellular co-localisation with Gag proteins. Our data demonstrate that the R peptide not only regulates membrane fusion but also mediates efficient Env protein particle incorporation in {gamma}-retrovirus infected cells.« less

Enfuvirtide (T20)-Based Lipopeptide Is a Potent HIV-1 Cell Fusion Inhibitor: Implications for Viral Entry and Inhibition.

PubMed

Ding, Xiaohui; Zhang, Xiujuan; Chong, Huihui; Zhu, Yuanmei; Wei, Huamian; Wu, Xiyuan; He, Jinsheng; Wang, Xinquan; He, Yuxian

2017-09-15

The peptide drug enfuvirtide (T20) is the only viral fusion inhibitor used in combination therapy for HIV-1 infection, but it has relatively low antiviral activity and easily induces drug resistance. Emerging studies demonstrate that lipopeptide-based fusion inhibitors, such as LP-11 and LP-19, which mainly target the gp41 pocket site, have greatly improved antiviral potency and in vivo stability. In this study, we focused on developing a T20-based lipopeptide inhibitor that lacks pocket-binding sequence and targets a different site. First, the C-terminal tryptophan-rich motif (TRM) of T20 was verified to be essential for its target binding and inhibition; then, a novel lipopeptide, termed LP-40, was created by replacing the TRM with a fatty acid group. LP-40 showed markedly enhanced binding affinity for the target site and dramatically increased inhibitory activity on HIV-1 membrane fusion, entry, and infection. Unlike LP-11 and LP-19, which required a flexible linker between the peptide sequence and the lipid moiety, addition of a linker to LP-40 sharply reduced its potency, implying different binding modes with the extended N-terminal helices of gp41. Also, interestingly, LP-40 showed more potent activity than LP-11 in inhibiting HIV-1 Env-mediated cell-cell fusion while it was less active than LP-11 in inhibiting pseudovirus entry, and the two inhibitors displayed synergistic antiviral effects. The crystal structure of LP-40 in complex with a target peptide revealed their key binding residues and motifs. Combined, our studies have not only provided a potent HIV-1 fusion inhibitor, but also revealed new insights into the mechanisms of viral inhibition. IMPORTANCE T20 is the only membrane fusion inhibitor available for treatment of viral infection; however, T20 requires high doses and has a low genetic barrier for resistance, and its inhibitory mechanism and structural basis remain unclear. Here, we report the design of LP-40, a T20-based lipopeptide inhibitor

Effects of ROCK inhibitor Y-27632 on cell fusion through a microslit.

PubMed

Wada, Ken-Ichi; Hosokawa, Kazuo; Ito, Yoshihiro; Maeda, Mizuo

2015-11-01

We previously reported a direct cytoplasmic transfer method using a microfluidic device, in which cell fusion was induced through a microslit (slit-through-fusion) by the Sendai virus envelope (HVJ-E) to prevent nuclear mixing. However, the method was impractical due to low efficiency of slit-through-fusion formation and insufficient prevention of nuclear mixing. The purpose of this study was to establish an efficient method for inducing slit-through-fusion without nuclear mixing. We hypothesized that modulation of cytoskeletal component can decrease nuclear migration through the microslit considering its functions. Here we report that supplementation with Y-27632, a specific ROCK inhibitor, significantly enhances cell fusion induction and prevention of nuclear mixing. Supplementation with Y-27632 increased the formation of slit-through-fusion efficiency by more than twofold. Disruption of F-actin by Y-27632 prevented nuclear migration between fused cells through the microslit. These two effects of Y-27632 led to promotion of the slit-through-fusion without nuclear mixing with a 16.5-fold higher frequency compared to our previous method (i.e., cell fusion induction by HVJ-E without supplementation with Y-27632). We also confirmed that mitochondria were successfully transferred to the fusion partner under conditions of Y-27632 supplementation. These findings demonstrate the practicality of our cell fusion system in producing direct cytoplasmic transfer between live cells. © 2015 Wiley Periodicals, Inc.

Rational improvement of gp41-targeting HIV-1 fusion inhibitors: an innovatively designed Ile-Asp-Leu tail with alternative conformations.

PubMed

Zhu, Yun; Su, Shan; Qin, Lili; Wang, Qian; Shi, Lei; Ma, Zhenxuan; Tang, Jianchao; Jiang, Shibo; Lu, Lu; Ye, Sheng; Zhang, Rongguang

2016-09-26

Peptides derived from the C-terminal heptad repeat (CHR) of HIV gp41 have been developed as effective fusion inhibitors against HIV-1, but facing the challenges of enhancing potency and stability. Here, we report a rationally designed novel HIV-1 fusion inhibitor derived from CHR-derived peptide (Trp628~Gln653, named CP), but with an innovative Ile-Asp-Leu tail (IDL) that dramatically increased the inhibitory activity by up to 100 folds. We also determined the crystal structures of artificial fusion peptides N36- and N43-L6-CP-IDL. Although the overall structures of both fusion peptides share the canonical six-helix bundle (6-HB) configuration, their IDL tails adopt two different conformations: a one-turn helix with the N36, and a hook-like structure with the longer N43. Structural comparison showed that the hook-like IDL tail possesses a larger interaction interface with NHR than the helical one. Further molecular dynamics simulations of the two 6-HBs and isolated CP-IDL peptides suggested that hook-like form of IDL tail can be stabilized by its binding to NHR trimer. Therefore, CP-IDL has potential for further development as a new HIV fusion inhibitor, and this strategy could be widely used in developing artificial fusion inhibitors against HIV and other enveloped viruses.

Novel design strategy for checkpoint kinase 2 inhibitors using pharmacophore modeling, combinatorial fusion, and virtual screening.

PubMed

Lin, Chun-Yuan; Wang, Yen-Ling

2014-01-01

Checkpoint kinase 2 (Chk2) has a great effect on DNA-damage and plays an important role in response to DNA double-strand breaks and related lesions. In this study, we will concentrate on Chk2 and the purpose is to find the potential inhibitors by the pharmacophore hypotheses (PhModels), combinatorial fusion, and virtual screening techniques. Applying combinatorial fusion into PhModels and virtual screening techniques is a novel design strategy for drug design. We used combinatorial fusion to analyze the prediction results and then obtained the best correlation coefficient of the testing set (r test) with the value 0.816 by combining the Best(train)Best(test) and Fast(train)Fast(test) prediction results. The potential inhibitors were selected from NCI database by screening according to Best(train)Best(test) + Fast(train)Fast(test) prediction results and molecular docking with CDOCKER docking program. Finally, the selected compounds have high interaction energy between a ligand and a receptor. Through these approaches, 23 potential inhibitors for Chk2 are retrieved for further study.

A high throughput Cre–lox activated viral membrane fusion assay identifies pharmacological inhibitors of HIV entry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Esposito, Anthony M.; Cheung, Pamela; Swartz, Talia H.

Enveloped virus entry occurs when viral and cellular membranes fuse releasing particle contents into the target cell. Human immunodeficiency virus (HIV) entry occurs by cell-free virus or virus transferred between infected and uninfected cells through structures called virological synapses. We developed a high-throughput cell-based assay to identify small molecule inhibitors of cell-free or virological synapse-mediated entry. An HIV clone carrying Cre recombinase as a Gag-internal gene fusion releases active Cre into cells upon viral entry activating a recombinatorial gene switch changing dsRed to GFP-expression. A screen of a 1998 known-biological profile small molecule library identified pharmacological HIV entry inhibitors thatmore » block both cell-free and cell-to-cell infection. Many top hits were noted as HIV inhibitors in prior studies, but not previously recognized as entry antagonists. Modest therapeutic indices for simvastatin and nigericin were observed in confirmatory HIV infection assays. This robust assay is adaptable to study HIV and heterologous viral pseudotypes. - Highlights: • Cre recombinase viral fusion assay screens cell-free or cell–cell entry inhibitors. • This Gag-iCre based assay is specific for the entry step of HIV replication. • Screened a library of known pharmacologic compounds for HIV fusion antagonists. • Many top hits were previously noted as HIV inhibitors, but here are classified as entry antagonists. Many top hits were previously noted as HIV inhibitors, but not as entry antagonists. • The assay is compatible with pseudotyping with HIV and heterologous viruses.« less

Targeting both viral and host determinants of human immunodeficiency virus entry, using a new lentiviral vector coexpressing the T20 fusion inhibitor and a selective CCL5 intrakine.

PubMed

Petit, Nicolas; Dorgham, Karim; Levacher, Béatrice; Burlion, Aude; Gorochov, Guy; Marodon, Gilles

2014-08-01

Numerous strategies targeting early and late steps of the HIV life cycle have been proposed for gene therapy. However, targeting viral and host determinants of HIV entry is the only strategy that would prevent viral DNA-mediated CD4(+) cell death while diminishing the possibility for the virus to escape. To this end, we devised a bicistronic lentiviral vector expressing the membrane-bound form of the T20 fusion inhibitor, referred to as the C46 peptide, and a CCR5 superagonist, modified to sequester CCR5 away from the cell surface, referred to as the P2-CCL5 intrakine. We tested the effects of the vector on HIV infection and replication, using the human CEMR5 cell line expressing CD4 and CCR5, and primary human T cells. Transduced cells expressed the C46 peptide, detected with the 2F5 monoclonal antibody by flow cytometry. Expression of the P2-CCL5 intrakine correlates with lower levels of cell surface CCR5. Complete protection against HIV infection could be observed in cells expressing the protective transgenes. Importantly, we show that the combination of the transgenes was more potent than either transgene alone, showing the interest of expressing two entry inhibitors to inhibit HIV infection. Last, genetically modified cells possessed a selective advantage over nonmodified cells on HIV challenge in vitro, showing that modified cells were protected from HIV-induced cell death. Our results demonstrate that lentiviral vectors coexpressing the T20 fusion inhibitor and the P2-CCL5 intrakine represent promising tools for HIV gene therapy.

The M-T Hook Structure Is Critical for Design of HIV-1 Fusion Inhibitors*

PubMed Central

Chong, Huihui; Yao, Xue; Sun, Jianping; Qiu, Zonglin; Zhang, Meng; Waltersperger, Sandro; Wang, Meitian; Cui, Sheng; He, Yuxian

2012-01-01

CP621-652 is a potent HIV-1 fusion inhibitor peptide derived from the C-terminal heptad repeat of gp41. We recently identified that its N-terminal residues Met-626 and Thr-627 adopt a unique hook-like structure (termed M-T hook) thus stabilizing the interaction of the inhibitor with the deep pocket on the N-terminal heptad repeat. In this study, we further demonstrated that the M-T hook structure is a key determinant of CP621-652 in terms of its thermostability and anti-HIV activity. To directly define the structure and function of the M-T hook, we generated the peptide MT-C34 by incorporating Met-626 and Thr-627 into the N terminus of the C-terminal heptad repeat-derived peptide C34. The high resolution crystal structure (1.9 Å) of MT-C34 complexed by an N-terminal heptad repeat-derived peptide reveals that the M-T hook conformation is well preserved at the N-terminal extreme of the inhibitor. Strikingly, addition of two hook residues could dramatically enhance the binding affinity and thermostability of 6-helix bundle core. Compared with C34, MT-C34 exhibited significantly increased activity to inhibit HIV-1 envelope-mediated cell fusion (6.6-fold), virus entry (4.5-fold), and replication (6-fold). Mechanistically, MT-C34 had a 10.5-fold higher increase than C34 in blocking 6-helix bundle formation. We further showed that MT-C34 possessed higher potency against T20 (Enfuvirtide, Fuzeon)-resistant HIV-1 variants. Therefore, this study provides convincing data for our proposed concept that the M-T hook structure is critical for designing HIV-1 fusion inhibitors. PMID:22879603

Overcoming resistance to single-agent therapy for oncogenic BRAF gene fusions via combinatorial targeting of MAPK and PI3K/mTOR signaling pathways

PubMed Central

Jain, Payal; Silva, Amanda; Han, Harry J.; Lang, Shih-Shan; Zhu, Yuankun; Boucher, Katie; Smith, Tiffany E.; Vakil, Aesha; Diviney, Patrick; Choudhari, Namrata; Raman, Pichai; Busch, Christine M.; Delaney, Tim; Yang, Xiaodong; Olow, Aleksandra K.; Mueller, Sabine; Haas-Kogan, Daphne; Fox, Elizabeth; Storm, Phillip B.; Resnick, Adam C.; Waanders, Angela J.

2017-01-01

Pediatric low-grade gliomas (PLGGs) are frequently associated with activating BRAF gene fusions, such as KIAA1549-BRAF, that aberrantly drive the mitogen activated protein kinase (MAPK) pathway. Although RAF inhibitors (RAFi) have been proven effective in BRAF-V600E mutant tumors, we have previously shown how the KIAA1549-BRAF fusion can be paradoxically activated by RAFi. While newer classes of RAFi, such as PLX8394, have now been shown to inhibit MAPK activation by KIAA1549-BRAF, we sought to identify alternative MAPK pathway targeting strategies using clinically relevant MEK inhibitors (MEKi), along with potential escape mechanisms of acquired resistance to single-agent MAPK pathway therapies. We demonstrate effectiveness of multiple MEKi against diverse BRAF-fusions with novel N-terminal partners, with trametinib being the most potent. However, resistance to MEKi or PLX8394 develops via increased RTK expression causing activation of PI3K/mTOR pathway in BRAF-fusion expressing resistant clones. To circumvent acquired resistance, we show potency of combinatorial targeting with trametinib and everolimus, an mTOR inhibitor (mTORi) against multiple BRAF-fusions. While single-agent mTORi and MEKi PLGG clinical trials are underway, our study provides preclinical rationales for using MEKi and mTORi combinatorial therapy to stave off or prevent emergent drug-resistance in BRAF-fusion driven PLGGs. PMID:29156677

JAK inhibitors suppress t(8;21) fusion protein-induced leukemia

PubMed Central

Lo, Miao-Chia; Peterson, Luke F.; Yan, Ming; Cong, Xiuli; Hickman, Justin H.; DeKelver, Russel C.; Niewerth, Denise; Zhang, Dong-Er

2014-01-01

Oncogenic mutations in components of the JAK/STAT pathway, including those in cytokine receptors and JAKs, lead to increased activity of downstream signaling and are frequently found in leukemia and other hematological disorders. Thus, small-molecule inhibitors of this pathway have been the focus of targeted therapy in these hematological diseases. We previously showed that t(8;21) fusion protein AML1-ETO and its alternatively spliced variant AML1-ETO9a (AE9a) enhance the JAK/STAT pathway via down-regulation of CD45, a negative regulator of this pathway. To investigate the therapeutic potential of targeting JAK/STAT in t(8;21) leukemia, we examined the effects of a JAK2-selective inhibitor TG101209 and a JAK1/2-selective inhibitor INCB18424 on t(8;21) leukemia cells. TG101209 and INCB18424 inhibited proliferation and promoted apoptosis of these cells. Furthermore, TG101209 treatment in AE9a leukemia mice reduced tumor burden and significantly prolonged survival. TG101209 also significantly impaired the leukemia-initiating potential of AE9a leukemia cells in secondary recipient mice. These results demonstrate the potential therapeutic efficacy of JAK inhibitors in treating t(8;21) AML. PMID:23812420

[Isolation and purification of recombinant soluble and non-fusion angiogenesis inhibitor Kringle 5 using chromatography].

PubMed

Ma, Lina; Wu, Dan; Bian, Liujiao

2012-08-01

The Kringle 5 domain of plasminogen is one of the most potent angiogenesis inhibitors known to date, which can inhibit cell proliferation and migration efficiently. In the study, on the foundation of successful clone and expression of recombinant soluble and non-fusion angiogenesis inhibitor Kringle 5, a two-step chromatographic method, including the use of SP Sepharose Fast Flow cation exchanger and Sephacryl S-100 HR size exclusion chromatography in sequence, was established to separate and purify angiogenesis inhibitor Kringle 5. On the SP Sepharose Fast Flow column, the buffer A consisted of 50.0 mmol/L acetic acid-sodium acetate (pH 5.2), and the buffer B consisted of buffer A with the addition of 0.5 mol/L sodium chloride (pH 5.2); on Sephacryl S-100 HR column, the elution buffer was 5.0 mmol/L phosphate solution (pH 7.0). Through the two-step chromatographic purification process, the purity of the obtained Kringle 5 was more than 98%. In addition, it was found that the obtained Kringle 5 could inhibit the blood vessel growth of chick embryo chorioallantoic membrane effectively. Finally it is concluded that this method can effectively separate active recombinant soluble and non-fusion angiogenesis inhibitor Kringle 5.

Fusion proteins comprising annexin V and Kunitz protease inhibitors are highly potent thrombogenic site-directed anticoagulants

PubMed Central

Chen, Hsiu-Hui; Vicente, Cristina P.; He, Li; Tollefsen, Douglas M.; Wun, Tze-Chein

2005-01-01

The anionic phospholipid, phosphatidyl-l-serine (PS), is sequestered in the inner layer of the plasma membrane in normal cells. Upon injury, activation, and apoptosis, PS becomes exposed on the surfaces of cells and sheds microparticles, which are procoagulant. Coagulation is initiated by formation of a tissue factor/factor VIIa complex on PS-exposed membranes and propagated through the assembly of intrinsic tenase (factor VIIIa/factor IXa), prothrombinase (factor Va/factor Xa), and factor XIa complexes on PS-exposed activated platelets. We constructed a novel series of recombinant anticoagulant fusion proteins by linking annexin V (ANV), a PS-binding protein, to the Kunitz-type protease inhibitor (KPI) domain of tick anticoagulant protein, an aprotinin mutant (6L15), amyloid β-protein precursor, or tissue factor pathway inhibitor. The resulting ANV-KPI fusion proteins were 6- to 86-fold more active than recombinant tissue factor pathway inhibitor and tick anticoagulant protein in an in vitro tissue factor–initiated clotting assay. The in vivo antithrombotic activities of the most active constructs were 3- to 10-fold higher than that of ANV in a mouse arterial thrombosis model. ANV-KPI fusion proteins represent a new class of anticoagulants that specifically target the anionic membrane-associated coagulation enzyme complexes present at sites of thrombogenesis and are potentially useful as antithrombotic agents. PMID:15677561

DOE Office of Scientific and Technical Information (OSTI.GOV)

Battles, Michael B.; Langedijk, Johannes P.; Furmanova-Hollenstein, Polina

Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. In this paper, we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitorsmore » or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Finally and collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors.« less

Transgenic tobacco plants as production platform for biologically active human interleukin 2 and its fusion with proteinase inhibitors.

PubMed

Redkiewicz, Patrycja; Więsyk, Aneta; Góra-Sochacka, Anna; Sirko, Agnieszka

2012-09-01

Transgenic plants offer a low-cost approach for the production of pharmaceutically important and commercially valuable recombinant proteins. Our studies were focused on the plant-based production of human interleukin 2 (hIL-2) and its fusion with proteinase inhibitors, either SPI2 from Galleria mellonella or CMTI from Cucurbita maxima. Finally, five plant expression cassettes were obtained. Three of them contained the single cDNA encoding CMTI I, SPI2 and hIL-2, respectively, while two of them contained the translational fusion, SPI2::hIL-2 and CMTI::hIL-2. In all cases, the transgenes were controlled by the RbcS1 promoter and terminator and the recombinant proteins were targeted to the endoplasmic reticulum. After tobacco transformation, five groups of transgenic plants were obtained and analysed. The level of recombinant proteins was estimated either by Western blot or by ELISA. The biological activity of plant-produced hIL-2 alone or in a fusion with SPI2 or CMTI was confirmed using the mammalian cells proliferation assay. The activities of proteinase inhibitors were confirmed in proteolysis assay using azocoll as a substrate. The usefulness of using proteinase inhibitor CMTI I in a fusion with hIL-2 as a protective agent against trypsin digestion was demonstrated. © 2012 The Authors. Plant Biotechnology Journal © 2012 Society for Experimental Biology, Association of Applied Biologists and Blackwell Publishing Ltd.

An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101.

PubMed

Doebele, Robert C; Davis, Lara E; Vaishnavi, Aria; Le, Anh T; Estrada-Bernal, Adriana; Keysar, Stephen; Jimeno, Antonio; Varella-Garcia, Marileila; Aisner, Dara L; Li, Yali; Stephens, Philip J; Morosini, Deborah; Tuch, Brian B; Fernandes, Michele; Nanda, Nisha; Low, Jennifer A

2015-10-01

Oncogenic TRK fusions induce cancer cell proliferation and engage critical cancer-related downstream signaling pathways. These TRK fusions occur rarely, but in a diverse spectrum of tumor histologies. LOXO-101 is an orally administered inhibitor of the TRK kinase and is highly selective only for the TRK family of receptors. Preclinical models of LOXO-101 using TRK-fusion-bearing human-derived cancer cell lines demonstrate inhibition of the fusion oncoprotein and cellular proliferation in vitro, and tumor growth in vivo. The tumor of a 41-year-old woman with soft-tissue sarcoma metastatic to the lung was found to harbor an LMNA-NTRK1 gene fusion encoding a functional LMNA-TRKA fusion oncoprotein as determined by an in situ proximity ligation assay. In a phase I study of LOXO-101 (ClinicalTrials.gov no. NCT02122913), this patient's tumors underwent rapid and substantial tumor regression, with an accompanying improvement in pulmonary dyspnea, oxygen saturation, and plasma tumor markers. TRK fusions have been deemed putative oncogenic drivers, but their clinical significance remained unclear. A patient with a metastatic soft-tissue sarcoma with an LMNA-NTRK1 fusion had rapid and substantial tumor regression with a novel, highly selective TRK inhibitor, LOXO-101, providing the first clinical evidence of benefit from inhibiting TRK fusions. ©2015 American Association for Cancer Research.

Discovery of methylsulfonyl indazoles as potent and orally active respiratory syncytial Virus(RSV) fusion inhibitors.

PubMed

Feng, Song; Li, Chao; Chen, Dongdong; Zheng, Xiufang; Yun, Hongying; Gao, Lu; Shen, Hong C

2017-09-29

Recently we described a novel class of imidazopyridine compounds that showed exceptional anti-RSV potency in cell culture. However, unfavorable pharmacokinetic (PK) properties and glutathione (GSH) adduct liabilities impeded their further development. In a bid to address the PK and early safety concerns, a small compound library consisting of dozens of scaffold-hopping analogues was designed and synthesized for RSV CPE assay screening, which led to the identification of a new chemical starting point: methylsulfonyl indole compound 8. In this paper, we report the discovery and optimization of a series of methylsulfonyl indazoles as potent RSV fusion inhibitors. In particular, compound 47 was orally efficacious in a RSV mouse model, with 1.6 log unit viral load reduction at 25 mg/kg BID upon oral dosing. The results may have broad implications for the design of new RSV fusion inhibitors, and demonstrate the potential for developing novel therapies for RSV infection. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Evaluation of EML4-ALK Fusion Proteins in Non-Small Cell Lung Cancer Using Small Molecule Inhibitors12

PubMed Central

Li, Yongjun; Ye, Xiaofen; Liu, Jinfeng; Zha, Jiping; Pei, Lin

2011-01-01

The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene resulting from an inversion within chromosome 2p occurs in approximately 5% of non-small cell lung cancer and is mutually exclusive with Ras and EGFR mutations. In this study, we have used a potent and selective ALK small molecule inhibitor, NPV-TAE684, to assess the oncogenic role of EML4-ALK in non-small cell lung cancer (NSCLC). We show here that TAE684 inhibits proliferation and induces cell cycle arrest, apoptosis, and tumor regression in two NSCLC models that harbor EML4-ALK fusions. TAE684 inhibits EML4-ALK activation and its downstream signaling including ERK, AKT, and STAT3. We used microarray analysis to carry out targeted pathway studies of gene expression changes in H2228 NSCLC xenograft model after TAE684 treatment and identified a gene signature of EML4-ALK inhibition. The gene signature represents 1210 known human genes, and the top biologic processes represented by these genes are cell cycle, DNA synthesis, cell proliferation, and cell death. We also compared the effect of TAE684 with PF2341066, a c-Met and ALK small molecule inhibitor currently in clinical trial in cancers harboring ALK fusions, and demonstrated that TAE684 is a much more potent inhibitor of EML4-ALK. Our data demonstrate that EML4-ALK plays an important role in the pathogenesis of a subset of NSCLC and provides insight into the mechanism of EML4-ALK inhibition by a small molecule inhibitor. PMID:21245935

Separating myoblast differentiation from muscle cell fusion using IGF-I and the p38 MAP kinase inhibitor SB202190.

PubMed

Gardner, Samantha; Gross, Sean M; David, Larry L; Klimek, John E; Rotwein, Peter

2015-10-01

The p38 MAP kinases play critical roles in skeletal muscle biology, but the specific processes regulated by these kinases remain poorly defined. Here we find that activity of p38α/β is important not only in early phases of myoblast differentiation, but also in later stages of myocyte fusion and myofibrillogenesis. By treatment of C2 myoblasts with the promyogenic growth factor insulin-like growth factor (IGF)-I, the early block in differentiation imposed by the p38 chemical inhibitor SB202190 could be overcome. Yet, under these conditions, IGF-I could not prevent the later impairment of muscle cell fusion, as marked by the nearly complete absence of multinucleated myofibers. Removal of SB202190 from the medium of differentiating myoblasts reversed the fusion block, as multinucleated myofibers were detected several hours later and reached ∼90% of the culture within 30 h. Analysis by quantitative mass spectroscopy of proteins that changed in abundance following removal of the inhibitor revealed a cohort of upregulated muscle-enriched molecules that may be important for both myofibrillogenesis and fusion. We have thus developed a model system that allows separation of myoblast differentiation from muscle cell fusion and should be useful in identifying specific steps regulated by p38 MAP kinase-mediated signaling in myogenesis. Copyright © 2015 the American Physiological Society.

Photodynamic therapy with simultaneous suppression of multiple treatment escape pathways (Conference Presentation)

NASA Astrophysics Data System (ADS)

Spring, Bryan Q.; Sears, R. Bryan; Zheng, Lei Z.; Mai, Zhiming; Watanabe, Reika; Sherwood, Margaret E.; Schoenfeld, David A.; Pogue, Brian W.; Pereira, Stephen P.; Villa, Elizabeth; Hasan, Tayyaba

2016-03-01

We introduce photoactivatable multi-inhibitor nanoliposomes (PMILs) for photodynamic tumor cell and microvessel damage in synchrony with photo-initiation of tumor-confined, multikinase inhibitor release. The PMIL is a biodegradable delivery system comprised of a nanoliposome carrying a photoactivable chromophore (benzoporphyrin derivative monoacid A, BPD) in its bilayer. A multikinase inhibitor-loaded PEG-PLGA nanoparticle is encapsulated within the liposome, which acts a barrier to nanoparticle erosion and drug release. Following intravenous PMIL administration, near infrared irradiation of tumors triggers photodynamic therapy and initiates tumor-confined drug release from the nanoparticle. This talk presents promising preclinical data in mouse models of pancreatic cancer utilizing this concept to suppress the VEGF and MET signaling pathways—both critical to cancer progression, metastasis and treatment escape. A single PMIL treatment using low doses of a multikanse inhibitor (cabozantinib, XL184) achieves sustained tumor reduction and suppresses metastatic escape, whereas combination therapy by co-administration of the individual agents has significantly reduced efficacy. The PMIL concept is amenable to a number of molecular inhibitors and offers new prospects for spatiotemporal synchronization of combination therapies whilst reducing systemic drug exposure and associated toxicities.

The cell clone ecology hypothesis and the cell fusion model of cancer progression and metastasis (II): three pathways for spontaneous cell-cell fusion and escape from the intercellular matrix.

PubMed

Parris, George

2006-01-01

The two-stage initiation-progression model of cancer is widely accepted. Initiation appears to result most often from accumulation of damage to the DNA expressed as multiple mutations in the phenotype. Unsymmetrical chromosome segregation during mitosis of normal or mutated cells produces aneuploid cells and also contributes to the evolution of neoplasia. However, it has been pointed out (Parris GE. Med Hypotheses 2005;65:993-4 and 2006;66:76-83) that DNA damage and loss of chromosomes are much more likely to lead the mutant clones of cells to extinction than to successful expansion (e.g., an example of Muller's Ratchet). It was argued that aneuploid neoplasia represent new parasite species that successfully evolve to devour their hosts by incorporating sex-like redistribution of chromosomes through spontaneous or virus-catalyzed cell-cell fusion into their life-cycle. Spontaneous cell-cell fusion is generally blocked by the intercellular matrix to which the cells are bound via surface adhesion molecules (frequently glycoproteins, e.g., CD44). In order for progression of matrix-contained neoplasia toward clinically significant cancer to occur, the parasite cells must escape from the matrix and fuse. Release from the matrix also allows the parasite cells to invade adjacent tissues and metastasize to remote locations. Both invasion and metastasis likely involve fusion of the migrating parasite cells with fusion-prone blast cells. There are at least three pathways through which parasite cells can be liberated from the confining matrix: (i) Their adhesion molecules may be modified (e.g., by hyper-glycosylation) so that they can no longer grip the matrix. (ii) Their adhesion molecules or matrix may be saturated with other ligands (e.g., polyamines). (iii) Their adhesion molecules may be cleaved from the cell surface or the matrix itself may be cleaved (e.g., by MMPs or ADAMs). It is hypothesized that mobilization of parasite cells and cell-cell fusion go hand-in-hand in

Improved Pharmacological and Structural Properties of HIV Fusion Inhibitor AP 3 over Enfuvirtide: Highlighting Advantages of Artificial Peptide Strategy

DOE PAGES

Zhu, Xiaojie; Zhu, Yun; Ye, Sheng; ...

2015-08-19

Enfuvirtide (T20), is the first HIV fusion inhibitor approved for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, its clinical application is limited because of short half-life, drug resistance and cross-reactivity with the preexisting antibodies in HIV-infected patients. Using an artificial peptide strategy, we designed a peptide with non-native protein sequence, AP 3, which exhibited potent antiviral activity against a broad spectrum of HIV-1 strains, including those resistant to T20, and had remarkably longer in vivo half-life than T20. While the preexisting antibodies in HIV-infected patients significantly suppressed T20’s antiviral activity, these antibodies neithermore » recognized AP 3, nor attenuated its anti-HIV-1 activity. Structurally different from T20, AP 3 could fold into single-helix and interact with gp41 NHR. The two residues, Met and Thr, at the N-terminus of AP 3 form a hook-like structure to stabilize interaction between AP 3 and NHR helices. Therefore, AP 3 has potential for further development as a new HIV fusion inhibitor with improved antiviral efficacy, resistance profile and pharmacological properties over enfuvirtide. Meanwhile, this study highlighted the advantages of artificially designed peptides, and confirmed that this strategy could be used in developing artificial peptide-based viral fusion inhibitors against HIV and other enveloped viruses.« less

Improved Pharmacological and Structural Properties of HIV Fusion Inhibitor AP 3 over Enfuvirtide: Highlighting Advantages of Artificial Peptide Strategy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Xiaojie; Zhu, Yun; Ye, Sheng

Enfuvirtide (T20), is the first HIV fusion inhibitor approved for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, its clinical application is limited because of short half-life, drug resistance and cross-reactivity with the preexisting antibodies in HIV-infected patients. Using an artificial peptide strategy, we designed a peptide with non-native protein sequence, AP 3, which exhibited potent antiviral activity against a broad spectrum of HIV-1 strains, including those resistant to T20, and had remarkably longer in vivo half-life than T20. While the preexisting antibodies in HIV-infected patients significantly suppressed T20’s antiviral activity, these antibodies neithermore » recognized AP 3, nor attenuated its anti-HIV-1 activity. Structurally different from T20, AP 3 could fold into single-helix and interact with gp41 NHR. The two residues, Met and Thr, at the N-terminus of AP 3 form a hook-like structure to stabilize interaction between AP 3 and NHR helices. Therefore, AP 3 has potential for further development as a new HIV fusion inhibitor with improved antiviral efficacy, resistance profile and pharmacological properties over enfuvirtide. Meanwhile, this study highlighted the advantages of artificially designed peptides, and confirmed that this strategy could be used in developing artificial peptide-based viral fusion inhibitors against HIV and other enveloped viruses.« less

Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein.

PubMed

Wang, Yu; Ding, Xiwei; Wang, Shaoqing; Moser, Catherine D; Shaleh, Hassan M; Mohamed, Essa A; Chaiteerakij, Roongruedee; Allotey, Loretta K; Chen, Gang; Miyabe, Katsuyuki; McNulty, Melissa S; Ndzengue, Albert; Barr Fritcher, Emily G; Knudson, Ryan A; Greipp, Patricia T; Clark, Karl J; Torbenson, Michael S; Kipp, Benjamin R; Zhou, Jie; Barrett, Michael T; Gustafson, Michael P; Alberts, Steven R; Borad, Mitesh J; Roberts, Lewis R

2016-09-28

Cholangiocarcinoma is a highly lethal cancer with limited therapeutic options. Recent genomic analysis of cholangiocarcinoma has revealed the presence of fibroblast growth factor receptor 2 (FGFR2) fusion proteins in up to 13% of intrahepatic cholangiocarcinoma (iCCA). FGFR fusions have been identified as a novel oncogenic and druggable target in a number of cancers. In this study, we established a novel cholangiocarcinoma patient derived xenograft (PDX) mouse model bearing an FGFR2-CCDC6 fusion protein from a metastatic lung nodule of an iCCA patient. Using this PDX model, we confirmed the ability of the FGFR inhibitors, ponatinib, dovitinib and BGJ398, to modulate FGFR signaling, inhibit cell proliferation and induce cell apoptosis in cholangiocarcinoma tumors harboring FGFR2 fusions. In addition, BGJ398 appeared to be superior in potency to ponatinib and dovitinib in this model. Our findings provide a strong rationale for the investigation of FGFR inhibitors, particularly BGJ398, as a therapeutic option for cholangiocarcinoma patients harboring FGFR2 fusions. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Escape from neutralization by the respiratory syncytial virus-specific neutralizing monoclonal antibody palivizumab is driven by changes in on-rate of binding to the fusion protein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bates, John T.; Keefer, Christopher J.; Slaughter, James C.

2014-04-15

The role of binding kinetics in determining neutralizing potency for antiviral antibodies is poorly understood. While it is believed that increased steady-state affinity correlates positively with increased virus-neutralizing activity, the relationship between association or dissociation rate and neutralization potency is unclear. We investigated the effect of naturally-occurring antibody resistance mutations in the RSV F protein on the kinetics of binding to palivizumab. Escape from palivizumab-mediated neutralization of RSV occurred with reduced association rate (K{sub on}) for binding to RSV F protein, while alteration of dissociation rate (K{sub off}) did not significantly affect neutralizing activity. Interestingly, linkage of reduced K{sub on}more » with reduced potency mirrored the effect of increased K{sub on} found in a high-affinity enhanced potency palivizumab variant (motavizumab). These data suggest that association rate is the dominant factor driving neutralization potency for antibodies to RSV F protein antigenic site A and determines the potency of antibody somatic variants or efficiency of escape of viral glycoprotein variants. - Highlights: • The relationship of affinity to neutralization for virus antibodies is uncertain. • Palivizumab binds to RSV escape mutant fusion proteins, but with reduced affinity. • Association rate (K{sub on}) correlated well with the potency of neutralization.« less

Functional characterization, localization, and inhibitor sensitivity of the TPR-FGFR1 fusion in 8p11 myeloproliferative syndrome.

PubMed

Malli, Theodora; Buxhofer-Ausch, Veronika; Rammer, Melanie; Erdel, Martin; Kranewitter, Wolfgang; Rumpold, Holger; Marschon, Renate; Deutschbauer, Sabine; Simonitsch-Klupp, Ingrid; Valent, Peter; Muellner-Ammer, Kirsten; Sebesta, Christian; Birkner, Thomas; Webersinke, Gerald

2016-01-01

Myeloid and lymphoid neoplasms with fibroblast growth factor receptor 1 (FGFR1) abnormalities, also known as 8p11 myeloproliferative syndrome (EMS), represent rare and aggressive disorders, associated with chromosomal aberrations that lead to the fusion of FGFR1 to different partner genes. We report on a third patient with a fusion of the translocated promoter region (TPR) gene, a component of the nuclear pore complex, to FGFR1 due to a novel ins(1;8)(q25;p11p23). The fact that this fusion is a rare but recurrent event in EMS prompted us to examine the localization and transforming potential of the chimeric protein. TPR-FGFR1 localizes in the cytoplasm, although the nuclear pore localization signal of TPR is retained in the fusion protein. Furthermore, TPR-FGFR1 enables cytokine-independent survival, proliferation, and granulocytic differentiation of the interleukin-3 dependent myeloid progenitor cell line 32Dcl3, reflecting the chronic phase of EMS characterized by myeloid hyperplasia. 32Dcl3 cells transformed with the TPR-FGFR1 fusion and treated with increasing concentrations of the tyrosine kinase inhibitors ponatinib (AP24534) and infigratinib (NVP-BGJ398) displayed reduced survival and proliferation with IC50 values of 49.8 and 7.7 nM, respectively. Ponatinib, a multitargeted tyrosine kinase inhibitor, is already shown to be effective against several FGFR1-fusion kinases. Infigratinib, tested only against FGFR1OP2-FGFR1 to date, is also efficient against TPR-FGFR1. Taking its high specificity for FGFRs into account, infigratinib could be beneficial for EMS patients and should be further investigated for the treatment of myeloproliferative neoplasms with FGFR1 abnormalities. © 2015 Wiley Periodicals, Inc.

Renal Cell Carcinoma Associated With Xp11.2 Translocation/TFE3 Gene-fusion: A Long Response to mammalian target of rapamycin (mTOR) Inhibitors.

PubMed

Rua Fernández, Oliver R; Escala Cornejo, Roberto; Navarro Martín, Miguel; García Muñoz, María; Antunez Plaza, Patricia; García Dominguez, Aracely Rocío; Cruz Hernández, Juan J

2018-04-24

To demonstrate that patients with Xp11.2/TFE3 gene-fusion translocation renal cell carcinoma (RCC), despite having an aggressive course in young adults, could have valid treatment options such as mammalian target of rapamycin (mTOR) inhibitors with good outcomes. Furthermore, to explain possible mechanisms of action of mTOR inhibitors in this type of RCC. We report a case of a 44-year-old man who has been treated with everolimus for a Xp11.2 translocation/TFE3 gene-fusion RCC after 2 previous failed treatments with tyrosine kinase inhibitor. During the follow-up, we evaluated type and duration of response with everolimus. The patient obtained a long-lasting response of disease of 25 months with everolimus without any symptom. We believe that mTOR inhibitors could be a good line option treatment to consider for this type of patients. Copyright © 2018 Elsevier Inc. All rights reserved.

A small molecule fusion inhibitor of dengue virus.

PubMed

Poh, Mee Kian; Yip, Andy; Zhang, Summer; Priestle, John P; Ma, Ngai Ling; Smit, Jolanda M; Wilschut, Jan; Shi, Pei-Yong; Wenk, Markus R; Schul, Wouter

2009-12-01

The dengue virus envelope protein plays an essential role in viral entry by mediating fusion between the viral and host membranes. The crystal structure of the envelope protein shows a pocket (located at a "hinge" between Domains I and II) that can be occupied by ligand n-octyl-beta-D-glucoside (betaOG). Compounds blocking the betaOG pocket are thought to interfere with conformational changes in the envelope protein that are essential for fusion. Two fusion assays were developed to examine the anti-fusion activities of compounds. The first assay measures the cellular internalization of propidium iodide upon membrane fusion. The second assay measures the protease activity of trypsin upon fusion between dengue virions and trypsin-containing liposomes. We performed an in silico virtual screening for small molecules that can potentially bind to the betaOG pocket and tested these candidate molecules in the two fusion assays. We identified one compound that inhibits dengue fusion in both assays with an IC(50) of 6.8 microM and reduces viral titers with an EC(50) of 9.8 microM. Time-of-addition experiments showed that the compound was only active when present during viral infection but not when added 1h later, in agreement with a mechanism of action through fusion inhibition.

Rigid amphipathic fusion inhibitors demonstrate antiviral activity against African swine fever virus.

PubMed

Hakobyan, Astghik; Galindo, Inmaculada; Nañez, Almudena; Arabyan, Erik; Karalyan, Zaven; Chistov, Alexey A; Streshnev, Philipp P; Korshun, Vladimir A; Alonso, Covadonga; Zakaryan, Hovakim

2018-01-01

Rigid amphipathic fusion inhibitors (RAFIs) are a family of nucleoside derivatives that inhibit the infectivity of several enveloped viruses by interacting with virion envelope lipids and inhibiting fusion between viral and cellular membranes. Here we tested the antiviral activity of two RAFIs, 5-(Perylen-3-ylethynyl)-arabino-uridine (aUY11) and 5-(Perylen-3-ylethynyl)uracil-1-acetic acid (cm1UY11) against African swine fever virus (ASFV), for which no effective vaccine is available. Both compounds displayed a potent, dose-dependent inhibitory effect on ASFV infection in Vero cells. The major antiviral effect was observed when aUY11 and cm1UY11 were added at early stages of infection and maintained during the complete viral cycle. Furthermore, virucidal assay revealed a significant extracellular anti-ASFV activity for both compounds. We also found decrease in the synthesis of early and late viral proteins in Vero cells treated with cm1UY11. Finally, the inhibitory effect of aUY11 and cm1UY11 on ASFV infection in porcine alveolar macrophages was confirmed. Overall, our study has identified novel anti-ASFV compounds with potential for future therapeutic developments.

Identification and Characterization of Influenza Virus Entry Inhibitors through Dual Myxovirus High-Throughput Screening.

PubMed

Weisshaar, Marco; Cox, Robert; Morehouse, Zachary; Kumar Kyasa, Shiva; Yan, Dan; Oberacker, Phil; Mao, Shuli; Golden, Jennifer E; Lowen, Anice C; Natchus, Michael G; Plemper, Richard K

2016-08-15

Influenza A virus (IAV) infections cause major morbidity and mortality, generating an urgent need for novel antiviral therapeutics. We recently established a dual myxovirus high-throughput screening protocol that combines a fully replication-competent IAV-WSN strain and a respiratory syncytial virus reporter strain for the simultaneous identification of IAV-specific, paramyxovirus-specific, and broad-spectrum inhibitors. In the present study, this protocol was applied to a screening campaign to assess a diverse chemical library with over 142,000 entries. Focusing on IAV-specific hits, we obtained a hit rate of 0.03% after cytotoxicity testing and counterscreening. Three chemically distinct hit classes with nanomolar potency and favorable cytotoxicity profiles were selected. Time-of-addition, minigenome, and viral entry studies demonstrated that these classes block hemagglutinin (HA)-mediated membrane fusion. Antiviral activity extends to an isolate from the 2009 pandemic and, in one case, another group 1 subtype. Target identification through biolayer interferometry confirmed binding of all hit compounds to HA. Resistance profiling revealed two distinct escape mechanisms: primary resistance, associated with reduced compound binding, and secondary resistance, associated with unaltered binding. Secondary resistance was mediated, unusually, through two different pairs of cooperative mutations, each combining a mutation eliminating the membrane-proximal stalk N-glycan with a membrane-distal change in HA1 or HA2. Chemical synthesis of an analog library combined with in silico docking extracted a docking pose for the hit classes. Chemical interrogation spotlights IAV HA as a major druggable target for small-molecule inhibition. Our study identifies novel chemical scaffolds with high developmental potential, outlines diverse routes of IAV escape from entry inhibition, and establishes a path toward structure-aided lead development. This study is one of the first to apply a

Identification and Characterization of Influenza Virus Entry Inhibitors through Dual Myxovirus High-Throughput Screening

PubMed Central

Weisshaar, Marco; Cox, Robert; Morehouse, Zachary; Kumar Kyasa, Shiva; Yan, Dan; Oberacker, Phil; Mao, Shuli; Lowen, Anice C.; Natchus, Michael G.

2016-01-01

ABSTRACT Influenza A virus (IAV) infections cause major morbidity and mortality, generating an urgent need for novel antiviral therapeutics. We recently established a dual myxovirus high-throughput screening protocol that combines a fully replication-competent IAV-WSN strain and a respiratory syncytial virus reporter strain for the simultaneous identification of IAV-specific, paramyxovirus-specific, and broad-spectrum inhibitors. In the present study, this protocol was applied to a screening campaign to assess a diverse chemical library with over 142,000 entries. Focusing on IAV-specific hits, we obtained a hit rate of 0.03% after cytotoxicity testing and counterscreening. Three chemically distinct hit classes with nanomolar potency and favorable cytotoxicity profiles were selected. Time-of-addition, minigenome, and viral entry studies demonstrated that these classes block hemagglutinin (HA)-mediated membrane fusion. Antiviral activity extends to an isolate from the 2009 pandemic and, in one case, another group 1 subtype. Target identification through biolayer interferometry confirmed binding of all hit compounds to HA. Resistance profiling revealed two distinct escape mechanisms: primary resistance, associated with reduced compound binding, and secondary resistance, associated with unaltered binding. Secondary resistance was mediated, unusually, through two different pairs of cooperative mutations, each combining a mutation eliminating the membrane-proximal stalk N-glycan with a membrane-distal change in HA1 or HA2. Chemical synthesis of an analog library combined with in silico docking extracted a docking pose for the hit classes. Chemical interrogation spotlights IAV HA as a major druggable target for small-molecule inhibition. Our study identifies novel chemical scaffolds with high developmental potential, outlines diverse routes of IAV escape from entry inhibition, and establishes a path toward structure-aided lead development. IMPORTANCE This study is one of

Influence of hydrophobic and electrostatic residues on SARS-coronavirus S2 protein stability: Insights into mechanisms of general viral fusion and inhibitor design

PubMed Central

Aydin, Halil; Al-Khooly, Dina; Lee, Jeffrey E

2014-01-01

Severe acute respiratory syndrome (SARS) is an acute respiratory disease caused by the SARS-coronavirus (SARS-CoV). SARS-CoV entry is facilitated by the spike protein (S), which consists of an N-terminal domain (S1) responsible for cellular attachment and a C-terminal domain (S2) that mediates viral and host cell membrane fusion. The SARS-CoV S2 is a potential drug target, as peptidomimetics against S2 act as potent fusion inhibitors. In this study, site-directed mutagenesis and thermal stability experiments on electrostatic, hydrophobic, and polar residues to dissect their roles in stabilizing the S2 postfusion conformation was performed. It was shown that unlike the pH-independent retroviral fusion proteins, SARS-CoV S2 is stable over a wide pH range, supporting its ability to fuse at both the plasma membrane and endosome. A comprehensive SARS-CoV S2 analysis showed that specific hydrophobic positions at the C-terminal end of the HR2, rather than electrostatics are critical for fusion protein stabilization. Disruption of the conserved C-terminal hydrophobic residues destabilized the fusion core and reduced the melting temperature by 30°C. The importance of the C-terminal hydrophobic residues led us to identify a 42-residue substructure on the central core that is structurally conserved in all existing CoV S2 fusion proteins (root mean squared deviation = 0.4 Å). This is the first study to identify such a conserved substructure and likely represents a common foundation to facilitate viral fusion. We have discussed the role of key residues in the design of fusion inhibitors and the potential of the substructure as a general target for the development of novel therapeutics against CoV infections. PMID:24519901

Influence of hydrophobic and electrostatic residues on SARS-coronavirus S2 protein stability: insights into mechanisms of general viral fusion and inhibitor design.

PubMed

Aydin, Halil; Al-Khooly, Dina; Lee, Jeffrey E

2014-05-01

Severe acute respiratory syndrome (SARS) is an acute respiratory disease caused by the SARS-coronavirus (SARS-CoV). SARS-CoV entry is facilitated by the spike protein (S), which consists of an N-terminal domain (S1) responsible for cellular attachment and a C-terminal domain (S2) that mediates viral and host cell membrane fusion. The SARS-CoV S2 is a potential drug target, as peptidomimetics against S2 act as potent fusion inhibitors. In this study, site-directed mutagenesis and thermal stability experiments on electrostatic, hydrophobic, and polar residues to dissect their roles in stabilizing the S2 postfusion conformation was performed. It was shown that unlike the pH-independent retroviral fusion proteins, SARS-CoV S2 is stable over a wide pH range, supporting its ability to fuse at both the plasma membrane and endosome. A comprehensive SARS-CoV S2 analysis showed that specific hydrophobic positions at the C-terminal end of the HR2, rather than electrostatics are critical for fusion protein stabilization. Disruption of the conserved C-terminal hydrophobic residues destabilized the fusion core and reduced the melting temperature by 30°C. The importance of the C-terminal hydrophobic residues led us to identify a 42-residue substructure on the central core that is structurally conserved in all existing CoV S2 fusion proteins (root mean squared deviation=0.4 Å). This is the first study to identify such a conserved substructure and likely represents a common foundation to facilitate viral fusion. We have discussed the role of key residues in the design of fusion inhibitors and the potential of the substructure as a general target for the development of novel therapeutics against CoV infections. © 2014 The Protein Society.

Two M-T hook residues greatly improve the antiviral activity and resistance profile of the HIV-1 fusion inhibitor SC29EK

PubMed Central

2014-01-01

Background Peptides derived from the C-terminal heptad repeat (CHR) of HIV-1 gp41 such as T20 (Enfuvirtide) and C34 are potent viral fusion inhibitors. We have recently found that two N-terminal residues (Met115 and Thr116) of CHR peptides form a unique M-T hook structure that can greatly enhance the binding and anti-HIV activity of inhibitors. Here, we applied two M-T hook residues to optimize SC29EK, an electrostatically constrained peptide inhibitor with a potent anti-HIV activity. Results The resulting peptide MT-SC29EK showed a dramatically increased binding affinity and could block the six-helical bundle (6-HB) formation more efficiently. As expected, MT-SC29EK potently inhibited HIV-1 entry and infection, especially against those T20- and SC29EK-resistant HIV-1 variants. More importantly, MT-SC29EK and its short form (MT-SC22EK) suffered from the difficulty to induce HIV-1 resistance during the in vitro selection, suggesting their high genetic barriers to the development of resistance. Conclusions Our studies have verified the M-T hook structure as a vital strategy to design novel HIV-1 fusion inhibitors and offered an ideal candidate for clinical development. PMID:24884671

THERMALLY DRIVEN ATMOSPHERIC ESCAPE: TRANSITION FROM HYDRODYNAMIC TO JEANS ESCAPE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkov, Alexey N.; Johnson, Robert E.; Tucker, Orenthal J.

2011-03-10

Thermally driven escape from planetary atmospheres changes in nature from an organized outflow (hydrodynamic escape) to escape on a molecule-by-molecule basis (Jeans escape) with increasing Jeans parameter, {lambda}, the ratio of the gravitational to thermal energy of the atmospheric molecules. This change is described here for the first time using the direct simulation Monte Carlo method. When heating is predominantly below the lower boundary of the simulation region, R{sub 0}, and well below the exobase of a single-component atmosphere, the nature of the escape process changes over a surprisingly narrow range of Jeans parameters, {lambda}{sub 0}, evaluated at R{sub 0}.more » For an atomic gas, the transition occurs over {lambda}{sub 0} {approx} 2-3, where the lower bound, {lambda}{sub 0} {approx} 2.1, corresponds to the upper limit for isentropic, supersonic outflow. For {lambda}{sub 0} > 3 escape occurs on a molecule-by-molecule basis and we show that, contrary to earlier suggestions, for {lambda}{sub 0} > {approx}6 the escape rate does not deviate significantly from the familiar Jeans rate. In a gas composed of diatomic molecules, the transition shifts to {lambda}{sub 0} {approx} 2.4-3.6 and at {lambda}{sub 0} > {approx}4 the escape rate increases a few tens of percent over that for the monatomic gas. Scaling by the Jeans parameter and the Knudsen number, these results can be applied to thermally induced escape of the major species from solar and extrasolar planets.« less

Putative role of membranes in the HIV fusion inhibitor enfuvirtide mode of action at the molecular level.

PubMed Central

Veiga, Salomé; Henriques, Sónia; Santos, Nuno C; Castanho, Miguel

2004-01-01

Partition of the intrinsically fluorescent HIV fusion inhibitor enfuvirtide into lipidic membranes is relatively high (Delta G =6.6 kcal x mol(-1)) and modulated by cholesterol. A shallow position in the lipidic matrix makes it readily available for interaction with gp41. No conformational energetic barrier prevents enfuvirtide from being active in both aqueous solution and lipidic membranes. Lipidic membranes may play a key role in the enfuvirtide biochemical mode of action. PMID:14514352

Intellectual property issues of immune checkpoint inhibitors

PubMed Central

Storz, Ulrich

2016-01-01

Immune checkpoint inhibitors are drugs that interfere with tumor escape responses. Some members of this class are already approved, and expected to be blockbusters in the future. Many companies have developed patent activities in this field. This article focuses on the patent landscape, and discusses key players and cases related to immune checkpoint inhibitors. PMID:26466763

A Helical Short-Peptide Fusion Inhibitor with Highly Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus

PubMed Central

Xiong, Shengwen; Borrego, Pedro; Ding, Xiaohui; Zhu, Yuanmei; Martins, Andreia; Chong, Huihui

2016-01-01

ABSTRACT Human immunodeficiency virus type 2 (HIV-2) has already spread to different regions worldwide, and currently about 1 to 2 million people have been infected, calling for new antiviral agents that are effective on both HIV-1 and HIV-2 isolates. T20 (enfuvirtide), a 36-mer peptide derived from the C-terminal heptad repeat region (CHR) of gp41, is the only clinically approved HIV-1 fusion inhibitor, but it easily induces drug resistance and is not active on HIV-2. In this study, we first demonstrated that the M-T hook structure was also vital to enhancing the binding stability and inhibitory activity of diverse CHR-based peptide inhibitors. We then designed a novel short peptide (23-mer), termed 2P23, by introducing the M-T hook structure, HIV-2 sequences, and salt bridge-forming residues. Promisingly, 2P23 was a highly stable helical peptide with high binding to the surrogate targets derived from HIV-1, HIV-2, and simian immunodeficiency virus (SIV). Consistent with this, 2P23 exhibited potent activity in inhibiting diverse subtypes of HIV-1 isolates, T20-resistant HIV-1 mutants, and a panel of primary HIV-2 isolates, HIV-2 mutants, and SIV isolates. Therefore, we conclude that 2P23 has high potential to be further developed for clinical use, and it is also an ideal tool for exploring the mechanisms of HIV-1/2- and SIV-mediated membrane fusion. IMPORTANCE The peptide drug T20 is the only approved HIV-1 fusion inhibitor, but it is not active on HIV-2 isolates, which have currently infected 1 to 2 million people and continue to spread worldwide. Recent studies have demonstrated that the M-T hook structure can greatly enhance the binding and antiviral activities of gp41 CHR-derived inhibitors, especially for short peptides that are otherwise inactive. By combining the hook structure, HIV-2 sequence, and salt bridge-based strategies, the short peptide 2P23 has been successfully designed. 2P23 exhibits prominent advantages over many other peptide fusion inhibitors

Inhibition of chaotic escape from a potential well by incommensurate escape-suppressing excitations.

PubMed

Chacón, R; Martínez, J A

2002-03-01

Theoretical results are presented concerning the reduction of chaotic escape from a potential well by means of a harmonic parametric excitation that satisfies an ultrasubharmonic resonance condition with the escape-inducing excitation. The possibility of incommensurate escape-suppressing excitations is demonstrated by studying rational approximations to the irrational escape-suppressing frequency. The analytical predictions for the suitable amplitudes and initial phases of the escape-suppressing excitation are tested against numerical simulations based on a high-resolution grid of initial conditions. These numerical results indicate that the reduction of escape is reliably achieved for small amplitudes and at, and only at, the predicted initial phases. For the case of irrational escape-suppressing frequencies, the effective escape-reducing initial phases are found to lie close to the accumulation points of the set of suitable initial phases that are associated with the complete series of convergents up to the convergent giving the chosen rational approximation.

Impact of Antiretroviral Regimens on CSF Viral Escape in a Prospective Multicohort Study of ART-Experienced HIV-1 Infected Adults in the United States.

PubMed

Mukerji, Shibani S; Misra, Vikas; Lorenz, David R; Uno, Hajime; Morgello, Susan; Franklin, Donald; Ellis, Ronald J; Letendre, Scott; Gabuzda, Dana

2018-04-03

Cerebrospinal fluid (CSF) viral escape occurs in 4-20% of HIV-infected adults, yet the impact of antiretroviral therapy (ART) on CSF escape is unclear. Prospective study of 1063 participants with baseline plasma viral load (VL) ≤400 copies/ml between 2005-2016. Odds ratio for ART regimens (PI with nucleoside reverse transcriptase inhibitor [PI+NRTI] versus other ART) and CSF escape was estimated using mixed-effects models. Drug resistance mutation frequencies were calculated. Baseline mean age was 46, median plasma VL, CD4 nadir, and CD4 count were 50 copies/mL, 88 cells/μL, and 424 cells/μL, respectively; 48% on PI+NRTI, 33% on non-NRTI, and 6% on integrase inhibitors. During median follow-up of 4.4 years, CSF escape occurred in 77 participants (7.2%). PI+NRTI use was an independent predictor of CSF escape (OR 3.1 [95% CI 1.8-5.0]) in adjusted analyses and models restricted to plasma VL ≤50 copies/ml (p<0.001). Regimens containing atazanavir (ATV) were a stronger predictor of CSF viral escape than non-ATV PI+NRTI regimens. Plasma and CSF M184V/I combined with thymidine-analog mutations were more frequent in CSF escape versus no escape (23% vs. 2.3%). Genotypic susceptibility score-adjusted CNS penetration-effectiveness (CPE) values were calculated for CSF escape with M184V/I mutations (n=34). Adjusted CPE values were low (<5) for CSF and plasma in 27 (79%) and 13 (38%), respectively, indicating suboptimal CNS drug availability. PI+NRTI regimens are independent predictors of CSF escape in HIV-infected adults. Reduced CNS ART bioavailability may predispose to CSF escape in patients with M184V/I mutations. Optimizing ART regimens may reduce risk of CSF escape.

A Fusion Protein of the p53 Transaction Domain and the p53-Binding Domain of the Oncoprotein MdmX as an Efficient System for High-Throughput Screening of MdmX Inhibitors.

PubMed

Chen, Rong; Zhou, Jingjing; Qin, Lingyun; Chen, Yao; Huang, Yongqi; Liu, Huili; Su, Zhengding

2017-06-27

In nearly half of cancers, the anticancer activity of p53 protein is often impaired by the overexpressed oncoprotein Mdm2 and its homologue, MdmX, demanding efficient therapeutics to disrupt the aberrant p53-MdmX/Mdm2 interactions to restore the p53 activity. While many potent Mdm2-specific inhibitors have already undergone clinical investigations, searching for MdmX-specific inhibitors has become very attractive, requiring a more efficient screening strategy for evaluating potential scaffolds or leads. In this work, considering that the intrinsic fluorescence residue Trp23 in the p53 transaction domain (p53p) plays an important role in determining the p53-MdmX/Mdm2 interactions, we constructed a fusion protein to utilize this intrinsic fluorescence signal to monitor high-throughput screening of a compound library. The fusion protein was composed of the p53p followed by the N-terminal domain of MdmX (N-MdmX) through a flexible amino acid linker, while the whole fusion protein contained a sole intrinsic fluorescence probe. The fusion protein was then evaluated using fluorescence spectroscopy against model compounds. Our results revealed that the variation of the fluorescence signal was highly correlated with the concentration of the ligand within 65 μM. The fusion protein was further evaluated with respect to its feasibility for use in high-throughput screening using a model compound library, including controls. We found that the imidazo-indole scaffold was a bona fide scaffold for template-based design of MdmX inhibitors. Thus, the p53p-N-MdmX fusion protein we designed provides a convenient and efficient tool for high-throughput screening of new MdmX inhibitors. The strategy described in this work should be applicable for other protein targets to accelerate drug discovery.

A pharmacological study of Arabidopsis cell fusion between the persistent synergid and endosperm.

PubMed

Motomura, Kazuki; Kawashima, Tomokazu; Berger, Frédéric; Kinoshita, Tetsu; Higashiyama, Tetsuya; Maruyama, Daisuke

2018-01-29

Cell fusion is a pivotal process in fertilization and multinucleate cell formation. A plant cell is ubiquitously surrounded by a hard cell wall, and very few cell fusions have been observed except for gamete fusions. We recently reported that the fertilized central cell (the endosperm) absorbs the persistent synergid, a highly differentiated cell necessary for pollen tube attraction. The synergid-endosperm fusion (SE fusion) appears to eliminate the persistent synergid from fertilized ovule in Arabidopsis thaliana Here, we analyzed the effects of various inhibitors on SE fusion in an in vitro culture system. Different from other cell fusions, neither disruption of actin polymerization nor protein secretion impaired SE fusion. However, transcriptional and translational inhibitors decreased the SE fusion success rate and also inhibited endosperm division. Failures of SE fusion and endosperm nuclear proliferation were also induced by roscovitine, an inhibitor of cyclin-dependent kinases (CDK). These data indicate unique aspects of SE fusion such as independence of filamentous actin support and the importance of CDK-mediated mitotic control. © 2018. Published by The Company of Biologists Ltd.

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

ERIC Educational Resources Information Center

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…

Automated Escape Guidance Algorithms for An Escape Vehicle

NASA Technical Reports Server (NTRS)

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

Discovery of natural mouse serum derived HIV-1 entry inhibitor(s).

PubMed

Wei, M; Chen, Y; Xi, J; Ru, S; Ji, M; Zhang, D; Fang, Q; Tang, B

Among rationally designed human immunodeficiency virus 1 (HIV-1) inhibitors, diverse natural factors have showed as potent anti-HIV activity in human blood. We have discovered that the boiled supernatant of healthy mouse serum could suppress HIV-1 entry, and exhibited reduced inhibitory activity after trypsin digestion. Further analysis demonstrated that only the fraction containing 10-25 K proteins could inhibit HIV-1 mediated cell-cell fusion. These results suggest that the 10-25 K protein(s) is novel natural HIV-1 entry inhibitor(s). Our findings provide important information about novel natural HIV entry inhibitors in mouse serum.

Hydrodynamic escape from planetary atmospheres

NASA Astrophysics Data System (ADS)

Tian, Feng

Hydrodynamic escape is an important process in the formation and evolution of planetary atmospheres. Due to the existence of a singularity point near the transonic point, it is difficult to find transonic steady state solutions by solving the time-independent hydrodynamic equations. In addition to that, most previous works assume that all energy driving the escape flow is deposited in one narrow layer. This assumption not only results in less accurate solutions to the hydrodynamic escape problem, but also makes it difficult to include other chemical and physical processes in the hydrodynamic escape models. In this work, a numerical model describing the transonic hydrodynamic escape from planetary atmospheres is developed. A robust solution technique is used to solve the time dependent hydrodynamic equations. The method has been validated in an isothermal atmosphere where an analytical solution is available. The hydrodynamic model is applied to 3 cases: hydrogen escape from small orbit extrasolar planets, hydrogen escape from a hydrogen rich early Earth's atmosphere, and nitrogen/methane escape from Pluto's atmosphere. Results of simulations on extrasolar planets are in good agreement with the observations of the transiting extrasolar planet HD209458b. Hydrodynamic escape of hydrogen from other hypothetical close-in extrasolar planets are simulated and the influence of hydrogen escape on the long-term evolution of these extrasolar planets are discussed. Simulations on early Earth suggest that hydrodynamic escape of hydrogen from a hydrogen rich early Earth's atmosphere is about two orders magnitude slower than the diffusion limited escape rate. A hydrogen rich early Earth's atmosphere could have been maintained by the balance between the hydrogen escape and the supply of hydrogen into the atmosphere by volcanic outgassing. Origin of life may have occurred in the organic soup ocean created by the efficient formation of prebiotic molecules in the hydrogen rich early

ESCAPE AS REINFORCEMENT AND ESCAPE EXTINCTION IN THE TREATMENT OF FEEDING PROBLEMS

PubMed Central

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 swallowing), escape as reinforcement for mouth clean plus escape extinction (EE), and EE alone as treatment for the food refusal of 5 children. Results were similar to those of previous studies, in that reinforcement alone did not result in increases in mouth clean or decreases in inappropriate behavior (e.g., Piazza, Patel, Gulotta, Sevin, & Layer, 2003). Increases in mouth clean and decreases in inappropriate behavior occurred when the therapist implemented EE independent of the presence or absence of reinforcement. Results are discussed in terms of the role of negative reinforcement in the etiology and treatment of feeding problems. PMID:22219525

Dust escape from Io

NASA Astrophysics Data System (ADS)

Flandes, Alberto

2004-08-01

The Dust ballerina skirt is a set of well defined streams composed of nanometric sized dust particles that escape from the Jovian system and may be accelerated up to >=200 km/s. The source of this dust is Jupiter's moon Io, the most volcanically active body in the Solar system. The escape of dust grains from Jupiter requires first the escape of these grains from Io. This work is basically devoted to explain this escape given that the driving of dust particles to great heights and later injection into the ionosphere of Io may give the particles an equilibrium potential that allow the magnetic field to accelerate them away from Io. The grain sizes obtained through this study match very well to the values required for the particles to escape from the Jovian system.

Line tension at lipid phase boundaries as driving force for HIV fusion peptide-mediated fusion

NASA Astrophysics Data System (ADS)

Yang, Sung-Tae; Kiessling, Volker; Tamm, Lukas K.

2016-04-01

Lipids and proteins are organized in cellular membranes in clusters, often called `lipid rafts'. Although raft-constituent ordered lipid domains are thought to be energetically unfavourable for membrane fusion, rafts have long been implicated in many biological fusion processes. For the case of HIV gp41-mediated membrane fusion, this apparent contradiction can be resolved by recognizing that the interfaces between ordered and disordered lipid domains are the predominant sites of fusion. Here we show that line tension at lipid domain boundaries contributes significant energy to drive gp41-fusion peptide-mediated fusion. This energy, which depends on the hydrophobic mismatch between ordered and disordered lipid domains, may contribute tens of kBT to fusion, that is, it is comparable to the energy required to form a lipid stalk intermediate. Line-active compounds such as vitamin E lower line tension in inhomogeneous membranes, thereby inhibit membrane fusion, and thus may be useful natural viral entry inhibitors.

42 CFR 84.51 - Entry and escape, or escape only; classification.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 42 Public Health 1 2013-10-01 2013-10-01 false Entry and escape, or escape only; classification. 84.51 Section 84.51 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH AND RELATED ACTIVITIES APPROVAL OF RESPIRATORY PROTECTIVE DEVICES...

42 CFR 84.51 - Entry and escape, or escape only; classification.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Entry and escape, or escape only; classification. 84.51 Section 84.51 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH AND RELATED ACTIVITIES APPROVAL OF RESPIRATORY PROTECTIVE DEVICES...

42 CFR 84.51 - Entry and escape, or escape only; classification.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false Entry and escape, or escape only; classification. 84.51 Section 84.51 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH AND RELATED ACTIVITIES APPROVAL OF RESPIRATORY PROTECTIVE DEVICES...

42 CFR 84.51 - Entry and escape, or escape only; classification.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 42 Public Health 1 2014-10-01 2014-10-01 false Entry and escape, or escape only; classification. 84.51 Section 84.51 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH AND RELATED ACTIVITIES APPROVAL OF RESPIRATORY PROTECTIVE DEVICES...

42 CFR 84.51 - Entry and escape, or escape only; classification.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 1 2012-10-01 2012-10-01 false Entry and escape, or escape only; classification. 84.51 Section 84.51 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH AND RELATED ACTIVITIES APPROVAL OF RESPIRATORY PROTECTIVE DEVICES...

Fusion-Driven Space Plane for Lunar Exploration

NASA Astrophysics Data System (ADS)

Kammash, T.; Cassenti, B.

A fusion hybrid reactor where the fusion component is the gasdynamic mirror (GDM) is proposed as the driver of a rocket that would allow a space vehicle of the size of Boeing 747 to travel to the moon in about one day. The energy produced by the reactor is induced by fusion neutrons that impinge on a thorium-232 blanket where they breed uranium-233 and simultane- ously burn it to produce power. For a vehicle of mass 500 metric tons (mT), the thrust required to accelerate it at 1 g is 5 MN, and the specific impulse, Isp, necessary to accelerate 90% of the launch mass to the escape velocity of 11,200 m/sec is found to be 10,182 seconds. For these propulsion parameters, the coolant mass flow rate would be 49 kg/sec. We note that the time it takes the launch mass, initially at rest and accelerated at 1g, to reach the escape velocity is 1,020 seconds. At the above noted rate, the total propellant mass is approximately 50 mT, which is about 10% of the launch mass, validating the Isp needed to accelerate the remainder to the escape velocity. If we assume that the trajectory to the moon is linear, and we account for the deceleration of the vehicle by the earth's gravitational force, and its acceleration by the moon's gravitational force, we can calculate the average velocity and the time it takes to reach the moon. We find that the travel time is about 1.66 days, which in this model is effectively the time for a fly-by. A more rigorous calculation using the restricted three body approach with the third body being the spacecraft, and allowing for a coordinate system that rotates at the circular frequency of the larger masses, shows that the transit time is about 0.65 days, which is comparable to the flight time between New York and Sidney, Australia.

Exploration of the chlorpyrifos escape pathway from acylpeptide hydrolases using steered molecular dynamics simulations.

PubMed

Wang, Dongmei; Jin, Hanyong; Wang, Junling; Guan, Shanshan; Zhang, Zuoming; Han, Weiwei

2016-01-01

Acylpeptide hydrolases (APH) catalyze the removal of an N-acylated amino acid from blocked peptides. APH is significantly more sensitive than acetylcholinesterase, a target of Alzheimer's disease, to inhibition by organophosphorus (OP) compounds. Thus, OP compounds can be used as a tool to probe the physiological functions of APH. Here, we report the results of a computational study of molecular dynamics simulations of APH bound to the OP compounds and an exploration of the chlorpyrifos escape pathway using steered molecular dynamics (SMD) simulations. In addition, we apply SMD simulations to identify potential escape routes of chlorpyrifos from hydrolase hydrophobic cavities in the APH-inhibitor complex. Two previously proposed APH pathways were reliably identified by CAVER 3.0, with the estimated relative importance of P1 > P2 for its size. We identify the major pathway, P2, using SMD simulations, and Arg526, Glu88, Gly86, and Asn65 are identified as important residues for the ligand leaving via P2. These results may help in the design of APH-targeting drugs with improved efficacy, as well as in understanding APH selectivity of the inhibitor binding in the prolyl oligopeptidase family.

Vibrio effector protein VopQ inhibits fusion of V-ATPase–containing membranes

PubMed Central

Sreelatha, Anju; Bennett, Terry L.; Carpinone, Emily M.; O’Brien, Kevin M.; Jordan, Kamyron D.; Burdette, Dara L.; Orth, Kim; Starai, Vincent J.

2015-01-01

Vesicle fusion governs many important biological processes, and imbalances in the regulation of membrane fusion can lead to a variety of diseases such as diabetes and neurological disorders. Here we show that the Vibrio parahaemolyticus effector protein VopQ is a potent inhibitor of membrane fusion based on an in vitro yeast vacuole fusion model. Previously, we demonstrated that VopQ binds to the Vo domain of the conserved V-type H+-ATPase (V-ATPase) found on acidic compartments such as the yeast vacuole. VopQ forms a nonspecific, voltage-gated membrane channel of 18 Å resulting in neutralization of these compartments. We now present data showing that VopQ inhibits yeast vacuole fusion. Furthermore, we identified a unique mutation in VopQ that delineates its two functions, deacidification and inhibition of membrane fusion. The use of VopQ as a membrane fusion inhibitor in this manner now provides convincing evidence that vacuole fusion occurs independently of luminal acidification in vitro. PMID:25453092

Vibrio effector protein VopQ inhibits fusion of V-ATPase-containing membranes.

PubMed

Sreelatha, Anju; Bennett, Terry L; Carpinone, Emily M; O'Brien, Kevin M; Jordan, Kamyron D; Burdette, Dara L; Orth, Kim; Starai, Vincent J

2015-01-06

Vesicle fusion governs many important biological processes, and imbalances in the regulation of membrane fusion can lead to a variety of diseases such as diabetes and neurological disorders. Here we show that the Vibrio parahaemolyticus effector protein VopQ is a potent inhibitor of membrane fusion based on an in vitro yeast vacuole fusion model. Previously, we demonstrated that VopQ binds to the V(o) domain of the conserved V-type H(+)-ATPase (V-ATPase) found on acidic compartments such as the yeast vacuole. VopQ forms a nonspecific, voltage-gated membrane channel of 18 Å resulting in neutralization of these compartments. We now present data showing that VopQ inhibits yeast vacuole fusion. Furthermore, we identified a unique mutation in VopQ that delineates its two functions, deacidification and inhibition of membrane fusion. The use of VopQ as a membrane fusion inhibitor in this manner now provides convincing evidence that vacuole fusion occurs independently of luminal acidification in vitro.

An empirical investigation of time-out with and without escape extinction to treat escape-maintained noncompliance.

PubMed

Everett, Gregory E; Joe Olmi, D; Edwards, Ron P; Tingstrom, Daniel H; Sterling-Turner, Heather E; Christ, Theodore J

2007-07-01

The present study evaluates the effectiveness of two time-out (TO) procedures in reducing escape-maintained noncompliance of 4 children. Noncompliant behavioral function was established via a functional assessment (FA), including indirect and direct descriptive procedures and brief confirmatory experimental analyses. Following FA, parents were taught to consequate noncompliance with two different TO procedures, one without and one with escape extinction following TO release. Although results indicate TO without escape extinction is effective in increasing compliance above baseline levels, more optimal levels of compliance were obtained for all 4 children when escape extinction was added to the TO procedures already in place. Results indicate efficacy of TO with escape extinction when applied to escape-maintained noncompliance and are discussed as an initial example of the successful application of TO to behaviors maintained by negative reinforcement.

Role of cytoskeleton in regulating fusion of nucleoli: a study using the activated mouse oocyte model.

PubMed

Lian, Hua-Yu; Jiao, Guang-Zhong; Wang, Hui-Li; Tan, Xiu-Wen; Wang, Tian-Yang; Zheng, Liang-Liang; Kong, Qiao-Qiao; Tan, Jing-He

2014-09-01

Although fusion of nucleoli was observed during pronuclear development of zygotes and the behavior of nucleoli in pronuclei has been suggested as an indicator of embryonic developmental potential, the mechanism for nucleolar fusion is unclear. Although both cytoskeleton and the nucleolus are important cellular entities, there are no special reports on the relationship between the two. Role of cytoskeleton in regulating fusion of nucleoli was studied using the activated mouse oocyte model. Mouse oocytes were cultured for 6 h in activating medium (Ca²⁺-free CZB medium containing 10 mM SrCl₂) supplemented with or without inhibitors for cytoskeleton or protein synthesis before pronuclear formation, nucleolar fusion, and the activity of maturation-promoting factor (MPF) were examined. Whereas treatment with microfilament inhibitor cytochalasin D or B or intermediate filament inhibitor acrylamide suppressed nucleolar fusion efficiently, treatment with microtubule inhibitor demecolcine or nocodazole or protein synthesis inhibitor cycloheximide had no effect. The cytochalasin D- or acrylamide-sensitive temporal window coincided well with the reported temporal window for nucleolar fusion in activated oocytes. Whereas a continuous incubation with demecolcine prevented pronuclear formation, pronuclei formed normally when demecolcine was excluded during the first hour of activation treatment when the MPF activity dropped dramatically. The results suggest that 1) microfilaments and intermediate filaments but not microtubules support nucleolar fusion, 2) proteins required for nucleolar fusion including microfilaments and intermediate filaments are not de novo synthesized, and 3) microtubule disruption prevents pronuclear formation by activating MPF. © 2014 by the Society for the Study of Reproduction, Inc.

Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation

PubMed Central

Bochicchio, Anna; Jordaan, Sandra; Losasso, Valeria; Chetty, Shivan; Casasnovas Perera, Rodrigo; Ippoliti, Emiliano; Barth, Stefan; Carloni, Paolo

2017-01-01

Targeted human cytolytic fusion proteins (hCFPs) are humanized immunotoxins for selective treatment of different diseases including cancer. They are composed of a ligand specifically binding to target cells genetically linked to a human apoptosis-inducing enzyme. hCFPs target cancer cells via an antibody or derivative (scFv) specifically binding to e.g., tumor associated antigens (TAAs). After internalization and translocation of the enzyme from endocytosed endosomes, the human enzymes introduced into the cytosol are efficiently inducing apoptosis. Under in vivo conditions such enzymes are subject to tight regulation by native inhibitors in order to prevent inappropriate induction of cell death in healthy cells. Tumor cells are known to up-regulate these inhibitors as a survival mechanism resulting in escape of malignant cells from elimination by immune effector cells. Cytosolic inhibitors of Granzyme B and Angiogenin (Serpin P9 and RNH1, respectively), reduce the efficacy of hCFPs with these enzymes as effector domains, requiring detrimentally high doses in order to saturate inhibitor binding and rescue cytolytic activity. Variants of Granzyme B and Angiogenin might feature reduced affinity for their respective inhibitors, while retaining or even enhancing their catalytic activity. A powerful tool to design hCFPs mutants with improved potency is given by in silico methods. These include molecular dynamics (MD) simulations and enhanced sampling methods (ESM). MD and ESM allow predicting the enzyme-protein inhibitor binding stability and the associated conformational changes, provided that structural information is available. Such “high-resolution” detailed description enables the elucidation of interaction domains and the identification of sites where particular point mutations may modify those interactions. This review discusses recent advances in the use of MD and ESM for hCFP development from the viewpoints of scientists involved in both fields. PMID

Designing the Sniper: Improving Targeted Human Cytolytic Fusion Proteins for Anti-Cancer Therapy via Molecular Simulation.

PubMed

Bochicchio, Anna; Jordaan, Sandra; Losasso, Valeria; Chetty, Shivan; Perera, Rodrigo Casasnovas; Ippoliti, Emiliano; Barth, Stefan; Carloni, Paolo

2017-02-17

Targeted human cytolytic fusion proteins (hCFPs) are humanized immunotoxins for selective treatment of different diseases including cancer. They are composed of a ligand specifically binding to target cells genetically linked to a human apoptosis-inducing enzyme. hCFPs target cancer cells via an antibody or derivative (scFv) specifically binding to e.g., tumor associated antigens (TAAs). After internalization and translocation of the enzyme from endocytosed endosomes, the human enzymes introduced into the cytosol are efficiently inducing apoptosis. Under in vivo conditions such enzymes are subject to tight regulation by native inhibitors in order to prevent inappropriate induction of cell death in healthy cells. Tumor cells are known to upregulate these inhibitors as a survival mechanism resulting in escape of malignant cells from elimination by immune effector cells. Cytosolic inhibitors of Granzyme B and Angiogenin (Serpin P9 and RNH1, respectively), reduce the efficacy of hCFPs with these enzymes as effector domains, requiring detrimentally high doses in order to saturate inhibitor binding and rescue cytolytic activity. Variants of Granzyme B and Angiogenin might feature reduced affinity for their respective inhibitors, while retaining or even enhancing their catalytic activity. A powerful tool to design hCFPs mutants with improved potency is given by in silico methods. These include molecular dynamics (MD) simulations and enhanced sampling methods (ESM). MD and ESM allow predicting the enzyme-protein inhibitor binding stability and the associated conformational changes, provided that structural information is available. Such "high-resolution" detailed description enables the elucidation of interaction domains and the identification of sites where particular point mutations may modify those interactions. This review discusses recent advances in the use of MD and ESM for hCFP development from the viewpoints of scientists involved in both fields.

Relationship of scores on the Escapism Scale of the MMPI to escape from minimum security federal custody.

PubMed

White, R B

1979-04-01

Investigated the ability of the Escapism (Ec) scale of the MMPI to differentiate between escape and non-escape minimum security federal prisoners. At the .05 level there was no difference between the scores of the two groups on the Ec scale or on comparisons of other correctional data, age, and ethnic composition. It appears that the Ec scale alone or in combination with other data will be a poor predictor of escape. Also, the rate of escape was so low as to make accurate prediction from any criteria extremely unlikely.

Recombinant Mucin-Type Fusion Proteins with a Galα1,3Gal Substitution as Clostridium difficile Toxin A Inhibitors

PubMed Central

Jin, Chunsheng; Liu, Jining; Karlsson, Niclas G.; Holgersson, Jan

2016-01-01

The capability of a recombinant mucin-like fusion protein, P-selectin glycoprotein ligand-1/mouse IgG2b (PSGL-1/mIgG2b), carrying Galα1,3Galβ1,4GlcNAc determinants to bind and inhibit Clostridium difficile toxin A (TcdA) was investigated. The fusion protein, produced by a glyco-engineered stable CHO-K1 cell line and designated C-PGC2, was purified by affinity and gel filtration chromatography from large-scale cultures. Liquid chromatography-mass spectrometry was used to characterize O-glycans released by reductive β-elimination, and new diagnostic ions to distinguish Galα1,3Gal- from Galα1,4Gal-terminated O-glycans were identified. The C-PGC2 cell line, which was 20-fold more sensitive to TcdA than the wild-type CHO-K1, is proposed as a novel cell-based model for TcdA cytotoxicity and neutralization assays. The C-PGC2-produced fusion protein could competitively inhibit TcdA binding to rabbit erythrocytes, making it a high-efficiency inhibitor of the hemagglutination property of TcdA. The fusion protein also exhibited a moderate capability for neutralization of TcdA cytotoxicity in both C-PGC2 and CHO-K1 cells, the former with and the latter without cell surface Galα1,3Galβ1,4GlcNAc sequences. Future studies in animal models of C. difficile infection will reveal its TcdA-inhibitory effect and therapeutic potential in C. difficile-associated diseases. PMID:27456831

A Cell-Cell Fusion Assay to Assess Arenavirus Envelope Glycoprotein Membrane-Fusion Activity.

PubMed

York, Joanne; Nunberg, Jack H

2018-01-01

For many viruses that enter their target cells through pH-dependent fusion of the viral and endosomal membranes, cell-cell fusion assays can provide an experimental platform for investigating the structure-function relationships that promote envelope glycoprotein membrane-fusion activity. Typically, these assays employ effector cells expressing the recombinant envelope glycoprotein on the cell surface and target cells engineered to quantitatively report fusion with the effector cell. In the protocol described here, Vero cells are transfected with a plasmid encoding the arenavirus envelope glycoprotein complex GPC and infected with the vTF7-3 vaccinia virus expressing the bacteriophage T7 RNA polymerase. These effector cells are mixed with target cells infected with the vCB21R-lacZ vaccinia virus encoding a β-galactosidase reporter under the control of the T7 promoter. Cell-cell fusion is induced upon exposure to low-pH medium (pH 5.0), and the resultant expression of the β-galactosidase reporter is quantitated using a chemiluminescent substrate. We have utilized this robust microplate cell-cell fusion assay extensively to study arenavirus entry and its inhibition by small-molecule fusion inhibitors.

Drosophila Cancer Models Identify Functional Differences between Ret Fusions.

PubMed

Levinson, Sarah; Cagan, Ross L

2016-09-13

We generated and compared Drosophila models of RET fusions CCDC6-RET and NCOA4-RET. Both RET fusions directed cells to migrate, delaminate, and undergo EMT, and both resulted in lethality when broadly expressed. In all phenotypes examined, NCOA4-RET was more severe than CCDC6-RET, mirroring their effects on patients. A functional screen against the Drosophila kinome and a library of cancer drugs found that CCDC6-RET and NCOA4-RET acted through different signaling networks and displayed distinct drug sensitivities. Combining data from the kinome and drug screens identified the WEE1 inhibitor AZD1775 plus the multi-kinase inhibitor sorafenib as a synergistic drug combination that is specific for NCOA4-RET. Our work emphasizes the importance of identifying and tailoring a patient's treatment to their specific RET fusion isoform and identifies a multi-targeted therapy that may prove effective against tumors containing the NCOA4-RET fusion. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Stochastic acidification, activation of hemagglutinin and escape of influenza viruses from an endosome

NASA Astrophysics Data System (ADS)

Lagache, Thibault; Sieben, Christian; Meyer, Tim; Herrmann, Andreas; Holcman, David

2017-06-01

Influenza viruses enter the cell inside an endosome. During the endosomal journey, acidification triggers a conformational change of the virus spike protein hemagglutinin (HA) that results in escape of the viral genome from the endosome into the cytoplasm. It is still unclear how the interplay between acidification and HA conformation changes affects the kinetics of the viral endosomal escape. We develop here a stochastic model to estimate the change of conformation of HAs inside the endosome nanodomain. Using a Markov process, we model the arrival of protons to HA binding sites and compute the kinetics of their accumulation. We compute the Mean First Passage Time (MFPT) of the number of HA bound sites to a threshold, which is used to estimate the HA activation rate for a given pH concentration. The present analysis reveals that HA proton binding sites possess a high chemical barrier, ensuring a stability of the spike protein at sub-acidic pH. We predict that activating more than 3 adjacent HAs is necessary to trigger endosomal fusion and this configuration prevents premature release of viruses from early endosomes

Hydrodynamical Modeling of Hydrogen Escape from Rocky Planets

NASA Astrophysics Data System (ADS)

Barringer, Daniel; Zugger, M.; Kasting, J.

2013-01-01

Hydrogen escape affects both the composition of primitive atmospheres of terrestrial planets and the planet’s state of oxidation. On Mars, hydrogen escape played a critical role in how long the planet remained in a warm wet state amenable to life. For both solar and extrasolar planets, hydrogen-rich atmospheres are better candidates for originating life by way of Miller-Urey-type prebiotic synthesis. However, calculating the rate of atmospheric hydrogen escape is difficult, for a number of reasons. First, the escape can be controlled either by diffusion through the homopause or by conditions in the upper atmosphere, whichever is slower. Second, both thermal and non-thermal escape mechanisms are typically important. Third, thermal escape itself can be subdivided into Jeans escape (thin upper atmosphere), and hydrodynamic escape, and hydrodynamic escape can be further subdivided into transonic escape and slower subsonic escape, depending on whether the exobase occurs above or below the sonic point. Additionally, the rate of escape for real terrestrial planet atmospheres, which are not 100% hydrogen, depends upon the concentration of infrared coolants, and upon heating and photochemistry driven largely by extreme ultraviolet (EUV) radiation. We have modified an existing 1-D model of hydrodynamic escape (F. Tian et al., JGR, 2008) to work in the high- hydrogen regime. Calculations are underway to determine hydrogen escape rates as a function of atmospheric H2 mixing ratio and the solar EUV flux. We will compare these rates with the estimated upper limit on the escape rate based on diffusion. Initial results for early Earth and Mars will later be extended to rocky exoplanets.

RET fusion as a novel driver of medullary thyroid carcinoma.

PubMed

Grubbs, Elizabeth G; Ng, Patrick Kwok-Shing; Bui, Jacquelin; Busaidy, Naifa L; Chen, Ken; Lee, Jeffrey E; Lu, Xinyan; Lu, Hengyu; Meric-Bernstam, Funda; Mills, Gordon B; Palmer, Gary; Perrier, Nancy D; Scott, Kenneth L; Shaw, Kenna R; Waguespack, Steven G; Williams, Michelle D; Yelensky, Roman; Cote, Gilbert J

2015-03-01

Oncogenic RET tyrosine kinase gene fusions and activating mutations have recently been identified in lung cancers, prompting initiation of targeted therapy trials in this disease. Although RET point mutation has been identified as a driver of tumorigenesis in medullary thyroid carcinoma (MTC), no fusions have been described to date. We evaluated the role of RET fusion as an oncogenic driver in MTC. We describe a patient who died from aggressive sporadic MTC < 10 months after diagnosis. Her tumor was evaluated by means of next-generation sequencing, including an intronic capture strategy. A reciprocal translocation involving RET intron 12 was identified. The fusion was validated using a targeted break apart fluorescence in situ hybridization probe, and RNA sequencing confirmed the existence of an in-frame fusion transcript joining MYH13 exon 35 with RET exon 12. Ectopic expression of fusion product in a murine Ba/F3 cell reporter model established strong oncogenicity. Three tyrosine kinase inhibitors currently used to treat MTC in clinical practice blocked tumorigenic cell growth. This finding represents the report of a novel RET fusion, the first of its kind described in MTC. The finding of this potential novel oncogenic mechanism has clear implications for sporadic MTC, which in the majority of cases has no driver mutation identified. The presence of a RET fusion also provides a plausible target for RET tyrosine kinase inhibitor therapies.

Creating Engaging Escape Rooms for the Classroom

ERIC Educational Resources Information Center

Nicholson, Scott

2018-01-01

Escape rooms are "live-action team-based games where players discover clues, solve puzzles, and accomplish tasks in one or more rooms in order to accomplish a specific goal (usually escaping from the room) in a limited amount of time." Escape Rooms are one type of Escape Game, which are narrative-based challenges that use puzzles, tasks,…

Coupling an EML4-ALK centric interactome with RNA interference identifies sensitizers to ALK inhibitors

PubMed Central

Zhang, Guolin; Scarborough, Hannah; Kim, Jihye; Rozhok, Andrii I.; Chen, Y. Ann; Zhang, Xiaohui; Song, Lanxi; Bai, Yun; Fang, Bin; Liu, Richard Z.; Koomen, John; Tan, Aik Choon; Degregori, James; Haura, Eric B.

2017-01-01

Patients with lung cancers harboring anaplastic lymphoma kinase (ALK) gene fusions benefit from treatment with ALK kinase inhibitors but acquired resistance inevitably arises. A better understanding of proximal ALK signaling mechanisms may identify sensitizers to ALK inhibitors that disrupt the balance between pro-survival and pro-apoptotic effector signals. Using affinity purification coupled with mass spectrometry in an ALK fusion lung cancer cell line (H3122), we generated an ALK signaling network and investigated signaling activity using tyrosine phosphoproteomics. We identified a network of 464 proteins composed of subnetworks with differential response to ALK inhibitors. A small hairpin RNA screen targeting 407 proteins in this network revealed 64 and 9 proteins whose loss sensitized cells to crizotinib and alectinib, respectively. Among these, knocking down fibroblast growth factor receptor substrate 2 (FRS2) or coiled-coil and C2 domain-containing protein 1A (CC2D1A, both scaffolding proteins, sensitized multiple ALK fusion cell lines to the ALK inhibitors crizotinib and alectinib. Collectively, our data provides a resource that enhances our understanding of signaling and drug resistance networks consequent to ALK fusions, and identifies potential targets to improve the efficacy of ALK inhibitors in patients. PMID:27811184

Wind-Induced Atmospheric Escape: Titan

NASA Technical Reports Server (NTRS)

Hartle, Richard; Johnson, Robert; Sittler, Edward, Jr.; Sarantos, Menelaos; Simpson, David

2012-01-01

Rapid thermospheric flows can significantly enhance the estimates of the atmospheric loss rate and the structure of the atmospheric corona of a planetary body. In particular, rapid horizontal flow at the exobase can increase the corresponding constituent escape rate. Here we show that such corrections, for both thermal and non-thermal escape, cannot be ignored when calculating the escape of methane from Titan, for which drastically different rates have been proposed. Such enhancements are also relevant to Pluto and exoplanets.

P2X-selective purinergic antagonists are strong inhibitors of HIV-1 fusion during both cell-to-cell and cell-free infection.

PubMed

Swartz, Talia H; Esposito, Anthony M; Durham, Natasha D; Hartmann, Boris M; Chen, Benjamin K

2014-10-01

Human immunodeficiency virus type 1 (HIV-1) infection is chronic and presently still incurable. Antiretroviral drugs effectively suppress replication; however, persistent activation of inflammatory pathways remains a key cause of morbidity. Recent studies proposed that purinergic signaling is required for HIV-1 infection. Purinergic receptors are distributed throughout a wide variety of tissue types and detect extracellular ATP as a danger signal released from dying cells. We have explored how these pathways are involved in the transmission of HIV-1 from cell to cell through virological synapses. Infection of CD4+ T lymphocytes with HIV-1 in the presence of an inhibitor of P2X receptors effectively inhibited HIV-1 infection through both cell-free and cell-to-cell contact in a dose-dependent manner. Inhibition of direct cell-to-cell infection did not affect the formation of virological synapses or the subsequent cell-to-cell transfer of HIV-1. During both cell-free and cell-to-cell CD4+ T lymphocyte infection, purinergic antagonists blocked infection at the level of viral membrane fusion. During cell-to-cell transmission, we observed CXCR4 colocalization with the newly internalized virus particles within target lymphocytes and found that the purinergic antagonists did not impair the recruitment of the coreceptor CXCR4 to the site of Gag internalization in the target cell. In a screen of a library of purinergic antagonists, we found that the most potent inhibitors of HIV-1 fusion were those that target P2X receptors, while P2Y-selective receptor antagonists or adenosine receptor antagonists were ineffective. Our results suggest that P2X receptors may provide a therapeutic target and that purinergic antagonists may have potent activity against viral infection of CD4+ T lymphocytes by both cell-free and cell-to-cell transmission. This study identifies purinergic antagonists to be potent inhibitors of HIV-1 cell-free and cell-to-cell-mediated infection and provides a

Distinct Requirements for HIV-Cell Fusion and HIV-mediated Cell-Cell Fusion*

PubMed Central

Kondo, Naoyuki; Marin, Mariana; Kim, Jeong Hwa; Desai, Tanay M.; Melikyan, Gregory B.

2015-01-01

Whether HIV-1 enters cells by fusing with the plasma membrane or with endosomes is a subject of active debate. The ability of HIV-1 to mediate fusion between adjacent cells, a process referred to as “fusion-from-without” (FFWO), shows that this virus can fuse with the plasma membrane. To compare FFWO occurring at the cell surface with HIV-cell fusion through a conventional entry route, we designed an experimental approach that enabled the measurements of both processes in the same sample. The following key differences were observed. First, a very small fraction of viruses fusing with target cells participated in FFWO. Second, whereas HIV-1 fusion with adherent cells was insensitive to actin inhibitors, post-CD4/coreceptor binding steps during FFWO were abrogated. A partial dependence of HIV-cell fusion on actin remodeling was observed in CD4+ T cells, but this effect appeared to be due to the actin dependence of virus uptake. Third, deletion of the cytoplasmic tail of HIV-1 gp41 dramatically enhanced the ability of the virus to promote FFWO, while having a modest effect on virus-cell fusion. Distinct efficiencies and actin dependences of FFWO versus HIV-cell fusion are consistent with the notion that, except for a minor fraction of particles that mediate fusion between the plasma membranes of adjacent cells, HIV-1 enters through an endocytic pathway. We surmise, however, that cell-cell contacts enabling HIV-1 fusion with the plasma membrane could be favored at the sites of high density of target cells, such as lymph nodes. PMID:25589785

Fitness-Balanced Escape Determines Resolution of Dynamic Founder Virus Escape Processes in HIV-1 Infection

PubMed Central

Sunshine, Justine E.; Larsen, Brendan B.; Maust, Brandon; Casey, Ellie; Deng, Wenje; Chen, Lennie; Westfall, Dylan H.; Kim, Moon; Zhao, Hong; Ghorai, Suvankar; Lanxon-Cookson, Erinn; Rolland, Morgane; Collier, Ann C.; Maenza, Janine; Mullins, James I.

2015-01-01

ABSTRACT To understand the interplay between host cytotoxic T-lymphocyte (CTL) responses and the mechanisms by which HIV-1 evades them, we studied viral evolutionary patterns associated with host CTL responses in six linked transmission pairs. HIV-1 sequences corresponding to full-length p17 and p24 gag were generated by 454 pyrosequencing for all pairs near the time of transmission, and seroconverting partners were followed for a median of 847 days postinfection. T-cell responses were screened by gamma interferon/interleukin-2 (IFN-γ/IL-2) FluoroSpot using autologous peptide sets reflecting any Gag variant present in at least 5% of sequence reads in the individual's viral population. While we found little evidence for the occurrence of CTL reversions, CTL escape processes were found to be highly dynamic, with multiple epitope variants emerging simultaneously. We found a correlation between epitope entropy and the number of epitope variants per response (r = 0.43; P = 0.05). In cases in which multiple escape mutations developed within a targeted epitope, a variant with no fitness cost became fixed in the viral population. When multiple mutations within an epitope achieved fitness-balanced escape, these escape mutants were each maintained in the viral population. Additional mutations found to confer escape but undetected in viral populations incurred high fitness costs, suggesting that functional constraints limit the available sites tolerable to escape mutations. These results further our understanding of the impact of CTL escape and reversion from the founder virus in HIV infection and contribute to the identification of immunogenic Gag regions most vulnerable to a targeted T-cell attack. IMPORTANCE Rapid diversification of the viral population is a hallmark of HIV-1 infection, and understanding the selective forces driving the emergence of viral variants can provide critical insight into the interplay between host immune responses and viral evolution. We used

Inhibition of Sendai virus fusion with phospholipid vesicles and human erythrocyte membranes by hydrophobic peptides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kelsey, D.R.; Flanagan, T.D.; Young, J.E.

1991-06-01

Hydrophobic di- and tripeptides which are capable of inhibiting enveloped virus infection of cells are also capable of inhibiting at least three different types of membrane fusion events. Large unilamellar vesicles (LUV) of N-methyl dioleoylphosphatidylethanolamine (N-methyl DOPE), containing encapsulated 1-aminonaphthalene-3,6,8-trisulfonic acid (ANTS) and/or p-xylene bis(pyridinium bromide) (DPX), were formed by extrusion. Vesicle fusion and leakage were then monitored with the ANTS/DPX fluorescence assay. Sendai virus fusion with lipid vesicles and Sendai virus fusion with human erythrocyte membranes were measured by following the relief of fluorescence quenching of virus labeled with octadecylrhodamine B chloride (R18). This study found that the effectivenessmore » of the peptides carbobenzoxy-L-Phe-L-Phe (Z-L-Phe-L-Phe), Z-L-Phe, Z-D-Phe, and Z-Gly-L-Phe-L-Phe in inhibiting N-methyl DOPE LUV fusion or fusion of virus with N-methyl DOPE LUV also paralleled their reported ability to block viral infectivity. Furthermore, Z-D-Phe-L-PheGly and Z-Gly-L-Phe inhibited Sendai virus fusion with human erythrocyte membranes with the same relative potency with which they inhibited vesicle-vesicle and virus-vesicle fusion. The evidence suggests a mechanism by which these peptides exert their inhibition of plaque formation by enveloped viruses. This class of inhibitors apparently acts by inhibiting fusion of the viral envelope with the target cell membrane, thereby preventing viral infection. The physical pathway by which these peptides inhibit membrane fusion was investigated. {sup 31}P nuclear magnetic resonance (NMR) of proposed intermediates in the pathway for membrane fusion in LUV revealed that the potent fusion inhibitor Z-D-Phe-L-PheGly selectively altered the structure (or dynamics) of the hypothesized fusion intermediates and that the poor inhibitor Z-Gly-L-Phe did not.« less

Physics escape room as an educational tool

NASA Astrophysics Data System (ADS)

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.

Non-Canonical Thinking for Targeting ALK-Fusion Onco-Proteins in Lung Cancer

PubMed Central

Wu, Wei; Haderk, Franziska; Bivona, Trever G.

2017-01-01

Anaplastic lymphoma kinase (ALK) gene rearrangements have been identified in lung cancer at 3–7% frequency, thus representing an important subset of genetic lesions that drive oncogenesis in this disease. Despite the availability of multiple FDA-approved small molecule inhibitors targeting ALK fusion proteins, drug resistance to ALK kinase inhibitors is a common problem in clinic. Thus, there is an unmet need to deepen the current understanding of genomic characteristics of ALK rearrangements and to develop novel therapeutic strategies that can overcome ALK inhibitor resistance. In this review, we present the genomic landscape of ALK fusions in the context of co-occurring mutations with other cancer-related genes, pointing to the central role of genetic epistasis (gene-gene interactions) in ALK-driven advanced-stage lung cancer. We discuss the possibility of targeting druggable domains within ALK fusion partners in addition to available strategies inhibiting the ALK kinase domain directly. Finally, we examine the potential of targeting ALK fusion-specific neoantigens in combination with other treatments, a strategy that could open a new avenue for the improved treatment of ALK positive lung cancer patients. PMID:29189709

Differential protein stability and clinical responses of EML4-ALK fusion variants to various ALK inhibitors in advanced ALK-rearranged non-small cell lung cancer.

PubMed

Woo, C G; Seo, S; Kim, S W; Jang, S J; Park, K S; Song, J Y; Lee, B; Richards, M W; Bayliss, R; Lee, D H; Choi, J

2017-04-01

Anaplastic lymphoma kinase (ALK) inhibition using crizotinib has become the standard of care in advanced ALK-rearranged non-small cell lung cancer (NSCLC), but the treatment outcomes and duration of response vary widely. Echinoderm microtubule-associated protein-like 4 (EML4)-ALK is the most common translocation, and the fusion variants show different sensitivity to crizotinib in vitro. However, there are only limited data on the specific EML4-ALK variants and clinical responses of patients to various ALK inhibitors. By multiplex reverse-transcriptase PCR, which detects 12 variants of known EML4-ALK rearrangements, we retrospectively determined ALK fusion variants in 54 advanced ALK rearrangement-positive NSCLCs. We subdivided the patients into two groups (variants 1/2/others and variants 3a/b) by protein stability and evaluated correlations of the variant status with clinical responses to crizotinib, alectinib, or ceritinib. Moreover, we established the EML4-ALK variant-expressing system and analyzed patterns of sensitivity of the variants to ALK inhibitors. Of the 54 tumors analyzed, EML4-ALK variants 3a/b (44.4%) was the most common type, followed by variants 1 (33.3%) and 2 (11.1%). The 2-year progression-free survival (PFS) rate was 76.0% [95% confidence interval (CI) 56.8-100] in group EML4-ALK variants 1/2/others versus 26.4% (95% CI 10.5-66.6) in group variants 3a/b (P = 0.034) among crizotinib-treated patients. Meanwhile, the 2-year PFS rate was 69.0% (95% CI 49.9-95.4) in group variants 1/2/others versus 32.7% (95% CI 15.6-68.4) in group variants 3a/b (P = 0.108) among all crizotinib-, alectinib-, and ceritinib-treated patients. Variant 3a- or 5a-harboring cells were resistant to ALK inhibitors with >10-fold higher half maximal inhibitory concentration in vitro. Our findings show that group EML4-ALK variants 3a/b may be a major source of ALK inhibitor resistance in the clinic. The variant-specific genotype of the EML4-ALK fusion allows for more

Fragments of Target Cells are Internalized into Retroviral Envelope Protein-Expressing Cells during Cell-Cell Fusion by Endocytosis

PubMed Central

Izumida, Mai; Kamiyama, Haruka; Suematsu, Takashi; Honda, Eri; Koizumi, Yosuke; Yasui, Kiyoshi; Hayashi, Hideki; Ariyoshi, Koya; Kubo, Yoshinao

2016-01-01

Retroviruses enter into host cells by fusion between viral and host cell membranes. Retroviral envelope glycoprotein (Env) induces the membrane fusion, and also mediates cell-cell fusion. There are two types of cell-cell fusions induced by the Env protein. Fusion-from-within is induced by fusion between viral fusogenic Env protein-expressing cells and susceptible cells, and virions induce fusion-from-without by fusion between adjacent cells. Although entry of ecotropic murine leukemia virus (E-MLV) requires host cell endocytosis, the involvement of endocytosis in cell fusion is unclear. By fluorescent microscopic analysis of the fusion-from-within, we found that fragments of target cells are internalized into Env-expressing cells. Treatment of the Env-expressing cells with an endocytosis inhibitor more significantly inhibited the cell fusion than that of the target cells, indicating that endocytosis in Env-expressing cells is required for the cell fusion. The endocytosis inhibitor also attenuated the fusion-from-without. Electron microscopic analysis suggested that the membrane fusion resulting in fusion-from-within initiates in endocytic membrane dents. This study shows that two types of the viral cell fusion both require endocytosis, and provides the cascade of fusion-from-within. PMID:26834711

30 CFR 75.382 - Mechanical escape facilities.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Mechanical escape facilities. 75.382 Section 75... HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Ventilation § 75.382 Mechanical escape facilities. (a) Mechanical escape facilities shall be provided with overspeed, overwind, and automatic stop...

Sargassum fusiforme fraction is a potent and specific inhibitor of HIV-1 fusion and reverse transcriptase

PubMed Central

Paskaleva, Elena E; Lin, Xudong; Duus, Karen; McSharry, James J; Veille, Jean-Claude L; Thornber, Carol; Liu, Yanze; Lee, David Yu-Wei; Canki, Mario

2008-01-01

Sargassum fusiforme (Harvey) Setchell has been shown to be a highly effective inhibitor of HIV-1 infection. To identify its mechanism of action, we performed bioactivity-guided fractionation on Sargassum fusiforme mixture. Here, we report isolation of a bioactive fraction SP4-2 (S. fusiforme), which at 8 μg/ml inhibited HIV-1 infection by 86.9%, with IC50 value of 3.7 μg. That represents 230-fold enhancement of antiretroviral potency as compared to the whole extract. Inhibition was mediated against both CXCR4 (X4) and CCR5 (R5) tropic HIV-1. Specifically, 10 μg/ml SP4-2 blocked HIV-1 fusion and entry by 53%. This effect was reversed by interaction of SP4-2 with sCD4, suggesting that S. fusiforme inhibits HIV-1 infection by blocking CD4 receptor, which also explained observed inhibition of both X4 and R5-tropic HIV-1. SP4-2 also inhibited HIV-1 replication after virus entry, by directly inhibiting HIV-1 reverse transcriptase (RT) in a dose dependent manner by up to 79%. We conclude that the SP4-2 fraction contains at least two distinct and biologically active molecules, one that inhibits HIV-1 fusion by interacting with CD4 receptor, and another that directly inhibits HIV-1 RT. We propose that S. fusiforme is a lead candidate for anti-HIV-1 drug development. PMID:18197976

Escape of magnetic toroids from the Sun

NASA Technical Reports Server (NTRS)

Bieber, John W.; Rust, David M.

1995-01-01

Analysis of heliospheric magnetic fields at 1 AU shows that 10(exp 24) Mx of net azimuthal flux escapes from the Sun per solar cycle. This rate is consistent with rates derived from other indicators of flux escape, including coronal mass ejections and filament eruptions. The toroidal flux escape rate is compared with the apparent rate of flux emergence at the solar surface, and it is concluded that escaping toroids will remove at least 20% of the emerging flux, and may remove as much as 100% of emerging flux if multiple eruptions occur on the toroids. The data imply that flux escapes the Sun with an efficiency far exceeding Parker's upper limit estimate of 3%. Toroidal flux escape is almost certainly the source of the observed overwinding of the interplanetary magnetic field spiral. Two mechanisms to facilitate net flux escape are discussed: helicity charging to push open the fields and flux transport with reconnection to close them off. We estimate the Sun will shed approximately 2 x 10(exp 45) of magnetic helicity per solar cycle, leading to a mean helicity density of 100 Mx(exp 2)cm(exp -3) at 1 AU, which agrees well with observations.

The atmospheric escape at Mars: complementing the scenario

NASA Astrophysics Data System (ADS)

Lilensten, Jean; Simon, Cyril; Barthélémy, Mathieu; Thissen, Roland; Ehrenreich, David; Gronoff, Guillaume; Witasse, Olivier

2013-04-01

In the recent years, the presence of dications in the atmospheres of Mars, Venus, Earth and Titan has been modeled and assessed. These studies also suggested that these ions could participate to the escape of the planetary atmospheres because a large fraction of them is unstable and highly ener- getic. When they dissociate, their internal energy is transformed into kinetic energy which may be larger than the escape energy. This study assesses the impact of the doubly-charged ions in the escape of CO2-dominated planetary atmospheres and to compare it to the escape of thermal photo-ions.We solve a Boltzmann transport equation at daytime taking into account the dissociative states of CO++ for a simplified single constituent atmosphere of a 2 case-study planet. We compute the escape of fast ions using a Beer-Lambert approach. We study three test-cases. On a Mars-analog planet in today's conditions, we retrieve the measured electron escape flux. When comparing the two mechanisms (i.e. excluding solar wind effects, sputtering ...), the escape due to the fast ions issuing from the dissociation of dications may account for up to 6% of the total and the escape of thermal ions for the remaining. We show that these two mechanisms cannot explain the escape of the atmosphere since the magnetic field vanished but complement the other processes and allow writing the scenario of the Mars escape. We show that the atmosphere of a Mars analog planet would empty in another giga years and a half. At Venus orbit, the contribution of the dications in the escape rate is negligible.When simulating the hot Jupiter HD209458b, the two processes cannot explain the measured escape flux of C+.

Neuroprotection with a brain-penetrating biologic tumor necrosis factor inhibitor.

PubMed

Zhou, Qing-Hui; Sumbria, Rachita; Hui, Eric Ka-Wai; Lu, Jeff Zhiqiang; Boado, Ruben J; Pardridge, William M

2011-11-01

Biologic tumor necrosis factor (TNF)-α inhibitors do not cross the blood-brain barrier (BBB). A BBB-penetrating TNF-α inhibitor was engineered by fusion of the extracellular domain of the type II human TNF receptor (TNFR) to the carboxyl terminus of the heavy chain of a mouse/rat chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), and this fusion protein is designated cTfRMAb-TNFR. The cTfRMAb-TNFR fusion protein and etanercept bound human TNF-α with high affinity and K(D) values of 374 ± 77 and 280 ± 80 pM, respectively. Neuroprotection in brain in vivo after intravenous administration of the fusion protein was examined in a mouse model of Parkinson's disease. Mice were also treated with saline or a non-BBB-penetrating TNF decoy receptor, etanercept. After intracerebral injection of the nigral-striatal toxin, 6-hydroxydopamine, mice were treated every other day for 3 weeks. Treatment with the cTfRMAb-TNFR fusion protein caused an 83% decrease in apomorphine-induced rotation, a 67% decrease in amphetamine-induced rotation, a 82% increase in vibrissae-elicited forelimb placing, and a 130% increase in striatal tyrosine hydroxylase (TH) enzyme activity. In contrast, chronic treatment with etanercept, which does not cross the BBB, had no effect on neurobehavior or striatal TH enzyme activity. A bridging enzyme-linked immunosorbent assay specific for the cTfRMAb-TNFR fusion protein showed that the immune response generated in the mice was low titer. In conclusion, a biologic TNF inhibitor is neuroprotective after intravenous administration in a mouse model of neurodegeneration, providing that the TNF decoy receptor is reengineered to cross the BBB.

Fusion reactor pumped laser

DOEpatents

Jassby, D.L.

1987-09-04

A nuclear pumped laser capable of producing long pulses of very high power laser radiation is provided. A toroidal fusion reactor provides energetic neutrons which are slowed down by a moderator. The moderated neutrons are converted to energetic particles capable of pumping a lasing medium. The lasing medium is housed in an annular cell surrounding the reactor. The cell includes an annular reflecting mirror at the bottom and an annular output window at the top. A neutron reflector is disposed around the cell to reflect escaping neutrons back into the cell. The laser radiation from the annular window is focused onto a beam compactor which generates a single coherent output laser beam. 10 figs.

Fusion reactor pumped laser

DOEpatents

Jassby, Daniel L.

1988-01-01

A nuclear pumped laser capable of producing long pulses of very high power laser radiation is provided. A toroidal fusion reactor provides energetic neutrons which are slowed down by a moderator. The moderated neutrons are converted to energetic particles capable of pumping a lasing medium. The lasing medium is housed in an annular cell surrounding the reactor. The cell includes an annular reflecting mirror at the bottom and an annular output window at the top. A neutron reflector is disposed around the cell to reflect escaping neutrons back into the cell. The laser radiation from the annular window is focused onto a beam compactor which generates a single coherent output laser beam.

Spacecraft Escape Capsule

NASA Technical Reports Server (NTRS)

Robertson, Edward A.; Charles, Dingell W.; Bufkin, Ann L.; Rodriggs, Liana M.; Peterson, Wayne; Cuthbert, Peter; Lee, David E.; Westhelle, Carlos

2006-01-01

A report discusses the Gumdrop capsule a conceptual spacecraft that would enable the crew to escape safely in the event of a major equipment failure at any time from launch through atmospheric re-entry. The scaleable Gumdrop capsule would comprise a command module (CM), a service module (SM), and a crew escape system (CES). The CM would contain a pressurized crew environment that would include avionic, life-support, thermal control, propulsive attitude control, and recovery systems. The SM would provide the primary propulsion and would also supply electrical power, life-support resources, and active thermal control to the CM. The CES would include a solid rocket motor, embedded within the SM, for pushing the CM away from the SM in the event of a critical thermal-protection-system failure or loss of control. The CM and SM would normally remain integrated with each other from launch through recovery, but could be separated using the CES, if necessary, to enable the safe recovery of the crew in the CM. The crew escape motor could be used, alternatively, as a redundant means of de-orbit propulsion for the CM in the event of a major system failure in the SM.

Light weight escape capsule for fighter aircraft

NASA Technical Reports Server (NTRS)

Robert, James A.

1988-01-01

Emergency crew escape capabilities have been less than adequate for fighter aircraft since before WW II. From the over-the-side bailout of those days through the current ejection seat with a rocket catapult, escaping from a disabled aircraft has been risky at best. Current efforts are underway toward developing a high-tech, smart ejection seat that will give fighter pilots more room to live in the sky, but an escape capsule is needed to meet current and future fighter envelopes. Escape capsules have a bad reputation due to past examples of high weight, poor performance and great complexity. However, the advantages available demand that a capsule be developed. This capsule concept will minimize the inherent disavantages and incorporate the benefits while integrating all aspects of crew station design. The resulting design is appropriate for a crew station of the year 2010 and includes improved combat acceleration protection, chemical or biological combat capability, improved aircraft to escape system interaction, and the highest level of escape performance achievable. The capsule is compact, which can allow a reduced aircraft size and weighs only 1200 lb. The escape system weight penalty is only 120 lb higher than that for the next ejection seat and the capsule has a corresponding increase in performance.

A Fusion-Inhibiting Peptide against Rift Valley Fever Virus Inhibits Multiple, Diverse Viruses

PubMed Central

Koehler, Jeffrey W.; Smith, Jeffrey M.; Ripoll, Daniel R.; Spik, Kristin W.; Taylor, Shannon L.; Badger, Catherine V.; Grant, Rebecca J.; Ogg, Monica M.; Wallqvist, Anders; Guttieri, Mary C.; Garry, Robert F.; Schmaljohn, Connie S.

2013-01-01

For enveloped viruses, fusion of the viral envelope with a cellular membrane is critical for a productive infection to occur. This fusion process is mediated by at least three classes of fusion proteins (Class I, II, and III) based on the protein sequence and structure. For Rift Valley fever virus (RVFV), the glycoprotein Gc (Class II fusion protein) mediates this fusion event following entry into the endocytic pathway, allowing the viral genome access to the cell cytoplasm. Here, we show that peptides analogous to the RVFV Gc stem region inhibited RVFV infectivity in cell culture by inhibiting the fusion process. Further, we show that infectivity can be inhibited for diverse, unrelated RNA viruses that have Class I (Ebola virus), Class II (Andes virus), or Class III (vesicular stomatitis virus) fusion proteins using this single peptide. Our findings are consistent with an inhibition mechanism similar to that proposed for stem peptide fusion inhibitors of dengue virus in which the RVFV inhibitory peptide first binds to both the virion and cell membranes, allowing it to traffic with the virus into the endocytic pathway. Upon acidification and rearrangement of Gc, the peptide is then able to specifically bind to Gc and prevent fusion of the viral and endocytic membranes, thus inhibiting viral infection. These results could provide novel insights into conserved features among the three classes of viral fusion proteins and offer direction for the future development of broadly active fusion inhibitors. PMID:24069485

Dications and thermal ions in planetary atmospheric escape

NASA Astrophysics Data System (ADS)

Lilensten, J.; Simon Wedlund, C.; Barthélémy, M.; Thissen, R.; Ehrenreich, D.; Gronoff, G.; Witasse, O.

2013-01-01

In the recent years, the presence of dications in the atmospheres of Mars, Venus, Earth and Titan has been modeled and assessed. These studies also suggested that these ions could participate to the escape of the planetary atmospheres because a large fraction of them is unstable and highly energetic. When they dissociate, their internal energy is transformed into kinetic energy which may be larger than the escape energy. The goal of this study is to assess the impact of the doubly-charged ions in the escape of CO2-dominated planetary atmospheres and to compare it to the escape of thermal photo-ions. We solve a Boltzmann transport equation at daytime taking into account the dissociative states of CO2++ for a simplified single constituent atmosphere of a case-study planet. We compute the escape of fast ions using a Beer-Lambert approach. We study three test-cases. On a Mars-analog planet in today's conditions, we retrieve the measured electron escape flux. When comparing the two mechanisms (i.e. excluding solar wind effects, sputtering, etc.), the escape due to the fast ions issuing from the dissociation of dications may account for up to 6% of the total and the escape of thermal ions for the remaining. We show that these two mechanisms cannot explain the escape of the atmosphere since the magnetic field vanished and even contribute only marginally to this loss. We show that with these two mechanisms, the atmosphere of a Mars analog planet would empty in another giga years and a half. At Venus orbit, the contribution of the dications in the escape rate is negligible. When simulating the hot Jupiter HD 209458 b, the two processes cannot explain the measured escape flux of C+. This study shows that the dications may constitute a source of the escape of planetary atmospheres which had not been taken into account until now. This source, although marginal, is not negligible. The influence of the photoionization is of course large, but cannot explain alone the loss of Mars

Induction of Cell-Cell Fusion by Ebola Virus Glycoprotein: Low pH Is Not a Trigger.

PubMed

Markosyan, Ruben M; Miao, Chunhui; Zheng, Yi-Min; Melikyan, Gregory B; Liu, Shan-Lu; Cohen, Fredric S

2016-01-01

Ebola virus (EBOV) is a highly pathogenic filovirus that causes hemorrhagic fever in humans and animals. Currently, how EBOV fuses its envelope membrane within an endosomal membrane to cause infection is poorly understood. We successfully measure cell-cell fusion mediated by the EBOV fusion protein, GP, assayed by the transfer of both cytoplasmic and membrane dyes. A small molecule fusion inhibitor, a neutralizing antibody, as well as mutations in EBOV GP known to reduce viral infection, all greatly reduce fusion. By monitoring redistribution of small aqueous dyes between cells and by electrical capacitance measurements, we discovered that EBOV GP-mediated fusion pores do not readily enlarge-a marked difference from the behavior of other viral fusion proteins. EBOV GP must be cleaved by late endosome-resident cathepsins B or L in order to become fusion-competent. Cleavage of cell surface-expressed GP appears to occur in endosomes, as evidenced by the fusion block imposed by cathepsin inhibitors, agents that raise endosomal pH, or an inhibitor of anterograde trafficking. Treating effector cells with a recombinant soluble cathepsin B or thermolysin, which cleaves GP into an active form, increases the extent of fusion, suggesting that a fraction of surface-expressed GP is not cleaved. Whereas the rate of fusion is increased by a brief exposure to acidic pH, fusion does occur at neutral pH. Importantly, the extent of fusion is independent of external pH in experiments in which cathepsin activity is blocked and EBOV GP is cleaved by thermolysin. These results imply that low pH promotes fusion through the well-known pH-dependent activity of cathepsins; fusion induced by cleaved EBOV GP is a process that is fundamentally independent of pH. The cell-cell fusion system has revealed some previously unappreciated features of EBOV entry, which could not be readily elucidated in the context of endosomal entry.

Induction of Cell-Cell Fusion by Ebola Virus Glycoprotein: Low pH Is Not a Trigger

PubMed Central

Zheng, Yi-Min; Melikyan, Gregory B.; Liu, Shan-Lu; Cohen, Fredric S.

2016-01-01

Ebola virus (EBOV) is a highly pathogenic filovirus that causes hemorrhagic fever in humans and animals. Currently, how EBOV fuses its envelope membrane within an endosomal membrane to cause infection is poorly understood. We successfully measure cell-cell fusion mediated by the EBOV fusion protein, GP, assayed by the transfer of both cytoplasmic and membrane dyes. A small molecule fusion inhibitor, a neutralizing antibody, as well as mutations in EBOV GP known to reduce viral infection, all greatly reduce fusion. By monitoring redistribution of small aqueous dyes between cells and by electrical capacitance measurements, we discovered that EBOV GP-mediated fusion pores do not readily enlarge—a marked difference from the behavior of other viral fusion proteins. EBOV GP must be cleaved by late endosome-resident cathepsins B or L in order to become fusion-competent. Cleavage of cell surface-expressed GP appears to occur in endosomes, as evidenced by the fusion block imposed by cathepsin inhibitors, agents that raise endosomal pH, or an inhibitor of anterograde trafficking. Treating effector cells with a recombinant soluble cathepsin B or thermolysin, which cleaves GP into an active form, increases the extent of fusion, suggesting that a fraction of surface-expressed GP is not cleaved. Whereas the rate of fusion is increased by a brief exposure to acidic pH, fusion does occur at neutral pH. Importantly, the extent of fusion is independent of external pH in experiments in which cathepsin activity is blocked and EBOV GP is cleaved by thermolysin. These results imply that low pH promotes fusion through the well-known pH-dependent activity of cathepsins; fusion induced by cleaved EBOV GP is a process that is fundamentally independent of pH. The cell-cell fusion system has revealed some previously unappreciated features of EBOV entry, which could not be readily elucidated in the context of endosomal entry. PMID:26730950

Interspecific evaluation of octopus escape behavior.

PubMed

Wood, James B; Anderson, Roland C

2004-01-01

The well-known ability of octopuses to escape enclosures is a behavior that can be fatal and, therefore, is an animal welfare issue. This study obtained survey data from 38 participants-primarily scientists and public aquarists who work with octopuses-on 25 described species of octopus. The study demonstrates that the likeliness to escape is species specific (p =.001). The study gives husbandry techniques to keep captive octopuses contained. This first interspecific study of octopus escape behavior allows readers to make informed species-specific husbandry choices.

Project Mercury Escape Tower Rockets Tests

NASA Image and Video Library

1960-04-21

A Mercury capsule is mounted inside the Altitude Wind Tunnel for a test of its escape tower rockets at the National Aeronautics and Space Administration (NASA) Lewis Research Center. In October 1959 NASA’s Space Task Group allocated several Project Mercury assignments to Lewis. The Altitude Wind Tunnel was quickly modified so that its 51-foot diameter western leg could be used as a test chamber. The final round of tests in the Altitude Wind Tunnel sought to determine if the smoke plume from the capsule’s escape tower rockets would shroud or compromise the spacecraft. The escape tower, a 10-foot steel rig with three small rockets, was attached to the nose of the Mercury capsule. It could be used to jettison the astronaut and capsule to safety in the event of a launch vehicle malfunction on the pad or at any point prior to separation from the booster. Once actuated, the escape rockets would fire, and the capsule would be ejected away from the booster. After the capsule reached its apex of about 2,500 feet, the tower, heatshield, retropackage, and antenna would be ejected and a drogue parachute would be released. Flight tests of the escape system were performed at Wallops Island as part of the series of Little Joe launches. Although the escape rockets fired prematurely on Little Joe’s first attempt in August 1959, the January 1960 follow-up was successful.

Non-thermal escape of molecular hydrogen from Mars

NASA Astrophysics Data System (ADS)

Gacesa, M.; Zhang, P.; Kharchenko, V.

2012-05-01

We present a detailed theoretical analysis of non-thermal escape of molecular hydrogen from Mars induced by collisions with hot atomic oxygen from the Martian corona. To accurately describe the energy transfer in O + H2(v, j) collisions, we performed extensive quantum-mechanical calculations of state-to-state elastic, inelastic, and reactive cross sections. The escape flux of H2 molecules was evaluated using a simplified 1D column model of the Martian atmosphere with realistic densities of atmospheric gases and hot oxygen production rates for low solar activity conditions. An average intensity of the non-thermal escape flux of H2 of 1.9 × 105 cm-2s-1 was obtained considering energetic O atoms produced in dissociative recombinations of O2+ ions. Predicted ro-vibrational distribution of the escaping H2 was found to contain a significant fraction of higher rotational states. While the non-thermal escape rate was found to be lower than Jeans rate for H2 molecules, the non-thermal escape rates of HD and D2 are significantly higher than their respective Jeans rates. The accurate evaluation of the collisional escape flux of H2 and its isotopes is important for understanding non-thermal escape of molecules from Mars, as well as for the formation of hot H2 Martian corona. The described molecular ejection mechanism is general and expected to contribute to atmospheric escape of H2 and other light molecules from planets, satellites, and exoplanetary bodies.

Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer.

PubMed

Lu, Hengyu; Villafane, Nicole; Dogruluk, Turgut; Grzeskowiak, Caitlin L; Kong, Kathleen; Tsang, Yiu Huen; Zagorodna, Oksana; Pantazi, Angeliki; Yang, Lixing; Neill, Nicholas J; Kim, Young Won; Creighton, Chad J; Verhaak, Roel G; Mills, Gordon B; Park, Peter J; Kucherlapati, Raju; Scott, Kenneth L

2017-07-01

Oncogenic gene fusions drive many human cancers, but tools to more quickly unravel their functional contributions are needed. Here we describe methodology permitting fusion gene construction for functional evaluation. Using this strategy, we engineered the known fusion oncogenes, BCR-ABL1, EML4-ALK , and ETV6-NTRK3, as well as 20 previously uncharacterized fusion genes identified in The Cancer Genome Atlas datasets. In addition to confirming oncogenic activity of the known fusion oncogenes engineered by our construction strategy, we validated five novel fusion genes involving MET, NTRK2 , and BRAF kinases that exhibited potent transforming activity and conferred sensitivity to FDA-approved kinase inhibitors. Our fusion construction strategy also enabled domain-function studies of BRAF fusion genes. Our results confirmed other reports that the transforming activity of BRAF fusions results from truncation-mediated loss of inhibitory domains within the N-terminus of the BRAF protein. BRAF mutations residing within this inhibitory region may provide a means for BRAF activation in cancer, therefore we leveraged the modular design of our fusion gene construction methodology to screen N-terminal domain mutations discovered in tumors that are wild-type at the BRAF mutation hotspot, V600. We identified an oncogenic mutation, F247L, whose expression robustly activated the MAPK pathway and sensitized cells to BRAF and MEK inhibitors. When applied broadly, these tools will facilitate rapid fusion gene construction for subsequent functional characterization and translation into personalized treatment strategies. Cancer Res; 77(13); 3502-12. ©2017 AACR . ©2017 American Association for Cancer Research.

Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kadam, Rameshwar U.; Wilson, Ian A.

The broad-spectrum antiviral drug Arbidol shows efficacy against influenza viruses by targeting the hemagglutinin (HA) fusion machinery. However, the structural basis of the mechanism underlying fusion inhibition by Arbidol has remained obscure, thereby hindering its further development as a specific and optimized influenza therapeutic. We determined crystal structures of Arbidol in complex with influenza virus HA from pandemic 1968 H3N2 and recent 2013 H7N9 viruses. Arbidol binds in a hydrophobic cavity in the HA trimer stem at the interface between two protomers. This cavity is distal to the conserved epitope targeted by broadly neutralizing stem antibodies and is ~16 Åmore » from the fusion peptide. Arbidol primarily makes hydrophobic interactions with the binding site but also induces some conformational rearrangements to form a network of inter- and intraprotomer salt bridges. By functioning as molecular glue, Arbidol stabilizes the prefusion conformation of HA that inhibits the large conformational rearrangements associated with membrane fusion in the low pH of the endosome. This unique binding mode compared with the small-molecule inhibitors of other class I fusion proteins enhances our understanding of how small molecules can function as fusion inhibitors and guides the development of broad-spectrum therapeutics against influenza virus.« less

Mechanisms of Ionospheric Mass Escape

NASA Technical Reports Server (NTRS)

Moore, T. E.; Khazanov, G. V.

2010-01-01

The dependence of ionospheric O+ escape flux on electromagnetic energy flux and electron precipitation into the ionosphere is derived for a hypothetical ambipolar pick-up process, powered the relative motion of plasmas and neutral upper atmosphere, and by electron precipitation, at heights where the ions are magnetized but influenced by photo-ionization, collisions with gas atoms, ambipolar and centrifugal acceleration. Ion pick-up by the convection electric field produces "ring-beam" or toroidal velocity distributions, as inferred from direct plasma measurements, from observations of the associated waves, and from the spectra of incoherent radar echoes. Ring-beams are unstable to plasma wave growth, resulting in rapid relaxation via transverse velocity diffusion, into transversely accelerated ion populations. Ion escape is substantially facilitated by the ambipolar potential, but is only weakly affected by centrifugal acceleration. If, as cited simulations suggest, ion ring beams relax into non-thermal velocity distributions with characteristic speed equal to the local ion-neutral flow speed, a generalized "Jeans escape" calculation shows that the escape flux of ionospheric O+ increases with Poynting flux and with precipitating electron density in rough agreement with observations.

Survival in Emergency Escape from Passenger Aircraft,

DTIC Science & Technology

ESCAPE SYSTEMS, *TRANSPORT AIRCRAFT, ESCAPE SYSTEMS, CIVIL AVIATION, STATISTICAL DATA, AIRCRAFT DOORS, EVACUATION, MORTALITY RATE, ADULTS , CHILDREN, SEX, AIRCRAFT FIRES, AIRCRAFT CABINS, FEMALES, BEHAVIOR.

Phase I/II study of alectinib in lung cancer with RET fusion gene: study protocol.

PubMed

Takeuchi, Shinji; Murayama, Toshinori; Yoshimura, Kenichi; Kawakami, Takahiro; Takahara, Shizuko; Imai, Yasuhito; Kuribayashi, Yoshikazu; Nagase, Katsuhiko; Goto, Koichi; Nishio, Makoto; Hasegawa, Yoshinori; Satouchi, Miyako; Kiura, Katsuyuki; Seto, Takashi; Yano, Seiji

2017-01-01

The rearranged during transfection (RET) fusion gene was discovered as a driver oncogene in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib is an approved anaplastic lymphoma kinase (ALK) inhibitor that may also be effective for RET fusion-positive NSCLC. RET fusion-positive NSCLC patients treated with at least one regimen of chemotherapy are being recruited. In step 1, alectinib (600 or 450 mg, twice daily) will be administered following a 3+3 design. The primary endpoint is safety. In step 2, alectinib will be administered at the recommended dose (RD) defined by step 1. The primary endpoint is the response rate of RET inhibitor treatment-naïve patients. This is the first study to investigate the safety and preliminary efficacy of alectinib in RET fusion-positive NSCLC patients. If successful, alectinib treatment may lead to substantial and important changes in the management of NSCLC with RET fusion genes. J. Med. Invest. 64: 317-320, August, 2017.

Titan impacts and escape

NASA Astrophysics Data System (ADS)

Korycansky, D. G.; Zahnle, Kevin J.

2011-01-01

We report on hydrodynamic calculations of impacts of large (multi-kilometer) objects on Saturn's moon Titan. We assess escape from Titan, and evaluate the hypothesis that escaping ejecta blackened the leading hemisphere of Iapetus and peppered the surface of Hyperion. We carried out two- and three-dimensional simulations of impactors ranging in size from 4 to 100 km diameter, impact velocities between 7 and 15 km s -1, and impact angles from 0° to 75° from the vertical. We used the ZEUSMP2 hydrocode for the calculations. Simulations were made using three different geometries: three-dimensional Cartesian, two-dimensional axisymmetric spherical polar, and two-dimensional plane polar. Three-dimensional Cartesian geometry calculations were carried out over a limited domain (e.g. 240 km on a side for an impactor of size di = 10 km), and the results compared to ones with the same parameters done by Artemieva and Lunine (2005); in general the comparison was good. Being computationally less demanding, two-dimensional calculations were possible for much larger domains, covering global regions of the satellite (from 800 km below Titan's surface to the exobase altitude 1700 km above the surface). Axisymmetric spherical polar calculations were carried out for vertical impacts. Two-dimensional plane-polar geometry calculations were made for both vertical and oblique impacts. In general, calculations among all three geometries gave consistent results. Our basic result is that the amount of escaping material is less than or approximately equal to the impactor mass even for the most favorable cases. Amounts of escaping material scaled most strongly as a function of velocity, with high-velocity impacts generating the largest amount, as expected. Dependence of the relative amount of escaping mass fesc = mesc/ Mi on impactor diameter di was weak. Oblique impacts (impact angle θi > 45°) were more effective than vertical or near-vertical impacts; ratios of mesc/ Mi ˜ 1-2 were

Apollo experience report: Launch escape propulsion subsystem

NASA Technical Reports Server (NTRS)

Townsend, N. A.

1973-01-01

The Apollo launch escape propulsion subsystem contained three solid rocket motors. The general design, development, and qualification of the solid-propellant pitch-control, tower-jettison, and launch-escape motors of the Apollo launch escape propulsion subsystem were completed during years 1961 to 1966. The launch escape system components are described in general terms, and the sequence of events through the ground-based test programs and flight-test programs is discussed. The initial ground rules established for this system were that it should use existing technology and designs as much as possible. The practicality of this decision is proved by the minimum number of problems that were encountered during the development and qualification program.

46 CFR 185.606 - Escape hatches and emergency exits.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 7 2012-10-01 2012-10-01 false Escape hatches and emergency exits. 185.606 Section 185... 100 GROSS TONS) OPERATIONS Markings Required § 185.606 Escape hatches and emergency exits. All escape hatches and other emergency exits used as means of escape must be marked on both sides in clearly legible...

46 CFR 185.606 - Escape hatches and emergency exits.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 7 2010-10-01 2010-10-01 false Escape hatches and emergency exits. 185.606 Section 185... 100 GROSS TONS) OPERATIONS Markings Required § 185.606 Escape hatches and emergency exits. All escape hatches and other emergency exits used as means of escape must be marked on both sides in clearly legible...

46 CFR 185.606 - Escape hatches and emergency exits.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 7 2014-10-01 2014-10-01 false Escape hatches and emergency exits. 185.606 Section 185... 100 GROSS TONS) OPERATIONS Markings Required § 185.606 Escape hatches and emergency exits. All escape hatches and other emergency exits used as means of escape must be marked on both sides in clearly legible...

46 CFR 185.606 - Escape hatches and emergency exits.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 7 2011-10-01 2011-10-01 false Escape hatches and emergency exits. 185.606 Section 185... 100 GROSS TONS) OPERATIONS Markings Required § 185.606 Escape hatches and emergency exits. All escape hatches and other emergency exits used as means of escape must be marked on both sides in clearly legible...

46 CFR 185.606 - Escape hatches and emergency exits.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 7 2013-10-01 2013-10-01 false Escape hatches and emergency exits. 185.606 Section 185... 100 GROSS TONS) OPERATIONS Markings Required § 185.606 Escape hatches and emergency exits. All escape hatches and other emergency exits used as means of escape must be marked on both sides in clearly legible...

Prosthetic Mitral Valve Leaflet Escape

PubMed Central

Kim, Darae; Hun, Sin Sang; Cho, In-Jeong; Shim, Chi-Young; Ha, Jong-Won; Chung, Namsik; Ju, Hyun Chul; Sohn, Jang Won

2013-01-01

Leaflet escape of prosthetic valve is rare but potentially life threatening. It is essential to make timely diagnosis in order to avoid mortality. Transesophageal echocardiography and cinefluoroscopy is usually diagnostic and the location of the missing leaflet can be identified by computed tomography (CT). Emergent surgical correction is mandatory. We report a case of fractured escape of Edward-Duromedics mitral valve 27 years after the surgery. The patient presented with symptoms of acute decompensated heart failure and cardiogenic shock. She was instantly intubated and mechanically ventilated. After prompt evaluation including transthoracic echocardiography and CT, the escape of the leaflet was confirmed. The patient underwent emergent surgery for replacement of the damaged prosthetic valves immediately. Eleven days after the surgery, the dislodged leaflet in iliac artery was removed safely and the patient recovered well. PMID:23837121

Risks incurred by hydrogen escaping from containers and conduits

DOE Office of Scientific and Technical Information (OSTI.GOV)

Swain, M.R.; Grilliot, E.S.

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.

Abelson Kinase Inhibitors Are Potent Inhibitors of Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus Fusion

PubMed Central

Coleman, Christopher M.; Sisk, Jeanne M.; Mingo, Rebecca M.; Nelson, Elizabeth A.; White, Judith M.

2016-01-01

ABSTRACT The highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) cause significant morbidity and morality. There is currently no approved therapeutic for highly pathogenic coronaviruses, even as MERS-CoV is spreading throughout the Middle East. We previously screened a library of FDA-approved drugs for inhibitors of coronavirus replication in which we identified Abelson (Abl) kinase inhibitors, including the anticancer drug imatinib, as inhibitors of both SARS-CoV and MERS-CoV in vitro. Here we show that the anti-CoV activity of imatinib occurs at the early stages of infection, after internalization and endosomal trafficking, by inhibiting fusion of the virions at the endosomal membrane. We specifically identified the imatinib target, Abelson tyrosine-protein kinase 2 (Abl2), as required for efficient SARS-CoV and MERS-CoV replication in vitro. These data demonstrate that specific approved drugs can be characterized in vitro for their anticoronavirus activity and used to identify host proteins required for coronavirus replication. This type of study is an important step in the repurposing of approved drugs for treatment of emerging coronaviruses. IMPORTANCE Both SARS-CoV and MERS-CoV are zoonotic infections, with bats as the primary source. The 2003 SARS-CoV outbreak began in Guangdong Province in China and spread to humans via civet cats and raccoon dogs in the wet markets before spreading to 37 countries. The virus caused 8,096 confirmed cases of SARS and 774 deaths (a case fatality rate of ∼10%). The MERS-CoV outbreak began in Saudi Arabia and has spread to 27 countries. MERS-CoV is believed to have emerged from bats and passed into humans via camels. The ongoing outbreak of MERS-CoV has resulted in 1,791 cases of MERS and 640 deaths (a case fatality rate of 36%). The emergence of SARS-CoV and MERS-CoV provides evidence that coronaviruses are currently spreading from zoonotic

30 CFR 77.1101 - Escape and evacuation; plan.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Fire Protection § 77.1101 Escape and evacuation; plan. (a) Before September 30, 1971, each operator of... event of a fire. (b) All employees shall be instructed on current escape and evacuation plans, fire alarm signals, and applicable procedures to be followed in case of fire. (c) Plans for escape and...

30 CFR 77.1101 - Escape and evacuation; plan.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Fire Protection § 77.1101 Escape and evacuation; plan. (a) Before September 30, 1971, each operator of... event of a fire. (b) All employees shall be instructed on current escape and evacuation plans, fire alarm signals, and applicable procedures to be followed in case of fire. (c) Plans for escape and...

30 CFR 77.1101 - Escape and evacuation; plan.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Fire Protection § 77.1101 Escape and evacuation; plan. (a) Before September 30, 1971, each operator of... event of a fire. (b) All employees shall be instructed on current escape and evacuation plans, fire alarm signals, and applicable procedures to be followed in case of fire. (c) Plans for escape and...

30 CFR 77.1101 - Escape and evacuation; plan.

Code of Federal Regulations, 2014 CFR

2014-07-01

... Fire Protection § 77.1101 Escape and evacuation; plan. (a) Before September 30, 1971, each operator of... event of a fire. (b) All employees shall be instructed on current escape and evacuation plans, fire alarm signals, and applicable procedures to be followed in case of fire. (c) Plans for escape and...

Martian Atmospheric and Ionospheric plasma Escape

NASA Astrophysics Data System (ADS)

Lundin, Rickard

2016-04-01

Solar forcing is responsible for the heating, ionization, photochemistry, and erosion processes in the upper atmosphere throughout the lifetime of the terrestrial planets. Of the four terrestrial planets, the Earth is the only one with a fully developed biosphere, while our kin Venus and Mars have evolved into arid inhabitable planets. As for Mars, there are ample evidences for an early Noachian, water rich period on Mars. The question is, what made Mars evolve so differently compared to the Earth? Various hydrosphere and atmospheric evolution scenarios for Mars have been forwarded based on surface morphology, chemical composition, simulations, semi-empiric (in-situ data) models, and the long-term evolution of the Sun. Progress has been made, but the case is still open regarding the changes that led to the present arid surface and tenuous atmosphere at Mars. This presentation addresses the long-term variability of the Sun, the solar forcing impact on the Martian atmosphere, and its interaction with the space environment - an electromagnetic wave and particle interaction with the upper atmosphere that has implications for its photochemistry, composition, and energization that governs thermal and non-thermal escape. Non-thermal escape implies an electromagnetic upward energization of planetary ions and molecules to velocities above escape velocity, a process governed by a combination of solar EUV radiation (ionization), and energy and momentum transfer by the solar wind. The ion escape issue dates back to the early Soviet and US-missions to Mars, but the first more accurate estimates of escape rates came with the Phobos-2 mission in 1989. Better-quality ion composition measurement results of atmospheric/ionospheric ion escape from Mars, obtained from ESA Mars Express (MEX) instruments, have improved our understanding of the ion escape mechanism. With the NASA MAVEN spacecraft orbiting Mars since Sept. 2014, dual in-situ measurement with plasma instruments are now

Narrow Escape of Interacting Diffusing Particles

NASA Astrophysics Data System (ADS)

Agranov, Tal; Meerson, Baruch

2018-03-01

The narrow escape problem deals with the calculation of the mean escape time (MET) of a Brownian particle from a bounded domain through a small hole on the domain's boundary. Here we develop a formalism which allows us to evaluate the nonescape probability of a gas of diffusing particles that may interact with each other. In some cases the nonescape probability allows us to evaluate the MET of the first particle. The formalism is based on the fluctuating hydrodynamics and the recently developed macroscopic fluctuation theory. We also uncover an unexpected connection between the narrow escape of interacting particles and thermal runaway in chemical reactors.

Mars atmospheric escape and evolution; interaction with the solar wind

NASA Astrophysics Data System (ADS)

Chassefière, Eric; Leblanc, François

2004-09-01

This tutorial deals with the question of atmospheric escape on Mars. After a brief introduction describing the general context of Mars escape studies, we will present in Section 2 a simplified theory of thermal escape, of both Jeans and hydrodynamic types. The phenomenon of hydrodynamic escape, still hypothetical and not proved to have ever existed on terrestrial planets, will be treated with the help of two well known examples: (i) the isotopic fractionation of xenon in Mars and Earth atmospheres, (ii) the paradox of missing oxygen in Venus atmosphere. In Section 3, a simplified approach of non-thermal escape will be developed, treating in a specific way the different kinds of escape (photochemical escape, ion sputtering, ion escape and ionospheric outflow). As a matter of illustration, some calculations of the relative contributions of these mechanisms, and of their time evolutions, will be given, and the magnitude of the total amount of atmosphere lost by non-thermal escape will be estimated. Section 4 will present the state of knowledge concerning the constraints derived from Mars isotopic geochemistry in terms of past escape and evolution. Finally, a few conclusions, which are more interrogations, will be proposed.

Cerebrospinal Fluid HIV Escape from Antiretroviral Therapy.

PubMed

Ferretti, Francesca; Gisslen, Magnus; Cinque, Paola; Price, Richard W

2015-06-01

CNS infection is a nearly constant facet of systemic CNS infection and is generally well controlled by suppressive systemic antiretroviral therapy (ART). However, there are instances when HIV can be detected in the cerebrospinal fluid (CSF) despite suppression of plasma viruses below the clinical limits of measurement. We review three types of CSF viral escape: asymptomatic, neuro-symptomatic, and secondary. The first, asymptomatic CSF escape, is seemingly benign and characterized by lack of discernable neurological deterioration or subsequent CNS disease progression. Neuro-symptomatic CSF escape is an uncommon, but important, entity characterized by new or progressive CNS disease that is critical to recognize clinically because of its management implications. Finally, secondary CSF escape, which may be even more uncommon, is defined by an increase of CSF HIV replication in association with a concomitant non-HIV infection, as a consequence of the local inflammatory response. Understanding these CSF escape settings not only is important for clinical diagnosis and management but also may provide insight into the CNS HIV reservoir.

Residential smoke alarms and fire escape plans.

PubMed

Harvey, P A; Sacks, J J; Ryan, G W; Bender, P F

1998-01-01

To estimate the proportion of U.S. homes with installed smoke alarms, smoke alarms on the same floor as occupants' bedrooms, and fire escape plans. The authors analyzed data on smoke alarm use and fire escape planning from a 1994 stratified random telephone survey of 5238 U.S. households. Respondents from 91% of surveyed households reported the presence of at least one installed smoke alarm, and 94% of respondents reported having an alarm on the same level of the home as their sleeping area. The prevalence of installed smoke alarms varied by highest education level in the household and income level. Sixty percent of all households had designed or discussed a fire escape plan at least once; only 17% of these households had actually practiced one. Although overall use of smoke alarms was high, certain population subgroups were less likely to have smoke alarms or to have them installed on the same floor as bedrooms. Fire escape planning, another important safety measure, was somewhat less common, and very few respondents reported having practiced a fire escape plan with the members of their household.

Synthesis of a Bifunctional Peptide Inhibitor-IgG1 Fc Fusion That Suppresses Experimental Autoimmune Encephalomyelitis.

PubMed

White, Derek R; Khedri, Zahra; Kiptoo, Paul; Siahaan, Teruna J; Tolbert, Thomas J

2017-07-19

Multiple sclerosis (MS) is a neurodegenerative disease that is estimated to affect over 2.3 million people worldwide. The exact cause for this disease is unknown but involves immune system attack and destruction of the myelin protein surrounding the neurons in the central nervous system. One promising class of compounds that selectively prevent the activation of immune cells involved in the pathway leading to myelin destruction are bifunctional peptide inhibitors (BPIs). Treatment with BPIs reduces neurodegenerative symptoms in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. In this work, as an effort to further improve the bioactivity of BPIs, BPI peptides were conjugated to the N- and C-termini of the fragment crystallizable (Fc) region of the human IgG1 antibody. Initially, the two peptides were conjugated to IgG1 Fc using recombinant DNA technology. However, expression in yeast resulted in low yields and one of the peptides being heavily proteolyzed. To circumvent this problem, the poorly expressed peptide was instead produced by solid phase peptide synthesis and conjugated enzymatically using a sortase-mediated ligation. The sortase-mediated method showed near-complete conjugation yield as observed by SDS-PAGE and mass spectrometry in small-scale reactions. This method was scaled up to obtain sufficient quantities for testing the BPI-Fc fusion in mice induced with EAE. Compared to the PBS-treated control, mice treated with the BPI-Fc fusion showed significantly reduced disease symptoms, did not experience weight loss, and showed reduced de-myelination. These results demonstrate that the BPI peptides were highly active at suppressing EAE when conjugated to the large Fc scaffold in this manner.

Escaping Antiangiogenic Therapy: Strategies Employed by Cancer Cells

PubMed Central

Pinto, Mauricio P.; Sotomayor, Paula; Carrasco-Avino, Gonzalo; Corvalan, Alejandro H.; Owen, Gareth I.

2016-01-01

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. PMID:27608016

Escaping Antiangiogenic Therapy: Strategies Employed by Cancer Cells.

PubMed

Pinto, Mauricio P; Sotomayor, Paula; Carrasco-Avino, Gonzalo; Corvalan, Alejandro H; Owen, Gareth I

2016-09-06

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.

Autophagy-deficient breast cancer shows early tumor recurrence and escape from dormancy

PubMed Central

Aqbi, Hussein F.; Tyutyunyk-Massey, Liliya; Keim, Rebecca C.; Butler, Savannah E.; Thekkudan, Theresa; Joshi, Supriya; Smith, Timothy M.; Bandyopadhyay, Dipankar; Idowu, Michael O.; Bear, Harry D.; Payne, Kyle K.; Gewirtz, David A.; Manjili, Masoud H.

2018-01-01

Breast cancer patients who initially respond to cancer therapies often succumb to distant recurrence of the disease. It is not clear why people with the same type of breast cancer respond to treatments differently; some escape from dormancy and relapse earlier than others. In addition, some tumor clones respond to immunotherapy while others do not. We investigated how autophagy plays a role in accelerating or delaying recurrence of neu-overexpressing mouse mammary carcinoma (MMC) following adriamycin (ADR) treatment, and in affecting response to immunotherapy. We explored two strategies: 1) transient blockade of autophagy with chloroquine (CQ), which blocks fusion of autophagosomes and lysosomes during ADR treatment, and 2) permanent inhibition of autophagy by a stable knockdown of ATG5 (ATG5KD), which inhibits the formation of autophagosomes in MMC during and after ADR treatment. We found that while CQ prolonged tumor dormancy, but that stable knockdown of autophagy resulted in early escape from dormancy and recurrence. Interestingly, ATG5KD MMC contained an increased frequency of ADR-induced polyploid-like cells and rendered MMC resistant to immunotherapy. On the other hand, a transient blockade of autophagy did not affect the sensitivity of MMC to immunotherapy. Our observations suggest that while chemotherapy-induced autophagy may facilitate tumor relapse, cell-intrinsic autophagy delays tumor relapse, in part, by inhibiting the formation of polyploid-like tumor dormancy. PMID:29774126

Decompression illness in goats following simulated submarine escape: 1993-2006.

PubMed

Seddon, F M; Thacker, J C; Fisher, A S; Jurd, K M; White, M G; Loveman, G A M

2014-01-01

The United Kingdom Ministry of Defence commissioned work to define the relationship between the internal pressure of a distressed submarine (DISSUB), the depth from which escape is made and the risk of decompression illness (DCI). The program of work used an animal model (goat) to define these risks and this paper reports the incidence and type of DCI observed. A total of 748 pressure exposures comprising saturation only, escape only or saturation followed by escape were conducted in the submarine escape simulator between 1993 and 2006. The DCI following saturation exposures was predominantly limb pain, whereas following escape exposures the DCI predominantly involved the central nervous system and was fast in onset. There was no strong relationship between the risk of DCI and the range of escape depths investigated. The risk of DCI incurred from escape following saturation was greater than that obtained by combining the risks for the independent saturation only, and escape only, exposures. The output from this program of work has led to improved advice on the safety of submarine escape.

Room Escape at Class: Escape Games Activities to Facilitate the Motivation and Learning in Computer Science

ERIC Educational Resources Information Center

Borrego, Carlos; Fernández, Cristina; Blanes, Ian; Robles, Sergi

2017-01-01

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…

Discovery of Critical Residues for Viral Entry and Inhibition through Structural Insight of HIV-1 Fusion Inhibitor CP621–652*

PubMed Central

Chong, Huihui; Yao, Xue; Qiu, Zonglin; Qin, Bo; Han, Ruiyun; Waltersperger, Sandro; Wang, Meitian; Cui, Sheng; He, Yuxian

2012-01-01

The core structure of HIV-1 gp41 is a stable six-helix bundle (6-HB) folded by its trimeric N- and C-terminal heptad repeats (NHR and CHR). We previously identified that the 621QIWNNMT627 motif located at the upstream region of gp41 CHR plays critical roles for the stabilization of the 6-HB core and peptide CP621–652 containing this motif is a potent HIV-1 fusion inhibitor, however, the molecular determinants underlying the stability and anti-HIV activity remained elusive. In this study, we determined the high-resolution crystal structure of CP621–652 complexed by T21. We find that the 621QIWNNMT627 motif does not maintain the α-helical conformation. Instead, residues Met626 and Thr627 form a unique hook-like structure (denoted as M-T hook), in which Thr627 redirects the peptide chain to position Met626 above the left side of the hydrophobic pocket on the NHR trimer. The side chain of Met626 caps the hydrophobic pocket, stabilizing the interaction between the pocket and the pocket-binding domain. Our mutagenesis studies demonstrate that mutations of the M-T hook residues could completely abolish HIV-1 Env-mediated cell fusion and virus entry, and significantly destabilize the interaction of NHR and CHR peptides and reduce the anti-HIV activity of CP621–652. Our results identify an unusual structural feature that stabilizes the six-helix bundle, providing novel insights into the mechanisms of HIV-1 fusion and inhibition. PMID:22511760

P20A inhibits HIV-1 fusion through its electrostatic interaction with the distal region of the gp41 fusion core.

PubMed

Fu, Shushu; Tong, Pei; Tan, Yue; Zhu, Yun; Chen, Ying-Hua

2015-09-01

We previously identified an HIV-1 fusion inhibitor P20A targeting HIV-1 gp41 6-HB fusion core. Using alanine scanning mutagenesis, we investigated the effect of 6-HB surface residue mutations on the binding affinity between P20A and 6-HB. Substitution of positively or negatively charged residues in the distal region of 6-HB with alanines resulted in significant decrease or increase of its binding affinity to P20A, respectively. The 6-HB with E630K, D632K, or E634K mutation exhibited enhanced binding affinity with P20A, suggesting that P20A blocks HIV-1 fusion through electrostatic interaction with the positively charged residues in the distal region of the gp41 fusion core. Copyright © 2015 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Orbital and escape dynamics in barred galaxies - III. The 3D system: correlations between the basins of escape and the NHIMs

NASA Astrophysics Data System (ADS)

Zotos, Euaggelos E.; Jung, Christof

2018-01-01

The escape dynamics of the stars in a barred galaxy composed of a spherically symmetric central nucleus, a bar, a flat thin disc and a dark matter halo component is investigated by using a realistic three degrees of freedom (3-d.o.f.) dynamical model. Modern colour-coded diagrams are used for distinguishing between bounded and escaping motion. In addition, the smaller alignment index method is deployed for determining the regular, sticky or chaotic nature of bounded orbits. We reveal the basins of escape corresponding to the escape through the two symmetrical escape channels around the Lagrange points L2 and L3 and also we relate them with the corresponding distribution of the escape times of the orbits. Furthermore, we demonstrate how the stable manifolds, around the index-1 saddle points, accurately define the fractal basin boundaries observed in the colour-coded diagrams. The development scenario of the fundamental vertical Lyapunov periodic orbit is thoroughly explored for obtaining a more complete view of the unfolding of the singular behaviour of the dynamics at the cusp values of the parameters. Finally, we examine how the combination of the most important parameters of the bar (such as the semimajor axis and the angular velocity) influences the observed stellar structures (rings and spirals), which are formed by escaping stars guided by the invariant manifolds near the saddle points.

Residential smoke alarms and fire escape plans.

PubMed Central

Harvey, P A; Sacks, J J; Ryan, G W; Bender, P F

1998-01-01

OBJECTIVE: To estimate the proportion of U.S. homes with installed smoke alarms, smoke alarms on the same floor as occupants' bedrooms, and fire escape plans. METHODS: The authors analyzed data on smoke alarm use and fire escape planning from a 1994 stratified random telephone survey of 5238 U.S. households. RESULTS: Respondents from 91% of surveyed households reported the presence of at least one installed smoke alarm, and 94% of respondents reported having an alarm on the same level of the home as their sleeping area. The prevalence of installed smoke alarms varied by highest education level in the household and income level. Sixty percent of all households had designed or discussed a fire escape plan at least once; only 17% of these households had actually practiced one. CONCLUSIONS: Although overall use of smoke alarms was high, certain population subgroups were less likely to have smoke alarms or to have them installed on the same floor as bedrooms. Fire escape planning, another important safety measure, was somewhat less common, and very few respondents reported having practiced a fire escape plan with the members of their household. PMID:9769771

The ubiquitin–proteasome system regulates membrane fusion of yeast vacuoles

PubMed Central

Kleijnen, Maurits F; Kirkpatrick, Donald S; Gygi, Steven P

2007-01-01

Ubiquitination is known to regulate early stages of intracellular vesicular transport, without proteasomal involvement. We now show that, in yeast, ubiquitination regulates a late-stage, membrane fusion, with proteasomal involvement. A known proteasome mutant had a vacuolar fragmentation phenotype in vivo often associated with vacuolar membrane fusion defects, suggesting a proteasomal role in fusion. Inhibiting vacuolar proteasomes interfered with membrane fusion in vitro, showing that fusion cannot occur without proteasomal degradation. If so, one would expect to find ubiquitinated proteins on vacuolar membranes. We found a small number of these, identified the most prevalent one as Ypt7 and mapped its two major ubiquitination sites. Ubiquitinated Ypt7 was linked to the degradation event that is necessary for fusion: vacuolar Ypt7 and vacuolar proteasomes were interdependent, ubiquitinated Ypt7 became a proteasomal substrate during fusion, and proteasome inhibitors reduced fusion to greater degree when we decreased Ypt7 ubiquitination. The strongest model holds that fusion cannot proceed without proteasomal degradation of ubiquitinated Ypt7. As Ypt7 is one of many Rab GTPases, ubiquitin–proteasome regulation may be involved in membrane fusion elsewhere. PMID:17183369

Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors

PubMed Central

Akbay, Esra A; Koyama, Shohei; Carretero, Julian; Altabef, Abigail; Tchaicha, Jeremy H; Christensen, Camilla L; Mikse, Oliver R; Cherniack, Andrew D; Beauchamp, Ellen M; Pugh, Trevor J; Wilkerson, Matthew D; Fecci, Peter E; Butaney, Mohit; Reibel, Jacob B; Soucheray, Margaret; Cohoon, Travis J; Janne, Pasi A; Meyerson, Matthew; Hayes, D. Neil; Shapiro, Geoffrey I; Shimamura, Takeshi; Sholl, Lynette M; Rodig, Scott J; Freeman, Gordon J; Hammerman, Peter S; Dranoff, Glenn; Wong, Kwok-Kin

2013-01-01

The success in lung cancer therapy with Programmed Death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased cytotoxic T cells and increased markers of T cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape, and mechanistically link treatment response to PD-1 inhibition. PMID:24078774

MAVEN Pickup Ion Constraints on Mars Neutral Escape

NASA Astrophysics Data System (ADS)

Rahmati, A.; Larson, D. E.; Cravens, T.; Lillis, R. J.; Dunn, P.; Halekas, J. S.; McFadden, J. P.; Mitchell, D. L.; Thiemann, E.; Connerney, J. E. P.; DiBraccio, G. A.; Espley, J. R.; Eparvier, F. G.

2017-12-01

Mars is currently losing its atmosphere mainly due to the escape of neutral hydrogen and oxygen. Directly measuring the rate of escaping neutrals is difficult, because the neutral density in the Mars exosphere is dominated, up to several Martian radii, by atoms that are gravitationally bound to the planet. Neutral atoms in the Martian exosphere, however, can get ionized, picked up, and accelerated by the solar wind motional electric field and energized to energies high enough for particle detectors to measure them. The MAVEN SEP instrument detects O+ pickup ions that are created at altitudes where the escaping part of the exosphere is dominant. Fluxes of these ions reflect neutral densities in the distant exosphere of Mars, allowing us to constrain neutral oxygen escape rates. The MAVEN SWIA and STATIC instruments measure pickup H+ and O+ created closer to Mars; comparisons of these data with models can be used to constrain exospheric hot O and thermal H densities and escape rates. In this work, pickup ion measurements from SEP, SWIA, and STATIC, taken during the first 3 Earth years of the MAVEN mission, are compared to the outputs of a pickup ion model to constrain the variability of neutral escape at Mars. The model is based on data from six MAVEN instruments, namely, MAG providing magnetic field used in calculating pickup ion trajectories, SWIA providing solar wind velocity as well as 3D pickup H+ and O+ spectra, SWEA providing solar wind electron spectrum used in electron impact ionization rate calculations, SEP providing pickup O+ spectra, STATIC providing mass resolved 3D pickup H+ and O+ spectra, and EUVM providing solar EUV spectra used in photoionization rate calculations. A variability of less than a factor of two is observed in hot oxygen escape rates, whereas thermal escape of hydrogen varies by an order of magnitude with Mars season. This hydrogen escape variability challenges our understanding of the H cycle at Mars, but is consistent with other

VEGFR2-targeted fusion antibody improved NK cell-mediated immunosurveillance against K562 cells.

PubMed

Ren, Xueyan; Xie, Wei; Wang, Youfu; Xu, Menghuai; Liu, Fang; Tang, Mingying; Li, Chenchen; Wang, Min; Zhang, Juan

2016-08-01

MHC class I polypeptide-related sequence A (MICA), which is normally expressed on cancer cells, activates NK cells via NK group 2-member D pathway. However, some cancer cells escape NK-mediated immune surveillance by shedding membrane MICA causing immune suppression. To address this issue, we designed an antibody-MICA fusion targeting tumor-specific antigen (vascular endothelial growth factor receptor 2, VEGFR2) based on our patented antibody (mAb04) against VEGFR2. In vitro results demonstrate that the fusion antibody retains both the antineoplastic and the immunomodulatory activity of mAb04. Further, we revealed that it enhanced NK-mediated immunosurveillance against K562 cells through increasing degranulation and cytokine production of NK cells. The overall data suggest our new fusion protein provides a promising approach for cancer-targeted immunotherapy and has prospects for potential application of chronic myeloid leukemia.

Fusion to Human Serum Albumin Extends the Circulatory Half-Life and Duration of Antithrombotic Action of the Kunitz Protease Inhibitor Domain of Protease Nexin 2.

PubMed

Sheffield, William P; Eltringham-Smith, Louise J; Bhakta, Varsha

2018-01-01

The Kunitz Protease Inhibitor (KPI) domain of protease nexin 2 (PN2) potently inhibits coagulation factor XIa. Recombinant KPI has been shown to inhibit thrombosis in mouse models, but its clearance from the murine circulation remains uncharacterized. The present study explored the pharmacokinetic and pharmacodynamic effects of fusing KPI to human serum albumin (HSA) in fusion protein KPIHSA. Hexahistidine-tagged KPI (63 amino acids) and KPIHSA (656 amino acids) were expressed in Pichia pastoris yeast and purified by nickel-chelate chromatography. Clearance profiles in mice were determined, as well as the effects of KPI or KPIHSA administration on FeCl3-induced vena cava thrombus size or carotid artery time to occlusion, respectively. Fusion to HSA increased the mean terminal half-life of KPI by 8-fold and eliminated its interaction with the low density lipoprotein receptor-related protein. KPI and KPIHSA similarly reduced thrombus size and occlusion in both venous and arterial thrombosis models when administered at the time of injury, but only KPI was effective when administered one hour before injury. Albumin fusion deflects KPI from rapid in vivo clearance without impairing its antithrombotic properties and widens its potential therapeutic window. © 2018 The Author(s). Published by S. Karger AG, Basel.

A New Paradigm for Evaluating Avoidance/Escape Motivation.

PubMed

Tsutsui-Kimura, Iku; Bouchekioua, Youcef; Mimura, Masaru; Tanaka, Kenji F

2017-07-01

Organisms have evolved to approach pleasurable opportunities and to avoid or escape from aversive experiences. These 2 distinct motivations are referred to as approach and avoidance/escape motivations and are both considered vital for survival. Despite several recent advances in understanding the neurobiology of motivation, most studies addressed approach but not avoidance/escape motivation. Here we develop a new experimental paradigm to quantify avoidance/escape motivation and examine the pharmacological validity. We set up an avoidance variable ratio 5 task in which mice were required to press a lever for variable times to avoid an upcoming aversive stimulus (foot shock) or to escape the ongoing aversive event if they failed to avoid it. We i.p. injected ketamine (0, 1, or 5 mg/kg) or buspirone (0, 5, or 10 mg/kg) 20 or 30 minutes before the behavioral task to see if ketamine enhanced avoidance/escape behavior and buspirone diminished it as previously reported. We found that the performance on the avoidance variable ratio 5 task was sensitive to the intensity of the aversive stimulus. Treatment with ketamine increased while that with buspirone decreased the probability of avoidance from an aversive stimulus in the variable ratio 5 task, being consistent with previous reports. Our new paradigm will prove useful for quantifying avoidance/escape motivation and will contribute to a more comprehensive understanding of motivation. © The Author 2017. Published by Oxford University Press on behalf of CINP.

HCV Genotype 6a Escape From and Resistance to Velpatasvir, Pibrentasvir, and Sofosbuvir in Robust Infectious Cell Culture Models.

PubMed

Pham, Long V; Ramirez, Santseharay; Gottwein, Judith M; Fahnøe, Ulrik; Li, Yi-Ping; Pedersen, Jannie; Bukh, Jens

2018-06-01

Chronic liver diseases caused by hepatitis C virus (HCV) genotype 6 are prevalent in Asia, and millions of people require treatment with direct-acting antiviral regimens, such as NS5A inhibitor velpatasvir combined with the NS5B polymerase inhibitor sofosbuvir. We developed infectious cell culture models of HCV genotype 6a infection to study the effects of these inhibitors and the development of resistance. The consensus sequences of strains HK2 (MG717925) and HK6a (MG717928), originating from serum of patients with chronic HCV infection, were determined by Sanger sequencing of genomes amplified by reverse-transcription polymerase chain reaction. In vitro noninfectious full-length clones of these 6a strains were subsequently adapted in Huh7.5 cells, primarily by using substitutions identified in JFH1-based Core-NS5A and Core-NS5B genotype 6a recombinants. We studied the efficacy of NS5A and NS5B inhibitors in concentration-response assays. We examined the effects of long-term culture of Huh7.5 cells incubated with velpatasvir and sofosbuvir singly or combined following infection with passaged full-length HK2 or HK6a recombinant viruses. Resistance-associated substitutions (RAS) were identified by Sanger and next-generation sequencing, and their effects on viral fitness and in drug susceptibility were determined in reverse-genetic experiments. Adapted full-length HCV genotype 6a recombinants HK2cc and HK6acc had fast propagation kinetics and high infectivity titers. Compared with an HCV genotype 1a recombinant, HCV genotype 6a recombinants of strains HK2 and HK6a were equally sensitive to daclatasvir, elbasvir, velpatasvir, pibrentasvir, and sofosbuvir, but less sensitive to ledipasvir, ombitasvir, and dasabuvir. Long-term exposure of HCV genotype 6a-infected Huh7.5 cells with a combination of velpatasvir and sofosbuvir resulted in clearance of the virus, but the virus escaped the effects of single inhibitors via emergence of the RAS L31V in NS5A (conferring

On the escape of oxygen and hydrogen from Mars

NASA Technical Reports Server (NTRS)

Fox, J. L.

1993-01-01

Escape rates of oxygen atoms from dissociative recombination of O2(+) above the Martian exobase are computed in light of new information from ab initio calculations of the dissociative recombination process and our recently revised understanding of the Martian dayside ionosphere. Only about 60 percent of the dissociative recombinations occur in channels in which the O atoms are released with energies in excess of the escape velocity. Futhermore, we find that the computed escape fluxes for O depend greatly on the nature of the ion loss process that has been found necessary to reproduce the topside ion density profiles measured by Viking. If it is assumed that the ions are not lost from the gravitational field of the planet, as required by an analysis of nitrogen escape, the computed average O escape rate is 3 x 10 exp 6/sq cm/s, much less than half the H escape rates inferred from measurements of the Lyman-alpha dayglow, which are in the range (1-2) x 10 exp 8/sq cm/s. Suggestions for restoring the relative escape rates of H and O to the stoichiometric ratio of water are explored.

Recombinant factor VIII Fc fusion protein for immune tolerance induction in patients with severe haemophilia A with inhibitors-A retrospective analysis.

PubMed

Carcao, M; Shapiro, A; Staber, J M; Hwang, N; Druzgal, C; Lieuw, K; Belletrutti, M; Thornburg, C D; Ahuja, S P; Morales-Arias, J; Dumont, J; Miyasato, G; Tsao, E; Jain, N; Pipe, S W

2018-03-01

Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources. Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high-titre inhibitors. Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI. Of 19 patients, 7 were first-time ITI and 12 were rescue ITI. Of 7 first-time patients, 6 had at least 1 high-risk feature for ITI failure. Four of 7 first-time patients were tolerized in a median of 7.8 months. The remaining 3 patients continue on rFVIIIFc ITI. Of 12 rescue patients, 7 initially achieved a negative Bethesda titre (≤0.6) in a median of 3.3 months, 1 had a decrease in Bethesda titre and continues on rFVIIIFc ITI and 4 have not demonstrated a decrease in Bethesda titre. Of these 4, 3 continue on rFVIIIFc ITI and 1 switched to bypass therapy alone. Two initially responsive patients transitioned to other factors due to recurrence. Overall, 16 of 19 patients remain on rFVIIIFc (prophylaxis or ITI). For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events reported. Recombinant factor VIII Fc fusion protein demonstrated rapid time to tolerization in high-risk first-time ITI patients. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI with other products. These findings highlight the need to further evaluate the use of rFVIIIFc for ITI. © 2018 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

Fire Won't Wait--Plan Your Escape!

ERIC Educational Resources Information Center

PTA Today, 1991

1991-01-01

Discusses the importance of home fire escape drills, detailing fire safety plans. Early detection and warning (smoke detectors) coupled with well-rehearsed escape plans help prevent serious injury. Children need to be taught about fire safety beginning at a very early age. (SM)

Some Possible Cases of Escape Mimicry in Neotropical Butterflies.

PubMed

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.

Nociception and escape behavior in planarians

NASA Astrophysics Data System (ADS)

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.

Managing Pacific salmon escapements: The gaps between theory and reality

USGS Publications Warehouse

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

46 CFR 122.606 - Escape hatches and emergency exits.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Escape hatches and emergency exits. 122.606 Section 122.606 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SMALL PASSENGER VESSELS CARRYING... Markings Required § 122.606 Escape hatches and emergency exits. All escape hatches and other emergency...

46 CFR 122.606 - Escape hatches and emergency exits.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 4 2013-10-01 2013-10-01 false Escape hatches and emergency exits. 122.606 Section 122.606 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SMALL PASSENGER VESSELS CARRYING... Markings Required § 122.606 Escape hatches and emergency exits. All escape hatches and other emergency...

46 CFR 122.606 - Escape hatches and emergency exits.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 4 2014-10-01 2014-10-01 false Escape hatches and emergency exits. 122.606 Section 122.606 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SMALL PASSENGER VESSELS CARRYING... Markings Required § 122.606 Escape hatches and emergency exits. All escape hatches and other emergency...

46 CFR 122.606 - Escape hatches and emergency exits.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 4 2012-10-01 2012-10-01 false Escape hatches and emergency exits. 122.606 Section 122.606 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SMALL PASSENGER VESSELS CARRYING... Markings Required § 122.606 Escape hatches and emergency exits. All escape hatches and other emergency...

46 CFR 122.606 - Escape hatches and emergency exits.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 4 2011-10-01 2011-10-01 false Escape hatches and emergency exits. 122.606 Section 122.606 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SMALL PASSENGER VESSELS CARRYING... Markings Required § 122.606 Escape hatches and emergency exits. All escape hatches and other emergency...

Escape from Mars

NASA Image and Video Library

2017-07-10

This image from NASA's Mars Reconnaissance Orbiter shows one of millions of small (10s of meters in diameter) craters and their ejecta material that dot the Elysium Planitia region of Mars. The small craters were likely formed when high-speed blocks of rock were thrown out by a much larger impact (about 10-kilometers in diameter) and fell back to the ground. Some of these blocks may actually escape Mars, which is how we get samples in the form of meteorites that fall to Earth. Other ejected blocks have insufficient velocity, or the wrong trajectory, to escape the Red Planet. As such, when one of these high-speed blocks impacts the surface, it makes what is called a "secondary" crater. These secondaries can form dense "chains" or "rays," which are radial to the crater that formed them. https://photojournal.jpl.nasa.gov/catalog/PIA21769

Determinants of Human Immunodeficiency Virus Type 1 Baseline Susceptibility to the Fusion Inhibitors Enfuvirtide and T-649 Reside outside the Peptide Interaction Site

PubMed Central

Heil, Marintha L.; Decker, Julie M.; Sfakianos, Jeffrey N.; Shaw, George M.; Hunter, Eric; Derdeyn, Cynthia A.

2004-01-01

The peptide fusion inhibitor (PFI) enfuvirtide is the first of a new class of entry inhibitors to receive FDA approval. We previously determined the susceptibility of 55 PFI-naïve-patient isolates to enfuvirtide and a second peptide inhibitor, T-649. Seven of the 55 viral isolates were insusceptible to enfuvirtide, T-649, or both inhibitors in the absence of prior exposure. To determine the molecular basis of the insusceptible phenotypes, we PCR amplified and cloned five PFI-insusceptible and one PFI-susceptible, full-length, biologically functional env genes and characterized viruses pseudotyped with the Env proteins in a single-round drug sensitivity assay. Overall, the mean 50% inhibitory concentrations of enfuvirtide and T-649 for the PFI-insusceptible Env pseudotypes were 1.4 to 1.7 log10 and 1.2 to 1.8 log10 greater, respectively, than those for a PFI-susceptible lab strain, NLHX; however, all of the PFI-insusceptible Env proteins conserved the sequence of a critical enfuvirtide interaction site (residues 36 to 38 of gp41, GIV) in HR-1. In contrast, multiple amino acid changes were observed C-terminal to HR-1, many of which were located in regions of HR-2 corresponding to the PFI. Nevertheless, peptides based on patient-derived HR-2 sequences were not more potent inhibitors than enfuvirtide or T-649, arguing that the basis of PFI susceptibility is not a higher-affinity, competitive HR-1/HR-2 interaction. These results demonstrate that regions of Env outside the enfuvirtide interaction site can significantly impact the PFI susceptibility of patient-derived Env, even prior to drug exposure. We hypothesize that both gp120 gene- and gp41 gene-encoded determinants that minimize the window of opportunity for PFI to bind provide a growth advantage and possibly a predisposition to resistance to this new class of drugs in vivo. PMID:15220433

Trapped as a Group, Escape as a Team: Applying Gamification to Incorporate Team-building Skills Through an 'Escape Room' Experience.

PubMed

Zhang, Xiao Chi; Lee, Hyunjoo; Rodriguez, Carlos; Rudner, Joshua; Chan, Teresa M; Papanagnou, Dimitrios

2018-03-02

Teamwork, a skill critical for quality patient care, is recognized as a core competency by the Accreditation Council for Graduate Medical Education (ACGME). To date, there is no consensus on how to effectively teach these skills in a forum that engages learners, immerses members in life-like activities, and builds both trust and rapport. Recreational 'Escape Rooms' have gained popularity in creating a life-like environment that rewards players for working together, solving puzzles, and completing successions of mind-bending tasks in order to effectively 'escape the room' in the time allotted. In this regard, escape rooms share many parallels with the multitasking and teamwork that is essential for a successful emergency department (ED) shift. A pilot group of nine emergency medicine (EM) residents and one senior EM faculty member underwent a commercial escape room as part of a team-building exercise in January 2018. The escape room required participants to practice teamwork, communication, task delegation, and critical thinking to tackle waves of increasingly complex puzzles, ranging from hidden objects, physical object assembly (i.e., jigsaw puzzles), and symbol matching. Activities required members to recognize and utilize the collective experiences, skills, knowledge base, and physical abilities of the group. After the game, players underwent a structured 'game-master' debriefing facilitated by an employee of the commercial escape room; this was followed by a post-event survey facilitated by a faculty member, which focused on participants' feelings, experiences, and problem-solving techniques. Escape rooms afford learners the opportunity to engage in an activity that rewards teamwork and effective leadership through experiences that directly link to specific ACGME milestones and educational learning theories. EM participants were engaged in the activity and felt that the escape room reproduced an environment analogous to the ED. The debriefing that followed

A phorbol ester-binding protein is required downstream of Rab5 in endosome fusion.

PubMed

Aballay, A; Barbieri, M A; Colombo, M I; Arenas, G N; Stahl, P D; Mayorga, L S

1998-12-28

Previous observations indicate that a zinc and phorbol ester binding factor is necessary for endosome fusion. To further characterize the role of this factor in the process, we used an in vitro endosome fusion assay supplemented with recombinant Rab5 proteins. Both zinc depletion and addition of calphostin C, an inhibitor of protein kinase C, inhibited endosome fusion in the presence of active Rab5. Addition of the phorbol ester PMA (phorbol 12-myristate 13-acetate) reversed the inhibition of endosome fusion caused by a Rab5 negative mutant. Moreover, PMA stimulated fusion in the presence of Rab5 immunodepleted cytosol. These results suggest that the phorbol ester binding protein is acting downstream of Rab5 in endosome fusion.

GREEN PEA GALAXIES REVEAL SECRETS OF Lyα ESCAPE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Huan; Wang, Junxian; Malhotra, Sangeeta

2016-04-01

We analyze archival Lyα spectra of 12 “Green Pea” galaxies observed with the Hubble Space Telescope, model their Lyα profiles with radiative transfer models, and explore the dependence of the Lyα escape fraction on various properties. Green Pea galaxies are nearby compact starburst galaxies with [O iii] λ5007 equivalent widths (EWs) of hundreds of Å. All 12 Green Pea galaxies in our sample show Lyα lines in emission, with an Lyα EW distribution similar to high-redshift Lyα emitters. Combining the optical and UV spectra of Green Pea galaxies, we estimate their Lyα escape fractions and find correlations between Lyα escape fractionmore » and kinematic features of Lyα profiles. The escape fraction of Lyα in these galaxies ranges from 1.4% to 67%. We also find that the Lyα escape fraction depends strongly on metallicity and moderately on dust extinction. We compare their high-quality Lyα profiles with single H i shell radiative transfer models and find that the Lyα escape fraction anticorrelates with the derived H i column densities. Single-shell models fit most Lyα profiles well, but not the ones with the highest escape fractions of Lyα. Our results suggest that low H i column density and low metallicity are essential for Lyα escape and make a galaxy an Lyα emitter.« less

Escape strategies for turboprop aircraft in microburst windshear

NASA Technical Reports Server (NTRS)

Bobbitt, Richard B.; Howard, Richard M.

1991-01-01

The dynamic reponse of a P-3 aircraft and a light twin-engine turboprop to a low-level microburst encounter is modeled. The response to the microburst is depicted for various escape maneuvers. Plots of altitude, velocity, and specific energy are shown for all cases. Takeoff escape strategies are discussed. The optimal escape procedure is found to be flying a constant value of pitch angle. Constant angle of attack maneuvers sometimes result in superior performance.

Centrifugally Stimulated Exospheric Ion Escape at Mercury

NASA Technical Reports Server (NTRS)

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.

Photochemical Escape of Atomic Carbon from Mars

NASA Astrophysics Data System (ADS)

Fox, J. L.; Hac, A. B.

2009-12-01

Determining the escape rate of C over time is necessary to reconstructing the time-dependent history of volatiles on Mars. We report initial results from a one-dimensional spherical Monte Carlo calculation of photochemical escape fluxes and rates of atomic carbon from the Martian atmosphere. This model has recently been used to estimate the photochemical escape flux of O from Mars. We include as sources photodissociation of CO, dissociative recombination of CO+, photoelectron-impact dissociation of CO, photodissociative ionization and photoelectron impact dissociative ionization. Dissociative recombination of CO2+ has been suggested as a source of C (in the channel that produces C + O2) but later studies have found that the yield of this channel is negligible. We test the potential importance of this reaction by comparing the final results produced by including it and excluding it. Finally we compare the range of the escape rate to that of C in ions that have been modeled or measured by ASPERA instruments on MEX and Phobos.

46 CFR 169.745 - Escape hatches and emergency exits.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 7 2013-10-01 2013-10-01 false Escape hatches and emergency exits. 169.745 Section 169... VESSELS Vessel Control, Miscellaneous Systems, and Equipment Markings § 169.745 Escape hatches and emergency exits. Each escape hatch and other emergency exit must be marked on both sides using at least 1...

46 CFR 169.745 - Escape hatches and emergency exits.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 7 2011-10-01 2011-10-01 false Escape hatches and emergency exits. 169.745 Section 169... VESSELS Vessel Control, Miscellaneous Systems, and Equipment Markings § 169.745 Escape hatches and emergency exits. Each escape hatch and other emergency exit must be marked on both sides using at least 1...

46 CFR 169.745 - Escape hatches and emergency exits.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 7 2014-10-01 2014-10-01 false Escape hatches and emergency exits. 169.745 Section 169... VESSELS Vessel Control, Miscellaneous Systems, and Equipment Markings § 169.745 Escape hatches and emergency exits. Each escape hatch and other emergency exit must be marked on both sides using at least 1...

46 CFR 169.745 - Escape hatches and emergency exits.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 7 2012-10-01 2012-10-01 false Escape hatches and emergency exits. 169.745 Section 169... VESSELS Vessel Control, Miscellaneous Systems, and Equipment Markings § 169.745 Escape hatches and emergency exits. Each escape hatch and other emergency exit must be marked on both sides using at least 1...

46 CFR 169.745 - Escape hatches and emergency exits.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 7 2010-10-01 2010-10-01 false Escape hatches and emergency exits. 169.745 Section 169... VESSELS Vessel Control, Miscellaneous Systems, and Equipment Markings § 169.745 Escape hatches and emergency exits. Each escape hatch and other emergency exit must be marked on both sides using at least 1...

DR-induced escape of O and C from early Mars

NASA Astrophysics Data System (ADS)

Zhao, Jinjin; Tian, Feng; Ni, Yufang; Huang, Xiaomeng

2017-03-01

Energetic particles produced in Dissociative recombination (DR) reactions could escape planets with low gravity, such as Mars, if they could overcome collisions with the surrounding background gases. In this work, a 3-D Monte Carlo model is developed to study these photochemical escape processes on early Mars. Although the DR reaction rates of O2+, CO2+, and CO+ increase monotonically with solar soft X-ray and extreme ultraviolet (XUV) flux, the peak of the calculated DR-induced escape rates of O is near 3 × XUV, and the DR-induced escape rates of C increase with XUV until 10 × XUV. The non-monotonic behavior can be explained by the increased column densities of background species in high XUV conditions, which can deflect energetic particles through collisions more efficiently. At 20 × XUV, CO+ DR is the main source of escaping O and C, and the escape of secondary particles could contribute to 30∼40% and 10% of the total escape of O and C respectively. The time-integrated DR-induced escape of O and C is equivalent to 1 m of H2O and 20 mbar of CO2 escaping early Mars since 4.5 billion years ago. The accumulated CO2 loss is much lower than what's needed to explain the carbon isotopic ratios on Mars and much lower than the total CO2 needed to warm up early Mars. If more vigorous escape mechanisms were absent on early Mars, substantial inventories of volatiles have not been detected yet.

Lunar mission safety and rescue: Escape/rescue analysis and plan

NASA Technical Reports Server (NTRS)

1971-01-01

The results are presented of the technical analysis of escape/rescue/survival situations, crew survival techniques, alternate escape/rescue approaches and vehicles, and the advantages and disadvantages of each for advanced lunar exploration. Candidate escape/rescue guidelines are proposed and elements of a rescue plan developed. The areas of discussions include the following: lunar arrival/departure operations, lunar orbiter operations, lunar surface operations, lunar surface base escape/rescue analysis, lander tug location operations, portable airlock, emergency pressure suit, and the effects of no orbiting lunar station, no lunar surface base, and no foreign lunar orbit/surface operations on the escape/rescue plan.

Escape Geography--Developing Middle-School Students' Sense of Place.

ERIC Educational Resources Information Center

Allen, Rodney F.; Molina, Laurie E. S.

1992-01-01

Suggests a social studies unit on escaping geography. Examines escape from dangerous places including an airliner, hotel fire, or war zone or from a social situation such as a boring speech or party. Describes historic escapes such as the Underground Railroad and the Berlin Wall. Lists learning strategies such as awareness of space and cognitive…

Strong FGFR3 staining is a marker for FGFR3 fusions in diffuse gliomas

PubMed Central

Annala, Matti; Lehtinen, Birgitta; Kesseli, Juha; Haapasalo, Joonas; Ruusuvuori, Pekka; Yli-Harja, Olli; Visakorpi, Tapio; Haapasalo, Hannu; Nykter, Matti; Zhang, Wei

2017-01-01

Abstract Background Inhibitors of fibroblast growth factor receptors (FGFRs) have recently arisen as a promising treatment option for patients with FGFR alterations. Gene fusions involving FGFR3 and transforming acidic coiled-coil protein 3 (TACC3) have been detected in diffuse gliomas and other malignancies, and fusion-positive cases have responded well to FGFR inhibition. As high FGFR3 expression has been detected in fusion-positive tumors, we sought to determine the clinical significance of FGFR3 protein expression level as well as its potential for indicating FGFR3 fusions. Methods We performed FGFR3 immunohistochemistry on tissue microarrays containing 676 grades II–IV astrocytomas and 116 grades II–III oligodendroglial tumor specimens. Fifty-one cases were further analyzed using targeted sequencing. Results Moderate to strong FGFR3 staining was detected in gliomas of all grades, was more common in females, and was associated with poor survival in diffuse astrocytomas. Targeted sequencing identified FGFR3-TACC3 fusions and an FGFR3-CAMK2A fusion in 10 of 15 strongly stained cases, whereas no fusions were found in 36 negatively to moderately stained cases. Fusion-positive cases were predominantly female and negative for IDH and EGFR/PDGFRA/MET alterations. These and moderately stained cases show lower MIB-1 proliferation index than negatively to weakly stained cases. Furthermore, stronger FGFR3 expression was commonly observed in malignant tissue regions of lower cellularity in fusion-negative cases. Importantly, subregional negative FGFR3 staining was also observed in a few fusion-positive cases. Conclusions Strong FGFR3 protein expression is indicative of FGFR3 fusions and may serve as a clinically applicable predictive marker for treatment regimens based on FGFR inhibitors. PMID:28379477

The influence of panic on the efficiency of escape

NASA Astrophysics Data System (ADS)

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.

Treatment with escitalopram but not desipramine decreases escape latency times in a learned helplessness model using juvenile rats.

PubMed

Reed, Abbey L; Anderson, Jeffrey C; Bylund, David B; Petty, Frederick; El Refaey, Hesham; Happe, H Kevin

2009-08-01

The pharmacological treatment of depression in children and adolescents is different from that of adults due to the lack of efficacy of certain antidepressants in the pediatric age group. Our current understanding of why these differences occur is very limited. To develop more effective treatments, a juvenile animal model of depression was tested to validate it as a possible model to specifically study pediatric depression. Procedures for use with juvenile rats at postnatal day (PND) 21 and 28 were adapted from the adult learned helplessness model in which, 24 h after exposure to inescapable stress, animals are unable to remove themselves from an easily escapable stressor. Rats were treated for 7 days with either the selective serotonin reuptake inhibitor escitalopram at 10 mg/kg or the tricyclic antidepressant desipramine at 3, 10, or 15 mg/kg to determine if treatment could decrease escape latency times. Escitalopram treatment was effective at decreasing escape latency times in all ages tested. Desipramine treatment did not decrease escape latency times for PND 21 rats, but did decrease times for PND 28 and adult animals. The learned helplessness model with PND 21 rats predicts the efficacy of escitalopram and the lack of efficacy of desipramine seen in the treatment of pediatric depression. These findings suggest that the use of PND 21 rats in a modified learned helplessness procedure may be a valuable model of human pediatric depression that can predict pediatric antidepressant efficacy and be used to study antidepressant mechanisms involved in pediatric depression.

46 CFR 169.313 - Means of escape.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 7 2011-10-01 2011-10-01 false Means of escape. 169.313 Section 169.313 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) NAUTICAL SCHOOLS SAILING SCHOOL VESSELS Construction and Arrangement Hull Structure § 169.313 Means of escape. (a) Except as provided by paragraph (f) of...

Arginine supplementation induces myoblast fusion via augmentation of nitric oxide production.

PubMed

Long, Jodi H D; Lira, Vitor A; Soltow, Quinlyn A; Betters, Jenna L; Sellman, Jeff E; Criswell, David S

2006-01-01

The semi-essential amino acid, L-arginine (L-Arg), is the substrate for endogenous synthesis of nitric oxide, a molecule that is involved in myoblast proliferation and fusion. Since L-Arg supply may limit nitric oxide synthase (NOS) activity in endothelial cells, we examined L-Arg supplementation in differentiating mouse myoblasts and tested the hypothesis that L-Arg exerts direct effects on myoblast fusion via augmentation of endogenous nitric oxide production. C(2)C(12) myoblasts in differentiation media received one of the following treatments for 120 h: 1 mM L-Arg, 0.1 mM N-nitro-L-arginine methyl ester (L-NAME), L-Arg + L-NAME, 10 mM L-Lysine, or no supplement (Control). Cultures were fixed and stained with hematoxylin and eosin for microphotometric image analysis of myotube density, nuclear density, and fusion index (% of total nuclei in myotubes). Endogenous production of nitric oxide during the treatment period peaked between 24 and 48 h. L-Arg amplified nitric oxide production between 0 and 24 h and increased myotube density, total nuclei number, and nuclear fusion index. These L-Arg effects were prevented by the NOS inhibitor, L-NAME. Further, L-Lysine, a competitive inhibitor of L-Arg uptake, repressed nitric oxide production and reduced myotube density and fusion index. In summary, L-Arg augments myotube formation and increases nitric oxide production in a process limited by cellular L-Arg uptake.

Indoleamine 2,3-dioxygenase pathways of pathgenic inflammation and immune escape in cancer

PubMed Central

Prendergast, George C.; Smith, Courtney; Thomas, Sunil; Mandik-Nayak, Laura; Laury-Kleintop, Lisa; Metz, Richard; Muller, Alexander J.

2014-01-01

Genetic and pharmacological studies of indoleamine 2,3-dioxygenase (IDO) have established this tryptophan catabolic enzyme as a central driver of malignant development and progression. IDO acts in tumor, stromal and immune cells to support pathogenic inflammatory processes that engender immune tolerance to tumor antigens. The multifaceted effects of IDO activation in cancer include the suppression of T and NK cells, the generation and activation of T regulatory cells (Treg) and myeloid-derived suppressor cells (MDSC), and the promotion of tumor angiogenesis. Mechanistic investigations have defined the aryl hydrocarbon receptor AhR, the master metabolic regulator mTORC1 and the stress kinase Gcn2 as key effector signaling elements for IDO, which also exerts a non-catalytic role in TGF-β signaling. Small molecule inhibitors of IDO exhibit anticancer activity and cooperate with immunotherapy, radiotherapy or chemotherapy to trigger rapid regression of aggressive tumors otherwise resistant to treatment. Notably, the dramatic antitumor activity of certain targeted therapeutics such as imatinib (Gleevec) in GIST has been traced in part to IDO downregulation. Further, antitumor responses to immune checkpoint inhibitors can be heightened safely by a clinical lead inhibitor of the IDO pathway that relieves IDO-mediated suppression of mTORC1 in T cells. In this personal perspective on IDO as a nodal mediator of pathogenic inflammation and immune escape in cancer, we provide a conceptual foundation for the clinical development of IDO inhibitors as a novel class of immunomodulators with broad application in the treatment of advanced human cancer. PMID:24711084

Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer.

PubMed

Prendergast, George C; Smith, Courtney; Thomas, Sunil; Mandik-Nayak, Laura; Laury-Kleintop, Lisa; Metz, Richard; Muller, Alexander J

2014-07-01

Genetic and pharmacological studies of indoleamine 2,3-dioxygenase (IDO) have established this tryptophan catabolic enzyme as a central driver of malignant development and progression. IDO acts in tumor, stromal and immune cells to support pathogenic inflammatory processes that engender immune tolerance to tumor antigens. The multifaceted effects of IDO activation in cancer include the suppression of T and NK cells, the generation and activation of T regulatory cells and myeloid-derived suppressor cells, and the promotion of tumor angiogenesis. Mechanistic investigations have defined the aryl hydrocarbon receptor, the master metabolic regulator mTORC1 and the stress kinase Gcn2 as key effector signaling elements for IDO, which also exerts a non-catalytic role in TGF-β signaling. Small-molecule inhibitors of IDO exhibit anticancer activity and cooperate with immunotherapy, radiotherapy or chemotherapy to trigger rapid regression of aggressive tumors otherwise resistant to treatment. Notably, the dramatic antitumor activity of certain targeted therapeutics such as imatinib (Gleevec) in gastrointestinal stromal tumors has been traced in part to IDO downregulation. Further, antitumor responses to immune checkpoint inhibitors can be heightened safely by a clinical lead inhibitor of the IDO pathway that relieves IDO-mediated suppression of mTORC1 in T cells. In this personal perspective on IDO as a nodal mediator of pathogenic inflammation and immune escape in cancer, we provide a conceptual foundation for the clinical development of IDO inhibitors as a novel class of immunomodulators with broad application in the treatment of advanced human cancer.

MAVEN in situ measurements of photochemical escape of oxygen from Mars

NASA Astrophysics Data System (ADS)

Lillis, Robert; Deighan, Justin; Fox, Jane; Bougher, Stephen; Lee, Yuni; Cravens, Thomas; Rahmati, Ali; Mahaffy, Paul; Benna, Mehdi; Groller, Hannes; Jakosky, Bruce

2016-04-01

One of the primary goals of the MAVEN mission is to characterize rates of atmospheric escape from Mars at the present epoch and relate those escape rates to solar drivers. One of the known escape processes is photochemical escape, where a) an exothermic chemical reaction in the atmosphere results in an upward-traveling neutral particle whose velocity exceeds planetary escape velocity and b) the particle is not prevented from escaping through subsequent collisions. At Mars, photochemical escape of oxygen is expected to be a significant channel for atmospheric escape, particularly in the early solar system when extreme ultraviolet (EUV) fluxes were much higher. Thus characterizing this escape process and its variability with solar drivers is central to understanding the role escape to space has played in Mars' climate evolution. We use near-periapsis (<400 km altitude) data from three MAVEN instruments: the Langmuir Probe and Waves (LPW) instrument measures electron density and temperature, the Suprathermal And Thermal Ion Composition (STATIC) experiment measures ion temperature and the Neutral Gas and Ion Mass Spectrometer (NGIMS) measures neutral and ion densities. For each profile of in situ measurements, we make several calculations, each as a function of altitude. The first uses electron and temperatures and simulates the dissociative recombination of both O2+ and CO2+ to calculate the probability distribution for the initial energies of the resulting hot oxygen atoms. The second is a Monte Carlo hot atom transport model that takes that distribution of initial O energies and the measured neutral density profiles and calculates the probability that a hot atom born at that altitude will escape. The third takes the measured electron and ion densities and electron temperatures and calculates the production rate of hot O atoms. We then multiply together the profiles of hot atom production and escape probability to get profiles of the production rate of escaping atoms

Orbiter escape pole

NASA Technical Reports Server (NTRS)

Goodrich, Winston D. (Inventor); Wesselski, Clarence J. (Inventor); Pelischek, Timothy E. (Inventor); Becker, Bruce H. (Inventor); Kahn, Jon B. (Inventor); Grimaldi, Margaret E. (Inventor); McManamen, John P. (Inventor); Castro, Edgar O. (Inventor)

1989-01-01

A Shuttle type of aircraft (10) with an escape hatch (12) has an arcuately shaped pole housing (16) attachable to an interior wall and ceiling with its open end adjacent to the escape hatch. The pole housing 16 contains a telescopically arranged and arcuately shaped primary pole member (22) and extension pole member (23) which are guided by roller assemblies (30,35). The extension pole member (23) is slidable and extendable relative to the primary pole member (22). For actuation, a spring actuated system includes a spring (52) in the pole housing. A locking member (90) engages both pole members (22,23) through notch portions (85,86) in the pole members. The locking member selectively releases the extension pole member (23) and the primary pole member (22). An internal one-way clutch or anti-return mechanism prevents retraction of the extension pole member from an extended position. Shock absorbers (54)(150,152) are for absoring the energy of the springs. A manual backup deployment system is provided which includes a canted ring (104) biased by a spring member (108). A lever member (100) with a slot and pin connection (102) permits the mechanical manipulation of the canted ring to move the primary pole member. The ring (104) also prevents retraction of the main pole. The crew escape mechanism includes a magazine (60) and a number of lanyards (62), each lanyard being mounted by a roller loop (68) over the primary pole member (22). The strap on the roller loop has stitching for controlled release, a protection sheath (74) to prevent tangling and a hook member (69) for attachment to a crew harness.

Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion.

PubMed

Veazey, Ronald S; Klasse, Per Johan; Schader, Susan M; Hu, Qinxue; Ketas, Thomas J; Lu, Min; Marx, Preston A; Dufour, Jason; Colonno, Richard J; Shattock, Robin J; Springer, Martin S; Moore, John P

2005-11-03

Human immunodeficiency virus type 1 (HIV-1) continues to spread, principally by heterosexual sex, but no vaccine is available. Hence, alternative prevention methods are needed to supplement educational and behavioural-modification programmes. One such approach is a vaginal microbicide: the application of inhibitory compounds before intercourse. Here, we have evaluated the microbicide concept using the rhesus macaque 'high dose' vaginal transmission model with a CCR5-receptor-using simian-human immunodeficiency virus (SHIV-162P3) and three compounds that inhibit different stages of the virus-cell attachment and entry process. These compounds are BMS-378806, a small molecule that binds the viral gp120 glycoprotein and prevents its attachment to the CD4 and CCR5 receptors, CMPD167, a small molecule that binds to CCR5 to inhibit gp120 association, and C52L, a bacterially expressed peptide inhibitor of gp41-mediated fusion. In vitro, all three compounds inhibit infection of T cells and cervical tissue explants, and C52L acts synergistically with CMPD167 or BMS-378806 to inhibit infection of cell lines. In vivo, significant protection was achieved using each compound alone and in combinations. CMPD167 and BMS-378806 were protective even when applied 6 h before challenge.

Trapped as a Group, Escape as a Team: Applying Gamification to Incorporate Team-building Skills Through an ‘Escape Room’ Experience

PubMed Central

Lee, Hyunjoo; Rodriguez, Carlos; Rudner, Joshua; Chan, Teresa M; Papanagnou, Dimitrios

2018-01-01

Teamwork, a skill critical for quality patient care, is recognized as a core competency by the Accreditation Council for Graduate Medical Education (ACGME). To date, there is no consensus on how to effectively teach these skills in a forum that engages learners, immerses members in life-like activities, and builds both trust and rapport. Recreational ‘Escape Rooms’ have gained popularity in creating a life-like environment that rewards players for working together, solving puzzles, and completing successions of mind-bending tasks in order to effectively ‘escape the room’ in the time allotted. In this regard, escape rooms share many parallels with the multitasking and teamwork that is essential for a successful emergency department (ED) shift. A pilot group of nine emergency medicine (EM) residents and one senior EM faculty member underwent a commercial escape room as part of a team-building exercise in January 2018. The escape room required participants to practice teamwork, communication, task delegation, and critical thinking to tackle waves of increasingly complex puzzles, ranging from hidden objects, physical object assembly (i.e., jigsaw puzzles), and symbol matching. Activities required members to recognize and utilize the collective experiences, skills, knowledge base, and physical abilities of the group. After the game, players underwent a structured ‘game-master’ debriefing facilitated by an employee of the commercial escape room; this was followed by a post-event survey facilitated by a faculty member, which focused on participants’ feelings, experiences, and problem-solving techniques. Escape rooms afford learners the opportunity to engage in an activity that rewards teamwork and effective leadership through experiences that directly link to specific ACGME milestones and educational learning theories. EM participants were engaged in the activity and felt that the escape room reproduced an environment analogous to the ED. The debriefing

Advanced Crew Escape Suit.

PubMed

1995-09-01

Design of the S1032 Launch Entry Suit (LES) began following the Challenger loss and NASA's decision to incorporate a Shuttle crew escape system. The LES (see Figure 1) has successfully supported Shuttle missions since NASA's Return to Flight with STS-26 in September 1988. In 1990, engineers began developing the S1035 Advanced Crew Escape Suit (ACES) to serve as a replacement for the LES. The ACES was designed to be a simplified, lightweight, low-bulk pressure suit which aided self donning/doffing, provided improved comfort, and enhanced overall performance to reduce crew member stress and fatigue. Favorable crew member evaluations of a prototype led to full-scale development and qualification of the S1035 ACES between 1990 and 1992. Production of the S1035 ACES began in February 1993, with the first unit delivered to NASA in May 1994. The S1035 ACES first flew aboard STS-68 in August 1994 and will become the primary crew escape suit when the S1032 LES ends its service life in late 1995. The primary goal of the S1035 development program was to provide improved performance over that of the S1032 to minimize the stress and fatigue typically experienced by crew members. To achieve this, five fundamental design objectives were established, resulting in various material/configuration changes.

Adeno-associated virus capsid antigen presentation is dependent on endosomal escape

PubMed Central

Li, Chengwen; He, Yi; Nicolson, Sarah; Hirsch, Matt; Weinberg, Marc S.; Zhang, Ping; Kafri, Tal; Samulski, R. Jude

2013-01-01

Adeno-associated virus (AAV) vectors are attractive for gene delivery-based therapeutics, but data from recent clinical trials have indicated that AAV capsids induce a cytotoxic T lymphocyte (CTL) response that eliminates transduced cells. In this study, we used traditional pharmacological agents and AAV mutants to elucidate the pathway of capsid cross-presentation in AAV-permissive cells. Endosomal acidification inhibitors blocked AAV2 antigen presentation by over 90%, while proteasome inhibitors completely abrogated antigen presentation. Using mutant viruses that are defective for nuclear entry, we observed a 90% decrease in capsid antigen presentation. Different antigen presentation efficiencies were achieved by selectively mutating virion nuclear localization signals. Low antigen presentation was demonstrated with basic region 1 (BR1) mutants, despite relatively high transduction efficiency, whereas there was no difference in antigen presentation between BR2 and BR3 mutants defective for transduction, as compared with wild-type AAV2. These results suggest that effective AAV2 capsid antigen presentation is dependent on AAV virion escape from the endosome/lysosome for antigen degradation by proteasomes, but is independent of nuclear uncoating. These results should facilitate the design of effective strategies to evade capsid-specific CTL-mediated elimination of AAV-transduced target cells in future clinical trials. PMID:23454772

How moths escape bats: predicting outcomes of predator-prey interactions.

PubMed

Corcoran, Aaron J; Conner, William E

2016-09-01

What determines whether fleeing prey escape from attacking predators? To answer this question, biologists have developed mathematical models that incorporate attack geometries, pursuit and escape trajectories, and kinematics of predator and prey. These models have rarely been tested using data from actual predator-prey encounters. To address this problem, we recorded multi-camera infrared videography of bat-insect interactions in a large outdoor enclosure. We documented 235 attacks by four Myotis volans bats on a variety of moths. Bat and moth flight trajectories from 50 high-quality attacks were reconstructed in 3-D. Despite having higher maximum velocity, deceleration and overall turning ability, bats only captured evasive prey in 69 of 184 attacks (37.5%); bats captured nearly all moths not evading attack (50 of 51; 98%). Logistic regression indicated that prey radial acceleration and escape angle were the most important predictors of escape success (44 of 50 attacks correctly classified; 88%). We found partial support for the turning gambit mathematical model; however, it underestimated the escape threshold by 25% of prey velocity and did not account for prey escape angle. Whereas most prey escaping strikes flee away from predators, moths typically escaped chasing bats by turning with high radial acceleration toward 'safety zones' that flank the predator. This strategy may be widespread in prey engaged in chases. Based on these findings, we developed a novel geometrical model of predation. We discuss implications of this model for the co-evolution of predator and prey kinematics and pursuit and escape strategies. © 2016. Published by The Company of Biologists Ltd.

Prevalence and prognostic significance of adrenergic escape during chronic beta-blocker therapy in chronic heart failure.

PubMed

Frankenstein, Lutz; Zugck, Christian; Schellberg, Dieter; Nelles, Manfred; Froehlich, Hanna; Katus, Hugo; Remppis, Andrew

2009-02-01

Like aldosterone escape to ACE-inhibitors, adrenergic escape (AE) to beta-blockers appears conceivable in chronic heart failure (CHF), as generalized systemic neurohumoral activation has been described as the pathophysiological basis of this syndrome. The aim of this study was to examine the prevalence and prognostic value of AE with respect to different beta-blocker agents and doses. This was a prospective, observational study of 415 patients with systolic CHF receiving chronic stable beta-blocker therapy. AE was defined by norepinephrine levels above the upper limit of normal. Irrespective of the individual beta-blocker agents used and the dose equivalent taken, the prevalence of AE was 31-39%. Norepinephrine levels neither correlated with heart rate (r=0.02; 95% CI: -0.08-0.11; P=0.74) nor were they related to underlying rhythm (P=0.09) or the individual beta-blocker agent used (P=0.87). The presence of AE was a strong and independent indicator of mortality (adjusted HR: 1.915; 95% CI: 1.387-2.645; chi2: 15.60). We verified the presence of AE in CHF patients on chronic stable beta-blocker therapy, irrespective of the individual beta-blocker agent and the dose equivalent. As AE might indicate therapeutic failure, the determination of AE could help to identify those patients with CHF that might benefit from more aggressive treatment modalities. Heart rate, however, is not a surrogate for adrenergic escape.

Prevalence and prognostic significance of adrenergic escape during chronic β-blocker therapy in chronic heart failure

PubMed Central

Frankenstein, Lutz; Zugck, Christian; Schellberg, Dieter; Nelles, Manfred; Froehlich, Hanna; Katus, Hugo; Remppis, Andrew

2009-01-01

Aims Like aldosterone escape to ACE-inhibitors, adrenergic escape (AE) to β-blockers appears conceivable in chronic heart failure (CHF), as generalized systemic neurohumoral activation has been described as the pathophysiological basis of this syndrome. The aim of this study was to examine the prevalence and prognostic value of AE with respect to different β-blocker agents and doses. Methods and results This was a prospective, observational study of 415 patients with systolic CHF receiving chronic stable β-blocker therapy. AE was defined by norepinephrine levels above the upper limit of normal. Irrespective of the individual β-blocker agents used and the dose equivalent taken, the prevalence of AE was 31–39%. Norepinephrine levels neither correlated with heart rate (r = 0.02; 95% CI: −0.08–0.11; P = 0.74) nor were they related to underlying rhythm (P = 0.09) or the individual β-blocker agent used (P = 0.87). The presence of AE was a strong and independent indicator of mortality (adjusted HR: 1.915; 95% CI: 1.387–2.645; χ2: 15.60). Conclusion We verified the presence of AE in CHF patients on chronic stable β-blocker therapy, irrespective of the individual β-blocker agent and the dose equivalent. As AE might indicate therapeutic failure, the determination of AE could help to identify those patients with CHF that might benefit from more aggressive treatment modalities. Heart rate, however, is not a surrogate for adrenergic escape. PMID:19168516

A metabolic function of FGFR3-TACC3 gene fusions in cancer.

PubMed

Frattini, Véronique; Pagnotta, Stefano M; Tala; Fan, Jerry J; Russo, Marco V; Lee, Sang Bae; Garofano, Luciano; Zhang, Jing; Shi, Peiguo; Lewis, Genevieve; Sanson, Heloise; Frederick, Vanessa; Castano, Angelica M; Cerulo, Luigi; Rolland, Delphine C M; Mall, Raghvendra; Mokhtari, Karima; Elenitoba-Johnson, Kojo S J; Sanson, Marc; Huang, Xi; Ceccarelli, Michele; Lasorella, Anna; Iavarone, Antonio

2018-01-11

Chromosomal translocations that generate in-frame oncogenic gene fusions are notable examples of the success of targeted cancer therapies. We have previously described gene fusions of FGFR3-TACC3 (F3-T3) in 3% of human glioblastoma cases. Subsequent studies have reported similar frequencies of F3-T3 in many other cancers, indicating that F3-T3 is a commonly occuring fusion across all tumour types. F3-T3 fusions are potent oncogenes that confer sensitivity to FGFR inhibitors, but the downstream oncogenic signalling pathways remain unknown. Here we show that human tumours with F3-T3 fusions cluster within transcriptional subgroups that are characterized by the activation of mitochondrial functions. F3-T3 activates oxidative phosphorylation and mitochondrial biogenesis and induces sensitivity to inhibitors of oxidative metabolism. Phosphorylation of the phosphopeptide PIN4 is an intermediate step in the signalling pathway of the activation of mitochondrial metabolism. The F3-T3-PIN4 axis triggers the biogenesis of peroxisomes and the synthesis of new proteins. The anabolic response converges on the PGC1α coactivator through the production of intracellular reactive oxygen species, which enables mitochondrial respiration and tumour growth. These data illustrate the oncogenic circuit engaged by F3-T3 and show that F3-T3-positive tumours rely on mitochondrial respiration, highlighting this pathway as a therapeutic opportunity for the treatment of tumours with F3-T3 fusions. We also provide insights into the genetic alterations that initiate the chain of metabolic responses that drive mitochondrial metabolism in cancer.

Quantifying the kinetics and morphological changes of the fusion of spheroid building blocks.

PubMed

Susienka, Michael J; Wilks, Benjamin T; Morgan, Jeffrey R

2016-10-10

Tissue fusion, whereby two or more spheroids coalesce, is a process that is fundamental to biofabrication. We have designed a quantitative, high-throughput platform to investigate the fusion of multicellular spheroids using agarose micro-molds. Spheroids of primary human chondrocytes (HCH) or human breast cancer cells (MCF-7) were self-assembled for 24 h and then brought together to form an array comprised of two spheroids (one doublet) per well. To quantify spheroid fusogenicity, we developed two assays: (1) an initial tack assay, defined as the minimum amount of time for two spheroids to form a mechanically stable tissue complex or doublet, and (2) a fusion assay, in which we defined and tracked key morphological parameters of the doublets as a function of time using wide-field fluorescence microscopy over a 24 h time-lapse. The initial tack of spheroid fusion was measured by inverting the micro-molds and centrifuging doublets at various time points to assess their connectedness. We found that the initial tack between two spheroids forms rapidly, with the majority of doublets remaining intact after centrifugation following just 30 min of fusion. Over the course of 24 h of fusion, several morphological changes occurred, which were quantified using a custom image analysis pipeline. End-to-end doublet lengths decreased over time, doublet widths decreased for chondrocytes and increased for MCF-7, contact lengths increased over time, and chondrocyte doublets exhibited higher intersphere angles at the end of fusion. We also assessed fusion by measuring the fluorescence intensity at the plane of fusion, which increased over time for both cell types. Interestingly, we observed that doublets moved and rotated in the micro-wells during fusion and this rotation was inhibited by ROCK inhibitor Y-27632 and myosin II inhibitor blebbistatin. Understanding and optimizing tissue fusion is essential for creating larger tissues, organs, or other structures using individual

Learning from escaped prescribed fire reviews [Abstract

Treesearch

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...

46 CFR 177.500 - Means of escape.

Code of Federal Regulations, 2012 CFR

2012-10-01

... this section, each space accessible to passengers or used by the crew on a regular basis, must have at... escape must be widely separated and, if possible, at opposite ends or sides of the space to minimize the... windows. (d) The number and dimensions of the means of escape from each space must be sufficient for rapid...

46 CFR 177.500 - Means of escape.

Code of Federal Regulations, 2013 CFR

2013-10-01

... this section, each space accessible to passengers or used by the crew on a regular basis, must have at... escape must be widely separated and, if possible, at opposite ends or sides of the space to minimize the... windows. (d) The number and dimensions of the means of escape from each space must be sufficient for rapid...

46 CFR 177.500 - Means of escape.

Code of Federal Regulations, 2014 CFR

2014-10-01

... this section, each space accessible to passengers or used by the crew on a regular basis, must have at... escape must be widely separated and, if possible, at opposite ends or sides of the space to minimize the... windows. (d) The number and dimensions of the means of escape from each space must be sufficient for rapid...

46 CFR 177.500 - Means of escape.

Code of Federal Regulations, 2011 CFR

2011-10-01

... this section, each space accessible to passengers or used by the crew on a regular basis, must have at... escape must be widely separated and, if possible, at opposite ends or sides of the space to minimize the... windows. (d) The number and dimensions of the means of escape from each space must be sufficient for rapid...

46 CFR 116.500 - Means of escape.

Code of Federal Regulations, 2010 CFR

2010-10-01

... this section, each space accessible to passengers or used by the crew on a regular basis, must have at... escape must be widely separated and, if possible, at opposite ends or sides of the space to minimize the... windows. (d) The number and dimensions of the means of escape from each space must be sufficient for rapid...

46 CFR 116.500 - Means of escape.

Code of Federal Regulations, 2014 CFR

2014-10-01

... this section, each space accessible to passengers or used by the crew on a regular basis, must have at... escape must be widely separated and, if possible, at opposite ends or sides of the space to minimize the... windows. (d) The number and dimensions of the means of escape from each space must be sufficient for rapid...

46 CFR 116.500 - Means of escape.

Code of Federal Regulations, 2011 CFR

2011-10-01

... this section, each space accessible to passengers or used by the crew on a regular basis, must have at... escape must be widely separated and, if possible, at opposite ends or sides of the space to minimize the... windows. (d) The number and dimensions of the means of escape from each space must be sufficient for rapid...

46 CFR 116.500 - Means of escape.

Code of Federal Regulations, 2012 CFR

2012-10-01

... this section, each space accessible to passengers or used by the crew on a regular basis, must have at... escape must be widely separated and, if possible, at opposite ends or sides of the space to minimize the... windows. (d) The number and dimensions of the means of escape from each space must be sufficient for rapid...

46 CFR 116.500 - Means of escape.

Code of Federal Regulations, 2013 CFR

2013-10-01

... this section, each space accessible to passengers or used by the crew on a regular basis, must have at... escape must be widely separated and, if possible, at opposite ends or sides of the space to minimize the... windows. (d) The number and dimensions of the means of escape from each space must be sufficient for rapid...

Thermal escape from extrasolar giant planets.

PubMed

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.

New insights on the collisional escape of light neutrals from Mars

NASA Astrophysics Data System (ADS)

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).

Efficiently estimating salmon escapement uncertainty using systematically sampled data

USGS Publications Warehouse

Reynolds, Joel H.; Woody, Carol Ann; Gove, Nancy E.; Fair, Lowell F.

2007-01-01

Fish escapement is generally monitored using nonreplicated systematic sampling designs (e.g., via visual counts from towers or hydroacoustic counts). These sampling designs support a variety of methods for estimating the variance of the total escapement. Unfortunately, all the methods give biased results, with the magnitude of the bias being determined by the underlying process patterns. Fish escapement commonly exhibits positive autocorrelation and nonlinear patterns, such as diurnal and seasonal patterns. For these patterns, poor choice of variance estimator can needlessly increase the uncertainty managers have to deal with in sustaining fish populations. We illustrate the effect of sampling design and variance estimator choice on variance estimates of total escapement for anadromous salmonids from systematic samples of fish passage. Using simulated tower counts of sockeye salmon Oncorhynchus nerka escapement on the Kvichak River, Alaska, five variance estimators for nonreplicated systematic samples were compared to determine the least biased. Using the least biased variance estimator, four confidence interval estimators were compared for expected coverage and mean interval width. Finally, five systematic sampling designs were compared to determine the design giving the smallest average variance estimate for total annual escapement. For nonreplicated systematic samples of fish escapement, all variance estimators were positively biased. Compared to the other estimators, the least biased estimator reduced bias by, on average, from 12% to 98%. All confidence intervals gave effectively identical results. Replicated systematic sampling designs consistently provided the smallest average estimated variance among those compared.

Early Endosomal Escape of a Cyclic Cell-Penetrating Peptide Allows Effective Cytosolic Cargo Delivery

PubMed Central

2015-01-01

Cyclic heptapeptide cyclo(FΦRRRRQ) (cFΦR4, where Φ is l-2-naphthylalanine) was recently found to be efficiently internalized by mammalian cells. In this study, its mechanism of internalization was investigated by perturbing various endocytic events through the introduction of pharmacologic agents and genetic mutations. The results show that cFΦR4 binds directly to membrane phospholipids, is internalized into human cancer cells through endocytosis, and escapes from early endosomes into the cytoplasm. Its cargo capacity was examined with a wide variety of molecules, including small-molecule dyes, linear and cyclic peptides of various charged states, and proteins. Depending on the nature of the cargos, they may be delivered by endocyclic (insertion of cargo into the cFΦR4 ring), exocyclic (attachment of cargo to the Gln side chain), or bicyclic approaches (fusion of cFΦR4 and cyclic cargo rings). The overall delivery efficiency (i.e., delivery of cargo into the cytoplasm and nucleus) of cFΦR4 was 4–12-fold higher than those of nonaarginine, HIV Tat-derived peptide, or penetratin. The higher delivery efficiency, coupled with superior serum stability, minimal toxicity, and synthetic accessibility, renders cFΦR4 a useful transporter for intracellular cargo delivery and a suitable system for investigating the mechanism of endosomal escape. PMID:24896852

Molecular docking studies shows tivozanib and lapatinib as potential inhibitors of EML4-ALK translocation mediated fusion protein in non small cell lung cancer.

PubMed

Ramshankar, Vijayalakshmi; Yegnaswamy, Subha; P, Kumarasamy; Arvind, Krishnamurthy

2014-01-01

Identification of activating mutations in non-small cell lung cancers (NSCLC) has been a focus in recent years. This led to successful evidence of using tyrosine kinase inhibitors (TKIs) over the standard platinum doublet based chemotherapy as the first line treatment in the metastatic setting.The rearrangements of fusion protein EML4-ALK in NSCLC lead to the use of crizotinib for this class of tumors. Preclinical and Phase 1 clinical studies show that ceritinib is more effective against both crizotinib sensitive and resistant tumors. Although robust responses to crizotinib are observed in NSCLC harboring ALK mutations, majority of tumors eventually become resistant, posing a major challenge in treatment course. Thus, there is a need for the identification and development of second-generation of ALK inhibitors. Computer aided molecular docking data show Tivozanib and Lapatinib bind EML4-ALK with high score. Tivozanib is in clinical trials for renal cell cancer and Lapatinib is a known dual tyrosine kinase inhibitor effective in breast cancer patients with HER2 over-expression. Additional data on these compounds for use in EML4-ALK positive NSCLC will provide evidence for use in patients treated with crizotinib. Data shows the importance of computer aided molecular docking in developing candidates with improved activity for further consideration in vitro and in vivo validation.

Molecular docking studies shows tivozanib and lapatinib as potential inhibitors of EML4-ALK translocation mediated fusion protein in non small cell lung cancer

PubMed Central

Ramshankar, Vijayalakshmi; Yegnaswamy, Subha; P, Kumarasamy; Arvind, Krishnamurthy

2014-01-01

Identification of activating mutations in non-small cell lung cancers (NSCLC) has been a focus in recent years. This led to successful evidence of using tyrosine kinase inhibitors (TKIs) over the standard platinum doublet based chemotherapy as the first line treatment in the metastatic setting.The rearrangements of fusion protein EML4-ALK in NSCLC lead to the use of crizotinib for this class of tumors. Preclinical and Phase 1 clinical studies show that ceritinib is more effective against both crizotinib sensitive and resistant tumors. Although robust responses to crizotinib are observed in NSCLC harboring ALK mutations, majority of tumors eventually become resistant, posing a major challenge in treatment course. Thus, there is a need for the identification and development of second-generation of ALK inhibitors. Computer aided molecular docking data show Tivozanib and Lapatinib bind EML4-ALK with high score. Tivozanib is in clinical trials for renal cell cancer and Lapatinib is a known dual tyrosine kinase inhibitor effective in breast cancer patients with HER2 over-expression. Additional data on these compounds for use in EML4-ALK positive NSCLC will provide evidence for use in patients treated with crizotinib. Data shows the importance of computer aided molecular docking in developing candidates with improved activity for further consideration in vitro and in vivo validation. PMID:25489176

Live imaging of mouse secondary palate fusion

PubMed Central

Kim, Seungil; Prochazka, Jan; Bush, Jeffrey O.

2017-01-01

LONG ABSTRACT The fusion of the secondary palatal shelves to form the intact secondary palate is a key process in mammalian development and its disruption can lead to cleft secondary palate, a common congenital anomaly in humans. Secondary palate fusion has been extensively studied leading to several proposed cellular mechanisms that may mediate this process. However, these studies have been mostly performed on fixed embryonic tissues at progressive timepoints during development or in fixed explant cultures analyzed at static timepoints. Static analysis is limited for the analysis of dynamic morphogenetic processes such a palate fusion and what types of dynamic cellular behaviors mediate palatal fusion is incompletely understood. Here we describe a protocol for live imaging of ex vivo secondary palate fusion in mouse embryos. To examine cellular behaviors of palate fusion, epithelial-specific Keratin14-cre was used to label palate epithelial cells in ROSA26-mTmGflox reporter embryos. To visualize filamentous actin, Lifeact-mRFPruby reporter mice were used. Live imaging of secondary palate fusion was performed by dissecting recently-adhered secondary palatal shelves of embryonic day (E) 14.5 stage embryos and culturing in agarose-containing media on a glass bottom dish to enable imaging with an inverted confocal microscope. Using this method, we have detected a variety of novel cellular behaviors during secondary palate fusion. An appreciation of how distinct cell behaviors are coordinated in space and time greatly contributes to our understanding of this dynamic morphogenetic process. This protocol can be applied to mutant mouse lines, or cultures treated with pharmacological inhibitors to further advance understanding of how secondary palate fusion is controlled. PMID:28784960

Enhancing endosomal escape for nanoparticle mediated siRNA delivery

NASA Astrophysics Data System (ADS)

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.

Enhanced Endosomal Escape by Light-Fueled Liquid-Metal Transformer.

PubMed

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.

Split-second escape decisions in blue tits (Parus caeruleus)

NASA Astrophysics Data System (ADS)

Lind, Johan; Kaby, Ulrika; Jakobsson, Sven

2002-07-01

Bird mortality is heavily affected by birds of prey. Under attack, take-off is crucial for survival and even minor mistakes in initial escape response can have devastating consequences. Birds may respond differently depending on the character of the predator's attack and these split-second decisions were studied using a model merlin (Falco columbarius) that attacked feeding blue tits (Parus caeruleus) from two different attack angles in two different speeds. When attacked from a low attack angle they took off more steeply than when attacked from a high angle. This is the first study to show that escape behaviour also depends on predator attack speed. The blue tits responded to a high-speed attack by dodging sideways more often than when attacked at a low speed. Escape speed was not significantly affected by the different treatments. Although they have only a split-second before escaping an attack, blue tits do adjust their escape strategy to the prevailing attack conditions.

Pharmacokinetics and pharmacodynamics of CD4-anchoring bi-functional fusion inhibitor in monkeys.

PubMed

Liu, Xingrong; Ou, Ying C; Zhang, Jun; Ahene, Ago; Clark, Douglas; Hsieh, Su-Chun; Cooper, Matthew; Ji, Changhua

2014-03-01

This study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a chimeric protein, CD4-anchoring bi-functional fusion inhibitor (CD4-BFFI), in monkeys and assess the feasibility for HIV-1 treatment in humans. The serum concentrations of CD4-BFFI and CD4 receptors were determined and modeled using a target-mediated drug disposition (TMDD) model following intravenous administration of 1 or 10 mg/kg in monkeys. In vitro CD4 internalization was examined in human peripheral blood mononuclear cells. Noncompartmental analysis showed a decrease in clearance (1.35 to 0.563 mL/h/kg) and an increase in half-lives (35 to 50 h) with increasing doses. Dose-dependent CD4 occupancy was observed. The TMDD model reasonably captured the PK/PD profiles and suggested greater degradation rate constant for the free CD4 than the bound CD4. In vitro assay showed CD4-BFFI did not reduce the internalization of cell surface CD4. The simulated serum concentrations of CD4-BFFI were 20-fold above its in vitro IC50 for HIV-1 at 3 mg/kg weekly or biweekly following subcutaneous administration in humans. The TMDD modeling and in vitro CD4 internalization study indicate that CD4-BFFI does not induce CD4 internalization and CD4-BFFI short half-life is likely due to normal CD4 internalization. The simulated human PK supports CD4-BFFI as a promising anti-HIV-1 agent.

A New Strategy to Reduce Influenza Escape: Detecting Therapeutic Targets Constituted of Invariance Groups

PubMed Central

Lao, Julie; Vanet, Anne

2017-01-01

The pathogenicity of the different flu species is a real public health problem worldwide. To combat this scourge, we established a method to detect drug targets, reducing the possibility of escape. Besides being able to attach a drug candidate, these targets should have the main characteristic of being part of an essential viral function. The invariance groups that are sets of residues bearing an essential function can be detected genetically. They consist of invariant and synthetic lethal residues (interdependent residues not varying or slightly varying when together). We analyzed an alignment of more than 10,000 hemagglutinin sequences of influenza to detect six invariance groups, close in space, and on the protein surface. In parallel we identified five potential pockets on the surface of hemagglutinin. By combining these results, three potential binding sites were determined that are composed of invariance groups located respectively in the vestigial esterase domain, in the bottom of the stem and in the fusion area. The latter target is constituted of residues involved in the spring-loaded mechanism, an essential step in the fusion process. We propose a model describing how this potential target could block the reorganization of the hemagglutinin HA2 secondary structure and prevent viral entry into the host cell. PMID:28257108

Fusion loop peptide of the West Nile virus envelope protein is essential for pathogenesis and is recognized by a therapeutic cross-reactive human monoclonal antibody.

PubMed

Sultana, Hameeda; Foellmer, Harald G; Neelakanta, Girish; Oliphant, Theodore; Engle, Michael; Ledizet, Michel; Krishnan, Manoj N; Bonafé, Nathalie; Anthony, Karen G; Marasco, Wayne A; Kaplan, Paul; Montgomery, Ruth R; Diamond, Michael S; Koski, Raymond A; Fikrig, Erol

2009-07-01

West Nile virus is an emerging pathogen that can cause fatal neurological disease. A recombinant human mAb, mAb11, has been described as a candidate for the prevention and treatment of West Nile disease. Using a yeast surface display epitope mapping assay and neutralization escape mutant, we show that mAb11 recognizes the fusion loop, at the distal end of domain II of the West Nile virus envelope protein. Ab mAb11 cross-reacts with all four dengue viruses and provides protection against dengue (serotypes 2 and 4) viruses. In contrast to the parental West Nile virus, a neutralization escape variant failed to cause lethal encephalitis (at higher infectious doses) or induce the inflammatory responses associated with blood-brain barrier permeability in mice, suggesting an important role for the fusion loop in viral pathogenesis. Our data demonstrate that an intact West Nile virus fusion loop is critical for virulence, and that human mAb11 targeting this region is efficacious against West Nile virus infection. These experiments define the molecular determinant on the envelope protein recognized by mAb11 and demonstrate the importance of this region in causing West Nile encephalitis.

Inhibition of Henipavirus fusion and infection by heptad-derived peptides of the Nipah virus fusion glycoprotein

PubMed Central

Bossart, Katharine N; Mungall, Bruce A; Crameri, Gary; Wang, Lin-Fa; Eaton, Bryan T; Broder, Christopher C

2005-01-01

Background The recent emergence of four new members of the paramyxovirus family has heightened the awareness of and re-energized research on new and emerging diseases. In particular, the high mortality and person to person transmission associated with the most recent Nipah virus outbreaks, as well as the very recent re-emergence of Hendra virus, has confirmed the importance of developing effective therapeutic interventions. We have previously shown that peptides corresponding to the C-terminal heptad repeat (HR-2) of the fusion envelope glycoprotein of Hendra virus and Nipah virus were potent inhibitors of both Hendra virus and Nipah virus-mediated membrane fusion using recombinant expression systems. In the current study, we have developed shorter, second generation HR-2 peptides which include a capped peptide via amidation and acetylation and two poly(ethylene glycol)-linked (PEGylated) peptides, one with the PEG moity at the C-terminus and the other at the N-terminus. Here, we have evaluated these peptides as well as the corresponding scrambled peptide controls in Nipah virus and Hendra virus-mediated membrane fusion and against infection by live virus in vitro. Results Unlike their predecessors, the second generation HR-2 peptides exhibited high solubility and improved synthesis yields. Importantly, both Nipah virus and Hendra virus-mediated fusion as well as live virus infection were potently inhibited by both capped and PEGylated peptides with IC50 concentrations similar to the original HR-2 peptides, whereas the scrambled modified peptides had no inhibitory effect. These data also indicate that these chemical modifications did not alter the functional properties of the peptides as inhibitors. Conclusion Nipah virus and Hendra virus infection in vitro can be potently blocked by specific HR-2 peptides. The improved synthesis and solubility characteristics of the second generation HR-2 peptides will facilitate peptide synthesis for pre-clinical trial

Thermal escape from extrasolar giant planets

PubMed Central

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

2014-01-01

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. PMID:24664923

Lyman-Werner escape fractions from the first galaxies

NASA Astrophysics Data System (ADS)

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.

75 FR 61386 - Emergency Escape Breathing Apparatus Standards

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-05

...-0044, Notice No. 1] RIN 2130-AC14 Emergency Escape Breathing Apparatus Standards AGENCY: Federal... breathing apparatus (EEBA) to the members of the train crew and certain other employees while they are... EEBA--emergency escape breathing apparatus FRA--Federal Railroad Administration FRSA--the former...

High Resolution Observations of Escaping Ions in the Martian Magnetotail

NASA Astrophysics Data System (ADS)

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.

Compensatory escape mechanism at low Reynolds number

PubMed Central

Gemmell, Brad J.; Sheng, Jian; Buskey, Edward J.

2013-01-01

Despite high predation pressure, planktonic copepods remain one of the most abundant groups on the planet. Their escape response provides one of most effective mechanisms to maximize evolutionary fitness. Owing to their small size (100 µm) compared with their predators (>1 mm), increasing viscosity is believed to have detrimental effects on copepods’ fitness at lower temperature. Using high-speed digital holography we acquire 3D kinematics of the nauplius escape including both location and detailed appendage motion. By independently varying temperature and viscosity we demonstrate that at natural thermal extremes, contrary to conventional views, nauplii achieve equivalent escape distance while maintaining optimal velocity. Using experimental results and kinematic simulations from a resistive force theory propulsion model, we demonstrate that a shift in appendage timing creates an increase in power stroke duration relative to recovery stroke duration. This change allows the nauplius to limit losses in velocity and maintain distance during escapes at the lower bound of its natural thermal range. The shift in power stroke duration relative to recovery stroke duration is found to be regulated by the temperature dependence of swimming appendage muscle groups, not a dynamic response to viscosity change. These results show that copepod nauplii have natural adaptive mechanisms to compensate for viscosity variations with temperature but not in situations in which viscosity varies independent of temperature, such as in some phytoplankton blooms. Understanding the robustness of escapes in the wake of environmental changes such as temperature and viscosity has implications in assessing the future health of performance compensation. PMID:23487740

Sensitivity Changes over the Course of Infection Increases the Likelihood of Resistance Against Fusion but Not CCR5 Receptor Blockers

PubMed Central

Chatziandreou, Nikolaos; Arauz, Ana Belen; Freitas, Ines; Nyein, Phyu Hninn; Fenton, Gregory; Mehta, Shruti H.; Kirk, Gregory D.

2012-01-01

Abstract As HIV-1 evolves over the course of infection, resistance against antiretrovirals may arise in the absence of drug pressure, especially against receptor and fusion blockers because of the extensive changes observed in the envelope glycoprotein. Here we show that viruses from the chronic phase of disease are significantly less sensitive to CCR5 receptor and fusion blockers compared to early infection variants. Differences in susceptibility to CCR5 antagonists were observed in spite of no demonstrable CXCR4 receptor utilization. No significant sensitivity differences were observed to another entry blocker, soluble CD4, or to reverse transcriptase, protease, or integrase inhibitors. Chronic as compared to early phase variants demonstrated greater replication when passaged in the presence of subinhibitory concentrations of fusion but not CCR5 receptor inhibitors. Fusion antagonist resistance, however, emerged from only one chronic phase virus culture. Because sensitivity to receptor and fusion antagonists is correlated with receptor affinity and fusion capacity, respectively, changes that occur in the envelope glycoprotein over the course of infection confer greater ability to use the CCR5 receptor and increased fusion ability. Our in vitro passage studies suggest that these evolving phenotypes increase the likelihood of resistance against fusion but not CCR5 receptor blockers. PMID:22650962

Single-File Escape of Colloidal Particles from Microfluidic Channels

NASA Astrophysics Data System (ADS)

Locatelli, Emanuele; Pierno, Matteo; Baldovin, Fulvio; Orlandini, Enzo; Tan, Yizhou; Pagliara, Stefano

2016-07-01

Single-file diffusion is a ubiquitous physical process exploited by living and synthetic systems to exchange molecules with their environment. It is paramount to quantify the escape time needed for single files of particles to exit from constraining synthetic channels and biological pores. This quantity depends on complex cooperative effects, whose predominance can only be established through a strict comparison between theory and experiments. By using colloidal particles, optical manipulation, microfluidics, digital microscopy, and theoretical analysis we uncover the self-similar character of the escape process and provide closed-formula evaluations of the escape time. We find that the escape time scales inversely with the diffusion coefficient of the last particle to leave the channel. Importantly, we find that at the investigated microscale, bias forces as tiny as 10-15 N determine the magnitude of the escape time by drastically reducing interparticle collisions. Our findings provide crucial guidelines to optimize the design of micro- and nanodevices for a variety of applications including drug delivery, particle filtering, and transport in geometrical constrictions.

Verge and Foliot Clock Escapement: A Simple Dynamical System

NASA Astrophysics Data System (ADS)

Denny, Mark

2010-09-01

The earliest mechanical clocks appeared in Europe in the 13th century. From about 1250 CE to 1670 CE, these simple clocks consisted of a weight suspended from a rope or chain that was wrapped around a horizontal axle. To tell time, the weight must fall with a slow uniform speed, but, under the action of gravity alone, such a suspended weight would accelerate. To prevent this acceleration, an escapement mechanism was required. The best such escapement mechanism was called the verge and foliot escapement, and it was so successful that it lasted until about 1800 CE. These simple weight-driven clocks with verge and foliot escapements were accurate enough to mark the hours but not minutes or seconds. From 1670, significant improvements were made (principally by introducing pendulums and the newly invented anchor escapement) that justified the introduction of hands to mark minutes, and then seconds. By the end of the era of mechanical clocks, in the first half of the 20th century, these much-studied and much-refined machines were accurate to a millisecond a day.

Inferring HIV Escape Rates from Multi-Locus Genotype Data

DOE PAGES

Kessinger, Taylor A.; Perelson, Alan S.; Neher, Richard A.

2013-09-03

Cytotoxic T-lymphocytes (CTLs) recognize viral protein fragments displayed by major histocompatibility complex 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 mutationsmore » 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.« less

Behavioral analyses of wind-evoked escape of the cricket, Gryllodes sigillatus.

PubMed

Kanou, Masamichi; Konishi, Atsuko; Suenaga, Rie

2006-04-01

The wind-evoked escape behavior of the cricket Gryllodes sigillatus was investigated using an air puff stimulus. A high velocity air puff elicited the escape behavior in many crickets. The crickets tended to escape away from the stimulus source, but the direction was not accurately oriented 180 degrees from the stimulus. After bilateral cercal ablation, only a few crickets showed wind-evoked escape behavior, and their response rates did not increase even 19 days after ablation. Therefore, information on air motion detected by cercal filiform hairs is essential for triggering wind-evoked behavior. After unilateral cercal ablation, the 81.3% response rate of intact crickets decreased to 16.5%, that is, it decreased to almost 20% that of intact crickets. One week after unilateral cercal ablation, the response rate recovered to more than 60% that of intact crickets. However, the accuracy rate of the escape direction of G. sigillatus showed no change even immediately after the unilateral cercal ablation. Therefore, both cerci are not necessarily required to determine the escape direction. The behavioral characteristics of wind-evoked escape of G. sigillatus are compared with those of another species of cricket, Gryllus bimaculatus. The two species of cricket employ different strategies for wind-evoked escape.

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

NASA Astrophysics Data System (ADS)

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.

16. INTERIOR VIEW OF SUBMARINE SECTION AT 110FOOT LEVEL, ESCAPE ...

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

16. INTERIOR VIEW OF SUBMARINE SECTION AT 110-FOOT LEVEL, ESCAPE TRAINING TANK, SHOWING LADDER TO ESCAPE TANK, LOOKING SOUTH - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

Modelling the Evolution and Spread of HIV Immune Escape Mutants

PubMed Central

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

2010-01-01

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. PMID:21124991

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

PubMed Central

Gilabert-Oriol, Roger; Thakur, Mayank; von Mallinckrodt, Benedicta; Bhargava, Cheenu; Wiesner, Burkhard; Eichhorst, Jenny; Melzig, Matthias F.; Fuchs, Hendrik; Weng, Alexander

2014-01-01

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. PMID:24859158

Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer

PubMed Central

Nakaoku, Takashi; Tsuta, Koji; Tsuchihara, Katsuya; Matsumoto, Shingo; Yoh, Kiyotaka; Goto, Koichi

2015-01-01

Fusions of the RET and ROS1 protein tyrosine kinase oncogenes with several partner genes were recently identified as new targetable genetic aberrations in cases of non-small cell lung cancer (NSCLC) lacking activating EGFR, KRAS, ALK, BRAF, or HER2 oncogene aberrations. RET and ROS1 fusion-positive tumors are mainly observed in young, female, and/or never smoking patients. Studies based on in vitro and in vivo (i.e., mouse) models and studies of several fusion-positive patients indicate that inhibiting the kinase activity of the RET and ROS1 fusion proteins is a promising therapeutic strategy. Accordingly, there are several ongoing clinical trials aimed at examining the efficacy of tyrosine kinase inhibitors (TKIs) against RET and ROS1 proteins in patients with fusion-positive lung cancer. Other gene fusions (NTRK1, NRG1, and FGFR1/2/3) that are targetable by existing TKIs have also been identified in NSCLCs. Options for personalized lung cancer therapy will be increased with the help of multiplex diagnosis systems able to detect multiple druggable gene fusions. PMID:25870798

Flunarizine Prevents Hepatitis C Virus Membrane Fusion in a Genotype-dependent Manner by Targeting the Potential Fusion Peptide within E1

PubMed Central

Perin, Paula M.; Haid, Sibylle; Brown, Richard J. P.; Doerrbecker, Juliane; Schulze, Kai; Zeilinger, Carsten; von Schaewen, Markus; Heller, Brigitte; Vercauteren, Koen; Luxenburger, Eva; Baktash, Yasmine M.; Vondran, Florian W. R.; Speerstra, Sietkse; Awadh, Abdullah; Mukhtarov, Furkat; Schang, Luis M; Kirschning, Andreas; Müller, Rolf; Guzman, Carlos A.; Kaderali, Lars; Randall, Glenn; Meuleman, Philip; Ploss, Alexander; Pietschmann, Thomas

2015-01-01

To explore mechanisms of hepatitis C virus (HCV) replication we screened a compound library including licensed drugs. Flunarizine, a diphenylmethylpiperazine used to treat migraine, inhibited HCV cell entry in vitro and in vivo in a genotype-dependent fashion. Analysis of mosaic viruses between susceptible and resistant strains revealed that E1 and E2 glycoproteins confer susceptibility to flunarizine. Time of addition experiments and single particle tracking of HCV demonstrated that flunarizine specifically prevents membrane fusion. Related phenothiazines and pimozide also inhibited HCV infection and preferentially targeted HCV genotype 2 viruses. However, phenothiazines and pimozide exhibited improved genotype coverage including the difficult to treat genotype 3. Flunarizine-resistant HCV carried mutations within the alleged fusion peptide and displayed cross-resistance to these compounds, indicating that these drugs have a common mode of action. Conclusion: These observations reveal novel details about HCV membrane fusion. Moreover, flunarizine and related compounds represent first-in-class HCV fusion inhibitors that merit consideration for repurposing as cost-effective component of HCV combination therapies. PMID:26248546

Slow fusion pore expansion creates a unique reaction chamber for co-packaged cargo

PubMed Central

Bittner, Mary A.; Lawrence, Daniel A.

2017-01-01

A lumenal secretory granule protein, tissue plasminogen activator (tPA), greatly slows fusion pore dilation and thereby slows its own discharge. We investigated another outcome of the long-lived narrow fusion pore: the creation of a nanoscale chemical reaction chamber for granule contents in which the pH is suddenly neutralized upon fusion. Bovine adrenal chromaffin cells endogenously express both tPA and its primary protein inhibitor, plasminogen activator inhibitor 1 (PAI). We found by immunocytochemistry that tPA and PAI are co-packaged in the same secretory granule. It is known that PAI irreversibly and covalently inactivates tPA at neutral pH. We demonstrate with zymography that the acidic granule lumen protects tPA from inactivation by PAI. Immunocytochemistry, total internal reflection fluorescence (TIRF) microscopy, and polarized TIRF microscopy demonstrated that co-packaged PAI and tPA remain together in granules for many seconds in the nanoscale reaction chamber, more than enough time to inhibit tPA and create a new secreted protein species. PMID:28882880

Cold Ion Escape from the Martian Ionosphere

NASA Astrophysics Data System (ADS)

Fränz, M.; Dubinin, E.; Wei, Y.; Woch, J.; Morgan, D.; Barabash, S.; Fedorov, A.

2012-09-01

It has always been challenging to observe the flux of ions with energies of less than 10eV escaping from the planetary ionospheres. We here report on new measurements of the ionospheric ion flows at Mars by the ASPERA-3 experiment on board Mars Express. We first use support from the MARSIS radar experiment for some orbits with fortunate observation geometry. Here we have observed a transterminator flow of O+ and O+ 2 ions with a super-sonic velocity of around 5km/s and fluxes of 0.8 · 109/cm2s. If we assume a symmetric flux around the terminator this corresponds to an ion flow of 3.1 ± 0.5 × 1025/s half of which is expected to escape from Mars (Fraenz et al, 2010). This escape flux is significantly higher than previously observed on the tailside of Mars, we discuss possible reasons for the difference. Since 2008 the MARSIS radar does nightside local plasma density measurement which often coincide with ASPERA-3 measurements. In a new analysis of the combined nightside datasets (Fig. 1) we show that the main escape channel is along the shadow boundary on the tailside of Mars. At a distance of about 0.5 R_M the flux settles at a constant value (Fig. 2) which indicates that about half of the transterminator ionospheric flow escapes from the planet. Possible mechanism to generate this flux can be the ionospheric pressure gradient between dayside and nightside or momentum transfer from the solar wind via the induced magnetic field since the flow velocity is in the Alfvénic regime.

Cold Ion Escape from the Martian Ionosphere

NASA Astrophysics Data System (ADS)

Fränz, Markus; Dubinin, Eduard; Wei, Yong; Morgan, David; Barabash, Stas; Lundin, Rickard; Fedorov, Andrei

2013-04-01

It has always been challenging to observe the flux of ions with energies of less than 10eV escaping from the planetary ionospheres. We here report on new measurements of the ionospheric ion flows at Mars by the ASPERA-3 experiment on board Mars Express. We first use support from the MARSIS radar experiment for some orbits with fortunate observation geometry. Here we have observed a transterminator flow of O+ and O2+ ions with a super-sonic velocity of around 5km/s and fluxes of 0.8 ? 109/cm2s. If we assume a symmetric flux around the terminator this corresponds to an ion flow of 3.1 ± 0.5 × 1025-s half of which is expected to escape from Mars (Fraenz et al, Plan.Space Sci., 2010). This escape flux is significantly higher than previously observed on the tailside of Mars, we discuss possible reasons for the difference. Since 2008 the MARSIS radar does nightside local plasma density measurements which often coincide with ASPERA-3 measurements. In a new analysis of the combined nightside datasets we show that the main escape channel is along the shadow boundary on the tailside of Mars. At a distance of half a Martian radius the flux settles at a constant value which indicates that about half of the transterminator ionospheric flow escapes from the planet. Possible mechanism to generate this flux can be the ionospheric pressure gradient between dayside and nightside or momentum transfer from the solar wind via the induced magnetic field since the flow velocity is in the Alfvénic regime.

Escape driven by alpha-stable white noises.

PubMed

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 beta of the Lévy noise, the escape can either become enhanced or suppressed: a negative asymmetry parameter beta typically yields a decrease for the escape rate while the rate itself depicts a non-monotonic behavior as a function of the stability index alpha that characterizes the jump length distribution of Lévy noise, exhibiting a marked discontinuity at alpha=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.

Life events and escape in conversion disorder.

PubMed

Nicholson, T R; Aybek, S; Craig, T; Harris, T; Wojcik, W; David, A S; Kanaan, R A

2016-09-01

Psychological models of conversion disorder (CD) traditionally assume that psychosocial stressors are identifiable around symptom onset. In the face of limited supportive evidence such models are being challenged. Forty-three motor CD patients, 28 depression patients and 28 healthy controls were assessed using the Life Events and Difficulties Schedule in the year before symptom onset. A novel 'escape' rating for events was developed to test the Freudian theory that physical symptoms of CD could provide escape from stressors, a form of 'secondary gain'. CD patients had significantly more severe life events and 'escape' events than controls. In the month before symptom onset at least one severe event was identified in 56% of CD patients - significantly more than 21% of depression patients [odds ratio (OR) 4.63, 95% confidence interval (CI) 1.56-13.70] and healthy controls (OR 5.81, 95% CI 1.86-18.2). In the same time period 53% of CD patients had at least one 'high escape' event - again significantly higher than 14% in depression patients (OR 6.90, 95% CI 2.05-23.6) and 0% in healthy controls. Previous sexual abuse was more commonly reported in CD than controls, and in one third of female patients was contextually relevant to life events at symptom onset. The majority (88%) of life events of potential aetiological relevance were not identified by routine clinical assessments. Nine per cent of CD patients had no identifiable severe life events. Evidence was found supporting the psychological model of CD, the Freudian notion of escape and the potential aetiological relevance of childhood traumas in some patients. Uncovering stressors of potential aetiological relevance requires thorough psychosocial evaluation.

Photochemical escape of oxygen from Mars: constraints from MAVEN in situ measurements

NASA Astrophysics Data System (ADS)

Lillis, R. J.; Deighan, J.; Fox, J. L.; Bougher, S. W.; Lee, Y.; Cravens, T.; Rahmati, A.; Mahaffy, P. R.; Andersson, L.; Combi, M. R.; Benna, M.; Jakosky, B. M.; Gröller, H.

2016-12-01

One of the primary goals of the MAVEN mission is to characterize rates of atmospheric escape from Mars at the present epoch and relate those escape rates to solar drivers. Photochemical escape of oxygen is expected to be a significant channel for atmospheric loss, particularly in the early solar system when extreme ultraviolet (EUV) fluxes were much higher. We use near-periapsis (<400 km altitude) data from three instruments. The Langmuir Probe and Waves (LPW) instrument measures electron density and temperature, the Suprathermal And Thermal Ion Composition (STATIC) experiment measures ion temperature and the Neutral Gas and Ion Mass Spectrometer (NGIMS) measures neutral and ion densities. For each profile of in situ measurements, we make a series of calculations, each as a function of altitude. The first uses electron and ion temperatures to calculate the probability distribution for initial energies of hot O atoms. The second calculates the probability that a hot atom born at that altitude will escape. The third takes calculates the production rate of the hot O atoms. We then multiply together the profiles of hot atom production and escape probability to get profiles of the production rate of escaping atoms. We integrate with respect to altitude to give us the escape flux of hot oxygen atoms for that periapsis pass. We will present escape fluxes and derived escape rates from the first Mars year of data collected. Total photochemical loss over time is not very useful to calculate from such escape fluxes derived from current conditions because a thicker atmosphere and much higher solar EUV in the past may change the dynamics of escape dramatically. In the future, we intend to use 3-D Monte Carlo models of global atmospheric escape, in concert with our in situ and remote measurements, to fully characterize photochemical escape under current conditions and carefully extrapolate back in time using further simulations with new boundary conditions.

Effects of selective serotonin reuptake inhibitors on thought-action fusion, metacognitions, and thought suppression in obsessive-compulsive disorder.

PubMed

Besiroglu, Lutfullah; Çetinkaya, Nuralay; Selvi, Yavuz; Atli, Abdullah

2011-01-01

We aimed to assess whether cognitive processes change over time in patients with obsessive-compulsive disorder (OCD) receiving selective serotonin reuptake inhibitors without cognitive behavioral therapy and to investigate the factors associated with probable cognitive changes. During the 16 weeks of the study, 55 patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for OCD received open-label treatment with sertraline (100-200 mg/d) or fluoxetine (40-80 mg/d) and were assessed using the Yale-Brown Obsessive-Compulsive Scale, Beck Depression Inventory (BDI), Thought-Action Fusion Scale (TAFS), Metacognitions Questionnaire (MCQ-30), and White Bear Suppression Inventory (WBSI). The Yale-Brown Obsessive-Compulsive Scale (P < .001), BDI (P < .001), TAFS morality (P < .005), MCQ-30 (P < .01), and WBSI (P < .005) scores at follow-up were significantly lower than baseline scores. When we excluded OCD patients with depressive disorder (n = 12), statistical significance in paired comparisons for MCQ and WBSI disappeared. Similarly, when OCD patients with religious obsessions (n = 16) were excluded, paired comparisons for MCQ and TAF morality were not statistically significant. Changes in BDI, TAFS morality, MCQ-30, and WBSI (P < .005) were significantly correlated with changes in severity of obsessions, but not that of compulsions. After controlling for the change in depression severity, significant correlations between changes in obsessive and cognitive scales did not continue to have statistical significance. The BDI changes (P < .05) significantly explained the changes in symptom severity in a linear regression model. Our findings suggest that selective serotonin reuptake inhibitors can change appraisals of obsessive intrusions via their effects on negative emotions. Copyright © 2011 Elsevier Inc. All rights reserved.

Escape from rich-to-lean transitions: Stimulus change and timeout.

PubMed

Retzlaff, Billie J; Parthum, Elizabeth T P; Pitts, Raymond C; Hughes, Christine E

2017-01-01

Extended pausing during discriminable transitions from rich-to-lean conditions can be viewed as escape (i.e., rich-to-lean transitions function aversively). In the current experiments, pigeons' key pecking was maintained by a multiple fixed-ratio fixed-ratio schedule of rich or lean reinforcers. Pigeons then were provided with another, explicit, mechanism of escape by changing the stimulus from the transition-specific stimulus used in the multiple schedule to a mixed-schedule stimulus (Experiment 1) or by producing a period of timeout in which the stimulus was turned off and the schedule was suspended (Experiment 2). Overall, escape was under joint control of past and upcoming reinforcer magnitudes, such that responses on the escape key were most likely during rich-to-lean transitions, and second-most likely during lean-to-lean transitions. Even though pigeons pecked the escape key, they paused before doing so, and the latency to begin the fixed ratio (i.e., the pause) remained extended during rich-to-lean transitions. These findings suggest that although the stimulus associated with rich-to-lean transitions functioned aversively, pausing is more than simply escape responding from the stimulus. © 2017 Society for the Experimental Analysis of Behavior.

Progesterone After Estradiol Modulates Shuttle-Cage Escape by Facilitating Volition

PubMed Central

Mayeaux, Darryl J.; Tandle, Sarah M.; Cilano, Sean M.; Fitzharris, Matthew J.

2015-01-01

In animal models of depression, depression is defined as performance on a learning task. That task is typically escaping a mild electric shock in a shuttle cage by moving from one side of the cage to the other. Ovarian hormones influence learning in other kinds of tasks, and these hormones are associated with depressive symptoms in humans. The role of these hormones in shuttle-cage escape learning, however, is less clear. This study manipulated estradiol and progesterone in ovariectomized female rats to examine their performance in shuttle-cage escape learning without intentionally inducing a depressive-like state. Progesterone, not estradiol, within four hours of testing affected latencies to escape. The improvement produced by progesterone was in the decision to act, not in the speed of learning or speed of escaping. This parallels depression in humans in that depressed people are slower in volition, in their decisions to take action. PMID:26823653

Escape probability of the super-Penrose process

NASA Astrophysics Data System (ADS)

Ogasawara, Kota; Harada, Tomohiro; Miyamoto, Umpei; Igata, Takahisa

2017-06-01

We consider a head-on collision of two massive particles that move in the equatorial plane of an extremal Kerr black hole, which results in the production of two massless particles. Focusing on a typical case, where both of the colliding particles have zero angular momenta, we show that a massless particle produced in such a collision can escape to infinity with arbitrarily large energy in the near-horizon limit of the collision point. Furthermore, if we assume that the emission of the produced massless particles is isotropic in the center-of-mass frame but confined to the equatorial plane, the escape probability of the produced massless particle approaches 5 /12 , and almost all escaping massless particles have arbitrarily large energy at infinity and an impact parameter approaching 2 G M /c2, where M is the mass of the black hole.

Contrasting effects of acute and chronic treatment with imipramine and fluoxetine on inhibitory avoidance and escape responses in mice exposed to the elevated T-maze.

PubMed

Gomes, Karina Santos; de Carvalho-Netto, Eduardo Ferreira; Monte, Kátia Cristina Da Silva; Acco, Bruno; Nogueira, Paulo José de Campos; Nunes-de-Souza, Ricardo Luiz

2009-03-30

The elevated T-maze (ETM) is an animal model of anxiety-like behavior that assesses two different defensive behavioral tasks in the same animal-acquisition of inhibitory avoidance and latency to escape from an open and elevated arm. In rats, cute and chronic treatments with anxiolytic-like drugs impair avoidance acquisition while only chronic administration of panicolytic-like drugs impairs open arm withdrawal. To date, only the acute effects of anxiolytic/anxiogenic or panicolytic/panicogenic drugs have been tested in the mouse ETM and the results have partially corroborated those found in the rat ETM. This study investigated the effects of acute (a single intraperitoneal injection 30 min before testing) and chronic (daily i.p. injections for 15 consecutive days) treatment with imipramine or fluoxetine, non-selective and selective serotonin reuptake inhibitors, respectively, on inhibitory avoidance and escape tasks in the mouse ETM. Neither acute nor chronic treatment with imipramine (0, 1, 5 or 10 mg/kg, i.p.) significantly changed the behavioral profile of mice in the two ETM tasks. Interestingly, while acute fluoxetine (0, 5, 10, 20 or 40 mg/kg, i.p.) facilitated inhibitory avoidance and impaired escape latency, chronic treatment (0, 5, 20 or 40 mg/kg, i.p.) with this selective serotonin reuptake inhibitor (SSRI) produced an opposite effect, i.e., it impaired inhibitory avoidance acquisition and facilitated open arm withdrawal. Importantly, acute or chronic treatment with imipramine (except at the highest dose that increased locomotion when given acutely) or fluoxetine failed to alter general locomotor activity in mice as assessed in an ETM in which all arms were enclosed by lateral walls (eETM). These results suggest that inhibitory avoidance acquisition is a useful task for the evaluation of acute and chronic effects of SSRI treatment on anxiety in mice. However, as open arm latency was actually increased and reduced by acute and chronic fluoxetine

Escape from the competence state in Streptococcus mutans is governed by the bacterial population density.

PubMed

Dufour, D; Villemin, C; Perry, J A; Lévesque, C M

2016-12-01

Horizontal gene transfer through natural DNA transformation is an important evolutionary mechanism among bacteria. Transformation requires that the bacteria are physiologically competent to take and incorporate free DNA directly from the environment. Although natural genetic transformation is a remarkable feature of many naturally competent bacteria, the process is energetically expensive for the cells. Consequently, a tight control of the competence state is necessary. The objective of the present work was to help decipher the molecular mechanisms regulating the escape from the competence state in Streptococcus mutans, the principal etiological agent responsible for tooth decay in humans. Our results showed that the cessation of competence in S. mutans was abrupt, and did not involve the accumulation of a competence inhibitor nor the depletion of a competence activator in the extracellular environment. The competence state was repressed at high cell population density via concomitant repression of sigX gene encoding the master regulator of the competence regulon. Co-culture experiments performed with oral and non-oral bacteria showed that S. mutans assesses its own population density and also the microbial density of its surroundings to regulate its competence escape. Interestingly, neither the intra-species and extra-species quorum-sensing systems nor the other 13 two-component regulatory systems identified in S. mutans were involved in the cell-density-dependent escape of the competence state. Altogether, our results suggest a complex mechanism regulating the competence shut-off involving cell-density-dependent repression of sigX through an as yet undefined system, and possibly SigX protein stability. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The Origins and Underpinning Principles of E-Scape

ERIC Educational Resources Information Center

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…

Quantification of simian immunodeficiency virus cytotoxic T lymphocyte escape mutant viruses.

PubMed

Loh, Liyen; Kent, Stephen J

2008-08-01

Escape from cytotoxic T-lymphocyte (CTL) pressure is common in HIV-1 infection of humans and simian immunodeficiency virus (SIV) infections of macaques. CTL escape typically incurs a fitness cost as reversion back to wild-type can occur upon transmission. We utilized sequence-specific primers and DNA probes with real-time polymerase chain reaction (PCR) to sensitively and specifically track wild-type and escape mutant viremia at the Mane-A*17-restricted SIV Gag(371379) epitope AF9 in pigtail macaques. The generation of minor escape mutant populations is detected by the real-time PCR 2 weeks earlier than observed using standard sequencing techniques. We passaged the AF9 CTL escape mutant virus into two naïve Mane-A*17-negative pigtail macaques and showed that reversion to wild-type was rapid during acute infection and then slowed considerably at later stages of the infection. These data help refine our understanding of how CTL escape mutant viruses evolve.

Staphylococcus aureus synthesizes adenosine to escape host immune responses

PubMed Central

Thammavongsa, Vilasack; Kern, Justin W.; Missiakas, Dominique M.

2009-01-01

Staphylococcus aureus infects hospitalized or healthy individuals and represents the most frequent cause of bacteremia, treatment of which is complicated by the emergence of methicillin-resistant S. aureus. We examined the ability of S. aureus to escape phagocytic clearance in blood and identified adenosine synthase A (AdsA), a cell wall–anchored enzyme that converts adenosine monophosphate to adenosine, as a critical virulence factor. Staphylococcal synthesis of adenosine in blood, escape from phagocytic clearance, and subsequent formation of organ abscesses were all dependent on adsA and could be rescued by an exogenous supply of adenosine. An AdsA homologue was identified in the anthrax pathogen, and adenosine synthesis also enabled escape of Bacillus anthracis from phagocytic clearance. Collectively, these results suggest that staphylococci and other bacterial pathogens exploit the immunomodulatory attributes of adenosine to escape host immune responses. PMID:19808256

Nanoparticle delivery of miR-223 to attenuate macrophage fusion

PubMed Central

Moore, Laura Beth; Sawyer, Andrew J.; Saucier-Sawyer, Jennifer; Saltzman, W. Mark; Kyriakides, Themis R.

2016-01-01

The foreign body response (FBR) begins with injury acquired during implantation of a biomaterial (BM) and is detrimental due to the eventual encapsulation of the implant. Fusion of macrophages to form foreign body giant cells (FBGC), a hallmark of the FBR, is the consequence of a multistep mechanism induced by interleukin (IL)-4 that includes the acquisition of a fusion competent state and subsequent cytoskeletal rearrangements. However, the precise mechanism, regulation, and interplay among molecular mediators to generate FBGCs are insufficiently understood. Seeking novel mediators of fusion that might be regulated at the post-transcriptional level, we examined the role of microRNAs (miRs) in this process. A miR microarray was screened and identified miR-223 as a negative regulator of macrophage fusion. In addition, transfection of primary macrophages with a mir-223 mimic attenuated IL-4-induced fusion. Furthermore, miR-223 KO mice and mir-223 deficient cells displayed increased fusion in vivo and in vitro, respectively. Finally, we developed a method for in vivo delivery of miR-223 mimic utilizing PLGA nanoparticles, which inhibited FBGC formation in a biomaterial implant model. Our results identify miR-223 as a negative regulator of fusion and demonstrate miR-223 mimic-loaded nanoparticles as a therapeutic inhibitor of macrophage fusion. PMID:26967647

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

PubMed

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.

Danger detection and escape behaviour in wood crickets.

PubMed

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

Launch Pad Escape System Design (Human Spaceflight)

NASA Technical Reports Server (NTRS)

Maloney, Kelli

2011-01-01

A launch pad escape system for human spaceflight is one of those things that everyone hopes they will never need but is critical for every manned space program. Since men were first put into space in the early 1960s, the need for such an Emergency Escape System (EES) has become apparent. The National Aeronautics and Space Administration (NASA) has made use of various types of these EESs over the past 50 years. Early programs, like Mercury and Gemini, did not have an official launch pad escape system. Rather, they relied on a Launch Escape System (LES) of a separate solid rocket motor attached to the manned capsule that could pull the astronauts to safety in the event of an emergency. This could only occur after hatch closure at the launch pad or during the first stage of flight. A version of a LES, now called a Launch Abort System (LAS) is still used today for all manned capsule type launch vehicles. However, this system is very limited in that it can only be used after hatch closure and it is for flight crew only. In addition, the forces necessary for the LES/LAS to get the capsule away from a rocket during the first stage of flight are quite high and can cause injury to the crew. These shortcomings led to the development of a ground based EES for the flight crew and ground support personnel as well. This way, a much less dangerous mode of egress is available for any flight or ground personnel up to a few seconds before launch. The early EESs were fairly simple, gravity-powered systems to use when thing's go bad. And things can go bad very quickly and catastrophically when dealing with a flight vehicle fueled with millions of pounds of hazardous propellant. With this in mind, early EES designers saw such a passive/unpowered system as a must for last minute escapes. This and other design requirements had to be derived for an EES, and this section will take a look at the safety design requirements had to be derived for an EES, and this section will take a look at

Escape of asteroids from the main belt

NASA Astrophysics Data System (ADS)

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 < 4.1 au is essentially complete, with an absolute magnitude limit ranging from HV < 15.9 in the inner belt (a < 2.5 au) to HV < 14.4 in the outer belt (2.5 au < a < 4.1 au). We modeled the semimajor-axis drift caused by the Yarkovsky force and assigned four different sizes (diameters of 0.1, 0.3, 1.0, and 3.0 km) and 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

The emerging role of ALK inhibitors in the treatment of advanced non-small cell lung cancer.

PubMed

Galetta, Domenico; Rossi, Antonio; Pisconti, Salvatore; Colucci, Giuseppe

2012-04-01

Most NSCLC patients are diagnosed in the advanced stage of the disease. Recently, chemotherapeutic agents have reached a plateau of effectiveness. Increased understanding of cancer biology has revealed several potential therapeutic strategies that have led to marketing of new biologic agents. The echinoderm microtubule-associated protein like-4-anaplastic lymphoma kinase (EML4-ALK) fusion oncogene represents one of the newest molecular targets in NSCLC, identifying a subset of NSCLC patients characterized by distinct clinicopathological features. The available results concerning ALK inhibitors for the treatment of advanced NSCLC patients. An electronic search was used to retrieve the articles addressing this topic. In a pivotal Phase I clinical trial, crizotinib (PF-02341066), a small-molecule ALK inhibitor, demonstrated impressive antitumor activity in the majority of NSCLC patients with ALK fusions. Phase III randomized trials investigating crizotinib in this subgroup of patients are ongoing. If the results from these large international trials confirm the efficacy of crizotinib in the subset of patients, the next few years could see the treatment of advanced NSCLC patients with ALK fusions. Specific inhibitors would realize the so called personalized medicine in subsets of this disease.

Mars H Escape is potentially dominated by a high-altitude water source

NASA Astrophysics Data System (ADS)

Chaffin, Michael; Deighan, Justin; Schneider, Nick; Stewart, Ian

2017-04-01

H escape from the Mars atmosphere has removed a large part of Mars' initial water inventory. Until recently, this escape was thought to be slow and steady, sourced from long-lived molecular hydrogen whose lightness and volatility in comparison with water allow it to penetrate the upper atmosphere. Contradicting this thinking, observations from the Hubble Space Telescope and Mars Express, as well as more recent MAVEN measurements, indicate that H escape varies by at least a factor of ten over the Mars year and is largest in Southern Summer near perihelion. At the largest rates, H escape exceeds the ability of molecular hydrogen to supply the escape fluxes observed. At the same time in Southern Summer, Mars Express solar occultations have shown unexpectedly large concentrations of water at high altitude, potentially providing a source of escaping H unaccounted for in standard models. Here we show via photochemical modeling that the presence of this high altitude water can partially explain the large escape rates observed in Southern Summer. We further show that this escaping H is not in immediate balance with O escape, and therefore that short-term atmospheric dynamics can drive long-term variations in the oxidation balance and volatile content of planetary atmospheres. Future simultaneous observations by MAVEN, Mars Express, and the Trace Gas Orbiter may provide a direct test of this mechanism.

Ion kinetic effects on the ignition and burn of inertial confinement fusion targets: A multi-scale approach

NASA Astrophysics Data System (ADS)

Peigney, B. E.; Larroche, O.; Tikhonchuk, V.

2014-12-01

In this article, we study the hydrodynamics and burn of the thermonuclear fuel in inertial confinement fusion pellets at the ion kinetic level. The analysis is based on a two-velocity-scale Vlasov-Fokker-Planck kinetic model that is specially tailored to treat fusion products (suprathermal α-particles) in a self-consistent manner with the thermal bulk. The model assumes spherical symmetry in configuration space and axial symmetry in velocity space around the mean flow velocity. A typical hot-spot ignition design is considered. Compared with fluid simulations where a multi-group diffusion scheme is applied to model α transport, the full ion-kinetic approach reveals significant non-local effects on the transport of energetic α-particles. This has a direct impact on hydrodynamic spatial profiles during combustion: the hot spot reactivity is reduced, while the inner dense fuel layers are pre-heated by the escaping α-suprathermal particles, which are transported farther out of the hot spot. We show how the kinetic transport enhancement of fusion products leads to a significant reduction of the fusion yield.

Ion kinetic effects on the ignition and burn of inertial confinement fusion targets: A multi-scale approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peigney, B. E.; Larroche, O.; Tikhonchuk, V.

2014-12-15

In this article, we study the hydrodynamics and burn of the thermonuclear fuel in inertial confinement fusion pellets at the ion kinetic level. The analysis is based on a two-velocity-scale Vlasov-Fokker-Planck kinetic model that is specially tailored to treat fusion products (suprathermal α-particles) in a self-consistent manner with the thermal bulk. The model assumes spherical symmetry in configuration space and axial symmetry in velocity space around the mean flow velocity. A typical hot-spot ignition design is considered. Compared with fluid simulations where a multi-group diffusion scheme is applied to model α transport, the full ion-kinetic approach reveals significant non-local effectsmore » on the transport of energetic α-particles. This has a direct impact on hydrodynamic spatial profiles during combustion: the hot spot reactivity is reduced, while the inner dense fuel layers are pre-heated by the escaping α-suprathermal particles, which are transported farther out of the hot spot. We show how the kinetic transport enhancement of fusion products leads to a significant reduction of the fusion yield.« less

Cold Ion Escape from Mars

NASA Astrophysics Data System (ADS)

Fränz, M.; Dubinin, E.; Wei, Y.; Morgan, D.; Andrews, D.; Barabash, S.; Lundin, R.; Fedorov, A.

2013-09-01

It has always been challenging to observe the flux of ions with energies of less than 10eV escaping from the planetary ionospheres. We here report on new measurements of the ionospheric ion flows at Mars by the ASPERA-3 experiment on board Mars Express in combination with the MARSIS radar experiment. We first compare calculations of the mean ion flux observed by ASPERA-3 alone with previously published results. We then combine observations of the cold ion velocity by ASPERA-3 with observations of the cold plasma density by MARSIS since ASPERA-3 misses the cold core of the ion distribution. We show that the mean density of the nightside plasma observed by MARSIS is about two orders higher than observed by ASPERA-3 (Fig.1). Combining both datasets we show that the main escape channel is along the shadow boundary on the tailside of Mars (Fig. 2). At a distance of about 0.5 R_M the flux settles at a constant value (Fig. 3) which indicates that about half of the transterminator ionospheric flow escapes from the planet. Possible mechanism to generate this flux can be the ionospheric pressure gradient between dayside and nightside or momentum transfer from the solar wind via the induced magnetic field since the flow velocity is in the Alfvénic regime.

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

NASA Astrophysics Data System (ADS)

Dandouras, I.; Yamauchi, M.; Rème, H.; De Keyser, J.; Marghitu, O.; Fazakerley, A.; Grison, B.; Kistler, L.; Milillo, A.; Nakamura, R.; Paschalidis, N.; Paschalis, A.; Pinçon, J.-L.; Sakanoi, T.; Wieser, M.; Wurz, P.; Yoshikawa, I.; Häggström, I.; Liemohn, M.; Tian, F.

2017-09-01

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 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 atmospheric composition 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, which is essential for habitability.

Rational Design of Novel Allosteric Dihydrofolate Reductase Inhibitors Showing Antibacterial Effects on Drug-Resistant Escherichia coli Escape Variants.

PubMed

Srinivasan, Bharath; Rodrigues, João V; Tonddast-Navaei, Sam; Shakhnovich, Eugene; Skolnick, Jeffrey

2017-07-21

In drug discovery, systematic variations of substituents on a common scaffold and bioisosteric replacements are often used to generate diversity and obtain molecules with better biological effects. However, this could saturate the small-molecule diversity pool resulting in drug resistance. On the other hand, conventional drug discovery relies on targeting known pockets on protein surfaces leading to drug resistance by mutations of critical pocket residues. Here, we present a two-pronged strategy of designing novel drugs that target unique pockets on a protein's surface to overcome the above problems. Dihydrofolate reductase, DHFR, is a critical enzyme involved in thymidine and purine nucleotide biosynthesis. Several classes of compounds that are structural analogues of the substrate dihydrofolate have been explored for their antifolate activity. Here, we describe 10 novel small-molecule inhibitors of Escherichia coli DHFR, EcDHFR, belonging to the stilbenoid, deoxybenzoin, and chalcone family of compounds discovered by a combination of pocket-based virtual ligand screening and systematic scaffold hopping. These inhibitors show a unique uncompetitive or noncompetitive inhibition mechanism, distinct from those reported for all known inhibitors of DHFR, indicative of binding to a unique pocket distinct from either substrate or cofactor-binding pockets. Furthermore, we demonstrate that rescue mutants of EcDHFR, with reduced affinity to all known classes of DHFR inhibitors, are inhibited at the same concentration as the wild-type. These compounds also exhibit antibacterial activity against E. coli harboring the drug-resistant variant of DHFR. This discovery is the first report on a novel class of inhibitors targeting a unique pocket on EcDHFR.

In vitro assay using engineered yeast vacuoles for neuronal SNARE-mediated membrane fusion

PubMed Central

Ko, Young-Joon; Lee, Miriam; Kang, KyeongJin; Song, Woo Keun; Jun, Youngsoo

2014-01-01

Intracellular membrane fusion requires not only SNARE proteins but also other regulatory proteins such as the Rab and Sec1/Munc18 (SM) family proteins. Although neuronal SNARE proteins alone can drive the fusion between synthetic liposomes, it remains unclear whether they are also sufficient to induce the fusion of biological membranes. Here, through the use of engineered yeast vacuoles bearing neuronal SNARE proteins, we show that neuronal SNAREs can induce membrane fusion between yeast vacuoles and that this fusion does not require the function of the Rab protein Ypt7p or the SM family protein Vps33p, both of which are essential for normal yeast vacuole fusion. Although excess vacuolar SNARE proteins were also shown to mediate Rab-bypass fusion, this fusion required homotypic fusion and vacuole protein sorting complex, which bears Vps33p and was accompanied by extensive membrane lysis. We also show that this neuronal SNARE-driven vacuole fusion can be stimulated by the neuronal SM protein Munc18 and blocked by botulinum neurotoxin serotype E, a well-known inhibitor of synaptic vesicle fusion. Taken together, our results suggest that neuronal SNARE proteins are sufficient to induce biological membrane fusion, and that this new assay can be used as a simple and complementary method for investigating synaptic vesicle fusion mechanisms. PMID:24821814

Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC: Implication for optional anti-PD-1/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients.

PubMed

Hong, Shaodong; Chen, Nan; Fang, Wenfeng; Zhan, Jianhua; Liu, Qing; Kang, Shiyang; He, Xiaobo; Liu, Lin; Zhou, Ting; Huang, Jiaxing; Chen, Ying; Qin, Tao; Zhang, Yaxiong; Ma, Yuxiang; Yang, Yunpeng; Zhao, Yuanyuan; Huang, Yan; Zhang, Li

2016-03-01

Driver mutations were reported to upregulate programmed death-ligand 1 (PD-L1) expression. However, how PD-L1 expression and immune function was affected by ALK-TKIs and anti-PD-1/PD-L1 treatment in ALK positive non-small-cell lung cancer (NSCLC) remains poorly understood. In the present study, western-blot, real-time PCR, flow cytometry and immunofluorescence were employed to explore how PD-L1 was regulated by ALK fusion protein. ALK-TKIs and relevant inhibitors were used to identify the downstream signaling pathways involved in PD-L1 regulation. Cell apoptosis, viability and Elisa test were used to study the immune suppression by ALK activation and immune reactivation by ALK-TKIs and/or PD-1 blocking in tumor cells and DC-CIK cells co-culture system. We found that PD-L1 expression was associated with EGFR mutations and ALK fusion genes in NSCLC cell lines. Over-expression of ALK fusion protein increased PD-L1 expression. PD-L1 mediated by ALK fusion protein increased the apoptosis of T cells in tumor cells and DC-CIK cells co-culture system. Inhibiting ALK by sensitive TKIs could enhance the production of IFNγ. Anti-PD-1 antibody was effective in both crizotinib sensitive and resistant NSCLC cells. Synergistic tumor killing effects were not observed with ALK-TKIs and anti-PD-1 antibody combination in co-culture system. ALK-TKIs not only directly inhibited tumor viability but also indirectly enhanced the antitumor immunity via the downregulation of PD-L1. Anti-PD-1/PD-L1 antibodies could be an optional therapy for crizotinib sensitive, especially crizotinib resistant NSCLC patients with ALK fusion gene. Combination of ALK-TKIs and anti-PD-1/PD-L1 antibodies treatment for ALK positive NSCLC warrants more data before moving into clinical practice.

Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC: Implication for optional anti-PD-1/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients

PubMed Central

Hong, Shaodong; Chen, Nan; Fang, Wenfeng; Zhan, Jianhua; Liu, Qing; Kang, Shiyang; He, Xiaobo; Liu, Lin; Zhou, Ting; Huang, Jiaxing; Chen, Ying; Qin, Tao; Zhang, Yaxiong; Ma, Yuxiang; Yang, Yunpeng; Zhao, Yuanyuan; Huang, Yan; Zhang, Li

2016-01-01

ABSTRACT Driver mutations were reported to upregulate programmed death-ligand 1 (PD-L1) expression. However, how PD-L1 expression and immune function was affected by ALK-TKIs and anti-PD-1/PD-L1 treatment in ALK positive non-small-cell lung cancer (NSCLC) remains poorly understood. In the present study, western-blot, real-time PCR, flow cytometry and immunofluorescence were employed to explore how PD-L1 was regulated by ALK fusion protein. ALK-TKIs and relevant inhibitors were used to identify the downstream signaling pathways involved in PD-L1 regulation. Cell apoptosis, viability and Elisa test were used to study the immune suppression by ALK activation and immune reactivation by ALK-TKIs and/or PD-1 blocking in tumor cells and DC-CIK cells co-culture system. We found that PD-L1 expression was associated with EGFR mutations and ALK fusion genes in NSCLC cell lines. Over-expression of ALK fusion protein increased PD-L1 expression. PD-L1 mediated by ALK fusion protein increased the apoptosis of T cells in tumor cells and DC-CIK cells co-culture system. Inhibiting ALK by sensitive TKIs could enhance the production of IFNγ. Anti-PD-1 antibody was effective in both crizotinib sensitive and resistant NSCLC cells. Synergistic tumor killing effects were not observed with ALK-TKIs and anti-PD-1 antibody combination in co-culture system. ALK-TKIs not only directly inhibited tumor viability but also indirectly enhanced the antitumor immunity via the downregulation of PD-L1. Anti-PD-1/PD-L1 antibodies could be an optional therapy for crizotinib sensitive, especially crizotinib resistant NSCLC patients with ALK fusion gene. Combination of ALK-TKIs and anti-PD-1/PD-L1 antibodies treatment for ALK positive NSCLC warrants more data before moving into clinical practice. PMID:27141355

Dynamin-related protein-1 controls fusion pore dynamics during platelet granule exocytosis.

PubMed

Koseoglu, Secil; Dilks, James R; Peters, Christian G; Fitch-Tewfik, Jennifer L; Fadel, Nathalie A; Jasuja, Reema; Italiano, Joseph E; Haynes, Christy L; Flaumenhaft, Robert

2013-03-01

Platelet granule exocytosis serves a central role in hemostasis and thrombosis. Recently, single-cell amperometry has shown that platelet membrane fusion during granule exocytosis results in the formation of a fusion pore that subsequently expands to enable the extrusion of granule contents. However, the molecular mechanisms that control platelet fusion pore expansion and collapse are not known. We identified dynamin-related protein-1 (Drp1) in platelets and found that an inhibitor of Drp1, mdivi-1, blocked exocytosis of both platelet dense and α-granules. We used single-cell amperometry to monitor serotonin release from individual dense granules and, thereby, measured the effect of Drp1 inhibition on fusion pore dynamics. Inhibition of Drp1 increased spike width and decreased prespike foot events, indicating that Drp1 influences fusion pore formation and expansion. Platelet-mediated thrombus formation in vivo after laser-induced injury of mouse cremaster arterioles was impaired after infusion of mdivi-1. These results demonstrate that inhibition of Drp1 disrupts platelet fusion pore dynamics and indicate that Drp1 can be targeted to control thrombus formation in vivo.

Water-escape velocities in jumping blacktip sharks

PubMed Central

Brunnschweiler, Juerg M

2005-01-01

This paper describes the first determination of water-escape velocities in free-ranging sharks. Two approximations are used to estimate the final swimming speed at the moment of penetrating the water surface. Blacktip sharks were videotaped from below the surface and parameters were estimated by analysing the sequences frame by frame. Water-escape velocities averaged 6.3 m s−1. These velocities for blacktip sharks seem accurate and are similar to estimates obtained for other shark species of similar size. PMID:16849197

Ventilation and oxygen uptake during escape from a civil aircraft.

PubMed

Ross, J A; Watt, S J; Henderson, G D; Vant, J H

1990-01-01

To help develop a specification for equipment providing personal respiratory protection in the event of aircraft fire a study was carried out to quantify ventilation and oxygen consumption during escape from a Trident aircraft. Data were gathered using the P.K. Morgan 'Oxylog' apparatus after its response time to rapid changes in inspired to expired oxygen concentration difference was assessed using a bench test. The 'Oxylog' had a lag time of 30-32 s and a 5-95% response typified by a half time of 20 s. The data gathered were corrected in the light of these findings. Fourteen male subjects aged 17-38 years were studied under two conditions. Four mass evacuations each involving 40 people; a total of nine subjects escaping from the front rank over eight seats being monitored. Six evacuations each involving only two people escaping from the rear of the cabin; a total of 11 subjects escaping over 14 seats being monitored. Escape was made over the seat backs, down an escape chute to a position 12 m from the base of the chute. Resting minute ventilation (mean 16.7 1 STPD) and oxygen consumption (mean 0.41 min-1 STPD) were similar before both evacuations. There were no significant differences between the two conditions either during, or up to 180 s after escape. Ventilation and oxygen consumption were greatest in the recovery period. The highest oxygen consumption seen was 2.08 l min-1 and maximum minute ventilation was 641. Mean total oxygen consumption for the escape and a 150 s recovery period was 2.41 l (s.d. 0.64, max. 3.11) for the mass evacuation and 2.97 l (s.d. 0.68, max. 4.09) for the two person evacuation. The mean total amount of gas inhaled during the same time period was 89.3 l (s.d. 25.6, max. 121.3) for the mass evacuation and 99.01 (s.d. 26.2, max. 137.3) for the other. These was no correlation between ventilation or oxygen consumption and either escape time, body weight, height or age.

Dissection of the Role of the Stable Signal Peptide of the Arenavirus Envelope Glycoprotein in Membrane Fusion

PubMed Central

Messina, Emily L.; York, Joanne

2012-01-01

The arenavirus envelope glycoprotein (GPC) retains a stable signal peptide (SSP) as an essential subunit in the mature complex. The 58-amino-acid residue SSP comprises two membrane-spanning hydrophobic regions separated by a short ectodomain loop that interacts with the G2 fusion subunit to promote pH-dependent membrane fusion. Small-molecule compounds that target this unique SSP-G2 interaction prevent arenavirus entry and infection. The interaction between SSP and G2 is sensitive to the phylogenetic distance between New World (Junín) and Old World (Lassa) arenaviruses. For example, heterotypic GPC complexes are unable to support virion entry. In this report, we demonstrate that the hybrid GPC complexes are properly assembled, proteolytically cleaved, and transported to the cell surface but are specifically defective in their membrane fusion activity. Chimeric SSP constructs reveal that this incompatibility is localized to the first transmembrane segment of SSP (TM1). Genetic changes in TM1 also affect sensitivity to small-molecule fusion inhibitors, generating resistance in some cases and inhibitor dependence in others. Our studies suggest that interactions of SSP TM1 with the transmembrane domain of G2 may be important for GPC-mediated membrane fusion and its inhibition. PMID:22438561

A study of carbobenzoxy-D-phenylalanine-L-phenylalanine-glycine, an inhibitor of membrane fusion, in phospholipid bilayers with multinuclear magnetic resonance.

PubMed

Dentino, A R; Westerman, P W; Yeagle, P L

1995-05-04

The anti-viral and membrane fusion inhibitor, carbobenzoxy-D-phenylalanine-L-phenylalanine-glycine (ZfFG), was studied in phospholipid bilayers, where earlier studies had indicated this peptide functioned. Multinuclear magnetic resonance (NMR) studies were performed with isotopically labeled peptide. A peptide labeled in the glycine carboxyl with 13C was synthesized, and the isotropic 13C-NMR chemical shift of that carbon was measured as a function of pH. A pKa of 3.6 for the carboxyl was determined from the peptide bound to a phosphatidylcholine bilayer. ZfFG inhibits the formation by sonication of highly curved, small unilamellar vesicles. Experiments as a function of pH revealed that this ability of ZfFG was governed by a pKa of 3.7. Therefore the protonation state of the carboxyl of ZfFG appeared to regulate the effectiveness of this anti-viral peptide at destabilizing highly curved phospholipid assemblies. Such destabilization had previously been discovered to be related to the mechanism of the anti-fusion and anti-viral activity of this peptide. The location of the carboxyl of ZfFG in the membrane was probed with paramagnetic relaxation enhancement of the 13C spin lattice relaxation of the carboxyl carbon in the glycine of ZfFG (enriched in 13C). Results suggested that this carboxyl is at or above the surface of the phospholipid bilayer. The dynamics of the molecule in the membrane were examined with 2H-NMR studies of ZfFG, deuterated in the alpha-carbon protons of the glycine. When ZfFG was bound to membranes of phosphatidylcholine, a sharp 2H-NMR spectral component was observed, consistent with a disordering of the glycine methylene segment of the peptide. When ZfFG was bound to N-methyl dioleoylphosphatidylethanolamine (N-methyl DOPE) bilayers at temperatures below 30 degrees C, a large quadrupole splitting was observed. These results suggest that ZfFG likely inhibits membrane fusion from the surface of the lipid bilayer, but not by forming a tight

Noise-induced escape in an excitable system

NASA Astrophysics Data System (ADS)

Khovanov, I. A.; Polovinkin, A. V.; Luchinsky, D. G.; McClintock, P. V. E.

2013-03-01

We consider the stochastic dynamics of escape in an excitable system, the FitzHugh-Nagumo (FHN) neuronal model, for different classes of excitability. We discuss, first, the threshold structure of the FHN model as an example of a system without a saddle state. We then develop a nonlinear (nonlocal) stability approach based on the theory of large fluctuations, including a finite-noise correction, to describe noise-induced escape in the excitable regime. We show that the threshold structure is revealed via patterns of most probable (optimal) fluctuational paths. The approach allows us to estimate the escape rate and the exit location distribution. We compare the responses of a monostable resonator and monostable integrator to stochastic input signals and to a mixture of periodic and stochastic stimuli. Unlike the commonly used local analysis of the stable state, our nonlocal approach based on optimal paths yields results that are in good agreement with direct numerical simulations of the Langevin equation.

Almost certain escape from black holes in final state projection models.

PubMed

Lloyd, Seth

2006-02-17

Recent models of the black-hole final state suggest that quantum information can escape from a black hole by a process akin to teleportation. These models rely on a controversial process called final-state projection. This Letter discusses the self-consistency of the final-state projection hypothesis and investigates escape from black holes for arbitrary final states and for generic interactions between matter and Hawking radiation. Quantum information escapes with fidelity approximately = (8/3pi)2: only half a bit of quantum information is lost on average, independent of the number of bits that escape from the hole.

Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy

PubMed Central

Kong, Xiangju; Hong, Aayoung; Koya, Richard C.; Moriceau, Gatien; Chodon, Thinle; Guo, Rongqing; Johnson, Douglas B.; Dahlman, Kimberly B.; Kelley, Mark C.; Kefford, Richard F.; Chmielowski, Bartosz; Glaspy, John A.; Sosman, Jeffrey A.; van Baren, Nicolas; Long, Georgina V.; Ribas, Antoni; Lo, Roger S.

2013-01-01

BRAF inhibitors elicit rapid anti-tumor responses in the majority of patients with V600BRAF mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that MAPK reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification and alternative splicing being most common. We also detected PI3K-PTEN-AKT-upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions, in both core drug escape pathways, were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma re-growth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, co-targeting of two core pathways as an essential strategy for durable responses. PMID:24265155

14. DETAIL VIEW OF ESCAPE TRAINING TANK, SHOWING HOLDDOWN RODS, ...

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

14. DETAIL VIEW OF ESCAPE TRAINING TANK, SHOWING HOLD-DOWN RODS, LOOKING SOUTH - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

34. VIEW OF SUBMARINE ESCAPE TRAINING TANK PRIOR TO ADDITION ...

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

34. VIEW OF SUBMARINE ESCAPE TRAINING TANK PRIOR TO ADDITION OF BLISTERS IN 1959, LOOKING SOUTHEAST - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

Teachers Offering Healthy Escape Options for Teenagers in Pain

ERIC Educational Resources Information Center

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…

Selection of High-Affinity Peptidic Serine Protease Inhibitors with Increased Binding Entropy from a Back-Flip Library of Peptide-Protease Fusions.

PubMed

Sørensen, Hans Peter; Xu, Peng; Jiang, Longguang; Kromann-Hansen, Tobias; Jensen, Knud J; Huang, Mingdong; Andreasen, Peter A

2015-09-25

We have developed a new concept for designing peptidic protein modulators, by recombinantly fusing the peptidic modulator, with randomized residues, directly to the target protein via a linker and screening for internal modulation of the activity of the protein. We tested the feasibility of the concept by fusing a 10-residue-long, disulfide-bond-constrained inhibitory peptide, randomized in selected positions, to the catalytic domain of the serine protease murine urokinase-type plasminogen activator. High-affinity inhibitory peptide variants were identified as those that conferred to the fusion protease the lowest activity for substrate hydrolysis. The usefulness of the strategy was demonstrated by the selection of peptidic inhibitors of murine urokinase-type plasminogen activator with a low nanomolar affinity. The high affinity could not have been predicted by rational considerations, as the high affinity was associated with a loss of polar interactions and an increased binding entropy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mechanism for Active Membrane Fusion Triggering by Morbillivirus Attachment Protein

PubMed Central

Ader, Nadine; Brindley, Melinda; Avila, Mislay; Örvell, Claes; Horvat, Branka; Hiltensperger, Georg; Schneider-Schaulies, Jürgen; Vandevelde, Marc; Zurbriggen, Andreas; Plemper, Richard K.

2013-01-01

The paramyxovirus entry machinery consists of two glycoproteins that tightly cooperate to achieve membrane fusion for cell entry: the tetrameric attachment protein (HN, H, or G, depending on the paramyxovirus genus) and the trimeric fusion protein (F). Here, we explore whether receptor-induced conformational changes within morbillivirus H proteins promote membrane fusion by a mechanism requiring the active destabilization of prefusion F or by the dissociation of prefusion F from intracellularly preformed glycoprotein complexes. To properly probe F conformations, we identified anti-F monoclonal antibodies (MAbs) that recognize conformation-dependent epitopes. Through heat treatment as a surrogate for H-mediated F triggering, we demonstrate with these MAbs that the morbillivirus F trimer contains a sufficiently high inherent activation energy barrier to maintain the metastable prefusion state even in the absence of H. This notion was further validated by exploring the conformational states of destabilized F mutants and stabilized soluble F variants combined with the use of a membrane fusion inhibitor (3g). Taken together, our findings reveal that the morbillivirus H protein must lower the activation energy barrier of metastable prefusion F for fusion triggering. PMID:23077316

18. VIEW OF ESCAPE TRAINING TANK, SHOWING ENCLOSED PASSAGEWAY FROM ...

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

18. VIEW OF ESCAPE TRAINING TANK, SHOWING ENCLOSED PASSAGEWAY FROM 50-FOOT LOCK TO ELEVATOR, LOOKING WEST - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

21. VIEW OF ESCAPE TRAINING TANK, SHOWING INTERIOR OF CUPOLA ...

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

21. VIEW OF ESCAPE TRAINING TANK, SHOWING INTERIOR OF CUPOLA AND TOP OF THE TANK, LOOKING NORTHEAST - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

17. VIEW OF ESCAPE TRAINING TANK, SHOWING ENCLOSED PASSAGEWAY FROM ...

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

17. VIEW OF ESCAPE TRAINING TANK, SHOWING ENCLOSED PASSAGEWAY FROM ELEVATOR TO 18-FOOT LOCK, LOOKING EAST - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

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

NASA Astrophysics Data System (ADS)

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.

Diversity of the Lyman continuum escape fractions of high-z galaxies and its origins

NASA Astrophysics Data System (ADS)

Sumida, Takumi; Kashino, Daichi; Hasegawa, Kenji

2018-04-01

The Lyman continuum (LyC) escape fraction is a key quantity to determine the contribution of galaxies to cosmic reionization. It has been known that the escape fractions estimated by observations and numerical simulations show a large diversity. However, the origins of the diversity are still uncertain. In this work, to understand what quantities of galaxies are responsible for controlling the escape fraction, we numerically evaluate the escape fraction by performing ray-tracing calculation with simplified disc galaxy models. With a smooth disc model, we explore the dependence of the escape fraction on the disposition of ionizing sources and find that the escape fraction varies up to ˜3 orders of magnitude. It is also found that the halo mass dependence of disc scale height determines whether the escape fraction increases or decreases with halo mass. With a clumpy disc model, it turns out that the escape fraction increases as the clump mass fraction increases because the density in the inter-clump region decreases. In addition, we find that clumpiness regulates the escape fraction via two ways when the total clump mass dominates the total gas mass; the escape fraction is controlled by the covering factor of clumps if the clumps are dense sufficient to block LyC photons, otherwise the clumpiness works to reduce the escape fraction by increasing the total number of recombination events in a galaxy.

Danger Comes from All Fronts: Predator-Dependent Escape Tactics of Túngara Frogs

PubMed Central

Bulbert, Matthew W.; Page, Rachel A.; Bernal, Ximena E.

2015-01-01

The escape response of an organism is generally its last line of defense against a predator. Because the effectiveness of an escape varies with the approach behaviour of the predator, it should be advantageous for prey to alter their escape trajectories depending on the mode of predator attack. To test this hypothesis we examined the escape responses of a single prey species, the ground-dwelling túngara frog (Engystomops pustulosus), to disparate predators approaching from different spatial planes: a terrestrial predator (snake) and an aerial predator (bat). Túngara frogs showed consistently distinct escape responses when attacked by terrestrial versus aerial predators. The frogs fled away from the snake models (Median: 131°). In stark contrast, the frogs moved toward the bat models (Median: 27°); effectively undercutting the bat’s flight path. Our results reveal that prey escape trajectories reflect the specificity of their predators’ attacks. This study emphasizes the flexibility of strategies performed by prey to outcompete predators with diverse modes of attack. PMID:25874798

Triton: topside ionosphere and nitrogen escape.

PubMed

Yung, Y L; Lyons, J R

1990-09-01

The principal ion in the ionosphere of Triton is N+. Energetic electrons of magnetospheric origin are the primary source of ionization, with a smaller contribution due to photoionization. To explain the topside plasma scale height, we postulate that N+ ions escape from Triton. The loss rate is 3.4 x 10(7) cm-2 s-1 or 7.9 x 10(24) ions s-1. Dissociative recombination of N2+ produces neutral exothermic fragments that can escape from Triton. The rate is estimated to be 8.6 x 10(6) N cm-2 s-1 or 2.0 x 10(24) atoms s-1. Implications for the magnetosphere of Neptune and Triton's evolution are discussed.

Escape manoeuvres in the spiny dogfish (Squalus acanthias).

PubMed

Domenici, Paolo; Standen, Emily M; Levine, Robert P

2004-06-01

The locomotor performance of dogfish during escape responses was observed by means of high-speed video. Dogfish show C-type escape responses that are comparable with those shown previously in teleosts. Dogfish show high variability of turning rates of the anterior part of the body (head to centre of mass), i.e. with peak values from 434 to 1023 deg. s(-1). We suggest that this variability may be due to the presence of two types of escape manoeuvres, i.e. responses with high and low turning rates, as previously found in a teleost species. Fast responses (i.e. with high maximum turning rates, ranging between 766 and 1023 deg. s(-1)) showed significantly higher locomotor performance than slow responses (i.e. with low maximum turning rates, ranging between 434 and 593 deg. s(-1)) in terms of distance covered, speed and acceleration, although no differences were found in the turning radius of the centre of mass during the escape manoeuvres. The existence of two types of escape responses would have implications in terms of both neural control and muscular activation patterns. When compared with literature data for the locomotor performance of bony fishes, dogfish showed relatively low speed and acceleration, comparable turning rates and a turning radius that is in the low part of the range when compared with teleosts, indicating relatively high manoeuvrability. The locomotor performance observed in dogfish is consistent with their morphological characteristics: (1) low locomotor performance associated with low thrust developed by their relatively small posterior depth of section and (2) relatively high manoeuvrability associated with their high flexibility.

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

PubMed Central

Chung, Yuan-Kai

2017-01-01

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. PMID:28355235

Elevated atmospheric escape of atomic hydrogen from Mars induced by high-altitude water

NASA Astrophysics Data System (ADS)

Chaffin, M. S.; Deighan, J.; Schneider, N. M.; Stewart, A. I. F.

2017-01-01

Atmospheric loss has controlled the history of Martian habitability, removing most of the planet’s initial water through atomic hydrogen and oxygen escape from the upper atmosphere to space. In standard models, H and O escape in a stoichiometric 2:1 ratio because H reaches the upper atmosphere via long-lived molecular hydrogen, whose abundance is regulated by a photochemical feedback sensitive to atmospheric oxygen content. The relatively constant escape rates these models predict are inconsistent with known H escape variations of more than an order of magnitude on seasonal timescales, variation that requires escaping H to have a source other than H2. The best candidate source is high-altitude water, detected by the Mars Express spacecraft in seasonally variable concentrations. Here we use a one-dimensional time-dependent photochemical model to show that the introduction of high-altitude water can produce a large increase in the H escape rate on a timescale of weeks, quantitatively linking these observations. This H escape pathway produces prompt H loss that is not immediately balanced by O escape, influencing the oxidation state of the atmosphere for millions of years. Martian atmospheric water loss may be dominated by escape via this pathway, which may therefore potentially control the planet’s atmospheric chemistry. Our findings highlight the influence that seasonal atmospheric variability can have on planetary evolution.

Biomechanics of Tetrahymena escaping from a dead end

PubMed Central

Kikuchi, Kenji

2018-01-01

Understanding the behaviours of swimming microorganisms in various environments is important for understanding cell distribution and growth in nature and industry. However, cell behaviour in complex geometries is largely unknown. In this study, we used Tetrahymena thermophila as a model microorganism and experimentally investigated cell behaviour between two flat plates with a small angle. In this configuration, the geometry provided a ‘dead end' line where the two flat plates made contact. The results showed that cells tended to escape from the dead end line more by hydrodynamics than by a biological reaction. In the case of hydrodynamic escape, the cell trajectories were symmetric as they swam to and from the dead end line. Near the dead end line, T. thermophila cells were compressed between the two flat plates while cilia kept beating with reduced frequency; those cells again showed symmetric trajectories, although the swimming velocity decreased. These behaviours were well reproduced by our computational model based on biomechanics. The mechanism of hydrodynamic escape can be understood in terms of the torque balance induced by lubrication flow. We therefore conclude that a cell's escape from the dead end was assisted by hydrodynamics. These findings pave the way for understanding cell behaviour and distribution in complex geometries. PMID:29491169

23. VIEW OF ESCAPE TRAINING TANK, LOOKING NORTHWEST, SHOWING TWOLOCK ...

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

23. VIEW OF ESCAPE TRAINING TANK, LOOKING NORTHWEST, SHOWING TWO-LOCK RECOMPRESSION CHAMBER IN PASSAGEWAY FROM ELEVATOR TO CUPOLA - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

15. VIEW OF ESCAPE TRAINING TANK, LOOKING EAST ACROSS MEZZANINE, ...

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

15. VIEW OF ESCAPE TRAINING TANK, LOOKING EAST ACROSS MEZZANINE, SHOWING ENTRANCE TO SUBMARINE SECTION AT 110-FOOT LEVEL - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

Behavioral regulation of gravity - Schedule effects under escape-avoidance procedures

NASA Technical Reports Server (NTRS)

Clark, F. C.; Lange, K. O.; Belleville, R. E.

1973-01-01

Squirrel monkeys were restrained in a centrifuge capsule and trained to escape and avoid increases in artificial gravity. During escape-avoidance, lever responses reduced centrifugally simulated gravity or postponed scheduled increases. The effect of variation in the interval of postponement (equal to the duration of decrease produced by escape responses) was studied under a multiple schedule of four components. Three components were gravity escape-avoidance with postponement times of 20, 40, and 60 sec. The fourth component was extinction. Each component was associated with a different auditory stimulus. Rate of responding decreased with increasing postponement time and higher mean g-levels occurred at shorter intervals of postponement. Effects of the schedule parameter on response rate and mean g-level were similar to effects of the schedule on free-operant avoidance and on titration behavior maintained by shock.

Escape Performance Following Exposure to Inescapable Shock: Deficits in Motor Response Maintenance

ERIC Educational Resources Information Center

Anisman, Hymie; And Others

1978-01-01

A series of 13 experiments employing mice systematically investigated shock-elicited activity in a circular field and escape performance in a shuttle box following exposure to either escapable or inescapable shock. Results show that escape interference induced by inescapable shock may be comfortably interpreted in terms of a decreased tendency for…

STUMP un"stumped": anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion.

PubMed

Subbiah, Vivek; McMahon, Caitlin; Patel, Shreyaskumar; Zinner, Ralph; Silva, Elvio G; Elvin, Julia A; Subbiah, Ishwaria M; Ohaji, Chimela; Ganeshan, Dhakshina Moorthy; Anand, Deepa; Levenback, Charles F; Berry, Jenny; Brennan, Tim; Chmielecki, Juliann; Chalmers, Zachary R; Mayfield, John; Miller, Vincent A; Stephens, Philip J; Ross, Jeffrey S; Ali, Siraj M

2015-06-11

Recurrent, metastatic mesenchymal myxoid tumors of the gynecologic tract present a management challenge as there is minimal evidence to guide systemic therapy. Such tumors also present a diagnostic dilemma, as myxoid features are observed in leiomyosarcomas, inflammatory myofibroblastic tumors (IMT), and mesenchymal myxoid tumors. Comprehensive genomic profiling was performed in the course of clinical care on a case of a recurrent, metastatic myxoid uterine malignancy (initially diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP)), to guide identify targeted therapeutic options. To our knowledge, this case represents the first report of clinical response to targeted therapy in a tumor harboring a DCTN1-ALK fusion protein. Hybridization capture of 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from this sample and sequenced to high, uniform coverage. Therapy was given in the context of a phase I clinical trial ClinicalTrials.gov Identifier: ( NCT01548144 ). Immunostains showed diffuse positivity for ALK1 expression and comprehensive genomic profiling identified an in frame DCTN1-ALK gene fusion. The diagnosis of STUMP was revised to that of an IMT with myxoid features. The patient was enrolled in a clinical trial and treated with an anaplastic lymphoma kinase (ALK) inhibitor (crizotinib/Xalkori®) and a multikinase VEGF inhibitor (pazopanib/Votrient®). The patient experienced an ongoing partial response (6+ months) by response evaluation criteria in solid tumors (RECIST) 1.1 criteria. For myxoid tumors of the gynecologic tract, comprehensive genomic profiling can identify clinical relevant genomic alterations that both direct treatment targeted therapy and help discriminate between similar diagnostic entities.

An anticipative escape system for vehicles in water crashes

NASA Astrophysics Data System (ADS)

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.

22. VIEW OF ESCAPE TRAINING TANK, LOOKING WEST FROM EAST ...

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

22. VIEW OF ESCAPE TRAINING TANK, LOOKING WEST FROM EAST SIDE OF CUPOLA TOWARD ELEVATOR. TWO-LOCK RECOMPRESSION CHAMBER AT REAR - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

Animal escapology II: escape trajectory case studies

PubMed Central

Domenici, Paolo; Blagburn, Jonathan M.; Bacon, Jonathan P.

2011-01-01

Summary Escape trajectories (ETs; measured as the angle relative to the direction of the threat) have been studied in many taxa using a variety of methodologies and definitions. Here, we provide a review of methodological issues followed by a survey of ET studies across animal taxa, including insects, crustaceans, molluscs, lizards, fish, amphibians, birds and mammals. Variability in ETs is examined in terms of ecological significance and morpho-physiological constraints. The survey shows that certain escape strategies (single ETs and highly variable ETs within a limited angular sector) are found in most taxa reviewed here, suggesting that at least some of these ET distributions are the result of convergent evolution. High variability in ETs is found to be associated with multiple preferred trajectories in species from all taxa, and is suggested to provide unpredictability in the escape response. Random ETs are relatively rare and may be related to constraints in the manoeuvrability of the prey. Similarly, reports of the effect of refuges in the immediate environment are relatively uncommon, and mainly confined to lizards and mammals. This may be related to the fact that work on ETs carried out in laboratory settings has rarely provided shelters. Although there are a relatively large number of examples in the literature that suggest trends in the distribution of ETs, our understanding of animal escape strategies would benefit from a standardization of the analytical approach in the study of ETs, using circular statistics and related tests, in addition to the generation of large data sets. PMID:21753040

How does ionizing radiation escape from galaxies?

NASA Astrophysics Data System (ADS)

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.

How to Escape a Home Fire (Take This Safety Quiz).

ERIC Educational Resources Information Center

PTA Today, 1994

1994-01-01

A checklist/safety quiz from the National Fire Protection Association examines individual knowledge of how to escape if a home fire breaks out. The organization recommends that every household develop a fire escape plan and practice it at least twice a year. (SM)

29. VIEW OF SUBMARINE ESCAPE TRAINING TANK DURING CONSTRUCTION AT ...

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

29. VIEW OF SUBMARINE ESCAPE TRAINING TANK DURING CONSTRUCTION AT POINT JUST ABOVE THE SUBMARINE SECTION AT THE 110-FOOT LEVEL 1929-1930 - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

35. INTERIOR VIEW OF EQUIPMENT HOUSE, SUBMARINE ESCAPE TRAINING TANK, ...

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

35. INTERIOR VIEW OF EQUIPMENT HOUSE, SUBMARINE ESCAPE TRAINING TANK, PRIOR TO ENLARGEMENT OF ROOM AND INSTALLATION OF TRIPLE-LOCK RECOMPRESSION CHAMBER IN 1957 - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

31. VIEW OF SUBMARINE ESCAPE TRAINING TANK DURING CONSTRUCTION OF ...

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

31. VIEW OF SUBMARINE ESCAPE TRAINING TANK DURING CONSTRUCTION OF THE ELEVATOR AND PASSAGEWAYS TO THE 18- AND 50-FOOT LOCKS AND CUPOLA 1932 - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

Perceived risk of home fire and escape plans in rural households.

PubMed

Yang, Jingzhen; Peek-Asa, Corinne; Allareddy, Veerasathpurush; Zwerling, Craig; Lundell, John

2006-01-01

Homes in rural areas have a higher fire death rate. Although successful exit from a home fire could greatly reduce fire-related deaths and injuries, little is known about factors associated with behaviors of developing and practicing an escape plan. Between July 2003 and June 2004, a baseline survey was administered, in person, to 691 rural households. Information collected included a history of previous home fire, perceived risk of home fire, existing smoke alarms and their working status, and home fire safety practices, as well as home and occupant characteristics. The association of residents' perceived risk of home fire and fire escape plans was assessed. Forty-two percent of rural households reported having a fire escape plan. Of the households with a plan, less than two thirds (56.9%) discussed or practiced the plan. Households with children were more likely to develop and practice a fire escape plan. Households with an elderly or disabled person were less likely to develop or practice the plan. Compared to respondents who perceived low or very low risk of home fire, those who perceived a high or very high risk had 3.5 times greater odds of having a fire escape plan and 5.5 times greater odds of discussion or practicing their plan. Increasing awareness of the potential risk of home fires may help occupants develop and practice home fire escape plans. In order to reduce fire deaths and injuries, different strategies need to be developed for those households in which the occupants lack the ability to escape.

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

PubMed Central

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

Venus, Earth, Mars: Comparative ion escape caused by the interaction with the solar wind

NASA Astrophysics Data System (ADS)

Barabash, Stas

For the solar system planets the non-thermal atmospheric escape exceeds by far the Jean escape for particles heavier than helium. In this talk we consider only ion escape and compare the total ion escape rates for Venus, Earth, and Mars caused by the interaction with the solar wind. We review the most recent data on the escape rates based on measurements from Mars Express, Venus Express, and Cluster. The comparison of the available numbers show that despite large differences in the atmospheric masses between these three planets (a factor of 100 -200), different types of the interactions with the solar wind (magnetized and non-magnetized obstacles), the escape rates for Mars, Venus, and the Earth are within the range 1024 - 1025 s-1 . Surprisingly, the expected shielding of the Earth atmosphere by the intrinsic magnetic field is not as efficient as one may think. The reason for this is the non-thermal escape caused by the solar wind interaction is a energy -limited process. Indeed, normalizing the escape rates to the planet-dependent escape energy and power available in the solar wind results in the normalized escape rates deferring only on a factor between three planets. The larger Earth's magnetosphere intercepts and tunnels down to the ionosphere more energy from the solar wind than more compact interaction regions of non-magnetized planets.

Why an intrinsic magnetic field does not protect a planet against atmospheric escape

NASA Astrophysics Data System (ADS)

Gunell, Herbert; Maggiolo, Romain; Nilsson, Hans; Stenberg Wieser, Gabriella; Slapak, Rikard; Lindkvist, Jesper; Hamrin, Maria; De Keyser, Johan

2018-06-01

The presence or absence of a magnetic field determines the nature of how a planet interacts with the solar wind and what paths are available for atmospheric escape. Magnetospheres form both around magnetised planets, such as Earth, and unmagnetised planets, like Mars and Venus, but it has been suggested that magnetised planets are better protected against atmospheric loss. However, the observed mass escape rates from these three planets are similar (in the approximate (0.5-2) kg s-1 range), putting this latter hypothesis into question. Modelling the effects of a planetary magnetic field on the major atmospheric escape processes, we show that the escape rate can be higher for magnetised planets over a wide range of magnetisations due to escape of ions through the polar caps and cusps. Therefore, contrary to what has previously been believed, magnetisation is not a sufficient condition for protecting a planet from atmospheric loss. Estimates of the atmospheric escape rates from exoplanets must therefore address all escape processes and their dependence on the planet's magnetisation.

Fusion mutants of Newcastle disease virus selected with monoclonal antibodies to the hemagglutinin-neuraminidase.

PubMed Central

Iorio, R M; Glickman, R L

1992-01-01

The Australia-Victoria (AV) isolate of Newcastle disease virus (NDV) induces fusion from within but not fusion from without. L1, a neuraminidase (NA)-deficient virus derived from AV, has the opposite fusion phenotype from the wild-type virus. It fails to induce the former mode of fusion, but has gained a limited ability to promote the latter. Monoclonal antibodies to antigenic site 23 on the hemagglutinin-neuraminidase (HN) glycoprotein have previously been shown to select variants of the AV isolate that have altered NA activity or receptor-binding affinity. By using an antibody to this site, variants of L1 have been selected. Three of the variants have gained an increased affinity for sialic acid-containing receptors, as evidenced by the resistance of their hemagglutinating activity to the presence of reduced amounts of sialic acid on the surface of chicken erythrocytes. All four variants still have very low levels of NA activity, comparable to that of the parent virus, L1. The alteration in receptor-binding affinity results in a decreased potential for elution from cellular receptors and correlates with an increased ability to promote both modes of fusion. A single amino acid substitution in the HN protein of each variant, responsible for its escape from neutralization, has been identified. These studies identify two HN residues, 193 and 203, at which monoclonal antibody-selected substitution influences the receptor recognition properties of NDV and may influence its ability to promote syncytium formation. Images PMID:1404607

Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK

PubMed Central

Katayama, Ryohei; Khan, Tahsin M.; Benes, Cyril; Lifshits, Eugene; Ebi, Hiromichi; Rivera, Victor M.; Shakespeare, William C.; Iafrate, A. John; Engelman, Jeffrey A.; Shaw, Alice T.

2011-01-01

The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion oncogene represents a molecular target in a small subset of non-small cell lung cancers (NSCLCs). This fusion leads to constitutive ALK activation with potent transforming activity. In a pivotal phase 1 clinical trial, the ALK tyrosine kinase inhibitor (TKI) crizotinib (PF-02341066) demonstrated impressive antitumor activity in the majority of patients with NSCLC harboring ALK fusions. However, despite these remarkable initial responses, cancers eventually develop resistance to crizotinib, usually within 1 y, thereby limiting the potential clinical benefit. To determine how cancers acquire resistance to ALK inhibitors, we established a model of acquired resistance to crizotinib by exposing a highly sensitive EML4-ALK–positive NSCLC cell line to increasing doses of crizotinib until resistance emerged. We found that cells resistant to intermediate doses of crizotinib developed amplification of the EML4-ALK gene. Cells resistant to higher doses (1 μM) also developed a gatekeeper mutation, L1196M, within the kinase domain, rendering EML4-ALK insensitive to crizotinib. This gatekeeper mutation was readily detected using a unique and highly sensitive allele-specific PCR assay. Although crizotinib was ineffectual against EML4-ALK harboring the gatekeeper mutation, we observed that two structurally different ALK inhibitors, NVP-TAE684 and AP26113, were highly active against the resistant cancer cells in vitro and in vivo. Furthermore, these resistant cells remained highly sensitive to the Hsp90 inhibitor 17-AAG. Thus, we have developed a model of acquired resistance to ALK inhibitors and have shown that second-generation ALK TKIs or Hsp90 inhibitors are effective in treating crizotinib-resistant tumors harboring secondary gatekeeper mutations. PMID:21502504

Effects of Visual Information on Wind-Evoked Escape Behavior of the Cricket, Gryllus bimaculatus.

PubMed

Kanou, Masamichi; Matsuyama, Akane; Takuwa, Hiroyuki

2014-09-01

We investigated the effects of visual information on wind-evoked escape behavior in the cricket, Gryllus bimaculatus. Most agitated crickets were found to retreat into a shelter made of cardboard installed in the test arena within a short time. As this behavior was thought to be a type of escape, we confirmed how a visual image of a shelter affected wind-evoked escape behavior. Irrespective of the brightness of the visual background (black or white) or the absence or presence of a shelter, escape jumps were oriented almost 180° opposite to the source of the air puff stimulus. Therefore, the direction of wind-evoked escape depends solely depended on the direction of the stimulus air puff. In contrast, the turning direction of the crickets during the escape was affected by the position of the visual image of the shelter. During the wind-evoked escape jump, most crickets turned in the direction in which a shelter was presented. This behavioral nature is presumably necessary for crickets to retreat into a shelter within a short time after their escape jump.

A conserved role for calpains during myoblast fusion.

PubMed

Buffolo, Marcio; Batista Possidonio, Ana Claudia; Mermelstein, Claudia; Araujo, Helena

2015-07-01

Myoblast fusion is a key step during skeletal muscle differentiation as it enables the formation of contractile fibers. Calpains have been implicated in some aspects of myogenesis in mammals, but whether they exert a conserved function during myoblast fusion has not been investigated. Here, we studied Calpain function in two models of myogenesis: in vitro analysis of chick myogenic cultures and in vivo analysis of Drosophila melanogaster muscle development. First we showed that Calpain A is important for fly muscle function. In addition, Calpain A knockdown reduced lateral body wall muscle length and width, as well as the number of nuclei in dorsal oblique muscles, consistent with fewer cells fusing to form fibers. Treatment of chick cultures with a selective Calpain inhibitor led to the formation of thinner myotubes containing a reduced number of nuclei, consistent with decreased myoblast fusion. Dynamic changes in IκBα labeling and transfection with a dominant-negative IκBα suggest a role for the NFκB pathway during chick myogenesis and a possible role of Calpains in attenuating NFκB signals that restrict myoblast fusion. Our data suggest that different model organisms may be used to study the role of Calpains in regular myogenesis and Calpain-related muscular degenerative disorders. © 2015 Wiley Periodicals, Inc.

Tropism-independent protection of macaques against vaginal transmission of three SHIVs by the HIV-1 fusion inhibitor T-1249.

PubMed

Veazey, Ronald S; Ketas, Thomas A; Klasse, Per Johan; Davison, Donna K; Singletary, Morgan; Green, Linda C; Greenberg, Michael L; Moore, John P

2008-07-29

We have assessed the potential of the fusion inhibitory peptide T-1249 for development as a vaginal microbicide to prevent HIV-1 sexual transmission. When formulated as a simple gel, T-1249 provided dose-dependent protection to macaques against high-dose challenge with three different SHIVs that used either CCR5 or CXCR4 for infection (the R5 virus SHIV-162P3, the X4 virus SHIV-KU1 and the R5X4 virus SHIV-89.6P), and it also protected against SIVmac251 (R5). Protection of half of the test animals was estimated by interpolation to occur at T-1249 concentrations of approximately 40-130 muM, whereas complete protection was observed at 0.1-2 mM. In vitro, T-1249 had substantial breadth of activity against HIV-1 strains from multiple genetic subtypes and in a coreceptor-independent manner. Thus, at 1 muM in a peripheral blood mononuclear cell-based replication assay, T-1249 inhibited all 29 R5 viruses, all 12 X4 viruses and all 7 R5X4 viruses in the test panel, irrespective of their genetic subtype. Combining lower concentrations of T-1249 with other entry inhibitors (CMPD-167, BMS-C, or AMD3465) increased the proportion of test viruses that could be blocked. In the PhenoSense assay, T-1249 was active against 636 different HIV-1 Env-pseudotyped viruses of varying tropism and derived from clinical samples, with IC(50) values typically clustered in a 10-fold range approximately 10 nM. Overall, these results support the concept of using T-1249 as a component of an entry inhibitor-based combination microbicide to prevent the sexual transmission of diverse HIV-1 variants.

7. VIEW OF ESCAPE TRAINING TANK, LOOKING UP SOUTH SIDE ...

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

7. VIEW OF ESCAPE TRAINING TANK, LOOKING UP SOUTH SIDE FROM 50-FOOT PASSAGEWAY, SHOWING 25-FOOT BLISTER AT LEFT, 18-FOOT PASSAGEWAY AND PLATFORM AT RIGHT - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

Xenon Fractionation and Archean Hydrogen Escape

NASA Technical Reports Server (NTRS)

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.

Lipid raft-like liposomes used for targeted delivery of a chimeric entry-inhibitor peptide with anti-HIV-1 activity.

PubMed

Gómara, María José; Pérez-Pomeda, Ignacio; Gatell, José María; Sánchez-Merino, Victor; Yuste, Eloisa; Haro, Isabel

2017-02-01

The work reports the design and synthesis of a chimeric peptide that is composed of the peptide sequences of two entry inhibitors which target different sites of HIV-1 gp41. The chimeric peptide offers the advantage of targeting two gp41 regions simultaneously: the fusion peptide and the loop both of which are membrane active and participate in the membrane fusion process. We therefore use lipid raft-like liposomes as a tool to specifically direct the chimeric inhibitor peptide to the membrane domains where the HIV-1 envelope protein is located. Moreover, the liposomes that mimic the viral membrane composition protect the chimeric peptide against proteolytic digestion thereby increasing the stability of the peptide. The described liposome preparations are suitable nanosystems for managing hydrophobic entry-inhibitor peptides as putative therapeutics. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of the crustal magnetic fields on the Martian atmospheric ion escape rate

NASA Astrophysics Data System (ADS)

Ramstad, Robin; Barabash, Stas; Futaana, Yoshifumi; Nilsson, Hans; Holmström, Mats

2016-10-01

Eight years (2007-2015) of ion flux measurements from Mars Express are used to statistically investigate the influence of the Martian magnetic crustal fields on the atmospheric ion escape rate. We combine all Analyzer of Space Plasmas and Energetic Atoms/Ion Mass Analyzer (ASPERA-3/IMA) measurements taken during nominal upstream solar wind and solar extreme ultraviolet conditions to compute global average ion distribution functions, individually for the north/south hemispheres and for varying solar zenith angles (SZAs) of the strongest crustal magnetic field. Escape rates are subsequently calculated from each of the average distribution functions. The maximum escape rate (4.2 ± 1.2) × 1024s-1 is found for SZA = 60°-80°, while the minimum escape rate (1.7 ± 0.6) × 1024s-1 is found for SZA = 28°-60°, showing that the dayside orientation of the crustal fields significantly affects the global escape rate (p = 97%). However, averaged over time, independent of SZA, we find no statistically significant difference in the escape rates from the two hemispheres (escape from southern hemisphere 46% ± 18% of global rate).

Escaping and Falling into Poverty in India Today.

PubMed

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.

Escaping and Falling into Poverty in India Today

PubMed Central

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

2017-01-01

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. PMID:28966435

Dynamin Regulates Specific Membrane Fusion Events Necessary for Acrosomal Exocytosis in Mouse Spermatozoa

PubMed Central

Reid, Andrew T.; Lord, Tessa; Stanger, Simone J.; Roman, Shaun D.; McCluskey, Adam; Robinson, Phillip J.; Aitken, R. John; Nixon, Brett

2012-01-01

Mammalian spermatozoa must complete an acrosome reaction prior to fertilizing an oocyte. The acrosome reaction is a unique exocytotic event involving a series of prolonged membrane fusions that ultimately result in the production of membrane vesicles and release of the acrosomal contents. This event requires the concerted action of a large number of fusion-competent signaling and scaffolding proteins. Here we show that two different members of the dynamin GTPase family localize to the developing acrosome of maturing mouse germ cells. Both dynamin 1 and 2 also remain within the periacrosomal region of mature mouse spermatozoa and are thus well positioned to regulate the acrosome reaction. Two pharmacological inhibitors of dynamin, dynasore and Dyngo-4a, blocked the in vitro induction of acrosomal exocytosis by progesterone, but not by the calcium ionophore A23187, and elicited a concomitant reduction of in vitro fertilization. In vivo treatment with these inhibitors also resulted in spermatozoa displaying reduced acrosome reaction potential. Dynamin 1 and 2 phosphorylation increased on progesterone treatment, and this was also selectively blocked by dynasore. On the basis of our collective data, we propose that dynamin could regulate specific membrane fusion events necessary for acrosomal exocytosis in mouse spermatozoa. PMID:22977254

The influence of Mars' magnetic topology on atmospheric escape

NASA Astrophysics Data System (ADS)

Curry, S.; Luhmann, J. G.; DiBraccio, G. A.; Dong, C.; Xu, S.; Mitchell, D.; Gruesbeck, J.; Espley, J. R.; Connerney, J. E. P.; McFadden, J. P.; Ma, Y. J.; Brain, D.

2017-12-01

At weakly magnetized planets such as Mars and Venus, the solar wind directly interacts with the upper atmosphere where ions can be picked up and swept away by the background convection electric field. These pick-up ions have a gyroradius on the planetary scale that is largely dominated by the interplanetary magnetic field (IMF). But at Mars, their trajectory is also influenced by the existence of remanent crustal magnetic fields, which are thought to create a shielding effect for escaping planetary ions when they are on the dayside. Consequently, the magnetic topology changes at Mars as magnetic reconnection occurs between the draped (IMF) and the crustal magnetic fields (closed). The resulting topology includes open field lines in the solar wind with one footprint attached to the planet. Using magnetohydrodynamic (MHD) and test particle simulations, we will explore the influence of the magnetic topology on ion escape. We will present escape rates for planetary ions for different crustal field positions during different IMF configurations, with +/-BY and +/-BZ components in the Mars Sun Orbit (MSO) coordinate system. We will also compare global maps of ion outflow and escape with open / closed magnetic field line maps and compare our results with ion fluxes and magnetic field data from the Mars Atmospheric and Volatile EvolutioN (MAVEN) mission. Our results relating the dynamic magnetic field topology at Mars and planetary ion escape are an important aspect of magnetospheric physics and planetary evolution, both of which have applications to our own solar system and the increasing number of exoplanets discovered every year.

Entry inhibitors in the treatment of HIV-1 infection.

PubMed

Tilton, John C; Doms, Robert W

2010-01-01

Infection of target cells by HIV is a complex, multi-stage process involving attachment to host cells and CD4 binding, coreceptor binding, and membrane fusion. Drugs that block HIV entry are collectively known as entry inhibitors, but comprise a complex group of drugs with multiple mechanisms of action depending on the stage of the entry process at which they act. Two entry inhibitors, maraviroc and enfuvirtide, have been approved for the treatment of HIV-1 infection, and a number of agents are in development. This review covers the entry inhibitors and their use in the management of HIV-1 infection. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010. Copyright 2009 Elsevier B.V. All rights reserved.

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

NASA Astrophysics Data System (ADS)

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.

In Vivo Efficacy of Measles Virus Fusion Protein-Derived Peptides Is Modulated by the Properties of Self-Assembly and Membrane Residence

PubMed Central

Figueira, T. N.; Palermo, L. M.; Veiga, A. S.; Huey, D.; Alabi, C. A.; Santos, N. C.; Welsch, J. C.; Mathieu, C.; Niewiesk, S.; Moscona, A.

2016-01-01

ABSTRACT Measles virus (MV) infection is undergoing resurgence and remains one of the leading causes of death among young children worldwide despite the availability of an effective measles vaccine. MV infects its target cells by coordinated action of the MV hemagglutinin (H) and fusion (F) envelope glycoproteins; upon receptor engagement by H, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. By interfering with this structural transition of F, peptides derived from the heptad repeat (HR) regions of F can inhibit MV infection at the entry stage. In previous work, we have generated potent MV fusion inhibitors by dimerizing the F-derived peptides and conjugating them to cholesterol. We have shown that prophylactic intranasal administration of our lead fusion inhibitor efficiently protects from MV infection in vivo. We show here that peptides tagged with lipophilic moieties self-assemble into nanoparticles until they reach the target cells, where they are integrated into cell membranes. The self-assembly feature enhances biodistribution and the half-life of the peptides, while integration into the target cell membrane increases fusion inhibitor potency. These factors together modulate in vivo efficacy. The results suggest a new framework for developing effective fusion inhibitory peptides. IMPORTANCE Measles virus (MV) infection causes an acute illness that may be associated with infection of the central nervous system (CNS) and severe neurological disease. No specific treatment is available. We have shown that fusion-inhibitory peptides delivered intranasally provide effective prophylaxis against MV infection. We show here that specific biophysical properties regulate the in vivo efficacy of MV F-derived peptides. PMID:27733647

In Vivo Efficacy of Measles Virus Fusion Protein-Derived Peptides Is Modulated by the Properties of Self-Assembly and Membrane Residence.

PubMed

Figueira, T N; Palermo, L M; Veiga, A S; Huey, D; Alabi, C A; Santos, N C; Welsch, J C; Mathieu, C; Horvat, B; Niewiesk, S; Moscona, A; Castanho, M A R B; Porotto, M

2017-01-01

Measles virus (MV) infection is undergoing resurgence and remains one of the leading causes of death among young children worldwide despite the availability of an effective measles vaccine. MV infects its target cells by coordinated action of the MV hemagglutinin (H) and fusion (F) envelope glycoproteins; upon receptor engagement by H, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. By interfering with this structural transition of F, peptides derived from the heptad repeat (HR) regions of F can inhibit MV infection at the entry stage. In previous work, we have generated potent MV fusion inhibitors by dimerizing the F-derived peptides and conjugating them to cholesterol. We have shown that prophylactic intranasal administration of our lead fusion inhibitor efficiently protects from MV infection in vivo We show here that peptides tagged with lipophilic moieties self-assemble into nanoparticles until they reach the target cells, where they are integrated into cell membranes. The self-assembly feature enhances biodistribution and the half-life of the peptides, while integration into the target cell membrane increases fusion inhibitor potency. These factors together modulate in vivo efficacy. The results suggest a new framework for developing effective fusion inhibitory peptides. Measles virus (MV) infection causes an acute illness that may be associated with infection of the central nervous system (CNS) and severe neurological disease. No specific treatment is available. We have shown that fusion-inhibitory peptides delivered intranasally provide effective prophylaxis against MV infection. We show here that specific biophysical properties regulate the in vivo efficacy of MV F-derived peptides. Copyright © 2016 American Society for Microbiology.

20. DETAIL VIEW IN 18FOOT LOCK, ESCAPE TRAINING TANK, SHOWING ...

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

20. DETAIL VIEW IN 18-FOOT LOCK, ESCAPE TRAINING TANK, SHOWING DOOR INTO TANK AT RIGHT - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

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

PubMed

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.

Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells.

PubMed

Korkut, Anil; Wang, Weiqing; Demir, Emek; Aksoy, Bülent Arman; Jing, Xiaohong; Molinelli, Evan J; Babur, Özgün; Bemis, Debra L; Onur Sumer, Selcuk; Solit, David B; Pratilas, Christine A; Sander, Chris

2015-08-18

Resistance to targeted cancer therapies is an important clinical problem. The discovery of anti-resistance drug combinations is challenging as resistance can arise by diverse escape mechanisms. To address this challenge, we improved and applied the experimental-computational perturbation biology method. Using statistical inference, we build network models from high-throughput measurements of molecular and phenotypic responses to combinatorial targeted perturbations. The models are computationally executed to predict the effects of thousands of untested perturbations. In RAF-inhibitor resistant melanoma cells, we measured 143 proteomic/phenotypic entities under 89 perturbation conditions and predicted c-Myc as an effective therapeutic co-target with BRAF or MEK. Experiments using the BET bromodomain inhibitor JQ1 affecting the level of c-Myc protein and protein kinase inhibitors targeting the ERK pathway confirmed the prediction. In conclusion, we propose an anti-cancer strategy of co-targeting a specific upstream alteration and a general downstream point of vulnerability to prevent or overcome resistance to targeted drugs.

Evidence that maturation of the N-linked glycans of the respiratory syncytial virus (RSV) glycoproteins is required for virus-mediated cell fusion: The effect of {alpha}-mannosidase inhibitors on RSV infectivity

DOE Office of Scientific and Technical Information (OSTI.GOV)

McDonald, Terence P.; Jeffree, Chris E.; Li, Ping

2006-07-05

Glycan heterogeneity of the respiratory syncytial virus (RSV) fusion (F) protein was demonstrated by proteomics. The effect of maturation of the virus glycoproteins-associated glycans on virus infectivity was therefore examined using the {alpha}-mannosidase inhibitors deoxymannojirimycin (DMJ) and swainsonine (SW). In the presence of SW the N-linked glycans on the F protein appeared in a partially mature form, whereas in the presence of DMJ no maturation of the glycans was observed. Neither inhibitor had a significant effect on G protein processing or on the formation of progeny virus. Although the level of infectious virus and syncytia formation was not significantly affectedmore » by SW-treatment, DMJ-treatment correlated with a one hundred-fold reduction in virus infectivity. Our data suggest that glycan maturation of the RSV glycoproteins, in particular those on the F protein, is an important step in virus maturation and is required for virus infectivity.« less

Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion.

PubMed

Mauthe, Mario; Orhon, Idil; Rocchi, Cecilia; Zhou, Xingdong; Luhr, Morten; Hijlkema, Kerst-Jan; Coppes, Robert P; Engedal, Nikolai; Mari, Muriel; Reggiori, Fulvio

2018-06-25

Macroautophagy/autophagy is a conserved transport pathway where targeted structures are sequestered by phagophores, which mature into autophagosomes, and then delivered into lysosomes for degradation. Autophagy is involved in the pathophysiology of numerous diseases and its modulation is beneficial for the outcome of numerous specific diseases. Several lysosomal inhibitors such as bafilomycin A 1 (BafA 1 ), protease inhibitors and chloroquine (CQ), have been used interchangeably to block autophagy in in vitro experiments assuming that they all primarily block lysosomal degradation. Among them, only CQ and its derivate hydroxychloroquine (HCQ) are FDA-approved drugs and are thus currently the principal compounds used in clinical trials aimed to treat tumors through autophagy inhibition. However, the precise mechanism of how CQ blocks autophagy remains to be firmly demonstrated. In this study, we focus on how CQ inhibits autophagy and directly compare its effects to those of BafA 1 . We show that CQ mainly inhibits autophagy by impairing autophagosome fusion with lysosomes rather than by affecting the acidity and/or degradative activity of this organelle. Furthermore, CQ induces an autophagy-independent severe disorganization of the Golgi and endo-lysosomal systems, which might contribute to the fusion impairment. Strikingly, HCQ-treated mice also show a Golgi disorganization in kidney and intestinal tissues. Altogether, our data reveal that CQ and HCQ are not bona fide surrogates for other types of late stage lysosomal inhibitors for in vivo experiments. Moreover, the multiple cellular alterations caused by CQ and HCQ call for caution when interpreting results obtained by blocking autophagy with this drug.

The role of nitric oxide in the PKA inhibitor induced spatial memory deficits in rat: involvement of choline acetyltransferase.

PubMed

Najafi, Sheyda; Payandemehr, Borna; Tabrizian, Kaveh; Shariatpanahi, Marjan; Nassireslami, Ehsan; Azami, Kian; Mohammadi, Mojdeh; Asadi, Farideh; Roghani, Ali; Sharifzadeh, Mohammad

2013-08-15

Several lines of evidence show that cAMP-PKA signaling pathway plays critical role in memory functions and suggest nitric oxide as an important modulator in learning and memory. In this study, we assessed the effects of intra-hippocampal infusion of H-89, a selective PKAII inhibitor, and 1400 W, a selective inducible nitric oxide synthase (iNOS) inhibitor, on spatial memory in rats. By using the Morris water maze, spatial memory retention parameters were examined 48 h after the infusions through measuring escape latency, traveled distance, and swimming speed. The rats receiving intra-hippocampal infusions of 1400 W (100 µM/side) showed a significant reduction (*P<0.05) in escape latency and traveled distance in comparison with the control saline group. In contrast, a significant increase (**P<0.01) in escape latency and traveled distance was observed after infusion of 10 µM H-89. Moreover, among combination groups, co-administration of 1400 W (400 µM/side) with 10 µM/side of H-89 caused a significant reduction (*P<0.05) in escape latency and traveled distance in comparison with the H-89 group. Also, we evaluated the molecular effects of 1400 W on the expression of choline acetyltransferase (ChAT), a cholinergic marker, in the CA1 region of the hippocampus and medial septal area (MSA). Immunohistochemical analysis of post-training bilateral intra-hippocampal infusion of 1400 W revealed a significant increase in ChAT immunoreactivity levels in both the CA1 and the MSA regions. Overall, the results suggest that 1400 W has protective effect against H89-induced spatial memory impairment. Moreover, the observed memory improvements caused by 1400 W infusions, might be due to interaction of iNOS with the cholinergic system. © 2013 Elsevier B.V. All rights reserved.

Wind Enhanced Escape, Ion Pickup and the Evolution of Water on Mars

NASA Technical Reports Server (NTRS)

Hartle, Richard

1999-01-01

Preferential loss of hydrogen over deuterium from Mars has produced a deuterium rich atmosphere possessing a D/B ratio 5.2 times that of terrestrial water. Rayleigh fractionation is applied, constrained by the deuterium enrichment factor, to determine the magnitudes of ancient and present water reservoirs on the planet. The dominant lose mechanisms of R and D from the current atmosphere are thought to be thermal escape and solar wind ion pickup of the neutral and ion forms of theme constituents, respectively. During an earlier martian epoch, only thermal escape was significant because Mars had a terrestrial sized magnetosphere that protected the atmosphere from solar wind scavenging processes. The magnitudes of present and ancient water reservoirs are estimated when thermal escape is considered alone and subsequently when the effects of ion pickup are added. The escape fluxes of R and D are significantly increased above the respective Jeans fluxes when the effects of thermospheric winds and planetary rotation are accounted for at the exobase. Such wind enhanced escape also increases as the mass of an escaping constituent increases; thus, the increase in the escape flux of D is greater than that of H. When the fractionation process is also constrained by the D/H ratio observed in hydrous minerals of SNC meteorites, an ancient crustal reservoir of Martian water in derived, tens of meters in global-equivalent depth, considerably exceeding that obtained with no winds. The reservoir becomes even larger when ion pickup processes are added.

Elucidation of Resistance Mechanisms to Second-Generation ALK Inhibitors Alectinib and Ceritinib in Non-Small Cell Lung Cancer Cells.

PubMed

Dong, Xuyuan; Fernandez-Salas, Ester; Li, Enxiao; Wang, Shaomeng

2016-03-01

Crizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non-small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro. Prolonged treatment of the parental H3122 cells with alectinib and ceritinib led to two cell lines which are 10 times less sensitive to alectinib and ceritinib than the parental H3122 cell line. Although mutations of ALK in its kinase domain are a common resistance mechanism for crizotinib, we did not detect any ALK mutation in these resistant cell lines. Rather, overexpression of phospho-ALK and alternative receptor tyrosine kinases such as phospho-EGFR, phospho-HER3, and phospho-IGFR-1R was observed in both resistant cell lines. Additionally, NRG1, a ligand for HER3, is upregulated and responsible for resistance by activating the EGFR family pathways through the NRG1-HER3-EGFR axis. Combination treatment with EGFR inhibitors, in particular afatinib, was shown to be effective at overcoming resistance. Our study provides new mechanistic insights into adaptive resistance to second-generation ALK inhibitors and suggests a potential clinical strategy to combat resistance to these second-generation ALK inhibitors in NSCLC. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Elucidation of Resistance Mechanisms to Second-Generation ALK Inhibitors Alectinib and Ceritinib in Non–Small Cell Lung Cancer Cells

PubMed Central

Dong, Xuyuan; Fernandez-Salas, Ester; Li, Enxiao; Wang, Shaomeng

2016-01-01

Crizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non–small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro. Prolonged treatment of the parental H3122 cells with alectinib and ceritinib led to two cell lines which are 10 times less sensitive to alectinib and ceritinib than the parental H3122 cell line. Although mutations of ALK in its kinase domain are a common resistance mechanism for crizotinib, we did not detect any ALK mutation in these resistant cell lines. Rather, overexpression of phospho-ALK and alternative receptor tyrosine kinases such as phospho-EGFR, phospho-HER3, and phospho-IGFR-1R was observed in both resistant cell lines. Additionally, NRG1, a ligand for HER3, is upregulated and responsible for resistance by activating the EGFR family pathways through the NRG1-HER3-EGFR axis. Combination treatment with EGFR inhibitors, in particular afatinib, was shown to be effective at overcoming resistance. Our study provides new mechanistic insights into adaptive resistance to second-generation ALK inhibitors and suggests a potential clinical strategy to combat resistance to these second-generation ALK inhibitors in NSCLC. PMID:26992917

Active avoidance: escape and dodging behaviors for reactive control

NASA Astrophysics Data System (ADS)

Arkin, Ronald C.; Carter, William M.

1992-03-01

New methods for producing avoidance behavior among moving obstacles within the context of reactive robotic control are described. These specifically include escape and dodging behaviors. Dodging is concerned with the avoidance of a ballistic projectile while escape is more useful within the context of chase. The motivation and formulation of these new reactive behaviors are presented. Simulation results of a robot in a cluttered and moving world are also provided.

36. VIEW OF CUPOLA, SUBMARINE ESCAPE TRAINING TANK, SHOWING ROVING ...

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

36. VIEW OF CUPOLA, SUBMARINE ESCAPE TRAINING TANK, SHOWING ROVING RESCUE BELL SUSPENDED ABOVE TANK, WITH TWO-LOCK RECOMPRESSION CHAMBER AT REAR, LOOKING WEST. Photo taken after installation of recompression chamber in 1956. - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

Plasma Clouds and Snowplows: Bulk Plasma Escape from Mars Observed by MAVEN

NASA Technical Reports Server (NTRS)

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.;

Behavioral regulation of gravity: schedule effects under escape-avoidance procedures1

PubMed Central

Clark, Fogle C.; Lange, Karl O.; Belleville, Richard E.

1973-01-01

Squirrel monkeys were restrained in a centrifuge capsule and trained to escape and avoid increases in artificial gravity. During escape-avoidance, lever responses reduced centrifugally simulated gravity or postponed scheduled increases. The effect of variation in the interval of postponement (equal to the duration of decrease produced by escape responses) was studied under a multiple schedule of four components. Three components were gravity escape-avoidance with postponement times of 20, 40, and 60 sec. The fourth component was extinction. Each component was associated with a different auditory stimulus. Rate of responding decreased with increasing postponement time and higher mean g-levels occurred at shorter intervals of postponement. Effects of the schedule parameter on response rate and mean g-level were similar to effects of the schedule on free-operant avoidance and on titration behavior maintained by shock. ImagesFig. 1. PMID:4202386

Kinase fusions are frequent in Spitz tumors and spitzoid melanomas

PubMed Central

Esteve-Puig, Rosaura; Botton, Thomas; Yeh, Iwei; Lipson, Doron; Otto, Geoff; Brennan, Kristina; Murali, Rajmohan; Garrido, Maria; Miller, Vincent A.; Ross, Jeffrey S; Berger, Michael F.; Sparatta, Alyssa; Palmedo, Gabriele; Cerroni, Lorenzo; Busam, Klaus J.; Kutzner, Heinz; Cronin, Maureen T; Stephens, Philip J; Bastian, Boris C.

2014-01-01

Spitzoid neoplasms are a group of melanocytic tumors with distinctive histopathologic features. They include benign tumors (Spitz nevi), malignant tumors (spitzoid melanomas), and tumors with borderline histopathologic features and uncertain clinical outcome (atypical Spitz tumors). Their genetic underpinnings are poorly understood, and alterations in common melanoma-associated oncogenes are typically absent. Here we show that spitzoid neoplasms harbor kinase fusions of ROS1 (17%), NTRK1 (16%), ALK (10%), BRAF (5%), and RET (3%) in a mutually exclusive pattern. The chimeric proteins are constitutively active, stimulate oncogenic signaling pathways, are tumorigenic, and are found in the entire biologic spectrum of spitzoid neoplasms, including 55% of Spitz nevi, 56% of atypical Spitz tumors, and 39% of spitzoid melanomas. Kinase inhibitors suppress the oncogenic signaling of the fusion proteins in vitro. In summary, kinase fusions account for the majority of oncogenic aberrations in spitzoid neoplasms, and may serve as therapeutic targets for metastatic spitzoid melanomas. PMID:24445538

Kinase fusions are frequent in Spitz tumours and spitzoid melanomas

NASA Astrophysics Data System (ADS)

Wiesner, Thomas; He, Jie; Yelensky, Roman; Esteve-Puig, Rosaura; Botton, Thomas; Yeh, Iwei; Lipson, Doron; Otto, Geoff; Brennan, Kristina; Murali, Rajmohan; Garrido, Maria; Miller, Vincent A.; Ross, Jeffrey S.; Berger, Michael F.; Sparatta, Alyssa; Palmedo, Gabriele; Cerroni, Lorenzo; Busam, Klaus J.; Kutzner, Heinz; Cronin, Maureen T.; Stephens, Philip J.; Bastian, Boris C.

2014-01-01

Spitzoid neoplasms are a group of melanocytic tumours with distinctive histopathological features. They include benign tumours (Spitz naevi), malignant tumours (spitzoid melanomas) and tumours with borderline histopathological features and uncertain clinical outcome (atypical Spitz tumours). Their genetic underpinnings are poorly understood, and alterations in common melanoma-associated oncogenes are typically absent. Here we show that spitzoid neoplasms harbour kinase fusions of ROS1 (17%), NTRK1 (16%), ALK (10%), BRAF (5%) and RET (3%) in a mutually exclusive pattern. The chimeric proteins are constitutively active, stimulate oncogenic signalling pathways, are tumourigenic and are found in the entire biologic spectrum of spitzoid neoplasms, including 55% of Spitz naevi, 56% of atypical Spitz tumours and 39% of spitzoid melanomas. Kinase inhibitors suppress the oncogenic signalling of the fusion proteins in vitro. In summary, kinase fusions account for the majority of oncogenic aberrations in spitzoid neoplasms and may serve as therapeutic targets for metastatic spitzoid melanomas.

Recording Field Potentials From Zebrafish Larvae During Escape Responses

PubMed Central

Monesson-Olson, Bryan D.; Troconis, Eileen L.; Trapani, Josef G.

2014-01-01

Among vertebrates, startle responses are a ubiquitous method for alerting, and avoiding or escaping from alarming or dangerous stimuli. In zebrafish larvae, fast escape behavior is easily evoked through either acoustic or tactile stimuli. For example, a light touch to the head will excite trigeminal neurons that in turn excite a large reticulospinal neuron in the hindbrain called the Mauthner cell (M-cell). The M-cell action potential then travels down the contralateral trunk of the larva exciting motoneurons, which subsequently excite the entire axial musculature, producing a large amplitude body bend away from the source of the stimulus. This body conformation is known as the “C-bend” due to the shape of the larva during the behavior. As a result of the semi-synchronized activation of the M-cell, the population of motor neurons, and the axial trunk muscles, a large field potential is generated and can be recorded from free-swimming or fixed-position larvae. Undergraduate laboratories that record field potentials during escape responses in larval zebrafish are relatively simple to setup and allow students to observe and study the escape reflex circuit. Furthermore, by testing hypotheses, analyzing data and writing journal-style laboratory reports, students have multiple opportunities to learn about many neuroscience topics including vertebrate reflexes; sensory transduction; synaptic-, neuro-, and muscle-physiology; the M-cell mediated escape response; and the zebrafish as a model organism. Here, we detail the equipment, software, and recording setup necessary to observe field potentials in an undergraduate teaching lab. Additionally, we discuss potential advanced laboratory exercises and pedagogical outcomes. Finally, we note possible low-cost alternatives for recording field potentials. PMID:25565920

Dynamical Effects on the Escape of H and D: Martian Water Reservoirs

NASA Technical Reports Server (NTRS)

Hartle, Richard E.; Einaudi, Franco (Technical Monitor)

2002-01-01

The evolution of water on Mars is dependent on the loss rates of H and D from its atmosphere, where the dominant loss mechanism for these constituents is Jeans escape. Throughout time, preferential escape of H over D has produced a deuterium rich atmosphere with a D/H ratio 5.2 times that of terrestrial water. Motion in the atmosphere of Mars is shown to change the Jeans escape rates of H and D in two important ways: (1) Atmospheric wind and rotation at the exobase increase the escape fluxes of H and D above the corresponding Jeans fluxes. (2) The percentage increase in escape flux due to motion is greatest for D. Recently, several models have been used to estimate the magnitudes of current and ancient crustal water reservoirs on Mars that freely exchange with its atmosphere. Differences in the reservoir sizes are influenced by differences in the composition at the exobase, thermal history of the atmosphere and the D/H ratio of earlier epochs as inferred from meteorites. When motion enhanced Jeans escape is applied to each of these models, it is shown in every case that factors (1) and (2) above lead to current and ancient crustal water reservoirs that are larger than those obtained without motion.

Thio-Linked UDP–Peptide Conjugates as O-GlcNAc Transferase Inhibitors

PubMed Central

2018-01-01

O-GlcNAc transferase (OGT) is an essential glycosyltransferase that installs the O-GlcNAc post-translational modification on the nucleocytoplasmic proteome. We report the development of S-linked UDP–peptide conjugates as potent bisubstrate OGT inhibitors. These compounds were assembled in a modular fashion by photoinitiated thiol–ene conjugation of allyl-UDP and optimal acceptor peptides in which the acceptor serine was replaced with cysteine. The conjugate VTPVC(S-propyl-UDP)TA (Ki = 1.3 μM) inhibits the OGT activity in HeLa cell lysates. Linear fusions of this conjugate with cell penetrating peptides were explored as prototypes of cell-penetrant OGT inhibitors. A crystal structure of human OGT with the inhibitor revealed mimicry of the interactions seen in the pseudo-Michaelis complex. Furthermore, a fluorophore-tagged derivative of the inhibitor works as a high affinity probe in a fluorescence polarimetry hOGT assay. PMID:29723473

8. VIEW OF ESCAPE TRAINING TANK, LOOKING NORTHEAST FROM 50FOOT ...

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

8. VIEW OF ESCAPE TRAINING TANK, LOOKING NORTHEAST FROM 50-FOOT PASSAGEWAY, SHOWING PORTION OF SPIRAL STAIR AND REPRESENTATIVE FLOOD LIGHT BLISTER - U.S. Naval Submarine Base, New London Submarine Escape Training Tank, Albacore & Darter Roads, Groton, New London County, CT

A Supramolecular Approach toward Bioinspired PAMAM-Dendronized Fusion Toxins.

PubMed

Kuan, Seah Ling; Förtsch, Christina; Ng, David Yuen Wah; Fischer, Stephan; Tokura, Yu; Liu, Weina; Wu, Yuzhou; Koynov, Kaloian; Barth, Holger; Weil, Tanja

2016-06-01

Nature has provided a highly optimized toolbox in bacterial endotoxins with precise functions dictated by their clear structural division. Inspired by this streamlined design, a supramolecular approach capitalizing on the strong biomolecular (streptavidin (SA))-biotin interactions is reported herein to prepare two multipartite fusion constructs, which involves the generation 2.0 (D2) or generation 3.0 (D3) polyamidoamine-dendronized transporter proteins (dendronized streptavidin (D3SA) and dendronized human serum albumin (D2HSA)) non-covalently fused to the C3bot1 enzyme from Clostridium botulinum, a potent and specific Rho-inhibitor. The fusion constructs, D3SA-C3 and D2HSA-C3, represent the first examples of dendronized protein transporters that are fused to the C3 enzyme, and it is successfully demonstrated that the C3 Rho-inhibitor is delivered into the cytosol of mammalian cells as determined from the characteristic C3-mediated changes in cell morphology and confocal microscopy. The design circumvents the low uptake of the C3 enzyme by eukaryotic cells and holds great promise for reprogramming the properties of toxin enzymes using a supramolecular approach to broaden their therapeutic applications. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Escape Excel: A tool for preventing gene symbol and accession conversion errors.

PubMed

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.

Escape Excel: A tool for preventing gene symbol and accession conversion errors

PubMed Central

Stewart, Paul A.; Kuenzi, Brent M.; Eschrich, James A.

2017-01-01

Background 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. Results 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/). Conclusions 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. PMID:28953918

Photoelectron escape fluxes over the equatorial and midlatitude regions

NASA Technical Reports Server (NTRS)

Narasingarao, B. C.; Singh, R. N.; Maier, E. J.

1972-01-01

Satellite measurements of photoelectron escape flux around noontime made by Explorer 31 in 600-800 km altitude range are reported for the equatorial and midlatitude regions. The pitch angle distributions and the spectral distributions are derived from the data. Analyzed data show that the flux for equatorial regions is lower by a factor 2 to 3 in comparison to that of midlatitude regions. Theoretical calculations are also made to compare with observed escape fluxes.

Lise Meitner's escape from Germany

NASA Astrophysics Data System (ADS)

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.

Scrunching: a novel escape gait in planarians

NASA Astrophysics Data System (ADS)

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.

Escape problem under stochastic volatility: The Heston model

NASA Astrophysics Data System (ADS)

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.

Reviving Antibiotics: Efflux Pump Inhibitors That Interact with AcrA, a Membrane Fusion Protein of the AcrAB-TolC Multidrug Efflux Pump

DOE PAGES

Abdali, Narges; Parks, Jerry M.; Haynes, Keith M.; ...

2016-10-21

Antibiotic resistance is a major threat to human welfare. Inhibitors of multidrug efflux pumps (EPIs) are promising alternative therapeutics that could revive activities of antibiotics and reduce bacterial virulence. Identification of new druggable sites for inhibition is critical for developing effective EPIs, especially in light of constantly emerging resistance. We describe new EPIs that interact with and possibly inhibit the function of periplasmic membrane fusion proteins, critical components of efflux pumps that are responsible for the activation of the transporter and the recruitment of the outer-membrane channel. The discovered EPIs bind to AcrA, a component of the prototypical AcrAB-TolC pump,more » change its structure in vivo, inhibit efflux of fluorescent probes and potentiate the activities of antibiotics in Escherichia coli cells. These findings expand the chemical and mechanistic diversity of EPIs, suggest the mechanism for regulation of the efflux pump assembly and activity, and provide a promising path for reviving the activities of antibiotics in resistant bacteria.« less

Reviving Antibiotics: Efflux Pump Inhibitors That Interact with AcrA, a Membrane Fusion Protein of the AcrAB-TolC Multidrug Efflux Pump

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abdali, Narges; Parks, Jerry M.; Haynes, Keith M.

Antibiotic resistance is a major threat to human welfare. Inhibitors of multidrug efflux pumps (EPIs) are promising alternative therapeutics that could revive activities of antibiotics and reduce bacterial virulence. Identification of new druggable sites for inhibition is critical for developing effective EPIs, especially in light of constantly emerging resistance. We describe new EPIs that interact with and possibly inhibit the function of periplasmic membrane fusion proteins, critical components of efflux pumps that are responsible for the activation of the transporter and the recruitment of the outer-membrane channel. The discovered EPIs bind to AcrA, a component of the prototypical AcrAB-TolC pump,more » change its structure in vivo, inhibit efflux of fluorescent probes and potentiate the activities of antibiotics in Escherichia coli cells. These findings expand the chemical and mechanistic diversity of EPIs, suggest the mechanism for regulation of the efflux pump assembly and activity, and provide a promising path for reviving the activities of antibiotics in resistant bacteria.« less

Animal escapology I: theoretical issues and emerging trends in escape trajectories

PubMed Central

Domenici, Paolo; Blagburn, Jonathan M.; Bacon, Jonathan P.

2011-01-01

Summary Escape responses are used by many animal species as their main defence against predator attacks. Escape success is determined by a number of variables; important are the directionality (the percentage of responses directed away from the threat) and the escape trajectories (ETs) measured relative to the threat. Although logic would suggest that animals should always turn away from a predator, work on various species shows that these away responses occur only approximately 50–90% of the time. A small proportion of towards responses may introduce some unpredictability and may be an adaptive feature of the escape system. Similar issues apply to ETs. Theoretically, an optimal ET can be modelled on the geometry of predator–prey encounters. However, unpredictability (and hence high variability) in trajectories may be necessary for preventing predators from learning a simple escape pattern. This review discusses the emerging trends in escape trajectories, as well as the modulating key factors, such as the surroundings and body design. The main ET patterns identified are: (1) high ET variability within a limited angular sector (mainly 90–180 deg away from the threat; this variability is in some cases based on multiple peaks of ETs), (2) ETs that allow sensory tracking of the threat and (3) ETs towards a shelter. These characteristic features are observed across various taxa and, therefore, their expression may be mainly related to taxon-independent animal design features and to the environmental context in which prey live – for example whether the immediate surroundings of the prey provide potential refuges. PMID:21753039

Hot oxygen escape from Mars: Simple scaling with solar EUV irradiance

NASA Astrophysics Data System (ADS)

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.

Generalized Jeans' Escape of Pick-Up Ions in Quasi-Linear Relaxation

NASA Technical Reports Server (NTRS)

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].

Extinction Correction Significantly Influences the Estimate of the Lyα Escape Fraction

NASA Astrophysics Data System (ADS)

An, Fang Xia; Zheng, Xian Zhong; Hao, Cai-Na; Huang, Jia-Sheng; Xia, Xiao-Yang

2017-02-01

The Lyα escape fraction is a key measure to constrain the neutral state of the intergalactic medium and then to understand how the universe was fully reionized. We combine deep narrowband imaging data from the custom-made filter NB393 and the {{{H}}}2S1 filter centered at 2.14 μm to examine the Lyα emitters and Hα emitters at the same redshift z = 2.24. The combination of these two populations allows us to determine the Lyα escape fraction at z = 2.24. Over an area of 383 arcmin2 in the Extended Chandra Deep Field South (ECDFS), 124 Lyα emitters are detected down to NB393 = 26.4 mag at the 5σ level, and 56 Hα emitters come from An et al. Of these, four have both Lyα and Hα emissions (LAHAEs). We also collect the Lyα emitters and Hα emitters at z = 2.24 in the COSMOS field from the literature, and increase the number of LAHAEs to 15 in total. About one-third of them are AGNs. We measure the individual/volumetric Lyα escape fraction by comparing the observed Lyα luminosity/luminosity density to the extinction-corrected Hα luminosity/luminosity density. We revisit the extinction correction for Hα emitters using the Galactic extinction law with color excess for nebular emission. We also adopt the Calzetti extinction law together with an identical color excess for stellar and nebular regions to explore how the uncertainties in extinction correction affect the estimate of individual and global Lyα escape fractions. In both cases, an anti-correlation between the Lyα escape fraction and dust attenuation is found among the LAHAEs, suggesting that dust absorption is responsible for the suppression of the escaping Lyα photons. However, the estimated Lyα escape fraction of individual LAHAEs varies by up to ˜3 percentage points between the two methods of extinction correction. We find the global Lyα escape fraction at z = 2.24 to be (3.7 ± 1.4)% in the ECDFS. The variation in the color excess of the extinction causes a discrepancy of ˜1 percentage point

Cold Ion Escape from the Martian Ionosphere

NASA Astrophysics Data System (ADS)

Fraenz, M.; Dubinin, E.; Wei, Y.; Woch, J. G.; Morgan, D. D.; Barabash, S. V.; Lundin, R. N.; Fedorov, A.

2012-12-01

It has always been challenging to observe the flux of ions with energies of less than 10eV escaping from the planetary ionospheres. We here report on new measurements of the ionospheric ion flows at Mars by the ASPERA-3 experiment on board Mars Express. We first use support from the MARSIS radar experiment for some orbits with fortunate observation geometry. Here we have observed a transterminator flow of O+ and O2+ ions with a super-sonic velocity of around 5km/s and fluxes of 0.8x10^9/cm^2s. If we assume a symmetric flux around the terminator this corresponds to an ion flow of 3.1x10^25/s half of which is expected to escape from Mars (Fraenz et al, 2010). This escape flux is significantly higher than previously observed on the tailside of Mars, we discuss possible reasons for the difference. Since 2008 the MARSIS radar does nightside local plasma density measurement which often coincide with ASPERA-3 measurements. In a new analysis of the combined nightside datasets (Fig. 1) we show that the main escape channel is along the shadow boundary on the tailside of Mars. At a distance of about 0.5 R_M the flux settles at a constant value (Fig. 2) which indicates that about half of the transterminator ionospheric flow escapes from the planet. Possible mechanism to generate this flux can be the ionospheric pressure gradient between dayside and nightside or momentum transfer from the solar wind via the induced magnetic field since the flow velocity is in the Alfvenic regime.; Median oxygen ion flux reconstructed by combining ion velocity observations of the Mars Express ASPERA-3 IMA sensor and local plasma density observations by the MARSIS radar. Each bin value is the median from observations on about 3000 orbits between May 2007 and July 2011. Horizontal axis is MSO X-axis (Sun towards the left), vertical axis is vertical distance from MSO X-axis. ; Ring median flux of cylindrical ring regions of all bins shown in previous figure. The different colors show median fluxes

Introduction of transformed chloroplasts from tobacco into petunia by asymmetric cell fusion.

PubMed

Sigeno, Asako; Hayashi, Sugane; Terachi, Toru; Yamagishi, Hiroshi

2009-11-01

Plastid engineering technique has been established only in Nicotiana tabacum, and the widespread application is severely limited so far. In order to exploit a method to transfer the genetically transformed plastomes already obtained in tobacco into other plant species, somatic cell fusion was conducted between a plastome transformant of tobacco and a cultivar of petunia (Petunia hybrida). A tobacco strain whose plastids had been transformed with aadA (a streptomycin/spectinomycin adenylyltransferase gene) and mdar [a gene for monodehydroascorbate reductase (MDAR)] and a petunia variety, 'Telstar', were used as cell fusion partners. An efficient regeneration system from the protoplasts of both the parents, and effectiveness of selection for the aadA gene with spectinomycin were established before the cell fusion. In addition, the influence of UV irradiation on the callus development from the protoplasts and shoot regeneration of tobacco was investigated. Protoplasts were cultured after cell fusion treatment with polyethylene glycol, and asymmetric somatic cybrids were selected using the aadA gene as a marker. Although many shoots of tobacco that had escaped the UV irradiation regenerated, several shoots possessing the morphology of petunia and the resistance to spectinomycin were obtained. Molecular analyses of the petunia type regenerants demonstrated that they had the nuclear and mitochondrial genomes derived from petunia besides the chloroplasts of tobacco transformed with aadA and mdar. Furthermore, it was ascertained that mdar was transcribed in the somatic cybrids. The results indicate the success in intergeneric transfer of transformed plastids of tobacco into petunia.

On ion escape from Venus

NASA Astrophysics Data System (ADS)

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

On ion escape from Venus

NASA Astrophysics Data System (ADS)

Jarvinen, Riku

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

Strong plume fluxes at Mars observed by MAVEN: An important planetary ion escape channel

NASA Astrophysics Data System (ADS)

Dong, Y.; Fang, X.; Brain, D. A.; McFadden, J. P.; Halekas, J. S.; Connerney, J. E.; Curry, S. M.; Harada, Y.; Luhmann, J. G.; Jakosky, B. M.

2015-11-01

We present observations by the Mars Atmosphere and Volatile EvolutioN (MAVEN) mission of a substantial plume-like distribution of escaping ions from the Martian atmosphere, organized by the upstream solar wind convection electric field. From a case study of MAVEN particle-and-field data during one spacecraft orbit, we identified three escaping planetary ion populations: plume fluxes mainly along the upstream electric field over the north pole region of the Mars-Sun-Electric field (MSE) coordinate system, antisunward ion fluxes in the tail region, and much weaker upstream pickup ion fluxes. A statistical study of O+ fluxes using 3 month MAVEN data shows that the plume is a constant structure with strong fluxes widely distributed in the MSE northern hemisphere, which constitutes an important planetary ion escape channel. The escape rate through the plume is estimated to be ~30% of the tailward escape and ~23% of the total escape for > 25 eV O+ ions.

Estimating Collisionally-Induced Escape Rates of Light Neutrals from Early Mars

NASA Astrophysics Data System (ADS)

Gacesa, M.; Zahnle, K. J.

2016-12-01

Collisions of atmospheric gases with hot oxygen atoms constitute an important non-thermal mechanism of escape of light atomic and molecular species at Mars. In this study, we present revised theoretical estimates of non-thermal escape rates of neutral O, H, He, and H2 based on recent atmospheric density profiles obtained from the NASA Mars Atmosphere and Volatile Evolution (MAVEN) mission and related theoretical models. As primary sources of hot oxygen, we consider dissociative recombination of O2+ and CO2+ molecular ions. We also consider hot oxygen atoms energized in primary and secondary collisions with energetic neutral atoms (ENAs) produced in charge-exchange of solar wind H+ and He+ ions with atmospheric gases1,2. Scattering of hot oxygen and atmospheric species of interest is modeled using fully-quantum reactive scattering formalism3. This approach allows us to construct distributions of vibrationally and rotationally excited states and predict the products' emission spectra. In addition, we estimate formation rates of excited, translationally hot hydroxyl molecules in the upper atmosphere of Mars. The escape rates are calculated from the kinetic energy distributions of the reaction products using an enhanced 1D model of the atmosphere for a range of orbital and solar parameters. Finally, by considering different scenarios, we estimate the influence of these escape mechanisms on the evolution of Mars's atmosphere throughout previous epochs and their impact on the atmospheric D/H ratio. M.G.'s research was supported by an appointment to the NASA Postdoctoral Program at the NASA Ames Research Center, administered by Universities Space Research Association under contract with NASA. 1N. Lewkow and V. Kharchenko, "Precipitation of Energetic Neutral Atoms and Escape Fluxes induced from the Mars Atmosphere", Astroph. J., 790, 98 (2014) 2M. Gacesa, N. Lewkow, and V. Kharchenko, "Non-thermal production and escape of OH from the upper atmosphere of Mars", arXiv:1607

Speed kills: ineffective avian escape responses to oncoming vehicles

PubMed Central

DeVault, Travis L.; Blackwell, Bradley F.; Seamans, Thomas W.; Lima, Steven L.; Fernández-Juricic, Esteban

2015-01-01

Animal–vehicle collisions cause high levels of vertebrate mortality worldwide, and what goes wrong when animals fail to escape and ultimately collide with vehicles is not well understood. We investigated alert and escape behaviours of captive brown-headed cowbirds (Molothrus ater) in response to virtual vehicle approaches of different sizes and at speeds ranging from 60 to 360 km h−1. Alert and flight initiation distances remained similar across vehicle speeds, and accordingly, alert and flight initiation times decreased at higher vehicle speeds. Thus, avoidance behaviours in cowbirds appeared to be based on distance rather than time available for escape, particularly at 60–150 km h−1; however, at higher speeds (more than or equal to 180 km h−1) no trend in response behaviour was discernible. As vehicle speed increased, cowbirds did not have enough time to assess the approaching vehicle, and cowbirds generally did not initiate flight with enough time to avoid collision when vehicle speed exceeded 120 km h−1. Although potentially effective for evading predators, the decision-making process used by cowbirds in our study appears maladaptive in the context of avoiding fast-moving vehicles. Our methodological approach and findings provide a framework to assess how novel management strategies could affect escape rules, and the sensory and cognitive abilities animals use to avoid vehicle collisions. PMID:25567648

Norovirus Escape from Broadly Neutralizing Antibodies Is Limited to Allostery-Like Mechanisms

PubMed Central

Kolawole, Abimbola O.; Smith, Hong Q.; Svoboda, Sophia A.; Lewis, Madeline S.; Sherman, Michael B.; Lynch, Gillian C.; Pettitt, B. Montgomery

2017-01-01

ABSTRACT Ideal antiviral vaccines elicit antibodies (Abs) with broad strain recognition that bind to regions that are difficult to mutate for escape. Using 10 murine norovirus (MNV) strains and 5 human norovirus (HuNoV) virus-like particles (VLPs), we identified monoclonal antibody (MAb) 2D3, which broadly neutralized all MNV strains tested. Importantly, escape mutants corresponding to this antibody were very slow to develop and were distal to those raised against our previously studied antibody, A6.2. To understand the atomic details of 2D3 neutralization, we determined the cryo-electron microscopy (cryo-EM) structure of the 2D3/MNV1 complex. Interestingly, 2D3 binds to the top of the P domain, very close to where A6.2 binds, but the only escape mutations identified to date fall well outside the contact regions of both 2D3 and A6.2. To determine how mutations in distal residues could block antibody binding, we used molecular dynamics flexible fitting simulations of the atomic structures placed into the density map to examine the 2D3/MNV1 complex and these mutations. Our findings suggest that the escape mutant, V339I, may stabilize a salt bridge network at the P-domain dimer interface that, in an allostery-like manner, affects the conformational relaxation of the P domain and the efficiency of binding. They further highlight the unusual antigenic surface bound by MAb 2D3, one which elicits cross-reactive antibodies but which the virus is unable to alter to escape neutralization. These results may be leveraged to generate norovirus (NoV) vaccines containing broadly neutralizing antibodies. IMPORTANCE The simplest and most common way for viruses to escape antibody neutralization is by mutating residues that are essential for antibody binding. Escape mutations are strongly selected for by their effect on viral fitness, which is most often related to issues of protein folding, particle assembly, and capsid function. The studies presented here demonstrated that a

A comparison of positive and negative reinforcement for compliance to treat problem behavior maintained by escape.

PubMed

Slocum, Sarah K; Vollmer, Timothy R

2015-09-01

Previous research has shown that problem behavior maintained by escape can be treated using positive reinforcement. In the current study, we directly compared functional (escape) and nonfunctional (edible) reinforcers in the treatment of escape-maintained problem behavior for 5 subjects. In the first treatment, compliance produced a break from instructions. In the second treatment, compliance produced a small edible item. Neither treatment included escape extinction. Results suggested that the delivery of a positive reinforcer for compliance was effective for treating escape-maintained problem behavior for all 5 subjects, and the delivery of escape for compliance was ineffective for 3 of the 5 subjects. Implications and future directions related to the use of positive reinforcers in the treatment of escape behavior are discussed. © Society for the Experimental Analysis of Behavior.

Hepatitis A Virus Vaccine Escape Variants and Potential New Serotype Emergence

PubMed Central

Pérez-Sautu, Unai; Costafreda, M. Isabel; Caylà, Joan; Tortajada, Cecilia; Lite, Josep; Bosch, Albert

2011-01-01

Six hepatitis A virus antigenic variants that likely escaped the protective effect of available vaccines were isolated, mostly from men who have sex with men. The need to complete the proper vaccination schedules is critical, particularly in the immunocompromised population, to prevent the emergence of vaccine-escaping variants.

A mature and fusogenic form of the Nipah virus fusion protein requires proteolytic processing by cathepsin L

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pager, Cara Theresia; Craft, Willie Warren; Patch, Jared

2006-03-15

The Nipah virus fusion (F) protein is proteolytically processed to F{sub 1} + F{sub 2} subunits. We demonstrate here that cathepsin L is involved in this important maturation event. Cathepsin inhibitors ablated cleavage of Nipah F. Proteolytic processing of Nipah F and fusion activity was dramatically reduced in cathepsin L shRNA-expressing Vero cells. Additionally, Nipah virus F-mediated fusion was inhibited in cathepsin L-deficient cells, but coexpression of cathepsin L restored fusion activity. Both purified cathepsin L and B could cleave immunopurified Nipah F protein, but only cathepsin L produced products of the correct size. Our results suggest that endosomal cathepsinsmore » can cleave Nipah F, but that cathepsin L specifically converts Nipah F to a mature and fusogenic form.« less

Time Intervals in Sequence Sampling, Not Data Modifications, Have a Major Impact on Estimates of HIV Escape Rates

PubMed Central

2018-01-01

The ability of human immunodeficiency virus (HIV) to avoid recognition by humoral and cellular immunity (viral escape) is well-documented, but the strength of the immune response needed to cause such a viral escape remains poorly quantified. Several previous studies observed a more rapid escape of HIV from CD8 T cell responses in the acute phase of infection compared to chronic infection. The rate of HIV escape was estimated with the help of simple mathematical models, and results were interpreted to suggest that CD8 T cell responses causing escape in acute HIV infection may be more efficient at killing virus-infected cells than responses that cause escape in chronic infection, or alternatively, that early escapes occur in epitopes mutations in which there is minimal fitness cost to the virus. However, these conclusions were challenged on several grounds, including linkage and interference of multiple escape mutations due to a low population size and because of potential issues associated with modifying the data to estimate escape rates. Here we use a sampling method which does not require data modification to show that previous results on the decline of the viral escape rate with time since infection remain unchanged. However, using this method we also show that estimates of the escape rate are highly sensitive to the time interval between measurements, with longer intervals biasing estimates of the escape rate downwards. Our results thus suggest that data modifications for early and late escapes were not the primary reason for the observed decline in the escape rate with time since infection. However, longer sampling periods for escapes in chronic infection strongly influence estimates of the escape rate. More frequent sampling of viral sequences in chronic infection may improve our understanding of factors influencing the rate of HIV escape from CD8 T cell responses. PMID:29495443

Time Intervals in Sequence Sampling, Not Data Modifications, Have a Major Impact on Estimates of HIV Escape Rates.

PubMed

Ganusov, Vitaly V

2018-02-27

The ability of human immunodeficiency virus (HIV) to avoid recognition by humoral and cellular immunity (viral escape) is well-documented, but the strength of the immune response needed to cause such a viral escape remains poorly quantified. Several previous studies observed a more rapid escape of HIV from CD8 T cell responses in the acute phase of infection compared to chronic infection. The rate of HIV escape was estimated with the help of simple mathematical models, and results were interpreted to suggest that CD8 T cell responses causing escape in acute HIV infection may be more efficient at killing virus-infected cells than responses that cause escape in chronic infection, or alternatively, that early escapes occur in epitopes mutations in which there is minimal fitness cost to the virus. However, these conclusions were challenged on several grounds, including linkage and interference of multiple escape mutations due to a low population size and because of potential issues associated with modifying the data to estimate escape rates. Here we use a sampling method which does not require data modification to show that previous results on the decline of the viral escape rate with time since infection remain unchanged. However, using this method we also show that estimates of the escape rate are highly sensitive to the time interval between measurements, with longer intervals biasing estimates of the escape rate downwards. Our results thus suggest that data modifications for early and late escapes were not the primary reason for the observed decline in the escape rate with time since infection. However, longer sampling periods for escapes in chronic infection strongly influence estimates of the escape rate. More frequent sampling of viral sequences in chronic infection may improve our understanding of factors influencing the rate of HIV escape from CD8 T cell responses.

Neural circuits underlying visually evoked escapes in larval zebrafish

PubMed Central

Dunn, Timothy W.; Gebhardt, Christoph; Naumann, Eva A.; Riegler, Clemens; Ahrens, Misha B.; Engert, Florian; Del Bene, Filippo

2015-01-01

SUMMARY Escape behaviors deliver organisms away from imminent catastrophe. Here, we characterize behavioral responses of freely swimming larval zebrafish to looming visual stimuli simulating predators. We report that the visual system alone can recruit lateralized, rapid escape motor programs, similar to those elicited by mechanosensory modalities. Two-photon calcium imaging of retino-recipient midbrain regions isolated the optic tectum as an important center processing looming stimuli, with ensemble activity encoding the critical image size determining escape latency. Furthermore, we describe activity in retinal ganglion cell terminals and superficial inhibitory interneurons in the tectum during looming and propose a model for how temporal dynamics in tectal periventricular neurons might arise from computations between these two fundamental constituents. Finally, laser ablations of hindbrain circuitry confirmed that visual and mechanosensory modalities share the same premotor output network. Together, we establish a circuit for the processing of aversive stimuli in the context of an innate visual behavior. PMID:26804997

Response to crizotinib in a lung adenocarcinoma patient harboring a novel SLC34A2-ROS1 fusion variant.

PubMed

Zhao, Zheng; Song, Zhangjun; Wang, Xuwei; Sun, Haifeng; Yang, Xiaomin; Yuan, Yong; Yu, Pan

2017-01-01

ROS1 fusion is a common genetic alteration in non-small-cell lung cancer. Crizotinib, an anaplastic lymphoma kinase inhibitor, shows efficacy in the treatment of lung cancer cases with ROS1 translocation. We report the response to crizotinib of a lung adenocarcinoma patient harboring a novel SLC34A2 - ROS1 fusion variant, which was different from the two common SLC34A2 - ROS1 fusion types reported in the literature. After crizotinib administration, overall recovery was good in this patient; the primary lesion was successfully treated, the lymph node metastases had disappeared, and the metabolism was normal.

Response to crizotinib in a lung adenocarcinoma patient harboring a novel SLC34A2-ROS1 fusion variant

PubMed Central

Zhao, Zheng; Song, Zhangjun; Wang, Xuwei; Sun, Haifeng; Yang, Xiaomin; Yuan, Yong; Yu, Pan

2017-01-01

ROS1 fusion is a common genetic alteration in non-small-cell lung cancer. Crizotinib, an anaplastic lymphoma kinase inhibitor, shows efficacy in the treatment of lung cancer cases with ROS1 translocation. We report the response to crizotinib of a lung adenocarcinoma patient harboring a novel SLC34A2-ROS1 fusion variant, which was different from the two common SLC34A2-ROS1 fusion types reported in the literature. After crizotinib administration, overall recovery was good in this patient; the primary lesion was successfully treated, the lymph node metastases had disappeared, and the metabolism was normal. PMID:28860822

Assessment of a New Procedure to Prevent Timeout Escape in Preschoolers.

ERIC Educational Resources Information Center

McNeil, Cheryl Bodiford; And Others

1994-01-01

Many agencies provide parent training to groups for whom spanking as a response to timeout escape is not an option. An alternative was developed, the "two-chair hold" technique, which showed some success in decreasing timeout escape and improving overall behavior. Discusses clinical issues regarding use of this technique. (LKS)

Inhibition of herpes simplex virus type 1 entry by chloride channel inhibitors tamoxifen and NPPB

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng, Kai; College of Life Science and Technology, Jinan University, Guangzhou; Chen, Maoyun

2014-04-18

Highlights: • We analyze the anti-HSV potential of chloride channel inhibitors. • Tamoxifen and NPPB show anti-HSV-1 and anti-ACV-resistant HSV-1 activities. • HSV-1 infection induces intracellular chloride concentration increasing. • Tamoxifen and NPPB inhibit HSV-1 early infection. • Tamoxifen and NPPB prevent the fusion process of HSV-1. - Abstract: Herpes simplex virus type 1 (HSV-1) infection is very common worldwide and can cause significant health problems from periodic skin and corneal lesions to encephalitis. Appearance of drug-resistant viruses in clinical therapy has made exploring novel antiviral agents emergent. Here we show that chloride channel inhibitors, including tamoxifen and 5-nitro-2-(3-phenyl-propylamino) benzoicmore » acid (NPPB), exhibited extensive antiviral activities toward HSV-1 and ACV-resistant HSV viruses. HSV-1 infection induced chloride ion influx while treatment with inhibitors reduced the increase of intracellular chloride ion concentration. Pretreatment or treatment of inhibitors at different time points during HSV-1 infection all suppressed viral RNA synthesis, protein expression and virus production. More detailed studies demonstrated that tamoxifen and NPPB acted as potent inhibitors of HSV-1 early entry step by preventing viral binding, penetration and nuclear translocation. Specifically the compounds appeared to affect viral fusion process by inhibiting virus binding to lipid rafts and interrupting calcium homeostasis. Taken together, the observation that tamoxifen and NPPB can block viral entry suggests a stronger potential for these compounds as well as other ion channel inhibitors in antiviral therapy against HSV-1, especially the compound tamoxifen is an immediately actionable drug that can be reused for treatment of HSV-1 infections.« less

Companion Protease Inhibitors for the In Situ Protection of Recombinant Proteins in Plants.

PubMed

Robert, Stéphanie; Jutras, Philippe V; Khalf, Moustafa; D'Aoust, Marc-André; Goulet, Marie-Claire; Sainsbury, Frank; Michaud, Dominique

2016-01-01

We previously described a procedure for the use of plant protease inhibitors as "companion" accessory proteins to prevent unwanted proteolysis of clinically useful recombinant proteins in leaf crude protein extracts (Benchabane et al. Methods Mol Biol 483:265-273, 2009). Here we describe the use of these inhibitors for the protection of recombinant proteins in planta, before their extraction from leaf tissues. A procedure is first described involving inhibitors co-expressed along-and co-migrating-with the protein of interest in host plant cells. An alternative, single transgene scheme is then described involving translational fusions of the recombinant protein and companion inhibitor. These approaches may allow for a significant improvement of protein steady-state levels in leaves, comparable to yield improvements observed with protease-deficient strains of less complex protein expression hosts such as E. coli or yeasts.

Effects of metamorphosis on the aquatic escape response of the two-lined salamander (Eurycea bislineata).

PubMed

Azizi, Emanuel; Landberg, Tobias

2002-03-01

Although numerous studies have described the escape kinematics of fishes, little is known about the aquatic escape responses of salamanders. We compare the escape kinematics of larval and adult Eurycea bislineata, the two-lined salamander, to examine the effects of metamorphosis on aquatic escape performance. We hypothesize that shape changes associated with resorption of the larval tail fin at metamorphosis will affect aquatic locomotor performance. Escape responses were recorded using high-speed video, and the effects of life stage and total length on escape kinematics were analyzed statistically using analysis of covariance. Our results show that both larval and adult E. bislineata use a two-stage escape response (similar to the C-starts of fishes) that consists of a preparatory (stage 1) and a propulsive (stage 2) stroke. The duration of both kinematic stages and the distance traveled during stage 2 increased with total length. Both larval and adult E. bislineata had final escape trajectories that were directed away from the stimulus. The main kinematic difference between larvae and adults is that adults exhibit significantly greater maximum curvature during stage 1. Total escape duration and the distance traveled during stage 2 did not differ significantly between larvae and adults. Despite the significantly lower tail aspect ratio of adults, we found no significant decrease in the overall escape performance of adult E. bislineata. Our results suggest that adults may compensate for the decrease in tail aspect ratio by increasing their maximum curvature. These findings do not support the hypothesis that larvae exhibit better locomotor performance than adults as a result of stronger selective pressures on early life stages.

Hydrogen escape from Mars enhanced by deep convection in dust storms

NASA Astrophysics Data System (ADS)

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.

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

DTIC Science & Technology

1992-02-01

purchased from: National Tecnical Information Service 5285 Port Royal Road Springfield VA 22161 Federal Governmet agencies and their contractors registered...Engineering Incpora:ted (IME) to organize and executi a tecnical approach to the QP= 14. SUIUECT TERMS Mission Area Requiremts, REST Escape SystM IS...the aerodynamic stabilization subsystems to become effective (drogue parachutes, or fins for the S4S), and the time required for the recovery parachute

Several immune escape patterns in non-Hodgkin's lymphomas

PubMed Central

Laurent, Camille; Charmpi, Konstantina; Gravelle, Pauline; Tosolini, Marie; Franchet, Camille; Ysebaert, Loïc; Brousset, Pierre; Bidaut, Alexandre; Ycart, Bernard; Fournié, Jean-Jacques

2015-01-01

Follicular Lymphomas (FL) and diffuse large B cell lymphomas (DLBCL) must evolve some immune escape strategy to develop from lymphoid organs, but their immune evasion pathways remain poorly characterized. We investigated this issue by transcriptome data mining and immunohistochemistry (IHC) of FL and DLBCL lymphoma biopsies. A set of genes involved in cancer immune-evasion pathways (Immune Escape Gene Set, IEGS) was defined and the distribution of the expression levels of these genes was compared in FL, DLBCL and normal B cell transcriptomes downloaded from the GEO database. The whole IEGS was significantly upregulated in all the lymphoma samples but not in B cells or other control tissues, as shown by the overexpression of the PD-1, PD-L1, PD-L2 and LAG3 genes. Tissue microarray immunostainings for PD-1, PD-L1, PD-L2 and LAG3 proteins on additional biopsies from 27 FL and 27 DLBCL patients confirmed the expression of these proteins. The immune infiltrates were more abundant in FL than DLBCL samples, and the microenvironment of FL comprised higher rates of PD-1+ lymphocytes. Further, DLBCL tumor cells comprised a higher proportion of PD-1+, PD-L1+, PD-L2+ and LAG3+ lymphoma cells than the FL tumor cells, confirming that DLBCL mount immune escape strategies distinct from FL. In addition, some cases of DLBCL had tumor cells co-expressing both PD-1, PD-L1 and PD-L2. Among the DLBCLs, the activated B cell (ABC) subtype comprised more PD-L1+ and PD-L2+ lymphoma cells than the GC subtype. Thus, we infer that FL and DLBCL evolved several pathways of immune escape. PMID:26405585

Injury rate in a helicopter underwater escape trainer (HUET) from 2005-2012.

PubMed

Brooks, Christopher J; MacDonald, Conor V; Gibbs, Peter N A

2014-08-01

Helicopter underwater escape training (HUET) carries a potential for injury and this paper identifies the injury rate. A marine survival training school registry of all students trained between 2005-2012 in HUET and the coinciding accident records were examined. There were 8902 students trained in a helicopter underwater escape simulator for a total of 59,245 underwater escapes. There were 40 cases where only first-aid was required and 3 serious injuries (a laceration requiring 5 sutures, 1 dislocated shoulder, and 1 water aspiration requiring hospitalization). There were no deaths and no problems reported with using the Emergency Breathing System (EBS) or Air Pocket. Of the injuries, 11 were due to the student using a poor escape technique. The overall probability of injury was 0.74 per 1000 ascents. In HUET training, there is a very low injury rate with almost no significant severity. Although not scientifically proven, this would suggest that the low incident rate is due to good medical screening and the attention given by instructors to anxious students. Compared to other training such as diving, parachute jumping, and submarine escape training, the rate of injury was considerably lower.

Escape Distance in Ground-Nesting Birds Differs with Individual Level of Camouflage.

PubMed

Wilson-Aggarwal, Jared K; Troscianko, Jolyon T; Stevens, Martin; Spottiswoode, Claire N

2016-08-01

Camouflage is one of the most widespread antipredator strategies in the animal kingdom, yet no animal can match its background perfectly in a complex environment. Therefore, selection should favor individuals that use information on how effective their camouflage is in their immediate habitat when responding to an approaching threat. In a field study of African ground-nesting birds (plovers, coursers, and nightjars), we tested the hypothesis that individuals adaptively modulate their escape behavior in relation to their degree of background matching. We used digital imaging and models of predator vision to quantify differences in color, luminance, and pattern between eggs and their background, as well as the plumage of incubating adult nightjars. We found that plovers and coursers showed greater escape distances when their eggs were a poorer pattern match to the background. Nightjars sit on their eggs until a potential threat is nearby, and, correspondingly, they showed greater escape distances when the pattern and color match of the incubating adult's plumage-rather than its eggs-was a poorer match to the background. Finally, escape distances were shorter in the middle of the day, suggesting that escape behavior is mediated by both camouflage and thermoregulation.

Escape rate for nonequilibrium processes dominated by strong non-detailed balance force

NASA Astrophysics Data System (ADS)

Tang, Ying; Xu, Song; Ao, Ping

2018-02-01

Quantifying the escape rate from a meta-stable state is essential to understand a wide range of dynamical processes. Kramers' classical rate formula is the product of an exponential function of the potential barrier height and a pre-factor related to the friction coefficient. Although many applications of the rate formula focused on the exponential term, the prefactor can have a significant effect on the escape rate in certain parameter regions, such as the overdamped limit and the underdamped limit. There have been continuous interests to understand the effect of non-detailed balance on the escape rate; however, how the prefactor behaves under strong non-detailed balance force remains elusive. In this work, we find that the escape rate formula has a vanishing prefactor with decreasing friction strength under the strong non-detailed balance limit. We both obtain analytical solutions in specific examples and provide a derivation for more general cases. We further verify the result by simulations and propose a testable experimental system of a charged Brownian particle in electromagnetic field. Our study demonstrates that a special care is required to estimate the effect of prefactor on the escape rate when non-detailed balance force dominates.

Transitions between three swimming gaits in Paramecium escape.

PubMed

Hamel, Amandine; Fisch, Cathy; Combettes, Laurent; Dupuis-Williams, Pascale; Baroud, Charles N

2011-05-03

Paramecium and other protists are able to swim at velocities reaching several times their body size per second by beating their cilia in an organized fashion. The cilia beat in an asymmetric stroke, which breaks the time reversal symmetry of small scale flows. Here we show that Paramecium uses three different swimming gaits to escape from an aggression, applied in the form of a focused laser heating. For a weak aggression, normal swimming is sufficient and produces a steady swimming velocity. As the heating amplitude is increased, a higher acceleration and faster swimming are achieved through synchronized beating of the cilia, which begin by producing oscillating swimming velocities and later give way to the usual gait. Finally, escape from a life-threatening aggression is achieved by a "jumping" gait, which does not rely on the cilia but is achieved through the explosive release of a group of trichocysts in the direction of the hot spot. Measurements through high-speed video explain the role of trichocysts in defending against aggressions while showing unexpected transitions in the swimming of microorganisms. These measurements also demonstrate that Paramecium optimizes its escape pattern by taking advantage of its inertia.

Transitions between three swimming gaits in Paramecium escape

PubMed Central

Hamel, Amandine; Fisch, Cathy; Combettes, Laurent; Dupuis-Williams, Pascale; Baroud, Charles N.

2011-01-01

Paramecium and other protists are able to swim at velocities reaching several times their body size per second by beating their cilia in an organized fashion. The cilia beat in an asymmetric stroke, which breaks the time reversal symmetry of small scale flows. Here we show that Paramecium uses three different swimming gaits to escape from an aggression, applied in the form of a focused laser heating. For a weak aggression, normal swimming is sufficient and produces a steady swimming velocity. As the heating amplitude is increased, a higher acceleration and faster swimming are achieved through synchronized beating of the cilia, which begin by producing oscillating swimming velocities and later give way to the usual gait. Finally, escape from a life-threatening aggression is achieved by a “jumping” gait, which does not rely on the cilia but is achieved through the explosive release of a group of trichocysts in the direction of the hot spot. Measurements through high-speed video explain the role of trichocysts in defending against aggressions while showing unexpected transitions in the swimming of microorganisms. These measurements also demonstrate that Paramecium optimizes its escape pattern by taking advantage of its inertia. PMID:21464291

Effects of photon escape on diagnostic diagrams for H II regions

NASA Astrophysics Data System (ADS)

Giammanco, C.; Beckman, J. E.; Cedrés, B.

2005-08-01

In this article we first outline the mounting evidence that a significant fraction of the ionizing photons emitted by OB stars within H ii regions escape from their immediate surroundings, i.e from what is normally defined as the H ii region, and explain how an H ii region structure containing high density contrast inhomogeneities facilitates this escape. Next we describe sets of models containing inhomogeneities which are used to predict tracks in the commonly used diagnostic diagrams (based on ratios of emission lines) whose only independent variable is the photon escape fraction, ξ. We show that the tracks produced by the models in two of the most cited of these diagrams conform well to the distribution of observed data points, with the models containing optically thick inhomogeneities (“CLUMPY” models) yielding somewhat better agreement than those with optically thin inhomogeneities (“FF” models). We show how variations in the ionization parameter U, derived from emission line ratios, could be due to photon escape, such that for a given region from which 50% of its ionizing photons leak out we would derive the same value of U as for a region with no photon escape but with an input ionizing flux almost an order of magnitude higher. This effect will occur whether the individual inhomogeneities are optically thick or thin. Photon escape will also lead to a change in the derived value of the radiation hardness parameter, and this change differs significantly between models with optically thin and optically thick clumps. Using a rather wide range of assumptions about the filling factor of dense clumps we find, for a selected set of regions observed in M 51 by Díaz et al. (1991) an extreme limiting range of computed photon escape fractions between near zero and 90%, but with the most plausible values ranging between 30% and 50%. We show, using oxygen as the test element, that models with different assumptions about the gas inhomogeneity will tend to give

Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lewis-Ballester, Ariel; Pham, Khoa N.; Batabyal, Dipanwita

Human indoleamine 2,3-dioxygenase 1 (hIDO1) is an attractive cancer immunotherapeutic target owing to its role in promoting tumoral immune escape. However, drug development has been hindered by limited structural information. Here, we report the crystal structures of hIDO1 in complex with its substrate, Trp, an inhibitor, epacadostat, and/or an effector, indole ethanol (IDE). The data reveal structural features of the active site (Sa) critical for substrate activation; in addition, they disclose a new inhibitor-binding mode and a distinct small molecule binding site (Si). Structure-guided mutation of a critical residue, F270, to glycine perturbs the Si site, allowing structural determination ofmore » an inhibitory complex, where both the Sa and Si sites are occupied by Trp. The Si site offers a novel target site for allosteric inhibitors and a molecular explanation for the previously baffling substrate-inhibition behavior of the enzyme. Taken together, the data open exciting new avenues for structure-based drug design.« less

Shuttle crew escape systems test conducted in JSC Bldg 9A CCT

NASA Image and Video Library

1987-03-20

Shuttle crew escape systems test is conducted by astronauts Steven R. Nagel (left) and Manley L. (Sonny) Carter in JSC One Gravity Mockup and Training Facilities Bldg 9A crew compartment trainer (CCT). Nagel and Carter are evaluating methods for crew escape during Space Shuttle controlled gliding flight. JSC test was done in advance of tests scheduled for facilities in California and Utah. Here, Carter serves as test subject evaluating egress positioning for the tractor rocket escape method - one of the two systems currently being closely studied by NASA.

Novel Small Molecule Entry Inhibitors of Ebola Virus

PubMed Central

Basu, Arnab; Mills, Debra M.; Mitchell, Daniel; Ndungo, Esther; Williams, John D.; Herbert, Andrew S.; Dye, John M.; Moir, Donald T.; Chandran, Kartik; Patterson, Jean L.; Rong, Lijun; Bowlin, Terry L.

2015-01-01

Background. The current Ebola virus (EBOV) outbreak has highlighted the troubling absence of available antivirals or vaccines to treat infected patients and stop the spread of EBOV. The EBOV glycoprotein (GP) plays critical roles in the early stage of virus infection, including receptor binding and membrane fusion, making it a potential target for the development of anti-EBOV drugs. We report the identification of 2 novel EBOV inhibitors targeting viral entry. Methods. To identify small molecule inhibitors of EBOV entry, we carried out a cell-based high-throughput screening using human immunodeficiency virus–based pseudotyped viruses expressing EBOV-GP. Two compounds were identified, and mechanism-of-action studies were performed using immunoflourescence, AlphaLISA, and enzymatic assays for cathepsin B inhibition. Results. We report the identification of 2 novel entry inhibitors. These inhibitors (1) inhibit EBOV infection (50% inhibitory concentration, approximately 0.28 and approximately 10 µmol/L) at a late stage of entry, (2) induce Niemann-Pick C phenotype, and (3) inhibit GP–Niemann-Pick C1 (NPC1) protein interaction. Conclusions. We have identified 2 novel EBOV inhibitors, MBX2254 and MBX2270, that can serve as starting points for the development of an anti-EBOV therapeutic agent. Our findings also highlight the importance of NPC1-GP interaction in EBOV entry and the attractiveness of NPC1 as an antifiloviral therapeutic target. PMID:26206510

Macrophage fusion is controlled by the cytoplasmic protein tyrosine phosphatase PTP-PEST/PTPN12.

PubMed

Rhee, Inmoo; Davidson, Dominique; Souza, Cleiton Martins; Vacher, Jean; Veillette, André

2013-06-01

Macrophages can undergo cell-cell fusion, leading to the formation of multinucleated giant cells and osteoclasts. This process is believed to promote the proteolytic activity of macrophages toward pathogens, foreign bodies, and extracellular matrices. Here, we examined the role of PTP-PEST (PTPN12), a cytoplasmic protein tyrosine phosphatase, in macrophage fusion. Using a macrophage-targeted PTP-PEST-deficient mouse, we determined that PTP-PEST was not needed for macrophage differentiation or cytokine production. However, it was necessary for interleukin-4-induced macrophage fusion into multinucleated giant cells in vitro. It was also needed for macrophage fusion following implantation of a foreign body in vivo. Moreover, in the RAW264.7 macrophage cell line, PTP-PEST was required for receptor activator of nuclear factor kappa-B ligand (RANKL)-triggered macrophage fusion into osteoclasts. PTP-PEST had no impact on expression of fusion mediators such as β-integrins, E-cadherin, and CD47, which enable macrophages to become fusion competent. However, it was needed for polarization of macrophages, migration induced by the chemokine CC chemokine ligand 2 (CCL2), and integrin-induced spreading, three key events in the fusion process. PTP-PEST deficiency resulted in specific hyperphosphorylation of the protein tyrosine kinase Pyk2 and the adaptor paxillin. Moreover, a fusion defect was induced upon treatment of normal macrophages with a Pyk2 inhibitor. Together, these data argue that macrophage fusion is critically dependent on PTP-PEST. This function is seemingly due to the ability of PTP-PEST to control phosphorylation of Pyk2 and paxillin, thereby regulating cell polarization, migration, and spreading.

Fusion proteins in head and neck neoplasms: Clinical implications, genetics, and future directions for targeting

PubMed Central

Escalante, Derek A.; Wang, He; Fundakowski, Christopher E.

2016-01-01

ABSTRACT Fusion proteins resulting from chromosomal rearrangements are known to drive the pathogenesis of a variety of hematological and solid neoplasms such as chronic myeloid leukemia and non-small-cell lung cancer. Efforts to elucidate the role they play in these malignancies have led to important diagnostic and therapeutic triumphs, including the famous development of the tyrosine kinase inhibitor dasatinib targeting the BCR-ABL fusion. Until recently, there has been a paucity of research investigating fusion proteins harbored by head and neck neoplasms. The discovery and characterization of novel fusion proteins in neoplasms originating from the thyroid, nasopharynx, salivary glands, and midline head and neck structures offer substantial contributions to our understanding of the pathogenesis and biological behavior of these neoplasms, while raising new therapeutic and diagnostic opportunities. Further characterization of these fusion proteins promises to facilitate advances on par with those already achieved with regard to hematologic malignancies in the precise, molecularly guided diagnosis and treatment of head and neck neoplasms. The following is a subsite specific review of the clinical implications of fusion proteins in head and neck neoplasms and the future potential for diagnostic targeting. PMID:27636353

Acquired and intrinsic BRAF inhibitor resistance in BRAF V600E mutant melanoma

PubMed Central

Fedorenko, Inna V.; Paraiso, Kim H. T.; Smalley, Keiran S. M.

2014-01-01

The discovery of activating BRAF V600E mutations in 50% of all cutaneous melanomas has revolutionized the understanding of melanoma biology and provided new strategies for the therapeutic management of this deadly disease. Highly potent small molecule inhibitors of BRAF are now showing great promise as a novel therapeutic strategy for melanomas harboring activating BRAF V600E mutations and are associated with high levels of response. This commentary article discusses the latest data on the role of mutated BRAF in the development and progression of melanoma as the basis for understanding the mechanism of action of BRAF inhibitors in the preclinical and clinical settings. We further address the issue of BRAF inhibitor resistance and outline the latest insights into the mechanisms of therapeutic escape as well as describing approaches to prevent and abrogate the onset of both intrinsic and acquired drug resistance. It is likely that our evolving understanding of melanoma genetics and signaling will allow for the further personalization of melanoma therapy with the goal of improving clinical responses. PMID:21635872

Perturbation biology nominates upstream–downstream drug combinations in RAF inhibitor resistant melanoma cells

PubMed Central

Korkut, Anil; Wang, Weiqing; Demir, Emek; Aksoy, Bülent Arman; Jing, Xiaohong; Molinelli, Evan J; Babur, Özgün; Bemis, Debra L; Onur Sumer, Selcuk; Solit, David B; Pratilas, Christine A; Sander, Chris

2015-01-01

Resistance to targeted cancer therapies is an important clinical problem. The discovery of anti-resistance drug combinations is challenging as resistance can arise by diverse escape mechanisms. To address this challenge, we improved and applied the experimental-computational perturbation biology method. Using statistical inference, we build network models from high-throughput measurements of molecular and phenotypic responses to combinatorial targeted perturbations. The models are computationally executed to predict the effects of thousands of untested perturbations. In RAF-inhibitor resistant melanoma cells, we measured 143 proteomic/phenotypic entities under 89 perturbation conditions and predicted c-Myc as an effective therapeutic co-target with BRAF or MEK. Experiments using the BET bromodomain inhibitor JQ1 affecting the level of c-Myc protein and protein kinase inhibitors targeting the ERK pathway confirmed the prediction. In conclusion, we propose an anti-cancer strategy of co-targeting a specific upstream alteration and a general downstream point of vulnerability to prevent or overcome resistance to targeted drugs. DOI: http://dx.doi.org/10.7554/eLife.04640.001 PMID:26284497

Development of three-layered rumen escapable capsules for cattle

PubMed Central

SEYAMA, Tomohiro; HIRAYASU, Hirofumi; YAMAWAKI, Kenji; ADACHI, Takuhiko; SUGIMOTO, Takayuki; KASAI, Koji

2016-01-01

A new rumen escapable tool is presented for cattle in prospect of developing medical treatment or supplementing trace elements for disease prevention. This tool consists of a three-layered capsule that dissolves in the lower digestive tract, but not in the rumen. The capsule was manufactured by capsule-forming techniques through the use of liquid surface tension. This method does not involve high-temperature treatment, so the capsule can contain not only lipophilic substances but also hydrophilic or heat-sensitive substances. Furthermore, the capsule has a specific gravity of 1.3 and diameter of 6.0 mm, which were previously shown to be appropriate to avoid rumination. The objective of this study was to confirm the effectiveness of the capsule pertinent to rumen escaping. In order to validate rumen escape, capsules containing 30 g of water-soluble vitamin (thiamine hydrochloride) per head were administered to four lactating cows assigned in a crossover trial. In the group administered encapsulated thiamine hydrochloride, blood thiamine levels increased from 12.4 ± 1.03 ng/ml before administration to 54.8 ± 2.21 ng/ml at 6 hr following administration, whereas the level remained at 13.3 ± 2.05 ng/ml in the control group administered via aqueous solution. This indicates that the three-layered capsules passed through the rumen and dissolved in the lower digestive tract, thus functioning as a rumen escapable tool. PMID:27546371

Noise induced escape from a nonhyperbolic chaotic attractor of a periodically driven nonlinear oscillator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Zhen, E-mail: czkillua@icloud.com, E-mail: xbliu@nuaa.edu.cn; Li, Yang; Liu, Xianbin, E-mail: czkillua@icloud.com, E-mail: xbliu@nuaa.edu.cn

2016-06-15

Noise induced escape from the domain of attraction of a nonhyperbolic chaotic attractor in a periodically excited nonlinear oscillator is investigated. The general mechanism of the escape in the weak noise limit is studied in the continuous case, and the fluctuational path is obtained by statistical analysis. Selecting the primary homoclinic tangency as the initial condition, the action plot is presented by parametrizing the set of escape trajectories and the global minimum gives rise to the optimal path. Results of both methods show good agreements. The entire process of escape is discussed in detail step by step using the fluctuationalmore » force. A structure of hierarchical heteroclinic crossings of stable and unstable manifolds of saddle cycles is found, and the escape is observed to take place through successive jumps through this deterministic hierarchical structure.« less

Fusion 2.0: The Next Generation of Fusion in California: Aligning State and Regional Fusion Centers

DTIC Science & Technology

2010-03-01

bible ” for fusion center management, as evidenced by the theme of the 2009 National Fusion Center Conference; appropriately called “Achieving Baseline...NAVAL POSTGRADUATE SCHOOL MONTEREY, CALIFORNIA THESIS FUSION 2.0: THE NEXT GENERATION OF FUSION IN CALIFORNIA: ALIGNING STATE AND...Master’s Thesis 4. TITLE AND SUBTITLE Fusion 2.0: The Next Generation of Fusion in California: Aligning State and Regional Fusion

A Substantial Plume of Escaping Planetary Ions in the MSE Northern Hemisphere Observed by MAVEN

NASA Astrophysics Data System (ADS)

Dong, Y.; Fang, X.; Brain, D. A.; McFadden, J. P.; Halekas, J. S.; Connerney, J. E. P.; Curry, S.; Harada, Y.; Luhmann, J. G.; Jakosky, B. M.

2015-12-01

The Mars-solar wind interaction accelerates and transports planetary ions away from Mars through a number of processes, including pick-up by the electromagnetic fields. The Mars Atmospheric and Volatile EvolutioN (MAVEN) spacecraft has frequently detected strong escaping planetary ion fluxes in both tailward and upstream solar wind motional electric field directions since the beginning of its science phase in November 2014. Our statistical study using three-month MAVEN data from November 2014 through February 2015 illustrates a substantial plume-like escaping planetary ion population organized by the upstream electric field with strong fluxes widely distributed in the northern hemisphere of the Mars-Sun-Electric-field (MSE) coordinate system, which is generally consistent with model predictions. The plume constitutes an important planetary ion escape channel from the Martian atmosphere in addition to the tailward escape. The >25eV O+ escape rate through the plume is estimated to be ~35% of the tailward escape and ~25% of the total escape. We will compare the dynamics of the plume and tailward escaping ions based on their velocity-space distributions with respect to the electromagnetic fields. We will also discuss the variations of the plume characteristics between different ion species (O+, O2+, and CO2+) and from the effect of different solar wind and interplanetary magnetic field (IMF) conditions.

Energy transfer in O collisions with He isotopes and helium escape from Mars

NASA Astrophysics Data System (ADS)

Bovino, S.; Zhang, P.; Kharchenko, V.; Dalgarno, A.

2010-12-01

Helium is one of the dominant constituents in the upper atmosphere of Mars [1]. Thermal (Jeans’) escape of He is negligible on Mars [2] and major mechanism of escape is related to the collisional ejection of He atoms by energetic oxygen. Collisional ejection dominates over ion-related mechanisms [3] and evaluation of the escape flux of neutral He becomes an important issue. The dissociative recombination of O2+ is considered to be the major source of energetic oxygen atoms [4]. We report accurate data on energy-transfer collisions between hot oxygen atoms and the atmospheric helium gas. Angular dependent scattering cross sections for elastic collisions of O(3P) and O(1D) atoms with helium gas have been calculated quantum mechanically and found to be surprisingly similar. Cross sections, computed for collisions with both helium isotopes, 3He and 4He, have been used to construct the kernel of the Boltzmann equation, describing the energy relaxation of hot oxygen atoms. Computed rates of energy transfer in O + He collisions have been used to evaluate the flux of He atoms escaping from the Mars atmosphere at different solar conditions. We have identified atmospheric layers mostly responsible for production of the He escape flux. Our results are consistent with recent data from Monte Carlo simulations of the escape of O atoms: strong angular anisotropy of atomic cross sections leads to an increased transparency of the upper atmosphere for escaping O flux [5] and stimulate the collisional ejection of He atoms. References [1] Krasnopolsky, V. A., and G. R. Gladstone (2005), Helium on Mars and Venus: EUVE observations and modeling, Icarus, 176, 395. [2] Chassefiere E. and F. Leblanc (2004), Mars atmospheric escape and evolution; interaction with the solar wind, Planetary and Space Science, 52, 1039 [3] Krasnopolsky, V. (2010), Solar activity variations of thermospheric temperatures on Mars and a problem of CO in the lower atmoshpere, Icarus, 207, 638. [4] Fox, J. L

Inner/Outer nuclear membrane fusion in nuclear pore assembly: biochemical demonstration and molecular analysis.

PubMed

Fichtman, Boris; Ramos, Corinne; Rasala, Beth; Harel, Amnon; Forbes, Douglass J

2010-12-01

Nuclear pore complexes (NPCs) are large proteinaceous channels embedded in double nuclear membranes, which carry out nucleocytoplasmic exchange. The mechanism of nuclear pore assembly involves a unique challenge, as it requires creation of a long-lived membrane-lined channel connecting the inner and outer nuclear membranes. This stabilized membrane channel has little evolutionary precedent. Here we mapped inner/outer nuclear membrane fusion in NPC assembly biochemically by using novel assembly intermediates and membrane fusion inhibitors. Incubation of a Xenopus in vitro nuclear assembly system at 14°C revealed an early pore intermediate where nucleoporin subunits POM121 and the Nup107-160 complex were organized in a punctate pattern on the inner nuclear membrane. With time, this intermediate progressed to diffusion channel formation and finally to complete nuclear pore assembly. Correct channel formation was blocked by the hemifusion inhibitor lysophosphatidylcholine (LPC), but not if a complementary-shaped lipid, oleic acid (OA), was simultaneously added, as determined with a novel fluorescent dextran-quenching assay. Importantly, recruitment of the bulk of FG nucleoporins, characteristic of mature nuclear pores, was not observed before diffusion channel formation and was prevented by LPC or OA, but not by LPC+OA. These results map the crucial inner/outer nuclear membrane fusion event of NPC assembly downstream of POM121/Nup107-160 complex interaction and upstream or at the time of FG nucleoporin recruitment.

Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia

PubMed Central

Boer, Judith M.; Steeghs, Elisabeth M.P.; Marchante, João R.M.; Boeree, Aurélie; Beaudoin, James J.; Berna Beverloo, H.; Kuiper, Roland P.; Escherich, Gabriele; van der Velden, Vincent H.J.; van der Schoot, C. Ellen; de Groot-Kruseman, Hester A.; Pieters, Rob; den Boer, Monique L.

2017-01-01

Approximately 15% of pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by gene expression similar to that of BCR-ABL1-positive disease and unfavorable prognosis. This BCR-ABL1-like subtype shows a high frequency of B-cell development gene aberrations and tyrosine kinase-activating lesions. To evaluate the clinical significance of tyrosine kinase gene fusions in children with BCP-ALL, we studied the frequency of recently identified tyrosine kinase fusions, associated genetic features, and prognosis in a representative Dutch/German cohort. We identified 14 tyrosine kinase fusions among 77 BCR-ABL1-like cases (18%) and none among 76 non-BCR-ABL1-like B-other cases. Novel exon fusions were identified for RCSD1-ABL2 and TERF2-JAK2. JAK2 mutation was mutually exclusive with tyrosine kinase fusions and only occurred in cases with high CRLF2 expression. The non/late response rate and levels of minimal residual disease in the fusion-positive BCR-ABL1-like group were higher than in the non-BCR-ABL1-like B-others (p<0.01), and also higher, albeit not statistically significant, compared with the fusion-negative BCR-ABL1-like group. The 8-year cumulative incidence of relapse in the fusion-positive BCR-ABL1-like group (35%) was comparable with that in the fusion-negative BCR-ABL1-like group (35%), and worse than in the non-BCR-ABL1-like B-other group (17%, p=0.07). IKZF1 deletions, predominantly other than the dominant-negative isoform and full deletion, co-occurred with tyrosine kinase fusions. This study shows that tyrosine kinase fusion-positive cases are a high-risk subtype of BCP-ALL, which warrants further studies with specific kinase inhibitors to improve outcome. PMID:27894077

Analysis of Snail1 function and regulation by Twist1 in palatal fusion.

PubMed

Yu, Wenli; Zhang, Yanping; Ruest, L Bruno; Svoboda, Kathy K H

2013-01-01

Palatal fusion is a tightly controlled process which comprises multiple cellular events, including cell movement and differentiation. Midline epithelial seam (MES) degradation is essential to palatal fusion. In this study, we analyzed the function of Snail1 during the degradation of the MES. We also analyzed the mechanism regulating the expression of the Snail1 gene in palatal shelves. Palatal explants treated with Snail1 siRNA did not degrade the MES and E-cadherin was not repressed leading to failure of palatal fusion. Transforming growth factor beta 3 (Tgfβ3) regulated Snail1 mRNA, as Snail1 expression decreased in response to Tgfβ3 neutralizing antibody and a PI-3 kinase (PI3K) inhibitor. Twist1, in collaboration with E2A factors, regulated the expression of Snail1. Twist1/E47 dimers bond to the Snail1 promoter to activate expression. Without E47, Twist1 repressed Snail1 expression. These results support the hypothesis that Tgfβ3 may signal through Twist1 and then Snail1 to downregulate E-cadherin expression during palatal fusion.

Escape from Albuquerque: An Apache Memorate.

ERIC Educational Resources Information Center

Greenfeld, Philip J.

2001-01-01

Clarence Hawkins, a White Mountain Apache, escaped from the Albuquerque Indian School around 1920. His 300-mile trip home, made with two other boys, exemplifies the reaction of many Indian youths to the American government's plans for cultural assimilation. The tale is told in the form of traditional Apache narrative. (TD)

Fluctuating bottleneck model studies on kinetics of DNA escape from α-hemolysin nanopores

NASA Astrophysics Data System (ADS)

Bian, Yukun; Wang, Zilin; Chen, Anpu; Zhao, Nanrong

2015-11-01

We have proposed a fluctuation bottleneck (FB) model to investigate the non-exponential kinetics of DNA escape from nanometer-scale pores. The basic idea is that the escape rate is proportional to the fluctuating cross-sectional area of DNA escape channel, the radius r of which undergoes a subdiffusion dynamics subjected to fractional Gaussian noise with power-law memory kernel. Such a FB model facilitates us to obtain the analytical result of the averaged survival probability as a function of time, which can be directly compared to experimental results. Particularly, we have applied our theory to address the escape kinetics of DNA through α-hemolysin nanopores. We find that our theoretical framework can reproduce the experimental results very well in the whole time range with quite reasonable estimation for the intrinsic parameters of the kinetics processes. We believe that FB model has caught some key features regarding the long time kinetics of DNA escape through a nanopore and it might provide a sound starting point to study much wider problems involving anomalous dynamics in confined fluctuating channels.

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

PubMed

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.

Monocyte-lymphocyte fusion induced by the HIV-1 envelope generates functional heterokaryons with an activated monocyte-like phenotype.

PubMed

Martínez-Méndez, David; Rivera-Toledo, Evelyn; Ortega, Enrique; Licona-Limón, Ileana; Huerta, Leonor

2017-03-01

Enveloped viruses induce cell-cell fusion when infected cells expressing viral envelope proteins interact with target cells, or through the contact of cell-free viral particles with adjoining target cells. CD4 + T lymphocytes and cells from the monocyte-macrophage lineage express receptors for HIV envelope protein. We have previously reported that lymphoid Jurkat T cells expressing the HIV-1 envelope protein (Env) can fuse with THP-1 monocytic cells, forming heterokaryons with a predominantly myeloid phenotype. This study shows that the expression of monocytic markers in heterokaryons is stable, whereas the expression of lymphoid markers is mostly lost. Like THP-1 cells, heterokaryons exhibited FcγR-dependent phagocytic activity and showed an enhanced expression of the activation marker ICAM-1 upon stimulation with PMA. In addition, heterokaryons showed morphological changes compatible with maturation, and high expression of the differentiation marker CD11b in the absence of differentiation-inducing agents. No morphological change nor increase in CD11b expression were observed when an HIV-fusion inhibitor blocked fusion, or when THP-1 cells were cocultured with Jurkat cells expressing a non-fusogenic Env protein, showing that differentiation was not induced merely by cell-cell interaction but required cell-cell fusion. Inhibition of TLR2/TLR4 signaling by a TIRAP inhibitor greatly reduced the expression of CD11b in heterokaryons. Thus, lymphocyte-monocyte heterokaryons induced by HIV-1 Env are stable and functional, and fusion prompts a phenotype characteristic of activated monocytes via intracellular TLR2/TLR4 signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

Viral Membrane Fusion and Nucleocapsid Delivery into the Cytoplasm are Distinct Events in Some Flaviviruses

PubMed Central

Nour, Adel M.; Li, Yue; Wolenski, Joseph; Modis, Yorgo

2013-01-01

Flaviviruses deliver their genome into the cell by fusing the viral lipid membrane to an endosomal membrane. The sequence and kinetics of the steps required for nucleocapsid delivery into the cytoplasm remain unclear. Here we dissect the cell entry pathway of virions and virus-like particles from two flaviviruses using single-particle tracking in live cells, a biochemical membrane fusion assay and virus infectivity assays. We show that the virus particles fuse with a small endosomal compartment in which the nucleocapsid remains trapped for several minutes. Endosomal maturation inhibitors inhibit infectivity but not membrane fusion. We propose a flavivirus cell entry mechanism in which the virus particles fuse preferentially with small endosomal carrier vesicles and depend on back-fusion of the vesicles with the late endosomal membrane to deliver the nucleocapsid into the cytoplasm. Virus entry modulates intracellular calcium release and phosphatidylinositol-3-phosphate kinase signaling. Moreover, the broadly cross-reactive therapeutic antibody scFv11 binds to virus-like particles and inhibits fusion. PMID:24039574

Photochemical escape of oxygen from Mars: First results from MAVEN in situ data

NASA Astrophysics Data System (ADS)

Lillis, Robert J.; Deighan, Justin; Fox, Jane L.; Bougher, Stephen W.; Lee, Yuni; Combi, Michael R.; Cravens, Thomas E.; Rahmati, Ali; Mahaffy, Paul R.; Benna, Mehdi; Elrod, Meredith K.; McFadden, James P.; Ergun, Robert. E.; Andersson, Laila; Fowler, Christopher M.; Jakosky, Bruce M.; Thiemann, Ed; Eparvier, Frank; Halekas, Jasper S.; Leblanc, François; Chaufray, Jean-Yves

2017-03-01

Photochemical escape of atomic oxygen is thought to be one of the dominant channels for Martian atmospheric loss today and played a potentially major role in climate evolution. Mars Atmosphere and Volatile Evolution Mission (MAVEN) is the first mission capable of measuring, in situ, the relevant quantities necessary to calculate photochemical escape fluxes. We utilize 18 months of data from three MAVEN instruments: Langmuir Probe and Waves, Neutral Gas and Ion Mass Spectrometer, and SupraThermal And Thermal Ion Composition. From these data, we calculate altitude profiles of the production rate of hot oxygen atoms from the dissociative recombination of O2+ and the probability that such atoms will escape the Mars atmosphere. From this, we determine escape fluxes for 815 periapsis passes. Derived average dayside hot O escape rates range from 1.2 to 5.5 × 1025 s-1, depending on season and EUV flux, consistent with several pre-MAVEN predictions and in broad agreement with estimates made with other MAVEN measurements. Hot O escape fluxes do not vary significantly with dayside solar zenith angle or crustal magnetic field strength but depend on CO2 photoionization frequency with a power law whose exponent is 2.6 ± 0.6, an unexpectedly high value which may be partially due to seasonal and geographic sampling. From this dependence and historical EUV measurements over 70 years, we estimate a modern-era average escape rate of 4.3 × 1025 s-1. Extrapolating this dependence to early solar system, EUV conditions gives total losses of 13, 49, 189, and 483 mbar of oxygen over 1-3 and 3.5 Gyr, respectively, with uncertainties significantly increasing with time in the past.

P2X1 Receptor Antagonists Inhibit HIV-1 Fusion by Blocking Virus-Coreceptor Interactions

PubMed Central

Giroud, Charline; Marin, Mariana; Hammonds, Jason; Spearman, Paul

2015-01-01

ABSTRACT HIV-1 Env glycoprotein-mediated fusion is initiated upon sequential binding of Env to CD4 and the coreceptor CXCR4 or CCR5. Whereas these interactions are thought to be necessary and sufficient to promote HIV-1 fusion, other host factors can modulate this process. Previous studies reported potent inhibition of HIV-1 fusion by selective P2X1 receptor antagonists, including NF279, and suggested that these receptors play a role in HIV-1 entry. Here we investigated the mechanism of antiviral activity of NF279 and found that this compound does not inhibit HIV-1 fusion by preventing the activation of P2X1 channels but effectively blocks the binding of the virus to CXCR4 or CCR5. The notion of an off-target effect of NF279 on HIV-1 fusion is supported by the lack of detectable expression of P2X1 receptors in cells used in fusion experiments and by the fact that the addition of ATP or the enzymatic depletion of ATP in culture medium does not modulate viral fusion. Importantly, NF279 fails to inhibit HIV-1 fusion with cell lines and primary macrophages when added at an intermediate stage downstream of Env-CD4-coreceptor engagement. Conversely, in the presence of NF279, HIV-1 fusion is arrested downstream of CD4 binding but prior to coreceptor engagement. NF279 also antagonizes the signaling function of CCR5, CXCR4, and another chemokine receptor, as evidenced by the suppression of calcium responses elicited by specific ligands and by recombinant gp120. Collectively, our results demonstrate that NF279 is a dual HIV-1 coreceptor inhibitor that interferes with the functional engagement of CCR5 and CXCR4 by Env. IMPORTANCE Inhibition of P2X receptor activity suppresses HIV-1 fusion and replication, suggesting that P2X signaling is involved in HIV-1 entry. However, mechanistic experiments conducted in this study imply that P2X1 receptor is not expressed in target cells or involved in viral fusion. Instead, we found that inhibition of HIV-1 fusion by a specific P2X1

P2X1 Receptor Antagonists Inhibit HIV-1 Fusion by Blocking Virus-Coreceptor Interactions.

PubMed

Giroud, Charline; Marin, Mariana; Hammonds, Jason; Spearman, Paul; Melikyan, Gregory B

2015-09-01

HIV-1 Env glycoprotein-mediated fusion is initiated upon sequential binding of Env to CD4 and the coreceptor CXCR4 or CCR5. Whereas these interactions are thought to be necessary and sufficient to promote HIV-1 fusion, other host factors can modulate this process. Previous studies reported potent inhibition of HIV-1 fusion by selective P2X1 receptor antagonists, including NF279, and suggested that these receptors play a role in HIV-1 entry. Here we investigated the mechanism of antiviral activity of NF279 and found that this compound does not inhibit HIV-1 fusion by preventing the activation of P2X1 channels but effectively blocks the binding of the virus to CXCR4 or CCR5. The notion of an off-target effect of NF279 on HIV-1 fusion is supported by the lack of detectable expression of P2X1 receptors in cells used in fusion experiments and by the fact that the addition of ATP or the enzymatic depletion of ATP in culture medium does not modulate viral fusion. Importantly, NF279 fails to inhibit HIV-1 fusion with cell lines and primary macrophages when added at an intermediate stage downstream of Env-CD4-coreceptor engagement. Conversely, in the presence of NF279, HIV-1 fusion is arrested downstream of CD4 binding but prior to coreceptor engagement. NF279 also antagonizes the signaling function of CCR5, CXCR4, and another chemokine receptor, as evidenced by the suppression of calcium responses elicited by specific ligands and by recombinant gp120. Collectively, our results demonstrate that NF279 is a dual HIV-1 coreceptor inhibitor that interferes with the functional engagement of CCR5 and CXCR4 by Env. Inhibition of P2X receptor activity suppresses HIV-1 fusion and replication, suggesting that P2X signaling is involved in HIV-1 entry. However, mechanistic experiments conducted in this study imply that P2X1 receptor is not expressed in target cells or involved in viral fusion. Instead, we found that inhibition of HIV-1 fusion by a specific P2X1 receptor antagonist, NF

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

PubMed

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.

The Impact of Escaped Farmed Atlantic Salmon (Salmo salar L.) on Catch Statistics in Scotland

PubMed Central

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. PMID:22970132

Amplification of the Gp41 gene for detection of mutations conferring resistance to HIV-1 fusion inhibitors on genotypic assay

NASA Astrophysics Data System (ADS)

Tanumihardja, J.; Bela, B.

2017-08-01

Fusion inhibitors have potential for future use in HIV control programs in Indonesia, so the capacity to test resistance to such drugs needs to be developed. Resistance-detection with a genotypic assay began with amplification of the target gene, gp41. Based on the sequence of the two most common HIV subtypes in Indonesia, AE and B, a primer pair was designed. Plasma samples containing both subtypes were extracted to obtain HIV RNA. Using PCR, the primer pair was used to produce the amplification product, the identity of which was checked based on length under electrophoresis. Eleven plasma samples were included in this study. One-step PCR using the primer pair was able to amplify gp41 from 54.5% of the samples, and an unspecific amplification product was seen in 1.1% of the samples. Amplification failed in 36.4% of the samples, which may be due to an inappropriate primer sequence. It was also found that the optimal annealing temperature for producing the single expected band was 57.2 °C. With one-step PCR, the designed primer pair amplified the HIV-1 gp41 gene from subtypes AE and B. However, further research should be done to determine the conditions that will increase the sensitivity and specificity of the amplification process.

Constraining Lyman continuum escape using Machine Learning

NASA Astrophysics Data System (ADS)

Giri, Sambit K.; Zackrisson, Erik; Binggeli, Christian; Pelckmans, Kristiaan; Cubo, Rubén; Mellema, Garrelt

2018-05-01

The James Webb Space Telescope (JWST) will observe the rest-frame ultraviolet/optical spectra of galaxies from the epoch of reionization (EoR) in unprecedented detail. While escaping into the intergalactic medium, hydrogen-ionizing (Lyman continuum; LyC) photons from the galaxies will contribute to the bluer end of the UV slope and make nebular emission lines less prominent. We present a method to constrain leakage of the LyC photons using the spectra of high redshift (z >~ 6) galaxies. We simulate JWST/NIRSpec observations of galaxies at z =6-9 by matching the fluxes of galaxies observed in the Frontier Fields observations of galaxy cluster MACS-J0416. Our method predicts the escape fraction fesc with a mean absolute error Δfesc ~ 0.14. The method also predicts the redshifts of the galaxies with an error .

Competing Contingencies for Escape Behavior: Effects of Negative Reinforcement Magnitude and Quality

ERIC Educational Resources Information Center

Hammond, Jennifer L.

2009-01-01

Previous research has shown that problem behavior maintained by social-negative reinforcement can be treated without escape extinction by enhancing the quality of positive reinforcement for an appropriate alternative response such as compliance. By contrast, negative reinforcement (escape) for compliance generally has been ineffective in the…

Cytokinin is required for escape but not release from auxin mediated apical dominance

PubMed Central

Müller, Dörte; Waldie, Tanya; Miyawaki, Kaori; To, Jennifer PC; Melnyk, Charles W; Kieber, Joseph J; Kakimoto, Tatsuo; Leyser, Ottoline

2015-01-01

Auxin produced by an active primary shoot apex is transported down the main stem and inhibits the growth of the axillary buds below it, contributing to apical dominance. Here we use Arabidopsis thaliana cytokinin (CK) biosynthetic and signalling mutants to probe the role of CK in this process. It is well established that bud outgrowth is promoted by CK, and that CK synthesis is inhibited by auxin, leading to the hypothesis that release from apical dominance relies on an increased supply of CK to buds. Our data confirm that decapitation induces the expression of at least one ISOPENTENYLTRANSFERASE (IPT) CK biosynthetic gene in the stem. We further show that transcript abundance of a clade of the CK-responsive type-A Arabidopsis response regulator (ARR) genes increases in buds following CK supply, and that, contrary to their typical action as inhibitors of CK signalling, these genes are required for CK-mediated bud activation. However, analysis of the relevant arr and ipt multiple mutants demonstrates that defects in bud CK response do not affect auxin-mediated bud inhibition, and increased IPT transcript levels are not needed for bud release following decapitation. Instead, our data suggest that CK acts to overcome auxin-mediated bud inhibition, allowing buds to escape apical dominance under favourable conditions, such as high nitrate availability. Significance Statement It has been proposed that the release of buds from auxin-mediated apical dominance following decapitation requires increased cytokinin biosynthesis and consequent increases in cytokinin supply to buds. Here we show that in Arabidopsis, increases in cytokinin appear to be unnecessary for the release of buds from apical dominance, but rather allow buds to escape the inhibitory effect of apical auxin, thereby promoting bud activation in favourable growth conditions. PMID:25904120

A Maltose-Binding Protein Fusion Construct Yields a Robust Crystallography Platform for MCL1

PubMed Central

Clifton, Matthew C.; Dranow, David M.; Leed, Alison; Fulroth, Ben; Fairman, James W.; Abendroth, Jan; Atkins, Kateri A.; Wallace, Ellen; Fan, Dazhong; Xu, Guoping; Ni, Z. J.; Daniels, Doug; Van Drie, John; Wei, Guo; Burgin, Alex B.; Golub, Todd R.; Hubbard, Brian K.; Serrano-Wu, Michael H.

2015-01-01

Crystallization of a maltose-binding protein MCL1 fusion has yielded a robust crystallography platform that generated the first apo MCL1 crystal structure, as well as five ligand-bound structures. The ability to obtain fragment-bound structures advances structure-based drug design efforts that, despite considerable effort, had previously been intractable by crystallography. In the ligand-independent crystal form we identify inhibitor binding modes not observed in earlier crystallographic systems. This MBP-MCL1 construct dramatically improves the structural understanding of well-validated MCL1 ligands, and will likely catalyze the structure-based optimization of high affinity MCL1 inhibitors. PMID:25909780

Non-thermal escape rates of atmospheric H and D from Mars using MAVEN data

NASA Astrophysics Data System (ADS)

Gacesa, M.; Zahnle, K. J.

2017-12-01

Geological evidence suggests that an ocean of liquid water existed on Mars until at least middle to late Noachian era (4.1 to 3.8 Ga) and possibly, at least episodically, as late as Hesperian. Between 67% and 87% of the total primordial amount of water, equal to about 70 to 110 meters equivalent (spread over the entire Mars' surface), is believed to have escape to space, while about 35 meters remains on or beneath the surface as water ice. Establishing better constraints on these numbers and identifying the responsible atmospheric loss processes remains the major objective of NASA's Mars Atmosphere and Volatile EvolutioN (MAVEN) mission. The ratio of atmospheric Deuterium and Hydrogen (D/H) on Mars is one of the best indicators of water loss to space. While majority of H and D escape through thermal Jeans escape, up to 10% of D can escape to space via non-thermal mechanisms, such as collisions with superthermal neutral atoms. In this study, we present new estimates of non-thermal escape rates of light molecules of interest to the water evolution, including H2, HD, OH, and OD, based on recent measurements of atmospheric density and temperature profiles by MAVEN. The escape mechanisms considered include photochemical sources of hot O, as well as collisions with energetic neutral atoms produced in charge-exchange of solar wind ions with atmospheric gases1,2. Energy transport and escape rates are modeled using quantum reactive scattering formalism3 and seasonal variations are illustrated. Finally, a simple estimate of the role of the non-thermal escape mechanisms in previous eras is given. We conclude that D escape rates can be affected by the non-thermal processes with consequences on the estimates of primordial water inventory based on the D/H ratio. [1] N. Lewkow and V. Kharchenko, Astroph. J., 790, 98 (2014) [2] M. Gacesa, N. Lewkow, V. Kharchenko, Icarus 284, 90 (2017) [3] M. Gacesa and V. Kharchenko, Geophys. Res. Lett., 39, L10203 (2012)

Studying Lyman-alpha escape and reionization in Green Pea galaxies

NASA Astrophysics Data System (ADS)

Yang, Huan; Malhotra, Sangeeta; Rhoads, James E.; Gronke, Max; Leitherer, Claus; Wofford, Aida; Dijkstra, Mark

2017-01-01

Green Pea galaxies are low-redshift galaxies with extreme [OIII]5007 emission line. We built the first statistical sample of Green Peas observed by HST/COS and used them as analogs of high-z Lyman-alpha emitters to study Ly-alpha escape and Ly-alpha sizes. Using the HST/COS 2D spectra, we found that Ly-alpha sizes of Green Peas are larger than the UV continuum sizes. We found many correlations between Ly-alpha escape fraction and galactic properties -- dust extinction, Ly-alpha kinematic features, [OIII]/[OII] ratio, and gas outflow velocities. We fit an empirical relation to predict Ly-alpha escape fraction from dust extinction and Ly-alpha red-peak velocity. In the JWST era, we can use this relation to derive the IGM HI column density along the line of sight of each high-z Ly-alpha emitter and probe the reionization process.

Bovine Pancreatic Trypsin Inhibitor-Trypsin Complex as a Detection System for Recombinant Proteins

NASA Astrophysics Data System (ADS)

Borjigin, Jimo; Nathans, Jeremy

1993-01-01

Bovine pancreatic trypsin inhibitor (BPTI) binds to trypsin and anhydrotrypsin (an enzymatically inactive derivative of trypsin) with affinities of 6 x 10-14 and 1.1 x 10-13 M, respectively. We have taken advantage of the high affinity and specificity of this binding reaction to develop a protein tagging system in which biotinylated trypsin or biotinylated anhydrotrypsin is used as the reagent to detect recombinant fusion proteins into which BPTI has been inserted. Two proteins, opsin and growth hormone, were used as targets for insertional mutagenesis with BPTI. In each case, both domains of the fusion protein appear to be correctly folded. The fusion proteins can be specifically and efficiently detected by biotinylated trypsin or biotinylated anhydrotrypsin, as demonstrated by staining of transfected cells, protein blotting, affinity purification, and a mobility shift assay in SDS/polyacrylamide gels.

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

NASA Astrophysics Data System (ADS)

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.

Survival in emergency escape from passenger aircraft.

DOT National Transportation Integrated Search

1970-10-01

The human factors data from three aircraft accidents involving emergency evacuations are reviewed. Of the 261 passengers aboard, 105 died in attempts to escape during the 1- to 3-minutes prior to the build-up of a lethal thermotoxic environment withi...

Learning from escaped prescribed fire reviews

Treesearch

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...

Helium escape from the Earth's atmosphere - The charge exchange mechanism revisited

NASA Technical Reports Server (NTRS)

Lie-Svendsen, O.; Rees, M. H.; Stamnes, K.

1992-01-01

We have studied the escape of neutral helium from the terrestrial atmosphere through exothermic charge exchange reactions between He(+) ions and the major atmospheric constituents N2, O2 and O. Elastic collisions with the neutral background particles were treated quantitatively using a recently developed kinetic theory approach. An interhemispheric plasma transport model was employed to provide a global distribution of He(+) ions as a function of altitude, latitude and local solar time and for different levels of solar ionization. Combining these ion densities with neutral densities from an MSIS model and best estimates for the reaction rate coefficients of the charge exchange reactions, we computed the global distribution of the neutral He escape flux. The escape rates show large diurnal and latitudinal variations, while the global average does not vary by more than a factor of three over a solar cycle. We find that this escape mechanism is potentially important for the overall balance of helium in the Earth's atmosphere. However, more accurate values for the reaction rate coefficients of the charge exchange reactions are required to make a definitive assessment of its importance.

Never ever? Characteristics, outcomes and motivations of patients who abscond or escape: A 5-year review of escapes and absconds from two medium and low secure forensic units.

PubMed

Mezey, Gillian; Durkin, Catherine; Dodge, Liam; White, Sarah

2015-12-01

Absconds and escapes by psychiatric patients from secure forensic psychiatric settings create public anxiety and are poorly understood. To describe secure hospital patients who escape from within the secure perimeter or abscond, and test for differences between these groups. Escapes and absconds between 2008 and 2012 from the medium and low secure forensic psychiatric inpatient units of two London National Health Service Trusts were identified through the Trusts' databases. Demographic, offending, mental health and incident data were extracted from records for each. Seventy-seven incidents, involving 54 patients, were identified over the five years. These were 13 escapes involving 12 patients, representing a rate of 0.04 per 1000 bed days, and 64 absconds involving 42 patients, a rate of 0.26 per 1000 bed days; 15 (28%) patients were absent without leave more than once. Over half of the patients came back voluntarily within 24 hours of leaving. Over 50% of them had drunk alcohol or taken drugs while away from the unit. Escapees were more likely to be transferred prisoners and to have planned their escape, less likely to return to the unit voluntarily and away longer than patients who absconded. Offending was rare during unauthorised leave--just three offences among the 77 incidents; self-harm was more likely. Motives for absconding included: wanting freedom or drink or drugs, family worries and/or dissatisfaction with aspects of treatment. Escapes or absconding from secure healthcare units have different characteristics, but may best be prevented by convergent strategies. Relational security is likely to be as important for foiling plans for the former as it is for reducing boredom, building strong family support and managing substance misuse in the latter. Copyright © 2015 John Wiley & Sons, Ltd.

Macrophage Fusion Is Controlled by the Cytoplasmic Protein Tyrosine Phosphatase PTP-PEST/PTPN12

PubMed Central

Rhee, Inmoo; Davidson, Dominique; Souza, Cleiton Martins; Vacher, Jean

2013-01-01

Macrophages can undergo cell-cell fusion, leading to the formation of multinucleated giant cells and osteoclasts. This process is believed to promote the proteolytic activity of macrophages toward pathogens, foreign bodies, and extracellular matrices. Here, we examined the role of PTP-PEST (PTPN12), a cytoplasmic protein tyrosine phosphatase, in macrophage fusion. Using a macrophage-targeted PTP-PEST-deficient mouse, we determined that PTP-PEST was not needed for macrophage differentiation or cytokine production. However, it was necessary for interleukin-4-induced macrophage fusion into multinucleated giant cells in vitro. It was also needed for macrophage fusion following implantation of a foreign body in vivo. Moreover, in the RAW264.7 macrophage cell line, PTP-PEST was required for receptor activator of nuclear factor kappa-B ligand (RANKL)-triggered macrophage fusion into osteoclasts. PTP-PEST had no impact on expression of fusion mediators such as β-integrins, E-cadherin, and CD47, which enable macrophages to become fusion competent. However, it was needed for polarization of macrophages, migration induced by the chemokine CC chemokine ligand 2 (CCL2), and integrin-induced spreading, three key events in the fusion process. PTP-PEST deficiency resulted in specific hyperphosphorylation of the protein tyrosine kinase Pyk2 and the adaptor paxillin. Moreover, a fusion defect was induced upon treatment of normal macrophages with a Pyk2 inhibitor. Together, these data argue that macrophage fusion is critically dependent on PTP-PEST. This function is seemingly due to the ability of PTP-PEST to control phosphorylation of Pyk2 and paxillin, thereby regulating cell polarization, migration, and spreading. PMID:23589331

The escape problem for mortal walkers

NASA Astrophysics Data System (ADS)

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.

Identification of a Novel Inhibitor against Middle East Respiratory Syndrome Coronavirus

PubMed Central

Sun, Yaping; Zhang, Huaidong; Shi, Jian; Zhang, Zhe; Gong, Rui

2017-01-01

The Middle East respiratory syndrome coronavirus (MERS-CoV) was first isolated in 2012, and circulated worldwide with high mortality. The continual outbreaks of MERS-CoV highlight the importance of developing antiviral therapeutics. Here, we rationally designed a novel fusion inhibitor named MERS-five-helix bundle (MERS-5HB) derived from the six-helix bundle (MERS-6HB) which was formed by the process of membrane fusion. MERS-5HB consists of three copies of heptad repeat 1 (HR1) and two copies of heptad repeat 2 (HR2) while MERS-6HB includes three copies each of HR1 and HR2. As it lacks one HR2, MERS-5HB was expected to interact with viral HR2 to interrupt the fusion step. What we found was that MERS-5HB could bind to HR2P, a peptide derived from HR2, with a strong affinity value (KD) of up to 0.24 nM. Subsequent assays indicated that MERS-5HB could inhibit pseudotyped MERS-CoV entry effectively with 50% inhibitory concentration (IC50) of about 1 μM. In addition, MERS-5HB significantly inhibited spike (S) glycoprotein-mediated syncytial formation in a dose-dependent manner. Further biophysical characterization showed that MERS-5HB was a thermo-stable α-helical secondary structure. The inhibitory potency of MERS-5HB may provide an attractive basis for identification of a novel inhibitor against MERS-CoV, as a potential antiviral agent. PMID:28906430

Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628

PubMed Central

Stathis, Anastasios; Zucca, Emanuele; Bekradda, Mohamed; Gomez-Roca, Carlos; Delord, Jean-Pierre; de La Motte Rouge, Thibault; Uro-Coste, Emmanuelle; de Braud, Filippo; Pelosi, Giuseppe; French, Christopher A.

2016-01-01

The anti-neoplastic, pro-differentiative effects of bromodomain and extra-terminal (BET) bromodomain (BRD) inhibitors were initially discovered in NUT midline carcinoma (NMC), an aggressive subtype of squamous cancer driven by the BRD4-NUT fusion oncoprotein. BRD4-NUT blocks differentiation and maintains tumor growth through a potent chromatin modifying mechanism. OTX015/MK-8628, a novel oral BET inhibitor, targets BRD2/3/4/T with preclinical activity in NMC and several other tumor types, and is currently in clinical development. Antitumor activity was evaluated in four advanced stage NMC patients with confirmed BRD4-NUT fusions who were treated with 80 mg OTX015/MK-8628 once daily in a compassionate-use context. Two patients responded rapidly with tumor regression and symptomatic relief, and a third had meaningful disease stabilization with a minor metabolic response. The main side effects were mild to moderate gastrointestinal toxicity and fatigue, and reversible grade 3 thrombocytopenia. This is the first proof-of-concept evidence of clinical activity of a bromodomain inhibitor in targeting BRD4-NUT. PMID:26976114

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

NASA Astrophysics Data System (ADS)

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.

How Hospitable Are Space Weather Affected Habitable Zones? The Role of Ion Escape

NASA Astrophysics Data System (ADS)

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.

Inhibition of the Hantavirus Fusion Process by Predicted Domain III and Stem Peptides from Glycoprotein Gc.

PubMed

Barriga, Gonzalo P; Villalón-Letelier, Fernando; Márquez, Chantal L; Bignon, Eduardo A; Acuña, Rodrigo; Ross, Breyan H; Monasterio, Octavio; Mardones, Gonzalo A; Vidal, Simon E; Tischler, Nicole D

2016-07-01

Hantaviruses can cause hantavirus pulmonary syndrome or hemorrhagic fever with renal syndrome in humans. To enter cells, hantaviruses fuse their envelope membrane with host cell membranes. Previously, we have shown that the Gc envelope glycoprotein is the viral fusion protein sharing characteristics with class II fusion proteins. The ectodomain of class II fusion proteins is composed of three domains connected by a stem region to a transmembrane anchor in the viral envelope. These fusion proteins can be inhibited through exogenous fusion protein fragments spanning domain III (DIII) and the stem region. Such fragments are thought to interact with the core of the fusion protein trimer during the transition from its pre-fusion to its post-fusion conformation. Based on our previous homology model structure for Gc from Andes hantavirus (ANDV), here we predicted and generated recombinant DIII and stem peptides to test whether these fragments inhibit hantavirus membrane fusion and cell entry. Recombinant ANDV DIII was soluble, presented disulfide bridges and beta-sheet secondary structure, supporting the in silico model. Using DIII and the C-terminal part of the stem region, the infection of cells by ANDV was blocked up to 60% when fusion of ANDV occurred within the endosomal route, and up to 95% when fusion occurred with the plasma membrane. Furthermore, the fragments impaired ANDV glycoprotein-mediated cell-cell fusion, and cross-inhibited the fusion mediated by the glycoproteins from Puumala virus (PUUV). The Gc fragments interfered in ANDV cell entry by preventing membrane hemifusion and pore formation, retaining Gc in a non-resistant homotrimer stage, as described for DIII and stem peptide inhibitors of class II fusion proteins. Collectively, our results demonstrate that hantavirus Gc shares not only structural, but also mechanistic similarity with class II viral fusion proteins, and will hopefully help in developing novel therapeutic strategies against hantaviruses.

Developing the E-Scape Software System

ERIC Educational Resources Information Center

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…

Automated guidance algorithms for a space station-based crew escape vehicle.

PubMed

Flanary, R; Hammen, D G; Ito, D; Rabalais, B W; Rishikof, B H; Siebold, K H

2003-04-01

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 first 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 first 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 requires

The Escaping Upper Atmospheres of Hot Jupiters

NASA Astrophysics Data System (ADS)

Davidson, Eric; Jones, Gabrielle; Uribe, Ana; Carson, Joseph

2017-01-01

Hot Jupiters are massive gaseous planets which orbit closely to their parent star. The strong stellar irradiation at these small orbital separations causes the temperature of the upper atmosphere of the planet to rise. This can cause the planet's atmosphere to escape into space, creating an exoplanet outflow. We ascertained which factors determine the presence and structure of these outflows by creating one dimensional simulations of the density, pressure, velocity, optical depth, and neutral fraction of hot Jupiter atmospheres. This was done for planets of masses and radii ranging from 0.5-1.5 Mj and 0.5-1.5 Rj. We found the outflow rate to be highest for a planet of 0.5 Mj and 1.5 Rj at 5.3×10-14 Mj/Yr. We also found that the higher the escape velocity, the lower the chance of the planet having an outflow.

EDITORIAL: The Nuclear Fusion Award The Nuclear Fusion Award

NASA Astrophysics Data System (ADS)

Kikuchi, M.

2011-01-01

The Nuclear Fusion Award ceremony for 2009 and 2010 award winners was held during the 23rd IAEA Fusion Energy Conference in Daejeon. This time, both 2009 and 2010 award winners were celebrated by the IAEA and the participants of the 23rd IAEA Fusion Energy Conference. The Nuclear Fusion Award is a paper prize to acknowledge the best distinguished paper among the published papers in a particular volume of the Nuclear Fusion journal. Among the top-cited and highly-recommended papers chosen by the Editorial Board, excluding overview and review papers, and by analyzing self-citation and non-self-citation with an emphasis on non-self-citation, the Editorial Board confidentially selects ten distinguished papers as nominees for the Nuclear Fusion Award. Certificates are given to the leading authors of the Nuclear Fusion Award nominees. The final winner is selected among the ten nominees by the Nuclear Fusion Editorial Board voting confidentially. 2009 Nuclear Fusion Award nominees For the 2009 award, the papers published in the 2006 volume were assessed and the following papers were nominated, most of which are magnetic confinement experiments, theory and modeling, while one addresses inertial confinement. Sabbagh S.A. et al 2006 Resistive wall stabilized operation in rotating high beta NSTX plasmas Nucl. Fusion 46 635-44 La Haye R.J. et al 2006 Cross-machine benchmarking for ITER of neoclassical tearing mode stabilization by electron cyclotron current drive Nucl. Fusion 46 451-61 Honrubia J.J. et al 2006 Three-dimensional fast electron transport for ignition-scale inertial fusion capsules Nucl. Fusion 46 L25-8 Ido T. et al 2006 Observation of the interaction between the geodesic acoustic mode and ambient fluctuation in the JFT-2M tokamak Nucl. Fusion 46 512-20 Plyusnin V.V. et al 2006 Study of runaway electron generation during major disruptions in JET Nucl. Fusion 46 277-84 Pitts R.A. et al 2006 Far SOL ELM ion energies in JET Nucl. Fusion 46 82-98 Berk H.L. et al 2006

Fusion

NASA Astrophysics Data System (ADS)

Herman, Robin

1990-10-01

The book abounds with fascinating anecdotes about fusion's rocky path: the spurious claim by Argentine dictator Juan Peron in 1951 that his country had built a working fusion reactor, the rush by the United States to drop secrecy and publicize its fusion work as a propaganda offensive after the Russian success with Sputnik; the fortune Penthouse magazine publisher Bob Guccione sank into an unconventional fusion device, the skepticism that met an assertion by two University of Utah chemists in 1989 that they had created "cold fusion" in a bottle. Aimed at a general audience, the book describes the scientific basis of controlled fusion--the fusing of atomic nuclei, under conditions hotter than the sun, to release energy. Using personal recollections of scientists involved, it traces the history of this little-known international race that began during the Cold War in secret laboratories in the United States, Great Britain and the Soviet Union, and evolved into an astonishingly open collaboration between East and West.

Detection of Escaping Lyman Continuum Radiation in Two Local Starbursts Using FUSE

NASA Astrophysics Data System (ADS)

Leitet, E.; Bergvall, N.; Andersson, B.-G.; Zackrisson, E.

2007-05-01

Dwarf galaxies may play a significant role in the reionization history of the universe, and as such also for the history of structure formation. These galaxies are however too faint to be observed at high redshifts, and it is therefore important to establish the amount of Lyman continuum (LyC) radiation that escape local starbursting dwarf galaxies. The amount of leakage is important to know also in order to improve models of star formation and spectral evolution of galaxies, which if neglected, might lead to false conclusions about the properties of the galaxies themself. Previous attempts to directly observe the leakage of hydrogen-ionizing radiation from local galaxies has before this resulted only in one successful case. In Bergvall et al. (2006 A&A 448, 513) an escape fraction of 4-10 % for the blue compact galaxy Haro 11, was found. In this work the detection and quantification of the LyC escape fractions for two additional local starburst galaxies using the Far Ultraviolet Spectroscopic Explorer, FUSE, is presented. The detections were made using FUSE archival data reduced with the latest, and much improved, pipeline. The LyC continuum can be seen as a faint structure between the Lyman limit of the target galaxies and the Milky Way. From line profile fitting it was found that both galaxies have high column densities of neutral gas, indicating that the LyC radiation is escaping through holes in the ISM. The escape fractions are calculated using spectral evolutionary models, based on the f(900Å), f(960Å) and f(Ha) fluxes. The fact that LyC leakage now is detected in three local starbursting dwarf galaxies is going to have a deep impact on future research on structure formation and galaxy evolution. The next challenge would be to statistically determine the escape fraction in extended surveys of starbursting dwarf galaxies.

On the temperature prediction in a fire escape passage

NASA Astrophysics Data System (ADS)

Casano, G.; Piva, S.

2017-11-01

Fire safety engineering requires a detailed understanding of fire behaviour and of its effects on structures and people. Many factors may condition the fire scenario, as for example, heat transfer between the flame and the boundary structures. Currently advanced numerical codes for the prediction of the fire behaviour are available. However, these solutions often require heavy calculations and long times. In this context analytical solutions can be useful for a fast analysis of simplified schematizations. After that, it is more effective the final utilization of the advanced fire codes. In this contribution, the temperature in a fire escape passage, separated with a thermally resistant wall from a fire room, is analysed. The escape space is included in a building where the neighbouring rooms are at a constant undisturbed temperature. The presence of the neighbouring rooms is considered with an equivalent heat transfer coefficient, in a boundary condition of the third type. An analytical solution is used to predict the temperature distribution during the fire. It allows to obtain useful information on the temperature reached in the escape area in contact with a burning room; it is useful also for a fast choice of the thermal characteristics of a firewall.

Identification of a novel fusion gene HMGA2-EGFR in glioblastoma.

PubMed

Komuro, Akiyoshi; Raja, Erna; Iwata, Caname; Soda, Manabu; Isogaya, Kazunobu; Yuki, Keiko; Ino, Yasushi; Morikawa, Masato; Todo, Tomoki; Aburatani, Hiroyuki; Suzuki, Hiromichi; Ranjit, Melissa; Natsume, Atsushi; Mukasa, Akitake; Saito, Nobuhito; Okada, Hitoshi; Mano, Hiroyuki; Miyazono, Kohei; Koinuma, Daizo

2018-04-15

Glioblastoma is one of the most malignant forms of cancer, for which no effective targeted therapy has been found. Although The Cancer Genome Atlas has provided a list of fusion genes in glioblastoma, their role in progression of glioblastoma remains largely unknown. To search for novel fusion genes, we obtained RNA-seq data from TGS-01 human glioma-initiating cells, and identified a novel fusion gene (HMGA2-EGFR), encoding a protein comprising the N-terminal region of the high-mobility group AT-hook protein 2 (HMGA2) fused to the C-terminal region of epidermal growth factor receptor (EGFR), which retained the transmembrane and kinase domains of the EGFR. This fusion gene product showed transforming potential and a high tumor-forming capacity in cell culture and in vivo. Mechanistically, HMGA2-EGFR constitutively induced a higher level of phosphorylated STAT5B than EGFRvIII, an in-frame exon deletion product of the EGFR gene that is commonly found in primary glioblastoma. Forced expression of HMGA2-EGFR enhanced orthotopic tumor formation of the U87MG human glioma cell line. Furthermore, the EGFR kinase inhibitor erlotinib blocked sphere formation of TGS-01 cells in culture and inhibited tumor formation in vivo. These findings suggest that, in addition to gene amplification and in-frame exon deletion, EGFR signaling can also be activated by gene fusion, suggesting a possible avenue for treatment of glioblastoma. © 2017 UICC.

How single mutations affect viral escape from broad and narrow antibodies to H1 influenza hemagglutinin.