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Sample records for fusion inhibitory complex

  1. Isolation of virus-cell fusion inhibitory components from the stem bark of Styrax japonica S. et Z.

    PubMed

    Lee, Dung Gun; Jin, Qinglong; Jin, Hong-Guang; Shin, Ji Eun; Choi, Eun Jin; Woo, Eun-Rhan

    2010-06-01

    Five compounds, styraxjaponoside A (1), matairesinoside (2), egonol glucoside (3), dihydrodehydrodiconiferyl alcohol 9'-O-glucoside (4), and styraxjaponoside B (5) were isolated from the stem bark of Styrax japonica. Among them, compounds 1 and 5 showed significantly high virus-cell fusion inhibitory activity. In addition, compound 5 exhibited almost equivalent virus-cell fusion inhibitory activity to that of dextran sulfate, which is used as a positive control.

  2. Broad spectrum antiviral activity for paramyxoviruses is modulated by biophysical properties of fusion inhibitory peptides

    PubMed Central

    Mathieu, Cyrille; Augusto, Marcelo T.; Niewiesk, Stefan; Horvat, Branka; Palermo, Laura M.; Sanna, Giuseppina; Madeddu, Silvia; Huey, Devra; Castanho, Miguel A. R. B.; Porotto, Matteo; Santos, Nuno C.; Moscona, Anne

    2017-01-01

    Human paramyxoviruses include global causes of lower respiratory disease like the parainfluenza viruses, as well as agents of lethal encephalitis like Nipah virus. Infection is initiated by viral glycoprotein-mediated fusion between viral and host cell membranes. Paramyxovirus viral fusion proteins (F) insert into the target cell membrane, and form a transient intermediate that pulls the viral and cell membranes together as two heptad-repeat regions refold to form a six-helix bundle structure that can be specifically targeted by fusion-inhibitory peptides. Antiviral potency can be improved by sequence modification and lipid conjugation, and by adding linkers between the protein and lipid components. We exploit the uniquely broad spectrum antiviral activity of a parainfluenza F-derived peptide sequence that inhibits both parainfluenza and Nipah viruses, to investigate the influence of peptide orientation and intervening linker length on the peptides’ interaction with transitional states of F, solubility, membrane insertion kinetics, and protease sensitivity. We assessed the impact of these features on biodistribution and antiviral efficacy in vitro and in vivo. The engineering approach based on biophysical parameters resulted in a peptide that is a highly effective inhibitor of both paramyxoviruses and a set of criteria to be used for engineering broad spectrum antivirals for emerging paramyxoviruses. PMID:28344321

  3. No simple brake--the complex functions of inhibitory synapses.

    PubMed

    Birke, G; Draguhn, A

    2010-05-01

    Synaptic inhibition can be viewed as a counterbalance of synaptic excitation. However, multiple recent studies at the cellular and network level show that inhibition serves a variety of additional, highly specific functions in the mammalian nervous system. At the molecular and cellular level, inhibitory synapses express diverse postsynaptic reversal potentials, kinetics, plasticity, and pharmacological modulation. This heterogeneity corresponds to the complexity of inhibition at the network level, where interneurons are now perceived as diverse and highly specific organizers of coherent activity patterns. We review some important new developments in the molecular, cellular and network physiology of inhibition. It turns out that understanding inhibition is a key to understanding neuronal network behaviour and, ultimately, may provide important clues for the development of novel therapeutic strategies in neuro-psychiatric diseases. (c) Georg Thieme Verlag KG Stuttgart-New York.

  4. DNA Triplex-Based Complexes Display Anti-HIV-1-Cell Fusion Activity.

    PubMed

    Xu, Liang; Zhang, Tao; Xu, Xiaoyu; Chong, Huihui; Lai, Wenqing; Jiang, Xifeng; Wang, Chao; He, Yuxian; Liu, Keliang

    2015-08-01

    DNA triplexes with hydrophobic modifications were designed and evaluated for their activity as inhibitors of the cell fusion of human immunodeficiency virus type 1 (HIV-1). Triplex inhibitors displayed low micromolar activities in the cell-cell fusion assay and nanomolar activities in the anti-HIV-1 pseudovirus test. Helix structure and the presence of sufficient numbers of hydrophobic regions were essential for the antifusion activity. Results from native polyacrylamide gel electrophoresis and a fluorescent resonance energy transfer-based inhibitory assay indicated that these triplexes may interact with the primary pocket at the glycoprotein 41 (gp41) N-heptad repeat, thereby inhibiting formation of the HIV-1 gp41 6-helical bundle. Triplex-based complexes may represent a novel category of HIV-1 inhibitors in anti-HIV-1 drug discovery.

  5. Reproducible cold fusion reaction using a complex cathode

    SciTech Connect

    Arata, Y.; Zhang, Y.C. )

    1992-09-01

    This paper discusses a new complex cathode which was developed, consisting of a nickel (or palladium) rod with a palladium layer applied by plasma spraying. High reproducibility of a cold fusion reaction is confirmed by using this cathode. The palladium layer activates the surface functions of the deuterated cathode, and reliable evidence is obtained that a new type of heat generation occurred in the complex cathode.

  6. Association of vaccinia virus fusion regulatory proteins with the multicomponent entry/fusion complex.

    PubMed

    Wagenaar, Timothy R; Moss, Bernard

    2007-06-01

    The proteins encoded by the A56R and K2L genes of vaccinia virus form a heterodimer (A56/K2) and have a fusion regulatory role as deletion or mutation of either causes infected cells to form large syncytia spontaneously. Here, we showed that syncytia formation is dependent on proteins of the recently described entry fusion complex (EFC), which are also required for virus-cell fusion and low-pH-triggered cell-cell fusion. This finding led us to consider that A56/K2 might prevent fusion by direct or indirect interaction with the EFC. To test this hypothesis, we made a panel of recombinant vaccinia viruses that have a tandem affinity purification tag attached to A56, K2, or the A28 EFC protein. Interaction between A56/K2 and the EFC was demonstrated by their copurification from detergent-treated lysates of infected cells and identification by mass spectrometry or Western blotting. In addition, a purified soluble transmembrane-deleted form of A56/K2 was shown to interact with the EFC. Tagged A56 did not interact with the EFC in the absence of K2, nor did tagged K2 interact with the EFC in the absence of A56. The finding that both A56 and K2 are required for efficient binding to the EFC fits well with prior experiments showing that mutation of either A56 or K2 results in spontaneous fusion of infected cells. Because A56 and K2 are located on the surface of infected cells, they are in position to interact with the EFC of released progeny virions and prevent back-fusion and syncytia formation.

  7. Biochemical and Functional Studies of Cortical Vesicle Fusion: The SNARE Complex and Ca2+ Sensitivity

    PubMed Central

    Coorssen, Jens R.; Blank, Paul S.; Tahara, Masahiro; Zimmerberg, Joshua

    1998-01-01

    Cortical vesicles (CV) possess components critical to the mechanism of exocytosis. The homotypic fusion of CV centrifuged or settled into contact has a sigmoidal Ca2+ activity curve comparable to exocytosis (CV–PM fusion). Here we show that Sr2+ and Ba2+ also trigger CV–CV fusion, and agents affecting different steps of exocytotic fusion block Ca2+, Sr2+, and Ba2+-triggered CV–CV fusion. The maximal number of active fusion complexes per vesicle, Max, was quantified by NEM inhibition of fusion, showing that CV–CV fusion satisfies many criteria of a mathematical analysis developed for exocytosis. Both Max and the Ca2+ sensitivity of fusion complex activation were comparable to that determined for CV–PM fusion. Using Ca2+-induced SNARE complex disruption, we have analyzed the relationship between membrane fusion (CV–CV and CV–PM) and the SNARE complex. Fusion and complex disruption have different sensitivities to Ca2+, Sr2+, and Ba2+, the complex remains Ca2+- sensitive on fusion-incompetent CV, and disruption does not correlate with the quantified activation of fusion complexes. Under conditions which disrupt the SNARE complex, CV on the PM remain docked and fusion competent, and isolated CV still dock and fuse, but with a markedly reduced Ca2+ sensitivity. Thus, in this system, neither the formation, presence, nor disruption of the SNARE complex is essential to the Ca2+-triggered fusion of exocytotic membranes. Therefore the SNARE complex alone cannot be the universal minimal fusion machine for intracellular fusion. We suggest that this complex modulates the Ca2+ sensitivity of fusion. PMID:9864359

  8. Complexity versus availability for fusion: The potential advantages of inertial fusion energy

    SciTech Connect

    Perkins, L.J.,

    1996-09-05

    Probably the single largest advantage of the inertial route to fusion energy (IFE) is the perception that its power plant embodiments could achieve acceptable capacity factors. This is a result of its relative simplicity, the decoupling of the driver and reactor chamber, and the potential to employ thick liquid walls. We examine these issues in terms of the complexity, reliability, maintainability and, therefore, availability of both magnetic and inertial fusion power plants and compare these factors with corresponding scheduled and unscheduled outage data from present day fission experience. We stress that, given the simple nature of a fission core, the vast majority of unplanned outages in fission plants are due to failures outside the reactor vessel itself Given we must be prepared for similar outages in the analogous plant external to a fusion power core, this puts severe demands on the reliability required of the fusion core itself. We indicate that such requirements can probably be met for IFE plants. We recommend that this advantage be promoted by performing a quantitative reliability and availability study for a representative IFE power plant and suggest that databases are probably adequate for this task.

  9. The MARVEL domain protein, Singles Bar, is required for progression past the pre-fusion complex stage of myoblast fusion.

    PubMed

    Estrada, Beatriz; Maeland, Anne D; Gisselbrecht, Stephen S; Bloor, James W; Brown, Nicholas H; Michelson, Alan M

    2007-07-15

    Multinucleated myotubes develop by the sequential fusion of individual myoblasts. Using a convergence of genomic and classical genetic approaches, we have discovered a novel gene, singles bar (sing), that is essential for myoblast fusion. sing encodes a small multipass transmembrane protein containing a MARVEL domain, which is found in vertebrate proteins involved in processes such as tight junction formation and vesicle trafficking where--as in myoblast fusion--membrane apposition occurs. sing is expressed in both founder cells and fusion competent myoblasts preceding and during myoblast fusion. Examination of embryos injected with double-stranded sing RNA or embryos homozygous for ethane methyl sulfonate-induced sing alleles revealed an identical phenotype: replacement of multinucleated myofibers by groups of single, myosin-expressing myoblasts at a stage when formation of the mature muscle pattern is complete in wild-type embryos. Unfused sing mutant myoblasts form clusters, suggesting that early recognition and adhesion of these cells are unimpaired. To further investigate this phenotype, we undertook electron microscopic ultrastructural studies of fusing myoblasts in both sing and wild-type embryos. These experiments revealed that more sing mutant myoblasts than wild-type contain pre-fusion complexes, which are characterized by electron-dense vesicles paired on either side of the fusing plasma membranes. In contrast, embryos mutant for another muscle fusion gene, blown fuse (blow), have a normal number of such complexes. Together, these results lead to the hypothesis that sing acts at a step distinct from that of blow, and that sing is required on both founder cell and fusion-competent myoblast membranes to allow progression past the pre-fusion complex stage of myoblast fusion, possibly by mediating fusion of the electron-dense vesicles to the plasma membrane.

  10. The MARVEL domain protein, Singles Bar, is required for progression past the pre-fusion complex stage of myoblast fusion

    PubMed Central

    Estrada, Beatriz; Maeland, Anne D.; Gisselbrecht, Stephen S.; Bloor, James W.; Brown, Nicholas H.; Michelson, Alan M.

    2007-01-01

    Summary Multinucleated myotubes develop by the sequential fusion of individual myoblasts. Using a convergence of genomic and classical genetic approaches, we have discovered a novel gene, singles bar (sing), that is essential for myoblast fusion. sing encodes a small multipass transmembrane protein containing a MARVEL domain, which is found in vertebrate proteins involved in processes such as tight junction formation and vesicle trafficking where—as in myoblast fusion—membrane apposition occurs. sing is expressed in both founder cells and fusion competent myoblasts preceding and during myoblast fusion. Examination of embryos injected with double-stranded sing RNA or embryos homozygous for ethane methyl sulfonate-induced sing alleles revealed an identical phenotype: replacement of multinucleated myofibers by groups of single, myosin-expressing myoblasts at a stage when formation of the mature muscle pattern is complete in wild-type embryos. Unfused sing mutant myoblasts form clusters, suggesting that early recognition and adhesion of these cells is unimpaired. To further investigate this phenotype, we undertook electron microscopic ultrastructural studies of fusing myoblasts in both sing and wild-type embryos. These experiments revealed that more sing mutant myoblasts than wild-type contain pre-fusion complexes, which are characterized by electron-dense vesicles paired on either side of the fusing plasma membranes. In contrast, embryos mutant for another muscle fusion gene, blown fuse (blow), have a normal number of such complexes. Together, these results lead to the hypothesis that sing acts at a step distinct from that of blow, and that sing is required on both founder cell and fusion-competent myoblast membranes to allow progression past the pre-fusion complex stage of myoblast fusion, possibly by mediating fusion of the electron-dense vesicles to the plasma membrane. PMID:17537424

  11. Inhibitory effects of a peptide-fusion protein (Latarcin-PAP1-Thanatin) against chikungunya virus.

    PubMed

    Rothan, Hussin A; Bahrani, Hirbod; Shankar, Esaki M; Rahman, Noorsaadah Abd; Yusof, Rohana

    2014-08-01

    Chikungunya virus (CHIKV) outbreaks have led to a serious economic burden, as the available treatment strategies can only alleviate disease symptoms, and no effective therapeutics or vaccines are currently available for human use. Here, we report the use of a new cost-effective approach involving production of a recombinant antiviral peptide-fusion protein that is scalable for the treatment of CHIKV infection. A peptide-fusion recombinant protein LATA-PAP1-THAN that was generated by joining Latarcin (LATA) peptide with the N-terminus of the PAP1 antiviral protein, and the Thanatin (THAN) peptide to the C-terminus, was produced in Escherichia coli as inclusion bodies. The antiviral LATA-PAP1-THAN protein showed 89.0% reduction of viral plaque formation compared with PAP1 (46.0%), LATA (67.0%) or THAN (79.3%) peptides alone. The LATA-PAP1-THAN protein reduced the viral RNA load that was 0.89-fold compared with the untreated control cells. We also showed that PAP1 resulted in 0.44-fold reduction, and THAN and LATA resulting in 0.78-fold and 0.73-fold reductions, respectively. The LATA-PAP1-THAN protein inhibited CHIKV replication in the Vero cells at an EC50 of 11.2μg/ml, which is approximately half of the EC50 of PAP1 (23.7μg/ml) and protected the CHIKV-infected mice at the dose of 0.75mg/ml. We concluded that production of antiviral peptide-fusion protein in E. coli as inclusion bodies could accentuate antiviral activities, enhance cellular internalisation, and could reduce product toxicity to host cells and is scalable to epidemic response quantities.

  12. Structural Insight into Anaphase Promoting Complex 3 Structure and Docking with a Natural Inhibitory Compound

    PubMed Central

    Rahimi, Hamzeh; Shokrgozar, Mohammad Ali; Madadkar-Sobhani, Armin; Mahdian, Reza; Foroumadi, Alireza; Karimipoor, Morteza

    2017-01-01

    Background: Anaphase promoting complex (APC) is the biggest Cullin-RING E3 ligase and is very important in cell cycle control; many anti-cancer agents target this. APC controls the onset of chromosome separation and mitotic exit through securin and cyclin B degradation, respectively. Its APC3 subunit identifies the APC activators-Cdh1 and Cdc20. Materials and Methods: The structural model of the APC3 subunit of APC was developed by means of computational techniques; the binding of a natural inhibitory compound to APC3 was also investigated. Results: It was found that APC3 structure consists of numerous helices organized in anti-parallel and the overall model is superhelical of tetratrico-peptide repeat (TPR) domains. Furthermore, binding pocket of the natural inhibitory compound as APC3 inhibitor was shown. Conclusion: The findings are beneficial to understand the mechanism of the APC activation and design inhibitory compounds. PMID:28401073

  13. GM-CSF-neuroantigen fusion proteins reverse experimental autoimmune encephalomyelitis and mediate tolerogenic activity in adjuvant-primed environments: association with inflammation-dependent, inhibitory antigen presentation2

    PubMed Central

    Islam, S.M. Touhidul; Curtis, Alan D.; Taslim, Najla; Wilkinson, Daniel S.; Mannie, Mark D.

    2014-01-01

    Single-chain fusion proteins comprised of GM-CSF and neuroantigen (NAg) are potent, NAg-specific inhibitors of experimental autoimmune encephalomyelitis (EAE). An important question was whether GMCSF-NAg tolerogenic vaccines retained inhibitory activity within inflammatory environments or were contingent upon steady-state conditions. A GMCSF-MOG fusion protein reversed established paralytic disease in both passive and active models of EAE in C57BL/6 mice. The fusion protein also reversed EAE in CD4-deficient and B cell-deficient mice. Notably, GMCSF-MOG inhibited EAE when co-injected adjacent to the MOG35-55/CFA emulsion. GMCSF-MOG also retained dominant inhibitory activity when directly emulsified with MOG35-55 in the CFA emulsion in both C57BL/6 or B cell-deficient models of EAE. Likewise, when combined with PLP139-151 in CFA, GMCSF-PLP inhibited EAE in SJL mice. When deliberately emulsified in CFA with the NAg, GMCSF-NAg inhibited EAE even though NAg was present at more than a 30-fold molar excess. In vitro studies revealed that the GMCSF domain of GMCSF-MOG stimulated growth and differentiation of inflammatory dendritic cells (DC) and simultaneously targeted the MOG35-55 domain for enhanced presentation by these DC. These inflammatory DC presented MOG35-55 to MOG-specific T cells by an inhibitory mechanism that was mediated in part by IFN-γ signaling and NO production. In conclusion, GMCSF-NAg was tolerogenic in CFA-primed pro-inflammatory environments by a mechanism associated with targeted antigen presentation by inflammatory DC and an inhibitory IFN-γ/ NO pathway. The inhibitory activity of GMCSF-NAg in CFA-primed lymphatics distinguishes GMCSF-NAg fusion proteins as a unique class of inflammation-dependent tolerogens that are mechanistically distinct from naked peptide or protein-based tolerogens. PMID:25049359

  14. Model cell membranes: Techniques to form complex biomimetic supported lipid bilayers via vesicle fusion

    PubMed Central

    Hardy, Gregory J.; Nayak, Rahul

    2013-01-01

    Vesicle fusion has long provided an easy and reliable method to form supported lipid bilayers (SLBs) from simple, zwitterionic vesicles on siliceous substrates. However, for complex compositions, such as vesicles with high cholesterol content and multiple lipid types, the energy barrier for the vesicle-to-bilayer transition is increased or the required vesicle-vesicle and vesicle-substrate interactions are insufficient for vesicle fusion. Thus, for vesicle compositions that more accurately mimic native membranes, vesicle fusion often fails to form SLBs. In this paper, we review three approaches to overcome these barriers to form complex, biomimetic SLBs via vesicle fusion: (i) optimization of experimental conditions (e.g., temperature, buffer ionic strength, osmotic stress, cation valency, and buffer pH), (ii) α-helical (AH) peptide-induced vesicle fusion, and (iii) bilayer edge-induced vesicle fusion. AH peptide-induced vesicle fusion can form complex SLBs on multiple substrate types without the use of additional equipment. Bilayer edge-induced vesicle fusion uses microfluidics to form SLBs from vesicles with complex composition, including vesicles derived from native cell membranes. Collectively, this review introduces vesicle fusion techniques that can be generalized for many biomimetic vesicle compositions and many substrate types, and thus will aid efforts to reliably create complex SLB platforms on a range of substrates. PMID:24031164

  15. Inhibitory effects of NAMI-A-like ruthenium complexes on prion neuropeptide fibril formation.

    PubMed

    Wang, Xuesong; Zhu, Dengsen; Zhao, Cong; He, Lei; Du, Weihong

    2015-05-01

    Prion diseases are a group of infectious and fatal neurodegenerative disorders caused by the conformational conversion of a cellular prion protein (PrP) into its abnormal isoform PrP(Sc). PrP106-126 resembles PrP(Sc) in terms of physicochemical and biological characteristics and is used as a common model for the treatment of prion diseases. Inhibitory effects on fibril formation and neurotoxicity of the prion neuropeptide PrP106-126 have been investigated using metal complexes as potential inhibitors. Nevertheless, the binding mechanism between metal complexes and the peptide remains unclear. The present study is focused on the interaction of PrP106-126 with NAMI-A and NAMI-A-like ruthenium complexes, including KP418, KP1019, and KP1019-2. Results demonstrated that these ruthenium complexes could bind to PrP106-126 in a distinctive binding mode through electrostatic and hydrophobic interactions. NAMI-A-like ruthenium complexes can also effectively inhibit the aggregation and fibril formation of PrP106-126. The complex KP1019 demonstrated the optimal inhibitory ability upon peptide aggregation, and cytotoxicity because of its large aromatic ligand contribution. The studied complexes could also regulate the copper redox chemistry of PrP106-126 and effectually inhibit the formation of reactive oxygen species. Given these findings, ruthenium complexes with relatively low cellular toxicity may be used to develop potential pharmaceutical products against prion diseases.

  16. Synthesis, characterization and enzyme inhibitory activity of new pyrazinamide iron complexes.

    PubMed

    Ali, Mohsin; Qader, Shah Aliul; Shahid, Faiza; Arayne, M Saeed; Mumtaz, Majid

    2017-05-01

    The present paper deals with synthesis, characterization and amylase inhibitory activity of pyrazinamide (PYZ) with iron in its both (II) and (III) oxidation states. The synthesized complexes were characterized on the basis of IR, UV, (1)H-NMR, (13)C-NMR, elemental analysis and SEM. Changes in IR data shows that PYZ form complex with octahedral geometry and binding sites are ring nitrogen and carbonyl group, wherein two sides are satisfied with two chloride ions. SEM images indicate the crystalline state and surface morphology of PYZ and its complexes. Elemental analysis proves the composition of complexes. Pyrazinamide and the complexes showed no significant effect on amylase activity but the activity was inhibited in the presence of ferrous chloride.

  17. Membrane-Anchored Inhibitory Peptides Capture Human Immunodeficiency Virus Type 1 gp41 Conformations That Engage the Target Membrane prior to Fusion

    PubMed Central

    Melikyan, Gregory B.; Egelhofer, Marc; von Laer, Dorothee

    2006-01-01

    Soluble peptides derived from the C-terminal heptad repeat domain of human immunodeficiency virus type 1 (HIV-1) gp41 are potent inhibitors of HIV-1 entry and gp41-induced fusion. Target membrane-anchored variants of these peptides have been shown to retain inhibitory activity. Both soluble and membrane-anchored C peptides (MACs) are thought to block fusion by binding to the N-terminal coiled coil domain of gp41 and preventing formation of the final six-helix bundle structure. However, interactions of target MACs with gp41 must be restricted to a subset of trimers that have their hydrophobic fusion peptides inserted into the target membrane. This unique feature of MACs was used to identify the intermediate step of fusion at which gp41 engaged the target membrane. Fusion between HIV envelope-expressing effector cells and target cells was measured by fluorescence microscopy. Expression of MACs in target cells led to less than twofold reduction in the extent of fusion. However, when reaction was first arrested by adding lysolipids that disfavored membrane merger, and the lipids were subsequently removed by washing, control cells supported fusion, whereas those that expressed MACs did not. The drastically improved potency of MACs implies that, at lipid-arrested stage, gp41 bridges the viral and target cell membranes and therefore more optimally binds the membrane-anchored peptides. Experimental demonstration of this intermediate shows that, similar to fusion induced by many other viral glycoproteins, engaging the target membrane by HIV-1 gp41 permits coupling between six-helix bundle formation and membrane merger. PMID:16537592

  18. Gene flow despite complex Robertsonian fusions among rock-wallaby (Petrogale) species

    PubMed Central

    Potter, Sally; Moritz, Craig; Eldridge, Mark D. B.

    2015-01-01

    Complex Robertsonian rearrangements, with shared arms in different fusions, are expected to prevent gene flow between hybrids through missegregation during meiosis. Here, we estimate gene flow between recently diverged and chromosomally diverse rock-wallabies (Petrogale) to test for this form of chromosomal speciation. Contrary to expectations, we observe relatively high admixture among species with complex fusions. Our results reinforce the need to consider alternative roles of chromosome change, together with genic divergence, in driving speciation. PMID:26445985

  19. 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.

  20. Inhibitory factors associated with anaphase-promoting complex/cylosome in mitotic checkpoint

    PubMed Central

    Braunstein, Ilana; Miniowitz, Shirly; Moshe, Yakir; Hershko, Avram

    2007-01-01

    The mitotic (or spindle assembly) checkpoint system ensures accurate chromosome segregation by preventing anaphase initiation until all chromosomes are correctly attached to the mitotic spindle. It affects the activity of the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that targets inhibitors of anaphase initiation for degradation. The mechanisms by which this system regulates APC/C remain obscure. Some models propose that the system promotes sequestration of the APC/C activator Cdc20 by binding to the checkpoint proteins Mad2 and BubR1. A different model suggests that a mitotic checkpoint complex (MCC) composed of BubR1, Bub3, Cdc20, and Mad2 inhibits APC/C in mitotic checkpoint [Sudakin V, Chan GKT, Yen TJ (2001) J Cell Biol 154:925–936]. We examined this problem by using extracts from nocodazole-arrested cells that reproduce some downstream events of the mitotic checkpoint system, such as lag kinetics of the degradation of APC/C substrate. Incubation of extracts with adenosine-5′-(γ-thio)triphosphate (ATP[γS]) stabilized the checkpoint-arrested state, apparently by stable thiophosphorylation of some proteins. By immunoprecipitation of APC/C from stably checkpoint-arrested extracts, followed by elution with increased salt concentration, we isolated inhibitory factors associated with APC/C. A part of the inhibitory material consists of Cdc20 associated with BubR1 and Mad2, and is thus similar to MCC. Contrary to the original MCC hypothesis, we find that MCC disassembles upon exit from the mitotic checkpoint. Thus, the requirement of the mitotic checkpoint system for the binding of Mad2 and BubR1 to Cdc20 may be for the assembly of the inhibitory complex rather than for Cdc20 sequestration. PMID:17360335

  1. Synthesis, structures and urease inhibitory activity of cobalt(III) complexes with Schiff bases.

    PubMed

    Jing, Changling; Wang, Cunfang; Yan, Kai; Zhao, Kedong; Sheng, Guihua; Qu, Dan; Niu, Fang; Zhu, Hailiang; You, Zhonglu

    2016-01-15

    A series of new cobalt(III) complexes were prepared. They are [CoL(1)(py)3]·NO3 (1), [CoL(2)(bipy)(N3)]·CH3OH (2), [CoL(3)(HL(3))(N3)]·NO3 (3), and [CoL(4)(MeOH)(N3)] (4), where L(1), L(2), L(3) and L(4) are the deprotonated form of N'-(2-hydroxy-5-methoxybenzylidene)-3-methylbenzohydrazide, N'-(2-hydroxybenzylidene)-3-hydroxylbenzohydrazide, 2-[(2-dimethylaminoethylimino)methyl]-4-methylphenol, and N,N'-bis(5-methylsalicylidene)-o-phenylenediamine, respectively, py is pyridine, and bipy is 2,2'-bipyridine. The complexes were characterized by infrared and UV-Vis spectra, and single crystal X-ray diffraction. The Co atoms in the complexes are in octahedral coordination. Complexes 1 and 4 show effective urease inhibitory activities, with IC50 values of 4.27 and 0.35 μmol L(-1), respectively. Complex 2 has medium activity against urease, with IC50 value of 68.7 μmol L(-1). While complex 3 has no activity against urease. Molecular docking study of the complexes with Helicobacter pylori urease was performed.

  2. SNARE Complex Zipping as a Driving Force in the Dilation of Proteinaceous Fusion Pores

    PubMed Central

    Jackson, Meyer B.

    2010-01-01

    The assembly of SNARE proteins into a tight complex has been hypothesized to drive membrane fusion. A model of the initial fusion pore as a proteinaceous channel formed by SNARE proteins places their membrane anchors in separate membranes. This leaves the possibility of a final assembly step that brings the membrane anchors together and drives fusion pore expansion. The present study develops a model for expansion in which the final SNARE complex zipping step drives a transition from a proteinaceous fusion pore to a lipidic fusion pore. An estimate of the energy released upon merger of the helical segment of the SNARE motif with the helical membrane anchor indicates that completing the assembly of a few SNARE complexes can overcome the elastic energy that opposes lipid bilayer deformation into a narrow fusion pore. The angle between the long axes of membrane anchor and SNARE motif serves as a useful reaction coordinate for this transition. Energy was calculated as a function of this angle, incorporating contributions from membrane bending, SNARE complex assembly, membrane anchor flexing, and hydrophobic interactions. The rate of this transition was evaluated as a process of diffusion over the barrier imposed by these combined energies, and the rates estimated were consistent with experimental measurements. PMID:20512644

  3. GM-CSF-neuroantigen fusion proteins reverse experimental autoimmune encephalomyelitis and mediate tolerogenic activity in adjuvant-primed environments: association with inflammation-dependent, inhibitory antigen presentation.

    PubMed

    Islam, S M Touhidul; Curtis, Alan D; Taslim, Najla; Wilkinson, Daniel S; Mannie, Mark D

    2014-09-01

    Single-chain fusion proteins comprised of GM-CSF and neuroantigen (NAg) are potent, NAg-specific inhibitors of experimental autoimmune encephalomyelitis (EAE). An important question was whether GMCSF-NAg tolerogenic vaccines retained inhibitory activity within inflammatory environments or were contingent upon steady-state conditions. GM-CSF fused to the myelin oligodendrocyte glycoprotein MOG35-55 peptide (GMCSF-MOG) reversed established paralytic disease in both passive and active models of EAE in C57BL/6 mice. The fusion protein also reversed EAE in CD4-deficient and B cell-deficient mice. Notably, GMCSF-MOG inhibited EAE when coinjected adjacent to the MOG35-55/CFA emulsion. GMCSF-MOG also retained dominant inhibitory activity when directly emulsified with MOG35-55 in the CFA emulsion in both C57BL/6 or B cell-deficient models of EAE. Likewise, when combined with proteolipid protein 139-151 in CFA, GM-CSF fused to proteolipid protein 139-151 peptide inhibited EAE in SJL mice. When deliberately emulsified in CFA with the NAg, GMCSF-NAg inhibited EAE even though NAg was present at >30-fold molar excess. In vitro studies revealed that the GM-CSF domain of GMCSF-MOG stimulated growth and differentiation of inflammatory dendritic cells (DC) and simultaneously targeted the MOG35-55 domain for enhanced presentation by these DC. These inflammatory DC presented MOG35-55 to MOG-specific T cells by an inhibitory mechanism that was mediated in part by IFN-γ signaling and NO production. In conclusion, GMCSF-NAg was tolerogenic in CFA-primed proinflammatory environments by a mechanism associated with targeted Ag presentation by inflammatory DC and an inhibitory IFN-γ/NO pathway. The inhibitory activity of GMCSF-NAg in CFA-primed lymphatics distinguishes GMCSF-NAg fusion proteins as a unique class of inflammation-dependent tolerogens that are mechanistically distinct from naked peptide or protein-based tolerogens.

  4. Inhibitory effect of Disulfiram/copper complex on non-small cell lung cancer cells

    SciTech Connect

    Duan, Lincan; Shen, Hongmei; Zhao, Guangqiang; Yang, Runxiang; Cai, Xinyi; Zhang, Lijuan; Jin, Congguo; Huang, Yunchao

    2014-04-18

    Highlights: • Disulfiram and copper synergistically inhibit lung cancer cell proliferation. • Lung cancer cell colony formation ability is inhibited by Disulfiram/copper. • Disulfiram/copper increases the sensitivity of cisplatin to lung cancer cells. • Lung cancer stem cells are specifically targeted by Disulfiram/copper complex. - Abstract: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related death in both men and women worldwide. Recently, Disulfiram has been reported to be able to inhibit glioblastoma, prostate, or breast cancer cell proliferation. In this study, the synergistic effect of Disulfiram and copper on NSCLC cell growth was investigated. Inhibition of cancer cell proliferation was detected by 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) assay and cell cycle analysis. Liquid colony formation and tumor spheroid formation assays were used to evaluate their effect on cancer cell clonogenicity. Real-time PCR was performed to test the mRNA level of cancer stem cell related genes. We found that Disulfiram or copper alone did not potently inhibit NSCLC cell proliferation in vitro. However, the presence of copper significantly enhanced inhibitory effect of Disulfiram on NSCLC cell growth, indicating a synergistic effect between Disulfiram and copper. Cell cycle analysis showed that Disulfiram/copper complex caused NSCLC cell cycle arrest in G2/M phase. Furthermore, Disulfiram/copper significantly increased the sensitivity of cisplatin in NSCLC cells tested by MTT assay. Liquid colony formation assay revealed that copper dramatically increased the inhibitory effect of Disulfiram on NSCLC cell colony forming ability. Disulfiram combined with copper significantly attenuated NSCLC cell spheroid formation and recuded the mRNA expression of lung cancer stem cell related genes. Our data suggest that Disulfiram/copper complex alone or combined with other chemotherapy is a potential therapeutic strategy for NSCLC patients.

  5. CTA with fluoroscopy image fusion guidance in endovascular complex aortic aneurysm repair.

    PubMed

    Sailer, A M; de Haan, M W; Peppelenbosch, A G; Jacobs, M J; Wildberger, J E; Schurink, G W H

    2014-04-01

    To evaluate the effect of intraoperative guidance by means of live fluoroscopy image fusion with computed tomography angiography (CTA) on iodinated contrast material volume, procedure time, and fluoroscopy time in endovascular thoraco-abdominal aortic repair. CTA with fluoroscopy image fusion road-mapping was prospectively evaluated in patients with complex aortic aneurysms who underwent fenestrated and/or branched endovascular repair (FEVAR/BEVAR). Total iodinated contrast material volume, overall procedure time, and fluoroscopy time were compared between the fusion group (n = 31) and case controls (n = 31). Reasons for potential fusion image inaccuracy were analyzed. Fusion imaging was feasible in all patients. Fusion image road-mapping was used for navigation and positioning of the devices and catheter guidance during access to target vessels. Iodinated contrast material volume and procedure time were significantly lower in the fusion group than in case controls (159 mL [95% CI 132-186 mL] vs. 199 mL [95% CI 170-229 mL], p = .037 and 5.2 hours [95% CI 4.5-5.9 hours] vs. 6.3 hours (95% CI 5.4-7.2 hours), p = .022). No significant differences in fluoroscopy time were observed (p = .38). Respiration-related vessel displacement, vessel elongation, and displacement by stiff devices as well as patient movement were identified as reasons for fusion image inaccuracy. Image fusion guidance provides added value in complex endovascular interventions. The technology significantly reduces iodinated contrast material dose and procedure time. Copyright © 2014 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

  6. Inhibitory Effects of Amorphigenin on the Mitochondrial Complex I of Culex pipiens pallens Coquillett (Diptera: Culicidae).

    PubMed

    Ji, Mingshan; Liang, Yaping; Gu, Zumin; Li, Xiuwei

    2015-08-20

    Previous studies in our laboratory found that the extract from seeds of Amorpha fruticosa in the Leguminosae family had lethal effects against mosquito larvae, and an insecticidal compound amorphigenin was isolated. In this study, the inhibitory effects of amorphigenin against the mitochondrial complex I of Culex pipiens pallens (Diptera: Culicidae) were investigated and compared with that of rotenone. The results showed that amorphigenin and rotenone can decrease the mitochondrial complex I activity both in vivo and in vitro as the in vivo IC50 values (the inhibitor concentrations leading to 50% of the enzyme activity lost) were determined to be 2.4329 and 2.5232 μmol/L, respectively, while the in vitro IC50 values were 2.8592 and 3.1375 μmol/L, respectively. Both amorphigenin and rotenone were shown to be reversible and mixed-I type inhibitors of the mitochondrial complex I of Cx. pipiens pallens, indicating that amorphigenin and rotenone inhibited the enzyme activity not only by binding with the free enzyme but also with the enzyme-substrate complex, and the values of KI and KIS for amorphigenin were determined to be 20.58 and 87.55 μM, respectively, while the values for rotenone were 14.04 and 69.23 μM, respectively.

  7. Inhibitory Effects of Amorphigenin on the Mitochondrial Complex I of Culex pipiens pallens Coquillett (Diptera: Culicidae)

    PubMed Central

    Ji, Mingshan; Liang, Yaping; Gu, Zumin; Li, Xiuwei

    2015-01-01

    Previous studies in our laboratory found that the extract from seeds of Amorpha fruticosa in the Leguminosae family had lethal effects against mosquito larvae, and an insecticidal compound amorphigenin was isolated. In this study, the inhibitory effects of amorphigenin against the mitochondrial complex I of Culex pipiens pallens (Diptera: Culicidae) were investigated and compared with that of rotenone. The results showed that amorphigenin and rotenone can decrease the mitochondrial complex I activity both in vivo and in vitro as the in vivo IC50 values (the inhibitor concentrations leading to 50% of the enzyme activity lost) were determined to be 2.4329 and 2.5232 μmol/L, respectively, while the in vitro IC50 values were 2.8592 and 3.1375 μmol/L, respectively. Both amorphigenin and rotenone were shown to be reversible and mixed-I type inhibitors of the mitochondrial complex I of Cx. pipiens pallens, indicating that amorphigenin and rotenone inhibited the enzyme activity not only by binding with the free enzyme but also with the enzyme-substrate complex, and the values of KI and KIS for amorphigenin were determined to be 20.58 and 87.55 μM, respectively, while the values for rotenone were 14.04 and 69.23 μM, respectively. PMID:26307964

  8. Identification of a Potent and Broad-Spectrum Hepatitis C Virus Fusion Inhibitory Peptide from the E2 Stem Domain

    PubMed Central

    Chi, Xiaojing; Niu, Yuqiang; Cheng, Min; Liu, Xiuying; Feng, Yetong; Zheng, Fuxiang; Fan, Jingjing; Li, Xiang; Jin, Qi; Zhong, Jin; Li, Yi-Ping; Yang, Wei

    2016-01-01

    Hepatitis C virus (HCV) envelope proteins E1 and E2 play an essential role in virus entry. However, the fusion mechanisms of HCV remain largely unclear, hampering the development of efficient fusion inhibitors. Here, we developed two cell-based membrane fusion models that allow for screening a peptide library covering the full-length E1 and E2 amino acid sequences. A peptide from the E2 stem domain, named E27, was found to possess the ability to block E1E2-mediated cell-cell fusion and inhibit cell entry of HCV pseudoparticles and infection of cell culture-derived HCV at nanomolar concentrations. E27 demonstrated broad-spectrum inhibition of the major genotypes 1 to 6. A time-of-addition experiment revealed that E27 predominantly functions in the late steps during HCV entry, without influencing the expression and localization of HCV co-receptors. Moreover, we demonstrated that E27 interfered with hetero-dimerization of ectopically expressed E1E2 in cells, and mutational analysis suggested that E27 might target a conserved region in E1. Taken together, our findings provide a novel candidate as well as a strategy for developing potent and broad-spectrum HCV fusion inhibitors, which may complement the current direct-acting antiviral medications for chronic hepatitis C, and shed light on the mechanism of HCV membrane fusion. PMID:27121372

  9. Nanoluciferase as a novel quantitative protein fusion tag: Application for overexpression and bioluminescent receptor-binding assays of human leukemia inhibitory factor.

    PubMed

    He, Sheng-Xiang; Song, Ge; Shi, Jia-Ping; Guo, Yu-Qi; Guo, Zhan-Yun

    2014-11-01

    Nanoluciferase (NanoLuc) is a newly developed small luciferase reporter with the brightest bioluminescence reported to date. In the present work, we developed NanoLuc as a novel quantitative protein fusion tag for efficient overexpression in Escherichia coli and ultrasensitive bioluminescent assays using human leukemia inhibitory factor (LIF) as a model protein. LIF is an interleukin 6 family cytokine that elicits pleiotropic effects on a diverse range of cells by activating a heterodimeric LIFR/gp130 receptor. Recombinant preparation of the biologically active LIF protein is quite difficult due to its hydrophobic nature and three disulfide bonds. Using the novel NanoLuc-fusion approach, soluble 6×His-NanoLuc-LIF fusion protein was efficiently overexpressed in E. coli and enzymatically converted to monomeric mature LIF. Both the mature LIF and the NanoLuc-fused LIF had high biological activities in a leukemia M1 cell proliferation inhibition assay and in a STAT3 signaling activation assay. The NanoLuc-fused LIF retained high binding affinities with the overexpressed LIFR (Kd = 1.4 ± 0.4 nM, n = 3), the overexpressed LIFR/gp130 (Kd = 115 ± 8 pM, n = 3), and the endogenously expressed LIFR/gp130 (Kd = 33.1 ± 3.2 pM, n = 3), with a detection limit of less than 10 receptors per cell. Thus, the novel NanoLuc-fusion strategy not only provided an efficient approach for preparation of recombinant LIF protein but also provided a novel ultrasensitive bioluminescent tracer for ligand-receptor interaction studies. The novel NanoLuc-fusion approach could be extended to other proteins for both efficient sample preparation and various bioluminescent quantitative assays in future studies.

  10. Inhibitory effect of Disulfiram/copper complex on non-small cell lung cancer cells.

    PubMed

    Duan, Lincan; Shen, Hongmei; Zhao, Guangqiang; Yang, Runxiang; Cai, Xinyi; Zhang, Lijuan; Jin, Congguo; Huang, Yunchao

    2014-04-18

    Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related death in both men and women worldwide. Recently, Disulfiram has been reported to be able to inhibit glioblastoma, prostate, or breast cancer cell proliferation. In this study, the synergistic effect of Disulfiram and copper on NSCLC cell growth was investigated. Inhibition of cancer cell proliferation was detected by 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) assay and cell cycle analysis. Liquid colony formation and tumor spheroid formation assays were used to evaluate their effect on cancer cell clonogenicity. Real-time PCR was performed to test the mRNA level of cancer stem cell related genes. We found that Disulfiram or copper alone did not potently inhibit NSCLC cell proliferation in vitro. However, the presence of copper significantly enhanced inhibitory effect of Disulfiram on NSCLC cell growth, indicating a synergistic effect between Disulfiram and copper. Cell cycle analysis showed that Disulfiram/copper complex caused NSCLC cell cycle arrest in G2/M phase. Furthermore, Disulfiram/copper significantly increased the sensitivity of cisplatin in NSCLC cells tested by MTT assay. Liquid colony formation assay revealed that copper dramatically increased the inhibitory effect of Disulfiram on NSCLC cell colony forming ability. Disulfiram combined with copper significantly attenuated NSCLC cell spheroid formation and recuded the mRNA expression of lung cancer stem cell related genes. Our data suggest that Disulfiram/copper complex alone or combined with other chemotherapy is a potential therapeutic strategy for NSCLC patients.

  11. A mitofusin-dependent docking ring complex triggers mitochondrial fusion in vitro

    PubMed Central

    Brandt, Tobias; Cavellini, Laetitia; Kühlbrandt, Werner; Cohen, Mickaël M

    2016-01-01

    Fusion of mitochondrial outer membranes is crucial for proper organelle function and involves large GTPases called mitofusins. The discrete steps that allow mitochondria to attach to one another and merge their outer membranes are unknown. By combining an in vitro mitochondrial fusion assay with electron cryo-tomography (cryo-ET), we visualize the junction between attached mitochondria isolated from Saccharomyces cerevisiae and observe complexes that mediate this attachment. We find that cycles of GTP hydrolysis induce progressive formation of a docking ring structure around extended areas of contact. Further GTP hydrolysis triggers local outer membrane fusion at the periphery of the contact region. These findings unravel key features of mitofusin-dependent fusion of outer membranes and constitute an important advance in our understanding of how mitochondria connect and merge. DOI: http://dx.doi.org/10.7554/eLife.14618.001 PMID:27253069

  12. Structure of influenza hemagglutinin in complex with an inhibitor of membrane fusion

    PubMed Central

    Russell, Rupert J.; Kerry, Philip S.; Stevens, David J.; Steinhauer, David A.; Martin, Stephen R.; Gamblin, Steven J.; Skehel, John J.

    2008-01-01

    The influenza surface glycoprotein hemagglutinin (HA) is a potential target for antiviral drugs because of its key roles in the initial stages of infection: receptor binding and the fusion of virus and cell membranes. The structure of HA in complex with a known inhibitor of membrane fusion and virus infectivity, tert-butyl hydroquinone (TBHQ), shows that the inhibitor binds in a hydrophobic pocket formed at an interface between HA monomers. Occupation of this site by TBHQ stabilizes the neutral pH structure through intersubunit and intrasubunit interactions that presumably inhibit the conformational rearrangements required for membrane fusion. The nature of the binding site suggests routes for the chemical modification of TBHQ that could lead to the development of more potent inhibitors of membrane fusion and potential anti-influenza drugs. PMID:19004788

  13. Preparation and crystallization of the stimulatory and inhibitory complexes of GTP cyclohydrolase I and its feedback regulatory protein GFRP.

    PubMed

    Maita, N; Okada, K; Hirotsu, S; Hatakeyama, K; Hakoshima, T

    2001-08-01

    Mammalian GTP cyclohydrolase I is a decameric enzyme in the first and rate-limiting step in the biosynthesis of tetrahydrobiopterin, which is an essential cofactor for enzymes producing neurotransmitters such as catecholamines and for nitric oxide synthases. The enzyme is dually regulated by its feedback regulatory protein GFRP in the presence of its stimulatory effector phenylalanine and its inhibitory effector biopterin. Here, both the stimulatory and inhibitory complexes of rat GTP cyclohydrolase I bound to GFRP were crystallized by vapour diffusion. Diffraction data sets at resolutions of 3.0 and 2.64 A were collected for the stimulatory and inhibitory complexes, respectively. Each complex consists of two GTPCHI pentamer rings and two GFRP pentamer rings, with pseudo-52 point-group symmetry.

  14. Importin beta negatively regulates nuclear membrane fusion and nuclear pore complex assembly.

    PubMed

    Harel, Amnon; Chan, Rene C; Lachish-Zalait, Aurelie; Zimmerman, Ella; Elbaum, Michael; Forbes, Douglass J

    2003-11-01

    Assembly of a eukaryotic nucleus involves three distinct events: membrane recruitment, fusion to form a double nuclear membrane, and nuclear pore complex (NPC) assembly. We report that importin beta negatively regulates two of these events, membrane fusion and NPC assembly. When excess importin beta is added to a full Xenopus nuclear reconstitution reaction, vesicles are recruited to chromatin but their fusion is blocked. The importin beta down-regulation of membrane fusion is Ran-GTP reversible. Indeed, excess RanGTP (RanQ69L) alone stimulates excessive membrane fusion, leading to intranuclear membrane tubules and cytoplasmic annulate lamellae-like structures. We propose that a precise balance of importin beta to Ran is required to create a correct double nuclear membrane and simultaneously to repress undesirable fusion events. Interestingly, truncated importin beta 45-462 allows membrane fusion but produces nuclei lacking any NPCs. This reveals distinct importin beta-regulation of NPC assembly. Excess full-length importin beta and beta 45-462 act similarly when added to prefused nuclear intermediates, i.e., both block NPC assembly. The importin beta NPC block, which maps downstream of GTPgammaS and BAPTA-sensitive steps in NPC assembly, is reversible by cytosol. Remarkably, it is not reversible by 25 microM RanGTP, a concentration that easily reverses fusion inhibition. This report, using a full reconstitution system and natural chromatin substrates, significantly expands the repertoire of importin beta. Its roles now encompass negative regulation of two of the major events of nuclear assembly: membrane fusion and NPC assembly.

  15. Cleaved thioredoxin fusion protein enables the crystallization of poorly soluble ERα in complex with synthetic ligands

    SciTech Connect

    Cura, Vincent; Gangloff, Monique; Eiler, Sylvia; Moras, Dino; Ruff, Marc

    2008-01-01

    A new crystallization strategy: the presence of cleaved thioredoxin fusion is critical for crystallization of the estrogen nuclear receptor ligand binding domain in complex with synthetic ligands. This novel technique should be regarded as an interesting alternative for crystallization of difficult proteins. The ligand-binding domain (LBD) of human oestrogen receptor α was produced in Escherichia coli as a cleavable thioredoxin (Trx) fusion in order to improve solubility. Crystallization trials with either cleaved and purified LBD or with the purified fusion protein both failed to produce crystals. In another attempt, Trx was not removed from the LBD after endoproteolytic cleavage and its presence promoted nucleation and subsequent crystal growth, which allowed the structure determination of two different LBD–ligand–coactivator peptide complexes at 2.3 Å resolution. This technique is likely to be applicable to other low-solubility proteins.

  16. Novel BRD4-NUT fusion isoforms increase the pathogenic complexity in NUT midline carcinoma.

    PubMed

    Thompson-Wicking, K; Francis, R W; Stirnweiss, A; Ferrari, E; Welch, M D; Baker, E; Murch, A R; Gout, A M; Carter, K W; Charles, A K; Phillips, M B; Kees, U R; Beesley, A H

    2013-09-26

    Nuclear protein in testis (NUT)-midline carcinoma (NMC) is a rare, aggressive disease typically presenting with a single t(15;19) translocation that results in the generation of a bromodomain-containing protein 4 (BRD4)-NUT fusion. PER-624 is a cell line generated from an NMC patient with an unusually complex karyotype that gave no initial indication of the involvement of the NUT locus. Analysis of PER-624 next-generation transcriptome sequencing (RNA-Seq) using the algorithm FusionFinder identified a novel transcript in which Exon 15 of BRD4 was fused to Exon 2 of NUT, therefore differing from all published NMC fusion transcripts. The three additional exons contained in the PER-624 fusion encode a series of polyproline repeats, with one predicted to form a helix. In the NMC cell line PER-403, we identified the 'standard' NMC fusion and two novel isoforms. Knockdown by small interfering RNA in either cell line resulted in decreased proliferation, increased cell size and expression of cytokeratins consistent with epithelial differentiation. These data demonstrate that the novel BRD4-NUT fusion in PER-624 encodes a functional protein that is central to the oncogenic mechanism in these cells. Genomic PCR indicated that in both PER-624 and PER-403, the translocation fuses an intron of BRD4 to a region upstream of the NUT coding sequence. Thus, the generation of BRD4-NUT fusion transcripts through post-translocation RNA-splicing appears to be a common feature of these carcinomas that has not previously been appreciated, with the mechanism facilitating the expression of alternative isoforms of the fusion. Finally, ectopic expression of wild-type NUT, a protein normally restricted to the testis, could be demonstrated in PER-403, indicating additional pathways for aberrant cell signaling in NMC. This study contributes to our understanding of the genetic diversity of NMC, an important step towards finding therapeutic targets for a disease that is refractory to current

  17. Structural-Functional Properties of Identified Excitatory and Inhibitory Interneurons within Pre-Bötzinger Complex Respiratory Microcircuits

    PubMed Central

    Koizumi, Hidehiko; Koshiya, Naohiro; Chia, Justine X.; Cao, Fang; Nugent, Joseph; Zhang, Ruli

    2013-01-01

    We comparatively analyzed cellular and circuit properties of identified rhythmic excitatory and inhibitory interneurons within respiratory microcircuits of the neonatal rodent pre-Bötzinger complex (pre-BötC), the structure generating inspiratory rhythm in the brainstem. We combined high-resolution structural–functional imaging, molecular assays for neurotransmitter phenotype identification in conjunction with electrophysiological property phenotyping, and morphological reconstruction of interneurons in neonatal rat and mouse slices in vitro. This approach revealed previously undifferentiated structural–functional features that distinguish excitatory and inhibitory interneuronal populations. We identified distinct subpopulations of pre-BötC glutamatergic, glycinergic, GABAergic, and glycine-GABA coexpressing interneurons. Most commissural pre-BötC inspiratory interneurons were glutamatergic, with a substantial subset exhibiting intrinsic oscillatory bursting properties. Commissural excitatory interneurons projected with nearly planar trajectories to the contralateral pre-BötC, many also with axon collaterals to areas containing inspiratory hypoglossal (XII) premotoneurons and motoneurons. Inhibitory neurons as characterized in the present study did not exhibit intrinsic oscillatory bursting properties, but were electrophysiologically distinguished by more pronounced spike frequency adaptation properties. Axons of many inhibitory neurons projected ipsilaterally also to regions containing inspiratory XII premotoneurons and motoneurons, whereas a minority of inhibitory neurons had commissural axonal projections. Dendrites of both excitatory and inhibitory interneurons were arborized asymmetrically, primarily in the coronal plane. The dendritic fields of inhibitory neurons were more spatially compact than those of excitatory interneurons. Our results are consistent with the concepts of a compartmental circuit organization, a bilaterally coupled excitatory

  18. Cleaved thioredoxin fusion protein enables the crystallization of poorly soluble ERα in complex with synthetic ligands

    PubMed Central

    Cura, Vincent; Gangloff, Monique; Eiler, Sylvia; Moras, Dino; Ruff, Marc

    2008-01-01

    The ligand-binding domain (LBD) of human oestrogen receptor α was produced in Escherichia coli as a cleavable thioredoxin (Trx) fusion in order to improve solubility. Crystallization trials with either cleaved and purified LBD or with the purified fusion protein both failed to produce crystals. In another attempt, Trx was not removed from the LBD after endoproteolytic cleavage and its presence promoted nucleation and subsequent crystal growth, which allowed the structure determination of two different LBD–ligand–coactivator peptide complexes at 2.3 Å resolution. This technique is likely to be applicable to other low-solubility proteins. PMID:18097104

  19. Cleaved thioredoxin fusion protein enables the crystallization of poorly soluble ERalpha in complex with synthetic ligands.

    PubMed

    Cura, Vincent; Gangloff, Monique; Eiler, Sylvia; Moras, Dino; Ruff, Marc

    2008-01-01

    The ligand-binding domain (LBD) of human oestrogen receptor alpha was produced in Escherichia coli as a cleavable thioredoxin (Trx) fusion in order to improve solubility. Crystallization trials with either cleaved and purified LBD or with the purified fusion protein both failed to produce crystals. In another attempt, Trx was not removed from the LBD after endoproteolytic cleavage and its presence promoted nucleation and subsequent crystal growth, which allowed the structure determination of two different LBD-ligand-coactivator peptide complexes at 2.3 A resolution. This technique is likely to be applicable to other low-solubility proteins.

  20. Sec3 promotes the initial binary t-SNARE complex assembly and membrane fusion

    PubMed Central

    Yue, Peng; Zhang, Yubo; Mei, Kunrong; Wang, Shaoxiao; Lesigang, Johannes; Zhu, Yueyao; Dong, Gang; Guo, Wei

    2017-01-01

    The soluble N-ethylmaleimide-sensitive factor-attachment protein receptors (SNAREs) constitute the core machinery for membrane fusion during eukaryotic cell vesicular trafficking. However, how the assembly of the SNARE complex is initiated is unknown. Here we report that Sec3, a component of the exocyst complex that mediates vesicle tethering during exocytosis, directly interacts with the t-SNARE protein Sso2. This interaction promotes the formation of an Sso2-Sec9 ‘binary' t-SNARE complex, the early rate-limiting step in SNARE complex assembly, and stimulates membrane fusion. The crystal structure of the Sec3-Sso2 complex suggests that Sec3 binding induces conformational changes of Sso2 that are crucial for the relief of its auto-inhibition. Interestingly, specific disruption of the Sec3–Sso2 interaction in cells blocks exocytosis without affecting the function of Sec3 in vesicle tethering. Our study reveals an activation mechanism for SNARE complex assembly, and uncovers a role of the exocyst in promoting membrane fusion in addition to vesicle tethering. PMID:28112172

  1. Sec17/Sec18 act twice, enhancing membrane fusion and then disassembling cis-SNARE complexes

    PubMed Central

    Song, Hongki; Orr, Amy; Duan, Mengtong; Merz, Alexey J; Wickner, William

    2017-01-01

    At physiological protein levels, the slow HOPS- and SNARE-dependent fusion which occurs upon complete SNARE zippering is stimulated by Sec17 and Sec18:ATP without requiring ATP hydrolysis. To stimulate, Sec17 needs its central residues which bind the 0-layer of the SNARE complex and its N-terminal apolar loop. Adding a transmembrane anchor to the N-terminus of Sec17 bypasses this requirement for apolarity of the Sec17 loop, suggesting that the loop functions for membrane binding rather than to trigger bilayer rearrangement. In contrast, when complete C-terminal SNARE zippering is prevented, fusion strictly requires Sec18 and Sec17, and the Sec17 apolar loop has functions beyond membrane anchoring. Thus Sec17 and Sec18 act twice in the fusion cycle, binding to trans-SNARE complexes to accelerate fusion, then hydrolyzing ATP to disassemble cis-SNARE complexes. DOI: http://dx.doi.org/10.7554/eLife.26646.001 PMID:28718762

  2. Positively charged amino acids at the SNAP-25 C terminus determine fusion rates, fusion pore properties, and energetics of tight SNARE complex zippering.

    PubMed

    Fang, Qinghua; Zhao, Ying; Herbst, Adam Drew; Kim, Brian N; Lindau, Manfred

    2015-02-18

    SNAP-25 is a Q-SNARE protein mediating exocytosis of neurosecretory vesicles including chromaffin granules. Previous results with a SNAP-25 construct lacking the nine C terminal residues (SNAP-25Δ9) showed changed fusion pore properties (Fang et al., 2008), suggesting a model for fusion pore mechanics that couple C terminal zipping of the SNARE complex to the opening of the fusion pore. The deleted fragment contains the positively charged residues R198 and K201, adjacent to layers 7 and 8 of the SNARE complex. To determine how fusion pore conductance and dynamics depend on these residues, single exocytotic events in bovine chromaffin cells expressing R198Q, R198E, K201Q, or K201E mutants were investigated by carbon fiber amperometry and cell-attached patch capacitance measurements. Coarse grain molecular dynamics simulations revealed spontaneous transitions between a loose and tightly zippered state at the SNARE complex C terminus. The SNAP-25 K201Q mutant showed no changes compared with SNAP-25 wild-type. However, K201E, R198Q, and R198E displayed reduced release frequencies, slower release kinetics, and prolonged fusion pore duration that were correlated with reduced probability to engage in the tightly zippered state. The results show that the positively charged amino acids at the SNAP-25 C terminus promote tight SNARE complex zippering and are required for high release frequency and rapid release in individual fusion events.

  3. Complex synchronous behavior in interneuronal networks with delayed inhibitory and fast electrical synapses

    NASA Astrophysics Data System (ADS)

    Guo, Daqing; Wang, Qingyun; Perc, Matjaž

    2012-06-01

    Networks of fast-spiking interneurons are crucial for the generation of neural oscillations in the brain. Here we study the synchronous behavior of interneuronal networks that are coupled by delayed inhibitory and fast electrical synapses. We find that both coupling modes play a crucial role by the synchronization of the network. In addition, delayed inhibitory synapses affect the emerging oscillatory patterns. By increasing the inhibitory synaptic delay, we observe a transition from regular to mixed oscillatory patterns at a critical value. We also examine how the unreliability of inhibitory synapses influences the emergence of synchronization and the oscillatory patterns. We find that low levels of reliability tend to destroy synchronization and, moreover, that interneuronal networks with long inhibitory synaptic delays require a minimal level of reliability for the mixed oscillatory pattern to be maintained.

  4. Complex epithelial remodeling underlie the fusion event in early fetal development of the human penile urethra.

    PubMed

    Shen, Joel; Overland, Maya; Sinclair, Adriane; Cao, Mei; Yue, Xuan; Cunha, Gerald; Baskin, Laurence

    We recently described a two-step process of urethral plate canalization and urethral fold fusion to form the human penile urethra. Canalization ("opening zipper") opens the solid urethral plate into a groove, and fusion ("closing zipper") closes the urethral groove to form the penile urethra. We hypothesize that failure of canalization and/or fusion during human urethral formation can lead to hypospadias. Herein, we use scanning electron microscopy (SEM) and analysis of transverse serial sections to better characterize development of the human fetal penile urethra as contrasted to the development of the human fetal clitoris. Eighteen 7-13 week human fetal external genitalia specimens were analyzed by SEM, and fifteen additional human fetal specimens were sectioned for histologic analysis. SEM images demonstrate canalization of the urethral/vestibular plate in the developing male and female external genitalia, respectively, followed by proximal to distal fusion of the urethral folds in males only. The fusion process during penile development occurs sequentially in multiple layers and through the interlacing of epidermal "cords". Complex epithelial organization is also noted at the site of active canalization. The demarcation between the epidermis of the shaft and the glans becomes distinct during development, and the epithelial tag at the distal tip of the penile and clitoral glans regresses as development progresses. In summary, SEM analysis of human fetal specimens supports the two-zipper hypothesis of formation of the penile urethra. The opening zipper progresses from proximal to distal along the shaft of the penis and clitoris into the glans in identical fashion in both sexes. The closing zipper mechanism is active only in males and is not a single process but rather a series of layered fusion events, uniquely different from the simple fusion of two epithelial surfaces as occurs in formation of the palate and neural tube.

  5. Complex epithelial remodeling underlie the fusion event in early fetal development of the human penile urethra

    PubMed Central

    Sinclair, Adriane; Cao, Mei; Yue, Xuan; Cunha, Gerald; Baskin, Laurence

    2016-01-01

    We recently described a two-step process of urethral plate canalization and urethral fold fusion to form the human penile urethra. Canalization (“opening zipper”) opens the solid urethral plate into a groove, and fusion (“closing zipper”) closes the urethral groove to form the penile urethra. We hypothesize that failure of canalization and/or fusion during human urethral formation can lead to hypospadias. Herein, we use scanning electron microscopy (SEM) and analysis of transverse serial sections to better characterize development of the human fetal penile urethra as contrasted to the development of the human fetal clitoris. Eighteen 7-13 week human fetal external genitalia specimens were analyzed by SEM, and fifteen additional human fetal specimens were sectioned for histologic analysis. SEM images demonstrate canalization of the urethral/vestibular plate in the developing male and female external genitalia, respectively, followed by proximal to distal fusion of the urethral folds in males only. The fusion process during penile development occurs sequentially in multiple layers and through the interlacing of epidermal “cords”. Complex epithelial organization is also noted at the site of active canalization. The demarcation between the epidermis of the shaft and the glans becomes distinct during development, and the epithelial tag at the distal tip of the penile and clitoral glans regresses as development progresses. In summary, SEM analysis of human fetal specimens supports the two-zipper hypothesis of formation of the penile urethra. The opening zipper progresses from proximal to distal along the shaft of the penis and clitoris into the glans in identical fashion in both sexes. The closing zipper mechanism is active only in males and is not a single process but rather a series of layered fusion events, uniquely different from the simple fusion of two epithelial surfaces as occurs in formation of the palate and neural tube. PMID:27397682

  6. Improving image classification in a complex wetland ecosystem through image fusion techniques

    NASA Astrophysics Data System (ADS)

    Kumar, Lalit; Sinha, Priyakant; Taylor, Subhashni

    2014-01-01

    The aim of this study was to evaluate the impact of image fusion techniques on vegetation classification accuracies in a complex wetland system. Fusion of panchromatic (PAN) and multispectral (MS) Quickbird satellite imagery was undertaken using four image fusion techniques: Brovey, hue-saturation-value (HSV), principal components (PC), and Gram-Schmidt (GS) spectral sharpening. These four fusion techniques were compared in terms of their mapping accuracy to a normal MS image using maximum-likelihood classification (MLC) and support vector machine (SVM) methods. Gram-Schmidt fusion technique yielded the highest overall accuracy and kappa value with both MLC (67.5% and 0.63, respectively) and SVM methods (73.3% and 0.68, respectively). This compared favorably with the accuracies achieved using the MS image. Overall, improvements of 4.1%, 3.6%, 5.8%, 5.4%, and 7.2% in overall accuracies were obtained in case of SVM over MLC for Brovey, HSV, GS, PC, and MS images, respectively. Visual and statistical analyses of the fused images showed that the Gram-Schmidt spectral sharpening technique preserved spectral quality much better than the principal component, Brovey, and HSV fused images. Other factors, such as the growth stage of species and the presence of extensive background water in many parts of the study area, had an impact on classification accuracies.

  7. A structural model of the anaphase promoting complex co-activator (Cdh1) and in silico design of inhibitory compounds

    PubMed Central

    Rahimi, H.; Negahdari, B.; Shokrgozar, M.A.; Madadkar-Sobhani, A.; Mahdian, R.; Foroumadi, A.; Amin, M. Kafshdouzi; Karimipoor, M.

    2015-01-01

    Anaphase promoting complex (APC) controls cell cycle and chromosome segregation. The APC activation occurs after binding of co-activators, cdh1 and cdc20. Cdh1 plays a role in cancer pathogenesis and is known as a potential drug target. The main aim of this study was prediction of 3D structure of cdh1 and designing the inhibitory compounds based on the structural model. First, 3D structure of cdh1 was predicted by means of homology modelling and molecular dynamics tools, MODELLER and Gromacs package, respectively. Then, inhibitory compounds were designed using virtual screening and molecular docking by means AutoDock package. The overall structure of cdh1 is propeller like and each DW40 repeat contains four anti-parallel beta-sheets. Moreover, binding pocket of the inhibitory compounds was determined. The results might be helpful in finding a suitable cdh1 inhibitor for the treatment of cancer. PMID:26430458

  8. A structural model of the anaphase promoting complex co-activator (Cdh1) and in silico design of inhibitory compounds.

    PubMed

    Rahimi, H; Negahdari, B; Shokrgozar, M A; Madadkar-Sobhani, A; Mahdian, R; Foroumadi, A; Amin, M Kafshdouzi; Karimipoor, M

    2015-01-01

    Anaphase promoting complex (APC) controls cell cycle and chromosome segregation. The APC activation occurs after binding of co-activators, cdh1 and cdc20. Cdh1 plays a role in cancer pathogenesis and is known as a potential drug target. The main aim of this study was prediction of 3D structure of cdh1 and designing the inhibitory compounds based on the structural model. First, 3D structure of cdh1 was predicted by means of homology modelling and molecular dynamics tools, MODELLER and Gromacs package, respectively. Then, inhibitory compounds were designed using virtual screening and molecular docking by means AutoDock package. The overall structure of cdh1 is propeller like and each DW40 repeat contains four anti-parallel beta-sheets. Moreover, binding pocket of the inhibitory compounds was determined. The results might be helpful in finding a suitable cdh1 inhibitor for the treatment of cancer.

  9. Field Theoretic Study of Bilayer Membrane Fusion: II. Mechanism of a Stalk-Hole Complex

    PubMed Central

    Katsov, K.; Müller, M.; Schick, M.

    2006-01-01

    We use self-consistent field theory to determine structural and energetic properties of intermediates and transition states involved in bilayer membrane fusion. In particular, we extend our original calculations from those of the standard hemifusion mechanism, which was studied in detail in the first article of this series, to consider a possible alternative to it. This mechanism involves non-axial stalk expansion, in contrast to the axially symmetric evolution postulated in the classical mechanism. Elongation of the initial stalk facilitates the nucleation of holes and leads to destabilization of the fusing membranes via the formation of a stalk-hole complex. We study properties of this complex in detail, and show how transient leakage during fusion, previously predicted and recently observed in experiment, should vary with lipid architecture and tension. We also show that the barrier to fusion in the alternative mechanism is lower than that of the standard mechanism by a few kBT over most of the relevant region of system parameters, so that this alternative mechanism is a viable alternative to the standard pathway. We emphasize that any mechanism, such as this alternative one, which affects, even modestly, the line tension of a hole in a membrane, affects greatly the ability of that membrane to undergo fusion. PMID:16272437

  10. Combinatorial SNARE complexes with VAMP7 or VAMP8 define different late endocytic fusion events.

    PubMed

    Pryor, Paul R; Mullock, Barbara M; Bright, Nicholas A; Lindsay, Margaret R; Gray, Sally R; Richardson, Simon C W; Stewart, Abigail; James, David E; Piper, Robert C; Luzio, J Paul

    2004-06-01

    Both heterotypic and homotypic fusion events are required to deliver endocytosed macromolecules to lysosomes and remodel late endocytic organelles. A trans-SNARE complex consisting of Q-SNAREs syntaxin 7, Vti1b and syntaxin 8 and the R-SNARE VAMP8 has been shown by others to be responsible for homotypic fusion of late endosomes. Using antibody inhibition experiments in rat liver cell-free systems, we confirmed this result, but found that the same Q-SNAREs can combine with an alternative R-SNARE, namely VAMP7, for heterotypic fusion between late endosomes and lysosomes. Co-immunoprecipitation demonstrated separate syntaxin 7 complexes with either VAMP7 or VAMP8 in solubilized rat liver membranes. Additionally, overexpression of the N-terminal domain of VAMP7, in cultured fibroblastic cells, inhibited the mixing of a preloaded lysosomal content marker with a marker delivered to late endosomes. These data show that combinatorial interactions of SNAREs determine whether late endosomes undergo homotypic or heterotypic fusion events.

  11. Figure-ground discrimination in the avian brain: The nucleus rotundus and its inhibitory complex

    PubMed Central

    Acerbo, Martin J.; Lazareva, Olga F.; McInnerney, John; Leiker, Emily; Wasserman, Edward A.; Poremba, Amy

    2012-01-01

    In primates, neurons sensitive to figure-ground status are located in striate cortex (area V1) and extrastriate cortex (area V2). Although much is known about the anatomical structure and connectivity of the avian visual pathway, the functional organization of the avian brain remains largely unexplored. To pinpoint the areas associated with figure-ground segregation in the avian brain, we used a radioactively labeled glucose analog to compare differences in glucose uptake after figure-ground, color, and shape discriminations. We also included a control group that received food on a variable-interval schedule, but was not required to learn a visual discrimination. Although the discrimination task depended on group assignment, the stimulus displays were identical for all three experimental groups, ensuring that all animals were exposed to the same visual input. Our analysis concentrated on the primary thalamic nucleus associated with visual processing, the nucleus rotundus (Rt), and two nuclei providing regulatory feedback, the pretectum (PT) and the nucleus subpretectalis/interstitio-pretecto-subpretectalis complex (SP/IPS). We found that figure-ground discrimination was associated with strong and nonlateralized activity of Rt and SP/IPS, whereas color discrimination produced strong and lateralized activation in Rt alone. Shape discrimination was associated with lower activity of Rt than in the control group. Taken together, our results suggest that figure-ground discrimination is associated with Rt and that SP/IPS may be a main source of inhibitory control. Thus, figure-ground segregation in the avian brain may occur earlier than in the primate brain. PMID:22917681

  12. Regression of anterior disc-osteophyte complex following cervical laminectomy and fusion for cervical spondylotic myelopathy

    PubMed Central

    Ashana, Adedayo O.; Cohen, Jeremiah R.; Evans, Brandon; Holly, Langston T.

    2014-01-01

    Study Design Retrospective case control study Objective To investigate whether posterior cervical laminectomy and fusion modifies the natural course of anterior disc-osteophyte complex in patients with multilevel CSM Summary of Background Data Dorsal migration of the spinal cord is the main purported mechanism of spinal cord decompression following cervical laminectomy and fusion but other potential mechanisms have received scant attention in the literature. This study was conducted to investigate whether cervical laminectomy and fusion affects the size of anterior disc osteophyte complex. Methods The medical records and radiographical imaging of 44 patients that underwent cervical laminectomy and fusion for CSM between 2006 and 2013 were analyzed. The size of the anterior disc osteophyte complex was measured pre and postoperatively on MR images taken at an interval of > 3 months apart. A control group consisted of 20 non-operatively treated advanced cervical spondylosis patients. Patients in the control met the same inclusion and exclusion criteria and also had sequential MRI taken at an interval of > 3 months apart. Results The nonoperative and operative groups were statistically similar in the pertinent patient demographics and characteristics including gender, age, time to second MRI, size of anterior disc-osteophyte complex on baseline MRI, mean number of levels affected, and percentage of patients with T2 signal change. As expected the mJOA scores were significantly lower in the operative versus nonoperative cohort (13.6 vs. 16.5, P<0.01). A significant decrease in the size of anterior disc osteophyte was observed in the operative group postoperatively (P<0.01). In comparison, there was no statistically significant change in the size of the anterior disc osteophyte complex in the control group (P > 0.05). The magnitude of the change in disc size between the two groups was statistically significant (P <0.01). Conclusion The findings of this study suggest that

  13. Feature level fusion for enhanced geological mapping of ophiolile complex using ASTER and Landsat TM data

    NASA Astrophysics Data System (ADS)

    Pournamdari, M.; Hashim, M.

    2014-02-01

    Chromite ore deposit occurrence is related to ophiolite complexes as a part of the oceanic crust and provides a good opportunity for lithological mapping using remote sensing data. The main contribution of this paper is a novel approaches to discriminate different rock units associated with ophiolite complex using the Feature Level Fusion technique on ASTER and Landsat TM satellite data at regional scale. In addition this study has applied spectral transform approaches, consisting of Spectral Angle Mapper (SAM) to distinguish the concentration of high-potential areas of chromite and also for determining the boundary between different rock units. Results indicated both approaches show superior outputs compared to other methods and can produce a geological map for ophiolite complex rock units in the arid and the semi-arid region. The novel technique including feature level fusion and Spectral Angle Mapper (SAM) discriminated ophiolitic rock units and produced detailed geological maps of the study area. As a case study, Sikhoran ophiolite complex located in SE, Iran has been selected for image processing techniques. In conclusion, a suitable approach for lithological mapping of ophiolite complexes is demonstrated, this technique contributes meaningfully towards economic geology in terms of identifying new prospects.

  14. Data fusion for QRS complex detection in multi-lead electrocardiogram recordings

    NASA Astrophysics Data System (ADS)

    Ledezma, Carlos A.; Perpiñan, Gilberto; Severeyn, Erika; Altuve, Miguel

    2015-12-01

    Heart diseases are the main cause of death worldwide. The first step in the diagnose of these diseases is the analysis of the electrocardiographic (ECG) signal. In turn, the ECG analysis begins with the detection of the QRS complex, which is the one with the most energy in the cardiac cycle. Numerous methods have been proposed in the bibliography for QRS complex detection, but few authors have analyzed the possibility of taking advantage of the information redundancy present in multiple ECG leads (simultaneously acquired) to produce accurate QRS detection. In our previous work we presented such an approach, proposing various data fusion techniques to combine the detections made by an algorithm on multiple ECG leads. In this paper we present further studies that show the advantages of this multi-lead detection approach, analyzing how many leads are necessary in order to observe an improvement in the detection performance. A well known QRS detection algorithm was used to test the fusion techniques on the St. Petersburg Institute of Cardiological Technics database. Results show improvement in the detection performance with as little as three leads, but the reliability of these results becomes interesting only after using seven or more leads. Results were evaluated using the detection error rate (DER). The multi-lead detection approach allows an improvement from DER = 3:04% to DER = 1:88%. Further works are to be made in order to improve the detection performance by implementing further fusion steps.

  15. Crystal structure of the conserved herpes virus fusion regulator complex gH-gL

    SciTech Connect

    Chowdary, Tirumala K; Cairns, Tina M; Atanasiu, Doina; Cohen, Gary H; Eisenberg, Roselyn J; Heldwein, Ekaterina E

    2010-09-13

    Herpesviruses, which cause many incurable diseases, infect cells by fusing viral and cellular membranes. Whereas most other enveloped viruses use a single viral catalyst called a fusogen, herpesviruses, inexplicably, require two conserved fusion-machinery components, gB and the heterodimer gH-gL, plus other nonconserved components. gB is a class III viral fusogen, but unlike other members of its class, it does not function alone. We determined the crystal structure of the gH ectodomain bound to gL from herpes simplex virus 2. gH-gL is an unusually tight complex with a unique architecture that, unexpectedly, does not resemble any known viral fusogen. Instead, we propose that gH-gL activates gB for fusion, possibly through direct binding. Formation of a gB-gH-gL complex is critical for fusion and is inhibited by a neutralizing antibody, making the gB-gH-gL interface a promising antiviral target.

  16. Crystal Structure of the Conserved Herpes Virus Fusion Regulator Complex gH–gL

    SciTech Connect

    Chowdary, T.; Cairns, T; Atanasiu, D; Cohen, G; Eisenberg, R; Heldwein, E

    2010-01-01

    Herpesviruses, which cause many incurable diseases, infect cells by fusing viral and cellular membranes. Whereas most other enveloped viruses use a single viral catalyst called a fusogen, herpesviruses, inexplicably, require two conserved fusion-machinery components, gB and the heterodimer gH-gL, plus other nonconserved components. gB is a class III viral fusogen, but unlike other members of its class, it does not function alone. We determined the crystal structure of the gH ectodomain bound to gL from herpes simplex virus 2. gH-gL is an unusually tight complex with a unique architecture that, unexpectedly, does not resemble any known viral fusogen. Instead, we propose that gH-gL activates gB for fusion, possibly through direct binding. Formation of a gB-gH-gL complex is critical for fusion and is inhibited by a neutralizing antibody, making the gB-gH-gL interface a promising antiviral target.

  17. Crystal structure of the conserved herpesvirus fusion regulator complex gH—gL

    SciTech Connect

    Chowdary, Tirumala K.; Cairns, Tina M.; Atanasiu, Doina; Cohen, Gary H.; Eisenberg, Roselyn J.; Heldwein, Ekaterina E.

    2015-02-09

    Herpesviruses, which cause many incurable diseases, infect cells by fusing viral and cellular membranes. Whereas most other enveloped viruses use a single viral catalyst called a fusogen, herpesviruses, inexplicably, require two conserved fusion-machinery components, gB and the heterodimer gH–gL, plus other nonconserved components. gB is a class III viral fusogen, but unlike other members of its class, it does not function alone. We determined the crystal structure of the gH ectodomain bound to gL from herpes simplex virus 2. gH–gL is an unusually tight complex with a unique architecture that, unexpectedly, does not resemble any known viral fusogen. Instead, we propose that gH–gL activates gB for fusion, possibly through direct binding. Formation of a gB–gH–gL complex is critical for fusion and is inhibited by a neutralizing antibody, making the gB–gH–gL interface a promising antiviral target.

  18. Structure of the human factor VIII C2 domain in complex with the 3E6 inhibitory antibody

    DOE PAGES

    Wuerth, Michelle E.; Cragerud, Rebecca K.; Spiegel, P. Clint

    2015-11-24

    Blood coagulation factor VIII is a glycoprotein cofactor that is essential for the intrinsic pathway of the blood coagulation cascade. Inhibitory antibodies arise either spontaneously or in response to therapeutic infusion of functional factor VIII into hemophilia A patients, many of which are specific to the factor VIII C2 domain. The immune response is largely parsed into “classical” and “non-classical” inhibitory antibodies, which bind to opposing faces cooperatively. In this study, the 2.61 Å resolution structure of the C2 domain in complex with the antigen-binding fragment of the 3E6 classical inhibitory antibody is reported. The binding interface is largely conservedmore » when aligned with the previously determined structure of the C2 domain in complex with two antibodies simultaneously. Further inspection of the B factors for the C2 domain in various X-ray crystal structures indicates that 3E6 antibody binding decreases the thermal motion behavior of surface loops in the C2 domain on the opposing face, thereby suggesting that cooperative antibody binding is a dynamic effect. Furthermore, understanding the structural nature of the immune response to factor VIII following hemophilia A treatment will help lead to the development of better therapeutic reagents.« less

  19. Structure of the human factor VIII C2 domain in complex with the 3E6 inhibitory antibody

    SciTech Connect

    Wuerth, Michelle E.; Cragerud, Rebecca K.; Spiegel, P. Clint

    2015-11-24

    Blood coagulation factor VIII is a glycoprotein cofactor that is essential for the intrinsic pathway of the blood coagulation cascade. Inhibitory antibodies arise either spontaneously or in response to therapeutic infusion of functional factor VIII into hemophilia A patients, many of which are specific to the factor VIII C2 domain. The immune response is largely parsed into “classical” and “non-classical” inhibitory antibodies, which bind to opposing faces cooperatively. In this study, the 2.61 Å resolution structure of the C2 domain in complex with the antigen-binding fragment of the 3E6 classical inhibitory antibody is reported. The binding interface is largely conserved when aligned with the previously determined structure of the C2 domain in complex with two antibodies simultaneously. Further inspection of the B factors for the C2 domain in various X-ray crystal structures indicates that 3E6 antibody binding decreases the thermal motion behavior of surface loops in the C2 domain on the opposing face, thereby suggesting that cooperative antibody binding is a dynamic effect. Furthermore, understanding the structural nature of the immune response to factor VIII following hemophilia A treatment will help lead to the development of better therapeutic reagents.

  20. Structure of the Human Factor VIII C2 Domain in Complex with the 3E6 Inhibitory Antibody

    PubMed Central

    Wuerth, Michelle E.; Cragerud, Rebecca K.; Clint Spiegel, P.

    2015-01-01

    Blood coagulation factor VIII is a glycoprotein cofactor that is essential for the intrinsic pathway of the blood coagulation cascade. Inhibitory antibodies arise either spontaneously or in response to therapeutic infusion of functional factor VIII into hemophilia A patients, many of which are specific to the factor VIII C2 domain. The immune response is largely parsed into “classical” and “non-classical” inhibitory antibodies, which bind to opposing faces cooperatively. In this study, the 2.61 Å resolution structure of the C2 domain in complex with the antigen-binding fragment of the 3E6 classical inhibitory antibody is reported. The binding interface is largely conserved when aligned with the previously determined structure of the C2 domain in complex with two antibodies simultaneously. Further inspection of the B factors for the C2 domain in various X-ray crystal structures indicates that 3E6 antibody binding decreases the thermal motion behavior of surface loops in the C2 domain on the opposing face, thereby suggesting that cooperative antibody binding is a dynamic effect. Understanding the structural nature of the immune response to factor VIII following hemophilia A treatment will help lead to the development of better therapeutic reagents. PMID:26598467

  1. Structure of the Human Factor VIII C2 Domain in Complex with the 3E6 Inhibitory Antibody.

    PubMed

    Wuerth, Michelle E; Cragerud, Rebecca K; Spiegel, P Clint

    2015-11-24

    Blood coagulation factor VIII is a glycoprotein cofactor that is essential for the intrinsic pathway of the blood coagulation cascade. Inhibitory antibodies arise either spontaneously or in response to therapeutic infusion of functional factor VIII into hemophilia A patients, many of which are specific to the factor VIII C2 domain. The immune response is largely parsed into "classical" and "non-classical" inhibitory antibodies, which bind to opposing faces cooperatively. In this study, the 2.61 Å resolution structure of the C2 domain in complex with the antigen-binding fragment of the 3E6 classical inhibitory antibody is reported. The binding interface is largely conserved when aligned with the previously determined structure of the C2 domain in complex with two antibodies simultaneously. Further inspection of the B factors for the C2 domain in various X-ray crystal structures indicates that 3E6 antibody binding decreases the thermal motion behavior of surface loops in the C2 domain on the opposing face, thereby suggesting that cooperative antibody binding is a dynamic effect. Understanding the structural nature of the immune response to factor VIII following hemophilia A treatment will help lead to the development of better therapeutic reagents.

  2. Use of a Proximal Humeral Locking Plate for Complex Ankle and Hindfoot Fusion.

    PubMed

    Shearman, Alexander D; Eleftheriou, Kyriacos Iordanis; Patel, Akash; Pradhan, Rajib; Rosenfeld, Peter Francis

    2016-01-01

    Arthrodesis of the ankle and hindfoot in the setting of major deformity is challenging and associated with substantial risks. Patients often have significant comorbidities that lead to unforgiving soft tissues, poor vascularity, and poor bone quality. This creates the high-risk scenario of poor wound healing and poor implant fixation. Complications can be devastating, leading to loss of the limb and sepsis. The use of locking plate technology might provide biomechanical and operative technique advantages in such patients. We retrospectively assessed the results of the modified use of the PHILOS(™) (Synthes(®), Zuchwil, Switzerland) proximal humeral locking plate in 21 patients (11 males, 10 females; mean age 56.1 years, range 25 to 74 years) who had undergone complex fusions, including tibiotalar (n = 4), tibiocalcaneal (n = 7), or tibiotalocalcaneal (n =10) fusions. The average follow-up period was 14.6 (median 10, range 6 to 49) months. Of the 21 fusions, 18 achieved union (85.7%) at an average period of 4.8 (median 4.3, range 3 to 12) months. The overall deep infection rate was 14.3%. Overall, 17 of the 21 patients (81%) were satisfied with the result (good to excellent), 1 reported the result was fair (4.8%), and 3 patients developed nonunion and were dissatisfied with the procedure (14.3%). The present study is the largest series to date of patients undergoing complex ankle and hindfoot arthrodesis with the use of a proximal humeral locking plate and confirms previous findings that the technique is reliable with union, satisfaction, and complication rates comparable to those of other techniques. Copyright © 2016 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

  3. Comprehensive tire-road friction coefficient estimation based on signal fusion method under complex maneuvering operations

    NASA Astrophysics Data System (ADS)

    Li, L.; Yang, K.; Jia, G.; Ran, X.; Song, J.; Han, Z.-Q.

    2015-05-01

    The accurate estimation of the tire-road friction coefficient plays a significant role in the vehicle dynamics control. The estimation method should be timely and reliable for the controlling requirements, which means the contact friction characteristics between the tire and the road should be recognized before the interference to ensure the safety of the driver and passengers from drifting and losing control. In addition, the estimation method should be stable and feasible for complex maneuvering operations to guarantee the control performance as well. A signal fusion method combining the available signals to estimate the road friction is suggested in this paper on the basis of the estimated ones of braking, driving and steering conditions individually. Through the input characteristics and the states of the vehicle and tires from sensors the maneuvering condition may be recognized, by which the certainty factors of the friction of the three conditions mentioned above may be obtained correspondingly, and then the comprehensive road friction may be calculated. Experimental vehicle tests validate the effectiveness of the proposed method through complex maneuvering operations; the estimated road friction coefficient based on the signal fusion method is relatively timely and accurate to satisfy the control demands.

  4. Inhibitory effects of ascorbic acid, vitamin E, and vitamin B-complex on the biological activities induced by Bothrops venom.

    PubMed

    Oliveira, Carlos Henrique de Moura; Assaid Simão, Anderson; Marcussi, Silvana

    2016-01-01

    Natural compounds have been widely studied with the aim of complementing antiophidic serum therapy. The present study evaluated the inhibitory potential of ascorbic acid and a vitamin complex, composed of ascorbic acid, vitamin E, and all the B-complex vitamins, on the biological activities induced by snake venoms. The effect of vitamins was evaluated on the phospholipase, proteolytic, coagulant, and fibrinogenolytic activities induced by Bothrops moojeni (Viperidae), B. jararacussu, and B. alternatus snake venoms, and the hemagglutinating activity induced by B. jararacussu venom. The vitamin complex (1:5 and 1:10 ratios) totally inhibited the fibrinogenolytic activity and partially the phospholipase activity and proteolytic activity on azocasein induced by the evaluated venoms. Significant inhibition was observed in the coagulation of human plasma induced by venoms from B. alternatus (1:2.5 and 1:5, to vitamin complex and ascorbic acid) and B. moojeni (1:2.5 and 1:5, to vitamin complex and ascorbic acid). Ascorbic acid inhibited 100% of the proteolytic activities of B. moojeni and B. alternatus on azocasein, at 1:10 ratio, the effects of all the venoms on fibrinogen, the hemagglutinating activity of B. jararacussu venom, and also extended the plasma coagulation time induced by all venoms analyzed. The vitamins analyzed showed relevant in vitro inhibitory potential over the activities induced by Bothrops venoms, suggesting their interaction with toxins belonging to the phospholipase A2, protease, and lectin classes. The results can aid further research in clarifying the possible mechanisms of interaction between vitamins and snake enzymes.

  5. Structure of the malaria vaccine candidate antigen CyRPA and its complex with a parasite invasion inhibitory antibody.

    PubMed

    Favuzza, Paola; Guffart, Elena; Tamborrini, Marco; Scherer, Bianca; Dreyer, Anita M; Rufer, Arne C; Erny, Johannes; Hoernschemeyer, Joerg; Thoma, Ralf; Schmid, Georg; Gsell, Bernard; Lamelas, Araceli; Benz, Joerg; Joseph, Catherine; Matile, Hugues; Pluschke, Gerd; Rudolph, Markus G

    2017-02-14

    Invasion of erythrocytes by Plasmodial merozoites is a composite process involving the interplay of several proteins. Among them, the Plasmodium falciparum Cysteine-Rich Protective Antigen (PfCyRPA) is a crucial component of a ternary complex, including Reticulocyte binding-like Homologous protein 5 (PfRH5) and the RH5-interacting protein (PfRipr), essential for erythrocyte invasion. Here we present the crystal structure of PfCyRPA and of its complex with the antigen-binding fragment of a parasite growth inhibitory antibody. While PfCyRPA adopts a 6-bladed β-propeller structure with similarity to the classic sialidase fold, it possesses no sialidase activity, indicating that it fulfills a non-enzymatic function. Characterization of the epitope recognized by protective antibodies will facilitate design of peptidomimetics that focus vaccine responses on protective epitopes. Both in vitro and in vivo anti-PfCyRPA and anti-PfRH5 antibodies showed more potent parasite growth inhibitory activity in combination than on their own, supporting a combined delivery of PfCyRPA and PfRH5 in vaccines.

  6. Structure of the malaria vaccine candidate antigen CyRPA and its complex with a parasite invasion inhibitory antibody

    PubMed Central

    Favuzza, Paola; Guffart, Elena; Tamborrini, Marco; Scherer, Bianca; Dreyer, Anita M; Rufer, Arne C; Erny, Johannes; Hoernschemeyer, Joerg; Thoma, Ralf; Schmid, Georg; Gsell, Bernard; Lamelas, Araceli; Benz, Joerg; Joseph, Catherine; Matile, Hugues; Pluschke, Gerd; Rudolph, Markus G

    2017-01-01

    Invasion of erythrocytes by Plasmodial merozoites is a composite process involving the interplay of several proteins. Among them, the Plasmodium falciparum Cysteine-Rich Protective Antigen (PfCyRPA) is a crucial component of a ternary complex, including Reticulocyte binding-like Homologous protein 5 (PfRH5) and the RH5-interacting protein (PfRipr), essential for erythrocyte invasion. Here, we present the crystal structures of PfCyRPA and its complex with the antigen-binding fragment of a parasite growth inhibitory antibody. PfCyRPA adopts a 6-bladed β-propeller structure with similarity to the classic sialidase fold, but it has no sialidase activity and fulfills a purely non-enzymatic function. Characterization of the epitope recognized by protective antibodies may facilitate design of peptidomimetics to focus vaccine responses on protective epitopes. Both in vitro and in vivo anti-PfCyRPA and anti-PfRH5 antibodies showed more potent parasite growth inhibitory activity in combination than on their own, supporting a combined delivery of PfCyRPA and PfRH5 in vaccines. DOI: http://dx.doi.org/10.7554/eLife.20383.001 PMID:28195038

  7. Oscillations, complex spatiotemporal behavior, and information transport in networks of excitatory and inhibitory neurons

    SciTech Connect

    Destexhe, A. )

    1994-08-01

    Various types of spatiotemporal behavior are described for two-dimensional networks of excitatory and inhibitory neurons with time delayed interactions. It is described how the network behaves as several structural parameters are varied, such as the number of neurons, the connectivity, and the values of synaptic weights. A transition from spatially uniform oscillations to spatiotemporal chaos via intermittentlike behavior is observed. The properties of spatiotemporally chaotic solutions are investigated by evaluating the largest positive Lyapunov exponent and the loss of correlation with distance. Finally, properties of information transport are evaluated during uniform oscillations and spatiotemporal chaos. It is shown that the diffusion coefficient increases significantly in the spatiotemporal phase similar to the increase of transport coefficients at the onset of fluid turbulence. It is proposed that such a property should be seen in other media, such as chemical turbulence or networks of oscillators. The possibility of measuring information transport from appropriate experiments is also discussed.

  8. Determination of haplotypes at structurally complex regions using emulsion haplotype fusion PCR

    PubMed Central

    2012-01-01

    Background Genotyping and massively-parallel sequencing projects result in a vast amount of diploid data that is only rarely resolved into its constituent haplotypes. It is nevertheless this phased information that is transmitted from one generation to the next and is most directly associated with biological function and the genetic causes of biological effects. Despite progress made in genome-wide sequencing and phasing algorithms and methods, problems assembling (and reconstructing linear haplotypes in) regions of repetitive DNA and structural variation remain. These dynamic and structurally complex regions are often poorly understood from a sequence point of view. Regions such as these that are highly similar in their sequence tend to be collapsed onto the genome assembly. This is turn means downstream determination of the true sequence haplotype in these regions poses a particular challenge. For structurally complex regions, a more focussed approach to assembling haplotypes may be required. Results In order to investigate reconstruction of spatial information at structurally complex regions, we have used an emulsion haplotype fusion PCR approach to reproducibly link sequences of up to 1kb in length to allow phasing of multiple variants from neighbouring loci, using allele-specific PCR and sequencing to detect the phase. By using emulsion systems linking flanking regions to amplicons within the CNV, this led to the reconstruction of a 59kb haplotype across the DEFA1A3 CNV in HapMap individuals. Conclusion This study has demonstrated a novel use for emulsion haplotype fusion PCR in addressing the issue of reconstructing structural haplotypes at multiallelic copy variable regions, using the DEFA1A3 locus as an example. PMID:23231411

  9. Structure of a Major Antigenic Site on the Respiratory Syncytial Virus Fusion Glycoprotein in Complex with Neutralizing Antibody 101F

    SciTech Connect

    McLellan, Jason S.; Chen, Man; Chang, Jung-San; Yang, Yongping; Kim, Albert; Graham, Barney S.; Kwong, Peter D.

    2010-11-19

    Respiratory syncytial virus (RSV) is a major cause of pneumonia and bronchiolitis in infants and elderly people. Currently there is no effective vaccine against RSV, but passive prophylaxis with neutralizing antibodies reduces hospitalizations. To investigate the mechanism of antibody-mediated RSV neutralization, we undertook structure-function studies of monoclonal antibody 101F, which binds a linear epitope in the RSV fusion glycoprotein. Crystal structures of the 101F antigen-binding fragment in complex with peptides from the fusion glycoprotein defined both the extent of the linear epitope and the interactions of residues that are mutated in antibody escape variants. The structure allowed for modeling of 101F in complex with trimers of the fusion glycoprotein, and the resulting models suggested that 101F may contact additional surfaces located outside the linear epitope. This hypothesis was supported by surface plasmon resonance experiments that demonstrated 101F bound the peptide epitope {approx}16,000-fold more weakly than the fusion glycoprotein. The modeling also showed no substantial clashes between 101F and the fusion glycoprotein in either the pre- or postfusion state, and cell-based assays indicated that 101F neutralization was not associated with blocking virus attachment. Collectively, these results provide a structural basis for RSV neutralization by antibodies that target a major antigenic site on the fusion glycoprotein.

  10. Represent and fuse bimodal biometric images at the feature level: complex-matrix-based fusion scheme

    NASA Astrophysics Data System (ADS)

    Xu, Yong; Zhang, David

    2010-03-01

    Multibiometrics can obtain a higher accuracy than the single biometrics by simultaneously using multiple biometric traits of the subject. We note that biometric traits are usually in the form of images. Thus, how to properly fuse the information of multiple biometric images of the subject for authentication is crucial for multibiometrics. We propose a novel image-based linear discriminant analysis (IBLDA) approach to fuse two biometric traits (i.e., bimodal biometric images) of the same subject in the form of matrix at the feature level. IBLDA first integrates two biometric traits of one subject into a complex matrix and then directly extracts low-dimensional features for the integrated biometric traits. IBLDA also enables more information to be exploited than the matching score level fusion and the decision level fusion. Compared to linear discriminant analysis (LDA), IBLDA has the following advantages: First, it can overcome the small sample size problem that conventional LDA usually suffers from. Second, IBLDA solves the eigenequation at a low computational cost. Third, when storing the scatter matrices IBLDA will not bring as heavy a memory burden as conventional LDA. We also clearly show the theoretical foundation of the proposed method. The experiment result shows that the proposed method can obtain a high classification accuracy.

  11. Advances and challenges in deformable image registration: From image fusion to complex motion modelling.

    PubMed

    Schnabel, Julia A; Heinrich, Mattias P; Papież, Bartłomiej W; Brady, Sir J Michael

    2016-10-01

    Over the past 20 years, the field of medical image registration has significantly advanced from multi-modal image fusion to highly non-linear, deformable image registration for a wide range of medical applications and imaging modalities, involving the compensation and analysis of physiological organ motion or of tissue changes due to growth or disease patterns. While the original focus of image registration has predominantly been on correcting for rigid-body motion of brain image volumes acquired at different scanning sessions, often with different modalities, the advent of dedicated longitudinal and cross-sectional brain studies soon necessitated the development of more sophisticated methods that are able to detect and measure local structural or functional changes, or group differences. Moving outside of the brain, cine imaging and dynamic imaging required the development of deformable image registration to directly measure or compensate for local tissue motion. Since then, deformable image registration has become a general enabling technology. In this work we will present our own contributions to the state-of-the-art in deformable multi-modal fusion and complex motion modelling, and then discuss remaining challenges and provide future perspectives to the field.

  12. Dynamic function of the alkyl spacer of acetogenins in their inhibitory action with mitochondrial complex I (NADH-ubiquinone oxidoreductase).

    PubMed

    Abe, Masato; Murai, Masatoshi; Ichimaru, Naoya; Kenmochi, Atsushi; Yoshida, Takehiko; Kubo, Akina; Kimura, Yuka; Moroda, Aki; Makabe, Hidefumi; Nishioka, Takaaki; Miyoshi, Hideto

    2005-11-15

    Studies on the inhibitory mechanism of acetogenins, the most potent inhibitors of mitochondrial complex I (NADH-ubiquinone oxidoreductase), are useful for elucidating the structural and functional features of the terminal electron transfer step of this enzyme. Previous studies of the structure-activity relationship revealed that except for the alkyl spacer linking the two toxophores (i.e., the hydroxylated THF and the gamma-lactone rings), none of the multiple functional groups of these inhibitors is essential for potent inhibition. To elucidate the function of the alkyl spacer, two sets of systematically selected analogues were synthesized. First, the length of the spacer was varied widely. Second, the local flexibility of the spacer was specifically reduced by introducing multiple bond(s) into different regions of the spacer. The optimal length of the spacer for inhibition was approximately 13 carbon atoms. The decrease in the strength of the inhibitory effect caused by elongating the spacer from 13 carbons was much more drastic than that caused by shortening. Local flexibility in a specific region of the spacer was not important for the inhibition. These observations indicate that the active conformation of the spacer is not an extended form, and is not necessarily restricted to a certain rigid shape. Moreover, an analogue in which a spacer covering 10 carbon atoms was hardened into a rodlike shape still maintained a potent inhibitory effect. Our results strongly suggest that the spacer portion is free from steric congestion arising from the putative binding site probably because there is no cavity-like binding site for the spacer portion. The manner of acetogenin binding to the enzyme may not be explained by a simple "key and keyhole" analogy.

  13. Novel Findings from CNVs Implicate Inhibitory and Excitatory Signaling Complexes in Schizophrenia

    PubMed Central

    Pocklington, Andrew J.; Rees, Elliott; Walters, James T.R.; Han, Jun; Kavanagh, David H.; Chambert, Kimberly D.; Holmans, Peter; Moran, Jennifer L.; McCarroll, Steven A.; Kirov, George; O’Donovan, Michael C.; Owen, Michael J.

    2015-01-01

    Summary We sought to obtain novel insights into schizophrenia pathogenesis by exploiting the association between the disorder and chromosomal copy number (CNV) burden. We combined data from 5,745 cases and 10,675 controls with other published datasets containing genome-wide CNV data. In this much-enlarged sample of 11,355 cases and 16,416 controls, we show for the first time that case CNVs are enriched for genes involved in GABAergic neurotransmission. Consistent with non-genetic reports of GABAergic deficits in schizophrenia, our findings now show disrupted GABAergic signaling is of direct causal relevance, rather than a secondary effect or due to confounding. Additionally, we independently replicate and greatly extend previous findings of CNV enrichment among genes involved in glutamatergic signaling. Given the strong functional links between the major inhibitory GABAergic and excitatory glutamatergic systems, our findings converge on a broad, coherent set of pathogenic processes, providing firm foundations for studies aimed at dissecting disease mechanisms. PMID:26050040

  14. RNA sequencing of esophageal adenocarcinomas identifies novel fusion transcripts, including NPC1-MELK, arising from a complex chromosomal rearrangement.

    PubMed

    Wang, Zhixiong; Cheng, Yulan; Abraham, John M; Yan, Rong; Liu, Xi; Chen, Wei; Ibrahim, Sariat; Schroth, Gary P; Ke, Xiquan; He, Yulong; Meltzer, Stephen J

    2017-06-22

    Studies of chromosomal rearrangements and fusion transcripts have elucidated mechanisms of tumorigenesis and led to targeted cancer therapies. This study was aimed at identifying novel fusion transcripts in esophageal adenocarcinoma (EAC). To identify new fusion transcripts associated with EAC, targeted RNA sequencing and polymerase chain reaction (PCR) verification were performed in 40 EACs and matched nonmalignant specimens from the same patients. Genomic PCR and Sanger sequencing were performed to find the breakpoint of fusion genes. Five novel in-frame fusion transcripts were identified and verified in 40 EACs and in a validation cohort of 15 additional EACs (55 patients in all): fibroblast growth factor receptor 2 (FGFR2)-GRB2-associated binding protein 2 (GAB2) in 2 of 55 or 3.6%, Niemann-Pick C1 (NPC1)-maternal embryonic leucine zipper kinase (MELK) in 2 of 55 or 3.6%, ubiquitin-specific peptidase 54 (USP54)-calcium/calmodulin dependent protein kinase II γ (CAMK2G) in 2 of 55 or 3.6%, megakaryoblastic leukemia (translocation) 1 (MKL1)-fibulin 1 (FBLN1) in 1 of 55 or 1.8%, and CCR4-NOT transcription complex subunit 2 (CNOT2)-chromosome 12 open reading frame 49 (C12orf49) in 1 of 55 or 1.8%. A genomic analysis indicated that NPC1-MELK arose from a complex interchromosomal translocation event involving chromosomes 18, 3, and 9 with 3 rearrangement points, and this was consistent with chromoplexy. These data indicate that fusion transcripts occur at a stable frequency in EAC. Furthermore, our results indicate that chromoplexy is an underlying mechanism that generates fusion transcripts in EAC. These and other fusion transcripts merit further study as diagnostic markers and potential therapeutic targets in EAC. Cancer 2017. © 2017 American Cancer Society. © 2017 American Cancer Society.

  15. Reversibility of the inhibitory effect of atrazine and lindane on cytosol 5. alpha. -dihydrotestosterone receptor complex formation in rat prostate

    SciTech Connect

    Simic, B.; Kniewald, Z.; Kniewald, J. ); Davies, J.E. )

    1991-01-01

    Once entering the bloodstream, most toxic substances, including pesticides, can reach organs involved in the reproductive system. They can cross the placenta, as well as the brain barrier, posing various risks to the reproductive processes. The organochlorine insecticide lindane and the s-triazine herbicide atrazine produce changes in hormone-dependent reactions in the rat hypothalamus, anterior pituitary, and prostate. Lindane also causes histological and biochemical alterations in the rat testis. In vivo treatment with atrazine produces a markedly inhibitory influence of 5{alpha}-dihydrotestosterone - receptor complex formation in rat prostate cytosol. Therefore, the aim of this study was to investigate whether such changes in the crucial step in the reproductive process are reversible. A parallel investigation using lindane was also undertaken.

  16. Live simian immunodeficiency virus vaccine correlate of protection: immune complex-inhibitory Fc receptor interactions that reduce target cell availability.

    PubMed

    Smith, Anthony J; Wietgrefe, Stephen W; Shang, Liang; Reilly, Cavan S; Southern, Peter J; Perkey, Katherine E; Duan, Lijie; Kohler, Heinz; Müller, Sybille; Robinson, James; Carlis, John V; Li, Qingsheng; Johnson, R Paul; Haase, Ashley T

    2014-09-15

    Principles to guide design of an effective vaccine against HIV are greatly needed, particularly to protect women in the pandemic's epicenter in Africa. We have been seeking these principles by identifying correlates of the robust protection associated with SIVmac239Δnef vaccination in the SIV-rhesus macaque animal model of HIV-1 transmission to women. We identified one correlate of SIVmac239Δnef protection against vaginal challenge as a resident mucosal system for SIV-gp41 trimer Ab production and neonatal FcR-mediated concentration of these Abs on the path of virus entry to inhibit establishment of infected founder populations at the portal of entry. In this study, we identify blocking CD4(+) T cell recruitment to thereby inhibit local expansion of infected founder populations as a second correlate of protection. Virus-specific immune complex interactions with the inhibitory FcγRIIb receptor in the epithelium lining the cervix initiate expression of genes that block recruitment of target cells to fuel local expansion. Immune complex-FcγRIIb receptor interactions at mucosal frontlines to dampen the innate immune response to vaginal challenge could be a potentially general mechanism for the mucosal immune system to sense and modulate the response to a previously encountered pathogen. Designing vaccines to provide protection without eliciting these transmission-promoting innate responses could contribute to developing an effective HIV-1 vaccine.

  17. Live SIV vaccine correlate of protection: immune complex-inhibitory Fc receptor interactions that reduce target cell availability

    PubMed Central

    Smith, Anthony J; Wietgrefe, Stephen W.; Shang, Liang; Reilly, Cavan S.; Southern, Peter J.; Perkey, Katherine E.; Duan, Lijie; Kohler, Heinz; Muller, Sybille; Robinson, James; Carlis, John V.; Li, Qingsheng; Johnson, R. Paul; Haase, Ashley T.

    2014-01-01

    Principles to guide design of an effective vaccine against HIV are greatly needed, particularly to protect women in the pandemic’s epicentre in Africa. We have been seeking these principles by identifying correlates of the robust protection associated with SIVmac239Δnef vaccination in the SIV-rhesus macaque animal model of HIV-1 transmission to women. We have identified one correlate of SIVmac239Δnef protection against vaginal challenge as a resident mucosal system for SIV-gp41 trimer antibody production and neonatal Fc receptor (FcRn)-mediated concentration of these antibodies on the path of virus entry to inhibit establishment of infected founder populations at the portal of entry. Here we identify as a second protection correlate, blocking CD4+ T cell recruitment to inhibit local expansion of infected founder populations. Virus-specific immune complex interactions with the inhibitory FcγRIIb receptor in the epithelium lining the cervix initiate expression of genes that block recruitment of target cells to fuel local expansion. Immune complex-FcγRIIb receptor interactions at mucosal frontlines to dampen the innate immune response to vaginal challenge could be a potentially general mechanism for the mucosal immune system to sense and modulate the response to a previously encountered pathogen. Designing vaccines to provide protection without eliciting these transmission-promoting innate responses could contribute to developing an effective HIV-1 vaccine. PMID:25143442

  18. The mobility of small vacancy/helium complexes in tungsten and its impact on retention in fusion-relevant conditions.

    PubMed

    Perez, Danny; Sandoval, Luis; Blondel, Sophie; Wirth, Brian D; Uberuaga, Blas P; Voter, Arthur F

    2017-05-30

    Tungsten is a promising plasma facing material for fusion reactors. Despite many favorable properties, helium ions incoming from the plasma are known to dramatically affect the microstructure of tungsten, leading to bubble growth, blistering, and/or to the formation of fuzz. In order to develop mitigation strategies, it is essential to understand the atomistic processes that lead to bubble formation and subsequent microstructural changes. In this work, we use large-scale Accelerated Molecular Dynamics simulations to investigate small (N = 1,2) V N He M vacancy/helium complexes, which serve as the nuclei for larger helium bubble growth, over timescales reaching into the milliseconds under conditions typical of the operation of fusion reactors. These complexes can interconvert between different I L V N+L He M variants via Frenkel pair nucleation (leading to the creation of a additional vacancy/interstitial pair) and annihilation events; sequences of these events can lead to net migration of these embryonic bubbles. The competition between nucleation and annihilation produces a very complex dependence of the diffusivity on the number of heliums. Finally, through cluster dynamics simulations, we show that diffusion of these complexes provides an efficient pathway for helium release at fluxes expected in fusion reactors, and hence that accounting for the mobility of these complexes is crucial.

  19. Human Cytomegalovirus gH/gL Forms a Stable Complex with the Fusion Protein gB in Virions.

    PubMed

    Vanarsdall, Adam L; Howard, Paul W; Wisner, Todd W; Johnson, David C

    2016-04-01

    Human cytomegalovirus (HCMV) is a ubiquitous virus that is a major pathogen in newborns and immunocompromised or immunosuppressed patients. HCMV infects a wide variety of cell types using distinct entry pathways that involve different forms of the gH/gL glycoprotein: gH/gL/gO and gH/gL/UL128-131 as well as the viral fusion glycoprotein, gB. However, the minimal or core fusion machinery (sufficient for cell-cell fusion) is just gH/gL and gB. Here, we demonstrate that HCMV gB and gH/gL form a stable complex early after their synthesis and in the absence of other viral proteins. gH/gL can interact with gB mutants that are unable to mediate cell-cell fusion. gB-gH/gL complexes included as much as 16-50% of the total gH/gL in HCMV virus particles. In contrast, only small amounts of gH/gL/gO and gH/gL/UL128-131 complexes were found associated with gB. All herpesviruses express gB and gH/gL molecules and most models describing herpesvirus entry suggest that gH/gL interacts with gB to mediate membrane fusion, although there is no direct evidence for this. For herpes simplex virus (HSV-1) it has been suggested that after receptor binding gH/gL binds to gB either just before, or coincident with membrane fusion. Therefore, our results have major implications for these models, demonstrating that HCMV gB and gH/gL forms stable gB-gH/gL complexes that are incorporated virions without receptor binding or membrane fusion. Moreover, our data is the best support to date for the proposal that gH/gL interacts with gB.

  20. Human Cytomegalovirus gH/gL Forms a Stable Complex with the Fusion Protein gB in Virions

    PubMed Central

    Vanarsdall, Adam L.; Howard, Paul W.; Wisner, Todd W.; Johnson, David C.

    2016-01-01

    Human cytomegalovirus (HCMV) is a ubiquitous virus that is a major pathogen in newborns and immunocompromised or immunosuppressed patients. HCMV infects a wide variety of cell types using distinct entry pathways that involve different forms of the gH/gL glycoprotein: gH/gL/gO and gH/gL/UL128-131 as well as the viral fusion glycoprotein, gB. However, the minimal or core fusion machinery (sufficient for cell-cell fusion) is just gH/gL and gB. Here, we demonstrate that HCMV gB and gH/gL form a stable complex early after their synthesis and in the absence of other viral proteins. gH/gL can interact with gB mutants that are unable to mediate cell-cell fusion. gB-gH/gL complexes included as much as 16–50% of the total gH/gL in HCMV virus particles. In contrast, only small amounts of gH/gL/gO and gH/gL/UL128-131 complexes were found associated with gB. All herpesviruses express gB and gH/gL molecules and most models describing herpesvirus entry suggest that gH/gL interacts with gB to mediate membrane fusion, although there is no direct evidence for this. For herpes simplex virus (HSV-1) it has been suggested that after receptor binding gH/gL binds to gB either just before, or coincident with membrane fusion. Therefore, our results have major implications for these models, demonstrating that HCMV gB and gH/gL forms stable gB-gH/gL complexes that are incorporated virions without receptor binding or membrane fusion. Moreover, our data is the best support to date for the proposal that gH/gL interacts with gB. PMID:27082872

  1. Migration inhibitory factor (MIF) released by macrophages upon recognition of immune complexes is critical to inflammation in Arthus reaction.

    PubMed

    Paiva, Claudia N; Arras, Rosa H; Magalhães, Elisabeth S; Alves, Letícia S; Lessa, Luiz Paulo; Silva, Maria Helena; Ejzemberg, Regina; Canetti, Cláudio; Bozza, Marcelo T

    2009-05-01

    Deposition of immune complexes (IC) triggers Fc gamma R-dependent inflammation, leading to tissue damage in rheumatoid arthritis, systemic lupus erythematous, immune glomerulonephritis, and several immune vasculitides. Evidences support a role for macrophage migration inhibitory factor (MIF) in a number of inflammatory diseases, but the triggering of its secretion and its physiopathological role upon IC deposition remain elusive. Herein, we show that human macrophages secreted MIF after IC recognition, which in turn controlled the secretion of TNF. Macrophages from Mif-/- mice produced smaller amounts of TNF when stimulated with IgG-opsonized erythrocytes than wild-type (WT) cells. Using passive reverse Arthus reaction in the peritoneum and lungs as a model for IC-induced inflammation, we demonstrated that Mif-/- mice had a milder response, observed by reduced neutrophil recruitment, vascular leakage, and secretion of TNF, MIP-2, and keratinocyte-derived chemokine compared with WT controls. Adoptive transfer of alveolar macrophages from WT to Mif-/- mice rescued pulmonary neutrophil recruitment and TNF production upon passive reverse Arthus reaction. Our study indicates that Arthus inflammatory reaction is largely dependent on MIF and poses macrophages as a source of the MIF released upon IC recognition. These results give experimental support to the proposition that blockade of MIF might constitute an adjunctive, therapeutic approach to IC disease.

  2. Catalytic Features of the Botulinum Neurotoxin A Light Chain Revealed by High Resolution Structure of an Inhibitory Peptide Complex

    SciTech Connect

    Silvaggi,N.; Wilson, D.; Tzipori, S.; Allen, K.

    2008-01-01

    The Clostridium botulinum neurotoxin serotype A light chain (BoNT/A-LC) is a Zn(II)-dependent metalloprotease that blocks the release of acetylcholine at the neuromuscular junction by cleaving SNAP-25, one of the SNARE proteins required for exocytosis. Because of the potential for use of the toxin in bioterrorism and the increasingly widespread application of the toxin in the medical field, there is significant interest in the development of small-molecule inhibitors of the metalloprotease. Efforts to design such inhibitors have not benefited from knowledge of how peptides bind to the active site since the enzyme-peptide structures available previously either were not occupied in the vicinity of the catalytic Zn(II) ion or did not represent the product of SNAP-25 substrate cleavage. Herein we report the 1.4 Angstroms-resolution X-ray crystal structure of a complex between the BoNT/A-LC and the inhibitory peptide N-Ac-CRATKML, the first structure of the light chain with an inhibitory peptide bound at the catalytic Zn(II) ion. The peptide is bound with the Cys S? atom coordinating the metal ion. Surprisingly, the cysteine sulfur is oxidized to the sulfenic acid form. Given the unstable nature of this species in solution, is it likely that oxidation occurs on the enzyme. In addition to the peptide-bound structure, we report two structures of the unliganded light chain with and without the Zn(II) cofactor bound at 1.25 and 1.20 Angstroms resolution, respectively. The two structures are nearly identical, confirming that the Zn(II) ion plays a purely catalytic role. Additionally, the structure of the Zn(II)-bound uncomplexed enzyme allows identification of the catalytic water molecule and a second water molecule that occupies the same position as the peptidic oxygen in the tetrahedral intermediate. This observation suggests that the enzyme active site is prearranged to stabilize the tetrahedral intermediate of the protease reaction.

  3. Nonsubsampled rotated complex wavelet transform (NSRCxWT) for medical image fusion related to clinical aspects in neurocysticercosis.

    PubMed

    Chavan, Satishkumar S; Mahajan, Abhishek; Talbar, Sanjay N; Desai, Subhash; Thakur, Meenakshi; D'cruz, Anil

    2017-02-01

    Neurocysticercosis (NCC) is a parasite infection caused by the tapeworm Taenia solium in its larvae stage which affects the central nervous system of the human body (a definite host). It results in the formation of multiple lesions in the brain at different locations during its various stages. During diagnosis of such symptomatic patients, these lesions can be better visualized using a feature based fusion of Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). This paper presents a novel approach to Multimodality Medical Image Fusion (MMIF) used for the analysis of the lesions for the diagnostic purpose and post treatment review of NCC. The MMIF presented here is a technique of combining CT and MRI data of the same patient into a new slice using a Nonsubsampled Rotated Complex Wavelet Transform (NSRCxWT). The forward NSRCxWT is applied on both the source modalities separately to extract the complementary and the edge related features. These features are then combined to form a composite spectral plane using average and maximum value selection fusion rules. The inverse transformation on this composite plane results into a new, visually better, and enriched fused image. The proposed technique is tested on the pilot study data sets of patients infected with NCC. The quality of these fused images is measured using objective and subjective evaluation metrics. Objective evaluation is performed by estimating the fusion parameters like entropy, fusion factor, image quality index, edge quality measure, mean structural similarity index measure, etc. The fused images are also evaluated for their visual quality using subjective analysis with the help of three expert radiologists. The experimental results on 43 image data sets of 17 patients are promising and superior when compared with the state of the art wavelet based fusion algorithms. The proposed algorithm can be a part of computer-aided detection and diagnosis (CADD) system which assists the radiologists in

  4. Design and construction of self-assembling supramolecular protein complexes using artificial and fusion proteins as nanoscale building blocks.

    PubMed

    Kobayashi, Naoya; Arai, Ryoichi

    2017-02-01

    The central goal of nanobiotechnology is to design and construct novel biomaterials of nanometer sizes. In this short review, we describe recent progress of several approaches for designing and creating artificial self-assembling protein complexes and primarily focus on the following biotechnological strategies for using artificial and fusion proteins as nanoscale building blocks: fusion proteins designed for symmetrical self-assembly; three-dimensional domain-swapped oligomers; self-assembling designed coiled-coil peptide modules; metal-directed self-assembling engineered proteins; computationally designed self-assembling de novo proteins; and self-assembling protein nanobuilding blocks (PN-Blocks) using an intermolecularly folded dimeric de novo protein. These state-of-the-art nanobiotechnologies for designing supramolecular protein complexes will facilitate the development of novel functional nanobiomaterials.

  5. A Type-2 fuzzy data fusion approach for building reliable weighted protein interaction networks with application in protein complex detection.

    PubMed

    Mehranfar, Adele; Ghadiri, Nasser; Kouhsar, Morteza; Golshani, Ashkan

    2017-09-01

    Detecting the protein complexes is an important task in analyzing the protein interaction networks. Although many algorithms predict protein complexes in different ways, surveys on the interaction networks indicate that about 50% of detected interactions are false positives. Consequently, the accuracy of existing methods needs to be improved. In this paper we propose a novel algorithm to detect the protein complexes in 'noisy' protein interaction data. First, we integrate several biological data sources to determine the reliability of each interaction and determine more accurate weights for the interactions. A data fusion component is used for this step, based on the interval type-2 fuzzy voter that provides an efficient combination of the information sources. This fusion component detects the errors and diminishes their effect on the detection protein complexes. So in the first step, the reliability scores have been assigned for every interaction in the network. In the second step, we have proposed a general protein complex detection algorithm by exploiting and adopting the strong points of other algorithms and existing hypotheses regarding real complexes. Finally, the proposed method has been applied for the yeast interaction datasets for predicting the interactions. The results show that our framework has a better performance regarding precision and F-measure than the existing approaches. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Low-dose ionizing radiation induces mitochondrial fusion and increases expression of mitochondrial complexes I and III in hippocampal neurons

    PubMed Central

    Chang, Chuang-Rung; Kao, Mou-Chieh; Chen, Kuan-Wei; Chiu, Shih-Che; Hsu, Ming-Ling; Hsiang, I-Chou; Chen, Yu-Jen; Chen, Linyi

    2015-01-01

    High energy ionizing radiation can cause DNA damage and cell death. During clinical radiation therapy, the radiation dose could range from 15 to 60 Gy depending on targets. While 2 Gy radiation has been shown to cause cancer cell death, studies also suggest a protective potential by low dose radiation. In this study, we examined the effect of 0.2-2 Gy radiation on hippocampal neurons. Low dose 0.2 Gy radiation treatment increased the levels of MTT. Since hippocampal neurons are post-mitotic, this result reveals a possibility that 0.2 Gy irradiation may increase mitochondrial activity to cope with stimuli. Maintaining neural plasticity is an energy-demanding process that requires high efficient mitochondrial function. We thus hypothesized that low dose radiation may regulate mitochondrial dynamics and function to ensure survival of neurons. Our results showed that five days after 0.2 Gy irradiation, no obvious changes on neuronal survival, neuronal synapses, membrane potential of mitochondria, reactive oxygen species levels, and mitochondrial DNA copy numbers. Interestingly, 0.2 Gy irradiation promoted the mitochondria fusion, resulting in part from the increased level of a mitochondrial fusion protein, Mfn2, and inhibition of Drp1 fission protein trafficking to the mitochondria. Accompanying with the increased mitochondrial fusion, the expressions of complexes I and III of the electron transport chain were also increased. These findings suggest that, hippocampal neurons undergo increased mitochondrial fusion to modulate cellular activity as an adaptive mechanism in response to low dose radiation. PMID:26415228

  7. Photoactivatable green fluorescent protein-based visualization and quantification of mitochondrial fusion and mitochondrial network complexity in living cells.

    PubMed

    Karbowski, Mariusz; Cleland, Megan M; Roelofs, Brian A

    2014-01-01

    Technological improvements in microscopy and the development of mitochondria-specific imaging molecular tools have illuminated the dynamic rearrangements of these essential organelles. These rearrangements are mainly the result of two opposing processes: mitochondrial fusion and mitochondrial fission. Consistent with this, in addition to mitochondrial motility, these two processes are major factors determining the overall degree of continuity of the mitochondrial network, as well as the average size of mitochondria within the cell. In this chapter, we detail the use of advanced confocal microscopy and mitochondrial matrix-targeted photoactivatable green fluorescent protein (mito-PAGFP) for the investigation of mitochondrial dynamics. We focus on direct visualization and quantification of mitochondrial fusion and mitochondrial network complexity in living mammalian cells. These assays were instrumental in important recent discoveries within the field of mitochondrial biology, including the role of mitochondrial fusion in the activation of mitochondrial steps in apoptosis, participation of Bcl-2 family proteins in mitochondrial morphogenesis, and stress-induced mitochondrial hyperfusion. We present some basic directions that should be helpful in designing mito-PAGFP-based experiments. Furthermore, since analyses of mitochondrial fusion using mito-PAGFP-based assays rely on time-lapse imaging, critical parameters of time-lapse microscopy and cell preparation are also discussed.

  8. Low-dose ionizing radiation induces mitochondrial fusion and increases expression of mitochondrial complexes I and III in hippocampal neurons.

    PubMed

    Chien, Ling; Chen, Wun-Ke; Liu, Szu-Ting; Chang, Chuang-Rung; Kao, Mou-Chieh; Chen, Kuan-Wei; Chiu, Shih-Che; Hsu, Ming-Ling; Hsiang, I-Chou; Chen, Yu-Jen; Chen, Linyi

    2015-10-13

    High energy ionizing radiation can cause DNA damage and cell death. During clinical radiation therapy, the radiation dose could range from 15 to 60 Gy depending on targets. While 2 Gy radiation has been shown to cause cancer cell death, studies also suggest a protective potential by low dose radiation. In this study, we examined the effect of 0.2-2 Gy radiation on hippocampal neurons. Low dose 0.2 Gy radiation treatment increased the levels of MTT. Since hippocampal neurons are post-mitotic, this result reveals a possibility that 0.2 Gy irradiation may increase mitochondrial activity to cope with stimuli. Maintaining neural plasticity is an energy-demanding process that requires high efficient mitochondrial function. We thus hypothesized that low dose radiation may regulate mitochondrial dynamics and function to ensure survival of neurons. Our results showed that five days after 0.2 Gy irradiation, no obvious changes on neuronal survival, neuronal synapses, membrane potential of mitochondria, reactive oxygen species levels, and mitochondrial DNA copy numbers. Interestingly, 0.2 Gy irradiation promoted the mitochondria fusion, resulting in part from the increased level of a mitochondrial fusion protein, Mfn2, and inhibition of Drp1 fission protein trafficking to the mitochondria. Accompanying with the increased mitochondrial fusion, the expressions of complexes I and III of the electron transport chain were also increased. These findings suggest that, hippocampal neurons undergo increased mitochondrial fusion to modulate cellular activity as an adaptive mechanism in response to low dose radiation.

  9. Crystal Structure of Plasmodium knowlesi Apical Membrane Antigen 1 and Its Complex with an Invasion-Inhibitory Monoclonal Antibody

    PubMed Central

    van der Eijk, Marjolein; Thomas, Alan W.; Singh, Balbir; Kocken, Clemens H. M.

    2015-01-01

    The malaria parasite Plasmodium knowlesi, previously associated only with infection of macaques, is now known to infect humans as well and has become a significant public health problem in Southeast Asia. This species should therefore be targeted in vaccine and therapeutic strategies against human malaria. Apical Membrane Antigen 1 (AMA1), which plays a role in Plasmodium merozoite invasion of the erythrocyte, is currently being pursued in human vaccine trials against P. falciparum. Recent vaccine trials in macaques using the P. knowlesi orthologue PkAMA1 have shown that it protects against infection by this parasite species and thus should be developed for human vaccination as well. Here, we present the crystal structure of Domains 1 and 2 of the PkAMA1 ectodomain, and of its complex with the invasion-inhibitory monoclonal antibody R31C2. The Domain 2 (D2) loop, which is displaced upon binding the Rhoptry Neck Protein 2 (RON2) receptor, makes significant contacts with the antibody. R31C2 inhibits binding of the Rhoptry Neck Protein 2 (RON2) receptor by steric blocking of the hydrophobic groove and by preventing the displacement of the D2 loop which is essential for exposing the complete binding site on AMA1. R31C2 recognizes a non-polymorphic epitope and should thus be cross-strain reactive. PkAMA1 is much less polymorphic than the P. falciparum and P. vivax orthologues. Unlike these two latter species, there are no polymorphic sites close to the RON2-binding site of PkAMA1, suggesting that P. knowlesi has not developed a mechanism of immune escape from the host’s humoral response to AMA1. PMID:25886591

  10. Distinct Domains of Complexins Bind SNARE Complexes and Clamp Fusion in Vitro*

    PubMed Central

    Giraudo, Claudio G.; Garcia-Diaz, Alejandro; Eng, William S.; Yamamoto, Ai; Melia, Thomas J.; Rothman, James E.

    2008-01-01

    In regulated exocytosis, the core membrane fusion machinery proteins, the SNARE proteins, are assisted by a group of regulatory factors in order to couple membrane fusion to an increase of intracellular calcium ion (Ca2+) concentration. Complexin-I and synaptotagmin-I have been shown to be key elements for this tightly regulated process. Many studies suggest that complexin-I can arrest the fusion reaction and that synaptotagmin-I can release the complexin-I blockage in a calcium-dependent manner. Although the actual molecular mechanism by which they exert their function is still unknown, recent in vivo experiments postulate that domains of complexin-I produce different effects on neurotransmitter release. Herein, by using an in vitro flipped SNARE cell fusion assay, we have identified and characterized the minimal functional domains of complexin-I necessary to couple calcium and synaptotagmin-I to membrane fusion. Moreover, we provide evidence that other isoforms of complexin, complexin-II, -III, and -IV, can also be functionally coupled to synaptotagmin-I and calcium. These correspond closely to results from in vivo experiments, providing further validation of the physiological relevance of the flipped SNARE system. PMID:18499660

  11. Distinct domains of complexins bind SNARE complexes and clamp fusion in vitro.

    PubMed

    Giraudo, Claudio G; Garcia-Diaz, Alejandro; Eng, William S; Yamamoto, Ai; Melia, Thomas J; Rothman, James E

    2008-07-25

    In regulated exocytosis, the core membrane fusion machinery proteins, the SNARE proteins, are assisted by a group of regulatory factors in order to couple membrane fusion to an increase of intracellular calcium ion (Ca(2+)) concentration. Complexin-I and synaptotagmin-I have been shown to be key elements for this tightly regulated process. Many studies suggest that complexin-I can arrest the fusion reaction and that synaptotagmin-I can release the complexin-I blockage in a calcium-dependent manner. Although the actual molecular mechanism by which they exert their function is still unknown, recent in vivo experiments postulate that domains of complexin-I produce different effects on neurotransmitter release. Herein, by using an in vitro flipped SNARE cell fusion assay, we have identified and characterized the minimal functional domains of complexin-I necessary to couple calcium and synaptotagmin-I to membrane fusion. Moreover, we provide evidence that other isoforms of complexin, complexin-II, -III, and -IV, can also be functionally coupled to synaptotagmin-I and calcium. These correspond closely to results from in vivo experiments, providing further validation of the physiological relevance of the flipped SNARE system.

  12. High-resolution structures of two complexes between thrombin and thrombin-binding aptamer shed light on the role of cations in the aptamer inhibitory activity

    PubMed Central

    Russo Krauss, Irene; Merlino, Antonello; Randazzo, Antonio; Novellino, Ettore; Mazzarella, Lelio; Sica, Filomena

    2012-01-01

    The G-quadruplex architecture is a peculiar structure adopted by guanine-rich oligonucleotidic sequences, and, in particular, by several aptamers, including the thrombin-binding aptamer (TBA) that has the highest inhibitory activity against human α-thrombin. A crucial role in determining structure, stability and biological properties of G-quadruplexes is played by ions. In the case of TBA, K+ ions cause an enhancement of the aptamer clotting inhibitory activity. A detailed picture of the interactions of TBA with the protein and with the ions is still lacking, despite the importance of this aptamer in biomedical field for detection and inhibition of α-thrombin. Here, we fill this gap by presenting a high-resolution crystallographic structural characterization of the thrombin–TBA complex formed in the presence of Na+ or K+ and a circular dichroism study of the structural stability of the aptamer both free and complexed with α-thrombin, in the presence of the two ionic species. The results indicate that the different effects exerted by Na+ and K+ on the inhibitory activity of TBA are related to a subtle perturbation of a few key interactions at the protein–aptamer interface. The present data, in combination with those previously obtained on the complex between α-thrombin and a modified aptamer, may allow the design of new TBA variants with a pharmacological performance enhancement. PMID:22669903

  13. Dual-tree complex wavelet transform and image block residual-based multi-focus image fusion in visual sensor networks.

    PubMed

    Yang, Yong; Tong, Song; Huang, Shuying; Lin, Pan

    2014-11-26

    This paper presents a novel framework for the fusion of multi-focus images explicitly designed for visual sensor network (VSN) environments. Multi-scale based fusion methods can often obtain fused images with good visual effect. However, because of the defects of the fusion rules, it is almost impossible to completely avoid the loss of useful information in the thus obtained fused images. The proposed fusion scheme can be divided into two processes: initial fusion and final fusion. The initial fusion is based on a dual-tree complex wavelet transform (DTCWT). The Sum-Modified-Laplacian (SML)-based visual contrast and SML are employed to fuse the low- and high-frequency coefficients, respectively, and an initial composited image is obtained. In the final fusion process, the image block residuals technique and consistency verification are used to detect the focusing areas and then a decision map is obtained. The map is used to guide how to achieve the final fused image. The performance of the proposed method was extensively tested on a number of multi-focus images, including no-referenced images, referenced images, and images with different noise levels. The experimental results clearly indicate that the proposed method outperformed various state-of-the-art fusion methods, in terms of both subjective and objective evaluations, and is more suitable for VSNs.

  14. Dual-Tree Complex Wavelet Transform and Image Block Residual-Based Multi-Focus Image Fusion in Visual Sensor Networks

    PubMed Central

    Yang, Yong; Tong, Song; Huang, Shuying; Lin, Pan

    2014-01-01

    This paper presents a novel framework for the fusion of multi-focus images explicitly designed for visual sensor network (VSN) environments. Multi-scale based fusion methods can often obtain fused images with good visual effect. However, because of the defects of the fusion rules, it is almost impossible to completely avoid the loss of useful information in the thus obtained fused images. The proposed fusion scheme can be divided into two processes: initial fusion and final fusion. The initial fusion is based on a dual-tree complex wavelet transform (DTCWT). The Sum-Modified-Laplacian (SML)-based visual contrast and SML are employed to fuse the low- and high-frequency coefficients, respectively, and an initial composited image is obtained. In the final fusion process, the image block residuals technique and consistency verification are used to detect the focusing areas and then a decision map is obtained. The map is used to guide how to achieve the final fused image. The performance of the proposed method was extensively tested on a number of multi-focus images, including no-referenced images, referenced images, and images with different noise levels. The experimental results clearly indicate that the proposed method outperformed various state-of-the-art fusion methods, in terms of both subjective and objective evaluations, and is more suitable for VSNs. PMID:25587878

  15. Chemotropism and Cell Fusion in Neurospora crassa Relies on the Formation of Distinct Protein Complexes by HAM-5 and a Novel Protein HAM-14

    PubMed Central

    Jonkers, Wilfried; Fischer, Monika S.; Do, Hung P.; Starr, Trevor L.; Glass, N. Louise

    2016-01-01

    In filamentous fungi, communication is essential for the formation of an interconnected, multinucleate, syncytial network, which is constructed via hyphal fusion or fusion of germinated asexual spores (germlings). Anastomosis in filamentous fungi is comparable to other somatic cell fusion events resulting in syncytia, including myoblast fusion during muscle differentiation, macrophage fusion, and fusion of trophoblasts during placental development. In Neurospora crassa, fusion of genetically identical germlings is a highly dynamic and regulated process that requires components of a MAP kinase signal transduction pathway. The kinase pathway components (NRC-1, MEK-2 and MAK-2) and the scaffold protein HAM-5 are recruited to hyphae and germling tips undergoing chemotropic interactions. The MAK-2/HAM-5 protein complex shows dynamic oscillation to hyphae/germling tips during chemotropic interactions, and which is out-of-phase to the dynamic localization of SOFT, which is a scaffold protein for components of the cell wall integrity MAP kinase pathway. In this study, we functionally characterize HAM-5 by generating ham-5 truncation constructs and show that the N-terminal half of HAM-5 was essential for function. This region is required for MAK-2 and MEK-2 interaction and for correct cellular localization of HAM-5 to “fusion puncta.” The localization of HAM-5 to puncta was not perturbed in 21 different fusion mutants, nor did these puncta colocalize with components of the secretory pathway. We also identified HAM-14 as a novel member of the HAM-5/MAK-2 pathway by mining MAK-2 phosphoproteomics data. HAM-14 was essential for germling fusion, but not for hyphal fusion. Colocalization and coimmunoprecipitation data indicate that HAM-14 interacts with MAK-2 and MEK-2 and may be involved in recruiting MAK-2 (and MEK-2) to complexes containing HAM-5. PMID:27029735

  16. An unusual cytokine:Ig-domain interaction revealed in the crystal structure of leukemia inhibitory factor (LIF) in complex with the LIF receptor

    PubMed Central

    Huyton, Trevor; Zhang, Jian-Guo; Luo, Cindy S.; Lou, Mei-Zhen; Hilton, Douglas J.; Nicola, Nicos A.; Garrett, Thomas P. J.

    2007-01-01

    Leukemia inhibitory factor (LIF) receptor is a cell surface receptor that mediates the actions of LIF and other IL-6 type cytokines through the formation of high-affinity signaling complexes with gp130. Here we present the crystal structure of a complex of mouse LIF receptor with human LIF at 4.0 Å resolution. The structure is, to date, the largest cytokine receptor fragment determined by x-ray crystallography. The binding of LIF to its receptor via the central Ig-like domain is unlike other cytokine receptor complexes that bind ligand predominantly through their cytokine-binding modules. This structure, in combination with previous crystallographic studies, also provides a structural template to understand the formation and orientation of the high-affinity signaling complex between LIF, LIF receptor, and gp130. PMID:17652170

  17. Vaccinia Mature Virus Fusion Regulator A26 Protein Binds to A16 and G9 Proteins of the Viral Entry Fusion Complex and Dissociates from Mature Virions at Low pH

    PubMed Central

    Chang, Shu-Jung; Shih, Ao-Chun; Tang, Yin-Liang

    2012-01-01

    Vaccinia mature virus enters cells through either endocytosis or plasma membrane fusion, depending on virus strain and cell type. Our previous results showed that vaccinia virus mature virions containing viral A26 protein enter HeLa cells preferentially through endocytosis, whereas mature virions lacking A26 protein enter through plasma membrane fusion, leading us to propose that A26 acts as an acid-sensitive fusion suppressor for mature virus (S. J. Chang, Y. X. Chang, R. Izmailyan R, Y. L. Tang, and W. Chang, J. Virol. 84:8422–8432, 2010). In the present study, we investigated the fusion suppression mechanism of A26 protein. We found that A26 protein was coimmunoprecipitated with multiple components of the viral entry-fusion complex (EFC) in infected HeLa cells. Transient expression of viral EFC components in HeLa cells revealed that vaccinia virus A26 protein interacted directly with A16 and G9 but not with G3, L5 and H2 proteins of the EFC components. Consistently, a glutathione S-transferase (GST)-A26 fusion protein, but not GST, pulled down A16 and G9 proteins individually in vitro. Together, our results supported the idea that A26 protein binds to A16 and G9 protein at neutral pH contributing to suppression of vaccinia virus-triggered membrane fusion from without. Since vaccinia virus extracellular envelope proteins A56/K2 were recently shown to bind to the A16/G9 subcomplex to suppress virus-induced fusion from within, our results also highlight an evolutionary convergence in which vaccinia viral fusion suppressor proteins regulate membrane fusion by targeting the A16 and G9 components of the viral EFC complex. Finally, we provide evidence that acid (pH 4.7) treatment induced A26 protein and A26-A27 protein complexes of 70 kDa and 90 kDa to dissociate from mature virions, suggesting that the structure of A26 protein is acid sensitive. PMID:22278246

  18. Vaccinia mature virus fusion regulator A26 protein binds to A16 and G9 proteins of the viral entry fusion complex and dissociates from mature virions at low pH.

    PubMed

    Chang, Shu-Jung; Shih, Ao-Chun; Tang, Yin-Liang; Chang, Wen

    2012-04-01

    Vaccinia mature virus enters cells through either endocytosis or plasma membrane fusion, depending on virus strain and cell type. Our previous results showed that vaccinia virus mature virions containing viral A26 protein enter HeLa cells preferentially through endocytosis, whereas mature virions lacking A26 protein enter through plasma membrane fusion, leading us to propose that A26 acts as an acid-sensitive fusion suppressor for mature virus (S. J. Chang, Y. X. Chang, R. Izmailyan R, Y. L. Tang, and W. Chang, J. Virol. 84:8422-8432, 2010). In the present study, we investigated the fusion suppression mechanism of A26 protein. We found that A26 protein was coimmunoprecipitated with multiple components of the viral entry-fusion complex (EFC) in infected HeLa cells. Transient expression of viral EFC components in HeLa cells revealed that vaccinia virus A26 protein interacted directly with A16 and G9 but not with G3, L5 and H2 proteins of the EFC components. Consistently, a glutathione S-transferase (GST)-A26 fusion protein, but not GST, pulled down A16 and G9 proteins individually in vitro. Together, our results supported the idea that A26 protein binds to A16 and G9 protein at neutral pH contributing to suppression of vaccinia virus-triggered membrane fusion from without. Since vaccinia virus extracellular envelope proteins A56/K2 were recently shown to bind to the A16/G9 subcomplex to suppress virus-induced fusion from within, our results also highlight an evolutionary convergence in which vaccinia viral fusion suppressor proteins regulate membrane fusion by targeting the A16 and G9 components of the viral EFC complex. Finally, we provide evidence that acid (pH 4.7) treatment induced A26 protein and A26-A27 protein complexes of 70 kDa and 90 kDa to dissociate from mature virions, suggesting that the structure of A26 protein is acid sensitive.

  19. Copper(II) complexes with cyanoguanidine and o-phenanthroline: Theoretical studies, in vitro antimicrobial activity and alkaline phosphatase inhibitory effect

    NASA Astrophysics Data System (ADS)

    Martínez Medina, Juan J.; Islas, María S.; López Tévez, Libertad L.; Ferrer, Evelina G.; Okulik, Nora B.; Williams, Patricia A. M.

    2014-01-01

    Calculations based on density functional methods are carried out for two Cu(II) complexes with cyanoguanidine (cnge) and o-phenanthroline (o-phen): [Cu(o-phen)2(cnge)](NO3)2ṡ2H2O (1) and [Cu(o-phen)(cnge)(H2O)(NO3)2] (2). The calculated geometrical parameters are in agreement with the experimental values. The results of Atoms in Molecules (AIM) topological analysis of the electron density indicate that the Cu-N(phen) bonds in complex (1) have lower electron density, suggesting that those bonds are stronger in complex (2). Moreover, the ionic character of the Cu-N bond in the complex (1) is slightly stronger than that in the complex (2) and this situation would explain the fact that only complex (2) was stable in water solution. For this reason, the antimicrobial and enzymatic assays were performed using complex (2). It is well known that the increased use of antibiotics has resulted in the development of resistant bacterial and fungal strains. In this context, the study of novel antimicrobial agents has an enormous importance and metal complexes represent an interesting alternative for the treatment of infectious diseases. The aim of this work is to prove the modification of some biological properties like antimicrobial activity or alkaline phosphatase inhibitory activity upon copper complexation.

  20. Fusion of Epstein-Barr virus nuclear antigen-1-derived glycine-alanine repeat to trans-dominant HIV-1 Gag increases inhibitory activities and survival of transduced cells in vivo.

    PubMed

    Hammer, Diana; Wild, Jens; Ludwig, Christine; Asbach, Benedikt; Notka, Frank; Wagner, Ralf

    2008-06-01

    Trans-dominant human immunodeficiency virus type 1 (HIV-1) Gag derivatives have been shown to efficiently inhibit late steps of HIV-1 replication in vitro by interfering with Gag precursor assembly, thus ranking among the interesting candidates for gene therapy approaches. However, efficient antiviral activities of corresponding transgenes are likely to be counteracted in particular by cell-mediated host immune responses toward the transgene-expressing cells. To decrease this potential immunogenicity, a 24-amino acid Gly-Ala (GA) stretch derived from Epstein-Barr virus nuclear antigen-1 (EBNA1) and known to overcome proteasomal degradation was fused to a trans-dominant Gag variant (sgD1). To determine the capacity of this fusion polypeptide to repress viral replication, PM-1 cells were transduced with sgD1 and GAsgD1 transgenes, using retroviral gene transfer. Challenge of stably transfected permissive cell lines with various viral strains indicated that N-terminal GA fusion even enhanced the inhibitory properties of sgD1. Further studies revealed that the GA stretch increased protein stability by blocking proteasomal degradation of Gag proteins. Immunization of BALB/c mice with a DNA vaccine vector expressing sgD1 induced substantial Gag-specific immune responses that were, however, clearly diminished in the presence of GA. Furthermore, recognition of cells expressing the GA-fused transgene by CD8(+) T cells was drastically reduced, both in vitro and in vivo, resulting in prolonged survival of the transduced cells in recipient mice.

  1. ER-associated retrograde SNAREs and the Dsl1 complex mediate an alternative, Sey1p-independent homotypic ER fusion pathway

    PubMed Central

    Rogers, Jason V.; McMahon, Conor; Baryshnikova, Anastasia; Hughson, Frederick M.; Rose, Mark D.

    2014-01-01

    The peripheral endoplasmic reticulum (ER) network is dynamically maintained by homotypic (ER–ER) fusion. In Saccharomyces cerevisiae, the dynamin-like GTPase Sey1p can mediate ER–ER fusion, but sey1Δ cells have no growth defect and only slightly perturbed ER structure. Recent work suggested that ER-localized soluble N-ethylmaleimide–sensitive factor attachment protein receptors (SNAREs) mediate a Sey1p-independent ER–ER fusion pathway. However, an alternative explanation—that the observed phenotypes arose from perturbed vesicle trafficking—could not be ruled out. In this study, we used candidate and synthetic genetic array (SGA) approaches to more fully characterize SNARE-mediated ER–ER fusion. We found that Dsl1 complex mutations in sey1Δ cells cause strong synthetic growth and ER structure defects and delayed ER–ER fusion in vivo, additionally implicating the Dsl1 complex in SNARE-mediated ER–ER fusion. In contrast, cytosolic coat protein I (COPI) vesicle coat mutations in sey1Δ cells caused no synthetic defects, excluding perturbed retrograde trafficking as a cause for the previously observed synthetic defects. Finally, deleting the reticulons that help maintain ER architecture in cells disrupted for both ER–ER fusion pathways caused almost complete inviability. We conclude that the ER SNAREs and the Dsl1 complex directly mediate Sey1p-independent ER–ER fusion and that, in the absence of both pathways, cell viability depends upon membrane curvature–promoting reticulons. PMID:25187651

  2. Phosphorylation of the effector complex HOPS by the vacuolar kinase Yck3p confers Rab nucleotide specificity for vacuole docking and fusion

    PubMed Central

    Zick, Michael; Wickner, William

    2012-01-01

    The homotypic fusion of yeast vacuoles requires the Rab-family GTPase Ypt7p and its effector complex, homotypic fusion and vacuole protein sorting complex (HOPS). Although the vacuolar kinase Yck3p is required for the sensitivity of vacuole fusion to proteins that regulate the Rab GTPase cycle—Gdi1p (GDP-dissociation inhibitor [GDI]) or Gyp1p/Gyp7p (GTPase-activating protein)—this kinase phosphorylates HOPS rather than Ypt7p. We addressed this puzzle in reconstituted proteoliposome fusion reactions with all-purified components. In the presence of HOPS and Sec17p/Sec18p, there is comparable fusion of 4-SNARE (soluble N-ethylmaleimide–sensitive factor attachment protein receptor) proteoliposomes when they have Ypt7p bearing either GDP or GTP, a striking exception to the rule that only GTP-bound forms of Ras-superfamily GTPases have active conformations. However, the phosphorylation of HOPS by recombinant Yck3p confers a strict requirement for GTP-bound Ypt7p for binding phosphorylated HOPS, for optimal membrane tethering, and for proteoliposome fusion. Added GTPase-activating protein promotes GTP hydrolysis by Ypt7p, and added GDI captures Ypt7p in its GDP-bound state during nucleotide cycling. In either case, the net conversion of Ypt7:GTP to Ypt7:GDP has no effect on HOPS binding or activity but blocks fusion mediated by phosphorylated HOPS. Thus guanine nucleotide specificity of the vacuolar fusion Rab Ypt7p is conferred through downstream posttranslational modification of its effector complex. PMID:22787280

  3. Enhanced damage localization for complex structures through statistical modeling and sensor fusion

    NASA Astrophysics Data System (ADS)

    Haynes, Colin; Todd, Michael

    2015-03-01

    Ultrasonic guided waves represent a promising technique for detecting and localizing structural damage, but their application to realistic structures has been hampered by the complicated interference patterns produced by scattering from geometric features. This work presents a new damage localization paradigm based on a statistical approach to dealing with uncertainty in the guided wave signals. A bolted frame and a section of a fuselage rib are tested with different simulated damage conditions and used to conduct a detailed comparison between the proposed solution and other sparse-array localization approaches. After establishing the superiority of the statistical approach, two novel innovations to the localization procedure are proposed: an approach to sensor fusion based on the Neyman-Pearson criterion, and a method of constructing simple models of geometrical features. Including the sensor fusion and geometrical models produces a substantial improvement in the system's localization accuracy. The final result is a robust and accurate framework for single-site damage localization that moves structural health monitoring towards practical implementation on a much broader range of structures.

  4. Inhibitory effect of lactone fractions and individual components from three species of the Achillea millefolium complex of Bulgarian origin on the human neutrophils respiratory burst activity.

    PubMed

    Choudhary, Muhammad Iqbal; Jalil, Saima; Todorova, M; Trendafilova, A; Mikhova, B; Duddeck, H; Atta-ur-Rahman

    2007-09-01

    Achillea species are widely used in folk medicine for treatment of inflammatory diseases. The inhibitory effect on the human neutrophils respiratory burst activity of total extracts, their fractions and some main constituents of the flower heads from Achillea asplenifolia, A. collina and A. distans belonging to A. millefolium complex of Bulgarian origin, were tested by the modified method of Tan and Berridge. Seven from the investigated fractions showed activity similar or higher than that of indomethacine and might be evaluated as nonsteroidal anti-inflammatory agents.

  5. Interaction between the G3 and L5 proteins of the vaccinia virus entry-fusion complex

    SciTech Connect

    Wolfe, Cindy L.; Moss, Bernard

    2011-04-10

    The vaccinia virus entry-fusion complex (EFC) consists of 10 to 12 proteins that are embedded in the viral membrane and individually required for fusion with the cell and entry of the core into the cytoplasm. The architecture of the EFC is unknown except for information regarding two pair-wise interactions: A28 with H2 and A16 with G9. Here we used a technique to destabilize the EFC by repressing the expression of individual components and identified a third pair-wise interaction: G3 with L5. These two proteins remained associated under several different EFC destabilization conditions and in each case were immunopurified together as demonstrated by Western blotting. Further evidence for the specific interaction of G3 and L5 was obtained by mass spectrometry. This interaction also occurred when G3 and L5 were expressed in uninfected cells, indicating that no other viral proteins were required. Thus, the present study extends our knowledge of the protein interactions important for EFC assembly and stability.

  6. Role of angular momentum in the production of complex fragments in fusion and quasifission reactions

    SciTech Connect

    Kalandarov, Sh. A.; Adamian, G. G.; Antonenko, N. V.; Scheid, W.

    2011-05-15

    The influence of angular momentum on the competition between complete fusion followed by the decay of compound nucleus and quasifission channels is treated within the dinuclear system model. The charge distributions of the products in the reactions {sup 28}Si+{sup 96}Zr, {sup 4}He+{sup 130}Te, and {sup 40}Ca+{sup 82}Kr are predicted at bombarding energies above the Coulomb barrier. The results of calculations for the reactions {sup 93}Nb+{sup 9}Be,{sup 12}C,{sup 27}Al; {sup 84}Kr+{sup 27}Al; {sup 86}Kr+{sup 63}Cu; {sup 139}La+{sup 12}C,{sup 27}Al; and {sup 45}Sc+{sup 65}Cu are compared with the available experimental data.

  7. Learning curve of a complex surgical technique: minimally invasive transforaminal lumbar interbody fusion (MIS TLIF).

    PubMed

    Lee, Kong Hwee; Yeo, William; Soeharno, Henry; Yue, Wai Mun

    2014-10-01

    Prospective cohort study. This study aimed to evaluate the learning curve of minimally invasive transforaminal lumbar interbody fusion (MIS TLIF). Very few studies have evaluated the learning curve of this technically demanding surgery. We intend to evaluate the learning curve of MIS TLIF with a larger sample size and assess surgical competence based not only on operative time but with perioperative variables, clinical and radiologic outcomes, incidence of complications, and patient satisfaction. From 2005 to 2009, the first 90 single-level MIS TLIF, which utilized a consistent technique and spinal instrumentation, performed by a single surgeon at our tertiary institution were studied. Variables studied included operative time, perioperative variables, clinical (Visual Analogue Scores for back and leg pain, Oswestry Disability Index, North American Spine Society Scores for neurogenic symptoms) and radiologic outcomes, incidence of complications and patient rating of expectation met, and the overall result of surgery. The asymptote of the surgeon's learning curve for MIS TLIF was achieved at the 44th case. Comparing the early group of 44 patients to the latter 46, the demographics were similar. For operative parameters, only 3 variables showed differences between the 2 groups: mean operative duration, fluoroscopy duration, and usage of patient-controlled analgesia. At the final follow-up, for clinical outcome parameters, the 2 groups were different in 3 parameters: VAS scores for back, leg pain, and neurogenic symptom scores. For radiologic outcome, both groups showed similar good fusion rates. For complications, none of the MIS TLIF cases were converted to open TLIF intraoperatively. In the early group, there were 3 complications: 1 incidental durotomy and 2 asymptomatic cage migrations; and in the latter group, there was 1 asymptomatic cage migration. In our study, technical proficiency in MIS TLIF was achieved after 44 surgeries, and the latter patients benefited

  8. Heterologous expression of mycobacterial Esx complexes in Escherichia coli for structural studies is facilitated by the use of maltose binding protein fusions.

    PubMed

    Arbing, Mark A; Chan, Sum; Harris, Liam; Kuo, Emmeline; Zhou, Tina T; Ahn, Christine J; Nguyen, Lin; He, Qixin; Lu, Jamie; Menchavez, Phuong T; Shin, Annie; Holton, Thomas; Sawaya, Michael R; Cascio, Duilio; Eisenberg, David

    2013-01-01

    The expression of heteroligomeric protein complexes for structural studies often requires a special coexpression strategy. The reason is that the solubility and proper folding of each subunit of the complex requires physical association with other subunits of the complex. The genomes of pathogenic mycobacteria encode many small protein complexes, implicated in bacterial fitness and pathogenicity, whose characterization may be further complicated by insolubility upon expression in Escherichia coli, the most common heterologous protein expression host. As protein fusions have been shown to dramatically affect the solubility of the proteins to which they are fused, we evaluated the ability of maltose binding protein fusions to produce mycobacterial Esx protein complexes. A single plasmid expression strategy using an N-terminal maltose binding protein fusion to the CFP-10 homolog proved effective in producing soluble Esx protein complexes, as determined by a small-scale expression and affinity purification screen, and coupled with intracellular proteolytic cleavage of the maltose binding protein moiety produced protein complexes of sufficient purity for structural studies. In comparison, the expression of complexes with hexahistidine affinity tags alone on the CFP-10 subunits failed to express in amounts sufficient for biochemical characterization. Using this strategy, six mycobacterial Esx complexes were expressed, purified to homogeneity, and subjected to crystallization screening and the crystal structures of the Mycobacterium abscessus EsxEF, M. smegmatis EsxGH, and M. tuberculosis EsxOP complexes were determined. Maltose binding protein fusions are thus an effective method for production of Esx complexes and this strategy may be applicable for production of other protein complexes.

  9. Mechanochemical synthesis and in vitro anti-Helicobacter pylori and uresase inhibitory activities of novel zinc(II)-famotidine complex.

    PubMed

    Amin, Muhammad; Iqbal, Mohammad S; Hughes, Roy W; Khan, Safyan A; Reynolds, Paul A; Enne, Virve I; Sajjad-ur-Rahman; Mirza, Akmal S

    2010-06-01

    The mechanochemical synthesis and characterization of a zinc complex with famotidine is described. The complex was characterized by microanalysis and a number of spectroscopic techniques. The complex was of M:L dihydrate type. Derivatization of famotidine with zinc appears to enhance the activity of the drug by inhibiting the growth of Helicobacter pylori (two reference and 34 clinical isolates). The complex inhibited the growth of H. pylori in an MIC range of 1-8 microg mL(-1). The anti-H. pylori activity of the zinc-famotidine complex against antibiotic-resistant strains was nearly comparable to that of antibiotic-susceptible strains. The complex was found to be far less toxic than the parent drug, as demonstrated by its higher LD(50) value. In the human urease enzyme inhibition assay the complex exhibited significant inhibition. The new complex appears to be more useful in eradicating both the antibiotic-susceptible and antibiotic-resistant strains of H. pylori.

  10. Preserving Posterior Complex Can Prevent Adjacent Segment Disease following Posterior Lumbar Interbody Fusion Surgeries: A Finite Element Analysis

    PubMed Central

    Huang, Yun-Peng; Du, Cheng-Fei; Cheng, Cheng-Kung; Zhong, Zheng-Cheng; Chen, Xuan-Wei; Wu, Gui; Li, Zhe-Cheng; Ye, Jin-Duo; Lin, Jian-Hua; Wang, Li Zhen

    2016-01-01

    Objective To investigate the biomechanical effects of the lumbar posterior complex on the adjacent segments after posterior lumbar interbody fusion (PLIF) surgeries. Methods A finite element model of the L1–S1 segment was modified to simulate PLIF with total laminectomy (PLIF-LAM) and PLIF with hemilaminectomy (PLIF-HEMI) procedures. The models were subjected to a 400N follower load with a 7.5-N.m moment of flexion, extension, torsion, and lateral bending. The range of motion (ROM), intradiscal pressure (IDP), and ligament force were compared. Results In Flexion, the ROM, IDP and ligament force of posterior longitudinal ligament, intertransverse ligament, and capsular ligament remarkably increased at the proximal adjacent segment in the PLIF-LAM model, and slightly increased in the PLIF-HEMI model. There was almost no difference for the ROM, IDP and ligament force at L5-S1 level between the two PLIF models although the ligament forces of ligamenta flava remarkably increased compared with the intact lumbar spine (INT) model. For the other loading conditions, these two models almost showed no difference in ROM, IDP and ligament force on the adjacent discs. Conclusions Preserved posterior complex acts as the posterior tension band during PLIF surgery and results in less ROM, IDP and ligament forces on the proximal adjacent segment in flexion. Preserving the posterior complex during decompression can be effective on preventing adjacent segment degeneration (ASD) following PLIF surgeries. PMID:27870867

  11. Immune complex-induced inhibition of osteoclastogenesis is mediated via activating but not inhibitory Fcγ receptors on myeloid precursor cells.

    PubMed

    Grevers, Lilyanne C; de Vries, Teun J; Everts, Vincent; Verbeek, J Sjef; van den Berg, Wim B; van Lent, Peter L E M

    2013-02-01

    To investigate the role of Fcγ receptors (FcγRs) in osteoclastogenesis and osteoclast function. Bone destruction was analysed in arthritic knee joints of several FcγR-knockout mouse strains. Unfractionated bone marrow cells were differentiated in vitro towards osteoclasts in the absence or presence of immune complexes (ICs) and stimulated thereafter for 24 h with tumour necrosis factor α (TNFα) or lipopolysaccharide (LPS). In addition, mature osteoclasts were stimulated with ICs. Experiments were analysed for osteoclast formation, bone resorption and the expression of FcγRs and osteoclast markers. Bone destruction was significantly increased in arthritic knee joints of FcγRIIB-deficient mice. All FcγR classes were highly expressed on osteoclast precursors. Expression of the inhibitory FcγRIIB was similar on mature osteoclasts compared to macrophages, whereas activating FcγR levels were significantly lower. IC stimulation of mature osteoclasts did not affect their number or their bone resorptive capacity. ICs significantly inhibited differentiation of unfractionated bone marrow cells towards osteoclasts, bone resorption and expression of osteoclast markers. In the presence of ICs, osteoclastogenesis of FcγRIIB(-/-) precursors and bone resorption remained inhibited. In contrast, ICs could not inhibit osteoclast formation or bone resorption of FcRγ-chain(-/-) precursors. When IC-inhibited osteoclastogenesis was followed by stimulation with TNFα or LPS, the inhibitory effects of ICs were overruled. Activating FcγRs mediate IC-induced inhibition of osteoclastogenesis, which might be overruled in the presence of proinflammatory mediators. This suggests that the balance of FcγR-mediated inflammation, through proinflammatory cytokine production, as well as the direct inhibitory effect of ICs on osteoclastogenesis determines the net effect on bone loss.

  12. Disassembly of the reconstituted synaptic vesicle membrane fusion complex in vitro.

    PubMed Central

    Hayashi, T; Yamasaki, S; Nauenburg, S; Binz, T; Niemann, H

    1995-01-01

    The interaction of the presynaptic membrane proteins SNAP-25 and syntaxin with the synaptic vesicle protein synaptobrevin (VAMP) plays a key role in the regulated exocytosis of neurotransmitters. Clostridial neurotoxins, which proteolyze these polypeptides, are potent inhibitors of neurotransmission. The cytoplasmic domains of the three membrane proteins join into a tight SDS-resistant complex (Hayashi et al., 1994). Here, we show that this reconstituted complex, as well as heterodimers composed of syntaxin and SNAP-25, can be disassembled by the concerted action of the N-ethylmaleimide-sensitive factor, NSF, and the soluble NSF attachment protein, alpha-SNAP. alpha-SNAP binds to predicted alpha-helical coiled-coil regions of syntaxin and SNAP-25, shown previously to be engaged in their direct interaction. Synaptobrevin, although incapable of binding alpha-SNAP individually, induced a third alpha-SNAP binding site when associated with syntaxin and SNAP-25 into heterotrimers. NSF released prebound alpha-SNAP from full-length syntaxin but not from a syntaxin derivative truncated at the N-terminus. Disassembly of complexes containing this syntaxin mutant was impaired, indicating a critical role for the N-terminal domain in the alpha-SNAP/NSF-mediated dissociation process. Complexes containing C-terminally deleted SNAP-25 derivatives, as generated by botulinal toxins type A and E, were dissociated more efficiently. In contrast, the N-terminal fragment generated from synaptobrevin by botulinal toxin type F produced an SDS-sensitive complex that was poorly dissociated. Images PMID:7774590

  13. A Fluorescence Polarization Assay for Binding to Macrophage Migration Inhibitory Factor and Crystal Structures for Complexes of Two Potent Inhibitors

    PubMed Central

    2016-01-01

    Human macrophage migration inhibitory factor (MIF) is both a keto–enol tautomerase and a cytokine associated with numerous inflammatory diseases and cancer. Consistent with observed correlations between inhibition of the enzymatic and biological activities, discovery of MIF inhibitors has focused on monitoring the tautomerase activity using l-dopachrome methyl ester or 4-hydroxyphenyl pyruvic acid as substrates. The accuracy of these assays is compromised by several issues including substrate instability, spectral interference, and short linear periods for product formation. In this work, we report the syntheses of fluorescently labeled MIF inhibitors and their use in the first fluorescence polarization-based assay to measure the direct binding of inhibitors to the active site. The assay allows the accurate and efficient identification of competitive, noncompetitive, and covalent inhibitors of MIF in a manner that can be scaled for high-throughput screening. The results for 22 compounds show that the most potent MIF inhibitors bind with Kd values of ca. 50 nM; two are from our laboratory, and the other is a compound from the patent literature. X-ray crystal structures for two of the most potent compounds bound to MIF are also reported here. Striking combinations of protein–ligand hydrogen bonding, aryl–aryl, and cation−π interactions are responsible for the high affinities. A new chemical series was then designed using this knowledge to yield two more strong MIF inhibitors/binders. PMID:27299179

  14. Feasibility of three-dimensional magnetic resonance angiography-fluoroscopy image fusion technique in guiding complex endovascular aortic procedures in patients with renal insufficiency.

    PubMed

    Schwein, Adeline; Chinnadurai, Ponraj; Shah, Dipan J; Lumsden, Alan B; Bechara, Carlos F; Bismuth, Jean

    2017-05-01

    Three-dimensional image fusion of preoperative computed tomography (CT) angiography with fluoroscopy using intraoperative noncontrast cone-beam CT (CBCT) has been shown to improve endovascular procedures by reducing procedure length, radiation dose, and contrast media volume. However, patients with a contraindication to CT angiography (renal insufficiency, iodinated contrast allergy) may not benefit from this image fusion technique. The primary objective of this study was to evaluate the feasibility of magnetic resonance angiography (MRA) and fluoroscopy image fusion using noncontrast CBCT as a guidance tool during complex endovascular aortic procedures, especially in patients with renal insufficiency. All endovascular aortic procedures done under MRA image fusion guidance at a single-center were retrospectively reviewed. The patients had moderate to severe renal insufficiency and underwent diagnostic contrast-enhanced magnetic resonance imaging after gadolinium or ferumoxytol injection. Relevant vascular landmarks electronically marked in MRA images were overlaid on real-time two-dimensional fluoroscopy for image guidance, after image fusion with noncontrast intraoperative CBCT. Technical success, time for image registration, procedure time, fluoroscopy time, number of digital subtraction angiography (DSA) acquisitions before stent deployment or vessel catheterization, and renal function before and after the procedure were recorded. The image fusion accuracy was qualitatively evaluated on a binary scale by three physicians after review of image data showing virtual landmarks from MRA on fluoroscopy. Between November 2012 and March 2016, 10 patients underwent endovascular procedures for aortoiliac aneurysmal disease or aortic dissection using MRA image fusion guidance. All procedures were technically successful. A paired t-test analysis showed no difference between preimaging and postoperative renal function (P = .6). The mean time required for MRA-CBCT image

  15. Novel Three-Dimensional Image Fusion Software to Facilitate Guidance of Complex Cardiac Catheterization : 3D image fusion for interventions in CHD.

    PubMed

    Goreczny, Sebastian; Dryzek, Pawel; Morgan, Gareth J; Lukaszewski, Maciej; Moll, Jadwiga A; Moszura, Tomasz

    2017-08-01

    We report initial experience with novel three-dimensional (3D) image fusion software for guidance of transcatheter interventions in congenital heart disease. Developments in fusion imaging have facilitated the integration of 3D roadmaps from computed tomography or magnetic resonance imaging datasets. The latest software allows live fusion of two-dimensional (2D) fluoroscopy with pre-registered 3D roadmaps. We reviewed all cardiac catheterizations guided with this software (Philips VesselNavigator). Pre-catheterization imaging and catheterization data were collected focusing on fusion of 3D roadmap, intervention guidance, contrast and radiation exposure. From 09/2015 until 06/2016, VesselNavigator was applied in 34 patients for guidance (n = 28) or planning (n = 6) of cardiac catheterization. In all 28 patients successful 2D-3D registration was performed. Bony structures combined with the cardiovascular silhouette were used for fusion in 26 patients (93%), calcifications in 9 (32%), previously implanted devices in 8 (29%) and low-volume contrast injection in 7 patients (25%). Accurate initial 3D roadmap alignment was achieved in 25 patients (89%). Six patients (22%) required realignment during the procedure due to distortion of the anatomy after introduction of stiff equipment. Overall, VesselNavigator was applied successfully in 27 patients (96%) without any complications related to 3D image overlay. VesselNavigator was useful in guidance of nearly all of cardiac catheterizations. The combination of anatomical markers and low-volume contrast injections allowed reliable 2D-3D registration in the vast majority of patients.

  16. Bioassay-guided preparative separation of angiotensin-converting enzyme inhibitory C-flavone glycosides from Desmodium styracifolium by recycling complexation high-speed counter-current chromatography.

    PubMed

    Zhang, Ying-Qi; Luo, Jian-Guang; Han, Chao; Xu, Jin-Fang; Kong, Ling-Yi

    2015-01-01

    A new strategy of the convergence of high-speed counter-current chromatography (HSCCC) and bioactive assay technique was developed for rapidly screening and separating the angiotensin-converting enzyme (ACE) inhibitors from the aerial parts of Desmodium styracifolium. Bioactivity-guided fractionation of the crude extract was first established to target the bioactive fractions based on HSCCC coupled with in vitro ACE inhibitory assay. Subsequently, the bioactive fractions were further separated by the recycling complexation HSCCC respectively, using 0.10 mol/L copper sulfate in the lower phase of two-phase solvent system composed of n-butanol/water (1:1, v/v). Five C-glycosylflavones, vicenin 2 (1), carlinoside (2), vicenin 1 (3), schaftoside (4) and vicenin 3 (5), were successfully obtained. Their chemical structures were identified using ESI-MS and NMR. All the isolates showed in vitro ACE inhibitory activity with the IC50 values between 33.62 and 58.37 μM. The results demonstrated that the established method was proposed as an excellent strategy to systematically screen and purify active compounds from traditional Chinese medicines.

  17. The inhibitory effects of steroidal and non-steroidal antirheumatic drugs on articular cartilage in osteoarthrosis and its counteraction by a biological GAG-peptide complex (Rumalon).

    PubMed

    Kalbhen, D A

    1982-01-01

    In-vitro studies have confirmed that various corticosteroids and also many nonsteroidal antirheumatic drugs exert inhibitory effects on anabolic processes in connective tissue cells. Depending on dose and at concentrations that in many cases correspond to therapeutic plasma levels, these drugs may lead to a pronounced reduction or complete blockade of synthesis of the proteoglycans and collagen of the cartilage matrix. Our in-vivo animal experiments have shown that single or repeated intraarticular applications of various antiinflammatory antirheumatics into the knee joint of hens or rats can induce progressive joint degeneration within 3-4 months. The degenerative process was monitored by macroscopic, radiological, histological, biochemical, and stereoelectronmicroscopic methods and corresponded very well with the pathology of human osteoarthrosis. Our experimental osteoarthrosis, induced by metabolic lesions or inhibition of chondrocytes, can be influenced therapeutically by intraarticular or intramuscular treatment with the biological GAG-peptide complex (Rumalon) or with its high molecular fraction DAK-16. These compounds significantly reduce or even stop the degenerative progression in the osteoarthrotic knee joints. The chondroprotective and anti-arthritic properties of Rumalon or DAK-16 can be explained by its stimulation of connective tissue anabolism as well as by its inhibitory effect on catabolic enzymes responsible for cartilage breakdown. Our experiments also indicate that catabolic reactions of corticosteroids on articular cartilage can be counteracted or reduced by concomitant administration of the chondroprotective agents. This effect might be desirable and beneficial during treatment of inflammatory phases of osteoarthrosis with intraarticular injections of corticosteroids.

  18. Modern spectroscopic technique in the characterization of biosensitive macrocyclic Schiff base ligand and its complexes: Inhibitory activity against plantpathogenic fungi

    NASA Astrophysics Data System (ADS)

    Tyagi, Monika; Chandra, Sulekh; Akhtar, Jameel; Chand, Dinesh

    2014-01-01

    Complexes of the type [M(L)Cl2], where M = Co(II), Ni(II) and Cu(II) have been synthesized with a macrocyclic Schiff base ligand (1,4,5,7,10,11,12,15-octaaza,5,11,16,18-tetraphenyl, 3,4,12,13-tetramethyl cyclo-octadecane) derived from Schiff base (obtained by the condensation of 4-aminoantipyrine and dibenzoyl methane) and ethylenediamine. The ligand was characterized on the basis of elemental analysis, IR, 1H NMR, EI Mass and molecular modeling studies while the complexes were characterized by elemental analysis, molar conductance measurements, magnetic susceptibility measurements, IR, electronic and EPR spectral studies. All the complexes are non-electrolyte in nature. The covalency factor (β) and coefficient factor (α) suggest the covalent nature of the complexes. The ligand and its metal complexes have shown antifungal activity with their LD50 values determined by probit analysis against two economically important fungal plant pathogens i.e. Macrophomina phaseolina and Fusarium solani.

  19. Inhibitory complex of the transmembrane ammonia channel, AmtB, and the cytosolic regulatory protein, GlnK, at 1.96 Å

    PubMed Central

    Gruswitz, Franz; O'Connell, Joseph; Stroud, Robert M.

    2007-01-01

    Ammonia conductance is highly regulated. A PII signal transduction protein, GlnK, is the final regulator of transmembrane ammonia conductance by the ammonia channel AmtB in Escherichia coli. The complex formed between AmtB and inhibitory GlnK at 1.96-Å resolution shows that the trimeric channel is blocked directly by GlnK and how, in response to intracellular nitrogen status, the ability of GlnK to block the channel is regulated by uridylylation/deuridylylation at Y51. ATP and Mg2+ augment the interaction of GlnK. The hydrolyzed product, adenosine 5′-diphosphate orients the surface of GlnK for AmtB blockade. 2-Oxoglutarate diminishes AmtB/GlnK association, and sites for 2-oxoglutarate are evaluated. PMID:17190799

  20. Inhibitory motor control based on complex stopping goals relies on the same brain network as simple stopping.

    PubMed

    Wessel, Jan R; Aron, Adam R

    2014-12-01

    Much research has modeled action-stopping using the stop-signal task (SST), in which an impending response has to be stopped when an explicit stop-signal occurs. A limitation of the SST is that real-world action-stopping rarely involves explicit stop-signals. Instead, the stopping-system engages when environmental features match more complex stopping goals. For example, when stepping into the street, one monitors path, velocity, size, and types of objects and only stops if there is a vehicle approaching. Here, we developed a task in which participants compared the visual features of a multidimensional go-stimulus to a complex stopping-template, and stopped their go-response if all features matched the template. We used independent component analysis of EEG data to show that the same motor inhibition brain network that explains action-stopping in the SST also implements motor inhibition in the complex-stopping task. Furthermore, we found that partial feature overlap between go-stimulus and stopping-template led to motor slowing, which also corresponded with greater stopping-network activity. This shows that the same brain system for action-stopping to explicit stop-signals is recruited to slow or stop behavior when stimuli match a complex stopping goal. The results imply a generalizability of the brain's network for simple action-stopping to more ecologically valid scenarios.

  1. Ligand binding to the inhibitory and stimulatory GTP cyclohydrolase I/GTP cyclohydrolase I feedback regulatory protein complexes.

    PubMed

    Yoneyama, T; Hatakeyama, K

    2001-04-01

    GTP cyclohydrolase I feedback regulatory protein (GFRP) mediates feedback inhibition of GTP cyclohydrolase I activity by 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4), which is an essential cofactor for key enzymes producing catecholamines, serotonin, and nitric oxide as well as phenylalanine hydroxylase. GFRP also mediates feed-forward stimulation of GTP cyclohydrolase I activity by phenylalanine at subsaturating GTP levels. These ligands, BH4 and phenylalanine, induce complex formation between one molecule of GTP cyclohydrolase I and two molecules of GFRP. Here, we report the analysis of ligand binding using the gel filtration method of Hummel and Dreyer. BH4 binds to the GTP cyclohydrolase I/GFRP complex with a Kd of 4 microM, and phenylalanine binds to the protein complex with a Kd of 94 microM. The binding of BH4 is enhanced by dGTP. The binding stoichiometrics of BH4 and phenylalanine were estimated to be 10 molecules of each per protein complex, in other words, one molecule per subunit of protein, because GTP cyclohydrolase I is a decamer and GFRP is a pentamer. These findings were corroborated by data from equilibrium dialysis experiments. Regarding ligand binding to free proteins, BH4 binds weakly to GTP cyclohydrolase I but not to GFRP, and phenylalanine binds weakly to GFRP but not to GTP cyclohydrolase I. These results suggest that the overall structure of the protein complex contributes to binding of BH4 and phenylalanine but also that each binding site of BH4 and phenylalanine may be primarily composed of residues of GTP cyclohydrolase I and GFRP, respectively.

  2. The Potent Inhibitory Effect of a Naproxen-Appended Cobalt(III)-Cyclam Complex on Cancer Stem Cells.

    PubMed

    Cressey, Paul B; Eskandari, Arvin; Bruno, Peter M; Lu, Chunxin; Hemann, Michael T; Suntharalingam, Kogularamanan

    2016-09-15

    We report the potency against cancer stem cells (CSCs) of a new cobalt(III)-cyclam complex (1) that bears the nonsteroidal anti-inflammatory drug, naproxen. The complex displays selective potency for breast CSC-enriched HMLER-shEcad cells over breast CSC-depleted HMLER cells. Additionally, it inhibited the formation of three-dimensional tumour-like mammospheres, and reduced their viability to a greater extent than clinically used breast cancer drugs (vinorelbine, cisplatin and paclitaxel). The anti-mammosphere potency of 1 was enhanced under hypoxia-mimicking conditions. Detailed mechanistic studies revealed that DNA damage and cyclooxygenase-2 (COX-2) inhibition contribute to the cytotoxic mechanism of 1. To the best of our knowledge, 1 is the first cobalt-containing compound to show selective potency for CSCs over bulk cancer cells. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. ETV6-NTRK3 fusion oncogene initiates breast cancer from committed mammary progenitors via activation of AP1 complex

    PubMed Central

    Li, Zhe; Tognon, Cristina E.; Godinho, Frank J.; Yasaitis, Laura; Hock, Hanno; Herschkowitz, Jason I.; Lannon, Chris L.; Cho, Eunah; Kim, Seong-Jin; Bronson, Roderick T.; Perou, Charles M.; Sorensen, Poul H.; Orkin, Stuart H.

    2007-01-01

    SUMMARY To better understand the cellular origin of breast cancer, we developed a mouse model that recapitulates expression of the ETV6-NTRK3 (EN) fusion oncoprotein, the product of the t(12;15)(p13;q25) translocation characteristic of human secretory breast carcinoma. Activation of EN expression in mammary tissues by Wap-Cre leads to fully penetrant, multifocal malignant breast cancer with short latency. We provide genetic evidence that in nulliparous Wap-Cre;EN females, committed alveolar bipotent or CD61+ luminal progenitors, are targets of tumorigenesis. Furthermore, EN transforms these otherwise transient progenitors through activation of the AP1 complex. Given increasing relevance of chromosomal translocations in epithelial cancers, such mice serve as a paradigm for the study of their genetic pathogenesis and cellular origins, and generation of novel preclinical models. SIGNIFICANCE For the largest class of human tumors, those of epithelial origin, little is known about their initiating genetic hits or cells of origin. Whether tissue stem cells or more committed progenitors are targets for transformation is uncertain. We developed a system in which epithelial tumorigenesis can be assessed from the initial event to frank malignancy. In this breast cancer model based on chromosomal translocation, we show through genetic marking that committed mammary progenitors, rather than mammary stem cells, are direct targets of transformation. We show that activation of the AP1 complex represents a critical downstream event of the ETV6-NTRK3 translocation. Further focus on this transcriptional complex as a target in human breast cancer is warranted. PMID:18068631

  4. Role of organic cation/carnitine transporter 1 in uptake of phenformin and inhibitory effect on complex I respiration in mitochondria.

    PubMed

    Shitara, Yoshihisa; Nakamichi, Noritaka; Norioka, Misaki; Shima, Hiroyo; Kato, Yukio; Horie, Toshiharu

    2013-03-01

    Phenformin causes lactic acidosis in clinical situations due to inhibition of mitochondrial respiratory chain complex I. It is reportedly taken up by hepatocytes and exhibits mitochondrial toxicity in the liver. In this study, uptake of phenformin and [(14)C]tetraethylammonium (TEA) and complex I inhibition by phenformin were examined in isolated liver and heart mitochondria. Uptake of phenformin into isolated rat liver mitochondria was higher than that into heart mitochondria. It was inhibited by several cat ionic compounds, which suggests the involvement of multispecific transport system(s). Similar characteristics were also observed for uptake of TEA; however, uptake of phenformin into mitochondria of organic cation/carnitine transporter 1 (OCTN1) knockout mice was lower than that in wild-type mice, whereas uptake of TEA was comparable between the two strains, suggesting the involvement of distinct transport mechanisms for these two cations in mitochondria. Inhibition by phenformin of oxygen consumption via complex I respiration in isolated rat liver mitochondria was greater than that in heart mitochondria, whereas inhibitory effect of phenformin on complex I respiration was similar in inside-out structured submitochondrial particles prepared from rat livers and hearts. Lactic acidosis provoked by iv infusion of phenformin was weaker in octn1(-/-) mice than that in wild-type mice. These observations suggest that uptake of phenformin into liver mitochondria is at least partly mediated by OCTN1 and functionally relevant to its inhibition potential of complex I respiration. This study was, thus, the first to demonstrate OCTN1-mediated mitochondrial transport and toxicity of biguanide in vivo in rodents.

  5. NSF- and SNARE-mediated membrane fusion is required for nuclear envelope formation and completion of nuclear pore complex assembly in Xenopus laevis egg extracts.

    PubMed

    Baur, Tina; Ramadan, Kristijan; Schlundt, Andreas; Kartenbeck, Jürgen; Meyer, Hemmo H

    2007-08-15

    Despite the progress in understanding nuclear envelope (NE) reformation after mitosis, it has remained unclear what drives the required membrane fusion and how exactly this is coordinated with nuclear pore complex (NPC) assembly. Here, we show that, like other intracellular fusion reactions, NE fusion in Xenopus laevis egg extracts is mediated by SNARE proteins that require activation by NSF. Antibodies against Xenopus NSF, depletion of NSF or the dominant-negative NSF(E329Q) variant specifically inhibited NE formation. Staging experiments further revealed that NSF was required until sealing of the envelope was completed. Moreover, excess exogenous alpha-SNAP that blocks SNARE function prevented membrane fusion and caused accumulation of non-flattened vesicles on the chromatin surface. Under these conditions, the nucleoporins Nup107 and gp210 were fully recruited, whereas assembly of FxFG-repeat-containing nucleoporins was blocked. Together, we define NSF- and SNARE-mediated membrane fusion events as essential steps during NE formation downstream of Nup107 recruitment, and upstream of membrane flattening and completion of NPC assembly.

  6. The tail domain of tomosyn controls membrane fusion through tomosyn displacement by VAMP2

    SciTech Connect

    Yamamoto, Yasunori; Fujikura, Kohei; Sakaue, Mio; Okimura, Kenjiro; Kobayashi, Yuta; Nakamura, Toshihiro; Sakisaka, Toshiaki

    2010-08-13

    Research highlights: {yields} The tail domain of tomosyn has no effect on the tomosyn-SNARE complex formation. {yields} The tail domain binding to the VAMP-like domain allows VAMP2 to displace tomosyn. {yields} Tomosyn displacement by VAMP2 leads to SNARE complex formation. {yields} The SNARE complex formation drives membrane fusion. -- Abstract: Neurotransmitter release is regulated by SNARE complex-mediated synaptic vesicle fusion. Tomosyn sequesters target SNAREs (t-SNAREs) through its C-terminal VAMP-like domain (VLD). Cumulative biochemical results suggest that the tomosyn-SNARE complex is so tight that VAMP2 cannot displace tomosyn. Based on these results, the tomosyn-SNARE complex has been believed to be a dead-end complex to inhibit neurotransmitter release. On the other hand, some studies using siRNA depletion of tomosyn suggest that tomosyn positively regulates exocytosis. Therefore, it is still controversial whether tomosyn is a simple inhibitor for neurotransmitter release. We recently reported that the inhibitory activity of tomosyn is regulated by the tail domain binding to the VLD. In this study, we employed the liposome fusion assay in order to further understand modes of action of tomosyn in detail. The tail domain unexpectedly had no effect on binding of the VLD to t-SNARE-bearing liposomes. Nonetheless, the tail domain decreased the inhibitory activity of the VLD on the SNARE complex-mediated liposome fusion. These results indicate that the tail domain controls membrane fusion through tomosyn displacement by VAMP2. Deletion of the tail domain-binding region in the VLD retained the binding to t-SNAREs and promoted the liposome fusion. Together, we propose here a novel mechanism of tomosyn that controls synaptic vesicle fusion positively by serving as a placeholder for VAMP2.

  7. HAL-2 Promotes Homologous Pairing during Caenorhabditis elegans Meiosis by Antagonizing Inhibitory Effects of Synaptonemal Complex Precursors

    PubMed Central

    Zhang, Weibin; Miley, Natasha; Zastrow, Michael S.; MacQueen, Amy J.; Sato, Aya; Nabeshima, Kentaro; Martinez-Perez, Enrique; Mlynarczyk-Evans, Susanna; Carlton, Peter M.; Villeneuve, Anne M.

    2012-01-01

    During meiosis, chromosomes align with their homologous pairing partners and stabilize this alignment through assembly of the synaptonemal complex (SC). Since the SC assembles cooperatively yet is indifferent to homology, pairing and SC assembly must be tightly coordinated. We identify HAL-2 as a key mediator in this coordination, showing that HAL-2 promotes pairing largely by preventing detrimental effects of SC precursors (SYP proteins). hal-2 mutants fail to establish pairing and lack multiple markers of chromosome movement mediated by pairing centers (PCs), chromosome sites that link chromosomes to cytoplasmic microtubules through nuclear envelope-spanning complexes. Moreover, SYP proteins load inappropriately along individual unpaired chromosomes in hal-2 mutants, and markers of PC-dependent movement and function are restored in hal-2; syp double mutants. These and other data indicate that SYP proteins can impede pairing and that HAL-2 promotes pairing predominantly but not exclusively by counteracting this inhibition, thereby enabling activation and regulation of PC function. HAL-2 concentrates in the germ cell nucleoplasm and colocalizes with SYP proteins in nuclear aggregates when SC assembly is prevented. We propose that HAL-2 functions to shepherd SYP proteins prior to licensing of SC assembly, preventing untimely interactions between SC precursors and chromosomes and allowing sufficient accumulation of precursors for rapid cooperative assembly upon homology verification. PMID:22912597

  8. Studies on Inhibition of Respiratory Cytochrome bc1 Complex by the Fungicide Pyrimorph Suggest a Novel Inhibitory Mechanism

    PubMed Central

    Xiao, Yu-Mei; Esser, Lothar; Zhou, Fei; Li, Chang; Zhou, Yi-Hui; Yu, Chang-An; Qin, Zhao-Hai; Xia, Di

    2014-01-01

    The respiratory chain cytochrome bc1 complex (cyt bc1) is a major target of numerous antibiotics and fungicides. All cyt bc1 inhibitors act on either the ubiquinol oxidation (QP) or ubiquinone reduction (QN) site. The primary cause of resistance to bc1 inhibitors is target site mutations, creating a need for novel agents that act on alternative sites within the cyt bc1 to overcome resistance. Pyrimorph, a synthetic fungicide, inhibits the growth of a broad range of plant pathogenic fungi, though little is known concerning its mechanism of action. In this study, using isolated mitochondria from pathogenic fungus Phytophthora capsici, we show that pyrimorph blocks mitochondrial electron transport by affecting the function of cyt bc1. Indeed, pyrimorph inhibits the activities of both purified 11-subunit mitochondrial and 4-subunit bacterial bc1 with IC50 values of 85.0 μM and 69.2 μM, respectively, indicating that it targets the essential subunits of cyt bc1 complexes. Using an array of biochemical and spectral methods, we show that pyrimorph acts on an area near the QP site and falls into the category of a mixed-type, noncompetitive inhibitor with respect to the substrate ubiquinol. In silico molecular docking of pyrimorph to cyt b from mammalian and bacterial sources also suggests that pyrimorph binds in the vicinity of the quinol oxidation site. PMID:24699450

  9. Vaccinia virus entry/fusion complex subunit A28 is a target of neutralizing and protective antibodies

    SciTech Connect

    Nelson, Gretchen E.; Sisler, Jerry R.; Chandran, Dev; Moss, Bernard

    2008-10-25

    The vaccinia virus entry/fusion complex (EFC) is comprised of at least eight transmembrane proteins that are conserved in all poxviruses. However, neither the physical structure of the EFC nor the immunogenicity of the individual components has been determined. We prepared soluble forms of two EFC components, A28 and H2, by replacing the transmembrane domain with a signal peptide and adding a polyhistidine tail. The proteins were expressed by baculoviruses, secreted from insect cells, purified by affinity chromatography and used to raise antibodies in rabbits. The antibodies recognized the viral proteins but only the antibody to recombinant A28 bound intact virions and neutralized infectivity. Analyses with a set of overlapping peptides revealed a neutralizing epitope between residues 73 and 92 of A28. Passive immunization of mice with IgG purified from the anti-A28 serum provided partial protection against a vaccinia virus intranasal challenge, whereas IgG from the anti-H2 serum did not.

  10. Anticipatory Monitoring and Control of Complex Systems using a Fuzzy based Fusion of Support Vector Regressors

    SciTech Connect

    Miltiadis Alamaniotis; Vivek Agarwal

    2014-10-01

    This paper places itself in the realm of anticipatory systems and envisions monitoring and control methods being capable of making predictions over system critical parameters. Anticipatory systems allow intelligent control of complex systems by predicting their future state. In the current work, an intelligent model aimed at implementing anticipatory monitoring and control in energy industry is presented and tested. More particularly, a set of support vector regressors (SVRs) are trained using both historical and observed data. The trained SVRs are used to predict the future value of the system based on current operational system parameter. The predicted values are then inputted to a fuzzy logic based module where the values are fused to obtain a single value, i.e., final system output prediction. The methodology is tested on real turbine degradation datasets. The outcome of the approach presented in this paper highlights the superiority over single support vector regressors. In addition, it is shown that appropriate selection of fuzzy sets and fuzzy rules plays an important role in improving system performance.

  11. Crystal Structure of Snake Venom Acetylcholinesterase in Complex with Inhibitory Antibody Fragment Fab410 Bound at the Peripheral Site

    PubMed Central

    Bourne, Yves; Renault, Ludovic; Marchot, Pascale

    2015-01-01

    The acetylcholinesterase found in the venom of Bungarus fasciatus (BfAChE) is produced as a soluble, non-amphiphilic monomer with a canonical catalytic domain but a distinct C terminus compared with the other vertebrate enzymes. Moreover, the peripheral anionic site of BfAChE, a surface site located at the active site gorge entrance, bears two substitutions altering sensitivity to cationic inhibitors. Antibody Elec410, generated against Electrophorus electricus acetylcholinesterase (EeAChE), inhibits EeAChE and BfAChE by binding to their peripheral sites. However, both complexes retain significant residual catalytic activity, suggesting incomplete gorge occlusion by bound antibody and/or high frequency back door opening. To explore a novel acetylcholinesterase species, ascertain the molecular bases of inhibition by Elec410, and document the determinants and mechanisms for back door opening, we solved a 2.7-Å resolution crystal structure of natural BfAChE in complex with antibody fragment Fab410. Crystalline BfAChE forms the canonical dimer found in all acetylcholinesterase structures. Equally represented open and closed states of a back door channel, associated with alternate positions of a tyrosine phenol ring at the active site base, coexist in each subunit. At the BfAChE molecular surface, Fab410 is seated on the long Ω-loop between two N-glycan chains and partially occludes the gorge entrance, a position that fully reflects the available mutagenesis and biochemical data. Experimentally based flexible molecular docking supports a similar Fab410 binding mode onto the EeAChE antigen. These data document the molecular and dynamic peculiarities of BfAChE with high frequency back door opening, and the mode of action of Elec410 as one of the largest peptidic inhibitors targeting the acetylcholinesterase peripheral site. PMID:25411244

  12. Protection against lethal measles virus infection in mice by immune-stimulating complexes containing the hemagglutinin or fusion protein.

    PubMed Central

    Varsanyi, T M; Morein, B; Löve, A; Norrby, E

    1987-01-01

    The importance of each of the two surface glycoproteins of measles virus in active and passive immunization was examined in mice. Infected-cell lysates were depleted of either the hemagglutinin (H) or fusion (F) glycoprotein by using multiple cycles of immunoaffinity chromatography. The products were used to prepare immune-stimulating complexes (iscoms) containing either F or H glycoprotein. Such complexes are highly immunogenic, possibly as a result of effective presentation of viral proteins to the immune system [B. Morein, B. Sundquist, S. Höglund, K. Dalsgaard, and A. Osterhaus, Nature (London) 308:457-460, 1984]. Groups of 3-week-old BALB/c mice were inoculated with the iscom preparations. All animals developed hemolysis-inhibiting antibodies, whereas only sera of animals immunized with the iscoms containing the H glycoprotein had hemagglutination-inhibiting antibodies. Sera from animals immunized with the H or F preparation only precipitated the homologous glycoprotein in radioimmune precipitation assays. The immunized animals were challenged with a lethal dose of the hamster neurotropic variant of measles virus. Of the 7-week-old animals in the nonimmunized control group, 50% died within 10 days after challenge. No animals in the immunized groups showed symptoms of disease throughout the observation period of 3 months. Passive administration of anti-H monoclonal antibodies gave full protection against the 100% lethal acute infection with the hamster neurotropic variant of measles virus in newborn mice, whereas anti-F monoclonal antibodies failed to protect the animals. This study emphasizes that both H and F glycoproteins need to be considered in the development of measles virus subunit vaccines. Images PMID:2960833

  13. Symmetric covalent linkage of N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) results in novel derivatives with increased inhibitory activities against calcium/calmodulin complex.

    PubMed

    Yokokura, H; Osawa, M; Inoue, T; Umezawa, I; Naito, Y; Ikura, M; Hidaka, H

    1999-11-01

    A useful calmodulin (CaM) antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), was invented by Hidaka et al. in 1978 (J. Pharmacol. Exp. Ther. 207, 8-15). Here, we have designed new CaM antagonists on the basis of the three-dimensional structure of Ca2+/CaM complexed with W-7. Eleven new compounds all share a similar architecture, in which two W-7 molecules are linked between their aminohexyl termini by a linker with different functionalities. A wide range of inhibitory activities against Ca2+/CaM-dependent protein kinase I (CaM kinase I) has been observed with these self-crosslinked W-7 analogs, (W-7)2. In vitro competitive CaM kinase I assays using CaM kinase I and nuclear magnetic resonance studies indicated that one (W-7)2 molecule binds to one CaM molecule as expected, with the two chloronaphthalene rings of (W-7)2 being anchored separately to the N- and C-terminal hydrophobic pockets of Ca2+/CaM. The most potent compound, N,N'-bis[6-(5-chloro-1-naphthalenesulfonyl)-amino-1-hexyl]-p-xylen e-diamine ((W-7)2 - 10), inhibits CaM kinase I activity at an IC50 value of 0.23 microM; about 75 times more effectively than W-7. The length and basicity of the linker sequence in (W-7)2 significantly contribute to inhibitory activity. The present study opens an avenue for developing powerful CaM antagonists that could be used at low doses in vivo.

  14. Molecular studies reveal a MLL-MLLT3 gene fusion displaced in a case of childhood acute lymphoblastic leukemia with complex karyotype.

    PubMed

    Ney Garcia, Daniela Ribeiro; Liehr, Thomas; Emerenciano, Mariana; Meyer, Claus; Marschalek, Rolf; Pombo-de-Oliveira, Maria do Socorro; Ribeiro, Raul C; Poirot Land, Marcelo Gerardin; Macedo Silva, Maria Luiza

    2015-04-01

    Rearrangement of the mixed lineage-leukemia gene (MLL-r) is common in hematological diseases and is generally associated with poor prognosis. The mixed-lineage leukemia gene translocated to, 3 (MLLT3) gene (9p22) is a frequent MLL-r partner (∼18% of leukemias with MLL rearrangement) and is characterized by the translocation t(9;11) (p22;q23), forming an MLL-MLLT3 gene fusion. MLL-r are usually simple reciprocal translocations between two different chromosomes, although karyotypes with complex MLL-r have been observed. We present a rare case of a child with acute lymphoblastic leukemia with a complex karyotype in which the classical t(9;11) (p22;q23) was cryptically relocated into a third chromosome in a balanced three-way translocation. At the genome level, however, the MLL-MLLT3 three-way translocation still displayed both reciprocal fusion transcripts. This argues in favor for a model where a simple two-way t(9;11) (p22;q23) was likely the first step that then evolved in to a more complex karyotype. Multicolor banding techniques can be used to greatly refine complex karyotypes and its chromosomal breakpoints. Also in the presence of putative new rearrangements, Long distance inverse-PCR is an important tool to identify which gene fusion is involved.

  15. In vitro inhibitory activity of terpenic derivatives against clinical and environmental strains of the Sporothrix schenkii complex.

    PubMed

    Brilhante, Raimunda Sâmia Nogueira; Silva, Natalya Fechine; Marques, Francisca Jakelyne de Farias; Castelo-Branco, Débora de Souza Collares Maia; de Lima, Rita Amanda Chaves; Malaquias, Angela Donato Maia; Caetano, Erica Pacheco; Barbosa, Giovanna Riello; de Camargo, Zoilo Pires; Rodrigues, Anderson Messias; Monteiro, André Jalles; Bandeira, Tereza de Jesus Pinheiro Gomes; Cordeiro, Rossana de Aguiar; Sidrim, José Júlio Costa; Moreira, José Luciano Bezerra; Rocha, Marcos Fábio Gadelha

    2015-02-01

    Sporotrichosis is a subacute or chronic subcutaneous infection, caused by the fungus Sporothrix schenkii complex, occurring in human and animal tissues. Potassium iodide and itraconazole have been used as effective therapy for first-choice treatment, while amphotericin B may be indicated for disseminated infection. However, the adverse effects of potassium iodide and amphotericin B or the long duration of therapy with itraconazole often weigh against their use, leading to the search for alternatives for the treatment of severe infections. Terpinen-4-ol and farnesol are components of essential oils present in many plant species and have been described to have antifungal activity against microorganisms. In this study, 40 strains of Sporothrix spp. were tested for the susceptibility to terpinen-4-ol and farnesol. Changes in cytoplasmic membrane permeability were also investigated. Terpenes inhibited all Sporothrix strains with MIC values ranging from 87.9 to 1,429.8 μg/ml for terpinen-4-ol and from 0.003 to 0.222 μg/ml for farnesol. The MFC values ranged from 177.8 to 5,722.6 μg/ml and from 0.027 to 0.88 μg/ml, respectively, for terpinen-4-ol and farnesol. Farnesol was the most active compound for the Sporothrix strains. Significant loss of 260 and 280 nm-absorbing material did not occur after treatment with concentrations equivalent to the MIC and sub-MIC of the tested terpenes, when compared to corresponding untreated samples. The failure of terpenes to lyse Sporothrix cells suggests that their primary mechanism of action is not by causing irreversible cell membrane damage. Thus, new studies are needed to better understand the mechanisms involved in the antifungal activity.

  16. [The inhibitory effect and the mechanism of ethanol absorption by L-carnosine zinc complex in mouse gastrointestinal tract].

    PubMed

    Natsuki, R; Nozaki, M; Fujimura, H

    1998-12-01

    The effect of L-carnosine-zinc complex(Car-Zn) on ethanol absorption was investigated after oral administration(adm) to mice. One hour after oral adm of Car-Zn, and 14C-ethanol was given orally or intraperitoneally(i.p.). After passage of time, the blood was drawn from the tail vein, and 14C-radioactivities determined. The Car-Zn showed a dose-dependent inhibition of the appearance of 14C-radioactivities in blood following oral 14C-ethanol loading, while Zn acetate did not induce any alteration as compared with control. Car-Zn pretreatment did not induce any change in the blood 14C-radioactivity when ethanol was given i.p. The 14C-radioactivity and zinc in gastrointestinal tract after oral adm of Car-Zn and 14C-ethanol showed significantly higher levels than those of control for 7 hr. Distribution of 14C-radioactivities in other organs of Car-Zn treated mice were lower than those of control 3 hr after adm, while it was similar or higher than those of control 7 hr after adm. The excretions of 14C-radioactivity through expiration in Car-Zn group was a lower than that of control. Also, the urinary and fecal excretions of 14C-radioactivity were low values at 5.0% and 0.5% of the administered dose 72 hr after adm, respectively. Also, the 14C-radioactivities remaining in the organs did not detect or were very low values. In vitro study, Car-Zn stimulated the metabolism of ethanol to acetaldehyde and acetic acid in 9,000 g supernatant of small intestine. The major route of excretions of 14C-radioactivity may be excreted into the expired air. The results suggest that Car-Zn shows a long-term adhesive and permeable action on gastrointestinal tract in the mouse; as a result, this may inhibited ethanol absorption.

  17. Structures of native and complexed complement factor D: implications of the atypical His57 conformation and self-inhibitory loop in the regulation of specific serine protease activity.

    PubMed

    Jing, H; Babu, Y S; Moore, D; Kilpatrick, J M; Liu, X Y; Volanakis, J E; Narayana, S V

    1998-10-09

    Factor D is a serine protease essential for the activation of the alternative pathway of complement. The structures of native factor D and a complex formed with isatoic anhydride inhibitor were determined at resolution of 2.3 and 1.5 A, respectively, in an isomorphous monoclinic crystal form containing one molecule per asymmetric unit. The native structure was compared with structures determined previously in a triclinic cell containing two molecules with different active site conformations. The current structure shows greater similarity with molecule B in the triclinic cell, suggesting that this may be the dominant factor D conformation in solution. The major conformational differences with molecule A in the triclinic cell are located in four regions, three of which are close to the active site and include some of the residues shown to be critical for factor D catalytic activity. The conformational flexibility associated with these regions is proposed to provide a structural basis for the previously proposed substrate-induced reversible conformational changes in factor D. The high-resolution structure of the factor D/isatoic anhydride complex reveals the binding mode of the mechanism-based inhibitor. The higher specificity towards factor D over trypsin and thrombin is based on hydrophobic interactions between the inhibitor benzyl ring and the aliphatic side-chain of Arg218 that is salt bridged with Asp189 at the bottom of the primary specificity (S1) pocket. Comparison of factor D structural variants with other serine protease structures revealed the presence of a unique "self-inhibitory loop". This loop (214-218) dictates the resting-state conformation of factor D by (1) preventing His57 from adopting active tautomer conformation, (2) preventing the P1 to P3 residues of the substrate from forming anti-parallel beta-sheets with the non-specific substrate binding loop, and (3) blocking the accessibility of Asp189 to the positive1y charged P1 residue of the

  18. Functional NifD-K fusion protein in Azotobacter vinelandii is a homodimeric complex equivalent to the native heterotetrameric MoFe protein

    SciTech Connect

    Lahiri, Surobhi; Pulakat, Lakshmi; Gavini, Nara . E-mail: gavini@biology.msstate.edu

    2005-11-18

    The MoFe protein of the complex metalloenzyme nitrogenase folds as a heterotetramer containing two copies each of the homologous {alpha} and {beta} subunits, encoded by the nifD and the nifK genes respectively. Recently, the functional expression of a fusion NifD-K protein of nitrogenase was demonstrated in Azotobacter vinelandii, strongly implying that the MoFe protein is flexible as it could accommodate major structural changes, yet remain functional [M.H. Suh, L. Pulakat, N. Gavini, J. Biol. Chem. 278 (2003) 5353-5360]. This finding led us to further explore the type of interaction between the fused MoFe protein units. We aimed to determine whether an interaction exists between the two fusion MoFe proteins to form a homodimer that is equivalent to native heterotetrameric MoFe protein. Using the Bacteriomatch Two-Hybrid System, translationally fused constructs of NifD-K (fusion) with the full-length {lambda}CI of the pBT bait vector and also NifD-K (fusion) with the N-terminal {alpha}-RNAP of the pTRG target vector were made. To compare the extent of interaction between the fused NifD-K proteins to that of the {beta}-{beta} interactions in the native MoFe protein, we proceeded to generate translationally fused constructs of NifK with the {alpha}-RNAP of the pTRG vector and {lambda}CI protein of the pBT vector. The strength of the interaction between the proteins in study was determined by measuring the {beta}-galactosidase activity and extent of ampicillin resistance of the colonies expressing these proteins. This analysis demonstrated that direct protein-protein interaction exists between NifD-K fusion proteins, suggesting that they exist as homodimers. As the interaction takes place at the {beta}-interfaces of the NifD-K fusion proteins, we propose that these homodimers of NifD-K fusion protein may function in a similar manner as that of the heterotetrameric native MoFe protein. The observation that the extent of protein-protein interaction between the {beta

  19. Characterization of the telomere complex, TERF1 and TERF2 genes in muntjac species with fusion karyotypes

    SciTech Connect

    Hartmann, Nils; Scherthan, Harry . E-mail: scherth@web.de

    2005-05-15

    The telomere binding proteins TRF1 and TRF2 maintain and protect chromosome ends and confer karyotypic stability. Chromosome evolution in the genus Muntiacus is characterized by numerous tandem (end-to-end) fusions. To study TRF1 and TRF2 telomere binding proteins in Muntiacus species, we isolated and characterized the TERF1 and -2 genes from Indian muntjac (Muntiacus muntjak vaginalis; 2n = 6 female) and from Chinese muntjac (Muntiacus reveesi; 2n = 46). Expression analysis revealed that both genes are ubiquitously expressed and sequence analysis identified several transcript variants of both TERF genes. Control experiments disclosed a novel testis-specific splice variant of TERF1 in human testes. Amino acid sequence comparisons demonstrate that Muntiacus TRF1 and in particular TRF2 are highly conserved between muntjac and human. In vivo TRF2-GFP and immuno-staining studies in muntjac cell lines revealed telomeric TRF2 localization, while deletion of the DNA binding domain abrogated this localization, suggesting muntjac TRF2 represents a functional telomere protein. Finally, expression analysis of a set of telomere-related genes revealed their presence in muntjac fibroblasts and testis tissue, which suggests the presence of a conserved telomere complex in muntjacs. However, a deviation from the common theme was noted for the TERT gene, encoding the catalytic subunit of telomerase; TERT expression could not be detected in Indian or Chinese muntjac cDNA or genomic DNA using a series of conserved primers, while TRAP assay revealed functional telomerase in Chinese muntjac testis tissues. This suggests muntjacs may harbor a diverged telomerase sequence.

  20. Extreme lateral interbody fusion relieves symptoms of spinal stenosis and low-grade spondylolisthesis by indirect decompression in complex patients.

    PubMed

    Pereira, Erlick A C; Farwana, Mohammad; Lam, Khai S

    2017-01-01

    Spinal stenosis and low-grade spondylolisthesis produce symptoms of neural compression that can be treated with extreme lateral lumbar interbody fusion (XLIF) via indirect decompression. This study aimed to investigate whether the restoration of disc dimensions would relieve symptoms of radiculopathy, claudication and back pain. In this retrospective study, patients undergoing XLIF surgery for relief of radicular symptoms or degenerative disc disease were included. Radiologically proven changes were used to assess the modes of degeneration. Objective measures such as the Visual Analogue Scale (VAS) for back and legs and the Oswestry Disability Index (ODI) were used. Complications were collated post-operatively from clinical notes and outpatient appointments. Twenty-three consecutive patients were included, of whom 91% had spinal stenosis. The cohort presented with multiple comorbidities and 35% of the cohort had undergone previous lumbar surgery. There was a 61% improvement of coronal Cobb angle and an 11% correction of the lordosis sustained 1year after surgery. Clinical outcomes at 1year showed 39%, 50% and 60% improvements in the ODI, back and leg VAS scores respectively. 48% of patients had reduced sensation related to lumbosacral plexus manipulation and one retroperitoneal haematoma was conservatively managed. Minimally invasive spinal (MIS) XLIF resulted in effective restoration of disc dimensions via indirect decompression, providing good relief of clinical symptoms evidenced by significant improvement in clinical outcome scores. XLIF corrected scoliosis and improved lumbar lordosis significantly. Several plexopathies did not hinder long-term recovery. XLIF is highly suited to treating complex patients with multiple comorbidities and degenerative disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Big fusion, little fusion

    NASA Astrophysics Data System (ADS)

    Chen, Frank; ddtuttle

    2016-08-01

    In reply to correspondence from George Scott and Adam Costley about the Physics World focus issue on nuclear energy, and to news of construction delays at ITER, the fusion reactor being built in France.

  2. Relationship between SU Subdomains That Regulate the Receptor-Mediated Transition from the Native (Fusion-Inhibited) to the Fusion-Active Conformation of the Murine Leukemia Virus Glycoprotein

    PubMed Central

    Lavillette, Dimitri; Ruggieri, Alessia; Boson, Bertrand; Maurice, Marielle; Cosset, François-Loïc

    2002-01-01

    Envelope glycoproteins (Env) of retroviruses are trimers of SU (surface) and TM (transmembrane) heterodimers and are expressed on virions in fusion-competent forms that are likely to be metastable. Activation of the viral receptor-binding domain (RBD) via its interaction with a cell surface receptor is thought to initiate a cascade of events that lead to refolding of the Env glycoprotein into its stable fusion-active conformation. While the fusion-active conformation of the TM subunit has been described in detail for several retroviruses, little is known about the fusion-competent structure of the retroviral glycoproteins or the molecular events that mediate the transition between the two conformations. By characterizing Env chimeras between the ecotropic and amphotropic murine leukemia virus (MLV) SUs as well as a set of point mutants, we show that alterations of the conformation of the SU glycoprotein strongly elevate Env fusogenicity by disrupting the stability of the Env complex. Compensatory mutations that restored both Env stability and fusion control were also identified, allowing definition of interactions within the Env complex that maintain the stability of the native Env complex. We show that, in the receptor-unbound form, structural interactions between the N terminus of the viral RBD (NTR domain), the proline-rich region (PRR), and the distal part of the C-terminal domain of the SU subunit maintain a conformation of the glycoprotein that is fusion inhibitory. Additionally, we identified mutations that disrupt this fusion-inhibitory conformation and allow fusion activation in the absence of viral receptors, provided that receptor-activated RBD fragments are added in trans during infection. Other mutations were identified that allow fusion activation in the absence of receptors for both the viral glycoprotein and the trans-acting RBD. Finally, we found mutations of the SU that bypass in cis the requirement for the NTR domain in fusion activation. All

  3. Relationship between SU subdomains that regulate the receptor-mediated transition from the native (fusion-inhibited) to the fusion-active conformation of the murine leukemia virus glycoprotein.

    PubMed

    Lavillette, Dimitri; Ruggieri, Alessia; Boson, Bertrand; Maurice, Marielle; Cosset, François-Loïc

    2002-10-01

    Envelope glycoproteins (Env) of retroviruses are trimers of SU (surface) and TM (transmembrane) heterodimers and are expressed on virions in fusion-competent forms that are likely to be metastable. Activation of the viral receptor-binding domain (RBD) via its interaction with a cell surface receptor is thought to initiate a cascade of events that lead to refolding of the Env glycoprotein into its stable fusion-active conformation. While the fusion-active conformation of the TM subunit has been described in detail for several retroviruses, little is known about the fusion-competent structure of the retroviral glycoproteins or the molecular events that mediate the transition between the two conformations. By characterizing Env chimeras between the ecotropic and amphotropic murine leukemia virus (MLV) SUs as well as a set of point mutants, we show that alterations of the conformation of the SU glycoprotein strongly elevate Env fusogenicity by disrupting the stability of the Env complex. Compensatory mutations that restored both Env stability and fusion control were also identified, allowing definition of interactions within the Env complex that maintain the stability of the native Env complex. We show that, in the receptor-unbound form, structural interactions between the N terminus of the viral RBD (NTR domain), the proline-rich region (PRR), and the distal part of the C-terminal domain of the SU subunit maintain a conformation of the glycoprotein that is fusion inhibitory. Additionally, we identified mutations that disrupt this fusion-inhibitory conformation and allow fusion activation in the absence of viral receptors, provided that receptor-activated RBD fragments are added in trans during infection. Other mutations were identified that allow fusion activation in the absence of receptors for both the viral glycoprotein and the trans-acting RBD. Finally, we found mutations of the SU that bypass in cis the requirement for the NTR domain in fusion activation. All

  4. Inhibitory effect of beta-diketones and their metal complexes on TNF-alpha induced expression of ICAM-1 on human endothelial cells.

    PubMed

    Caruso, Francesco; Pettinari, Claudio; Marchetti, Fabio; Rossi, Miriam; Opazo, Cristian; Kumar, Sarvesh; Balwani, Sakshi; Ghosh, Balaram

    2009-09-01

    Recent reports show that the natural beta-diketone curcumin displays important biological properties regarding the intercellular adhesion molecule-1 (ICAM-1), which plays a critical role in the immune responses and inflammation. In this study the ICAM-1 inhibitory activity of beta-diketone compounds, which are curcumin models lacking aromatic peripheral hydroxyl and methoxy groups, along with some metal derivatives is investigated. Beta-diketones are systematically more active than metal complexes and the best obtained inhibition is 75% for both groups. The best inhibitors are 4-benzoyl-3-methyl-1-phenyl-pyrazol-5-one (HQ(Ph)) among the ligands, and sodium benzoylacetonato among metal derivatives. These results appear in line with the reported antitumor activity of related species. Since 4-acyl-5-pyrazolones posses four tautomeric forms, those corresponding to HQ(Ph) were investigated using density functional theory. Docking of all HQ(Ph) tautomers on ICAM-1 protein was performed suggesting one keto-enol form favored to act in biological environment.

  5. Proteolytic Cleavage of the Fusion Protein but Not Membrane Fusion Is Required for Measles Virus-Induced Immunosuppression In Vitro

    PubMed Central

    Weidmann, Armin; Maisner, Andrea; Garten, Wolfgang; Seufert, Marion; ter Meulen, Volker; Schneider-Schaulies, Sibylle

    2000-01-01

    Immunosuppression induced by measles virus (MV) is associated with unresponsiveness of peripheral blood lymphocytes (PBL) to mitogenic stimulation ex vivo and in vitro. In mixed lymphocyte cultures and in an experimental animal model, the expression of the MV glycoproteins on the surface of UV-inactivated MV particles, MV-infected cells, or cells transfected to coexpress the MV fusion (F) and the hemagglutinin (H) proteins was found to be necessary and sufficient for this phenomenon. We now show that MV fusion-inhibitory peptides do not interfere with the induction of immunosuppression in vitro, indicating that MV F-H-mediated fusion is essentially not involved in this process. Proteolytic cleavage of MV F0 protein by cellular proteases, such as furin, into the F1-F2 subunits is, however, an absolute requirement, since (i) the inhibitory activity of MV-infected BJAB cells was significantly impaired in the presence of a furin-inhibitory peptide and (ii) cells expressing or viruses containing uncleaved F0 proteins revealed a strongly reduced inhibitory activity which was improved following trypsin treatment. The low inhibitory activity of effector structures containing mainly F0 proteins was not due to an impaired F0-H interaction, since both surface expression and cocapping efficiencies were similar to those found with the authentic MV F and H proteins. These results indicate that the fusogenic activity of the MV F-H complexes can be uncoupled from their immunosuppressive activity and that the immunosuppressive domains of these proteins are exposed only after proteolytic activation of the MV F0 protein. PMID:10644371

  6. Magnetic-confinement fusion

    NASA Astrophysics Data System (ADS)

    Ongena, J.; Koch, R.; Wolf, R.; Zohm, H.

    2016-05-01

    Our modern society requires environmentally friendly solutions for energy production. Energy can be released not only from the fission of heavy nuclei but also from the fusion of light nuclei. Nuclear fusion is an important option for a clean and safe solution for our long-term energy needs. The extremely high temperatures required for the fusion reaction are routinely realized in several magnetic-fusion machines. Since the early 1990s, up to 16 MW of fusion power has been released in pulses of a few seconds, corresponding to a power multiplication close to break-even. Our understanding of the very complex behaviour of a magnetized plasma at temperatures between 150 and 200 million °C surrounded by cold walls has also advanced substantially. This steady progress has resulted in the construction of ITER, a fusion device with a planned fusion power output of 500 MW in pulses of 400 s. ITER should provide answers to remaining important questions on the integration of physics and technology, through a full-size demonstration of a tenfold power multiplication, and on nuclear safety aspects. Here we review the basic physics underlying magnetic fusion: past achievements, present efforts and the prospects for future production of electrical energy. We also discuss questions related to the safety, waste management and decommissioning of a future fusion power plant.

  7. Magnetic fusion reactor economics

    SciTech Connect

    Krakowski, R.A.

    1995-12-01

    An almost primordial trend in the conversion and use of energy is an increased complexity and cost of conversion systems designed to utilize cheaper and more-abundant fuels; this trend is exemplified by the progression fossil fission {yields} fusion. The present projections of the latter indicate that capital costs of the fusion ``burner`` far exceed any commensurate savings associated with the cheapest and most-abundant of fuels. These projections suggest competitive fusion power only if internal costs associate with the use of fossil or fission fuels emerge to make them either uneconomic, unacceptable, or both with respect to expensive fusion systems. This ``implementation-by-default`` plan for fusion is re-examined by identifying in general terms fusion power-plant embodiments that might compete favorably under conditions where internal costs (both economic and environmental) of fossil and/or fission are not as great as is needed to justify the contemporary vision for fusion power. Competitive fusion power in this context will require a significant broadening of an overly focused program to explore the physics and simbiotic technologies leading to more compact, simplified, and efficient plasma-confinement configurations that reside at the heart of an attractive fusion power plant.

  8. Inhibitory functioning in Alzheimer's disease.

    PubMed

    Amieva, Hélène; Phillips, Louise H; Della Sala, Sergio; Henry, Julie D

    2004-05-01

    We present a comprehensive review of studies assessing inhibitory functioning in Alzheimer's disease. The objectives of this review are: (i) to establish whether Alzheimer's disease affects all inhibitory mechanisms equally, and (ii) where possible, to assess whether any effects of Alzheimer's disease on inhibition tasks might be caused by other cognitive deficits, such as slowed processing. We review inhibitory mechanisms considered to play a crucial role in various domains of cognition, such as inhibition involved in working memory, selective attention and shifting abilities, and the inhibition of motor and verbal responses. It was found that whilst most inhibitory mechanisms are affected by the disorder, some are relatively preserved, suggesting that inhibitory deficits in Alzheimer's disease may not be the result of a general inhibitory breakdown. In particular, the experimental results reviewed showed that Alzheimer's disease has a strong effect on tasks requiring controlled inhibition processes, such as the Stroop task. However, the presence of the disease appears to have relatively little effect on tasks requiring more automatic inhibition, such as the inhibition of return task. Thus, the distinction between automatic, reflexive inhibitory mechanisms and controlled inhibitory mechanisms may be critical when predicting the integrity of inhibitory mechanisms in Alzheimer's disease. Substantial effects of Alzheimer's disease on tasks such as negative priming, which are not cognitively complex but do require some degree of controlled inhibition, support this hypothesis. A meta-analytic review of seven studies on the Stroop paradigm revealed substantially larger effects of Alzheimer's disease on the inhibition condition relative to the baseline condition, suggesting that these deficits do not simply reflect general slowing.

  9. Kinetically coupled folding of a single HIV-1 glycoprotein 41 complex in viral membrane fusion and inhibition.

    PubMed

    Jiao, Junyi; Rebane, Aleksander A; Ma, Lu; Gao, Ying; Zhang, Yongli

    2015-06-02

    HIV-1 glycoprotein 41 (gp41) mediates viral entry into host cells by coupling its folding energy to membrane fusion. Gp41 folding is blocked by fusion inhibitors, including the commercial drug T20, to treat HIV/AIDS. However, gp41 folding intermediates, energy, and kinetics are poorly understood. Here, we identified the folding intermediates of a single gp41 trimer-of-hairpins and measured their associated energy and kinetics using high-resolution optical tweezers. We found that folding of gp41 hairpins was energetically independent but kinetically coupled: Each hairpin contributed a folding energy of ∼-23 kBT, but folding of one hairpin successively accelerated the folding rate of the next one by ∼20-fold. Membrane-mimicking micelles slowed down gp41 folding and reduced the stability of the six-helix bundle. However, the stability was restored by cooperative folding of the membrane-proximal external region. Surprisingly, T20 strongly inhibited gp41 folding by actively displacing the C-terminal hairpin strand in a force-dependent manner. The inhibition was abolished by a T20-resistant gp41 mutation. The energetics and kinetics of gp41 folding established by us provides a basis to understand viral membrane fusion, infection, and therapeutic intervention.

  10. Characterization of fusion genes and the significantly expressed fusion isoforms in breast cancer by hybrid sequencing.

    PubMed

    Weirather, Jason L; Afshar, Pegah Tootoonchi; Clark, Tyson A; Tseng, Elizabeth; Powers, Linda S; Underwood, Jason G; Zabner, Joseph; Korlach, Jonas; Wong, Wing Hung; Au, Kin Fai

    2015-10-15

    We developed an innovative hybrid sequencing approach, IDP-fusion, to detect fusion genes, determine fusion sites and identify and quantify fusion isoforms. IDP-fusion is the first method to study gene fusion events by integrating Third Generation Sequencing long reads and Second Generation Sequencing short reads. We applied IDP-fusion to PacBio data and Illumina data from the MCF-7 breast cancer cells. Compared with the existing tools, IDP-fusion detects fusion genes at higher precision and a very low false positive rate. The results show that IDP-fusion will be useful for unraveling the complexity of multiple fusion splices and fusion isoforms within tumorigenesis-relevant fusion genes.

  11. Characterization of fusion genes and the significantly expressed fusion isoforms in breast cancer by hybrid sequencing

    PubMed Central

    Weirather, Jason L.; Afshar, Pegah Tootoonchi; Clark, Tyson A.; Tseng, Elizabeth; Powers, Linda S.; Underwood, Jason G.; Zabner, Joseph; Korlach, Jonas; Wong, Wing Hung; Au, Kin Fai

    2015-01-01

    We developed an innovative hybrid sequencing approach, IDP-fusion, to detect fusion genes, determine fusion sites and identify and quantify fusion isoforms. IDP-fusion is the first method to study gene fusion events by integrating Third Generation Sequencing long reads and Second Generation Sequencing short reads. We applied IDP-fusion to PacBio data and Illumina data from the MCF-7 breast cancer cells. Compared with the existing tools, IDP-fusion detects fusion genes at higher precision and a very low false positive rate. The results show that IDP-fusion will be useful for unraveling the complexity of multiple fusion splices and fusion isoforms within tumorigenesis-relevant fusion genes. PMID:26040699

  12. The separation of platinum, palladium and gold from silicate rocks by the anion exchange separation of chloro complexes after a sodium peroxide fusion: an investigation of low recoveries.

    PubMed

    Enzweiler, J; Potts, P J

    1995-10-01

    A series of experiments was undertaken to measure the recovery efficiency of platinum, palladium and gold from silicate rocks using a sodium peroxide fusion followed by anion exchange separation of the analytes as chloro complexes. Results obtained by graphite furnace atomic absorption spectrometric analysis of standard solutions prepared in dilute HCl or HCl-acidified sodium peroxide solution showed that recoveries were near quantitative. However, when standard solutions were added to an alkaline sodium peroxide solution, which was then acidified, low results were obtained for platinum and gold (46% and 76% respectively). Low and variable results were also obtained when standard solutions were added to a peridotite sample that had been dissolved by the state procedure, and in the analysis of the South African Bureau of Standards certified reference material, SARM 7. Various experiments were undertaken to investigate these low recoveries, but the reason proposed here is the formation of hydroxychloro compounds in alkaline solution which are not, on acidification with HCl, converted quantitatively to the chloro complex necessary for quantitative anion exchange separation. It is concluded that a sodium peroxide fusion followed by an anion-exchange separation does not appear to form the basis of a successful technique for the determination of platinum, palladium and gold in silicate rocks.

  13. Effects of Cr on H and He trapping and vacancy complexes in V in a fusion environment: a first-principles study

    NASA Astrophysics Data System (ADS)

    Hua, Juan; Liu, Yue-Lin; Zhao, Ming-Wen; Liu, Xiang-Dong

    2017-06-01

    First-principles density functional theory was used to investigate the interaction between hydrogen (H) and helium (He) in V-Cr alloy, which is a potential structural material for use in fusion reactors. When vacancies are present in the V-Cr alloy, a single He atom prefers to occupy the octahedral site near the Cr atom rather than vacancy centre, which differs from the cases of iron and tungsten. Because of the decrease of the electron density around the He atom, there was a strong interaction between He and H. In the vicinity of He-vac complexes, H atoms tend to stay in the tetrahedral site rather than occupy the octahedral-interstitial site. A single He-vac complex can trap as many as six H atoms, which is more than can be trapped by an empty vacancy in the V-Cr alloy because of the electronic density redistribution of vacancy vicinity. This strong attraction explains the enhanced retention of H and He observed near the surface of V and V-based alloys under both sequential and simultaneous bombardments. The results provide useful insight into the application of the V-based alloys as candidate structural materials in fusion Tokamaks.

  14. Antibody raised against soluble CD4-rgp120 complex recognizes the CD4 moiety and blocks membrane fusion without inhibiting CD4-gp120 binding

    PubMed Central

    1990-01-01

    We studied the humoral response of mice immunized with soluble CD4- rgp120 complex, testing polyclonal and monoclonal antibodies (mAbs) with the aim of identifying molecular changes that take place after the first interaction between human immunodeficiency virus and the cell surface. The antisera had a paradoxically high syncytia-blocking titer associated with anti-CD4 specificity, while their capacity to inhibit CD4-gp120 binding was relatively modest. One of the mAbs produced from these responders blocks syncytia formation but does not inhibit CD4 interaction with gp120. Apparently, this mAb interacts with the CD4 moiety of CD4-gp120 complex and prevents a post-binding event necessary for membrane fusion and viral infection. PMID:2212945

  15. Spinal Fusion

    MedlinePlus

    ... concept of fusion is similar to that of welding in industry. Spinal fusion surgery, however, does not ... bone taken from the patient has a long history of use and results in predictable healing. Autograft ...

  16. Spinal Fusion

    MedlinePlus

    ... concept of fusion is similar to that of welding in industry. Spinal fusion surgery, however, does not ... bone taken from the patient has a long history of use and results in predictable healing. Autograft ...

  17. Synthesis, crystal structures, molecular docking, in vitro monoamine oxidase-B inhibitory activity of transition metal complexes with 2-{4-[bis (4-fluorophenyl)methyl]piperazin-1-yl} acetic acid

    NASA Astrophysics Data System (ADS)

    Yang, Dan-dan; Wang, Riu; Zhu, Jin-long; Cao, Qi-yue; Qin, Jie; Zhu, Hai-liang; Qian, Shao-song

    2017-01-01

    Three novel complexes, [Cu(L)2(H2O)](1), [Zn(L)2(H2O)2]·CH3OH·1.5H2O(2), and [Ni(L)2(H2O)1.8]·CH3OH·1.2H2O (3) (HL = 2-{4-[bis(4-fluorophenyl)methyl]pipera-zin-1-yl} acetic acid), were synthesized and structurally determined by single-crystal X-ray diffraction. Molecular docking study preliminarily revealed that complex 1 had potential Monoamine oxidase B inhibitory activity. All acquired compounds were tested against rat brain MAO-B in vitro. In accordance with the result of calculation, it showed complex 1 (IC50 = 1.85 ± 0.31 μM) have good inhibitory activity against MAO-B at the same micromolar concentrations with positive control Iproniazid Phosphate (IP, IC50 = 7.59 ± 1.17 μM). These results indicated that complex 1 was a potent MAO-B inhibitor.

  18. Radioscapholunate Fusions

    PubMed Central

    McGuire, Duncan Thomas; Bain, Gregory Ian

    2012-01-01

    Radiocarpal fusions are performed for a variety of indications, most commonly for debilitating painful arthritis. The goal of a wrist fusion is to fuse the painful, diseased joints and to preserve motion through the healthy joints. Depending on the extent of the disease process, radiocarpal fusions may take the form of radiolunate, radioscapholunate, or total wrist fusions. Surgical techniques and instrumentation have advanced over the last few decades, and consequently the functional outcomes have improved and complications decreased. Techniques for partial carpal fusions have improved and now include distal scaphoid and triquetrum excision, which improves range of motion and fusion rates. In this article we discuss the various surgical techniques and fixation methods available and review the corresponding evidence in the literature. The authors' preferred surgical technique of radioscapholunate fusion with distal scaphoid and triquetrum excision is outlined. New implants and new concepts are also discussed. PMID:24179717

  19. NUP98 fusion oncoproteins interact with the APC/C(Cdc20) as a pseudosubstrate and prevent mitotic checkpoint complex binding.

    PubMed

    Salsi, Valentina; Fantini, Sebastian; Zappavigna, Vincenzo

    2016-09-01

    NUP98 is a recurrent partner gene in translocations causing acute myeloid leukemias and myelodisplastic syndrome. The expression of NUP98 fusion oncoproteins has been shown to induce mitotic spindle defects and chromosome missegregation, which correlate with the capability of NUP98 fusions to cause mitotic checkpoint attenuation. We show that NUP98 oncoproteins physically interact with the APC/C(Cdc20) in the absence of the NUP98 partner protein RAE1, and prevent the binding of the mitotic checkpoint complex to the APC/C(Cdc20). NUP98 oncoproteins require the GLEBS-like domain present in their NUP98 moiety to bind the APC/C(Cdc20). We found that NUP98 wild-type is a substrate of APC/C(Cdc20) prior to mitotic entry, and that its binding to APC/C(Cdc20) is controlled via phosphorylation of a PEST sequence located within its C-terminal portion. We identify S606, within the PEST sequence, as a key target site, whose phosphorylation modulates the capability of NUP98 to interact with APC/C(Cdc20). We finally provide evidence for an involvement of the peptidyl-prolyl isomerase PIN1 in modulating the possible conformational changes within NUP98 that lead to its dissociation from the APC/C(Cdc20) during mitosis. Our results provide novel insight into the mechanisms underlying the aberrant capability of NUP98 oncoproteins to interact with APC/C(Cdc20) and to interfere with its function.

  20. Transcriptional Repression and RNA Silencing Act Synergistically To Demonstrate the Function of the Eleventh Component of the Vaccinia Virus Entry-Fusion Complex

    PubMed Central

    Wolfe, Cindy L.; Ojeda, Suany

    2012-01-01

    Poxviruses have an elaborate system for infecting cells comprising several proteins for attachment and a larger number dedicated to membrane fusion and entry. Thus far, 11 proteins have been identified as components of the vaccinia virus (VACV) entry-fusion complex (EFC), and 10 of these proteins have been shown to be required for entry. J5, the remaining functionally uncharacterized component of the complex, is conserved in all poxviruses, has a predicted C-terminal transmembrane domain, and is an N-terminally truncated paralog of two other EFC proteins. To determine the role of J5, we constructed a mutant that inducibly regulates J5 transcription. Although the virus yield was reduced only about 80% without inducer, the inability to isolate a J5 deletion mutant suggested an essential function. To enhance stringency, we employed RNA silencing alone and together with transcriptional repression of the inducible mutant. The yield of infectious virus was reduced 4- to 5-fold by repression, 2-fold by silencing, and 60-fold by the combination of the two. Virus particles made under the latter conditions appeared to contain a full complement of proteins excluding J5 but had very low infectivity. Further studies indicated that after binding to cells, J5-deficient virions had a defect in core entry and an inability to induce syncytium formation. In addition, we confirmed that J5 is associated with the EFC by affinity purification. These data indicate that J5 is a functional component of the EFC and highlights the advantage of combining transcriptional repression and RNA silencing for stringent reduction of gene expression. PMID:22013036

  1. Role of nucleotides in stabilization of the phospholamban/cardiac Ca²⁺ pump inhibitory complex examined with use of metal fluorides.

    PubMed

    Chen, Zhenhui

    2015-11-01

    Phospholamban (PLB) inhibits the activity of the cardiac calcium pump SERCA2a. We previously showed that PLB with engineered Cys residues only cross-linked with the Ca(2+) -free E2 intermediate of SERCA2a. Formation of E2•PLB prevents Ca(2+) binding at the high-affinity Ca(2+) binding sites, blocking the enzyme kinetic cycle. Here we further studied the synergistic action of PLB and ATP on E2 in terms of prevention of formation of the phosphorylated E2P-like states stabilized by metal fluorides. SERCA2a was co-expressed in insect cell microsomes with PLB mutants of normal or super-inhibitory strength, with cross-linkable mutations at either the cytosolic side (N30C) or the luminal side (V49C) of PLB. For normal-strength PLB mutants, in the absence of nucleotide, metal fluorides totally inhibited both SERCA2a enzyme activity and cross-linking of PLB to SERCA2a at both sites, suggesting that PLB dissociates from SERCA2a in the E2P-like states. However, under the same conditions, super-inhibitory PLB mutants prevented total enzyme inhibition by metal fluorides. Further, the cross-linking of super-inhibitory PLB to SERCA2a was only partially inhibited by metal fluorides, but was drastically restored upon sequential addition of ATP. These results revealed the equilibrium between E2•PLB, E2•ATP, or E2•ATP•PLB states and E2P-like states, suggesting that the synergistic binding of ATP and PLB to SERCA is very strong, sufficient to prevent formation of E2 phosphoenzymes, even when stabilized by metal fluorides.

  2. Separating Fusion from Rivalry

    PubMed Central

    Dechent, Peter; Forster, Clemens; von Steinbüchel, Nicole; Wüstenberg, Torsten; Strasburger, Hans

    2014-01-01

    Visual fusion is the process in which differing but compatible binocular information is transformed into a unified percept. Even though this is at the basis of binocular vision, the underlying neural processes are, as yet, poorly understood. In our study we therefore aimed to investigate neural correlates of visual fusion. To this end, we presented binocularly compatible, fusible (BF), and incompatible, rivaling (BR) stimuli, as well as an intermediate stimulus type containing both binocularly fusible and monocular, incompatible elements (BFR). Comparing BFR stimuli with BF and BR stimuli, respectively, we were able to disentangle brain responses associated with either visual fusion or rivalry. By means of functional magnetic resonance imaging, we measured brain responses to these stimulus classes in the visual cortex, and investigated them in detail at various retinal eccentricities. Compared with BF stimuli, the response to BFR stimuli was elevated in visual cortical areas V1 and V2, but not in V3 and V4 – implying that the response to monocular stimulus features decreased from V1 to V4. Compared to BR stimuli, the response to BFR stimuli decreased with increasing eccentricity, specifically within V3 and V4. Taken together, it seems that although the processing of exclusively monocular information decreases from V1 to V4, the processing of binocularly fused information increases from earlier to later visual areas. Our findings suggest the presence of an inhibitory neural mechanism which, depending on the presence of fusion, acts differently on the processing of monocular information. PMID:25054904

  3. Inheritance of skeletal deformities in gilthead seabream (Sparus aurata) - lack of operculum, lordosis, vertebral fusion and LSK complex.

    PubMed

    Negrín-Báez, D; Navarro, A; Lee-Montero, I; Soula, M; Afonso, J M; Zamorano, M J

    2015-01-01

    Morphological abnormalities in farmed gilthead seabream (Sparus aurata) are a major problem as it entails significant economic losses. In this study, 3 large scale experiments under different conditions of spawning, offspring handling and breeders phenotype were performed to analyze the inheritance of 4 types of deformities in this species: lack of operculum, lordosis, vertebral fusion, which are 3 of the most important skeletal deformities, and LSK, which is a consecutive repetition of lordosis/scoliosis/kyphosis. In Exp. [1] (mass spawning and fingerling sorting), 900 fish were analyzed at 509 d post-hatching: 846 fish that had been on-grown in a farm and 54 LSK-deformed fish that had been reared separately after being selected during the fingerling sorting process. A total of 89 families were represented. A statistically significant association between 5 of these families (from 6 breeders) and LSK-deformed fish was found. In Exp. [2] (mass spawning and no fingerling sorting), 810 fish were analyzed at 2 ages: 179 and 689 d post-hatching. Significant relationships between 2 of the breeders and 2 of the families with the lack of operculum prevalence of their descendants were found at 689 d but not at 179 d. Heritabilities: 0.09 ± 0.09 at 179 d and 0.17 ± 0.08 at 689 d. Column deformities prevalence was low and no association with family was observed. Family relationships were determined by microsatellites multiplex PCR in both experiments. In Exp. [3] (designed mating), sires suffering from lordosis or lack of operculum or vertebral fusion deformities were mated with non-deformed dams and a mass-spawning mating was considered as a control. After analyzing 11,503 offspring at 159 d post-hatching, a significant relationship between each deformity prevalence and the mating of breeders suffering from the same deformity was observed. In addition, a significant prevalence of lack of operculum in offspring from lordotic matings was observed. Heritabilities ranged from

  4. Fusion breeder

    SciTech Connect

    Moir, R.W.

    1982-04-20

    The fusion breeder is a fusion reactor designed with special blankets to maximize the transmutation by 14 MeV neutrons of uranium-238 to plutonium or thorium to uranium-233 for use as a fuel for fission reactors. Breeding fissile fuels has not been a goal of the US fusion energy program. This paper suggests it is time for a policy change to make the fusion breeder a goal of the US fusion program and the US nuclear energy program. The purpose of this paper is to suggest this policy change be made and tell why it should be made, and to outline specific research and development goals so that the fusion breeder will be developed in time to meet fissile fuel needs.

  5. Fusion breeder

    SciTech Connect

    Moir, R.W.

    1982-02-22

    The fusion breeder is a fusion reactor designed with special blankets to maximize the transmutation by 14 MeV neutrons of uranium-238 to plutonium or thorium to uranium-233 for use as a fuel for fission reactors. Breeding fissile fuels has not been a goal of the US fusion energy program. This paper suggests it is time for a policy change to make the fusion breeder a goal of the US fusion program and the US nuclear energy program. The purpose of this paper is to suggest this policy change be made and tell why it should be made, and to outline specific research and development goals so that the fusion breeder will be developed in time to meet fissile fuel needs.

  6. Recognition of Membrane-Bound Fusion-Peptide/MPER Complexes by the HIV-1 Neutralizing 2F5 Antibody: Implications for Anti-2F5 Immunogenicity

    PubMed Central

    Huarte, Nerea; Araujo, Aitziber; Arranz, Rocio; Lorizate, Maier; Quendler, Heribert; Kunert, Renate; Valpuesta, José M.; Nieva, José L.

    2012-01-01

    The membrane proximal external region (MPER) of the fusogenic HIV-1 glycoprotein-41 harbors the epitope sequence recognized by 2F5, a broadly neutralizing antibody isolated from an infected individual. Structural mimicry of the conserved MPER 2F5 epitope constitutes a pursued goal in the field of anti-HIV vaccine development. It has been proposed that 2F5 epitope folding into its native state is attained in the vicinity of the membrane interface and might involve interactions with other viral structures. Here we present results indicating that oligomeric complexes established between MPER and the conserved amino-terminal fusion peptide (FP) can partition into lipid vesicles and be specifically bound by the 2F5 antibody at their surfaces. Cryo-transmission electron microscopy of liposomes doped with MPER:FP peptide mixtures provided the structural grounds for complex recognition by antibody at lipid bilayer surfaces. Supporting the immunogenicity of the membrane-bound complex, these MPER:FP peptide-vesicle formulations could trigger cross-reactive anti-MPER antibodies in rabbits. Thus, our observations suggest that contacts with N-terminal regions of gp41 may stabilize the 2F5 epitope as a membrane-surface antigen. PMID:23285173

  7. "Polarized" Fusion

    NASA Astrophysics Data System (ADS)

    Schieck, Hans Paetz Gen.

    Increasing energy demand in view of limited supply, as well as environmental and nuclear-safety concerns leading to increased emphasis on renewable energy sources such as solar or wind energy are expected to focus public and scientific interest increasingly also on fusion energy. With the decision to build ITER (low-density magnetic confinement) and also continuing research on (high-density) inertial-confinement fusion (cf. the inauguration of the laser fusion facility at the Lawrence Livermore National Laboratory) prospects of fusion energy have probably entered a new era.

  8. Inhibitory control of hippocampal inhibitory neurons

    PubMed Central

    Chamberland, Simon; Topolnik, Lisa

    2012-01-01

    Information processing within neuronal networks is determined by a dynamic partnership between principal neurons and local circuit inhibitory interneurons. The population of GABAergic interneurons is extremely heterogeneous and comprises, in many brain regions, cells with divergent morphological and physiological properties, distinct molecular expression profiles, and highly specialized functions. GABAergic interneurons have been studied extensively during the past two decades, especially in the hippocampus, which is a relatively simple cortical structure. Different types of hippocampal inhibitory interneurons control spike initiation [e.g., axo-axonic and basket cells (BCs)] and synaptic integration (e.g., bistratified and oriens–lacunosum moleculare interneurons) within pyramidal neurons and synchronize local network activity, providing a means for functional segregation of neuronal ensembles and proper routing of hippocampal information. Thus, it is thought that, at least in the hippocampus, GABAergic inhibitory interneurons represent critical regulating elements at all stages of information processing, from synaptic integration and spike generation to large-scale network activity. However, this raises an important question: if inhibitory interneurons are fundamental for network computations, what are the mechanisms that control the activity of the interneurons themselves? Given the essential role of synaptic inhibition in the regulation of neuronal activity, it would be logical to expect that specific inhibitory mechanisms have evolved to control the operation of interneurons. Here, we review the mechanisms of synaptic inhibition of interneurons and discuss their role in the operation of hippocampal inhibitory circuits. PMID:23162426

  9. Plasma fusion and cold fusion

    SciTech Connect

    Hideo, Kozima

    1996-12-31

    Fundamental problems of plasma fusion (controlled thermonuclear fusion) due to the contradicting demands of the magnetic confinement of plasma and suppression of instabilities occurring on and in plasma are surveyed in contrast with problems of cold fusion. Problems in cold fusion due to the complicated constituents and types of force are explained. Typical cold fusion events are explained by a model based on the presence of trapped neutrons in cold fusion materials. The events include Pons-Fleishmann effect, tritium anomaly, helium 4 production, and nuclear transmutation. Fundamental hypothesis of the model is an effectiveness of a new concept--neutron affinity of elements. The neutron affinity is defined and some bases supporting it are explained. Possible justification of the concept by statistical approach is given.

  10. Studies on DNA binding behaviour of biologically active transition metal complexes of new tetradentate N2O2 donor Schiff bases: Inhibitory activity against bacteria

    NASA Astrophysics Data System (ADS)

    Sobha, S.; Mahalakshmi, R.; Raman, N.

    A series of Cu(II), Ni(II) and Zn(II) complexes of the type ML have been synthesized with Schiff bases derived from o-acetoacetotoluidide, 2-hydroxybenzaldehyde and o-phenylenediamine/1,4-diaminobutane. The complexes are insoluble in common organic solvents but soluble in DMF and DMSO. The measured molar conductance values in DMSO indicate that the complexes are non-electrolytic in nature. All the six metal complexes have been fully characterized with the help of elemental analyses, molecular weights, molar conductance values, magnetic moments and spectroscopic data. The analytical data helped to elucidate the structure of the metal complexes. The Schiff bases are found to act as tetradentate ligands using N2O2 donor set of atoms leading to a square-planar geometry for the complexes around all the metal ions. The binding properties of metal complexes with DNA were investigated by absorption spectra, viscosity measurements and cyclic voltammetry. Detailed analysis reveals that the metal complexes intercalate into the DNA base stack as intercalators. All the metal complexes cleave the pUC19 DNA in presence of H2O2. The Schiff bases and their complexes have been screened for their antibacterial activity against five bacterial strains (Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus epidermidis, Klebsiella pneumoniae) by disk diffusion method. All the metal complexes have potent biocidal activity than the free ligands.

  11. Studies on DNA binding behaviour of biologically active transition metal complexes of new tetradentate N2O2 donor Schiff bases: inhibitory activity against bacteria.

    PubMed

    Sobha, S; Mahalakshmi, R; Raman, N

    2012-06-15

    A series of Cu(II), Ni(II) and Zn(II) complexes of the type ML have been synthesized with Schiff bases derived from o-acetoacetotoluidide, 2-hydroxybenzaldehyde and o-phenylenediamine/1,4-diaminobutane. The complexes are insoluble in common organic solvents but soluble in DMF and DMSO. The measured molar conductance values in DMSO indicate that the complexes are non-electrolytic in nature. All the six metal complexes have been fully characterized with the help of elemental analyses, molecular weights, molar conductance values, magnetic moments and spectroscopic data. The analytical data helped to elucidate the structure of the metal complexes. The Schiff bases are found to act as tetradentate ligands using N(2)O(2) donor set of atoms leading to a square-planar geometry for the complexes around all the metal ions. The binding properties of metal complexes with DNA were investigated by absorption spectra, viscosity measurements and cyclic voltammetry. Detailed analysis reveals that the metal complexes intercalate into the DNA base stack as intercalators. All the metal complexes cleave the pUC19 DNA in presence of H(2)O(2.) The Schiff bases and their complexes have been screened for their antibacterial activity against five bacterial strains (Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus epidermidis, Klebsiella pneumoniae) by disk diffusion method. All the metal complexes have potent biocidal activity than the free ligands.

  12. Image fusion

    NASA Technical Reports Server (NTRS)

    Pavel, M.

    1993-01-01

    The topics covered include the following: a system overview of the basic components of a system designed to improve the ability of a pilot to fly through low-visibility conditions such as fog; the role of visual sciences; fusion issues; sensor characterization; sources of information; image processing; and image fusion.

  13. Stockpile tritium production from fusion

    SciTech Connect

    Lokke, W.A.; Fowler, T.K.

    1986-03-21

    A fusion breeder holds the promise of a new capability - ''dialable'' reserve capacity at little additional cost - that offers stockpile planners a new way to deal with today's uncertainties in forecasting long range needs. Though still in the research stage, fusion can be developed in time to meet future military requirements. Much of the necessary technology will be developed by the ongoing magnetic fusion energy program. However, a specific program to develop the nuclear technology required for materials production is needed if fusion is to become a viable option for a new production complex around the turn of the century.

  14. Synthesis, spectroscopic studies and inhibitory activity against bactria and fungi of acyclic and macrocyclic transition metal complexes containing a triamine coumarine Schiff base ligand

    NASA Astrophysics Data System (ADS)

    Abou-Hussein, A. A.; Linert, Wolfgang

    2015-04-01

    Two series of new mono and binuclear complexes with a Schiff base ligand derived from the condensation of 3-acetylcoumarine and diethylenetriamine, in the molar ratio 2:1 have been prepared. The ligand was characterized by elemental analysis, IR, UV-visible, 1H-NMR and mass spectra. The reaction of the Schiff base ligand with cobalt(II), nickel(II), copper(II), zinc(II) and oxovanadium(IV) lead to mono or binuclear species of cyclic or macrocyclic complexes, depending on the mole ratio of metal to ligand and as well as on the method of preparation. The Schiff base ligand behaves as a cyclic bidentate, tetradendate or pentaentadentae ligand. The formation of macrocyclic complexes depends significantly on the dimension of the internal cavity, the rigidity of the macrocycles, the nature of its donor atoms and on the complexing properties of the anion involved in the coordination. Electronic spectra and magnetic moments of the complexes indicate that the geometries of the metal centers are either square pyramidal or octahedral for acyclic or macro-cyclic complexes. The structures are consistent with the IR, UV-visible, ESR, 1H-NMR, mass spectra as well as conductivity and magnetic moment measurements. The Schiff base ligand and its metal complexes were tested against two pathogenic bacteria as Gram-positive and Gram-negative bacteria as well as one kind of fungi. Most of the complexes exhibit mild antibacterial and antifungal activities against these organisms.

  15. The Path to Magnetic Fusion Energy

    SciTech Connect

    Prager, Stewart

    2011-05-04

    When the possibility of fusion as an energy source for electricity generation was realized in the 1950s, understanding of the plasma state was primitive. The fusion goal has been paced by, and has stimulated, the development of plasma physics. Our understanding of complex, nonlinear processes in plasmas is now mature. We can routinely produce and manipulate 100 million degree plasmas with remarkable finesse, and we can identify a path to commercial fusion power. The international experiment, ITER, will create a burning (self-sustained) plasma and produce 500 MW of thermal fusion power. This talk will summarize the progress in fusion research to date, and the remaining steps to fusion power.

  16. Membrane fusion in muscle development and repair

    PubMed Central

    Demonbreun, Alexis R.; Biersmith, Bridget H.

    2015-01-01

    Mature skeletal muscle forms from the fusion of skeletal muscle precursor cells, myoblasts. Myoblasts fuse to other myoblasts to generate multinucleate myotubes during myogenesis, and myoblasts also fuse to other myotubes during muscle growth and repair. Proteins within myoblasts and myotubes regulate complex processes such as elongation, migration, cell adherence, cytoskeletal reorganization, membrane coalescence, and ultimately fusion. Recent studies have identified cell surface proteins, intracellular proteins, and extracellular signaling molecules required for the proper fusion of muscle. Many proteins that actively participate in myoblast fusion also coordinate membrane repair. Here we will review mammalian membrane fusion with specific attention to proteins that mediate myoblast fusion and muscle repair. PMID:26537430

  17. Tandem recombineering by SLIC cloning and Cre-LoxP fusion to generate multigene expression constructs for protein complex research.

    PubMed

    Haffke, Matthias; Viola, Cristina; Nie, Yan; Berger, Imre

    2013-01-01

    A robust protocol to generate recombinant DNA containing multigene expression cassettes by using sequence and ligation independent cloning (SLIC) followed by multiplasmid Cre-LoxP recombination in tandem for multiprotein complex research is described. The protocol includes polymerase chain reaction (PCR) amplification of the desired genes, seamless insertion into the target vector via SLIC, and Cre-LoxP recombination of specific donor and acceptor plasmid molecules, optionally in a robotic setup. This procedure, called tandem recombineering, has been implemented for multiprotein expression in E. coli and mammalian cells, and also for insect cells using a recombinant baculovirus.

  18. Ubiquitin fusion constructs allow the expression and purification of multi-KOW domain complexes of the Saccharomyces cerevisiae transcription elongation factor Spt4/5.

    PubMed

    Blythe, Amanda; Gunasekara, Sanjika; Walshe, James; Mackay, Joel P; Hartzog, Grant A; Vrielink, Alice

    2014-08-01

    Spt4/5 is a hetero-dimeric transcription elongation factor that can both inhibit and promote transcription elongation by RNA polymerase II (RNAPII). However, Spt4/5's mechanism of action remains elusive. Spt5 is an essential protein and the only universally-conserved RNAP-associated transcription elongation factor. The protein contains multiple Kyrpides, Ouzounis and Woese (KOW) domains. These domains, in other proteins, are thought to bind RNA although there is little direct evidence in the literature to support such a function in Spt5. This could be due, at least in part, to difficulties in expressing and purifying recombinant Spt5. When expressed in Escherichia coli (E. coli), Spt5 is innately insoluble. Here we report a new approach for the successful expression and purification of milligram quantities of three different multi-KOW domain complexes of Saccharomyces cerevisiae Spt4/5 for use in future functional studies. Using the E. coli strain Rosetta2 (DE3) we have developed strategies for co-expression of Spt4 and multi-KOW domain Spt5 complexes from the bi-cistronic pET-Duet vector. In a second strategy, Spt4/5 was expressed via co-transformation of Spt4 in the vector pET-M11 with Spt5 ubiquitin fusion constructs in the vector pHUE. We characterized the multi-KOW domain Spt4/5 complexes by Western blot, limited proteolysis, circular dichroism, SDS-PAGE and size exclusion chromatography-multiangle light scattering and found that the proteins are folded with a Spt4:Spt5 hetero-dimeric stoichiometry of 1:1. These expression constructs encompass a larger region of Spt5 than has previously been reported, and will provide the opportunity to elucidate the biological function of the multi-KOW containing Spt5.

  19. Secretion induces cell pH dynamics impacting assembly-disassembly of the fusion protein complex: A combined fluorescence and atomic force microscopy study.

    PubMed

    Lewis, Kenneth T; Naik, Akshata R; Laha, Suvra S; Wang, Sunxi; Mao, Guangzhao; Kuhn, Eric; Jena, Bhanu P

    2017-08-03

    A wide range of cellular activities including protein folding and cell secretion, such as neurotransmission or insulin release, are all governed by intracellular pH homeostasis, underscoring the importance of pH on critical life processes. Nano- scale pH measurements of cells and biomolecules therefore hold great promise in understanding a plethora of cellular functions, in addition to disease detection and therapy. In the current study, a novel approach using cadmium telluride quantum dots (CdTeQDs) as pH sensors, combined with fluorescent imaging, spectrofluorimetry, atomic force microscopy (AFM), and Western blot analysis, enabled the study of intracellular pH dynamics at 1 milli-pH sensitivity and 80nm pixel resolution, during insulin secretion. Additionally, the pH-dependent interaction between membrane fusion proteins, also called the soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE), was determined. Glucose stimulation of CdTeQD-loaded insulin secreting Min-6 mouse insulinoma cell line demonstrated the initial (5-6min) intracellular acidification reflected as a loss in QD fluorescence, followed by alkalization and a return to resting pH in 10min. Analysis of the SNARE complex in insulin secreting Min-6 cells demonstrated an initial gain followed by loss of complexed SNAREs in 10min. Stabilization of the SNARE complex at low intracellular pH is further supported by results from studies utilizing both native and AFM measurements of liposome-reconstituted recombinant neuronal SNAREs, providing a molecular understanding of the role of pH during cell secretion. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Catalytically-relevant electron transfer between two hemes bL in the hybrid cytochrome bc1-like complex containing a fusion of Rhodobacter sphaeroides and capsulatus cytochromes b.

    PubMed

    Czapla, Monika; Cieluch, Ewelina; Borek, Arkadiusz; Sarewicz, Marcin; Osyczka, Artur

    2013-06-01

    To address mechanistic questions about the functioning of dimeric cytochrome bc1 new genetic approaches have recently been developed. They were specifically designed to enable construction of asymmetrically-mutated variants suitable for functional studies. One approach exploited a fusion of two cytochromes b that replaced the separate subunits in the dimer. The fusion protein, built from two copies of the same cytochrome b of purple bacterium Rhodobacter capsulatus, served as a template to create a series of asymmetrically-mutated cytochrome bc1-like complexes (B-B) which, through kinetic studies, disclosed several important principles of dimer engineering. Here, we report on construction of another fusion protein complex that adds a new tool to investigate dimeric function of the enzyme through the asymmetrically mutated forms of the protein. This complex (BS-B) contains a hybrid protein that combines two different cytochromes b: one coming from R. capsulatus and the other - from a closely related species, R. sphaeroides. With this new fusion we addressed a still controversial issue of electron transfer between the two hemes bL in the core of dimer. Kinetic data obtained with a series of BS-B variants provided new evidence confirming the previously reported observations that electron transfer between those two hemes occurs on a millisecond timescale, thus is a catalytically-relevant event. Both types of the fusion complexes (B-B and BS-B) consistently implicate that the heme-bL-bL bridge forms an electronic connection available for inter-monomer electron transfer in cytochrome bc1. Copyright © 2013 Elsevier B.V. All rights reserved.

  1. Role of Mediator and Effects of Temperature on ortho-C-N Bond Fusion Reactions of Aniline Using Ruthenium Templates: Isolation and Characterization of New Ruthenium Complexes of the in-Situ-Generated Ligands.

    PubMed

    Roy, Suman K; Sengupta, Debabrata; Rath, Santi Prasad; Saha, Tanushri; Samanta, Subhas; Goswami, Sreebrata

    2017-05-01

    In this work, ortho-C-N bond fusion reactions of aniline are followed by the use of two different ruthenium mediators. Reaction of aniline with [Ru(III)(terpy)Cl3] (terpy = 2,2':6',2″-terpyridine) resulted in a trans bis-aniline ruthenium(II) complex [1](+) which upon oxidation with H2O2 produced compound [2](+) of a bidentate ligand, N-phenyl-1,2-benzoquinonediimine, due to an oxidative ortho-C-N bond fusion reaction. Complex [1](+) and aniline (neat) at 185 °C produced a bis-chelated ruthenium complex (3). A previously reported complex [Ru(II)(N-phenyl-1,2-benzoquinonediimine)(aniline)2(Cl)2] (5) undergoes similar oxidation by air at 185 °C to produce complex [3]. A separate chemical reaction between aniline and strongly oxidizing tetra-n-propylammonium perruthenate [(n-pr)4N](+)[RuO4](-) in air produced a ruthenium complex [4] of a N(4)-tetraamidophenylmacrocycle ligand via multiple ortho-C-N bond fusion reaction. Notably, the yield of this product is low (5%) at 100 °C but increases to 25% in refluxing aniline. All these complexes are characterized fully by their physicochemical characterizations and X-ray structure determination. From their structural parameters and other spectroscopic studies, complex [2](+) is assigned as [Ru(II)(terpy)(N-phenyl-1,2-benzoquinonediimine)(Cl)](+) whereas complex [4] is described as a ruthenium(VI) complex comprised of a reduced deprotonated N-phenyl-1,2-diamidobenzene and N(4)-tetraamidophenylmacrocyclic ligand. Complex [2](+) exhibits one reversible oxidation at 1.32 V and one reversible reduction at -0.75 V vs Ag/AgCl reference electrode. EPR of the electrogenerated complexes has revealed that the oxidized complex is a ruthenium(III) complex with an axial EPR spectrum at gav= 2.06. The reduced complex [2], on the other hand, shows a single-line EPR signal at gav= 1.998. In contrast, complex [4] shows two successive one-electron oxidation waves at 0.5 and 0.8 V and an irreversible reduction wave at -0.9 V. EPR studies of

  2. The Diversity of Cortical Inhibitory Synapses

    PubMed Central

    Kubota, Yoshiyuki; Karube, Fuyuki; Nomura, Masaki; Kawaguchi, Yasuo

    2016-01-01

    The most typical and well known inhibitory action in the cortical microcircuit is a strong inhibition on the target neuron by axo-somatic synapses. However, it has become clear that synaptic inhibition in the cortex is much more diverse and complicated. Firstly, at least ten or more inhibitory non-pyramidal cell subtypes engage in diverse inhibitory functions to produce the elaborate activity characteristic of the different cortical states. Each distinct non-pyramidal cell subtype has its own independent inhibitory function. Secondly, the inhibitory synapses innervate different neuronal domains, such as axons, spines, dendrites and soma, and their inhibitory postsynaptic potential (IPSP) size is not uniform. Thus, cortical inhibition is highly complex, with a wide variety of anatomical and physiological modes. Moreover, the functional significance of the various inhibitory synapse innervation styles and their unique structural dynamic behaviors differ from those of excitatory synapses. In this review, we summarize our current understanding of the inhibitory mechanisms of the cortical microcircuit. PMID:27199670

  3. Fusion Power.

    ERIC Educational Resources Information Center

    Dingee, David A.

    1979-01-01

    Discusses the extraordinary potential, the technical difficulties, and the financial problems that are associated with research and development of fusion power plants as a major source of energy. (GA)

  4. Fusion Power.

    ERIC Educational Resources Information Center

    Dingee, David A.

    1979-01-01

    Discusses the extraordinary potential, the technical difficulties, and the financial problems that are associated with research and development of fusion power plants as a major source of energy. (GA)

  5. Leukemia inhibitory factor (LIF).

    PubMed

    Nicola, Nicos A; Babon, Jeffrey J

    2015-10-01

    Leukemia inhibitory factor (LIF) is the most pleiotropic member of the interleukin-6 family of cytokines. It utilises a receptor that consists of the LIF receptor β and gp130 and this receptor complex is also used by ciliary neurotrophic growth factor (CNTF), oncostatin M, cardiotrophin1 (CT1) and cardiotrophin-like cytokine (CLC). Despite common signal transduction mechanisms (JAK/STAT, MAPK and PI3K) LIF can have paradoxically opposite effects in different cell types including stimulating or inhibiting each of cell proliferation, differentiation and survival. While LIF can act on a wide range of cell types, LIF knockout mice have revealed that many of these actions are not apparent during ordinary development and that they may be the result of induced LIF expression during tissue damage or injury. Nevertheless LIF does appear to have non-redundant actions in maternal receptivity to blastocyst implantation, placental formation and in the development of the nervous system. LIF has also found practical use in the maintenance of self-renewal and totipotency of embryonic stem cells and induced pluripotent stem cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Leukemia Inhibitory Factor (LIF)

    PubMed Central

    Nicola, Nicos A; Babon, Jeffrey J

    2015-01-01

    Leukemia inhibitory factor (LIF) is the most pleiotropic member of the interleukin-6 family of cytokines. It utilises a receptor that consists of the LIF receptor β and gp130 and this receptor complex is also used by ciliary neurotrophic growth factor (CNTF), oncostatin M, cardiotrophin1 (CT1) and cardiotrophin-like cytokine (CLC). Despite common signal transduction mechanisms (JAK/STAT, MAPK and PI3K) LIF can have paradoxically opposite effects in different cell types including stimulating or inhibiting each of cell proliferation, differentiation and survival. While LIF can act on a wide range of cell types, LIF knockout mice have revealed that many of these actions are not apparent during ordinary development and that they may be the result of induced LIF expression during tissue damage or injury. Nevertheless LIF does appear to have non-redundant actions in maternal receptivity to blastocyst implantation, placental formation and in the development of the nervous system. LIF has also found practical use in the maintenance of self-renewal and totipotency of embryonic stem cells and induced pluripotent stem cells. PMID:26187859

  7. The Vps13p–Cdc31p complex is directly required for TGN late endosome transport and TGN homotypic fusion

    PubMed Central

    De, Mithu; Oleskie, Austin N.; Ayyash, Mariam; Dutta, Somnath; Mancour, Liliya; Brace, Eddy J.; Skiniotis, Georgios

    2017-01-01

    Yeast VPS13 is the founding member of a eukaryotic gene family of growing interest in cell biology and medicine. Mutations in three of four human VPS13 genes cause autosomal recessive neurodegenerative or neurodevelopmental disease, making yeast Vps13p an important structural and functional model. Using cell-free reconstitution with purified Vps13p, we show that Vps13p is directly required both for transport from the trans-Golgi network (TGN) to the late endosome/prevacuolar compartment (PVC) and for TGN homotypic fusion. Vps13p must be in complex with the small calcium-binding protein Cdc31p to be active. Single-particle electron microscopic analysis of negatively stained Vps13p indicates that this 358-kD protein is folded into a compact rod-shaped density (20 × 4 nm) with a loop structure at one end with a circular opening ∼6 nm in diameter. Vps13p exhibits ATP-stimulated binding to yeast membranes and specific interactions with phosphatidic acid and phosphorylated forms of phosphatidyl inositol at least in part through the binding affinities of conserved N- and C-terminal domains. PMID:28122955

  8. Membrane fusion during poxvirus entry.

    PubMed

    Moss, Bernard

    2016-12-01

    Poxviruses comprise a large family of enveloped DNA viruses that infect vertebrates and invertebrates. Poxviruses, unlike most DNA viruses, replicate in the cytoplasm and encode enzymes and other proteins that enable entry, gene expression, genome replication, virion assembly and resistance to host defenses. Entry of vaccinia virus, the prototype member of the family, can occur at the plasma membrane or following endocytosis. Whereas many viruses encode one or two proteins for attachment and membrane fusion, vaccinia virus encodes four proteins for attachment and eleven more for membrane fusion and core entry. The entry-fusion proteins are conserved in all poxviruses and form a complex, known as the Entry Fusion Complex (EFC), which is embedded in the membrane of the mature virion. An additional membrane that encloses the mature virion and is discarded prior to entry is present on an extracellular form of the virus. The EFC is held together by multiple interactions that depend on nine of the eleven proteins. The entry process can be divided into attachment, hemifusion and core entry. All eleven EFC proteins are required for core entry and at least eight for hemifusion. To mediate fusion the virus particle is activated by low pH, which removes one or more fusion repressors that interact with EFC components. Additional EFC-interacting fusion repressors insert into cell membranes and prevent secondary infection. The absence of detailed structural information, except for two attachment proteins and one EFC protein, is delaying efforts to determine the fusion mechanism.

  9. Doubly end-on azido bridged mixed-valence cobalt trinuclear complex: Spectral study, VTM, inhibitory effect and antimycobacterial activity on human carcinoma and tuberculosis cells

    NASA Astrophysics Data System (ADS)

    Datta, Amitabha; Das, Kuheli; Sen, Chandana; Karan, Nirmal Kumar; Huang, Jui-Hsien; Lin, Chia-Her; Garribba, Eugenio; Sinha, Chittaranjan; Askun, Tulin; Celikboyun, Pinar; Mane, Sandeep B.

    2015-09-01

    Doubly end-on azido-bridged mixed-valence trinuclear cobalt complex, [Co3(L)2(N3)6(CH3OH)2] (1) is afforded by employing a potential monoanionic tetradentate-N2O2 Schiff base precursor (2-[{[2-(dimethylamino)ethyl]imino}methyl]-6-methoxyphenol; HL). Single crystal X-ray structure reveals that in 1, the adjacent CoII and CoIII ions are linked by double end-on azido bridges and thus the full molecule is generated by the site symmetry of a crystallographic twofold rotation axis. Complex 1 is subjected on different spectral analysis such as IR, UV-vis, emission and EPR spectroscopy. On variable temperature magnetic study, we observe that during cooling, the χMT values decrease smoothly until 15 K and then reaches to the value 1.56 cm3 K mol-1 at 2 K. Complex 1 inhibits the cell growth on human lung carcinoma (A549 cells), human colorectal (COLO 205 and HT-29 cells), and human heptacellular (PLC5 cells) carcinoma cells. Complex 1 exhibits anti-mycobacterial activity and considerable efficacy on Mycobacterium tuberculosis H37Rv ATCC 27294 and H37Ra ATCC 25177 strains.

  10. Glioma-associated Oncogene 2 Is Essential for Trophoblastic Fusion by Forming a Transcriptional Complex with Glial Cell Missing-a.

    PubMed

    Tang, Chao; Tang, Lanfang; Wu, Xiaokai; Xiong, Wenyi; Ruan, Hongfeng; Hussain, Musaddique; Wu, Junsong; Zou, Chaochun; Wu, Ximei

    2016-03-11

    Cell-cell fusion of human villous trophoblasts, referred to as a process of syncytialization, acts as a prerequisite for the proper development and functional maintenance of the human placenta. Given the fact that the main components of the Hedgehog signaling pathway are expressed predominantly in the syncytial layer of human placental villi, in this study, we investigated the potential roles and underlying mechanisms of Hedgehog signaling in trophoblastic fusion. Activation of Hedgehog signaling by a variety of approaches robustly induced cell fusion and the expression of syncytial markers, whereas suppression of Hedgehog signaling significantly attenuated cell fusion and the expression of syncytial markers in both human primary cytotrophoblasts and trophoblast-like BeWo cells. Moreover, among glioma-associated oncogene (GLI) family transcriptional factors in Hedgehog signaling, knockdown of GLI2 but not GLI1 and GLI3 significantly attenuated Hedgehog-induced cell fusion, whereas overexpression of the GLI2 activator alone was sufficient to induce cell fusion. Finally, GLI2 not only stabilized glial cell missing-a, a pivotal transcriptional factor for trophoblastic syncytialization, but also formed a transcriptional heterodimer with glial cell missing-a to transactivate syncytin-1, a trophoblastic fusogen, and promote trophoblastic syncytialization. Taken together, this study uncovered a so far uncharacterized role of Hedgehog/GLI2 signaling in trophoblastic fusion, implicating that Hedgehog signaling, through GLI2, could be required for human placental development and pregnancy maintenance.

  11. Glioma-associated Oncogene 2 Is Essential for Trophoblastic Fusion by Forming a Transcriptional Complex with Glial Cell Missing-a*

    PubMed Central

    Tang, Chao; Tang, Lanfang; Wu, Xiaokai; Xiong, Wenyi; Ruan, Hongfeng; Hussain, Musaddique; Wu, Junsong; Zou, Chaochun; Wu, Ximei

    2016-01-01

    Cell-cell fusion of human villous trophoblasts, referred to as a process of syncytialization, acts as a prerequisite for the proper development and functional maintenance of the human placenta. Given the fact that the main components of the Hedgehog signaling pathway are expressed predominantly in the syncytial layer of human placental villi, in this study, we investigated the potential roles and underlying mechanisms of Hedgehog signaling in trophoblastic fusion. Activation of Hedgehog signaling by a variety of approaches robustly induced cell fusion and the expression of syncytial markers, whereas suppression of Hedgehog signaling significantly attenuated cell fusion and the expression of syncytial markers in both human primary cytotrophoblasts and trophoblast-like BeWo cells. Moreover, among glioma-associated oncogene (GLI) family transcriptional factors in Hedgehog signaling, knockdown of GLI2 but not GLI1 and GLI3 significantly attenuated Hedgehog-induced cell fusion, whereas overexpression of the GLI2 activator alone was sufficient to induce cell fusion. Finally, GLI2 not only stabilized glial cell missing-a, a pivotal transcriptional factor for trophoblastic syncytialization, but also formed a transcriptional heterodimer with glial cell missing-a to transactivate syncytin-1, a trophoblastic fusogen, and promote trophoblastic syncytialization. Taken together, this study uncovered a so far uncharacterized role of Hedgehog/GLI2 signaling in trophoblastic fusion, implicating that Hedgehog signaling, through GLI2, could be required for human placental development and pregnancy maintenance. PMID:26769961

  12. Crystal structure of the HIV-1 integrase core domain in complex with sucrose reveals details of an allosteric inhibitory binding site

    SciTech Connect

    Wielens, Jerome; Headey, Stephen J.; Jeevarajah, Dharshini; Rhodes, David I.; Deadman, John; Chalmers, David K.; Scanlon, Martin J.; Parker, Michael W.

    2010-04-19

    HIV integrase (IN) is an essential enzyme in HIV replication and an important target for drug design. IN has been shown to interact with a number of cellular and viral proteins during the integration process. Disruption of these important interactions could provide a mechanism for allosteric inhibition of IN. We present the highest resolution crystal structure of the IN core domain to date. We also present a crystal structure of the IN core domain in complex with sucrose which is bound at the dimer interface in a region that has previously been reported to bind integrase inhibitors.

  13. Laser fusion

    SciTech Connect

    Smit, W.A.; Boskma, P.

    1980-12-01

    Unrestricted laser fusion offers nations an opportunity to circumvent arms control agreements and develop thermonuclear weapons. Early laser weapons research sought a clean radiation-free bomb to replace the fission bomb, but this was deceptive because a fission bomb was needed to trigger the fusion reaction and additional radioactivity was induced by generating fast neutrons. As laser-implosion experiments focused on weapons physics, simulating weapons effects, and applications for new weapons, the military interest shifted from developing a laser-ignited hydrogen bomb to more sophisticated weapons and civilian applications for power generation. Civilian and military research now overlap, making it possible for several countries to continue weapons activities and permitting proliferation of nuclear weapons. These countries are reluctant to include inertial confinement fusion research in the Non-Proliferation Treaty. 16 references. (DCK)

  14. Monofunctional platinum(II) complexes with potent tumor cell growth inhibitory activity: the effect of a hydrogen-bond donor/acceptor N-heterocyclic ligand.

    PubMed

    Margiotta, Nicola; Savino, Salvatore; Gandin, Valentina; Marzano, Christine; Natile, Giovanni

    2014-06-01

    In this paper we investigate the possibility of further increase the role of the N-donor aromatic base in antitumor Hollis-type compounds by conferring the possibility to act as a hydrogen-bond donor/acceptor. Therefore, we synthesized the Pt(II) complex cis-[PtCl(NH3 )2 (naph)]NO3 (1) containing the 1,8-naphthyridine (naph) ligand. The naphthyridine ligand is generally monodentate, and the second nitrogen atom can act as H-bond donor/acceptor depending upon its protonation state. The possibility of forming such an H-bond could be crucial in the interaction of the drug with DNA or proteins. Apart from the synthesis of the compound, in this study we evaluated its in vitro antitumor activity in a wide panel of tumor cell lines, also including cells selected for their sensitivity/resistance to oxaliplatin, which was compared with that of previously reported complex 2 ([PtI(2,9-dimethyl-1,10-phenanthroline)(1-methyl-cytosine)]I) and oxaliplatin and cisplatin as reference compounds. The cytotoxicity data were correlated with the cellular uptake and the DNA platination levels. Finally, the reactivity of 1 towards guanosine 5'-monophosphate (5'-GMP) and glutathione was investigated to provide insights into its mechanism of action.

  15. Structure of the fusion core and inhibition of fusion by a heptad repeat peptide derived from the S protein of Middle East respiratory syndrome coronavirus.

    PubMed

    Gao, Jing; Lu, Guangwen; Qi, Jianxun; Li, Yan; Wu, Ying; Deng, Yao; Geng, Heyuan; Li, Hongbin; Wang, Qihui; Xiao, Haixia; Tan, Wenjie; Yan, Jinghua; Gao, George F

    2013-12-01

    Middle East respiratory syndrome coronavirus (MERS-CoV) recently emerged as a severe worldwide public health concern. The virus is highly pathogenic, manifesting in infected patients with an approximately 50% fatality rate. It is known that the surface spike (S) proteins of coronaviruses mediate receptor recognition and membrane fusion, thereby playing an indispensable role in initiating infection. In this process, heptad repeats 1 and 2 (HR1 and HR2) of the S protein assemble into a complex called the fusion core, which represents a key membrane fusion architecture. To date, however, the MERS-CoV fusion core remains uncharacterized. In this study, we performed a series of biochemical and biophysical analyses characterizing the HR1/HR2 complexes of this novel virus. The HR sequences were variably truncated and then connected with a flexible amino acid linker. In each case, the recombinant protein automatically assembled into a trimer in solution, displaying a typical α-helical structure. One of these trimers was successfully crystallized, and its structure was solved at a resolution of 1.9 Å. A canonical 6-helix bundle, like those reported for other coronaviruses, was revealed, with three HR1 helices forming the central coiled-coil core and three HR2 chains surrounding the core in the HR1 side grooves. This demonstrates that MERS-CoV utilizes a mechanism similar to those of other class I enveloped viruses for membrane fusion. With this notion, we further identified an HR2-based peptide that could potently inhibit MERS-CoV fusion and entry by using a pseudotyped-virus system. These results lay the groundwork for future inhibitory peptidic drug design.

  16. Structure of the Fusion Core and Inhibition of Fusion by a Heptad Repeat Peptide Derived from the S Protein of Middle East Respiratory Syndrome Coronavirus

    PubMed Central

    Gao, Jing; Lu, Guangwen; Qi, Jianxun; Li, Yan; Wu, Ying; Deng, Yao; Geng, Heyuan; Li, Hongbin; Wang, Qihui; Xiao, Haixia; Tan, Wenjie; Yan, Jinghua

    2013-01-01

    Middle East respiratory syndrome coronavirus (MERS-CoV) recently emerged as a severe worldwide public health concern. The virus is highly pathogenic, manifesting in infected patients with an approximately 50% fatality rate. It is known that the surface spike (S) proteins of coronaviruses mediate receptor recognition and membrane fusion, thereby playing an indispensable role in initiating infection. In this process, heptad repeats 1 and 2 (HR1 and HR2) of the S protein assemble into a complex called the fusion core, which represents a key membrane fusion architecture. To date, however, the MERS-CoV fusion core remains uncharacterized. In this study, we performed a series of biochemical and biophysical analyses characterizing the HR1/HR2 complexes of this novel virus. The HR sequences were variably truncated and then connected with a flexible amino acid linker. In each case, the recombinant protein automatically assembled into a trimer in solution, displaying a typical α-helical structure. One of these trimers was successfully crystallized, and its structure was solved at a resolution of 1.9 Å. A canonical 6-helix bundle, like those reported for other coronaviruses, was revealed, with three HR1 helices forming the central coiled-coil core and three HR2 chains surrounding the core in the HR1 side grooves. This demonstrates that MERS-CoV utilizes a mechanism similar to those of other class I enveloped viruses for membrane fusion. With this notion, we further identified an HR2-based peptide that could potently inhibit MERS-CoV fusion and entry by using a pseudotyped-virus system. These results lay the groundwork for future inhibitory peptidic drug design. PMID:24067982

  17. β-cyclodextrin complex containing Lippia grata leaf essential oil reduces orofacial nociception in mice - evidence of possible involvement of descending inhibitory pain modulation pathway.

    PubMed

    Siqueira-Lima, Pollyana S; Araújo, Adriano A S; Lucchese, Angélica M; Quintans, Jullyana S S; Menezes, Paula P; Alves, Péricles B; de Lucca Júnior, Waldecy; Santos, Marcio R V; Bonjardim, Leonardo R; Quintans-Júnior, Lucindo J

    2014-02-01

    The treatment of orofacial pain remains a major challenge for modern medicine. Thus, we prepared and physicochemically characterized a new β-cyclodextrin complex containing Lippia grata leaf essential oil (β-CD/EO) to investigate their possible antinociceptive activity in animal models of orofacial pain. The results of Differential scanning calorimeter (DSC) and Thermogravimetry/derivative thermogravimetry (TG/DTG) showed that the products prepared by Slurry complexation (SC) method were able to incorporate greater amounts of EO. In the X-ray diffractogram, it was shown that complex between EO and β-CD was formed. Male Swiss mice were pre-treated with β-CD/EO (6, 12 or 24 mg/kg, per os, gavage, p.o.), morphine (5 mg/kg, i.p.) or vehicle (distilled water, p.o.) 1 hr before treatment with formalin (20 μL, 2%), capsaicin (20 μL, 2.5 μg) or glutamate (40 μL, 25 μM) into the right upper lip. Our results demonstrated that p.o. treatment with β-CD/EO was significantly (p < 0.05 or p < 0.001) capable of reducing the nociceptive face-rubbing behaviour in both phases of the formalin test. β-CD/EO-treated mice were also significantly (p < 0.05 or p < 0.001) protected against nociception induced by capsaicin and glutamate. For the action in the central nervous system (CNS), ninety minutes after the treatment, the mice were perfused, the brains collected, crioprotected, cut in a criostate and submitted to an immunofluorescence protocol for Fos protein. The immunofluorescence protocol demonstrated that the β-CD/EO significantly activated (p < 0.05; p < 0.01 or p < 0.001) the motor cortex, the Locus ceruleus, the nucleus raphe magnus and the periaqueductal gray of the CNS. These effects apparently did not alter, in tested doses, the motor coordination of mice in the rota-rod test. Our results proposed that β-CD/EO might present an important draft of drug to the study of new compounds for the treatment of orofacial pain.

  18. Synthesis, structural characterization and in vitro inhibitory studies against human breast cancer of the bis-(2,6-di-tert-butylphenol)tin(IV) dichloride and its complexes.

    PubMed

    Shpakovsky, D B; Banti, C N; Beaulieu-Houle, G; Kourkoumelis, N; Manoli, M; Manos, M J; Tasiopoulos, A J; Hadjikakou, S K; Milaeva, E R; Charalabopoulos, K; Bakas, T; Butler, I S; Hadjiliadis, N

    2012-12-28

    Four new organotin(IV) complexes of bis-(2,6-di-tert-butylphenol)tin(IV) dichloride [(tert-Bu-)(2)(HO-Ph)](2)SnCl(2) (1) with the heterocyclic thioamides 2-mercapto-pyrimidine (PMTH), 2-mercapto-4-methyl-pyrimidine (MPMTH), 2-mercapto-pyridine (PYTH) and 2-mercapto-benzothiazole (MBZTH), of formulae {[(tert-Bu-)(2)(HO-Ph)](2)Sn(PMT)(2)} (2), {[(tert-Bu-)(2)(HO-Ph)](2)Sn(MPMT)(2)} (3), {[(tert-Bu-)(2)(HO-Ph)](2)SnCl(PYT)} (4) and {[(tert-Bu-)(2)(HO-Ph)](2)SnCl(MBZT)} (5), have been synthesized and characterized by elemental analysis, (1)H-, (13)C-, (119)Sn-NMR, EPR, FT-IR, Raman and Mössbauer spectroscopic techniques. The crystal and molecular structures of compounds 1–5 have been determined by X-ray diffraction. The geometries around the metal center adopted in complexes 1–5 varied between tetrahedral in 1, trigonal bipyramidal in 3, 4, 5 and distorted octahedral in 2. Two carbon atoms from aryl groups and two chlorine atoms form a distorted tetrahedron in the case of 1. Two carbon, two sulfur and two nitrogen atoms from thione ligands form a distorted octahedral geometry around tin(IV) with trans-C(2), cis-N(2), cis-S(2)-configurations in 2. However, in the case of 4 and 5 complexes two carbon, one sulfur, one nitrogen and one chloride atom form a distorted trigonal bipyramidal arrangement. Finally, in the case of 3 the trigonal bipyramidal geometry is achieved by two carbon, two sulfur and one nitrogen atom in a unique coordination mode of thioamides toward the tin(IV) cation. Compounds 1–5 were tested for their in vitro cytotoxicity against the human breast adenocarcinoma (MCF-7) cell line. Compound 3 exhibits strong cytotoxic activity against MCF-7 cells (IC(50) = 0.58 ± 0.1 μM).

  19. Sequence-Divergent Chordopoxvirus Homologs of the O3 Protein Maintain Functional Interactions with Components of the Vaccinia Virus Entry-Fusion Complex

    PubMed Central

    Satheshkumar, P. S.

    2012-01-01

    Composed of 35 amino acids, O3 is the smallest characterized protein encoded by vaccinia virus (VACV) and is an integral component of the entry-fusion complex (EFC). O3 is conserved with 100% identity in all orthopoxviruses except for monkeypox viruses, whose O3 homologs have 2 to 3 amino acid substitutions. Since O3 is part of the EFC, high conservation could suggest an immutable requirement for interaction with multiple proteins. Chordopoxviruses of other genera also encode small proteins with a characteristic predicted N-terminal α-helical hydrophobic domain followed by basic amino acids and proline in the same relative genome location as that of VACV O3. However, the statistical significance of their similarity to VACV O3 is low due to the large contribution of the transmembrane domain, their small size, and their sequence diversity. Nevertheless, trans-complementation experiments demonstrated the ability of a representative O3-like protein from each chordopoxvirus genus to rescue the infectivity of a VACV mutant that was unable to express endogenous O3. Moreover, recombinant viruses expressing O3 homologs in place of O3 replicated and formed plaques as well or nearly as well as wild-type VACV. The O3 homologs expressed by the recombinant VACVs were incorporated into the membranes of mature virions and, with one exception, remained stably associated with the detergent-extracted and affinity-purified EFC. The ability of the sequence-divergent O3 homologs to coordinate function with VACV entry proteins suggests the conservation of structural motifs. Analysis of chimeras formed by swapping domains of O3 with those of other proteins indicated that the N-terminal transmembrane segment was responsible for EFC interactions and for the complementation of infectivity. PMID:22114343

  20. Inhibitory effect of 1,2,4,5-tetramethoxybenzene on mast cell-mediated allergic inflammation through suppression of IκB kinase complex

    SciTech Connect

    Je, In-Gyu; Choi, Hyun Gyu; Kim, Hui-Hun; Lee, Soyoung; Choi, Jin Kyeong; Kim, Sung-Wan; Kim, Duk-Sil; Kwon, Taeg Kyu; Shin, Tae-Yong; Park, Pil-Hoon; Khang, Dongwoo; Kim, Sang-Hyun

    2015-09-01

    As the importance of allergic disorders such as atopic dermatitis and allergic asthma, research on potential drug candidates becomes more necessary. Mast cells play an important role as initiators of allergic responses through the release of histamine; therefore, they should be the target of pharmaceutical development for the management of allergic inflammation. In our previous study, anti-allergic effect of extracts of Amomum xanthioides was demonstrated. To further investigate improved candidates, 1,2,4,5-tetramethoxybenzene (TMB) was isolated from methanol extracts of A. xanthioides. TMB dose-dependently attenuated the degranulation of mast cells without cytotoxicity by inhibiting calcium influx. TMB decreased the expression of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-4 at both the transcriptional and translational levels. Increased expression of these cytokines was caused by translocation of nuclear factor-κB into the nucleus, and it was hindered by suppressing activation of IκB kinase complex. To confirm the effect of TMB in vivo, the ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) and IgE-mediated passive cutaneous anaphylaxis (PCA) models were used. In the ASA model, hypothermia was decreased by oral administration of TMB, which attenuated serum histamine, OVA-specific IgE, and IL-4 levels. Increased pigmentation of Evans blue was reduced by TMB in a dose-dependent manner in the PCA model. Our results suggest that TMB is a possible therapeutic candidate for allergic inflammatory diseases that acts through the inhibition of mast cell degranulation and expression of pro-inflammatory cytokines. - Highlights: • TMB reduced the degranulation of mast cells. • TMB inhibited the production of pro-inflammatory cytokines. • TMB suppressed both active and passive anaphylaxis. • Anti-allergic inflammatory effects of TMB might be due to the blocking IKK complex. • TMB might be a candidate for the treatment of

  1. Maltose binding protein-fusion enhances the bioactivity of truncated forms of pig myostatin propeptide produced in E. coli

    PubMed Central

    Lee, Sang Beum; Park, Sung Kwon

    2017-01-01

    Myostatin (MSTN) is a potent negative regulator of skeletal muscle growth. MSTN propeptide (MSTNpro) inhibits MSTN binding to its receptor through complex formation with MSTN, implying that MSTNpro can be a useful agent to improve skeletal muscle growth in meat-producing animals. Four different truncated forms of pig MSTNpro containing N-terminal maltose binding protein (MBP) as a fusion partner were expressed in E. coli, and purified by the combination of affinity chromatography and gel filtration. The MSTN-inhibitory capacities of these proteins were examined in an in vitro gene reporter assay. A MBP-fused, truncated MSTNpro containing residues 42–175 (MBP-Pro42-175) exhibited the same MSTN-inhibitory potency as the full sequence MSTNpro. Truncated MSTNpro proteins containing either residues 42–115 (MBP-Pro42-115) or 42–98 (MBP-Pro42-98) also exhibited MSTN-inhibitory capacity even though the potencies were significantly lower than that of full sequence MSTNpro. In pull-down assays, MBP-Pro42-175, MBP-Pro42-115, and MBP-Pro42-98 demonstrated their binding to MSTN. MBP was removed from the truncated MSTNpro proteins by incubation with factor Xa to examine the potential role of MBP on MSTN-inhibitory capacity of those proteins. Removal of MBP from MBP-Pro42-175 and MBP-Pro42-98 resulted in 20-fold decrease in MSTN-inhibitory capacity of Pro42-175 and abolition of MSTN-inhibitory capacity of Pro42-98, indicating that MBP as fusion partner enhanced the MSTN-inhibitory capacity of those truncated MSTNpro proteins. In summary, this study shows that MBP is a very useful fusion partner in enhancing MSTN-inhibitory potency of truncated forms of MSTNpro proteins, and MBP-fused pig MSTNpro consisting of amino acid residues 42–175 is sufficient to maintain the full MSTN-inhibitory capacity. PMID:28369115

  2. Formation in vitro of complexes between an abnormal fusion protein and the heat shock proteins from Escherichia coli and yeast mitochondria.

    PubMed Central

    Sherman, M Y; Goldberg, A L

    1991-01-01

    Heat shock proteins (HSPs) of the Hsp70 and GroEL families associate with a variety of cell proteins in vivo. However, the formation of such complexes has not been systematically studied. A 31-kDa fusion protein (CRAG), which contains 12 residues of cro repressor, truncated protein A, and 14 residues of beta-galactosidase, when expressed in Escherichia coli, was found in complexes with DnaK, GrpE, protease La, and GroEL. When an E. coli extract not containing CRAG was applied to an affinity column containing CRAG, DnaK, GroEL, and GrpE were selectively bound. These HSPs did not bind to a normal protein A column. DnaK, GrpE, and the fraction of GroEL could be eluted from the CRAG column with ATP but not with a nonhydrolyzable ATP analog. The ATP-dependent release of DnaK and GroEL also required Mg2+, but GrpE dissociated with ATP alone. The binding and release of DnaK and GroEL were independent events, but the binding of GrpE required DnaK. Inactivation of DnaJ, GrpE, and GroES did not affect the association or dissociation of DnaK or GroEL from CRAG. The DnaK and GrpE proteins could be eluted with 10(-6) M ATP, but 10(-4) M was required for GroEL release. This approach allows a one-step purification of these proteins from E. coli and also the isolation of the DnaK and GroEL homologs from yeast mitochondria. Competition experiments with oligopeptide fragments of CRAG showed that DnaK and GroEL interact with different sites on CRAG and that the cro-derived domain of CRAG contains the DnaK-binding site. Images FIG. 1 FIG. 2 FIG. 3 FIG. 4 FIG. 5 FIG. 7 FIG. 8 PMID:1938919

  3. Inhibitory function of adapter-related protein complex 2 alpha 1 subunit in the process of nuclear translocation of human immunodeficiency virus type 1 genome

    SciTech Connect

    Kitagawa, Yukiko; Kameoka, Masanori Shoji-Kawata, Sanae; Iwabu, Yukie; Mizuta, Hiroyuki; Tokunaga, Kenzo; Fujino, Masato; Natori, Yukikazu; Yura, Yoshiaki; Ikuta, Kazuyoshi

    2008-03-30

    The transfection of human cells with siRNA against adapter-related protein complex 2 alpha 1 subunit (AP2{alpha}) was revealed to significantly up-regulate the replication of human immunodeficiency virus type 1 (HIV-1). This effect was confirmed by cell infection with vesicular stomatitis virus G protein-pseudotyped HIV-1 as well as CXCR4-tropic and CCR5-tropic HIV-1. Viral adsorption, viral entry and reverse transcription processes were not affected by cell transfection with siRNA against AP2{alpha}. In contrast, viral nuclear translocation as well as the integration process was significantly up-regulated in cells transfected with siRNA against AP2{alpha}. Confocal fluorescence microscopy revealed that a subpopulation of AP2{alpha} was not only localized in the cytoplasm but was also partly co-localized with lamin B, importin {beta} and Nup153, implying that AP2{alpha} negatively regulates HIV-1 replication in the process of nuclear translocation of viral DNA in the cytoplasm or the perinuclear region. We propose that AP2{alpha} may be a novel target for disrupting HIV-1 replication in the early stage of the viral life cycle.

  4. Synergistic inhibitory effect of nicotine plus oral contraceptive on mitochondrial complex-IV is mediated by estrogen receptor-β in female rats.

    PubMed

    Raval, Ami P; Dave, Kunjan R; Saul, Isabel; Gonzalez, Gabriel J; Diaz, Francisca

    2012-04-01

    Chronic nicotine and oral contraceptive (NOC) exposure caused significant loss of hippocampal membrane-bound estrogen receptor-beta (ER-β) in female rats compared with exposure to nicotine alone. Mitochondrial ER-β regulates estrogen-mediated mitochondrial structure and function; therefore, investigating the impact of NOC on mitochondrial ER-β and its function could help delineate the harmful synergism between nicotine and OC. In this study, we tested the hypothesis that NOC-induced loss of mitochondrial ER-β alters the oxidative phosphorylation system protein levels and mitochondrial respiratory function. This hypothesis was tested in hippocampal mitochondria isolated from female rats exposed to saline, nicotine, OC or NOC for 16 days. NOC decreased the mitochondrial ER-β protein levels and reduced oxygen consumption and complex IV (CIV) activity by 34% and 26% compared with saline- or nicotine-administered groups, respectively. We also observed significantly low protein levels of all mitochondrial-encoded CIV subunits after NOC as compared with the nicotine or saline groups. Similarly, the silencing of ER-β reduced the phosphorylation of cyclic-AMP response element binding protein, and also reduced levels of CIV mitochondrial-encoded subunits after estrogen stimulation. Overall, these results suggest that mitochondrial ER-β loss is responsible for mitochondrial malfunction after NOC.

  5. Inhibitory Effect of Endomorphin-2 Binding to the μ-Opioid Receptor in the Rat Pre-Bötzinger Complex on the Breathing Activity.

    PubMed

    Qi, Jian; Li, Hui; Zhao, Ting-Bao; Lu, Ya-Cheng; Zhang, Ting; Li, Jin-Lian; Dong, Yu-Lin; Li, Yun-Qing

    2017-01-01

    Opiates are commonly used analgesics that often cause clinical respiratory depression. However, their underlying mechanisms remain unclear. Endomorphin-2 (EM2) is a novel, endogenous tetrapeptide opioid with very high affinity and selectivity for the μ-opioid receptor (MOR). The pre-Bötzinger complex (pre-BötC) is considered the center of respiratory rhythm generation, and the synaptic connections in this region are essential for respiratory rhythm. The present study identified EM2-like immunoreactive (LI) axonal terminals in the pre-BötC of adult rats. Some EM2-LI axonal terminals made principally symmetric synapses with neurokinin 1 receptor (NK1R)-LI or MOR-LI neuronal dendritic processes in the pre-BötC. Unilateral microinjection of EM2 into the pre-BötC decreased breathing frequency and amplitude. A prior microinjection of the selective MOR antagonist β-funaltrexamine (β-FNA) into the pre-BötC prevented the effects of EM2. The present results suggest that EM2-LI axonal terminals modulate NK1R-expressing neurons in the pre-BötC and that EM2 plays a role in respiratory depression through MORs in the pre-BötC.

  6. Inhibitory effect of 1,2,4,5-tetramethoxybenzene on mast cell-mediated allergic inflammation through suppression of IκB kinase complex.

    PubMed

    Je, In-Gyu; Choi, Hyun Gyu; Kim, Hui-Hun; Lee, Soyoung; Choi, Jin Kyeong; Kim, Sung-Wan; Kim, Duk-Sil; Kwon, Taeg Kyu; Shin, Tae-Yong; Park, Pil-Hoon; Khang, Dongwoo; Kim, Sang-Hyun

    2015-09-01

    As the importance of allergic disorders such as atopic dermatitis and allergic asthma, research on potential drug candidates becomes more necessary. Mast cells play an important role as initiators of allergic responses through the release of histamine; therefore, they should be the target of pharmaceutical development for the management of allergic inflammation. In our previous study, anti-allergic effect of extracts of Amomum xanthioides was demonstrated. To further investigate improved candidates, 1,2,4,5-tetramethoxybenzene (TMB) was isolated from methanol extracts of A. xanthioides. TMB dose-dependently attenuated the degranulation of mast cells without cytotoxicity by inhibiting calcium influx. TMB decreased the expression of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-4 at both the transcriptional and translational levels. Increased expression of these cytokines was caused by translocation of nuclear factor-κB into the nucleus, and it was hindered by suppressing activation of IκB kinase complex. To confirm the effect of TMB in vivo, the ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) and IgE-mediated passive cutaneous anaphylaxis (PCA) models were used. In the ASA model, hypothermia was decreased by oral administration of TMB, which attenuated serum histamine, OVA-specific IgE, and IL-4 levels. Increased pigmentation of Evans blue was reduced by TMB in a dose-dependent manner in the PCA model. Our results suggest that TMB is a possible therapeutic candidate for allergic inflammatory diseases that acts through the inhibition of mast cell degranulation and expression of pro-inflammatory cytokines.

  7. Rabies Virus-Induced Membrane Fusion Pathway

    PubMed Central

    Gaudin, Yves

    2000-01-01

    Fusion of rabies virus with membranes is triggered at low pH and is mediated by the viral glycoprotein (G). The rabies virus-induced fusion pathway was studied by investigating the effects of exogenous lipids having various dynamic molecular shapes on the fusion process. Inverted cone-shaped lysophosphatidylcholines (LPCs) blocked fusion at a stage subsequent to fusion peptide insertion into the target membrane. Consistent with the stalk-hypothesis, LPC with shorter alkyl chains inhibited fusion at lower membrane concentrations and this inhibition was compensated by the presence of oleic acid. However, under suboptimal fusion conditions, short chain LPCs, which were translocated in the inner leaflet of the membranes, considerably reduced the lag time preceding membrane merging, resulting in faster kinetics of fusion. This indicated that the rate limiting step for fusion is the formation of a fusion pore in a diaphragm of restricted hemifusion. The previously described cold-stabilized prefusion complex was also characterized. This intermediate is at a well-advanced stage of the fusion process when the hemifusion diaphragm is destabilized, but lipid mixing is still restricted, probably by a ring-like complex of glycoproteins. I provide evidence that this state has a dynamic character and that its lipid organization can reverse back to two lipid bilayers. PMID:10931871

  8. Organotypic three-dimensional culture model of mesenchymal and epithelial cells to examine tissue fusion events.

    EPA Science Inventory

    Tissue fusion during early mammalian development requires coordination of multiple cell types, the extracellular matrix, and complex signaling pathways. Fusion events during processes including heart development, neural tube closure, and palatal fusion are dependent on signaling ...

  9. Organotypic three-dimensional culture model of mesenchymal and epithelial cells to examine tissue fusion events.

    EPA Science Inventory

    Tissue fusion during early mammalian development requires coordination of multiple cell types, the extracellular matrix, and complex signaling pathways. Fusion events during processes including heart development, neural tube closure, and palatal fusion are dependent on signaling ...

  10. An inhibitory corticostriatal pathway

    PubMed Central

    Rock, Crystal; Zurita, Hector; Wilson, Charles; Apicella, Alfonso junior

    2016-01-01

    Anatomical and physiological studies have led to the assumption that the dorsal striatum receives exclusively excitatory afferents from the cortex. Here we test the hypothesis that the dorsal striatum receives also GABAergic projections from the cortex. We addressed this fundamental question by taking advantage of optogenetics and directly examining the functional effects of cortical GABAergic inputs to spiny projection neurons (SPNs) of the mouse auditory and motor cortex. We found that the cortex, via corticostriatal somatostatin neurons (CS-SOM), has a direct inhibitory influence on the output of the striatum SPNs. Our results describe a corticostriatal long-range inhibitory circuit (CS-SOM inhibitory projections → striatal SPNs) underlying the control of spike timing/generation in SPNs and attributes a specific function to a genetically defined type of cortical interneuron in corticostriatal communication. DOI: http://dx.doi.org/10.7554/eLife.15890.001 PMID:27159237

  11. Complexes With Biologically Active Ligands. Part 111. Synthesis and Carbonic Anhydrase Inhibitory Activity of Metal Complexes of 4,5-Disubstituted-3-Mercapto-1,2,4-Triazole Derivatives

    PubMed Central

    Scozzafava, Andrea; Cavazza, Christine; Saramet, Ioana; Briganti, Fabrizio; Banciu, Mircea D.

    1998-01-01

    Complexes containing five 4,5-disubstituted-3-mercapto-1,2,4-triazoles and Zn(II), Hg(II) and Cu(I) were synthesized and characterized by standard procedures (elemental analysis; IR, electronic and NMR spectroscopy, conductimetry and TG analysis). Both the thione as well as the thiolate forms of the ligands were evidenced to interact with the metal ions in the prepared complexes. The original mercaptans and their metal complexes behave as inhibitors of three carbonic anhydrase (CA) isozymes, CA I, II and IV, but did not lower intraocular pressure in rabbits in animal models of glaucoma. PMID:18475819

  12. Cold fusion, Alchemist's dream

    SciTech Connect

    Clayton, E.D.

    1989-09-01

    In this report the following topics relating to cold fusion are discussed: muon catalysed cold fusion; piezonuclear fusion; sundry explanations pertaining to cold fusion; cosmic ray muon catalysed cold fusion; vibrational mechanisms in excited states of D{sub 2} molecules; barrier penetration probabilities within the hydrogenated metal lattice/piezonuclear fusion; branching ratios of D{sub 2} fusion at low energies; fusion of deuterons into {sup 4}He; secondary D+T fusion within the hydrogenated metal lattice; {sup 3}He to {sup 4}He ratio within the metal lattice; shock induced fusion; and anomalously high isotopic ratios of {sup 3}He/{sup 4}He.

  13. Data fusion in entangled networks of quantum sensors

    NASA Astrophysics Data System (ADS)

    Lanzagorta, Marco; Jitrik, Oliverio; Uhlmann, Jeffrey; Venegas-Andraca, Salvador E.

    2017-05-01

    In this paper we discuss two potential areas of intersection between Quantum Information Technologies and Information Fusion. The first area we call Quantum (Data Fusion) and refers to the use of quantum computers to perform data fusion algorithms with classical data generated by quantum and classical sensors. As we discuss, we expect that these quantum fusion algorithms will have a better computational complexity than traditional fusion algorithms. This means that quantum computers could allow the efficient fusion of large data sets for complex multi-target tracking. On the other hand, (Quantum Data) Fusion refers to the fusion of quantum data that is being generated by quantum sensors. The output of the quantum sensors is considered in the form of qubits, and a quantum computer performs data fusion algorithms. Our theoretical models suggest that we expect that these algorithms can increase the sensitivity of the quantum sensor network.

  14. A lycopene β-cyclase/lycopene ε-cyclase/light-harvesting complex-fusion protein from the green alga Ostreococcus lucimarinus can be modified to produce α-carotene and β-carotene at different ratios.

    PubMed

    Blatt, Andreas; Bauch, Matthias E; Pörschke, Yvonne; Lohr, Martin

    2015-05-01

    Biosynthesis of asymmetric carotenoids such as α-carotene and lutein in plants and green algae involves the two enzymes lycopene β-cyclase (LCYB) and lycopene ε-cyclase (LCYE). The two cyclases are closely related and probably resulted from an ancient gene duplication. While in most plants investigated so far the two cyclases are encoded by separate genes, prasinophyte algae of the order Mamiellales contain a single gene encoding a fusion protein comprised of LCYB, LCYE and a C-terminal light-harvesting complex (LHC) domain. Here we show that the lycopene cyclase fusion protein from Ostreococcus lucimarinus catalyzed the simultaneous formation of α-carotene and β-carotene when heterologously expressed in Escherichia coli. The stoichiometry of the two products in E. coli could be altered by gradual truncation of the C-terminus, suggesting that the LHC domain may be involved in modulating the relative activities of the two cyclase domains in the algae. Partial deletions of the linker region between the cyclase domains or replacement of one or both cyclase domains with the corresponding cyclases from the green alga Chlamydomonas reinhardtii resulted in pronounced shifts of the α-carotene-to-β-carotene ratio, indicating that both the relative activities of the cyclase domains and the overall structure of the fusion protein have a strong impact on the product stoichiometry. The possibility to tune the product ratio of the lycopene cyclase fusion protein from Mamiellales renders it useful for the biotechnological production of the asymmetric carotenoids α-carotene or lutein in bacteria or fungi. © 2015 The Authors The Plant Journal © 2015 John Wiley & Sons Ltd.

  15. The Fusion Energy Option

    NASA Astrophysics Data System (ADS)

    Dean, Stephen O.

    2004-06-01

    Presentations from a Fusion Power Associates symposium, The Fusion Energy Option, are summarized. The topics include perspectives on fossil fuel reserves, fusion as a source for hydrogen production, status and plans for the development of inertial fusion, planning for the construction of the International Thermonuclear Experimental Reactor, status and promise of alternate approaches to fusion and the need for R&D now on fusion technologies.

  16. Complexity.

    PubMed

    Gómez-Hernández, J Jaime

    2006-01-01

    It is difficult to define complexity in modeling. Complexity is often associated with uncertainty since modeling uncertainty is an intrinsically difficult task. However, modeling uncertainty does not require, necessarily, complex models, in the sense of a model requiring an unmanageable number of degrees of freedom to characterize the aquifer. The relationship between complexity, uncertainty, heterogeneity, and stochastic modeling is not simple. Aquifer models should be able to quantify the uncertainty of their predictions, which can be done using stochastic models that produce heterogeneous realizations of aquifer parameters. This is the type of complexity addressed in this article.

  17. Carbon Nanotubes Mediate Fusion of Lipid Vesicles.

    PubMed

    Bhaskara, Ramachandra M; Linker, Stephanie M; Vögele, Martin; Köfinger, Jürgen; Hummer, Gerhard

    2017-02-28

    The fusion of lipid membranes is opposed by high energetic barriers. In living organisms, complex protein machineries carry out this biologically essential process. Here we show that membrane-spanning carbon nanotubes (CNTs) can trigger spontaneous fusion of small lipid vesicles. In coarse-grained molecular dynamics simulations, we find that a CNT bridging between two vesicles locally perturbs their lipid structure. Their outer leaflets merge as the CNT pulls lipids out of the membranes, creating an hourglass-shaped fusion intermediate with still intact inner leaflets. As the CNT moves away from the symmetry axis connecting the vesicle centers, the inner leaflets merge, forming a pore that completes fusion. The distinct mechanism of CNT-mediated membrane fusion may be transferable, providing guidance in the development of fusion agents, e.g., for the targeted delivery of drugs or nucleic acids.

  18. Revitalizing Fusion via Fission Fusion

    NASA Astrophysics Data System (ADS)

    Manheimer, Wallace

    2001-10-01

    Existing tokamaks could generate significant nuclear fuel. TFTR, operating steady state with DT might generate enough fuel for a 300 MW nuclear reactor. The immediate goals of the magnetic fusion program would necessarily shift from a study of advanced plasma regimes in larger sized devices, to mostly known plasmas regimes, but at steady state or high duty cycle operation in DT plasmas. The science and engineering of breeding blankets would be equally important. Follow on projects could possibly produce nuclear fuel in large quantity at low price. Although today there is strong opposition to nuclear power in the United States, in a 21st century world of 10 billion people, all of whom will demand a middle class life style, nuclear energy will be important. Concern over greenhouse gases will also drive the world toward nuclear power. There are studies indicating that the world will need 10 TW of carbon free energy by 2050. It is difficult to see how this can be achieved without the breeding of nuclear fuel. By using the thorium cycle, proliferation risks are minimized. [1], [2]. 1 W. Manheimer, Fusion Technology, 36, 1, 1999, 2.W. Manheimer, Physics and Society, v 29, #3, p5, July, 2000

  19. Fusion energy

    NASA Astrophysics Data System (ADS)

    1990-09-01

    The main purpose of the International Thermonuclear Experimental Reactor (ITER) is to develop an experimental fusion reactor through the united efforts of many technologically advanced countries. The ITER terms of reference, issued jointly by the European Community, Japan, the USSR, and the United States, call for an integrated international design activity and constitute the basis of current activities. Joint work on ITER is carried out under the auspices of the International Atomic Energy Agency (IAEA), according to the terms of quadripartite agreement reached between the European Community, Japan, the USSR, and the United States. The site for joint technical work sessions is at the Max Planck Institute of Plasma Physics. Garching, Federal Republic of Germany. The ITER activities have two phases: a definition phase performed in 1988 and the present design phase (1989 to 1990). During the definition phase, a set of ITER technical characteristics and supporting research and development (R and D) activities were developed and reported. The present conceptual design phase of ITER lasts until the end of 1990. The objectives of this phase are to develop the design of ITER, perform a safety and environmental analysis, develop site requirements, define future R and D needs, and estimate cost, manpower, and schedule for construction and operation. A final report will be submitted at the end of 1990. This paper summarizes progress in the ITER program during the 1989 design phase.

  20. Fusion energy

    SciTech Connect

    Not Available

    1990-09-01

    The main purpose of the International Thermonuclear Experimental Reactor (ITER) is to develop an experimental fusion reactor through the united efforts of many technologically advanced countries. The ITER terms of reference, issued jointly by the European Community, Japan, the USSR, and the United States, call for an integrated international design activity and constitute the basis of current activities. Joint work on ITER is carried out under the auspices of the International Atomic Energy Agency (IAEA), according to the terms of quadripartite agreement reached between the European Community, Japan, the USSR, and the United States. The site for joint technical work sessions is at the MaxPlanck Institute of Plasma Physics. Garching, Federal Republic of Germany. The ITER activities have two phases: a definition phase performed in 1988 and the present design phase (1989--1990). During the definition phase, a set of ITER technical characteristics and supporting research and development (R D) activities were developed and reported. The present conceptual design phase of ITER lasts until the end of 1990. The objectives of this phase are to develop the design of ITER, perform a safety and environmental analysis, develop site requirements, define future R D needs, and estimate cost, manpower, and schedule for construction and operation. A final report will be submitted at the end of 1990. This paper summarizes progress in the ITER program during the 1989 design phase.

  1. Inhibition of HIV-1 by fusion inhibitors.

    PubMed

    Eggink, Dirk; Berkhout, Ben; Sanders, Rogier W

    2010-01-01

    The envelope glycoprotein complex (Env) is responsible for entry of the human immunodeficiency virus type 1 (HIV-1) into cells by mediating attachment to target cells and subsequent membrane fusion. Env consists of three gp120 subunits that mediate receptor and co-receptor attachment and three gp41 subunits responsible for membrane fusion. Several steps of the entry process can serve as drug targets. Receptor antagonists prevent attachment of gp120 to the receptor or co-receptor and conformational changes within gp41 required for membrane fusion can be inhibited by fusion inhibitors. Enfuvirtide (T20, Fuzeon) is a peptide based on the gp41 sequence and is the only approved fusion inhibitor. It prevents membrane fusion by competitively binding to gp41 and blocking the formation of the post-fusion structure. New generations of T20-like peptides have been developed with improved potency and stability. Besides T20 and derivatives, other fusion inhibitors have been developed that target different domains of gp41. Here we discuss the development of fusion inhibitors, their mode of action and their potential for incorporation in future drug regimens.

  2. 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

  3. Resolving Extreme Rainfall from Space: A New Class of Algorithms for Precipitation Retrieval and Data Fusion/Assimilation with Emphasis on Extremes over Complex Terrain and Coastal Areas

    NASA Astrophysics Data System (ADS)

    Foufoula-Georgiou, E.; Ebtehaj, A.

    2015-12-01

    The increasing availability of precipitation observations from the Global Precipitation Measuring (GPM) Mission, has fueled renewed interest in developing frameworks for accurate estimation of precipitation extremes especially over ungauged mountainous terrains and coastal regions to improve hydro-geological hazard prediction and control. Our recent research has shown that treating precipitation retrieval and data fusion/assimilation as inverse problems and using a regularized variational approach with the regularization term(s) selected to impose desired smoothness in the solution, leads to improved representation of extremes. Here we present some new theoretical and computational developments which extend the ideas to a model-agnostic framework of retrieval via a regularized search within properly constructed data bases. We test the framework in several tropical storms over the Ganges-Brahmaputra delta region and over the Himalayas and compare the results with the standard retrieval algorithms currently used for operational purposes.

  4. Receptor signaling lymphocyte-activation molecule family 1 (Slamf1) regulates membrane fusion and NADPH oxidase 2 (NOX2) activity by recruiting a Beclin-1/Vps34/ultraviolet radiation resistance-associated gene (UVRAG) complex.

    PubMed

    Ma, Chunyan; Wang, Ninghai; Detre, Cynthia; Wang, Guoxing; O'Keeffe, Michael; Terhorst, Cox

    2012-05-25

    Phagocytosis is a pivotal process by which macrophages eliminate microorganisms upon recognition by pathogen sensors. Surprisingly, the self-ligand cell surface receptor Slamf1 functions not only as a co-stimulatory molecule but also as a microbial sensor of several Gram-negative bacteria. Upon entering the phagosome of macrophages Slamf1 induces production of phosphatidylinositol 3-phosphate, which positively regulates the activity of the NOX2 enzyme and phagolysosomal maturation. Here, we report that in Escherichia coli-containing phagosomes of mouse macrophages, Slamf1 interacts with the class III PI3K Vps34 in a complex with Beclin-1 and UVRAG. Upon phagocytosis of bacteria the NOX2 activity was reduced in macrophages isolated from Beclin-1(+/-) mice compared with wild-type mice. This Slamf1/Beclin-1/Vps34/UVRAG protein complex is formed in intracellular membrane compartments as it is found without inducing phagocytosis in macrophages, human chronic lymphocytic leukemia cells, and transfectant HEK293 cells. Elimination of its cytoplasmic tail abolished the interaction of Slamf1 with the complex, but deletion or mutation of the two ITAM motifs did not. Both the BD and CCD domains of Beclin-1 were required for efficient binding to Slamf1. Because Slamf1 did not interact with Atg14L or Rubicon, which can also form a complex with Vps34 and Beclin-1, we conclude that Slamf1 recruits a subset of Vps34-associated proteins, which is involved in membrane fusion and NOX2 regulation.

  5. Constraining a complex biogeochemical model for CO2 and N2O emission simulations from various land uses by model-data fusion

    NASA Astrophysics Data System (ADS)

    Houska, Tobias; Kraus, David; Kiese, Ralf; Breuer, Lutz

    2017-07-01

    This study presents the results of a combined measurement and modelling strategy to analyse N2O and CO2 emissions from adjacent arable land, forest and grassland sites in Hesse, Germany. The measured emissions reveal seasonal patterns and management effects, including fertilizer application, tillage, harvest and grazing. The measured annual N2O fluxes are 4.5, 0.4 and 0.1 kg N ha-1 a-1, and the CO2 fluxes are 20.0, 12.2 and 3.0 t C ha-1 a-1 for the arable land, grassland and forest sites, respectively. An innovative model-data fusion concept based on a multicriteria evaluation (soil moisture at different depths, yield, CO2 and N2O emissions) is used to rigorously test the LandscapeDNDC biogeochemical model. The model is run in a Latin-hypercube-based uncertainty analysis framework to constrain model parameter uncertainty and derive behavioural model runs. The results indicate that the model is generally capable of predicting trace gas emissions, as evaluated with RMSE as the objective function. The model shows a reasonable performance in simulating the ecosystem C and N balances. The model-data fusion concept helps to detect remaining model errors, such as missing (e.g. freeze-thaw cycling) or incomplete model processes (e.g. respiration rates after harvest). This concept further elucidates the identification of missing model input sources (e.g. the uptake of N through shallow groundwater on grassland during the vegetation period) and uncertainty in the measured validation data (e.g. forest N2O emissions in winter months). Guidance is provided to improve the model structure and field measurements to further advance landscape-scale model predictions.

  6. Inhibitory effects of antimicrobial agents against Fusarium species.

    PubMed

    Kawakami, Hideaki; Inuzuka, Hiroko; Hori, Nobuhide; Takahashi, Nobumichi; Ishida, Kyoko; Mochizuki, Kiyofumi; Ohkusu, Kiyofumi; Muraosa, Yasunori; Watanabe, Akira; Kamei, Katsuhiko

    2015-08-01

    We investigated the inhibitory effects of antibacterial, biocidal, and antifungal agents against Fusarium spp. Seven Fusarium spp: four F. falciforme (Fusarium solani species complex), one Fusarium spp, one Fusarium spp. (Fusarium incarnatum-equiseti species complex), and one F. napiforme (Gibberella fujikuroi species complex), isolated from eyes with fungal keratitis were used in this study. Their susceptibility to antibacterial agents: flomoxef, imipenem, gatifloxacin, levofloxacin, moxifloxacin, gentamicin, tobramycin, and Tobracin® (contained 3,000 μg/ml of tobramycin and 25 μg/ml of benzalkonium chloride (BAK), a biocidal agent: BAK, and antifungal agents: amphotericin B, pimaricin (natamycin), fluconazole, itraconazole, miconazole, voriconazole, and micafungin, was determined by broth microdilution tests. The half-maximal inhibitory concentration (IC50), 100% inhibitory concentration (IC100), and minimum inhibitory concentration (MIC) against the Fusarium isolates were determined. BAK had the highest activity against the Fusarium spp. except for the antifungal agents. Three fluoroquinolones and two aminoglycosides had inhibitory effects against the Fusarium spp. at relatively high concentrations. Tobracin® had a higher inhibitory effect against Fusarium spp. than tobramycin alone. Amphotericin B had the highest inhibitory effect against the Fusarium spp, although it had different degrees of activity against each isolate. Our findings showed that fluoroquinolones, aminoglycosides, and BAK had some degree of inhibitory effect against the seven Fusarium isolates, although these agents had considerably lower effect than amphotericin B. However, the inhibitory effects of amphotericin B against the Fusarium spp. varied for the different isolates. Further studies for more effective medications against Fusarium, such as different combinations of antibacterial, biocidal, and antifungal agents are needed.

  7. Measles virus transmembrane fusion protein synthesized de novo or presented in immunostimulating complexes is endogenously processed for HLA class I- and class II-restricted cytotoxic T cell recognition

    PubMed Central

    1992-01-01

    The routes used by antigen-presenting cells (APC) to convert the transmembrane fusion glycoprotein (F) of measles virus (MV) to HLA class I and class II presentable peptides have been examined, using cloned cytotoxic T lymphocytes in functional assays. Presentation by Epstein-Barr virus-transformed B lymphoblastoid cell lines was achieved using live virus, ultraviolet light-inactivated virus, and purified MV- F delivered either as such or incorporated in immunostimulating complexes (MV-F-ISCOM). Only live virus and MV-F-ISCOM allow presentation by class I molecules, while all antigen preparations permit class II-restricted presentation. We observe presentation of MV- F from live virus and as MV-F-ISCOM by class II molecules in a fashion that is not perturbed by chloroquine. Our studies visualize novel presentation pathways of type I transmembrane proteins. PMID:1613454

  8. Review of fusion synfuels

    SciTech Connect

    Fillo, J.A.

    1980-01-01

    Thermonuclear fusion offers an inexhaustible source of energy for the production of hydrogen from water. Depending on design, electric generation efficiencies of approx. 40 to 60% and hydrogen production efficiencies by high-temperature electrolysis of approx. 50 to 65% are projected for fusion reactors using high-temperatures blankets. Fusion/coal symbiotic systems appear economically promising for the first generation of commercial fusion synfuels plants. Coal production requirements and the environmental effects of large-scale coal usage would be greatly reduced by a fusion/coal system. In the long term, there could be a gradual transition to an inexhaustible energy system based solely on fusion.

  9. Mechanics of membrane fusion/pore formation.

    PubMed

    Fuhrmans, Marc; Marelli, Giovanni; Smirnova, Yuliya G; Müller, Marcus

    2015-01-01

    Lipid bilayers play a fundamental role in many biological processes, and a considerable effort has been invested in understanding their behavior and the mechanism of topological changes like fusion and pore formation. Due to the time- and length-scale on which these processes occur, computational methods have proven to be an especially useful tool in their study. With their help, a number of interesting findings about the shape of fusion intermediates could be obtained, and novel hypotheses about the mechanism of topological changes and the involvement of peptides therein were suggested. In this work, we try to present a summary of these developments together with some hitherto unpublished results, featuring, among others, the shape of stalks and fusion pores, possible modes of action of the influenza HA fusion peptide and the SNARE protein complex, the mechanism of supported lipid bilayer formation by vesicle spreading, and the free energy and transition pathway of the fusion process.

  10. Laser powder-bed fusion additive manufacturing: Physics of complex melt flow and formation mechanisms of pores, spatter, and denudation zones

    DOE PAGES

    Khairallah, Saad A.; Anderson, Andrew T.; Rubenchik, Alexander; ...

    2016-02-23

    Our study demonstrates the significant effect of the recoil pressure and Marangoni convection in laser powder bed fusion (L-PBF) of 316L stainless steel. A three-dimensional high fidelity powder-scale model reveals how the strong dynamical melt flow generates pore defects, material spattering (sparking), and denudation zones. The melt track is divided into three sections: a topological depression, a transition and a tail region, each being the location of specific physical effects. The inclusion of laser ray-tracing energy deposition in the powder-scale model improves over traditional volumetric energy deposition. It enables partial particle melting, which impacts pore defects in the denudation zone.more » Different pore formation mechanisms are observed at the edge of a scan track, at the melt pool bottom (during collapse of the pool depression), and at the end of the melt track (during laser power ramp down). Finally, we discuss remedies to these undesirable pores are discussed. The results are validated against the experiments and the sensitivity to laser absorptivity.« less

  11. Spatially addressable chemoselective C-terminal ligation of an intein fusion protein from a complex mixture to a hydrazine-terminated surface.

    PubMed

    Yang, Peng; Marinakos, Stella M; Chilkoti, Ashutosh

    2011-02-15

    Protein immobilization on surfaces is useful in many areas of research, including biological characterization, antibody purification, and clinical diagnostics. A critical limitation in the development of protein microarrays and heterogeneous protein-based assays is the enormous amount of work and associated costs in the purification of proteins prior to their immobilization onto a surface. Methods to address this problem would simplify the development of interfacial diagnostics that use a protein as the recognition element. Herein, we describe an approach for the facile, site-specific immobilization of proteins on a surface without any preprocessing or sample purification steps that ligates an intein fusion protein at its C-terminus by reaction with a hydrazine group presented by a surface. Furthermore, we demonstrate that this methodology can directly immobilize a protein directly from cell lysate onto a protein-resistant surface. This methodology is also compatible with soft lithography and inkjet printing so that one or more proteins can be patterned on a surface without the need for purification.

  12. Laser powder-bed fusion additive manufacturing: Physics of complex melt flow and formation mechanisms of pores, spatter, and denudation zones

    SciTech Connect

    Khairallah, Saad A.; Anderson, Andrew T.; Rubenchik, Alexander; King, Wayne E.

    2016-02-23

    Our study demonstrates the significant effect of the recoil pressure and Marangoni convection in laser powder bed fusion (L-PBF) of 316L stainless steel. A three-dimensional high fidelity powder-scale model reveals how the strong dynamical melt flow generates pore defects, material spattering (sparking), and denudation zones. The melt track is divided into three sections: a topological depression, a transition and a tail region, each being the location of specific physical effects. The inclusion of laser ray-tracing energy deposition in the powder-scale model improves over traditional volumetric energy deposition. It enables partial particle melting, which impacts pore defects in the denudation zone. Different pore formation mechanisms are observed at the edge of a scan track, at the melt pool bottom (during collapse of the pool depression), and at the end of the melt track (during laser power ramp down). Finally, we discuss remedies to these undesirable pores are discussed. The results are validated against the experiments and the sensitivity to laser absorptivity.

  13. ROM-1 potentiates photoreceptor specific membrane fusion processes.

    PubMed

    Boesze-Battaglia, Kathleen; Stefano, Frank P; Fitzgerald, Catherine; Muller-Weeks, Susan

    2007-01-01

    Photoreceptor outer segment (OS) renewal requires a series of tightly regulated membrane fusion events which are mediated by a fusion complex containing protein and lipid components. The best characterized of these components, is a unique photoreceptor specific tetraspanin, peripherin/rds (P/rds, a.k.a., peripherin-2, Rds and Prph). In these studies we investigated the role of peripherin's non-glycosylated homolog, ROM-1, in OS fusion using a COS cell heterologous expression system and a well characterized cell free fusion assay system. Membranes isolated from COS-7 cells transfected with either FLAG-tagged P/rds or HA-tagged ROM-1 or both proteins were assayed for their ability to merge with fluorescently labeled OS plasma membrane (PM). Such membrane merger is one measure of membrane fusogenicity. The highest percent fusion was observed when the proteins were co-expressed. Furthermore detailed analysis of the fusion kinetics between fluorescently labeled PM and proteo-liposomes containing either, pure P/rds, pure ROM-1 or the ROM-1-P/rds complex clearly demonstrated that optimal fusion requires an ROM-1/P/rds complex. Proteo-liposomes composed of ROM-1 alone were not fusogenic. Peptide competition studies suggest that optimization of fusion may be due to the formation of a fusion competent peripherin/rds C-terminus in the presence of ROM-1. These studies provide further support for the hypothesis that a P/rds dependent membrane fusion complex is involved in photoreceptor renewal processes.

  14. Reference model for data fusion systems

    NASA Astrophysics Data System (ADS)

    Kokar, Mieczyslaw M.; Bedworth, Mark D.; Frankel, Carl B.

    2000-04-01

    In this paper we offer an overview of design principles and propose a fusion process reference model that provides guidance for the design of data fusion systems. We incorporate a formal method approach to fusion system design and show the role of the psychology of the human/computer interface in the system design process. Data fusion is a complex, multi-faceted field that has evolved from a number of different disciplines. This disparate nature has lead to a largely bottom-up approach to data fusion system design where the components are constructed first and the system- level issues addressed afterwards. The result is an ad hoc, prototype driven philosophy which, we content, is neither efficient nor effective. We believe that design of data fusion systems needs to be given proper consideration, with a top-down approach that addresses system-level constraints first, thereby offering the possibility of re-usable, abstract structures. We offer an object-centered model of data fusion together with practical tools for studying and refining the model so that it can be useful in designing real data fusion systems.

  15. Viral membrane fusion

    PubMed Central

    Harrison, Stephen C.

    2015-01-01

    Membrane fusion is an essential step when enveloped viruses enter cells. Lipid bilayer fusion requires catalysis to overcome a high kinetic barrier; viral fusion proteins are the agents that fulfill this catalytic function. Despite a variety of molecular architectures, these proteins facilitate fusion by essentially the same generic mechanism. Stimulated by a signal associated with arrival at the cell to be infected (e.g., receptor or co-receptor binding, proton binding in an endosome), they undergo a series of conformational changes. A hydrophobic segment (a “fusion loop” or “fusion peptide”) engages the target-cell membrane and collapse of the bridging intermediate thus formed draws the two membranes (virus and cell) together. We know of three structural classes for viral fusion proteins. Structures for both pre- and postfusion conformations of illustrate the beginning and end points of a process that can be probed by single-virion measurements of fusion kinetics. PMID:25866377

  16. Multivalent Rab interactions determine tether-mediated membrane fusion

    PubMed Central

    Lürick, Anna; Gao, Jieqiong; Kuhlee, Anne; Yavavli, Erdal; Langemeyer, Lars; Perz, Angela; Raunser, Stefan; Ungermann, Christian

    2017-01-01

    Membrane fusion at endomembranes requires cross-talk between Rab GTPases and tethers to drive SNARE-mediated lipid bilayer mixing. Several tethers have multiple Rab-binding sites with largely untested function. Here we dissected the lysosomal HOPS complex as a tethering complex with just two binding sites for the Rab7-like Ypt7 protein to determine their relevance for fusion. Using tethering and fusion assays combined with HOPS mutants, we show that HOPS-dependent fusion requires both Rab-binding sites, with Vps39 being the stronger Ypt7 interactor than Vps41. The intrinsic amphipathic lipid packaging sensor (ALPS) motif within HOPS Vps41, a target of the vacuolar kinase Yck3, is dispensable for tethering and fusion but can affect tethering if phosphorylated. In combination, our data demonstrate that a multivalent tethering complex uses its two Rab bindings to determine the place of SNARE assembly and thus fusion at endomembranes. PMID:27852901

  17. Magneto-Inertial Fusion

    SciTech Connect

    Wurden, G. A.; Hsu, S. C.; Intrator, T. P.; Grabowski, T. C.; Degnan, J. H.; Domonkos, M.; Turchi, P. J.; Campbell, E. M.; Sinars, D. B.; Herrmann, M. C.; Betti, R.; Bauer, B. S.; Lindemuth, I. R.; Siemon, R. E.; Miller, R. L.; Laberge, M.; Delage, M.

    2015-11-17

    In this community white paper, we describe an approach to achieving fusion which employs a hybrid of elements from the traditional magnetic and inertial fusion concepts, called magneto-inertial fusion (MIF). The status of MIF research in North America at multiple institutions is summarized including recent progress, research opportunities, and future plans.

  18. Cold fusion coatings

    SciTech Connect

    Wachtler, W.R.

    1993-12-31

    Historically, fusion of metals was accomplished through the use of heat. Cold fusion has become a reality with metal to metal fusion occurring at room temperature. The basics of this new technology which can be done in tank, brush or solid form is covered in this paper.

  19. Hot and cold fusion

    SciTech Connect

    Not Available

    1990-08-01

    This article presents an overview of research in cold fusion research and development in cold fusion at the Tokomak Fusion Test Reactor at the Princeton Plasma Physics Lab, and at the inertial containment facility at Lawrence Livermore National Lab. is described.

  20. Magneto-Inertial Fusion

    DOE PAGES

    Wurden, G. A.; Hsu, S. C.; Intrator, T. P.; ...

    2015-11-17

    In this community white paper, we describe an approach to achieving fusion which employs a hybrid of elements from the traditional magnetic and inertial fusion concepts, called magneto-inertial fusion (MIF). Furthermore, the status of MIF research in North America at multiple institutions is summarized including recent progress, research opportunities, and future plans.

  1. Cluster-impact fusion

    SciTech Connect

    Echenique, P.M.; Manson, J.R.; Ritchie, R.H. )

    1990-03-19

    We present a model for the cluster-impact-fusion experiments of Buehler, Friedlander, and Friedman, Calculated fusion rates as a function of bombarding energy for constant cluster size agree well with experiment. The dependence of the fusion rate on cluster size at fixed bombarding energy is explained qualitatively. The role of correlated, coherent collisions in enhanced energy loss by clusters is emphasized.

  2. Cold fusion research

    SciTech Connect

    1989-11-01

    I am pleased to forward to you the Final Report of the Cold Fusion Panel. This report reviews the current status of cold fusion and includes major chapters on Calorimetry and Excess Heat, Fusion Products and Materials Characterization. In addition, the report makes a number of conclusions and recommendations, as requested by the Secretary of Energy.

  3. Inhibition of Calpains Protects Mn-Induced Neurotransmitter release disorders in Synaptosomes from Mice: Involvement of SNARE Complex and Synaptic Vesicle Fusion.

    PubMed

    Wang, Can; Xu, Bin; Ma, Zhuo; Liu, Chang; Deng, Yu; Liu, Wei; Xu, Zhao-Fa

    2017-06-16

    Overexposure to manganese (Mn) could disrupt neurotransmitter release via influencing the formation of SNARE complex, but the underlying mechanisms are still unclear. A previous study demonstrated that SNAP-25 is one of substrate of calpains. The current study investigated whether calpains were involved in Mn-induced disorder of SNARE complex. After mice were treated with Mn for 24 days, Mn deposition increased significantly in basal nuclei in Mn-treated and calpeptin pre-treated groups. Behaviorally, less time spent in the center of the area and decreased average velocity significantly in an open field test after 24 days of Mn exposure. With the increase in MnCl2 dosage, intracellular Ca(2+) increased significantly, but pretreatment with calpeptin caused a dose-dependent decrease in calpains activity. There were fragments of N-terminal of SNAP-25 protein appearance in Mn-treated groups, but it is decreased with pretreatment of calpeptin. FM1-43-labeled synaptic vesicles also provided evidence that the treatment with Mn resulted in increasing first and then decreasing, which was consistent with Glu release and the 80 kDa protein levels of SNARE complexes. In summary, Mn induced the disorder of neurotransmitter release through influencing the formation of SNARE complex via cleaving SNAP-25 by overactivation of calpains in vivo.

  4. Magnetized target fusion and fusion propulsion

    NASA Astrophysics Data System (ADS)

    Kirkpatrick, Ronald C.

    2002-01-01

    Magnetized target fusion (MTF) is a thermonuclear fusion concept that is intermediate between the two mainline approaches, magnetic confinement and inertial confinement fusion (MCF and ICF). MTF incorporates some aspects of each and offers advantages over each of the mainline approaches. First, it provides a means of reducing the driver power requirements, thereby admitting a wider range of drivers than ICF. Second, the magnetic field is only used for insulation, not confinement, and the plasma is wall confined, so that plasma instabilities are traded in for hydrodynamic instabilities. However, the degree of compression required to reach fusion condition is lower than for ICF, so that hydrodynamic instabilities are much less threatening. The standoff driver innovation proposes to dynamically form the target plasma and a gaseous shell that compresses and confines the target plasma. Therefore, fusion target fabrication is traded in for a multiplicity of plasma guns, which must work in synchrony. The standoff driver embodiment of MTF leads to a fusion propulsion system concept that is potentially compact and lightweight. We will discuss the underlying physics of MTF and some of the details of the fusion propulsion concept using the standoff driver approach. We discuss here the optimization of an MTF target design for space propulsion. .

  5. Individual Vesicle Fusion Events Mediated by Lipid-Anchored DNA

    PubMed Central

    van Lengerich, Bettina; Rawle, Robert J.; Bendix, Poul Martin; Boxer, Steven G.

    2013-01-01

    Membrane fusion consists of a complex rearrangement of lipids and proteins that results in the merger of two lipid bilayers. We have developed a model system that employs synthetic DNA-lipid conjugates as a surrogate for the membrane proteins involved in the biological fusion reaction. We previously showed that complementary DNA-lipids, inserted into small unilamellar vesicles, can mediate membrane fusion in bulk. Here, we use a model membrane architecture developed in our lab to directly observe single-vesicle fusion events using fluorescence microscopy. In this system, a planar tethered membrane patch serves as the target membrane for incoming vesicles. This allows us to quantify the kinetics and characteristics of individual fusion events from the perspective of the lipids or the DNA-lipids involved in the process. We find that the fusion pathways are heterogeneous, with an arrested hemi-fusion state predominating, and we quantitate the outcome and rate of fusion events to construct a mechanistic model of DNA-mediated vesicle fusion. The waiting times between docking and fusion are distributed exponentially, suggesting that fusion occurs in a single step. Our analysis indicates that when two lipid bilayers are brought into close proximity, fusion occurs spontaneously, with little or no dependence on the number of DNA hybrids formed. PMID:23870262

  6. THE FINE STRUCTURE OF INHIBITORY SYNAPSES IN THE CRAYFISH

    PubMed Central

    Peterson, R. Price; Pepe, Frank A.

    1961-01-01

    Physiological investigations have shown that the synaptic input to the sensory neuron of the stretch receptor in the abdominal muscles of the crayfish is purely inhibitory. This neuron was chosen, therefore, as a site in which to study the fine structure of inhibitory synaptic endings. It was hoped that this fine structure might (a) provide a morphological prototype for the study of more complex synaptic systems and (b) reflect the inhibitory mechanisms. Stretch receptors were fixed in situ in buffered OsO4, dehydrated, and embedded in Araldite. Both cross and longitudinal sections were examined after staining with phosphotungstic acid. The inhibitory endings were easily identified by their great similarity to previously described excitatory endings. Small circular profiles (synaptic vesicles) about 460 A in diameter and an accumulation of mitochondria were consistently observed within the presynaptic endings. An increased osmiophilia of pre- and postsynaptic membranes, where they were in apposition, was also seen. The only observed difference between these inhibitory endings and excitatory endings, described by other authors, was the variable presence of a latticework of 230 A tubules in the connective tissue immediately adjacent to the inhibitory endings. Inhibitory endings were observed on all parts of the sensory neuron except the axon. PMID:14485811

  7. Viral membrane fusion

    SciTech Connect

    Harrison, Stephen C.

    2015-05-15

    Membrane fusion is an essential step when enveloped viruses enter cells. Lipid bilayer fusion requires catalysis to overcome a high kinetic barrier; viral fusion proteins are the agents that fulfill this catalytic function. Despite a variety of molecular architectures, these proteins facilitate fusion by essentially the same generic mechanism. Stimulated by a signal associated with arrival at the cell to be infected (e.g., receptor or co-receptor binding, proton binding in an endosome), they undergo a series of conformational changes. A hydrophobic segment (a “fusion loop” or “fusion peptide”) engages the target-cell membrane and collapse of the bridging intermediate thus formed draws the two membranes (virus and cell) together. We know of three structural classes for viral fusion proteins. Structures for both pre- and postfusion conformations of illustrate the beginning and end points of a process that can be probed by single-virion measurements of fusion kinetics. - Highlights: • Viral fusion proteins overcome the high energy barrier to lipid bilayer merger. • Different molecular structures but the same catalytic mechanism. • Review describes properties of three known fusion-protein structural classes. • Single-virion fusion experiments elucidate mechanism.

  8. Inhibitory mechanisms of glabridin on tyrosinase

    NASA Astrophysics Data System (ADS)

    Chen, Jianmin; Yu, Xiaojing; Huang, Yufeng

    2016-11-01

    Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin in the human body. Overproduction of melanin could lead to a variety of skin disorders. Glabridin, an isoflavan, isolated from the root of Glycyrrhiza glabra Linn, has exhibited several pharmacological activities, including excellent inhibitory effects on tyrosinase. In this paper, the inhibitory kinetics of glabridin on tyrosinase and their binding mechanisms were determined using spectroscopic, zebrafish model and molecular docking techniques. The results indicate that glabridin reversibly inhibits tyrosinase in a noncompetitive manner through a multiphase kinetic process with the IC50 of 0.43 μmol/L. It has been shown that glabridin had a strong ability to quench the intrinsic fluorescence of tyrosinase mainly through a static quenching procedure, suggesting a stable glabridin-tyrosinase complex may be generated. The results of molecular docking suggest that glabridin did not directly bind to the active site of tyrosinase. Moreover, according to the results of zebrafish model system, glabridin shows no effects on melanin synthesis in zebrafish but presents toxicity to zebrafish embryo. The possible inhibitory mechanisms, which will help to design and search for tyrosinase inhibitors especially for glabridin analogues, were proposed.

  9. Fusion research: the past is prologue

    SciTech Connect

    Post, R F

    1998-10-14

    At this juncture fusion research can be viewed as being at a turning point, a time to review its past and to imagine its future. Today, almost 50 years since the first serious attempts to address the daunting problem of achieving controlled fusion, we have both an opportunity and a challenge. Some predictions place fusion research today at a point midway between its first inception and its eventual maturation - in the middle of the 21st century - when fusion would become a major source of energy. Our opportunity therefore is to assess what we have learned from 50 years of hard work and use that knowledge as a starting point for new and better approaches to solving the fusion problem. Our challenge is to prove the "50 more years" prophesy wrong, by finding ways to shorten the time when fusion power becomes a reality. The thesis will be advanced that in the magnetic confinement approach to fusion open-ended magnetic confinement geometries offer much in responding to the challenge. A major advantage of open systems is that, owing to their theoretically and experimentally demonstrated ability to suppress plasma instabilities of both the MHD and the high-frequency wave-particle variety, the confinement becomes predictable from "classical," i.e., Fokker-Planck-type analysis. In a time of straitened budgetary circumstances for magnetic fusion research now being faced in the United States, the theoretical tractability of mirror-based systems is a substantial asset. In pursuing this avenue it is also necessary to keep an open mind as to the forms that mirror-based fusion power plants might take. For example, one can look to the high-energy physics community for a possible model: This community has shown the feasibility of constructing large and complex particle accelerators using superconducting magnets, vacuum chambers and complicated particle-handling technology, housed in underground tunnels that are 20 or more kilometers long. In the paper examples of mirror

  10. Mixed ligand complexes of Cu(II)/Zn(II) ions containing (m-)/(p-) carboxylato phenyl azo pentane 2,4-dione and 2,2'-bipyridine/1,10 phenanthroline: Synthesis, characterization, DNA binding, nuclease and topoisomerase I inhibitory activity.

    PubMed

    Hasan, Md Amin; Kumari, Niraj; Singh, Kanhaiya; Singh, Kiran; Mishra, Lallan

    2016-01-05

    Metal complexes of type [Cu(L1H)2(bpy)] (1), [Zn(L1H)2(bpy)] (2), [Cu(L2H)2(bpy)] (3) and [Cu(L2H)2(Phen)] (4) (L1H2=3-[N'-(1-acetyl-2-oxo-propylidene)-hydrazino]-benzoic acid, L2H2=4-[N'-(1-acetyl-2-oxo-propylidene)-hydrazino]-benzoic acid, bpy=2,2'-bipyridine, Phen=1,10 phenanthroline) are synthesized and characterized using spectroscopic techniques (FT-IR, (1)H NMR, (13)C NMR, electronic absorption and emission) and elemental analysis data. The assembly of the complexes involving intramolecular H-bonding is displayed using corresponding crystal structure. Binding of the complexes separately with Calf Thymus DNA is monitored using UV-vis spectral titrations. The displacement of ethidium bromide (EB) bound to DNA by the complexes, in phosphate buffer solution (pH∼7.2) is monitored using fluorescence spectral titrations. Nuclease activity of the complexes follow the order 4>3>1>2. The gel electrophoretic mobility assay measurement in presence of minor groove binder 4',6-diamidino-2-phenylindole (DAPI), suggests that complexes preferably bind with the minor groove of DNA. Topoisomerase I inhibitory activity of the complexes 3 and 4 inhibit topoisomerase I activity with IC50 values of 112 and 87μM respectively. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Mixed ligand complexes of Cu(II)/Zn(II) ions containing (m-)/(p-) carboxylato phenyl azo pentane 2,4-dione and 2,2‧-bipyridine/1,10 phenanthroline: Synthesis, characterization, DNA binding, nuclease and topoisomerase I inhibitory activity

    NASA Astrophysics Data System (ADS)

    Hasan, Md. Amin; Kumari, Niraj; Singh, Kanhaiya; Singh, Kiran; Mishra, Lallan

    2016-01-01

    Metal complexes of type [Cu(L1H)2(bpy)] (1), [Zn(L1H)2(bpy)] (2), [Cu(L2H)2(bpy)] (3) and [Cu(L2H)2(Phen)] (4) (L1H2 = 3-[N‧-(1-acetyl-2-oxo-propylidene)-hydrazino]-benzoic acid, L2H2 = 4-[N‧-(1-acetyl-2-oxo-propylidene)-hydrazino]-benzoic acid, bpy = 2,2‧-bipyridine, Phen = 1,10 phenanthroline) are synthesized and characterized using spectroscopic techniques (FT-IR, 1H NMR, 13C NMR, electronic absorption and emission) and elemental analysis data. The assembly of the complexes involving intramolecular H-bonding is displayed using corresponding crystal structure. Binding of the complexes separately with Calf Thymus DNA is monitored using UV-vis spectral titrations. The displacement of ethidium bromide (EB) bound to DNA by the complexes, in phosphate buffer solution (pH ∼ 7.2) is monitored using fluorescence spectral titrations. Nuclease activity of the complexes follow the order 4 > 3 > 1 > 2. The gel electrophoretic mobility assay measurement in presence of minor groove binder 4‧,6-diamidino-2-phenylindole (DAPI), suggests that complexes preferably bind with the minor groove of DNA. Topoisomerase I inhibitory activity of the complexes 3 and 4 inhibit topoisomerase I activity with IC50 values of 112 and 87 μM respectively.

  12. Drunken Membranes: Short-Chain Alcohols Alter Fusion of Liposomes to Planar Lipid Bilayers.

    PubMed

    Paxman, Jason; Hunt, Brady; Hallan, David; Zarbock, Samuel R; Woodbury, Dixon J

    2017-01-10

    Although the effects of ethanol on protein receptors and lipid membranes have been studied extensively, ethanol's effect on vesicles fusing to lipid bilayers is not known. To determine the effect of alcohols on fusion rates, we utilized the nystatin/ergosterol fusion assay to measure fusion of liposomes to a planar lipid bilayer (BLM). The addition of ethanol excited fusion when applied on the cis (vesicle) side, and inhibited fusion on the trans side. Other short-chain alcohols followed a similar pattern. In general, the inhibitory effect of alcohols (trans) occurs at lower doses than the excitatory (cis) effect, with a decrease of 29% in fusion rates at the legal driving limit of 0.08% (w/v) ethanol (IC50 = 0.2% v/v, 34 mM). Similar inhibitory effects were observed with methanol, propanol, and butanol, with ethanol being the most potent. Significant variability was observed with different alcohols when applied to the cis side. Ethanol and propanol enhanced fusion, butanol also enhanced fusion but was less potent, and low doses of methanol mildly inhibited fusion. The inhibition by trans addition of alcohols implies that they alter the planar membrane structure and thereby increase the activation energy required for fusion, likely through an increase in membrane fluidity. The cis data are likely a combination of the above effect and a proportionally greater lowering of the vesicle lysis tension and hydration repulsive pressure that combine to enhance fusion. Alternate hypotheses are also discussed. The inhibitory effect of ethanol on liposome-membrane fusion is large enough to provide a possible biophysical explanation of compromised neuronal behavior.

  13. Multimeric complexes of the PML-retinoic acid receptor alpha fusion protein in acute promyelocytic leukemia cells and interference with retinoid and peroxisome-proliferator signaling pathways.

    PubMed Central

    Jansen, J H; Mahfoudi, A; Rambaud, S; Lavau, C; Wahli, W; Dejean, A

    1995-01-01

    The t(15;17) chromosomal translocation, specific for acute promyelocytic leukemia (APL), fuses the PML gene to the retinoic acid receptor alpha (RAR alpha) gene, resulting in expression of a PML-RAR alpha hybrid protein. In this report, we analyzed the nature of PML-RAR alpha-containing complexes in nuclear protein extracts of t(15;17)-positive cells. We show that endogenous PML-RAR alpha can bind to DNA as a homodimer, in contrast to RAR alpha that requires the retinoid X receptor (RXR) dimerization partner. In addition, these cells contain oligomeric complexes of PML-RAR alpha and endogenous RXR. Treatment with retinoic acid results in a decrease of PML-RAR alpha protein levels and, as a consequence, of DNA binding by the different complexes. Using responsive elements from various hormone signaling pathways, we show that PML-RAR alpha homodimers have altered DNA-binding characteristics when compared to RAR alpha-RXR alpha heterodimers. In transfected Drosophila SL-3 cells that are devoid of endogenous retinoid receptors PML-RAR alpha inhibits transactivation by RAR alpha-RXR alpha heterodimers in a dominant fashion. In addition, we show that both normal retinoid receptors and the PML-RAR alpha hybrid bind and activate the peroxisome proliferator-activated receptor responsive element from the Acyl-CoA oxidase gene, indicating that retinoids and peroxisome proliferator receptors may share common target genes. These properties of PML-RAR alpha may contribute to the transformed phenotype of APL cells. Images Fig. 1 Fig. 2 Fig. 3 PMID:7638205

  14. Statistical label fusion with hierarchical performance models

    PubMed Central

    Asman, Andrew J.; Dagley, Alexander S.; Landman, Bennett A.

    2014-01-01

    Label fusion is a critical step in many image segmentation frameworks (e.g., multi-atlas segmentation) as it provides a mechanism for generalizing a collection of labeled examples into a single estimate of the underlying segmentation. In the multi-label case, typical label fusion algorithms treat all labels equally – fully neglecting the known, yet complex, anatomical relationships exhibited in the data. To address this problem, we propose a generalized statistical fusion framework using hierarchical models of rater performance. Building on the seminal work in statistical fusion, we reformulate the traditional rater performance model from a multi-tiered hierarchical perspective. This new approach provides a natural framework for leveraging known anatomical relationships and accurately modeling the types of errors that raters (or atlases) make within a hierarchically consistent formulation. Herein, we describe several contributions. First, we derive a theoretical advancement to the statistical fusion framework that enables the simultaneous estimation of multiple (hierarchical) performance models within the statistical fusion context. Second, we demonstrate that the proposed hierarchical formulation is highly amenable to the state-of-the-art advancements that have been made to the statistical fusion framework. Lastly, in an empirical whole-brain segmentation task we demonstrate substantial qualitative and significant quantitative improvement in overall segmentation accuracy. PMID:24817809

  15. Statistical label fusion with hierarchical performance models

    NASA Astrophysics Data System (ADS)

    Asman, Andrew J.; Dagley, Alexander S.; Landman, Bennett A.

    2014-03-01

    Label fusion is a critical step in many image segmentation frameworks (e.g., multi-atlas segmentation) as it provides a mechanism for generalizing a collection of labeled examples into a single estimate of the underlying segmentation. In the multi-label case, typical label fusion algorithms treat all labels equally - fully neglecting the known, yet complex, anatomical relationships exhibited in the data. To address this problem, we propose a generalized statistical fusion framework using hierarchical models of rater performance. Building on the seminal work in statistical fusion, we reformulate the traditional rater performance model from a multi-tiered hierarchical perspective. This new approach provides a natural framework for leveraging known anatomical relationships and accurately modeling the types of errors that raters (or atlases) make within a hierarchically consistent formulation. Herein, we describe several contributions. First, we derive a theoretical advancement to the statistical fusion framework that enables the simultaneous estimation of multiple (hierarchical) performance models within the statistical fusion context. Second, we demonstrate that the proposed hierarchical formulation is highly amenable to the state-of-the-art advancements that have been made to the statistical fusion framework. Lastly, in an empirical whole-brain segmentation task we demonstrate substantial qualitative and significant quantitative improvement in overall segmentation accuracy.

  16. Multisensor image fusion guidelines in remote sensing

    NASA Astrophysics Data System (ADS)

    Pohl, C.

    2016-04-01

    Remote sensing delivers multimodal and -temporal data from the Earth's surface. In order to cope with these multidimensional data sources and to make the most of them, image fusion is a valuable tool. It has developed over the past few decades into a usable image processing technique for extracting information of higher quality and reliability. As more sensors and advanced image fusion techniques have become available, researchers have conducted a vast amount of successful studies using image fusion. However, the definition of an appropriate workflow prior to processing the imagery requires knowledge in all related fields - i.e. remote sensing, image fusion and the desired image exploitation processing. From the findings of this research it can be seen that the choice of the appropriate technique, as well as the fine-tuning of the individual parameters of this technique, is crucial. There is still a lack of strategic guidelines due to the complexity and variability of data selection, processing techniques and applications. This paper gives an overview on the state-of-the-art in remote sensing image fusion including sensors and applications. Putting research results in image fusion from the past 15 years into a context provides a new view on the subject and helps other researchers to build their innovation on these findings. Recommendations of experts help to understand further needs to achieve feasible strategies in remote sensing image fusion.

  17. INTRODUCTION: Status report on fusion research

    NASA Astrophysics Data System (ADS)

    Burkart, Werner

    2005-10-01

    A major milestone on the path to fusion energy was reached in June 2005 on the occasion of the signing of the joint declaration of all parties to the ITER negotiations, agreeing on future arrangements and on the construction site at Cadarache in France. The International Atomic Energy Agency has been promoting fusion activities since the late 1950s; it took over the auspices of the ITER Conceptual Design Activities in 1988, and of the ITER Engineering and Design Activities in 1992. The Agency continues its support to Member States through the organization of consultancies, workshops and technical meetings, the most prominent being the series of International Fusion Energy Conferences (formerly called the International Conference on Plasma Physics and Controlled Nuclear Fusion Research). The meetings serve as a platform for experts from all Member States to have open discussions on their latest accomplishments as well as on their problems and eventual solutions. The papers presented at the meetings and conferences are routinely published, many being sent to the journal it Nuclear Fusion, co-published monthly by Institute of Physics Publishing, Bristol, UK. The journal's reputation is reflected in the fact that it is a world-renowned publication, and the International Fusion Research Council has used it for the publication of a Status Report on Controlled Thermonuclear Fusion in 1978 and 1990. This present report marks the conclusion of the preparatory phases of ITER activities. It provides background information on the progress of fusion research within the last 15 years. The International Fusion Research Council (IFRC), which initiated the report, was fully aware of the complexities of including all scientific results in just one paper, and so decided to provide an overview and extensive references for the interested reader who need not necessarily be a fusion specialist. Professor Predhiman K. Kaw, Chairman, prepared the report on behalf of the IFRC, reflecting

  18. Materials research for fusion

    NASA Astrophysics Data System (ADS)

    Knaster, J.; Moeslang, A.; Muroga, T.

    2016-05-01

    Fusion materials research started in the early 1970s following the observation of the degradation of irradiated materials used in the first commercial fission reactors. The technological challenges of fusion energy are intimately linked with the availability of suitable materials capable of reliably withstanding the extremely severe operational conditions of fusion reactors. Although fission and fusion materials exhibit common features, fusion materials research is broader. The harder mono-energetic spectrum associated with the deuterium-tritium fusion neutrons (14.1 MeV compared to <2 MeV on average for fission neutrons) releases significant amounts of hydrogen and helium as transmutation products that might lead to a (at present undetermined) degradation of structural materials after a few years of operation. Overcoming the historical lack of a fusion-relevant neutron source for materials testing is an essential pending step in fusion roadmaps. Structural materials development, together with research on functional materials capable of sustaining unprecedented power densities during plasma operation in a fusion reactor, have been the subject of decades of worldwide research efforts underpinning the present maturity of the fusion materials research programme.

  19. Fusion probability in heavy nuclei

    NASA Astrophysics Data System (ADS)

    Banerjee, Tathagata; Nath, S.; Pal, Santanu

    2015-03-01

    Background: Fusion between two massive nuclei is a very complex process and is characterized by three stages: (a) capture inside the potential barrier, (b) formation of an equilibrated compound nucleus (CN), and (c) statistical decay of the CN leading to a cold evaporation residue (ER) or fission. The second stage is the least understood of the three and is the most crucial in predicting yield of superheavy elements (SHE) formed in complete fusion reactions. Purpose: A systematic study of average fusion probability, , is undertaken to obtain a better understanding of its dependence on various reaction parameters. The study may also help to clearly demarcate onset of non-CN fission (NCNF), which causes fusion probability, PCN, to deviate from unity. Method: ER excitation functions for 52 reactions leading to CN in the mass region 170-220, which are available in the literature, have been compared with statistical model (SM) calculations. Capture cross sections have been obtained from a coupled-channels code. In the SM, shell corrections in both the level density and the fission barrier have been included. for these reactions has been extracted by comparing experimental and theoretical ER excitation functions in the energy range ˜5 %-35% above the potential barrier, where known effects of nuclear structure are insignificant. Results: has been shown to vary with entrance channel mass asymmetry, η (or charge product, ZpZt ), as well as with fissility of the CN, χCN. No parameter has been found to be adequate as a single scaling variable to determine . Approximate boundaries have been obtained from where starts deviating from unity. Conclusions: This study quite clearly reveals the limits of applicability of the SM in interpreting experimental observables from fusion reactions involving two massive nuclei. Deviation of from unity marks the beginning of the domain of dynamical models of fusion. Availability of precise ER cross

  20. Surgical techniques for lumbo-sacral fusion.

    PubMed

    Tropiano, P; Giorgi, H; Faure, A; Blondel, B

    2017-02-01

    Lumbo-sacral (L5-S1) fusion is a widely performed procedure that has become the reference standard treatment for refractory low back pain. L5-S1 is a complex transition zone between the mobile lordotic distal lumbar spine and the fixed sacral region. The goal is to immobilise the lumbo-sacral junction in order to relieve pain originating from this site. Apart from achieving inter-vertebral fusion, the main challenge lies in the preoperative determination of the fixed L5-S1 position that will be optimal for the patient. Many lumbo-sacral fusion techniques are available. Stabilisation can be achieved using various methods. An anterior, posterior, or combined approach may be used. Recently developed minimally invasive techniques are gaining in popularity based on their good clinical outcomes and high fusion rates. The objective of this conference is to resolve the main issues faced by spinal surgeons in their everyday practice.

  1. Magnetic mirror fusion: status and prospects

    SciTech Connect

    Post, R.F.

    1980-02-11

    Two improved mirror systems, the tandem mirror (TM) and the field-reversed mirror (FRM) are being intensively studied. The twin practical aims of these studies: to improve the economic prospects for mirror fusion power plants and to reduce the size and/or complexity of such plants relative to earlier approaches to magnetic fusion. While at the present time the program emphasis is still strongly oriented toward answering scientific questions, the emphasis is shifting as the data accumulates and as larger facilities - ones with a heavy technological and engineering orientation - are being prepared. The experimental and theoretical progress that led to the new look in mirror fusion research is briefly reviewed, the new TM and the FRM ideas are outlined, and the projected future course of mirror fusion research is discussed.

  2. Collagen-derived matricryptins promote inhibitory nerve terminal formation in the developing neocortex

    PubMed Central

    Su, Jianmin; Chen, Jiang; Lippold, Kumiko; Monavarfeshani, Aboozar; Carrillo, Gabriela Lizana; Jenkins, Rachel

    2016-01-01

    Inhibitory synapses comprise only ∼20% of the total synapses in the mammalian brain but play essential roles in controlling neuronal activity. In fact, perturbing inhibitory synapses is associated with complex brain disorders, such as schizophrenia and epilepsy. Although many types of inhibitory synapses exist, these disorders have been strongly linked to defects in inhibitory synapses formed by Parvalbumin-expressing interneurons. Here, we discovered a novel role for an unconventional collagen—collagen XIX—in the formation of Parvalbumin+ inhibitory synapses. Loss of this collagen results not only in decreased inhibitory synapse number, but also in the acquisition of schizophrenia-related behaviors. Mechanistically, these studies reveal that a proteolytically released fragment of this collagen, termed a matricryptin, promotes the assembly of inhibitory nerve terminals through integrin receptors. Collectively, these studies not only identify roles for collagen-derived matricryptins in cortical circuit formation, but they also reveal a novel paracrine mechanism that regulates the assembly of these synapses. PMID:26975851

  3. Muon Catalyzed Fusion

    NASA Technical Reports Server (NTRS)

    Armour, Edward A.G.

    2007-01-01

    Muon catalyzed fusion is a process in which a negatively charged muon combines with two nuclei of isotopes of hydrogen, e.g, a proton and a deuteron or a deuteron and a triton, to form a muonic molecular ion in which the binding is so tight that nuclear fusion occurs. The muon is normally released after fusion has taken place and so can catalyze further fusions. As the muon has a mean lifetime of 2.2 microseconds, this is the maximum period over which a muon can participate in this process. This article gives an outline of the history of muon catalyzed fusion from 1947, when it was first realised that such a process might occur, to the present day. It includes a description of the contribution that Drachrnan has made to the theory of muon catalyzed fusion and the influence this has had on the author's research.

  4. Hepatitis C virus NS5A replication complex inhibitors. Part 6: Discovery of a novel and highly potent biarylimidazole chemotype with inhibitory activity toward genotypes 1a and 1b replicons.

    PubMed

    Belema, Makonen; Nguyen, Van N; Romine, Jeffrey L; St Laurent, Denis R; Lopez, Omar D; Goodrich, Jason T; Nower, Peter T; O'Boyle, Donald R; Lemm, Julie A; Fridell, Robert A; Gao, Min; Fang, Hua; Krause, Rudolph G; Wang, Ying-Kai; Oliver, A Jayne; Good, Andrew C; Knipe, Jay O; Meanwell, Nicholas A; Snyder, Lawrence B

    2014-03-13

    A medicinal chemistry campaign that was conducted to address a potential genotoxic liability associated with an aniline-derived scaffold in a series of HCV NS5A inhibitors with dual GT-1a/-1b inhibitory activity is described. Anilides 3b and 3c were used as vehicles to explore structural modifications that retained antiviral potency while removing the potential for metabolism-based unmasking of the embedded aniline. This effort resulted in the discovery of a highly potent biarylimidazole chemotype that established a potency benchmark in replicon assays, particularly toward HCV GT-1a, a strain with significant clinical importance. Securing potent GT-1a activity in a chemotype class lacking overt structural liabilities was a critical milestone in the effort to realize the full clinical potential of targeting the HCV NS5A protein.

  5. Airborne Infrared and Visible Image Fusion Combined with Region Segmentation.

    PubMed

    Zuo, Yujia; Liu, Jinghong; Bai, Guanbing; Wang, Xuan; Sun, Mingchao

    2017-05-15

    This paper proposes an infrared (IR) and visible image fusion method introducing region segmentation into the dual-tree complex wavelet transform (DTCWT) region. This method should effectively improve both the target indication and scene spectrum features of fusion images, and the target identification and tracking reliability of fusion system, on an airborne photoelectric platform. The method involves segmenting the region in an IR image by significance, and identifying the target region and the background region; then, fusing the low-frequency components in the DTCWT region according to the region segmentation result. For high-frequency components, the region weights need to be assigned by the information richness of region details to conduct fusion based on both weights and adaptive phases, and then introducing a shrinkage function to suppress noise; Finally, the fused low-frequency and high-frequency components are reconstructed to obtain the fusion image. The experimental results show that the proposed method can fully extract complementary information from the source images to obtain a fusion image with good target indication and rich information on scene details. They also give a fusion result superior to existing popular fusion methods, based on eithers subjective or objective evaluation. With good stability and high fusion accuracy, this method can meet the fusion requirements of IR-visible image fusion systems.

  6. Airborne Infrared and Visible Image Fusion Combined with Region Segmentation

    PubMed Central

    Zuo, Yujia; Liu, Jinghong; Bai, Guanbing; Wang, Xuan; Sun, Mingchao

    2017-01-01

    This paper proposes an infrared (IR) and visible image fusion method introducing region segmentation into the dual-tree complex wavelet transform (DTCWT) region. This method should effectively improve both the target indication and scene spectrum features of fusion images, and the target identification and tracking reliability of fusion system, on an airborne photoelectric platform. The method involves segmenting the region in an IR image by significance, and identifying the target region and the background region; then, fusing the low-frequency components in the DTCWT region according to the region segmentation result. For high-frequency components, the region weights need to be assigned by the information richness of region details to conduct fusion based on both weights and adaptive phases, and then introducing a shrinkage function to suppress noise; Finally, the fused low-frequency and high-frequency components are reconstructed to obtain the fusion image. The experimental results show that the proposed method can fully extract complementary information from the source images to obtain a fusion image with good target indication and rich information on scene details. They also give a fusion result superior to existing popular fusion methods, based on eithers subjective or objective evaluation. With good stability and high fusion accuracy, this method can meet the fusion requirements of IR-visible image fusion systems. PMID:28505137

  7. FusionAnalyser: a new graphical, event-driven tool for fusion rearrangements discovery

    PubMed Central

    Piazza, Rocco; Pirola, Alessandra; Spinelli, Roberta; Valletta, Simona; Redaelli, Sara; Magistroni, Vera; Gambacorti-Passerini, Carlo

    2012-01-01

    Gene fusions are common driver events in leukaemias and solid tumours; here we present FusionAnalyser, a tool dedicated to the identification of driver fusion rearrangements in human cancer through the analysis of paired-end high-throughput transcriptome sequencing data. We initially tested FusionAnalyser by using a set of in silico randomly generated sequencing data from 20 known human translocations occurring in cancer and subsequently using transcriptome data from three chronic and three acute myeloid leukaemia samples. in all the cases our tool was invariably able to detect the presence of the correct driver fusion event(s) with high specificity. In one of the acute myeloid leukaemia samples, FusionAnalyser identified a novel, cryptic, in-frame ETS2–ERG fusion. A fully event-driven graphical interface and a flexible filtering system allow complex analyses to be run in the absence of any a priori programming or scripting knowledge. Therefore, we propose FusionAnalyser as an efficient and robust graphical tool for the identification of functional rearrangements in the context of high-throughput transcriptome sequencing data. PMID:22570408

  8. Fusion: The controversy continues

    SciTech Connect

    1989-07-01

    Nuclear fusion-the power of the stars that promises mankind an inexhaustible supply of energy-seems concurrently much closer and still distant this month. The recent flurry of announcements concerning the achievement of a cold fusion reaction has-if nothing else-underscored the historic importance of the basic fusion reaction which uses hydrogen ions to fuel an energy-producing reaction.

  9. Still wishful on fusion

    NASA Astrophysics Data System (ADS)

    Evans, John

    2009-08-01

    In Cris W Barnes' review of Charles Seife's book Sun in a Bottle: The Strange History of Fusion and the Art of Wishful Thinking (May pp42-43), Barnes, as a member of the fusion community, admits to "wishful thinking" on the basis that "a strong and exciting vision always helps focus and drive effort". This may be true, but wishful thinking has also distorted and ignored several aspects of the fusion dream.

  10. Advanced fusion diagnostics

    NASA Astrophysics Data System (ADS)

    Moses, K. G.

    1993-07-01

    Key among various issues of ignited plasmas is understanding the physics of energy transfer between thermal plasma particles and magnetically confined, highly energetic charged ions in a tokamak device. The superthermal particles are products of fusion reactions. The efficiency of energy transfer by collisions, from charged fusion products (e.g., (alpha)-particles) to plasma ions, grossly determines whether or not plasma conditions are self-sustaining without recourse to auxiliary heating. Furthermore, should energy transfer efficiency be poor, and substantial auxiliary heating power is required to maintain reacting conditions within the plasma, economics may preclude commercial viability of fusion reactors. The required charged fusion product information is contained in the energy distribution function of these particles. Knowledge of temporal variations of the superthermal particle energy distribution function could be used by a fusion reactor control system to balance plasma conditions between thermal runaway and a modicum of fusion product energy transfer. Therefore, diagnostics providing data on the dynamical transfer of alpha-particle and other charged fusion product energy to the plasma ions are essential elements for a fusion reactor control system to insure that proper plasma conditions are maintained. The objective of this work is to assess if spectral analysis of RF radiation emitted by charged fusion products confined in a magnetized plasma, called ion cyclotron emission (ICE), can reveal the vital data of the distribution function of the superthermal particles.

  11. Optimal percentage of inhibitory synapses in multi-task learning.

    PubMed

    Capano, Vittorio; Herrmann, Hans J; de Arcangelis, Lucilla

    2015-04-22

    Performing more tasks in parallel is a typical feature of complex brains. These are characterized by the coexistence of excitatory and inhibitory synapses, whose percentage in mammals is measured to have a typical value of 20-30%. Here we investigate parallel learning of more Boolean rules in neuronal networks. We find that multi-task learning results from the alternation of learning and forgetting of the individual rules. Interestingly, a fraction of 30% inhibitory synapses optimizes the overall performance, carving a complex backbone supporting information transmission with a minimal shortest path length. We show that 30% inhibitory synapses is the percentage maximizing the learning performance since it guarantees, at the same time, the network excitability necessary to express the response and the variability required to confine the employment of resources.

  12. Inhibitory Control Predicts Grammatical Ability

    PubMed Central

    Ibbotson, Paul; Kearvell-White, Jennifer

    2015-01-01

    We present evidence that individual variation in grammatical ability can be predicted by individual variation in inhibitory control. We tested 81 5-year-olds using two classic tests from linguistics and psychology (Past Tense and the Stroop). Inhibitory control was a better predicator of grammatical ability than either vocabulary or age. Our explanation is that giving the correct response in both tests requires using a common cognitive capacity to inhibit unwanted competition. The implications are that understanding the developmental trajectory of language acquisition can benefit from integrating the developmental trajectory of non-linguistic faculties, such as executive control. PMID:26659926

  13. Heptad repeat 2-based peptides inhibit avian sarcoma and leukosis virus subgroup a infection and identify a fusion intermediate.

    PubMed

    Netter, Robert C; Amberg, Sean M; Balliet, John W; Biscone, Mark J; Vermeulen, Arwen; Earp, Laurie J; White, Judith M; Bates, Paul

    2004-12-01

    Fusion proteins of enveloped viruses categorized as class I are typified by two distinct heptad repeat domains within the transmembrane subunit. These repeats are important structural elements that assemble into the six-helix bundles characteristic of the fusion-activated envelope trimer. Peptides derived from these domains can be potent and specific inhibitors of membrane fusion and virus infection. To facilitate our understanding of retroviral entry, peptides corresponding to the two heptad repeat domains of the avian sarcoma and leukosis virus subgroup A (ASLV-A) TM subunit of the envelope protein were characterized. Two peptides corresponding to the C-terminal heptad repeat (HR2), offset from one another by three residues, were effective inhibitors of infection, while two overlapping peptides derived from the N-terminal heptad repeat (HR1) were not. Analysis of envelope mutants containing substitutions within the HR1 domain revealed that a single amino acid change, L62A, significantly reduced sensitivity to peptide inhibition. Virus bound to cells at 4 degrees C became sensitive to peptide within the first 5 min of elevating the temperature to 37 degrees C and lost sensitivity to peptide after 15 to 30 min, consistent with a transient intermediate in which the peptide binding site is exposed. In cell-cell fusion experiments, peptide inhibitor sensitivity occurred prior to a fusion-enhancing low-pH pulse. Soluble receptor for ASLV-A induces a lipophilic character in the envelope which can be measured by stable liposome binding, and this activation was found to be unaffected by inhibitory HR2 peptide. Finally, receptor-triggered conformational changes in the TM subunit were also found to be unaffected by inhibitory peptide. These changes are marked by a dramatic shift in mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, from a subunit of 37 kDa to a complex of about 80 kDa. Biotinylated HR2 peptide bound specifically to the 80-kDa complex

  14. Cell fusion and nuclear fusion in plants.

    PubMed

    Maruyama, Daisuke; Ohtsu, Mina; Higashiyama, Tetsuya

    2016-12-01

    Eukaryotic cells are surrounded by a plasma membrane and have a large nucleus containing the genomic DNA, which is enclosed by a nuclear envelope consisting of the outer and inner nuclear membranes. Although these membranes maintain the identity of cells, they sometimes fuse to each other, such as to produce a zygote during sexual reproduction or to give rise to other characteristically polyploid tissues. Recent studies have demonstrated that the mechanisms of plasma membrane or nuclear membrane fusion in plants are shared to some extent with those of yeasts and animals, despite the unique features of plant cells including thick cell walls and intercellular connections. Here, we summarize the key factors in the fusion of these membranes during plant reproduction, and also focus on "non-gametic cell fusion," which was thought to be rare in plant tissue, in which each cell is separated by a cell wall. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Viral membrane fusion.

    PubMed

    Harrison, Stephen C

    2015-05-01

    Membrane fusion is an essential step when enveloped viruses enter cells. Lipid bilayer fusion requires catalysis to overcome a high kinetic barrier; viral fusion proteins are the agents that fulfill this catalytic function. Despite a variety of molecular architectures, these proteins facilitate fusion by essentially the same generic mechanism. Stimulated by a signal associated with arrival at the cell to be infected (e.g., receptor or co-receptor binding, proton binding in an endosome), they undergo a series of conformational changes. A hydrophobic segment (a "fusion loop" or "fusion peptide") engages the target-cell membrane and collapse of the bridging intermediate thus formed draws the two membranes (virus and cell) together. We know of three structural classes for viral fusion proteins. Structures for both pre- and postfusion conformations of illustrate the beginning and end points of a process that can be probed by single-virion measurements of fusion kinetics. Copyright © 2015 The Author. Published by Elsevier Inc. All rights reserved.

  16. Two Horizons of Fusion

    ERIC Educational Resources Information Center

    Lo, Mun Ling; Chik, Pakey Pui Man

    2016-01-01

    In this paper, we aim to differentiate the internal and external horizons of "fusion." "Fusion" in the internal horizon relates to the structure and meaning of the object of learning as experienced by the learner. It clarifies the interrelationships among an object's critical features and aspects. It also illuminates the…

  17. Controlled Nuclear Fusion.

    ERIC Educational Resources Information Center

    Glasstone, Samuel

    This publication is one of a series of information booklets for the general public published by The United States Atomic Energy Commission. Among the topics discussed are: Importance of Fusion Energy; Conditions for Nuclear Fusion; Thermonuclear Reactions in Plasmas; Plasma Confinement by Magnetic Fields; Experiments With Plasmas; High-Temperature…

  18. Two Horizons of Fusion

    ERIC Educational Resources Information Center

    Lo, Mun Ling; Chik, Pakey Pui Man

    2016-01-01

    In this paper, we aim to differentiate the internal and external horizons of "fusion." "Fusion" in the internal horizon relates to the structure and meaning of the object of learning as experienced by the learner. It clarifies the interrelationships among an object's critical features and aspects. It also illuminates the…

  19. Fusion of Polarized Deuterons

    NASA Astrophysics Data System (ADS)

    Hofmann, H. M.; Fick, D.

    1984-06-01

    The nuclear physics aspects of the d-d reactions initiated by low-energy polarized deuterons are discussed. It is shown that the use of polarized deuterons does not suppress the fusion of deuterons with deuterons and hence does not suppress neutron production. Therefore a recently proposed "neutron-free" d-3He fusion reactor is unlikely to work.

  20. Fusion Science Education Outreach

    NASA Astrophysics Data System (ADS)

    Danielson, C. A.; DIII-D Education Group

    1996-11-01

    This presentation will focus on education outreach activities at General Atomics that have been expanded to include the general population on science education with a focus on fusion energy. Outreach materials are distributed upon request both nationally and internationally. These materials include a notebook containing copies of DIII--D tour panels, fusion poster, new fusion energy video, new fusion energy brochure, and the electromagnetic spectrum curriculum. The 1996 Fusion Forum (held in the House Caucus Room) included a student/ teacher lunch with Energy Secretary Hazel O'Leary and a private visit to the Forum exhibits. The continuing partnership with Kearny High School includes lectures, job shadowing, internship, equipment donations and an award-winning electric car-racing program. Development of distribution by CD of the existing interactive fusion energy kiosk and a virtual reality tour of the DIII--D facility are underway. The DIII--D fusion education WWW site includes e-mail addresses to ``Ask the Wizard,'' and/or receive GA's outreach materials. Steve Rodecker, a local science teacher, aided by DIII--D fusion staff, won his second Tapestry Award; he also was named the ``1995 National Science Teacher of the Year'' and will be present to share his experiences with the DIII--D educational outreach program.

  1. Antiproton catalyzed fusion

    SciTech Connect

    Morgan, D.L. Jr.; Perkins, L.J.; Haney, S.W.

    1995-05-15

    Because of the potential application to power production, it is important to investigate a wide range of possible means to achieve nuclear fusion, even those that may appear initially to be infeasible. In antiproton catalyzed fusion, the negative antiproton shields the repulsion between the positively charged nuclei of hydrogen isotopes, thus allowing a much higher level of penetration through the repulsive Coulomb barrier, and thereby greatly enhancing the fusion cross section. Because of their more compact wave function, the more massive antiprotons offer considerably more shielding than do negative muons. The effects of the shielding on fusion cross sections are most predominate, at low energies. If the antiproton could exist in the ground state with a nucleus for a sufficient time without annihilating, the fusion cross sections are so enhanced that at room temperature energies, values up to about 1,000 barns (that for d+t) would be possible. Unfortunately, the cross section for antiproton annihilation with the incoming nucleus is even higher. A model that provides an upper bound for the fusion to annihilation cross section for all relevant energies indicates that each antiproton will catalyze no more than about one fusion. Because the energy required to make one antiproton greatly exceeds the fusion energy that is released, this level of catalysis is far from adequate for power production.

  2. Fusion Power Deployment

    SciTech Connect

    J.A. Schmidt; J.M. Ogden

    2002-02-06

    Fusion power plants could be part of a future portfolio of non-carbon dioxide producing energy supplies such as wind, solar, biomass, advanced fission power, and fossil energy with carbon dioxide sequestration. In this paper, we discuss key issues that could impact fusion energy deployment during the last half of this century. These include geographic issues such as resource availability, scale issues, energy storage requirements, and waste issues. The resource needs and waste production associated with fusion deployment in the U.S. should not pose serious problems. One important feature of fusion power is the fact that a fusion power plant should be locatable within most local or regional electrical distribution systems. For this reason, fusion power plants should not increase the burden of long distance power transmission to our distribution system. In contrast to fusion power, regional factors could play an important role in the deployment of renewable resources such as wind, solar and biomass or fossil energy with CO2 sequestration. We examine the role of these regional factors and their implications for fusion power deployment.

  3. Diverse Ensembles of Inhibitory Interneurons.

    PubMed

    Crandall, Shane R; Connors, Barry W

    2016-04-06

    In this issue of Neuron, Karnani et al. (2016) show that ensembles of specific types of inhibitory interneurons generate coordinated activity in mouse visual cortex. They also describe chemical and electrical synaptic mechanisms that may enable diverse interneuron ensembles to function as distinct operational units. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Inhibitory Control in Childhood Stuttering

    ERIC Educational Resources Information Center

    Eggers, Kurt; De Nil, Luc F.; Van den Bergh, Bea R. H.

    2013-01-01

    Purpose: The purpose of this study was to investigate whether previously reported parental questionnaire-based differences in inhibitory control (IC; Eggers, De Nil, & Van den Bergh, 2010) would be supported by direct measurement of IC using a computer task. Method: Participants were 30 children who stutter (CWS; mean age = 7;05 years) and 30…

  5. Inhibitory Control in Childhood Stuttering

    ERIC Educational Resources Information Center

    Eggers, Kurt; De Nil, Luc F.; Van den Bergh, Bea R. H.

    2013-01-01

    Purpose: The purpose of this study was to investigate whether previously reported parental questionnaire-based differences in inhibitory control (IC; Eggers, De Nil, & Van den Bergh, 2010) would be supported by direct measurement of IC using a computer task. Method: Participants were 30 children who stutter (CWS; mean age = 7;05 years) and 30…

  6. Electropionics and fusion

    SciTech Connect

    Kenny, J.P. )

    1991-05-01

    This paper reports on the electropionic mass formula which does not differentiate between nuclei and elementary particles, but gives the deuteron a unique bifurcated space-time description. This hints at fusion products produced by anomalous intermediate mass states of 3026, 3194, and 3515 MeV/c{sup 2} that then decay to produce energy. Another unique possibility in electropionics is that no fusion of deuterons occurs, but the deuteron is changed by electron capture into a D-meson that then decays to produce observed cold fusion energies. All these cold fusion electropionic reactions violate baryon conservation but do produce energy yields consistent with reported cold fusion decay products and energy levels.

  7. InFusion: Advancing Discovery of Fusion Genes and Chimeric Transcripts from Deep RNA-Sequencing Data

    PubMed Central

    Okonechnikov, Konstantin; Imai-Matsushima, Aki; Seitz, Alexander; Meyer, Thomas F.; Garcia-Alcalde, Fernando

    2016-01-01

    Analysis of fusion transcripts has become increasingly important due to their link with cancer development. Since high-throughput sequencing approaches survey fusion events exhaustively, several computational methods for the detection of gene fusions from RNA-seq data have been developed. This kind of analysis, however, is complicated by native trans-splicing events, the splicing-induced complexity of the transcriptome and biases and artefacts introduced in experiments and data analysis. There are a number of tools available for the detection of fusions from RNA-seq data; however, certain differences in specificity and sensitivity between commonly used approaches have been found. The ability to detect gene fusions of different types, including isoform fusions and fusions involving non-coding regions, has not been thoroughly studied yet. Here, we propose a novel computational toolkit called InFusion for fusion gene detection from RNA-seq data. InFusion introduces several unique features, such as discovery of fusions involving intergenic regions, and detection of anti-sense transcription in chimeric RNAs based on strand-specificity. Our approach demonstrates superior detection accuracy on simulated data and several public RNA-seq datasets. This improved performance was also evident when evaluating data from RNA deep-sequencing of two well-established prostate cancer cell lines. InFusion identified 26 novel fusion events that were validated in vitro, including alternatively spliced gene fusion isoforms and chimeric transcripts that include intergenic regions. The toolkit is freely available to download from http:/bitbucket.org/kokonech/infusion. PMID:27907167

  8. InFusion: Advancing Discovery of Fusion Genes and Chimeric Transcripts from Deep RNA-Sequencing Data.

    PubMed

    Okonechnikov, Konstantin; Imai-Matsushima, Aki; Paul, Lukas; Seitz, Alexander; Meyer, Thomas F; Garcia-Alcalde, Fernando

    2016-01-01

    Analysis of fusion transcripts has become increasingly important due to their link with cancer development. Since high-throughput sequencing approaches survey fusion events exhaustively, several computational methods for the detection of gene fusions from RNA-seq data have been developed. This kind of analysis, however, is complicated by native trans-splicing events, the splicing-induced complexity of the transcriptome and biases and artefacts introduced in experiments and data analysis. There are a number of tools available for the detection of fusions from RNA-seq data; however, certain differences in specificity and sensitivity between commonly used approaches have been found. The ability to detect gene fusions of different types, including isoform fusions and fusions involving non-coding regions, has not been thoroughly studied yet. Here, we propose a novel computational toolkit called InFusion for fusion gene detection from RNA-seq data. InFusion introduces several unique features, such as discovery of fusions involving intergenic regions, and detection of anti-sense transcription in chimeric RNAs based on strand-specificity. Our approach demonstrates superior detection accuracy on simulated data and several public RNA-seq datasets. This improved performance was also evident when evaluating data from RNA deep-sequencing of two well-established prostate cancer cell lines. InFusion identified 26 novel fusion events that were validated in vitro, including alternatively spliced gene fusion isoforms and chimeric transcripts that include intergenic regions. The toolkit is freely available to download from http:/bitbucket.org/kokonech/infusion.

  9. Information Fusion of Conflicting Input Data.

    PubMed

    Mönks, Uwe; Dörksen, Helene; Lohweg, Volker; Hübner, Michael

    2016-10-29

    Sensors, and also actuators or external sources such as databases, serve as data sources in order to realise condition monitoring of industrial applications or the acquisition of characteristic parameters like production speed or reject rate. Modern facilities create such a large amount of complex data that a machine operator is unable to comprehend and process the information contained in the data. Thus, information fusion mechanisms gain increasing importance. Besides the management of large amounts of data, further challenges towards the fusion algorithms arise from epistemic uncertainties (incomplete knowledge) in the input signals as well as conflicts between them. These aspects must be considered during information processing to obtain reliable results, which are in accordance with the real world. The analysis of the scientific state of the art shows that current solutions fulfil said requirements at most only partly. This article proposes the multilayered information fusion system MACRO (multilayer attribute-based conflict-reducing observation) employing the μBalTLCS (fuzzified balanced two-layer conflict solving) fusion algorithm to reduce the impact of conflicts on the fusion result. The performance of the contribution is shown by its evaluation in the scope of a machine condition monitoring application under laboratory conditions. Here, the MACRO system yields the best results compared to state-of-the-art fusion mechanisms. The utilised data is published and freely accessible.

  10. Information Fusion of Conflicting Input Data

    PubMed Central

    Mönks, Uwe; Dörksen, Helene; Lohweg, Volker; Hübner, Michael

    2016-01-01

    Sensors, and also actuators or external sources such as databases, serve as data sources in order to realise condition monitoring of industrial applications or the acquisition of characteristic parameters like production speed or reject rate. Modern facilities create such a large amount of complex data that a machine operator is unable to comprehend and process the information contained in the data. Thus, information fusion mechanisms gain increasing importance. Besides the management of large amounts of data, further challenges towards the fusion algorithms arise from epistemic uncertainties (incomplete knowledge) in the input signals as well as conflicts between them. These aspects must be considered during information processing to obtain reliable results, which are in accordance with the real world. The analysis of the scientific state of the art shows that current solutions fulfil said requirements at most only partly. This article proposes the multilayered information fusion system MACRO (multilayer attribute-based conflict-reducing observation) employing the μBalTLCS (fuzzified balanced two-layer conflict solving) fusion algorithm to reduce the impact of conflicts on the fusion result. The performance of the contribution is shown by its evaluation in the scope of a machine condition monitoring application under laboratory conditions. Here, the MACRO system yields the best results compared to state-of-the-art fusion mechanisms. The utilised data is published and freely accessible. PMID:27801874

  11. Trends in fusion reactor safety research

    SciTech Connect

    Herring, J.S.; Holland, D.F.; Piet, S.J.

    1991-01-01

    Fusion has the potential to be an attractive energy source. From the safety and environmental perspective, fusion must avoid concerns about catastrophic accidents and unsolvable waste disposal. In addition, fusion must achieve an acceptable level of risk from operational accidents that result in public exposure and economic loss. Finally, fusion reactors must control routine radioactive effluent, particularly tritium. Major progress in achieving this potential rests on development of low-activation materials or alternative fuels. The safety and performance of various material choices and fuels for commercial fusion reactors can be investigated relatively inexpensively through reactor design studies. These studies bring together experts in a wide range of backgrounds and force the group to either agree on a reactor design or identify areas for further study. Fusion reactors will be complex with distributed radioactive inventories. The next generation of experiments will be critical in demonstrating that acceptable levels of safe operation can be achieved. These machines will use materials which are available today and for which a large database exists (e.g. for 316 stainless steel). Researchers have developed a good understanding of the risks associated with operation of these devices. Specifically, consequences from coolant system failures, loss of vacuum events, tritium releases, and liquid metal reactions have been studied. Recent studies go beyond next step designs and investigate commercial reactor concerns including tritium release and liquid metal reactions. 18 refs.

  12. Mutual control of membrane fission and fusion proteins.

    PubMed

    Peters, Christopher; Baars, Tonie L; Bühler, Susanne; Mayer, Andreas

    2004-11-24

    Membrane fusion and fission are antagonistic reactions controlled by different proteins. Dynamins promote membrane fission by GTP-driven changes of conformation and polymerization state, while SNAREs fuse membranes by forming complexes between t- and v-SNAREs from apposed vesicles. Here, we describe a role of the dynamin-like GTPase Vps1p in fusion of yeast vacuoles. Vps1p forms polymers that couple several t-SNAREs together. At the onset of fusion, the SNARE-activating ATPase Sec18p/NSF and the t-SNARE depolymerize Vps1p and release it from the membrane. This activity is independent of the SNARE coactivator Sec17p/alpha-SNAP and of the v-SNARE. Vps1p release liberates the t-SNAREs for initiating fusion and at the same time disrupts fission activity. We propose that reciprocal control between fusion and fission components exists, which may prevent futile cycles of fission and fusion.

  13. Structural characterization of Mumps virus fusion protein core

    SciTech Connect

    Liu Yueyong; Xu Yanhui; Lou Zhiyong; Zhu Jieqing; Hu Xuebo; Gao, George F.; Qiu Bingsheng . E-mail: Qiubs@sun.im.ac.cn; Rao Zihe . E-mail: raozh@xtal.tsinghua.edu.cn; Tien, Po . E-mail: tienpo@sun.im.ac.cn

    2006-09-29

    The fusion proteins of enveloped viruses mediating the fusion between the viral and cellular membranes comprise two discontinuous heptad repeat (HR) domains located at the ectodomain of the enveloped glycoproteins. The crystal structure of the fusion protein core of Mumps virus (MuV) was determined at 2.2 A resolution. The complex is a six-helix bundle in which three HR1 peptides form a central highly hydrophobic coiled-coil and three HR2 peptides pack against the hydrophobic grooves on the surface of central coiled-coil in an oblique antiparallel manner. Fusion core of MuV, like those of simian virus 5 and human respiratory syncytium virus, forms typical 3-4-4-4-3 spacing. The similar charecterization in HR1 regions, as well as the existence of O-X-O motif in extended regions of HR2 helix, suggests a basic rule for the formation of the fusion core of viral fusion proteins.

  14. Hohlraum manufacture for inertial confinement fusion

    SciTech Connect

    Foreman, L.R.; Gobby, P.; Bartos, J.

    1994-07-01

    Hohlraums are an integral part of indirect drive targets for Inertial Confinement Fusion (ICF) research. Hohlraums are made by an electroforming process that combines elements of micromachining and coating technology. The authors describe how these target element are made and extension of the method that allow fabrication of other, more complex target components.

  15. Engineered staphylococcal protein A's IgG-binding domain with cathepsin L inhibitory activity

    SciTech Connect

    Bratkovic, Tomaz . E-mail: tomaz.bratkovic@ffa.uni-lj.si; Berlec, Ales; Popovic, Tatjana; Lunder, Mojca; Kreft, Samo; Urleb, Uros; Strukelj, Borut

    2006-10-13

    Inhibitory peptide of papain-like cysteine proteases, affinity selected from a random disulfide constrained phage-displayed peptide library, was grafted to staphylococcal protein A's B domain. Scaffold protein was additionally modified in order to allow solvent exposed display of peptide loop. Correct folding of fusion proteins was confirmed by CD-spectroscopy and by the ability to bind the Fc-region of rabbit IgG, a characteristic of parent domain. The recombinant constructs inhibited cathepsin L with inhibitory constants in the low-micromolar range.

  16. New algorithm for CBR-RBR fusion with robust thresholds

    NASA Astrophysics Data System (ADS)

    Xu, Man; Yu, Haiyan; Shen, Jiang

    2012-11-01

    The case-based reasoning(CBR) and rule-based reasoning(RBR) fusion systems include a diverse range of fusion methods and their tasks are characterized by interleaving combination of the reasoning procedures. Existing approaches cannot clarify the complex relationships between data from the knowledge sources nor uniformly represent the heterogeneous case and rule knowledge in one fusion space. As a result, existing approaches fail to solve system fragility due to knowledge uncertainty and reasoning unreliability. For the purpose of addressing the difficulties, a novel algorithm for CBR-RBR fusion with robust thresholds(CRFRT) is proposed. Heterogeneous case and rule knowledge are uniformly represented in one defined fusion unitary space. The robust thresholds have been achieved to distinguish the complex relationships between meta-knowledge in the fusion space and to enhance system capacity of knowledge identification. Furthermore, fusion reasoning strategies are constructed for CRFRT and its procedure based on which robust solution of the fusion reasoning problem is obtained. Finally, CRFRT is validated by benchmark problems in machine learning. Compared with other CBR and RBR approaches, the reasoning efficiency and accuracy are increased by 5% and 2.2% respectively. The variations of system accuracy are decreased by 2% to 3.8%. The above results show that the CRFRT algorithm boosts the system's effectiveness and robustness. The proposed CRFRT can solve the fragility of complex intelligence decision system and give quality performance for fault diagnosis.

  17. Fusion Studies in Japan

    NASA Astrophysics Data System (ADS)

    Ogawa, Yuichi

    2016-05-01

    A new strategic energy plan decided by the Japanese Cabinet in 2014 strongly supports the steady promotion of nuclear fusion development activities, including the ITER project and the Broader Approach activities from the long-term viewpoint. Atomic Energy Commission (AEC) in Japan formulated the Third Phase Basic Program so as to promote an experimental fusion reactor project. In 2005 AEC has reviewed this Program, and discussed on selection and concentration among many projects of fusion reactor development. In addition to the promotion of ITER project, advanced tokamak research by JT-60SA, helical plasma experiment by LHD, FIREX project in laser fusion research and fusion engineering by IFMIF were highly prioritized. Although the basic concept is quite different between tokamak, helical and laser fusion researches, there exist a lot of common features such as plasma physics on 3-D magnetic geometry, high power heat load on plasma facing component and so on. Therefore, a synergetic scenario on fusion reactor development among various plasma confinement concepts would be important.

  18. Particle beam fusion

    SciTech Connect

    1980-12-31

    Today, in keeping with Sandia Laboratories` designation by the Department of Energy as the lead laboratory for the pulsed power approach to fusion, its efforts include major research activities and the construction of new facilities at its Albuquerque site. Additionally, in its capacity as lead laboratory, Sandia coordinates DOE-supported pulsed power fusion work at other government operated laboratories, with industrial contractors, and universities. The beginning of Sandia`s involvement in developing fusion power was an outgrowth of its contributions to the nation`s nuclear weapon program. The Laboratories` work in the early 1960`s emphasized the use of pulsed radiation environments to test the resistance of US nuclear weapons to enemy nuclear bursts. A careful study of options for fusion power indicated that Sandia`s expertise in the pulsed power field could provide a powerful match to ignite fusion fuel. Although creating test environments is an achieved goal of Sandia`s overall program, this work and other military tasks protected by appropriate security regulations will continue, making full use of the same pulsed power technology and accelerators as the fusion-for-energy program. Major goals of Sandia`s fusion program including the following: (1) complete a particle accelerator to deliver sufficient beam energy for igniting fusion targets; (2) obtain net energy gain, this goal would provide fusion energy output in excess of energy stored in the accelerator; (3) develop a technology base for the repetitive ignition of pellets in a power reactor. After accomplishing these goals, the technology will be introduced to the nation`s commercial sector.

  19. Mixed-mode synchronization between two inhibitory neurons with post-inhibitory rebound

    NASA Astrophysics Data System (ADS)

    Nagornov, Roman; Osipov, Grigory; Komarov, Maxim; Pikovsky, Arkady; Shilnikov, Andrey

    2016-07-01

    We study an array of activity rhythms generated by a half-center oscillator (HCO), represented by a pair of reciprocally coupled neurons with post-inhibitory rebounds (PIR). Such coupling-induced bursting possesses two time scales, one for fast spiking and another for slow quiescent periods, is shown to exhibit an array of synchronization properties. We discuss several HCO configurations constituted by two endogenous bursters, by tonic-spiking and quiescent neurons, as well as mixed-mode configurations composed of neurons of different type. We demonstrate that burst synchronization can be accompanied by complex, often chaotic, interactions of fast spikes within synchronized bursts.

  20. Spherical torus fusion reactor

    DOEpatents

    Martin Peng, Y.K.M.

    1985-10-03

    The object of this invention is to provide a compact torus fusion reactor with dramatic simplification of plasma confinement design. Another object of this invention is to provide a compact torus fusion reactor with low magnetic field and small aspect ratio stable plasma confinement. In accordance with the principles of this invention there is provided a compact toroidal-type plasma confinement fusion reactor in which only the indispensable components inboard of a tokamak type of plasma confinement region, mainly a current conducting medium which carries electrical current for producing a toroidal magnet confinement field about the toroidal plasma region, are retained.

  1. Vaccination with Dendritic Cell Myeloma Fusions in Conjunction With Stem Cell Transplantation and PD1 Blockade

    DTIC Science & Technology

    2010-05-01

    glycol. Mean expression of PDL- 1 was 97% on DCs (n=5, Figure 1), and 45% on patient derived myeloma cells (n=6, Figure 1). In addition, mean... expression of PDL-1 was 90% on DC/ myeloma fusions (n=2, Figure 2), suggesting this pathway may provide an inhibitory signal that blunts fusion mediated...immunologic response. Expression of PD-1 on T cells isolated from patients with multiple myeloma : In infectious disease models, upregulation of T

  2. Characterization of the cell growth inhibitory effects of a novel DNA-intercalating bipyridyl-thiourea-Pt(II) complex in cisplatin-sensitive and -resistant human ovarian cancer cells.

    PubMed

    Marverti, Gaetano; Ligabue, Alessio; Montanari, Monica; Guerrieri, Davide; Cusumano, Matteo; Di Pietro, Maria Letizia; Troiano, Leonarda; Di Vono, Elena; Iotti, Stefano; Farruggia, Giovanna; Wolf, Federica; Monti, Maria Giuseppina; Frassineti, Chiara

    2011-02-01

    The cellular effects of a novel DNA-intercalating agent, the bipyridyl complex of platinum(II) with diphenyl thiourea, [Pt(bipy)(Ph(2)-tu)(2)]Cl(2), has been analyzed in the cisplatin (cDDP)-sensitive human ovarian carcinoma cell line, 2008, and its -resistant variant, C13* cells, in which the highest accumulation and cytotoxicity was found among six related bipyridyl thiourea complexes. We also show here that this complex causes reactive oxygen species to form and inhibits topoisomerase II activity to a greater extent in the sensitive than in the resistant line. The impairment of this enzyme led to DNA damage, as shown by the comet assay. As a consequence, cell cycle distribution has also been greatly perturbed in both lines. Morphological analysis revealed deep cellular derangement with the presence of cellular masses, together with increased membrane permeability and depolarization of the mitochondrial membrane. Some of these effects, sometimes differentially evident between the two cell lines, might also be related to the decrease of total cell magnesium content caused by this thiourea complex both in sensitive and resistant cells, though the basal content of this ion was higher in the cDDP-resistant line. Altogether these results suggest that this compound exerts its cytotoxicity by mechanisms partly mediated by the resistance phenotype. In particular, cDDP-sensitive cells were affected mostly by impairing topoisomerase II activity and by increasing membrane permeability and the formation of reactive oxygen species; conversely, mitochondrial impairment appeared to play the most important role in the action of complex F in resistant cells.

  3. Fusion for Space Propulsion

    NASA Technical Reports Server (NTRS)

    Thio, Y. C. Francis; Schafer, Charles (Technical Monitor)

    2001-01-01

    There is little doubt that humans will attempt to explore and develop the solar system in this century. A large amount of energy will be required for accomplishing this. The need for fusion propulsion is discussed. For a propulsion system, there are three important thermodynamical attributes: (1) The absolute amount of energy available, (2) the propellant exhaust velocity, and (3) the jet power per unit mass of the propulsion system (specific power). For human exploration and development of the solar system, propellant exhaust velocity in excess of 100 km/s and specific power in excess of 10 kW/kg are required. Chemical combustion can produce exhaust velocity up to about 5 km/s. Nuclear fission processes typically result in producing energy in the form of heat that needs to be manipulated at temperatures limited by materials to about 2,800 K. Using the energy to heat a hydrogen propellant increases the exhaust velocity by only a factor of about two. Alternatively the energy can be converted into electricity which is then used to accelerate particles to high exhaust velocity. The necessary power conversion and conditioning equipment, however, increases the mass of the propulsion system for the same jet power by more than two orders of magnitude over chemical system, thus greatly limits the thrust-to-weight ratio attainable. The principal advantage of the fission process is that its development is relatively mature and is available right now. If fusion can be developed, fusion appears to have the best of all worlds in terms of propulsion - it can provide the absolute amount, the propellant exhaust velocity, and the high specific jet power. An intermediate step towards pure fusion propulsion is a bimodal system in which a fission reactor is used to provide some of the energy to drive a fusion propulsion unit. The technical issues related to fusion for space propulsion are discussed. The technical priorities for developing and applying fusion for propulsion are

  4. Adrenoceptors and colocolonic inhibitory reflex.

    PubMed

    Hughes, S F; Scott, S M; Pilot, M A; Williams, N S

    1999-12-01

    The colocolonic inhibitory reflex is characterized by inhibition of proximal colonic motility induced by distal colonic distension. The aim of this study was to investigate the underlying neural mechanisms of this reflex, in vivo, using an isolated loop of canine colon. In five beagle dogs, motility was recorded from an exteriorized colonic loop via a serosal strain gauge connected to a digital data logger and chart recorder. Inflation of a balloon in the distal colon resulted in inhibition of motility in the isolated loop. Inhibition of motor activity persisted following injection of propranolol (100 microg/kg intravenously), a beta-adrenoceptor antagonist, but was abolished following administration of the alpha2-adrenoceptor antagonist yohimbine (200 microg/kg intravenously). This study confirms that the colocolonic inhibitory reflex is mediated via the extrinsic nerves to the colon. As the reflex was abolished by alpha2-, but not beta-adrenoceptor blockade, this indicates that the reflex pathway involves alpha2-adrenoceptors.

  5. Autoinhibition of SNARE complex assembly by a conformational switch represents a conserved feature of syntaxins

    PubMed Central

    MacDonald, Chris; Munson, Mary; Bryant, Nia J.

    2017-01-01

    Regulation and specificity of membrane trafficking are required to maintain organelle integrity while performing essential cellular transport. Membrane fusion events in all eukaryotic cells are facilitated by the formation of specific SNARE (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor) complexes between proteins on opposing lipid bilayers. Although regulation of SNARE complex assembly is not well understood, it is clear that two conserved protein families, the Sx (syntaxin) and the SM (Sec1p/Munc18) proteins, are central to this process. Sxs are a subfamily of SNARE proteins; in addition to the coiled-coil SNARE motif, Sxs possess an N-terminal, autonomously folded, triple-helical (Habc) domain. For some Sxs, it has been demonstrated that this Habc domain exerts an autoinhibitory effect on SNARE complex assembly by making intramolecular contacts with the SNARE motif. SM proteins regulate membrane fusion through interactions with their cognate Sxs. One hypothesis for SM protein function is that they facilitate a switch of the Sx from a closed to an open conformation, thus lifting the inhibitory action of the Habc domain and freeing the SNARE motif to participate in SNARE complexes. However, whether these regulatory mechanisms are conserved throughout the Sx/SM protein families remains contentious as it is not clear whether the closed conformation represents a universal feature of Sxs. PMID:20074061

  6. Autoinhibition of SNARE complex assembly by a conformational switch represents a conserved feature of syntaxins.

    PubMed

    MacDonald, Chris; Munson, Mary; Bryant, Nia J

    2010-02-01

    Regulation and specificity of membrane trafficking are required to maintain organelle integrity while performing essential cellular transport. Membrane fusion events in all eukaryotic cells are facilitated by the formation of specific SNARE (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor) complexes between proteins on opposing lipid bilayers. Although regulation of SNARE complex assembly is not well understood, it is clear that two conserved protein families, the Sx (syntaxin) and the SM (Sec1p/Munc18) proteins, are central to this process. Sxs are a subfamily of SNARE proteins; in addition to the coiled-coil SNARE motif, Sxs possess an N-terminal, autonomously folded, triple-helical (Habc) domain. For some Sxs, it has been demonstrated that this Habc domain exerts an autoinhibitory effect on SNARE complex assembly by making intramolecular contacts with the SNARE motif. SM proteins regulate membrane fusion through interactions with their cognate Sxs. One hypothesis for SM protein function is that they facilitate a switch of the Sx from a closed to an open conformation, thus lifting the inhibitory action of the Habc domain and freeing the SNARE motif to participate in SNARE complexes. However, whether these regulatory mechanisms are conserved throughout the Sx/SM protein families remains contentious as it is not clear whether the closed conformation represents a universal feature of Sxs.

  7. Cortical neurodynamics of inhibitory control.

    PubMed

    Hwang, Kai; Ghuman, Avniel S; Manoach, Dara S; Jones, Stephanie R; Luna, Beatriz

    2014-07-16

    The ability to inhibit prepotent responses is critical for successful goal-directed behaviors. To investigate the neural basis of inhibitory control, we conducted a magnetoencephalography study where human participants performed the antisaccade task. Results indicated that neural oscillations in the prefrontal cortex (PFC) showed significant task modulations in preparation to suppress saccades. Before successfully inhibiting a saccade, beta-band power (18-38 Hz) in the lateral PFC and alpha-band power (10-18 Hz) in the frontal eye field (FEF) increased. Trial-by-trial prestimulus FEF alpha-band power predicted successful saccadic inhibition. Further, inhibitory control enhanced cross-frequency amplitude coupling between PFC beta-band (18-38 Hz) activity and FEF alpha-band activity, and the coupling appeared to be initiated by the PFC. Our results suggest a generalized mechanism for top-down inhibitory control: prefrontal beta-band activity initiates alpha-band activity for functional inhibition of the effector and/or sensory system.

  8. Cortical Neurodynamics of Inhibitory Control

    PubMed Central

    Ghuman, Avniel S.; Manoach, Dara S.; Jones, Stephanie R.; Luna, Beatriz

    2014-01-01

    The ability to inhibit prepotent responses is critical for successful goal-directed behaviors. To investigate the neural basis of inhibitory control, we conducted a magnetoencephalography study where human participants performed the antisaccade task. Results indicated that neural oscillations in the prefrontal cortex (PFC) showed significant task modulations in preparation to suppress saccades. Before successfully inhibiting a saccade, beta-band power (18–38 Hz) in the lateral PFC and alpha-band power (10–18 Hz) in the frontal eye field (FEF) increased. Trial-by-trial prestimulus FEF alpha-band power predicted successful saccadic inhibition. Further, inhibitory control enhanced cross-frequency amplitude coupling between PFC beta-band (18–38 Hz) activity and FEF alpha-band activity, and the coupling appeared to be initiated by the PFC. Our results suggest a generalized mechanism for top-down inhibitory control: prefrontal beta-band activity initiates alpha-band activity for functional inhibition of the effector and/or sensory system. PMID:25031398

  9. On cold fusion

    SciTech Connect

    Spinrad, B.I. )

    1990-03-01

    This paper argues that a high negative voltage on a metal into which deuterium is soaked might enhance fusion reactions. The author discusses how this may have been the way Fleischmann and Pons achieved their results.

  10. Laser-Driven Fusion.

    ERIC Educational Resources Information Center

    Gibson, A. F.

    1980-01-01

    Discusses the present status and future prospects of laser-driven fusion. Current research (which is classified under three main headings: laser-matter interaction processes, compression, and laser development) is also presented. (HM)

  11. Laser-Driven Fusion.

    ERIC Educational Resources Information Center

    Gibson, A. F.

    1980-01-01

    Discusses the present status and future prospects of laser-driven fusion. Current research (which is classified under three main headings: laser-matter interaction processes, compression, and laser development) is also presented. (HM)

  12. Viral membrane fusion

    PubMed Central

    Harrison, Stephen C

    2008-01-01

    Infection by viruses having lipid-bilayer envelopes proceeds through fusion of the viral membrane with a membrane of the target cell. Viral ‘fusion proteins’ facilitate this process. They vary greatly in structure, but all seem to have a common mechanism of action, in which a ligand-triggered, large-scale conformational change in the fusion protein is coupled to apposition and merger of the two bilayers. We describe three examples—the influenza virus hemagglutinin, the flavivirus E protein and the vesicular stomatitis virus G protein—in some detail, to illustrate the ways in which different structures have evolved to implement this common mechanism. Fusion inhibitors can be effective antiviral agents. PMID:18596815

  13. Fusion-breeder program

    SciTech Connect

    Moir, R.W.

    1982-11-19

    The various approaches to a combined fusion-fission reactor for the purpose of breeding /sup 239/Pu and /sup 233/U are described. Design aspects and cost estimates for fuel production and electricity generation are discussed. (MOW)

  14. Virus—Cell—Fusion

    NASA Astrophysics Data System (ADS)

    Aranda, S.; Aranda-Espinoza, H.

    1998-08-01

    The first step of the viral-fusion mechanism is studied in terms of energetically favorable configurations of the target membrane and the haemagglutinin (HA) protein, which is presumed to be involved in the influenza viral fusion. It is found that this first step of viral-fusion depends strongly on the elastic moduli of the target membrane. Two viral-fusion mechanisms are studied: i).—When the HA protein is tilted, and therefore induces a distortion of the target membrane. In this case, the acceptance of the configuration depends on the stiffness of the target membrane. ii).—The HA protein has a conformational change and a subunit of HA penetrates the target membrane. In this case, the acceptance of the configuration depends on the spontaneous curvature of the target membrane.

  15. Cold nuclear fusion

    SciTech Connect

    Tsyganov, E. N.

    2012-02-15

    Recent accelerator experiments on fusion of various elements have clearly demonstrated that the effective cross-sections of these reactions depend on what material the target particle is placed in. In these experiments, there was a significant increase in the probability of interaction when target nuclei are imbedded in a conducting crystal or are a part of it. These experiments open a new perspective on the problem of so-called cold nuclear fusion.

  16. Glossary of fusion energy

    NASA Astrophysics Data System (ADS)

    Whitson, M. O.

    1985-02-01

    The Glossary of Fusion Energy is an attempt to present a concise, yet comprehensive collection of terms that may be beneficial to scientists and laymen who are directly or tangentially concerned with this burgeoning energy enterprise. Included are definitions of terms in theoretical plasma physics, controlled thermonuclear fusion, and some related physics concepts. Also, short descriptions of some of the major thermonuclear experiments currently under way in the world today are included.

  17. Fusion ignition research experiment

    SciTech Connect

    Dale Meade

    2000-07-18

    Understanding the properties of high gain (alpha-dominated) fusion plasmas in an advanced toroidal configuration is the largest remaining open issue that must be addressed to provide the scientific foundation for an attractive magnetic fusion reactor. The critical parts of this science can be obtained in a compact high field tokamak which is also likely to provide the fastest and least expensive path to understanding alpha-dominated plasmas in advanced toroidal systems.

  18. Gene Fusion: A Genome Wide Survey

    NASA Technical Reports Server (NTRS)

    Liang, Ping; Riley, Monica

    2001-01-01

    As a well known fact, organisms form larger and complex multimodular (composite or chimeric) and mostly multi-functional proteins through gene fusion of two or more individual genes which have independent evolution histories and functions. We call each of these components a module. The existence of multimodular proteins may improves the efficiency in gene regulation and in cellular functions, and thus may give the host organism advantages in adaptation to environments. Analysis of all gene fusions in present-day organisms should allow us to examine the patterns of gene fusion in context with cellular functions, to trace back the evolution processes from the ancient smaller and uni-functional proteins to the present-day larger and complex multi-functional proteins, and to estimate the minimal number of ancestor proteins that existed in the last common ancestor for all life on earth. Although many multimodular proteins have been experimentally known, identification of gene fusion events systematically at genome scale had not been possible until recently when large number of completed genome sequences have been becoming available. In addition, technical difficulties for such analysis also exist due to the complexity of this biological and evolutionary process. We report from this study a new strategy to computationally identify multimodular proteins using completed genome sequences and the results surveyed from 22 organisms with the data from over 40 organisms to be presented during the meeting. Additional information is contained in the original extended abstract.

  19. ITER Fusion Energy

    ScienceCinema

    Dr. Norbert Holtkamp

    2016-07-12

    ITER (in Latin “the way”) is designed to demonstrate the scientific and technological feasibility of fusion energy. Fusion is the process by which two light atomic nuclei combine to form a heavier over one and thus release energy. In the fusion process two isotopes of hydrogen – deuterium and tritium – fuse together to form a helium atom and a neutron. Thus fusion could provide large scale energy production without greenhouse effects; essentially limitless fuel would be available all over the world. The principal goals of ITER are to generate 500 megawatts of fusion power for periods of 300 to 500 seconds with a fusion power multiplication factor, Q, of at least 10. Q ? 10 (input power 50 MW / output power 500 MW). The ITER Organization was officially established in Cadarache, France, on 24 October 2007. The seven members engaged in the project – China, the European Union, India, Japan, Korea, Russia and the United States – represent more than half the world’s population. The costs for ITER are shared by the seven members. The cost for the construction will be approximately 5.5 billion Euros, a similar amount is foreseen for the twenty-year phase of operation and the subsequent decommissioning.

  20. Magnetized Target Fusion

    NASA Technical Reports Server (NTRS)

    Griffin, Steven T.

    2002-01-01

    Magnetized target fusion (MTF) is under consideration as a means of building a low mass, high specific impulse, and high thrust propulsion system for interplanetary travel. This unique combination is the result of the generation of a high temperature plasma by the nuclear fusion process. This plasma can then be deflected by magnetic fields to provide thrust. Fusion is initiated by a small traction of the energy generated in the magnetic coils due to the plasma's compression of the magnetic field. The power gain from a fusion reaction is such that inefficiencies due to thermal neutrons and coil losses can be overcome. Since the fusion reaction products are directly used for propulsion and the power to initiate the reaction is directly obtained from the thrust generation, no massive power supply for energy conversion is required. The result should be a low engine mass, high specific impulse and high thrust system. The key is to successfully initiate fusion as a proof-of-principle for this application. Currently MSFC is implementing MTF proof-of-principle experiments. This involves many technical details and ancillary investigations. Of these, selected pertinent issues include the properties, orientation and timing of the plasma guns and the convergence and interface development of the "pusher" plasma. Computer simulations of the target plasma's behavior under compression and the convergence and mixing of the gun plasma are under investigation. This work is to focus on the gun characterization and development as it relates to plasma initiation and repeatability.

  1. Magnetized Target Fusion

    NASA Technical Reports Server (NTRS)

    Griffin, Steven T.

    2002-01-01

    Magnetized target fusion (MTF) is under consideration as a means of building a low mass, high specific impulse, and high thrust propulsion system for interplanetary travel. This unique combination is the result of the generation of a high temperature plasma by the nuclear fusion process. This plasma can then be deflected by magnetic fields to provide thrust. Fusion is initiated by a small traction of the energy generated in the magnetic coils due to the plasma's compression of the magnetic field. The power gain from a fusion reaction is such that inefficiencies due to thermal neutrons and coil losses can be overcome. Since the fusion reaction products are directly used for propulsion and the power to initiate the reaction is directly obtained from the thrust generation, no massive power supply for energy conversion is required. The result should be a low engine mass, high specific impulse and high thrust system. The key is to successfully initiate fusion as a proof-of-principle for this application. Currently MSFC is implementing MTF proof-of-principle experiments. This involves many technical details and ancillary investigations. Of these, selected pertinent issues include the properties, orientation and timing of the plasma guns and the convergence and interface development of the "pusher" plasma. Computer simulations of the target plasma's behavior under compression and the convergence and mixing of the gun plasma are under investigation. This work is to focus on the gun characterization and development as it relates to plasma initiation and repeatability.

  2. 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.

  3. Membrane fusion mediated by coiled coils: a hypothesis.

    PubMed Central

    Bentz, J

    2000-01-01

    A molecular model of the low-pH-induced membrane fusion by influenza hemagglutinin (HA) is proposed based upon the hypothesis that the conformational change to the extended coiled coil creates a high-energy hydrophobic membrane defect in the viral envelope or HA expressing cell. It is known that 1) an aggregate of at least eight HAs is required at the fusion site, yet only two or three of these HAs need to undergo the "essential" conformational change for the first fusion pore to form (Bentz, J. 2000. Biophys. J. 78:000-000); 2) the formation of the first fusion pore signifies a stage of restricted lipid flow into the nascent fusion site; and 3) some HAs can partially insert their fusion peptides into their own viral envelopes at low pH. This suggests that the committed step for HA-mediated fusion begins with a tightly packed aggregate of HAs whose fusion peptides are inserted into their own viral envelope, which causes restricted lateral lipid flow within the HA aggregate. The transition of two or three HAs in the center of the aggregate to the extended coiled coil extracts the fusion peptide and creates a hydrophobic defect in the outer monolayer of the virion, which is stabilized by the closely packed HAs. These HAs are inhibited from diffusing away from the site to admit lateral lipid flow, in part because that would initially increase the surface area of hydrophobic exposure. The other obvious pathway to heal this hydrophobic defect, or some descendent, is recruitment of lipids from the outer monolayer of the apposed target membrane, i.e., fusion. Other viral fusion proteins and the SNARE fusion protein complex appear to fit within this hypothesis. PMID:10653801

  4. Review of the Inertial Fusion Energy Program

    SciTech Connect

    none,

    2004-03-29

    Igniting fusion fuel in the laboratory remains an alluring goal for two reasons: the desire to study matter under the extreme conditions needed for fusion burn, and the potential of harnessing the energy released as an attractive energy source for mankind. The inertial confinement approach to fusion involves rapidly compressing a tiny spherical capsule of fuel, initially a few millimeters in radius, to densities and temperatures higher than those in the core of the sun. The ignited plasma is confined solely by its own inertia long enough for a significant fraction of the fuel to burn before the plasma expands, cools down and the fusion reactions are quenched. The potential of this confinement approach as an attractive energy source is being studied in the Inertial Fusion Energy (IFE) program, which is the subject of this report. A complex set of interrelated requirements for IFE has motivated the study of novel potential solutions. Three types of “drivers” for fuel compression are presently studied: high-averagepower lasers (HAPL), heavy-ion (HI) accelerators, and Z-Pinches. The three main approaches to IFE are based on these drivers, along with the specific type of target (which contains the fuel capsule) and chamber that appear most promising for a particular driver.

  5. Materials issues in fusion reactors

    NASA Astrophysics Data System (ADS)

    Suri, A. K.; Krishnamurthy, N.; Batra, I. S.

    2010-02-01

    The world scientific community is presently engaged in one of the toughest technological tasks of the current century, namely, exploitation of nuclear fusion in a controlled manner for the benefit of mankind. Scientific feasibility of controlled fusion of the light elements in plasma under magnetic confinement has already been proven. International efforts in a coordinated and co-operative manner are presently being made to build ITER - the International Thermonuclear Experimental Reactor - to test, in this first step, the concept of 'Tokamak' for net fusion energy production. To exploit this new developing option of making energy available through the route of fusion, India too embarked on a robust fusion programme under which we now have a working tokamak - the Aditya and a steady state tokamak (SST-1), which is on the verge of functioning. The programme envisages further development in terms of making SST-2 followed by a DEMO and finally the fusion power reactor. Further, with the participation of India in the ITER program in 2005, and recent allocation of half - a - port in ITER for placing our Lead - Lithium Ceramic Breeder (LLCB) based Test Blanket Module (TBM), meant basically for breeding tritium and extracting high grade heat, the need to understand and address issues related to materials for these complex systems has become all the more necessary. Also, it is obvious that with increasing power from the SST stages to DEMO and further to PROTOTYPE, the increasing demands on performance of materials would necessitate discovery and development of new materials. Because of the 14.1 MeV neutrons that are generated in the D+T reaction exploited in a tokamak, the materials, especially those employed for the construction of the first wall, the diverter and the blanket segments, suffer crippling damage due to the high He/dpa ratios that result due to the high energy of the neutrons. To meet this challenge, the materials that need to be developed for the tokamaks

  6. Monetary rewards modulate inhibitory control.

    PubMed

    Herrera, Paula M; Speranza, Mario; Hampshire, Adam; Bekinschtein, Tristán A

    2014-01-01

    The ability to override a dominant response, often referred to as behavioral inhibition, is considered a key element of executive cognition. Poor behavioral inhibition is a defining characteristic of several neurological and psychiatric populations. Recently, there has been increasing interest in the motivational dimension of behavioral inhibition, with some experiments incorporating emotional contingencies in classical inhibitory paradigms such as the Go/NoGo and Stop Signal Tasks (SSTs). Several studies have reported a positive modulatory effect of reward on performance in pathological conditions such as substance abuse, pathological gambling, and Attention Deficit Hyperactive Disorder (ADHD). However, experiments that directly investigate the modulatory effects of reward magnitudes on the performance of inhibitory tasks are scarce and little is known about the finer grained relationship between motivation and inhibitory control. Here we probed the effect of reward magnitude and context on behavioral inhibition with three modified versions of the widely used SST. The pilot study compared inhibition performance during six blocks alternating neutral feedback, low, medium, and high monetary rewards. Study One compared increasing vs. decreasing rewards, with low, high rewards, and neutral feedback; whilst Study Two compared low and high reward magnitudes alone also in an increasing and decreasing reward design. The reward magnitude effect was not demonstrated in the pilot study, probably due to a learning effect induced by practice in this lengthy task. The reward effect per se was weak but the context (order of reward) was clearly suggested in Study One, and was particularly strongly confirmed in study two. In addition, these findings revealed a "kick start effect" over global performance measures. Specifically, there was a long lasting improvement in performance throughout the task when participants received the highest reward magnitudes at the beginning of the

  7. Monetary rewards modulate inhibitory control

    PubMed Central

    Herrera, Paula M.; Speranza, Mario; Hampshire, Adam; Bekinschtein, Tristán A.

    2014-01-01

    The ability to override a dominant response, often referred to as behavioral inhibition, is considered a key element of executive cognition. Poor behavioral inhibition is a defining characteristic of several neurological and psychiatric populations. Recently, there has been increasing interest in the motivational dimension of behavioral inhibition, with some experiments incorporating emotional contingencies in classical inhibitory paradigms such as the Go/NoGo and Stop Signal Tasks (SSTs). Several studies have reported a positive modulatory effect of reward on performance in pathological conditions such as substance abuse, pathological gambling, and Attention Deficit Hyperactive Disorder (ADHD). However, experiments that directly investigate the modulatory effects of reward magnitudes on the performance of inhibitory tasks are scarce and little is known about the finer grained relationship between motivation and inhibitory control. Here we probed the effect of reward magnitude and context on behavioral inhibition with three modified versions of the widely used SST. The pilot study compared inhibition performance during six blocks alternating neutral feedback, low, medium, and high monetary rewards. Study One compared increasing vs. decreasing rewards, with low, high rewards, and neutral feedback; whilst Study Two compared low and high reward magnitudes alone also in an increasing and decreasing reward design. The reward magnitude effect was not demonstrated in the pilot study, probably due to a learning effect induced by practice in this lengthy task. The reward effect per se was weak but the context (order of reward) was clearly suggested in Study One, and was particularly strongly confirmed in study two. In addition, these findings revealed a “kick start effect” over global performance measures. Specifically, there was a long lasting improvement in performance throughout the task when participants received the highest reward magnitudes at the beginning of the

  8. Crystal structure of snake venom acetylcholinesterase in complex with inhibitory antibody fragment Fab410 bound at the peripheral site: evidence for open and closed states of a back door channel.

    PubMed

    Bourne, Yves; Renault, Ludovic; Marchot, Pascale

    2015-01-16

    The acetylcholinesterase found in the venom of Bungarus fasciatus (BfAChE) is produced as a soluble, non-amphiphilic monomer with a canonical catalytic domain but a distinct C terminus compared with the other vertebrate enzymes. Moreover, the peripheral anionic site of BfAChE, a surface site located at the active site gorge entrance, bears two substitutions altering sensitivity to cationic inhibitors. Antibody Elec410, generated against Electrophorus electricus acetylcholinesterase (EeAChE), inhibits EeAChE and BfAChE by binding to their peripheral sites. However, both complexes retain significant residual catalytic activity, suggesting incomplete gorge occlusion by bound antibody and/or high frequency back door opening. To explore a novel acetylcholinesterase species, ascertain the molecular bases of inhibition by Elec410, and document the determinants and mechanisms for back door opening, we solved a 2.7-Å resolution crystal structure of natural BfAChE in complex with antibody fragment Fab410. Crystalline BfAChE forms the canonical dimer found in all acetylcholinesterase structures. Equally represented open and closed states of a back door channel, associated with alternate positions of a tyrosine phenol ring at the active site base, coexist in each subunit. At the BfAChE molecular surface, Fab410 is seated on the long Ω-loop between two N-glycan chains and partially occludes the gorge entrance, a position that fully reflects the available mutagenesis and biochemical data. Experimentally based flexible molecular docking supports a similar Fab410 binding mode onto the EeAChE antigen. These data document the molecular and dynamic peculiarities of BfAChE with high frequency back door opening, and the mode of action of Elec410 as one of the largest peptidic inhibitors targeting the acetylcholinesterase peripheral site. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Fusion for Space Propulsion

    NASA Technical Reports Server (NTRS)

    Thio, Y. C. Francis; Schafer, Charles (Technical Monitor)

    2001-01-01

    There is little doubt that humans will attempt to explore and develop the solar system in this century. A large amount of energy will be required for accomplishing this. The need for fusion propulsion is discussed. For a propulsion system, there are three important thermodynamical attributes: (1) The absolute amount of energy available, (2) the propellant exhaust velocity, and (3) the jet power per unit mass of the propulsion system (specific power). For human exploration and development of the solar system, propellant exhaust velocity in excess of 100 km/s and specific power in excess of 10 kW/kg are required. Chemical combustion can produce exhaust velocity up to about 5 km/s. Nuclear fission processes typically result in producing energy in the form of heat that needs to be manipulated at temperatures limited by materials to about 2,800 K. Using the energy to heat a hydrogen propellant increases the exhaust velocity by only a factor of about two. Alternatively the energy can be converted into electricity which is then used to accelerate particles to high exhaust velocity. The necessary power conversion and conditioning equipment, however, increases the mass of the propulsion system for the same jet power by more than two orders of magnitude over chemical system, thus greatly limits the thrust-to-weight ratio attainable. The principal advantage of the fission process is that its development is relatively mature and is available right now. If fusion can be developed, fusion appears to have the best of all worlds in terms of propulsion - it can provide the absolute amount, the propellant exhaust velocity, and the high specific jet power. An intermediate step towards pure fusion propulsion is a bimodal system in which a fission reactor is used to provide some of the energy to drive a fusion propulsion unit. The technical issues related to fusion for space propulsion are discussed. The technical priorities for developing and applying fusion for propulsion are

  10. Fusion for Space Propulsion

    NASA Technical Reports Server (NTRS)

    Thio, Y. C. Francis; Schafer, Charles (Technical Monitor)

    2001-01-01

    There is little doubt that humans will attempt to explore and develop the solar system in this century. A large amount of energy will be required for accomplishing this. The need for fusion propulsion is discussed. For a propulsion system, there are three important thermodynamical attributes: (1) The absolute amount of energy available, (2) the propellant exhaust velocity, and (3) the jet power per unit mass of the propulsion system (specific power). For human exploration and development of the solar system, propellant exhaust velocity in excess of 100 km/s and specific power in excess of 10 kW/kg are required. Chemical combustion can produce exhaust velocity up to about 5 km/s. Nuclear fission processes typically result in producing energy in the form of heat that needs to be manipulated at temperatures limited by materials to about 2,800 K. Using the energy to heat a hydrogen propellant increases the exhaust velocity by only a factor of about two. Alternatively the energy can be converted into electricity which is then used to accelerate particles to high exhaust velocity. The necessary power conversion and conditioning equipment, however, increases the mass of the propulsion system for the same jet power by more than two orders of magnitude over chemical system, thus greatly limits the thrust-to-weight ratio attainable. The principal advantage of the fission process is that its development is relatively mature and is available right now. If fusion can be developed, fusion appears to have the best of all worlds in terms of propulsion - it can provide the absolute amount, the propellant exhaust velocity, and the high specific jet power. An intermediate step towards pure fusion propulsion is a bimodal system in which a fission reactor is used to provide some of the energy to drive a fusion propulsion unit. The technical issues related to fusion for space propulsion are discussed. The technical priorities for developing and applying fusion for propulsion are

  11. Multi-source data fusion and modeling to assess and communicate complex flood dynamics to support decision-making for downstream areas of dams: The 2011 hurricane irene and schoharie creek floods, NY

    NASA Astrophysics Data System (ADS)

    Renschler, Chris S.; Wang, Zhihao

    2017-10-01

    In light of climate and land use change, stakeholders around the world are interested in assessing historic and likely future flood dynamics and flood extents for decision-making in watersheds with dams as well as limited availability of stream gages and costly technical resources. This research evaluates an assessment and communication approach of combining GIS, hydraulic modeling based on latest remote sensing and topographic imagery by comparing the results to an actual flood event and available stream gages. On August 28th 2011, floods caused by Hurricane Irene swept through a large rural area in New York State, leaving thousands of people homeless, devastating towns and cities. Damage was widespread though the estimated and actual floods inundation and associated return period were still unclear since the flooding was artificially increased by flood water release due to fear of a dam break. This research uses the stream section right below the dam between two stream gages North Blenheim and Breakabeen along Schoharie Creek as a case study site to validate the approach. The data fusion approach uses a GIS, commonly available data sources, the hydraulic model HEC-RAS as well as airborne LiDAR data that were collected two days after the flood event (Aug 30, 2011). The aerial imagery of the airborne survey depicts a low flow event as well as the evidence of the record flood such as debris and other signs of damage to validate the hydrologic simulation results with the available stream gauges. Model results were also compared to the official Federal Emergency Management Agency (FEMA) flood scenarios to determine the actual flood return period of the event. The dynamic of the flood levels was then used to visualize the flood and the actual loss of the Old Blenheim Bridge using Google Sketchup. Integration of multi-source data, cross-validation and visualization provides new ways to utilize pre- and post-event remote sensing imagery and hydrologic models to better

  12. Selective control of inhibitory synapse development by Slitrk3-PTPδ trans-synaptic interaction

    PubMed Central

    Takahashi, Hideto; Katayama, Kei-ichi; Sohya, Kazuhiro; Miyamoto, Hiroyuki; Prasad, Tuhina; Matsumoto, Yoshifumi; Ota, Maya; Yasuda, Hiroki; Tsumoto, Tadaharu; Aruga, Jun; Craig, Ann Marie

    2012-01-01

    Balanced development of excitatory and inhibitory synapses is required for normal brain function, and their imbalance may underlie pathogenesis of neuropsychiatric disorders. Compared with many identified trans-synaptic adhesion complexes that organize excitatory synapses, little is known about organizers specific for inhibitory synapses. Here we report Slit and NTRK-like family member 3 (Slitrk3) as a postsynaptic adhesion molecule that selectively regulates inhibitory synapse development via trans-interaction with axonal tyrosine phosphatase receptor PTPδ. Slitrk3 expressed in fibroblasts triggers only inhibitory presynaptic differentiation in contacting axons of cocultured rat hippocampal neurons. Recombinant Slitrk3 preferentially localizes to inhibitory postsynaptic sites. Slitrk3-deficient mice exhibit decreases in inhibitory but not excitatory synapse number and function in hippocampal CA1 neurons and exhibit increased seizure susceptibility and spontaneous epileptiform activity. Slitrk3 requires trans-interaction with axonal PTPδ to induce inhibitory presynaptic differentiation. These results identify Slitrk3-PTPδ as an inhibitory-specific trans-synaptic organizing complex required for normal functional GABAergic synapse development. PMID:22286174

  13. Fusion, magnetic confinement

    SciTech Connect

    Berk, H.L.

    1992-08-06

    An overview is presented of the principles of magnetic confinement of plasmas for the purpose of achieving controlled fusion conditions. Sec. 1 discusses the different nuclear fusion reactions which can be exploited in prospective fusion reactors and explains why special technologies need to be developed for the supply of tritium or {sup 3}He, the probable fuels. In Sec. 2 the Lawson condition, a criterion that is a measure of the quality of confinement relative to achieving fusion conditions, is explained. In Sec. 3 fluid equations are used to describe plasma confinement. Specific confinement configurations are considered. In Sec. 4 the orbits of particle sin magneti and electric fields are discussed. In Sec. 5 stability considerations are discussed. It is noted that confinement systems usually need to satisfy stability constraints imposed by ideal magnetohydrodynamic (MHD) theory. The paper culminates with a summary of experimental progress in magnetic confinement. Present experiments in tokamaks have reached the point that the conditions necessary to achieve fusion are being satisfied.

  14. Myoblast fusion in Drosophila

    SciTech Connect

    Haralalka, Shruti; Abmayr, Susan M.

    2010-11-01

    The body wall musculature of a Drosophila larva is composed of an intricate pattern of 30 segmentally repeated muscle fibers in each abdominal hemisegment. Each muscle fiber has unique spatial and behavioral characteristics that include its location, orientation, epidermal attachment, size and pattern of innervation. Many, if not all, of these properties are dictated by founder cells, which determine the muscle pattern and seed the fusion process. Myofibers are then derived from fusion between a specific founder cell and several fusion competent myoblasts (FCMs) fusing with as few as 3-5 FCMs in the small muscles on the most ventral side of the embryo and as many as 30 FCMs in the larger muscles on the dorsal side of the embryo. The focus of the present review is the formation of the larval muscles in the developing embryo, summarizing the major issues and players in this process. We have attempted to emphasize experimentally-validated details of the mechanism of myoblast fusion and distinguish these from the theoretically possible details that have not yet been confirmed experimentally. We also direct the interested reader to other recent reviews that discuss myoblast fusion in Drosophila, each with their own perspective on the process . With apologies, we use gene nomenclature as specified by Flybase (http://flybase.org) but provide Table 1 with alternative names and references.

  15. Fusion, magnetic confinement

    SciTech Connect

    Berk, H.L.

    1992-08-06

    An overview is presented of the principles of magnetic confinement of plasmas for the purpose of achieving controlled fusion conditions. Sec. 1 discusses the different nuclear fusion reactions which can be exploited in prospective fusion reactors and explains why special technologies need to be developed for the supply of tritium or {sup 3}He, the probable fuels. In Sec. 2 the Lawson condition, a criterion that is a measure of the quality of confinement relative to achieving fusion conditions, is explained. In Sec. 3 fluid equations are used to describe plasma confinement. Specific confinement configurations are considered. In Sec. 4 the orbits of particle sin magneti and electric fields are discussed. In Sec. 5 stability considerations are discussed. It is noted that confinement systems usually need to satisfy stability constraints imposed by ideal magnetohydrodynamic (MHD) theory. The paper culminates with a summary of experimental progress in magnetic confinement. Present experiments in tokamaks have reached the point that the conditions necessary to achieve fusion are being satisfied.

  16. Characterization of the HIV N-terminal fusion peptide-containing region in context of key gp41 fusion conformations.

    PubMed

    Sackett, Kelly; Wexler-Cohen, Yael; Shai, Yechiel

    2006-08-04

    Central to our understanding of human immunodeficiency virus-induced fusion is the high resolution structure of fragments of the gp41 fusion protein folded in a low energy core conformation. However, regions fundamental to fusion, like the fusion peptide (FP), have yet to be characterized in the context of the cognate protein regardless of its conformation. Based on conformation-specific monoclonal antibody recognition, we identified the polar region consecutive to the N36 fragment as a stabilizer of trimeric coiled-coil assembly, thereby enhancing inhibitory potency. This tertiary organization is retained in the context of the hydrophobic FP (N70 fragment). Our data indicate that the N70 fragment recapitulates the expected organization of this region in the viral fusion intermediate (N-terminal half of the pre-hairpin intermediate (N-PHI)), which happens to be the prime target for fusion inhibitors. Regarding the low energy conformation, we show for the first time core formation in the context of the FP (N70 core). The alpha-helical and coiled-coil stabilizing polar region confers substantial thermal stability to the core, whereas the hydrophobic FP does not add further stability. For the two key fusion conformations, N-PHI and N70 core, we find that the FP adopts a nonhelical structure and directs higher order assembly (assembly of coiled coils in N-PHI and assembly of bundles in the N70 core). This supra-molecular organization of coiled coils or folded cores is seen only in the context of the FP. This study is the first to characterize the FP region in the context of the folded core and provides a basic understanding of the role of the elusive FP for key gp41 fusion conformations.

  17. Nuclear Fusion Award 2009 speech Nuclear Fusion Award 2009 speech

    NASA Astrophysics Data System (ADS)

    Sabbagh, Steven Anthony

    2011-01-01

    of Dr Todd Evans, another significant mentor of mine, as winner of this prestigious award? Then, it happened. The paper covers several key topics related to high beta tokamak physics. For me, the greatest satisfaction in receiving this award is because it was the first Nuclear Fusion Award to recognize research on the National Spherical Torus Experiment (NSTX) located at the Princeton Plasma Physics Laboratory. The achievement of record stability parameters in a mega-Ampere class spherical torus (ST) device reported in the paper represents a multi-year effort, contributed to by the entire research team. Research to maintain such plasmas for an indefinite period continues today. Understanding RWM stabilization physics is crucial for this goal, and leveraging the high beta ST operating space uniquely tests theory for application to future STs and to tokamaks in general, including advanced operational scenarios of ITER. For instance, the RWM was found to have significant amplitude in components with the toroidal mode number greater than unity. This has important implications for general active RWM control. Evidence that the RWM passive stabilization physics and marginal stability criterion are indeed more complex than originally thought was shown in this paper. Present work shows the greater complexity has a direct impact on how we should extrapolate RWM stabilization to future devices. The paper also reported the qualitative observation of neoclassical toroidal viscosity (NTV), followed by a companion paper by our group in 2006 reporting the quantitative observation of this effect and comparison to theory. The physics of this interesting and important phenomenon was introduced to me by Professor J. Callen (who has given an overview talk at this conference including this subject) and Professor Kerchung Shaing of the University of Wisconsin, to whom I am quite indebted. The paper also reported the first measurement of resonant field amplification at high beta in the NSTX

  18. Liposome reconstitution of a minimal protein-mediated membrane fusion machine

    PubMed Central

    Top, Deniz; de Antueno, Roberto; Salsman, Jayme; Corcoran, Jennifer; Mader, Jamie; Hoskin, David; Touhami, Ahmed; Jericho, Manfred H; Duncan, Roy

    2005-01-01

    Biological membrane fusion is dependent on protein catalysts to mediate localized restructuring of lipid bilayers. A central theme in current models of protein-mediated membrane fusion involves the sequential refolding of complex homomeric or heteromeric protein fusion machines. The structural features of a new family of fusion-associated small transmembrane (FAST) proteins appear incompatible with existing models of membrane fusion protein function. While the FAST proteins function to induce efficient cell–cell fusion when expressed in transfected cells, it was unclear whether they function on their own to mediate membrane fusion or are dependent on cellular protein cofactors. Using proteoliposomes containing the purified p14 FAST protein of reptilian reovirus, we now show via liposome–cell and liposome–liposome fusion assays that p14 is both necessary and sufficient for membrane fusion. Stoichiometric and kinetic analyses suggest that the relative efficiency of p14-mediated membrane fusion rivals that of the more complex cellular and viral fusion proteins, making the FAST proteins the simplest known membrane fusion machines. PMID:16079913

  19. An Approach to Automated Fusion System Design and Adaptation

    PubMed Central

    Fritze, Alexander; Mönks, Uwe; Holst, Christoph-Alexander; Lohweg, Volker

    2017-01-01

    Industrial applications are in transition towards modular and flexible architectures that are capable of self-configuration and -optimisation. This is due to the demand of mass customisation and the increasing complexity of industrial systems. The conversion to modular systems is related to challenges in all disciplines. Consequently, diverse tasks such as information processing, extensive networking, or system monitoring using sensor and information fusion systems need to be reconsidered. The focus of this contribution is on distributed sensor and information fusion systems for system monitoring, which must reflect the increasing flexibility of fusion systems. This contribution thus proposes an approach, which relies on a network of self-descriptive intelligent sensor nodes, for the automatic design and update of sensor and information fusion systems. This article encompasses the fusion system configuration and adaptation as well as communication aspects. Manual interaction with the flexibly changing system is reduced to a minimum. PMID:28300762

  20. A fast, single-vesicle fusion assay mimics physiological SNARE requirements

    PubMed Central

    Karatekin, Erdem; Di Giovanni, Jérôme; Iborra, Cécile; Coleman, Jeff; O'Shaughnessy, Ben; Seagar, Michael; Rothman, James E.

    2010-01-01

    Almost all known intracellular fusion reactions are driven by formation of trans-SNARE complexes through pairing of vesicle-associated v-SNAREs with complementary t-SNAREs on target membranes. However, the number of SNARE complexes required for fusion is unknown, and there is controversy about whether additional proteins are required to explain the fast fusion which can occur in cells. Here we show that single vesicles containing the synaptic/exocytic v-SNAREs VAMP/synaptobrevin fuse rapidly with planar, supported bilayers containing the synaptic/exocytic t-SNAREs syntaxin-SNAP25. Fusion rates decreased dramatically when the number of externally oriented v-SNAREs per vesicle was reduced below 5–10, directly establishing this as the minimum number required for rapid fusion. Docking-to-fusion delay time distributions were consistent with a requirement that 5–11 t-SNAREs be recruited to achieve fusion, closely matching the v-SNARE requirement. PMID:20133592

  1. Peaceful Uses of Fusion

    DOE R&D Accomplishments Database

    Teller, E.

    1958-07-03

    Applications of thermonuclear energy for peaceful and constructive purposes are surveyed. Developments and problems in the release and control of fusion energy are reviewed. It is pointed out that the future of thermonuclear power reactors will depend upon the construction of a machine that produces more electric energy than it consumes. The fuel for thermonuclear reactors is cheap and practically inexhaustible. Thermonuclear reactors produce less dangerous radioactive materials than fission reactors and, when once brought under control, are not as likely to be subject to dangerous excursions. The interaction of the hot plasma with magnetic fields opens the way for the direct production of electricity. It is possible that explosive fusion energy released underground may be harnessed for the production of electricity before the same feat is accomplished in controlled fusion processes. Applications of underground detonations of fission devices in mining and for the enhancement of oil flow in large low-specific-yield formations are also suggested.

  2. Simulation of Fusion Plasmas

    ScienceCinema

    Holland, Chris [UC San Diego, San Diego, California, United States

    2016-07-12

    The upcoming ITER experiment (www.iter.org) represents the next major milestone in realizing the promise of using nuclear fusion as a commercial energy source, by moving into the “burning plasma” regime where the dominant heat source is the internal fusion reactions. As part of its support for the ITER mission, the US fusion community is actively developing validated predictive models of the behavior of magnetically confined plasmas. In this talk, I will describe how the plasma community is using the latest high performance computing facilities to develop and refine our models of the nonlinear, multiscale plasma dynamics, and how recent advances in experimental diagnostics are allowing us to directly test and validate these models at an unprecedented level.

  3. Fusion research at ORNL

    SciTech Connect

    Not Available

    1982-03-01

    The ORNL Fusion Program includes the experimental and theoretical study of two different classes of magnetic confinement schemes - systems with helical magnetic fields, such as the tokamak and stellarator, and the ELMO Bumpy Torus (EBT) class of toroidally linked mirror systems; the development of technologies, including superconducting magnets, neutral atomic beam and radio frequency (rf) heating systems, fueling systems, materials, and diagnostics; the development of databases for atomic physics and radiation effects; the assessment of the environmental impact of magnetic fusion; and the design of advanced demonstration fusion devices. The program involves wide collaboration, both within ORNL and with other institutions. The elements of this program are shown. This document illustrates the program's scope; and aims by reviewing recent progress.

  4. Spherical torus fusion reactor

    DOEpatents

    Peng, Yueng-Kay M.

    1989-01-01

    A fusion reactor is provided having a near spherical-shaped plasma with a modest central opening through which straight segments of toroidal field coils extend that carry electrical current for generating a toroidal magnet plasma confinement fields. By retaining only the indispensable components inboard of the plasma torus, principally the cooled toroidal field conductors and in some cases a vacuum containment vessel wall, the fusion reactor features an exceptionally small aspect ratio (typically about 1.5), a naturally elongated plasma cross section without extensive field shaping, requires low strength magnetic containment fields, small size and high beta. These features combine to produce a spherical torus plasma in a unique physics regime which permits compact fusion at low field and modest cost.

  5. Spherical torus fusion reactor

    DOEpatents

    Peng, Yueng-Kay M.

    1989-04-04

    A fusion reactor is provided having a near spherical-shaped plasma with a modest central opening through which straight segments of toroidal field coils extend that carry electrical current for generating a toroidal magnet plasma confinement fields. By retaining only the indispensable components inboard of the plasma torus, principally the cooled toroidal field conductors and in some cases a vacuum containment vessel wall, the fusion reactor features an exceptionally small aspect ratio (typically about 1.5), a naturally elongated plasma cross section without extensive field shaping, requires low strength magnetic containment fields, small size and high beta. These features combine to produce a spherical torus plasma in a unique physics regime which permits compact fusion at low field and modest cost.

  6. Quantum Controlled Nuclear Fusion

    NASA Astrophysics Data System (ADS)

    Gruebele, Martin

    2017-06-01

    Laser-assisted nuclear fusion is a potential means for providing short, well-controlled particle bursts in the lab, such as neutron or alpha particle pulses. I will discuss computational results of how coherent control by shaped, amplified 800 nm laser pulses can be used to enhance the nuclear fusion cross section of diatomic molecules such as BH or DT. Quantum dynamics simulations show that a strong laser pulse can simultaneously field-bind the diatomic molecule after electron ejection, and increase the amplitude of the vibrational wave function at small internuclear distances. When VUV shaped laser pulses become available, coherent laser control may also be extended to muonic molecules such as D-mu-T, held together by muons instead of electrons. Muonic fusion has been extensively investigated for many decades, but without coherent laser control it falls slightly short of the break-evne point.

  7. Ceramics for fusion applications

    SciTech Connect

    Clinard, F.W. Jr.

    1986-01-01

    Ceramics are required for a variety of uses in both near-term fusion devices and in commercial powerplants. These materials must retain adequate structural and electrical properties under conditions of neutron, particle, and ionizing irradiation; thermal and applied stresses; and physical and chemical sputtering. Ceramics such as Al/sub 2/O/sub 3/, MgAl/sub 2/O/sub 4/, BeO, Si/sub 3/N/sub 4/ and SiC are currently under study for fusion applications, and results to date show widely-varying response to the fusion environment. Materials can be identified today which will meet initial operating requirements, but improvements in physical properties are needed to achieve satisfactory lifetimes for critical applications.

  8. 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

  9. [Construction of prokaryotic expression vector for Ag85A-HA2 fusion gene and studies on the immunity efficacy of fusion protein against influenza A virus].

    PubMed

    Shao, Jing-Jing; Yang, Jing; Dai, Jun; Meng, Jun-Jie; Pei, De-Cui; Li, Hong; Pan, Xing; Li, Wan-Yi

    2014-07-01

    To construct Ag85A-HA2 prokaryotic expression vector, express the fusion protein and study the immunity efficacy of fusion protein against influenza A virus. Ag85A-HA2 prokaryotic expression vector was constructed and induced with IPTG. The fusion protein was identified by SDS-PAGE and purified with His-Tag affinity chromatography. The BALB/c mice were immunized with fusion protein. Then the pathological section, lung index, lung inhibitory rate and death-protection rate were tested to evaluate the immunity efficacy of fusion protein. pET-32a(+)/Ag85A-HA2 prokaryotic expression vector was constructed successfully. And SDS-PAGE indicated that fusion protein was expressed correctly with a molecular mass of 70 x 10(3). The lung index and death-protection rate in experimental group were 39.30% and 80%, higher than that of control group. The pathological section also demonstrated that Ag85A-HA2 fusion protein had a protective effect on murine lungs. Ag85A-HA2 prokaryotic expression vector was successfully constructed, inducible expression and the fusion protein had an immunity efficacy against influenza A virus in animal experiment.

  10. Intense fusion neutron sources

    NASA Astrophysics Data System (ADS)

    Kuteev, B. V.; Goncharov, P. R.; Sergeev, V. Yu.; Khripunov, V. I.

    2010-04-01

    The review describes physical principles underlying efficient production of free neutrons, up-to-date possibilities and prospects of creating fission and fusion neutron sources with intensities of 1015-1021 neutrons/s, and schemes of production and application of neutrons in fusion-fission hybrid systems. The physical processes and parameters of high-temperature plasmas are considered at which optimal conditions for producing the largest number of fusion neutrons in systems with magnetic and inertial plasma confinement are achieved. The proposed plasma methods for neutron production are compared with other methods based on fusion reactions in nonplasma media, fission reactions, spallation, and muon catalysis. At present, intense neutron fluxes are mainly used in nanotechnology, biotechnology, material science, and military and fundamental research. In the near future (10-20 years), it will be possible to apply high-power neutron sources in fusion-fission hybrid systems for producing hydrogen, electric power, and technological heat, as well as for manufacturing synthetic nuclear fuel and closing the nuclear fuel cycle. Neutron sources with intensities approaching 1020 neutrons/s may radically change the structure of power industry and considerably influence the fundamental and applied science and innovation technologies. Along with utilizing the energy produced in fusion reactions, the achievement of such high neutron intensities may stimulate wide application of subcritical fast nuclear reactors controlled by neutron sources. Superpower neutron sources will allow one to solve many problems of neutron diagnostics, monitor nano-and biological objects, and carry out radiation testing and modification of volumetric properties of materials at the industrial level. Such sources will considerably (up to 100 times) improve the accuracy of neutron physics experiments and will provide a better understanding of the structure of matter, including that of the neutron itself.

  11. Atomic data for fusion

    SciTech Connect

    Hunter, H.T.; Kirkpatrick, M.I.; Alvarez, I.; Cisneros, C.; Phaneuf, R.A.; Barnett, C.F.

    1990-07-01

    This report provides a handbook of recommended cross-section and rate-coefficient data for inelastic collisions between hydrogen, helium and lithium atoms, molecules and ions, and encompasses more than 400 different reactions of primary interest in fusion research. Published experimental and theoretical data have been collected and evaluated, and the recommended data are presented in tabular, graphical and parametrized form. Processes include excitation and spectral line emission, charge exchange, ionization, stripping, dissociation and particle interchange reactions. The range of collision energies is appropriate to applications in fusion-energy research.

  12. Fusion welding process

    DOEpatents

    Thomas, Kenneth C.; Jones, Eric D.; McBride, Marvin A.

    1983-01-01

    A process for the fusion welding of nickel alloy steel members wherein a ferrite containing pellet is inserted into a cavity in one member and melted by a welding torch. The resulting weld nugget, a fusion of the nickel containing alloy from the members to be welded and the pellet, has a composition which is sufficiently low in nickel content such that ferrite phases occur within the weld nugget, resulting in improved weld properties. The steel alloys encompassed also include alloys containing carbon and manganese, considered nickel equivalents.

  13. Fusion for Space Propulsion

    NASA Technical Reports Server (NTRS)

    Thio, Y. C. Francis; Schmidt, George R.; Santarius, John F.; Turchi, Peter J.; Siemon, Richard E.; Rodgers, Stephen L. (Technical Monitor)

    2002-01-01

    The need for fusion propulsion for interplanetary flights is discussed. For a propulsion system, there are three important system attributes: (1) The absolute amount of energy available, (2) the propellant exhaust velocity, and (3) the jet power per unit mass of the propulsion system (specific power). For efficient and affordable human exploration of the solar system, propellant exhaust velocity in excess of 100 km/s and specific power in excess of 10 kW/kg are required. Chemical combustion obviously cannot meet the requirement in propellant exhaust velocity. Nuclear fission processes typically result in producing energy in the form of heat that needs to be manipulated at temperatures limited by materials to about 2,800 K. Using the fission energy to heat a low atomic weight propellant produces propellant velocity of the order of 10 kinds. Alternatively the fission energy can be converted into electricity that is used to accelerate particles to high exhaust velocity. However, the necessary power conversion and conditioning equipment greatly increases the mass of the propulsion system. Fundamental considerations in waste heat rejection and power conditioning in a fission electric propulsion system place a limit on its jet specific power to the order of about 0.2 kW/kg. If fusion can be developed for propulsion, it appears to have the best of all worlds - it can provide the largest absolute amount of energy, the propellant exhaust velocity (> 100 km/s), and the high specific jet power (> 10 kW/kg). An intermediate step towards fusion propulsion might be a bimodal system in which a fission reactor is used to provide some of the energy to drive a fusion propulsion unit. There are similarities as well as differences between applying fusion to propulsion and to terrestrial electrical power generation. The similarities are the underlying plasma and fusion physics, the enabling component technologies, the computational and the diagnostics capabilities. These physics and

  14. Quantum controlled fusion

    NASA Astrophysics Data System (ADS)

    Berrios, Eduardo; Gruebele, Martin; Wolynes, Peter G.

    2017-09-01

    Quantum-controlled motion of nuclei, starting from the nanometer-size ground state of a molecule, can potentially overcome some of the difficulties of thermonuclear fusion by compression of a fuel pellet or in a bulk plasma. Coherent laser control can manipulate nuclear motion precisely, achieving large phase space densities for the colliding nuclei. We combine quantum wavepacket propagation of D and T nuclei in a field-bound molecule with coherent control by a shaped laser pulse to demonstrate enhancement of nuclear collision rates. Atom-smashers powered by coherent control may become laboratory sources of particle bursts, and even assist muonic fusion.

  15. Fusion for Space Propulsion

    NASA Technical Reports Server (NTRS)

    Thio, Y. C. Francis; Schmidt, George R.; Santarius, John F.; Turchi, Peter J.; Siemon, Richard E.; Rodgers, Stephen L. (Technical Monitor)

    2002-01-01

    The need for fusion propulsion for interplanetary flights is discussed. For a propulsion system, there are three important system attributes: (1) The absolute amount of energy available, (2) the propellant exhaust velocity, and (3) the jet power per unit mass of the propulsion system (specific power). For efficient and affordable human exploration of the solar system, propellant exhaust velocity in excess of 100 km/s and specific power in excess of 10 kW/kg are required. Chemical combustion obviously cannot meet the requirement in propellant exhaust velocity. Nuclear fission processes typically result in producing energy in the form of heat that needs to be manipulated at temperatures limited by materials to about 2,800 K. Using the fission energy to heat a low atomic weight propellant produces propellant velocity of the order of 10 kinds. Alternatively the fission energy can be converted into electricity that is used to accelerate particles to high exhaust velocity. However, the necessary power conversion and conditioning equipment greatly increases the mass of the propulsion system. Fundamental considerations in waste heat rejection and power conditioning in a fission electric propulsion system place a limit on its jet specific power to the order of about 0.2 kW/kg. If fusion can be developed for propulsion, it appears to have the best of all worlds - it can provide the largest absolute amount of energy, the propellant exhaust velocity (> 100 km/s), and the high specific jet power (> 10 kW/kg). An intermediate step towards fusion propulsion might be a bimodal system in which a fission reactor is used to provide some of the energy to drive a fusion propulsion unit. There are similarities as well as differences between applying fusion to propulsion and to terrestrial electrical power generation. The similarities are the underlying plasma and fusion physics, the enabling component technologies, the computational and the diagnostics capabilities. These physics and

  16. Measles Virus Fusion Protein: Structure, Function and Inhibition

    PubMed Central

    Plattet, Philippe; Alves, Lisa; Herren, Michael; Aguilar, Hector C.

    2016-01-01

    Measles virus (MeV), a highly contagious member of the Paramyxoviridae family, causes measles in humans. The Paramyxoviridae family of negative single-stranded enveloped viruses includes several important human and animal pathogens, with MeV causing approximately 120,000 deaths annually. MeV and canine distemper virus (CDV)-mediated diseases can be prevented by vaccination. However, sub-optimal vaccine delivery continues to foster MeV outbreaks. Post-exposure prophylaxis with antivirals has been proposed as a novel strategy to complement vaccination programs by filling herd immunity gaps. Recent research has shown that membrane fusion induced by the morbillivirus glycoproteins is the first critical step for viral entry and infection, and determines cell pathology and disease outcome. Our molecular understanding of morbillivirus-associated membrane fusion has greatly progressed towards the feasibility to control this process by treating the fusion glycoprotein with inhibitory molecules. Current approaches to develop anti-membrane fusion drugs and our knowledge on drug resistance mechanisms strongly suggest that combined therapies will be a prerequisite. Thus, discovery of additional anti-fusion and/or anti-attachment protein small-molecule compounds may eventually translate into realistic therapeutic options. PMID:27110811

  17. Topological arrangement of the intracellular membrane fusion machinery

    PubMed Central

    Rathore, Shailendra S.; Ghosh, Nilanjan; Ouyang, Yan; Shen, Jingshi

    2011-01-01

    Soluble N-ethylmaleimide–sensitive factor attachment protein receptors (SNAREs) form a four-helix coiled-coil bundle that juxtaposes two bilayers and drives a basal level of membrane fusion. The Sec1/Munc18 (SM) protein binds to its cognate SNARE bundle and accelerates the basal fusion reaction. The question of how the topological arrangement of the SNARE helices affects the reactivity of the fusion proteins remains unanswered. Here we address the problem for the first time in a reconstituted system containing both SNAREs and SM proteins. We find that to be fusogenic a SNARE topology must support both basal fusion and SM stimulation. Certain topological combinations of exocytic SNAREs result in basal fusion but cannot support SM stimulation, whereas other topologies support SM stimulation without inducing basal fusion. It is striking that of all the possible topological combinations of exocytic SNARE helices, only one induces efficient fusion. Our results suggest that the intracellular membrane fusion complex is designed to fuse bilayers according to one genetically programmed topology. PMID:21633111

  18. Multisensor data fusion algorithm development

    SciTech Connect

    Yocky, D.A.; Chadwick, M.D.; Goudy, S.P.; Johnson, D.K.

    1995-12-01

    This report presents a two-year LDRD research effort into multisensor data fusion. We approached the problem by addressing the available types of data, preprocessing that data, and developing fusion algorithms using that data. The report reflects these three distinct areas. First, the possible data sets for fusion are identified. Second, automated registration techniques for imagery data are analyzed. Third, two fusion techniques are presented. The first fusion algorithm is based on the two-dimensional discrete wavelet transform. Using test images, the wavelet algorithm is compared against intensity modulation and intensity-hue-saturation image fusion algorithms that are available in commercial software. The wavelet approach outperforms the other two fusion techniques by preserving spectral/spatial information more precisely. The wavelet fusion algorithm was also applied to Landsat Thematic Mapper and SPOT panchromatic imagery data. The second algorithm is based on a linear-regression technique. We analyzed the technique using the same Landsat and SPOT data.

  19. Workmanship standards for fusion welding

    NASA Technical Reports Server (NTRS)

    Phillips, M. D.

    1967-01-01

    Workmanship standards manual defines practices, that adhere to rigid codes and specifications, for fusion welding of component piping, assemblies, and systems. With written and pictorial presentations, it is part of the operating procedure for fusion welding.

  20. Systematic identification and analysis of frequent gene fusion events in metabolic pathways

    DOE PAGES

    Henry, Christopher S.; Lerma-Ortiz, Claudia; Gerdes, Svetlana Y.; ...

    2016-06-24

    Here, gene fusions are the most powerful type of in silico-derived functional associations. However, many fusion compilations were made when <100 genomes were available, and algorithms for identifying fusions need updating to handle the current avalanche of sequenced genomes. The availability of a large fusion dataset would help probe functional associations and enable systematic analysis of where and why fusion events occur. As a result, here we present a systematic analysis of fusions in prokaryotes. We manually generated two training sets: (i) 121 fusions in the model organism Escherichia coli; (ii) 131 fusions found in B vitamin metabolism. These setsmore » were used to develop a fusion prediction algorithm that captured the training set fusions with only 7 % false negatives and 50 % false positives, a substantial improvement over existing approaches. This algorithm was then applied to identify 3.8 million potential fusions across 11,473 genomes. The results of the analysis are available in a searchable database. A functional analysis identified 3,000 reactions associated with frequent fusion events and revealed areas of metabolism where fusions are particularly prevalent. In conclusion, customary definitions of fusions were shown to be ambiguous, and a stricter one was proposed. Exploring the genes participating in fusion events showed that they most commonly encode transporters, regulators, and metabolic enzymes. The major rationales for fusions between metabolic genes appear to be overcoming pathway bottlenecks, avoiding toxicity, controlling competing pathways, and facilitating expression and assembly of protein complexes. Finally, our fusion dataset provides powerful clues to decipher the biological activities of domains of unknown function.« less

  1. Systematic identification and analysis of frequent gene fusion events in metabolic pathways

    SciTech Connect

    Henry, Christopher S.; Lerma-Ortiz, Claudia; Gerdes, Svetlana Y.; Mullen, Jeffrey D.; Colasanti, Ric; Zhukov, Aleksey; Frelin, Oceane; Thiaville, Jennifer J.; Zallot, Remi; Niehaus, Thomas D.; Hasnain, Ghulam; Conrad, Neal; Hanson, Andrew D.; de Crecy-Lagard, Valerie

    2016-06-24

    Here, gene fusions are the most powerful type of in silico-derived functional associations. However, many fusion compilations were made when <100 genomes were available, and algorithms for identifying fusions need updating to handle the current avalanche of sequenced genomes. The availability of a large fusion dataset would help probe functional associations and enable systematic analysis of where and why fusion events occur. As a result, here we present a systematic analysis of fusions in prokaryotes. We manually generated two training sets: (i) 121 fusions in the model organism Escherichia coli; (ii) 131 fusions found in B vitamin metabolism. These sets were used to develop a fusion prediction algorithm that captured the training set fusions with only 7 % false negatives and 50 % false positives, a substantial improvement over existing approaches. This algorithm was then applied to identify 3.8 million potential fusions across 11,473 genomes. The results of the analysis are available in a searchable database. A functional analysis identified 3,000 reactions associated with frequent fusion events and revealed areas of metabolism where fusions are particularly prevalent. In conclusion, customary definitions of fusions were shown to be ambiguous, and a stricter one was proposed. Exploring the genes participating in fusion events showed that they most commonly encode transporters, regulators, and metabolic enzymes. The major rationales for fusions between metabolic genes appear to be overcoming pathway bottlenecks, avoiding toxicity, controlling competing pathways, and facilitating expression and assembly of protein complexes. Finally, our fusion dataset provides powerful clues to decipher the biological activities of domains of unknown function.

  2. Inhibitory control is slowed in patients with right superior medial frontal damage.

    PubMed

    Floden, Darlene; Stuss, Donald T

    2006-11-01

    Inhibitory control is an essential part of behavior. Comprehensive knowledge of the neural underpinnings will shed light on complex behavior, its breakdown in neurological and psychological disorders, and current and future techniques for the pharmacological or structural remediation of disinhibition. This study investigated the neural mechanisms involved in rapid response inhibition. The stop signal task was used to estimate inhibitory speed in a group of neurologically normal control subjects and patients with discrete frontal lobe lesions. Task procedures were controlled to rule out probable confounds related to strategic changes in task effort. The findings indicate that the frontal lobes are necessary for inhibitory control and, furthermore, that the integrity of the right superior medial frontal region is key for rapid inhibitory control under conditions controlling for strategically slow responses, forcing reliance more on a rapid, "kill-switch" inhibitory system. These results are interpreted within an anatomical framework of corticospinal motor control.

  3. The Multifaceted Role of SNARE Proteins in Membrane Fusion

    PubMed Central

    Han, Jing; Pluhackova, Kristyna; Böckmann, Rainer A.

    2017-01-01

    Membrane fusion is a key process in all living organisms that contributes to a variety of biological processes including viral infection, cell fertilization, as well as intracellular transport, and neurotransmitter release. In particular, the various membrane-enclosed compartments in eukaryotic cells need to exchange their contents and communicate across membranes. Efficient and controllable fusion of biological membranes is known to be driven by cooperative action of SNARE proteins, which constitute the central components of the eukaryotic fusion machinery responsible for fusion of synaptic vesicles with the plasma membrane. During exocytosis, vesicle-associated v-SNARE (synaptobrevin) and target cell-associated t-SNAREs (syntaxin and SNAP-25) assemble into a core trans-SNARE complex. This complex plays a versatile role at various stages of exocytosis ranging from the priming to fusion pore formation and expansion, finally resulting in the release or exchange of the vesicle content. This review summarizes current knowledge on the intricate molecular mechanisms underlying exocytosis triggered and catalyzed by SNARE proteins. Particular attention is given to the function of the peptidic SNARE membrane anchors and the role of SNARE-lipid interactions in fusion. Moreover, the regulatory mechanisms by synaptic auxiliary proteins in SNARE-driven membrane fusion are briefly outlined. PMID:28163686

  4. The Multifaceted Role of SNARE Proteins in Membrane Fusion.

    PubMed

    Han, Jing; Pluhackova, Kristyna; Böckmann, Rainer A

    2017-01-01

    Membrane fusion is a key process in all living organisms that contributes to a variety of biological processes including viral infection, cell fertilization, as well as intracellular transport, and neurotransmitter release. In particular, the various membrane-enclosed compartments in eukaryotic cells need to exchange their contents and communicate across membranes. Efficient and controllable fusion of biological membranes is known to be driven by cooperative action of SNARE proteins, which constitute the central components of the eukaryotic fusion machinery responsible for fusion of synaptic vesicles with the plasma membrane. During exocytosis, vesicle-associated v-SNARE (synaptobrevin) and target cell-associated t-SNAREs (syntaxin and SNAP-25) assemble into a core trans-SNARE complex. This complex plays a versatile role at various stages of exocytosis ranging from the priming to fusion pore formation and expansion, finally resulting in the release or exchange of the vesicle content. This review summarizes current knowledge on the intricate molecular mechanisms underlying exocytosis triggered and catalyzed by SNARE proteins. Particular attention is given to the function of the peptidic SNARE membrane anchors and the role of SNARE-lipid interactions in fusion. Moreover, the regulatory mechanisms by synaptic auxiliary proteins in SNARE-driven membrane fusion are briefly outlined.

  5. Fusion Engineering Device design description

    SciTech Connect

    Flanagan, C.A.; Steiner, D.; Smith, G.E.

    1981-12-01

    The US Magnetic Fusion Engineering Act of 1980 calls for the operation of a Fusion Engineering Device (FED) by 1990. It is the intent of the Act that the FED, in combination with other testing facilities, will establish the engineering feasibility of magnetic fusion energy. During 1981, the Fusion Engineering Design Center (FEDC), under the guidance of a Technical Management Board (TMB), developed a baseline design for the FED. This design is summarized herein.

  6. Fusion engineering device design description

    SciTech Connect

    Flanagan, C.A.; Steiner, D.; Smith, G.E.

    1981-12-01

    The US Magnetic Fusion Engineering Act of 1980 calls for the operation of a Fusion Engineering Device (FED) by 1990. It is the intent of the Act that the FED, in combination with other testing facilities, will establish the engineering feasibility of magnetic fusion energy. During 1981, the Fusion Engineering Design Center (FEDC), under the guidance of a Technical Management Board (TMB), developed a baseline design for the FED. This design is summarized herein.

  7. A fusion of minds

    NASA Astrophysics Data System (ADS)

    Corfield, Richard

    2013-02-01

    Mystery still surrounds the visit of the astronomer Sir Bernard Lovell to the Soviet Union in 1963. But his collaboration - and that of other British scientists - eased geopolitical tensions at the height of the Cold War and paved the way for today's global ITER fusion project, as Richard Corfield explains.

  8. Synergetic Multisensor Fusion

    DTIC Science & Technology

    1990-11-30

    technology have led to increased interest in using DEMs for navigation and other applications. In particular, DEMs are attractive for use in aircraft...Multisensor Fusion for Computer Vision [67]. 30 6. POSI!IONAL zSTIM&TION TECEnIQUzs FOR AN OUTDOOR MOBLE ROBOT The autonomous navigation of mobile robots is

  9. Auditory Fusion in Children.

    ERIC Educational Resources Information Center

    Davis, Sylvia M.; McCroskey, Robert L.

    1980-01-01

    Focuses on auditory fusion (defined in terms of a listerner's ability to distinguish paired acoustic events from single acoustic events) in 3- to 12-year-old children. The subjects listened to 270 pairs of tones controlled for frequency, intensity, and duration. (CM)

  10. Mars manned fusion spaceship

    SciTech Connect

    Hedrick, J.; Buchholtz, B.; Ward, P.; Freuh, J.; Jensen, E.

    1991-01-01

    Fusion Propulsion has an enormous potential for space exploration in the near future. In the twenty-first century, a usable and efficient fusion rocket will be developed and in use. Because of the great distance between other planets and Earth, efficient use of time, fuel, and payload is essential. A nuclear spaceship would provide greater fuel efficiency, less travel time, and a larger payload. Extended missions would give more time for research, experiments, and data acquisition. With the extended mission time, a need for an artificial environment exists. The topics of magnetic fusion propulsion, living modules, artificial gravity, mass distribution, space connection, and orbital transfer to Mars are discussed. The propulsion system is a magnetic fusion reactor based on a tandem mirror design. This allows a faster, shorter trip time and a large thrust to weight ratio. The fuel proposed is a mixture of deuterium and helium. Helium can be obtained from lunar mining. There will be minimal external radiation from the reactor resulting in a safe, efficient propulsion system.

  11. Fusion reactor materials

    SciTech Connect

    none,

    1989-01-01

    This paper discuses the following topics on fusion reactor materials: irradiation, facilities, test matrices, and experimental methods; dosimetry, damage parameters, and activation calculations; materials engineering and design requirements; fundamental mechanical behavior; radiation effects; development of structural alloys; solid breeding materials; and ceramics.

  12. Mars manned fusion spaceship

    NASA Technical Reports Server (NTRS)

    Hedrick, James; Buchholtz, Brent; Ward, Paul; Freuh, Jim; Jensen, Eric

    1991-01-01

    Fusion Propulsion has an enormous potential for space exploration in the near future. In the twenty-first century, a usable and efficient fusion rocket will be developed and in use. Because of the great distance between other planets and Earth, efficient use of time, fuel, and payload is essential. A nuclear spaceship would provide greater fuel efficiency, less travel time, and a larger payload. Extended missions would give more time for research, experiments, and data acquisition. With the extended mission time, a need for an artificial environment exists. The topics of magnetic fusion propulsion, living modules, artificial gravity, mass distribution, space connection, and orbital transfer to Mars are discussed. The propulsion system is a magnetic fusion reactor based on a tandem mirror design. This allows a faster, shorter trip time and a large thrust to weight ratio. The fuel proposed is a mixture of deuterium and helium-3. Helium-3 can be obtained from lunar mining. There will be minimal external radiation from the reactor resulting in a safe, efficient propulsion system.

  13. Fusion gamma diagnostics

    NASA Astrophysics Data System (ADS)

    Medley, S. S.; Cecil, F. E.; Cole, D.; Conway, M. A.; Wilkinson, F. J., III

    1985-05-01

    Nuclear reactions of interest in fusion research often possess a branch yielding prompt emission of gamma radiation in excess of 15 MeV which can be exploited to provide a new fusion reaction diagnostic having applications similar to conventional neutron emission measurements. Conceptual aspects of fusion gamma diagnostics are discussed with emphasis on application to the Tokamak Fusion Test Reactor (TFTR) during deuterium neutral beam heating of D-T and D-3He plasmas. Recent measurements of the D (T, γ)5He, D(3He, γ)5Li, and D(D, γ)4He branching ratios at low center-of-mass energy (30-100 keV) and of the response of a large volume Ne226 detector for gamma detection in high neutron backgrounds are presented. Using a well-shielded Ne226 detector during 20 MW-120 kV deuterium beam heating of a tritium plasma in TFTR, the D(T, γ)5He gamma signal level is estimated to be 3.5×105 cps.

  14. Bubble fusion: Preliminary estimates

    SciTech Connect

    Krakowski, R.A.

    1995-02-01

    The collapse of a gas-filled bubble in disequilibrium (i.e., internal pressure {much_lt} external pressure) can occur with a significant focusing of energy onto the entrapped gas in the form of pressure-volume work and/or acoustical shocks; the resulting heating can be sufficient to cause ionization and the emission of atomic radiations. The suggestion that extreme conditions necessary for thermonuclear fusion to occur may be possible has been examined parametrically in terms of the ratio of initial bubble pressure relative to that required for equilibrium. In this sense, the disequilibrium bubble is viewed as a three-dimensional ``sling shot`` that is ``loaded`` to an extent allowed by the maximum level of disequilibrium that can stably be achieved. Values of this disequilibrium ratio in the range 10{sup {minus}5}--10{sup {minus}6} are predicted by an idealized bubble-dynamics model as necessary to achieve conditions where nuclear fusion of deuterium-tritium might be observed. Harmonic and aharmonic pressurizations/decompressions are examined as means to achieve the required levels of disequilibrium required to create fusion conditions. A number of phenomena not included in the analysis reported herein could enhance or reduce the small levels of nuclear fusions predicted.

  15. Nattoh model for cold fusion

    SciTech Connect

    Matsumoto, T. . Dept. of Nuclear Engineering)

    1989-12-01

    A hypothetical model, the Nattoh model, is proposed to answer the questions that result from cold fusion experiments. This model proposes the formation of a small cluster of deuterons and examines the feasibility of many-body fusion reactions. The gamma-ray spectrum, heat production, neutron emissions, and fusion products are discussed.

  16. Graphite for fusion energy applications

    SciTech Connect

    Eatherly, W.P.; Clausing, R.E.; Strehlow, R.A.; Kennedy, C.R.; Mioduszewski, P.K.

    1987-03-01

    Graphite is in widespread and beneficial use in present fusion energy devices. This report reflects the view of graphite materials scientists on using graphite in fusion devices. Graphite properties are discussed with emphasis on application to fusion reactors. This report is intended to be introductory and descriptive and is not intended to serve as a definitive information source. (JDH)

  17. Muon-catalysed fusion revisited

    NASA Astrophysics Data System (ADS)

    Jones, S. E.

    1986-05-01

    Muons introduced into relatively cold, dense deuterium-tritium mixtures can replace the atomic electrons and form muonic molecules which participate readily in nuclear fusion reactions. Catalysis yields of about 150 fusions per muon have been achieved, renewing interest in muon-catalyzed fusion as a possible source of energy.

  18. Human-Centered Fusion Framework

    SciTech Connect

    Posse, Christian; White, Amanda M.; Beagley, Nathaniel

    2007-05-16

    In recent years the benefits of fusing signatures extracted from large amounts of distributed and/or heterogeneous data sources have been largely documented in various problems ranging from biological protein function prediction to cyberspace monitoring. In spite of significant progress in information fusion research, there is still no formal theoretical framework for defining various types of information fusion systems, defining and analyzing relations among such types, and designing information fusion systems using a formal method approach. Consequently, fusion systems are often poorly understood, are less than optimal, and/or do not suit user needs. To start addressing these issues, we outline a formal humancentered fusion framework for reasoning about fusion strategies. Our approach relies on a new taxonomy for fusion strategies, an alternative definition of information fusion in terms of parameterized paths in signature related spaces, an algorithmic formalization of fusion strategies and a library of numeric and dynamic visual tools measuring the impact as well as the impact behavior of fusion strategies. Using a real case of intelligence analysis we demonstrate that the proposed framework enables end users to rapidly 1) develop and implement alternative fusion strategies, 2) understand the impact of each strategy, 3) compare the various strategies, and 4) perform the above steps without having to know the mathematical foundations of the framework. We also demonstrate that the human impact on a fusion system is critical in the sense that small changes in strategies do not necessarily correspond to small changes in results.

  19. LASSA: Emotion Detection via Information Fusion

    PubMed Central

    Yu, Ning; Kübler, Sandra; Herring, Joshua; Hsu, Yu-Yin; Israel, Ross; Smiley, Charese

    2012-01-01

    Due to the complexity of emotions in suicide notes and the subtle nature of sentiments, this study proposes a fusion approach to tackle the challenge of sentiment classification in suicide notes: leveraging WordNet-based lexicons, manually created rules, character-based n-grams, and other linguistic features. Although our results are not satisfying, some valuable lessons are learned and promising future directions are identified. PMID:22879762

  20. Vacuolar ATPase in Phagosome-Lysosome Fusion

    PubMed Central

    Kissing, Sandra; Hermsen, Christina; Repnik, Urska; Nesset, Cecilie Kåsi; von Bargen, Kristine; Griffiths, Gareth; Ichihara, Atsuhiro; Lee, Beth S.; Schwake, Michael; De Brabander, Jef; Haas, Albert; Saftig, Paul

    2015-01-01

    The vacuolar H+-ATPase (v-ATPase) complex is instrumental in establishing and maintaining acidification of some cellular compartments, thereby ensuring their functionality. Recently it has been proposed that the transmembrane V0 sector of v-ATPase and its a-subunits promote membrane fusion in the endocytic and exocytic pathways independent of their acidification functions. Here, we tested if such a proton-pumping independent role of v-ATPase also applies to phagosome-lysosome fusion. Surprisingly, endo(lyso)somes in mouse embryonic fibroblasts lacking the V0 a3 subunit of the v-ATPase acidified normally, and endosome and lysosome marker proteins were recruited to phagosomes with similar kinetics in the presence or absence of the a3 subunit. Further experiments used macrophages with a knockdown of v-ATPase accessory protein 2 (ATP6AP2) expression, resulting in a strongly reduced level of the V0 sector of the v-ATPase. However, acidification appeared undisturbed, and fusion between latex bead-containing phagosomes and lysosomes, as analyzed by electron microscopy, was even slightly enhanced, as was killing of non-pathogenic bacteria by V0 mutant macrophages. Pharmacologically neutralized lysosome pH did not affect maturation of phagosomes in mouse embryonic cells or macrophages. Finally, locking the two large parts of the v-ATPase complex together by the drug saliphenylhalamide A did not inhibit in vitro and in cellulo fusion of phagosomes with lysosomes. Hence, our data do not suggest a fusion-promoting role of the v-ATPase in the formation of phagolysosomes. PMID:25903133

  1. Developing inertial fusion energy - Where do we go from here?

    SciTech Connect

    Meier, W.R.; Logan, G.

    1996-06-11

    Development of inertial fusion energy (IFE) will require continued R&D in target physics, driver technology, target production and delivery systems, and chamber technologies. It will also require the integration of these technologies in tests and engineering demonstrations of increasing capability and complexity. Development needs in each of these areas are discussed. It is shown how IFE development will leverage off the DOE Defense Programs funded inertial confinement fusion (ICF) work.

  2. A new GTF2I-BRAF fusion mediating MAPK pathway activation in pilocytic astrocytoma

    PubMed Central

    Tomić, Tajana Tešan; Olausson, Josefin; Wilzén, Annica; Sabel, Magnus; Truvé, Katarina; Sjögren, Helene; Dósa, Sándor; Tisell, Magnus; Lannering, Birgitta; Enlund, Fredrik; Martinsson, Tommy; Åman, Pierre

    2017-01-01

    Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. A recurrent feature of PA is deregulation of the mitogen activated protein kinase (MAPK) pathway most often through KIAA1549-BRAF fusion, but also by other BRAF- or RAF1-gene fusions and point mutations (e.g. BRAFV600E). These features may serve as diagnostic and prognostic markers, and also facilitate development of targeted therapy. The aims of this study were to characterize the genetic alterations underlying the development of PA in six tumor cases, and evaluate methods for fusion oncogene detection. Using a combined analysis of RNA sequencing and copy number variation data we identified a new BRAF fusion involving the 5’ gene fusion partner GTF2I (7q11.23), not previously described in PA. The new GTF2I-BRAF 19–10 fusion was found in one case, while the other five cases harbored the frequent KIAA1549-BRAF 16–9 fusion gene. Similar to other BRAF fusions, the GTF2I-BRAF fusion retains an intact BRAF kinase domain while the inhibitory N-terminal domain is lost. Functional studies on GTF2I-BRAF showed elevated MAPK pathway activation compared to BRAFWT. Comparing fusion detection methods, we found Fluorescence in situ hybridization with BRAF break apart probe as the most sensitive method for detection of different BRAF rearrangements (GTF2I-BRAF and KIAA1549-BRAF). Our finding of a new BRAF fusion in PA further emphasis the important role of B-Raf in tumorigenesis of these tumor types. Moreover, the consistency and growing list of BRAF/RAF gene fusions suggests these rearrangements to be informative tumor markers in molecular diagnostics, which could guide future treatment strategies. PMID:28448514

  3. Measures of Dogs' Inhibitory Control Abilities Do Not Correlate across Tasks

    PubMed Central

    Brucks, Désirée; Marshall-Pescini, Sarah; Wallis, Lisa Jessica; Huber, Ludwig; Range, Friederike

    2017-01-01

    Inhibitory control, the ability to overcome prepotent but ineffective behaviors, has been studied extensively across species, revealing the involvement of this ability in many different aspects of life. While various different paradigms have been created in order to measure inhibitory control, only a limited number of studies have investigated whether such measurements indeed evaluate the same underlying mechanism, especially in non-human animals. In humans, inhibitory control is a complex construct composed of distinct behavioral processes rather than of a single unified measure. In the current study, we aimed to investigate the validity of inhibitory control paradigms in dogs. Sixty-seven dogs were tested in a battery consisting of frequently used inhibitory control tests. Additionally, dog owners were asked to complete an impulsivity questionnaire about their dog. No correlation of dogs' performance across tasks was found. In order to understand whether there are some underlying behavioral aspects explaining dogs' performance across tests, we performed principle component analyses. Results revealed that three components (persistency, compulsivity and decision speed) explained the variation across tasks. The questionnaire and dogs' individual characteristics (i.e., age and sex) provided only limited information for the derived components. Overall, results suggest that no unique measurement for inhibitory control exists in dogs, but tests rather measure different aspects of this ability. Considering the context-specificity of inhibitory control in dogs and most probably also in other non-human animals, extreme caution is needed when making conclusions about inhibitory control abilities based on a single test. PMID:28596749

  4. Measures of Dogs' Inhibitory Control Abilities Do Not Correlate across Tasks.

    PubMed

    Brucks, Désirée; Marshall-Pescini, Sarah; Wallis, Lisa Jessica; Huber, Ludwig; Range, Friederike

    2017-01-01

    Inhibitory control, the ability to overcome prepotent but ineffective behaviors, has been studied extensively across species, revealing the involvement of this ability in many different aspects of life. While various different paradigms have been created in order to measure inhibitory control, only a limited number of studies have investigated whether such measurements indeed evaluate the same underlying mechanism, especially in non-human animals. In humans, inhibitory control is a complex construct composed of distinct behavioral processes rather than of a single unified measure. In the current study, we aimed to investigate the validity of inhibitory control paradigms in dogs. Sixty-seven dogs were tested in a battery consisting of frequently used inhibitory control tests. Additionally, dog owners were asked to complete an impulsivity questionnaire about their dog. No correlation of dogs' performance across tasks was found. In order to understand whether there are some underlying behavioral aspects explaining dogs' performance across tests, we performed principle component analyses. Results revealed that three components (persistency, compulsivity and decision speed) explained the variation across tasks. The questionnaire and dogs' individual characteristics (i.e., age and sex) provided only limited information for the derived components. Overall, results suggest that no unique measurement for inhibitory control exists in dogs, but tests rather measure different aspects of this ability. Considering the context-specificity of inhibitory control in dogs and most probably also in other non-human animals, extreme caution is needed when making conclusions about inhibitory control abilities based on a single test.

  5. Inhibitory Basal Ganglia Inputs Induce Excitatory Motor Signals in the Thalamus.

    PubMed

    Kim, Jeongjin; Kim, Youngsoo; Nakajima, Ryuichi; Shin, Anna; Jeong, Minju; Park, Ah Hyung; Jeong, Yongcheol; Jo, Seonmi; Yang, Seungkyoung; Park, Hosung; Cho, Sung-Hwan; Cho, Kwang-Hyun; Shim, Insop; Chung, Jae Hoon; Paik, Se-Bum; Augustine, George J; Kim, Daesoo

    2017-08-30

    Basal ganglia (BG) circuits orchestrate complex motor behaviors predominantly via inhibitory synaptic outputs. Although these inhibitory BG outputs are known to reduce the excitability of postsynaptic target neurons, precisely how this change impairs motor performance remains poorly understood. Here, we show that optogenetic photostimulation of inhibitory BG inputs from the globus pallidus induces a surge of action potentials in the ventrolateral thalamic (VL) neurons and muscle contractions during the post-inhibitory period. Reduction of the neuronal population with this post-inhibitory rebound firing by knockout of T-type Ca(2+) channels or photoinhibition abolishes multiple motor responses induced by the inhibitory BG input. In a low dopamine state, the number of VL neurons showing post-inhibitory firing increases, while reducing the number of active VL neurons via photoinhibition of BG input, effectively prevents Parkinson disease (PD)-like motor symptoms. Thus, BG inhibitory input generates excitatory motor signals in the thalamus and, in excess, promotes PD-like motor abnormalities. VIDEO ABSTRACT. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Neuregulin-1 Regulates Cortical Inhibitory Neuron Dendrite and Synapse Growth through DISC1

    PubMed Central

    Kwan, Vickie

    2016-01-01

    Cortical inhibitory neurons play crucial roles in regulating excitatory synaptic networks and cognitive function and aberrant development of these cells have been linked to neurodevelopmental disorders. The secreted neurotrophic factor Neuregulin-1 (NRG1) and its receptor ErbB4 are established regulators of inhibitory neuron connectivity, but the developmental signalling mechanisms regulating this process remain poorly understood. Here, we provide evidence that NRG1-ErbB4 signalling functions through the multifunctional scaffold protein, Disrupted in Schizophrenia 1 (DISC1), to regulate the development of cortical inhibitory interneuron dendrite and synaptic growth. We found that NRG1 increases inhibitory neuron dendrite complexity and glutamatergic synapse formation onto inhibitory neurons and that this effect is blocked by expression of a dominant negative DISC1 mutant, or DISC1 knockdown. We also discovered that NRG1 treatment increases DISC1 expression and its localization to glutamatergic synapses being made onto cortical inhibitory neurons. Mechanistically, we determined that DISC1 binds ErbB4 within cortical inhibitory neurons. Collectively, these data suggest that a NRG1-ErbB4-DISC1 signalling pathway regulates the development of cortical inhibitory neuron dendrite and synaptic growth. Given that NRG1, ErbB4, and DISC1 are schizophrenia-linked genes, these findings shed light on how independent risk factors may signal in a common developmental pathway that contributes to neural connectivity defects and disease pathogenesis. PMID:27847649

  7. Identification of candidate angiogenic inhibitors processed by matrix metalloproteinase 2 (MMP-2) in cell-based proteomic screens: disruption of vascular endothelial growth factor (VEGF)/heparin affin regulatory peptide (pleiotrophin) and VEGF/Connective tissue growth factor angiogenic inhibitory complexes by MMP-2 proteolysis.

    PubMed

    Dean, Richard A; Butler, Georgina S; Hamma-Kourbali, Yamina; Delbé, Jean; Brigstock, David R; Courty, José; Overall, Christopher M

    2007-12-01

    Matrix metalloproteinases (MMPs) exert both pro- and antiangiogenic functions by the release of cytokines or proteolytically generated angiogenic inhibitors from extracellular matrix and basement membrane remodeling. In the Mmp2-/- mouse neovascularization is greatly reduced, but the mechanistic aspects of this remain unclear. Using isotope-coded affinity tag labeling of proteins analyzed by multidimensional liquid chromatography and tandem mass spectrometry we explored proteome differences between Mmp2-/- cells and those rescued by MMP-2 transfection. Proteome signatures that are hallmarks of proteolysis revealed cleavage of many known MMP-2 substrates in the cellular context. Proteomic evidence of MMP-2 processing of novel substrates was found. Insulin-like growth factor binding protein 6, follistatin-like 1, and cystatin C protein cleavage by MMP-2 was biochemically confirmed, and the cleavage sites in heparin affin regulatory peptide (HARP; pleiotrophin) and connective tissue growth factor (CTGF) were sequenced by matrix-assisted laser desorption ionization-time of flight mass spectrometry. MMP-2 processing of HARP and CTGF released vascular endothelial growth factor (VEGF) from angiogenic inhibitory complexes. The cleaved HARP N-terminal domain increased HARP-induced cell proliferation, whereas the HARP C-terminal domain was antagonistic and decreased cell proliferation and migration. Hence the unmasking of cytokines, such as VEGF, by metalloproteinase processing of their binding proteins is a new mechanism in the control of cytokine activation and angiogenesis.

  8. Identification of Candidate Angiogenic Inhibitors Processed by Matrix Metalloproteinase 2 (MMP-2) in Cell-Based Proteomic Screens: Disruption of Vascular Endothelial Growth Factor (VEGF)/Heparin Affin Regulatory Peptide (Pleiotrophin) and VEGF/Connective Tissue Growth Factor Angiogenic Inhibitory Complexes by MMP-2 Proteolysis▿ †

    PubMed Central

    Dean, Richard A.; Butler, Georgina S.; Hamma-Kourbali, Yamina; Delbé, Jean; Brigstock, David R.; Courty, José; Overall, Christopher M.

    2007-01-01

    Matrix metalloproteinases (MMPs) exert both pro- and antiangiogenic functions by the release of cytokines or proteolytically generated angiogenic inhibitors from extracellular matrix and basement membrane remodeling. In the Mmp2−/− mouse neovascularization is greatly reduced, but the mechanistic aspects of this remain unclear. Using isotope-coded affinity tag labeling of proteins analyzed by multidimensional liquid chromatography and tandem mass spectrometry we explored proteome differences between Mmp2−/− cells and those rescued by MMP-2 transfection. Proteome signatures that are hallmarks of proteolysis revealed cleavage of many known MMP-2 substrates in the cellular context. Proteomic evidence of MMP-2 processing of novel substrates was found. Insulin-like growth factor binding protein 6, follistatin-like 1, and cystatin C protein cleavage by MMP-2 was biochemically confirmed, and the cleavage sites in heparin affin regulatory peptide (HARP; pleiotrophin) and connective tissue growth factor (CTGF) were sequenced by matrix-assisted laser desorption ionization-time of flight mass spectrometry. MMP-2 processing of HARP and CTGF released vascular endothelial growth factor (VEGF) from angiogenic inhibitory complexes. The cleaved HARP N-terminal domain increased HARP-induced cell proliferation, whereas the HARP C-terminal domain was antagonistic and decreased cell proliferation and migration. Hence the unmasking of cytokines, such as VEGF, by metalloproteinase processing of their binding proteins is a new mechanism in the control of cytokine activation and angiogenesis. PMID:17908800

  9. Association of Vaccinia Virus Fusion Regulatory Proteins with the Multicomponent Entry/Fusion Complex▿

    PubMed Central

    Wagenaar, Timothy R.; Moss, Bernard

    2007-01-01

    The proteins encoded by the A56R and K2L genes of vaccinia virus form a heterodimer (A56/K2) and have a fusion regulatory role as deletion or mutation of either causes infected cells to form large syncytia spontaneously. Here, we showed that syncytia formation is dependent on proteins of the recently described entry fusion complex (EFC), which are also required for virus-cell fusion and low-pH-triggered cell-cell fusion. This finding led us to consider that A56/K2 might prevent fusion by direct or indirect interaction with the EFC. To test this hypothesis, we made a panel of recombinant vaccinia viruses that have a tandem affinity purification tag attached to A56, K2, or the A28 EFC protein. Interaction between A56/K2 and the EFC was demonstrated by their copurification from detergent-treated lysates of infected cells and identification by mass spectrometry or Western blotting. In addition, a purified soluble transmembrane-deleted form of A56/K2 was shown to interact with the EFC. Tagged A56 did not interact with the EFC in the absence of K2, nor did tagged K2 interact with the EFC in the absence of A56. The finding that both A56 and K2 are required for efficient binding to the EFC fits well with prior experiments showing that mutation of either A56 or K2 results in spontaneous fusion of infected cells. Because A56 and K2 are located on the surface of infected cells, they are in position to interact with the EFC of released progeny virions and prevent back-fusion and syncytia formation. PMID:17409143

  10. The role of the C terminus of the SNARE protein SNAP-25 in fusion pore opening and a model for fusion pore mechanics

    PubMed Central

    Fang, Qinghua; Berberian, Khajak; Gong, Liang-Wei; Hafez, Ismail; Sørensen, Jakob B.; Lindau, Manfred

    2008-01-01

    Formation of a fusion pore between a vesicle and its target membrane is thought to involve the so-called SNARE protein complex. However, there is no mechanistic model explaining how the fusion pore is opened by conformational changes in the SNARE complex. It has been suggested that C-terminal zipping triggers fusion pore opening. A SNAP-25 mutant named SNAP-25Δ9 (lacking the last nine C-terminal residues) should lead to a less-tight C-terminal zipping. Single exocytotic events in chromaffin cells expressing this mutant were characterized by carbon fiber amperometry and cell-attached patch capacitance measurements. Cells expressing SNAP-25Δ9 displayed smaller amperometric “foot-current” currents, reduced fusion pore conductances, and lower fusion pore expansion rates. We propose that SNARE/lipid complexes form proteolipid fusion pores. Fusion pores involving the SNAP-25Δ9 mutant will be less tightly zipped and may lead to a longer fusion pore structure, consistent with the observed decrease of fusion pore conductance. PMID:18829435

  11. Surgical fusion in childhood spondylolisthesis.

    PubMed

    Stanton, R P; Meehan, P; Lovell, W W

    1985-01-01

    Twenty cases of surgical fusion for spondylolisthesis were reviewed at the Scottish Rite Hospital (Atlanta, GA, U.S.A.) to determine whether a procedure other than a simple posterolateral fusion is necessary for most patients. The patients were treated postoperatively with pantaloon spica cast immobilization. The fusion rate was high (90%), and patient satisfaction was high. One patient developed neurologic loss postoperatively. Two patients' slips progressed greater than 10% before solid fusion occurred. Thus, bilateral posterolateral fusion, followed by pantaloon spica cast immobilization, is effective for patients with symptomatic spondylolisthesis or asymptomatic children with grade 3 or greater slips. Reduction was not performed in this series.

  12. Accelerators for heavy ion fusion

    SciTech Connect

    Bangerter, R.O.

    1985-10-01

    Large fusion devices will almost certainly produce net energy. However, a successful commercial fusion energy system must also satisfy important engineering and economic constraints. Inertial confinement fusion power plants driven by multi-stage, heavy-ion accelerators appear capable of meeting these constraints. The reasons behind this promising outlook for heavy-ion fusion are given in this report. This report is based on the transcript of a talk presented at the Symposium on Lasers and Particle Beams for Fusion and Strategic Defense at the University of Rochester on April 17-19, 1985.

  13. Physiological Awareness Is Negatively Related to Inhibitory Functioning in Tourette Syndrome.

    PubMed

    Eddy, Clare M; Rickards, Hugh E; Cavanna, Andrea E

    2014-03-01

    In Tourette syndrome (TS), tics are characteristically preceded by subjective bodily experiences referred to as premonitory sensations. Premonitory sensory phenomena play a key role in behavior therapy for tics, the success of which has also been suggested to be related to inhibitory functioning. We investigated whether TS was associated with altered internal physiological awareness and how this may interact with the neuropsychological characteristics of TS. We compared the awareness of bodily sensations and inhibitory functioning in 18 adult patients with uncomplicated TS and 18 healthy controls. We also explored relationships between these factors, tic severity, and premonitory sensations. Patients with TS exhibited significantly higher scores on the Private Body Consciousness (PBC) scale and inhibitory deficits on traditional and emotional Stroop tests. PBC scores were not correlated with premonitory sensations or tic severity. However, inhibitory functioning was negatively related to PBC scores and premonitory sensations. Relationships between inhibitory performance and tic severity were complex. In conclusion, patients with TS exhibit increased PBC in addition to inhibitory deficits. Aspects of inhibitory functioning are related to PBC, premonitory sensations, and tic severity. Complex interplay between neuropsychological and neurophysiological mechanisms could therefore determine tic severity and the success of behavioral treatments.

  14. The spheromak as a compact fusion reactor

    SciTech Connect

    Hagenson, R.L.; Krakowski, R.A.

    1987-03-01

    After summarizing the economic and utility-based rationale for compact, higher-power-density fusion reactors, the gun-sustained spheromak concept is explored as one of a number of poloidal-field-dominated confinement configurations that might improve the prospects for economically attractive and operationally simplified fusion power plants. Using a comprehensive physics/engineering/costing model for the spheromak, guided by realistic engineering constraints and physics extrapolation, a range of cost-optimized reactor design points is presented, and the sensitivity of cost to key physics, engineering, and operational variables is reported. The results presented herein provide the basis for conceptual engineering designs of key fusion-power-core (FPC) subsystems and more detailed plasma modeling of this promising, high mass-power-density concept, which stresses single-piece FPC maintenance, steady-state current drive through electrostatic magnetic helicity injection, a simplified co-axial electrode-divertor, and efficient resistive-coal equilibrium-field coils. The optimal FPC size and the cost estimates project a system that competes aggressively with the best offered by alternative energy sources while simplifying considerably the complexity that has generally been associated with most approaches to magnetic fusion energy.

  15. The three lives of viral fusion peptides

    PubMed Central

    Apellániz, Beatriz; Huarte, Nerea; Largo, Eneko; Nieva, José L.

    2014-01-01

    Fusion peptides comprise conserved hydrophobic domains absolutely required for the fusogenic activity of glycoproteins from divergent virus families. After 30 years of intensive research efforts, the structures and functions underlying their high degree of sequence conservation are not fully elucidated. The long-hydrophobic viral fusion peptide (VFP) sequences are structurally constrained to access three successive states after biogenesis. Firstly, the VFP sequence must fulfill the set of native interactions required for (meta) stable folding within the globular ectodomains of glycoprotein complexes. Secondly, at the onset of the fusion process, they get transferred into the target cell membrane and adopt specific conformations therein. According to commonly accepted mechanistic models, membrane-bound states of the VFP might promote the lipid bilayer remodeling required for virus-cell membrane merger. Finally, at least in some instances, several VFPs co-assemble with transmembrane anchors into membrane integral helical bundles, following a locking movement hypothetically coupled to fusion-pore expansion. Here we review different aspects of the three major states of the VFPs, including the functional assistance by other membrane-transferring glycoprotein regions, and discuss briefly their potential as targets for clinical intervention. PMID:24704587

  16. Simultaneous Segmentation and Statistical Label Fusion.

    PubMed

    Asman, Andrew J; Landmana, Bennett A

    2012-02-23

    Labeling or segmentation of structures of interest in medical imaging plays an essential role in both clinical and scientific understanding. Two of the common techniques to obtain these labels are through either fully automated segmentation or through multi-atlas based segmentation and label fusion. Fully automated techniques often result in highly accurate segmentations but lack the robustness to be viable in many cases. On the other hand, label fusion techniques are often extremely robust, but lack the accuracy of automated algorithms for specific classes of problems. Herein, we propose to perform simultaneous automated segmentation and statistical label fusion through the reformulation of a generative model to include a linkage structure that explicitly estimates the complex global relationships between labels and intensities. These relationships are inferred from the atlas labels and intensities and applied to the target using a non-parametric approach. The novelty of this approach lies in the combination of previously exclusive techniques and attempts to combine the accuracy benefits of automated segmentation with the robustness of a multi-atlas based approach. The accuracy benefits of this simultaneous approach are assessed using a multi-label multi- atlas whole-brain segmentation experiment and the segmentation of the highly variable thyroid on computed tomography images. The results demonstrate that this technique has major benefits for certain types of problems and has the potential to provide a paradigm shift in which the lines between statistical label fusion and automated segmentation are dramatically blurred.

  17. The path to fusion power.

    PubMed

    Llewellyn Smith, Chris; Ward, David

    2007-04-15

    Fusion is potentially an environmentally responsible and intrinsically safe source of essentially limitless power. It should be possible to build viable fusion power stations, and it looks as if the cost of fusion power will be reasonable. But time is needed to further develop the technology and to test in power station conditions the materials that would be used in their construction. Assuming no major adverse surprises, an orderly fusion development programme could lead to a prototype fusion power station putting electricity into the grid within 30 years, with commercial fusion power following some 10 or more years later. In the second half of the century, fusion could therefore be an important part of the portfolio of measures that are needed to cope with rising demand for energy in an environmentally responsible manner. In this paper, we describe the basics of fusion, its potential attractions, the status of fusion R&D, the remaining challenges and how they will be tackled at the International Tokamak Experimental Reactor and the proposed International Fusion Materials Irradiation Facility, and the timetable for the subsequent commercialization of fusion power.

  18. An invasive podosome-like structure promotes fusion pore formation during myoblast fusion

    PubMed Central

    Sens, Kristin L.; Zhang, Shiliang; Jin, Peng; Duan, Rui; Zhang, Guofeng; Luo, Fengbao; Parachini, Lauren

    2010-01-01

    Recent studies in Drosophila have implicated actin cytoskeletal remodeling in myoblast fusion, but the cellular mechanisms underlying this process remain poorly understood. Here we show that actin polymerization occurs in an asymmetric and cell type–specific manner between a muscle founder cell and a fusion-competent myoblast (FCM). In the FCM, a dense F-actin–enriched focus forms at the site of fusion, whereas a thin sheath of F-actin is induced along the apposing founder cell membrane. The FCM-specific actin focus invades the apposing founder cell with multiple finger-like protrusions, leading to the formation of a single-channel macro fusion pore between the two muscle cells. Two actin nucleation–promoting factors of the Arp2/3 complex, WASP and Scar, are required for the formation of the F-actin foci, whereas WASP but not Scar promotes efficient foci invasion. Our studies uncover a novel invasive podosome-like structure (PLS) in a developing tissue and reveal a previously unrecognized function of PLSs in facilitating cell membrane juxtaposition and fusion. PMID:21098115

  19. Transient inhibitory seizures mimicking crescendo TIAs.

    PubMed

    Lee, H; Lerner, A

    1990-01-01

    Somatic inhibitory seizures are thought to occur rarely. We describe a patient with somatic inhibitory seizures who initially presented with a clinical picture of crescendo transient ischemic attacks. He did not improve with anticoagulation, but the episodes ceased promptly after the administration of an anticonvulsant.

  20. Defining inhibitory neurone function in respiratory circuits: opportunities with optogenetics?

    PubMed Central

    Abdala, Ana Paula; Paton, Julian F R; Smith, Jeffrey C

    2015-01-01

    Pharmacological and mathematical modelling studies support the view that synaptic inhibition in mammalian brainstem respiratory circuits is essential for generating normal and stable breathing movements. GABAergic and glycinergic neurones are known components of these circuits but their precise functional roles have not been established, especially within key microcircuits of the respiratory pre-Bötzinger (pre-BötC) and Bötzinger (BötC) complexes involved in phasic control of respiratory pump and airway muscles. Here, we review briefly current concepts of relevant complexities of inhibitory synapses and the importance of synaptic inhibition in the operation of these microcircuits. We highlight results and limitations of classical pharmacological studies that have suggested critical functions of synaptic inhibition. We then explore the potential opportunities for optogenetic strategies that represent a promising new approach for interrogating function of inhibitory circuits, including a hypothetical wish list for optogenetic approaches to allow expedient application of this technology. We conclude that recent technical advances in optogenetics should provide a means to understand the role of functionally select and regionally confined subsets of inhibitory neurones in key respiratory circuits such as those in the pre-BötC and BötC. PMID:25384785

  1. Defining inhibitory neurone function in respiratory circuits: opportunities with optogenetics?

    PubMed

    Abdala, Ana Paula; Paton, Julian F R; Smith, Jeffrey C

    2015-07-15

    Pharmacological and mathematical modelling studies support the view that synaptic inhibition in mammalian brainstem respiratory circuits is essential for generating normal and stable breathing movements. GABAergic and glycinergic neurones are known components of these circuits but their precise functional roles have not been established, especially within key microcircuits of the respiratory pre-Bötzinger (pre-BötC) and Bötzinger (BötC) complexes involved in phasic control of respiratory pump and airway muscles. Here, we review briefly current concepts of relevant complexities of inhibitory synapses and the importance of synaptic inhibition in the operation of these microcircuits. We highlight results and limitations of classical pharmacological studies that have suggested critical functions of synaptic inhibition. We then explore the potential opportunities for optogenetic strategies that represent a promising new approach for interrogating function of inhibitory circuits, including a hypothetical wish list for optogenetic approaches to allow expedient application of this technology. We conclude that recent technical advances in optogenetics should provide a means to understand the role of functionally select and regionally confined subsets of inhibitory neurones in key respiratory circuits such as those in the pre-BötC and BötC.

  2. The Need for Fusion Propulsion

    NASA Technical Reports Server (NTRS)

    Cassibry, Jason

    2005-01-01

    Fusion propulsion is inevitable if the human race remains dedicated to exploration of the solar system. There are fundamental reasons why fusion surpasses more traditional approaches to routine crewed missions to Mars, crewed missions to the outer planets, and deep space high speed robotic missions, assuming that reduced trip times, increased payloads, and higher available power are desired. A recent series of informal discussions were held among members from government, academia, and industry concerning fusion propulsion. We compiled a sufficient set of arguments for utilizing fusion in space. If the U.S. is to lead the effort and produce a working system in a reasonable amount of time, NASA must take the initiative, relying on, but not waiting for, DOE guidance. In this talk those arguments for fusion propulsion are presented, along with fusion enabled mission examples, fusion technology trade space, and a proposed outline for future efforts.

  3. Alphavirus Entry and Membrane Fusion

    PubMed Central

    Kielian, Margaret; Chanel-Vos, Chantal; Liao, Maofu

    2010-01-01

    The study of enveloped animal viruses has greatly advanced our understanding of the general properties of membrane fusion and of the specific pathways that viruses use to infect the host cell. The membrane fusion proteins of the alphaviruses and flaviviruses have many similarities in structure and function. As reviewed here, alphaviruses use receptor-mediated endocytic uptake and low pH-triggered membrane fusion to deliver their RNA genomes into the cytoplasm. Recent advances in understanding the biochemistry and structure of the alphavirus membrane fusion protein provide a clearer picture of this fusion reaction, including the protein’s conformational changes during fusion and the identification of key domains. These insights into the alphavirus fusion mechanism suggest new areas for experimental investigation and potential inhibitor strategies for anti-viral therapy. PMID:21546978

  4. Molecular inhibitory mechanism of tricin on tyrosinase

    NASA Astrophysics Data System (ADS)

    Mu, Yan; Li, Lin; Hu, Song-Qing

    2013-04-01

    Tricin was evaluated as a type of tyrosinase inhibitor with good efficacy compared to arbutin. Tricin functioned as a non-competitive inhibitor of tyrosinase, with an equilibrium constant of 2.30 mmol/L. The molecular mechanisms underlying the inhibition of tyrosinase by tricin were investigated by means of circular dichroism spectra, fluorescence quenching and molecular docking. These assays demonstrated that the interactions between tricin and tyrosinase did not change the secondary structure. The interaction of tricin with residues in the hydrophobic pocket of tyrosinase was revealed by fluorescence quenching; the complex was stabilized by hydrophobic associations and hydrogen bonding (with residues Asn80 and Arg267). Docking results implied that the possible inhibitory mechanisms may be attributed to the stereospecific blockade effects of tricin on substrates or products and flexible conformation alterations in the tyrosinase active center caused by weak interactions between tyrosinase and tricin. The application of this type of flavonoid as a tyrosinase inhibitor will lead to significant advances in the field of depigmentation.

  5. Developmental broadening of inhibitory sensory maps.

    PubMed

    Quast, Kathleen B; Ung, Kevin; Froudarakis, Emmanouil; Huang, Longwen; Herman, Isabella; Addison, Angela P; Ortiz-Guzman, Joshua; Cordiner, Keith; Saggau, Peter; Tolias, Andreas S; Arenkiel, Benjamin R

    2017-02-01

    Sensory maps are created by networks of neuronal responses that vary with their anatomical position, such that representations of the external world are systematically and topographically organized in the brain. Current understanding from studying excitatory maps is that maps are sculpted and refined throughout development and/or through sensory experience. Investigating the mouse olfactory bulb, where ongoing neurogenesis continually supplies new inhibitory granule cells into existing circuitry, we isolated the development of sensory maps formed by inhibitory networks. Using in vivo calcium imaging of odor responses, we compared functional responses of both maturing and established granule cells. We found that, in contrast to the refinement observed for excitatory maps, inhibitory sensory maps became broader with maturation. However, like excitatory maps, inhibitory sensory maps are sensitive to experience. These data describe the development of an inhibitory sensory map as a network, highlighting the differences from previously described excitatory maps.

  6. Presynaptic Neuronal Pentraxin Receptor Organizes Excitatory and Inhibitory Synapses

    PubMed Central

    Wei, Mengping; Zhang, Chen; Pak, ChangHui; Trotter, Justin

    2017-01-01

    Three neuronal pentraxins are expressed in brain, the membrane-bound “neuronal pentraxin receptor” (NPR) and the secreted proteins NP1 and NARP (i.e., NP2). Neuronal pentraxins bind to AMPARs at excitatory synapses and play important, well-documented roles in the activity-dependent regulation of neural circuits via this binding activity. However, it is unknown whether neuronal pentraxins perform roles in synapses beyond modulating postsynaptic AMPAR-dependent plasticity, and whether they may even act in inhibitory synapses. Here, we show that NPR expressed in non-neuronal cells potently induces formation of both excitatory and inhibitory postsynaptic specializations in cocultured hippocampal neurons. Knockdown of NPR in hippocampal neurons, conversely, dramatically decreased assembly and function of both excitatory and inhibitory postsynaptic specializations. Overexpression of NPR rescued the NPR knockdown phenotype but did not in itself change synapse numbers or properties. However, the NPR knockdown decreased the levels of NARP, whereas NPR overexpression produced a dramatic increase in the levels of NP1 and NARP, suggesting that NPR recruits and stabilizes NP1 and NARP on the presynaptic plasma membrane. Mechanistically, NPR acted in excitatory synapse assembly by binding to the N-terminal domain of AMPARs; antagonists of AMPA and GABA receptors selectively inhibited NPR-induced heterologous excitatory and inhibitory synapse assembly, respectively, but did not affect neurexin-1β-induced synapse assembly as a control. Our data suggest that neuronal pentraxins act as signaling complexes that function as general trans-synaptic organizers of both excitatory and inhibitory synapses by a mechanism that depends, at least in part, on the activity of the neurotransmitter receptors at these synapses. SIGNIFICANCE STATEMENT Neuronal pentraxins comprise three neuronal proteins, neuronal pentraxin receptor (NPR) which is a type-II transmembrane protein on the neuronal

  7. Presynaptic Neuronal Pentraxin Receptor Organizes Excitatory and Inhibitory Synapses.

    PubMed

    Lee, Sung-Jin; Wei, Mengping; Zhang, Chen; Maxeiner, Stephan; Pak, ChangHui; Calado Botelho, Salome; Trotter, Justin; Sterky, Fredrik H; Südhof, Thomas C

    2017-02-01

    Three neuronal pentraxins are expressed in brain, the membrane-bound "neuronal pentraxin receptor" (NPR) and the secreted proteins NP1 and NARP (i.e., NP2). Neuronal pentraxins bind to AMPARs at excitatory synapses and play important, well-documented roles in the activity-dependent regulation of neural circuits via this binding activity. However, it is unknown whether neuronal pentraxins perform roles in synapses beyond modulating postsynaptic AMPAR-dependent plasticity, and whether they may even act in inhibitory synapses. Here, we show that NPR expressed in non-neuronal cells potently induces formation of both excitatory and inhibitory postsynaptic specializations in cocultured hippocampal neurons. Knockdown of NPR in hippocampal neurons, conversely, dramatically decreased assembly and function of both excitatory and inhibitory postsynaptic specializations. Overexpression of NPR rescued the NPR knockdown phenotype but did not in itself change synapse numbers or properties. However, the NPR knockdown decreased the levels of NARP, whereas NPR overexpression produced a dramatic increase in the levels of NP1 and NARP, suggesting that NPR recruits and stabilizes NP1 and NARP on the presynaptic plasma membrane. Mechanistically, NPR acted in excitatory synapse assembly by binding to the N-terminal domain of AMPARs; antagonists of AMPA and GABA receptors selectively inhibited NPR-induced heterologous excitatory and inhibitory synapse assembly, respectively, but did not affect neurexin-1β-induced synapse assembly as a control. Our data suggest that neuronal pentraxins act as signaling complexes that function as general trans-synaptic organizers of both excitatory and inhibitory synapses by a mechanism that depends, at least in part, on the activity of the neurotransmitter receptors at these synapses. Neuronal pentraxins comprise three neuronal proteins, neuronal pentraxin receptor (NPR) which is a type-II transmembrane protein on the neuronal surface, and secreted

  8. DNA topoisomerase I inhibitory alkaloids from Corydalis saxicola.

    PubMed

    Cheng, Xuanxuan; Wang, Dongmei; Jiang, Lin; Yang, Depo

    2008-07-01

    Chemical studies of the Chinese herb Corydalis saxicola Bunting led to the isolation and identification of 14 alkaloids, 1-14. Seven of these compounds, 4-9 and 11, were obtained from this plant for the first time. Feruloylagmatine (7) is the first guanidine-type alkaloid to be identified in the family Papaveraceae and in dicotyledonous plants. All of the isolated compounds were assayed for inhibitory activity against human DNA topoisomerase I. A DNA cleavage assay demonstrated that these alkaloids specifically inhibit topoisomerase through stabilization of the enzyme-DNA complex. Among the isolated alkaloids, (-)-pallidine (8) and (-)-scoulerine (11) showed strong inhibitory activities toward topoisomerase I that were comparable to camptothecin, a typical topoisomerase I inhibitor. A preliminary structure-activity relationship study suggested that the quaternary ammonium ion might play an important role in topoisomerase I inhibition by the isoquinoline alkaloids. These data indicated that DNA topoisomerase I inhibition represents probably one of the anticarcinogenic mechanisms of C. saxicola.

  9. The effect of therapies for osteoporosis on spine fusion: a systematic review.

    PubMed

    Hirsch, Brandon P; Unnanuntana, Aasis; Cunningham, Matthew E; Lane, Joseph M

    2013-02-01

    Fusion of the spine requires de novo bone formation and remodeling, processes that rely heavily on the action of the osteoblast and osteoclast. Bisphosphonate drugs and intermittent parathyroid hormone (PTH) therapy are widely prescribed to treat osteoporosis and act on the osteoblast/osteoclast complex. The impact of these medications on spine fusion is not known. To evaluate the available evidence on the potential impact of bisphosphonates and PTH on fusion rate and fusion quality in spinal arthrodesis. A systematic review of the literature. All available literature regarding the impact of bisphosphonates and PTH on spinal fusion. Fusion rate and histologic, microstructural, or biomechanical measures of fusion quality. A systematic review of the literature published between 1980 and 2011 was conducted using major electronic databases. The results of studies meeting criteria for inclusion were then aggregated and examined for consensus on the effect of these medications on spine fusion. The literature contained 18 animal studies and one clinical trial investigating the impact of these medications on spine fusion. Most animal studies evaluating the impact of bisphosphonates on fusion rate have not found statistically significant changes with treatment, although this fact may be attributable to low statistical power. The animal literature does suggest that bisphosphonate therapy results in a less histologically mature fusion mass; however, the impact of these changes on fusion mass biomechanics is unclear. The only available human study suggests that these bisphosphonates may increase the radiographically defined fusion rate but did not demonstrate an impact on clinical outcome. In animals, PTH improves the fusion rate and fusion mass microstructure, but data on its effect on fusion mass biomechanics are lacking. No studies have evaluated the impact of PTH on spine fusion in humans. In animals, bisphosphonate therapy appears to impede maturation of the fusion mass

  10. Capturing a fusion intermediate of influenza hemagglutinin with a cholesterol-conjugated peptide, a new antiviral strategy for influenza virus.

    PubMed

    Lee, Kelly K; Pessi, Antonello; Gui, Long; Santoprete, Alessia; Talekar, Aparna; Moscona, Anne; Porotto, Matteo

    2011-12-09

    We previously described fusion-inhibitory peptides that are targeted to the cell membrane by cholesterol conjugation and potently inhibit enveloped viruses that fuse at the cell surface, including HIV, parainfluenza, and henipaviruses. However, for viruses that fuse inside of intracellular compartments, fusion-inhibitory peptides have exhibited very low antiviral activity. We propose that for these viruses, too, membrane targeting via cholesterol conjugation may yield potent compounds. Here we compare the activity of fusion-inhibitory peptides derived from the influenza hemagglutinin (HA) and show that although the unconjugated peptides are inactive, the cholesterol-conjugated compounds are effective inhibitors of infectivity and membrane fusion. We hypothesize that the cholesterol moiety, by localizing the peptides to the target cell membrane, allows the peptides to follow the virus to the intracellular site of fusion. The cholesterol-conjugated peptides trap HA in a transient intermediate state after fusion is triggered but before completion of the refolding steps that drive the merging of the viral and cellular membranes. These results provide proof of concept for an antiviral strategy that is applicable to intracellularly fusing viruses, including known and emerging viral pathogens.

  11. Capturing a Fusion Intermediate of Influenza Hemagglutinin with a Cholesterol-conjugated Peptide, a New Antiviral Strategy for Influenza Virus*

    PubMed Central

    Lee, Kelly K.; Pessi, Antonello; Gui, Long; Santoprete, Alessia; Talekar, Aparna; Moscona, Anne; Porotto, Matteo

    2011-01-01

    We previously described fusion-inhibitory peptides that are targeted to the cell membrane by cholesterol conjugation and potently inhibit enveloped viruses that fuse at the cell surface, including HIV, parainfluenza, and henipaviruses. However, for viruses that fuse inside of intracellular compartments, fusion-inhibitory peptides have exhibited very low antiviral activity. We propose that for these viruses, too, membrane targeting via cholesterol conjugation may yield potent compounds. Here we compare the activity of fusion-inhibitory peptides derived from the influenza hemagglutinin (HA) and show that although the unconjugated peptides are inactive, the cholesterol-conjugated compounds are effective inhibitors of infectivity and membrane fusion. We hypothesize that the cholesterol moiety, by localizing the peptides to the target cell membrane, allows the peptides to follow the virus to the intracellular site of fusion. The cholesterol-conjugated peptides trap HA in a transient intermediate state after fusion is triggered but before completion of the refolding steps that drive the merging of the viral and cellular membranes. These results provide proof of concept for an antiviral strategy that is applicable to intracellularly fusing viruses, including known and emerging viral pathogens. PMID:21994935

  12. Fusion Data Grid Service

    NASA Astrophysics Data System (ADS)

    Shasharina, Svetlana; Wang, Nanbor

    2004-11-01

    Simulations and experiments in the fusion and plasma physics community generate large datasets at remote sites. Visualization and analysis of these datasets are difficult because of the incompatibility among the various data formats adopted by simulation, experiments, and analysis tools, and the large sizes of analyzed data. Grids and Web Services technologies are capable of providing solutions for such heterogeneous settings, but need to be customized to the field-specific needs and merged with distributed technologies currently used by the community. This paper describes how we are addressing these issues in the Fusion Grid Service under development. We also present performance results of relevant data transfer mechanisms including binary SOAP, DIME, GridFTP and MDSplus and CORBA. We will describe the status of data converters (between HDF5 and MDSplus data types), developed in collaboration with MIT (J. Stillerman). Finally, we will analyze bottlenecks of MDSplus data transfer mechanism (work performed in collaboration with General Atomics (D. Schissel and M. Qian).

  13. Unconventional approaches to fusion

    SciTech Connect

    Brunelli, B.; Leotta, G.G.

    1982-01-01

    This volume is dedicated to unconventional approaches to fusionthose thermonuclear reactors that, in comparison with Tokamak and other main lines, have received little attention in the worldwide scientific community. Many of the approaches considered are still in the embryonic stages. The authors-an international group of active nuclear scientists and engineers-focus on the parameters achieved in the use of these reactors and on the meaning of the most recent physical studies and their implications for the future. They also compare these approaches with conventional ones, the Tokamak in particular, stressing the non-plasma-physics requirements of fusion reactors. Unconventional compact toroids, linear systems, and multipoles are considered, as are the ''almost conventional'' fusion machines: stellarators, mirrors, reversed-field pinches, and EBT.

  14. Experiments in cold fusion

    SciTech Connect

    Palmer, E.P.

    1986-03-28

    The work of Steve Jones and others in muon-catalyzed cold fusion of deuterium and hydrogen suggests the possibility of such fusion catalyzed by ions, or combinations of atoms, or more-or-less free electrons in solid and liquid materials. A hint that this might occur naturally comes from the heat generated in volcanic action in subduction zones on the earth. It is questionable whether the potential energy of material raised to the height of a midocean ridge and falling to the depth of an ocean trench can produce the geothermal effects seen in the volcanoes of subduction zones. If the ridge, the trench, the plates, and the asthenosphere are merely visible effects of deeper density-gradient driven circulations, it is still uncertain that observed energy-concentration effects fit the models.

  15. Fusion pumped laser

    DOEpatents

    Pappas, D.S.

    1987-07-31

    The apparatus of this invention may comprise a system for generating laser radiation from a high-energy neutron source. The neutron source is a tokamak fusion reactor generating a long pulse of high-energy neutrons and having a temperature and magnetic field effective to generate a neutron flux of at least 10/sup 15/ neutrons/cm/sup 2//center dot/s. Conversion means are provided adjacent the fusion reactor at a location operable for converting the high-energy neutrons to an energy source with an intensity and energy effective to excite a preselected lasing medium. A lasing medium is spaced about and responsive to the energy source to generate a population inversion effective to support laser oscillations for generating output radiation. 2 figs., 2 tabs.

  16. Modular Aneutronic Fusion Engine

    SciTech Connect

    Gary Pajer, Yosef Razin, Michael Paluszek, A.H. Glasser and Samuel Cohen

    2012-05-11

    NASA's JUNO mission will arrive at Jupiter in July 2016, after nearly five years in space. Since operational costs tend to rise with mission time, minimizing such times becomes a top priority. We present the conceptual design for a 10MW aneutronic fusion engine with high exhaust velocities that would reduce transit time for a Jupiter mission to eighteen months and enable more challenging exploration missions in the solar system and beyond. __________________________________________________

  17. Inertial Confinement fusion targets

    NASA Technical Reports Server (NTRS)

    Hendricks, C. D.

    1982-01-01

    Inertial confinement fusion (ICF) targets are made as simple flat discs, as hollow shells or as complicated multilayer structures. Many techniques were devised for producing the targets. Glass and metal shells are made by using drop and bubble techniques. Solid hydrogen shells are also produced by adapting old methods to the solution of modern problems. Some of these techniques, problems, and solutions are discussed. In addition, the applications of many of the techniques to fabrication of ICF targets is presented.

  18. Fusion development and technology

    SciTech Connect

    Montgomery, D.B.

    1992-01-01

    This report discusses the following: superconducting magnet technology; high field superconductors; advanced magnetic system and divertor development; poloidal field coils; gyrotron development; commercial reactor studies--aries; ITER physics: alpha physics and alcator R D for ITER; lower hybrid current drive and heating in the ITER device; ITER superconducting PF scenario and magnet analysis; ITER systems studies; and safety, environmental and economic factors in fusion development.

  19. Accelerator based fusion reactor

    NASA Astrophysics Data System (ADS)

    Liu, Keh-Fei; Chao, Alexander Wu

    2017-08-01

    A feasibility study of fusion reactors based on accelerators is carried out. We consider a novel scheme where a beam from the accelerator hits the target plasma on the resonance of the fusion reaction and establish characteristic criteria for a workable reactor. We consider the reactions d+t\\to n+α,d+{{}3}{{H}\\text{e}}\\to p+α , and p+{{}11}B\\to 3α in this study. The critical temperature of the plasma is determined from overcoming the stopping power of the beam with the fusion energy gain. The needed plasma lifetime is determined from the width of the resonance, the beam velocity and the plasma density. We estimate the critical beam flux by balancing the energy of fusion production against the plasma thermo-energy and the loss due to stopping power for the case of an inert plasma. The product of critical flux and plasma lifetime is independent of plasma density and has a weak dependence on temperature. Even though the critical temperatures for these reactions are lower than those for the thermonuclear reactors, the critical flux is in the range of {{10}22}-{{10}24}~\\text{c}{{\\text{m}}-2}~{{\\text{s}}-1} for the plasma density {ρt}={{10}15}~\\text{c}{{\\text{m}}-3} in the case of an inert plasma. Several approaches to control the growth of the two-stream instability are discussed. We have also considered several scenarios for practical implementation which will require further studies. Finally, we consider the case where the injected beam at the resonance energy maintains the plasma temperature and prolongs its lifetime to reach a steady state. The equations for power balance and particle number conservation are given for this case.

  20. Transforaminal lumbar interbody fusion.

    PubMed

    Moskowitz, Alan

    2002-04-01

    Indication and technique of TLIF procedure are described. TLIF provides for anterior column support and posterior tension band. It is a unilateral approach to the spine, and there is no need to expose or manipulate the dura. It provides the benefits of a 360 degrees fusion without performing an anterior approach. It restores the normal anatomy of the motion segment and maintains normal lumbar lordosis. Patients are mobilized quickly and resume activities early.

  1. (Fusion energy research)

    SciTech Connect

    Phillips, C.A.

    1988-01-01

    This report discusses the following topics: principal parameters achieved in experimental devices (FY88); tokamak fusion test reactor; Princeton beta Experiment-Modification; S-1 Spheromak; current drive experiment; x-ray laser studies; spacecraft glow experiment; plasma deposition and etching of thin films; theoretical plasma; tokamak modeling; compact ignition tokamak; international thermonuclear experimental reactor; Engineering Department; Project Planning and Safety Office; quality assurance and reliability; and technology transfer.

  2. Stabilized Spheromak Fusion Reactors

    SciTech Connect

    Fowler, T

    2007-04-03

    The U.S. fusion energy program is focused on research with the potential for studying plasmas at thermonuclear temperatures, currently epitomized by the tokamak-based International Thermonuclear Experimental Reactor (ITER) but also continuing exploratory work on other plasma confinement concepts. Among the latter is the spheromak pursued on the SSPX facility at LLNL. Experiments in SSPX using electrostatic current drive by coaxial guns have now demonstrated stable spheromaks with good heat confinement, if the plasma is maintained near a Taylor state, but the anticipated high current amplification by gun injection has not yet been achieved. In future experiments and reactors, creating and maintaining a stable spheromak configuration at high magnetic field strength may require auxiliary current drive using neutral beams or RF power. Here we show that neutral beam current drive soon to be explored on SSPX could yield a compact spheromak reactor with current drive efficiency comparable to that of steady state tokamaks. Thus, while more will be learned about electrostatic current drive in coming months, results already achieved in SSPX could point to a productive parallel development path pursuing auxiliary current drive, consistent with plans to install neutral beams on SSPX in the near future. Among possible outcomes, spheromak research could also yield pulsed fusion reactors at lower capital cost than any fusion concept yet proposed.

  3. Cold fusion studies

    NASA Astrophysics Data System (ADS)

    Hembree, D. M.; Burchfield, L. A.; Fuller, E. L., Jr.; Perey, F. G.; Mamantov, G.

    1990-06-01

    A series of experiments designed to detect the by-products expected from deuterium fusion occurring in the palladium and titanium cathodes of heavy water, D2O, electrolysis cells is reported. The primary purpose of this account is to outline the integrated experimental design developed to test the cold fusion hypothesis and to report preliminary results that support continuing the investigation. Apparent positive indicators of deuterium fusion were observed, but could not be repeated or proved to originate from the electrochemical cells. In one instance, two large increases in the neutron count rate, the largest of which exceeded the background by 27 standard deviations, were observed. In a separate experiment, one of the calorimetry cells appeared to be producing approximately 18 percent more power that the input value, but thermistor failure prevented an accurate recording of the event as a function of time. In general, the tritium levels in most cells followed the slow enrichment expected from the electrolysis of D2O containing a small amount of tritium. However, after 576 hours of electrolysis, one cell developed a tritium concentration approximately seven times greater than expected level.

  4. Classifier Fusion With Contextual Reliability Evaluation.

    PubMed

    Liu, Zhunga; Pan, Quan; Dezert, Jean; Han, Jun-Wei; He, You

    2017-06-08

    Classifier fusion is an efficient strategy to improve the classification performance for the complex pattern recognition problem. In practice, the multiple classifiers to combine can have different reliabilities and the proper reliability evaluation plays an important role in the fusion process for getting the best classification performance. We propose a new method for classifier fusion with contextual reliability evaluation (CF-CRE) based on inner reliability and relative reliability concepts. The inner reliability, represented by a matrix, characterizes the probability of the object belonging to one class when it is classified to another class. The elements of this matrix are estimated from the $K$-nearest neighbors of the object. A cautious discounting rule is developed under belief functions framework to revise the classification result according to the inner reliability. The relative reliability is evaluated based on a new incompatibility measure which allows to reduce the level of conflict between the classifiers by applying the classical evidence discounting rule to each classifier before their combination. The inner reliability and relative reliability capture different aspects of the classification reliability. The discounted classification results are combined with Dempster-Shafer's rule for the final class decision making support. The performance of CF-CRE have been evaluated and compared with those of main classical fusion methods using real data sets. The experimental results show that CF-CRE can produce substantially higher accuracy than other fusion methods in general. Moreover, CF-CRE is robust to the changes of the number of nearest neighbors chosen for estimating the reliability matrix, which is appealing for the applications.

  5. Trainable fusion rules. II. Small sample-size effects.

    PubMed

    Raudys, Sarunas

    2006-12-01

    Profound theoretical analysis is performed of small-sample properties of trainable fusion rules to determine in which situations neural network ensembles can improve or degrade classification results. We consider small sample effects, specific only to multiple classifiers system design in the two-category case of two important fusion rules: (1) linear weighted average (weighted voting), realized either by the standard Fisher classifier or by the single-layer perceptron, and (2) the non-linear Behavior-Knowledge-Space method. The small sample effects include: (i) training bias, i.e. learning sample size influence on generalization error of the base experts or of the fusion rule, (ii) optimistic biased outputs of the experts (self-boasting effect) and (iii) sample size impact on determining optimal complexity of the fusion rule. Correction terms developed to reduce the self-boasting effect are studied. It is shown that small learning sets increase classification error of the expert classifiers and damage correlation structure between their outputs. If the sizes of learning sets used to develop the expert classifiers are too small, non-trainable fusion rules can outperform more sophisticated trainable ones. A practical technique to fight sample size problems is a noise injection technique. The noise injection reduces the fusion rule's complexity and diminishes the expert's boasting bias.

  6. Health-Enabled Smart Sensor Fusion Technology

    NASA Technical Reports Server (NTRS)

    Wang, Ray

    2012-01-01

    A process was designed to fuse data from multiple sensors in order to make a more accurate estimation of the environment and overall health in an intelligent rocket test facility (IRTF), to provide reliable, high-confidence measurements for a variety of propulsion test articles. The object of the technology is to provide sensor fusion based on a distributed architecture. Specifically, the fusion technology is intended to succeed in providing health condition monitoring capability at the intelligent transceiver, such as RF signal strength, battery reading, computing resource monitoring, and sensor data reading. The technology also provides analytic and diagnostic intelligence at the intelligent transceiver, enhancing the IEEE 1451.x-based standard for sensor data management and distributions, as well as providing appropriate communications protocols to enable complex interactions to support timely and high-quality flow of information among the system elements.

  7. Dust in fusion plasmas: theory and modeling

    SciTech Connect

    Smirnov, R. D.; Pigarov, A. Yu.; Krasheninnikov, S. I.; Mendis, D. A.; Rosenberg, M.; Rudakov, D.; Tanaka, Y.; Rognlien, T. D.; Soboleva, T. K.; Shukla, P. K.; Bray, B. D.; West, W. P.; Roquemore, A. L.; Skinner, C. H.

    2008-09-07

    Dust may have a large impact on ITER-scale plasma experiments including both safety and performance issues. However, the physics of dust in fusion plasmas is very complex and multifaceted. Here, we discuss different aspects of dust dynamics including dust-plasma, and dust-surface interactions. We consider the models of dust charging, heating, evaporation/sublimation, dust collision with material walls, etc., which are suitable for the conditions of fusion plasmas. The physical models of all these processes have been incorporated into the DUST Transport (DUSTT) code. Numerical simulations demonstrate that dust particles are very mobile and accelerate to large velocities due to the ion drag force (cruise speed >100 m/s). Deep penetration of dust particles toward the plasma core is predicted. It is shown that DUSTT is capable of reproducing many features of recent dust-related experiments, but much more work is still needed.

  8. From nucleons to nuclei to fusion reactions

    NASA Astrophysics Data System (ADS)

    Quaglioni, S.; Navrátil, P.; Roth, R.; Horiuchi, W.

    2012-12-01

    Nuclei are prototypes of many-body open quantum systems. Complex aggregates of protons and neutrons that interact through forces arising from quantum chromo-dynamics, nuclei exhibit both bound and unbound states, which can be strongly coupled. In this respect, one of the major challenges for computational nuclear physics, is to provide a unified description of structural and reaction properties of nuclei that is based on the fundamental underlying physics: the constituent nucleons and the realistic interactions among them. This requires a combination of innovative theoretical approaches and high-performance computing. In this contribution, we present one of such promising techniques, the ab initio no-core shell model/resonating-group method, and discuss applications to light nuclei scattering and fusion reactions that power stars and Earth-base fusion facilities.

  9. From Nucleons To Nuclei To Fusion Reactions

    SciTech Connect

    Quaglioni, S; Navratil, P; Roth, R; Horiuchi, W

    2012-02-15

    Nuclei are prototypes of many-body open quantum systems. Complex aggregates of protons and neutrons that interact through forces arising from quantum chromo-dynamics, nuclei exhibit both bound and unbound states, which can be strongly coupled. In this respect, one of the major challenges for computational nuclear physics, is to provide a unified description of structural and reaction properties of nuclei that is based on the fundamental underlying physics: the constituent nucleons and the realistic interactions among them. This requires a combination of innovative theoretical approaches and high-performance computing. In this contribution, we present one of such promising techniques, the ab initio no-core shell model/resonating-group method, and discuss applications to light nuclei scattering and fusion reactions that power stars and Earth-base fusion facilities.

  10. IM30 triggers membrane fusion in cyanobacteria and chloroplasts.

    PubMed

    Hennig, Raoul; Heidrich, Jennifer; Saur, Michael; Schmüser, Lars; Roeters, Steven J; Hellmann, Nadja; Woutersen, Sander; Bonn, Mischa; Weidner, Tobias; Markl, Jürgen; Schneider, Dirk

    2015-05-08

    The thylakoid membrane of chloroplasts and cyanobacteria is a unique internal membrane system harbouring the complexes of the photosynthetic electron transfer chain. Despite their apparent importance, little is known about the biogenesis and maintenance of thylakoid membranes. Although membrane fusion events are essential for the formation of thylakoid membranes, proteins involved in membrane fusion have yet to be identified in photosynthetic cells or organelles. Here we show that IM30, a conserved chloroplast and cyanobacterial protein of approximately 30 kDa binds as an oligomeric ring in a well-defined geometry specifically to membranes containing anionic lipids. Triggered by Mg(2+), membrane binding causes destabilization and eventually results in membrane fusion. We propose that IM30 establishes contacts between internal membrane sites and promotes fusion to enable regulated exchange of proteins and/or lipids in cyanobacteria and chloroplasts.

  11. TRPM7 facilitates cholinergic vesicle fusion with the plasma membrane.

    PubMed

    Brauchi, Sebastian; Krapivinsky, Grigory; Krapivinsky, Luba; Clapham, David E

    2008-06-17

    TRPM7, of the transient receptor potential (TRP) family, is both an ion channel and a kinase. Previously, we showed that TRPM7 is located in the membranes of acetylcholine (ACh)-secreting synaptic vesicles of sympathetic neurons, forms a molecular complex with proteins of the vesicular fusion machinery, and is critical for stimulated neurotransmitter release. Here, we targeted pHluorin to small synaptic-like vesicles (SSLV) in PC12 cells and demonstrate that it can serve as a single-vesicle plasma membrane fusion reporter. In PC12 cells, as in sympathetic neurons, TRPM7 is located in ACh-secreting SSLVs. TRPM7 knockdown by siRNA, or abolishing channel activity by expression of a dominant negative TRPM7 pore mutant, decreased the frequency of spontaneous and voltage-stimulated SSLV fusion events without affecting large dense core vesicle secretion. We conclude that the conductance of TRPM7 across the vesicle membrane is important in SSLV fusion.

  12. Role of the synaptobrevin C terminus in fusion pore formation

    PubMed Central

    Ngatchou, Annita N.; Kisler, Kassandra; Fang, Qinghua; Walter, Alexander M.; Zhao, Ying; Bruns, Dieter; Sørensen, Jakob B.; Lindau, Manfred

    2010-01-01

    Neurotransmitter release is mediated by the SNARE proteins synaptobrevin II (sybII, also known as VAMP2), syntaxin, and SNAP-25, generating a force transfer to the membranes and inducing fusion pore formation. However, the molecular mechanism by which this force leads to opening of a fusion pore remains elusive. Here we show that the ability of sybII to support exocytosis is inhibited by addition of one or two residues to the sybII C terminus depending on their energy of transfer from water to the membrane interface, following a Boltzmann distribution. These results suggest that following stimulation, the SNARE complex pulls the C terminus of sybII deeper into the vesicle membrane. We propose that this movement disrupts the vesicular membrane continuity leading to fusion pore formation. In contrast to current models, the experiments suggest that fusion pore formation begins with molecular rearrangements at the intravesicular membrane leaflet and not between the apposed cytoplasmic leaflets. PMID:20937897

  13. Excitatory and inhibitory learning with absent stimuli.

    PubMed

    Wheeler, Daniel S; Sherwood, Andrew; Holland, Peter C

    2008-04-01

    Three experiments showed that 2 associatively activated stimulus representations may engage in excitatory or inhibitory learning, depending on their temporal relationship. Experiment 1a suggested that simultaneously activated stimulus representations show evidence of inhibitory learning in an acquisition test. Experiment 1b showed similar evidence of inhibition in a summation test. Experiment 2 found that activation of 2 stimulus representations in a serial compound resulted in excitatory learning between the antecedent and the subsequent (forward) and inhibitory learning between the subsequent and the antecedent (backward). The results show the dynamic influence of temporal contiguity on mediated learning.

  14. V-ATPase, ScNhx1p and yeast vacuole fusion.

    PubMed

    Qiu, Quan-Sheng

    2012-04-20

    Membrane fusion is the last step in trafficking pathways during which membrane vesicles fuse with target organelles to deliver cargos. It is a central cellular reaction that plays important roles in signal transduction, protein sorting and subcellular compartmentation. Recent progress in understanding the roles of ion transporters in vacuole fusion in yeast is summarized in this article. It is becoming increasingly evident that the vacuolar proton pump V-ATPase and vacuolar Na+/H+ antiporter ScNhx1p are key components of the vacuole fusion machinery in yeast. Yeast ScNhx1p regulates vacuole fusion by controlling the luminal pH. V-ATPases serve a dual role in vacuolar integrity in which they regulate both vacuole fusion and fission reactions in yeast. Fission defects are epistatic to fusion defects. Vacuole fission depends on the proton translocation activity of the V-ATPase; by contrast, the fusion reaction does not need the transport activity but requires the physical presence of the proton pump. V0, the membrane-integral sector of the V-ATPase, forms trans-complexes between the opposing vacuoles in the terminal phase of vacuole fusion where the V0trans-complexes build a continuous proteolipid channel at the fusion site to mediate the bilayer fusion. Copyright © 2012. Published by Elsevier Ltd.

  15. COG lobe B sub-complex engages v-SNARE GS15 and functions via regulated interaction with lobe A sub-complex

    PubMed Central

    Willett, Rose; Blackburn, Jessica Bailey; Climer, Leslie; Pokrovskaya, Irina; Kudlyk, Tetyana; Wang, Wei; Lupashin, Vladimir

    2016-01-01

    The conserved oligomeric Golgi (COG) complex is a peripheral membrane protein complex which orchestrates tethering of intra-Golgi vesicles. We found that COG1-4 (lobe A) and 5–8 (lobe B) protein assemblies are present as independent sub-complexes on cell membranes. Super-resolution microscopy demonstrates that COG sub-complexes are spatially separated on the Golgi with lobe A preferential localization on Golgi stacks and the presence of lobe B on vesicle-like structures, where it physically interacts with v-SNARE GS15. The localization and specific interaction of the COG sub-complexes with the components of vesicle tethering/fusion machinery suggests their different roles in the vesicle tethering cycle. We propose and test a novel model that employs association/disassociation of COG sub-complexes as a mechanism that directs vesicle tethering at Golgi membranes. We demonstrate that defective COG assembly or restriction of tethering complex disassembly by a covalent COG1-COG8 linkage is inhibitory to COG complex activity, supporting the model. PMID:27385402

  16. COG lobe B sub-complex engages v-SNARE GS15 and functions via regulated interaction with lobe A sub-complex.

    PubMed

    Willett, Rose; Blackburn, Jessica Bailey; Climer, Leslie; Pokrovskaya, Irina; Kudlyk, Tetyana; Wang, Wei; Lupashin, Vladimir

    2016-07-07

    The conserved oligomeric Golgi (COG) complex is a peripheral membrane protein complex which orchestrates tethering of intra-Golgi vesicles. We found that COG1-4 (lobe A) and 5-8 (lobe B) protein assemblies are present as independent sub-complexes on cell membranes. Super-resolution microscopy demonstrates that COG sub-complexes are spatially separated on the Golgi with lobe A preferential localization on Golgi stacks and the presence of lobe B on vesicle-like structures, where it physically interacts with v-SNARE GS15. The localization and specific interaction of the COG sub-complexes with the components of vesicle tethering/fusion machinery suggests their different roles in the vesicle tethering cycle. We propose and test a novel model that employs association/disassociation of COG sub-complexes as a mechanism that directs vesicle tethering at Golgi membranes. We demonstrate that defective COG assembly or restriction of tethering complex disassembly by a covalent COG1-COG8 linkage is inhibitory to COG complex activity, supporting the model.

  17. Laser-induced semicold fusion

    SciTech Connect

    Steinert, C. )

    1990-01-01

    The large high-energy lasers required for inertial fusion are at present beyond state-of-the-art, and there are other problems (instability of the fuel target, suprathermal electrons, etc.) as well. Therefore, it is hoped that the energy requirement for inertial fusion can be reduced with the help of cold fusion, which takes place within the electrode material confining the fuel (avoiding instability problems). With the semicold fusion cell, laser energy is transferred into the hot part of the fuel, which is confined within the cathode in a cavity, and credit is taken from fast projectiles (tritium) stemming from the (t,p) branch of cold fusion in the cold metal lattice. The latter is the key to the model of a dynamic process for potential growth between the cold electrode and the hot confined fuel in the semicold fusion cell.

  18. [Image fusion in medical radiology].

    PubMed

    Burger, C

    1996-07-20

    Image fusion supports the correlation between images of two or more studies of the same organ. First, the effect of differing geometries during image acquisitions, such as a head tilt, is compensated for. As a consequence, congruent images can easily be obtained. Instead of merely putting them side by side in a static manner and burdening the radiologist with the whole correlation task, image fusion supports him with interactive visualization techniques. This is especially worthwhile for small lesions as they can be more precisely located. Image fusion is feasible today. Easy and robust techniques are readily available, and furthermore DICOM, a rapidly evolving data exchange standard, diminishes the once severe compatibility problems for image data originating from systems of different manufacturers. However, the current solutions for image fusion are not yet established enough for a high throughput of fusion studies. Thus, for the time being image fusion is most appropriately confined to clinical research studies.

  19. Oncofuse: a computational framework for the prediction of the oncogenic potential of gene fusions.

    PubMed

    Shugay, Mikhail; Ortiz de Mendíbil, Iñigo; Vizmanos, José L; Novo, Francisco J

    2013-10-15

    Gene fusions resulting from chromosomal aberrations are an important cause of cancer. The complexity of genomic changes in certain cancer types has hampered the identification of gene fusions by molecular cytogenetic methods, especially in carcinomas. This is changing with the advent of next-generation sequencing, which is detecting a substantial number of new fusion transcripts in individual cancer genomes. However, this poses the challenge of identifying those fusions with greater oncogenic potential amid a background of 'passenger' fusion sequences. In the present work, we have used some recently identified genomic hallmarks of oncogenic fusion genes to develop a pipeline for the classification of fusion sequences, namely, Oncofuse. The pipeline predicts the oncogenic potential of novel fusion genes, calculating the probability that a fusion sequence behaves as 'driver' of the oncogenic process based on features present in known oncogenic fusions. Cross-validation and extensive validation tests on independent datasets suggest a robust behavior with good precision and recall rates. We believe that Oncofuse could become a useful tool to guide experimental validation studies of novel fusion sequences found during next-generation sequencing analysis of cancer transcriptomes. Oncofuse is a naive Bayes Network Classifier trained and tested using Weka machine learning package. The pipeline is executed by running a Java/Groovy script, available for download at www.unav.es/genetica/oncofuse.html.

  20. 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

  1. Presynaptic Inhibition at Inhibitory Nerve Terminals. A New Synapse in the Crayfish Stretch Receptor

    PubMed Central

    Nakajima, Yasuko; Tisdale, Ann D.; Henkart, Maryanna P.

    1973-01-01

    Previous physiological evidence has shown that the receptor neuron of the slowly adapting stretch receptor organ of crayfish receives synapses from three inhibitory axons, while the receptor muscle is innervated by both excitatory and inhibitory axons. Fine structural studies have indicated that after certain preparative procedures synaptic vesicles in the inhibitory terminals on dendrites of the receptor neuron appear small and elongate, while those in the excitatory terminals on the receptor muscle are round and larger. This study describes a new synapse between two inhibitory nerve endings on the receptor neuron. One axon, containing small elongate vesicles, forms a presynaptic chemical contact with another morphologically similar axon that, itself, presumably releases inhibitory transmitter onto the receptor neuron. A second type of presynaptic axo-axonic synapse, analogous to one previously described in another crustacean muscle, was also found between presumed inhibitory and excitatory nerve terminals on the receptor muscle. Thus, the stretch receptor has a relatively complex organization with a morphological basis for two types of presynaptic inhibition: one on excitatory terminals and the other on inhibitory terminals. Images PMID:4365382

  2. High Level Information Fusion (HLIF) with nested fusion loops

    NASA Astrophysics Data System (ADS)

    Woodley, Robert; Gosnell, Michael; Fischer, Amber

    2013-05-01

    Situation modeling and threat prediction require higher levels of data fusion in order to provide actionable information. Beyond the sensor data and sources the analyst has access to, the use of out-sourced and re-sourced data is becoming common. Through the years, some common frameworks have emerged for dealing with information fusion—perhaps the most ubiquitous being the JDL Data Fusion Group and their initial 4-level data fusion model. Since these initial developments, numerous models of information fusion have emerged, hoping to better capture the human-centric process of data analyses within a machine-centric framework. 21st Century Systems, Inc. has developed Fusion with Uncertainty Reasoning using Nested Assessment Characterizer Elements (FURNACE) to address challenges of high level information fusion and handle bias, ambiguity, and uncertainty (BAU) for Situation Modeling, Threat Modeling, and Threat Prediction. It combines JDL fusion levels with nested fusion loops and state-of-the-art data reasoning. Initial research has shown that FURNACE is able to reduce BAU and improve the fusion process by allowing high level information fusion (HLIF) to affect lower levels without the double counting of information or other biasing issues. The initial FURNACE project was focused on the underlying algorithms to produce a fusion system able to handle BAU and repurposed data in a cohesive manner. FURNACE supports analyst's efforts to develop situation models, threat models, and threat predictions to increase situational awareness of the battlespace. FURNACE will not only revolutionize the military intelligence realm, but also benefit the larger homeland defense, law enforcement, and business intelligence markets.

  3. Fusion by Diffusion Model Revisited

    NASA Astrophysics Data System (ADS)

    Cap, T.; Siwek-Wilczyńska, K.; Wilczyński, J.

    A complete set of 27 excitation functions for synthesis of superheavy nuclei produced in cold fusion reactions was analyzed in terms of the "Fusion by Diffusion Model" of Światecki et al., modified to account for the angular momentum dependence of the fusion hindrance factor. The data on cold fusion reactions originate from experiments carried out at GSI Darmstadt, RIKEN Tokyo and LBNL Berkeley in which 208Pb and 209Bi targets were bombarded with the variety of projectiles ranging from 48,50Ti to 70Zn.

  4. Economic potential of inertial fusion

    SciTech Connect

    Nuckolls, J.H.

    1984-04-01

    Beyond the achievement of scientific feasibility, the key question for fusion energy is: does it have the economic potential to be significantly cheaper than fission and coal energy. If fusion has this high economic potential then there are compelling commercial and geopolitical incentives to accelerate the pace of the fusion program in the near term, and to install a global fusion energy system in the long term. Without this high economic potential, fusion's success depends on the failure of all alternatives, and there is no real incentive to accelerate the program. If my conjectures on the economic potential of inertial fusion are approximately correct, then inertial fusion energy's ultimate costs may be only half to two-thirds those of advanced fission and coal energy systems. Relative cost escalation is not assumed and could increase this advantage. Both magnetic and inertial approaches to fusion potentially have a two-fold economic advantage which derives from two fundamental properties: negligible fuel costs and high quality energy which makes possible more efficient generation of electricity. The wining approach to fusion may excel in three areas: electrical generating efficiency, minimum material costs, and adaptability to manufacture in automated factories. The winning approach must also rate highly in environmental potential, safety, availability factor, lifetime, small 0 and M costs, and no possibility of utility-disabling accidents.

  5. The path to fusion power.

    PubMed

    Smith, Chris Llewellyn; Cowley, Steve

    2010-03-13

    The promise, status and challenges of developing fusion power are outlined. The key physics and engineering principles are described and recent progress quantified. As the successful demonstration of 16 MW of fusion in 1997 in the Joint European Torus showed, fusion works. The central issue is therefore to make it work reliably and economically on the scale of a power station. We argue that to meet this challenge in 30 years we must follow the aggressive programme known as the 'Fast Track to Fusion'. This programme is described in some detail.

  6. Radiologic assessment of spinal fusion.

    PubMed

    Selby, Michael Derrick; Clark, Simon Richard; Hall, David John; Freeman, Brian J C

    2012-11-01

    Since surgical fusion of the spine was first described in 1911, multiple methods have been used to assess it. Although open surgical exploration remains the standard of care for determination of fusion, it is impractical in most clinical situations. Static radiographs have long been used as a practical method of fusion assessment, but they tend to significantly overestimate the presence of a solid fusion. Dynamic radiographs improve accuracy but limitations include measurement reliability, disagreement on allowable motion, and the two-dimensional nature of radiographs. Ultimately, lack of movement at a fused segment does not confirm fusion. Radiostereometric analysis further improves accuracy; however, methodological demands make it largely impractical for routine use. CT is now widely accepted as the standard for noninvasive assessment of spinal fusion. Fine-cut imaging, multiplanar reconstruction, and metal artifact reduction have increased the ability to assess fusion on CT. However, significant concerns remain regarding the effects of high radiation exposure. Although MRI is appealing, its utility in assessing fusion remains unproven. Understanding the limitations of each technique allows judicious use of radiology in the assessment of spinal fusion.

  7. Network-centric data fusion

    NASA Astrophysics Data System (ADS)

    Nicholson, David; Lloyd, C. M.; Collins, Peter R. C.

    2002-08-01

    The performance of three distributed sensor fusion network architectures is investigated: a fully-connected and a partially-connected measurement fusion system and a partially-connected track fusion system. The investigation employs an advanced military scenario generator, FLAMES, which was customised for exercising a range of distributed data fusion experiments. Specifically, it includes a representative model of the delays in a communication system (such as JTIDS or Link 16). Here the delays were used to modify communication bandwidth and to evaluate how this affected the performance of the fusion architectures/algorithms. Under certain specific scenario conditions, it was found that decentralised measurement fusion system was severely affected by reduced bandwidth. This is because each node loads its communication buffer with every measurement and consequently some measurements are never transmitted. The decentralised track fusion system exhibits improved performance because it lumps measurements into tracks and thereby it makes much more effective use of the bandwidth. Moreover, it was found that the performance of the partially connected decentralised track fusion system was very close to the optimal performance achieved by the fully-connected decentralised measurement fusion system.

  8. OCULUS Sea Track Fusion Service

    NASA Astrophysics Data System (ADS)

    Panagiotou, Stylianos C.; Rizogiannis, Constantinos; Katsoulis, Stavros; Lampropoulos, Vassilis; Kanellopoulos, Sotirios; Thomopoulos, Stelios C. A.

    2015-06-01

    Oculus Sea is a complete solution regarding maritime surveillance and communications at Local as well as Central Command and Control level. It includes a robust and independent track fusion service whose main functions include: 1) Interaction with the User to suggest the fusion of two or more tracks, confirm Track ID and Vessel Metadata creation for the fused track, and suggest de-association of two tracks 2) Fusion of same vessel tracks arriving simultaneously from multiple radar sensors featuring track Association, track Fusion of associated tracks to produce a more accurate track, and Multiple tracking filters and fusion algorithms 3) Unique Track ID Generator for each fused track 4) Track Dissemination Service. Oculus Sea Track Fusion Service adopts a system architecture where each sensor is associated with a Kalman estimator/tracker that obtains an estimate of the state vector and its respective error covariance matrix. Finally, at the fusion center, association and track state estimation fusion are carried out. The expected benefits of this system include multi-sensor information fusion, enhanced spatial resolution, and improved target detection.

  9. Inhibitory Circuits in Cortical Layer 5

    PubMed Central

    Naka, Alexander; Adesnik, Hillel

    2016-01-01

    Inhibitory neurons play a fundamental role in cortical computation and behavior. Recent technological advances, such as two photon imaging, targeted in vivo recording, and molecular profiling, have improved our understanding of the function and diversity of cortical interneurons, but for technical reasons most work has been directed towards inhibitory neurons in the superficial cortical layers. Here we review current knowledge specifically on layer 5 (L5) inhibitory microcircuits, which play a critical role in controlling cortical output. We focus on recent work from the well-studied rodent barrel cortex, but also draw on evidence from studies in primary visual cortex and other cortical areas. The diversity of both deep inhibitory neurons and their pyramidal cell targets make this a challenging but essential area of study in cortical computation and sensory processing. PMID:27199675

  10. Cold nuclear fusion

    NASA Astrophysics Data System (ADS)

    Tsyganov, E. N.; Bavizhev, M. D.; Buryakov, M. G.; Dabagov, S. B.; Golovatyuk, V. M.; Lobastov, S. P.

    2015-07-01

    If target deuterium atoms were implanted in a metal crystal in accelerator experiments, a sharp increase in the probability of DD-fusion reaction was clearly observed when compared with the reaction's theoretical value. The electronic screening potential, which for a collision of free deuterium atoms is about 27 eV, reached 300-700 eV in the case of the DD-fusion in metallic crystals. These data leads to the conclusion that a ban must exist for deuterium atoms to be in the ground state 1s in a niche filled with free conduction electrons. At the same time, the state 2p whose energy level is only 10 eV above that of state 1s is allowed in these conditions. With anisotropy of 2p, 3p or above orbitals, their spatial positions are strictly determined in the lattice coordinate system. When filling out the same potential niches with two deuterium atoms in the states 2p, 3p or higher, the nuclei of these atoms can be permanently positioned without creating much Coulomb repulsion at a very short distance from each other. In this case, the transparency of the potential barrier increases dramatically compared to the ground state 1s for these atoms. The probability of the deuterium nuclei penetrating the Coulomb barrier by zero quantum vibration of the DD-system also increases dramatically. The so-called cold nuclear DD-fusion for a number of years was registered in many experiments, however, was still rejected by mainstream science for allegedly having no consistent scientific explanation. Finally, it received the validation. Below, we outline the concept of this explanation and give the necessary calculations. This paper also considers the further destiny of the formed intermediate state of 4He∗.

  11. Inhibitory Receptors of the Immune System: Functions and Therapeutic Implications

    PubMed Central

    Zhang, Jian; Xiao, Xiang; Liu, Wentao; Demirci, Gulcin; Li, Xian C

    2009-01-01

    The immune system has a remarkable ability to respond to seemingly endless antigens. In essence, a productive immune response takes place along a well defined but treacherous line, that is to effectively eradicate pathogens, and at the same time avoid causing damage to self organs. This type of response is fine-tuned, at least in part, by a complex array of pathways that either promote or inhibit the activation of innate and adaptive immune cells. Much effort has been focused on pathways that can support immune activation. In this article, we review specifically pathways that can inhibit immune responses and maintain immune homeostasis, highlighting our recent understanding on the role of inhibitory receptors that selectively engage the self MHC class I molecules and the B7 superfamily members, we also discuss the inhibitory Fc receptors and inhibitory cytokines and how such pathways, either individually or collectively, regulate innate and adaptive immune responses. Finally, we summarize new emerging approaches on how such negative pathways can be therapeutically modulated in various disease settings. PMID:20003816

  12. 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.

  13. Cold Fusion Verification.

    DTIC Science & Technology

    1991-03-01

    published work, talking with others in the field, and attending conferences, that CNF probably is chimera and will go the way of N-rays and polywater ...way of N-rays and polywater . To date, no one, including Pons and Fleischmann, has been able to construct a so-called CNF electrochemical cell that...Cold Nuclear Fusion (CNF), as originally reported in 1989. The conclusion is that CNF probably is chimera and will go the way of N-rays and polywater

  14. Peregrinations on cold fusion

    SciTech Connect

    Turner, L.

    1989-01-01

    Attention is focused on the possibility of resonance-enhanced deuteron Coulomb barrier penetration. Because of the many-body nature of the interactions of room-temperature deuterons diffusing through a lattice possessing deuterons in many of the interstitial positions, the diffusing deuterons can resonate on the atomic scale in the potential wells bounded by the ascending walls of adjacent Coulomb barriers and thereby penetrate the Coulomb barriers in a fashion vastly underestimated by two-body calculations in which wells for possible resonance are absent. Indeed, perhaps the lack of robust reproducibility in cold fusion originates from the narrowness of such transmission resonances. 4 refs., 1 fig.

  15. Physics of Fusion Welding

    NASA Technical Reports Server (NTRS)

    Nunes, A. C., Jr.

    1986-01-01

    Applicabilities and limitations of three techniques analyzed. NASA technical memorandum discusses physics of electron-beam, gas/ tungsten-arc, and laser-beam welding. From comparison of capabilities and limitations of each technique with regard to various welding conditions and materials, possible to develop criteria for selecting best welding technique in specific application. All three techniques classified as fusion welding; small volume of workpiece melted by intense heat source. Heat source moved along seam, leaving in wake solid metal that joins seam edges together.

  16. Physics of Fusion Welding

    NASA Technical Reports Server (NTRS)

    Nunes, A. C., Jr.

    1986-01-01

    Applicabilities and limitations of three techniques analyzed. NASA technical memorandum discusses physics of electron-beam, gas/ tungsten-arc, and laser-beam welding. From comparison of capabilities and limitations of each technique with regard to various welding conditions and materials, possible to develop criteria for selecting best welding technique in specific application. All three techniques classified as fusion welding; small volume of workpiece melted by intense heat source. Heat source moved along seam, leaving in wake solid metal that joins seam edges together.

  17. An extended helical conformation in domain 3a of Munc18-1 provides a template for SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex assembly.

    PubMed

    Parisotto, Daniel; Pfau, Maximilian; Scheutzow, Andrea; Wild, Klemens; Mayer, Matthias P; Malsam, Jörg; Sinning, Irmgard; Söllner, Thomas H

    2014-04-04

    Munc18-1, a SEC1/Munc18 protein and key regulatory protein in synaptic transmission, can either promote or inhibit SNARE complex assembly. Although the binary inhibitory interaction between Munc18-1 and closed syntaxin 1 is well described, the mechanism of how Munc18-1 stimulates membrane fusion remains elusive. Using a reconstituted assay that resolves vesicle docking, priming, clamping, and fusion during synaptic exocytosis, we show that helix 12 in domain 3a of Munc18-1 stimulates SNAREpin assembly and membrane fusion. A single point mutation (L348R) within helix 12 selectively abolishes VAMP2 binding and the stimulatory function of Munc18-1 in membrane fusion. In contrast, targeting a natural switch site (P335A) at the start of helix 12, which can result in an extended α-helical conformation, further accelerates lipid-mixing. Together with structural modeling, the data suggest that helix 12 provides a folding template for VAMP2, accelerating SNAREpin assembly and membrane fusion. Analogous SEC1/Munc18-SNARE interactions at other transport steps may provide a general mechanism to drive lipid bilayer merger. At the neuronal synapse, Munc18-1 may convert docked synaptic vesicles into a readily releasable pool.

  18. Report of the Fusion Energy Sciences Advisory Committee. Panel on Integrated Simulation and Optimization of Magnetic Fusion Systems

    SciTech Connect

    Dahlburg, Jill; Corones, James; Batchelor, Donald; Bramley, Randall; Greenwald, Martin; Jardin, Stephen; Krasheninnikov, Sergei; Laub, Alan; Leboeuf, Jean-Noel; Lindl, John; Lokke, William; Rosenbluth, Marshall; Ross, David; Schnack, Dalton

    2002-11-01

    Fusion is potentially an inexhaustible energy source whose exploitation requires a basic understanding of high-temperature plasmas. The development of a science-based predictive capability for fusion-relevant plasmas is a challenge central to fusion energy science, in which numerical modeling has played a vital role for more than four decades. A combination of the very wide range in temporal and spatial scales, extreme anisotropy, the importance of geometric detail, and the requirement of causality which makes it impossible to parallelize over time, makes this problem one of the most challenging in computational physics. Sophisticated computational models are under development for many individual features of magnetically confined plasmas and increases in the scope and reliability of feasible simulations have been enabled by increased scientific understanding and improvements in computer technology. However, full predictive modeling of fusion plasmas will require qualitative improvements and innovations to enable cross coupling of a wider variety of physical processes and to allow solution over a larger range of space and time scales. The exponential growth of computer speed, coupled with the high cost of large-scale experimental facilities, makes an integrated fusion simulation initiative a timely and cost-effective opportunity. Worldwide progress in laboratory fusion experiments provides the basis for a recent FESAC recommendation to proceed with a burning plasma experiment (see FESAC Review of Burning Plasma Physics Report, September 2001). Such an experiment, at the frontier of the physics of complex systems, would be a huge step in establishing the potential of magnetic fusion energy to contribute to the world’s energy security. An integrated simulation capability would dramatically enhance the utilization of such a facility and lead to optimization of toroidal fusion plasmas in general. This science-based predictive capability, which was cited in the FESAC

  19. Membrane fusion machines of paramyxoviruses: capture of intermediates of fusion

    PubMed Central

    Russell, Charles J.; Jardetzky, Theodore S.; Lamb, Robert A.

    2001-01-01

    Peptides derived from heptad repeat regions adjacent to the fusion peptide and transmembrane domains of many viral fusion proteins form stable helical bundles and inhibit fusion specifically. Paramyxovirus SV5 fusion (F) protein-mediated fusion and its inhibition by the peptides N-1 and C-1 were analyzed. The temperature dependence of fusion by F suggests that thermal energy, destabilizing proline residues and receptor binding by the hemagglutinin–neuraminidase (HN) protein collectively contribute to F activation from a metastable native state. F-mediated fusion was reversibly arrested by low temperature or membrane-incorporated lipids, and the resulting F intermediates were characterized. N-1 inhibited an earlier F intermediate than C-1. Co-expression of HN with F lowered the temperature required to attain the N-1-inhibited intermediate, consistent with HN binding to its receptor stimulating a conformational change in F. C-1 bound and inhibited an intermediate of F that could be detected until a point directly preceding membrane merger. The data are consistent with C-1 binding a pre-hairpin intermediate of F and with helical bundle formation being coupled directly to membrane fusion. PMID:11483506

  20. Whisker Deprivation Drives Two Phases of Inhibitory Synapse Weakening in Layer 4 of Rat Somatosensory Cortex.

    PubMed

    Gainey, Melanie A; Wolfe, Renna; Pourzia, Olivia; Feldman, Daniel E

    2016-01-01

    Inhibitory synapse development in sensory neocortex is experience-dependent, with sustained sensory deprivation yielding fewer and weaker inhibitory synapses. Whether this represents arrest of synapse maturation, or a more complex set of processes, is unclear. To test this, we measured the dynamics of inhibitory synapse development in layer 4 of rat somatosensory cortex (S1) during continuous whisker deprivation from postnatal day 7, and in age-matched controls. In deprived columns, spontaneous miniature inhibitory postsynaptic currents (mIPSCs) and evoked IPSCs developed normally until P15, when IPSC amplitude transiently decreased, recovering by P16 despite ongoing deprivation. IPSCs remained normal until P22, when a second, sustained phase of weakening began. Delaying deprivation onset by 5 days prevented the P15 weakening. Both early and late phase weakening involved measurable reduction in IPSC amplitude relative to prior time points. Thus, deprivation appears to drive two distinct phases of active IPSC weakening, rather than simple arrest of synapse maturation.

  1. Origin of the inhibitory activity of 4-O-substituted sialic derivatives of human parainfluenza virus.

    PubMed

    Itoh, Yuji; Sando, Ayumi; Ikeda, Kiyoshi; Suzuki, Takashi; Tokiwa, Hiroaki

    2012-05-01

    Human parainfluenza virus (hPIV) is a serious human pathogen causing upper and lower respiratory tract disease, yet there are no effective vaccines or therapies to control parainfluenza virus infections. Recently, we found that 4-O-substituted sialic derivatives have potent inhibitory activity against hPIV-1, whereas the anti-influenza inhibitor Zanamivir was less inhibitory. To elucidate the origin of the high potency inhibitory activities of these 4-O-substituted derivatives, we performed correlated fragment molecular orbital (FMO)-interfragment interaction energy (IFIE) analysis for hemagglutinin-neuraminidase (HN) glycoprotein complexes of hPIV with the derivatives and compared them with those for Zanamivir. We found key interactions between the inhibitors and the hPIV HN glycoprotein and identified important factors for the inhibitory activity. These theoretical results will be useful for the development of novel anti-hPIV drugs.

  2. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection.

    PubMed

    Khakoo, Salim I; Thio, Chloe L; Martin, Maureen P; Brooks, Collin R; Gao, Xiaojiang; Astemborski, Jacquie; Cheng, Jie; Goedert, James J; Vlahov, David; Hilgartner, Margaret; Cox, Steven; Little, Ann-Margeret; Alexander, Graeme J; Cramp, Matthew E; O'Brien, Stephen J; Rosenberg, William M C; Thomas, David L; Carrington, Mary

    2004-08-06

    Natural killer (NK) cells provide a central defense against viral infection by using inhibitory and activation receptors for major histocompatibility complex class I molecules as a means of controlling their activity. We show that genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group 1 (HLA-C1) ligand directly influence resolution of hepatitis C virus (HCV) infection. This effect was observed in Caucasians and African Americans with expected low infectious doses of HCV but not in those with high-dose exposure, in whom the innate immune response is likely overwhelmed. The data strongly suggest that inhibitory NK cell interactions are important in determining antiviral immunity and that diminished inhibitory responses confer protection against HCV.

  3. Alteration of Lysosome Fusion and Low-grade Inflammation Mediated by Super-low-dose Endotoxin*

    PubMed Central

    Baker, Bianca; Geng, Shuo; Chen, Keqiang; Diao, Na; Yuan, Ruoxi; Xu, Xiguang; Dougherty, Sean; Stephenson, Caroline; Xiong, Huabao; Chu, Hong Wei; Li, Liwu

    2015-01-01

    Subclinical super-low-dose endotoxin LPS is a risk factor for the establishment of low-grade inflammation during the pathogenesis and progression of chronic diseases. However, the underlying mechanisms are not well understood. At the cellular level, a disruption of lysosome fusion with endosomes or autophagosomes may contribute to the potentiation of low-grade inflammation. In this study, we identified that subclinical super-low-dose endotoxin LPS can potently inhibit the process of endosome acidification and lysosome fusion with endosomes or autophagosomes in primary macrophages. Super-low-dose LPS induced the inhibitory phosphorylation of VPS34, thus leading to the disruption of endosome-lysosome fusion. This effect may depend upon the clearance and relocation of Tollip in macrophages by super-low-dose LPS. Consistent with this notion, Tollip-deficient macrophages had constitutively elevated levels of VPS34 inhibitory phosphorylation and constitutive disruption of endosome-lysosome fusion. By employing a skin excision wound-healing model, we observed that Tollip-deficient mice had significantly elevated levels of cell stress and reduced wound repair. This study reveals a novel mechanism responsible for the modulation of endosome-lysosome fusion and low-grade inflammation in innate macrophages. PMID:25586187

  4. Recurrent fusion oncogenes in carcinomas.

    PubMed

    Teixeira, Manuel R

    2006-12-01

    Chromosome structural aberrations giving rise to fusion oncogenes is one of the most common mechanisms in oncogenesis. Although this type of gene rearrangement has long been recognized as a fundamental pathogenetic mechanism in hematologi-cal malignancies and soft-tissue tumors, it has until recently only rarely been described in the common carcinomas. In this review, the existing information on recurrent fusion oncogenes characterizing carcinomas is summarized, namely, the RET and NTRK1 fusion oncogenes in papillary thyroid carcinoma, PAX8-PPARG in follicular thyroid carcinoma, MECT1-MAML2 in mucoepidermoid carcinoma, the TFE3 and TFEB fusion oncogenes in kidney carcinomas, BRD4-NUT in midline carcinomas, ETV6-NTRK3 in secretory breast carcinomas, and TMPRSS2-ETS fusion oncogenes in prostate carcinomas. As in hematological and soft-tissue malignancies, the most common types of genes involved in fusion oncogenes in carcinomas are transcription factors and tyrosine kinases. With a few exceptions, most fusion oncogenes are tumor type specific in carcinomas, as in other cancers. The mechanisms behind the relative specificity of this type of somatic mutation involve the cellular environment influencing the selection of oncogenic fusions, and the oncogenic fusions in turn driving differentiation programs that may alter the cellular environment. The data summarized on different types of carcinomas characterized by fusion oncogenes indicate that the pathogenetic mechanisms involved in epithelial carcino-genesis may be similar to those known to operate in hematological and soft-tissue malignancies, and further anticipates that many more fusion oncogenes await identification in the most common types of human cancer.

  5. Probing the mechanism of fusion in a two-dimensional computer simulation.

    PubMed Central

    Chanturiya, Alexandr; Scaria, Puthurapamil; Kuksenok, Oleksandr; Woodle, Martin C

    2002-01-01

    A two-dimensional (2D) model of lipid bilayers was developed and used to investigate a possible role of membrane lateral tension in membrane fusion. We found that an increase of lateral tension in contacting monolayers of 2D analogs of liposomes and planar membranes could cause not only hemifusion, but also complete fusion when internal pressure is introduced in the model. With a certain set of model parameters it was possible to induce hemifusion-like structural changes by a tension increase in only one of the two contacting bilayers. The effect of lysolipids was modeled as an insertion of a small number of extra molecules into the cis or trans side of the interacting bilayers at different stages of simulation. It was found that cis insertion arrests fusion and trans insertion has no inhibitory effect on fusion. The possibility of protein participation in tension-driven fusion was tested in simulation, with one of two model liposomes containing a number of structures capable of reducing the area occupied by them in the outer monolayer. It was found that condensation of these structures was sufficient to produce membrane reorganization similar to that observed in simulations with "protein-free" bilayers. These data support the hypothesis that changes in membrane lateral tension may be responsible for fusion in both model phospholipid membranes and in biological protein-mediated fusion. PMID:12023230

  6. Information Operations: Creating New Frontiers for Data Fusion and Mining Technology

    DTIC Science & Technology

    1999-01-01

    operations pose new challenges to the application of data fusion and data mining technologies. This paper describes the basic reasoning processes...underlying both data fusion and data mining , and discusses the critical role of these processes to enable the development of increasingly complex information

  7. Statistics in fusion experiments

    NASA Astrophysics Data System (ADS)

    McNeill, D. H.

    1997-11-01

    Since the reasons for the variability in data from plasma experiments are often unknown or uncontrollable, statistical methods must be applied. Reliable interpretation and public accountability require full data sets. Two examples of data misrepresentation at PPPL are analyzed: Te >100 eV on S-1 spheromak.(M. Yamada, Nucl. Fusion 25, 1327 (1985); reports to DoE; etc.) The reported high values (statistical artifacts of Thomson scattering measurements) were selected from a mass of data with an average of 40 eV or less. ``Correlated'' spectroscopic data were meaningless. (2) Extrapolation to Q >=0.5 for DT in TFTR.(D. Meade et al., IAEA Baltimore (1990), V. 1, p. 9; H. P. Furth, Statements to U. S. Congress (1989).) The DD yield used there was the highest through 1990 (>= 50% above average) and the DT to DD power ratio used was about twice any published value. Average DD yields and published yield ratios scale to Q<0.15 for DT, in accord with the observed performance over the last 3 1/2 years. Press reports of outlier data from TFTR have obscured the fact that the DT behavior follows from trivial scaling of the DD data. Good practice in future fusion research would have confidence intervals and other descriptive statistics accompanying reported numerical values (cf. JAMA).

  8. Overview of MRB fusion

    SciTech Connect

    Maschke, A.W.

    1984-01-01

    The Momentum-Rich Beam (MRB) fusion concept is a new method of achieving thermonuclear ignition in a single shell DT target. The advantage of the system is that only 1/4 to 1/2 MJ is needed for ignition, and the acceleration system for producing the beams may be 80% efficient or better. This combination of circumstances means that the driver costs for a full-scale ignition system are an order of magnitude less expensive than a comparable laser or heavy ion driver. This is especially important when one realizes that the cost of a conventional 5 MJ driver is in the 1-2 G$ range. This same problem has arisen for magnetic confinement fusion, where the cost of the next step, a full-scale reactor, is prohibitive. The program at BNL is divided into two parts. One part is a program to investigate the physics of interaction between the MRB's and the pellet. This is done with the LASNEX hydro code at LANL. The purpose of this report is to determine the minimum requirements the MRB's must have in order to achieve ignition.

  9. Magnetless magnetic fusion

    SciTech Connect

    Beklemishev, A.D. |; Tajima, T.

    1994-02-01

    The authors propose a concept of thermonuclear fusion reactor in which the plasma pressure is balanced by direct gas-wall interaction in a high-pressure vessel. The energy confinement is achieved by means of the self-contained toroidal magnetic configuration sustained by an external current drive or charged fusion products. This field structure causes the plasma pressure to decrease toward the inside of the discharge and thus it should be magnetohydrodynamically stable. The maximum size, temperature and density profiles of the reactor are estimated. An important feature of confinement physics is the thin layer of cold gas at the wall and the adjacent transitional region of dense arc-like plasma. The burning condition is determined by the balance between these nonmagnetized layers and the current-carrying plasma. They suggest several questions for future investigation, such as the thermal stability of the transition layer and the possibility of an effective heating and current drive behind the dense edge plasma. The main advantage of this scheme is the absence of strong external magnets and, consequently, potentially cheaper design and lower energy consumption.

  10. Inertial confinement fusion

    SciTech Connect

    Powers, L.; Condouris, R.; Kotowski, M.; Murphy, P.W.

    1992-01-01

    This issue of the ICF Quarterly contains seven articles that describe recent progress in Lawrence Livermore National Laboratory's ICF program. The Department of Energy recently initiated an effort to design a 1--2 MJ glass laser, the proposed National Ignition Facility (NIF). These articles span various aspects of a program which is aimed at moving forward toward such a facility by continuing to use the Nova laser to gain understanding of NIF-relevant target physics, by developing concepts for an NIF laser driver, and by envisioning a variety of applications for larger ICF facilities. This report discusses research on the following topics: Stimulated Rotational Raman Scattering in Nitrogen; A Maxwell Equation Solver in LASNEX for the Simulation of Moderately Intense Ultrashort Pulse Experiments; Measurements of Radial Heat-Wave Propagation in Laser-Produced Plasmas; Laser-Seeded Modulation Growth on Directly Driven Foils; Stimulated Raman Scattering in Large-Aperture, High-Fluence Frequency-Conversion Crystals; Fission Product Hazard Reduction Using Inertial Fusion Energy; Use of Inertial Confinement Fusion for Nuclear Weapons Effects Simulations.

  11. Collaborations in fusion research

    SciTech Connect

    Barnes, D.; Davis, S.; Roney, P.

    1995-01-01

    This paper reviews current experimental collaborative efforts in the fusion community and extrapolates to operational scenarios for the Tokamak Physics Experiment (TPX) and the International Thermonuclear Experimental Reactor (ITER). Current requirements, available technologies and tools, and problems, issues and concerns are discussed. This paper specifically focuses on the issues that apply to experimental operational collaborations. Special requirements for other types of collaborations, such as theoretical or design and construction efforts, will not be addressed. Our current collaborative efforts have been highly successful, even though the tools in use will be viewed as primitive by tomorrow`s standards. An overview of the tools and technologies in today`s collaborations can be found in the first section of this paper. The next generation of fusion devices will not be primarily institutionally based, but will be national (TPX) and international (ITER) in funding, management, operation and in ownership of scientific results. The TPX will present the initial challenge of real-time remotely distributed experimental data analysis for a steady state device. The ITER will present new challenges with the possibility of several remote control rooms all participating in the real-time operation of the experimental device. A view to the future of remote collaborations is provided in the second section of this paper.

  12. Expression, Purification and Characterization of GMZ2'.10C, a Complex Disulphide-Bonded Fusion Protein Vaccine Candidate against the Asexual and Sexual Life-Stages of the Malaria-Causing Plasmodium falciparum Parasite.

    PubMed

    Mistarz, Ulrik H; Singh, Susheel K; Nguyen, Tam T T N; Roeffen, Will; Yang, Fen; Lissau, Casper; Madsen, Søren M; Vrang, Astrid; Tiendrebeogo, Régis W; Kana, Ikhlaq H; Sauerwein, Robert W; Theisen, Michael; Rand, Kasper D

    2017-09-01

    Production and characterization of a chimeric fusion protein (GMZ2'.10C) which combines epitopes of key malaria parasite antigens: glutamate-rich protein (GLURP), merozoite surface protein 3 (MSP3), and the highly disulphide bonded Pfs48/45 (10C). GMZ2'.10C is a potential candidate for a multi-stage malaria vaccine that targets both transmission and asexual life-cycle stages of the parasite. GMZ2'.10C was produced in Lactococcus lactis and purified using either an immunoaffinity purification (IP) or a conventional purification (CP) method. Protein purity and stability was analysed by RP-HPLC, SEC-HPLC, 2-site ELISA, gel-electrophoresis and Western blotting. Structural characterization (mass analysis, peptide mapping and cysteine connectivity mapping) was performed by LC-MS/MS. CP-GMZ2'.10C resulted in similar purity, yield, structure and stability as compared to IP-GMZ2'.10C. CP-GMZ2'.10C and IP-GMZ2'.10C both elicited a high titer of transmission blocking (TB) antibodies in rodents. The intricate disulphide-bond connectivity of C-terminus Pfs48/45 was analysed by tandem mass spectrometry and was established for GMZ2'.10C and two reference fusion proteins encompassing similar parts of Pfs48/45. GMZ2'.10C, combining GMZ2' and correctly-folded Pfs48/45 can be produced by the Lactoccus lactis P170 based expression system in purity and quality for pharmaceutical development and elicit high level of TB antibodies. The cysteine connectivity for the 10C region of Pfs48/45 was revealed experimentally, providing an important guideline for employing the Pfs48/45 antigen in vaccine design.

  13. Two coiled-coil domains of Chlamydia trachomatis IncA affect membrane fusion events during infection.

    PubMed

    Ronzone, Erik; Paumet, Fabienne

    2013-01-01

    Chlamydia trachomatis replicates in a parasitophorous membrane-bound compartment called an inclusion. The inclusions corrupt host vesicle trafficking networks to avoid the degradative endolysosomal pathway but promote fusion with each other in order to sustain higher bacterial loads in a process known as homotypic fusion. The Chlamydia protein IncA (Inclusion protein A) appears to play central roles in both these processes as it participates to homotypic fusion and inhibits endocytic SNARE-mediated membrane fusion. How IncA selectively inhibits or activates membrane fusion remains poorly understood. In this study, we analyzed the spatial and molecular determinants of IncA's fusogenic and inhibitory functions. Using a cell-free membrane fusion assay, we found that inhibition of SNARE-mediated fusion requires IncA to be on the same membrane as the endocytic SNARE proteins. IncA displays two coiled-coil domains showing high homology with SNARE proteins. Domain swap and deletion experiments revealed that although both these domains are capable of independently inhibiting SNARE-mediated fusion, these two coiled-coil domains cooperate in mediating IncA multimerization and homotypic membrane interaction. Our results support the hypothesis that Chlamydia employs SNARE-like virulence factors that positively and negatively affect membrane fusion and promote infection.

  14. Two Coiled-Coil Domains of Chlamydia trachomatis IncA Affect Membrane Fusion Events during Infection

    PubMed Central

    Ronzone, Erik; Paumet, Fabienne

    2013-01-01

    Chlamydia trachomatis replicates in a parasitophorous membrane-bound compartment called an inclusion. The inclusions corrupt host vesicle trafficking networks to avoid the degradative endolysosomal pathway but promote fusion with each other in order to sustain higher bacterial loads in a process known as homotypic fusion. The Chlamydia protein IncA (Inclusion protein A) appears to play central roles in both these processes as it participates to homotypic fusion and inhibits endocytic SNARE-mediated membrane fusion. How IncA selectively inhibits or activates membrane fusion remains poorly understood. In this study, we analyzed the spatial and molecular determinants of IncA’s fusogenic and inhibitory functions. Using a cell-free membrane fusion assay, we found that inhibition of SNARE-mediated fusion requires IncA to be on the same membrane as the endocytic SNARE proteins. IncA displays two coiled-coil domains showing high homology with SNARE proteins. Domain swap and deletion experiments revealed that although both these domains are capable of independently inhibiting SNARE-mediated fusion, these two coiled-coil domains cooperate in mediating IncA multimerization and homotypic membrane interaction. Our results support the hypothesis that Chlamydia employs SNARE-like virulence factors that positively and negatively affect membrane fusion and promote infection. PMID:23936096

  15. The possible hot nature of cold fusion

    SciTech Connect

    Kuehne, R.W. )

    1994-03-01

    Based on the model of micro hot fusion, the neutron emission rate of cold fusion is determined without the need for fine-tuning parameters. Moreover, the experimental conditions that are essential to reproduce fusion are determined. 84 refs.

  16. Helium Find Thaws the Cold Fusion Trail.

    ERIC Educational Resources Information Center

    Pennisi, E.

    1991-01-01

    Reported is a study of cold fusion in which trace amounts of helium, possible evidence of an actual fusion reaction, were found. Research methodology is detailed. The controversy over the validity of experimental results with cold fusion are reviewed. (CW)

  17. Helium Find Thaws the Cold Fusion Trail.

    ERIC Educational Resources Information Center

    Pennisi, E.

    1991-01-01

    Reported is a study of cold fusion in which trace amounts of helium, possible evidence of an actual fusion reaction, were found. Research methodology is detailed. The controversy over the validity of experimental results with cold fusion are reviewed. (CW)

  18. Identification and Characterization of a Small Inhibitory Peptide That Can Target DNA-PKcs Autophosphorylation and Increase Tumor Radiosensitivity

    SciTech Connect

    Sun Xiaonan; Yang Chunying; Liu Hai; Wang Qi; Wu Shixiu; Li Xia; Xie Tian; Brinkman, Kathryn L.; Teh, Bin S.; Butler, E. Brian; Xu Bo; Zheng, Shu

    2012-12-01

    Purpose: The DNA protein kinase catalytic subunit (DNA-PKcs) is one of the critical elements involved in the DNA damage repair process. Inhibition of DNA-PKcs results in hypersensitivity to ionizing radiation (IR); therefore, this approach has been explored to develop molecular targeted radiosensitizers. Here, we aimed to develop small inhibitory peptides that could specifically target DNA-PKcs autophosphorylation, a critical step for the enzymatic activation of the kinase in response to IR. Methods and Materials: We generated several small fusion peptides consisting of 2 functional domains, 1 an internalization domain and the other a DNA-PKcs autophosphorylation inhibitory domain. We characterized the internalization, toxicity, and radiosensitization activities of the fusion peptides. Furthermore, we studied the mechanisms of the inhibitory peptides on DNA-PKcs autophosphorylation and DNA repair. Results: We found that among several peptides, the biotin-labeled peptide 3 (BTW3) peptide, which targets DNA-PKcs threonine 2647 autophosphorylation, can abrogate IR-induced DNA-PKcs activation and cause prolonged {gamma}-H2AX focus formation. We demonstrated that BTW3 exposure led to hypersensitivity to IR in DNA-PKcs-proficient cells but not in DNA-PKcs-deficient cells. Conclusions: The small inhibitory peptide BTW3 can specifically target DNA-PKcs autophosphorylation and enhance radiosensitivity; therefore, it can be further developed as a novel class of radiosensitizer.

  19. Cold Fusion, A Journalistic Investigation

    NASA Astrophysics Data System (ADS)

    Krivit, Steven B.

    2005-03-01

    Author of the recent book, The Rebirth of Cold Fusion, and founder of New Energy Times, Steven B. Krivit presents a summary of cold fusion's, past, present and possible future. This talk will briefly review five highlights of the recent New Energy Times investigation into cold fusion research:1. Analysis of early studies that supposedly disproved cold fusion.2. Key early corroborations that supported the claims of Fleischmann and Pons.3. The evolving understanding of cold fusion reaction paths and by-products.4. A look at volumetric power density.5. Brief comparison of the progress in hot fusion research as compared to cold fusion research.New Energy Times, founded in 2000, is an independent communications company which currently specializes in reporting on cold fusion researchootnotetextReferences and copies of the presentation are available at www.newenergytimes.com/reports/aps2005.htmhttp://www.newenergytimes.com/reports/aps2005.htm. It has no affiliations with any organization, entity or party which invests in these technologies, nor any individual researcher or research facility.

  20. Herpes simplex virus Membrane Fusion.

    PubMed

    Weed, Darin J; Nicola, Anthony V

    2017-01-01

    Herpes simplex virus mediates multiple distinct fusion events during infection. HSV entry is initiated by fusion of the viral envelope with either the limiting membrane of a host cell endocytic compartment or the plasma membrane. In the infected cell during viral assembly, immature, enveloped HSV particles in the perinuclear space fuse with the outer nuclear membrane in a process termed de-envelopment. A cell infected with some strains of HSV with defined mutations spread to neighboring cells by a fusion event called syncytium formation. Two experimental methods, the transient cell-cell fusion approach and fusion from without, are useful surrogate assays of HSV fusion. These five fusion processes are considered in terms of their requirements, mechanism, and regulation. The execution and modulation of these events require distinct yet often overlapping sets of viral proteins and host cell factors. The core machinery of HSV gB, gD, and the heterodimer gH/gL is required for most if not all of the HSV fusion mechanisms.

  1. Cold fusion; Myth versus reality

    SciTech Connect

    Rabinowitz, M. )

    1990-01-01

    Experiments indicate that several different nuclear reactions are taking place. Some of the experiments point to D-D fusion with a cominant tritium channel as one of the reactions. The article notes a similarity between Prometheus and the discoveries of cold fusion.

  2. Cellulose binding domain fusion proteins

    DOEpatents

    Shoseyov, O.; Yosef, K.; Shpiegl, I.; Goldstein, M.A.; Doi, R.H.

    1998-02-17

    A cellulose binding domain (CBD) having a high affinity for crystalline cellulose and chitin is disclosed, along with methods for the molecular cloning and recombinant production. Fusion products comprising the CBD and a second protein are likewise described. A wide range of applications are contemplated for both the CBD and the fusion products, including drug delivery, affinity separations, and diagnostic techniques. 16 figs.

  3. Cellulose binding domain fusion proteins

    SciTech Connect

    Shoseyov, Oded; Shpiegl, Itai; Goldstein, Marc A.; Doi, Roy H.

    1998-01-01

    A cellulose binding domain (CBD) having a high affinity for crystalline cellulose and chitin is disclosed, along with methods for the molecular cloning and recombinant production thereof. Fusion products comprising the CBD and a second protein are likewise described. A wide range of applications are contemplated for both the CBD and the fusion products, including drug delivery, affinity separations, and diagnostic techniques.

  4. Fusion Power measurement at ITER

    SciTech Connect

    Bertalot, L.; Barnsley, R.; Krasilnikov, V.; Stott, P.; Suarez, A.; Vayakis, G.; Walsh, M.

    2015-07-01

    Nuclear fusion research aims to provide energy for the future in a sustainable way and the ITER project scope is to demonstrate the feasibility of nuclear fusion energy. ITER is a nuclear experimental reactor based on a large scale fusion plasma (tokamak type) device generating Deuterium - Tritium (DT) fusion reactions with emission of 14 MeV neutrons producing up to 700 MW fusion power. The measurement of fusion power, i.e. total neutron emissivity, will play an important role for achieving ITER goals, in particular the fusion gain factor Q related to the reactor performance. Particular attention is given also to the development of the neutron calibration strategy whose main scope is to achieve the required accuracy of 10% for the measurement of fusion power. Neutron Flux Monitors located in diagnostic ports and inside the vacuum vessel will measure ITER total neutron emissivity, expected to range from 1014 n/s in Deuterium - Deuterium (DD) plasmas up to almost 10{sup 21} n/s in DT plasmas. The neutron detection systems as well all other ITER diagnostics have to withstand high nuclear radiation and electromagnetic fields as well ultrahigh vacuum and thermal loads. (authors)

  5. Multi-sensor fusion development

    NASA Astrophysics Data System (ADS)

    Bish, Sheldon; Rohrer, Matthew; Scheffel, Peter; Bennett, Kelly

    2016-05-01

    The U.S. Army Research Laboratory (ARL) and McQ Inc. are developing a generic sensor fusion architecture that involves several diverse processes working in combination to create a dynamic task-oriented, real-time informational capability. Processes include sensor data collection, persistent and observational data storage, and multimodal and multisensor fusion that includes the flexibility to modify the fusion program rules for each mission. Such a fusion engine lends itself to a diverse set of sensing applications and architectures while using open-source software technologies. In this paper, we describe a fusion engine architecture that combines multimodal and multi-sensor fusion within an Open Standard for Unattended Sensors (OSUS) framework. The modular, plug-and-play architecture of OSUS allows future fusion plugin methodologies to have seamless integration into the fusion architecture at the conceptual and implementation level. Although beyond the scope of this paper, this architecture allows for data and information manipulation and filtering for an array of applications.

  6. The quest for fusion power

    NASA Astrophysics Data System (ADS)

    Cowley, Steven C.

    2016-05-01

    Fusion power is one of a very few sustainable options to replace fossil fuels as the world's primary energy source. Although the conditions for fusion have been reached, much remains to be done to turn scientific success into commercial electrical power.

  7. Fusion Policy Advisory Committee (FPAC)

    SciTech Connect

    Not Available

    1990-09-01

    This document is the final report of the Fusion Policy Advisory Committee. The report conveys the Committee's views on the matters specified by the Secretary in his charge and subsequent letters to the Committee, and also satisfies the provisions of Section 7 of the Magnetic Fusion Energy Engineering Act of 1980, Public Law 96-386, which require a triennial review of the conduct of the national Magnetic Fusion Energy program. Three sub-Committee's were established to address the large number of topics associated with fusion research and development. One considered magnetic fusion energy, a second considered inertial fusion energy, and the third considered issues common to both. For many reasons, the promise of nuclear fusion as a safe, environmentally benign, and affordable source of energy is bright. At the present state of knowledge, however, it is uncertain that this promise will become reality. Only a vigorous, well planned and well executed program of research and development will yield the needed information. The Committee recommends that the US commit to a plan that will resolve this critically important issue. It also outlines the first steps in a development process that will lead to a fusion Demonstration Power Plant by 2025. The recommended program is aggressive, but we believe the goal is reasonable and attainable. International collaboration at a significant level is an important element in the plan.

  8. Overexpression of PKM2 promotes mitochondrial fusion through attenuated p53 stability

    PubMed Central

    Wu, Haili; Yang, Peng; Hu, Wanglai; Wang, Yingying; Lu, Yangxu; Zhang, Lichao; Fan, Yongsheng; Xiao, Hong; Li, Zhuoyu

    2016-01-01

    M2-type pyruvate kinase (PKM2) contributes to the Warburg effect. However, it remains unknown as to whether PKM2 has an inhibitory effect on mitochondrial function. We report in this work that PKM2 overexpression inhibits the expression of Drp1 and results in the mitochondrial fusion. The ATP production was found to be decreased, the mtDNA copy number elevated and the expression level of electron transport chain (ETC) complex I, III, V depressed in PKM2 overexpressed cells. PKM2 overexpression showed a decreased p53 protein level and a shorter p53 half-life. In contrast, PKM2 knockdown resulted in increased p53 expression and prolonged half-life of p53. PKM2 could directly bind with both p53 and MDM2 and promote MDM2-mediated p53 ubiquitination. The dimeric PKM2 significantly suppressed p53 expression compared with the other PKM2 mutants. The reverse relationship between PKM2 and Drp1 was further confirmed in a large number of clinical samples. Taken together, the present results highlight a new mechanism that link PKM2 to mitochondrial function, based on p53-Drp1 axis down regulation, revealing a novel therapeutic target in patients with abnormal mitochondria. PMID:27801666

  9. Glutathione-S-transferase (GST)-fusion based assays for studying protein-protein interactions.

    PubMed

    Vikis, Haris G; Guan, Kun-Liang

    2015-01-01

    Glutathione-S-transferase (GST)-fusion proteins have become an effective reagent to use in the study of protein-protein interactions. GST-fusion proteins can be produced in bacterial and mammalian cells in large quantities and purified rapidly. GST can be coupled to a glutathione matrix, which permits its use as an effective affinity column to study interactions in vitro or to purify protein complexes in cells expressing the GST-fusion protein. Here, we provide a technical description of the utilization of GST-fusion proteins as both a tool to study protein-protein interactions and also as a means to purify interacting proteins.

  10. Using gaming engines and editors to construct simulations of fusion algorithms for situation management

    NASA Astrophysics Data System (ADS)

    Lewis, Lundy M.; DiStasio, Nolan; Wright, Christopher

    2010-04-01

    In this paper we discuss issues in testing various cognitive fusion algorithms for situation management. We provide a proof-of-principle discussion and demo showing how gaming technologies and platforms could be used to devise and test various fusion algorithms, including input, processing, and output, and we look at how the proof-of-principle could lead to more advanced test beds and methods for high-level fusion in support of situation management. We develop four simple fusion scenarios and one more complex scenario in which a simple rule-based system is scripted to govern the behavior of battlespace entities.

  11. Magnetic fusion energy and computers

    SciTech Connect

    Killeen, J.

    1982-01-01

    The application of computers to magnetic fusion energy research is essential. In the last several years the use of computers in the numerical modeling of fusion systems has increased substantially. There are several categories of computer models used to study the physics of magnetically confined plasmas. A comparable number of types of models for engineering studies are also in use. To meet the needs of the fusion program, the National Magnetic Fusion Energy Computer Center has been established at the Lawrence Livermore National Laboratory. A large central computing facility is linked to smaller computer centers at each of the major MFE laboratories by a communication network. In addition to providing cost effective computing services, the NMFECC environment stimulates collaboration and the sharing of computer codes among the various fusion research groups.

  12. Is there hope for fusion

    SciTech Connect

    Fowler, T.K. . Dept. of Nuclear Engineering)

    1990-04-12

    From the outset in the 1950's, fusion research has been motivated by environmental concerns as well as long-term fuel supply issues. Compared to fossil fuels both fusion and fission would produce essentially zero emissions to the atmosphere. Compared to fission, fusion reactors should offer high demonstrability of public protection from accidents and a substantial amelioration of the radioactive waste problem. Fusion still requires lengthy development, the earliest commercial deployment being likely to occur around 2025--2050. However, steady scientific progress is being made and there is a wide consensus that it is time to plan large-scale engineering development. A major international effort, called the International Thermonuclear Experimental Reactor (ITER), is being carried out under IAEA auspices to design the world's first fusion engineering test reactor, which could be constructed in the 1990's. 4 figs., 3 tabs.

  13. Adjoint affine fusion and tadpoles

    SciTech Connect

    Urichuk, Andrew; Walton, Mark A.

    2016-06-15

    We study affine fusion with the adjoint representation. For simple Lie algebras, elementary and universal formulas determine the dec