WorldWideScience

Sample records for aptamer-derived molecular adaptors

  1. Molecular physiology of the tensin brotherhood of integrin adaptor proteins.

    Science.gov (United States)

    Haynie, Donald T

    2014-07-01

    Numerous proteins have been identified as constituents of the adhesome, the totality of molecular components in the supramolecular assemblies known as focal adhesions, fibrillar adhesions and other kinds of adhesive contact. The transmembrane receptor proteins called integrins are pivotal adhesome members, providing a physical link between the extracellular matrix (ECM) and the actin cytoskeleton. Tensins are ever more widely investigated intracellular adhesome constituents. Involved in cell attachment and migration, cytoskeleton reorganization, signal transduction and other processes relevant to cancer research, tensins have recently been linked to functional properties of deleted in liver cancer 1 (DLC1) and a mitogen-activated protein kinases (MAPK), to cell migration in breast cancer, and to metastasis suppression in the kidney. Tensins are close relatives of phosphatase homolog/tensin homolog (PTEN), an extensively studied tumor suppressor. Such findings are recasting the earlier vision of tensin (TNS) as an actin-filament (F-actin) capping protein in a different light. This critical review aims to summarize current knowledge on tensins and thus to highlight key points concerning the expression, structure, function, and evolution of the various members of the TNS brotherhood. Insight is sought by comparisons with homologous proteins. Some historical points are added for perspective. PMID:24634006

  2. Molecular basis of substrate selection by the N-end rule adaptor protein ClpS

    Energy Technology Data Exchange (ETDEWEB)

    Román-Hernández, Giselle; Grant, Robert A.; Sauer, Robert T.; Baker, Tania A.; (HHMI)

    2009-06-19

    The N-end rule is a conserved degradation pathway that relates the stability of a protein to its N-terminal amino acid. Here, we present crystal structures of ClpS, the bacterial N-end rule adaptor, alone and engaged with peptides containing N-terminal phenylalanine, leucine, and tryptophan. These structures, together with a previous structure of ClpS bound to an N-terminal tyrosine, illustrate the molecular basis of recognition of the complete set of primary N-end rule amino acids. In each case, the alpha-amino group and side chain of the N-terminal residue are the major determinants of recognition. The binding pocket for the N-end residue is preformed in the free adaptor, and only small adjustments are needed to accommodate N-end rule residues having substantially different sizes and shapes. M53A ClpS is known to mediate degradation of an expanded repertoire of substrates, including those with N-terminal valine or isoleucine. A structure of Met53A ClpS engaged with an N-end rule tryptophan reveals an essentially wild-type mechanism of recognition, indicating that the Met(53) side chain directly enforces specificity by clashing with and excluding beta-branched side chains. Finally, experimental and structural data suggest mechanisms that make proteins with N-terminal methionine bind very poorly to ClpS, explaining why these high-abundance proteins are not degraded via the N-end rule pathway in the cell.

  3. Molecular protein adaptor with genetically encoded interaction sites guiding the hierarchical assembly of plasmonically active nanoparticle architectures

    Science.gov (United States)

    Schreiber, Andreas; Huber, Matthias C.; Cölfen, Helmut; Schiller, Stefan M.

    2015-03-01

    The control over the defined assembly of nano-objects with nm-precision is important to create systems and materials with enhanced properties, for example, metamaterials. In nature, the precise assembly of inorganic nano-objects with unique features, for example, magnetosomes, is accomplished by efficient and reliable recognition schemes involving protein effectors. Here we present a molecular approach using protein-based ‘adaptors/connectors’ with genetically encoded interaction sites to guide the assembly and functionality of different plasmonically active gold nanoparticle architectures (AuNP). The interaction of the defined geometricaly shaped protein adaptors with the AuNP induces the self-assembly of nanoarchitectures ranging from AuNP encapsulation to one-dimensional chain-like structures, complex networks and stars. Synthetic biology and bionanotechnology are applied to co-translationally encode unnatural amino acids as additional site-specific modification sites to generate functionalized biohybrid nanoarchitectures. This protein adaptor-based nano-object assembly approach might be expanded to other inorganic nano-objects creating biohybrid materials with unique electronic, photonic, plasmonic and magnetic properties.

  4. Molecular analysis of the prostacyclin receptor's interaction with the PDZ1 domain of its adaptor protein PDZK1.

    Directory of Open Access Journals (Sweden)

    Gabriel Birrane

    Full Text Available The prostanoid prostacyclin, or prostaglandin I2, plays an essential role in many aspects of cardiovascular disease. The actions of prostacyclin are mainly mediated through its activation of the prostacyclin receptor or, in short, the IP. In recent studies, the cytoplasmic carboxy-terminal domain of the IP was shown to bind several PDZ domains of the multi-PDZ adaptor PDZK1. The interaction between the two proteins was found to enhance cell surface expression of the IP and to be functionally important in promoting prostacyclin-induced endothelial cell migration and angiogenesis. To investigate the interaction of the IP with the first PDZ domain (PDZ1 of PDZK1, we generated a nine residue peptide (KK(411IAACSLC(417 containing the seven carboxy-terminal amino acids of the IP and measured its binding affinity to a recombinant protein corresponding to PDZ1 by isothermal titration calorimetry. We determined that the IP interacts with PDZ1 with a binding affinity of 8.2 µM. Using the same technique, we also determined that the farnesylated form of carboxy-terminus of the IP does not bind to PDZ1. To understand the molecular basis of these findings, we solved the high resolution crystal structure of PDZ1 bound to a 7-residue peptide derived from the carboxy-terminus of the non-farnesylated form of IP ((411IAACSLC(417. Analysis of the structure demonstrates a critical role for the three carboxy-terminal amino acids in establishing a strong interaction with PDZ1 and explains the inability of the farnesylated form of IP to interact with the PDZ1 domain of PDZK1 at least in vitro.

  5. Molecular basis for the specific recognition of the metazoan cyclic GMP-AMP by the innate immune adaptor protein STING.

    Science.gov (United States)

    Shi, Heping; Wu, Jiaxi; Chen, Zhijian J; Chen, Chuo

    2015-07-21

    Cyclic GMP-AMP containing a unique combination of mixed phosphodiester linkages (2'3'-cGAMP) is an endogenous second messenger molecule that activates the type-I IFN pathway upon binding to the homodimer of the adaptor protein STING on the surface of endoplasmic reticulum membrane. However, the preferential binding of the asymmetric ligand 2'3'-cGAMP to the symmetric dimer of STING represents a physicochemical enigma. Here we show that 2'3'-cGAMP, but not its linkage isomers, adopts an organized free-ligand conformation that resembles the STING-bound conformation and pays low entropy and enthalpy costs in converting into the active conformation. Our results demonstrate that analyses of free-ligand conformations can be as important as analyses of protein conformations in understanding protein-ligand interactions.

  6. Molecular cloning and functional analysis of the duck TIR domain-containing adaptor inducing IFN-β (TRIF) gene.

    Science.gov (United States)

    Wei, Xiaoqin; Qian, Wei; Sizhu, Suolang; Shi, Lijuan; Jin, Meilin; Zhou, Hongbo

    2016-12-01

    Toll-like receptors (TLRs) trigger the innate immune response by responding to specific components of microorganisms. The TIR domain-containing adaptor inducing IFN-β (TRIF) plays an essential role in mammalian TLR-mediated signaling. The role of TRIF in ducks (duTRIF) remains poorly understood. In this study, we cloned and characterized the full-length coding sequence of duTRIF from duck embryo fibroblasts (DEFs). In healthy ducks, duTRIF transcripts were broadly expressed in different tissues, with higher expression levels in the spleen and liver. Using quantitative real-time PCR (qRT-PCR), we demonstrated the upregulation of duTRIF in DEFs infected with AIV or DTMUV, and DEFs treated with Poly I:C or LPS. Overexpression of duTRIF was able to induce the NF-κB and IFN-β expression. Furthermore, the IFN induction function of duTRIF was impaired when Ala517 was mutated to Pro or His. Taken together, these results suggested that duTRIF regulated duck innate immune responses. PMID:27539203

  7. Crystal structure of Toll-like receptor adaptor MAL/TIRAP reveals the molecular basis for signal transduction and disease protection

    OpenAIRE

    Valkov, Eugene; Stamp, Anna; DiMaio, Frank; Baker, David; Verstak, Brett; Roversi, Pietro; Kellie, Stuart; Sweet, Matthew J.; Mansell, Ashley; Gay, Nicholas J.; Jennifer L Martin; Kobe, Bostjan

    2011-01-01

    Initiation of the innate immune response requires agonist recognition by pathogen-recognition receptors such as the Toll-like receptors (TLRs). Toll/interleukin-1 receptor (TIR) domain-containing adaptors are critical in orchestrating the signal transduction pathways after TLR and interleukin-1 receptor activation. Myeloid differentiation primary response gene 88 (MyD88) adaptor-like (MAL)/TIR domain-containing adaptor protein (TIRAP) is involved in bridging MyD88 to TLR2 and TLR4 in response...

  8. Triplex molecular beacons for sensitive recognition of melamine based on abasic-site-containing DNA and fluorescent silver nanoclusters.

    Science.gov (United States)

    Wang, Ya; Sun, Qianqian; Zhu, Linling; Zhang, Junying; Wang, Fengyang; Lu, Linlin; Yu, Haijun; Xu, Zhiai; Zhang, Wen

    2015-05-01

    A melamine aptamer derived from an abasic-site-containing triplex molecular beacon (tMB) was designed and developed for sensitive recognition of melamine by integrating tMBs and fluorescent silver nanoclusters (Ag NCs). PMID:25865656

  9. Optimization of multiplexed RADseq libraries using low-cost adaptors.

    Science.gov (United States)

    Henri, Hélène; Cariou, Marie; Terraz, Gabriel; Martinez, Sonia; El Filali, Adil; Veyssiere, Marine; Duret, Laurent; Charlat, Sylvain

    2015-04-01

    Reduced representation genomics approaches, of which RADseq is currently the most popular form, offer the possibility to produce genome wide data from potentially any species, without previous genomic information. The application of RADseq to highly multiplexed libraries (including numerous specimens, and potentially numerous different species) is however limited by technical constraints. First, the cost of synthesis of Illumina adaptors including molecular identifiers (MIDs) becomes excessive when numerous specimens are to be multiplexed. Second, the necessity to empirically adjust the ratio of adaptors to genomic DNA concentration impedes the high throughput application of RADseq to heterogeneous samples, of variable DNA concentration and quality. In an attempt to solve these problems, we propose here some adjustments regarding the adaptor synthesis. First, we show that the common and unique (MID) parts of adaptors can be synthesized separately and subsequently ligated, which drastically reduces the synthesis cost, and thus allows multiplexing hundreds of specimens. Second, we show that self-ligation of adaptors, which makes the adaptor concentration so critical, can be simply prevented by using unphosphorylated adaptors, which significantly improves the ligation and sequencing yield.

  10. The fifth adaptor protein complex.

    OpenAIRE

    Jennifer Hirst; Barlow, Lael D.; Gabriel Casey Francisco; Sahlender, Daniela A.; Seaman, Matthew N.J.; Dacks, Joel B.; Robinson, Margaret S.

    2011-01-01

    Adaptor protein (AP) complexes sort cargo into vesicles for transport from one membrane compartment of the cell to another. Four distinct AP complexes have been identified, which are present in most eukaryotes. We report the existence of a fifth AP complex, AP-5. Tagged AP-5 localises to a late endosomal compartment in HeLa cells. AP-5 does not associate with clathrin and is insensitive to brefeldin A. Knocking down AP-5 subunits interferes with the trafficking of the cation-independent manno...

  11. The Fifth Adaptor Protein Complex

    OpenAIRE

    Hirst, Jennifer; D. Barlow, Lael; Francisco, Gabriel Casey; Sahlender, Daniela A.; Seaman, Matthew N.J.; Dacks, Joel B.; Robinson, Margaret S.

    2011-01-01

    Adaptor protein (AP) complexes sort cargo into vesicles for transport from one membrane compartment of the cell to another. Four distinct AP complexes have been identified, which are present in most eukaryotes. We report the existence of a fifth AP complex, AP-5. Tagged AP-5 localises to a late endosomal compartment in HeLa cells. AP-5 does not associate with clathrin and is insensitive to brefeldin A. Knocking down AP-5 subunits interferes with the trafficking of the cation-independent manno...

  12. The fifth adaptor protein complex.

    Directory of Open Access Journals (Sweden)

    Jennifer Hirst

    2011-10-01

    Full Text Available Adaptor protein (AP complexes sort cargo into vesicles for transport from one membrane compartment of the cell to another. Four distinct AP complexes have been identified, which are present in most eukaryotes. We report the existence of a fifth AP complex, AP-5. Tagged AP-5 localises to a late endosomal compartment in HeLa cells. AP-5 does not associate with clathrin and is insensitive to brefeldin A. Knocking down AP-5 subunits interferes with the trafficking of the cation-independent mannose 6-phosphate receptor and causes the cell to form swollen endosomal structures with emanating tubules. AP-5 subunits can be found in all five eukaryotic supergroups, but they have been co-ordinately lost in many organisms. Concatenated phylogenetic analysis provides robust resolution, for the first time, into the evolutionary order of emergence of the adaptor subunit families, showing AP-3 as the basal complex, followed by AP-5, AP-4, and AP-1 and AP-2. Thus, AP-5 is an evolutionarily ancient complex, which is involved in endosomal sorting, and which has links with hereditary spastic paraplegia.

  13. Adaptor protein complexes and intracellular transport

    OpenAIRE

    2014-01-01

    The AP (adaptor protein) complexes are heterotetrameric protein complexes that mediate intracellular membrane trafficking along endocytic and secretory transport pathways. There are five different AP complexes: AP-1, AP-2 and AP-3 are clathrin-associated complexes; whereas AP-4 and AP-5 are not. These five AP complexes localize to different intracellular compartments and mediate membrane trafficking in distinct pathways. They recognize and concentrate cargo proteins into vesicular carriers th...

  14. Nck adaptors are positive regulators of the size and sensitivity of the T-cell repertoire

    OpenAIRE

    Roy, Edwige; Togbe, Dieudonnée; Holdorf, Amy D.; Trubetskoy, Dmitry; Nabti, Sabrina; Küblbeck, Günter; Klevenz, Alexandra; Kopp-Schneider, Annette; Leithäuser, Frank; Möller, Peter; Bladt, Friedhelm; Hämmerling, Günter; Arnold, Bernd; Pawson, Tony; Tafuri, Anna

    2010-01-01

    The size and sensitivity of the T-cell repertoire governs the effectiveness of immune responses against invading pathogens. Both are modulated by T-cell receptor (TCR) activity through molecular mechanisms, which remain unclear. Here, we provide genetic evidence that the SH2/SH3 domain containing proteins Nck lower the threshold of T-cell responsiveness. The hallmarks of Nck deletion were T-cell lymphopenia and hyporeactivity to TCR-mediated stimulation. In the absence of the Nck adaptors, pe...

  15. Autoinhibition of Mint1 adaptor protein regulates amyloid precursor protein binding and processing

    OpenAIRE

    Matos, Maria F.; Xu, Yibin; Dulubova, Irina; Otwinowski, Zbyszek; Richardson, John M.; Tomchick, Diana R.; Rizo, Josep; Ho, Angela

    2012-01-01

    Mint adaptor proteins bind to the amyloid precursor protein (APP) and regulate APP processing associated with Alzheimer’s disease; however, the molecular mechanisms underlying Mint regulation in APP binding and processing remain unclear. Biochemical, biophysical, and cellular experiments now show that the Mint1 phosphotyrosine binding (PTB) domain that binds to APP is intramolecularly inhibited by the adjacent C-terminal linker region. The crystal structure of a C-terminally extended Mint1 PT...

  16. Nck adaptors are positive regulators of the size and sensitivity of the T-cell repertoire.

    Science.gov (United States)

    Roy, Edwige; Togbe, Dieudonnée; Holdorf, Amy D; Trubetskoy, Dmitry; Nabti, Sabrina; Küblbeck, Günter; Klevenz, Alexandra; Kopp-Schneider, Annette; Leithäuser, Frank; Möller, Peter; Bladt, Friedhelm; Hämmerling, Günter; Arnold, Bernd; Pawson, Tony; Tafuri, Anna

    2010-08-31

    The size and sensitivity of the T-cell repertoire governs the effectiveness of immune responses against invading pathogens. Both are modulated by T-cell receptor (TCR) activity through molecular mechanisms, which remain unclear. Here, we provide genetic evidence that the SH2/SH3 domain containing proteins Nck lower the threshold of T-cell responsiveness. The hallmarks of Nck deletion were T-cell lymphopenia and hyporeactivity to TCR-mediated stimulation. In the absence of the Nck adaptors, peripheral T cells expressing a TCR with low avidity for self-antigens were strongly reduced, whereas an overall impairment of T-cell activation by weak antigenic stimulation was observed. Mechanistically, Nck deletion resulted in a significant decrease in calcium mobilization and ERK phosphorylation upon TCR engagement. Taken together, our findings unveil a crucial role for the Nck adaptors in shaping the T-cell repertoire to ensure maximal antigenic coverage and optimal T cell excitability. PMID:20709959

  17. Nck adaptors are positive regulators of the size and sensitivity of the T-cell repertoire.

    Science.gov (United States)

    Roy, Edwige; Togbe, Dieudonnée; Holdorf, Amy D; Trubetskoy, Dmitry; Nabti, Sabrina; Küblbeck, Günter; Klevenz, Alexandra; Kopp-Schneider, Annette; Leithäuser, Frank; Möller, Peter; Bladt, Friedhelm; Hämmerling, Günter; Arnold, Bernd; Pawson, Tony; Tafuri, Anna

    2010-08-31

    The size and sensitivity of the T-cell repertoire governs the effectiveness of immune responses against invading pathogens. Both are modulated by T-cell receptor (TCR) activity through molecular mechanisms, which remain unclear. Here, we provide genetic evidence that the SH2/SH3 domain containing proteins Nck lower the threshold of T-cell responsiveness. The hallmarks of Nck deletion were T-cell lymphopenia and hyporeactivity to TCR-mediated stimulation. In the absence of the Nck adaptors, peripheral T cells expressing a TCR with low avidity for self-antigens were strongly reduced, whereas an overall impairment of T-cell activation by weak antigenic stimulation was observed. Mechanistically, Nck deletion resulted in a significant decrease in calcium mobilization and ERK phosphorylation upon TCR engagement. Taken together, our findings unveil a crucial role for the Nck adaptors in shaping the T-cell repertoire to ensure maximal antigenic coverage and optimal T cell excitability.

  18. Selective autophagy of non-ubiquitylated targets in plants: looking for cognate receptor/adaptor proteins

    Directory of Open Access Journals (Sweden)

    Vasko eVeljanovski

    2014-06-01

    Full Text Available Cellular homeostasis is essential for the physiology of eukaryotic cells. Eukaryotic cells, including plant cells, utilize two main pathways to adjust the level of cytoplasmic components, namely the proteasomal and the lysosomal/vacuolar pathways. Macroautophagy is a lysosomal/vacuolar pathway which, until recently, was thought to be non-specific and a bulk degradation process. However, selective autophagy which can be activated in the cell under various physiological conditions, involves the specific degradation of defined macromolecules or organelles by a conserved molecular mechanism. For this process to be efficient, the mechanisms underlying the recognition and selection of the cargo to be engulfed by the double-membrane autophagosome are critical, and not yet well understood. Ubiquitin (poly-ubiquitin conjugation to the target appears to be a conserved ligand mechanism in many types of selective autophagy, and defined receptors/adaptors recognizing and regulating the autophagosomal capture of the ubiquitylated target have been characterized. However, non-proteinaceous and non-ubiquitylated cargoes are also selectively degraded by this pathway. This ubiquitin-independent selective autophagic pathway also involves receptor and/or adaptor proteins linking the cargo to the autophagic machinery. Some of these receptor/adaptor proteins including accessory autophagy-related (Atg and non-Atg proteins have been described in yeast and animal cells but not yet in plants. In this review we discuss the ubiquitin-independent cargo selection mechanisms in selective autophagy degradation of organelles and macromolecules and speculate on potential plant receptor/adaptor proteins.

  19. The adaptor molecule CARD9 is essential for tuberculosis control

    OpenAIRE

    Dorhoi, Anca; Desel, Christiane; Yeremeev, Vladimir; Pradl, Lydia; Brinkmann, Volker; Mollenkopf, Hans J; Hanke, Karin; Gross, Olaf; Ruland, Jürgen; Stefan H. E. Kaufmann

    2010-01-01

    The cross talk between host and pathogen starts with recognition of bacterial signatures through pattern recognition receptors (PRRs), which mobilize downstream signaling cascades. We investigated the role of the cytosolic adaptor caspase recruitment domain family, member 9 (CARD9) in tuberculosis. This adaptor was critical for full activation of innate immunity by converging signals downstream of multiple PRRs. Card9(-/-) mice succumbed early after aerosol infection, with higher mycobacteria...

  20. Structural basis for the interaction of the adaptor protein grb14 with activated ras.

    Directory of Open Access Journals (Sweden)

    Rohini Qamra

    Full Text Available Grb14, a member of the Grb7-10-14 family of cytoplasmic adaptor proteins, is a tissue-specific negative regulator of insulin signaling. Grb7-10-14 contain several signaling modules, including a Ras-associating (RA domain, a pleckstrin-homology (PH domain, a family-specific BPS (between PH and SH2 region, and a C-terminal Src-homology-2 (SH2 domain. We showed previously that the RA and PH domains, along with the BPS region and SH2 domain, are necessary for downregulation of insulin signaling. Here, we report the crystal structure at 2.4-Å resolution of the Grb14 RA and PH domains in complex with GTP-loaded H-Ras (G12V. The structure reveals that the Grb14 RA and PH domains form an integrated structural unit capable of binding simultaneously to small GTPases and phosphoinositide lipids. The overall mode of binding of the Grb14 RA domain to activated H-Ras is similar to that of the RA domains of RalGDS and Raf1 but with important distinctions. The integrated RA-PH structural unit in Grb7-10-14 is also found in a second adaptor family that includes Rap1-interacting adaptor molecule (RIAM and lamellipodin, proteins involved in actin-cytoskeleton rearrangement. The structure of Grb14 RA-PH in complex with H-Ras represents the first detailed molecular characterization of tandem RA-PH domains bound to a small GTPase and provides insights into the molecular basis for specificity.

  1. Chemical-genetic disruption of clathrin function spares adaptor complex 3–dependent endosome vesicle biogenesis

    OpenAIRE

    Zlatic, Stephanie A.; Grossniklaus, Emily J.; Ryder, Pearl V.; Salazar, Gloria; Mattheyses, Alexa L.; Peden, Andrew A.; Faundez, Victor

    2013-01-01

    A role for clathrin in AP-3–dependent vesicle biogenesis has been inferred from biochemical interactions and colocalization between this adaptor and clathrin. The functionality of these molecular associations, however, is controversial. We comprehensively explore the role of clathrin in AP-3–dependent vesicle budding, using rapid chemical-genetic perturbation of clathrin function with a clathrin light chain–FKBP chimera oligomerizable by the drug AP20187. We find that AP-3 interacts and coloc...

  2. Negative Group Velocity and Spin-Flip in Microwave Adaptors

    CERN Document Server

    Carot, Alexander; Nimtz, Guenter

    2012-01-01

    A Fabry-Perot like interferometer with two microwaveguide adaptors as reflectors creates a passive dielectric medium with a negative group delay time due to polarization shift. A rotational strain of the polarization vector by one of the adaptors is coupled with a drastic negative group velocity. The adapted rectangular and circular waveguides have the same dispersion. The input rectangular waveguide mode is linearly polarized, whereas the basic mode of the adapted circular waveguide is circularly polarized. A 667 wavelengths long circular waveguide connects the input with the output adaptor. Experiments are performed in the frequency and in the time domain. We describe, how the helical polarization change and the spin-flip of the two different circular wave modes produce the observed negative group velocity.

  3. Optimized Adaptor Polymerase Chain Reaction Method for Efficient Genomic Walking

    Institute of Scientific and Technical Information of China (English)

    Peng XU; Rui-Ying HU; Xiao-Yan DING

    2006-01-01

    Genomic walking is one of the most useful approaches in genome-related research. Three kinds of PCR-based methods are available for this purpose. However, none of them has been generally applied because they are either insensitive or inefficient. Here we present an efficient PCR protocol, an optimized adaptor PCR method for genomic walking. Using a combination of a touchdown PCR program and a special adaptor, the optimized adaptor PCR protocol achieves high sensitivity with low background noise. By applying this protocol, the insertion sites of a gene trap mouse line and two gene promoters from the incompletely sequenced Xenopus laevis genome were successfully identified with high efficiency. The general application of this protocol in genomic walking was promising.

  4. The Clathrin Adaptor AP-1A Mediates Basolateral Polarity

    OpenAIRE

    Gravotta, Diego; Carvajal-Gonzalez, Jose Maria; Mattera, Rafael; Deborde, Sylvie; Banfelder, Jason R.; Bonifacino, Juan S.; Rodriguez-Boulan, Enrique

    2012-01-01

    Clathrin and the epithelial-specific clathrin adaptor AP-1B mediate basolateral trafficking in epithelia. However, several epithelia lack AP-1B and mice knocked-out for AP-1B are viable, suggesting the existence of additional mechanisms that control basolateral polarity. Here, we demonstrate a distinct role of the ubiquitous clathrin adaptor AP-1A in basolateral protein sorting. Knock-down of AP-1A causes missorting of basolateral proteins in MDCK cells but only after knock-down of AP-1B, sug...

  5. DMPD: Adaptor usage and Toll-like receptor signaling specificity. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15876435 Adaptor usage and Toll-like receptor signaling specificity. Dunne A, O'Nei...sage and Toll-like receptor signaling specificity. PubmedID 15876435 Title Adaptor usage and Toll-like receptor signaling specific

  6. Cytosol- and clathrin-dependent stimulation of endocytosis in vitro by purified adaptors

    OpenAIRE

    1992-01-01

    Using stage-specific assays for receptor-mediated endocytosis of transferrin (Tfn) into perforated A431 cells we show that purified adaptors stimulate coated pit assembly and ligand sequestration into deeply invaginated coated pits. Late events in endocytosis involving membrane fission and coated vesicle budding which lead to the internalization of Tfn are unaffected. AP2, plasma membrane adaptors, are active at physiological concentrations, whereas AP1, Golgi adaptors, are inactive. Adaptor-...

  7. DMPD: The SAP family of adaptors in immune regulation. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15541655 The SAP family of adaptors in immune regulation. Latour S, Veillette A. Se...min Immunol. 2004 Dec;16(6):409-19. (.png) (.svg) (.html) (.csml) Show The SAP family of adaptors in immune ...regulation. PubmedID 15541655 Title The SAP family of adaptors in immune regulation. Authors Latour S, Veill

  8. Distinct adaptor proteins assist exit of Kre2-family proteins from the yeast ER

    Directory of Open Access Journals (Sweden)

    Yoichi Noda

    2014-07-01

    Full Text Available The Svp26 protein of S. cerevisiae is an ER- and Golgi-localized integral membrane protein with 4 potential membrane-spanning domains. It functions as an adaptor protein that facilitates the ER exit of Ktr3, a mannosyltransferase required for biosynthesis of O-linked oligosaccharides, and the ER exit of Mnn2 and Mnn5, mannosyltransferases, which participate in the biosynthesis of N-linked oligosaccharides. Ktr3 belongs to the Kre2 family, which consists of 9 members of type-II membrane proteins sharing sequence similarities. In this report, we examined all Kre2 family members and found that the Golgi localizations of two others, Kre2 and Ktr1, were dependent on Svp26 by immunofluorescence microscopy and cell fractionations in sucrose density gradients. We show that Svp26 functions in facilitating the ER exit of Kre2 and Ktr1 by an in vitro COPII budding assay. Golgi localization of Ktr4 was not dependent on Svp26. Screening null mutants of the genes encoding abundant COPII membrane proteins for those showing mislocalization of Ktr4 in the ER revealed that Erv41 and Erv46 are required for the correct Golgi localization of Ktr4. We provide biochemical evidence that the Erv41-Erv46 complex functions as an adaptor protein for ER exit of Ktr4. This is the first demonstration of the molecular function of this evolutionally conserved protein complex. The domain switching experiments show that the lumenal domain of Ktr4 is responsible for recognition by the Erv41-Erv46 complex. Thus, ER exit of Kre2-family proteins is dependent on distinct adaptor proteins and our results provide new insights into the traffic of Kre2-family mannosyltransferases.

  9. A dimer of the Toll-like receptor 4 cytoplasmic domain provides a specific scaffold for the recruitment of signalling adaptor proteins.

    Directory of Open Access Journals (Sweden)

    Ricardo Núñez Miguel

    Full Text Available The Toll-like receptor 4 (TLR4 is a class I transmembrane receptor expressed on the surface of immune system cells. TLR4 is activated by exposure to lipopolysaccharides derived from the outer membrane of Gram negative bacteria and forms part of the innate immune response in mammals. Like other class 1 receptors, TLR4 is activated by ligand induced dimerization, and recent studies suggest that this causes concerted conformational changes in the receptor leading to self association of the cytoplasmic Toll/Interleukin 1 receptor (TIR signalling domain. This homodimerization event is proposed to provide a new scaffold that is able to bind downstream signalling adaptor proteins. TLR4 uses two different sets of adaptors; TRAM and TRIF, and Mal and MyD88. These adaptor pairs couple two distinct signalling pathways leading to the activation of interferon response factor 3 (IRF-3 and nuclear factor kappaB (NFkappaB respectively. In this paper we have generated a structural model of the TLR4 TIR dimer and used molecular docking to probe for potential sites of interaction between the receptor homodimer and the adaptor molecules. Remarkably, both the Mal and TRAM adaptors are strongly predicted to bind at two symmetry-related sites at the homodimer interface. This model of TLR4 activation is supported by extensive functional studies involving site directed mutagenesis, inhibition by cell permeable peptides and stable protein phosphorylation of receptor and adaptor TIR domains. Our results also suggest a molecular mechanism for two recent findings, the caspase 1 dependence of Mal signalling and the protective effects conferred by the Mal polymorphism Ser180Leu.

  10. Spiral biasing adaptor for use in Si drift detectors and Si drift detector arrays

    Energy Technology Data Exchange (ETDEWEB)

    Li, Zheng; Chen, Wei

    2016-07-05

    A drift detector array, preferably a silicon drift detector (SDD) array, that uses a low current biasing adaptor is disclosed. The biasing adaptor is customizable for any desired geometry of the drift detector single cell with minimum drift time of carriers. The biasing adaptor has spiral shaped ion-implants that generate the desired voltage profile. The biasing adaptor can be processed on the same wafer as the drift detector array and only one biasing adaptor chip/side is needed for one drift detector array to generate the voltage profiles on the front side and back side of the detector array.

  11. Anti-adaptors use distinct modes of binding to inhibit the RssB-dependent turnover of RpoS (σS by ClpXP.

    Directory of Open Access Journals (Sweden)

    Dimce eMicevski

    2015-04-01

    Full Text Available In Escherichia coli, σS is the master regulator of the general stress response. The level of σS changes in response to multiple stress conditions and it is regulated at many levels including protein turnover. In the absence of stress, σS is rapidly degraded by the AAA+ protease, ClpXP in a regulated manner that depends on the adaptor protein RssB. This two-component response regulator mediates the recognition of σS and its delivery to ClpXP. The turnover of σS however, can be inhibited in a stress specific manner, by one of three anti-adaptor proteins. Each anti-adaptor binds to RssB and inhibits its activity, but how this is achieved is not fully understood at a molecular level. Here we describe details of the interaction between each anti-adaptor and RssB that leads to the stabilization of σS. By defining the domains of RssB using partial proteolysis we demonstrate that each anti-adaptor uses a distinct mode of binding to inhibit RssB activity. IraD docks specifically to the N-terminal domain of RssB, IraP interacts primarily with the C-terminal domain, while IraM interacts with both domains. Despite these differences in binding, we propose that docking of each anti-adaptor induces a conformational change in RssB, which resembles the inactive dimer of RssB. This dimer-like state of RssB not only prevents substrate binding but also triggers substrate release from a pre-bound complex.

  12. XB130: A novel adaptor protein in cancer signal transduction

    Science.gov (United States)

    ZHANG, RUIYAO; ZHANG, JINGYAO; WU, QIFEI; MENG, FANDI; LIU, CHANG

    2016-01-01

    Adaptor proteins are functional proteins that contain two or more protein-binding modules to link signaling proteins together, which affect cell growth and shape and have no enzymatic activity. The actin filament-associated protein (AFAP) family is an important member of the adaptor proteins, including AFAP1, AFAP1L1 and AFAP1L2/XB130. AFAP1 and AFAP1L1 share certain common characteristics and function as an actin-binding protein and a cSrc-activating protein. XB130 exhibits certain unique features in structure and function. The mRNA of XB130 is expressed in human spleen, thyroid, kidney, brain, lung, pancreas, liver, colon and stomach, and the most prominent disease associated with XB130 is cancer. XB130 has a controversial effect on cancer. Studies have shown that XB130 can promote cancer progression and downregulation of XB130-reduced growth of tumors derived from certain cell lines. A higher mRNA level of XB130 was shown to be associated with a better survival in non-small cell lung cancer. Previous studies have shown that XB130 can regulate cell growth, migration and invasion and possibly has the effect through the cAMP-cSrc-phosphoinositide 3-kinase/Akt pathway. Except for cancer, XB130 is also associated with other pathological or physiological procedures, such as airway repair and regeneration. PMID:26998266

  13. DMPD: Signalling adaptors used by Toll-like receptors: an update. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18706831 Signalling adaptors used by Toll-like receptors: an update. Kenny EF, O'Ne...tors used by Toll-like receptors: an update. PubmedID 18706831 Title Signalling adaptors used by Toll-like receptors: an update

  14. A Big-Five Personality Profile of the Adaptor and Innovator.

    Science.gov (United States)

    Kwang, Ng Aik; Rodrigues, Daphne

    2002-01-01

    A study explored the relationship between two creative types (adaptor and innovator) and the Big Five personality traits (extraversion, agreeableness, conscientiousness, neuroticism, and openness to experience), in 164 teachers in Singapore. Adaptors were significantly more conscientious than innovators, while innovators were significantly more…

  15. Structure of the periplasmic adaptor protein from a major facilitator superfamily (MFS) multidrug efflux pump.

    Science.gov (United States)

    Hinchliffe, Philip; Greene, Nicholas P; Paterson, Neil G; Crow, Allister; Hughes, Colin; Koronakis, Vassilis

    2014-08-25

    Periplasmic adaptor proteins are key components of bacterial tripartite efflux pumps. The 2.85 Å resolution structure of an MFS (major facilitator superfamily) pump adaptor, Aquifex aeolicus EmrA, shows linearly arranged α-helical coiled-coil, lipoyl, and β-barrel domains, but lacks the fourth membrane-proximal domain shown in other pumps to interact with the inner membrane transporter. The adaptor α-hairpin, which binds outer membrane TolC, is exceptionally long at 127 Å, and the β-barrel contains a conserved disordered loop. The structure extends the view of adaptors as flexible, modular components that mediate diverse pump assembly, and suggests that in MFS tripartite pumps a hexamer of adaptors could provide a periplasmic seal. PMID:24996185

  16. DMPD: TIR domain-containing adaptors define the specificity of TLR signaling. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 14698224 TIR domain-containing adaptors define the specificity of TLR signaling. Ya...in-containing adaptors define the specificity of TLR signaling. PubmedID 14698224 Title TIR domain-containing adaptors define the spe...cificity of TLR signaling. Authors Yamamoto M, Takeda K,

  17. Evolutionary Genomics Suggests That CheV Is an Additional Adaptor for Accommodating Specific Chemoreceptors within the Chemotaxis Signaling Complex.

    Directory of Open Access Journals (Sweden)

    Davi R Ortega

    2016-02-01

    Full Text Available Escherichia coli and Salmonella enterica are models for many experiments in molecular biology including chemotaxis, and most of the results obtained with one organism have been generalized to another. While most components of the chemotaxis pathway are strongly conserved between the two species, Salmonella genomes contain some chemoreceptors and an additional protein, CheV, that are not found in E. coli. The role of CheV was examined in distantly related species Bacillus subtilis and Helicobacter pylori, but its role in bacterial chemotaxis is still not well understood. We tested a hypothesis that in enterobacteria CheV functions as an additional adaptor linking the CheA kinase to certain types of chemoreceptors that cannot be effectively accommodated by the universal adaptor CheW. Phylogenetic profiling, genomic context and comparative protein sequence analyses suggested that CheV interacts with specific domains of CheA and chemoreceptors from an orthologous group exemplified by the Salmonella McpC protein. Structural consideration of the conservation patterns suggests that CheV and CheW share the same binding spot on the chemoreceptor structure, but have some affinity bias towards chemoreceptors from different orthologous groups. Finally, published experimental results and data newly obtained via comparative genomics support the idea that CheV functions as a "phosphate sink" possibly to off-set the over-stimulation of the kinase by certain types of chemoreceptors. Overall, our results strongly suggest that CheV is an additional adaptor for accommodating specific chemoreceptors within the chemotaxis signaling complex.

  18. Evolutionary Genomics Suggests That CheV Is an Additional Adaptor for Accommodating Specific Chemoreceptors within the Chemotaxis Signaling Complex.

    Science.gov (United States)

    Ortega, Davi R; Zhulin, Igor B

    2016-02-01

    Escherichia coli and Salmonella enterica are models for many experiments in molecular biology including chemotaxis, and most of the results obtained with one organism have been generalized to another. While most components of the chemotaxis pathway are strongly conserved between the two species, Salmonella genomes contain some chemoreceptors and an additional protein, CheV, that are not found in E. coli. The role of CheV was examined in distantly related species Bacillus subtilis and Helicobacter pylori, but its role in bacterial chemotaxis is still not well understood. We tested a hypothesis that in enterobacteria CheV functions as an additional adaptor linking the CheA kinase to certain types of chemoreceptors that cannot be effectively accommodated by the universal adaptor CheW. Phylogenetic profiling, genomic context and comparative protein sequence analyses suggested that CheV interacts with specific domains of CheA and chemoreceptors from an orthologous group exemplified by the Salmonella McpC protein. Structural consideration of the conservation patterns suggests that CheV and CheW share the same binding spot on the chemoreceptor structure, but have some affinity bias towards chemoreceptors from different orthologous groups. Finally, published experimental results and data newly obtained via comparative genomics support the idea that CheV functions as a "phosphate sink" possibly to off-set the over-stimulation of the kinase by certain types of chemoreceptors. Overall, our results strongly suggest that CheV is an additional adaptor for accommodating specific chemoreceptors within the chemotaxis signaling complex.

  19. Structure of the periplasmic adaptor protein from a major facilitator superfamily (MFS) multidrug efflux pump

    OpenAIRE

    Hinchliffe, Philip; Greene, Nicholas P.; Paterson, Neil G.; Crow, Allister; Hughes, Colin; Koronakis, Vassilis

    2014-01-01

    Periplasmic adaptor proteins are key components of bacterial tripartite efflux pumps. The 2.85 Å resolution structure of an MFS (major facilitator superfamily) pump adaptor, Aquifex aeolicus EmrA, shows linearly arranged α-helical coiled-coil, lipoyl, and β-barrel domains, but lacks the fourth membrane-proximal domain shown in other pumps to interact with the inner membrane transporter. The adaptor α-hairpin, which binds outer membrane TolC, is exceptionally long at 127 Å, and the β-barrel co...

  20. Study on the isothermal forging process of MB26 magnesium alloy adaptor

    Directory of Open Access Journals (Sweden)

    Xu Wenchen

    2015-01-01

    Full Text Available The isothermal forging process is an effective method to manufacture complex-shaped components of hard-to-work materials, such as magnesium alloys. This study investigates the isothermal forging process of an MB26 magnesium alloy adaptor with three branches. The results show that two-step forging process is appropriate to form the adaptor forging, which not only improves the filling quality but also reduces the forging load compared with one-step forging process. Moreover, the flow line is distributed along the contour of the complex-shaped adaptor forging.

  1. Highly pathogenic avian influenza virus nucleoprotein interacts with TREX complex adaptor protein Aly/REF.

    Science.gov (United States)

    Balasubramaniam, Vinod R M T; Hong Wai, Tham; Ario Tejo, Bimo; Omar, Abdul Rahman; Syed Hassan, Sharifah

    2013-01-01

    We constructed a novel chicken (Gallus gallus) lung cDNA library fused inside yeast acting domain vector (pGADT7). Using yeast two-hybrid screening with highly pathogenic avian influenza (HPAI) nucleoprotein (NP) from the strain (A/chicken/Malaysia/5858/2004(H5N1)) as bait, and the Gallus gallus lung cDNA library as prey, a novel interaction between the Gallus gallus cellular RNA export adaptor protein Aly/REF and the viral NP was identified. This interaction was confirmed and validated with mammalian two hybrid studies and co-immunoprecipitation assay. Cellular localization studies using confocal microscopy showed that NP and Aly/REF co-localize primarily in the nucleus. Further investigations by mammalian two hybrid studies into the binding of NP of other subtypes of influenza virus such as the swine A/New Jersey/1976/H1N1 and pandemic A/Malaysia/854/2009(H1N1) to human Aly/REF, also showed that the NP of these viruses interacts with human Aly/REF. Our findings are also supported by docking studies which showed tight and favorable binding between H5N1 NP and human Aly/REF, using crystal structures from Protein Data Bank. siRNA knockdown of Aly/REF had little effect on the export of HPAI NP and other viral RNA as it showed no significant reduction in virus titer. However, UAP56, another component of the TREX complex, which recruits Aly/REF to mRNA was found to interact even better with H5N1 NP through molecular docking studies. Both these proteins also co-localizes in the nucleus at early infection similar to Aly/REF. Intriguingly, knockdown of UAP56 in A549 infected cells shows significant reduction in viral titer (close to 10 fold reduction). Conclusively, our study have opened new avenues for research of other cellular RNA export adaptors crucial in aiding viral RNA export such as the SRSF3, 9G8 and ASF/SF2 that may play role in influenza virus RNA nucleocytoplasmic transport.

  2. Dengue virus targets the adaptor protein MITA to subvert host innate immunity.

    Science.gov (United States)

    Yu, Chia-Yi; Chang, Tsung-Hsien; Liang, Jian-Jong; Chiang, Ruei-Lin; Lee, Yi-Ling; Liao, Ching-Len; Lin, Yi-Ling

    2012-01-01

    Dengue is one of the most important arboviral diseases caused by infection of four serotypes of dengue virus (DEN). We found that activation of interferon regulatory factor 3 (IRF3) triggered by viral infection and by foreign DNA and RNA stimulation was blocked by DEN-encoded NS2B3 through a protease-dependent mechanism. The key adaptor protein in type I interferon pathway, human mediator of IRF3 activation (MITA) but not the murine homologue MPYS, was cleaved in cells infected with DEN-1 or DEN-2 and with expression of the enzymatically active protease NS2B3. The cleavage site of MITA was mapped to LRR↓(96)G and the function of MITA was suppressed by dengue protease. DEN replication was reduced with overexpression of MPYS but not with MITA, while DEN replication was enhanced by MPYS knockdown, indicating an antiviral role of MITA/MPYS against DEN infection. The involvement of MITA in DEN-triggered innate immune response was evidenced by reduction of IRF3 activation and IFN induction in cells with MITA knockdown upon DEN-2 infection. NS2B3 physically interacted with MITA, and the interaction and cleavage of MITA could be further enhanced by poly(dA:dT) stimulation. Thus, we identified MITA as a novel host target of DEN protease and provide the molecular mechanism of how DEN subverts the host innate immunity.

  3. Dengue virus targets the adaptor protein MITA to subvert host innate immunity.

    Directory of Open Access Journals (Sweden)

    Chia-Yi Yu

    Full Text Available Dengue is one of the most important arboviral diseases caused by infection of four serotypes of dengue virus (DEN. We found that activation of interferon regulatory factor 3 (IRF3 triggered by viral infection and by foreign DNA and RNA stimulation was blocked by DEN-encoded NS2B3 through a protease-dependent mechanism. The key adaptor protein in type I interferon pathway, human mediator of IRF3 activation (MITA but not the murine homologue MPYS, was cleaved in cells infected with DEN-1 or DEN-2 and with expression of the enzymatically active protease NS2B3. The cleavage site of MITA was mapped to LRR↓(96G and the function of MITA was suppressed by dengue protease. DEN replication was reduced with overexpression of MPYS but not with MITA, while DEN replication was enhanced by MPYS knockdown, indicating an antiviral role of MITA/MPYS against DEN infection. The involvement of MITA in DEN-triggered innate immune response was evidenced by reduction of IRF3 activation and IFN induction in cells with MITA knockdown upon DEN-2 infection. NS2B3 physically interacted with MITA, and the interaction and cleavage of MITA could be further enhanced by poly(dA:dT stimulation. Thus, we identified MITA as a novel host target of DEN protease and provide the molecular mechanism of how DEN subverts the host innate immunity.

  4. Adaptor protein LNK is a negative regulator of brain neural stem cell proliferation after stroke.

    Science.gov (United States)

    Ahlenius, Henrik; Devaraju, Karthikeyan; Monni, Emanuela; Oki, Koichi; Wattananit, Somsak; Darsalia, Vladimer; Iosif, Robert E; Torper, Olof; Wood, James C; Braun, Sebastian; Jagemann, Lucas; Nuber, Ulrike A; Englund, Elisabet; Jacobsen, Sten-Eirik W; Lindvall, Olle; Kokaia, Zaal

    2012-04-11

    Ischemic stroke causes transient increase of neural stem and progenitor cell (NSPC) proliferation in the subventricular zone (SVZ), and migration of newly formed neuroblasts toward the damaged area where they mature to striatal neurons. The molecular mechanisms regulating this plastic response, probably involved in structural reorganization and functional recovery, are poorly understood. The adaptor protein LNK suppresses hematopoietic stem cell self-renewal, but its presence and role in the brain are poorly understood. Here we demonstrate that LNK is expressed in NSPCs in the adult mouse and human SVZ. Lnk(-/-) mice exhibited increased NSPC proliferation after stroke, but not in intact brain or following status epilepticus. Deletion of Lnk caused increased NSPC proliferation while overexpression decreased mitotic activity of these cells in vitro. We found that Lnk expression after stroke increased in SVZ through the transcription factors STAT1/3. LNK attenuated insulin-like growth factor 1 signaling by inhibition of AKT phosphorylation, resulting in reduced NSPC proliferation. Our findings identify LNK as a stroke-specific, endogenous negative regulator of NSPC proliferation, and suggest that LNK signaling is a novel mechanism influencing plastic responses in postischemic brain. PMID:22496561

  5. Increasing the efficiency of SAGE adaptor ligation by directed ligation chemistry

    Science.gov (United States)

    So, Austin P.; Turner, Robin F. B.; Haynes, Charles A.

    2004-01-01

    The ability of Serial Analysis of Gene Expression (SAGE) to provide a quantitative picture of global gene expression relies not only on the depth and accuracy of sequencing into the SAGE library, but also on the efficiency of each step required to generate the SAGE library from the starting mRNA material. The first critical step is the ligation of adaptors containing a Type IIS recognition sequence to the anchored 3′ end cDNA population that permits the release of short sequence tags (SSTs) from defined sites within the 3′ end of each transcript. Using an in vitro transcript as a template, we observed that only a small fraction of anchored 3′ end cDNA are successfully ligated with added SAGE adaptors under typical reaction conditions currently used in the SAGE protocol. Although the introduction of ∼500-fold molar excess of adaptor or the inclusion of 15% (w/v) PEG-8000 increased the yield of the adaptor-modified product, complete conversion to the desired adaptor:cDNA hetero-ligation product is not achieved. An alternative method of ligation, termed as directed ligation, is described which exploits a favourable mass-action condition created by the presence of NlaIII during ligation in combination with a novel SAGE adaptor containing a methylated base within the ligation site. Using this strategy, we were able to achieve near complete conversion of the anchored 3′ end cDNA into the desired adaptor-modified product. This new protocol therefore greatly increases the probability that a SST will be generated from every transcript, greatly enhancing the fidelity of SAGE. Directed ligation also provides a powerful means to achieve near-complete ligation of any appropriately designed adaptor to its respective target. PMID:15247329

  6. Negative regulation of lymphocyte activation by the adaptor protein LAX.

    Science.gov (United States)

    Zhu, Minghua; Granillo, Olivia; Wen, Renren; Yang, Kaiyong; Dai, Xuezhi; Wang, Demin; Zhang, Weiguo

    2005-05-01

    The membrane-associated adaptor protein LAX is a linker for activation of T cells (LAT)-like molecule that is expressed in lymphoid tissues. Upon stimulation of T or B cells, it is phosphorylated and interacts with Grb2 and the p85 subunit of PI3K. LAX, however, is not capable of replacing LAT in the TCR signaling pathway. In this study we report that upon T or B cell activation, the LAX protein was up-regulated dramatically. Although disruption of the LAX gene by homologous recombination had no major impact on lymphocyte development, it caused a significant reduction in CD23 expression on mature B cells. Interestingly, naive LAX(-/-) mice had spontaneous germinal center formation. Compared with normal T and B cells, LAX(-/-) T and B cells were hyperresponsive and had enhanced calcium flux, protein tyrosine phosphorylation, MAPK and Akt activation, and cell survival upon engagement of the T or B AgRs. Our data demonstrate that LAX functions as a negative regulator in lymphocyte signaling.

  7. The TIR-domain containing adaptor TRAM is required for TLR7 mediated RANTES production.

    Directory of Open Access Journals (Sweden)

    Enda Shevlin

    Full Text Available Toll-like receptor 7 (TLR7 plays a vital role in the immune response to ssRNA viruses such as human rhinovirus (HRV and Influenza, against which there are currently no treatments or vaccines with long term efficacy available. Clearly, a more comprehensive understanding of the TLR7 signaling axis will contribute to its molecular targeting. TRIF related adaptor molecule (TRAM plays a vital role in TLR4 signaling by recruiting TRIF to TLR4, followed by endosomal trafficking of the complex and initiation of IRF3 dependent type I interferon production as well as NF-κB dependent pro-inflammatory cytokine production. Towards understanding the molecular mechanisms that regulate TLR7 functionality, we found that TRAM(-/- murine macrophages exhibited a transcriptional and translational impairment in TLR7 mediated RANTES, but not TNFα, production. Suppression of TRAM expression in human macrophages also resulted in an impairment in TLR7 mediated CCL5 and IFN-β, but not TNFα, gene induction. Furthermore, suppression of endogenous human TRAM expression in human macrophages significantly impaired RV16 induced CCL5 and IFNβ, but not TNFα gene induction. Additionally, TRAM-G2A dose-dependently inhibited TLR7 mediated activation of CCL5, IFNβ and IFNα reporter genes. TLR7-mediated phosphorylation and nuclear translocation of IRF3 was impaired in TRAM(-/- cells. Finally, co-immunoprecipitation studies indicated that TRAM physically interacts with MyD88 upon TLR7 stimulation, but not under basal conditions. Our results clearly demonstrate that TRAM plays a, hitherto unappreciated, role in TLR7 signaling through a novel signaling axis containing, but not limited to, MyD88, TRAM and IRF3 towards the activation of anti-viral immunity.

  8. Ascent Heating Thermal Analysis on Spacecraft Adaptor Fairings

    Science.gov (United States)

    Wang, Xiao Yen; Yuko, James; Motil, Brian

    2011-01-01

    When the Crew Exploration Vehicle (CEV) is launched, the spacecraft adaptor (SA) fairings that cover the CEV service module (SM) are exposed to aero heating. Thermal analysis is performed to compute the fairing temperatures and to investigate whether the temperatures are within the material limits for nominal ascent aeroheating case. The ascent heating is analyzed by using computational fluid dynamics (CFD) and engineering codes at Marshall Space Flight Center. The aeroheating environment data used for this work is known as Thermal Environment 3 (TE3) heating data. One of the major concerns is with the SA fairings covering the CEV SM and the SM/crew launch vehicle (CLV) flange interface. The TE3 heating rate is a function of time, wall temperature, and the spatial locations. The implementation of the TE3 heating rate as boundary conditions in the thermal analysis becomes challenging. The ascent heating thermal analysis on SA fairings and SM/CLV flange interface are performed using two commercial software packages: Cullimore & Ring (C&R) Thermal Desktop (TD) 5.1 and MSC Patran 2007r1 b. TD is the pre-and post-processor for SINDA, which is a finite-difference-based solver. In TD, the geometry is built and meshed, the boundary conditions are defined, and then SINDA is used to compute temperatures. MSC Pthermal is a finite-element- based thermal solver. MSC Patran is the pre- and post-processor for Pthermal. Regarding the boundary conditions, the convection, contact resistance, and heat load can be imposed in different ways in both programs. These two software packages are used to build the thermal model for the same analysis to validate each other and show the differences in the modeling details.

  9. Biophysical basis of the binding of WWOX tumor suppressor to WBP1 and WBP2 adaptors.

    Science.gov (United States)

    McDonald, Caleb B; Buffa, Laura; Bar-Mag, Tomer; Salah, Zaidoun; Bhat, Vikas; Mikles, David C; Deegan, Brian J; Seldeen, Kenneth L; Malhotra, Arun; Sudol, Marius; Aqeilan, Rami I; Nawaz, Zafar; Farooq, Amjad

    2012-09-01

    The WW-containing oxidoreductase (WWOX) tumor suppressor participates in a diverse array of cellular activities by virtue of its ability to recognize WW-binding protein 1 (WBP1) and WW-binding protein 2 (WBP2) signaling adaptors among a wide variety of other ligands. Herein, using a multitude of biophysical techniques, we provide evidence that while the WW1 domain of WWOX binds to PPXY motifs within WBP1 and WBP2 in a physiologically relevant manner, the WW2 domain exhibits no affinity toward any of these PPXY motifs. Importantly, our data suggest that while R25/W44 residues located within the binding pocket of a triple-stranded β-fold of WW1 domain are critical for the recognition of PPXY ligands, they are replaced by the chemically distinct E66/Y85 duo at structurally equivalent positions within the WW2 domain, thereby accounting for its failure to bind PPXY ligands. Predictably, not only does the introduction of E66R/Y85W double substitution within the WW2 domain result in gain of function but the resulting engineered domain, hereinafter referred to as WW2_RW, also appears to be a much stronger binding partner of WBP1 and WBP2 than the wild-type WW1 domain. We also show that while the WW1 domain is structurally disordered and folds upon ligand binding, the WW2 domain not only adopts a fully structured conformation but also aids stabilization and ligand binding to WW1 domain. This salient observation implies that the WW2 domain likely serves as a chaperone to augment the physiological function of WW1 domain within WWOX. Collectively, our study lays the groundwork for understanding the molecular basis of a key protein-protein interaction pertinent to human health and disease. PMID:22634283

  10. Fuel combustion test in constant volume combustion chamber with built-in adaptor

    Institute of Scientific and Technical Information of China (English)

    JEONG; DongSoo; CHO; GyuBack; CHOI; SuJin; LEE; JinSoo

    2010-01-01

    Combustion tests of pre-mixture of methane and air in constant volume combustion chamber(CVCC) have been carried out by means of flame propagation photo and gas pressure measurement,the effects of CVCC body temperature,intake pressure of pre-mixture of methane and air,equivalence ratio and location of the built-in adaptor have been investigated.The whole combustion chamber can be divided into two parts,i.e.the upper combustion chamber and the lower combustion chamber,by the built-in adaptor with through hole.Owing to the built-in adaptor with through hole,jet ignition or compression ignition(auto-ignition) phenomena may occur in the lower combustion chamber,which is helpful to getting higher flame propagation velocity,higher combustion peak pressure,low cycle-to-cycle variation and more stable combustion process.

  11. Stepping motor adaptor actuator for a commercial uhv linear motion feedthrough

    International Nuclear Information System (INIS)

    An adaptor coupling has been developed that will allow the attachment of a standard stepping motor to a precision commercial (Varian) uhv linear motion feedthrough. The assembly, consisting of the motor, motor adaptor, limit switches, etc. is clamped to the feedthrough body which can be done under vacuum conditions if necessary. With a 500 step/rev. stepping motor the resolution is 1.27 μm per step. We presently use this assembly in a remote location for the precise positioning of a beam sensing monitor. 2 refs., 3 figs

  12. The Emerging and Diverse Roles of Src-Like Adaptor Proteins in Health and Disease

    Directory of Open Access Journals (Sweden)

    Nikolett Marton

    2015-01-01

    Full Text Available Although Src-like adaptor proteins (SLAP-1 and SLAP-2 were mainly studied in lymphocytes, where they act as negative regulators and provide fine control of receptor signaling, recently, several other functions of these proteins were discovered. In addition to the well-characterized immunoregulatory functions, SLAP proteins appear to have an essential role in the pathogenesis of type I hypersensitivity, osteoporosis, and numerous malignant diseases. Both adaptor proteins are expressed in a wide variety of tissues, where they have mostly inhibitory effects on multiple intracellular signaling pathways. In this review, we summarize the diverse effects of SLAP proteins.

  13. DMPD: Structure, function and regulation of the Toll/IL-1 receptor adaptor proteins. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17667936 Structure, function and regulation of the Toll/IL-1 receptor adaptor prote... (.svg) (.html) (.csml) Show Structure, function and regulation of the Toll/IL-1 receptor adaptor proteins. ...PubmedID 17667936 Title Structure, function and regulation of the Toll/IL-1 recep

  14. EAT-2, a SAP-like adaptor, controls NK cell activation through phospholipase Cγ, Ca++, and Erk, leading to granule polarization.

    Science.gov (United States)

    Pérez-Quintero, Luis-Alberto; Roncagalli, Romain; Guo, Huaijian; Latour, Sylvain; Davidson, Dominique; Veillette, André

    2014-04-01

    Ewing's sarcoma-associated transcript 2 (EAT-2) is an Src homology 2 domain-containing intracellular adaptor related to signaling lymphocytic activation molecule (SLAM)-associated protein (SAP), the X-linked lymphoproliferative gene product. Both EAT-2 and SAP are expressed in natural killer (NK) cells, and their combined expression is essential for NK cells to kill abnormal hematopoietic cells. SAP mediates this function by coupling SLAM family receptors to the protein tyrosine kinase Fyn and the exchange factor Vav, thereby promoting conjugate formation between NK cells and target cells. We used a variety of genetic, biochemical, and imaging approaches to define the molecular and cellular mechanisms by which EAT-2 controls NK cell activation. We found that EAT-2 mediates its effects in NK cells by linking SLAM family receptors to phospholipase Cγ, calcium fluxes, and Erk kinase. These signals are triggered by one or two tyrosines located in the carboxyl-terminal tail of EAT-2 but not found in SAP. Unlike SAP, EAT-2 does not enhance conjugate formation. Rather, it accelerates polarization and exocytosis of cytotoxic granules toward hematopoietic target cells. Hence, EAT-2 promotes NK cell activation by molecular and cellular mechanisms distinct from those of SAP. These findings explain the cooperative and essential function of these two adaptors in NK cell activation.

  15. The AP-3 adaptor complex is required for vacuolar function in Arabidopsis

    NARCIS (Netherlands)

    Zwiewka, M.; Feraru, E.; Moller, B.K.; Hwang, I.; Feraru, M.I.; Kleine-Vehn, J.; Weijers, D.; Friml, J.

    2011-01-01

    Subcellular trafficking is required for a multitude of functions in eukaryotic cells. It involves regulation of cargo sorting, vesicle formation, trafficking and fusion processes at multiple levels. Adaptor protein (AP) complexes are key regulators of cargo sorting into vesicles in yeast and mammals

  16. SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export.

    Science.gov (United States)

    Müller-McNicoll, Michaela; Botti, Valentina; de Jesus Domingues, Antonio M; Brandl, Holger; Schwich, Oliver D; Steiner, Michaela C; Curk, Tomaz; Poser, Ina; Zarnack, Kathi; Neugebauer, Karla M

    2016-03-01

    Nuclear export factor 1 (NXF1) exports mRNA to the cytoplasm after recruitment to mRNA by specific adaptor proteins. How and why cells use numerous different export adaptors is poorly understood. Here we critically evaluate members of the SR protein family (SRSF1-7) for their potential to act as NXF1 adaptors that couple pre-mRNA processing to mRNA export. Consistent with this proposal, >1000 endogenous mRNAs required individual SR proteins for nuclear export in vivo. To address the mechanism, transcriptome-wide RNA-binding profiles of NXF1 and SRSF1-7 were determined in parallel by individual-nucleotide-resolution UV cross-linking and immunoprecipitation (iCLIP). Quantitative comparisons of RNA-binding sites showed that NXF1 and SR proteins bind mRNA targets at adjacent sites, indicative of cobinding. SRSF3 emerged as the most potent NXF1 adaptor, conferring sequence specificity to RNA binding by NXF1 in last exons. Interestingly, SRSF3 and SRSF7 were shown to bind different sites in last exons and regulate 3' untranslated region length in an opposing manner. Both SRSF3 and SRSF7 promoted NXF1 recruitment to mRNA. Thus, SRSF3 and SRSF7 couple alternative splicing and polyadenylation to NXF1-mediated mRNA export, thereby controlling the cytoplasmic abundance of transcripts with alternative 3' ends. PMID:26944680

  17. Scaffold functions of 14-3-3 adaptors in B cell immunoglobulin class switch DNA recombination.

    Directory of Open Access Journals (Sweden)

    Tonika Lam

    Full Text Available Class switch DNA recombination (CSR of the immunoglobulin heavy chain (IgH locus crucially diversifies antibody biological effector functions. CSR involves the induction of activation-induced cytidine deaminase (AID expression and AID targeting to switch (S regions by 14-3-3 adaptors. 14-3-3 adaptors specifically bind to 5'-AGCT-3' repeats, which make up for the core of all IgH locus S regions. They selectively target the upstream and downstream S regions that are set to undergo S-S DNA recombination. We hypothesized that 14-3-3 adaptors function as scaffolds to stabilize CSR enzymatic elements on S regions. Here we demonstrate that all seven 14-3-3β, 14-3-3ε, 14-3-3γ, 14-3-3η, 14-3-3σ, 14-3-3τ and 14-3-3ζ adaptors directly interacted with AID, PKA-Cα (catalytic subunit and PKA-RIα (regulatory inhibitory subunit and uracil DNA glycosylase (Ung. 14-3-3 adaptors, however, did not interact with AID C-terminal truncation mutant AIDΔ(180-198 or AIDF193A and AIDL196A point-mutants (which have been shown not to bind to S region DNA and fail to mediate CSR. 14-3-3 adaptors colocalized with AID and replication protein A (RPA in B cells undergoing CSR. 14-3-3 and AID binding to S region DNA was disrupted by viral protein R (Vpr, an accessory protein of human immunodeficiency virus type-1 (HIV-1, which inhibited CSR without altering AID expression or germline IH-CH transcription. Accordingly, we demonstrated that 14-3-3 directly interact with Vpr, which in turn, also interact with AID, PKA-Cα and Ung. Altogether, our findings suggest that 14-3-3 adaptors play important scaffold functions and nucleate the assembly of multiple CSR factors on S regions. They also show that such assembly can be disrupted by a viral protein, thereby allowing us to hypothesize that small molecule compounds that specifically block 14-3-3 interactions with AID, PKA and/or Ung can be used to inhibit unwanted CSR.

  18. Scaffold functions of 14-3-3 adaptors in B cell immunoglobulin class switch DNA recombination.

    Science.gov (United States)

    Lam, Tonika; Thomas, Lisa M; White, Clayton A; Li, Guideng; Pone, Egest J; Xu, Zhenming; Casali, Paolo

    2013-01-01

    Class switch DNA recombination (CSR) of the immunoglobulin heavy chain (IgH) locus crucially diversifies antibody biological effector functions. CSR involves the induction of activation-induced cytidine deaminase (AID) expression and AID targeting to switch (S) regions by 14-3-3 adaptors. 14-3-3 adaptors specifically bind to 5'-AGCT-3' repeats, which make up for the core of all IgH locus S regions. They selectively target the upstream and downstream S regions that are set to undergo S-S DNA recombination. We hypothesized that 14-3-3 adaptors function as scaffolds to stabilize CSR enzymatic elements on S regions. Here we demonstrate that all seven 14-3-3β, 14-3-3ε, 14-3-3γ, 14-3-3η, 14-3-3σ, 14-3-3τ and 14-3-3ζ adaptors directly interacted with AID, PKA-Cα (catalytic subunit) and PKA-RIα (regulatory inhibitory subunit) and uracil DNA glycosylase (Ung). 14-3-3 adaptors, however, did not interact with AID C-terminal truncation mutant AIDΔ(180-198) or AIDF193A and AIDL196A point-mutants (which have been shown not to bind to S region DNA and fail to mediate CSR). 14-3-3 adaptors colocalized with AID and replication protein A (RPA) in B cells undergoing CSR. 14-3-3 and AID binding to S region DNA was disrupted by viral protein R (Vpr), an accessory protein of human immunodeficiency virus type-1 (HIV-1), which inhibited CSR without altering AID expression or germline IH-CH transcription. Accordingly, we demonstrated that 14-3-3 directly interact with Vpr, which in turn, also interact with AID, PKA-Cα and Ung. Altogether, our findings suggest that 14-3-3 adaptors play important scaffold functions and nucleate the assembly of multiple CSR factors on S regions. They also show that such assembly can be disrupted by a viral protein, thereby allowing us to hypothesize that small molecule compounds that specifically block 14-3-3 interactions with AID, PKA and/or Ung can be used to inhibit unwanted CSR.

  19. Expression of Chicken Toll-Like Receptors and Signal Adaptors in Spleen and Cecum of Young Chickens Infected with Eimeria tenella

    Institute of Scientific and Technical Information of China (English)

    ZHOU Zuo-yong; HU Shi-jun; WANG Zhi-ying; GUO Zhi-li; QIN Bo; NIE Kui

    2014-01-01

    Toll-like receptors (TLRs) are a group of highly conserved molecules which initiate the innate immune response to pathogens by recognizing structural motifs of microbes. Understanding the changes in chicken Toll-like receptors (ChTLRs) and signal adaptors expression that occur with Eimeria tenella infection will help to elucidate the molecular basis of immune control of coccidiosis caused by Eimeria. The present study detected the dynamic changes in the expression of ChTLRs and associated signal adaptors in the spleen and cecum of E. tenella-infected chickens during the early stage of infection. The results showed that the expression peak for ChTLRs, MyD88 and TRIF occurred at 12 h post-infection (hpi), ChTLR3, ChTLR15 and MyD88 mRNA expression in the spleen of E. tenella infected chickens were signiifcantly higher (P<0.05) than that of negative control chickens, and there were similar tendencies of these molecules expression in the cecum and spleen of E. tenella-infected chickens. The expression of MyD88 was upregulated at four time points in the cecum of E. tenella-infected chickens. The results of this study indicate that ChTLR3, ChTLR15 and MyD88 play a role in young chickens infected with E. tenella.

  20. ER Adaptor SCAP Translocates and Recruits IRF3 to Perinuclear Microsome Induced by Cytosolic Microbial DNAs

    Science.gov (United States)

    Yu, Huansha; Liu, Xing; Huang, Lulu; Wang, Qiang; Liu, Heng; Cui, Ye; Tang, Yijun; Zhang, Peng; Wang, Chen

    2016-01-01

    Stimulator of interferon genes (STING, also known as MITA, ERIS or MPYS) induces the activation of TBK1 kinase and IRF3 transcription factor, upon sensing of microbial DNAs. How IRF3 is recruited onto the STING signalosome remains unknown. We report here that silencing of the ER adaptor SCAP markedly impairs the IRF3-responsive gene expression induced by STING. Scap knockdown mice are more susceptible to HSV-1 infection. Interestingly, SCAP translocates from ER, via Golgi, to perinuclear microsome in a STING-dependent manner. Mechanistically, the N-terminal transmembrane domain of SCAP interacts with STING, and the C-terminal cytosolic domain of SCAP binds to IRF3, thus recruiting IRF3 onto STING signalosome. Mis-localization of SCAP abolishes its antiviral function. Collectively, this study characterizes SCAP as an essential adaptor in the STING signaling pathway, uncovering a critical missing link in DNAs-triggered host antiviral responses. PMID:26900919

  1. ER Adaptor SCAP Translocates and Recruits IRF3 to Perinuclear Microsome Induced by Cytosolic Microbial DNAs.

    Directory of Open Access Journals (Sweden)

    Wei Chen

    2016-02-01

    Full Text Available Stimulator of interferon genes (STING, also known as MITA, ERIS or MPYS induces the activation of TBK1 kinase and IRF3 transcription factor, upon sensing of microbial DNAs. How IRF3 is recruited onto the STING signalosome remains unknown. We report here that silencing of the ER adaptor SCAP markedly impairs the IRF3-responsive gene expression induced by STING. Scap knockdown mice are more susceptible to HSV-1 infection. Interestingly, SCAP translocates from ER, via Golgi, to perinuclear microsome in a STING-dependent manner. Mechanistically, the N-terminal transmembrane domain of SCAP interacts with STING, and the C-terminal cytosolic domain of SCAP binds to IRF3, thus recruiting IRF3 onto STING signalosome. Mis-localization of SCAP abolishes its antiviral function. Collectively, this study characterizes SCAP as an essential adaptor in the STING signaling pathway, uncovering a critical missing link in DNAs-triggered host antiviral responses.

  2. PIP2: choreographer of actin-adaptor proteins in the HIV-1 dance

    Science.gov (United States)

    Rocha-Perugini, Vera; Gordon-Alonso, Mónica; Sánchez-Madrid, Francisco

    2014-01-01

    The actin cytoskeleton plays a key role during the replication cycle of human immunodeficiency virus-1 (HIV-1). HIV-1 infection is affected by cellular proteins that influence the clustering of viral receptors or the subcortical actin cytoskeleton. Several of these actin-adaptor proteins are controlled by the second messenger phosphatidylinositol 4,5-biphosphate (PIP2), an important regulator of actin organization. PIP2 production is induced by HIV-1 attachment and facilitates viral infection. However, the importance of PIP2 in regulating cytoskeletal proteins and thus HIV-1 infection has been overlooked. This review examines recent reports describing the roles played by actin-adaptor proteins during HIV-1 infection of CD4+ T cells, highlighting the influence of the signaling lipid PIP2 in this process. PMID:24768560

  3. Role of SRC-like adaptor protein (SLAP) in immune and malignant cell signaling.

    Science.gov (United States)

    Kazi, Julhash U; Kabir, Nuzhat N; Rönnstrand, Lars

    2015-07-01

    SRC-like adaptor protein (SLAP) is an adaptor protein structurally similar to the SRC family protein kinases. Like SRC, SLAP contains an SH3 domain followed by an SH2 domain but the kinase domain has been replaced by a unique C-terminal region. SLAP is expressed in a variety of cell types. Current studies suggest that it regulates signaling of various cell surface receptors including the B cell receptor, the T cell receptor, cytokine receptors and receptor tyrosine kinases which are important regulator of immune and cancer cell signaling. SLAP targets receptors, or its associated components, by recruiting the ubiquitin machinery and thereby destabilizing signaling. SLAP directs receptors to ubiquitination-mediated degradation and controls receptors turnover as well as signaling. Thus, SLAP appears to be an important component in regulating signal transduction required for immune and malignant cells.

  4. Chromatin Adaptor Brd4 Modulates E2 Transcription Activity and Protein Stability*

    OpenAIRE

    Lee, A-Young; Chiang, Cheng-Ming

    2009-01-01

    Brd4 is a chromatin adaptor containing tandem bromodomains binding to acetylated histone H3 and H4. Although Brd4 has been implicated in the transcriptional control of papillomavirus-encoded E2 protein, it is unclear how Brd4 regulates E2 function and whether the involvement of Brd4 in transactivation and transrepression is common to different types of E2 proteins. Using DNase I footprinting performed with in vitro reconstituted human papillomavirus (HPV) chromatin and...

  5. Clathrin and HA2 adaptors: effects of potassium depletion, hypertonic medium, and cytosol acidification

    OpenAIRE

    1993-01-01

    The effects of methods known to perturb endocytosis from clathrin- coated pits on the localization of clathrin and HA2 adaptors in HEp-2 carcinoma cells have been studied by immunofluorescence and ultrastructural immunogold microscopy, using internalization of transferrin as a functional assay. Potassium depletion, as well as incubation in hypertonic medium, remove membrane-associated clathrin lattices: flat clathrin lattices and coated pits from the plasma membrane, and clathrin-coated vesic...

  6. Bias in ligation-based small RNA sequencing library construction is determined by adaptor and RNA structure.

    Directory of Open Access Journals (Sweden)

    Ryan T Fuchs

    Full Text Available High-throughput sequencing (HTS has become a powerful tool for the detection of and sequence characterization of microRNAs (miRNA and other small RNAs (sRNA. Unfortunately, the use of HTS data to determine the relative quantity of different miRNAs in a sample has been shown to be inconsistent with quantitative PCR and Northern Blot results. Several recent studies have concluded that the major contributor to this inconsistency is bias introduced during the construction of sRNA libraries for HTS and that the bias is primarily derived from the adaptor ligation steps, specifically where single stranded adaptors are sequentially ligated to the 3' and 5'-end of sRNAs using T4 RNA ligases. In this study we investigated the effects of ligation bias by using a pool of randomized ligation substrates, defined mixtures of miRNA sequences and several combinations of adaptors in HTS library construction. We show that like the 3' adaptor ligation step, the 5' adaptor ligation is also biased, not because of primary sequence, but instead due to secondary structures of the two ligation substrates. We find that multiple secondary structural factors influence final representation in HTS results. Our results provide insight about the nature of ligation bias and allowed us to design adaptors that reduce ligation bias and produce HTS results that more accurately reflect the actual concentrations of miRNAs in the defined starting material.

  7. The Lnk adaptor protein: a key regulator of normal and pathological hematopoiesis.

    Science.gov (United States)

    Velazquez, Laura

    2012-12-01

    The development and function of blood cells are regulated by specific growth factors/cytokines and their receptors' signaling pathways. In this way, these factors influence cell survival, proliferation and differentiation of hematopoietic cells. Central to this positive and/or negative control are the adaptor proteins. Since their identification 10 years ago, members of the Lnk adaptor protein family have proved to be important activators and/or inhibitors in the hematopoietic, immune and vascular system. In particular, the generation of animal and cellular models for the Lnk and APS proteins has helped establish the physiological role of these molecules through the identification of their specific signaling pathways and the characterization of their binding partners. Moreover, the recent identification of mutations in the LNK gene in myeloproliferative disorders, as well as the correlation of a single nucleotide polymorphism on LNK with hematological, immune and vascular diseases have suggested its involvement in the pathophysiology of these malignancies. The latter findings have thus raised the possibility of addressing Lnk signaling for the treatment of certain human diseases. This review therefore describes the pathophysiological role of this adaptor protein in hematological malignancies and the potential benefits of Lnk therapeutic targeting.

  8. The adaptor molecule Trif contributes to murine host defense during Leptospiral infection.

    Science.gov (United States)

    Jayaraman, Priya A; Devlin, Amy A; Miller, Jennifer C; Scholle, Frank

    2016-09-01

    Leptospirosis is a zoonotic disease and is caused by pathogenic species of the Leptospira genus, including Leptospira interrogans (L. interrogans). Humans, domestic and wild animals are susceptible to acute or chronic infection. The innate immune response is a critical defense mechanism against Leptospira interrogans, and has been investigated in mouse models. Murine Toll-like receptors (TLRs) have been shown to be key factors in sensing and responding to L. interrogans infection. Specifically, TLR2, TLR4 and the TLR adaptor molecule MyD88 are essential for host defense against L. interrogans; however, the role of the TLR adaptor molecule TIR-domain-containing adaptor-inducing interferon β (TRIF) in the response to L. interrogans has not been previously determined. In the present study, TRIF was found to play an important role during leptospiral infection. Following challenge with L. interrogans, Trif(-/-) mice exhibited delayed weight gain compared to wild-type mice. Moreover, Trif(-/-) mice exhibited an increase in L. interrogans burden in the kidneys, lungs, and blood at early time points (less than 7days post infection). Multiple components of the innate immune responses were dampened in response to leptospiral infection including transcription and production of cytokines, and the humoral response, which suggested that TRIF contributes to expression and production of cytokines important for the host defense against L. interrogans. PMID:27259371

  9. Science Signaling Podcast for 12 July 2016: Adaptor proteins limit signaling.

    Science.gov (United States)

    Wiley, H Steven; VanHook, Annalisa M

    2016-01-01

    This Podcast features an interview with Steven Wiley, senior author of a Research Article that appears in the 12 July 2016 issue of Science Signaling, about how the abundance of adaptor proteins and feedback regulators affect the flow of information downstream of the epidermal growth factor receptor (EGFR). Information flows through a signaling pathway by sequential interactions between core components of the pathway, many of which have enzymatic activity. Adaptor proteins do not directly participate in relaying the signal and do not have enzymatic activity, but are important for signaling because they facilitate interactions between the core components. Using quantitative methods, Shi et al demonstrated that core components of the EGFR pathway were highly abundant in both normal cells and cancer cells. However, adaptor proteins were present in much lower abundance in both cell types, indicating that it is the abundance of these proteins that limit signaling downstream of EGFR. The authors also found that differences in EGFR signaling between different cell types likely resulted from the variable abundance of feedback regulators.Listen to Podcast. PMID:27405978

  10. Versatile modes of peptide recognition by the AAA+ adaptor protein SspB

    Energy Technology Data Exchange (ETDEWEB)

    Levchenko, Igor; Grant, Robert A.; Flynn, Julia M.; Sauer, Robert T.; Baker, Tania A. (MIT)

    2010-07-19

    Energy-dependent proteases often rely on adaptor proteins to modulate substrate recognition. The SspB adaptor binds peptide sequences in the stress-response regulator RseA and in ssrA-tagged proteins and delivers these molecules to the AAA+ ClpXP protease for degradation. The structure of SspB bound to an ssrA peptide is known. Here, we report the crystal structure of a complex between SspB and its recognition peptide in RseA. Notably, the RseA sequence is positioned in the peptide-binding groove of SspB in a direction opposite to the ssrA peptide, the two peptides share only one common interaction with the adaptor, and the RseA interaction site is substantially larger than the overlapping ssrA site. This marked diversity in SspB recognition of different target proteins indicates that it is capable of highly flexible and dynamic substrate delivery.

  11. New Insights to Clathrin and Adaptor Protein 2 for the Design and Development of Therapeutic Strategies

    Directory of Open Access Journals (Sweden)

    Ebbe Toftgaard Poulsen

    2015-12-01

    Full Text Available The Amyloid Precursor Protein (APP has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ in Alzheimer’s disease (AD. However, our understanding of the normal function of APP is still patchy. Emerging evidence indicates that a dysfunction in APP trafficking and degradation can be responsible for neuronal deficits and progressive degeneration in humans. We recently reported that the Y682 mutation in the 682YENPTY687 domain of APP affects its binding to specific adaptor proteins and leads to its anomalous trafficking, to defects in the autophagy machinery and to neuronal degeneration. In order to identify adaptors that influence APP function, we performed pull-down experiments followed by quantitative mass spectrometry (MS on hippocampal tissue extracts of three month-old mice incubated with either the 682YENPTY687 peptide, its mutated form, 682GENPTY687 or its phosphorylated form, 682pYENPTY687. Our experiments resulted in the identification of two proteins involved in APP internalization and trafficking: Clathrin heavy chain (hc and its Adaptor Protein 2 (AP-2. Overall our results consolidate and refine the importance of Y682 in APP normal functions from an animal model of premature aging and dementia. Additionally, they open the perspective to consider Clathrin hc and AP-2 as potential targets for the design and development of new therapeutic strategies.

  12. TRAM is involved in IL-18 signaling and functions as a sorting adaptor for MyD88.

    Directory of Open Access Journals (Sweden)

    Hidenori Ohnishi

    Full Text Available MyD88, a Toll/interleukin-1 receptor homology (TIR domain-containing adaptor protein, mediates signals from the Toll-like receptors (TLR or IL-1/IL-18 receptors to downstream kinases. In MyD88-dependent TLR4 signaling, the function of MyD88 is enhanced by another TIR domain-containing adaptor, Mal/TIRAP, which brings MyD88 to the plasma membrane and promotes its interaction with the cytosolic region of TLR4. Hence, Mal is recognized as the "sorting adaptor" for MyD88. In this study, a direct interaction between MyD88-TIR and another membrane-sorting adaptor, TRAM/TICAM-2, was demonstrated in vitro. Cell-based assays including RNA interference experiments and TRAM deficient mice revealed that the interplay between MyD88 and TRAM in cells is important in mediating IL-18 signal transduction. Live cell imaging further demonstrated the co-localized accumulation of MyD88 and TRAM in the membrane regions in HEK293 cells. These findings suggest that TRAM serves as the sorting adaptor for MyD88 in IL-18 signaling, which then facilitates the signal transduction. The binding sites for TRAM are located in the TIR domain of MyD88 and actually overlap with the binding sites for Mal. MyD88, the multifunctional signaling adaptor that works together with most of the TLR members and with the IL-1/IL-18 receptors, can interact with two distinct sorting adaptors, TRAM and Mal, in a conserved manner in a distinct context.

  13. Evidence for an evolutionary relationship between the large adaptor nucleoporin Nup192 and karyopherins.

    Science.gov (United States)

    Stuwe, Tobias; Lin, Daniel H; Collins, Leslie N; Hurt, Ed; Hoelz, André

    2014-02-18

    Nucleocytoplasmic transport is facilitated by nuclear pore complexes (NPCs), which are massive proteinaceous transport channels embedded in the nuclear envelope. Nup192 is a major component of an adaptor nucleoporin subcomplex proposed to link the NPC coat with the central transport channel. Here, we present the structure of the ∼110-kDa N-terminal domain (NTD) of Nup192 at 2.7-Å resolution. The structure reveals an open ring-shaped architecture composed of Huntingtin, EF3, PP2A, and TOR1 (HEAT) and Armadillo (ARM) repeats. A comparison of different conformations indicates that the NTD consists of two rigid halves connected by a flexible hinge. Unexpectedly, the two halves of the ring are structurally related to karyopherin-α (Kap-α) and β-karyopherin family members. Biochemically, we identify a conserved patch that binds an unstructured segment in Nup53 and show that a C-terminal tail region binds to a putative helical fragment in Nic96. The Nup53 segment that binds Nup192 is a classical nuclear localization-like sequence that interacts with Kap-α in a mutually exclusive and mechanistically distinct manner. The disruption of the Nup53 and Nic96 binding sites in vivo yields growth and mRNA export defects, revealing their critical role in proper NPC function. Surprisingly, both interactions are dispensable for NPC localization, suggesting that Nup192 possesses another nucleoporin interaction partner. These data indicate that the structured domains in the adaptor nucleoporin complex are held together by peptide interactions that resemble those found in karyopherin•cargo complexes and support the proposal that the adaptor nucleoporins arose from ancestral karyopherins. PMID:24505056

  14. The clathrin adaptor complexes as a paradigm for membrane-associated allostery

    OpenAIRE

    Canagarajah, Bertram J.; Ren, Xuefeng; Bonifacino, Juan S.; Hurley, James H.

    2013-01-01

    The clathrin-associated adaptor protein (AP) complexes AP-1 and AP-2 are two members of a family of heterotetrameric assemblies that connect transmembrane protein cargo to vesicular coats. Cargo binding by AP-1 is activated by the small GTPase Arf1, while AP-2 is activated by the phosphoinositide PI(4,5)P2. The structures of both AP-1 and AP-2 have been determined in their locked and unlocked conformations. The structures show how different activators use different mechanisms to trigger simil...

  15. The CRKL gene encoding an adaptor protein is amplified, overexpressed, and a possible therapeutic target in gastric cancer

    Directory of Open Access Journals (Sweden)

    Natsume Hiroko

    2012-07-01

    Full Text Available Abstract Background Genomic DNA amplification is a genetic factor involved in cancer, and some oncogenes, such as ERBB2, are highly amplified in gastric cancer. We searched for the possible amplification of other genes in gastric cancer. Methods and Results A genome-wide single nucleotide polymorphism microarray analysis was performed using three cell lines of differentiated gastric cancers, and 22 genes (including ERBB2 in five highly amplified chromosome regions (with a copy number of more than 6 were identified. Particular attention was paid to the CRKL gene, the product of which is an adaptor protein containing Src homology 2 and 3 (SH2/SH3 domains. An extremely high CRKL copy number was confirmed in the MKN74 gastric cancer cell line using fluorescence in situ hybridization (FISH, and a high level of CRKL expression was also observed in the cells. The RNA-interference-mediated knockdown of CRKL in MKN74 disclosed the ability of CRKL to upregulate gastric cell proliferation. An immunohistochemical analysis revealed that CRKL protein was overexpressed in 24.4% (88/360 of the primary gastric cancers that were analyzed. The CRKL copy number was also examined in 360 primary gastric cancers using a FISH analysis, and CRKL amplification was found to be associated with CRKL overexpression. Finally, we showed that MKN74 cells with CRKL amplification were responsive to the dual Src/BCR-ABL kinase inhibitor BMS354825, likely via the inhibition of CRKL phosphorylation, and that the proliferation of MKN74 cells was suppressed by treatment with a CRKL-targeting peptide. Conclusion These results suggested that CRKL protein is overexpressed in a subset of gastric cancers and is associated with CRKL amplification in gastric cancer. Furthermore, our results suggested that CRKL protein has the ability to regulate gastric cell proliferation and has the potential to serve as a molecular therapy target for gastric cancer.

  16. Effectiveness of Needleless Vial Adaptors and Blunt Cannulas for Drug Administration in a Microgravity Environment

    Science.gov (United States)

    Hailey, M.; Bayuse, T.

    2010-01-01

    Fluid Isolation in the medication vial: Air/ fluid isolation maneuvers were used to move the medication to the septum end of vial. This isolation may be achieved in multiple ways based on the experience of the astronaut with fluid management in microgravity. If vial adaptors/blunt cannula or syringe assembly is inserted into the to vial before fluid isolation commences, the stability of this assembly should be considered in an effort to limit the risk of "slinging off" of the vial during isolation. Alternatively, fluid isolation can be performed prior to attaching the syringe/vial adaptor assembly. Terrestrial practices for medication withdrawal from a nonvented vial require injection of an equivalent amount of air as the expected medication volume prior to withdrawing liquid. In microgravity, this action is still valid, however the injection of additional air into the vial creates a multitude of micro bubbles and increases the volume of medication mixed with air that then must be withdrawn to achieve the desired drug volume in syringe. This practice is more likely to be required when using vials >30ml in size and injection volumes >10mL. It is felt that based on the microgravity flight, the practice of air injection is more of a hindrance than help.

  17. Chimeric adaptor proteins translocate diverse type VI secretion system effectors in Vibrio cholerae.

    Science.gov (United States)

    Unterweger, Daniel; Kostiuk, Benjamin; Ötjengerdes, Rina; Wilton, Ashley; Diaz-Satizabal, Laura; Pukatzki, Stefan

    2015-08-13

    Vibrio cholerae is a diverse species of Gram-negative bacteria, commonly found in the aquatic environment and the causative agent of the potentially deadly disease cholera. These bacteria employ a type VI secretion system (T6SS) when they encounter prokaryotic and eukaryotic competitors. This contractile puncturing device translocates a set of effector proteins into neighboring cells. Translocated effectors are toxic unless the targeted cell produces immunity proteins that bind and deactivate incoming effectors. Comparison of multiple V. cholerae strains indicates that effectors are encoded in T6SS effector modules on mobile genetic elements. We identified a diverse group of chimeric T6SS adaptor proteins required for the translocation of diverse effectors encoded in modules. An example for a T6SS effector that requires T6SS adaptor protein 1 (Tap-1) is TseL found in pandemic V. cholerae O1 serogroup strains and other clinical isolates. We propose a model in which Tap-1 is required for loading TseL onto the secretion apparatus. After T6SS-mediated TseL export is completed, Tap-1 is retained in the bacterial cell to load other T6SS machines.

  18. The Adaptor Protein Rai/ShcC Promotes Astrocyte-Dependent Inflammation during Experimental Autoimmune Encephalomyelitis.

    Science.gov (United States)

    Ulivieri, Cristina; Savino, Maria Teresa; Luccarini, Ilaria; Fanigliulo, Emanuela; Aldinucci, Alessandra; Bonechi, Elena; Benagiano, Marisa; Ortensi, Barbara; Pelicci, Giuliana; D'Elios, Mario Milco; Ballerini, Clara; Baldari, Cosima Tatiana

    2016-07-15

    Th17 cells have been casually associated to the pathogenesis of autoimmune disease. We have previously demonstrated that Rai/ShcC, a member of the Shc family of adaptor proteins, negatively regulates Th17 cell differentiation and lupus autoimmunity. In this study, we have investigated the pathogenic outcome of the Th17 bias associated with Rai deficiency on multiple sclerosis development, using the experimental autoimmune encephalomyelitis (EAE) mouse model. We found that, unexpectedly, EAE was less severe in Rai(-/-) mice compared with their wild-type counterparts despite an enhanced generation of myelin-specific Th17 cells that infiltrated into the CNS. Nevertheless, when adoptively transferred into immunodeficient Rai(+/+) mice, these cells promoted a more severe disease compared with wild-type encephalitogenic Th17 cells. This paradoxical phenotype was caused by a dampened inflammatory response of astrocytes, which were found to express Rai, to IL-17. The results provide evidence that Rai plays opposite roles in Th17 cell differentiation and astrocyte activation, with the latter dominant over the former in EAE, highlighting this adaptor as a potential novel target for the therapy of multiple sclerosis. PMID:27288534

  19. The endocytic adaptor Eps15 controls marginal zone B cell numbers.

    Directory of Open Access Journals (Sweden)

    Benedetta Pozzi

    Full Text Available Eps15 is an endocytic adaptor protein involved in clathrin and non-clathrin mediated endocytosis. In Caenorhabditis elegans and Drosophila melanogaster lack of Eps15 leads to defects in synaptic vesicle recycling and synapse formation. We generated Eps15-KO mice to investigate its function in mammals. Eps15-KO mice are born at the expected Mendelian ratio and are fertile. Using a large-scale phenotype screen covering more than 300 parameters correlated to human disease, we found that Eps15-KO mice did not show any sign of disease or neural deficits. Instead, altered blood parameters pointed to an immunological defect. By competitive bone marrow transplantation we demonstrated that Eps15-KO hematopoietic precursor cells were more efficient than the WT counterparts in repopulating B220⁺ bone marrow cells, CD19⁻ thymocytes and splenic marginal zone (MZ B cells. Eps15-KO mice showed a 2-fold increase in MZ B cell numbers when compared with controls. Using reverse bone marrow transplantation, we found that Eps15 regulates MZ B cell numbers in a cell autonomous manner. FACS analysis showed that although MZ B cells were increased in Eps15-KO mice, transitional and pre-MZ B cell numbers were unaffected. The increase in MZ B cell numbers in Eps15 KO mice was not dependent on altered BCR signaling or Notch activity. In conclusion, in mammals, the endocytic adaptor protein Eps15 is a regulator of B-cell lymphopoiesis.

  20. Src-like-adaptor protein (SLAP) differentially regulates normal and oncogenic c-Kit signaling.

    Science.gov (United States)

    Kazi, Julhash U; Agarwal, Shruti; Sun, Jianmin; Bracco, Enrico; Rönnstrand, Lars

    2014-02-01

    The Src-like-adaptor protein (SLAP) is an adaptor protein sharing considerable structural homology with Src. SLAP is expressed in a variety of cells and regulates receptor tyrosine kinase signaling by direct association. In this report, we show that SLAP associates with both wild-type and oncogenic c-Kit (c-Kit-D816V). The association involves the SLAP SH2 domain and receptor phosphotyrosine residues different from those mediating Src interaction. Association of SLAP triggers c-Kit ubiquitylation which, in turn, is followed by receptor degradation. Although SLAP depletion potentiates c-Kit downstream signaling by stabilizing the receptor, it remains non-functional in c-Kit-D816V signaling. Ligand-stimulated c-Kit or c-Kit-D816V did not alter membrane localization of SLAP. Interestingly oncogenic c-Kit-D816V, but not wild-type c-Kit, phosphorylates SLAP on residues Y120, Y258 and Y273. Physical interaction between c-Kit-D816V and SLAP is mandatory for the phosphorylation to take place. Although tyrosine-phosphorylated SLAP does not affect c-Kit-D816V signaling, mutation of these tyrosine sites to phenylalanine can restore SLAP activity. Taken together the data demonstrate that SLAP negatively regulates wild-type c-Kit signaling, but not its oncogenic counterpart, indicating a possible mechanism by which the oncogenic c-Kit bypasses the normal cellular negative feedback control.

  1. Synthetic protein scaffolds based on peptide motifs and cognate adaptor domains for improving metabolic productivity

    Directory of Open Access Journals (Sweden)

    Anselm H.C. Horn

    2015-11-01

    Full Text Available The efficiency of many cellular processes relies on the defined interaction among different proteins within the same metabolic or signaling pathway. Consequently, a spatial colocalization of functionally interacting proteins has frequently emerged during evolution. This concept has been adapted within the synthetic biology community for the purpose of creating artificial scaffolds. A recent advancement of this concept is the use of peptide motifs and their cognate adaptor domains. SH2, SH3, GBD, and PDZ domains have been used most often in research studies to date. The approach has been successfully applied to the synthesis of a variety of target molecules including catechin, D-glucaric acid, H2, hydrochinone, resveratrol, butyrate, gamma-aminobutyric acid, and mevalonate. Increased production levels of up to 77-fold have been observed compared to non-scaffolded systems. A recent extension of this concept is the creation of a covalent linkage between peptide motifs and adaptor domains, which leads to a more stable association of the scaffolded systems and thus bears the potential to further enhance metabolic productivity.

  2. The crucial role of the MyD88 adaptor protein in the inflammatory response induced by Bothrops atrox venom.

    Science.gov (United States)

    Moreira, Vanessa; Teixeira, Catarina; Borges da Silva, Henrique; D'Império Lima, Maria Regina; Dos-Santos, Maria Cristina

    2013-06-01

    Most snake accidents in North Brazil are attributed to Bothrops atrox, a snake species of the Viperidae family whose venom simultaneously induces local and systemic effects in the victims. The former are clinically more important than the latter, as they cause severe tissue lesions associated with strong inflammatory responses. Although several studies have shown that inflammatory mediators are produced in response to B. atrox venom (BaV), there is little information concerning the molecular pathways involved in innate immune system signaling. Myeloid differentiation factor 88 (MyD88) is an adaptor molecule responsible for transmitting intracellular signals from most toll-like receptors (TLRs) after they interact with pathogen-associated molecular patterns (PAMPs) or other stimuli such as endogenous damage-associated molecular patterns (DAMPs). The MyD88-dependent pathway leads to activation of transcription factors, which in turn induce synthesis of inflammatory mediators such as eicosanoids, cytokines and chemokines. The aim of this study was to investigate the involvement of MyD88 on the acute inflammatory response induced by BaV. Wild-type (WT) C57BL/6 mice and MyD88 knockout (MyD88(-/-)) mice were intraperitoneally injected with BaV. Compared to WT mice, MyD88(-/-) animals showed an impaired inflammatory response to BaV, with lower influx of polymorphonuclear and mononuclear cells to the peritoneal cavity. Furthermore, peritoneal leukocytes from BaV-injected MyD88(-/-) mice did not induce COX-2 or LTB4 protein expression and released low concentrations of PGE2. These mice also failed to produce Th1 and Th17 cytokines and CCL-2, but IL-10 levels were similar to those of BaV-injected WT mice. Our results indicate that MyD88 signaling is required for activation of the inflammatory response elicited by BaV, raising the possibility of developing new therapeutic targets to treat Bothrops sp. poisoning. PMID:23474268

  3. Regulation and function of the CD3¿ DxxxLL motif: a binding site for adaptor protein-1 and adaptor protein-2 in vitro

    DEFF Research Database (Denmark)

    Dietrich, J; Kastrup, J; Nielsen, B L;

    1997-01-01

    /CD3gamma chimeras; and in vitro by binding CD3gamma peptides to clathrin-coated vesicle adaptor proteins (APs). We find that the CD3gamma D127xxxLL131/132 sequence represents one united motif for binding of both AP-1 and AP-2, and that this motif functions as an active sorting motif in monomeric CD4....../ CD3gamma molecules independently of S126. An acidic amino acid is required at position 127 and a leucine (L) is required at position 131, whereas the requirements for position 132 are more relaxed. The spacing between aspartic acid 127 (D127) and L131 is crucial for the function of the motif in vivo...... subunit clusters of differentiation (CD)3gamma. Thus, phosphorylation of CD3gamma serine 126 (S126) causes a downregulation of the TCR. In this study, we have analyzed the CD3gamma internalization motif in three different systems in parallel: in the context of the complete multimeric TCR; in monomeric CD4...

  4. The late endosomal adaptor p14 is a macrophage host-defense factor against Salmonella infection.

    Science.gov (United States)

    Taub, Nicole; Nairz, Manfred; Hilber, Diana; Hess, Michael W; Weiss, Günter; Huber, Lukas A

    2012-06-01

    The outcome of an infection depends on the balance between host resistance and bacterial virulence. Here, we show that the late endosomal adaptor p14 (also known as LAMTOR2) is one of the components for cellular host defense against the intracellular pathogen Salmonella enterica serovar Typhimurium. During Salmonella infection, the complex of p14 and MP1 is required for the accurately timed transport of Salmonella through the endolysosomal system. Loss of p14 opens a time window that allows Salmonella to populate a replication niche, in which early and late antimicrobial effector systems, comprising NADPH phagocytic oxidase and inducible nitric oxide synthase, respectively, are inappropriately activated. Thus, p14 supports the accurate transport of Salmonella through the endolysosomal system, thereby limiting bacterial replication in both, professional phagocytes and in non-phagocytic cells in vitro, and helps mice to successfully battle Salmonella infection in vivo.

  5. A role for adaptor protein-3 complex in the organization of the endocytic pathway in Dictyostelium.

    Science.gov (United States)

    Charette, Steve J; Mercanti, Valentina; Letourneur, François; Bennett, Nelly; Cosson, Pierre

    2006-11-01

    Dictyostelium discoideum cells continuously internalize extracellular material, which accumulates in well-characterized endocytic vacuoles. In this study, we describe a new endocytic compartment identified by the presence of a specific marker, the p25 protein. This compartment presents features reminiscent of mammalian recycling endosomes: it is localized in the pericentrosomal region but distinct from the Golgi apparatus. It specifically contains surface proteins that are continuously endocytosed but rapidly recycled to the cell surface and thus absent from maturing endocytic compartments. We evaluated the importance of each clathrin-associated adaptor complex in establishing a compartmentalized endocytic system by studying the phenotype of the corresponding mutants. In knockout cells for mu3, a subunit of the AP-3 clathrin-associated complex, membrane proteins normally restricted to p25-positive endosomes were mislocalized to late endocytic compartments. Our results suggest that AP-3 plays an essential role in the compartmentalization of the endocytic pathway in Dictyostelium. PMID:17010123

  6. Alternatively spliced short and long isoforms of adaptor protein intersectin 1 form complexes in mammalian cells

    Directory of Open Access Journals (Sweden)

    Rynditch A. V.

    2012-12-01

    Full Text Available Intersectin 1 (ITSN1 is an adaptor protein involved in membrane trafficking and cell signaling. Long and short isoforms of ITSN1 (ITSN1-L and ITSN1-S are produced by alternative splicing. The aim of our study was to investigate whether ITSN1-L and ITSN1-S could interact in mammalian cells. Methods. During this study we employed immunoprecipitation and confocal microscopy. Results. We have shown that endogenous ITSN1-S co-precipitates with overexpressed ITSN1-L in PC12, 293 and 293T cells. Long and short isoforms of ITSN1 also co-localize in 293T cells. Conclusions. ITSN1-L and ITSN1-S form complexes in mammalian cells.

  7. The Hypoxic Regulator of Sterol Synthesis Nro1 Is a Nuclear Import Adaptor

    Energy Technology Data Exchange (ETDEWEB)

    T Yeh; C Lee; L Amzel; P Espenshade; M Bianchet

    2011-12-31

    Fission yeast protein Sre1, the homolog of the mammalian sterol regulatory element-binding protein (SREBP), is a hypoxic transcription factor required for sterol homeostasis and low-oxygen growth. Nro1 regulates the stability of the N-terminal transcription factor domain of Sre1 (Sre1N) by inhibiting the action of the prolyl 4-hydroxylase-like Ofd1 in an oxygen-dependent manner. The crystal structure of Nro1 determined at 2.2 {angstrom} resolution shows an all-{alpha}-helical fold that can be divided into two domains: a small N-terminal domain, and a larger C-terminal HEAT-repeat domain. Follow-up studies showed that Nro1 defines a new class of nuclear import adaptor that functions both in Ofd1 nuclear localization and in the oxygen-dependent inhibition of Ofd1 to control the hypoxic response.

  8. Effectiveness of Needles Vial Adaptors and Blunt Cannulas for Drug Administration in a Microgravity Environment

    Science.gov (United States)

    Hailey, Melinda; Bayuse, Tina

    2009-01-01

    The need for a new system of injectable medications aboard the International Space Station (ISS) was identified. It is desired that this system fly medications in their original manufacturer's packaging, allowing the system to comply with United States Pharmacopeia (USP) guidelines while minimizing the resupply frequency due to medication expiration. Pre-filled syringes are desired, however, the evolving nature of the healthcare marketplace requires flexibility in the redesign. If medications must be supplied in a vial, a system is required that allows for the safe withdrawal of medication from the vial into a syringe for administration in microgravity. During two reduced gravity flights, the effectiveness of two versions of a blunt cannula and needleless vial adaptors was evaluated to facilitate the withdrawal of liquid medication from a vial into a syringe for injection. Other parameters assessed included the ability to withdraw the required amount of medication and whether this is dependent on vial size, liquid, or the total volume of fluid within the vial. Injectable medications proposed for flight on ISS were used for this evaluation. Due to differing sizes of vials and the fluid properties of the medications, the needleless vial adaptors proved to be too cumbersome to recommend for use on the ISS. The blunt cannula, specifically the plastic version, proved to be more effective at removing medication from the various sizes of vials and are the recommended hardware for ISS. Fluid isolation within the vials and syringes is an important step in preparing medication for injection regardless of the hardware used. Although isolation is a challenge in the relatively short parabolas during flight, it is not an obstacle for sustained microgravity. This presentation will provide an overview of the products tested as well as the challenges identified during the microgravity flights.

  9. The Influences of Connectors and Adaptors to Fiber-To-The-Home Network Performance

    Directory of Open Access Journals (Sweden)

    Mohammad S. Ab-Rahman

    2012-01-01

    Full Text Available Problem statement: The reliability of the entire communications network was dependent on the reliability of each single element. Connector was important devices that can affect the performance of the fiber communication. There were a large number of issues that affect the performance of fiber optic connectors in todays networks. These factors were increasingly as data rates, the number of wavelengths and transmission distances continue to escalate. Approach: Therefore this study was carried out to test on the influence of connectors and adapters to the performance of the optical network. Initially the actual attenuation of connector and adaptor were tested by using multifunction loss tester. The first two 1 m corning optical fibers with a connector at each end are measured. Then, both the 1 m corning optical fibers were joined together by an adaptor and connected to the Multifunction loss tester. Three types of wavelength are used as the source to test the attenuation of the fiber which is 1310, 1490-1550 nm. In order to measure the Bit Error Rate (BER and the power loss in optical fiber communication, a simple simulation was carried out by using software opti sys. Results: The attenuation on the connector was caused mainly by existence of impurities in the connector, less perfect connection, scattering of beam and others. These causes the parameter such as power received, Q-factor, minimum BER and also the eye-height to change. Changes in these parameters also affect the performance at the user end. It was very critical that causes of attenuation to be eliminated. Conclusion/Recommendations: From the result it can be concluded that, the greater the attenuation, the greater the decrease in power received. It also affects the Q-factor of the system where as the attenuation increase, the maximum Q-factor decreases. As for the minimum BER, minimum BER changes as the attenuation increase initially, after a maximum value it decreases as the

  10. Probing heterobivalent binding to the endocytic AP-2 adaptor complex by DNA-based spatial screening.

    Science.gov (United States)

    Diezmann, F; von Kleist, L; Haucke, V; Seitz, O

    2015-08-01

    The double helical DNA scaffold offers a unique set of properties, which are particularly useful for studies of multivalency in biomolecular interactions: (i) multivalent ligand displays can be formed upon nucleic acid hybridization in a self-assembly process, which facilitates spatial screening (ii) valency and spatial arrangement of the ligand display can be precisely controlled and (iii) the flexibility of the ligand display can be adjusted by integrating nick sites and unpaired template regions. Herein we describe the use of DNA-based spatial screening for the characterization of the adaptor complex 2 (AP-2), a central interaction hub within the endocytic protein network in clathrin-mediated endocytosis. AP-2 is comprised of a core domain and two, so-called appendage domains, the α- and the β2-ear, which associate with cytoplasmatic proteins required for the formation or maturation of clathrin/AP-2 coated pits. Each appendage domain has two binding grooves which recognize distinct peptide motives with micromolar affinity. This provides opportunities for enhanced interactions with protein molecules that contain two (or more) different peptide motives. To determine whether a particular, spatial arrangement of binding motifs is required for high affinity binding we probed the distance-affinity relationships by means of DNA-programmed spatial screening with self-assembled peptide-DNA complexes. By using trimolecular and tetramolecular assemblies two different peptides were positioned in 2-22 nucleotide distance. The binding data obtained with both recombinant protein in well-defined buffer systems and native AP-2 in brain extract suggests that the two binding sites of the AP-2 α-appendage can cooperate to provide up to 40-fold enhancement of affinity compared to the monovalent interaction. The distance between the two recognized peptide motives was less important provided that the DNA duplex segments were connected by flexible, single strand segments. By

  11. Comparison Study on Finite Element Model for Structural Analysis of Lower CTS Cylinder Lifting Adaptor in ITER Assembly Tool

    International Nuclear Information System (INIS)

    The ITER tokamak assembly tools are purpose-built and specially designed to complete the ITER tokamak machine which includes; Vacuum Vessel (VV), VV Thermal Shield (VVTS) and Cryostat Thermal Shield (CTS), Toroidal Field Coil (TFC) and Poloidal Field (PF) coils, and other components contained in the cryostat. Based on the engineering design and design description documents prepared by the ITER organization (IO). In this paper, FE models to verify the structural integrity of the Lower Cryostat Thermal Shield (LCTS) Lifting Adaptor are prepared and compared with their structure analysis result. In the paper, each analysis result with difference BC applied was compared with the equivalent stress and the results of analysis were evaluated according to SM490YB's allowable stress. And the conclusions of this paper are summarized as following. - The structural stabilities of the LCTS lift adaptor have been studied using ANSYS codes for verifying structural strength for this tool

  12. Cell cycle-dependent adaptor complex for ClpXP-mediated proteolysis directly integrates phosphorylation and second messenger signals.

    Science.gov (United States)

    Smith, Stephen C; Joshi, Kamal K; Zik, Justin J; Trinh, Katherine; Kamajaya, Aron; Chien, Peter; Ryan, Kathleen R

    2014-09-30

    The cell-division cycle of Caulobacter crescentus depends on periodic activation and deactivation of the essential response regulator CtrA. Although CtrA is critical for transcription during some parts of the cell cycle, its activity must be eliminated before chromosome replication because CtrA also blocks the initiation of DNA replication. CtrA activity is down-regulated both by dephosphorylation and by proteolysis, mediated by the ubiquitous ATP-dependent protease ClpXP. Here we demonstrate that proteins needed for rapid CtrA proteolysis in vivo form a phosphorylation-dependent and cyclic diguanylate (cdG)-dependent adaptor complex that accelerates CtrA degradation in vitro by ClpXP. The adaptor complex includes CpdR, a single-domain response regulator; PopA, a cdG-binding protein; and RcdA, a protein whose activity cannot be predicted. When CpdR is unphosphorylated and when PopA is bound to cdG, they work together with RcdA in an all-or-none manner to reduce the Km of CtrA proteolysis 10-fold. We further identified a set of amino acids in the receiver domain of CtrA that modulate its adaptor-mediated degradation in vitro and in vivo. Complex formation between PopA and CtrA depends on these amino acids, which reside on alpha-helix 1 of the CtrA receiver domain, and on cdG binding by PopA. These results reveal that each accessory factor plays an essential biochemical role in the regulated proteolysis of CtrA and demonstrate, to our knowledge, the first example of a multiprotein, cdG-dependent proteolytic adaptor.

  13. ATP binding to p97/VCP D1 domain regulates selective recruitment of adaptors to its proximal N-domain.

    Directory of Open Access Journals (Sweden)

    Wei Sheng Chia

    Full Text Available p97/Valosin-containing protein (VCP is a member of the AAA-ATPase family involved in many cellular processes including cell division, intracellular trafficking and extraction of misfolded proteins in endoplasmic reticulum-associated degradation (ERAD. It is a homohexamer with each subunit containing two tandem D1 and D2 ATPase domains and N- and C-terminal regions that function as adaptor protein binding domains. p97/VCP is directed to its many different functional pathways by associating with various adaptor proteins. The regulation of the recruitment of the adaptor proteins remains unclear. Two adaptor proteins, Ufd1/Npl4 and p47, which bind exclusively to the p97/VCP N-domain and direct p97/VCP to either ERAD-related processes or homotypic fusion of Golgi fragments, were studied here. Surface plasmon resonance biosensor-based assays allowed the study of binding kinetics in real time. In competition experiments, it was observed that in the presence of ATP, Ufd1/Npl4 was able to compete more effectively with p47 for binding to p97/VCP. By using non-hydrolysable ATP analogues and the hexameric truncated p97/N-D1 fragment, it was shown that binding rather than hydrolysis of ATP to the proximal D1 domain strengthened the Ufd1/Npl4 association with the N-domain, thus regulating the recruitment of either Ufd1/Npl4 or p47. This novel role of ATP and an assigned function to the D1 AAA-ATPase domain link the multiple functions of p97/VCP to the metabolic status of the cell.

  14. Lymphocytes and the Dap12 adaptor are key regulators of osteoclast activation associated with gonadal failure.

    Directory of Open Access Journals (Sweden)

    Adrienne Anginot

    Full Text Available Bone resorption by osteoclasts is necessary to maintain bone homeostasis. Osteoclast differentiation from hematopoietic progenitors and their activation depend on M-CSF and RANKL, but also requires co-stimulatory signals acting through receptors associated with DAP12 and FcRgamma adaptors. Dap12 mutant mice (KDelta75 are osteopetrotic due to inactive osteoclasts but, surprisingly, these mice are more sensitive than WT mice to bone loss following an ovariectomy. Because estrogen withdrawal is known to disturb bone mass, at least in part, through lymphocyte interaction, we looked at the role of mature lymphocytes on osteoclastogenesis and bone mass in the absence of functional DAP12. Lymphocytes were found to stimulate an early osteoclast differentiation response from Dap12-deficient progenitors in vitro. In vivo, Rag1-/- mice lacking mature lymphocytes did not exhibit any bone phenotype, but lost their bone mass after ovariectomy like KDelta75 mice. KDelta75;Rag1-/- double mutant female mice exhibited a more severe osteopetrosis than Dap12-deficient animals but lost their bone mass after ovariectomy, like single mutants. These results suggest that both DAP12 and mature lymphocytes act synergistically to maintain bone mass under physiological conditions, while playing similar but not synergistic co-stimulatory roles in protecting bone loss after gonadal failure. Thus, our data support a role for lymphocytes during osteoclast differentiation and suggest that they may function as accessory cells when regular osteoclast function is compromised.

  15. Losses, Expansions, and Novel Subunit Discovery of Adaptor Protein Complexes in Haptophyte Algae.

    Science.gov (United States)

    Lee, Laura J Y; Klute, Mary J; Herman, Emily K; Read, Betsy; Dacks, Joel B

    2015-11-01

    The phylum Haptophyta (Diaphoratickes) contains marine algae that perform biomineralization, extruding large, distinctive calcium carbonate scales (coccoliths) that completely cover the cell. Coccolith production is an important part of global carbon cycling; however, the membrane trafficking pathway by which they are secreted has not yet been elucidated. In most eukaryotes, post-Golgi membrane trafficking involves five heterotetrameric adaptor protein (AP) complexes, which impart cargo selection specificity. To better understand coccolith secretion, we performed comparative genomic, phylogenetic, and transcriptomic analyses of the AP complexes in Emiliania huxleyi strains 92A, Van556, EH2, and CCMP1516, and related haptophytes Gephyrocapsa oceanica and Isochrysis galbana; the latter has lost the ability to biomineralize. We show that haptophytes have a modified membrane trafficking system (MTS), as we found both AP subunit losses and duplications. Additionally, we identified a single conserved subunit of the AP-related TSET complex, whose expression suggests a functional role in membrane trafficking. Finally, we detected novel alpha adaptin ear and gamma adaptin ear proteins, the first of their kind to be described outside of opisthokonts. These novel ear proteins and the sculpting of the MTS may support the capacity for biomineralization in haptophytes, enhancing their ability to perform this highly specialized form of secretion.

  16. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation.

    Science.gov (United States)

    Zhong, Bo; Yang, Yan; Li, Shu; Wang, Yan-Yi; Li, Ying; Diao, Feici; Lei, Caoqi; He, Xiao; Zhang, Lu; Tien, Po; Shu, Hong-Bing

    2008-10-17

    Viral infection triggers activation of transcription factors such as NF-kappaB and IRF3, which collaborate to induce type I interferons (IFNs) and elicit innate antiviral response. Here, we identified MITA as a critical mediator of virus-triggered type I IFN signaling by expression cloning. Overexpression of MITA activated IRF3, whereas knockdown of MITA inhibited virus-triggered activation of IRF3, expression of type I IFNs, and cellular antiviral response. MITA was found to localize to the outer membrane of mitochondria and to be associated with VISA, a mitochondrial protein that acts as an adaptor in virus-triggered signaling. MITA also interacted with IRF3 and recruited the kinase TBK1 to the VISA-associated complex. MITA was phosphorylated by TBK1, which is required for MITA-mediated activation of IRF3. Our results suggest that MITA is a critical mediator of virus-triggered IRF3 activation and IFN expression and further demonstrate the importance of certain mitochondrial proteins in innate antiviral immunity.

  17. The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA.

    Science.gov (United States)

    Zhong, Bo; Zhang, Lu; Lei, Caoqi; Li, Ying; Mao, Ai-Ping; Yang, Yan; Wang, Yan-Yi; Zhang, Xiao-Lian; Shu, Hong-Bing

    2009-03-20

    Viral infection activates transcription factors NF-kappaB and IRF3, which collaborate to induce type I interferons (IFNs) and elicit innate antiviral response. MITA (also known as STING) has recently been identified as an adaptor that links virus-sensing receptors to IRF3 activation. Here, we showed that the E3 ubiquitin ligase RNF5 interacted with MITA in a viral-infection-dependent manner. Overexpression of RNF5 inhibited virus-triggered IRF3 activation, IFNB1 expression, and cellular antiviral response, whereas knockdown of RNF5 had opposite effects. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection. Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) and viral infection caused their redistribution to the ER and mitochondria, respectively. We further found that virus-induced ubiquitination and degradation of MITA by RNF5 occurred at the mitochondria. These findings suggest that RNF5 negatively regulates virus-triggered signaling by targeting MITA for ubiquitination and degradation at the mitochondria.

  18. The adaptor molecule SAP plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation.

    Science.gov (United States)

    Das, Rupali; Bassiri, Hamid; Guan, Peng; Wiener, Susan; Banerjee, Pinaki P; Zhong, Ming-Chao; Veillette, André; Orange, Jordan S; Nichols, Kim E

    2013-04-25

    The adaptor molecule signaling lymphocytic activation molecule-associated protein (SAP) plays critical roles during invariant natural killer T (iNKT) cell ontogeny. As a result, SAP-deficient humans and mice lack iNKT cells. The strict developmental requirement for SAP has made it difficult to discern its possible involvement in mature iNKT cell functions. By using temporal Cre recombinase-mediated gene deletion to ablate SAP expression after completion of iNKT cell development, we demonstrate that SAP is essential for T-cell receptor (TCR)-induced iNKT cell cytotoxicity against T-cell and B-cell leukemia targets in vitro and iNKT-cell-mediated control of T-cell leukemia growth in vivo. These findings are not restricted to the murine system: silencing RNA-mediated suppression of SAP expression in human iNKT cells also significantly impairs TCR-induced cytolysis. Mechanistic studies reveal that iNKT cell killing requires the tyrosine kinase Fyn, a known SAP-binding protein. Furthermore, SAP expression is required within iNKT cells to facilitate their interaction with T-cell targets and induce reorientation of the microtubule-organizing center to the immunologic synapse (IS). Collectively, these studies highlight a novel and essential role for SAP during iNKT cell cytotoxicity and formation of a functional IS.

  19. Transmembrane adaptor proteins in the high-affinity IgE receptor signaling

    Directory of Open Access Journals (Sweden)

    Petr eDraber

    2012-01-01

    Full Text Available Aggregation of the high-affinity IgE receptor (FcεRI initiates a cascade of signaling events leading to release of preformed inflammatory and allergy mediators and de novo synthesis and secretion of cytokines and other compounds. The first biochemically well defined step of this signaling cascade is tyrosine phosphorylation of the FcεRI subunits by Src family kinase Lyn, followed by recruitment and activation of Syk kinase. Activity of Syk is decisive for the formation of multicomponent signaling assemblies, the signalosomes, in the vicinity of the receptors. Formation of the signalosomes is dependent on the presence of transmembrane adaptor proteins (TRAPs. These proteins are characterized by a short extracellular domain, a single transmembrane domain and a cytoplasmic tail with various motifs serving as anchors for cytoplasmic signaling molecules. In mast cells five TRAPs have been identified (LAT, NTAL, LAX, PAG and GAPT; engagement of four of them (LAT, NTAL, LAX and PAG in FcεRI signaling has been documented. Here we discuss recent progress in the understanding of how TRAPs affect FcεRI-mediated mast cell signaling. The combined data indicate that individual TRAPs have irreplaceable roles in important signaling events such as calcium response, degranulation, cytokines production and chemotaxis.

  20. The Role of the Clathrin Adaptor AP-1: Polarized Sorting and Beyond

    Directory of Open Access Journals (Sweden)

    Fubito Nakatsu

    2014-11-01

    Full Text Available The selective transport of proteins or lipids by vesicular transport is a fundamental process supporting cellular physiology. The budding process involves cargo sorting and vesicle formation at the donor membrane and constitutes an important process in vesicular transport. This process is particularly important for the polarized sorting in epithelial cells, in which the cargo molecules need to be selectively sorted and transported to two distinct destinations, the apical or basolateral plasma membrane. Adaptor protein (AP-1, a member of the AP complex family, which includes the ubiquitously expressed AP-1A and the epithelium-specific AP-1B, regulates polarized sorting at the trans-Golgi network and/or at the recycling endosomes. A growing body of evidence, especially from studies using model organisms and animals, demonstrates that the AP-1-mediated polarized sorting supports the development and physiology of multi-cellular units as functional organs and tissues (e.g., cell fate determination, inflammation and gut immune homeostasis. Furthermore, a possible involvement of AP-1B in the pathogenesis of human diseases, such as Crohn’s disease and cancer, is now becoming evident. These data highlight the significant contribution of AP-1 complexes to the physiology of multicellular organisms, as master regulators of polarized sorting in epithelial cells.

  1. Novel isoform of adaptor protein ITSN1 forms homodimers via its C-terminus

    Directory of Open Access Journals (Sweden)

    Skrypkina I. Ya.

    2011-06-01

    Full Text Available Aim. Previously we have identified a novel isoform of endocytic adaptor protein ITSN1 designated as ITSN122a. Western blot revealed two immunoreactive bands of 120 and 250 kDa that corresponded to ITSN1-22a. The goal of this study was to investigate the possibility of dimer formation by the novel isoform. Methods. Dimerization ability of ITSN1-22a was tested by immunoprecipitation and subsequent Western blot analysis. To specify the region responsible for dimerization, site-directed mutagenesis and truncation analysis were carried out. Inhibition of endocytosis by potassium depletion and EGF stimulation of HEK293 were performed. Results. We have found that ITSN1-22a forms dimers in HEK293 cells. The dimerization of ITSN1-22a was mediated by C-terminal domain. We showed that cysteines C1016 and C1019 were involved in homodimerization. Inhibition of clathrin-mediated endocytosis and mitogen stimulation did not affect ITSN1-22a dimer formation. Conclusions. ITSN1-22a is the only one known ITSN1 isoform, which is capable to form homodimers via disulphide bonds. This could be important for the formation of protein complexes containing ITSN1 molecules.

  2. Allostery mediates ligand binding to Grb2 adaptor in a mutually exclusive manner.

    Science.gov (United States)

    McDonald, Caleb B; El Hokayem, Jimmy; Zafar, Nawal; Balke, Jordan E; Bhat, Vikas; Mikles, David C; Deegan, Brian J; Seldeen, Kenneth L; Farooq, Amjad

    2013-02-01

    Allostery plays a key role in dictating the stoichiometry and thermodynamics of multi-protein complexes driving a plethora of cellular processes central to health and disease. Herein, using various biophysical tools, we demonstrate that although Sos1 nucleotide exchange factor and Gab1 docking protein recognize two non-overlapping sites within the Grb2 adaptor, allostery promotes the formation of two distinct pools of Grb2-Sos1 and Grb2-Gab1 binary signaling complexes in concert in lieu of a composite Sos1-Grb2-Gab1 ternary complex. Of particular interest is the observation that the binding of Sos1 to the nSH3 domain within Grb2 sterically blocks the binding of Gab1 to the cSH3 domain and vice versa in a mutually exclusive manner. Importantly, the formation of both the Grb2-Sos1 and Grb2-Gab1 binary complexes is governed by a stoichiometry of 2:1, whereby the respective SH3 domains within Grb2 homodimer bind to Sos1 and Gab1 via multivalent interactions. Collectively, our study sheds new light on the role of allostery in mediating cellular signaling machinery. PMID:23334917

  3. Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52

    Science.gov (United States)

    Jo, Chulman; Gundemir, Soner; Pritchard, Susanne; Jin, Youngnam N.; Rahman, Irfan; Johnson, Gail V. W.

    2014-03-01

    Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal transcription factor in the defence against oxidative stress. Here we provide evidence that activation of the Nrf2 pathway reduces the levels of phosphorylated tau by induction of an autophagy adaptor protein NDP52 (also known as CALCOCO2) in neurons. The expression of NDP52, which we show has three antioxidant response elements (AREs) in its promoter region, is strongly induced by Nrf2, and its overexpression facilitates clearance of phosphorylated tau in the presence of an autophagy stimulator. In Nrf2-knockout mice, phosphorylated and sarkosyl-insoluble tau accumulates in the brains concurrent with decreased levels of NDP52. Moreover, NDP52 associates with phosphorylated tau from brain cortical samples of Alzheimer disease cases, and the amount of phosphorylated tau in sarkosyl-insoluble fractions is inversely proportional to that of NDP52. These results suggest that NDP52 plays a key role in autophagy-mediated degradation of phosphorylated tau in vivo.

  4. Impairment of dendritic cell functions in patients with adaptor protein-3 complex deficiency.

    Science.gov (United States)

    Prandini, Alberto; Salvi, Valentina; Colombo, Francesca; Moratto, Daniele; Lorenzi, Luisa; Vermi, William; De Francesco, Maria Antonia; Notarangelo, Lucia Dora; Porta, Fulvio; Plebani, Alessandro; Facchetti, Fabio; Sozzani, Silvano; Badolato, Raffaele

    2016-06-30

    Hermansky-Pudlak syndrome type 2 (HPS2) is a primary immunodeficiency due to adaptor protein-3 (AP-3) complex deficiency. HPS2 patients present neutropenia, partial albinism, and impaired lysosomal vesicles formation in hematopoietic cells. Given the role of dendritic cells (DCs) in the immune response, we studied monocyte-derived DCs (moDCs) and plasmacytoid DCs (pDCs) in two HPS2 siblings. Mature HPS2 moDCs showed impaired expression of CD83 and DC-lysosome-associated membrane protein (LAMP), low levels of MIP1-β/CCL4, MIG/CXCL9, and severe defect of interleukin-12 (IL-12) secretion. DCs in lymph-node biopsies from the same patients showed a diffuse cytoplasm reactivity in a large fraction of DC-LAMP(+) cells, instead of the classical dot-like stain. In addition, analysis of pDC-related functions of blood-circulating mononuclear cells revealed reduced interferon-α secretion in response to herpes simplex virus-1 (HSV-1), whereas granzyme-B induction upon IL-3/IL-10 stimulation was normal. Finally, T-cell costimulatory activity, as measured by mixed lymphocyte reaction assay, was lower in patients, suggesting that function and maturation of DCs is abnormal in patients with HPS2.

  5. Transmembrane adaptor molecules: a new category of lymphoid-cell markers.

    Science.gov (United States)

    Tedoldi, Sara; Paterson, Jennifer C; Hansmann, Martin-Leo; Natkunam, Yasodha; Rüdiger, Thomas; Angelisova, Pavla; Du, Ming Q; Roberton, Helen; Roncador, Giovanna; Sanchez, Lydia; Pozzobon, Michela; Masir, Noraidah; Barry, Richard; Pileri, Stefano; Mason, David Y; Marafioti, Teresa; Horejsí, Václav

    2006-01-01

    Transmembrane adaptor proteins (of which 7 have been identified so far) are involved in receptor signaling in immune cells. They have only a short extracellular region, with most of the molecule comprising a substantial intracytoplasmic region carrying multiple tyrosine residues that can be phosphorylated by Src- or Syk-family kinases. In this paper, we report an immunohistologic study of 6 of these molecules in normal and neoplastic human tissue sections and show that they are restricted to subpopulations of lymphoid cells, being present in either T cells (LAT, LIME, and TRIM), B cells (NTAL), or subsets of both cell types (PAG and SIT). Their expression in neoplastic lymphoid cells broadly reflects that of normal lymphoid tissue, including the positivity of plasma cells and myeloma/plasmacytoma for LIME, NTAL, PAG, and SIT. However, this study also revealed some reactions that may be of diagnostic/prognostic value. For example, lymphocytic lymphoma and mantle-cell lymphoma showed similar profiles but differed clearly from follicle-center lymphoma, whereas PAG tended to be selectively expressed in germinal center-derived subsets of diffuse large B-cell lymphoma. These molecules represent a potentially important addition to the panel of immunophenotypic markers detectable in routine biopsies that can be used in hematopathologic studies. PMID:16160011

  6. Surfactant Protein A Enhances Constitutive Immune Functions of Clathrin Heavy Chain and Clathrin Adaptor Protein 2.

    Science.gov (United States)

    Moulakakis, Christina; Steinhäuser, Christine; Biedziak, Dominika; Freundt, Katja; Reiling, Norbert; Stamme, Cordula

    2016-07-01

    NF-κB transcription factors are key regulators of pulmonary inflammatory disorders and repair. Constitutive lung cell type- and microenvironment-specific NF-κB/inhibitor κBα (IκB-α) regulation, however, is poorly understood. Surfactant protein (SP)-A provides both a critical homeostatic and lung defense control, in part by immune instruction of alveolar macrophages (AMs) via clathrin-mediated endocytosis. The central endocytic proteins, clathrin heavy chain (CHC) and the clathrin adaptor protein (AP) complex AP2, have pivotal alternative roles in cellular homeostasis that are endocytosis independent. Here, we dissect endocytic from alternative functions of CHC, the α-subunit of AP2, and dynamin in basal and SP-A-modified LPS signaling of macrophages. As revealed by pharmacological inhibition and RNA interference in primary AMs and RAW264.7 macrophages, respectively, CHC and α-adaptin, but not dynamin, prevent IκB-α degradation and TNF-α release, independent of their canonical role in membrane trafficking. Kinetics studies employing confocal microscopy, Western analysis, and immunomagnetic sorting revealed that SP-A transiently enhances the basal protein expression of CHC and α-adaptin, depending on early activation of protein kinase CK2 (former casein kinase II) and Akt1 in primary AMs from rats, SP-A(+/+), and SP-A(-/-) mice, as well as in vivo when intratracheally administered to SP-A(+/+) mice. Constitutive immunomodulation by SP-A, but not SP-A-mediated inhibition of LPS-induced NF-κB activity and TNF-α release, requires CHC, α-adaptin, and dynamin. Our data demonstrate that endocytic proteins constitutively restrict NF-κB activity in macrophages and provide evidence that SP-A enhances the immune regulatory capacity of these proteins, revealing a previously unknown pathway of microenvironment-specific NF-κB regulation in the lung. PMID:26771574

  7. Hydrological Modeling Reproducibility Through Data Management and Adaptors for Model Interoperability

    Science.gov (United States)

    Turner, M. A.

    2015-12-01

    Because of a lack of centralized planning and no widely-adopted standards among hydrological modeling research groups, research communities, and the data management teams meant to support research, there is chaos when it comes to data formats, spatio-temporal resolutions, ontologies, and data availability. All this makes true scientific reproducibility and collaborative integrated modeling impossible without some glue to piece it all together. Our Virtual Watershed Integrated Modeling System provides the tools and modeling framework hydrologists need to accelerate and fortify new scientific investigations by tracking provenance and providing adaptors for integrated, collaborative hydrologic modeling and data management. Under global warming trends where water resources are under increasing stress, reproducible hydrological modeling will be increasingly important to improve transparency and understanding of the scientific facts revealed through modeling. The Virtual Watershed Data Engine is capable of ingesting a wide variety of heterogeneous model inputs, outputs, model configurations, and metadata. We will demonstrate one example, starting from real-time raw weather station data packaged with station metadata. Our integrated modeling system will then create gridded input data via geostatistical methods along with error and uncertainty estimates. These gridded data are then used as input to hydrological models, all of which are available as web services wherever feasible. Models may be integrated in a data-centric way where the outputs too are tracked and used as inputs to "downstream" models. This work is part of an ongoing collaborative Tri-state (New Mexico, Nevada, Idaho) NSF EPSCoR Project, WC-WAVE, comprised of researchers from multiple universities in each of the three states. The tools produced and presented here have been developed collaboratively alongside watershed scientists to address specific modeling problems with an eye on the bigger picture of

  8. The AP-3 adaptor complex is required for vacuolar function in Arabidopsis

    Institute of Scientific and Technical Information of China (English)

    Maria Zwiewka; Elena Feraru; Barbara M(o)ller; Inhwan Hwang; Mugurel I Feraru; Jürgen Kleine-Vehn; Dolf Weijers; Ji(n) Friml

    2011-01-01

    Subcellular trafficking is required for a multitude of functions in eukaryotic cells.It involves regulation of cargo sorting,vesicle formation,trafficking and fusion processes at multiple levels.Adaptor protein (AP) complexes are key regulators of cargo sorting into vesicles in yeast and mammals but their existence and function in plants have not been demonstrated.Here we report the identification of the protein-affected trafficking 4 (pat4) mutant defective in the putative δ subunit of the AP-3 complex.pat4 and pat2,a mutant isolated from the same GFP imaging-based forward genetic screen that lacks a functional putative AP-3 β,as well as dominant negative AP-3 μ transgenic lines display undistinguishable phenotypes characterized by largely normal morphology and development,but strong intracellular accumulation of membrane proteins in aberrant vacuolar structures.All mutants are defective in morphology and function of lytic and protein storage vacuoles (PSVs) but show normal sorting of reserve proteins to PSVs.Immunoprecipitation experiments and genetic studies revealed tight functional and physical associations of putative AP-3 β and AP-3 δ subunits.Furthermore,both proteins are closely linked with putative AP-3 μ and σ subunits and several components of the clathrin and dynamin machineries.Taken together,these results demonstrate that AP complexes,similar to those in other eukaryotes,exist in plants,and that AP-3 plays a specific role in the regulation of biogenesis and function of vacuoles in plant cells.

  9. The Toll-Like receptor adaptor TRIF contributes to otitis media pathogenesis and recovery

    Directory of Open Access Journals (Sweden)

    Pak Kwang

    2009-08-01

    Full Text Available Abstract Background Toll-like receptor (TLR signalling is crucial for innate immune responses to infection. The involvement of TLRs in otitis media (OM, the most prevalent childhood disease in developed countries, has been implicated by studies in middle ear cell lines, by association studies of TLR-related gene polymorphisms, and by altered OM in mice bearing mutations in TLR genes. Activated TLRs signal via two alternative intracellular signaling molecules with differing effects; MyD88 (Myeloid differentiation primary response gene 88 inducing primarily interleukin expression and TRIF (Tir-domain-containing adaptor inducing interferon β mediating type I interferon (IFN expression. We tested the hypothesis that TRIF and type I IFN signaling play a role in OM, using a murine model of OM induced by non-typeable Haemophilus influenzae (NTHi. The ME inflammatory response to NTHi was examined in wild-type (WT and TRIF-/- mice by qPCR, gene microarray, histopathology and bacterial culture. Results Expression of TRIF mRNA was only modesty enhanced during OM, but both type I IFN signalling genes and type I IFN-inducible genes were significantly up-regulated in WT mice. TRIF-deficient mice showed reduced but more persistent mucosal hyperplasia and less leukocyte infiltration into the ME in response to NTHi infection than did WT animals. Viable bacteria could be cultured from MEs of TRIF-/- mice for much longer in the course of disease than was the case for middle ears of WT mice. Conclusion Our results demonstrate that activation of TRIF/type I IFN responses is important in both the pathogenesis and resolution of NTHi-induced OM.

  10. UIF, a New mRNA export adaptor that works together with REF/ALY, requires FACT for recruitment to mRNA.

    Science.gov (United States)

    Hautbergue, Guillaume M; Hung, Ming-Lung; Walsh, Matthew J; Snijders, Ambrosius P L; Chang, Chung-Te; Jones, Rachel; Ponting, Chris P; Dickman, Mark J; Wilson, Stuart A

    2009-12-01

    Messenger RNA (mRNA) export adaptors play an important role in the transport of mRNA from the nucleus to the cytoplasm. They couple early mRNA processing events such as 5' capping and 3' end formation with loading of the TAP/NXF1 export receptor onto mRNA. The canonical adaptor REF/ALY/Yra1 is recruited to mRNA via UAP56 and subsequently delivers the mRNA to NXF1 [1]. Knockdown of UAP56 [2, 3] and NXF1 [4-7] in higher eukaryotes efficiently blocks mRNA export, whereas knockdown of REF only causes a modest reduction, suggesting the existence of additional adaptors [8-10]. Here we identify a new UAP56-interacting factor, UIF, which functions as an export adaptor, binding NXF1 and delivering mRNA to the nuclear pore. REF and UIF are simultaneously found on the same mRNA molecules, and both proteins are required for efficient export of mRNA. We show that the histone chaperone FACT specifically binds UIF, but not REF, via the SSRP1 subunit, and this interaction is required for recruitment of UIF to mRNA. Together the results indicate that REF and UIF represent key human adaptors for the export of cellular mRNAs via the UAP56-NXF1 pathway.

  11. The AP-1A and AP-1B clathrin adaptor complexes define biochemically and functionally distinct membrane domains

    OpenAIRE

    Fölsch, Heike; Pypaert, Marc; Maday, Sandra; Pelletier, Laurence; Mellman, Ira

    2003-01-01

    Most epithelial cells contain two AP-1 clathrin adaptor complexes. AP-1A is ubiquitously expressed and involved in transport between the TGN and endosomes. AP-1B is expressed only in epithelia and mediates the polarized targeting of membrane proteins to the basolateral surface. Both AP-1 complexes are heterotetramers and differ only in their 50-kD μ1A or μ1B subunits. Here, we show that AP-1A and AP-1B, together with their respective cargoes, define physically and functionally distinct membra...

  12. Functional analyses of Src-like adaptor (SLA), a glucocorticoid-regulated gene in acute lymphoblastic leukemia.

    Science.gov (United States)

    Mansha, Muhammad; Carlet, Michela; Ploner, Christian; Gruber, Georg; Wasim, Muhammad; Wiegers, Gerrit Jan; Rainer, Johannes; Geley, Stephan; Kofler, Reinhard

    2010-04-01

    Glucocorticoids (GCs) cause apoptosis and cell cycle arrest in lymphoid cells and are used in the therapy of lymphoid malignancies. SLA (Src-like-adaptor), an inhibitor of T- and B-cell receptor signaling, is a promising candidate derived from expression profiling analyses in children with acute lymphoblastic leukemia (ALL). Over-expression and knock-down experiments in ALL in vitro model revealed that transgenic SLA alone had no effect on survival or cell cycle progression, nor did it affect sensitivity to, or kinetics of, GC-induced apoptosis. Although SLA is a prominent GC response gene, it does not seem to contribute to the anti-leukemic effects of GC.

  13. Competitive and Cooperative Interactions Mediate RNA Transfer from Herpesvirus Saimiri ORF57 to the Mammalian Export Adaptor ALYREF

    OpenAIRE

    Tunnicliffe, Richard B.; Hautbergue, Guillaume M.; Wilson, Stuart A.; Priti Kalra; Golovanov, Alexander P.

    2014-01-01

    The essential herpesvirus adaptor protein HVS ORF57, which has homologs in all other herpesviruses, promotes viral mRNA export by utilizing the cellular mRNA export machinery. ORF57 protein specifically recognizes viral mRNA transcripts, and binds to proteins of the cellular transcription-export (TREX) complex, in particular ALYREF. This interaction introduces viral mRNA to the NXF1 pathway, subsequently directing it to the nuclear pore for export to the cytoplasm. Here we have used a range o...

  14. Downstream Toll-like receptor signaling mediates adaptor-specific cytokine expression following focal cerebral ischemia

    Directory of Open Access Journals (Sweden)

    Bolanle Famakin

    2012-07-01

    Full Text Available Abstract Background Deletion of some Toll-like receptors (TLRs affords protection against cerebral ischemia, but disruption of their known major downstream adaptors does not. To determine whether compensation in the production of downstream effectors by one pathway when the other is disrupted can explain these findings, we examined cytokine/chemokine expression and inflammatory infiltrates in wild-type (WT, MyD88−/− and TRIF-mutant mice following permanent middle cerebral artery occlusion (pMCAO. Methods Cytokine/chemokine expression was measured with a 25-plex bead array in the serum and brains of all three groups of mice at baseline (no surgery/naïve and at 3 hours and 24 hours following pMCAO. Brain inflammatory and neutrophil infiltrates were examined 24 hours following pMCAO. Results IL-6, keratinocyte chemoattractant (KC, granulocyte colony-stimulating factor (G-CSF and IL-10 were significantly decreased in MyD88−/− mice compared to WT mice following pMCAO. Significantly, decreased levels of the neutrophil chemoattractants KC and G-CSF corresponded with a trend toward fewer neutrophils in the brains of MyD88−/− mice. IP-10 was significantly decreased when either pathway was disrupted. MIP-1α was significantly decreased in TRIF-mutant mice, consistent with TRIF-dependent production. MyD88−/− mice showed elevations of a number of Th2 cytokines, such as IL-13, at baseline, which became significantly decreased following pMCAO. Conclusions Both MyD88 and TRIF mediate pathway-specific cytokine production following focal cerebral ischemia. Our results also suggest a compensatory Th2-type skew at baseline in MyD88−/− mice and a paradoxical switch to a Th1 phenotype following focal cerebral ischemia. The MyD88 pathway directs the expression of neutrophil chemoattractants following cerebral ischemia.

  15. The Mu subunit of Plasmodium falciparum clathrin-associated adaptor protein 2 modulates in vitro parasite response to artemisinin and quinine.

    Science.gov (United States)

    Henriques, Gisela; van Schalkwyk, Donelly A; Burrow, Rebekah; Warhurst, David C; Thompson, Eloise; Baker, David A; Fidock, David A; Hallett, Rachel; Flueck, Christian; Sutherland, Colin J

    2015-05-01

    The emergence of drug-resistant parasites is a serious threat faced by malaria control programs. Understanding the genetic basis of resistance is critical to the success of treatment and intervention strategies. A novel locus associated with antimalarial resistance, ap2-mu (encoding the mu chain of the adaptor protein 2 [AP2] complex), was recently identified in studies on the rodent malaria parasite Plasmodium chabaudi (pcap2-mu). Furthermore, analysis in Kenyan malaria patients of polymorphisms in the Plasmodium falciparum ap2-mu homologue, pfap2-mu, found evidence that differences in the amino acid encoded by codon 160 are associated with enhanced parasite survival in vivo following combination treatments which included artemisinin derivatives. Here, we characterize the role of pfap2-mu in mediating the in vitro antimalarial drug response of P. falciparum by generating transgenic parasites constitutively expressing codon 160 encoding either the wild-type Ser (Ser160) or the Asn mutant (160Asn) form of pfap2-mu. Transgenic parasites carrying the pfap2-mu 160Asn allele were significantly less sensitive to dihydroartemisinin using a standard 48-h in vitro test, providing direct evidence of an altered parasite response to artemisinin. Our data also provide evidence that pfap2-mu variants can modulate parasite sensitivity to quinine. No evidence was found that pfap2-mu variants contribute to the slow-clearance phenotype exhibited by P. falciparum in Cambodian patients treated with artesunate monotherapy. These findings provide compelling evidence that pfap2-mu can modulate P. falciparum responses to multiple drugs. We propose that this gene should be evaluated further as a potential molecular marker of antimalarial resistance.

  16. The cell signaling adaptor protein EPS-8 is essential for C. elegans epidermal elongation and interacts with the ankyrin repeat protein VAB-19.

    Directory of Open Access Journals (Sweden)

    Mei Ding

    Full Text Available The epidermal cells of the C. elegans embryo undergo coordinated cell shape changes that result in the morphogenetic process of elongation. The cytoskeletal ankyrin repeat protein VAB-19 is required for cell shape changes and localizes to cell-matrix attachment structures. The molecular functions of VAB-19 in this process are obscure, as no previous interactors for VAB-19 have been described.In screens for VAB-19 binding proteins we identified the signaling adaptor EPS-8. Within C. elegans epidermal cells, EPS-8 and VAB-19 colocalize at cell-matrix attachment structures. The central domain of EPS-8 is necessary and sufficient for its interaction with VAB-19. eps-8 null mutants, like vab-19 mutants, are defective in epidermal elongation and in epidermal-muscle attachment. The eps-8 locus encodes two isoforms, EPS-8A and EPS-8B, that appear to act redundantly in epidermal elongation. The function of EPS-8 in epidermal development involves its N-terminal PTB and central domains, and is independent of its C-terminal SH3 and actin-binding domains. VAB-19 appears to act earlier in the biogenesis of attachment structures and may recruit EPS-8 to these structures.EPS-8 and VAB-19 define a novel pathway acting at cell-matrix attachments to regulate epithelial cell shape. This is the first report of a role for EPS-8 proteins in cell-matrix attachments. The existence of EPS-8B-like isoforms in Drosophila suggests this function of EPS-8 proteins could be conserved among other organisms.

  17. VgrG C terminus confers the type VI effector transport specificity and is required for binding with PAAR and adaptor-effector complex.

    Science.gov (United States)

    Bondage, Devanand D; Lin, Jer-Sheng; Ma, Lay-Sun; Kuo, Chih-Horng; Lai, Erh-Min

    2016-07-01

    Type VI secretion system (T6SS) is a macromolecular machine used by many Gram-negative bacteria to inject effectors/toxins into eukaryotic hosts or prokaryotic competitors for survival and fitness. To date, our knowledge of the molecular determinants and mechanisms underlying the transport of these effectors remains limited. Here, we report that two T6SS encoded valine-glycine repeat protein G (VgrG) paralogs in Agrobacterium tumefaciens C58 specifically control the secretion and interbacterial competition activity of the type VI DNase toxins Tde1 and Tde2. Deletion and domain-swapping analysis identified that the C-terminal extension of VgrG1 specifically confers Tde1 secretion and Tde1-dependent interbacterial competition activity in planta, and the C-terminal variable region of VgrG2 governs this specificity for Tde2. Functional studies of VgrG1 and VgrG2 variants with stepwise deletion of the C terminus revealed that the C-terminal 31 aa (C31) of VgrG1 and 8 aa (C8) of VgrG2 are the molecular determinants specifically required for delivery of each cognate Tde toxin. Further in-depth studies on Tde toxin delivery mechanisms revealed that VgrG1 interacts with the adaptor/chaperone-effector complex (Tap-1-Tde1) in the absence of proline-alanine-alanine-arginine (PAAR) and the VgrG1-PAAR complex forms independent of Tap-1 and Tde1. Importantly, we identified the regions involved in these interactions. Although the entire C31 segment is required for binding with the Tap-1-Tde1 complex, only the first 15 aa of this region are necessary for PAAR binding. These results suggest that the VgrG1 C terminus interacts sequentially or simultaneously with the Tap-1-Tde1 complex and PAAR to govern Tde1 translocation across bacterial membranes and delivery into target cells for antibacterial activity. PMID:27313214

  18. Association between receptor protein-tyrosine phosphatase RPTPalpha and the Grb2 adaptor. Dual Src homology (SH) 2/SH3 domain requirement and functional consequences

    DEFF Research Database (Denmark)

    Su, J; Yang, L T; Sap, J

    1996-01-01

    Receptor protein-tyrosine phosphatase RPTPalpha is found associated in vivo with the adaptor protein Grb2. Formation of this complex, which contains no detectable levels of Sos, is known to depend on a C-terminal phosphorylated tyrosine residue (Tyr798) in RPTPalpha and on the Src homology (SH) 2...

  19. Disruption of adaptor protein 2mu (AP-2mu) in cochlear hair cells impairs vesicle reloading of synaptic release sites and hearing

    NARCIS (Netherlands)

    Jung, S.; Maritzen, T.; Wichmann, C.; Jing, Z.; Neef, A.; Revelo, N.H.; Al-Moyed, H.; Meese, S.; Wojcik, S.M.; Panou, I.; Bulut, H.; Schu, P.; Ficner, R.; Reisinger, E.; Rizzoli, S.O.; Neef, J.; Strenzke, N.; Haucke, V.; Moser, T.

    2015-01-01

    Active zones (AZs) of inner hair cells (IHCs) indefatigably release hundreds of vesicles per second, requiring each release site to reload vesicles at tens per second. Here, we report that the endocytic adaptor protein 2mu (AP-2mu) is required for release site replenishment and hearing. We show that

  20. Ubc2, an Ortholog of the Yeast Ste50p Adaptor, Possesses a Basidiomycete-Specific Carboxy terminal Extension Essential for Pathogenicity Independent of Pheromone Response.

    Science.gov (United States)

    Proteins involved in the MAP kinase pathway controlling mating, morphogenesis and pathogenicity have been identified previously in the fungus Ustilago maydis. One of these, the Ubc2 adaptor protein, possesses a basidiomycete-specific structure. In addition to containing SAM and RA domains typical of...

  1. Enigma interacts with adaptor protein with PH and SH2 domains to control insulin-induced actin cytoskeleton remodeling and glucose transporter 4 translocation

    DEFF Research Database (Denmark)

    Barres, Romain; Grémeaux, Thierry; Gual, Philippe;

    2006-01-01

    APS (adaptor protein with PH and SH2 domains) initiates a phosphatidylinositol 3-kinase-independent pathway involved in insulin-stimulated glucose transport. We recently identified Enigma, a PDZ and LIM domain-containing protein, as a partner of APS and showed that APS-Enigma complex plays...

  2. Brain-derived neurotrophic factor modulation of Kv1.3 channel is disregulated by adaptor proteins Grb10 and nShc

    Directory of Open Access Journals (Sweden)

    Marks David R

    2009-01-01

    Full Text Available Abstract Background Neurotrophins are important regulators of growth and regeneration, and acutely, they can modulate the activity of voltage-gated ion channels. Previously we have shown that acute brain-derived neurotrophic factor (BDNF activation of neurotrophin receptor tyrosine kinase B (TrkB suppresses the Shaker voltage-gated potassium channel (Kv1.3 via phosphorylation of multiple tyrosine residues in the N and C terminal aspects of the channel protein. It is not known how adaptor proteins, which lack catalytic activity, but interact with members of the neurotrophic signaling pathway, might scaffold with ion channels or modulate channel activity. Results We report the co-localization of two adaptor proteins, neuronal Src homology and collagen (nShc and growth factor receptor-binding protein 10 (Grb10, with Kv1.3 channel as demonstrated through immunocytochemical approaches in the olfactory bulb (OB neural lamina. To further explore the specificity and functional ramification of adaptor/channel co-localization, we performed immunoprecipitation and Western analysis of channel, kinase, and adaptor transfected human embryonic kidney 293 cells (HEK 293. nShc formed a direct protein-protein interaction with Kv1.3 that was independent of BDNF-induced phosphorylation of Kv1.3, whereas Grb10 did not complex with Kv1.3 in HEK 293 cells. Both adaptors, however, co-immunoprecipitated with Kv1.3 in native OB. Grb10 was interestingly able to decrease the total expression of Kv1.3, particularly at the membrane surface, and subsequently eliminated the BDNF-induced phosphorylation of Kv1.3. To examine the possibility that the Src homology 2 (SH2 domains of Grb10 were directly binding to basally phosphorylated tyrosines in Kv1.3, we utilized point mutations to substitute multiple tyrosine residues with phenylalanine. Removal of the tyrosines 111–113 and 449 prevented Grb10 from decreasing Kv1.3 expression. In the absence of either adaptor protein

  3. Receptor tyrosine phosphatase R-PTP-alpha is tyrosine-phosphorylated and associated with the adaptor protein Grb2

    DEFF Research Database (Denmark)

    Su, J; Batzer, A; Sap, J

    1994-01-01

    -phosphorylated and associated in vivo with the Grb2 protein. This association can be reproduced in stably and transiently transfected cells, as well as in vitro using recombinant Grb2 protein. Association requires the presence of an intact SH2 domain in Grb2, as well as tyrosine phosphorylation of R-PTP-alpha. This observation......Receptor tyrosine phosphatases (R-PTPases) have generated interest because of their suspected involvement in cellular signal transduction. The adaptor protein Grb2 has been implicated in coupling receptor tyrosine kinases to Ras. We report that a ubiquitous R-PTPase, R-PTP-alpha, is tyrosine...... links a receptor tyrosine phosphatase with a key component of a central cellular signalling pathway and provides a basis for addressing R-PTP-alpha function....

  4. Ascent Heating Thermal Analysis on the Spacecraft Adaptor (SA) Fairings and the Interface with the Crew Launch Vehicle (CLV)

    Science.gov (United States)

    Wang, Xiao-Yen; Yuko, James; Motil, Brian

    2009-01-01

    When the crew exploration vehicle (CEV) is launched, the spacecraft adaptor (SA) fairings that cover the CEV service module (SM) are exposed to aero heating. Thermal analysis is performed to compute the fairing temperatures and to investigate whether the temperatures are within the material limits for nominal ascent aero heating case. Heating rates from Thermal Environment (TE) 3 aero heating analysis computed by engineers at Marshall Space Flight Center (MSFC) are used in the thermal analysis. Both MSC Patran 2007r1b/Pthermal and C&R Thermal Desktop 5.1/Sinda models are built to validate each other. The numerical results are also compared with those reported by Lockheed Martin (LM) and show a reasonably good agreement.

  5. A Patient-Controlled Analgesia Adaptor to Mitigate Postsurgical Pain for Combat Casualties With Multiple Limb Amputation: A Case Series.

    Science.gov (United States)

    Pasquina, Paul F; Isaacson, Brad M; Johnson, Elizabeth; Rhoades, Daniel S; Lindholm, Mark P; Grindle, Garrett G; Cooper, Rory A

    2016-08-01

    The use of explosive armaments during Operation Iraqi Freedom, Operation Enduring Freedom, and Operation New Dawn has resulted in a significant number of injured U.S. service members. These weapons often generate substantial extremity trauma requiring multiple surgical procedures to preserve life, limb, and restore function. For those individuals who require multiple surgeries, the use of patient-controlled analgesia (PCA) devices can be an effective way to achieve adequate pain management and promote successful rehabilitation and recovery during inpatient treatment. A subpopulation of patients are unable to independently control a PCA device because of severe multiple limb dysfunction and/or loss. In response to the needs of these patients, our team designed and developed a custom adaptor to assist service members who would otherwise not be able to use a PCA. Patient feedback of the device indicated a positive response, improved independence, and overall satisfaction during inpatient hospitalization. PMID:27483540

  6. Analysis of Arf1 GTPase-dependent membrane binding and remodeling using the exomer secretory vesicle cargo adaptor

    Science.gov (United States)

    Paczkowski, Jon E.; Fromme, J. Christopher

    2016-01-01

    Summary Protein-protein and protein-membrane interactions play a critical role in shaping biological membranes through direct physical contact with the membrane surface. This is particularly evident in many steps of membrane trafficking, in which proteins deform the membrane and induce fission to form transport carriers. The small GTPase Arf1 and related proteins have the ability to remodel membranes by insertion of an amphipathic helix into the membrane. Arf1 and the exomer cargo adaptor coordinate cargo sorting into subset of secretory vesicle carriers in the model organism Saccharomyces cerevisiae. Here, we detail the assays we used to explore the cooperative action of Arf1 and exomer to bind and remodel membranes. We expect these methods are broadly applicable to other small GTPase/effector systems where investigation of membrane binding and remodeling is of interest. PMID:27632000

  7. Competitive and cooperative interactions mediate RNA transfer from herpesvirus saimiri ORF57 to the mammalian export adaptor ALYREF.

    Directory of Open Access Journals (Sweden)

    Richard B Tunnicliffe

    2014-02-01

    Full Text Available The essential herpesvirus adaptor protein HVS ORF57, which has homologs in all other herpesviruses, promotes viral mRNA export by utilizing the cellular mRNA export machinery. ORF57 protein specifically recognizes viral mRNA transcripts, and binds to proteins of the cellular transcription-export (TREX complex, in particular ALYREF. This interaction introduces viral mRNA to the NXF1 pathway, subsequently directing it to the nuclear pore for export to the cytoplasm. Here we have used a range of techniques to reveal the sites for direct contact between RNA and ORF57 in the absence and presence of ALYREF. A binding site within ORF57 was characterized which recognizes specific viral mRNA motifs. When ALYREF is present, part of this ORF57 RNA binding site, composed of an α-helix, binds preferentially to ALYREF. This competitively displaces viral RNA from the α-helix, but contact with RNA is still maintained by a flanking region. At the same time, the flexible N-terminal domain of ALYREF comes into contact with the viral RNA, which becomes engaged in an extensive network of synergistic interactions with both ALYREF and ORF57. Transfer of RNA to ALYREF in the ternary complex, and involvement of individual ORF57 residues in RNA recognition, were confirmed by UV cross-linking and mutagenesis. The atomic-resolution structure of the ORF57-ALYREF interface was determined, which noticeably differed from the homologous ICP27-ALYREF structure. Together, the data provides the first site-specific description of how viral mRNA is locked by a herpes viral adaptor protein in complex with cellular ALYREF, giving herpesvirus access to the cellular mRNA export machinery. The NMR strategy used may be more generally applicable to the study of fuzzy protein-protein-RNA complexes which involve flexible polypeptide regions.

  8. CD2v interacts with Adaptor Protein AP-1 during African swine fever infection

    OpenAIRE

    Pérez-Núñez, Daniel; García-Urdiales, Eduardo; Martínez Bonet, Marta; Nogal París, María Luisa; Barroso, Susana; Revilla, Yolanda; Madrid, Ricardo

    2015-01-01

    African swine fever virus (ASFV) CD2v protein is believed to be involved in virulence enhancement, viral hemadsorption, and pathogenesis, although the molecular mechanisms of the function of this viral protein are still not fully understood. Here we describe that CD2v localized around viral factories during ASFV infection, suggesting a role in the generation and/or dynamics of these viral structures and hence in disturbing cellular traffic. We show that CD2v targeted the regulatory trans-Golg...

  9. Regulation of ITAM adaptor molecules and their receptors by inhibition of calcineurin-NFAT signalling during late stage osteoclast differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Zawawi, M.S.F. [Universiti Sains Malaysia (USM) (Malaysia); Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005 (Australia); Dharmapatni, A.A.S.S.K.; Cantley, M.D. [Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005 (Australia); McHugh, K.P. [University of Florida, College of Dentistry, Fl (United States); Haynes, D.R. [Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005 (Australia); Crotti, T.N., E-mail: tania.crotti@adelaide.edu.au [Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005 (Australia)

    2012-10-19

    Highlights: Black-Right-Pointing-Pointer Calcineurin/NFAT inhibitors FK506 and VIVIT treated human PBMC derived osteoclasts in vitro. Black-Right-Pointing-Pointer Differential regulation of ITAM receptors and adaptor molecules by calcineurin/NFAT inhibitors. Black-Right-Pointing-Pointer FK506 and VIVIT suppress ITAM factors during late phase osteoclast differentiation. -- Abstract: Osteoclasts are specialised bone resorptive cells responsible for both physiological and pathological bone loss. Osteoclast differentiation and activity is dependent upon receptor activator NF-kappa-B ligand (RANKL) interacting with its receptor RANK to induce the transcription factor, nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1). The immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway has been identified as a co-stimulatory pathway in osteoclasts. Osteoclast-associated receptor (OSCAR) and triggering receptor expressed in myeloid cells (TREM2) are essential receptors that pair with adaptor molecules Fc receptor common gamma chain (FcR{gamma}) and DNAX-activating protein 12 kDa (DAP12) respectively to induce calcium signalling. Treatment with calcineurin-NFAT inhibitors, Tacrolimus (FK506) and the 11R-VIVIT (VIVIT) peptide, reduces NFATc1 expression consistent with a reduction in osteoclast differentiation and activity. This study aimed to investigate the effects of inhibiting calcineurin-NFAT signalling on the expression of ITAM factors and late stage osteoclast genes including cathepsin K (CathK), Beta 3 integrin ({beta}3) and Annexin VIII (AnnVIII). Human peripheral blood mononuclear cells (PBMCs) were differentiated with RANKL and macrophage-colony stimulating factor (M-CSF) over 10 days in the presence or absence of FK506 or VIVIT. Osteoclast formation (as assessed by tartrate resistant acid phosphatase (TRAP)) and activity (assessed by dentine pit resorption) were significantly reduced with treatment. Quantitative real

  10. Regulation of ITAM adaptor molecules and their receptors by inhibition of calcineurin-NFAT signalling during late stage osteoclast differentiation

    International Nuclear Information System (INIS)

    Highlights: ► Calcineurin/NFAT inhibitors FK506 and VIVIT treated human PBMC derived osteoclasts in vitro. ► Differential regulation of ITAM receptors and adaptor molecules by calcineurin/NFAT inhibitors. ► FK506 and VIVIT suppress ITAM factors during late phase osteoclast differentiation. -- Abstract: Osteoclasts are specialised bone resorptive cells responsible for both physiological and pathological bone loss. Osteoclast differentiation and activity is dependent upon receptor activator NF-kappa-B ligand (RANKL) interacting with its receptor RANK to induce the transcription factor, nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1). The immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway has been identified as a co-stimulatory pathway in osteoclasts. Osteoclast-associated receptor (OSCAR) and triggering receptor expressed in myeloid cells (TREM2) are essential receptors that pair with adaptor molecules Fc receptor common gamma chain (FcRγ) and DNAX-activating protein 12 kDa (DAP12) respectively to induce calcium signalling. Treatment with calcineurin-NFAT inhibitors, Tacrolimus (FK506) and the 11R-VIVIT (VIVIT) peptide, reduces NFATc1 expression consistent with a reduction in osteoclast differentiation and activity. This study aimed to investigate the effects of inhibiting calcineurin-NFAT signalling on the expression of ITAM factors and late stage osteoclast genes including cathepsin K (CathK), Beta 3 integrin (β3) and Annexin VIII (AnnVIII). Human peripheral blood mononuclear cells (PBMCs) were differentiated with RANKL and macrophage-colony stimulating factor (M-CSF) over 10 days in the presence or absence of FK506 or VIVIT. Osteoclast formation (as assessed by tartrate resistant acid phosphatase (TRAP)) and activity (assessed by dentine pit resorption) were significantly reduced with treatment. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis demonstrated that FK506 treatment

  11. Syk Kinase-Coupled C-type Lectin Receptors Engage Protein Kinase C-δ to Elicit Card9 Adaptor-Mediated Innate Immunity

    OpenAIRE

    Strasser, Dominikus; Neumann, Konstantin; Bergmann, Hanna; Marakalala, Mohlopheni J.; Guler, Reto; Rojowska, Anna; Hopfner, Karl-Peter; Brombacher, Frank; Urlaub, Henning; Baier, Gottfried; Brown, Gordon D.; Leitges, Michael; Ruland, Jürgen

    2012-01-01

    Summary C-type lectin receptors (CLRs) that couple with the kinase Syk are major pattern recognition receptors for the activation of innate immunity and host defense. CLRs recognize fungi and other forms of microbial or sterile danger, and they induce inflammatory responses through the adaptor protein Card9. The mechanisms relaying CLR proximal signals to the core Card9 module are unknown. Here we demonstrated that protein kinase C-δ (PKCδ) was activated upon Dectin-1-Syk signaling, mediated ...

  12. Molecular Structure, Function, and Dynamics of Clathrin-Mediated Membrane Traffic

    OpenAIRE

    Kirchhausen, Tom; Owen, David; Harrison, Stephen C.

    2014-01-01

    Clathrin is a molecular scaffold for vesicular uptake of cargo at the plasma membrane, where its assembly into cage-like lattices underlies the clathrin-coated pits of classical endocytosis. This review describes the structures of clathrin, major cargo adaptors, and other proteins that participate in forming a clathrin-coated pit, loading its contents, pinching off the membrane as a lattice-enclosed vesicle, and recycling the components. It integrates as much of the structural information as ...

  13. Adaptor protein complexes AP-1 and AP-3 are required by the HHV-7 Immunoevasin U21 for rerouting of class I MHC molecules to the lysosomal compartment.

    Directory of Open Access Journals (Sweden)

    Lisa A Kimpler

    Full Text Available The human herpesvirus-7 (HHV-7 U21 gene product binds to class I major histocompatibility complex (MHC molecules and reroutes them to a lysosomal compartment. Trafficking of integral membrane proteins to lysosomes is mediated through cytoplasmic sorting signals that recruit heterotetrameric clathrin adaptor protein (AP complexes, which in turn mediate protein sorting in post-Golgi vesicular transport. Since U21 can mediate rerouting of class I molecules to lysosomes even when lacking its cytoplasmic tail, we hypothesize the existence of a cellular protein that contains the lysosomal sorting information required to escort class I molecules to the lysosomal compartment. If such a protein exists, we expect that it might recruit clathrin adaptor protein complexes as a means of lysosomal sorting. Here we describe experiments demonstrating that the μ adaptins from AP-1 and AP-3 are involved in U21-mediated trafficking of class I molecules to lysosomes. These experiments support the idea that a cellular protein(s is necessary for U21-mediated lysosomal sorting of class I molecules. We also examine the impact of transient versus chronic knockdown of these adaptor protein complexes, and show that the few remaining μ subunits in the cells are eventually able to reroute class I molecules to lysosomes.

  14. Nuclear IKKbeta is an adaptor protein for IkappaBalpha ubiquitination and degradation in UV-induced NF-kappaB activation.

    Science.gov (United States)

    Tsuchiya, Yoshihiro; Asano, Tomoichiro; Nakayama, Keiko; Kato, Tomohisa; Karin, Michael; Kamata, Hideaki

    2010-08-27

    Proinflammatory cytokines activate NF-kappaB using the IkappaB kinase (IKK) complex that phosphorylates inhibitory proteins (IkappaBs) at N-terminal sites resulting in their ubiquitination and degradation in the cytoplasm. Although ultraviolet (UV) irradiation does not lead to IKK activity, it activates NF-kappaB by an unknown mechanism through IkappaBalpha degradation without N-terminal phosphorylation. Here, we describe an adaptor function of nuclear IKKbeta in UV-induced IkappaBalpha degradation. UV irradiation induces the nuclear translocation of IkappaBalpha and association with IKKbeta, which constitutively interacts with beta-TrCP through heterogeneous ribonucleoprotein-U (hnRNP-U) leading to IkappaBalpha ubiquitination and degradation. Furthermore, casein kinase 2 (CK2) and p38 associate with IKKbeta and promote IkappaBalpha degradation by phosphorylation at C-terminal sites. Thus, nuclear IKKbeta acts as an adaptor protein for IkappaBalpha degradation in UV-induced NF-kappaB activation. NF-kappaB activated by the nuclear IKKbeta adaptor protein suppresses anti-apoptotic gene expression and promotes UV-induced cell death.

  15. A Cyclic di-GMP-binding Adaptor Protein Interacts with Histidine Kinase to Regulate Two-component Signaling.

    Science.gov (United States)

    Xu, Linghui; Venkataramani, Prabhadevi; Ding, Yichen; Liu, Yang; Deng, Yinyue; Yong, Grace Lisi; Xin, Lingyi; Ye, Ruijuan; Zhang, Lianhui; Yang, Liang; Liang, Zhao-Xun

    2016-07-29

    The bacterial messenger cyclic di-GMP (c-di-GMP) binds to a diverse range of effectors to exert its biological effect. Despite the fact that free-standing PilZ proteins are by far the most prevalent c-di-GMP effectors known to date, their physiological function and mechanism of action remain largely unknown. Here we report that the free-standing PilZ protein PA2799 from the opportunistic pathogen Pseudomonas aeruginosa interacts directly with the hybrid histidine kinase SagS. We show that PA2799 (named as HapZ: histidine kinase associated PilZ) binds directly to the phosphoreceiver (REC) domain of SagS, and that the SagS-HapZ interaction is further enhanced at elevated c-di-GMP concentration. We demonstrate that binding of HapZ to SagS inhibits the phosphotransfer between SagS and the downstream protein HptB in a c-di-GMP-dependent manner. In accordance with the role of SagS as a motile-sessile switch and biofilm growth factor, we show that HapZ impacts surface attachment and biofilm formation most likely by regulating the expression of a large number of genes. The observations suggest a previously unknown mechanism whereby c-di-GMP mediates two-component signaling through a PilZ adaptor protein.

  16. Early Loss of Telomerase Action in Yeast Creates a Dependence on the DNA Damage Response Adaptor Proteins.

    Science.gov (United States)

    Jay, Kyle A; Smith, Dana L; Blackburn, Elizabeth H

    2016-07-15

    Telomeres cap the ends of chromosomes, protecting them from degradation and inappropriate DNA repair processes that can lead to genomic instability. A short telomere elicits increased telomerase action on itself that replenishes telomere length, thereby stabilizing the telomere. In the prolonged absence of telomerase activity in dividing cells, telomeres eventually become critically short, inducing a permanent cell cycle arrest (senescence). We recently showed that even early after telomerase inactivation (ETI), yeast cells have accelerated mother cell aging and mildly perturbed cell cycles. Here, we show that the complete disruption of DNA damage response (DDR) adaptor proteins in ETI cells causes severe growth defects. This synthetic-lethality phenotype was as pronounced as that caused by extensive DNA damage in wild-type cells but showed genetic dependencies distinct from such damage and was completely alleviated by SML1 deletion, which increases deoxynucleoside triphosphate (dNTP) pools. Our results indicated that these deleterious effects in ETI cells cannot be accounted for solely by the slow erosion of telomeres due to incomplete replication that leads to senescence. We propose that normally occurring telomeric DNA replication stress is resolved by telomerase activity and the DDR in two parallel pathways and that deletion of Sml1 prevents this stress. PMID:27161319

  17. Lipid raft-dependent FcepsilonRI ubiquitination regulates receptor endocytosis through the action of ubiquitin binding adaptors.

    Directory of Open Access Journals (Sweden)

    Rosa Molfetta

    Full Text Available The best characterized role for ubiquitination of membrane receptors is to negatively regulate signaling by targeting receptors for lysosomal degradation. The high affinity receptor for IgE (FcepsilonRI expressed on mast cells and basophils is rapidly ubiquitinated upon antigen stimulation. However, the nature and the role of this covalent modification are still largelly unknown. Here, we show that FcepsilonRI subunits are preferentially ubiquitinated at multiple sites upon stimulation, and provide evidence for a role of ubiquitin as an internalization signal: under conditions of impaired receptor ubiquitination a decrease of receptor entry is observed by FACS analysis and fluorescence microscopy. We also used biochemical approaches combined with fluorescence microscopy, to demonstrate that receptor endocytosis requires the integrity of specific membrane domains, namely lipid rafts. Additionally, by RNA interference we demonstrate the involvement of ubiquitin-binding endocytic adaptors in FcepsilonRI internalization and sorting. Notably, the triple depletion of Eps15, Eps15R and Epsin1 negatively affects the early steps of Ag-induced receptor endocytosis, whereas Hrs depletion retains ubiquitinated receptors into early endosomes and partially prevents their sorting into lysosomes for degradation. Our results are compatible with a scenario in which the accumulation of engaged receptor subunits into lipid rafts is required for receptor ubiquitination, a prerequisite for efficient receptor internalization, sorting and delivery to a lysosomal compartment.

  18. Matrilin-2, an extracellular adaptor protein, is needed for the regeneration of muscle, nerve and other tissues

    Institute of Scientific and Technical Information of China (English)

    va Korpos; Ferenc Dek; Ibolya Kiss

    2015-01-01

    The extracellular matrix (ECM) performs essential functions in the differentiation, maintenance and remodeling of tissues during development and regeneration, and it undergoes dynamic chang-es during remodeling concomitant to alterations in the cell-ECM interactions. Here we discuss recent data addressing the critical role of the widely expressed ECM protein, matrilin-2 (Matn2) in the timely onset of differentiation and regeneration processes in myogenic, neural and other tissues and in tumorigenesis. As a multiadhesion adaptor protein, it interacts with other ECM proteins and integrins. Matn2 promotes neurite outgrowth, Schwann cell migration, neuromuscular junc-tion formation, skeletal muscle and liver regeneration and skin wound healing. Matn2 deposition by myoblasts is crucial for the timely induction of the global switch toward terminal myogenic differentiation during muscle regeneration by affecting transforming growth factor beta/bone morphogenetic protein 7/Smad and other signal transduction pathways. Depending on the type of tissue and the pathomechanism, Matn2 can also promote or suppress tumor growth.

  19. The Pch2 AAA+ ATPase promotes phosphorylation of the Hop1 meiotic checkpoint adaptor in response to synaptonemal complex defects

    Science.gov (United States)

    Herruzo, Esther; Ontoso, David; González-Arranz, Sara; Cavero, Santiago; Lechuga, Ana; San-Segundo, Pedro A.

    2016-01-01

    Meiotic cells possess surveillance mechanisms that monitor critical events such as recombination and chromosome synapsis. Meiotic defects resulting from the absence of the synaptonemal complex component Zip1 activate a meiosis-specific checkpoint network resulting in delayed or arrested meiotic progression. Pch2 is an evolutionarily conserved AAA+ ATPase required for the checkpoint-induced meiotic block in the zip1 mutant, where Pch2 is only detectable at the ribosomal DNA array (nucleolus). We describe here that high levels of the Hop1 protein, a checkpoint adaptor that localizes to chromosome axes, suppress the checkpoint defect of a zip1 pch2 mutant restoring Mek1 activity and meiotic cell cycle delay. We demonstrate that the critical role of Pch2 in this synapsis checkpoint is to sustain Mec1-dependent phosphorylation of Hop1 at threonine 318. We also show that the ATPase activity of Pch2 is essential for its checkpoint function and that ATP binding to Pch2 is required for its localization. Previous work has shown that Pch2 negatively regulates Hop1 chromosome abundance during unchallenged meiosis. Based on our results, we propose that, under checkpoint-inducing conditions, Pch2 also possesses a positive action on Hop1 promoting its phosphorylation and its proper distribution on unsynapsed chromosome axes. PMID:27257060

  20. Positive and negative regulation of FcepsilonRI-mediated signaling by the adaptor protein LAB/NTAL.

    Science.gov (United States)

    Zhu, Minghua; Liu, Yan; Koonpaew, Surapong; Granillo, Olivia; Zhang, Weiguo

    2004-10-18

    Linker for activation of B cells (LAB, also called NTAL; a product of wbscr5 gene) is a newly identified transmembrane adaptor protein that is expressed in B cells, NK cells, and mast cells. Upon BCR activation, LAB is phosphorylated and interacts with Grb2. LAB is capable of rescuing thymocyte development in LAT-deficient mice. To study the in vivo function of LAB, LAB-deficient mice were generated. Although disruption of the Lab gene did not affect lymphocyte development, it caused mast cells to be hyperresponsive to stimulation via the FcepsilonRI, evidenced by enhanced Erk activation, calcium mobilization, degranulation, and cytokine production. These data suggested that LAB negatively regulates mast cell function. However, mast cells that lacked both linker for activation of T cells (LAT) and LAB proteins had a more severe block in FcepsilonRI-mediated signaling than LAT(-/-) mast cells, demonstrating that LAB also shares a redundant function with LAT to play a positive role in FcepsilonRI-mediated signaling.

  1. A Cyclic di-GMP-binding Adaptor Protein Interacts with Histidine Kinase to Regulate Two-component Signaling.

    Science.gov (United States)

    Xu, Linghui; Venkataramani, Prabhadevi; Ding, Yichen; Liu, Yang; Deng, Yinyue; Yong, Grace Lisi; Xin, Lingyi; Ye, Ruijuan; Zhang, Lianhui; Yang, Liang; Liang, Zhao-Xun

    2016-07-29

    The bacterial messenger cyclic di-GMP (c-di-GMP) binds to a diverse range of effectors to exert its biological effect. Despite the fact that free-standing PilZ proteins are by far the most prevalent c-di-GMP effectors known to date, their physiological function and mechanism of action remain largely unknown. Here we report that the free-standing PilZ protein PA2799 from the opportunistic pathogen Pseudomonas aeruginosa interacts directly with the hybrid histidine kinase SagS. We show that PA2799 (named as HapZ: histidine kinase associated PilZ) binds directly to the phosphoreceiver (REC) domain of SagS, and that the SagS-HapZ interaction is further enhanced at elevated c-di-GMP concentration. We demonstrate that binding of HapZ to SagS inhibits the phosphotransfer between SagS and the downstream protein HptB in a c-di-GMP-dependent manner. In accordance with the role of SagS as a motile-sessile switch and biofilm growth factor, we show that HapZ impacts surface attachment and biofilm formation most likely by regulating the expression of a large number of genes. The observations suggest a previously unknown mechanism whereby c-di-GMP mediates two-component signaling through a PilZ adaptor protein. PMID:27231351

  2. The cytoskeleton adaptor protein ankyrin-1 is upregulated by p53 following DNA damage and alters cell migration.

    Science.gov (United States)

    Hall, A E; Lu, W-T; Godfrey, J D; Antonov, A V; Paicu, C; Moxon, S; Dalmay, T; Wilczynska, A; Muller, P A J; Bushell, M

    2016-01-01

    The integrity of the genome is maintained by a host of surveillance and repair mechanisms that are pivotal for cellular function. The tumour suppressor protein p53 is a major component of the DNA damage response pathway and plays a vital role in the maintenance of cell-cycle checkpoints. Here we show that a microRNA, miR-486, and its host gene ankyrin-1 (ANK1) are induced by p53 following DNA damage. Strikingly, the cytoskeleton adaptor protein ankyrin-1 was induced over 80-fold following DNA damage. ANK1 is upregulated in response to a variety of DNA damage agents in a range of cell types. We demonstrate that miR-486-5p is involved in controlling G1/S transition following DNA damage, whereas the induction of the ankyrin-1 protein alters the structure of the actin cytoskeleton and sustains limited cell migration during DNA damage. Importantly, we found that higher ANK1 expression correlates with decreased survival in cancer patients. Thus, these observations highlight ANK1 as an important effector downstream of the p53 pathway. PMID:27054339

  3. Hippo Stabilises Its Adaptor Salvador by Antagonising the HECT Ubiquitin Ligase Herc4.

    Directory of Open Access Journals (Sweden)

    Birgit L Aerne

    Full Text Available Signalling through the Hippo (Hpo pathway involves a kinase cascade, which leads to the phosphorylation and inactivation of the pro-growth transcriptional co-activator Yorkie (Yki. Despite the identification of a large number of pathway members and modulators, our understanding of the molecular events that lead to activation of Hpo and the downstream kinase Warts (Wts remain incomplete. Recently, targeted degradation of several Hpo pathway components has been demonstrated as a means of regulating pathway activity. In particular, the stability of scaffold protein Salvador (Sav, which is believed to promote Hpo/Wts association, is crucially dependent on its binding partner Hpo. In a cell-based RNAi screen for ubiquitin regulators involved in Sav stability, we identify the HECT domain protein Herc4 (HECT and RLD domain containing E3 ligase as a Sav E3 ligase. Herc4 expression promotes Sav ubiquitylation and degradation, while Herc4 depletion stabilises Sav. Interestingly, Hpo reduces Sav/Herc4 interaction in a kinase-dependent manner. This suggests the existence of a positive feedback loop, where Hpo stabilises its own positive regulator by antagonising Herc4-mediated degradation of Sav.

  4. CD2v Interacts with Adaptor Protein AP-1 during African Swine Fever Infection.

    Directory of Open Access Journals (Sweden)

    Daniel Pérez-Núñez

    Full Text Available African swine fever virus (ASFV CD2v protein is believed to be involved in virulence enhancement, viral hemadsorption, and pathogenesis, although the molecular mechanisms of the function of this viral protein are still not fully understood. Here we describe that CD2v localized around viral factories during ASFV infection, suggesting a role in the generation and/or dynamics of these viral structures and hence in disturbing cellular traffic. We show that CD2v targeted the regulatory trans-Golgi network (TGN protein complex AP-1, a key element in cellular traffic. This interaction was disrupted by brefeldin A even though the location of CD2v around the viral factory remained unchanged. CD2v-AP-1 binding was independent of CD2v glycosylation and occurred on the carboxy-terminal part of CD2v, where a canonical di-Leu motif previously reported to mediate AP-1 binding in eukaryotic cells, was identified. This motif was shown to be functionally interchangeable with the di-Leu motif present in HIV-Nef protein in an AP-1 binding assay. However, we demonstrated that it was not involved either in CD2v cellular distribution or in CD2v-AP-1 binding. Taken together, these findings shed light on CD2v function during ASFV infection by identifying AP-1 as a cellular factor targeted by CD2v and hence elucidate the cellular pathways used by the virus to enhance infectivity.

  5. Revisiting the Timing of Action of the PAG Adaptor Using Quantitative Proteomics Analysis of Primary T Cells.

    Science.gov (United States)

    Reginald, Kavita; Chaoui, Karima; Roncagalli, Romain; Beau, Mathilde; Goncalves Menoita, Marisa; Monsarrat, Bernard; Burlet-Schiltz, Odile; Malissen, Marie; Gonzalez de Peredo, Anne; Malissen, Bernard

    2015-12-01

    The protein tyrosine kinase LCK plays a key role in TCR signaling, and its activity is dynamically controlled by the tyrosine kinase C-terminal Src kinase (CSK) and the tyrosine phosphatase CD45. CSK is brought in contiguity to LCK via binding to a transmembrane adaptor known as phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG). The lack of a blatant phenotype in PAG-deficient mice has impeded our understanding of the mechanisms through which PAG exerts its negative-regulatory role in TCR signaling. We used quantitative mass spectrometry and both thymocytes and CD4(+) T cells from mice in which a tag for affinity purification was knocked in the gene coding for PAG to determine the composition and dynamics of the multiprotein complexes that are found around PAG over 5 min of activation. Most of the high-confidence interactions that we observed were previously unknown. Using phosphoproteomic analysis, PAG showed low levels of tyrosine phosphorylation in resting primary mouse CD4(+) T cells; the levels of tyrosine phosphorylation increased and reached a maximum 2 min after stimulation. Analysis of the dynamics of association of the protein tyrosine phosphatase PTPN22 and lipid phosphatase SHIP-1 with PAG following T cell activation suggests that both cooperate with CSK to terminate T cell activation. Our findings provide a model of the role for PAG in mouse primary CD4(+) T cells that is consistent with recent phosphoproteomic studies of the Jurkat T cell line but difficult to reconcile with former biochemical studies indicating that PAG is constitutively phosphorylated in resting T cells and rapidly dephosphorylated once the TCR is engaged. PMID:26512138

  6. CRM1 and its ribosome export adaptor NMD3 localize to the nucleolus and affect rRNA synthesis.

    Science.gov (United States)

    Bai, Baoyan; Moore, Henna M; Laiho, Marikki

    2013-01-01

    CRM1 is an export factor that together with its adaptor NMD3 transports numerous cargo molecules from the nucleus to cytoplasm through the nuclear pore. Previous studies have suggested that CRM1 and NMD3 are detected in the nucleolus. However, their localization with subnucleolar domains or participation in the activities of the nucleolus are unclear. We demonstrate here biochemically and using imaging analyses that CRM1 and NMD3 co-localize with nucleolar marker proteins in the nucleolus. In particular, their nucleolar localization is markedly increased by inhibition of RNA polymerase I (Pol I) transcription by actinomycin D or by silencing Pol I catalytic subunit, RPA194. We show that CRM1 nucleolar localization is dependent on its activity and the expression of NMD3, whereas NMD3 nucleolar localization is independent of CRM1. This suggests that NMD3 provides nucleolar tethering of CRM1. While inhibition of CRM1 by leptomycin B inhibited processing of 28S ribosomal (r) RNA, depletion of NMD3 did not, suggesting that their effects on 28S rRNA processing are distinct. Markedly, depletion of NMD3 and inhibition of CRM1 reduced the rate of pre-47S rRNA synthesis. However, their inactivation did not lead to nucleolar disintegration, a hallmark of Pol I transcription stress, suggesting that they do not directly regulate transcription. These results indicate that CRM1 and NMD3 have complex functions in pathways that couple rRNA synthetic and processing engines and that the rRNA synthesis rate may be adjusted according to proficiency in rRNA processing and export.

  7. The adaptor molecule Nck localizes the WAVE complex to promote actin polymerization during CEACAM3-mediated phagocytosis of bacteria.

    Directory of Open Access Journals (Sweden)

    Stefan Pils

    Full Text Available BACKGROUND: CEACAM3 is a granulocyte receptor mediating the opsonin-independent recognition and phagocytosis of human-restricted CEACAM-binding bacteria. CEACAM3 function depends on an intracellular immunoreceptor tyrosine-based activation motif (ITAM-like sequence that is tyrosine phosphorylated by Src family kinases upon receptor engagement. The phosphorylated ITAM-like sequence triggers GTP-loading of Rac by directly associating with the guanine nucleotide exchange factor (GEF Vav. Rac stimulation in turn is critical for actin cytoskeleton rearrangements that generate lamellipodial protrusions and lead to bacterial uptake. PRINCIPAL FINDINGS: In our present study we provide biochemical and microscopic evidence that the adaptor proteins Nck1 and Nck2, but not CrkL, Grb2 or SLP-76, bind to tyrosine phosphorylated CEACAM3. The association is phosphorylation-dependent and requires the Nck SH2 domain. Overexpression of the isolated Nck1 SH2 domain, RNAi-mediated knock-down of Nck1, or genetic deletion of Nck1 and Nck2 interfere with CEACAM3-mediated bacterial internalization and with the formation of lamellipodial protrusions. Nck is constitutively associated with WAVE2 and directs the actin nucleation promoting WAVE complex to tyrosine phosphorylated CEACAM3. In turn, dominant-negative WAVE2 as well as shRNA-mediated knock-down of WAVE2 or the WAVE-complex component Nap1 reduce internalization of bacteria. CONCLUSIONS: Our results provide novel mechanistic insight into CEACAM3-initiated phagocytosis. We suggest that the CEACAM3 ITAM-like sequence is optimized to co-ordinate a minimal set of cellular factors needed to efficiently trigger actin-based lamellipodial protrusions and rapid pathogen engulfment.

  8. Dephosphorylation of the adaptor LAT and phospholipase C-γ by SHP-1 inhibits natural killer cell cytotoxicity.

    Science.gov (United States)

    Matalon, Omri; Fried, Sophia; Ben-Shmuel, Aviad; Pauker, Maor H; Joseph, Noah; Keizer, Danielle; Piterburg, Marina; Barda-Saad, Mira

    2016-01-01

    Natural killer (NK) cells discriminate between healthy cells and virally infected or transformed self-cells by tuning activating and inhibitory signals received through cell surface receptors. Inhibitory receptors inhibit NK cell function by recruiting and activating the tyrosine phosphatase Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-1 (SHP-1) to the plasma membrane. However, to date, the guanine nucleotide exchange factor VAV1 is the only direct SHP-1 substrate identified in NK cells. We reveal that the adaptor protein linker for activation of T cells (LAT) as well as phospholipase C-γ1 (PLC-γ1) and PLC-γ2 are SHP-1 substrates. Dephosphorylation of Tyr(132) in LAT by SHP-1 in NK cells abrogated the recruitment of PLC-γ1 and PLC-γ2 to the immunological synapse between the NK cell and a cancer cell target, which reduced NK cell degranulation and target cell killing. Furthermore, the ubiquitylation of LAT by the E3 ubiquitin ligases c-Cbl and Cbl-b, which was induced by LAT phosphorylation, led to the degradation of LAT in response to the engagement of inhibitory receptors on NK cells, which abrogated NK cell cytotoxicity. Knockdown of the Cbl proteins blocked LAT ubiquitylation, which promoted NK cell function. Expression of a ubiquitylation-resistant mutant LAT blocked inhibitory receptor signaling, enabling cells to become activated. Together, these data identify previously uncharacterized SHP-1 substrates and inhibitory mechanisms that determine the response of NK cells. PMID:27221712

  9. A transgenic Drosophila model demonstrates that the Helicobacter pylori CagA protein functions as a eukaryotic Gab adaptor.

    Directory of Open Access Journals (Sweden)

    Crystal M Botham

    2008-05-01

    Full Text Available Infection with the human gastric pathogen Helicobacter pylori is associated with a spectrum of diseases including gastritis, peptic ulcers, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. The cytotoxin-associated gene A (CagA protein of H. pylori, which is translocated into host cells via a type IV secretion system, is a major risk factor for disease development. Experiments in gastric tissue culture cells have shown that once translocated, CagA activates the phosphatase SHP-2, which is a component of receptor tyrosine kinase (RTK pathways whose over-activation is associated with cancer formation. Based on CagA's ability to activate SHP-2, it has been proposed that CagA functions as a prokaryotic mimic of the eukaryotic Grb2-associated binder (Gab adaptor protein, which normally activates SHP-2. We have developed a transgenic Drosophila model to test this hypothesis by investigating whether CagA can function in a well-characterized Gab-dependent process: the specification of photoreceptors cells in the Drosophila eye. We demonstrate that CagA expression is sufficient to rescue photoreceptor development in the absence of the Drosophila Gab homologue, Daughter of Sevenless (DOS. Furthermore, CagA's ability to promote photoreceptor development requires the SHP-2 phosphatase Corkscrew (CSW. These results provide the first demonstration that CagA functions as a Gab protein within the tissue of an organism and provide insight into CagA's oncogenic potential. Since many translocated bacterial proteins target highly conserved eukaryotic cellular processes, such as the RTK signaling pathway, the transgenic Drosophila model should be of general use for testing the in vivo function of bacterial effector proteins and for identifying the host genes through which they function.

  10. The membrane-associated adaptor protein DOK5 is upregulated in systemic sclerosis and associated with IGFBP-5-induced fibrosis.

    Directory of Open Access Journals (Sweden)

    Hidekata Yasuoka

    Full Text Available Systemic sclerosis (SSc is characterized by excessive fibrosis of the skin and internal organs due to fibroblast proliferation and excessive production of extracellular matrix (ECM. We have shown that insulin-like growth factor binding protein (IGFBP-5 plays an important role in the development of fibrosis in vitro, ex vivo, and in vivo. We identified a membrane-associated adaptor protein, downstream of tyrosine kinase/docking protein (DOK5, as an IGFBP-5-regulated target gene using gene expression profiling of primary fibroblasts expressing IGFBP-5. DOK5 is a tyrosine kinase substrate associated with intracellular signaling. Our objective was to determine the role of DOK5 in the pathogenesis of SSc and specifically in IGFBP-5-induced fibrosis. DOK5 mRNA and protein levels were increased in vitro by endogenous and exogenous IGFBP-5 in primary human fibroblasts. DOK5 upregulation required activation of the mitogen-activated protein kinase (MAPK signaling cascade. Further, IGFBP-5 triggered nuclear translocation of DOK5. DOK5 protein levels were also increased in vivo in mouse skin and lung by IGFBP-5. To determine the effect of DOK5 on fibrosis, DOK5 was expressed ex vivo in human skin in organ culture. Expression of DOK5 in human skin resulted in a significant increase in dermal thickness. Lastly, levels of DOK5 were compared in primary fibroblasts and lung tissues of patients with SSc and healthy donors. Both DOK5 mRNA and protein levels were significantly increased in fibroblasts and skin tissues of patients with SSc compared with those of healthy controls, as well as in lung tissues of SSc patients. Our findings suggest that IGFBP-5 induces its pro-fibrotic effects, at least in part, via DOK5. Furthermore, IGFBP-5 and DOK5 are both increased in SSc fibroblasts and tissues and may thus be acting in concert to promote fibrosis.

  11. The adaptor CARD9 is required for adaptive but not innate immunity to oral mucosal Candida albicans infections.

    Science.gov (United States)

    Bishu, Shrinivas; Hernández-Santos, Nydiaris; Simpson-Abelson, Michelle R; Huppler, Anna R; Conti, Heather R; Ghilardi, Nico; Mamo, Anna J; Gaffen, Sarah L

    2014-03-01

    Oropharyngeal candidiasis (OPC [thrush]) is an opportunistic infection caused by the commensal fungus Candida albicans. OPC is common in individuals with HIV/AIDS, infants, patients on chemotherapy, and individuals with congenital immune defects. Immunity to OPC is strongly dependent on the interleukin-23 (IL-23)/IL-17R axis, as mice and humans with defects in IL-17R signaling (IL17F, ACT1, IL-17RA) or in genes that direct Th17 differentiation (STAT3, STAT1, CARD9) are prone to mucocutaneous candidiasis. Conventional Th17 cells are induced in response to C. albicans infection via signals from C-type lectin receptors, which signal through the adaptor CARD9, leading to production of Th17-inducing cytokines such as IL-6, IL-1β, and IL-23. Recent data indicate that IL-17 can also be made by numerous innate cell subsets. These innate "type 17" cells resemble conventional Th17 cells, but they can be activated without need for prior antigen exposure. Because C. albicans is not a commensal organism in rodents and mice are thus naive to this fungus, we had the opportunity to assess the role of CARD9 in innate versus adaptive responses using an OPC infection model. As expected, CARD9(-/-) mice failed to mount an adaptive Th17 response following oral Candida infection. Surprisingly, however, CARD9(-/-) mice had preserved innate IL-17-dependent responses to Candida and were almost fully resistant to OPC. Thus, CARD9 is important primarily for adaptive immunity to C. albicans, whereas alternate recognition systems appear to be needed for effective innate responses. PMID:24379290

  12. Palmitoylation of protease-activated receptor-1 regulates adaptor protein complex-2 and -3 interaction with tyrosine-based motifs and endocytic sorting.

    Science.gov (United States)

    Canto, Isabel; Trejo, JoAnn

    2013-05-31

    Protease-activated receptor-1 (PAR1) is a G protein-coupled receptor for the coagulant protease thrombin. Thrombin binds to and cleaves the N terminus of PAR1, generating a new N terminus that functions as a tethered ligand that cannot diffuse away. In addition to rapid desensitization, PAR1 trafficking is critical for the regulation of cellular responses. PAR1 displays constitutive and agonist-induced internalization. Constitutive internalization of unactivated PAR1 is mediated by the clathrin adaptor protein complex-2 (AP-2), which binds to a distal tyrosine-based motif localized within the C-terminal tail (C-tail) domain. Once internalized, PAR1 is sorted from endosomes to lysosomes via AP-3 interaction with a second C-tail tyrosine motif proximal to the transmembrane domain. However, the regulatory processes that control adaptor protein recognition of PAR1 C-tail tyrosine-based motifs are not known. Here, we report that palmitoylation of PAR1 is critical for regulating proper utilization of tyrosine-based motifs and endocytic sorting. We show that PAR1 is basally palmitoylated at highly conserved C-tail cysteines. A palmitoylation-deficient PAR1 mutant is competent to signal and exhibits a marked increase in constitutive internalization and lysosomal degradation compared with wild type receptor. Intriguingly, enhanced constitutive internalization of PAR1 is mediated by AP-2 and requires the proximal tyrosine-based motif rather than the distal tyrosine motif used by wild type receptor. Moreover, palmitoylation-deficient PAR1 displays increased degradation that is mediated by AP-3. These findings suggest that palmitoylation of PAR1 regulates appropriate utilization of tyrosine-based motifs by adaptor proteins and endocytic trafficking, processes that are critical for maintaining appropriate expression of PAR1 at the cell surface. PMID:23580642

  13. Development of novel on-chip, customer-design spiral biasing adaptor on for Si drift detectors and detector arrays for X-ray and nuclear physics experiments

    Energy Technology Data Exchange (ETDEWEB)

    Li, Zheng, E-mail: lizheng@xtu.edu.cn [School of Materials, Optoelectronics and Physics, Xiangtan University, Xiangtan, Hunan 411105 (China); Chen, Wei [Brookhaven National Laboratory, Upton, NY 11973 (United States)

    2014-11-21

    A novel on-chip, customer-design spiral biasing adaptor (SBA) has been developed. A single SBA is used for biasing a Si drift detector (SDD) and SDD array. The use of an SBA reduces the biasing current. This paper shows the calculation of the geometry of an SBA and an SDD to get the best drift field in the SDD and SDD array. Prototype SBAs have been fabricated to verify the concept. Electrical measurements on these SBAs are in agreement with the expectations. The new SDD array with an SBA can be used for X-ray detection and in nuclear physics experiments.

  14. The Adaptor Protein Myd88 Is a Key Signaling Molecule in the Pathogenesis of Irinotecan-Induced Intestinal Mucositis.

    Directory of Open Access Journals (Sweden)

    Deysi V T Wong

    Full Text Available Intestinal mucositis is a common side effect of irinotecan-based anticancer regimens. Mucositis causes cell damage, bacterial/endotoxin translocation and production of cytokines including IL-1 and IL-18. These molecules and toll-like receptors (TLRs activate a common signaling pathway that involves the Myeloid Differentiation adaptor protein, MyD88, whose role in intestinal mucositis is unknown. Then, we evaluated the involvement of TLRs and MyD88 in the pathogenesis of irinotecan-induced intestinal mucositis. MyD88-, TLR2- or TLR9-knockout mice and C57BL/6 (WT mice were given either saline or irinotecan (75 mg/kg, i.p. for 4 days. On day 7, animal survival, diarrhea and bacteremia were assessed, and following euthanasia, samples of the ileum were obtained for morphometric analysis, myeloperoxidase (MPO assay and measurement of pro-inflammatory markers. Irinotecan reduced the animal survival (50% and induced a pronounced diarrhea, increased bacteremia, neutrophil accumulation in the intestinal tissue, intestinal damage and more than twofold increased expression of MyD88 (200%, TLR9 (400%, TRAF6 (236%, IL-1β (405%, IL-18 (365%, COX-2 (2,777% and NF-κB (245% in the WT animals when compared with saline-injected group (P<0.05. Genetic deletion of MyD88, TLR2 or TLR9 effectively controlled the signs of intestinal injury when compared with irinotecan-administered WT controls (P<0.05. In contrast to the MyD88-/- and TLR2-/- mice, the irinotecan-injected TLR9-/- mice showed a reduced survival, a marked diarrhea and an enhanced expression of IL-18 versus irinotecan-injected WT controls. Additionally, the expression of MyD88 was reduced in the TLR2-/- or TLR9-/- mice. This study shows a critical role of the MyD88-mediated TLR2 and TLR9 signaling in the pathogenesis of irinotecan-induced intestinal mucositis.

  15. Structural and Functional Characterization of Cargo-Binding Sites on the μ4-Subunit of Adaptor Protein Complex 4

    Science.gov (United States)

    Ross, Breyan H.; Lin, Yimo; Corales, Esteban A.; Burgos, Patricia V.; Mardones, Gonzalo A.

    2014-01-01

    Adaptor protein (AP) complexes facilitate protein trafficking by playing key roles in the selection of cargo molecules to be sorted in post-Golgi compartments. Four AP complexes (AP-1 to AP-4) contain a medium-sized subunit (μ1-μ4) that recognizes YXXØ-sequences (Ø is a bulky hydrophobic residue), which are sorting signals in transmembrane proteins. A conserved, canonical region in μ subunits mediates recognition of YXXØ-signals by means of a critical aspartic acid. Recently we found that a non-canonical YXXØ-signal on the cytosolic tail of the Alzheimer's disease amyloid precursor protein (APP) binds to a distinct region of the μ4 subunit of the AP-4 complex. In this study we aimed to determine the functionality of both binding sites of μ4 on the recognition of the non-canonical YXXØ-signal of APP. We found that substitutions in either binding site abrogated the interaction with the APP-tail in yeast-two hybrid experiments. Further characterization by isothermal titration calorimetry showed instead loss of binding to the APP signal with only the substitution R283D at the non-canonical site, in contrast to a decrease in binding affinity with the substitution D190A at the canonical site. We solved the crystal structure of the C-terminal domain of the D190A mutant bound to this non-canonical YXXØ-signal. This structure showed no significant difference compared to that of wild-type μ4. Both differential scanning fluorimetry and limited proteolysis analyses demonstrated that the D190A substitution rendered μ4 less stable, suggesting an explanation for its lower binding affinity to the APP signal. Finally, in contrast to overexpression of the D190A mutant, and acting in a dominant-negative manner, overexpression of μ4 with either a F255A or a R283D substitution at the non-canonical site halted APP transport at the Golgi apparatus. Together, our analyses support that the functional recognition of the non-canonical YXXØ-signal of APP is limited to the non

  16. TLR adaptor MyD88 is essential for pathogen control during oral toxoplasma gondii infection but not adaptive immunity induced by a vaccine strain of the parasite.

    Science.gov (United States)

    Sukhumavasi, Woraporn; Egan, Charlotte E; Warren, Amy L; Taylor, Gregory A; Fox, Barbara A; Bzik, David J; Denkers, Eric Y

    2008-09-01

    TLR adaptor MyD88 activation is important in host resistance to Toxoplasma gondii during i.p. infection, but the function of this signaling pathway during oral infection, in which mucosal immunity assumes a predominant role, has not been examined. In this study, we show that MyD88(-/-) mice fail to control the parasite and succumb within 2 wk of oral infection. Early during infection, T cell IFN-gamma production, recruitment of neutrophils and induction of p47 GTPase IGTP (Irgm3) in the intestinal mucosa were dependent upon functional MyD88. Unexpectedly, these responses were MyD88-independent later during acute infection. In particular, CD4(+) T cell IFN-gamma reached normal levels independently of MyD88, despite continued absence of IL-12 in these animals. The i.p. vaccination of MyD88(-/-) mice with an avirulent T. gondii uracil auxotroph elicited robust IFN-gamma responses and protective immunity to challenge with a high virulence T. gondii strain. Our results demonstrate that MyD88 is required to control Toxoplasma infection, but that the parasite can trigger adaptive immunity without the need for this TLR adaptor molecule. PMID:18714019

  17. Phosphorylation of APP-CTF-AICD domains and interaction with adaptor proteins: signal transduction and/or transcriptional role--relevance for Alzheimer pathology.

    Science.gov (United States)

    Schettini, Gennaro; Govoni, Stefano; Racchi, Marco; Rodriguez, Guido

    2010-12-01

    In recent decades, the study of the amyloid precursor protein (APP) and of its proteolytic products carboxy terminal fragment (CTF), APP intracellular C-terminal domain (AICD) and amyloid beta has been mostly focussed on the role of APP as a producer of the toxic amyloid beta peptide. Here, we reconsider the role of APP suggesting, in a provocative way, the protein as a central player in a putative signalling pathway. We highlight the presence in the cytosolic tail of APP of the YENPTY motif which is typical of tyrosine kinase receptors, the phosphorylation of the tyrosine, serine and threonine residues, the kinases involved and the interaction with intracellular adaptor proteins. In particular, we examine the interaction with Shc and Grb2 regulators, which through the activation of Ras proteins elicit downstream signalling events such as the MAPK pathway. The review also addresses the interaction of APP, CTFs and AICD with other adaptor proteins and in particular with Fe65 for nuclear transcriptional activity and the importance of phosphorylation for sorting the secretases involved in the amyloidogenic or non-amyloidogenic pathways. We provide a novel perspective on Alzheimer's disease pathogenesis, focussing on the perturbation of the physiological activities of APP-CTFs and AICD as an alternative perspective from that which normally focuses on the accumulation of neurotoxic proteolytic fragments. PMID:21039524

  18. Differential association of the Na+/H+ exchanger regulatory factor (NHERF) family of adaptor proteins with the raft- and the non-raft brush border membrane fractions of NHE3

    NARCIS (Netherlands)

    A. Sultan (Ayesha); M. Luo (Ma); Q. Yu (Qingbao); B. Riederer (Beat Michel); W. Xia (Weiliang); M. Chen (Mingmin); S. Lissner (Simone); J.E. Gessner (Johannes); M. Donowitz (Mark); C. Chris Yun (C.); H. deJonge (Hugo); G. Lamprecht (Georg); U. Seidler (Ursula)

    2013-01-01

    textabstractBackground/Aims: Trafficking, brush border membrane (BBM) retention, and signal-specific regulation of the Na+/H+ exchanger NHE3 is regulated by the Na+/H+ Exchanger Regulatory Factor (NHERF) family of PDZ-adaptor proteins, which enable the formation of multiprotein complexes. It is uncl

  19. Molecular characterization of transgenic shallots (Allium cepa L.) by adaptor ligation PCR (AL-PCR) and sequencing of genomic DNA flanking T-DNA borders

    NARCIS (Netherlands)

    Zheng, S.J.; Henken, G.; Sofiari, E.; Jacobsen, E.; Krens, F.A.

    2001-01-01

    Genomic DNA blot hybridization is traditionally used to demonstrate that, via genetic transformation, foreign genes are integrated into host genomes. However, in large genome species, such as Allium cepa L., the use of genomic DNA blot hybridization is pushed towards its limits, because a considerab

  20. Expression of the neuronal adaptor protein X11alpha protects against memory dysfunction in a transgenic mouse model of Alzheimer's disease.

    LENUS (Irish Health Repository)

    Mitchell, Jacqueline C

    2010-01-01

    X11alpha is a neuronal-specific adaptor protein that binds to the amyloid-beta protein precursor (AbetaPP). Overexpression of X11alpha reduces Abeta production but whether X11alpha also protects against Abeta-related memory dysfunction is not known. To test this possibility, we crossed X11alpha transgenic mice with AbetaPP-Tg2576 mice. AbetaPP-Tg2576 mice produce high levels of brain Abeta and develop age-related defects in memory function that correlate with increasing Abeta load. Overexpression of X11alpha alone had no detectable adverse effect upon behavior. However, X11alpha reduced brain Abeta levels and corrected spatial reference memory defects in aged X11alpha\\/AbetaPP double transgenics. Thus, X11alpha may be a therapeutic target for Alzheimer\\'s disease.

  1. RECOMBINANT FLUORESCENT SENSOR OF HYDROGEN PEROXIDE HyPer FUSED WITH ADAPTOR PROTEIN Ruk/CIN85: DESIGNING OF EXPRESSION VECTOR AND ITS FUNCTIONAL CHARACTERIZATION

    Directory of Open Access Journals (Sweden)

    А. V. Bazalii

    2015-10-01

    Full Text Available The aim of this study was to design the expression vector encoding fluorescent sensor of hydrogen peroxide HyPer fused with adaptor protein Ruk/CIN85 as well as to check its subcellular distribution and ability to sense hydrogen peroxide. It was demonstrated that in transiently transfected HEK293 and MCF-7 cells Ruk/CIN85-HyPer is concentrated in dot-like vesicular structures of different size while HyPer is diffusely distributed throughout the cell. Using live cell fluorescence microscopy we observed gradual increase in hydrogen peroxide concentration in representative vesicular structures during the time of experiment. Thus, the developed genetic construction encoding the chimeric Ruk/CIN85-HyPer fluorescent protein represents a new tool to study localized H2O2 production in living cells.

  2. RTK SLAP down: the emerging role of Src-like adaptor protein as a key player in receptor tyrosine kinase signaling.

    Science.gov (United States)

    Wybenga-Groot, Leanne E; McGlade, C Jane

    2015-02-01

    SLAP (Src like adaptor protein) contains adjacent Src homology 3 (SH3) and Src homology 2 (SH2) domains closely related in sequence to that of cytoplasmic Src family tyrosine kinases. Expressed most abundantly in the immune system, SLAP function has been predominantly studied in the context of lymphocyte signaling, where it functions in the Cbl dependent downregulation of antigen receptor signaling. However, accumulating evidence suggests that SLAP plays a role in the regulation of a broad range of membrane receptors including members of the receptor tyrosine kinase (RTK) family. In this review we highlight the role of SLAP in the ubiquitin dependent regulation of type III RTKs PDGFR, CSF-1R, KIT and Flt3, as well as Eph family RTKs. SLAP appears to bind activated type III and Eph RTKs via a conserved autophosphorylated juxtamembrane tyrosine motif in an SH2-dependent manner, suggesting that SLAP is important in regulating RTK signaling.

  3. Crk adaptor protein-induced phosphorylation of Gab1 on tyrosine 307 via Src is important for organization of focal adhesions and enhanced cell migration

    Institute of Scientific and Technical Information of China (English)

    Takuya Watanabe; Masumi Tsuda; Yoshinori Makino; Tassos Konstantinou; Hiroshi Nishihara; Tokifumi Majima; Akio Minami; Stephan M Feller; Shinya Tanaka

    2009-01-01

    Upon growth factor stimulation, the scaffold protein, Gabl, is tyrosine phosphorylated and subsequently the adaptor protein, Crk, transmits signals from Gabl. We have previously shown that Crk overexpression, which is detectable in various human cancers, induces tyrosine phosphorylation of Gab1 without extraceilular stimuli. In the present study, the underlying mechanisms were further investigated. Mutational analyses of Crkll demonstrated that the SH2 domain, but not the SH3(N) or the regulatory Y221 residue of Crkll, is critical for the induction of Gabl-Y307 phosphorylation. SH2 mutation of Crkll also decreased the interaction with Gab1. In GST pull-down assay, Crk-SH2 bound to wild-type Gabl, whereas Crk-SH3(N) interacted with the Gabl mutant, which lacks the clus-tered tyrosine region (residues 242-410). Tyrosine phosphorylation of Gabl was induced by all Crk family proteins, but not other SH2-containing signalling adaptors. Src-family kinase inhibitor, PP2, abrogates Crk-induced tyrosine phosphorylations of Gabl. Y307 phosphorylation was undetectable in fibroblasts lacking Src, Yes, and Fyn, even upon overexpression of Crk, whereas cells lacking only Yes and Fyn still contained Gabl with phosphorylated Y307. Furthermore, Crk induced the phosphorylation of Src-Y416; accordingly the interaction between Crk and Csk was increased. The GabI-Y307F mutant failed to localize near the plasma membrane even upon HGF stimulation and decreased cell migration. Moreover, Gabl-Y307F disturbed the localization of Crk, FAK, and paxiilin, which are the typical components of focal adhesions. Taken together, these results indicate that Crk facilitates tyrosine phosphory-lation of Gabl-Y307 through Src, contributing to the organization of focal adhesions and enhanced cell migration, thereby possibly promoting human cancer development.

  4. Molecular structure, function, and dynamics of clathrin-mediated membrane traffic.

    Science.gov (United States)

    Kirchhausen, Tom; Owen, David; Harrison, Stephen C

    2014-05-01

    Clathrin is a molecular scaffold for vesicular uptake of cargo at the plasma membrane, where its assembly into cage-like lattices underlies the clathrin-coated pits of classical endocytosis. This review describes the structures of clathrin, major cargo adaptors, and other proteins that participate in forming a clathrin-coated pit, loading its contents, pinching off the membrane as a lattice-enclosed vesicle, and recycling the components. It integrates as much of the structural information as possible at the time of writing into a sketch of the principal steps in coated-pit and coated-vesicle formation.

  5. Molecular physics

    CERN Document Server

    Williams, Dudley

    2013-01-01

    Methods of Experimental Physics, Volume 3: Molecular Physics focuses on molecular theory, spectroscopy, resonance, molecular beams, and electric and thermodynamic properties. The manuscript first considers the origins of molecular theory, molecular physics, and molecular spectroscopy, as well as microwave spectroscopy, electronic spectra, and Raman effect. The text then ponders on diffraction methods of molecular structure determination and resonance studies. Topics include techniques of electron, neutron, and x-ray diffraction and nuclear magnetic, nuclear quadropole, and electron spin reson

  6. The adaptor function of TRAPPC2 in mammalian TRAPPs explains TRAPPC2-associated SEDT and TRAPPC9-associated congenital intellectual disability.

    Directory of Open Access Journals (Sweden)

    Min Zong

    Full Text Available BACKGROUND: The TRAPP (Transport protein particle complex is a conserved protein complex functioning at various steps in vesicle transport. Although yeast has three functionally and structurally distinct forms, TRAPPI, II and III, emerging evidence suggests that mammalian TRAPP complex may be different. Mutations in the TRAPP complex subunit 2 (TRAPPC2 cause X-linked spondyloepiphyseal dysplasia tarda, while mutations in the TRAPP complex subunit 9 (TRAPPC9 cause postnatal mental retardation with microcephaly. The structural interplay between these subunits found in mammalian equivalent of TRAPPI and those specific to TRAPPII and TRAPPIII remains largely unknown and we undertook the present study to examine the interaction between these subunits. Here, we reveal that the mammalian equivalent of the TRAPPII complex is structurally distinct from the yeast counterpart thus leading to insight into mechanism of disease. PRINCIPAL FINDINGS: We analyzed how TRAPPII- or TRAPPIII- specific subunits interact with the six-subunit core complex of TRAPP by co-immunoprecipitation in mammalian cells. TRAPPC2 binds to TRAPPII-specific subunit TRAPPC9, which in turn binds to TRAPPC10. Unexpectedly, TRAPPC2 can also bind to the putative TRAPPIII-specific subunit, TRAPPC8. Endogenous TRAPPC9-positive TRAPPII complex does not contain TRAPPC8, suggesting that TRAPPC2 binds to either TRAPPC9 or TRAPPC8 during the formation of the mammalian equivalents of TRAPPII or TRAPPIII, respectively. Therefore, TRAPPC2 serves as an adaptor for the formation of these complexes. A disease-causing mutation of TRAPPC2, D47Y, failed to interact with either TRAPPC9 or TRAPPC8, suggesting that aspartate 47 in TRAPPC2 is at or near the site of interaction with TRAPPC9 or TRAPPC8, mediating the formation of TRAPPII and/or TRAPPIII. Furthermore, disease-causing deletional mutants of TRAPPC9 all failed to interact with TRAPPC2 and TRAPPC10. CONCLUSIONS: TRAPPC2 serves as an adaptor for the

  7. Human kidney anion exchanger 1 interacts with adaptor-related protein complex 1 {mu}1A (AP-1 mu1A)

    Energy Technology Data Exchange (ETDEWEB)

    Sawasdee, Nunghathai; Junking, Mutita [Division of Medical Molecular Biology and BIOTEC-Medical Biotechnology Unit, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 (Thailand); Ngaojanlar, Piengpaga [Division of Medical Molecular Biology and BIOTEC-Medical Biotechnology Unit, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 (Thailand); Department of Immunology and Graduate Program in Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 (Thailand); Sukomon, Nattakan; Ungsupravate, Duangporn [Division of Medical Molecular Biology and BIOTEC-Medical Biotechnology Unit, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 (Thailand); Limjindaporn, Thawornchai [Division of Medical Molecular Biology and BIOTEC-Medical Biotechnology Unit, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 (Thailand); Department of Anatomy, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 (Thailand); Akkarapatumwong, Varaporn [Institute of Molecular Biosciences, Mahidol University at Salaya Campus, Nakorn Pathom 73170 (Thailand); Noisakran, Sansanee [Division of Medical Molecular Biology and BIOTEC-Medical Biotechnology Unit, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 (Thailand); Yenchitsomanus, Pa-thai, E-mail: grpye@mahidol.ac.th [Division of Medical Molecular Biology and BIOTEC-Medical Biotechnology Unit, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700 (Thailand)

    2010-10-08

    Research highlights: {yields} Trafficking defect of kAE1 is a cause of dRTA but trafficking pathway of kAE1 has not been clearly described. {yields} Adaptor-related protein complex 1 {mu}1A (AP-1 mu1A) was firstly reported to interact with kAE1. {yields} The interacting site for AP-1 mu1A on Ct-kAE1 was found to be Y904DEV907, a subset of YXXO motif. {yields} AP-1 mu1A knockdown showed a marked reduction of kAE1 on the cell membrane and its accumulation in endoplasmic reticulum. {yields} AP-1 mu1A has a critical role in kAE1 trafficking to the plasma membrane. -- Abstract: Kidney anion exchanger 1 (kAE1) mediates chloride (Cl{sup -}) and bicarbonate (HCO{sub 3}{sup -}) exchange at the basolateral membrane of kidney {alpha}-intercalated cells. Impaired trafficking of kAE1 leads to defect of the Cl{sup -}/HCO{sub 3}{sup -} exchange at the basolateral membrane and failure of proton (H{sup +}) secretion at the apical membrane, causing a kidney disease - distal renal tubular acidosis (dRTA). To gain a better insight into kAE1 trafficking, we searched for proteins physically interacting with the C-terminal region of kAE1 (Ct-kAE1), which contains motifs crucial for intracellular trafficking, by a yeast two-hybrid (Y2H) system. An adaptor-related protein complex 1 {mu}1A (AP-1 mu1A) subunit was found to interact with Ct-kAE1. The interaction between either Ct-kAE1 or full-length kAE1 and AP-1 mu1A were confirmed in human embryonic kidney (HEK) 293T by co-immunoprecipitation, affinity co-purification, co-localization, yellow fluorescent protein (YFP)-based protein fragment complementation assay (PCA) and GST pull-down assay. The interacting site for AP-1 mu1A on Ct-kAE1 was found to be Y904DEV907, a subset of YXXO motif. Interestingly, suppression of endogenous AP-1 mu1A in HEK 293T by small interfering RNA (siRNA) decreased membrane localization of kAE1 and increased its intracellular accumulation, suggesting for the first time that AP-1 mu1A is involved in the kAE1

  8. Human kidney anion exchanger 1 interacts with adaptor-related protein complex 1 μ1A (AP-1 mu1A)

    International Nuclear Information System (INIS)

    Research highlights: → Trafficking defect of kAE1 is a cause of dRTA but trafficking pathway of kAE1 has not been clearly described. → Adaptor-related protein complex 1 μ1A (AP-1 mu1A) was firstly reported to interact with kAE1. → The interacting site for AP-1 mu1A on Ct-kAE1 was found to be Y904DEV907, a subset of YXXO motif. → AP-1 mu1A knockdown showed a marked reduction of kAE1 on the cell membrane and its accumulation in endoplasmic reticulum. → AP-1 mu1A has a critical role in kAE1 trafficking to the plasma membrane. -- Abstract: Kidney anion exchanger 1 (kAE1) mediates chloride (Cl-) and bicarbonate (HCO3-) exchange at the basolateral membrane of kidney α-intercalated cells. Impaired trafficking of kAE1 leads to defect of the Cl-/HCO3- exchange at the basolateral membrane and failure of proton (H+) secretion at the apical membrane, causing a kidney disease - distal renal tubular acidosis (dRTA). To gain a better insight into kAE1 trafficking, we searched for proteins physically interacting with the C-terminal region of kAE1 (Ct-kAE1), which contains motifs crucial for intracellular trafficking, by a yeast two-hybrid (Y2H) system. An adaptor-related protein complex 1 μ1A (AP-1 mu1A) subunit was found to interact with Ct-kAE1. The interaction between either Ct-kAE1 or full-length kAE1 and AP-1 mu1A were confirmed in human embryonic kidney (HEK) 293T by co-immunoprecipitation, affinity co-purification, co-localization, yellow fluorescent protein (YFP)-based protein fragment complementation assay (PCA) and GST pull-down assay. The interacting site for AP-1 mu1A on Ct-kAE1 was found to be Y904DEV907, a subset of YXXO motif. Interestingly, suppression of endogenous AP-1 mu1A in HEK 293T by small interfering RNA (siRNA) decreased membrane localization of kAE1 and increased its intracellular accumulation, suggesting for the first time that AP-1 mu1A is involved in the kAE1 trafficking of kidney α-intercalated cells.

  9. Increased abundance of the adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif (APPL1) in patients with obesity and type 2 diabetes: evidence for altered adiponectin signalling

    OpenAIRE

    Holmes, R.M.; Yi, Z; De Filippis, E.; Berria, R.; S. Shahani; P. Sathyanarayana; Sherman, V.; K. Fujiwara; Meyer, C.; Christ-Roberts, C.; Hwang, H; Finlayson, J.; Dong, L. Q.; Mandarino, L. J.; Bajaj, M.

    2011-01-01

    Aims/hypothesis The adiponectin signalling pathway is largely unknown, but recently the adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif (APPL1), has been shown to interact directly with adiponectin receptor (ADIPOR)1. APPL1 is present in C2C12 myoblasts and mouse skeletal muscle, but its presence in human skeletal muscle has not been investigated. Methods Samples from type 2 diabetic, and lean and non-diabetic obese participants w...

  10. The non-palindromic adaptor-PCR method for the identification of the T-cell receptor genes of an interferon-gamma-secreting T-cell hybridomaspecific for trans-sialidase, an immunodominant Trypanosoma cruzi antigen

    Directory of Open Access Journals (Sweden)

    M.I. Hiyane

    2006-03-01

    Full Text Available Cloning of the T-cell receptor genes is a critical step when generating T-cell receptor transgenic mice. Because T-cell receptor molecules are clonotypical, isolation of their genes requires reverse transcriptase-assisted PCR using primers specific for each different Valpha or Vß genes or by the screening of cDNA libraries generated from RNA obtained from each individual T-cell clone. Although feasible, these approaches are laborious and costly. The aim of the present study was to test the application of the non-palindromic adaptor-PCR method as an alternative to isolate the genes encoding the T-cell receptor of an antigen-specific T-cell hybridoma. For this purpose, we established hybridomas specific for trans-sialidase, an immunodominant Trypanosoma cruzi antigen. These T-cell hybridomas were characterized with regard to their ability to secrete interferon-gamma, IL-4, and IL-10 after stimulation with the antigen. A CD3+, CD4+, CD8- interferon-gamma-producing hybridoma was selected for the identification of the variable regions of the T-cell receptor by the non-palindromic adaptor-PCR method. Using this methodology, we were able to rapidly and efficiently determine the variable regions of both T-cell receptor chains. The results obtained by the non-palindromic adaptor-PCR method were confirmed by the isolation and sequencing of the complete cDNA genes and by the recognition with a specific antibody against the T-cell receptor variable ß chain. We conclude that the non-palindromic adaptor-PCR method can be a valuable tool for the identification of the T-cell receptor transcripts of T-cell hybridomas and may facilitate the generation of T-cell receptor transgenic mice.

  11. Interplays between Sumoylation, SUMO-Targeted Ubiquitin Ligases, and the Ubiquitin-Adaptor Protein Ufd1 in Fission Yeast

    DEFF Research Database (Denmark)

    Køhler, Julie Bonne

    and the specific molecular interactions and sequence of events linking sumoylation, ubiquitylation and substrate degradation, has been largely uncovered. Using the fission yeast model organism I here present evidence for a role of the Ufd1 (ubiquitinfusion degradation 1) protein, and by extension of the Cdc48-Ufd1...... other downstream fates. My work provides insight into how Cdc48-Ufd1-Npl4 also contributes to the processing of SUMO conjugates and suggests that at least some of these activities are coordinated with STUbL function. To gain insight into the sumoylated species regulated by Ufd1 and/or by STUbLs, I made......-Npl4 activities are coupled to dynamically regulate cellular processes....

  12. DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks.

    Science.gov (United States)

    Mosbech, Anna; Gibbs-Seymour, Ian; Kagias, Konstantinos; Thorslund, Tina; Beli, Petra; Povlsen, Lou; Nielsen, Sofie Vincents; Smedegaard, Stine; Sedgwick, Garry; Lukas, Claudia; Hartmann-Petersen, Rasmus; Lukas, Jiri; Choudhary, Chunaram; Pocock, Roger; Bekker-Jensen, Simon; Mailand, Niels

    2012-11-01

    Ubiquitin-mediated processes orchestrate critical DNA-damage signaling and repair pathways. We identify human DVC1 (C1orf124; Spartan) as a cell cycle-regulated anaphase-promoting complex (APC) substrate that accumulates at stalled replication forks. DVC1 recruitment to sites of replication stress requires its ubiquitin-binding UBZ domain and PCNA-binding PIP box motif but is independent of RAD18-mediated PCNA monoubiquitylation. Via a conserved SHP box, DVC1 recruits the ubiquitin-selective chaperone p97 to blocked replication forks, which may facilitate p97-dependent removal of translesion synthesis (TLS) DNA polymerase η (Pol η) from monoubiquitylated PCNA. DVC1 knockdown enhances UV light-induced mutagenesis, and depletion of human DVC1 or the Caenorhabditis elegans ortholog DVC-1 causes hypersensitivity to replication stress-inducing agents. Our findings establish DVC1 as a DNA damage-targeting p97 adaptor that protects cells from deleterious consequences of replication blocks and suggest an important role of p97 in ubiquitin-dependent regulation of TLS. PMID:23042605

  13. The adaptor protein SAP directly associates with PECAM-1 and regulates PECAM-1-mediated-cell adhesion in T-like cell lines.

    Science.gov (United States)

    Proust, Richard; Crouin, Catherine; Gandji, Leslie Yewakon; Bertoglio, Jacques; Gesbert, Franck

    2014-04-01

    SAP is a small cytosolic adaptor protein expressed in hematopoietic lineages whose main function is to regulate intracellular signaling pathways induced by the triggering of members of the SLAM receptor family. In this paper, we have identified the adhesion molecule PECAM-1 as a new partner for SAP in a conditional yeast two-hybrid screen. PECAM-1 is an immunoglobulin-like molecule expressed by endothelial cells and leukocytes, which possesses both pro- and anti-inflammatory properties. However, little is known about PECAM-1 functions in T cells. We show that SAP directly and specifically interacts with the cytosolic tyrosine 686 of PECAM-1. We generated different T-like cell lines in which SAP or PECAM-1 are expressed or down modulated and we demonstrate that a diminished SAP expression correlates with a diminished PECAM-1-mediated adhesion. Although SAP has mainly been shown to associate with SLAM receptors, we evidence here that SAP is a new actor downstream of PECAM-1.

  14. Involvement of Grb2 adaptor protein in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-mediated signaling and anaplastic large cell lymphoma growth.

    Science.gov (United States)

    Riera, Ludovica; Lasorsa, Elena; Ambrogio, Chiara; Surrenti, Nadia; Voena, Claudia; Chiarle, Roberto

    2010-08-20

    Most anaplastic large cell lymphomas (ALCL) express oncogenic fusion proteins derived from chromosomal translocations or inversions of the anaplastic lymphoma kinase (ALK) gene. Frequently ALCL carry the t(2;5) translocation, which fuses the ALK gene to the nucleophosmin (NPM1) gene. The transforming activity mediated by NPM-ALK fusion induces different pathways that control proliferation and survival of lymphoma cells. Grb2 is an adaptor protein thought to play an important role in ALK-mediated transformation, but its interaction with NPM-ALK, as well as its function in regulating ALCL signaling pathways and cell growth, has never been elucidated. Here we show that active NPM-ALK, but not a kinase-dead mutant, bound and induced Grb2 phosphorylation in tyrosine 160. An intact SH3 domain at the C terminus of Grb2 was required for Tyr(160) phosphorylation. Furthermore, Grb2 did not bind to a single region but rather to different regions of NPM-ALK, mainly Tyr(152-156), Tyr(567), and a proline-rich region, Pro(415-417). Finally, shRNA knockdown experiments showed that Grb2 regulates primarily the NPM-ALK-mediated phosphorylation of SHP2 and plays a key role in ALCL cell growth.

  15. Skb5, an SH3 adaptor protein, regulates Pmk1 MAPK signaling by controlling the intracellular localization of the MAPKKK Mkh1.

    Science.gov (United States)

    Kanda, Yuki; Satoh, Ryosuke; Matsumoto, Saki; Ikeda, Chisato; Inutsuka, Natsumi; Hagihara, Kanako; Matzno, Sumio; Tsujimoto, Sho; Kita, Ayako; Sugiura, Reiko

    2016-08-15

    The mitogen-activated protein kinase (MAPK) cascade is a highly conserved signaling module composed of MAPK kinase kinases (MAPKKKs), MAPK kinases (MAPKK) and MAPKs. The MAPKKK Mkh1 is an initiating kinase in Pmk1 MAPK signaling, which regulates cell integrity in fission yeast (Schizosaccharomyces pombe). Our genetic screen for regulators of Pmk1 signaling identified Shk1 kinase binding protein 5 (Skb5), an SH3-domain-containing adaptor protein. Here, we show that Skb5 serves as an inhibitor of Pmk1 MAPK signaling activation by downregulating Mkh1 localization to cell tips through its interaction with the SH3 domain. Consistent with this, the Mkh1(3PA) mutant protein, with impaired Skb5 binding, remained in the cell tips, even when Skb5 was overproduced. Intriguingly, Skb5 needs Mkh1 to localize to the growing ends as Mkh1 deletion and disruption of Mkh1 binding impairs Skb5 localization. Deletion of Pck2, an upstream activator of Mkh1, impaired the cell tip localization of Mkh1 and Skb5 as well as the Mkh1-Skb5 interaction. Interestingly, both Pck2 and Mkh1 localized to the cell tips at the G1/S phase, which coincided with Pmk1 MAPK activation. Taken together, Mkh1 localization to cell tips is important for transmitting upstream signaling to Pmk1, and Skb5 spatially regulates this process. PMID:27451356

  16. A conserved serine residue regulates the stability of Drosophila Salvador and human WW domain-containing adaptor 45 through proteasomal degradation

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Di, E-mail: DiWu@mail.nankai.edu.cn; Wu, Shian

    2013-04-19

    Highlights: •Ser-17 is key for the stability of Drosophila Sav. •Ala mutation of Ser-17 promotes the proteasomal degradation of Sav. •Ser-17 residue is not the main target of Hpo-induced Sav stabilization. •Hpo-dependent and -independent mechanisms regulate Sav stability. •This mechanism is conserved in the homologue of Sav, human WW45. -- Abstract: The Hippo (Hpo) pathway is a conserved tumor suppressor pathway that controls organ size through the coordinated regulation of apoptosis and proliferation. Drosophila Salvador (Sav), which limits organ size, is a core component of the Hpo pathway. In this study, Ser-17 was shown to be important for the stability of Sav. Alanine mutation of Ser-17 promoted the proteasomal degradation of Sav. Destabilization and stabilization of the Sav protein mediated by alanine mutation of Ser-17 and by Hpo, respectively, were independent of each other. This implies that the stability of Sav is controlled by two mechanisms, one that is Ser-17-dependent and Hpo-independent, and another that is Ser-17-independent and Hpo-dependent. These dual mechanisms also regulated the human counterpart of Drosophila Sav, WW domain-containing adaptor 45 (WW45). The conservation of this regulation adds to its significance in normal physiology and tumorigenesis.

  17. Identification and Characterization of KCASH2 and KCASH3, 2 Novel Cullin3 Adaptors Suppressing Histone Deacetylase and Hedgehog Activity in Medulloblastoma

    Directory of Open Access Journals (Sweden)

    Enrico De Smaele

    2011-04-01

    Full Text Available Medulloblastoma is the most common pediatric malignant brain tumor, arising from aberrant cerebellar precursors' development, a process mainly controlled by Hedgehog (Hh signaling pathway. Histone deacetylase HDAC1 has been recently shown to modulate Hh signaling, deacetylating its effectors Gli1/2 and enhancing their transcriptional activity. Therefore, HDAC may represent a potential therapeutic target for Hh-dependent tumors, but still little information is available on the physiological mechanisms of HDAC regulation. The putative tumor suppressor RENKCTD11 acts through ubiquitination-dependent degradation of HDAC1, thereby affecting Hh activity and medulloblastoma growth. We identify and characterize here two RENKCTD11 homologues, defining a new family of proteins named KCASH, as “KCTD containing, Cullin3 adaptor, suppressor of Hedgehog.” Indeed, the novel genes (KCASH2KCTD21 and KCASH3KCTD6 share with RENKCTD11 a number of features, such as a BTB domain required for the formation of a Cullin3 ubiquitin ligase complex and HDAC1 ubiquitination and degradation capability, suppressing the acetylation-dependent Hh/Gli signaling. Expression of KCASH2 and -3 is observed in cerebellum, whereas epigenetic silencing and allelic deletion are observed in human medulloblastoma. Rescuing KCASHs expression reduces the Hedgehog-dependent medulloblastoma growth, suggesting that loss of members of this novel family of native HDAC inhibitors is crucial in sustaining Hh pathway-mediated tumorigenesis. Accordingly, they might represent a promising class of endogenous “agents” through which this pathway may be targeted.

  18. Fission yeast arrestin-related trafficking adaptor, Arn1/Any1, is ubiquitinated by Pub1 E3 ligase and regulates endocytosis of Cat1 amino acid transporter

    Directory of Open Access Journals (Sweden)

    Akio Nakashima

    2014-05-01

    Full Text Available The Tsc1–Tsc2 complex homologous to human tuberous sclerosis complex proteins governs amino acid uptake by regulating the expression and intracellular distribution of amino acid transporters in Schizosaccharomyces pombe. Here, we performed a genetic screening for molecules that are involved in amino acid uptake and found Arn1 (also known as Any1. Arn1 is homologous to ART1, an arrestin-related trafficking adaptor (ART in Saccharomyces cerevisiae, and contains a conserved arrestin motif, a ubiquitination site, and two PY motifs. Overexpression of arn1+ confers canavanine resistance on cells, whereas its disruption causes hypersensitivity to canavanine. We also show that Arn1 regulates endocytosis of the Cat1 amino acid transporter. Furthermore, deletion of arn1+ suppresses a defect of amino acid uptake and the aberrant Cat1 localization in tsc2Δ. Arn1 interacts with and is ubiquitinated by the Pub1 ubiquitin ligase, which is necessary to regulate Cat1 endocytosis. Cat1 undergoes ubiquitinations on lysine residues within the N-terminus, which are mediated, in part, by Arn1 to determine Cat1 localization. Correctively, Arn1 is an ART in S. pombe and contributes to amino acid uptake through regulating Cat1 endocytosis in which Tsc2 is involved.

  19. Src-Like adaptor protein (SLAP) binds to the receptor tyrosine kinase Flt3 and modulates receptor stability and downstream signaling.

    Science.gov (United States)

    Kazi, Julhash U; Rönnstrand, Lars

    2012-01-01

    Fms-like tyrosine kinase 3 (Flt3) is an important growth factor receptor in hematopoiesis. Gain-of-function mutations of the receptor contribute to the transformation of acute myeloid leukemia (AML). Src-like adaptor protein (SLAP) is an interaction partner of the E3 ubiquitin ligase Cbl that can regulate receptor tyrosine kinases-mediated signal transduction. In this study, we analyzed the role of SLAP in signal transduction downstream of the type III receptor tyrosine kinase Flt3. The results show that upon ligand stimulation SLAP stably associates with Flt3 through multiple phosphotyrosine residues in Flt3. SLAP constitutively interacts with oncogenic Flt3-ITD and co-localizes with Flt3 near the cell membrane. This association initiates Cbl-dependent receptor ubiquitination and degradation. Depletion of SLAP expression by shRNA in Flt3-transfected Ba/F3 cells resulted in a weaker activation of FL-induced PI3K-Akt and MAPK signaling. Meta-analysis of microarray data from patient samples suggests that SLAP mRNA is differentially expressed in different cancers and its expression was significantly increased in patients carrying the Flt3-ITD mutation. Thus, our data suggest a novel role of SLAP in different cancers and in modulation of receptor tyrosine kinase signaling apart from its conventional role in regulation of receptor stability.

  20. Src-Like adaptor protein (SLAP binds to the receptor tyrosine kinase Flt3 and modulates receptor stability and downstream signaling.

    Directory of Open Access Journals (Sweden)

    Julhash U Kazi

    Full Text Available Fms-like tyrosine kinase 3 (Flt3 is an important growth factor receptor in hematopoiesis. Gain-of-function mutations of the receptor contribute to the transformation of acute myeloid leukemia (AML. Src-like adaptor protein (SLAP is an interaction partner of the E3 ubiquitin ligase Cbl that can regulate receptor tyrosine kinases-mediated signal transduction. In this study, we analyzed the role of SLAP in signal transduction downstream of the type III receptor tyrosine kinase Flt3. The results show that upon ligand stimulation SLAP stably associates with Flt3 through multiple phosphotyrosine residues in Flt3. SLAP constitutively interacts with oncogenic Flt3-ITD and co-localizes with Flt3 near the cell membrane. This association initiates Cbl-dependent receptor ubiquitination and degradation. Depletion of SLAP expression by shRNA in Flt3-transfected Ba/F3 cells resulted in a weaker activation of FL-induced PI3K-Akt and MAPK signaling. Meta-analysis of microarray data from patient samples suggests that SLAP mRNA is differentially expressed in different cancers and its expression was significantly increased in patients carrying the Flt3-ITD mutation. Thus, our data suggest a novel role of SLAP in different cancers and in modulation of receptor tyrosine kinase signaling apart from its conventional role in regulation of receptor stability.

  1. Activation of EphA receptors mediates the recruitment of the adaptor protein Slap, contributing to the downregulation of N-methyl-D-aspartate receptors.

    Science.gov (United States)

    Semerdjieva, Sophia; Abdul-Razak, Hayder H; Salim, Sharifah S; Yáñez-Muñoz, Rafael J; Chen, Philip E; Tarabykin, Victor; Alifragis, Pavlos

    2013-04-01

    Regulation of the activity of N-methyl-d-aspartate receptors (NMDARs) at glutamatergic synapses is essential for certain forms of synaptic plasticity underlying learning and memory and is also associated with neurotoxicity and neurodegenerative diseases. In this report, we investigate the role of Src-like adaptor protein (Slap) in NMDA receptor signaling. We present data showing that in dissociated neuronal cultures, activation of ephrin (Eph) receptors by chimeric preclustered eph-Fc ligands leads to recruitment of Slap and NMDA receptors at the sites of Eph receptor activation. Interestingly, our data suggest that prolonged activation of EphA receptors is as efficient in recruiting Slap and NMDA receptors as prolonged activation of EphB receptors. Using established heterologous systems, we examined whether Slap is an integral part of NMDA receptor signaling. Our results showed that Slap does not alter baseline activity of NMDA receptors and does not affect Src-dependent potentiation of NMDA receptor currents in Xenopus oocytes. We also demonstrate that Slap reduces excitotoxic cell death triggered by activation of NMDARs in HEK293 cells. Finally, we present evidence showing reduced levels of NMDA receptors in the presence of Slap occurring in an activity-dependent manner, suggesting that Slap is part of a mechanism that homeostatically modulates the levels of NMDA receptors.

  2. The adaptor protein DCAF7 mediates the interaction of the adenovirus E1A oncoprotein with the protein kinases DYRK1A and HIPK2.

    Science.gov (United States)

    Glenewinkel, Florian; Cohen, Michael J; King, Cason R; Kaspar, Sophie; Bamberg-Lemper, Simone; Mymryk, Joe S; Becker, Walter

    2016-01-01

    DYRK1A is a constitutively active protein kinase that has a critical role in growth and development which functions by regulating cell proliferation, differentiation and survival. DCAF7 (also termed WDR68 or HAN11) is a cellular binding partner of DYRK1A and also regulates signalling by the protein kinase HIPK2. DCAF7 is an evolutionarily conserved protein with a single WD40 repeat domain and has no catalytic activity. We have defined a DCAF7 binding motif of 12 amino acids in the N-terminal domain of class 1 DYRKs that is functionally conserved in DYRK1 orthologs from Xenopus, Danio rerio and the slime mold Dictyostelium discoideum. A similar sequence was essential for DCAF7 binding to HIPK2, whereas the closely related HIPK1 family member did not bind DCAF7. Immunoprecipitation and pulldown experiments identified DCAF7 as an adaptor for the association of the adenovirus E1A protein with DYRK1A and HIPK2. Furthermore, DCAF7 was required for the hyperphosphorylation of E1A in DYRK1A or HIPK2 overexpressing cells. Our results characterize DCAF7 as a substrate recruiting subunit of DYRK1A and HIPK2 and suggest that it is required for the negative effect of DYRK1A on E1A-induced oncogenic transformation. PMID:27307198

  3. Involvement of β3A Subunit of Adaptor Protein-3 in Intracellular Trafficking of Receptor-like Protein Tyrosine Phosphatase PCP-2

    Institute of Scientific and Technical Information of China (English)

    Hui DONG; Hong YUAN; Weirong JIN; Yan SHEN; Xiaojing XU; Hongyang WANG

    2007-01-01

    PCP-2 is a human receptor-like protein tyrosine phosphatase and a member of the MAM domain family cloned in human pancreatic adenocarcinoma cells. Previous studies showed that PCP-2 directly interacted with β-catenin through the juxtamembrane domain, dephosphorylated β-catenin and played an important role in the regulation of cell adhesion. Recent study showed that PCP-2 was also involved in the repression of β-catenin-induced transcriptional activity. Here we describe the interactions of PCP-2 with the β3A subunit of adaptor protein (AP)-3 and sorting nexin (SNX) 3. These protein complexes were detected using the yeast two-hybrid assay with the juxtamembrane and membrane-proximal catalytic domain of PCP-2 as "bait". Both AP-3 and SNX3 are molecules involved in intracellular trafficking of membrane receptors. The association between the β3A subunit of AP-3 and PCP-2 was further confirmed in mammalian cells. Our results suggested a possible mechanism of intracellular trafficking of PCP-2 mediated by AP-3 and SNX3 which might participate in the regulation of PCP-2 functions.

  4. Cul3 and the BTB adaptor insomniac are key regulators of sleep homeostasis and a dopamine arousal pathway in Drosophila.

    Directory of Open Access Journals (Sweden)

    Cory Pfeiffenberger

    Full Text Available Sleep is homeostatically regulated, such that sleep drive reflects the duration of prior wakefulness. However, despite the discovery of genes important for sleep, a coherent molecular model for sleep homeostasis has yet to emerge. To better understand the function and regulation of sleep, we employed a reverse-genetics approach in Drosophila. An insertion in the BTB domain protein CG32810/insomniac (inc exhibited one of the strongest baseline sleep phenotypes thus far observed, a ~10 h sleep reduction. Importantly, this is coupled to a reduced homeostatic response to sleep deprivation, consistent with a disrupted sleep homeostat. Knockdown of the INC-interacting protein, the E3 ubiquitin ligase Cul3, results in reduced sleep duration, consolidation, and homeostasis, suggesting an important role for protein turnover in mediating INC effects. Interestingly, inc and Cul3 expression in post-mitotic neurons during development contributes to their adult sleep functions. Similar to flies with increased dopaminergic signaling, loss of inc and Cul3 result in hyper-arousability to a mechanical stimulus in adult flies. Furthermore, the inc sleep duration phenotype can be rescued by pharmacological inhibition of tyrosine hydroxylase, the rate-limiting enzyme for dopamine biosynthesis. Taken together, these results establish inc and Cul3 as important new players in setting the sleep homeostat and a dopaminergic arousal pathway in Drosophila.

  5. Improved cytotoxic T-lymphocyte immune responses to a tumor antigen by vaccines co-expressing the SLAM-associated adaptor EAT-2.

    Science.gov (United States)

    Aldhamen, Y A; Seregin, S S; Kousa, Y A; Rastall, D P W; Appledorn, D M; Godbehere, S; Schutte, B C; Amalfitano, A

    2013-10-01

    The signaling lymphocytic activation molecule-associated adaptor Ewing's sarcoma's-activated transcript 2 (EAT-2) is primarily expressed in dendritic cells, macrophages and natural killer cells. Including EAT-2 in a vaccination regimen enhanced innate and adaptive immune responses toward pathogen-derived antigens, even in the face of pre-existing vaccine immunity. Herein, we investigate whether co-vaccinations with two recombinant Ad5 (rAd5) vectors, one expressing the carcinoembryonic antigen (CEA) and one expressing EAT-2, can induce more potent CEA-specific cytotoxic T lymphocyte (CTL) and antitumor activity in the therapeutic CEA-expressing MC-38 tumor model. Our results suggest that inclusion of EAT-2 significantly alters the kinetics of Th1-biasing proinflammatory cytokine and chemokine responses, and enhances anti-CEA-specific CTL responses. As a result, rAd5-EAT2-augmented rAd5-CEA vaccinations are more efficient in eliminating CEA-expressing target cells as measured by an in vivo CTL assay. Administration of rAd5-EAT2 vaccines also reduced the rate of growth of MC-38 tumor growth in vivo. Also, an increase in MC-38 tumor cell apoptosis (as measured by hematoxylin and eosin staining, active caspase-3 and granzyme B levels within the tumors) was observed. These data provide evidence that more efficient, CEA-specific effector T cells are generated by rAd5 vaccines expressing CEA, when augmented by rAd5 vaccines expressing EAT-2, and this regimen may be a promising approach for cancer immunotherapy in general.

  6. Impaired Lysosomal Integral Membrane Protein 2-dependent Peroxiredoxin 6 Delivery to Lamellar Bodies Accounts for Altered Alveolar Phospholipid Content in Adaptor Protein-3-deficient pearl Mice.

    Science.gov (United States)

    Kook, Seunghyi; Wang, Ping; Young, Lisa R; Schwake, Michael; Saftig, Paul; Weng, Xialian; Meng, Ying; Neculai, Dante; Marks, Michael S; Gonzales, Linda; Beers, Michael F; Guttentag, Susan

    2016-04-15

    The Hermansky Pudlak syndromes (HPS) constitute a family of disorders characterized by oculocutaneous albinism and bleeding diathesis, often associated with lethal lung fibrosis. HPS results from mutations in genes of membrane trafficking complexes that facilitate delivery of cargo to lysosome-related organelles. Among the affected lysosome-related organelles are lamellar bodies (LB) within alveolar type 2 cells (AT2) in which surfactant components are assembled, modified, and stored. AT2 from HPS patients and mouse models of HPS exhibit enlarged LB with increased phospholipid content, but the mechanism underlying these defects is unknown. We now show that AT2 in the pearl mouse model of HPS type 2 lacking the adaptor protein 3 complex (AP-3) fails to accumulate the soluble enzyme peroxiredoxin 6 (PRDX6) in LB. This defect reflects impaired AP-3-dependent trafficking of PRDX6 to LB, because pearl mouse AT2 cells harbor a normal total PRDX6 content. AP-3-dependent targeting of PRDX6 to LB requires the transmembrane protein LIMP-2/SCARB2, a known AP-3-dependent cargo protein that functions as a carrier for lysosomal proteins in other cell types. Depletion of LB PRDX6 in AP-3- or LIMP-2/SCARB2-deficient mice correlates with phospholipid accumulation in lamellar bodies and with defective intraluminal degradation of LB disaturated phosphatidylcholine. Furthermore, AP-3-dependent LB targeting is facilitated by protein/protein interaction between LIMP-2/SCARB2 and PRDX6 in vitro and in vivo Our data provide the first evidence for an AP-3-dependent cargo protein required for the maturation of LB in AT2 and suggest that the loss of PRDX6 activity contributes to the pathogenic changes in LB phospholipid homeostasis found HPS2 patients. PMID:26907692

  7. Structural basis for the recognition of the scaffold protein Frmpd4/Preso1 by the TPR domain of the adaptor protein LGN.

    Science.gov (United States)

    Takayanagi, Hiroki; Yuzawa, Satoru; Sumimoto, Hideki

    2015-02-01

    The adaptor protein LGN interacts via the N-terminal domain comprising eight tetratricopeptide-repeat (TPR) motifs with its partner proteins mInsc, NuMA, Frmpd1 and Frmpd4 in a mutually exclusive manner. Here, the crystal structure of the LGN TPR domain in complex with human Frmpd4 is described at 1.5 Å resolution. In the complex, the LGN-binding region of Frmpd4 (amino-acid residues 990-1011) adopts an extended structure that runs antiparallel to LGN along the concave surface of the superhelix formed by the TPR motifs. Comparison with the previously determined structures of the LGN-Frmpd1, LGN-mInsc and LGN-NuMA complexes reveals that these partner proteins interact with LGN TPR1-6 via a common core binding region with consensus sequence (E/Q)XEX4-5(E/D/Q)X1-2(K/R)X0-1(V/I). In contrast to Frmpd1, Frmpd4 makes additional contacts with LGN via regions N- and C-terminal to the core sequence. The N-terminal extension is replaced by a specific α-helix in mInsc, which drastically increases the direct contacts with LGN TPR7/8, consistent with the higher affinity of mInsc for LGN. A crystal structure of Frmpd4-bound LGN in an oxidized form is also reported, although oxidation does not appear to strongly affect the interaction with Frmpd4.

  8. Fit-to-Flow (F2F) interconnects: universal reversible adhesive-free microfluidic adaptors for lab-on-a-chip systems.

    Science.gov (United States)

    Chen, Arnold; Pan, Tingrui

    2011-02-21

    World-to-chip (macro-to-micro) interface continues to be one of the most complicated, ineffective, and unreliable components in the development of emerging lab-on-a-chip systems involving integrated microfluidic operations. A number of irreversible (e.g., adhesive gluing) and reversible techniques (e.g., press fitting) have attempted to provide dedicated fluidic passage from standard tubing to miniature on-chip devices, none of which completely addresses the above concerns. In this paper, we present standardized adhesive-free microfluidic adaptors, referred to as Fit-to-Flow (F2F) Interconnects, to achieve reliable hermetic seal, high-density tube packing, self-aligned plug-in, reworkable connectivity, straightforward scalability and expandability, and applicability to broad lab-on-a-chip platforms; analogous to the modular plug-and-play USB architecture employed in modern electronics. Specifically, two distinct physical packaging mechanisms are applied, with one utilizing induced tensile stress in elastomeric socket to establish reversible seal and the other using negative pressure to provide on demand vacuum shield, both of which can be adapted to a variety of experimental configurations. The non-leaking performance (up to 336 kPa) along with high tube-packing density (of 1 tube/mm(2)) and accurate self-guided alignment (of 10 μm) have been characterized. In addition, a 3D microfluidic mixer and a 6-level chemical gradient generator paired with the corresponding F2F Interconnects have been devised to illustrate the applicability of the universal fluidic connections to classic lab-on-a-chip operations.

  9. The Ras suppressor Rsu-1 binds to the LIM 5 domain of the adaptor protein PINCH1 and participates in adhesion-related functions

    International Nuclear Information System (INIS)

    Rsu-1 is a highly conserved leucine rich repeat (LRR) protein that is expressed ubiquitously in mammalian cells. Rsu-1 was identified based on its ability to inhibit transformation by Ras, and previous studies demonstrated that ectopic expression of Rsu-1 inhibited anchorage-independent growth of Ras-transformed cells and human tumor cell lines. Using GAL4-based yeast two-hybrid screening, the LIM domain protein, PINCH1, was identified as the binding partner of Rsu-1. PINCH1 is an adaptor protein that localizes to focal adhesions and it has been implicated in the regulation of adhesion functions. Subdomain mapping in yeast revealed that Rsu-1 binds to the LIM 5 domain of PINCH1, a region not previously identified as a specific binding domain for any other protein. Additional testing demonstrated that PINCH2, which is highly homologous to PINCH1, except in the LIM 5 domain, does not interact with Rsu-1. Glutathione transferase fusion protein binding studies determined that the LRR region of Rsu-1 interacts with PINCH1. Transient expression studies using epitope-tagged Rsu-1 and PINCH1 revealed that Rsu-1 co-immunoprecipitated with PINCH1 and colocalized with vinculin at sites of focal adhesions in mammalian cells. In addition, endogenous P33 Rsu-1 from 293T cells co-immunoprecipitated with transiently expressed myc-tagged PINCH1. Furthermore, RNAi-induced reduction in Rsu-1 RNA and protein inhibited cell attachment, and while previous studies demonstrated that ectopic expression of Rsu-1 inhibited Jun kinase activation, the depletion of Rsu-1 resulted in activation of Jun and p38 stress kinases. These studies demonstrate that Rsu-1 interacts with PINCH1 in mammalian cells and functions, in part, by altering cell adhesion

  10. Regulation of protease-activated receptor 1 signaling by the adaptor protein complex 2 and R4 subfamily of regulator of G protein signaling proteins.

    Science.gov (United States)

    Chen, Buxin; Siderovski, David P; Neubig, Richard R; Lawson, Mark A; Trejo, Joann

    2014-01-17

    The G protein-coupled protease-activated receptor 1 (PAR1) is irreversibly proteolytically activated by thrombin. Hence, the precise regulation of PAR1 signaling is important for proper cellular responses. In addition to desensitization, internalization and lysosomal sorting of activated PAR1 are critical for the termination of signaling. Unlike most G protein-coupled receptors, PAR1 internalization is mediated by the clathrin adaptor protein complex 2 (AP-2) and epsin-1, rather than β-arrestins. However, the function of AP-2 and epsin-1 in the regulation of PAR1 signaling is not known. Here, we report that AP-2, and not epsin-1, regulates activated PAR1-stimulated phosphoinositide hydrolysis via two different mechanisms that involve, in part, a subset of R4 subfamily of "regulator of G protein signaling" (RGS) proteins. A significantly greater increase in activated PAR1 signaling was observed in cells depleted of AP-2 using siRNA or in cells expressing a PAR1 (420)AKKAA(424) mutant with defective AP-2 binding. This effect was attributed to AP-2 modulation of PAR1 surface expression and efficiency of G protein coupling. We further found that ectopic expression of R4 subfamily members RGS2, RGS3, RGS4, and RGS5 reduced activated PAR1 wild-type signaling, whereas signaling by the PAR1 AKKAA mutant was minimally affected. Intriguingly, siRNA-mediated depletion analysis revealed a function for RGS5 in the regulation of signaling by the PAR1 wild type but not the AKKAA mutant. Moreover, activation of the PAR1 wild type, and not the AKKAA mutant, induced Gαq association with RGS3 via an AP-2-dependent mechanism. Thus, AP-2 regulates activated PAR1 signaling by altering receptor surface expression and through recruitment of RGS proteins. PMID:24297163

  11. Protease-activated Receptor-4 Signaling and Trafficking Is Regulated by the Clathrin Adaptor Protein Complex-2 Independent of β-Arrestins.

    Science.gov (United States)

    Smith, Thomas H; Coronel, Luisa J; Li, Julia G; Dores, Michael R; Nieman, Marvin T; Trejo, JoAnn

    2016-08-26

    Protease-activated receptor-4 (PAR4) is a G protein-coupled receptor (GPCR) for thrombin and is proteolytically activated, similar to the prototypical PAR1. Due to the irreversible activation of PAR1, receptor trafficking is intimately linked to signal regulation. However, unlike PAR1, the mechanisms that control PAR4 trafficking are not known. Here, we sought to define the mechanisms that control PAR4 trafficking and signaling. In HeLa cells depleted of clathrin by siRNA, activated PAR4 failed to internalize. Consistent with clathrin-mediated endocytosis, expression of a dynamin dominant-negative K44A mutant also blocked activated PAR4 internalization. However, unlike most GPCRs, PAR4 internalization occurred independently of β-arrestins and the receptor's C-tail domain. Rather, we discovered a highly conserved tyrosine-based motif in the third intracellular loop of PAR4 and found that the clathrin adaptor protein complex-2 (AP-2) is important for internalization. Depletion of AP-2 inhibited PAR4 internalization induced by agonist. In addition, mutation of the critical residues of the tyrosine-based motif disrupted agonist-induced PAR4 internalization. Using Dami megakaryocytic cells, we confirmed that AP-2 is required for agonist-induced internalization of endogenous PAR4. Moreover, inhibition of activated PAR4 internalization enhanced ERK1/2 signaling, whereas Akt signaling was markedly diminished. These findings indicate that activated PAR4 internalization requires AP-2 and a tyrosine-based motif and occurs independent of β-arrestins, unlike most classical GPCRs. Moreover, these findings are the first to show that internalization of activated PAR4 is linked to proper ERK1/2 and Akt activation. PMID:27402844

  12. The interaction of the cellular export adaptor protein Aly/REF with ICP27 contributes to the efficiency of herpes simplex virus 1 mRNA export.

    Science.gov (United States)

    Tian, Xiaochen; Devi-Rao, Gayathri; Golovanov, Alexander P; Sandri-Goldin, Rozanne M

    2013-07-01

    Herpes simplex virus 1 (HSV-1) protein ICP27 enables viral mRNA export by accessing the cellular mRNA export receptor TAP/NXF, which guides mRNA through the nuclear pore complex. ICP27 binds viral mRNAs and interacts with TAP/NXF, providing a link to the cellular mRNA export pathway. ICP27 also interacts with the mRNA export adaptor protein Aly/REF, which binds cellular mRNAs and also interacts with TAP/NXF. Studies using small interfering RNA (siRNA) knockdown indicated that Aly/REF is not required for cellular mRNA export, and similar knockdown studies during HSV-1 infection led us to conclude that Aly/REF may be dispensable for viral RNA export. Recently, the structural basis of the interaction of ICP27 with Aly/REF was elucidated at atomic resolution, and it was shown that three ICP27 residues, W105, R107, and L108, interface with the RNA recognition motif (RRM) domain of Aly/REF. Here, to determine the role the interaction of ICP27 and Aly/REF plays during infection, these residues were mutated to alanine, and a recombinant virus, WRL-A, was constructed. Virus production was reduced about 10-fold during WRL-A infection, and export of ICP27 protein and most viral mRNAs was less efficient. We conclude that interaction of ICP27 with Aly/REF contributes to efficient viral mRNA export.

  13. Analysis of Phosphorylation-dependent Protein Interactions of Adhesion and Degranulation Promoting Adaptor Protein (ADAP) Reveals Novel Interaction Partners Required for Chemokine-directed T cell Migration.

    Science.gov (United States)

    Kuropka, Benno; Witte, Amelie; Sticht, Jana; Waldt, Natalie; Majkut, Paul; Hackenberger, Christian P R; Schraven, Burkhart; Krause, Eberhard; Kliche, Stefanie; Freund, Christian

    2015-11-01

    Stimulation of T cells leads to distinct changes of their adhesive and migratory properties. Signal propagation from activated receptors to integrins depends on scaffolding proteins such as the adhesion and degranulation promoting adaptor protein (ADAP)(1). Here we have comprehensively investigated the phosphotyrosine interactome of ADAP in T cells and define known and novel interaction partners of functional relevance. While most phosphosites reside in unstructured regions of the protein, thereby defining classical SH2 domain interaction sites for master regulators of T cell signaling such as SLP76, Fyn-kinase, and NCK, other binding events depend on structural context. Interaction proteomics using different ADAP constructs comprising most of the known phosphotyrosine motifs as well as the structured domains confirm that a distinct set of proteins is attracted by pY571 of ADAP, including the ζ-chain-associated protein kinase of 70 kDa (ZAP70). The interaction of ADAP and ZAP70 is inducible upon stimulation either of the T cell receptor (TCR) or by chemokine. NMR spectroscopy reveals that the N-terminal SH2 domains within a ZAP70-tandem-SH2 construct is the major site of interaction with phosphorylated ADAP-hSH3(N) and microscale thermophoresis (MST) indicates an intermediate binding affinity (Kd = 2.3 μm). Interestingly, although T cell receptor dependent events such as T cell/antigen presenting cell (APC) conjugate formation and adhesion are not affected by mutation of Y571, migration of T cells along a chemokine gradient is compromised. Thus, although most phospho-sites in ADAP are linked to T cell receptor related functions we have identified a unique phosphotyrosine that is solely required for chemokine induced T cell behavior.

  14. Role of adaptor proteins and clathrin in the trafficking of human kidney anion exchanger 1 (kAE1) to the cell surface.

    Science.gov (United States)

    Junking, Mutita; Sawasdee, Nunghathai; Duangtum, Natapol; Cheunsuchon, Boonyarit; Limjindaporn, Thawornchai; Yenchitsomanus, Pa-thai

    2014-07-01

    Kidney anion exchanger 1 (kAE1) plays an important role in acid-base homeostasis by mediating chloride/bicarbornate (Cl-/HCO3-) exchange at the basolateral membrane of α-intercalated cells in the distal nephron. Impaired intracellular trafficking of kAE1 caused by mutations of SLC4A1 encoding kAE1 results in kidney disease - distal renal tubular acidosis (dRTA). However, it is not known how the intracellular sorting and trafficking of kAE1 from trans-Golgi network (TGN) to the basolateral membrane occurs. Here, we studied the role of basolateral-related sorting proteins, including the mu1 subunit of adaptor protein (AP) complexes, clathrin and protein kinase D, on kAE1 trafficking in polarized and non-polarized kidney cells. By using RNA interference, co-immunoprecipitation, yellow fluorescent protein-based protein fragment complementation assays and immunofluorescence staining, we demonstrated that AP-1 mu1A, AP-3 mu1, AP-4 mu1 and clathrin (but not AP-1 mu1B, PKD1 or PKD2) play crucial roles in intracellular sorting and trafficking of kAE1. We also demonstrated colocalization of kAE1 and basolateral-related sorting proteins in human kidney tissues by double immunofluorescence staining. These findings indicate that AP-1 mu1A, AP-3 mu1, AP-4 mu1 and clathrin are required for kAE1 sorting and trafficking from TGN to the basolateral membrane of acid-secreting α-intercalated cells.

  15. Magnetismo Molecular (Molecular Magentism)

    Energy Technology Data Exchange (ETDEWEB)

    Reis, Mario S [Universidade Federal Fluminense, Brasil; Moreira Dos Santos, Antonio F [ORNL

    2010-07-01

    The new synthesis processes in chemistry open a new world of research, new and surprising materials never before found in nature can now be synthesized and, as a wonderful result, observed a series of physical phenomena never before imagined. Among these are many new materials the molecular magnets, the subject of this book and magnetic properties that are often reflections of the quantum behavior of these materials. Aside from the wonderful experience of exploring something new, the theoretical models that describe the behavior these magnetic materials are, in most cases, soluble analytically, which allows us to know in detail the physical mechanisms governing these materials. Still, the academic interest in parallel this subject, these materials have a number of properties that are promising to be used in technological devices, such as in computers quantum magnetic recording, magnetocaloric effect, spintronics and many other devices. This volume will journey through the world of molecular magnets, from the structural description of these materials to state of the art research.

  16. Molecular Electronics

    OpenAIRE

    Heath, James R.

    2009-01-01

    Molecular electronics describes the field in which molecules are utilized as the active (switching, sensing, etc.) or passive (current rectifiers, surface passivants) elements in electronic devices. This review focuses on experimental aspects of molecular electronics that researchers have elucidated over the past decade or so and that relate to the fabrication of molecular electronic devices in which the molecular components are readily distinguished within the electronic properties of the de...

  17. Molecular Plasmonics

    Science.gov (United States)

    Wilson, Andrew J.; Willets, Katherine A.

    2016-06-01

    In this review, we survey recent advances in the field of molecular plasmonics beyond the traditional sensing modality. Molecular plasmonics is explored in the context of the complex interaction between plasmon resonances and molecules and the ability of molecules to support plasmons self-consistently. First, spectroscopic changes induced by the interaction between molecular and plasmonic resonances are discussed, followed by examples of how tuning molecular properties leads to active molecular plasmonic systems. Next, the role of the position and polarizability of a molecular adsorbate on surface-enhanced Raman scattering signals is examined experimentally and theoretically. Finally, we introduce recent research focused on using molecules as plasmonic materials. Each of these examples is intended to highlight the role of molecules as integral components in coupled molecule-plasmon systems, as well as to show the diversity of applications in molecular plasmonics.

  18. Molecular Gastronomy

    OpenAIRE

    Burke, Roisin; This, Herve; Kelly, Alan

    2016-01-01

    Molecular gastronomy may be defined as the scientific discipline that explores the phenomena occurring during culinary transformations. In contrast with traditional approaches of food science and technology, which considered mostly the chemistry, physics, or biology of food ingredients and industrial transformations, the focus is on phenomena occurring during the preparation of dishes. Applications building on the principles of molecular gastronomy, such as ‘Molecular Cooking’ and ‘Note-by-No...

  19. Molecular Magnetocapacitance

    OpenAIRE

    Wu, Yu-ning; Zhang, Xiao-Guang; Cheng, Hai-Ping

    2012-01-01

    Capacitance of a nanoscale system is usually thought of having two contributions, a classical electrostatic contribution and a quantum contribution dependent on the density of states and/or molecular orbitals close to the Fermi energy. In this letter we demonstrate that in molecular nano-magnets and other magnetic nanoscale systems, the quantum part of the capacitance becomes spin-dependent, and is tunable by an external magnetic field. This molecular magnetocapacitance can be realized using ...

  20. Molecular Spintronics

    OpenAIRE

    Shiraishi, Masashi; Ikoma, Tadaaki

    2011-01-01

    Molecular spintronics is recognized to as an attractive new research direction in a field of spintronics, following to metallic spintronics and inorganic semiconductor spintronics, and attracts many people in recent decades. The purpose of this manuscript is to describe the history of molecular spintronics by introducing important achievements and to show the current status of this field. In addition, the authors briefly introduce several theories for implementing studies in molecular spintro...

  1. Molecular pharmacognosy

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    This article analyzes the background and significance of molecular pharmacognosy,including the molecular identification of medicinal raw materials,phylogenetic evolution of medicinal plants and animals,evaluation and preservation of germplasm resources for medicinal plants and animals,etiology of endangerment and protection of endangered medicinal plants and animals,biosynthesis and bioregulation of active components in medicinal plants,and characteristics and the molecular bases of top-geoherbs.

  2. Molecular Diagnostics

    OpenAIRE

    Choe, Hyonmin; Deirmengian, Carl A; Hickok, Noreen J.; Morrison, Tiffany N.; Tuan, Rocky S.

    2015-01-01

    Orthopaedic infections are complex conditions that require immediate diagnosis and accurate identification of the causative organisms to facilitate appropriate management. Conventional methodologies for diagnosis of these infections sometimes lack accuracy or sufficient rapidity. Current molecular diagnostics are an emerging area of bench-to-bedside research in orthopaedic infections. Examples of promising molecular diagnostics include measurement of a specific biomarker in the synovial fluid...

  3. Molecular Electronics

    DEFF Research Database (Denmark)

    Jennum, Karsten Stein

    This thesis includes the synthesis and characterisation of organic compounds designed for molecular electronics. The synthesised organic molecules are mainly based on two motifs, the obigo(phenyleneethynylenes) (OPE)s and tetrathiafulvalene (TTF) as shown below. These two scaffolds (OPE and TTF......) are chemically merged together to form cruciform-like structures that are an essential part of the thesis. The cruciform molecules were subjected to molecular conductance measurements to explore their capability towards single-crystal field-effect transistors (Part 1), molecular wires, and single electron......, however, was obtained by a study of a single molecular transistor. The investigated OPE5-TTF compound was captured in a three-terminal experiment, whereby manipulation of the molecule’s electronic spin was possible in different charge states. Thus, we demonstrated how the cruciform molecules could...

  4. Molecular sciences

    International Nuclear Information System (INIS)

    The research in molecular sciences summarized includes photochemistry, radiation chemistry, geophysics, electromechanics, heavy-element oxidizers , heavy element chemistry collisions, atoms, organic solids. A list of publications is included

  5. Molecular farming

    OpenAIRE

    Merck, K.B.; Vereijken, J M

    2006-01-01

    Molecular Farming is a new and emerging technology that promises relatively cheap and flexible production of large quantities of pharmaceuticals in genetically modified plants. Many stakeholders are involved in the production of pharmaceuticals in plants, which complicates the discussion on the possible benefits and disadvantages to a great extent. Discussions about Molecular Farming are often about technical and economic aspects, but other aspects like safety and ethical and societal aspects...

  6. Molecular printing

    OpenAIRE

    Braunschweig, Adam B.; Huo, Fengwei; Mirkin, Chad A.

    2009-01-01

    Molecular printing techniques, which involve the direct transfer of molecules to a substrate with submicrometre resolution, have been extensively developed over the past decade and have enabled many applications. Arrays of features on this scale have been used to direct materials assembly, in nanoelectronics, and as tools for genetic analysis and disease detection. The past decade has witnessed the maturation of molecular printing led by two synergistic technologies: dip-pen nanolithography a...

  7. Molecular Nanoelectronics

    OpenAIRE

    Vuillaume, Dominique

    2010-01-01

    Molecular electronics is envisioned as a promising candidate for the nanoelectronics of the future. More than a possible answer to ultimate miniaturization problem in nanoelectronics, molecular electronics is foreseen as a possible way to assemble a large numbers of nanoscale objects (molecules, nanoparticules, nanotubes and nanowires) to form new devices and circuit architectures. It is also an interesting approach to significantly reduce the fabrication costs, as well as the energetical cos...

  8. Structural Molecular Components of Septate Junctions in Cnidarians Point to the Origin of Epithelial Junctions in Eukaryotes

    KAUST Repository

    Ganot, P.

    2014-09-21

    Septate junctions (SJs) insure barrier properties and control paracellular diffusion of solutes across epithelia in invertebrates. However, the origin and evolution of their molecular constituents in Metazoa have not been firmly established. Here, we investigated the genomes of early branching metazoan representatives to reconstruct the phylogeny of the molecular components of SJs. Although Claudins and SJ cytoplasmic adaptor components appeared successively throughout metazoan evolution, the structural components of SJs arose at the time of Placozoa/Cnidaria/Bilateria radiation. We also show that in the scleractinian coral Stylophora pistillata, the structural SJ component Neurexin IV colocalizes with the cortical actin network at the apical border of the cells, at the place of SJs. We propose a model for SJ components in Cnidaria. Moreover, our study reveals an unanticipated diversity of SJ structural component variants in cnidarians. This diversity correlates with gene-specific expression in calcifying and noncalcifying tissues, suggesting specific paracellular pathways across the cell layers of these diploblastic animals.

  9. Molecular physics

    CERN Document Server

    Demtröder, Wolfgang

    2008-01-01

    The richly illustrated book comprehensively explains the important principles of diatomic and polyatomic molecules and their spectra in two separate, distinct parts. The first part concentrates on the theoretical aspects of molecular physics, such as the vibration, rotation, electronic states, potential curves, and spectra of molecules. The different methods of approximation for the calculation of electronic wave functions and their energy are also covered. The introduction of basics terms used in group theory and their meaning in molecular physics enables an elegant description of polyatomic

  10. Molecular pathways

    DEFF Research Database (Denmark)

    Cox, Thomas R; Erler, Janine Terra

    2014-01-01

    45% of deaths in the developed world are linked to fibrotic disease. Fibrosis and cancer are known to be inextricably linked; however, we are only just beginning to understand the common and overlapping molecular pathways between the two. Here, we discuss what is known about the intersection of...... fibrosis and cancer, with a focus on cancer metastasis, and highlight some of the exciting new potential clinical targets that are emerging from analysis of the molecular pathways associated with these two devastating diseases. Clin Cancer Res; 20(14); 3637-43. ©2014 AACR....

  11. Molecular modeling

    Directory of Open Access Journals (Sweden)

    Aarti Sharma

    2009-01-01

    Full Text Available The use of computational chemistry in the development of novel pharmaceuticals is becoming an increasingly important tool. In the past, drugs were simply screened for effectiveness. The recent advances in computing power and the exponential growth of the knowledge of protein structures have made it possible for organic compounds to be tailored to decrease the harmful side effects and increase the potency. This article provides a detailed description of the techniques employed in molecular modeling. Molecular modeling is a rapidly developing discipline, and has been supported by the dramatic improvements in computer hardware and software in recent years.

  12. Molecular gastronomy

    Science.gov (United States)

    This, Hervé

    2005-01-01

    For centuries, cooks have been applying recipes without looking for the mechanisms of the culinary transformations. A scientific discipline that explores these changes from raw ingredients to eating the final dish, is developing into its own field, termed molecular gastronomy. Here, one of the founders of the discipline discusses its aims and importance.

  13. Molecular photobiology.

    OpenAIRE

    Nikkels, Arjen; Pierard, Claudine; Pierard, Gérald

    2005-01-01

    Photochemical reactions are numerous in the skin. They generate reactive oxygen species and other biochemical alterations as well. According to their nature, the molecular components of the skin which have been altered by these mechanisms can be repaired with various degrees of efficacy. Peer reviewed

  14. Molecular photovoltaics

    OpenAIRE

    Moser, Jacques E.; Bonnôte, Pierre; Grätzel, Michael

    1998-01-01

    Photoinduced charge transfer processes involving molecules adsorbed at interfaces are a fascinating topic which is presently attracting wide attention. Our investigations have focused on the identification of the factors that control the dynamics of such processes. The goal is to design molecular electronic devices that achieve efficient light-induced charge separation. Applications of similar systems in photochromic and electrochromic devices also appear feasible.

  15. Molecular farming

    NARCIS (Netherlands)

    Merck, K.B.; Vereijken, J.M.

    2006-01-01

    Molecular Farming is a new and emerging technology that promises relatively cheap and flexible production of large quantities of pharmaceuticals in genetically modified plants. Many stakeholders are involved in the production of pharmaceuticals in plants, which complicates the discussion on the poss

  16. Ubiquitination and Degradation of CFTR by the E3 Ubiquitin Ligase MARCH2 through Its Association with Adaptor Proteins CAL and STX6

    OpenAIRE

    Jie Cheng; William Guggino

    2013-01-01

    Golgi-localized cystic fibrosis transmembrane conductance regulator (CFTR)-associated ligand (CAL) and syntaxin 6 (STX6) regulate the abundance of mature, post-ER CFTR by forming a CAL/STX6/CFTR complex (CAL complex) that promotes CFTR degradation in lysosomes. However, the molecular mechanism underlying this degradation is unknown. Here we investigated the interaction of a Golgi-localized, membrane-associated RING-CH E3 ubiquitin ligase, MARCH2, with the CAL complex and the consequent bindin...

  17. Molecular Modelling

    Directory of Open Access Journals (Sweden)

    Aarti Sharma

    2009-12-01

    Full Text Available

    The use of computational chemistry in the development of novel pharmaceuticals is becoming an increasingly important
    tool. In the past, drugs were simply screened for effectiveness. The recent advances in computing power and
    the exponential growth of the knowledge of protein structures have made it possible for organic compounds to tailored to
    decrease harmful side effects and increase the potency. This article provides a detailed description of the techniques
    employed in molecular modeling. Molecular modelling is a rapidly developing discipline, and has been supported from
    the dramatic improvements in computer hardware and software in recent years.

  18. Molecular Mechanics

    OpenAIRE

    Vanommeslaeghe, Kenno; Guvench, Olgun; Alexander D MacKerell

    2014-01-01

    Molecular Mechanics (MM) force fields are the methods of choice for protein simulations, which are essential in the study of conformational flexibility. Given the importance of protein flexibility in drug binding, MM is involved in most if not all Computational Structure-Based Drug Discovery (CSBDD) projects. This section introduces the reader to the fundamentals of MM, with a special emphasis on how the target data used in the parametrization of force fields determine their strengths and wea...

  19. Molecular Quarkonium

    OpenAIRE

    Voloshin, M. B.

    2006-01-01

    I discuss topics related to four-quark states of the `molecular quarkonium' type, i.e. resonances that could be considered as (dominantly) made from a heavy meson and antimeson. Of the so far observed resonances such picture is very likely applicable to the state X(3872), and I also discuss its possible relevance to the peak near the $D^* {\\bar D}^*$ threshold in $e^+e^-$ annihilation.

  20. Molecular Morphology

    OpenAIRE

    Donath, Alexander

    2011-01-01

    A fundamental problem in biology is the reconstruction of the relatedness of all (extant) species. Traditionally, systematists employ visually recognizable characters of organisms for classification and evolutionary analysis. Recent developments in molecular and computational biology, however, lead to a whole different perspective on how to address the problem of inferring relatedness. The discovery of molecules, carrying genetic information, and the comparison of their primary structure h...

  1. Molecular Diagnosis

    OpenAIRE

    Hoar, David I.

    1987-01-01

    Recombinant DNA technology, one of the major controversial areas of biological research in the late 1970s, is now rapidly providing new avenues for diagnosis and treatment. With the early recognition that extensive DNA variation exists in human populations, molecular genetic diagnosis of a variety of common hereditary diseases has become a reality. Recent identification of the location of the gene (or genes) for cystic fibrosis and adult polycystic kidney disease, and characterization of the ...

  2. Molecular modeling

    OpenAIRE

    Aarti Sharma; Himanshu Gupta

    2009-01-01

    The use of computational chemistry in the development of novel pharmaceuticals is becoming an increasingly important tool. In the past, drugs were simply screened for effectiveness. The recent advances in computing power and the exponential growth of the knowledge of protein structures have made it possible for organic compounds to be tailored to decrease the harmful side effects and increase the potency. This article provides a detailed description of the techniques employed in molecular mod...

  3. Molecular Modeling

    Science.gov (United States)

    Holmes, Jon L.

    1999-06-01

    Molecular modeling has trickled down from the realm of pharmaceutical and research laboratories into the realm of undergraduate chemistry instruction. It has opened avenues for the visualization of chemical concepts that previously were difficult or impossible to convey. I am sure that many of you have developed exercises using the various molecular modeling tools. It is the desire of this Journal to become an avenue for you to share these exercises among your colleagues. It is to this end that Ron Starkey has agreed to edit such a column and to publish not only the description of such exercises, but also the software documents they use. The WWW is the obvious medium to distribute this combination and so accepted submissions will appear online as a feature of JCE Internet. Typical molecular modeling exercise: finding conformation energies. Molecular Modeling Exercises and Experiments is the latest feature column of JCE Internet, joining Conceptual Questions and Challenge Problems, Hal's Picks, and Mathcad in the Chemistry Curriculum. JCE Internet continues to seek submissions in these areas of interest and submissions of general interest. If you have developed materials and would like to submit them, please see our Guide to Submissions for more information. The Chemical Education Resource Shelf, Equipment Buyers Guide, and WWW Site Review would also like to hear about chemistry textbooks and software, equipment, and WWW sites, respectively. Please consult JCE Internet Features to learn more about these resources at JCE Online. Email Announcements Would you like to be informed by email when the latest issue of the Journal is available online? when a new JCE Software title is shipping? when a new JCE Internet article has been published or is available for Open Review? when your subscription is about to expire? A new feature of JCE Online makes this possible. Visit our Guestbook to learn how. When you submit the form on this page, which includes your email address

  4. Characterization of Toll-like receptors in primary lung epithelial cells: strong impact of the TLR3 ligand poly(I:C on the regulation of Toll-like receptors, adaptor proteins and inflammatory response

    Directory of Open Access Journals (Sweden)

    Weith Andreas

    2005-11-01

    Full Text Available Abstract Background Bacterial and viral exacerbations play a crucial role in a variety of lung diseases including COPD or asthma. Since the lung epithelium is a major source of various inflammatory mediators that affect the immune response, we analyzed the inflammatory reaction of primary lung epithelial cells to different microbial molecules that are recognized by Toll-like receptors (TLR. Methods The effects of TLR ligands on primary small airway epithelial cells were analyzed in detail with respect to cytokine, chemokine and matrix metalloproteinase secretion. In addition, the regulation of the expression of TLRs and their adaptor proteins in small airway epithelial cells was investigated. Results Our data demonstrate that poly(I:C, a synthetic analog of viral dsRNA, mediated the strongest proinflammatory effects among the tested ligands, including an increased secretion of IL-6, IL-8, TNF-α, GM-CSF, GRO-α, TARC, MCP-1, MIP-3α, RANTES, IFN-β, IP-10 and ITAC as well as an increased release of MMP-1, MMP-8, MMP-9, MMP-10 and MMP-13. Furthermore, our data show that poly(I:C as well as type-1 and type-2 cytokines have a pronounced effect on the expression of TLRs and molecules involved in TLR signaling in small airway epithelial cells. Poly(I:C induced an elevated expression of TLR1, TLR2 and TLR3 and increased the gene expression of the general TLR adaptor MyD88 and IRAK-2. Simultaneously, poly(I:C decreased the expression of TLR5, TLR6 and TOLLIP. Conclusion Poly(I:C, an analog of viral dsRNA and a TLR3 ligand, triggers a strong inflammatory response in small airway epithelial cells that is likely to contribute to viral exacerbations of pulmonary diseases like asthma or COPD. The pronounced effects of poly(I:C on the expression of Toll-like receptors and molecules involved in TLR signaling is assumed to influence the immune response of the lung epithelium to viral and bacterial infections. Likewise, the regulation of TLR expression by type

  5. Yeast Golgi-localized, γ-Ear–containing, ADP-Ribosylation Factor-binding Proteins Are but Adaptor Protein-1 Is Not Required for Cell-free Transport of Membrane Proteins from the Trans-Golgi Network to the Prevacuolar Compartment

    OpenAIRE

    Abazeed, Mohamed E.; Fuller, Robert S.

    2008-01-01

    Golgi-localized, γ-Ear–containing, ADP-ribosylation factor-binding proteins (GGAs) and adaptor protein-1 (AP-1) mediate clathrin-dependent trafficking of transmembrane proteins between the trans-Golgi network (TGN) and endosomes. In yeast, the vacuolar sorting receptor Vps10p follows a direct pathway from the TGN to the late endosome/prevacuolar compartment (PVC), whereas, the processing protease Kex2p partitions between the direct pathway and an indirect pathway through the early endosome. T...

  6. [Molecular mechanisms underlying the formation of neuromuscular junction].

    Science.gov (United States)

    Higuchi, Osamu; Yamanashi, Yuji

    2011-07-01

    The neuromuscular junction (NMJ) is a synapse between a motor neuron and skeletal muscle. The contraction of skeletal muscle is controlled by the neurotransmitter acetylcholine (ACh), which is released from the motor nerve terminal. To achieve efficient neuromuscular transmission, acetylcholine receptors (AChRs) must be densely clustered on the muscle membrane of the NMJ. Failure of AChR clustering is associated with disorders of neuromuscular transmission such as congenital myasthenic syndromes (CMS) and myasthenia gravis (MG). Motoneuronal agrin and muscle-specific receptor tyrosine kinase (MuSK) are known to play essential roles in the formation and maintenance of NMJs in the central region of each muscle. However, it had been unclear how agrin activates MuSK. Recent studies have elucidated the roles of several key molecules, including the cytoplasmic adaptor protein Dok-7 and LDL receptor-related protein 4 (Lrp4), in agrin-induced MuSK activation. Moreover, new evidence indicates that cyclin-dependent kinase 5 (Cdk5) regulates postsynaptic differentiation. In this review, we summarize the latest developments in molecular mechanisms underlying NMJ formation in vertebrates. PMID:21747134

  7. Toll-Like Receptor Adaptor MyD88 is Essential for Pathogen Control During Oral Toxoplasma gondii Infection but not Adaptive Immunity Induced by a Vaccine Strain of the Parasite1

    Science.gov (United States)

    Sukhumavasi, Woraporn; Egan, Charlotte E.; Warren, Amy L.; Taylor, Gregory A.; Fox, Barbara A.; Bzik, David J.; Denkers, Eric Y.

    2008-01-01

    Toll-like receptor (TLR)/MyD88 activation is important in host resistance to Toxoplasma gondii during i. p. infection, but the function of this signaling pathway during oral infection, in which mucosal immunity assumes a predominant role, has not been examined. Here, we show that MyD88−/− mice fail to control the parasite and succumb within two weeks of oral infection. Early during infection, T cell IFN-γ production, recruitment of neutrophils and induction of p47 GTPase Irgm3/IGTP in the intestinal mucosa were dependent upon functional MyD88. Unexpectedly, these responses were MyD88-independent later during acute infection. In particular, CD4+ T cell IFN-γ reached normal levels independently of MyD88, despite continued absence of IL-12 in these animals. Intraperitoneal vaccination of MyD88−/− mice with an avirulent T. gondii uracil axotroph elicited robust IFN-γ responses and protective immunity to challenge with a high virulence T. gondii strain. Our results demonstrate that MyD88 is required to control Toxoplasma infection, but that the parasite can trigger adaptive immunity without the need for this TLR adaptor molecule. PMID:18714019

  8. Ubiquitination and degradation of CFTR by the E3 ubiquitin ligase MARCH2 through its association with adaptor proteins CAL and STX6.

    Science.gov (United States)

    Cheng, Jie; Guggino, William

    2013-01-01

    Golgi-localized cystic fibrosis transmembrane conductance regulator (CFTR)-associated ligand (CAL) and syntaxin 6 (STX6) regulate the abundance of mature, post-ER CFTR by forming a CAL/STX6/CFTR complex (CAL complex) that promotes CFTR degradation in lysosomes. However, the molecular mechanism underlying this degradation is unknown. Here we investigated the interaction of a Golgi-localized, membrane-associated RING-CH E3 ubiquitin ligase, MARCH2, with the CAL complex and the consequent binding, ubiquitination, and degradation of mature CFTR. We found that MARCH2 not only co-immunoprecipitated and co-localized with CAL and STX6, but its binding to CAL was also enhanced by STX6, suggesting a synergistic interaction. In vivo ubiquitination assays demonstrated the ubiquitination of CFTR by MARCH2, and overexpression of MARCH2, like that of CAL and STX6, led to a dose-dependent degradation of mature CFTR that was blocked by bafilomycin A1 treatment. A catalytically dead MARCH2 RING mutant was unable to promote CFTR degradation. In addition, MARCH2 had no effect on a CFTR mutant lacking the PDZ motif, suggesting that binding to the PDZ domain of CAL is required for MARCH2-mediated degradation of CFTR. Indeed, silencing of endogenous CAL ablated the effect of MARCH2 on CFTR. Consistent with its Golgi localization, MARCH2 had no effect on ER-localized ΔF508-CFTR. Finally, siRNA-mediated silencing of endogenous MARCH2 in the CF epithelial cell line CFBE-CFTR increased the abundance of mature CFTR. Taken together, these data suggest that the recruitment of the E3 ubiquitin ligase MARCH2 to the CAL complex and subsequent ubiquitination of CFTR are responsible for the CAL-mediated lysosomal degradation of mature CFTR.

  9. The proteolysis adaptor, NblA, is essential for degradation of the core pigment of the cyanobacterial light-harvesting complex.

    Science.gov (United States)

    Sendersky, Eleonora; Kozer, Noga; Levi, Mali; Moizik, Michael; Garini, Yuval; Shav-Tal, Yaron; Schwarz, Rakefet

    2015-09-01

    The cyanobacterial light-harvesting complex, the phycobilisome, is degraded under nutrient limitation, allowing the cell to adjust light absorbance to its metabolic capacity. This large light-harvesting antenna comprises a core complex of the pigment allophycocyanin, and rod-shaped pigment assemblies emanating from the core. NblA, a low-molecular-weight protein, is essential for degradation of the phycobilisome. NblA mutants exhibit high absorbance of rod pigments under conditions that generally elicit phycobilisome degradation, implicating NblA in degradation of these pigments. However, the vast abundance of rod pigments and the substantial overlap between the absorbance spectra of rod and core pigments has made it difficult to directly associate NblA with proteolysis of the phycobilisome core. Furthermore, lack of allophycocyanin degradation in an NblA mutant may reflect a requirement for rod degradation preceding core degradation, and does not prove direct involvement of NblA in proteolysis of the core pigment. Therefore, in this study, we used a mutant lacking phycocyanin, the rod pigment of Synechococcus elongatusPCC7942, to examine whether NblA is required for allophycocyanin degradation. We demonstrate that NblA is essential for degradation of the core complex of the phycobilisome. Furthermore, fluorescence lifetime imaging microscopy provided in situ evidence for the interaction of NblA with allophycocyanin, and indicated that NblA interacts with allophycocyanin complexes that are associated with the photosynthetic membranes. Based on these data, as well as previous observations indicating interaction of NblA with phycobilisomes attached to the photosynthetic membranes, we suggest a model for sequential phycobilisome disassembly by NblA. PMID:26173720

  10. Structural analysis of intermolecular interactions in the kinesin adaptor complex fasciculation and elongation protein zeta 1/ short coiled-coil protein (FEZ1/SCOCO.

    Directory of Open Access Journals (Sweden)

    Marcos Rodrigo Alborghetti

    Full Text Available Cytoskeleton and protein trafficking processes, including vesicle transport to synapses, are key processes in neuronal differentiation and axon outgrowth. The human protein FEZ1 (fasciculation and elongation protein zeta 1 / UNC-76, in C. elegans, SCOCO (short coiled-coil protein / UNC-69 and kinesins (e.g. kinesin heavy chain / UNC116 are involved in these processes. Exploiting the feature of FEZ1 protein as a bivalent adapter of transport mediated by kinesins and FEZ1 protein interaction with SCOCO (proteins involved in the same path of axonal growth, we investigated the structural aspects of intermolecular interactions involved in this complex formation by NMR (Nuclear Magnetic Resonance, cross-linking coupled with mass spectrometry (MS, SAXS (Small Angle X-ray Scattering and molecular modelling. The topology of homodimerization was accessed through NMR (Nuclear Magnetic Resonance studies of the region involved in this process, corresponding to FEZ1 (92-194. Through studies involving the protein in its monomeric configuration (reduced and dimeric state, we propose that homodimerization occurs with FEZ1 chains oriented in an anti-parallel topology. We demonstrate that the interaction interface of FEZ1 and SCOCO defined by MS and computational modelling is in accordance with that previously demonstrated for UNC-76 and UNC-69. SAXS and literature data support a heterotetrameric complex model. These data provide details about the interaction interfaces probably involved in the transport machinery assembly and open perspectives to understand and interfere in this assembly and its involvement in neuronal differentiation and axon outgrowth.

  11. Challenges in using cultured primary rodent hepatocytes or cell lines to study hepatic HDL receptor SR-BI regulation by its cytoplasmic adaptor PDZK1.

    Directory of Open Access Journals (Sweden)

    Kosuke Tsukamoto

    Full Text Available BACKGROUND: PDZK1 is a four PDZ-domain containing cytoplasmic protein that binds to a variety of membrane proteins via their C-termini and can influence the abundance, localization and/or function of its target proteins. One of these targets in hepatocytes in vivo is the HDL receptor SR-BI. Normal hepatic expression of SR-BI protein requires PDZK1 - <5% of normal hepatic SR-BI is seen in the livers of PDZK1 knockout mice. Progress has been made in identifying features of PDZK1 required to control hepatic SR-BI in vivo using hepatic expression of wild-type and mutant forms of PDZK1 in wild-type and PDZK1 KO transgenic mice. Such in vivo studies are time consuming and expensive, and cannot readily be used to explore many features of the underlying molecular and cellular mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: Here we have explored the potential to use either primary rodent hepatocytes in culture using 2D collagen gels with newly developed optimized conditions or PDZK1/SR-BI co-transfected cultured cell lines (COS, HEK293 for such studies. SR-BI and PDZK1 protein and mRNA expression levels fell rapidly in primary hepatocyte cultures, indicating this system does not adequately mimic hepatocytes in vivo for analysis of the PDZK1 dependence of SR-BI. Although PDZK1 did alter SR-BI protein expression in the cell lines, its influence was independent of SR-BI's C-terminus, and thus is not likely to occur via the same mechanism as that which occurs in hepatocytes in vivo. CONCLUSIONS/SIGNIFICANCE: Caution must be exercised in using primary hepatocytes or cultured cell lines when studying the mechanism underlying the regulation of hepatic SR-BI by PDZK1. It may be possible to use SR-BI and PDZK1 expression as sensitive markers for the in vivo-like state of hepatocytes to further improve primary hepatocyte cell culture conditions.

  12. The adaptor molecule signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is essential in mechanisms involving the Fyn tyrosine kinase for induction and progression of collagen-induced arthritis.

    Science.gov (United States)

    Zhong, Ming-Chao; Veillette, André

    2013-11-01

    Signaling lymphocytic activation molecule-associated protein (SAP) is an Src homology 2 domain-only adaptor involved in multiple immune cell functions. It has also been linked to immunodeficiencies and autoimmune diseases, such as systemic lupus erythematosus. Here, we examined the role and mechanism of action of SAP in autoimmunity using a mouse model of autoimmune arthritis, collagen-induced arthritis (CIA). We found that SAP was essential for development of CIA in response to collagen immunization. It was also required for production of collagen-specific antibodies, which play a key role in disease pathogenesis. These effects required SAP expression in T cells, not in B cells. In mice immunized with a high dose of collagen, the activity of SAP was nearly independent of its ability to bind the protein tyrosine kinase Fyn and correlated with the capacity of SAP to promote full differentiation of follicular T helper (TFH) cells. However, with a lower dose of collagen, the role of SAP was more dependent on Fyn binding, suggesting that additional mechanisms other than TFH cell differentiation were involved. Further studies suggested that this might be due to a role of the SAP-Fyn interaction in natural killer T cell development through the ability of SAP-Fyn to promote Vav-1 activation. We also found that removal of SAP expression during progression of CIA attenuated disease severity. However, it had no effect on disease when CIA was clinically established. Together, these results indicate that SAP plays an essential role in CIA because of Fyn-independent and Fyn-dependent effects on TFH cells and, possibly, other T cell types.

  13. The microRNA mir-71 inhibits calcium signaling by targeting the TIR-1/Sarm1 adaptor protein to control stochastic L/R neuronal asymmetry in C. elegans.

    Science.gov (United States)

    Hsieh, Yi-Wen; Chang, Chieh; Chuang, Chiou-Fen

    2012-01-01

    The Caenorhabditis elegans left and right AWC olfactory neurons communicate to establish stochastic asymmetric identities, AWC(ON) and AWC(OFF), by inhibiting a calcium-mediated signaling pathway in the future AWC(ON) cell. NSY-4/claudin-like protein and NSY-5/innexin gap junction protein are the two parallel signals that antagonize the calcium signaling pathway to induce the AWC(ON) fate. However, it is not known how the calcium signaling pathway is downregulated by nsy-4 and nsy-5 in the AWC(ON) cell. Here we identify a microRNA, mir-71, that represses the TIR-1/Sarm1 adaptor protein in the calcium signaling pathway to promote the AWC(ON) identity. Similar to tir-1 loss-of-function mutants, overexpression of mir-71 generates two AWC(ON) neurons. tir-1 expression is downregulated through its 3' UTR in AWC(ON), in which mir-71 is expressed at a higher level than in AWC(OFF). In addition, mir-71 is sufficient to inhibit tir-1 expression in AWC through the mir-71 complementary site in the tir-1 3' UTR. Our genetic studies suggest that mir-71 acts downstream of nsy-4 and nsy-5 to promote the AWC(ON) identity in a cell autonomous manner. Furthermore, the stability of mature mir-71 is dependent on nsy-4 and nsy-5. Together, these results provide insight into the mechanism by which nsy-4 and nsy-5 inhibit calcium signaling to establish stochastic asymmetric AWC differentiation.

  14. The microRNA mir-71 inhibits calcium signaling by targeting the TIR-1/Sarm1 adaptor protein to control stochastic L/R neuronal asymmetry in C. elegans.

    Directory of Open Access Journals (Sweden)

    Yi-Wen Hsieh

    Full Text Available The Caenorhabditis elegans left and right AWC olfactory neurons communicate to establish stochastic asymmetric identities, AWC(ON and AWC(OFF, by inhibiting a calcium-mediated signaling pathway in the future AWC(ON cell. NSY-4/claudin-like protein and NSY-5/innexin gap junction protein are the two parallel signals that antagonize the calcium signaling pathway to induce the AWC(ON fate. However, it is not known how the calcium signaling pathway is downregulated by nsy-4 and nsy-5 in the AWC(ON cell. Here we identify a microRNA, mir-71, that represses the TIR-1/Sarm1 adaptor protein in the calcium signaling pathway to promote the AWC(ON identity. Similar to tir-1 loss-of-function mutants, overexpression of mir-71 generates two AWC(ON neurons. tir-1 expression is downregulated through its 3' UTR in AWC(ON, in which mir-71 is expressed at a higher level than in AWC(OFF. In addition, mir-71 is sufficient to inhibit tir-1 expression in AWC through the mir-71 complementary site in the tir-1 3' UTR. Our genetic studies suggest that mir-71 acts downstream of nsy-4 and nsy-5 to promote the AWC(ON identity in a cell autonomous manner. Furthermore, the stability of mature mir-71 is dependent on nsy-4 and nsy-5. Together, these results provide insight into the mechanism by which nsy-4 and nsy-5 inhibit calcium signaling to establish stochastic asymmetric AWC differentiation.

  15. Differential Association of the Na+/H+ Exchanger Regulatory Factor (NHERF Family of Adaptor Proteins with the Raft- and the Non-Raft Brush Border Membrane Fractions of NHE3

    Directory of Open Access Journals (Sweden)

    Ayesha Sultan

    2013-11-01

    Full Text Available Background/Aims: Trafficking, brush border membrane (BBM retention, and signal-specific regulation of the Na+/H+ exchanger NHE3 is regulated by the Na+/H+ Exchanger Regulatory Factor (NHERF family of PDZ-adaptor proteins, which enable the formation of multiprotein complexes. It is unclear, however, what determines signal specificity of these NHERFs. Thus, we studied the association of NHE3, NHERF1 (EBP50, NHERF2 (E3KARP, and NHERF3 (PDZK1 with lipid rafts in murine small intestinal BBM. Methods: Detergent resistant membranes (“lipid rafts” were isolated by floatation of Triton X-incubated small intestinal BBM from a variety of knockout mouse strains in an Optiprep step gradient. Acid-activated NHE3 activity was measured fluorometrically in BCECF-loaded microdissected villi, or by assessment of CO2/HCO3- mediated increase in fluid absorption in perfused jejunal loops of anethetized mice. Results: NHE3 was found to partially associate with lipid rafts in the native BBM, and NHE3 raft association had an impact on NHE3 transport activity and regulation in vivo. NHERF1, 2 and 3 were differentially distributed to rafts and non-rafts, with NHERF2 being most raft-associated and NHERF3 entirely non-raft associated. NHERF2 expression enhanced the localization of NHE3 to membrane rafts. The use of acid sphingomyelinase-deficient mice, which have altered membrane lipid as well as lipid raft composition, allowed us to test the validity of the lipid raft concept in vivo. Conclusions: The differential association of the NHERFs with the raft-associated and the non-raft fraction of NHE3 in the brush border membrane is one component of the differential and signal-specific NHE3 regulation by the different NHERFs.

  16. A Novel Interaction of the Catalytic Subunit of Protein Phosphatase 2A with the Adaptor Protein CIN85 Suppresses Phosphatase Activity and Facilitates Platelet Outside-in αIIbβ3 Integrin Signaling.

    Science.gov (United States)

    Khatlani, Tanvir; Pradhan, Subhashree; Da, Qi; Shaw, Tanner; Buchman, Vladimir L; Cruz, Miguel A; Vijayan, K Vinod

    2016-08-12

    The transduction of signals generated by protein kinases and phosphatases are critical for the ability of integrin αIIbβ3 to support stable platelet adhesion and thrombus formation. Unlike kinases, it remains unclear how serine/threonine phosphatases engage the signaling networks that are initiated following integrin ligation. Because protein-protein interactions form the backbone of signal transduction, we searched for proteins that interact with the catalytic subunit of protein phosphatase 2A (PP2Ac). In a yeast two-hybrid study, we identified a novel interaction between PP2Ac and an adaptor protein CIN85 (Cbl-interacting protein of 85 kDa). Truncation and alanine mutagenesis studies revealed that PP2Ac binds to the P3 block ((396)PAIPPKKPRP(405)) of the proline-rich region in CIN85. The interaction of purified PP2Ac with CIN85 suppressed phosphatase activity. Human embryonal kidney 293 αIIbβ3 cells overexpressing a CIN85 P3 mutant, which cannot support PP2Ac binding, displayed decreased adhesion to immobilized fibrinogen. Platelets contain the ∼85 kDa CIN85 protein along with the PP2Ac-CIN85 complex. A myristylated cell-permeable peptide derived from residues 395-407 of CIN85 protein (P3 peptide) disrupted the platelet PP2Ac-CIN85 complex and decreased αIIbβ3 signaling dependent functions such as platelet spreading on fibrinogen and thrombin-mediated fibrin clot retraction. In a phospho-profiling study P3 peptide treated platelets also displayed decreased phosphorylation of several signaling proteins including Src and GSK3β. Taken together, these data support a role for the novel PP2Ac-CIN85 complex in supporting integrin-dependent platelet function by dampening the phosphatase activity. PMID:27334924

  17. The cellular RNA export receptor TAP/NXF1 is required for ICP27-mediated export of herpes simplex virus 1 RNA, but the TREX complex adaptor protein Aly/REF appears to be dispensable.

    Science.gov (United States)

    Johnson, Lisa A; Li, Ling; Sandri-Goldin, Rozanne M

    2009-07-01

    Herpes simplex virus 1 (HSV-1) protein ICP27 has been shown to shuttle between the nucleus and cytoplasm and to bind viral RNA during infection. ICP27 was found to interact with the cellular RNA export adaptor protein Aly/REF, which is part of the TREX complex, and to relocalize Aly/REF to viral replication sites. ICP27 is exported to the cytoplasm through the export receptor TAP/NXF1, and ICP27 must be able to interact with TAP/NXF1 for efficient export of HSV-1 early and late transcripts. We examined the dynamics of ICP27 movement and its localization with respect to Aly/REF and TAP/NXF1 in living cells during viral infection. Recombinant viruses with a yellow fluorescent protein (YFP) tag on the N or C terminus of ICP27 were constructed. While the N-terminally tagged ICP27 virus behaved like wild-type HSV-1, the C-terminally tagged virus was defective in viral replication and gene expression, and ICP27 was confined to the nucleus, suggesting that the C-terminal YFP tag interfered with ICP27's C-terminal interactions, including the interaction with TAP/NXF1. To assess the role of Aly/REF and TAP/NXF1 in viral RNA export, these factors were knocked down using small interfering RNA. Knockdown of Aly/REF had little effect on the export of ICP27 or poly(A)(+) RNA during infection. In contrast, a decrease in TAP/NXF1 levels severely impaired export of ICP27 and poly(A)(+) RNA. We conclude that TAP/NXF1 is essential for ICP27-mediated export of RNA during HSV-1 infection, whereas Aly/REF may be dispensable.

  18. The RA domain of Ste50 adaptor protein is required for delivery of Ste11 to the plasma membrane in the filamentous growth signaling pathway of the yeast Saccharomyces cerevisiae.

    Science.gov (United States)

    Truckses, Dagmar M; Bloomekatz, Joshua E; Thorner, Jeremy

    2006-02-01

    In Saccharomyces cerevisiae, pheromone response requires Ste5 scaffold protein, which ensures efficient G-protein-dependent recruitment of mitogen-activated protein kinase (MAPK) cascade components Ste11 (MAPK kinase kinase), Ste7 (MAPK kinase), and Fus3 (MAPK) to the plasma membrane for activation by Ste20 protein kinase. Ste20, which phosphorylates Ste11 to initiate signaling, is activated by binding to Cdc42 GTPase (membrane anchored via its C-terminal geranylgeranylation). Less clear is how activated and membrane-localized Ste20 contacts Ste11 to trigger invasive growth signaling, which also requires Ste7 and the MAPK Kss1, but not Ste5. Ste50 protein associates constitutively via an N-terminal sterile-alpha motif domain with Ste11, and this interaction is required for optimal invasive growth and hyperosmotic stress (high-osmolarity glycerol [HOG]) signaling but has a lesser role in pheromone response. We show that a conserved C-terminal, so-called "Ras association" (RA) domain in Ste50 is also essential for invasive growth and HOG signaling in vivo. In vitro the Ste50 RA domain is not able to associate with Ras2, but it does associate with Cdc42 and binds to a different face than does Ste20. RA domain function can be replaced by the nine C-terminal, plasma membrane-targeting residues (KKSKKCAIL) of Cdc42, and membrane-targeted Ste50 also suppresses the signaling deficiency of cdc42 alleles specifically defective in invasive growth. Thus, Ste50 serves as an adaptor to tether Ste11 to the plasma membrane and can do so via association with Cdc42, thereby permitting the encounter of Ste11 with activated Ste20. PMID:16428446

  19. Correlated Flexible Molecular Coding and Molecular Evolvability

    OpenAIRE

    Husimi, Y; Aita, T.; Tabuchi, I.

    2002-01-01

    Evolvability of biopolymers is based on molecular coding. The molecular coding is represented by biopolymer function vs monomeric sequence relationship, that is, a proper fitness landscape on the sequence space. On the other hand, molecular coding is mostly realized by monomeric sequence vs biopolymer structure relationship. We suggest the evolution of evolvability based on flexible or multiplex coding originating from flexible or polymorphic conformation of evolving biopolymers. We report a ...

  20. Role of polymorphisms of toll-like receptor (TLR 4, TLR9, toll-interleukin 1 receptor domain containing adaptor protein (TIRAP and FCGR2A genes in malaria susceptibility and severity in Burundian children

    Directory of Open Access Journals (Sweden)

    Esposito Susanna

    2012-06-01

    Full Text Available Abstract Background Malaria caused by Plasmodium falciparum is one of the leading causes of human morbidity and mortality from infectious diseases, predominantly in tropical and sub-tropical countries. As genetic variations in the toll-like receptors (TLRs-signalling pathway have been associated with either susceptibility or resistance to several infectious and inflammatory diseases, the supposition is that single nucleotide polymorphisms (SNPs of TLR2, TLR4, TLR9, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP and FCGR2A could modulate malaria susceptibility and severity. Methods This study was planned to make a further contribution to solving the problem of the real role of the most common polymorphisms of TLR4, TLR9, TIRAP and FCGR2A genes in modulating the risk of malaria and disease severity in children from Burundi, Central Africa. All the paediatric patients aged six months to 10 years admitted to the hospital of Kiremba, Burundi, between February 2011 and September 2011, for fever and suspicion of acute malaria were screened for malaria parasitaemia by light microscopy of thick and thin blood smears. In children with malaria and in uninfected controls enrolled during the study period in the same hospital, blood samples were obtained on filter paper and TLR4 Asp299Gly rs4986790, TLR9 G1174A rs352139, T-1486 C rs187084 TLR9 T-1237 C rs5743836, TIRAP Ser180Leu rs8177374 and the FCGR2A His131Arg rs1801274 polymorphisms were studied using an ABI PRISM 7900 HT Fast Real-time instrument. Results A total of 602 patients and 337 controls were enrolled. Among the malaria cases, 553 (91.9 % were considered as suffering from uncomplicated and 49 (8.1 % from severe malaria. TLR9 T1237C rs5743836CC was associated with an increased risk of developing malaria (p = 0.03, although it was found with the same frequency in uncomplicated and severe malaria cases. No other differences were found in all alleles studied and in

  1. FDDI network test adaptor error injection circuit

    Science.gov (United States)

    Eckenrode, Thomas (Inventor); Stauffer, David R. (Inventor); Stempski, Rebecca (Inventor)

    1994-01-01

    An apparatus for injecting errors into a FDDI token ring network is disclosed. The error injection scheme operates by fooling a FORMAC into thinking it sent a real frame of data. This is done by using two RAM buffers. The RAM buffer normally accessed by the RBC/DPC becomes a SHADOW RAM during error injection operation. A dummy frame is loaded into the shadow RAM in order to fool the FORMAC. This data is just like the data that would be used if sending a normal frame, with the restriction that it must be shorter than the error injection data. The other buffer, the error injection RAM, contains the error injection frame. The error injection data is sent out to the media by switching a multiplexor. When the FORMAC is done transmitting the data, the multiplexor is switched back to the normal mode. Thus, the FORMAC is unaware of what happened and the token ring remains operational.

  2. Contamination of sequence databases with adaptor sequences

    Energy Technology Data Exchange (ETDEWEB)

    Yoshikawa, Takeo; Sanders, A.R.; Detera-Wadleigh, S.D. [National Institute of Mental Health, Bethesda, MD (United States)

    1997-02-01

    Because of the exponential increase in the amount of DNA sequences being added to the public databases on a daily basis, it has become imperative to identify sources of contamination rapidly. Previously, contaminations of sequence databases have been reported to alert the scientific community to the problem. These contaminations can be divided into two categories. The first category comprises host sequences that have been difficult for submitters to manage or control. Examples include anomalous sequences derived from Escherichia coli, which are inserted into the chromosomes (and plasmids) of the bacterial hosts. Insertion sequences are highly mobile and are capable of transposing themselves into plasmids during cloning manipulation. Another example of the first category is the infection with yeast genomic DNA or with bacterial DNA of some commercially available cDNA libraries from Clontech. The second category of database contamination is due to the inadvertent inclusion of nonhost sequences. This category includes incorporation of cloning-vector sequences and multicloning sites in the database submission. M13-derived artifacts have been common, since M13-based vectors have been widely used for subcloning DNA fragments. Recognizing this problem, the National Center for Biotechnology Information (NCBI) started to screen, in April 1994, all sequences directly submitted to GenBank, against a set of vector data retrieved from GenBank by use of key-word searches, such as {open_quotes}vector.{close_quotes} In this report, we present evidence for another sequence artifact that is widespread but that, to our knowledge, has not yet been reported. 11 refs., 1 tab.

  3. Adaptive molecular convergence: Molecular evolution versus molecular phylogenetics

    OpenAIRE

    Castoe, Todd A.; de Koning, A. P. Jason; Pollock, David D.

    2010-01-01

    Definitive identification of convergent evolution, the acquisition of the same biological trait in unrelated lineages, provides one of the most compelling sources of evidence for natural selection. Although numerous examples of convergent morphological evolution are well known (such as the independent development of wings in birds and mammals), cases of convergent evolution at the molecular-genetic level appear to be quite rare. We recently discovered a remarkable case of convergent molecular...

  4. Advancement of Molecular Morphology

    Institute of Scientific and Technical Information of China (English)

    顾江

    2004-01-01

    @@ Molecular morphology is a new discipline of medical science that studies morphology at the molecular level. This includes the investigation of occurrence and distribution of proteins, peptides, DNA and RNA sequences at the tissue, cellular, and ultrastructural levels.

  5. Basic molecular spectroscopy

    CERN Document Server

    Gorry, PA

    1985-01-01

    BASIC Molecular Spectroscopy discusses the utilization of the Beginner's All-purpose Symbolic Instruction Code (BASIC) programming language in molecular spectroscopy. The book is comprised of five chapters that provide an introduction to molecular spectroscopy through programs written in BASIC. The coverage of the text includes rotational spectra, vibrational spectra, and Raman and electronic spectra. The book will be of great use to students who are currently taking a course in molecular spectroscopy.

  6. Polymer friction Molecular Dynamics

    OpenAIRE

    Sivebæk, Ion Marius; Samoilov, Vladimir N.; Persson, Bo N. J.

    2010-01-01

    We present molecular dynamics friction calculations for confined hydrocarbon solids with molecular lengths from 20 to 1400 carbon atoms. Two cases are considered: a) polymer sliding against a hard substrate, and b) polymer sliding on polymer. In the first setup the shear stresses are relatively independent of molecular length. For polymer sliding on polymer the friction is significantly larger, and dependent on the molecular chain length. In both cases, the shear stresses are proportional to ...

  7. Cardiovascular molecular MR imaging

    OpenAIRE

    Lamb, H J; van der Meer, R. W.; Roos, A. (Anna); Bax, J J

    2007-01-01

    Introduction Cardiovascular molecular imaging is a rapidly evolving field of research, aiming to image and quantify molecular and cellular targets in vivo. MR imaging has some inherent properties that make it very suitable for cardiovascular molecular imaging. Until now, only a limited number of studies have been published on cardiovascular molecular imaging using MR imaging. Review In the current review, MR techniques that have already shown potential are discussed. Metabolic MR imaging can ...

  8. Physical Chemistry of Molecular

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    @@ Established in 2009, the group consists of six researchers and more than 70 research assistants and graduate students from the CAS Key Laboratory of Molecular Nanostructures and Nanotechnologies at the CAS Institute of Chemistry.Its research focuses on the physical chemistry involved in molecular assembly, molecular nanostructures, functional nanomaterials and conceptual nano-devices.

  9. Engineering molecular machines

    Science.gov (United States)

    Erman, Burak

    2016-04-01

    Biological molecular motors use chemical energy, mostly in the form of ATP hydrolysis, and convert it to mechanical energy. Correlated thermal fluctuations are essential for the function of a molecular machine and it is the hydrolysis of ATP that modifies the correlated fluctuations of the system. Correlations are consequences of the molecular architecture of the protein. The idea that synthetic molecular machines may be constructed by designing the proper molecular architecture is challenging. In their paper, Sarkar et al (2016 New J. Phys. 18 043006) propose a synthetic molecular motor based on the coarse grained elastic network model of proteins and show by numerical simulations that motor function is realized, ranging from deterministic to thermal, depending on temperature. This work opens up a new range of possibilities of molecular architecture based engine design.

  10. Workshop on molecular animation.

    Science.gov (United States)

    Bromberg, Sarina; Chiu, Wah; Ferrin, Thomas E

    2010-10-13

    From February 25 to 26, 2010, in San Francisco, the Resource for Biocomputing, Visualization, and Informatics (RBVI) and the National Center for Macromolecular Imaging (NCMI) hosted a molecular animation workshop for 21 structural biologists, molecular animators, and creators of molecular visualization software. Molecular animation aims to visualize scientific understanding of biomolecular processes and structures. The primary goal of the workshop was to identify the necessary tools for producing high-quality molecular animations, understanding complex molecular and cellular structures, creating publication supplementary materials and conference presentations, and teaching science to students and the public. Another use of molecular animation emerged in the workshop: helping to focus scientific inquiry about the motions of molecules and enhancing informal communication within and between laboratories.

  11. Standardized molecular typing.

    Science.gov (United States)

    Müller, F M; Lischewski, A; Harmsen, D; Hacker, J

    1999-01-01

    Molecular typing methods are useful tools in molecular mycology. The results of these biotyping procedures may help to identify pathogenic strains in order to detect sources of nosocomial infection and for the investigation of epidemiological relationships. With respect to the facultative pathogen, Candida albicans, various methods such as pulse-field gel electrophoresis (PFGE), restriction fragment length polymorphism (RFLP), DNA fingerprinting methods and hybridization with repetitive DNA elements have been described as useful tools in molecular epidemiology. The previously described hybridization method with the Candida albicans specific CARE-2 probe and subsequent rehybridization with a molecular size marker is a standardized reproducible typing method for comparison of results obtained in different laboratories. In a larger epidemiological study conducted at the University Hospital of Würzburg analysing clinical C. albicans isolates, we were able to describe relationships between sequential patient isolates. These findings demonstrate that standardized molecular typing methods are a powerful tool in molecular mycology studies. PMID:10865907

  12. Sober Topological Molecular Lattices

    Institute of Scientific and Technical Information of China (English)

    张德学; 李永明

    2003-01-01

    A topological molecular lattice (TML) is a pair (L, T), where L is a completely distributive lattice and r is a subframe of L. There is an obvious forgetful functor from the category TML of TML's to the category Loc of locales. In this note,it is showed that this forgetful functor has a right adjoint. Then, by this adjunction,a special kind of topological molecular lattices called sober topological molecular lattices is introduced and investigated.

  13. Molecular imaging in oncology

    OpenAIRE

    Dzik-Jurasz, A S K

    2004-01-01

    Cancer is a genetic disease that manifests in loss of normal cellular homeostatic mechanisms. The biology and therapeutic modulation of neoplasia occurs at the molecular level. An understanding of these molecular processes is therefore required to develop novel prognostic and early biomarkers of response. In addition to clinical applications, increased impetus for the development of such technologies has been catalysed by pharmaceutical companies investing in the development of molecular ther...

  14. Molecular Epidemiology of Rotaviruses

    OpenAIRE

    Nakagomi, Osamu

    2004-01-01

    Molecular epidemiology of rotaviruses emerged a little over 25 years ago as a fascinating branch of science that utilized then cutting-edge technology of RNA polyacrylamide gel electrophoresis. Molecular epidemiology, as I have observed it closely almost since its dawn, is an ever-evolving discipline which has incorporated the advances of the related sciences including molecular evolutionary biology and ecology, while it is firmly and deeply rooted in the edifice of epidemiology of infectious...

  15. Dense molecular thermodynamics

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, J.D.; Shaw, M.S.; Holian, B.L.

    1983-01-01

    We are examining the thermodynamics of dense molecular fluids from the theoretical view. Our interests range from modeling single-species, spherically symmetric, atomic systems, through adding the complication of nonspherical molecular potentials, to mixing various molecular species with the inclusion of chemistry. We discuss what has been accomplished and evaluate the directions to be taken in attacking the unsolved problems. The various theoretical approaches, both analytic and numerical, are presented. We finish with a discussion of the recent advance in treating nonspherical molecular potentials with effective spherical potentials in the calculation of thermodynamics.

  16. Polymer friction Molecular Dynamics

    DEFF Research Database (Denmark)

    Sivebæk, Ion Marius; Samoilov, Vladimir N.; Persson, Bo N. J.

    We present molecular dynamics friction calculations for confined hydrocarbon solids with molecular lengths from 20 to 1400 carbon atoms. Two cases are considered: a) polymer sliding against a hard substrate, and b) polymer sliding on polymer. In the first setup the shear stresses are relatively...... independent of molecular length. For polymer sliding on polymer the friction is significantly larger, and dependent on the molecular chain length. In both cases, the shear stresses are proportional to the squeezing pressure and finite at zero load, indicating an adhesional contribution to the friction force....

  17. Mesoporous molecular sieve catalysts

    DEFF Research Database (Denmark)

    Højholt, Karen Thrane

    This thesis deals with a very specific class of molecular sieves known as zeolites. Zeolites are a class of crystalline aluminosilicates characterised by pores or cavities of molecular dimensions as part of their crystal structure. In this work zeolites were modified for the use and understanding...

  18. Making molecular machines work

    NARCIS (Netherlands)

    Browne, Wesley R.; Feringa, Ben L.

    2006-01-01

    In this review we chart recent advances in what is at once an old and very new field of endeavour the achievement of control of motion at the molecular level including solid-state and surface-mounted rotors, and its natural progression to the development of synthetic molecular machines. Besides a di

  19. Advancement of Molecular Morphology

    Institute of Scientific and Technical Information of China (English)

    顾江

    2004-01-01

    Molecular morphology is a new discipline of medical science that studies morphology at the molecular level. This includes the investigation of occurrence and distribution of proteins, peptides, DNA and RNA sequences at the tissue, cellular, and uhrastructural levels. Morphology is defined as a field of science investigating the shape,

  20. Multifunctionality in molecular magnetism.

    Science.gov (United States)

    Pinkowicz, Dawid; Czarnecki, Bernard; Reczyński, Mateusz; Arczyński, Mirosław

    2015-01-01

    Molecular magnetism draws from the fundamental ideas of structural chemistry and combines them with experimental physics resulting in one of the highest profile current topics, namely molecular materials that exhibit multifunctionality. Recent advances in the design of new generations of multifunctional molecular magnets that retain the functions of the building blocks and exhibit non-trivial magnetic properties at higher temperatures provide promising evidence that they may be useful for the future construction of nanoscale devices. This article is not a complete review but is rather an introduction into thefascinating world of multifunctional solids with magnetism as the leitmotif. We provide a subjective selection and discussion of the most inspiring examples of multifunctional molecular magnets: magnetic sponges, guest-responsive magnets, molecular magnets with ionic conductivity, photomagnets and non-centrosymmetric and chiral magnets.

  1. Molecular diodes and applications.

    Science.gov (United States)

    Kumar, M Jagadesh

    2007-01-01

    Due to the huge power consumption and expensive fabrication methods required, down scaling silicon devices to sub-100 nm dimensions is becoming very unattractive. On the other hand, it is easier to build electronic circuits using molecules since they are small and their properties can be tuned. In this review, we first discuss the building blocks of molecular electronics. We then describe how these building blocks can be used to build single molecule based digital logic such as AND, OR and XOR gates. The distinction of these molecular electronic building blocks is that for first time, (i) the Tour wires are used as the conductive backbone for the rectifying junctions, (ii) donor/acceptor principles are implemented in the molecular wire itself and (iii) the logic gates are realized using molecular rectifying diodes embedded in the molecular conducting wire itself. PMID:19076020

  2. Fragment oriented molecular shapes.

    Science.gov (United States)

    Hain, Ethan; Camacho, Carlos J; Koes, David Ryan

    2016-05-01

    Molecular shape is an important concept in drug design and virtual screening. Shape similarity typically uses either alignment methods, which dynamically optimize molecular poses with respect to the query molecular shape, or feature vector methods, which are computationally less demanding but less accurate. The computational cost of alignment can be reduced by pre-aligning shapes, as is done with the Volumetric-Aligned Molecular Shapes (VAMS) method. Here, we introduce and evaluate fragment oriented molecular shapes (FOMS), where shapes are aligned based on molecular fragments. FOMS enables the use of shape constraints, a novel method for precisely specifying molecular shape queries that provides the ability to perform partial shape matching and supports search algorithms that function on an interactive time scale. When evaluated using the challenging Maximum Unbiased Validation dataset, shape constraints were able to extract significantly enriched subsets of compounds for the majority of targets, and FOMS matched or exceeded the performance of both VAMS and an optimizing alignment method of shape similarity search. PMID:27085751

  3. Molecular Engineering of DNA: Molecular Beacons

    OpenAIRE

    Wang, Kemin; Tang, Zhiwen; Yang, Chaoyong James; Kim, Youngmi; Fang, Xiaohong; Li, Wei; Wu, Yanrong; Medley, Colin D.; Cao, Zehui; Jun LI; Colon, Patrick; Lin, Hui; Tan, Weihong

    2009-01-01

    Molecular beacons (MBs) are specifically designed DNA hairpin structures that are widely used as fluorescent probes. Applications of MBs range from genetic screening, biosensor development, biochip construction, and the detection of single-nucleotide polymorphisms to mRNA monitoring in living cells. The inherent signal-transduction mechanism of MBs enables the analysis of target oligonucleotides without the separation of unbound probes. The MB stem–loop structure holds the fluorescence-donor ...

  4. Modeling of molecular properties

    CERN Document Server

    Comba, Peter

    2011-01-01

    Molecular modeling encompasses applied theoretical approaches and computational techniques to model structures and properties of molecular compounds and materials in order to predict and / or interpret their properties. The modeling covered in this book ranges from methods for small chemical to large biological molecules and materials. With its comprehensive coverage of important research fields in molecular and materials science, this is a must-have for all organic, inorganic and biochemists as well as materials scientists interested in applied theoretical and computational chemistry. The 28

  5. Are there molecular signatures?

    Energy Technology Data Exchange (ETDEWEB)

    Bennett, W.P.

    1995-10-01

    This report describes molecular signatures and mutational spectrum analysis. The mutation spectrum is defined as the type and location of DNA base change. There are currently about five well documented cases. Mutations and radon-associated tumors are discussed.

  6. Molecular Mechanisms of Preeclampsia

    OpenAIRE

    Vitoratos, N.; Hassiakos, D.; C. Iavazzo

    2012-01-01

    Preeclampsia is one of the leading causes of maternal morbidity/mortality. The pathogenesis of preeclampsia is still under investigation. The aim of this paper is to present the molecular mechanisms implicating in the pathway leading to preeclampsia.

  7. Molecular Gastronomy: An Introduction

    OpenAIRE

    Burke, Roisin; Kelly, Alan L.; This, Hervé

    2016-01-01

    Abstract In the world of food science, Molecular Gastronomy is a term which is relatively new, but describes the convergence of the two long-established core food disciplines, i.e., food science and the art of the chef.

  8. Molecular ion photofragment spectroscopy

    International Nuclear Information System (INIS)

    A new molecular ion photofragment spectrometer is described which features a supersonic molecular beam ion source and a radio frequency octapole ion trap interaction region. This unique combination allows several techniques to be applied to the problem of detecting a photon absorption event of a molecular ion. In particular, it may be possible to obtain low resolution survey spectra of exotic molecular ions by using a direct vibrational predissociation process, or by using other more indirect detection methods. The use of the spectrometer is demonstrated by measuring the lifetime of the O2+(4π/sub u/) metastable state which is found to consist of two main components: the 4π/sub 5/2/ and 4π/sub -1/2/ spin components having a long lifetime (approx. 129 ms) and the 4π/sub 3/2/ and 4π/sub 1/2/ spin components having a short lifetime (approx. 6 ms)

  9. Atomic and Molecular Interactions

    International Nuclear Information System (INIS)

    The Gordon Research Conference (GRC) on Atomic and Molecular Interactions was held at Roger Williams University, Bristol, RI. Emphasis was placed on current unpublished research and discussion of the future target areas in this field

  10. Molecular electronic junction transport

    DEFF Research Database (Denmark)

    Solomon, Gemma C.; Herrmann, Carmen; Ratner, Mark

    2012-01-01

    Whenasinglemolecule,oracollectionofmolecules,isplacedbetween two electrodes and voltage is applied, one has a molecular transport junction. We discuss such junctions, their properties, their description, and some of their applications. The discussion is qualitative rather than quantitative, and f...

  11. Molecular imaging in oncology

    Energy Technology Data Exchange (ETDEWEB)

    Schober, Otmar; Riemann, Burkhard (eds.) [Universitaetsklinikum Muenster (Germany). Klinik fuer Nuklearmedizin

    2013-02-01

    Considers in detail all aspects of molecular imaging in oncology, ranging from basic research to clinical applications in the era of evidence-based medicine. Examines technological issues and probe design. Discusses preclinical studies in detail, with particular attention to multimodality imaging. Presents current clinical use of PET/CT, SPECT/CT, and optical imagingWritten by acknowledged experts. The impact of molecular imaging on diagnostics, therapy, and follow-up in oncology is increasing significantly. The process of molecular imaging includes key biotarget identification, design of specific molecular imaging probes, and their preclinical evaluation, e.g., in vivo using small animal studies. A multitude of such innovative molecular imaging probes have already entered clinical diagnostics in oncology. There is no doubt that in future the emphasis will be on multimodality imaging in which morphological, functional, and molecular imaging techniques are combined in a single clinical investigation that will optimize diagnostic processes. This handbook addresses all aspects of molecular imaging in oncology, ranging from basic research to clinical applications in the era of evidence-based medicine. The first section is devoted to technology and probe design, and examines a variety of PET and SPECT tracers as well as multimodality probes. Preclinical studies are then discussed in detail, with particular attention to multimodality imaging. In the third section, diverse clinical applications are presented, and the book closes by looking at future challenges. This handbook will be of value to all who are interested in the revolution in diagnostic oncology that is being brought about by molecular imaging.

  12. Phylogenetic molecular function annotation

    OpenAIRE

    Barbara E Engelhardt; Jordan, Michael I.; Repo, Susanna T; Brenner, Steven E

    2009-01-01

    It is now easier to discover thousands of protein sequences in a new microbial genome than it is to biochemically characterize the specific activity of a single protein of unknown function. The molecular functions of protein sequences have typically been predicted using homology-based computational methods, which rely on the principle that homologous proteins share a similar function. However, some protein families include groups of proteins with different molecular functions. A phylogenetic ...

  13. Cardiovascular Molecular Imaging

    OpenAIRE

    Khanicheh, Elham

    2009-01-01

    Although there have been significant improvements in the treatment of cardiovascular diseases they still remain the main cause of morbidity and mortality globally. Currently available diagnostic approaches may not be adequate to detect pathologic changes during the early disease stages, which may be valuable for risk stratification and also to assess a response to a therapy. Therefore molecular imaging techniques such as Contrast Enhanced Ultrasound (CEU) molecular imaging to noninvasively i...

  14. MOLECULAR REPLICATOR DYNAMICS

    OpenAIRE

    BÄRBEL M. R. STADLER; Stadler, Peter F

    2003-01-01

    Template-dependent replication at the molecular level is the basis of reproduction in nature. A detailed understanding of the peculiarities of the chemical reaction kinetics associated with replication processes is therefore an indispensible prerequisite for any understanding of evolution at the molecular level. Networks of interacting self-replicating species can give rise to a wealth of different dynamical phenomena, from competitive exclusion to permanent coexistence, from global stability...

  15. Molecular mechanisms in gliomagenesis

    DEFF Research Database (Denmark)

    Hulleman, Esther; Helin, Kristian

    2005-01-01

    , in order to design novel therapies and treatments for GBM, research has recently intensified to identify the cellular and molecular mechanisms leading to GBM formation. Modeling of astrocytomas by genetic manipulation of mice suggests that deregulation of the pathways that control gliogenesis during normal......-scale genomics and proteomics in combination with relevant mouse models will most likely provide novel insights into the molecular mechanisms underlying glioma formation and will hopefully lead to development of treatment modalities for GBM....

  16. Open source molecular modeling.

    Science.gov (United States)

    Pirhadi, Somayeh; Sunseri, Jocelyn; Koes, David Ryan

    2016-09-01

    The success of molecular modeling and computational chemistry efforts are, by definition, dependent on quality software applications. Open source software development provides many advantages to users of modeling applications, not the least of which is that the software is free and completely extendable. In this review we categorize, enumerate, and describe available open source software packages for molecular modeling and computational chemistry. An updated online version of this catalog can be found at https://opensourcemolecularmodeling.github.io.

  17. Towards molecular photochemionics

    OpenAIRE

    Margherita Venturi; Vincenzo Balzani; Roberto Ballardini; Alberto Credi; M. Teresa Gandolfi

    2004-01-01

    In the last few years there has been a great interest in developing electronics at a molecular level (molecular electronics), e.g. to construct miniaturized electric circuits that would be much smaller than the corresponding micron-scale digital logic circuits fabricated on conventional solid-state semiconductor chips. An alternative possibility to the use of electron fluxes as a means for information processing (electronics) is that of using optical beams (photonics), but up until now scarce...

  18. Interstellar molecular clouds

    Science.gov (United States)

    Bally, J.

    1986-04-01

    The physical properties of the molecular phase of the interstellar medium are studied with regard to star formation and the structure of the Galaxy. Most observations of molecular clouds are made with single-dish, high-surface precision radio telescopes, with the best resolution attainable at 0.2 to 1 arcmin; the smallest structures that can be resolved are of order 10 to the 17th cm in diameter. It is now believed that: (1) most of the mass of the Galaxy is in the form of giant molecular clouds; (2) the largest clouds and those responsible for most massive star formation are concentrated in spiral arms; (3) the molecular clouds are the sites of perpetual star formation, and are significant in the chemical evolution of the Galaxy; (4) giant molecular clouds determine the evolution of the kinematic properties of galactic disk stars; (5) the total gas content is diminishing with time; and (6) most clouds have supersonic internal motions and do not form stars on a free-fall time scale. It is concluded that though progress has been made, more advanced instruments are needed to inspect the processes operating within stellar nurseries and to study the distribution of the molecular clouds in more distant galaxies. Instruments presently under construction which are designed to meet these ends are presented.

  19. Structure of a PE–PPE–EspG complex from Mycobacterium tuberculosis reveals molecular specificity of ESX protein secretion

    Science.gov (United States)

    Ekiert, Damian C.; Cox, Jeffery S.

    2014-01-01

    Nearly 10% of the coding capacity of the Mycobacterium tuberculosis genome is devoted to two highly expanded and enigmatic protein families called PE and PPE, some of which are important virulence/immunogenicity factors and are secreted during infection via a unique alternative secretory system termed “type VII.” How PE-PPE proteins function during infection and how they are translocated to the bacterial surface through the five distinct type VII secretion systems [ESAT-6 secretion system (ESX)] of M. tuberculosis is poorly understood. Here, we report the crystal structure of a PE-PPE heterodimer bound to ESX secretion-associated protein G (EspG), which adopts a novel fold. This PE-PPE-EspG complex, along with structures of two additional EspGs, suggests that EspG acts as an adaptor that recognizes specific PE–PPE protein complexes via extensive interactions with PPE domains, and delivers them to ESX machinery for secretion. Surprisingly, secretion of most PE-PPE proteins in M. tuberculosis is likely mediated by EspG from the ESX-5 system, underscoring the importance of ESX-5 in mycobacterial pathogenesis. Moreover, our results indicate that PE-PPE domains function as cis-acting targeting sequences that are read out by EspGs, revealing the molecular specificity for secretion through distinct ESX pathways. PMID:25275011

  20. Molecular Programming Pseudo-code Representation to Molecular Electronics

    CERN Document Server

    Pradhan, Manas Ranjan

    2010-01-01

    This research paper is proposing the idea of pseudo code representation to molecular programming used in designing molecular electronics devices. Already the schematic representation of logical gates like AND, OR, NOT etc.from molecular diodes or resonant tunneling diode are available. This paper is setting a generic pseudo code model so that various logic gates can be formulated. These molecular diodes have designed from organic molecules or Bio-molecules. Our focus is on to give a scenario of molecular computation through molecular programming. We have restricted our study to molecular rectifying diode and logic device as AND gate from organic molecules only.

  1. Molecular vibrational energy flow

    Science.gov (United States)

    Gruebele, M.; Bigwood, R.

    This article reviews some recent work in molecular vibrational energy flow (IVR), with emphasis on our own computational and experimental studies. We consider the problem in various representations, and use these to develop a family of simple models which combine specific molecular properties (e.g. size, vibrational frequencies) with statistical properties of the potential energy surface and wavefunctions. This marriage of molecular detail and statistical simplification captures trends of IVR mechanisms and survival probabilities beyond the abilities of purely statistical models or the computational limitations of full ab initio approaches. Of particular interest is IVR in the intermediate time regime, where heavy-atom skeletal modes take over the IVR process from hydrogenic motions even upon X H bond excitation. Experiments and calculations on prototype heavy-atom systems show that intermediate time IVR differs in many aspects from the early stages of hydrogenic mode IVR. As a result, IVR can be coherently frozen, with potential applications to selective chemistry.

  2. Theoretical Molecular Biophysics

    CERN Document Server

    Scherer, Philipp

    2010-01-01

    "Theoretical Molecular Biophysics" is an advanced study book for students, shortly before or after completing undergraduate studies, in physics, chemistry or biology. It provides the tools for an understanding of elementary processes in biology, such as photosynthesis on a molecular level. A basic knowledge in mechanics, electrostatics, quantum theory and statistical physics is desirable. The reader will be exposed to basic concepts in modern biophysics such as entropic forces, phase separation, potentials of mean force, proton and electron transfer, heterogeneous reactions coherent and incoherent energy transfer as well as molecular motors. Basic concepts such as phase transitions of biopolymers, electrostatics, protonation equilibria, ion transport, radiationless transitions as well as energy- and electron transfer are discussed within the frame of simple models.

  3. Engines at molecular scales

    CERN Document Server

    Krishnan, R; Krishnan, Raishma

    2004-01-01

    In recent literature there has been a lot of interest in the phenomena of noise induced transport in the absence of an average bias occurring in spatially periodic systems far from equilibrium. One of the main motivations in this area is to understand the mechanism behind the operation of biological motors at molecular scale. These molecular motors convert chemical energy available during the hydrolysis of ATP into mechanical motion to transport cargo and vesicles in living cells with very high reliability, adaptability and efficiency in a very noisy environment. The basic principle behind such a motion, namely the Brownian ratchet principle, has applications in nanotechnology as novel nanoparticle separation devices. Also, the mechanism of ratchet operation finds applications in game theory. Here, we briefly focus on the physical concepts underlying the constructive role of noise in assisting transport at a molecular level. The nature of particle currents, the energetic efficiency of these motors, the entrop...

  4. Valency and molecular structure

    CERN Document Server

    Cartmell, E

    1977-01-01

    Valency and Molecular Structure, Fourth Edition provides a comprehensive historical background and experimental foundations of theories and methods relating to valency and molecular structures. In this edition, the chapter on Bohr theory has been removed while some sections, such as structures of crystalline solids, have been expanded. Details of structures have also been revised and extended using the best available values for bond lengths and bond angles. Recent developments are mostly noted in the chapter on complex compounds, while a new chapter has been added to serve as an introduction t

  5. Molecular epidemiology of Blastocystis

    Directory of Open Access Journals (Sweden)

    Fadime Eroğlu

    2015-12-01

    Full Text Available Blastocystis pathogenicity and classification was newly illuminated with molecular genetic studies and recently the parasite was found in the focus of many researchers. Several molecular methods such as; polymerase chain reaction (PCR, PCR-restriction fragment length polymorphism, random amplified polymorphic DNA, real-time polymerase chain reaction and DNA sequencing analyses can be used in genotyping of Blastocystis. Blastocystis parasites may cause diarrhea, abdominal pain, bloating, gas, irritability, anorexia, cramps, vomiting, dehydration, insomnia, nausea, loss of appetite, weight loss, fatigue symptoms and also could be asymptomatic cases. In this review, it was aimed to summarize the associations between Blastocystis subtypes and pathogenicity.

  6. Synergetics of molecular systems

    CERN Document Server

    Lupichev, Lev N; Kadantsev, Vasiliy N

    2014-01-01

    Synergetics is the quantitative study of multicomponent systems that exhibit nonlinear dynamics and cooperativity. This book specifically considers basic models of the nonlinear dynamics of molecular systems and discusses relevant applications in biological physics and the polymer sciences.Emphasis is placed on specific solutions to the dynamical equations that correspond to the coherent formation of spatial-temporal structures, such as solitons, kinks and breathers, in particular. The emergence of these patterns in molecular structures provides a variety of information on their structural pro

  7. Substructured multibody molecular dynamics.

    Energy Technology Data Exchange (ETDEWEB)

    Grest, Gary Stephen; Stevens, Mark Jackson; Plimpton, Steven James; Woolf, Thomas B. (Johns Hopkins University, Baltimore, MD); Lehoucq, Richard B.; Crozier, Paul Stewart; Ismail, Ahmed E.; Mukherjee, Rudranarayan M. (Rensselaer Polytechnic Institute, Troy, NY); Draganescu, Andrei I.

    2006-11-01

    We have enhanced our parallel molecular dynamics (MD) simulation software LAMMPS (Large-scale Atomic/Molecular Massively Parallel Simulator, lammps.sandia.gov) to include many new features for accelerated simulation including articulated rigid body dynamics via coupling to the Rensselaer Polytechnic Institute code POEMS (Parallelizable Open-source Efficient Multibody Software). We use new features of the LAMMPS software package to investigate rhodopsin photoisomerization, and water model surface tension and capillary waves at the vapor-liquid interface. Finally, we motivate the recipes of MD for practitioners and researchers in numerical analysis and computational mechanics.

  8. Molecular Rotors as Switches

    Directory of Open Access Journals (Sweden)

    Kang L. Wang

    2012-08-01

    Full Text Available The use of a functional molecular unit acting as a state variable provides an attractive alternative for the next generations of nanoscale electronics. It may help overcome the limits of conventional MOSFETd due to their potential scalability, low-cost, low variability, and highly integratable characteristics as well as the capability to exploit bottom-up self-assembly processes. This bottom-up construction and the operation of nanoscale machines/devices, in which the molecular motion can be controlled to perform functions, have been studied for their functionalities. Being triggered by external stimuli such as light, electricity or chemical reagents, these devices have shown various functions including those of diodes, rectifiers, memories, resonant tunnel junctions and single settable molecular switches that can be electronically configured for logic gates. Molecule-specific electronic switching has also been reported for several of these device structures, including nanopores containing oligo(phenylene ethynylene monolayers, and planar junctions incorporating rotaxane and catenane monolayers for the construction and operation of complex molecular machines. A specific electrically driven surface mounted molecular rotor is described in detail in this review. The rotor is comprised of a monolayer of redox-active ligated copper compounds sandwiched between a gold electrode and a highly-doped P+ Si. This electrically driven sandwich-type monolayer molecular rotor device showed an on/off ratio of approximately 104, a read window of about 2.5 V, and a retention time of greater than 104 s. The rotation speed of this type of molecular rotor has been reported to be in the picosecond timescale, which provides a potential of high switching speed applications. Current-voltage spectroscopy (I-V revealed a temperature-dependent negative differential resistance (NDR associated with the device. The analysis of the device

  9. Molecular beam epitaxy

    CERN Document Server

    Pamplin, Brian R

    1980-01-01

    Molecular Beam Epitaxy introduces the reader to the use of molecular beam epitaxy (MBE) in the generation of III-V and IV-VI compounds and alloys and describes the semiconductor and integrated optics reasons for using the technique. Topics covered include semiconductor superlattices by MBE; design considerations for MBE systems; periodic doping structure in gallium arsenide (GaAs); nonstoichiometry and carrier concentration control in MBE of compound semiconductors; and MBE techniques for IV-VI optoelectronic devices. The use of MBE to fabricate integrated optical devices and to study semicond

  10. Molecular theory of capillarity

    CERN Document Server

    Rowlinson, J S

    2002-01-01

    History of thought on molecular origins of surface phenomena offers a critical and detailed examination and assessment of modern theories, focusing on statistical mechanics and application of results in mean-field approximation to model systems. Emphasis on liquid-gas surface, with a focus on liquid-liquid surfaces in the final chapters. 1989 edition.

  11. Biophysics of molecular gastronomy.

    Science.gov (United States)

    Brenner, Michael P; Sörensen, Pia M

    2015-03-26

    Chefs and scientists exploring biophysical processes have given rise to molecular gastronomy. In this Commentary, we describe how a scientific understanding of recipes and techniques facilitates the development of new textures and expands the flavor palette. The new dishes that result engage our senses in unexpected ways. PAPERCLIP.

  12. Molecular ion photofragment spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Bustamente, S.W.

    1983-11-01

    A new molecular ion photofragment spectrometer is described which features a supersonic molecular beam ion source and a radio frequency octapole ion trap interaction region. This unique combination allows several techniques to be applied to the problem of detecting a photon absorption event of a molecular ion. In particular, it may be possible to obtain low resolution survey spectra of exotic molecular ions by using a direct vibrational predissociation process, or by using other more indirect detection methods. The use of the spectrometer is demonstrated by measuring the lifetime of the O/sub 2//sup +/(/sup 4/..pi../sub u/) metastable state which is found to consist of two main components: the /sup 4/..pi../sub 5/2/ and /sup 4/..pi../sub -1/2/ spin components having a long lifetime (approx. 129 ms) and the /sup 4/..pi../sub 3/2/ and /sup 4/..pi../sub 1/2/ spin components having a short lifetime (approx. 6 ms).

  13. Molecular Urban Revolutions?

    DEFF Research Database (Denmark)

    Samson, Kristine

    created by means of affective and assembled spaces. Finally, the paper will discuss notions of (spatial) singularization by elaborating on Suely Rolnik and Félix Guattari’s travel book, Molecular Revolutions in Brazil (2007). How, for instance, does spatial interventions relate to and transform global...

  14. Gymnastics of molecular chaperones.

    Science.gov (United States)

    Mayer, Matthias P

    2010-08-13

    Molecular chaperones assist folding processes and conformational changes in many proteins. In order to do so, they progress through complex conformational cycles themselves. In this review, I discuss the diverse conformational dynamics of the ATP-dependent chaperones of the Hsp60, Hsp70, Hsp90, and Hsp100 families. PMID:20705236

  15. Molecular Adsorber Coating

    Science.gov (United States)

    Straka, Sharon; Peters, Wanda; Hasegawa, Mark; Hedgeland, Randy; Petro, John; Novo-Gradac, Kevin; Wong, Alfred; Triolo, Jack; Miller, Cory

    2011-01-01

    A document discusses a zeolite-based sprayable molecular adsorber coating that has been developed to alleviate the size and weight issues of current ceramic puck-based technology, while providing a configuration that more projects can use to protect against degradation from outgassed materials within a spacecraft, particularly contamination-sensitive instruments. This coating system demonstrates five times the adsorption capacity of previously developed adsorber coating slurries. The molecular adsorber formulation was developed and refined, and a procedure for spray application was developed. Samples were spray-coated and tested for capacity, thermal optical/radiative properties, coating adhesion, and thermal cycling. Work performed during this study indicates that the molecular adsorber formulation can be applied to aluminum, stainless steel, or other metal substrates that can accept silicate-based coatings. The coating can also function as a thermal- control coating. This adsorber will dramatically reduce the mass and volume restrictions, and is less expensive than the currently used molecular adsorber puck design.

  16. Biophysics of molecular gastronomy.

    Science.gov (United States)

    Brenner, Michael P; Sörensen, Pia M

    2015-03-26

    Chefs and scientists exploring biophysical processes have given rise to molecular gastronomy. In this Commentary, we describe how a scientific understanding of recipes and techniques facilitates the development of new textures and expands the flavor palette. The new dishes that result engage our senses in unexpected ways. PAPERCLIP. PMID:25815978

  17. Molecular dynamics for fermions

    International Nuclear Information System (INIS)

    The time-dependent variational principle for many-body trial states is used to discuss the relation between the approaches of different molecular dynamics models to describe indistinguishable fermions. Early attempts to include effects of the Pauli principle by means of nonlocal potentials as well as more recent models which work with antisymmetrized many-body states are reviewed under these premises. (orig.)

  18. Reading the Molecular Clock.

    Science.gov (United States)

    McKean, Kevin

    1983-01-01

    Suggesting that the evolutionary record may be written in proteins and genes, discusses research in which species are compared by immunology, DNA, and radioimmunoassay. Molecular studies show that DNA from humans and chimps is 98 percent identical, a degree of similarity usually occurring only among animals of the same genus. (JN)

  19. Cellular and molecular inflammatory profile of the choroid plexus in depression and suicide

    Directory of Open Access Journals (Sweden)

    Julia eDevorak

    2015-10-01

    Full Text Available The inflammatory hypothesis of depression is one of the main theories that endeavors to explain and describe the underlying biological mechanisms of depression and suicide. While mounting evidence indicates altered peripheral and central inflammatory profiles in depressed patients and suicide completers, little is known about how peripheral and central inflammation might be linked in these contexts. The choroid plexus (ChP, a highly vascularized tissue that produces cerebrospinal fluid (CSF and lacks a blood-brain-barrier, is an interface between peripheral and central immune responses. In the present study, we investigated the cellular and molecular inflammatory profile of the ChP of the lateral ventricle in depressed suicides and psychiatrically healthy controls. Gene expression of macrophages, pro- and anti-inflammatory cytokines, and various factors implicated in immune cell trafficking were measured; and density of ionized calcium binding adaptor molecule 1-positive (Iba1+ macrophages associated with the ChP epithelial cell layer (ECL was examined. Significant downregulations of the genes encoding interleukin 1ß (IL1ß, a pro-inflammatory acute-phase protein; intercellular cell adhesion molecule 1 (ICAM1, a protein implicated in immune cell trafficking in the ChP; and IBA1, a monocyte/macrophage marker; were detected in depressed suicides as compared to controls. No difference in the density of Iba1+ macrophages associated with the ChP ECL was observed. While interpretation of these findings is challenging in the absence of corroborating data from the CSF, peripheral blood, or brain parenchyma of the present cohort, we hypothesize that these present findings reflect a ChP compensatory mechanism that attenuates the detrimental effects of chronically altered pro-inflammatory signaling caused by elevated levels of pro-inflammatory cytokines, such as IL-1ß, peripherally and/or centrally. Together, these findings further implicate neuroimmune

  20. Molecular Programming Pseudo-code Representation to Molecular Electronics

    OpenAIRE

    Pradhan, Manas Ranjan; E G Rajan

    2010-01-01

    This research paper is proposing the idea of pseudo code representation to molecular programming used in designing molecular electronics devices. Already the schematic representation of logical gates like AND, OR, NOT etc.from molecular diodes or resonant tunneling diode are available. This paper is setting a generic pseudo code model so that various logic gates can be formulated. These molecular diodes have designed from organic molecules or Bio-molecules. Our focus is on to give a scenario ...

  1. Molecular and Cellular Signaling

    CERN Document Server

    Beckerman, Martin

    2005-01-01

    A small number of signaling pathways, no more than a dozen or so, form a control layer that is responsible for all signaling in and between cells of the human body. The signaling proteins belonging to the control layer determine what kinds of cells are made during development and how they function during adult life. Malfunctions in the proteins belonging to the control layer are responsible for a host of human diseases ranging from neurological disorders to cancers. Most drugs target components in the control layer, and difficulties in drug design are intimately related to the architecture of the control layer. Molecular and Cellular Signaling provides an introduction to molecular and cellular signaling in biological systems with an emphasis on the underlying physical principles. The text is aimed at upper-level undergraduates, graduate students and individuals in medicine and pharmacology interested in broadening their understanding of how cells regulate and coordinate their core activities and how diseases ...

  2. Interactive molecular dynamics

    CERN Document Server

    Schroeder, Daniel V

    2015-01-01

    Physics students now have access to interactive molecular dynamics simulations that can model and animate the motions of hundreds of particles, such as noble gas atoms, that attract each other weakly at short distances but repel strongly when pressed together. Using these simulations, students can develop an understanding of forces and motions at the molecular scale, nonideal fluids, phases of matter, thermal equilibrium, nonequilibrium states, the Boltzmann distribution, the arrow of time, and much more. This article summarizes the basic features and capabilities of such a simulation, presents a variety of student exercises using it at the introductory and intermediate levels, and describes some enhancements that can further extend its uses. A working simulation code, in HTML5 and JavaScript for running within any modern Web browser, is provided as an online supplement.

  3. FORT Molecular Ecology Laboratory

    Science.gov (United States)

    Oyler-McCance, Sara J.; Stevens, P.D.

    2011-01-01

    The mission of the U.S. Geological Survey (USGS) at the Fort Collins Science Center Molecular Ecology Laboratory is to use the tools and concepts of molecular genetics to address a variety of complex management questions and conservation issues facing the management of the Nation's fish and wildlife resources. Together with our partners, we design and implement studies to document genetic diversity and the distribution of genetic variation among individuals, populations, and species. Information from these studies is used to support wildlife-management planning and conservation actions. Current and past studies have provided information to assess taxonomic boundaries, inform listing decisions made under the Endangered Species Act, identify unique or genetically depauperate populations, estimate population size or survival rates, develop management or recovery plans, breed wildlife in captivity, relocate wildlife from one location to another, and assess the effects of environmental change.

  4. Welding Molecular Crystals.

    Science.gov (United States)

    Adolf, Cyril R R; Ferlay, Sylvie; Kyritsakas, Nathalie; Hosseini, Mir Wais

    2015-12-16

    Both for fundamental and applied sciences, the design of complex molecular systems in the crystalline phase with strict control of order and periodicity at both microscopic and macroscopic levels is of prime importance for development of new solid-state materials and devices. The design and fabrication of complex crystalline systems as networks of crystals displaying task-specific properties is a step toward smart materials. Here we report on isostructural and almost isometric molecular crystals of different colors, their use for fabrication of core-shell crystals, and their welding by 3D epitaxial growth into networks of crystals as single-crystalline entities. Welding of crystals by self-assembly processes into macroscopic networks of crystals is a powerful strategy for the design of hierarchically organized periodic complex architectures composed of different subdomains displaying targeted characteristics. Crystal welding may be regarded as a first step toward the design of new hierarchically organized complex crystalline systems. PMID:26581391

  5. Topology in Molecular Biology

    CERN Document Server

    Monastyrsky, Michail Ilych

    2007-01-01

    The book presents a class of new results in molecular biology for which topological methods and ideas are important. These include: the large-scale conformation properties of DNA; computational methods (Monte Carlo) allowing the simulation of large-scale properties of DNA; the tangle model of DNA recombination and other applications of Knot theory; dynamics of supercoiled DNA and biocatalitic properties of DNA; the structure of proteins; and other very recent problems in molecular biology. The text also provides a short course of modern topology intended for the broad audience of biologists and physicists. The authors are renowned specialists in their fields and some of the new results presented here are documented for the first time in monographic form.

  6. Interactive molecular dynamics

    Science.gov (United States)

    Schroeder, Daniel V.

    2015-03-01

    Physics students now have access to interactive molecular dynamics simulations that can model and animate the motions of hundreds of particles, such as noble gas atoms, that attract each other weakly at short distances but repel strongly when pressed together. Using these simulations, students can develop an understanding of forces and motions at the molecular scale, nonideal fluids, phases of matter, thermal equilibrium, nonequilibrium states, the Boltzmann distribution, the arrow of time, and much more. This article summarizes the basic features and capabilities of such a simulation, presents a variety of student exercises using it at the introductory and intermediate levels, and describes some enhancements that can further extend its uses. A working simulation code, in html5 and javascript for running within any modern Web browser, is provided as an online supplement.

  7. Communication: Molecular gears.

    Science.gov (United States)

    Burnell, E Elliott; de Lange, Cornelis A; Meerts, W Leo

    2016-09-01

    The (1)H nuclear magnetic resonance spectrum of hexamethylbenzene orientationally ordered in the nematic liquid crystal ZLI-1132 is analysed using covariance matrix adaptation evolution strategy. The spectrum contains over 350 000 lines with many overlapping transitions, from which four independent direct dipolar couplings are obtained. The rotations of the six methyl groups appear to be correlated due to mutual steric hindrance. Adjacent methyl groups show counter-rotating or geared motion. Hexamethylbenzene thus behaves as a molecular hexagonal gear. PMID:27608981

  8. Molecular-beam scattering

    Science.gov (United States)

    Vernon, M. F.

    1983-07-01

    The molecular-beam technique has been used in three different experimental arrangements to study a wide range of inter-atomic and molecular forces. Chapter 1 reports results of a low-energy (0.2 kcal/mole) elastic-scattering study of the He-Ar pair potential. The purpose of the study was to accurately characterize the shape of the potential in the well region, by scattering slow He atoms produced by expanding a mixture of He in N2 from a cooled nozzle. Chapter 2 contains measurements of the vibrational predissociation spectra and product translational energy for clusters of water, benzene, and ammonia. The experiments show that most of the product energy remains in the internal molecular motions. Chapter 3 presents measurements of the reaction Na + HC1 (FEMALE) NAC1 + H at collision energies of 5.38 and 19.4 kcal/mole. This is the first study to resolve both scattering angle and velocity for the reaction of a short lived (16 nsec) electronic excited state. Descriptions are given of computer programs written to analyze molecular-beam expansions to extract information characterizing their velocity distributions, and to calculate accurate laboratory elastic-scattering differential cross sections accounting for the finite apparatus resolution. Experimental results which attempted to determine the efficiency of optically pumping the Li(2(2)P/sub 3/2/) and Na(3(2)P/sub 3/2) excited states are given. A simple three-level model for predicting the steady-state fraction of atoms in the excited state is included.

  9. Molecular opacities for exoplanets

    OpenAIRE

    Bernath, Peter F.

    2014-01-01

    Spectroscopic observations of exoplanets are now possible by transit methods and direct emission. Spectroscopic requirements for exoplanets are reviewed based on existing measurements and model predictions for hot Jupiters and super-Earths. Molecular opacities needed to simulate astronomical observations can be obtained from laboratory measurements, ab initio calculations or a combination of the two approaches. This discussion article focuses mainly on laboratory measurements of hot molecules...

  10. Exploring guanidinoglycoside molecular transporters

    OpenAIRE

    Dix, Andrew Vincent

    2011-01-01

    Guanidinium-rich molecular transporters have been shown to deliver otherwise non-permeable biologically relevant cargo into cells. While many such transporters have been reported, the studies reported here focus on guanidinoglycosides, which have been shown to permeate the cell-membrane in a heparan sulfate-dependent manner. In attempt to promote a cooperative interaction with cell- surface heparan sulfate, dimeric guanidinoglycosides were synthesized and studied for their cellular uptake pro...

  11. Molecular Aspects of Capacitation

    OpenAIRE

    Gulfidan Zulfikaroglu; Hulya Ozgur; Sait Polaturkey

    2010-01-01

    Male and female gamets are derived from the primordial germ cells, which migrate from the wall of the yolk sac toward the developing gonads. Following a series of mitotic divisions these cells increase in number at the gonads. The primordial germ cells differentiate into spermatogonia and take the form of mature spermatozoa after spermotogensis and spermotogenesis at puberty. Capacitation is the reaction, which includes all of the molecular and physiological events of mature sperm to gain the...

  12. Molecular Information Technology

    OpenAIRE

    Zauner, Klaus-Peter

    2005-01-01

    Molecular materials are endowed with unique properties of unrivaled potential for high density integration of computing systems. Present applications of molecules range from organic semiconductor materials for low-cost circuits to genetically modified proteins for commercial imaging equipment. To fully realize the potential of molecules in computation, information processing concepts that relinquish narrow prescriptive control over elementary structures and functions are needed, and self-orga...

  13. Communication: Molecular gears

    Science.gov (United States)

    Burnell, E. Elliott; de Lange, Cornelis A.; Meerts, W. Leo

    2016-09-01

    The 1H nuclear magnetic resonance spectrum of hexamethylbenzene orientationally ordered in the nematic liquid crystal ZLI-1132 is analysed using covariance matrix adaptation evolution strategy. The spectrum contains over 350 000 lines with many overlapping transitions, from which four independent direct dipolar couplings are obtained. The rotations of the six methyl groups appear to be correlated due to mutual steric hindrance. Adjacent methyl groups show counter-rotating or geared motion. Hexamethylbenzene thus behaves as a molecular hexagonal gear.

  14. Molecular-beam scattering

    Energy Technology Data Exchange (ETDEWEB)

    Vernon, M.F.

    1983-07-01

    The molecular-beam technique has been used in three different experimental arrangements to study a wide range of inter-atomic and molecular forces. Chapter 1 reports results of a low-energy (0.2 kcal/mole) elastic-scattering study of the He-Ar pair potential. The purpose of the study was to accurately characterize the shape of the potential in the well region, by scattering slow He atoms produced by expanding a mixture of He in N/sub 2/ from a cooled nozzle. Chapter 2 contains measurements of the vibrational predissociation spectra and product translational energy for clusters of water, benzene, and ammonia. The experiments show that most of the product energy remains in the internal molecular motions. Chapter 3 presents measurements of the reaction Na + HCl ..-->.. NaCl + H at collision energies of 5.38 and 19.4 kcal/mole. This is the first study to resolve both scattering angle and velocity for the reaction of a short lived (16 nsec) electronic excited state. Descriptions are given of computer programs written to analyze molecular-beam expansions to extract information characterizing their velocity distributions, and to calculate accurate laboratory elastic-scattering differential cross sections accounting for the finite apparatus resolution. Experimental results which attempted to determine the efficiency of optically pumping the Li(2/sup 2/P/sub 3/2/) and Na(3/sup 2/P/sub 3/2/) excited states are given. A simple three-level model for predicting the steady-state fraction of atoms in the excited state is included.

  15. Molecular-beam scattering

    International Nuclear Information System (INIS)

    The molecular-beam technique has been used in three different experimental arrangements to study a wide range of inter-atomic and molecular forces. Chapter 1 reports results of a low-energy (0.2 kcal/mole) elastic-scattering study of the He-Ar pair potential. The purpose of the study was to accurately characterize the shape of the potential in the well region, by scattering slow He atoms produced by expanding a mixture of He in N2 from a cooled nozzle. Chapter 2 contains measurements of the vibrational predissociation spectra and product translational energy for clusters of water, benzene, and ammonia. The experiments show that most of the product energy remains in the internal molecular motions. Chapter 3 presents measurements of the reaction Na + HCl → NaCl + H at collision energies of 5.38 and 19.4 kcal/mole. This is the first study to resolve both scattering angle and velocity for the reaction of a short lived (16 nsec) electronic excited state. Descriptions are given of computer programs written to analyze molecular-beam expansions to extract information characterizing their velocity distributions, and to calculate accurate laboratory elastic-scattering differential cross sections accounting for the finite apparatus resolution. Experimental results which attempted to determine the efficiency of optically pumping the Li(22P/sub 3/2/) and Na(32P/sub 3/2/) excited states are given. A simple three-level model for predicting the steady-state fraction of atoms in the excited state is included

  16. Glycobiology Current Molecular Biology

    OpenAIRE

    Sabire KARAÇALI

    2003-01-01

    Carbohydrate chemistry evolved into carbohydrate biochemistry and gradually into the biology of carbohydrates, or glycobiology, at the end of the last century. Glycobiology is the new research area of modern molecular biology, and it investigates the structure, biosynthesis and biological functions of glycans. The numbers, linkage types (a or b), positions, binding points and functional group differences of monosaccharides create microheterogeneity. Thus, numerous glycoforms with precise stru...

  17. Molecular diagnostics in endodontics

    OpenAIRE

    Rechenberg, Dan-Krister; Zehnder, Matthias

    2014-01-01

    Recent systematic reviews have substantiated the fact that current testing methods to assess the inflammatory state of the pulp and the periapical tissues are of limited value. Consequently, it may be time to search for alternative routes in endodontic diagnostics. Molecular assessment methods could be the future. However, in the field of endodontics, the research in that direction is only about to evolve. Because pulpal and periradicular diseases are related to opportunistic infections, diag...

  18. Untying molecular friction knots

    OpenAIRE

    Kirmizialtin, Serdal; Makarov, Dmitrii E.

    2006-01-01

    Motivated by recent advances in single molecule manipulation techniques that enabled several groups to tie knots in individual polymer strands and to monitor their dynamics, we have used computer simulations to study "friction knots" joining a pair of polymer strands. The key property of a friction knot splicing two ropes is that it becomes jammed when the ropes are pulled apart. In contrast, molecular friction knots eventually become undone by thermal motion. We show that depending on the kn...

  19. Primer on molecular genetics

    Energy Technology Data Exchange (ETDEWEB)

    1992-04-01

    This report is taken from the April 1992 draft of the DOE Human Genome 1991--1992 Program Report, which is expected to be published in May 1992. The primer is intended to be an introduction to basic principles of molecular genetics pertaining to the genome project. The material contained herein is not final and may be incomplete. Techniques of genetic mapping and DNA sequencing are described.

  20. Molecular Simulations of Dewetting

    OpenAIRE

    Koplik, Joel; Banavar, Jayanth R.

    1999-01-01

    We have studied the breakup and subsequent fluid flow in very thin films of partially wetting liquid on solid substrates, using molecular dynamics simulations. The liquid is made of short chain molecules interacting with Lennard-Jones interactions, and the solid is modeled as a clean crystal lattice whose atoms have thermal oscillations. Films below a critical thickness are found to exhibit a spontaneous spinodal-like instability leading to dry patches, as predicted theoretically and observed...

  1. Molecular biology of hearing [

    Directory of Open Access Journals (Sweden)

    Diensthuber, Marc

    2012-04-01

    Full Text Available [english] The inner ear is our most sensitive sensory organ and can be subdivided into three functional units: organ of Corti, stria vascularis and spiral ganglion. The appropriate stimulus for the organ of hearing is sound, which travels through the external auditory canal to the middle ear where it is transmitted to the inner ear. The inner ear houses the hair cells, the sensory cells of hearing. The inner hair cells are capable of mechanotransduction, the transformation of mechanical force into an electrical signal, which is the basic principle of hearing. The stria vascularis generates the endocochlear potential and maintains the ionic homeostasis of the endolymph. The dendrites of the spiral ganglion form synaptic contacts with the hair cells. The spiral ganglion is composed of neurons that transmit the electrical signals from the cochlea to the central nervous system. In recent years there has been significant progress in research on the molecular basis of hearing. An increasing number of genes and proteins related to hearing are being identified and characterized. The growing knowledge of these genes contributes not only to greater appreciation of the mechanism of hearing but also to a deeper understanding of the molecular basis of hereditary hearing loss. This basic research is a prerequisite for the development of molecular diagnostics and novel therapies for hearing loss.

  2. Molecular adsorption on graphene

    Science.gov (United States)

    Kong, Lingmei; Enders, Axel; Rahman, Talat S.; Dowben, Peter A.

    2014-11-01

    Current studies addressing the engineering of charge carrier concentration and the electronic band gap in epitaxial graphene using molecular adsorbates are reviewed. The focus here is on interactions between the graphene surface and the adsorbed molecules, including small gas molecules (H2O, H2, O2, CO, NO2, NO, and NH3), aromatic, and non-aromatic molecules (F4-TCNQ, PTCDA, TPA, Na-NH2, An-CH3, An-Br, Poly (ethylene imine) (PEI), and diazonium salts), and various biomolecules such as peptides, DNA fragments, and other derivatives. This is followed by a discussion on graphene-based gas sensor concepts. In reviewing the studies of the effects of molecular adsorption on graphene, it is evident that the strong manipulation of graphene’s electronic structure, including p- and n-doping, is not only possible with molecular adsorbates, but that this approach appears to be superior compared to these exploiting edge effects, local defects, or strain. However, graphene-based gas sensors, albeit feasible because huge adsorbate-induced variations in the relative conductivity are possible, generally suffer from the lack of chemical selectivity.

  3. Thermoelectric properties of molecular nanostructures

    OpenAIRE

    Ermakov, Vladimir N.; Kruchinin, Sergei P.; Kim, Hyun Taki; Pruschke, Thomas

    2011-01-01

    We use the concept of resonant tunneling to calculate the thermopower of molecular nanosystems. It turns out that the sign of the thermovoltage under resonant tunneling conditions depends sensitively on the participating molecular orbital, and one finds a sign change when the transport channel switches from the highest occupied molecular orbital to the lowest unoccupied molecular orbital. Comparing our results to recent experimental data obtained for a BDT molecule contacted with an STM tip, ...

  4. An improved molecular connectivity index

    Institute of Scientific and Technical Information of China (English)

    李新华; 俞庆森; 朱龙观

    2000-01-01

    Through modification of the delta values of the molecular connectivity indexes, and connecting the quantum chemistry with topology method effectively, the molecular connectivity indexes are converted into quantum-topology indexes. The modified indexes not only keep all information obtained from the original molecular connectivity method but also have their own virtue in application, and at the same time make up some disadvantages of the quantum and molecular connectivity methods.

  5. A Molecular Biology Database Digest

    OpenAIRE

    Bry, François; Kröger, Peer

    2000-01-01

    Computational Biology or Bioinformatics has been defined as the application of mathematical and Computer Science methods to solving problems in Molecular Biology that require large scale data, computation, and analysis [18]. As expected, Molecular Biology databases play an essential role in Computational Biology research and development. This paper introduces into current Molecular Biology databases, stressing data modeling, data acquisition, data retrieval, and the integration...

  6. Chaos Behaviour of Molecular Orbit

    Institute of Scientific and Technical Information of China (English)

    LIU Shu-Tang; SUN Fu-Yan; SHEN Shu-Lan

    2007-01-01

    Based on H(u)ckel's molecular orbit theory,the chaos and;bifurcation behaviour of a molecular orbit modelled by a nonlinear dynamic system is studied.The relationship between molecular orbit and its energy level in the nonlinear dynamic system is obtained.

  7. Computational methods for molecular imaging

    CERN Document Server

    Shi, Kuangyu; Li, Shuo

    2015-01-01

    This volume contains original submissions on the development and application of molecular imaging computing. The editors invited authors to submit high-quality contributions on a wide range of topics including, but not limited to: • Image Synthesis & Reconstruction of Emission Tomography (PET, SPECT) and other Molecular Imaging Modalities • Molecular Imaging Enhancement • Data Analysis of Clinical & Pre-clinical Molecular Imaging • Multi-Modal Image Processing (PET/CT, PET/MR, SPECT/CT, etc.) • Machine Learning and Data Mining in Molecular Imaging. Molecular imaging is an evolving clinical and research discipline enabling the visualization, characterization and quantification of biological processes taking place at the cellular and subcellular levels within intact living subjects. Computational methods play an important role in the development of molecular imaging, from image synthesis to data analysis and from clinical diagnosis to therapy individualization. This work will bring readers fro...

  8. Molecular Pathogenesis of Spondyloarthritis

    DEFF Research Database (Denmark)

    Carlsen, Thomas Gelsing

    This dissertation includes a presentation of knowledge on the molecular pathogenesis of spondyloarthritis achieved through a PhD programme at Aalborg University from 1.12.2011 - 1.12.2014. Work was carried out in the Laboratory of Medical Mass Spectrometry, headed by: Professor Svend Birkelund...... Associate Professor Allan Stensballe The output of this PhD programme, besides from this dissertation, includes 5 published papers, 30 ECTS PhD courses, oral presentations of posters in national and international research environment and a short-term scholarship at the La Jolla Institute for Allergy...

  9. Molecular anisotropic magnetoresistance

    Science.gov (United States)

    Otte, Fabian; Heinze, Stefan; Mokrousov, Yuriy

    2015-12-01

    Using density functional theory calculations, we demonstrate that the effect of anisotropic magnetoresistance (AMR) can be enhanced by orders of magnitude with respect to conventional bulk ferromagnets in junctions containing molecules sandwiched between ferromagnetic leads. We study ballistic transport in metal-benzene complexes contacted by 3 d transition-metal wires. We show that a gigantic AMR can arise from spin-orbit coupling effects in the leads, drastically enhanced by orbital-symmetry filtering properties of the molecules. We further discuss how this molecular anisotropic magnetoresistance (MAMR) can be tuned by the proper choice of materials and their electronic properties.

  10. Molecular water oxidation catalysis

    CERN Document Server

    Llobet, Antoni

    2014-01-01

    Photocatalytic water splitting is a promising strategy for capturing energy from the sun by coupling light harvesting and the oxidation of water, in order to create clean hydrogen fuel. Thus a deep knowledge of the water oxidation catalysis field is essential to be able to come up with useful energy conversion devices based on sunlight and water splitting. Molecular Water Oxidation Catalysis: A Key Topic for New Sustainable Energy Conversion Schemes presents a comprehensive and state-of-the-art overview of water oxidation catalysis in homogeneous phase, describing in detail the most importan

  11. Bienvenida la Medicina Molecular

    OpenAIRE

    Orlando R. Serrano-Barrera

    2015-01-01

    No ha cambiado la medicina, sino que ha avanzado. Los métodos clínico-epidemiológicos  incluyen hoy y se benefician del conocimiento de las bases moleculares del proceso salud-enfermedad, tanto las variaciones individuales, como los caracteres compartidos por comunidades y poblaciones, que las hacen resistentes o vulnerables a una enfermedad. La estimación presintomática e, incluso, prenatal del riesgo de enfermar, el diagnóstico, el pronóstico, la elección del tratamiento más ajustado al pac...

  12. Medical physics: molecular aspects

    International Nuclear Information System (INIS)

    Actual problems in medical physics have been considered. Features in the cell membrane structure promoting the action of anticancer drugs are studied. The mechanism of an invasive method for measuring the blood pressure is analyzed. The tension distribution in the left ventricle wall was calculated. Conditions that prevent magnetic particles, nanodiamonds, and fullerene molecules, which are used to transport drugs in human body, to aggregate in liquid systems are determined. A molecular mechanism of electric welding of biological tissues has been proposed, as well as a method to study the surface of biological structures, by using ultrasound. The origin of structural changes in human hair under the influence of chemicals is determined

  13. Massive molecular outflows

    OpenAIRE

    Beuther, H.; Schilke, P.; Menten, K. M.; Walmsley, C. M.; Sridharan, T. K.; Wyrowski, F.

    2001-01-01

    We present a mapping study of massive molecular outflows in 26 high-mass star-forming regions at 11'' spatial resolution. Bipolar morpholgy is found in 80% of the sources and the collimation is higher than previously thought. Additionally, we find that well known low-mass correlations continue up to the high-mass regime, and accretion rates are around 10^(-4) Msun/yr rising as high as 10^(-3) Msun/yr. A tight correlation between the outflow and the core mass is established, implying that the ...

  14. Molecular Genetics of Analbuminaemia

    DEFF Research Database (Denmark)

    Minchiotti, Lorenzo; Caridi, Gianluca; Campagnoli, Monica;

    2014-01-01

    the perinatal and childhood period. Twenty-one different molecular lesions in the ALB are now known as cause of the trait. These include one mutation in the start codon, one frameshift/insertion, five frameshift/deletions, seven nonsense mutations and seven mutations affecting splicing. Thus, nonsense mutations......, mutations affecting splicing and frameshift/deletions seem to be the most common causes of CAA. These results indicate that the trait is an allelic heterogeneous disorder caused by homozygous or, in a single case, compound heterozygous inheritance of defects. Most mutations are unique, but one, named...

  15. Handbook of molecular plasmonics

    CERN Document Server

    Sala, Fabio Della

    2013-01-01

    While several reviews and books on surface nanophotonics and fluorescence spectroscopy are available, an updated focus on molecular plasmonics, including both theoretical methods and experimental aspects, is still lacking. This handbook is a comprehensive overview on the physics of the plasmon-emitter interaction, ranging from electromagnetism to quantum mechanics, from metal-enhanced fluorescence to surface-enhanced Raman scattering, from optical microscopy to synthesis of metal nanoparticles, filling the gap in the literature of this merging field. It allows experimentalists to have a solid

  16. Molecular origin of friction

    Institute of Scientific and Technical Information of China (English)

    WANG; Hui; ZHANG; Tao; HU; Yuanzhong

    2004-01-01

    The wearless friction originating from molecular interactions has been discussed in this paper. We find that the frictional properties are closely related to the structural match of two surfaces in relative motion. For the surfaces with incommensurate structure and week inter-surface interaction, zero static and kinetic friction can be achieved. In a sliding considered as in a quasi-static state, the energy dissipation initiates when interfacial particles move in a discontinuous fashion, which gives rise to a finite kinetic friction. The state of superlubricity is a result of computer simulations, but the prediction will encourage people to look for a technical approach to realizing the state of super low friction.

  17. Nuclear molecular states

    International Nuclear Information System (INIS)

    The effects of polarization on the stability of α-cluster structures in 8Be and 12C nuclei are studied in the intrinsic states. The extent of the polarization of α-clusters is investigated by employing a molecular-orbital model. Two α-cluster structure of 8Be is shown to be extremely stable, and a triangular configuration of three α-clusters is also shown to be stable, but the polarizations of α-clusters are found rather large. Gruemmer--Faessler's method is discussed and their results are shown to be trivial

  18. Molecular collision theory

    CERN Document Server

    Child, M S

    2010-01-01

    This high-level monograph offers an excellent introduction to the theory required for interpretation of an increasingly sophisticated range of molecular scattering experiments. There are five helpful appendixes dealing with continuum wavefunctions, Green's functions, semi-classical connection formulae, curve-crossing in the momentum representation, and elements of classical mechanics.The contents of this volume have been chosen to emphasize the quantum mechanical and semi-classical nature of collision events, with little attention given to purely classical behavior. The treatment is essentiall

  19. Molecular Cloud Evolution

    CERN Document Server

    Vazquez-Semadeni, Enrique

    2010-01-01

    I describe the scenario of molecular cloud (MC) evolution that has emerged over the past decade or so. MCs can start out as cold atomic clouds formed by compressive motions in the warm neutral medium (WNM) of galaxies. Such motions can be driven by large-scale instabilities, or by local turbulence. The compressions induce a phase transition to the cold neutral medium (CNM) to form growing cold atomic clouds, which in their early stages may constitute thin CNM sheets. Several dynamical instabilities soon destabilize a cloud, rendering it turbulent. For solar neighborhood conditions, a cloud is coincidentally expected to become molecular, magnetically supercritical, and gravitationally dominated at roughly the same column density, $N \\sim 1.5 \\times 10^21 \\psc \\approx 10 \\Msun$ pc$^{-2}$. At this point, the cloud begins to contract gravitationally. However, before its global collapse is completed ($\\sim 10^7$ yr later), the nonlinear density fluctuations within the cloud, which have shorter local free-fall time...

  20. Towards graphyne molecular electronics.

    Science.gov (United States)

    Li, Zhihai; Smeu, Manuel; Rives, Arnaud; Maraval, Valérie; Chauvin, Remi; Ratner, Mark A; Borguet, Eric

    2015-01-01

    α-Graphyne, a carbon-expanded version of graphene ('carbo-graphene') that was recently evidenced as an alternative zero-gap semiconductor, remains a theoretical material. Nevertheless, using specific synthesis methods, molecular units of α-graphyne ('carbo-benzene' macrocycles) can be inserted between two anilinyl (4-NH2-C6H4)-anchoring groups that allow these fragments to form molecular junctions between gold electrodes. Here, electrical measurements by the scanning tunnelling microscopy (STM) break junction technique and electron transport calculations are carried out on such a carbo-benzene, providing unprecedented single molecule conductance values: 106 nS through a 1.94-nm N-N distance, essentially 10 times the conductance of a shorter nanographenic hexabenzocoronene analogue. Deleting a C4 edge of the rigid C18 carbo-benzene circuit results in a flexible 'carbo-butadiene' molecule that has a conductance 40 times lower. Furthermore, carbo-benzene junctions exhibit field-effect transistor behaviour when an electrochemical gate potential is applied, opening the way for device applications. All the results are interpreted on the basis of theoretical calculations. PMID:25699991

  1. The Molecular Atlas Project

    Science.gov (United States)

    Silverberg, Jesse; Yin, Peng

    The promise of super-resolution microscopy is a technology to discover new biological mechanisms that occur at smaller length scales then previously observable. However, with higher-resolution, we generally lose the larger spatial context of the image itself. The Molecular Atlas Project (MAP) directly asks how these competing interests between super-resolution imaging and broader spatially contextualized information can be reconciled. MAP enables us to acquire, visualize, explore, and annotate proteomic image data representing 7 orders of magnitude in length ranging from molecular (nm) to tissue (cm) scales. This multi-scale understanding is made possible by combining multiplexed DNA-PAINT, a DNA nanotechnology approach to super-resolution imaging, with ``big-data'' strategies for information management and image visualization. With these innovations combined, MAP enables us to explore cell-specific heterogeneity in ductal carcinoma for every cellin a cm-sized tissue section, analyze organoid growth for advances in high-throughput tissue-on-a-chip technology, and examine individual synapses for connectome mapping over extremely wide areas. Ultimately, MAP is a fundamentally new way to interact with multiscale biophysical data.

  2. Yeast Golgi-localized, gamma-Ear-containing, ADP-ribosylation factor-binding proteins are but adaptor protein-1 is not required for cell-free transport of membrane proteins from the trans-Golgi network to the prevacuolar compartment.

    Science.gov (United States)

    Abazeed, Mohamed E; Fuller, Robert S

    2008-11-01

    Golgi-localized, gamma-Ear-containing, ADP-ribosylation factor-binding proteins (GGAs) and adaptor protein-1 (AP-1) mediate clathrin-dependent trafficking of transmembrane proteins between the trans-Golgi network (TGN) and endosomes. In yeast, the vacuolar sorting receptor Vps10p follows a direct pathway from the TGN to the late endosome/prevacuolar compartment (PVC), whereas, the processing protease Kex2p partitions between the direct pathway and an indirect pathway through the early endosome. To examine the roles of the Ggas and AP-1 in TGN-PVC transport, we used a cell-free assay that measures delivery to the PVC of either Kex2p or a chimeric protein (K-V), in which the Vps10p cytosolic tail replaces the Kex2p tail. Either antibody inhibition or dominant-negative Gga2p completely blocked K-V transport but only partially blocked Kex2p transport. Deletion of APL2, encoding the beta subunit of AP-1, did not affect K-V transport but partially blocked Kex2p transport. Residual Kex2p transport seen with apl2Delta membranes was insensitive to dominant-negative Gga2p, suggesting that the apl2Delta mutation causes Kex2p to localize to a compartment that precludes Gga-dependent trafficking. These results suggest that yeast Ggas facilitate the specific and direct delivery of Vps10p and Kex2p from the TGN to the PVC and that AP-1 modulates Kex2p trafficking through a distinct pathway, presumably involving the early endosome. PMID:18784256

  3. Yeast Golgi-localized, γ-Ear–containing, ADP-Ribosylation Factor-binding Proteins Are but Adaptor Protein-1 Is Not Required for Cell-free Transport of Membrane Proteins from the Trans-Golgi Network to the Prevacuolar Compartment

    Science.gov (United States)

    Abazeed, Mohamed E.

    2008-01-01

    Golgi-localized, γ-Ear–containing, ADP-ribosylation factor-binding proteins (GGAs) and adaptor protein-1 (AP-1) mediate clathrin-dependent trafficking of transmembrane proteins between the trans-Golgi network (TGN) and endosomes. In yeast, the vacuolar sorting receptor Vps10p follows a direct pathway from the TGN to the late endosome/prevacuolar compartment (PVC), whereas, the processing protease Kex2p partitions between the direct pathway and an indirect pathway through the early endosome. To examine the roles of the Ggas and AP-1 in TGN–PVC transport, we used a cell-free assay that measures delivery to the PVC of either Kex2p or a chimeric protein (K-V), in which the Vps10p cytosolic tail replaces the Kex2p tail. Either antibody inhibition or dominant-negative Gga2p completely blocked K-V transport but only partially blocked Kex2p transport. Deletion of APL2, encoding the β subunit of AP-1, did not affect K-V transport but partially blocked Kex2p transport. Residual Kex2p transport seen with apl2Δ membranes was insensitive to dominant-negative Gga2p, suggesting that the apl2Δ mutation causes Kex2p to localize to a compartment that precludes Gga-dependent trafficking. These results suggest that yeast Ggas facilitate the specific and direct delivery of Vps10p and Kex2p from the TGN to the PVC and that AP-1 modulates Kex2p trafficking through a distinct pathway, presumably involving the early endosome. PMID:18784256

  4. Assessment of Molecular Modeling & Simulation

    Energy Technology Data Exchange (ETDEWEB)

    None

    2002-01-03

    This report reviews the development and applications of molecular and materials modeling in Europe and Japan in comparison to those in the United States. Topics covered include computational quantum chemistry, molecular simulations by molecular dynamics and Monte Carlo methods, mesoscale modeling of material domains, molecular-structure/macroscale property correlations like QSARs and QSPRs, and related information technologies like informatics and special-purpose molecular-modeling computers. The panel's findings include the following: The United States leads this field in many scientific areas. However, Canada has particular strengths in DFT methods and homogeneous catalysis; Europe in heterogeneous catalysis, mesoscale, and materials modeling; and Japan in materials modeling and special-purpose computing. Major government-industry initiatives are underway in Europe and Japan, notably in multi-scale materials modeling and in development of chemistry-capable ab-initio molecular dynamics codes.

  5. Molecular modification of proanthocyanidins.

    Science.gov (United States)

    Huo, Qing; Kong, Xiangye; Yang, Xiaofang; Wang, Yue; Ma, Lingling; Luo, Min; Xu, Diandou

    2016-07-01

    Regioselective enzymatic acylation of proanthocyanidin is proposed and investigated as a method by which to improve the solubility of proanthocyanidins in the oil phase and maintain its oxidation resistance. Experimental results indicate that butanol functions as the best solvent in the studied reaction, in which Lipase Novozym435 is used as biological catalyst enzyme and the molar ratio of lauric acid to proanthocyanidins is 4:1. To increase the esterification conversion, we propose the addition of molecular sieve at 5 h. The product was separated by TLC, and results indicate an optimal solvent ratio of ethyl acetate: petroleum ether: acetic acid = 2:3:0.5. This condition can effectively separate the ester and proanthocyanidins, achieving an esterification yield of 60.9%. PMID:27459598

  6. Molecular contingencies: reinforcement probability.

    Science.gov (United States)

    Hale, J M; Shimp, C P

    1975-11-01

    Pigeons obtained food by responding in a discrete-trials two-choice probability-learning experiment involving temporal stimuli. A given response alternative, a left- or right-key peck, had 11 associated reinforcement probabilities within each session. Reinforcement probability for a choice was an increasing or a decreasing function of the time interval immediately preceding the choice. The 11 equiprobable temporal stimuli ranged from 1 to 11 sec in 1-sec classes. Preference tended to deviate from probability matching in the direction of maximizing; i.e., the percentage of choices of the preferred response alternative tended to exceed the probability of reinforcement for that alternative. This result was qualitatively consistent with probability-learning experiments using visual stimuli. The result is consistent with a molecular analysis of operant behavior and poses a difficulty for molar theories holding that local variations in reinforcement probability may safely be disregarded in the analysis of behavior maintained by operant paradigms. PMID:16811883

  7. Molecular logic circuits.

    Science.gov (United States)

    Balzani, Vincenzo; Credi, Alberto; Venturi, Margherita

    2003-01-13

    Miniaturization has been an essential ingredient in the outstanding progress of information technology over the past fifty years. The next, perhaps ultimate, limit of miniaturization is that of molecules, which are the smallest entities with definite size, shape, and properties. Recently, great effort has been devoted to design and investigate molecular-level systems that are capable of transferring, processing, and storing information in binary form. Some of these nanoscale devices can, in fact, perform logic operations of remarkable complexity. This research--although far from being transferred into technology--is attracting interest, as the nanometer realm seems to be out of reach for the "top-down" techniques currently available to microelectronics industry. Moreover, such studies introduce new concepts in the "old" field of chemistry and stimulate the ingenuity of researchers engaged in the "bottom-up" approach to nanotechnology.

  8. Atomic and molecular manipulation

    CERN Document Server

    Mayne, Andrew J

    2011-01-01

    Work with individual atoms and molecules aims to demonstrate that miniaturized electronic, optical, magnetic, and mechanical devices can operate ultimately even at the level of a single atom or molecule. As such, atomic and molecular manipulation has played an emblematic role in the development of the field of nanoscience. New methods based on the use of the scanning tunnelling microscope (STM) have been developed to characterize and manipulate all the degrees of freedom of individual atoms and molecules with an unprecedented precision. In the meantime, new concepts have emerged to design molecules and substrates having specific optical, mechanical and electronic functions, thus opening the way to the fabrication of real nano-machines. Manipulation of individual atoms and molecules has also opened up completely new areas of research and knowledge, raising fundamental questions of "Optics at the atomic scale", "Mechanics at the atomic scale", Electronics at the atomic scale", "Quantum physics at the atomic sca...

  9. Molecular conduction: paradigms and possibilities

    OpenAIRE

    Ghosh, A. W.; Datta, S

    2003-01-01

    We discuss the factors that determine the overall shape and magnitude of the current-voltage (I-V) characteristics of a variety of molecular conductors sandwiched between two metallic contacts. We analyze the individual influences of the contact geometry, the molecular chemistry, the electrostatics of the environment, and charging on molecular conduction. Current conduction depends sensitively on the experimental geometry, as well as on the theoretical model for the molecule and the contacts....

  10. Lubricant characterization by molecular simulation

    Energy Technology Data Exchange (ETDEWEB)

    Moore, J.D.; Cui, S.T.; Cummings, P.T.; Cochran, H.D. [Univ. of Tennessee, Knoxville, TN (United States). Dept. of Chemical Engineering]|[Oak Ridge National Lab., TN (United States). Chemical Technology Div.

    1997-12-01

    The authors have reported the calculation of the kinematic viscosity index of squalane from nonequilibrium molecular dynamics simulations. This represents the first accurate quantitative prediction of this measure of lubricant performance by molecular simulation. Using the same general alkane potential model, this computational approach offers the possibility of predicting the performance of potential lubricants prior to synthesis. Consequently, molecular simulation is poised to become an important tool for future lubricant development.

  11. POPULAR MOLECULAR MARKERS IN BACTERIA

    OpenAIRE

    Weilong, Liu; Lv, Li; MD. ASADUZZAMAN KHAN AND FEIZHOU ZHU

    2012-01-01

    Molecular markers are defined as the fragments of DNA sequence associated with a genome, which are used to identify a particular DNA sequence. Nowadays, with the explosive growth of genetic research and bacterial classification, molecular marker is an important tool to identify bacterial species. Taking account to its significant roles in clinic, medicine and food industry, in this review article, we summarize the traditional research and new development about molecular markers (also called g...

  12. Metal-mediated molecular machines

    OpenAIRE

    Howgego, David Christopher

    2013-01-01

    Nature abounds with ingenious nanoscopic machines employed to carry out all of the requisite tasks that collectively contribute to the molecular basis of life. This thesis focuses primarily on a sub-set known as "molecular walkers" which can perambulate along intracellular molecular motorways carrying out such essential tasks as vesicle transport and muscle contraction. A summary of these incredible natural motors is presented in Chapter I along with a review of the artificial ...

  13. Time-resolved molecular imaging

    Science.gov (United States)

    Xu, Junliang; Blaga, Cosmin I.; Agostini, Pierre; DiMauro, Louis F.

    2016-06-01

    Time-resolved molecular imaging is a frontier of ultrafast optical science and physical chemistry. In this article, we review present and future key spectroscopic and microscopic techniques for ultrafast imaging of molecular dynamics and show their differences and connections. The advent of femtosecond lasers and free electron x-ray lasers bring us closer to this goal, which eventually will extend our knowledge about molecular dynamics to the attosecond time domain.

  14. Molecular electronic-structure theory

    CERN Document Server

    Helgaker, Trygve; Jorgensen, Poul

    2013-01-01

    Ab initio quantum chemistry is increasingly paired with computational methods to solve intractable problems in chemistry and molecular physics. Now in a paperback edition, this comprehensive and technical work covers all the important aspects of modern molecular electronic-structure theory, clearly explaining quantum-mechanical methods and applications to molecular equilibrium structure, atomization energies, and reaction enthalpies. Extensive numerical examples illustrate each method described. An excellent resource for researchers in quantum chemistry and anyone interested in the theory and its applications.

  15. Viscosity kernel of molecular fluids

    DEFF Research Database (Denmark)

    Puscasu, Ruslan; Todd, Billy; Daivis, Peter;

    2010-01-01

    The wave-vector dependent shear viscosities for butane and freely jointed chains have been determined. The transverse momentum density and stress autocorrelation functions have been determined by equilibrium molecular dynamics in both atomic and molecular hydrodynamic formalisms. The density, tem...... that generalized hydrodynamics must be applied in predicting the flow properties of molecular fluids on length scales where the strain rate varies sufficiently in the order of these dimensions (e.g., nanofluidic flows)....

  16. Viscosity kernel of molecular fluids

    DEFF Research Database (Denmark)

    Puscasu, Ruslan; Todd, Billy; Daivis, Peter;

    2010-01-01

    The wave-vector dependent shear viscosities for butane and freely jointed chains have been determined. The transverse momentum density and stress autocorrelation functions have been determined by equilibrium molecular dynamics in both atomic and molecular hydrodynamic formalisms. The density...... that generalized hydrodynamics must be applied in predicting the flow properties of molecular fluids on length scales where the strain rate varies sufficiently in the order of these dimensions (e.g., nanofluidic flows)....

  17. Molecular Epidemiology of Foodborne Pathogens

    Science.gov (United States)

    Chen, Yi; Brown, Eric; Knabel, Stephen J.

    The purpose of this chapter is to describe the basic principles and advancements in the molecular epidemiology of foodborne pathogens. Epidemiology is the study of the distribution and determinants of infectious diseases and/or the dynamics of disease transmission. The goals of epidemiology include the identification of physical sources, routes of transmission of infectious agents, and distribution and relationships of different subgroups. Molecular epidemiology is the study of epidemiology at the molecular level. It has been defined as "a science that focuses on the contribution of potential genetic and environmental risk factors, identified at the molecular level, to the etiology, distribution and prevention of diseases within families and across populations".

  18. Thermally driven molecular linear motors - A molecular dynamics study

    DEFF Research Database (Denmark)

    Zambrano, Harvey A; Walther, Jens Honore; Jaffe, Richard Lawrence

    2009-01-01

    We conduct molecular dynamics simulations of a molecular linear motor consisting of coaxial carbon nanotubes with a long outer carbon nanotube confining and guiding the motion of an inner short, capsule-like nanotube. The simulations indicate that the motion of the capsule can be controlled...

  19. Bienvenida la Medicina Molecular

    Directory of Open Access Journals (Sweden)

    Orlando R. Serrano-Barrera

    2015-11-01

    Full Text Available No ha cambiado la medicina, sino que ha avanzado. Los métodos clínico-epidemiológicos  incluyen hoy y se benefician del conocimiento de las bases moleculares del proceso salud-enfermedad, tanto las variaciones individuales, como los caracteres compartidos por comunidades y poblaciones, que las hacen resistentes o vulnerables a una enfermedad. La estimación presintomática e, incluso, prenatal del riesgo de enfermar, el diagnóstico, el pronóstico, la elección del tratamiento más ajustado al paciente, las posibilidades de rehabilitación y reinserción social, la educación y promoción sanitarias son todos momentos del proceso de toma de decisiones, que el médico debe asumir en el nuevo escenario de una ciencia que ha logrado discernir las implicaciones de un número creciente de moléculas, sus variantes, sus formas mutadas y sus interacciones con otras moléculas y con factores ambientales. (1 ¿Cuán lejos está tal panorama de nuestra práctica clínica? También en nuestros escenarios se hace medicina molecular. Así ha sido desde que en 1949 Pauling catalogara la primera enfermedad molecular: la anemia drepanocítica. (2 La más temprana acción de prevención, la vacunación, se realiza a diario en las áreas de salud e incluye preparados conformados por moléculas obtenidas por vía recombinante o síntesis química, como el antígeno de superficie del virus de la hepatitis B y el polisacárido de membrana del Haemophilus influenzae, respectivamente. (3 La pesquisa poblacional de cáncer de próstata, enfocado hacia los hombres mayores de 50 años o con síntomas sugestivos, se auxilia de la cuantificación en sangre del antígeno prostático específico. (4 El tratamiento del infarto agudo del miocardio, ahora la segunda causa de muerte en Cuba, incluye la trombolisis con estreptocinasa, otra biomolécula recombinante. (5 En desarrollo, en etapa de ensayos clínicos o ya como productos registrados algunas vacunas terap

  20. Molecular digital pathology: progress and potential of exchanging molecular data.

    Science.gov (United States)

    Roy, Somak; Pfeifer, John D; LaFramboise, William A; Pantanowitz, Liron

    2016-09-01

    Many of the demands to perform next generation sequencing (NGS) in the clinical laboratory can be resolved using the principles of telepathology. Molecular telepathology can allow facilities to outsource all or a portion of their NGS operation such as cloud computing, bioinformatics pipelines, variant data management, and knowledge curation. Clinical pathology laboratories can electronically share diverse types of molecular data with reference laboratories, technology service providers, and/or regulatory agencies. Exchange of electronic molecular data allows laboratories to perform validation of rare diseases using foreign data, check the accuracy of their test results against benchmarks, and leverage in silico proficiency testing. This review covers the emerging subject of molecular telepathology, describes clinical use cases for the appropriate exchange of molecular data, and highlights key issues such as data integrity, interoperable formats for massive genomic datasets, security, malpractice and emerging regulations involved with this novel practice. PMID:27471996

  1. Molecular sensors for MEMS

    Science.gov (United States)

    Huang, Chih-Yung

    Molecular sensors, known as pressure-sensitive paint and temperature-sensitive paint, are applied inside MEMS devices to obtain the internal and external flow fields. The spatial resolution for the PSP and TSP measurements has improved to 5 mum. The low-pressure PSP sensor has been investigated for use in MEMS measurements, with an application range from continuum flow to transition flow. PSP and TSP measurements in different micro devices have been obtained with the flow fields covering steady and unsteady, subsonic and supersonic flow. In microchannel measurements, the pressure distributions inside the microchannel have been obtained for Knudsen number from 0.006 to 0.8. Compressibility and rarefaction effects can be observed in the PSP data. Detailed information at the channel inlet was also collected to discuss the entrance effect for different flow regimes. For micronozzle experiments, four different micronozzles have been fabricated to study geometry effects at the micro scale. The pressure maps inside the micronozzle devices have been obtained with PSP sensors. A modified schlieren technique is used to compare the PSP results and investigate the shock wave behavior at high- and low-pressure conditions. Thick viscous layers in the micronozzle have been observed in the low-pressure measurements. For microjet impingements, heat transfer measurements have been collected with different microjet devices by using TSP sensors. For supersonic impinging microjet measurements, both pressure and temperature data have been obtained at different pressure ratios, impingement angles and impingement distances. Measurements reveal that the magnitude and number of shock cells decreases in the micro scale due to strong viscous effects. For microturbine measurements, averaged results of PSP and TSP measurements have been obtained for a rotation speed from 1300 to 4000 rpm. Phase-averaged results have been collected by using a laser triggering system at rotation speed of 1400 rpm

  2. HIV Molecular Immunology 2015

    Energy Technology Data Exchange (ETDEWEB)

    Yusim, Karina [Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Division; Korber, Bette Tina [Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Division; Brander, Christian [Institucio Catalana de Recerca i Estudis Avancats (ICREA), Barcelona (Spain); Barouch, Dan [Beth Israel Deaconess Medical Center, Boston, MA (United States). Division of Vaccine Research; de Boer, Rob [Utrecht University, Utrecht (Netherlands). Faculty of Biology; Haynes, Barton F. [Duke Univ., Durham, NC (United States). Duke Human Vaccine Institute and Departments of Medicine, Surgery and Immunology; Koup, Richard [National Inst. of Health (NIH), Bethesda, MD (United States). Vaccine Research Center; Moore, John P. [Cornell Univ., Ithaca, NY (United States). Weill Medical College; Walker, Bruce D. [Ragon Institute, Cambridge, MA (United States); Watkins, David [Wisconsin Regional Primate Research Center, Madison, WI (United States)

    2016-04-05

    The scope and purpose of the HIV molecular immunology database: HIV Molecular Immunology is a companion volume to HIV Sequence Compendium. This publication, the 2015 edition, is the PDF version of the web-based HIV Immunology Database (http://www.hiv.lanl.gov/ content/immunology/). The web interface for this relational database has many search options, as well as interactive tools to help immunologists design reagents and interpret their results. In the HIV Immunology Database, HIV-specific B-cell and T-cell responses are summarized and annotated. Immunological responses are divided into three parts, CTL, T helper, and antibody. Within these parts, defined epitopes are organized by protein and binding sites within each protein, moving from left to right through the coding regions spanning the HIV genome. We include human responses to natural HIV infections, as well as vaccine studies in a range of animal models and human trials. Responses that are not specifically defined, such as responses to whole proteins or monoclonal antibody responses to discontinuous epitopes, are summarized at the end of each protein section. Studies describing general HIV responses to the virus, but not to any specific protein, are included at the end of each part. The annotation includes information such as cross-reactivity, escape mutations, antibody sequence, TCR usage, functional domains that overlap with an epitope, immune response associations with rates of progression and therapy, and how specific epitopes were experimentally defined. Basic information such as HLA specificities for T-cell epitopes, isotypes of monoclonal antibodies, and epitope sequences are included whenever possible. All studies that we can find that incorporate the use of a specific monoclonal antibody are included in the entry for that antibody. A single T-cell epitope can have multiple entries, generally one entry per study. Finally, maps of all defined linear epitopes relative to the HXB2 reference proteins

  3. Optically controllable molecular logic circuits

    Energy Technology Data Exchange (ETDEWEB)

    Nishimura, Takahiro, E-mail: t-nishimura@ist.osaka-u.ac.jp; Fujii, Ryo; Ogura, Yusuke; Tanida, Jun [Graduate School of Information Science and Technology, Osaka University, 1-5 Yamadaoka, Suita, Osaka 565-0871 (Japan)

    2015-07-06

    Molecular logic circuits represent a promising technology for observation and manipulation of biological systems at the molecular level. However, the implementation of molecular logic circuits for temporal and programmable operation remains challenging. In this paper, we demonstrate an optically controllable logic circuit that uses fluorescence resonance energy transfer (FRET) for signaling. The FRET-based signaling process is modulated by both molecular and optical inputs. Based on the distance dependence of FRET, the FRET pathways required to execute molecular logic operations are formed on a DNA nanostructure as a circuit based on its molecular inputs. In addition, the FRET pathways on the DNA nanostructure are controlled optically, using photoswitching fluorescent molecules to instruct the execution of the desired operation and the related timings. The behavior of the circuit can thus be controlled using external optical signals. As an example, a molecular logic circuit capable of executing two different logic operations was studied. The circuit contains functional DNAs and a DNA scaffold to construct two FRET routes for executing Input 1 AND Input 2 and Input 1 AND NOT Input 3 operations on molecular inputs. The circuit produced the correct outputs with all possible combinations of the inputs by following the light signals. Moreover, the operation execution timings were controlled based on light irradiation and the circuit responded to time-dependent inputs. The experimental results demonstrate that the circuit changes the output for the required operations following the input of temporal light signals.

  4. Molecular ecology of aquatic microbes

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1994-12-31

    Abstracts of reports are presented from a meeting on Molecular Ecology of Aquatic Microbes. Topics included: opportunities offered to aquatic ecology by molecular biology; the role of aquatic microbes in biogeochemical cycles; characterization of the microbial community; the effect of the environment on aquatic microbes; and the targeting of specific biological processes.

  5. Cardiovascular molecular imaging of apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Wolters, S.L.; Reutelingsperger, C.P.M. [Maastricht University, Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht (Netherlands); Corsten, M.F.; Hofstra, L. [Maastricht University, Department of Cardiology, Cardiovascular Research Institute Maastricht, P.O. Box 616, Maastricht (Netherlands); Narula, J. [University of California Irvine, Department of Cardiology, Irvine (United States)

    2007-06-15

    Molecular imaging strives to visualise processes at the molecular and cellular level in vivo. Understanding these processes supports diagnosis and evaluation of therapeutic efficacy on an individual basis and thereby makes personalised medicine possible. Apoptosis is a well-organised mode of cell suicide that plays a role in cardiovascular diseases (CVD). Apoptosis is associated with loss of cardiomyocytes following myocardial infarction, atherosclerotic plaque instability, congestive heart failure and allograft rejection of the transplanted heart. Thus, apoptosis constitutes an attractive target for molecular imaging of CVD. Our current knowledge about the molecular players and mechanisms underlying apoptosis offers a rich palette of potential molecular targets for molecular imaging. However, only a few have been successfully developed so far. This review highlights aspects of the molecular machinery and biochemistry of apoptosis relevant to the development of molecular imaging probes. It surveys the role of apoptosis in four major areas of CVD and portrays the importance and future perspectives of apoptosis imaging. The annexin A5 imaging protocol is emphasised since it is the most advanced protocol to measure apoptosis in both preclinical and clinical studies. (orig.)

  6. Optically controllable molecular logic circuits

    International Nuclear Information System (INIS)

    Molecular logic circuits represent a promising technology for observation and manipulation of biological systems at the molecular level. However, the implementation of molecular logic circuits for temporal and programmable operation remains challenging. In this paper, we demonstrate an optically controllable logic circuit that uses fluorescence resonance energy transfer (FRET) for signaling. The FRET-based signaling process is modulated by both molecular and optical inputs. Based on the distance dependence of FRET, the FRET pathways required to execute molecular logic operations are formed on a DNA nanostructure as a circuit based on its molecular inputs. In addition, the FRET pathways on the DNA nanostructure are controlled optically, using photoswitching fluorescent molecules to instruct the execution of the desired operation and the related timings. The behavior of the circuit can thus be controlled using external optical signals. As an example, a molecular logic circuit capable of executing two different logic operations was studied. The circuit contains functional DNAs and a DNA scaffold to construct two FRET routes for executing Input 1 AND Input 2 and Input 1 AND NOT Input 3 operations on molecular inputs. The circuit produced the correct outputs with all possible combinations of the inputs by following the light signals. Moreover, the operation execution timings were controlled based on light irradiation and the circuit responded to time-dependent inputs. The experimental results demonstrate that the circuit changes the output for the required operations following the input of temporal light signals

  7. Molecular path for ligand search

    Institute of Scientific and Technical Information of China (English)

    Tao Lu; Yuan Yuan Qiao; Pan Wen Shen

    2011-01-01

    A ligand is a small molecule bind to several residues of a receptor. We adapt the concept of molecular path for effective ligand search with its contacting residues. Additionally, we allow wild type definitions on atoms and bonds of molecular paths for fuzzy algorithms on structural match. We choose hydrogen bond interactions to characterize the binding mode of a ligand by several proper molecular paths and use them to query the deposited ligands in PDBe that interact with their residues in the same way. Expression of molecular path and format of database entries are described with examples. Our molecular path provides a new approach to explore the ligand-receptor interactions and to provide structural framework reference on new ligand design.

  8. Molecular imaging in ovarian cancer.

    Science.gov (United States)

    Reyners, A K L; Broekman, K E; Glaudemans, A W J M; Brouwers, A H; Arts, H J G; van der Zee, A G J; de Vries, E G E; Jalving, M

    2016-04-01

    Ovarian cancer has a high mortality and novel-targeted treatment strategies have not resulted in breakthroughs for this disease. Insight into the molecular characteristics of ovarian tumors may improve diagnosis and selection of patients for treatment with targeted therapies. A potential way to achieve this is by means of molecular imaging. Generic tumor processes, such as glucose metabolism ((18)F-fluorodeoxyglucose) and DNA synthesis ((18)F-fluorodeoxythymidine), can be visualized non-invasively. More specific targets, such as hormone receptors, growth factor receptors, growth factors and targets of immunotherapy, can also be visualized. Molecular imaging can capture data on intra-patient tumor heterogeneity and is of potential value for individualized, target-guided treatment selection. Early changes in molecular characteristics during therapy may serve as early predictors of response. In this review, we describe the current knowledge on molecular imaging in the diagnosis and as an upfront or early predictive biomarker in patients with ovarian cancer. PMID:27141066

  9. Handbook of Molecular Force Spectroscopy

    CERN Document Server

    Noy, Aleksandr

    2008-01-01

    "...Noy's Handbook of Molecular Force Spectroscopy is both a timely and useful summary of fundamental aspects of molecular force spectroscopy, and I believe it would make a worthwhile addition to any good scientific library. New research groups that are entering this field would be well advisedto study this handbook in detail before venturing into the exciting and challenging world of molecular force spectroscopy." Matthew F. Paige, University of Saskatchewan, Journal of the American Chemical Society Modern materials science and biophysics are increasingly focused on studying and controlling intermolecular interactions on the single-molecule level. Molecular force spectroscopy was developed in the past decade as the result of several unprecedented advances in the capabilities of modern scientific instrumentation, and defines a number of techniques that use mechanical force measurements to study interactions between single molecules and molecular assemblies in chemical and biological systems. Examples of these...

  10. [Advances in Molecular Cloning].

    Science.gov (United States)

    Ashwini, M; Murugan, S B; Balamurugan, S; Sathishkumar, R

    2016-01-01

    "Molecular cloning" meaning creation of recombinant DNA molecules has impelled advancement throughout life sciences. DNA manipulation has become easy due to powerful tools showing exponential growth in applications and sophistication of recombinant DNA technology. Cloning genes has become simple what led to an explosion in the understanding of gene function by seamlessly stitching together multiple DNA fragments or by the use of swappable gene cassettes, maximizing swiftness and litheness. A novel archetype might materialize in the near future with synthetic biology techniques that will facilitate quicker assembly and iteration of DNA clones, accelerating the progress of gene therapy vectors, recombinant protein production processes and new vaccines by in vitro chemical synthesis of any in silico-specified DNA construct. The advent of innovative cloning techniques has opened the door to more refined applications such as identification and mapping of epigenetic modifications and high-throughput assembly of combinatorial libraries. In this review, we will examine the major breakthroughs in cloning techniques and their applications in various areas of biological research that have evolved mainly due to easy construction of novel expression systems. PMID:27028806

  11. Molecular profiling of chordoma

    Science.gov (United States)

    SCHEIL-BERTRAM, STEFANIE; KAPPLER, ROLAND; VON BAER, ALEXANDRA; HARTWIG, ERICH; SARKAR, MICHAEL; SERRA, MASSIMO; BRÜDERLEIN, SILKE; WESTHOFF, BETTINA; MELZNER, INGO; BASSALY, BIRGIT; HERMS, JOCHEN; HUGO, HEINZ-HERMANN; SCHULTE, MICHAEL; MÖLLER, PETER

    2014-01-01

    The molecular basis of chordoma is still poorly understood, particularly with respect to differentially expressed genes involved in the primary origin of chordoma. In this study, therefore, we compared the transcriptional expression profile of one sacral chordoma recurrence, two chordoma cell lines (U-CH1 and U-CH2) and one chondrosarcoma cell line (U-CS2) with vertebral disc using a high-density oligonucleotide array. The expression of 65 genes whose mRNA levels differed significantly (p<0.001; ≥6-fold change) between chordoma and control (vertebral disc) was identified. Genes with increased expression in chordoma compared to control and chondrosarcoma were most frequently located on chromosomes 2 (11%), 5 (8%), 1 and 7 (each 6%), whereas interphase cytogenetics of 33 chordomas demonstrated gains of chromosomal material most prevalent on 7q (42%), 12q (21%), 17q (21%), 20q (27%) and 22q (21%). The microarray data were confirmed for selected genes by quantitative polymerase chain reaction analysis. As in other studies, we showed the expression of brachyury. We demonstrate the expression of new potential candidates for chordoma tumorigenesis, such as CD24, ECRG4, RARRES2, IGFBP2, RAP1, HAI2, RAB38, osteopontin, GalNAc-T3, VAMP8 and others. Thus, we identified and validated a set of interesting candidate genes whose differential expression likely plays a role in chordoma. PMID:24452533

  12. Molecular screening in galactosemia

    Energy Technology Data Exchange (ETDEWEB)

    Elsas, L.J.; Singh, R.; Fernhoff, P.M. [Emory Univ., Atlanta, GA (United States)] [and others

    1994-09-01

    Classical galactosemia (G/G) is caused by the absence of galactose-1-phosphate uridyl transferase (GALT) activity while the Duarte allele produces partial impairment and a specific biochemical phenotype. Cloning and sequencing of the human GALT gene has enabled the identification of prevalent mutations for both Classical and Duarte alleles. The G allele is caused by a Q188R codon mutation in exon 6 in 70% of a Caucasian population while the D allele is caused by an N134D codon mutation in exon 10. Since the Q188R sequence creates a new Hpa II site and the N314D sequence creates a new Sin I site, it is relatively easy to screen for both mutations by multiplex PCR and restriction digest. Here we describe a method for detection of new mutations producing impaired GALT. Patient DNAs are subjected to SSCP (single strand conformational polymorphism) analysis of their 11 GALT exons. Direct sequencing of the exons targeted by SSCP has revealed many codon changes: IVSC 956 (a splice acceptor site loss), S135L, V151A, E203K, A320T, and Y323D. Two of these codon changes, V151A and S135L, have been confirmed as mutations by finding impaired GALT activity in a yeast expression system. We conclude that molecular screening of GALT DNA will clarify the structural biology of GALT and the pathophysiology of galactosemia.

  13. Radically enhanced molecular recognition

    KAUST Repository

    Trabolsi, Ali

    2009-12-17

    The tendency for viologen radical cations to dimerize has been harnessed to establish a recognition motif based on their ability to form extremely strong inclusion complexes with cyclobis(paraquat-p-phenylene) in its diradical dicationic redox state. This previously unreported complex involving three bipyridinium cation radicals increases the versatility of host-guest chemistry, extending its practice beyond the traditional reliance on neutral and charged guests and hosts. In particular, transporting the concept of radical dimerization into the field of mechanically interlocked molecules introduces a higher level of control within molecular switches and machines. Herein, we report that bistable and tristable [2]rotaxanes can be switched by altering electrochemical potentials. In a tristable [2]rotaxane composed of a cyclobis(paraquat-p-phenylene) ring and a dumbbell with tetrathiafulvalene, dioxynaphthalene and bipyridinium recognition sites, the position of the ring can be switched. On oxidation, it moves from the tetrathiafulvalene to the dioxynaphthalene, and on reduction, to the bipyridinium radical cation, provided the ring is also reduced simultaneously to the diradical dication. © 2010 Macmillan Publishers Limited. All rights reserved.

  14. Similarity of molecular shape.

    Science.gov (United States)

    Meyer, A Y; Richards, W G

    1991-10-01

    The similarity of one molecule to another has usually been defined in terms of electron densities or electrostatic potentials or fields. Here it is expressed as a function of the molecular shape. Formulations of similarity (S) reduce to very simple forms, thus rendering the computerised calculation straightforward and fast. 'Elements of similarity' are identified, in the same spirit as 'elements of chirality', except that the former are understood to be variable rather than present-or-absent. Methods are presented which bypass the time-consuming mathematical optimisation of the relative orientation of the molecules. Numerical results are presented and examined, with emphasis on the similarity of isomers. At the extreme, enantiomeric pairs are considered, where it is the dissimilarity (D = 1 - S) that is of consequence. We argue that chiral molecules can be graded by dissimilarity, and show that D is the shape-analog of the 'chirality coefficient', with the simple form of the former opening up numerical access to the latter. PMID:1770379

  15. Molecular genetics of ependymoma

    Institute of Scientific and Technical Information of China (English)

    Yuan Yao; Stephen C.Mack; Michael D.Taylor

    2011-01-01

    Brain tumors are the leading cause of cancer death in children,with ependymoma being the third most common and posing a significant clinical burden.Its mechanism of pathogenesis,reliable prognostic indicators,and effective treatments other than surgical resection have all remained elusive.Until recently,cytogenetic techniques,and lack of cell lines and animal models.Ependymoma heterogeneity,which manifests as variations in tumor location,patient age,histological grade,and clinical behavior,together with the observation of a balanced genomic profile in up to 50% of cases,presents additional challenges in understanding the development and progression of this disease.Despite these difficulties,we have made significant headway in the past decade in identifying the genetic alterations and pathways involved in ependymoma tumorigenesis through collaborative efforts and the application of microarray-based genetic (copy number) and transcriptome profiling platforms.Genetic characterization of ependymoma unraveled distinct mRNA-defined subclasses and led to the identification of radial glial cells as its cell type of origin.This review summarizes our current knowledge in the molecular genetics of ependymoma and proposesfuture research directions necessary to further advance this field.

  16. Molecular Motors and Apical CFTR Traffic in Epithelia

    Directory of Open Access Journals (Sweden)

    Dmitri V. Kravtsov

    2013-05-01

    Full Text Available Intracellular protein traffic plays an important role in the regulation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR chloride channels. Microtubule and actin-based motor proteins direct CFTR movement along trafficking pathways. As shown for other regulatory proteins such as adaptors, the involvement of protein motors in CFTR traffic is cell-type specific. Understanding motor specificity provides insight into the biology of the channel and opens opportunity for discovery of organ-specific drug targets for treating CFTR-mediated diseases.

  17. HIV Molecular Immunology 2014

    Energy Technology Data Exchange (ETDEWEB)

    Yusim, Karina [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Korber, Bette Tina Marie [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Barouch, Dan [Beth Israel Deaconess Medical Center, Boston, MA (United States); Koup, Richard [Vaccine Research Center National Institutes of Health (United States); de Boer, Rob [Utrecht Univ. (Netherlands). Dept. of Biology; Moore, John P. [Cornell Univ., Ithaca, NY (United States). Weill Medical College; Brander, Christian [Institucioi Catalana de Recerca i Estudis Avancats (ICREA), Barcelona (Spain); Haynes, Barton F. [Duke Univ., Durham, NC (United States). Duke Human Vaccine Institute and Departments of Medicine, Surgery and Immunology; Walker, Bruce D. [Ragon Institute of Massachusetts General Hospital, Cambridge, MA (United States); Harvard Univ., Cambridge, MA (United States); Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)

    2015-02-03

    HIV Molecular Immunology is a companion volume to HIV Sequence Compendium. This publication, the 2014 edition, is the PDF version of the web-based HIV Immunology Database (http://www.hiv.lanl.gov/content/immunology/). The web interface for this relational database has many search options, as well as interactive tools to help immunologists design reagents and interpret their results. In the HIV Immunology Database, HIV-specific B-cell and T-cell responses are summarized and annotated. Immunological responses are divided into three parts, CTL, T helper, and antibody. Within these parts, defined epitopes are organized by protein and binding sites within each protein, moving from left to right through the coding regions spanning the HIV genome. We include human responses to natural HIV infections, as well as vaccine studies in a range of animal models and human trials. Responses that are not specifically defined, such as responses to whole proteins or monoclonal antibody responses to discontinuous epitopes, are summarized at the end of each protein section. Studies describing general HIV responses to the virus, but not to any specific protein, are included at the end of each part. The annotation includes information such as crossreactivity, escape mutations, antibody sequence, TCR usage, functional domains that overlap with an epitope, immune response associations with rates of progression and therapy, and how specific epitopes were experimentally defined. Basic information such as HLA specificities for T-cell epitopes, isotypes of monoclonal antibodies, and epitope sequences are included whenever possible. All studies that we can find that incorporate the use of a specific monoclonal antibody are included in the entry for that antibody. A single T-cell epitope can have multiple entries, generally one entry per study. Finally, maps of all defined linear epitopes relative to the HXB2 reference proteins are provided.

  18. SOYBEAN - MOLECULAR ASPECTS OF BREEDING

    Directory of Open Access Journals (Sweden)

    Aleksandra Sudarić

    2012-12-01

    Full Text Available The book Soybean: Molecular Aspects of Breeding focuses recent progress in our understanding of the genetics and molecular biology of soybean. This book is divided into four parts and contains 22 chapters. Part I, Molecular Biology and Biotechnology focuses advances in molecular biology and laboratory procedures that have been developed recently to manipulate DNA. Part II, Breeding for abiotic stress covers proteomics approaches form as a powerful tool for investigating the molecular mechanisms of the plant responses to various types of abiotic stresses. Part III, Breeding for biotic stress addresses issues related to application of molecular based strategies in order to increase soybean resistance to various biotic factors. Part IV, Recent Technology reviews recent technologies into the realm of soybean monitoring, processing and product use. While the information accumulated in this book is of primary interest for plant breeders, valuable insights are also offered to agronomists, molecular biologists, physiologists, plant pathologists, food scientists and students. The book is a result of efforts made by many experts from different countries (USA, Japan, Croatia, Serbia, China, Canada, Malawi, Iran, Hong Kong, Brasil, Mexico.

  19. Molecular breast imaging. An update

    International Nuclear Information System (INIS)

    The aim of molecular imaging is to visualize and quantify biological, physiological and pathological processes at cellular and molecular levels. Molecular imaging using various techniques has recently become established in breast imaging. Currently molecular imaging techniques comprise multiparametric magnetic resonance imaging (MRI) using dynamic contrast-enhanced MRI (DCE-MRI), diffusion-weighted imaging (DWI), proton MR spectroscopy (1H-MRSI), nuclear imaging by breast-specific gamma imaging (BSGI), positron emission tomography (PET) and positron emission mammography (PEM) and combinations of techniques (e.g. PET-CT and multiparametric PET-MRI). Recently, novel techniques for molecular imaging of breast tumors, such as sodium imaging (23Na-MRI), phosphorus spectroscopy (31P-MRSI) and hyperpolarized MRI as well as specific radiotracers have been developed and are currently under investigation. It can be expected that molecular imaging of breast tumors will enable a simultaneous assessment of the multiple metabolic and molecular processes involved in cancer development and thus an improved detection, characterization, staging and monitoring of response to treatment will become possible. (orig.)

  20. Molecular-Coherent-States and Molecular-Fundamental-States

    OpenAIRE

    Irac-Astaud, Michele

    2000-01-01

    New families of Molecular-Coherent-States are constructed by the Perelomov group-method. Each family is generated by a Molecular-Fundamental-State that depends on an arbitrary sequence of complex numbers cj. Two of these families were already obtained by D.Janssen and by J. A. Morales, E. Deumens and Y. Ohrn. The properties of these families are investigated and we show that most of them are independent on the cj.

  1. Photoelectron photoion molecular beam spectroscopy

    International Nuclear Information System (INIS)

    The use of supersonic molecular beams in photoionization mass spectroscopy and photoelectron spectroscopy to assist in the understanding of photoexcitation in the vacuum ultraviolet is described. Rotational relaxation and condensation due to supersonic expansion were shown to offer new possibilities for molecular photoionization studies. Molecular beam photoionization mass spectroscopy has been extended above 21 eV photon energy by the use of Stanford Synchrotron Radiation Laboratory (SSRL) facilities. Design considerations are discussed that have advanced the state-of-the-art in high resolution vuv photoelectron spectroscopy. To extend gas-phase studies to 160 eV photon energy, a windowless vuv-xuv beam line design is proposed

  2. An introduction to molecular spintronics

    Institute of Scientific and Technical Information of China (English)

    JIANG ShangDa; GOβ Karin; CERVETTI Christian; BOGANI Lapo

    2012-01-01

    We review the progress and future possibilities in the emerging area of molecular spintronics,we nrst provide an overview of the different transport regimes in which electronic nanodevices can operate,then briefly overview the important characteristics of molecular magnetic materials that can be useful for application in spintronics and we eventually present several schemes to include such systems into spintronic nanodevices.We hightlight the importance of a chemical approach to the area,and in the last section we showcase some approaches to the creation of hybrids made of carbon nanostructures and molecular magnets,which are gaining increasing attention.

  3. Time Delay in Molecular Photoionization

    CERN Document Server

    Hockett, P; Villeneuve, D M; Corkum, P B

    2015-01-01

    Time-delays in the photoionization of molecules are investigated. As compared to atomic ionization, the time-delays expected from molecular ionization present a much richer phenomenon, with a strong spatial dependence due to the anisotropic nature of the molecular scattering potential. We investigate this from a scattering theory perspective, and make use of molecular photoionization calculations to examine this effect in representative homonuclear and hetronuclear diatomic molecules, nitrogen and carbon monoxide. We present energy and angle-resolved maps of the Wigner delay time for single-photon valence ionization, and discuss the possibilities for experimental measurements.

  4. Molecular electronic-structure theory

    CERN Document Server

    Helgaker, Trygve; Olsen, Jeppe

    2014-01-01

    Ab initio quantum chemistry has emerged as an important tool in chemical research and is appliced to a wide variety of problems in chemistry and molecular physics. Recent developments of computational methods have enabled previously intractable chemical problems to be solved using rigorous quantum-mechanical methods. This is the first comprehensive, up-to-date and technical work to cover all the important aspects of modern molecular electronic-structure theory. Topics covered in the book include: * Second quantization with spin adaptation * Gaussian basis sets and molecular-integral evaluati

  5. NASA Applications of Molecular Nanotechnology

    Science.gov (United States)

    Globus, Al; Bailey, David; Han, Jie; Jaffe, Richard; Levit, Creon; Merkle, Ralph; Srivastava, Deepak

    1998-01-01

    Laboratories throughout the world are rapidly gaining atomically precise control over matter. As this control extends to an ever wider variety of materials, processes and devices, opportunities for applications relevant to NASA's missions will be created. This document surveys a number of future molecular nanotechnology capabilities of aerospace interest. Computer applications, launch vehicle improvements, and active materials appear to be of particular interest. We also list a number of applications for each of NASA's enterprises. If advanced molecular nanotechnology can be developed, almost all of NASA's endeavors will be radically improved. In particular, a sufficiently advanced molecular nanotechnology can arguably bring large scale space colonization within our grasp.

  6. Molecular thermodynamics of nonideal fluids

    CERN Document Server

    Lee, Lloyd L

    2013-01-01

    Molecular Thermodynamics of Nonideal Fluids serves as an introductory presentation for engineers to the concepts and principles behind and the advances in molecular thermodynamics of nonideal fluids. The book covers related topics such as the laws of thermodynamics; entropy; its ensembles; the different properties of the ideal gas; and the structure of liquids. Also covered in the book are topics such as integral equation theories; theories for polar fluids; solution thermodynamics; and molecular dynamics. The text is recommended for engineers who would like to be familiarized with the concept

  7. Molecular hydrodynamics from memory kernels

    CERN Document Server

    Lesnicki, Dominika; Carof, Antoine; Rotenberg, Benjamin

    2016-01-01

    The memory kernel for a tagged particle in a fluid, computed from molecular dynamics simulations, decays algebraically as $t^{-3/2}$. We show how the hydrodynamic Basset-Boussinesq force naturally emerges from this long-time tail and generalize the concept of hydrodynamic added mass. This mass term is negative in the present case of a molecular solute, at odds with incompressible hydrodynamics predictions. We finally discuss the various contributions to the friction, the associated time scales and the cross-over between the molecular and hydrodynamic regimes upon increasing the solute radius.

  8. Molecular Hydrodynamics from Memory Kernels.

    Science.gov (United States)

    Lesnicki, Dominika; Vuilleumier, Rodolphe; Carof, Antoine; Rotenberg, Benjamin

    2016-04-01

    The memory kernel for a tagged particle in a fluid, computed from molecular dynamics simulations, decays algebraically as t^{-3/2}. We show how the hydrodynamic Basset-Boussinesq force naturally emerges from this long-time tail and generalize the concept of hydrodynamic added mass. This mass term is negative in the present case of a molecular solute, which is at odds with incompressible hydrodynamics predictions. Lastly, we discuss the various contributions to the friction, the associated time scales, and the crossover between the molecular and hydrodynamic regimes upon increasing the solute radius. PMID:27104730

  9. Bilingual teaching of molecular biology

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    Recently bilingual teaching in China's universities has been widely carried out and become a popular subject for study. In this paper, the reasons for bilingual teaching of molecular biology are pointed out, the textbook of molecular biology and teaching method in bilingual teaching classes are determined after investigation and the practice of bilingually teaching molecular biology use both English and Chinese in a class. The effect has proved good. The bilingual teaching methods, the problem of bilingual teaching, the importance of understanding its significance and the possibilities of improving such teaching of the subject are also discussed.

  10. Introduction to Accelerated Molecular Dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Perez, Danny [Los Alamos National Laboratory

    2012-07-10

    Molecular Dynamics is the numerical solution of the equations of motion of a set of atoms, given an interatomic potential V and some boundary and initial conditions. Molecular Dynamics is the largest scale model that gives unbiased dynamics [x(t),p(t)] in full atomistic detail. Molecular Dynamics: is simple; is 'exact' for classical dynamics (with respect to a given V); can be used to compute any (atomistic) thermodynamical or dynamical properties; naturally handles complexity -- the system does the right thing at the right time. The physics derives only from the interatomic potential.

  11. Modelos moleculares interactivos usando Jmol

    OpenAIRE

    Herráez Sánchez, Ángel; Miró Obradors, María Jesús; Palacios Alaiz, Evangelina

    2008-01-01

    El empleo de medios informáticos para examinar de forma interactiva modelos moleculares tridimensionales presenta ventajas bien conocidas para el estudio y la enseñanza de Química, Bioquímica, Biología Molecular y otras ciencias afines (Cristalografía, Ciencia de Materiales, etc.). Jmol es un programa escrito en Java, compatible con todos los sistemas operativos y navegadores de Internet, así como con otros programas de visualización molecular anteriores. Jmol destaca por ofrecer numerosas...

  12. Molecular Biomedical Imaging Laboratory (MBIL)

    Data.gov (United States)

    Federal Laboratory Consortium — The Molecular Biomedical Imaging Laboratory (MBIL) is adjacent-a nd has access-to the Department of Radiology and Imaging Sciences clinical imaging facilities. MBIL...

  13. Computer representation of molecular surfaces

    Energy Technology Data Exchange (ETDEWEB)

    Max, N.L.

    1981-07-06

    This review article surveys recent work on computer representation of molecular surfaces. Several different algorithms are discussed for producing vector or raster drawings of space-filling models formed as the union of spheres. Other smoother surfaces are also considered.

  14. Molecular motion in restricted geometries

    Indian Academy of Sciences (India)

    Siddharth Gautam; S Mitra; R Mukhopadhyay

    2008-10-01

    Molecular dynamics in restricted geometries is known to exhibit anomalous behaviour. Diffusion, translational or rotational, of molecules is altered significantly on confinement in restricted geometries. Quasielastic neutron scattering (QENS) offers a unique possibility of studying molecular motion in such systems. Both time scales involved in the motion and the geometry of motion can be studied using QENS. Molecular dynamics (MD) simulation not only provides insight into the details of the different types of motion possible but also does not suffer limitations of the experimental set-up. Here we report the effect of confinement on molecular dynamics in various restricted geometries as studied by QENS and MD simulations: An example where the QENS technique provided direct evidence of phase transition associated with change in the dynamical behaviour of the molecules is also discussed.

  15. AN OVERVIEW ON MOLECULAR DOCKING

    Directory of Open Access Journals (Sweden)

    Gaba Monika

    2010-06-01

    Full Text Available Molecular Docking is the computational modeling of the structure of complexes formed by two or more interacting molecules. The goal of molecular docking is the prediction of the three dimensional structures of interest. Docking itself only produces plausible candidate structures. These candidates are ranked using methods such as scoring functions to identify structures that are most likely to occur in nature. The state of the art of various computational aspects of molecular docking based virtual screening of database of small molecules is presented. This review encompasses molecular docking approaches, different search algorithms and the scoring functions used in docking methods and their applications to protein and nucleic acid drug targets. Limitations of current technologies as well as future prospects are also presented

  16. Transport properties of molecular junctions

    CERN Document Server

    Zimbovskaya, Natalya A

    2013-01-01

    A comprehensive overview of the physical mechanisms that control electron transport and the characteristics of metal-molecule-metal (MMM) junctions is presented. As far as possible, methods and formalisms presented elsewhere to analyze electron transport through molecules are avoided. This title introduces basic concepts—a description of the electron transport through molecular junctions—and briefly describes relevant experimental methods. Theoretical methods commonly used to analyze the electron transport through molecules are presented. Various effects that manifest in the electron transport through MMMs, as well as the basics of density-functional theory and its applications to electronic structure calculations in molecules are presented. Nanoelectronic applications of molecular junctions and similar systems are discussed as well. Molecular electronics is a diverse and rapidly growing field. Transport Properties of Molecular Junctions presents an up-to-date survey of the field suitable for researchers ...

  17. Quantum logic with molecular ions

    CERN Document Server

    Wolf, Fabian; Heip, Jan C; Gebert, Florian; Shi, Chunyan; Schmidt, Piet O

    2015-01-01

    Laser spectroscopy of cold and trapped molecular ions is a powerful tool for fundamental physics, including the determination of fundamental constants, the laboratory test for their possible variation, and the search for a possible electric dipole moment of the electron. Optical clocks based on molecular ions sensitive to some of these effects are expected to achieve uncertainties approaching the $10^{-18}$ level. While the complexity of molecular structure facilitates these applications, the absence of cycling transitions poses a challenge for direct laser cooling, quantum state control, and detection. Previously employed state detection techniques based on photo-dissociation or chemical reactions are destructive and therefore inefficient. Here we experimentally demonstrate non-destructive state detection of a single trapped molecular ion through its strong Coulomb coupling to a well-controlled co-trapped atomic ion. An algorithm based on a state-dependent optical dipole force(ODF) changes the internal state...

  18. Molecular Aggregation in Disodium Cromoglycate

    Science.gov (United States)

    Singh, Gautam; Agra-Kooijman, D.; Collings, P. J.; Kumar, Satyendra

    2012-02-01

    Details of molecular aggregation in the mesophases of the anti-asthmatic drug disodium cromoglycate (DSCG) have been studied using x-ray synchrotron scattering. The results show two reflections, one at wide angles corresponding to π-π stacking (3.32 å) of molecules, and the other at small angles which is perpendicular to the direction of molecular stacking and corresponds to the distance between the molecular aggregates. The latter varies from 35 - 41 å in the nematic (N) phase and 27 -- 32 å in the columnar (M) phase. The temperature evolution of the stack height, positional order correlations in the lateral direction, and orientation order parameter were determined in the N, M, and biphasic regions. The structure of the N and M phases and the nature of the molecular aggregation, together with their dependence on temperature and concentration, will be presented.

  19. Computerized molecular modeling of carbohydrates

    Science.gov (United States)

    Computerized molecular modleing continues to increase in capability and applicability to carbohydrates. This chapter covers nomenclature and conformational aspects of carbohydrates, perhaps of greater use to carbohydrate-inexperienced computational chemists. Its comments on various methods and studi...

  20. Emerging molecular phenotypes of asthma.

    Science.gov (United States)

    Ray, Anuradha; Oriss, Timothy B; Wenzel, Sally E

    2015-01-15

    Although asthma has long been considered a heterogeneous disease, attempts to define subgroups of asthma have been limited. In recent years, both clinical and statistical approaches have been utilized to better merge clinical characteristics, biology, and genetics. These combined characteristics have been used to define phenotypes of asthma, the observable characteristics of a patient determined by the interaction of genes and environment. Identification of consistent clinical phenotypes has now been reported across studies. Now the addition of various 'omics and identification of specific molecular pathways have moved the concept of clinical phenotypes toward the concept of molecular phenotypes. The importance of these molecular phenotypes is being confirmed through the integration of molecularly targeted biological therapies. Thus the global term asthma is poised to become obsolete, being replaced by terms that more specifically identify the pathology associated with the disease. PMID:25326577

  1. Synapse formation is regulated by the signaling adaptor GIT1

    OpenAIRE

    Zhang, Huaye; Webb, Donna J.; Asmussen, Hannelore; Horwitz, Alan F.

    2003-01-01

    Dendritic spines in the central nervous system undergo rapid actin-based shape changes, making actin regulators potential modulators of spine morphology and synapse formation. Although several potential regulators and effectors for actin organization have been identified, the mechanisms by which these molecules assemble and localize are not understood. Here we show that the G protein–coupled receptor kinase–interacting protein (GIT)1 serves such a function by targeting actin regulators and lo...

  2. Role of adaptor proteins in motor regulation and membrane transport

    NARCIS (Netherlands)

    M.A. Schlager (Max)

    2010-01-01

    markdownabstract__Abstract__ Active transport along the cytoskeleton is a process essential for proper cellular function. Although much is known about the motor proteins that generate the necessary force and the cytoskeleton that provides the cellular infrastructure, many questions still remain. Fo

  3. Molecular theory of graphene oxide

    OpenAIRE

    Sheka, Elena F.; Popova, Nadezhda A

    2012-01-01

    Applying to graphene oxides, molecular theory of graphene is based on the oxide molecular origin when it is considered as a final product in the succession of a graphene molecule polyderivatives related to a particular oxidation reaction. The graphene oxide structure is created in due course of calculations following the algorithms that take into account the graphene molecules natural radicalization, correlation of odd electrons, an extremely strong influence of structure on properties, a sha...

  4. MINT: the Molecular INTeraction database

    OpenAIRE

    Chatr-aryamontri, Andrew; Ceol, Arnaud; Palazzi, Luisa Montecchi; Nardelli, Giuliano; Schneider, Maria Victoria; Castagnoli, Luisa; Cesareni, Gianni

    2006-01-01

    The Molecular INTeraction database (MINT, ) aims at storing, in a structured format, information about molecular interactions (MIs) by extracting experimental details from work published in peer-reviewed journals. At present the MINT team focuses the curation work on physical interactions between proteins. Genetic or computationally inferred interactions are not included in the database. Over the past four years MINT has undergone extensive revision. The new version of MINT is based on a comp...

  5. [Knowledgebases in postgenomic molecular biology].

    Science.gov (United States)

    Lisitsa, A V; Shilov, B V; Evdokimov, P A; Gusev, S A

    2010-01-01

    Knowledgebases can become an effective tool essentially raising quality of information retrieval in molecular biology, promoting the development of new methods of education and forecasting of the biomedical R&D. Knowledge-based technologies should induce "paradigm shift" in the life science due to integrative focusing of research groups towards the challenges of postgenomic era. This paper debates concept of the knowledgebase, which exploits web usage mining to personalize the access of molecular biologist to the Internet resources. PMID:21328913

  6. Theoretical Aspects of Molecular Recognition

    OpenAIRE

    Harmat, Veronika; Náray-Szabó, Gábor

    2009-01-01

    Molecular recognition is a key process in non-covalent interactions, which determines, among others, host-guest complexation, drug action and protein-protein interaction. A simple and attractive formulation is the lock-and-key analogy defining the host as a lock accommodating the guest as a key. We stress three major aspects of molecular recognition, determining both complementarity between host and guest and similarity within a group of guest molecules. These aspects are: steric, i.e. maximi...

  7. Molecular mechanisms of rosacea pathogenesis

    Directory of Open Access Journals (Sweden)

    Davydova A.M.

    2013-09-01

    Full Text Available The article presents possible molecular mechanisms for rosacea pathogenesis from current domestic and foreign clinical observations and laboratory research: regulation and expression defects of antimicrobial peptides, vascular endothelial growth factor, the effect of serine proteases, oxidative stress, reactive oxygen species and ferritin on the occurrence and course of rosacea. New developments in molecular biology and genetics are advanced for researching the interaction of multiple factors involved in rosacea pathogenesis, as well as providing the bases for potentially new therapies.

  8. Molecular Gas at High Redshift

    CERN Document Server

    Solomon, P M

    2005-01-01

    The Early Universe Molecular Emission Line Galaxies (EMGs) are a population of galaxies with only 36 examples that hold great promise for the study of galaxy formation and evolution at high redshift. The classification, luminosity of molecular line emission, molecular mass, far-infrared (FIR) luminosity, star formation efficiency, morphology, and dynamical mass of the currently known sample are presented and discussed. The star formation rates derived from the FIR luminosity range from about 300 to 5000 M(sun)per year and the molecular mass from 4 x 10^9 to 1 x 10^{11} M(sun). At the lower end, these star formation rates, gas masses, and diameters are similar to those of local ultraluminous infrared galaxies, and represent starbursts in centrally concentrated disks, sometimes, but not always, associated with active galactic nuclei. The evidence for large (> 5 kpc) molecular disks is limited. Morphology and several high angular resolution images suggest that some EMGs are mergers with a massive molecular inter...

  9. Molecular Simulations in Astrobiology

    Science.gov (United States)

    Pohorille, Andrew; Wilson, Michael A.; Schweighofer, Karl; Chipot, Christophe; New, Michael H.; Vincenzi, Donald L. (Technical Monitor)

    2001-01-01

    One of the main goals of astrobiology is to understand the origin of cellular life. In the absence of any record of the earliest ancestors of contemporary cells, protocells, the most direct way to test our understanding of their characteristics is to construct laboratory models of protocells. Such efforts, currently underway in the NASA Astrobiology Program, are accompanied by computational studies aimed at explaining self-organization of simple molecules into ordered structures and developing designs of molecules that are capable of performing protocellular functions. Many of these functions, such as importing nutrients, capturing and storing energy, and responding to changes in the environment, are carried out by proteins bound to membranes. We use computer simulations to address the following, questions about these proteins: (1) How do small proteins (peptides) organize themselves into ordered structures at water-membrane interfaces and insert into membranes? (2) How do peptides aggregate to form membrane-spannin(y structures (e.g., channels)? (3) By what mechanisms do such aggregates perform their functions? The simulations are performed using the molecular dynamics (MD) method. In this method, Newton's equations of motion for each atom in the system are solved iteratively. At each time step, the forces exerted on each atom by the remaining atoms are evaluated by dividing them into two parts. Short-range forces are calculated directly in real space while long-range forces are evaluated in reciprocal space, usually using a particle-mesh algorithm which is of order O(NlnN). Currently, a time step of 2 femtoseconds is typically used, thereby making studies of problems occurring on multi-nanosecond time scales (10(exp 6) - 10(exp 8) time steps) accessible. To address a broader range of problems, simulations need to be extended by three orders of magnitude. Such an extension requires both algorithmic improvements and codes scalable to a large number of parallel

  10. Temperature Evolution of Molecular Clouds in the Central Molecular Zone

    CERN Document Server

    Krieger, Nico; Walter, Fabian; Kruijssen, J M Diederik; Beuther, Henrik

    2016-01-01

    We infer the absolute time dependence of kinematic gas temperature along a proposed orbit of molecular clouds in the Central Molecular Zone (CMZ) of the Galactic Center (GC). Ammonia gas temperature maps are one of the results of the "Survey of Water and Ammonia in the Galactic Center" (SWAG, PI: J. Ott); the dynamical model of molecular clouds in the CMZ was taken from Kruijssen et al. (2015). We find that gas temperatures increase as a function of time in both regimes before and after the cloud passes pericenter on its orbit in the GC potential. This is consistent with the recent proposal that pericenter passage triggers gravitational collapse. Other investigated quantities (line width, column density, opacity) show no strong sign of time dependence but are likely dominated by cloud-to-cloud variations.

  11. Contributions of plant molecular systematics to studies of molecular evolution.

    Science.gov (United States)

    Soltis, E D; Soltis, P S

    2000-01-01

    Dobzhansky stated that nothing in biology makes sense except in the light of evolution. A close corollary, and the central theme of this paper, is that everything makes a lot more sense in the light of phylogeny. Systematics is in the midst of a renaissance, heralded by the widespread application of new analytical approaches and the introduction of molecular techniques. Molecular phylogenetic analyses are now commonplace, and they have provided unparalleled insights into relationships at all levels of plant phylogeny. At deep levels, molecular studies have revealed that charophyte green algae are the closest relatives of the land plants and suggested that liverworts are sister to all other extant land plants. Other studies have suggested that lycopods are sister to all other vascular plants and clarified relationships among the ferns. The impact of molecular phylogenetics on the angiosperms has been particularly dramatic--some of the largest phylogenetic analyses yet conducted have involved the angiosperms. Inferences from three genes (rbcL, atpB, 18S rDNA) agree in the major features of angiosperm phylogeny and have resulted in a reclassification of the angiosperms. This ordinal-level reclassification is perhaps the most dramatic and important change in higher-level angiosperm taxonomy in the past 200 years. At lower taxonomic levels, phylogenetic analyses have revealed the closest relatives of many crops and 'model organisms' for studies of molecular genetics, concomitantly pointing to possible relatives for use in comparative studies and plant breeding. Furthermore, phylogenetic information has contributed to new perspectives on the evolution of polyploid genomes. The phylogenetic trees now available at all levels of the taxonomic hierarchy for angiosperms and other green plants should play a pivotal role in comparative studies in diverse fields from ecology to molecular evolution and comparative genetics.

  12. EDITORIAL: Molecular switches at surfaces Molecular switches at surfaces

    Science.gov (United States)

    Weinelt, Martin; von Oppen, Felix

    2012-10-01

    In nature, molecules exploit interaction with their environment to realize complex functionalities on the nanometer length scale. Physical, chemical and/or biological specificity is frequently achieved by the switching of molecules between microscopically different states. Paradigmatic examples are the energy production in proton pumps of bacteria or the signal conversion in human vision, which rely on switching molecules between different configurations or conformations by external stimuli. The remarkable reproducibility and unparalleled fatigue resistance of these natural processes makes it highly desirable to emulate nature and develop artificial systems with molecular functionalities. A promising avenue towards this goal is to anchor the molecular switches at surfaces, offering new pathways to control their functional properties, to apply electrical contacts, or to integrate switches into larger systems. Anchoring at surfaces allows one to access the full range from individual molecular switches to self-assembled monolayers of well-defined geometry and to customize the coupling between molecules and substrate or between adsorbed molecules. Progress in this field requires both synthesis and preparation of appropriate molecular systems and control over suitable external stimuli, such as light, heat, or electrical currents. To optimize switching and generate function, it is essential to unravel the geometric structure, the electronic properties and the dynamic interactions of the molecular switches on surfaces. This special section, Molecular Switches at Surfaces, collects 17 contributions describing different aspects of this research field. They analyze elementary processes, both in single molecules and in ensembles of molecules, which involve molecular switching and concomitant changes of optical, electronic, or magnetic properties. Two topical reviews summarize the current status, including both challenges and achievements in the field of molecular switches on

  13. Molecular classification of gastric cancer.

    Science.gov (United States)

    Chia, N-Y; Tan, P

    2016-05-01

    Gastric cancer (GC), a heterogeneous disease characterized by epidemiologic and histopathologic differences across countries, is a leading cause of cancer-related death. Treatment of GC patients is currently suboptimal due to patients being commonly treated in a uniform fashion irrespective of disease subtype. With the advent of next-generation sequencing and other genomic technologies, GCs are now being investigated in great detail at the molecular level. High-throughput technologies now allow a comprehensive study of genomic and epigenomic alterations associated with GC. Gene mutations, chromosomal aberrations, differential gene expression and epigenetic alterations are some of the genetic/epigenetic influences on GC pathogenesis. In addition, integrative analyses of molecular profiling data have led to the identification of key dysregulated pathways and importantly, the establishment of GC molecular classifiers. Recently, The Cancer Genome Atlas (TCGA) network proposed a four subtype classification scheme for GC based on the underlying tumor molecular biology of each subtype. This landmark study, together with other studies, has expanded our understanding on the characteristics of GC at the molecular level. Such knowledge may improve the medical management of GC in the future. PMID:26861606

  14. Molecular modelling of betalactamic antibiotic

    Directory of Open Access Journals (Sweden)

    Elso Manuel Cruz Cruz

    2010-02-01

    Full Text Available Background: The antibacterial properties of a compound are the result of its molecular structure. To establish the structural and electronic characteristics makes possible to understand the mechanisms of its action and becomes paramount for the rational design new drugs. Objective: To model some of the molecular properties of betalactamic antibiotics and inhibitors of the betalactamases and to relate them with their pharmacological actions. Method: The molecular structures were optimized with PM3• semiempiric calculus. The structure of the betalactamic ring in the different compounds was compared. The molecular properties were calculated according to the Density Functional Theory at a B3LYP/6-31G(d level. The density of the atomic charges and the frontier orbitals were analyzed. Results There are variations in the calculated properties that make possible to define two groups of compounds: one for the monobactams and the inhibitors of the betalactamases, with less planarity in the ring and less reactivity and another one with the penicillins, cephalosporins and carbapenems, planer, more structurally stable and reactive. Conclusions: The modelled molecular properties of the betalactamic antibiotics and inhibitors of the betalactamases show agreement with its pharmacological action.

  15. Ab-Initio Molecular Dynamics

    CERN Document Server

    Kühne, Thomas D

    2012-01-01

    Computer simulations and molecular dynamics in particular, is a very powerful method to provide detailed and essentially exact informations of classical many-body problems. With the advent of \\textit{ab-initio} molecular dynamics, where the forces are computed on-the-fly by accurate electronic structure calculations, the scope of either method has been greatly extended. This new approach, which unifies Newton's and Schr\\"odinger's equations, allows for complex simulations without relying on any adjustable parameter. This review is intended to outline the basic principles as well as a survey of the field. Beginning with the derivation of Born-Oppenheimer molecular dynamics, the Car-Parrinello method as well as novel hybrid scheme that unifies best of either approach are discussed. The predictive power is demonstrated by a series of applications ranging from insulators to semiconductors and even metals in condensed phases.

  16. Molecular morphology of cyanobacterial phycobilisomes

    Energy Technology Data Exchange (ETDEWEB)

    Siegelman, H.W.; Kycia, J.H.

    1982-09-01

    Phycobilisomes were isolated from several cyanobacteria following cell lysis with Triton X-100. They were purified by phosphate precipitation and hydrophobic-interaction chromatography. Their phycobiliprotein compositions were quantitatively determined by application of sets of simultaneous absorbance equations to gel chromatographic separations of the chromoproteins. Phycobilisomes purified from several cyanobacteria had characteristic elution times on agarose gel chromatography. Combining electron microscope observations of phycobilisome structure, phycobiliprotein composition, and agarose gel chromatography estimates of molecular weight permitted the calculation of many details of phycobilisome molecular structure. Complementary chromatic adaptation resulted in a change of phycobilisome composition and structure. The polypeptide compositions of phycobilisomes were examined by sodium dodecyl sulfate-agarose gel chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The phycobilisomes were composed of phycobilipeptides derived from the constituent phycobiliproteins. Higher molecular-weight phycobilipeptide aggregates were also observed. The dominant forces responsible for the maintenance of phycobilisome structure are concluded to be hydropohobic interactions.

  17. Molecular imaging in cancer treatment

    Energy Technology Data Exchange (ETDEWEB)

    Michalski, Mark H. [Stanford University School of Medicine, Stanford, CA (United States); Chen, Xiaoyuan [National Institutes of Health (NIH), Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), Bethesda, MD (United States)

    2011-02-15

    The success of cancer therapy can be difficult to predict, as its efficacy is often predicated upon characteristics of the cancer, treatment, and individual that are not fully understood or are difficult to ascertain. Monitoring the response of disease to treatment is therefore essential and has traditionally been characterized by changes in tumor volume. However, in many instances, this singular measure is insufficient for predicting treatment effects on patient survival. Molecular imaging allows repeated in vivo measurement of many critical molecular features of neoplasm, such as metabolism, proliferation, angiogenesis, hypoxia, and apoptosis, which can be employed for monitoring therapeutic response. In this review, we examine the current methods for evaluating response to treatment and provide an overview of emerging PET molecular imaging methods that will help guide future cancer therapies. (orig.)

  18. Molecular Processes in Biological Thermosensation

    Directory of Open Access Journals (Sweden)

    I. Digel

    2008-01-01

    Full Text Available Since thermal gradients are almost everywhere, thermosensation could represent one of the oldest sensory transduction processes that evolved in organisms. There are many examples of temperature changes affecting the physiology of living cells. Almost all classes of biological macromolecules in a cell (nucleic acids, lipids, proteins can present a target of the temperature-related stimuli. This review discusses some features of different classes of temperature-sensing molecules as well as molecular and biological processes that involve thermosensation. Biochemical, structural, and thermodynamic approaches are applied in the paper to organize the existing knowledge on molecular mechanisms of thermosensation. Special attention is paid to the fact that thermosensitive function cannot be assigned to any particular functional group or spatial structure but is rather of universal nature. For instance, the complex of thermodynamic, structural, and functional features of hemoglobin family proteins suggests their possible accessory role as “molecular thermometers”.

  19. State-Dependent Molecular Dynamics

    Directory of Open Access Journals (Sweden)

    Ciann-Dong Yang

    2014-10-01

    Full Text Available This paper proposes a new mixed quantum mechanics (QM—molecular mechanics (MM approach, where MM is replaced by quantum Hamilton mechanics (QHM, which inherits the modeling capability of MM, while preserving the state-dependent nature of QM. QHM, a single mechanics playing the roles of QM and MM simultaneously, will be employed here to derive the three-dimensional quantum dynamics of diatomic molecules. The resulting state-dependent molecular dynamics including vibration, rotation and spin are shown to completely agree with the QM description and well match the experimental vibration-rotation spectrum. QHM can be incorporated into the framework of a mixed quantum-classical Bohmian method to enable a trajectory interpretation of orbital-spin interaction and spin entanglement in molecular dynamics.

  20. Microwave regeneration of molecular sieves

    International Nuclear Information System (INIS)

    Molecular sieve driers have been included in the design of tritium handling systems for fusion reactors. In these systems there is a need to maintain extremely low exit dew points from the driers as well as a capability to rapidly reduce tritium concentrations following an accident. The required capacity of the driers is very high. The conventional method of regenerating these sieves after a water adsorption cycle is with hot air. However, because water is rapidly heated by microwave energy, this technology may be suitable for decreasing the bed regeneration time and hence may allow reduced capital and operating costs associated with a smaller bed. The present study was conducted to obtain preliminary information on the technical feasibility of regenerating molecular sieves with microwave energy. The study concentrated on Type 4A molecular sieve with a few tests on Type 13X sieve and also a silica gel adsorbent

  1. Nanofriction properties of molecular deposition films

    Institute of Scientific and Technical Information of China (English)

    王强斌; 高芒来; 张嗣伟

    2000-01-01

    The nanofriction properties of Au substrate and monolayer molecular deposition film and multilayer molecular deposition films on Au substrate and the molecular deposition films modified with alkyl-terminal molecule have been investigated by using an atomic force microscope. It is concluded that ( i ) the deposition of molecular deposition films on Au substrate and the modification of alkyl-terminal molecule to the molecular deposition films can reduce the frictional force; (ii) the molecular deposition films with the same terminal exhibit similar nanofriction properties, which has nothing to do with the molecular chain-length and the layer number; (iii) the unstable nanofriction properties of molecular deposition films are contributed to the active terminal of the molecular deposition film, which can be eliminated by decorating the active molecular deposition film with alkyl-terminal molecule, moreover, the decoration of alkyl-terminal molecule can lower the frictional force conspicuously; (iv) the relat

  2. Molecular replacement: tricks and treats

    International Nuclear Information System (INIS)

    To be successful, molecular replacement relies on the quality of the model and of the crystallographic data. Some tricks that could be applied to the models or to the crystal to increase the success rate of MR are discussed here. Molecular replacement is the method of choice for X-ray crystallographic structure determination provided that suitable structural homologues are available in the PDB. Presently, there are ∼80 000 structures in the PDB (8074 were deposited in the year 2012 alone), of which ∼70% have been solved by molecular replacement. For successful molecular replacement the model must cover at least 50% of the total structure and the Cα r.m.s.d. between the core model and the structure to be solved must be less than 2 Å. Here, an approach originally implemented in the CaspR server (http://www.igs.cnrs-mrs.fr/Caspr2/index.cgi) based on homology modelling to search for a molecular-replacement solution is discussed. How the use of as much information as possible from different sources can improve the model(s) is briefly described. The combination of structural information with distantly related sequences is crucial to optimize the multiple alignment that will define the boundaries of the core domains. PDB clusters (sequences with ≥30% identical residues) can also provide information on the eventual changes in conformation and will help to explore the relative orientations assumed by protein subdomains. Normal-mode analysis can also help in generating series of conformational models in the search for a molecular-replacement solution. Of course, finding a correct solution is only the first step and the accuracy of the identified solution is as important as the data quality to proceed through refinement. Here, some possible reasons for failure are discussed and solutions are proposed using a set of successful examples

  3. Molecular clouds near supernova remnants

    International Nuclear Information System (INIS)

    The physical properties of molecular clouds near supernova remnants were investigated. Various properties of the structure and kinematics of these clouds are used to establish their physical association with well-known remmnants. An infrared survey of the most massive clouds revealed embedded objects, probably stars whose formation was induced by the supernova blast wave. In order to understand the relationship between these and other molecular clouds, a control group of clouds was also observed. Excitation models for dense regions of all the clouds are constructed to evaluate molecular abundances in these regions. Those clouds that have embedded stars have lower molecular abundances than the clouds that do not. A cloud near the W28 supernova remnant also has low abundances. Molecular abundances are used to measure an important parameter, the electron density, which is not directly observable. In some clouds extensive deuterium fractionation is observed which confirms electron density measurements in those clouds. Where large deuterium fractionation is observed, the ionization rate in the cloud interior can also be measured. The electron density and ionization rate in the cloud near W28 are higher than in most clouds. The molecular abundances and electron densities are functions of the chemical and dynamical state of evolution of the cloud. Those clouds with lowest abundances are probably the youngest clouds. As low-abundance clouds, some clouds near supernova remnants may have been recently swept from the local interstellar material. Supernova remnants provide sites for star formation in ambient clouds by compressing them, and they sweep new clouds from more diffuse local matter

  4. Light and Redox Switchable Molecular Components for Molecular Electronics

    NARCIS (Netherlands)

    Browne, Wesley R.; Feringa, Bernard

    2010-01-01

    The field of molecular and organic electronics has seen rapid progress in recent years, developing from concept and design to actual demonstration devices in which both single molecules and self-assembled monolayers are employed as light-responsive components. Research in this field has seen numerou

  5. Molecular Modeling of Estrogen Receptor Using Molecular Operating Environment

    Science.gov (United States)

    Roy, Urmi; Luck, Linda A.

    2007-01-01

    Molecular modeling is pervasive in the pharmaceutical industry that employs many of our students from Biology, Chemistry and the interdisciplinary majors. To expose our students to this important aspect of their education we have incorporated a set of tutorials in our Biochemistry class. The present article describes one of our tutorials where…

  6. [MOLECULAR ASPECTS OF BRUCELLA PERSISTENCE].

    Science.gov (United States)

    Kulakov Yu K

    2016-01-01

    Brucellosis is a dangerous zoonotic disease of animals and humans caused by bacteria of the genus Brucella, which are able to survive, multiply, and persist in host cells. The review is devoted to the Brucella species persistence connected to the molecular mechanisms of escape from innate and adaptive immunity of the host and active interaction of effector proteins of the type IV secretion system with the host's signaling pathways. Understanding of the molecular mechanisms used by Brucella for the intracellular persistence in the host organism can allow us to develop new and effective means for the prevention and treatment of chronic brucellosis infection.

  7. Molecular calculations with B functions

    CERN Document Server

    Steinborn, E O; Ema, I; López, R; Ramírez, G

    1998-01-01

    A program for molecular calculations with B functions is reported and its performance is analyzed. All the one- and two-center integrals, and the three-center nuclear attraction integrals are computed by direct procedures, using previously developed algorithms. The three- and four-center electron repulsion integrals are computed by means of Gaussian expansions of the B functions. A new procedure for obtaining these expansions is also reported. Some results on full molecular calculations are included to show the capabilities of the program and the quality of the B functions to represent the electronic functions in molecules.

  8. Oscillations in molecular motor assemblies

    CERN Document Server

    Vilfan, A; Vilfan, Andrej; Frey, Erwin

    2005-01-01

    Autonomous oscillations in biological systems may have a biochemical origin or result from an interplay between force-generating and visco-elastic elements. In molecular motor assemblies the force-generating elements are molecular engines and the visco-elastic elements are stiff cytoskeletal polymers. The physical mechanism leading to oscillations depends on the particular architecture of the assembly. Existing models can be grouped into two distinct categories: systems with a {\\em delayed force activation} and {\\em anomalous force-velocity relations}. We discuss these systems within phase plane analysis known from the theory of dynamic systems and by adopting methods from control theory, the Nyquist criterion.

  9. Inverse strategies for molecular design

    International Nuclear Information System (INIS)

    An 'inverse' molecular design strategy is described to assist in the development of new molecules with optimized properties. This approach is based on a molecular orbital view and can be used to tailor ground state or excited state properties subject to particular constrains. In this scheme, wave functions are sought that optimize a chemical or electronic property, and then a Hamiltonian is constructed that generates these optimized wave functions. Analysis of the chemical properties in the optimized systems may suggest new synthetic targets. Examples are presented that optimize the transition dipole moment in some simple structures. 15 refs., 6 figs

  10. Molecular pathogenesis of intrahepatic cholangiocarcinoma

    DEFF Research Database (Denmark)

    Andersen, Jesper Bøje

    2014-01-01

    Cholangiocarcinoma (CCA) is an orphan cancer of the hepatobiliary tract, the incidence of which has increased in the past decade. The molecular pathogenesis of this treatment-refractory disease is poorly understood. Desmoplasia is a key causal feature of CCA; however, a majority of tumors develop...... underlying the diversity of growth patterns of this malignancy remain a clinical concern. It is crucial to advance our present understanding of the molecular pathogenesis of CCA to improve current clinical strategies and patient outcome. This will facilitate the delineation of patient subsets...

  11. Molecular design of allergy vaccines.

    Science.gov (United States)

    Linhart, Birgit; Valenta, Rudolf

    2005-12-01

    Recombinant-allergen-based diagnostic tests enable the dissection and monitoring of the molecular reactivity profiles of allergic patients, resulting in more specific diagnosis, disease monitoring, prevention and therapy. In vitro experiments, animal studies and clinical trials in patients demonstrate that allergenic molecules can be engineered to induce different immune responses ranging from tolerance to vigorous immunity. The available data thus suggest that molecular engineering of the disease-related antigens is a technology that may be applicable not only for the design of allergy vaccines but also for the design of vaccines against infectious diseases, autoimmunity and cancer.

  12. Industrial Applications of Molecular Simulations

    CERN Document Server

    Meunier, Marc

    2011-01-01

    The field of quantum and molecular simulations has experienced strong growth since the time of the early software packages. A recent study, showed a large increase in the number of people publishing papers based on ab initio methods from about 3,000 in 1991 to roughly 20,000 in 2009, with particularly strong growth in East Asia. Looking to the future, the question remains as to how these methods can be further integrated into the R&D value chain, bridging the gap from engineering to manufacturing. Using successful case studies as a framework, Industrial Applications of Molecular Simulations de

  13. Molecular catalytic coal liquid conversion

    Energy Technology Data Exchange (ETDEWEB)

    Stock, L.M.; Yang, Shiyong [Univ. of Chicago, IL (United States)

    1995-12-31

    This research, which is relevant to the development of new catalytic systems for the improvement of the quality of coal liquids by the addition of dihydrogen, is divided into two tasks. Task 1 centers on the activation of dihydrogen by molecular basic reagents such as hydroxide ion to convert it into a reactive adduct (OH{center_dot}H{sub 2}){sup {minus}} that can reduce organic molecules. Such species should be robust withstanding severe conditions and chemical poisons. Task 2 is focused on an entirely different approach that exploits molecular catalysts, derived from organometallic compounds that are capable of reducing monocyclic aromatic compounds under very mild conditions. Accomplishments and conclusions are discussed.

  14. [Opportunity and challenge on molecular epidemiology].

    Science.gov (United States)

    Duan, G C; Chen, S Y

    2016-08-10

    Molecular epidemiology, a branch of epidemiology, combines the theories and methods, both in epidemiology and molecular biology. Molecular epidemiology mainly focuses on biological markers, describing the distribution, occurrence, development and prognosis of diseases at the molecular level. The completion of Human Genome Project and rapid development of Precision Medicine and Big Data not only offer the new development opportunities but also bring about a higher demand and new challenge for molecular epidemiology. PMID:27539332

  15. Association analysis of Nitric oxide synthase 1 adaptor protein(NOS1AP)gene rs348624 polymorphisms ;with early-onset schizophrenia in the Han Chinese population%NOS1 AP基因rs348624多态性与中国汉族早发性精神分裂症的关联分析

    Institute of Scientific and Technical Information of China (English)

    胡国芹; 汪作为; 张晨; 禹顺英; 易正辉; 杨程青; 吕钦谕; 赵静; 朱明环; 郭向晴; 徐阿红; 介勇; 姜雅琴

    2015-01-01

    Objective:To investigate the association between the Nitric oxide synthase 1 adaptor protein (NOS1AP)gene polymorphisms with early-onset schizophrenia in the Han Chinese population. Method:NOS1AP tag single nucleotide polymorphisms(tag SNPs)rs348624 were genotyped using TaqMan SNP genoty-ping assay in 285 early-onset schizophrenia patients and 826 healthy controls. The allele and genotype frequen-cies were performed and the association with age at onset was evaluated. Results:There were significant difference in allele and genotype frequencies between patients and control subjects for rs348624(χ2 =149. 17, df=1,p=0. 00;χ2 =137. 25,df=2,p=0. 00). The T allele was significantly associated with an earlier age of onset in early-onset schizophrenia patients(Kaplan-Meier log rank test p=0. 00). Conclusion:The NOS1AP gene rs348624 polymorphisms may play important roles in the susceptibility and onset age to early-onset schizo-phrenia in the Han Chinese population.%目的:探讨中国汉族人群一氧化氮合酶1接头蛋白( NOS1AP)基因rs348624多态性与早发性精神分裂症的易感性及其首发年龄的关联性。方法:选取285例早发性精神分裂症患者为研究组和826名正常对照组,采用TaqMan法,检测NOS1AP基因rs348624位点多态性,并分析研究组危险等位基因的频率与首发年龄的关联性。结果:研究组与对照组rs348624等位基因和基因型频率分布比较差异有统计学意义[χ2=149.17,自由度(df)=1,p=0.00;χ2=137.25,自由度(df)=2,p=0.00];Kap-lan-Meier分析显示,rs348624等位基因T的频率与早发性精神分裂症首发年龄显著相关( Kaplan-Meier log rank 检验p=0.00)。结论:在中国汉族人群中NOS1AP基因与早发性精神分裂症存在关联,其rs348624多态性可能是导致早发性精神分裂症患者发病年龄提前的重要因素。

  16. Tuning molecular orbitals in molecular electronics and spintronics.

    Science.gov (United States)

    Kim, Woo Youn; Kim, Kwang S

    2010-01-19

    With the advance of nanotechnology, a variety of molecules, from single atoms to large-scale structures such as graphene or carbon nanotubes, have been investigated for possible use as molecular devices. Molecular orbitals (MOs) are a key ingredient in determining the transport properties of molecules, because they contain all the quantum mechanical information of molecular electronic structures and offer spatial conduction channels for electron transport. Therefore, the delicate modulation of the MOs enables us to tune the performance of electron transport through the molecule. Electric and magnetic fields are powerful and readily accessible means for that purpose. In this Account, we describe the effects of external fields on molecular electronic and spintronic devices. Quantum transport through a molecule that connects source and drain electrodes depends strongly on the alignment of molecular energy levels with respect to the chemical potentials at both electrodes. This dependence results from the energy levels being exploited in resonant tunneling processes when the molecule is weakly coupled to the electrodes in the molecular junction. Molecular energy levels can be shifted by the Stark effect of an external electric field. For a molecule with no permanent dipole moment, the polarizability is the primary factor determining the energy shift of each MO, according to the second-order Stark effect; more polarizable MOs undergo a larger energy shift. Interestingly, even a small shift may lead to a completely nontrivial result. For example, we show a magnetic on-off switching phenomenon of a molecule controlled by an electric field. If a molecule has a nonmagnetic ground state but a highly polarizable magnetic excited state with an energy slightly above the ground state, the magnetic excited state can have lower energy than the ground state under a sufficiently strong electric field. A magnetic field is normally used to control spin orientation in a ferromagnetic

  17. An invitation to molecular magnetism.

    Science.gov (United States)

    Pinkowicz, Dawid; Chorazy, Szymon; Stefańczyk, Olaf

    2011-01-01

    Molecular magnetism is a new and extremely fascinating field on the borders of chemistry, physics and materials science. The design and synthesis of molecule-based magnets requires the chemist to exert considerable control over the molecules to arrange them appropriately. It also demands the development of new theories to explain the complex magneto-structural behaviour of these intriguing solids. Molecular magnetism is still at a very early stage of development. The main challenge is to increase the strength of the magnetic interactions between spin carriers so the resulting materials can be usable at room temperature. However molecular magnets exhibit true potential to become multifunctional materials. They show some considerable advantages over conventional magnets: optical transparency, chemical sensitivity and low weight to name just a few. The following article is not a complete review of the field. Its aim is rather to show how beautiful and versatile magnetic molecular solids can be, and to encourage the in-depth study of the subject. PMID:21805910

  18. Bond resistances in molecular junctions

    Science.gov (United States)

    Painelli, Anna

    2006-03-01

    The description of molecular contacts is one of the hardest problems in modeling molecular junctions. In common approaches macroscopic leads ensure a finite potential drop and hence a driving force for the current. Recently, a different strategy is emerging where a steady-state DC current is forced in the molecule, by making resort to Lagrange multipliers, or by drawing a magnetic flux through the molecule. The strategy is promising, but two main problems remain to be solved: (1) the calculation of the potential drop needed to sustain the current, and (2) the definition of the potential profile along the molecule. Here the Joule law is used to evaluate the potential drop from the electrical power spent on the molecule, and continuity constraints for steady-state DC current are implemented to get information on the potential profile. Borrowing powerful concepts from the field of molecular spectroscopy, emphasis is put on the molecule, while clamping information about contacts in the molecular relaxation matrix. The molecule is described in a real-space approach, leading to a suggestive analogy between the molecule and an electrical circuit where resistances are associated with chemical bonds.

  19. Ordered structures of molecular bottlebrushes

    NARCIS (Netherlands)

    ten Brinke, G.; Ikkala, O.

    1997-01-01

    In this review 'molecular bottlebrushes' are flexible polymers densely loaded with equally flexible side chains. Interest in these structures arises from the possibility of lyotropic behaviour in dilute solution in a good solvent, as well as the possibility, of highly, ordered microphase-separated s

  20. Ordered Structures of Molecular Bottlebrushes

    NARCIS (Netherlands)

    Brinke, Gerrit ten; Ikkala, Olli

    1997-01-01

    In this review 'molecular bottlebrushes' are flexible polymers densely loaded with equally flexible side chains. Interest in these structures arises from the possibility of lyotropic behaviour in dilute solution in a good solvent, as well as the possibility of highly ordered microphase-separated sta

  1. Coherently Controlled Nanoscale Molecular Deposition

    OpenAIRE

    Dey, Bijoy K.; Shapiro, Moshe; Brumer, Paul

    2000-01-01

    Quantum interference effects are shown to provide a means of controlling and enhancing the focusing a collimated neutral molecular beam onto a surface. The nature of the aperiodic pattern formed can be altered by varying laser field characteristics and the system geometry.

  2. Molecular detection technologies for arboviruses

    Science.gov (United States)

    Arthropod-borne animal viruses (arboviruses) cause significant livestock and economic losses to world agriculture. This paper discusses the current and potential impact of these viruses, as well as the current and developing molecular diagnostic tools for these emerging and re-emerging insect transm...

  3. Papillomaviruses: Molecular and clinical aspects

    Energy Technology Data Exchange (ETDEWEB)

    Howley, P.M.; Broker, T.R.

    1985-01-01

    This book contains nine sections, each consisting of several papers. The section headings are : Papillomaviruses and Human Genital Tract Diseases;Papillomaviruses and Human Cutaneous Diseases, Papillomaviruses and Human Oral and Laryngeal Diseases;Therapeutic Approaches to Papillomavirus Infections;Animal Papillomaviruses;Molecular Biology;Transcription, Replication, and Genome Organization;Epithelial Cell Culture;Papillomavirus Transformation;and Viral Vectors.

  4. Rethinking a Mysterious Molecular Cloud

    CERN Document Server

    Imara, Nia

    2015-01-01

    I present high-resolution column density maps of two molecular clouds having strikingly different star formation rates. To better understand the unusual, massive G216-2.5, a molecular cloud with no massive star formation, the distribution of its molecular gas is compared to that of the Rosette Molecular Cloud. Far-infrared data from Herschel are used to derive $N(\\mathrm{H}_2)$ maps of each cloud and are combined with $I_{\\mathrm{CO}}$ data to determine the CO-to-H$_2$ ratio, $X_{\\mathrm{CO}}$. In addition, the probability distribution functions (PDFs) and cumulative mass fractions of the clouds are compared. For G216-2.5, $=7.8\\times 10^{20} cm^{-2}$ and $ =2.2\\times 10^{20} (K km s^{-1})^{-1}$; for the Rosette, $ =1.8\\times 10^{21} cm^{-2}$ and $ =2.8\\times 10^{20} (K km s^{-1})^{-1}$. The PDFs of both clouds are log-normal for extinctions below $\\sim 2$ mag and both show departures from log-normality at high extinctions. Although it is the less-massive cloud, the Rosette has a higher fraction of its mass ...

  5. Molecular Properties through Polarizable Embedding

    DEFF Research Database (Denmark)

    Olsen, Jógvan Magnus Haugaard; Kongsted, Jacob

    2011-01-01

    We review the theory related to the calculation of electric and magnetic molecular properties through polarizable embedding. In particular, we derive the expressions for the response functions up to the level of cubic response within the density functional theory-based polarizable embedding (PE...

  6. Molecular epidemiology of glanders, Pakistan.

    Science.gov (United States)

    Hornstra, Heidie; Pearson, Talima; Georgia, Shalamar; Liguori, Andrew; Dale, Julia; Price, Erin; O'Neill, Matthew; Deshazer, David; Muhammad, Ghulam; Saqib, Muhammad; Naureen, Abeera; Keim, Paul

    2009-12-01

    We collected epidemiologic and molecular data from Burkholderia mallei isolates from equines in Punjab, Pakistan from 1999 through 2007. We show that recent outbreaks are genetically distinct from available whole genome sequences and that these genotypes are persistent and ubiquitous in Punjab, probably due to human-mediated movement of equines.

  7. Thermoelectric efficiency of molecular junctions

    Science.gov (United States)

    Perroni, C. A.; Ninno, D.; Cataudella, V.

    2016-09-01

    Focus of the review is on experimental set-ups and theoretical proposals aimed to enhance thermoelectric performances of molecular junctions. In addition to charge conductance, the thermoelectric parameter commonly measured in these systems is the thermopower, which is typically rather low. We review recent experimental outcomes relative to several junction configurations used to optimize the thermopower. On the other hand, theoretical calculations provide estimations of all the thermoelectric parameters in the linear and non-linear regime, in particular of the thermoelectric figure of merit and efficiency, completing our knowledge of molecular thermoelectricity. For this reason, the review will mainly focus on theoretical studies analyzing the role of not only electronic, but also of the vibrational degrees of freedom. Theoretical results about thermoelectric phenomena in the coherent regime are reviewed focusing on interference effects which play a significant role in enhancing the figure of merit. Moreover, we review theoretical studies including the effects of molecular many-body interactions, such as electron-vibration couplings, which typically tend to reduce the efficiency. Since a fine tuning of many parameters and coupling strengths is required to optimize the thermoelectric conversion in molecular junctions, new theoretically proposed set-ups are discussed in the conclusions.

  8. Thermoelectric efficiency of molecular junctions.

    Science.gov (United States)

    Perroni, C A; Ninno, D; Cataudella, V

    2016-09-21

    Focus of the review is on experimental set-ups and theoretical proposals aimed to enhance thermoelectric performances of molecular junctions. In addition to charge conductance, the thermoelectric parameter commonly measured in these systems is the thermopower, which is typically rather low. We review recent experimental outcomes relative to several junction configurations used to optimize the thermopower. On the other hand, theoretical calculations provide estimations of all the thermoelectric parameters in the linear and non-linear regime, in particular of the thermoelectric figure of merit and efficiency, completing our knowledge of molecular thermoelectricity. For this reason, the review will mainly focus on theoretical studies analyzing the role of not only electronic, but also of the vibrational degrees of freedom. Theoretical results about thermoelectric phenomena in the coherent regime are reviewed focusing on interference effects which play a significant role in enhancing the figure of merit. Moreover, we review theoretical studies including the effects of molecular many-body interactions, such as electron-vibration couplings, which typically tend to reduce the efficiency. Since a fine tuning of many parameters and coupling strengths is required to optimize the thermoelectric conversion in molecular junctions, new theoretically proposed set-ups are discussed in the conclusions. PMID:27420149

  9. Measurement Frontiers in Molecular Biology

    Science.gov (United States)

    Laderman, Stephen

    2009-03-01

    Developments of molecular measurements and manipulations have long enabled forefront research in evolution, genetics, biological development and its dysfunction, and the impact of external factors on the behavior of cells. Measurement remains at the heart of exciting and challenging basic and applied problems in molecular and cell biology. Methods to precisely determine the identity and abundance of particular molecules amongst a complex mixture of similar and dissimilar types require the successful design and integration of multiple steps involving biochemical manipulations, separations, physical probing, and data processing. Accordingly, today's most powerful methods for characterizing life at the molecular level depend on coordinated advances in applied physics, biochemistry, chemistry, computer science, and engineering. This is well illustrated by recent approaches to the measurement of DNA, RNA, proteins, and intact cells. Such successes underlie well founded visions of how molecular biology can further assist in answering compelling scientific questions and in enabling the development of remarkable advances in human health. These visions, in turn, are motivating the interdisciplinary creation of even more comprehensive measurements. As a further and closely related consequence, they are motivating innovations in the conceptual and practical approaches to organizing and visualizing large, complex sets of interrelated experimental results and distilling from those data compelling, informative conclusions.

  10. EAACI Molecular Allergology User's Guide

    DEFF Research Database (Denmark)

    Matricardi, P M; Kleine-Tebbe, J; Hoffmann, H J;

    2016-01-01

    The availability of allergen molecules ('components') from several protein families has advanced our understanding of immunoglobulin E (IgE)-mediated responses and enabled 'component-resolved diagnosis' (CRD). The European Academy of Allergy and Clinical Immunology (EAACI) Molecular Allergology U...

  11. Molecular Mobility in Sugar Glasses

    NARCIS (Netherlands)

    Dries, van den I.J.

    2000-01-01

    Glasses are liquids that exhibit solid state behavior as a result of their extremely high viscosity. Regarding their application to foods, glasses play a role in the preservation of foods, due to their high viscosity and the concomitant low molecular mobility. This thesis focuses on sugar glasses. S

  12. STATINS AND MYOPATHY: MOLECULAR MECHANISMS

    Directory of Open Access Journals (Sweden)

    O. M. Drapkina

    2012-01-01

    Full Text Available The safety of statin therapy is considered. In particular the reasons of a complication such as myopathy are discussed in detail. The molecular mechanisms of statin myopathy , as well as its risk factors are presented. The role of coenzyme Q10 in the myopathy development and coenzyme Q10 application for the prevention of this complication are considered. 

  13. Molecular outflows in starburst nuclei

    Science.gov (United States)

    Roy, Arpita; Nath, Biman B.; Sharma, Prateek; Shchekinov, Yuri

    2016-08-01

    Recent observations have detected molecular outflows in a few nearby starburst nuclei. We discuss the physical processes at work in such an environment in order to outline a scenario that can explain the observed parameters of the phenomenon, such as the molecular mass, speed and size of the outflows. We show that outflows triggered by OB associations, with NOB ≥ 105 (corresponding to a star formation rate (SFR)≥1 M⊙ yr-1 in the nuclear region), in a stratified disk with mid-plane density n0 ˜ 200-1000 cm-3 and scale height z0 ≥ 200(n0/102 cm-3)-3/5 pc, can form molecules in a cool dense and expanding shell. The associated molecular mass is ≥107 M⊙ at a distance of a few hundred pc, with a speed of several tens of km s-1. We show that a SFR surface density of 10 ≤ ΣSFR ≤ 50 M⊙ yr-1 kpc-2 favours the production of molecular outflows, consistent with observed values.

  14. Low-dimensional molecular metals

    CERN Document Server

    Toyota, Naoki; Muller, Jens

    2007-01-01

    Assimilating research in the field of low-dimensional metals, this monograph provides an overview of the status of research on quasi-one- and two-dimensional molecular metals, describing normal-state properties, magnetic field effects, superconductivity, and the phenomena of interacting p and d electrons.

  15. Molecular dynamics simulation of diffusivity

    Institute of Scientific and Technical Information of China (English)

    Juanfang LIU; Danling ZENG; Qin LI; Hong GAO

    2008-01-01

    Equilibrium molecular dynamics simulation was performed on water to calculate its diffusivity by adopting different potential models. The results show that the potential models have great influence on the simulated results. In addition, the diffusivities obtained by the SPCE model conform well to the experimental values.

  16. Molecular outflows in starburst nuclei

    CERN Document Server

    Roy, Arpita; Sharma, Prateek; Shchekinov, Yuri

    2016-01-01

    Recent observations have detected molecular outflows in a few nearby starburst nuclei. We discuss the physical processes at work in such an environment in order to outline a scenario that can explain the observed parameters of the phenomenon, such as the molecular mass, speed and size of the outflows. We show that outflows triggered by OB associations, with $N_{OB}\\ge 10^5$ (corresponding to a star formation rate (SFR)$\\ge 1$ M$_{\\odot}$ yr$^{-1}$ in the nuclear region), in a stratified disk with mid-plane density $n_0\\sim 200\\hbox{--}1000$ cm$^{-3}$ and scale height $z_0\\ge 200 (n_0/10^2 \\, {\\rm cm}^{-3})^{-3/5}$ pc, can form molecules in a cool dense and expanding shell. The associated molecular mass is $\\ge 10^7$ M$_\\odot$ at a distance of a few hundred pc, with a speed of several tens of km s$^{-1}$. We show that a SFR surface density of $10 \\le \\Sigma_{SFR} \\le 50$ M$_\\odot$ yr$^{-1}$ kpc$^{-2}$ favours the production of molecular outflows, consistent with observed values.

  17. Excitons in tubular molecular aggregates

    NARCIS (Netherlands)

    Didraga, C; Knoester, J

    2004-01-01

    We present a brief overview of recent work on the optical properties of molecular aggregates with a tubular (cylindrical) shape. The exciton states responsible for these properties can be distinguished with regard to a transverse wave number, which directly relates to optical selection rules and pol

  18. Molecularly imprinted polymers for mycotoxins

    Science.gov (United States)

    Molecularly imprinted polymers (MIPs) are a class of synthetic receptors capable of selective recognition of analytes. Recent developments in imprinting technology have made it possible to apply this technology in a range of applications, including mycotoxin detection. Structure-activity relations...

  19. Molecular chaperones and neurodegenerative diseases

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Neurodegenerative diseases are characterized by the accumulation of intracellular or extracellular protein aggregates that result from conformational changes in proteins. These diseases may result from an imbalance between the production of misfolded proteins and normal chaperone capacity. Molecular chaperones provide a first line of defence against misfolded, aggregation-prone proteins and are, therefore, promising therapeutic targets for neurodegenerative diseases.

  20. EDITORIAL: Focus on Molecular Electronics FOCUS ON MOLECULAR ELECTRONICS

    Science.gov (United States)

    Scheer, Elke; Reineker, Peter

    2008-06-01

    The notion 'molecular electronics' has been used more frequently since the 1970s and summarizes a series of physical phenomena and ideas for their application in connection with organic molecules, oligomers, polymers, organic aggregates and solids. The properties studied in this field were connected to optical and electrical phenomena, such as optical absorption, fluorescence, nonlinear optics, energy transport, charge transfer, electrical conductance, and electron and nuclear spin-resonance. The final goal was and is to build devices which can compete or surpass some aspects of inorganic semiconductor devices. For example, on the basis of organic molecules there exist rectifiers, transistors, molecular wires, organic light emitting diodes, elements for photovoltaics, and displays. With respect to applications, one aspect of the organic materials is their broad variability and the lower effort and costs for their processability. The step from microstructures to the investigation of nanostructures is a big challenge also in this field and has lead to what nowadays is called molecular electronics in its narrow sense. In this field the subjects of the studies are often single molecules, e.g. single molecule optical spectroscopy, electrical conductance, i.e. charge transport through a single molecule, the influence of vibrational degrees of freedom, etc. A challenge here is to provide the techniques for addressing in a reproducible way the molecular scale. In another approach small molecular ensembles are studied in order to avoid artefacts from particular contact situations. The recent development of the field is presented in [1-8]. In this Focus Issue we present new results in the field of 'molecular electronics', both in its broad and specialized sense. One of the basic questions is the distribution of the energy levels responsible for optical absorption on the one hand and for the transport of charge on the other. A still unanswered question is whether the Wannier

  1. Advances in molecular vibrations and collision dynamics molecular clusters

    CERN Document Server

    Bacic, Zatko

    1998-01-01

    This volume focuses on molecular clusters, bound by van der Waals interactions and hydrogen bonds. Twelve chapters review a wide range of recent theoretical and experimental advances in the areas of cluster vibrations, spectroscopy, and reaction dynamics. The authors are leading experts, who have made significant contributions to these topics.The first chapter describes exciting results and new insights in the solvent effects on the short-time photo fragmentation dynamics of small molecules, obtained by combining heteroclusters with femtosecond laser excitation. The second is on theoretical work on effects of single solvent (argon) atom on the photodissociation dynamics of the solute H2O molecule. The next two chapters cover experimental and theoretical aspects of the energetics and vibrations of small clusters. Chapter 5 describes diffusion quantum Monte Carlo calculations and non additive three-body potential terms in molecular clusters. The next six chapters deal with hydrogen-bonded clusters, refle...

  2. HTMD: High-Throughput Molecular Dynamics for Molecular Discovery.

    Science.gov (United States)

    Doerr, S; Harvey, M J; Noé, Frank; De Fabritiis, G

    2016-04-12

    Recent advances in molecular simulations have allowed scientists to investigate slower biological processes than ever before. Together with these advances came an explosion of data that has transformed a traditionally computing-bound into a data-bound problem. Here, we present HTMD, a programmable, extensible platform written in Python that aims to solve the data generation and analysis problem as well as increase reproducibility by providing a complete workspace for simulation-based discovery. So far, HTMD includes system building for CHARMM and AMBER force fields, projection methods, clustering, molecular simulation production, adaptive sampling, an Amazon cloud interface, Markov state models, and visualization. As a result, a single, short HTMD script can lead from a PDB structure to useful quantities such as relaxation time scales, equilibrium populations, metastable conformations, and kinetic rates. In this paper, we focus on the adaptive sampling and Markov state modeling features. PMID:26949976

  3. Research Status of Molecular Biology in Flax

    Institute of Scientific and Technical Information of China (English)

    Wu Jian-zhong

    2016-01-01

    Flax is a kind of worldwide fiber and oil crops, and it has a very important role in economic crop production in the world. With the development of molecular biology techniques, the research of flax molecular level has a very big breakthrough. But, flax molecular biology researches are less reported due to the later starting. This paper summarized the latest research progress of molecular biology of flax, including molecular marker technology, construction of genetic map, gene engineering and omics researches, in order to provide the reference to understand the development and research status for flax molecular breeding researchers.

  4. Available Instruments for Analyzing Molecular Dynamics Trajectories.

    Science.gov (United States)

    Likhachev, I V; Balabaev, N K; Galzitskaya, O V

    2016-01-01

    Molecular dynamics trajectories are the result of molecular dynamics simulations. Trajectories are sequential snapshots of simulated molecular system which represents atomic coordinates at specific time periods. Based on the definition, in a text format trajectory files are characterized by their simplicity and uselessness. To obtain information from such files, special programs and information processing techniques are applied: from molecular dynamics animation to finding characteristics along the trajectory (versus time). In this review, we describe different programs for processing molecular dynamics trajectories. The performance of these programs, usefulness for analyses of molecular dynamics trajectories, strong and weak aspects are discussed. PMID:27053964

  5. Molecular Engineering of dosimetric materials; Ingenieria Molecular de materiales dosimetricos

    Energy Technology Data Exchange (ETDEWEB)

    Salas, P.; Castano, V.M. [Instituto de Fisica, UNAM, A.P. 1-1010, Queretaro (Mexico); Mendoza, D.; Gonzalez, P. [Instituto Nacional de Investigaciones Nucleares, A.P. 18-1027 Mexico D.F. (Mexico)

    1999-07-01

    It was studied the thermoluminescent response to the gamma radiation of a new family of solid materials of zircon-silica. In this study some materials have been prepared by the sol-gel method with different stoichiometric relations, finding that it is possible to control, at least, partially, the thermoluminescent behavior starting from the Molecular Engineering of those materials, since the mixture of both ceramics allows to produce materials with different spatial structures. (Author)

  6. The molecular biology of cancer.

    Science.gov (United States)

    Bertram, J S

    2000-12-01

    identifies key genes directly involved in carcinogenesis and demonstrates how mutations in these genes allow cells to circumvent cellular controls. This detailed understanding of the process of carcinogenesis at the molecular level has only been possible because of the advent of modern molecular biology. This new discipline, by precisely identifying the molecular basis of the differences between normal and malignant cells, has created novel opportunities and provided the means to specifically target these modified genes. Whenever possible this review highlights these opportunities and the attempts being made to generate novel, molecular based therapies against cancer. Successful use of these new therapies will rely upon a detailed knowledge of the genetic defects in individual tumors. The review concludes with a discussion of how the use of high throughput molecular arrays will allow the molecular pathologist/therapist to identify these defects and direct specific therapies to specific mutations.

  7. [Molecular diagnostics of lung cancer].

    Science.gov (United States)

    Ryska, A; Dziadziuszko, R; Olszewski, W; Berzinec, P; Öz, B; Gottfried, M; Cufer, T; Samarzija, M; Plank, L; Ostoros, Gy; Tímár, J

    2015-09-01

    Development of the target therapies of lung cancer was a rapid process which fundamentally changed the pathological diagnosis as well. Furthermore, molecular pathology became essential part of the routine diagnostics of lung cancer. These changes generated several practical problems and in underdeveloped countries or in those with reimbursement problems have been combined with further challenges. The central and eastern region of Europe are characterized by similar problems in this respect which promoted the foundation of NSCLC Working Group to provide up to date protocols or guidelines. This present paper is a summary of the molecular pathology and target therapy guidelines written with the notion that it has to be upgraded continuously according to the development of the field.

  8. Laser Controlled Molecular Orientation Dynamics

    International Nuclear Information System (INIS)

    Molecular orientation is a challenging control issue covering a wide range of applications from reactive collisions, high order harmonic generation, surface processing and catalysis, to nanotechnologies. The laser control scenario rests on the following three steps: (i) depict some basic mechanisms producing dynamical orientation; (ii) use them both as computational and interpretative tools in optimal control schemes involving genetic algorithms; (iii) apply what is learnt from optimal control to improve the basic mechanisms. The existence of a target molecular rotational state combining the advantages of efficient and post-pulse long duration orientation is shown. A strategy is developed for reaching such a target in terms of a train of successive short laser pulses applied at predicted time intervals. Each individual pulse imparts a kick to the molecule which orients. Transposition of such strategies to generic systems is now under investigation

  9. Molecular mimicry and multiple sclerosis

    Institute of Scientific and Technical Information of China (English)

    Michael Namaka; Michael R. Mulvey; Sabina Kapoor; Leann Simms; Christine Leong; Amy Grossberndt; Michael Prouta; Emma Frost; Farid Esfahani; Andrew Gomori

    2011-01-01

    Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. Although the exact underlying mechanism leading to myelin destruction is unknown, the molecular mimicry theory is the most commonly acknowledged elucidation of MS pathology. Although various antigens have been associated with MS induction, this review presents studies focused on key bacterial and viral antigens that lead to the development of MS. The research specific to a molecular mimicry theory of MS via each implicated agent is weak; however, collectively the reports provide credible support for this theory. Given that homologous sequences are not required to lead to antigenic cross-reactivity, it is reasonable to conclude that certain viral and bacterial antigens with 5-10 similar amino acids in sequence can lead to self destruction of similar myelin sequences. Thus, this literature review has provided insight to further the understanding of the etiology of multiple sclerosis.

  10. Prediction of molecular crystal structures

    CERN Document Server

    Beyer, T

    2001-01-01

    The ab initio prediction of molecular crystal structures is a scientific challenge. Reliability of first-principle prediction calculations would show a fundamental understanding of crystallisation. Crystal structure prediction is also of considerable practical importance as different crystalline arrangements of the same molecule in the solid state (polymorphs)are likely to have different physical properties. A method of crystal structure prediction based on lattice energy minimisation has been developed in this work. The choice of the intermolecular potential and of the molecular model is crucial for the results of such studies and both of these criteria have been investigated. An empirical atom-atom repulsion-dispersion potential for carboxylic acids has been derived and applied in a crystal structure prediction study of formic, benzoic and the polymorphic system of tetrolic acid. As many experimental crystal structure determinations at different temperatures are available for the polymorphic system of parac...

  11. Molecular dissociation in dilute gas

    International Nuclear Information System (INIS)

    The charge state distributions (CSD) produced during molecular dissociation are important to both Trace Element Accelerator Mass Spectrometry (TEAMS) and the ion implantation industry. The CSD of 1.3 - 1.7 MeV SiN+, SiMg+, SiMn+, and SiZn+ molecules have been measured for elements that do not form atomic negative ions (N, Mg, Mn, and Zn) using a NEC Tandem Pelletron accelerator. The molecules were produced in a Cs sputter negative ion source, accelerated, magnetically analyzed, and then passed through an N2 gas cell. The neutral and charged breakups where analyzed using an electrostatic deflector and measured with particle detectors. Equilibrium CSD were determined and comparisons made between molecular and atomic ion data. copyright 1999 American Institute of Physics

  12. Seebeck effect in molecular junctions

    International Nuclear Information System (INIS)

    Advances in the fabrication and characterization of nanoscale systems presently allow for a better understanding of their thermoelectric properties. As is known, the building blocks of thermoelectricity are the Peltier and Seebeck effects. In the present work we review results of theoretical studies of the Seebeck effect in single-molecule junctions and similar systems. The behavior of thermovoltage and thermopower in these systems is controlled by several factors including the geometry of molecular bridges, the characteristics of contacts between the bridge and the electrodes, the strength of the Coulomb interactions between electrons on the bridge, and of electron–phonon interactions. We describe the impact of these factors on the thermopower. Also, we discuss a nonlinear Seebeck effect in molecular junctions. (topical review)

  13. Molecular-specific urokinase antibodies

    Science.gov (United States)

    Atassi, M. Zouhair (Inventor); Morrison, Dennis R. (Inventor)

    2009-01-01

    Antibodies have been developed against the different molecular forms of urokinase using synthetic peptides as immunogens. The peptides were synthesized specifically to represent those regions of the urokinase molecules which are exposed in the three-dimensional configuration of the molecule and are uniquely homologous to urokinase. Antibodies are directed against the lysine 158-isoleucine 159 peptide bond which is cleaved during activation from the single-chain (ScuPA) form to the bioactive double chain (54 KDa and 33 KDa) forms of urokinase and against the lysine 135 lysine 136 bond that is cleaved in the process of removing the alpha-chain from the 54 KDa form to produce the 33 KDa form of urokinase. These antibodies enable the direct measurement of the different molecular forms of urokinase from small samples of conditioned medium harvested from cell cultures.

  14. Molecular Rheology of Complex Fluids

    DEFF Research Database (Denmark)

    Huang, Qian; Rasmussen, Henrik Koblitz

    –state viscosity between melts and solutions is still an open question. Branched polymer melts have more complex molecular structures. A stress maximum during the start–up of uniaxial extensional flow was reported in 1979 for a low–density polyethylene (LDPE) melt. Subsequently observations of a steady stress...... and branched polymer melts. We report the stress–strain measurements in extensional flows using a unique Filament Stretching Rheometer (FSR) in controlled strain rate mode and controlled stress mode. Extensional flow is difficult to measure reliably in Laboratory circumstances. In this thesis we first present...... fluids as a function of molecular chemistry has attracted a long history of collaboration between industry and academia. In industrial polymer processes, there is usually a combination of both shear and extensional flows. In some processing operations such as blow molding and fiber spinning, extensional...

  15. Metallic, magnetic and molecular nanocontacts

    Science.gov (United States)

    Requist, Ryan; Baruselli, Pier Paolo; Smogunov, Alexander; Fabrizio, Michele; Modesti, Silvio; Tosatti, Erio

    2016-06-01

    Scanning tunnelling microscopy and break-junction experiments realize metallic and molecular nanocontacts that act as ideal one-dimensional channels between macroscopic electrodes. Emergent nanoscale phenomena typical of these systems encompass structural, mechanical, electronic, transport, and magnetic properties. This Review focuses on the theoretical explanation of some of these properties obtained with the help of first-principles methods. By tracing parallel theoretical and experimental developments from the discovery of nanowire formation and conductance quantization in gold nanowires to recent observations of emergent magnetism and Kondo correlations, we exemplify the main concepts and ingredients needed to bring together ab initio calculations and physical observations. It can be anticipated that diode, sensor, spin-valve and spin-filter functionalities relevant for spintronics and molecular electronics applications will benefit from the physical understanding thus obtained.

  16. Molecular genetics of cutaneous lymphomas.

    Science.gov (United States)

    Whittaker, S

    2001-09-01

    The underlying molecular basis of primary cutaneous lymphomas has not yet been clarified. However, abnormalities of cell cycle control genes and well-defined tumor suppressor genes such as p53 are common and may contribute to disease progression and treatment resistance. Biallelic inactivation of tumor suppressor genes usually occurs by a combination of deletion, point mutation, and/or promotor hypermethylation. The detection of UVB-specific mutations of p53 requires confirmation but may have important implications for the management of patients with mycosis fungoides. Molecular cytogenetic studies have identified common regions of chromosomal deletion and amplification, which suggests the presence and location of genes that are of critical importance in the pathogenesis of cutaneous lymphoma.

  17. Hydantoin-based molecular photoswitches.

    Science.gov (United States)

    Martínez-López, David; Yu, Meng-Long; García-Iriepa, Cristina; Campos, Pedro J; Frutos, Luis Manuel; Golen, James A; Rasapalli, Sivappa; Sampedro, Diego

    2015-04-17

    A new family of molecular photoswitches based on arylidenehydantoins is described together with their synthesis and photochemical and photophysical studies. A series of hydantoin derivatives have been prepared as single isomers using simple and versatile chemistry in good yields. Our studies show that the photostationary states of these compounds can be easily controlled by means of external factors, such as the light source or filters. Moreover, the detailed investigations proved that these switches are efficient (i.e., they make efficient use of the light energy, are high fatigue resistant, and are very photostable). In some cases, the switches can be completely turned on/off, a desirable feature for specific applications. A series of theoretical calculations have also been carried out to understand the photoisomerization mechanism at the molecular level. PMID:25806596

  18. Molecular tailoring of solid surfaces

    CERN Document Server

    Evenson, S A

    1997-01-01

    The overall performance of a material can be dramatically improved by tailoring its surface at the molecular level. The aim of this project was to develop a universal technique for attaching dendrimers (well-defined, nanoscale, functional polymers) and Jeffamines (high molecular weight polymer chains) to the surface of any shaped solid substrate. This desire for controlled functionalization is ultimately driven by the need to improve material compatibility in various biomedical applications. Atomic force microscopy (AFM) was used initially to study the packing and structure of Langmuir-Blodgett films on surfaces, and subsequently resulted in the first visualization of individual, spherically shaped, nanoscopic polyamidoamine dendrimers. The next goal was to develop a methodology for attaching such macromolecules to inert surfaces. Thin copolymer films were deposited onto solid substrates to produce materials with a fixed concentration of surface anhydride groups. Vapor-phase functionalization reactions were t...

  19. Seebeck effect in molecular junctions

    Science.gov (United States)

    Zimbovskaya, Natalya A.

    2016-05-01

    Advances in the fabrication and characterization of nanoscale systems presently allow for a better understanding of their thermoelectric properties. As is known, the building blocks of thermoelectricity are the Peltier and Seebeck effects. In the present work we review results of theoretical studies of the Seebeck effect in single-molecule junctions and similar systems. The behavior of thermovoltage and thermopower in these systems is controlled by several factors including the geometry of molecular bridges, the characteristics of contacts between the bridge and the electrodes, the strength of the Coulomb interactions between electrons on the bridge, and of electron–phonon interactions. We describe the impact of these factors on the thermopower. Also, we discuss a nonlinear Seebeck effect in molecular junctions.

  20. Symmetry breaking in molecular ferroelectrics.

    Science.gov (United States)

    Shi, Ping-Ping; Tang, Yuan-Yuan; Li, Peng-Fei; Liao, Wei-Qiang; Wang, Zhong-Xia; Ye, Qiong; Xiong, Ren-Gen

    2016-07-11

    Ferroelectrics are inseparable from symmetry breaking. Accompanying the paraelectric-to-ferroelectric phase transition, the paraelectric phase adopting one of the 32 crystallographic point groups is broken into subgroups belonging to one of the 10 ferroelectric point groups, i.e. C1, C2, C1h, C2v, C4, C4v, C3, C3v, C6 and C6v. The symmetry breaking is captured by the order parameter known as spontaneous polarization, whose switching under an external electric field results in a typical ferroelectric hysteresis loop. In addition, the responses of spontaneous polarization to other external excitations are related to a number of physical effects such as second-harmonic generation, piezoelectricity, pyroelectricity and dielectric properties. Based on these, this review summarizes recent developments in molecular ferroelectrics since 2011 and focuses on the relationship between symmetry breaking and ferroelectricity, offering ideas for exploring high-performance molecular ferroelectrics. PMID:27051889

  1. 3D molecular imaging SIMS

    Energy Technology Data Exchange (ETDEWEB)

    Gillen, Greg [Surface and Microanalysis Science Division, National Institute of Standards and Technology, Gaithersburg, MD 20899-8371 (United States)]. E-mail: Greg.gillen@nist.gov; Fahey, Albert [Surface and Microanalysis Science Division, National Institute of Standards and Technology, Gaithersburg, MD 20899-8371 (United States); Wagner, Matt [Surface and Microanalysis Science Division, National Institute of Standards and Technology, Gaithersburg, MD 20899-8371 (United States); Mahoney, Christine [Surface and Microanalysis Science Division, National Institute of Standards and Technology, Gaithersburg, MD 20899-8371 (United States)

    2006-07-30

    Thin monolayer and bilayer films of spin cast poly(methyl methacrylate) (PMMA), poly(2-hydroxyethyl methacrylate) (PHEMA), poly(lactic) acid (PLA) and PLA doped with several pharmaceuticals have been analyzed by dynamic SIMS using SF{sub 5} {sup +} polyatomic primary ion bombardment. Each of these systems exhibited minimal primary beam-induced degradation under cluster ion bombardment allowing molecular depth profiles to be obtained through the film. By combing secondary ion imaging with depth profiling, three-dimensional molecular image depth profiles have been obtained from these systems. In another approach, bevel cross-sections are cut in the samples with the SF{sub 5} {sup +} primary ion beam to produce a laterally magnified cross-section of the sample that does not contain the beam-induced damage that would be induced by conventional focussed ion beam (FIB) cross-sectioning. The bevel surface can then be examined using cluster SIMS imaging or other appropriate microanalysis technique.

  2. Molecular imaging. Fundamentals and applications

    Energy Technology Data Exchange (ETDEWEB)

    Tian, Jie (ed.) [Chinese Academy of Sciences, Beijing (China). Intelligent Medical Research Center

    2013-07-01

    Covers a wide range of new theory, new techniques and new applications. Contributed by many experts in China. The editor has obtained the National Science and Technology Progress Award twice. ''Molecular Imaging: Fundamentals and Applications'' is a comprehensive monograph which describes not only the theory of the underlying algorithms and key technologies but also introduces a prototype system and its applications, bringing together theory, technology and applications. By explaining the basic concepts and principles of molecular imaging, imaging techniques, as well as research and applications in detail, the book provides both detailed theoretical background information and technical methods for researchers working in medical imaging and the life sciences. Clinical doctors and graduate students will also benefit from this book.

  3. Simulation of complex molecular systems

    International Nuclear Information System (INIS)

    The combined evolution of the electronic structure softwares and computational capabilities makes quantum molecular dynamics simulations available for increasingly complex systems, up to several hundred atoms. Among the various ab initio techniques, Density Functional Theory (DFT) is very successful due to its important computational efficiency with respect to Hartree-Fock type approaches. Its combination with empirical treatments of the weak van der Waals interactions allows the simulation of equilibrium or dynamics properties of numerous systems of interest for the nuclear and defense industry. We present 3 direct applications of quantum molecular dynamics: the determination of the structure of the complex Pu(DTPA) ion where DTPA means diethylen-triamine-penta-acid, the calculation of the equation of state and the Hugoniot curve of TATB monocrystal. (authors)

  4. Laser Cooling of Molecular Anions

    CERN Document Server

    Yzombard, Pauline; Gerber, Sebastian; Doser, Michael; Comparat, Daniel

    2015-01-01

    We propose a scheme for laser cooling of negatively charged molecules. We briefly summarise the requirements for such laser cooling and we identify a number of potential candidates. A detailed computation study with C$\\_2^-$, the most studied molecular anion, is carried out. Simulations of 3D laser cooling in a gas phase show that this molecule could be cooled down to below 1 mK in only a few tens of milliseconds, using standard lasers. Sisyphus cooling, where no photo-detachment process is present, as well as Doppler laser cooling of trapped C$\\_2^-$, are also simulated. This cooling scheme has an impact on the study of cold molecules, molecular anions, charged particle sources and antimatter physics.

  5. Fragmentation in filamentary molecular clouds

    CERN Document Server

    Contreras, Yanett; Rathborne, Jill M; Sanhueza, Patricio

    2015-01-01

    Recent surveys of dust continuum emission at sub-mm wavelengths have shown that filamentary molecular clouds are ubiquitous along the Galactic plane. These structures are inhomogeneous, with over-densities that are sometimes associated with infrared emission and active of star formation. To investigate the connection between filaments and star formation, requires an understanding of the processes that lead to the fragmentation of filaments and a determination of the physical properties of the over-densities (clumps). In this paper, we present a multi-wavelength study of five filamentary molecular clouds, containing several clumps in different evolutionary stages of star formation. We analyse the fragmentation of the filaments and derive the physical properties of their clumps. We find that the clumps in all filaments have a characteristic spacing consistent with the prediction of the `sausage' instability theory, regardless of the complex morphology of the filaments or their evolutionary stage. We also find t...

  6. Molecular deformation mechanisms in polyethylene

    CERN Document Server

    Coutry, S

    2001-01-01

    adjacent labelled stems is significantly larger when the DPE guest is a copolymer molecule. Our comparative studies on various types of polyethylene lead to the conclusion that their deformation behaviour under drawing has the same basis, with additional effects imputed to the presence of tie-molecules and branches. Three major points were identified in this thesis. The changes produced by drawing imply (1) the crystallisation of some of the amorphous polymer and the subsequent orientation of the newly formed crystals, (2) the re-orientation of the crystalline ribbons and (3) the beginning of crystallite break-up. However, additional effects were observed for the high molecular weight linear sample and the copolymer sample and were attributed, respectively, to the presence of tie-molecules and of branches. It was concluded that both the tie-molecules and the branches are restricting the molecular movement during deformation, and that the branches may be acting as 'anchors'. This work is concerned with details...

  7. Molecular imaging with terahertz waves.

    Science.gov (United States)

    Oh, Seung Jae; Choi, Jihye; Maeng, Inhee; Park, Jae Yeon; Lee, Kwangyeol; Huh, Yong-Min; Suh, Jin-Suck; Haam, Seungjoo; Son, Joo-Hiuk

    2011-02-28

    We demonstrate a highly sensitive THz molecular imaging (TMI) technique involving differential modulation of surface plasmons induced on nanoparticles and obtain target specific in vivo images of cancers. This technique can detect quantities of gold nanoparticles as small as 15 µM in vivo. A comparison of TMI images with near infrared absorption images shows the superior sensitivity of TMI. Furthermore, the quantification property of TMI is excellent, being linearly proportional to the concentration of nanoparticles. The target specificity issue is also addressed at the ex vivo and cell levels. The high thermal sensitivity of TMI can help extend photonic-based photothermal molecular imaging researches from the in vitro level to the in vivo level. The TMI technique can be used for monitoring drug delivery processes and for early cancer diagnosis.

  8. Molecular diagnostics of foodborne pathogens

    DEFF Research Database (Denmark)

    Hansen, Trine

    or accidental contamination of food, feed and water supplies pose a threat to human health worldwide and the need for generic detection methods that can screen for many pathogens at the time are highly desirable. A metagenomics based direct 16S rDNA sequencing approach was evaluated as a diagnostic tool......Illness caused by foodborne pathogens represents an important economic and public health burden worldwide. In order to minimize the occurrence of foodborne pathogens in the food production chain and thereby increase the food safety, better detection methods and knowledge about the behavior...... to investigate the use of different nucleic acid based methods for molecular diagnostics of foodborne pathogens focusing on Salmonellaand Bacillus cereuswith respect to improve food safety. The work represents two parts of molecular diagnostics; the characterization Salmonellafor better understanding of its...

  9. Molecular approaches for bacterial azoreductases

    Directory of Open Access Journals (Sweden)

    Montira Leelakriangsak

    2013-12-01

    Full Text Available Azo dyes are the dominant types of synthetic dyes, widely used in textiles, foods, leather, printing, tattooing, cosmetics, and pharmaceutical industries. Many microorganisms are able to decolorize azo dyes, and there is increasing interest in biological waste treatment methods. Bacterial azoreductases can cleave azo linkages (-N=N- in azo dyes, forming aromatic amines. This review mainly focuses on employing molecular approaches, including gene manipulation and recombinant strains, to study bacterial azoreductases. The construction of the recombinant protein by cloning and the overexpression of azoreductase is described. The mechanisms and function of bacterial azoreductases can be studied by other molecular techniques discussed in this review, such as RT-PCR, southern blot analysis, western blot analysis, zymography, and muta-genesis in order to understand bacterial azoreductase properties, function and application. In addition, understanding the regulation of azoreductase gene expression will lead to the systematic use of gene manipulation in bacterial strains for new strategies in future waste remediation technologies.

  10. Molecular Science Computing: 2010 Greenbook

    Energy Technology Data Exchange (ETDEWEB)

    De Jong, Wibe A.; Cowley, David E.; Dunning, Thom H.; Vorpagel, Erich R.

    2010-04-02

    This 2010 Greenbook outlines the science drivers for performing integrated computational environmental molecular research at EMSL and defines the next-generation HPC capabilities that must be developed at the MSC to address this critical research. The EMSL MSC Science Panel used EMSL’s vision and science focus and white papers from current and potential future EMSL scientific user communities to define the scientific direction and resulting HPC resource requirements presented in this 2010 Greenbook.

  11. Interactive Modelling of Molecular Structures

    Science.gov (United States)

    Rustad, J. R.; Kreylos, O.; Hamann, B.

    2004-12-01

    The "Nanotech Construction Kit" (NCK) [1] is a new project aimed at improving the understanding of molecular structures at a nanometer-scale level by visualization and interactive manipulation. Our very first prototype is a virtual-reality program allowing the construction of silica and carbon structures from scratch by assembling them one atom at a time. In silica crystals or glasses, the basic building block is an SiO4 unit, with the four oxygen atoms arranged around the central silicon atom in the shape of a regular tetrahedron. Two silicate units can connect to each other by their silicon atoms covalently bonding to one shared oxygen atom. Geometrically, this means that two tetrahedra can link at their vertices. Our program is based on geometric representations and uses simple force fields to simulate the interaction of building blocks, such as forming/breaking of bonds and repulsion. Together with stereoscopic visualization and direct manipulation of building blocks using wands or data gloves, this enables users to create realistic and complex molecular models in short amounts of time. The NCK can either be used as a standalone tool, to analyze or experiment with molecular structures, or it can be used in combination with "traditional" molecular dynamics (MD) simulations. In a first step, the NCK can create initial configurations for subsequent MD simulation. In a more evolved setup, the NCK can serve as a visual front-end for an ongoing MD simulation, visualizing changes in simulation state in real time. Additionally, the NCK can be used to change simulation state on-the-fly, to experiment with different simulation conditions, or force certain events, e.g., the forming of a bond, and observe the simulation's reaction. [1] http://graphics.cs.ucdavis.edu/~okreylos/ResDev/NanoTech

  12. Molecular markers for thyroid cancer

    International Nuclear Information System (INIS)

    The importance of the study of the thyroid nodule lies in excluding the possibility of a malignant lesion because the majority of lesions are benign but there is a malignancy risk of 5 to 10%. Most of them are well differentiated carcinomas originating in the follicular epithelium. In spite of the fact that the majority are benign lesions, distinguishing them from carcinomas is crucial to treatment and adequate follow-up. Fine-needle biopsy allows making the diagnosis in most of cases. However, this method is restricted, particularly when diagnosing follicular lesions. In an effort to improve the diagnostic accuracy of biopsy and to provide new diagnosing criteria, a number of molecular markers have been put forward, some of which has wide range of approval whereas others still awaits to be validated for further implementation. This article presented an updated review of molecular markers with higher number of evidence, more accessible and potentially usable from a methodological viewpoint for diagnosis of the thyroid nodule before surgery. The importance of the study of the thyroid nodule lies in excluding the possibility of a malignant lesion because the majority of lesions are benign but there is a malignancy risk of 5 to 10%. Most of them are well differentiated carcinomas originating in the follicular epithelium. In spite of the fact that the majority are benign lesions, distinguishing them from carcinomas is crucial to treatment and adequate follow-up. Fine-needle biopsy allows making the diagnosis in most of cases. However, this method is restricted, particularly when diagnosing follicular lesions. In an effort to improve the diagnostic accuracy of biopsy and to provide new diagnosing criteria, a number of molecular markers have been put forward, some of which has wide range of approval whereas others still awaits to be validated for further implementation. This article presented an updated review of molecular markers with higher number of evidence, more

  13. Fluorescent calixarenes as molecular receptors

    OpenAIRE

    Lynam, Carol

    2002-01-01

    The synthesis of calixarene L1 is described. This molecular sensor incorporates a fluorescent naphthyl moiety, the necessary fluorophore for optical transduction, whose fluorescent intensity alters to differing degrees on binding of enantiomers. Means of distinguishing between enantiomers of a chiral molecule are of critical importance in many areas of analytical chemistry and biotechnology, particularly in drug design and synthesis. Fluorescent quenching studies of calixarene L1 in methanol ...

  14. Gastronomic botany and molecular gastronomy

    OpenAIRE

    Pérez-Urria Carril, Elena; Gómez Garay, Aranzazu; Ávalos García, Adolfo; Martín Calvarro, Luisa; Pintos López, Beatriz; Saco Sierra, M. Dolores; Martín Gómez, M. Soledad; Pérez Alonso, M. José; Puelles Gallo, María; Palá Paúl, Jesús; Cifuentes Cuencas, Blanca; Llamas Ramos, José Eugenio

    2011-01-01

    Complutense University of Madrid through the "Vicerrectorado de Calidad" develops projects to innovate and improve teaching quality. Among these projects is "Gastronomic Botany and Molecular Gastronomy" which aims to develop new materials and tools for the Virtual Campus and consequently offer new possibilities for teaching and training. Also this project organize and structure a new teaching matter for post-graduate education that will be an example of approach, relationship and cooper...

  15. Harmful molecular mechanisms in sepsis

    OpenAIRE

    Rittirsch, Daniel; Flierl, Michael A; Ward, Peter A.

    2008-01-01

    Sepsis and sepsis-associated multi-organ failure are major challenges for scientists and clinicians and are a tremendous burden for health-care systems. Despite extensive basic research and clinical studies, the pathophysiology of sepsis is still poorly understood. We are now beginning to understand that sepsis is a heterogeneous, dynamic syndrome caused by imbalances in the ‘inflammatory network’. In this Review, we highlight recent insights into the molecular interactions that occur during ...

  16. Molecular fluctuation in living cells

    Institute of Scientific and Technical Information of China (English)

    唐孝威

    1997-01-01

    The concept of molecular fluctuation in living cells is introduced. Many apparently different experi-mental facts in living cells, including the velocity non-uniformity of organelle movement, the saltatory movement of transport vesicles in axoplasmic transport, the chromosome oscillation during metaphase in mitosis and the pauses in the chromosome movement during anaphase are explained using a unified viewpoint. A method of determination of average number of the attached motor protein molecules from the experimental data is also proposed.

  17. The molecular underpinnings of totipotency

    DEFF Research Database (Denmark)

    Morgani, Sophie Maria Christina; Brickman, Joshua Mark

    2014-01-01

    Embryonic stem (ES) cells are characterized by their functional potency and capacity to self-renew in culture. Historically, ES cells have been defined as pluripotent, able to make the embryonic but not the extraembryonic lineages (such as the yolk sac and the placenta). The functional capacity o...... lineages and, therefore, can be said to be totipotent. Here, we consider the molecular basis for this totipotent state, its transcriptional signature and the signalling pathways that define it....

  18. Molecular Organization of Vomeronasal Chemoreception

    OpenAIRE

    Isogai, Yoh; Si, Sheng; Pont-Lezica, Lorena; Tan, Taralyn Marie; Kapoor, Vikrant; Murthy, Venkatesh N.; Dulac, Catherine

    2011-01-01

    The vomeronasal organ (VNO) has a key role in mediating the social and defensive responses of many terrestrial vertebrates to species- and sex-specific chemosignals. More than 250 putative pheromone receptors have been identified in the mouse VNO, but the nature of the signals detected by individual VNO receptors has not yet been elucidated. To gain insight into the molecular logic of VNO detection leading to mating, aggression or defensive responses, we sought to uncover the response profile...

  19. Ideally Efficient Irreversible Molecular Gears

    OpenAIRE

    Sokolov, I. M.

    2000-01-01

    Typical man-made locomotive devices use reversible gears, as cranks, for transforming reciprocating motion into directed one. Such gears are holonomic and have the transduction efficiency of unity. On the other hand, a typical gear of molecular motors is a ratchet rectifier, which is irreversible. We discuss what properties of rectifier mostly influence the transduction efficiency and show that an apliance which locks under backwards force can achieve the energetic efficiency of unity, withou...

  20. Molecular Determinants of Lung Development

    OpenAIRE

    Morrisey, Edward E.; Cardoso, Wellington V.; Lane, Robert H.; Rabinovitch, Marlene; Abman, Steven H.; Ai, Xingbin; Albertine, Kurt H; Bland, Richard D.; Chapman, Harold A.; Checkley, William; Epstein, Jonathan A.; Kintner, Christopher R.; Kumar, Maya; Minoo, Parviz; Mariani, Thomas J.

    2013-01-01

    Development of the pulmonary system is essential for terrestrial life. The molecular pathways that regulate this complex process are beginning to be defined, and such knowledge is critical to our understanding of congenital and acquired lung diseases. A recent workshop was convened by the National Heart, Lung, and Blood Institute to discuss the developmental principles that regulate the formation of the pulmonary system. Emerging evidence suggests that key developmental pathways not only regu...