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FEBS Journal

Cover image for Vol. 280 Issue 23

December 2013

Volume 280, Issue 23

Pages i–iii, 5937–6275

  1. Front Cover

    1. Top of page
    2. Front Cover
    3. Editorial Information
    4. Minireview Series
    5. Minireviews
    6. Original Articles
    7. Corrigendum
    8. Author index
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      Front Cover (page i)

      Article first published online: 20 NOV 2013 | DOI: 10.1111/j.1742-4658.2013.08804.x

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      Novel pharmaceuticals and histopathology in systems medicine by D.B. Kell (pp. 5957–5980) and P.D. Caie et al. (pp. 5949–5956).

  2. Editorial Information

    1. Top of page
    2. Front Cover
    3. Editorial Information
    4. Minireview Series
    5. Minireviews
    6. Original Articles
    7. Corrigendum
    8. Author index
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      Editorial Information (pages ii–iii)

      Article first published online: 20 NOV 2013 | DOI: 10.1111/j.1742-4658.2013.08804_1.x

  3. Minireview Series

    1. Top of page
    2. Front Cover
    3. Editorial Information
    4. Minireview Series
    5. Minireviews
    6. Original Articles
    7. Corrigendum
    8. Author index
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      Systems medicine: opportunities and challenges for systems biology approaches (page 5937)

      Walter Kolch and Boris N. Kholodenko

      Article first published online: 30 OCT 2013 | DOI: 10.1111/febs.12560

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      Technological advance have not only dramatically accelerated progress in medical knowledge and practice, but also revealed the enormous complexity of diseases and pathogenetic mechanisms. Can systems biology approaches and computational modelling help defeat the challenge of exploding complexity? Four review articles discuss the challenges and opportunities for such systems level approaches in medicine, pathology and drug development.

  4. Minireviews

    1. Top of page
    2. Front Cover
    3. Editorial Information
    4. Minireview Series
    5. Minireviews
    6. Original Articles
    7. Corrigendum
    8. Author index
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      The search for organizing principles as a cure against reductionism in systems medicine (pages 5938–5948)

      Olaf Wolkenhauer and Sara Green

      Article first published online: 24 MAY 2013 | DOI: 10.1111/febs.12311

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      Complexity has forced scientists into developing reductive approaches. We investigate an old regulative ideal from systems theory to describe the organization of cellular systems “in general” by identifying key concepts, challenges and strategies to pursue the search for organizing principles. We argue that reductive approaches need to be complemented by integrative strategies that de-contextualize through abstraction.

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      Human tissue in systems medicine (pages 5949–5956)

      Peter D. Caie, Klaas Schuur, Anca Oniscu, Peter Mullen, Paul A. Reynolds and David J. Harrison

      Article first published online: 29 OCT 2013 | DOI: 10.1111/febs.12550

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      Histopathology remains the gold standard for patient diagnosis and prognosis. Advances in image analysis and molecular pathology have created an explosion of novel data which presents a challenge to this central role. Systems medicine seeks to integrate this information, available from human tissue, into predictive and personalised models to enrich histopathology and adopt 4P medicine.

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      Finding novel pharmaceuticals in the systems biology era using multiple effective drug targets, phenotypic screening and knowledge of transporters: where drug discovery went wrong and how to fix it (pages 5957–5980)

      Douglas B. Kell

      Article first published online: 22 APR 2013 | DOI: 10.1111/febs.12268

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      Pharmaceutical drug discovery went wrong when it abandoned high-level (function-first) phenotypic screening for hypothesis-dependent molecular target discovery. This was coupled to a widespread failure to recognize the importance of drug transporters, and the abandonment of natural products. Leveraging our knowledge of genome wide networks, a systems approach will be required to discover safe and effective drugs that hit multiple targets simultaneously.

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      The hallmarks of Parkinson's disease (pages 5981–5993)

      Paul M. A. Antony, Nico J. Diederich, Rejko Krüger and Rudi Balling

      Article first published online: 10 JUN 2013 | DOI: 10.1111/febs.12335

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      Parkinson's disease (PD) is an age-related multifactorial disease, influenced by both genetic and environmental factors. In this minireview, we propose a systems-based approach, organizing the available information around cellular disease hallmarks. The aim of this cell-based view is to improve communication in interdisciplinary research endeavors targeting the molecular events, modulatory cell-to-cell signaling pathways and emerging clinical phenotypes related to PD.

  5. Original Articles

    1. Top of page
    2. Front Cover
    3. Editorial Information
    4. Minireview Series
    5. Minireviews
    6. Original Articles
    7. Corrigendum
    8. Author index
    1. You have free access to this content
      A S52P mutation in the ‘α-crystallin domain’ of Mycobacterium leprae HSP18 reduces its oligomeric size and chaperone function (pages 5994–6009)

      Sandip K. Nandi, Elengikal A. A. Rehna, Alok K. Panda, Sugathan Shiburaj, Kuppamuthu Dharmalingam and Ashis Biswas

      Article first published online: 30 SEP 2013 | DOI: 10.1111/febs.12519

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      S52P mutation in the “α-crystallin domain” of Mycobacterium leprae HSP18 was observed in various leprotic patients. Mutant protein (HSP18P52) exhibited decreased surface hydrophobicity and structural stability than wild-type protein (HSP18S52). S52P mutation also lowered oligomeric size and chaperone activity of HSP18. As both variants differ in stability and function, they may have different roles in survival of M. leprae pathogen.

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      Heterologous expression and purification of an active human TRPV3 ion channel (pages 6010–6021)

      Stefan Kol, Christian Braun, Gerhard Thiel, Declan A. Doyle, Michael Sundström, Pontus Gourdon and Poul Nissen

      Article first published online: 30 SEP 2013 | DOI: 10.1111/febs.12520

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      Little is known about the atomic structure of TRP ion channels due to difficulties in obtaining pure and functionally active samples. We report on the Escherichia coli expression of the human TRPV3 channel. Purified recombinant TRPV3 forms multimers, adopts an α-helical conformation and retains its current inducing activity. The ability to produce TRPV3 heterologously will aid functional and structural studies.

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      Identification and polymorphism discovery of the cathelicidins, Lf-CATHs in ranid amphibian (Limnonectes fragilis) (pages 6022–6032)

      Haining Yu, Shasha Cai, Jiuxiang Gao, Songyan Zhang, Yiling Lu, Xue Qiao, Hailong Yang and Yipeng Wang

      Article first published online: 25 OCT 2013 | DOI: 10.1111/febs.12521

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      The identification and polymorphism discovery of the cathelicidins in amphibian, Limnonectes fragilis, were reported. The special processing site for amphibian cathelicidin precursors was predicted and proved. Expression profiles of two cathelicidins were studied. The mature peptide, Lf-CATH1 and 2 of both 30 aa generated were tested with various biological activities and homology modeled for 3D structures.

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      An experimental study of the regulation of glycolytic oscillations in yeast (pages 6033–6044)

      Tine D. Schrøder, Veli C. Özalp, Anita Lunding, Kit D. Jernshøj and Lars F. Olsen

      Article first published online: 11 OCT 2013 | DOI: 10.1111/febs.12522

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      Glycolysis in the yeast Saccharomyces cerevisiae can show oscillatory dynamics. Using the strain BY4743 and isogenic strains with deletions of genes encoding enzymes in glycolysis and oxidative phosphorylation we have provided new qualitative and quantitative data that can be used in the construction of new and better detailed models of yeast metabolism.

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      Full-length dysferlin expression driven by engineered human dystrophic blood derived CD133+ stem cells (pages 6045–6060)

      Mirella Meregalli, Claire Navarro, Clementina Sitzia, Andrea Farini, Erica Montani, Nicolas Wein, Paola Razini, Cyriaque Beley, Letizia Cassinelli, Daniele Parolini, Marzia Belicchi, Dario Parazzoli, Luis Garcia and Yvan Torrente

      Article first published online: 8 OCT 2013 | DOI: 10.1111/febs.12523

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      Miyoshi myopathy (MM) is a fatal muscle disease caused by mutations in the dysferlin gene. We developed, for the first time, a strategy based on the use of lentiviral vector which express the full-length dysferlin in blood-derived CD133+ stem cells isolated from MM patients. Transplantation of these cells into animal models of dysferlinopathy allowed the rescue of dystrophic muscle fibers.

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      Crystal structure of endo-xylogalacturonan hydrolase from Aspergillus tubingensis (pages 6061–6069)

      Henriëtte J. Rozeboom, Gerrit Beldman, Henk A. Schols and Bauke W. Dijkstra

      Article first published online: 11 OCT 2013 | DOI: 10.1111/febs.12524

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      Endo-xylogalacturonan hydrolase features a wide-open active site groove to accommodate its xylogalacturonan substrate. No specific xylose binding pockets are present that could hinder sliding movements of the substrate of this processive enzyme. A model of xylosylated tri-galacturonate in the active site explains the enzyme's preference for hydrolysis of the glycosidic bond linking two β-xylose substituted galacturonic acid residues.

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      Modulation of ligand–heme reactivity by binding pocket residues demonstrated in cytochrome c' over the femtosecond–second temporal range (pages 6070–6082)

      Henry J. Russell, Samantha J. O. Hardman, Derren J. Heyes, Michael A. Hough, Gregory M. Greetham, Michael Towrie, Sam Hay and Nigel S. Scrutton

      Article first published online: 11 OCT 2013 | DOI: 10.1111/febs.12526

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      Cytochrome c’ binds NO on opposite faces of the heme. The roles of R124 and L16 in maintaining NO affinity in the heme environment were investigated by using time resolved spectroscopy. Studies spanning the entire femtosecond-second temporal range in the UV-vis, and femtosecond-nanosecond by IR, revealed a NO binding mechanism for the R124A variant that is distinct from wild-type.

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      The oxygen-tolerant and NAD+-dependent formate dehydrogenase from Rhodobacter capsulatus is able to catalyze the reduction of CO2 to formate (pages 6083–6096)

      Tobias Hartmann and Silke Leimkühler

      Article first published online: 8 OCT 2013 | DOI: 10.1111/febs.12528

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      The NAD+ dependent formate dehydrogenase from Rhodobacter capsulatus is an oxygen-tolerant protein with a (αβγ)2 subunit composition. The purified enzyme expressed in Escherichia coli is able to catalyze the reduction of CO2 to formate in the presence of NADH. The FMN and [Fe4S4] containing β-subunit and the [Fe2S2] containing γ-subunit form a diaphorase unit catalyzing the reversible regeneration of NAD+/NADH.

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      G-protein coupled receptor 56 promotes myoblast fusion through serum response factor- and nuclear factor of activated T-cell-mediated signalling but is not essential for muscle development in vivo (pages 6097–6113)

      Melissa P. Wu, Jamie R. Doyle, Brenda Barry, Ariane Beauvais, Anete Rozkalne, Xianhua Piao, Michael W. Lawlor, Alan S. Kopin, Christopher A. Walsh and Emanuela Gussoni

      Article first published online: 8 OCT 2013 | DOI: 10.1111/febs.12529

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      Mutations in GPR56 cause abnormal neuronal migration. GPR56 is also expressed in fusing muscle cells, however the consequences of receptor dysfunction on muscle development have not been explored. Using knockout mice, we found GPR56−/− myoblasts have decreased fusion and smaller myotube sizes. GPR56−/− mice also presented a mild but statistically significant elevation of serum creatine kinase, but no other abnormalities.

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      Downregulation of postsynaptic density-95-interacting regulator of spine morphogenesis reduces glutamate-induced excitotoxicity by differentially regulating glutamate receptors in rat cortical neurons (pages 6114–6127)

      Peng Luo, Yuefan Yang, Wei Liu, Wei Rao, Huan Bian, Xin Li, Tao Chen, Mengdong Liu, Yongbo Zhao, Shuhui Dai, Xu Yan and Zhou Fei

      Article first published online: 16 OCT 2013 | DOI: 10.1111/febs.12531

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      Preso was related to excitatory synaptic transmission. Knockdown of Preso reduced the glutamate-induced excitotoxicity in neurons by inhibiting activation of mitochondria-associated apoptosis and overload of intracellular Ca2+, which is associated with its role in differentially regulating glutamate receptors. Our data suggest that Preso may be a candidate for the therapeutic target for neurological diseases.

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      Harmful effect of ERβ on BCRP-mediated drug resistance and cell proliferation in ERα/PR-negative breast cancer (pages 6128–6140)

      Weiwei Li, Ming Jia, Xiaomin Qin, Jing Hu, Xiaofang Zhang and Gengyin Zhou

      Article first published online: 8 OCT 2013 | DOI: 10.1111/febs.12533

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      Our study found that ERβ enhanced BCRP-mediated drug resistance and cellular proliferation of ERα-/PR-breast cancer in the presence of E2, whereas these effects were reversed by additional use of tamoxifen. These findings may provide the potential clinical guidance to inhibit the malignant transformation in drug resistance and cell proliferation of ERα-/PR-breast cancer phenotype through the targeting of ERβ.

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      Insights into subunit interactions in the Sulfolobus acidocaldarius archaellum cytoplasmic complex (pages 6141–6149)

      Ankan Banerjee, Tomasz Neiner, Patrick Tripp and Sonja-Verena Albers

      Article first published online: 18 OCT 2013 | DOI: 10.1111/febs.12534

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      Archaella form the archaeal motility structure that is the functional pendant of the bacterial flagellum but is assembled by a mechanism similar to type IV pili. In this study we show that the proteins FlaX, FlaH and FlaI form a tight complex and probably constitute the motor complex of the archaellum.

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      Thiol-blocking electrophiles interfere with labeling and detection of protein sulfenic acids (pages 6150–6161)

      Julie A. Reisz, Erika Bechtold, S. Bruce King, Leslie B. Poole and Cristina M. Furdui

      Article first published online: 16 OCT 2013 | DOI: 10.1111/febs.12535

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      Biochemical methods for investigating cysteine oxidation require the blocking of free thiols using electrophiles. Here we report the cross-reactivity of reagents that have been classically defined as ‘thiol-specific’ with both sulfenic acids and with chemical probes targeting sulfenic acids. We also discuss the implications of this reactivity for detection of cysteine redox changes in complex samples (e.g., cysteine nitrosation).

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      Expression of a type 2 diacylglycerol acyltransferase from Thalassiosira pseudonana in yeast leads to incorporation of docosahexaenoic acid β-oxidation intermediates into triacylglycerol (pages 6162–6172)

      Jingyu Xu, Michael Kazachkov, Yunhua Jia, Zhifu Zheng and Jitao Zou

      Article first published online: 16 OCT 2013 | DOI: 10.1111/febs.12537

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      Heterologous expression of algal TpDGAT2 in yeast exerted large impact on the fatty acid profile of TAG, resulting a 10–12% increase of 18 : 1 and a concomitant decrease of 16 : 0 relative to that of AtDGAT1. When fed DHA, the yeast mutant expressing TpDGAT2 incorporated high levels of EPA and DHA isomer derived from DHA β-oxidation.

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      Mutational and genetic determinants of λ6 light chain amyloidogenesis (pages 6173–6183)

      Martín González-Andrade, Baltazar Becerril-Luján, Rosana Sánchez-López, Héctor Ceceña-Álvarez, Julio I. Pérez-Carreón, Ernesto Ortiz, D. Alejandro Fernández-Velasco and Luis del Pozo-Yauner

      Article first published online: 28 OCT 2013 | DOI: 10.1111/febs.12538

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      This study evaluates the thermodynamic stability and the in vitro fibrillogenesis of the AL-derived recombinant l6 light chain variable domain (rVL) AR in the context of the allelic variant Gly25, present in around 25% of the l6 light chains reported in the literature. Our data indicates protein AR to be the least thermodynamically stable and most fibrillogenic disease-associated rVL characterized to date.

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      The antibrowning agent sulfite inactivates Agaricus bisporus tyrosinase through covalent modification of the copper-B site (pages 6184–6195)

      Tomas F. M. Kuijpers, Harry Gruppen, Stefano Sforza, Willem J. H. van Berkel and Jean-Paul Vincken

      Article first published online: 16 OCT 2013 | DOI: 10.1111/febs.12539

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      Sulfite was found to irreversibly inactivate mushroom (Agaricus bisporus) tyrosinase. The competitive inhibitors tropolone and kojic acid protect the enzyme from inactivation, indicating that sulfite acts in the active site of tyrosinase. LC-MS analysis of protease digests of sulfite–treated tyrosinase revealed that inactivation occurs through covalent modification of a single active site amino acid residue, most likely a copper-coordinating histidine residue.

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      Structure and dynamic behavior of Toll-like receptor 2 subfamily triggered by malarial glycosylphosphatidylinositols of Plasmodium falciparum (pages 6196–6212)

      Prasannavenkatesh Durai, Rajiv Gandhi Govindaraj and Sangdun Choi

      Article first published online: 16 OCT 2013 | DOI: 10.1111/febs.12541

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      Structural understanding of the TLR-GPI interaction is significant for the design of effective anti-malarial therapeutics. We adopted molecular docking method, molecular dynamics simulations and principal component analysis to predict the sites where malarial GPIs bind and to understand the GPIs-induced conformational changes of the TLR2 subfamily. We witnessed the anticipated structural changes of the TLR2 subfamily upon ligand binding.

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      Investigation of peptide splicing using two-peptide-chain analogs of trypsin inhibitor SFTI-1 (pages 6213–6222)

      Natalia Karna, Dawid Dębowski, Agata Gitlin, Anna Łęgowska and Krzysztof Rolka

      Article first published online: 25 OCT 2013 | DOI: 10.1111/febs.12542

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      Two-peptide-chained analogs of SFTI-1 were incubated with bovine β-trypsin or α-chymotrypsin. After enzyme-catalyzed degradation of a single peptide bond between Lys and Ser, a new bond was formed. This bond brought together both separated peptide chains. Finally, the monocyclic SFTI-1 was recovered. This proteolytic route of peptide rearrangement seems to be similar to the proposed peptide splicing catalyzed by proteasome.

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      N6-isopentenyladenosine improves nuclear shape in fibroblasts from humans with progeroid syndromes by inhibiting the farnesylation of prelamin A (pages 6223–6232)

      Maurizio Bifulco, Alba D'Alessandro, Simona Paladino, Anna M. Malfitano, Maria Notarnicola, Maria G. Caruso and Chiara Laezza

      Article first published online: 18 NOV 2013 | DOI: 10.1111/febs.12544

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      Hutchinson–Gilford progeria syndrome is caused by the accumulation of progerin at the nuclear envelope causing misshapen nuclei Here we observed that an inhibitor of the farnesyl diphosphate synthase, N6-isopentenyladenosine, impeded the farnesylation of prelamin A, by causing a decrease of the frequency of nuclear shape abnormalities and the redistribution of prelamin A away from the inner nuclear envelope.

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      miRNA expression is modulated over time after focal ischaemia: up-regulation of miR–347 promotes neuronal apoptosis (pages 6233–6246)

      Carme Gubern, Susanna Camós, Iván Ballesteros, Rocío Rodríguez, Víctor G. Romera, Roberto Cañadas, Ignacio Lizasoain, María A. Moro, Joaquín Serena, Judith Mallolas and Mar Castellanos

      Article first published online: 28 OCT 2013 | DOI: 10.1111/febs.12546

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      This study aims to analyse miRNA expression from acute to late phases of cerebral ischaemia to identify specific ischaemia-related miRNAs, elucidate their role, and identify potential targets involved in stroke pathophysiology. Specifically, miR-347 has been identified as a new ischaemia-regulated miRNA which induces neuronal apoptotic death and the up-regulation of three of its potential targets, Acsl4, Bnip3l and Phyhip.

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      Spider toxins comprising disulfide-rich and linear amphipathic domains: a new class of molecules identified in the lynx spider Oxyopes takobius (pages 6247–6261)

      Alexander A. Vassilevski, Maria Y. Sachkova, Anastasija A. Ignatova, Sergey A. Kozlov, Alexei V. Feofanov and Eugene V. Grishin

      Article first published online: 20 NOV 2013 | DOI: 10.1111/febs.12547

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      Venom of the lynx spider Oxyopes takobius contains two-domain modular toxins named OtTx or spiderines. The N-terminal part of spiderines is alike linear amphipathic α-helical cytotoxic peptides, whereas the C-terminal part corresponds to disulfide-rich spider neurotoxins and contains the inhibitor cystine knot (ICK/knottin) signature. The unique structure of spiderines fills up the missing part of the two-domain spider toxin ensemble.

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      Blockade of dopamine D1-like receptor signalling protects mice against OVA-induced acute asthma by inhibiting B-cell activating transcription factor signalling and Th17 function (pages 6262–6273)

      Subo Gong, Jinxiu Li, Libing Ma, Keng Li, Li Zhang, Guyi Wang, Yi Liu, Xiaoying Ji, Xiaokun Liu, Ping Chen, Ruoyun Ouyang, Shu Zhang, Zhiguang Zhou, Cong-Yi Wang, Xudong Xiang and Yu Yang

      Article first published online: 25 OCT 2013 | DOI: 10.1111/febs.12549

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      Pathological analysis of asthmatic mice. (A–D) Representative results for histological analysis of inflammatory infiltration. (E–H) Histological results for analysis of mucus production.

  6. Corrigendum

    1. Top of page
    2. Front Cover
    3. Editorial Information
    4. Minireview Series
    5. Minireviews
    6. Original Articles
    7. Corrigendum
    8. Author index
    1. You have free access to this content
      Corrigendum (page 6274)

      Article first published online: 20 NOV 2013 | DOI: 10.1111/febs.12493

      This article corrects:

      Human kynurenine aminotransferase II – reactivity with substrates and inhibitors

      Vol. 278, Issue 11, 1882–1900, Article first published online: 28 APR 2011

  7. Author index

    1. Top of page
    2. Front Cover
    3. Editorial Information
    4. Minireview Series
    5. Minireviews
    6. Original Articles
    7. Corrigendum
    8. Author index
    1. You have free access to this content
      Author index (page 6275)

      Article first published online: 20 NOV 2013 | DOI: 10.1111/j.1742-4658.2013.08803.x

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