ALBERT

Description:    It has been shown that the description of the details of the electronic spectra obtained by the combination of the dynamical mean field theory, quantum Monte Carlo methods, and the maximum entropy method can be significantly improved by changing the last method to optimal regularization of the analytic continuation of the Green’s function to the real frequency axis. Starting with the quantum Monte Carlo data, this method has reconstructed peaks in the structure of Hubbard subbands with a maximum error of 0.001 to 0.01. Owing to the universality of the quantum Monte Carlo method, by varying hybridization, it is possible to determine the features of the hybridized function that are responsible for the formation of the structure of Hubbard subbands. It has been shown that there is no direct relation between the peak structure of subbands and the central Kondo peak. The result indicates the charge nature of resonances responsible for the formation of the peak structure. Content Type Journal Article Category Methods of Theoretical Physics Pages 768-773 DOI 10.1134/S0021364011220073 Authors I. S. Krivenko, Faculty of Physics, Moscow State University, Moscow, 119992 Russia A. N. Rubtsov, Faculty of Physics, Moscow State University, Moscow, 119992 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 94 Journal Issue Volume 94, Number 10

Description:    The spallation of a nanometer-thick melt layer on a GaAs surface during its ablation by femtosecond laser pulses occurs with subnanosecond delays and lift-off velocities that depend on the laser fluence after its complete thermal (hydrodynamic) expansion/acoustic relaxation. The position of the spall interface in the melt is determined by the depth of the formation of a two-dimensional subsurface layer of nanobubbles (nanofoam), whereas the strongly heated surface layer of the melt above the nanofoam is partially removed in the form of a vapor-drop mixture. At the thermal expansion stage, acoustic reverberations are observed in the melt layer and characterize both the dynamics of an increase in its thickness and the shift of the cavitation region (nanofoam) inside the melt. Moreover, these reverberations can additionally stimulate spallation, promoting cavitation in the completely unloaded melt in the case of passage of a weak rarefaction wave. Content Type Journal Article Category Condensed Matter Pages 753-758 DOI 10.1134/S002136401122005X Authors A. A. Ionin, Lebedev Physical Institute, Russian Academy of Sciences, Leninskii pr. 53, Moscow, 119991 Russia S. I. Kudryashov, Lebedev Physical Institute, Russian Academy of Sciences, Leninskii pr. 53, Moscow, 119991 Russia L. V. Seleznev, Lebedev Physical Institute, Russian Academy of Sciences, Leninskii pr. 53, Moscow, 119991 Russia D. V. Sinitsyn, Lebedev Physical Institute, Russian Academy of Sciences, Leninskii pr. 53, Moscow, 119991 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 94 Journal Issue Volume 94, Number 10

Description:    A planar homogeneous waveguide array with two-level systems has been considered. The evolution of an electromagnetic field is described by the Maxwell-Bloch equations taking into account the action of the fields of neighboring waveguides beyond the slow-envelope approximation. It has been shown that the model in the continuous approximation is reduced to an integrable system of equations, including the case of a nonzero static dipole moment. The model can be used to analyze the nonlinear mechanism of the compression of pulses and the conditions of overcoming of the diffraction limit. Content Type Journal Article Category Optics and Laser Physics Pages 837-839 DOI 10.1134/S0021364011240106 Authors A. A. Zabolotskii, Institute of Automatics and Electrometry, Siberian Branch, Russian Academy of Sciences, Universitetskii pr. 1, Novosibirsk, 630090 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 94 Journal Issue Volume 94, Number 12

Description:    Defects in membrane trafficking and degradation are hallmarks of most, and maybe all, neurodegenerative disorders. Such defects typically result in the accumulation of undegraded proteins due to aberrant endosomal sorting, lysosomal degradation, or autophagy. The genetic or environmental cause of a specific disease may directly affect these membrane trafficking processes. Alternatively, changes in intracellular sorting and degradation can occur as cellular responses of degenerating neurons to unrelated primary defects such as insoluble protein aggregates or other neurotoxic insults. Importantly, altered membrane trafficking may contribute to the pathogenesis or indeed protect the neuron. The observation of dramatic changes to membrane trafficking thus comes with the challenging need to distinguish pathological from protective alterations. Here, we will review our current knowledge about the protective and destructive roles of membrane trafficking in neuronal maintenance and degeneration. In particular, we will first focus on the question of what type of membrane trafficking keeps healthy neurons alive in the first place. Next, we will discuss what alterations of membrane trafficking are known to occur in Alzheimer’s disease and other tauopathies, Parkinson’s disease, polyQ diseases, peripheral neuropathies, and lysosomal storage disorders. Combining the maintenance and degeneration viewpoints may yield insight into how to distinguish when membrane trafficking functions protectively or contributes to degeneration. Content Type Journal Article Category Review Pages 1-16 DOI 10.1007/s00018-012-1201-4 Authors Dong Wang, Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA Chih-Chiang Chan, Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA Smita Cherry, Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA P. Robin Hiesinger, Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    An array of non-overgrown InAs/GaAs quantum dots has been decorated with adsorbed metal atoms in situ in ultrahigh vacuum. Their electron and photoemission properties have been studied. The radical modification of the spectra of the threshold emission from the quantum dots with increasing cesium coating has been found. Two photoemission channels have been established; they are characterized by considerably different intensities, spectral locations, and widths of the selective bands. It has been shown that the decoration of the quantum dots makes it possible to control the electronic structure and quantum yield of photoemission, the nature of which is related to the excitation of the electronic states of the GaAs substrate and InAs/GaAs quantum dots. Content Type Journal Article Category Condensed Matter Pages 332-335 DOI 10.1134/S0021364012170031 Authors G. V. Benemanskaya, Ioffe Physical Technical Institute, Russian Academy of Sciences, St. Petersburg, 194021 Russia M. N. Lapushkin, Ioffe Physical Technical Institute, Russian Academy of Sciences, St. Petersburg, 194021 Russia V. P. Evtikhiev, Ioffe Physical Technical Institute, Russian Academy of Sciences, St. Petersburg, 194021 Russia A. S. Shkol’nik, Ioffe Physical Technical Institute, Russian Academy of Sciences, St. Petersburg, 194021 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 5

Description:    Hypermethylation of SOCS genes is associated with many human cancers, suggesting a role as tumor suppressors. As adaptor molecules for ubiquitin ligases, SOCS proteins modulate turnover of numerous target proteins. Few SOCS targets identified so far have a direct role in cell cycle progression; the mechanism by which SOCS regulate the cell cycle thus remains largely unknown. Here we show that SOCS1 overexpression inhibits in vitro and in vivo expansion of human melanoma cells, and that SOCS1 associates specifically with Cdh1, triggering its degradation by the proteasome. Cells therefore show a G1/S transition defect, as well as a secondary blockade in mitosis and accumulation of cells in metaphase. SOCS1 expression correlated with a reduction in cyclin D/E levels and an increase in the tumor suppressor p19, as well as the CDK inhibitor p53, explaining the G1/S transition defect. As a result of Cdh1 degradation, SOCS1-expressing cells accumulated cyclin B1 and securin, as well as apparently inactive Cdc20, in mitosis. Levels of the late mitotic Cdh1 substrate Aurora A did not change. These observations comprise a hitherto unreported mechanism of SOCS1 tumor suppression, suggesting this molecule as a candidate for the design of new therapeutic strategies for human melanoma. Content Type Journal Article Category Research article Pages 1-14 DOI 10.1007/s00018-012-1145-8 Authors Verónica Parrillas, Chemokines Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Cantoblanco, 28049 Madrid, Spain Laura Martínez-Muñoz, Chemokines Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Cantoblanco, 28049 Madrid, Spain Borja L. Holgado, Chemokines Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Cantoblanco, 28049 Madrid, Spain Amit Kumar, PI3K Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, 28049 Madrid, Spain Graciela Cascio, Chemokines Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Cantoblanco, 28049 Madrid, Spain Pilar Lucas, Chemokines Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Cantoblanco, 28049 Madrid, Spain José Miguel Rodríguez-Frade, Chemokines Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Cantoblanco, 28049 Madrid, Spain Marcos Malumbres, Cell Division and Cancer Group, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain Ana C. Carrera, PI3K Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, 28049 Madrid, Spain Karel HM van Wely, Genetic Instability Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, 28049 Madrid, Spain Mario Mellado, Chemokines Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Cantoblanco, 28049 Madrid, Spain Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The myosin isoform composition of the heart is dynamic in health and disease and has been shown to affect contractile velocity and force generation. While different mammalian species express different proportions of α and β myosin heavy chain, healthy human heart ventricles express these isoforms in a ratio of about 1:9 (α:β) while failing human ventricles express no detectable α-myosin. We report here fast-kinetic analysis of recombinant human α and β myosin heavy chain motor domains. This represents the first such analysis of any human muscle myosin motor and the first of α-myosin from any species. Our findings reveal substantial isoform differences in individual kinetic parameters, overall contractile character, and predicted cycle times. For these parameters, α-subfragment 1 (S1) is far more similar to adult fast skeletal muscle myosin isoforms than to the slow β isoform despite 91% sequence identity between the motor domains of α- and β-myosin. Among the features that differentiate α- from β-S1: the ATP hydrolysis step of α-S1 is ~ten-fold faster than β-S1, α-S1 exhibits ~five-fold weaker actin affinity than β-S1, and actin·α-S1 exhibits rapid ADP release, which is 〉ten-fold faster than ADP release for β-S1. Overall, the cycle times are ten-fold faster for α-S1 but the portion of time each myosin spends tightly bound to actin (the duty ratio) is similar. Sequence analysis points to regions that might underlie the basis for this finding. Content Type Journal Article Category Erratum Pages 1-17 DOI 10.1007/s00018-012-1111-5 Authors John C. Deacon, Department of Molecular, Cellular and Developmental Biology and Biofrontiers Institute, University of Colorado, MCDB, UCB 347, Boulder, CO 80309, USA Marieke J. Bloemink, School of Biosciences, University of Kent, Canterbury, CT2 7NJ UK Heresh Rezavandi, School of Biosciences, University of Kent, Canterbury, CT2 7NJ UK Michael A. Geeves, School of Biosciences, University of Kent, Canterbury, CT2 7NJ UK Leslie A. Leinwand, Department of Molecular, Cellular and Developmental Biology and Biofrontiers Institute, University of Colorado, MCDB, UCB 347, Boulder, CO 80309, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The T cell integrin receptor LFA-1 orchestrates adhesion between T cells and antigen-presenting cells (APCs), resulting in formation of a contact zone known as the immune synapse (IS) which is supported by the cytoskeleton. L-plastin is a leukocyte-specific actin bundling protein that rapidly redistributes to the immune synapse following T cell–APC engagement. We used single domain antibodies (nanobodies, derived from camelid heavy-chain only antibodies) directed against functional and structural modules of L-plastin to investigate its contribution to formation of an immune synapse between Raji cells and human peripheral blood mononuclear cells or Jurkat T cells. Nanobodies that interact either with the EF hands or the actin binding domains of L-plastin both trapped L-plastin in an inactive conformation, causing perturbation of IS formation, MTOC docking towards the plasma membrane, T cell proliferation and IL-2 secretion. Both nanobodies delayed Ser 5 phosphorylation of L-plastin which is required for enhanced bundling activity. Moreover, one nanobody delayed LFA-1 phosphorylation, reduced the association between LFA-1 and L-plastin and prevented LFA-1 enrichment at the IS. Our findings reveal subtle mechanistic details that are difficult to attain by conventional means and show that L-plastin contributes to immune synapse formation at distinct echelons. Content Type Journal Article Category Research article Pages 1-14 DOI 10.1007/s00018-012-1169-0 Authors Sarah De Clercq, Department of Medical Protein Research, VIB, 9000 Ghent, Belgium Olivier Zwaenepoel, Department of Medical Protein Research, VIB, 9000 Ghent, Belgium Evelien Martens, Department of Medical Protein Research, VIB, 9000 Ghent, Belgium Joël Vandekerckhove, Department of Medical Protein Research, VIB, 9000 Ghent, Belgium Aude Guillabert, Department of Medical Protein Research, VIB, 9000 Ghent, Belgium Jan Gettemans, Department of Medical Protein Research, VIB, 9000 Ghent, Belgium Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The yeast SUMO (small ubiquitin-like modifier) orthologue SMT3 was initially discovered in a genetic suppressors screen for the centromeric protein Mif2 (Meluh and Koshland in Mol Bio Cell 6:793–807, 1 ). Later, it turned out that the homologous mammalian proteins SUMO1 to SUMO4 are reversible protein modifiers that can form isopeptide bonds with lysine residues of respective target proteins (Mahajan et al. in Cell 88:97–107, 2 ). This was the discovery of a post-translational modification called sumoylation, which enzymatically resembles ubiquitination. However, very soon it became clear that SUMO attachments served a far more diverse role than ubiquitination. Meanwhile, numerous cellular processes are known to be subject to the impact of SUMO modification, including transcription, protein targeting, protein solubility, apoptosis or activity of various enzymes. In many instances, SUMO proteins create new protein interaction surfaces or block existing interaction domains (Geiss-Friedlander and Melchior in Nat Rev in Mol Cell Biol 8:947–956, 3 ). For the past few years, sumoylation attracted increasing attention as a versatile regulator of toxic protein properties in neurodegenerative diseases. In this review, we summarize the growing knowledge about the involvement of sumoylation in neurodegeneration, and discuss the underlying molecular principles affected by this multifaceted and intriguing post-translational modification. Content Type Journal Article Category Review Pages 1-16 DOI 10.1007/s00018-012-1158-3 Authors Petranka Krumova, Neuroscience, Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland Jochen H. Weishaupt, Neurology Department, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The vast majority of mammalian testes are located outside the body cavity for proper thermoregulation. Heat has an adverse effect on mammalian spermatogenesis and eventually leads to sub- or infertility. Recent studies have provided insights into the molecular response of male germ cells to high temperatures. Here, we review the effects of heat on male germ cells and discuss the mechanisms underlying germ cell loss and impairment. We also discuss the role of translational control in male germ cells as a potential protective mechanism against heat-induced germ cell apoptosis. Content Type Journal Article Category Review Pages 1-14 DOI 10.1007/s00018-012-1165-4 Authors Byunghyuk Kim, Department of Biological Sciences, Seoul National University, Seoul, 151-747 Korea Kyosun Park, Department of Biological Sciences, Seoul National University, Seoul, 151-747 Korea Kunsoo Rhee, Department of Biological Sciences, Seoul National University, Seoul, 151-747 Korea Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The mass spectrometry study has indicated that the magnetic field accelerates the oxidation of the surface of silicon crystals. The oxidation rate also depends on the nuclear spin of silicon: the oxidation rate of atoms with magnetic nuclei ( 29 Si) is almost twice as high as that of atoms with spinless, unmagnetized nuclei ( 28 Si and 30 Si). Both effects—magnetic field and magnetic isotope—reliably prove that the oxidation of silicon is a spin-selective reaction involving radicals and radical pairs as intermediate paramagnetic particles. A spin-selective magnetic sensitive oxidation mechanism is discussed. Content Type Journal Article Category Condensed Matter Pages 102-104 DOI 10.1134/S002136401214007X Authors O. V. Koplak, Scientific-Educational Center FKhM, Kyiv University and National Academy of Sciences of Ukraine, Kyiv, 01033 Ukraine R. B. Morgunov, Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka, Moscow region, 142432 Russia A. L. Buchachenko, Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka, Moscow region, 142432 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 2

Description:    An explanation of an anomalously narrow microwave absorption line in superfluid 4 He has been proposed. It has been shown that the experimentally observed resonance linewidth agrees with the assumption of parametric excitation of a macroscopic coherent roton state. Content Type Journal Article Category Condensed Matter Pages 98-98 DOI 10.1134/S0021364012140081 Authors L. A. Melnikovsky, Institute for Physical Problems, Russian Academy of Sciences, ul. Kosygina 2, Moscow, 119334 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 2

Description:    A light emitting diode has been developed on the basis of multilayer nanostructures in which CdSe/CdS semiconductor colloidal quantum dots serve as emitters. Their absorption, photo-, and electroluminescence spectra have been obtained. The strong influence of the size effect and the density of particles in the layer on the spectral and electrophysical characteristics of the diode has been demonstrated. It has been shown that the rates of the transfer of the exciton excitation energy from organic molecules to quantum dots increase strongly even at a small increase in the radius of the core (CdSe) of a particle and depend strongly on the thickness of the shell (CdS) of the particle. The optimal arrangement of the layer of quantum dots with respect to the p-n junction has been estimated from the experimental data. The results demonstrate that the spectral characteristics and rates of the electron processes in light-emitting devices based on quantum dots incorporated into an organic matrix can be efficiently controlled. Content Type Journal Article Category Condensed Matter Pages 113-117 DOI 10.1134/S0021364012140135 Authors A. A. Vashchenko, Lebedev Physical Institute, Russian Academy of Sciences, Moscow, 119991 Russia V. S. Lebedev, Lebedev Physical Institute, Russian Academy of Sciences, Moscow, 119991 Russia A. G. Vitukhnovskii, Lebedev Physical Institute, Russian Academy of Sciences, Moscow, 119991 Russia R. B. Vasiliev, Faculty of Materials Science, Moscow State University, Moscow, 119992 Russia I. G. Samatov, Faculty of Materials Science, Moscow State University, Moscow, 119992 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 2

Description:    The polarization properties of extraordinary microwave transmission through perforated duralumin films are investigated both theoretically and experimentally. It is shown that resonance wavelength at which transmission efficiency reaches maximum value depends on the incident radiation polarization. Content Type Journal Article Category Condensed Matter Pages 99-101 DOI 10.1134/S0021364012140068 Authors S. E. Grigas, Faculty of Physics, Moscow State University, Moscow, 119992 Russia A. G. Rzhanov, Faculty of Physics, Moscow State University, Moscow, 119992 Russia V. N. Semenenko, Institute for Theoretical and Applied Electrodynamics, Russian Academy of Sciences, Moscow, 125412 Russia V. A. Chistyaev, Institute for Theoretical and Applied Electrodynamics, Russian Academy of Sciences, Moscow, 125412 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 2

Description:    We investigate the disturbance of the InAs nanowire resistance by a conductive tip of a scanning probe micro-scope at helium temperature as a function of the tip position in close vicinity to the nanowire. At the tip displacement along the wire the resistance ( R wire ∼ 30 kΩ, what is typical for diffusive regime) demonstrates quasi-periodical oscillations with an amplitude about 3%. The period of the oscillations depends on the number of electrons in the nanowire and is consistent with expected for standing electron waves caused by ballistic electrons in the top subband of the InAs nanowire. Content Type Journal Article Category Condensed Matter Pages 109-112 DOI 10.1134/S0021364012140159 Authors A. A. Zhukov, Institute of Solid State Physics, Russian Academy of Sciences, Chernogolovka, Moscow region, 142432 Russia Ch. Volk, Grünberg Institut (PGI-9), Forschungszentrum Jülich, 52425 Jülich, Germany A. Winden, Grünberg Institut (PGI-9), Forschungszentrum Jülich, 52425 Jülich, Germany H. Hardtdegen, Grünberg Institut (PGI-9), Forschungszentrum Jülich, 52425 Jülich, Germany Th. Schäpers, Grünberg Institut (PGI-9), Forschungszentrum Jülich, 52425 Jülich, Germany Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 2

Description:    Schramm-Loewner evolution (SLE) and conformal field theory (CFT) are popular and widely used instruments to study critical behavior of two-dimensional models, but they use different objects. While SLE has natural connection with lattice models and is suitable for strict proofs, it lacks computational and predictive power of conformal field theory. To provide a way for the concurrent use of SLE and CFT, CFT correlation functions, which are martingales with respect to SLE, are considered. A relation between parameters of Schramm-Loewner evolution on coset space and algebraic data of coset conformal field theory is revealed. The consistency of this approach with the behavior of parafermionic and minimal models is tested. Coset models are connected with off-critical massive field theories and implications of SLE are discussed. Content Type Journal Article Category Fields, Particles, and Nuclei Pages 90-93 DOI 10.1134/S0021364012140093 Authors A. Nazarov, Department of High-Energy and Elementary Particle Physics, Faculty of Physics and Chebyshev Laboratory, Faculty of Mathematics and Mechanics, St. Petersburg State University, St. Petersburg, 198904 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 2

Description:    Hadron production in lepton-nucleus interactions at high energies is considered in the framework of developing Monte Carlo event generator HARDPING (HARD Probe INteraction Generator). Such effects as formation length, energy loss and multiple rescattering for produced hadrons and their constituents are implemented in the HARDPING 2.0 generator. Available data from HERMES collaboration on hadron production in lepton-nucleus collisions are described by the present version of the HARDPING generator in a reasonable agreement. Content Type Journal Article Category Fields, Particles, and Nuclei Pages 85-89 DOI 10.1134/S0021364012140020 Authors Ya. A. Berdnikov, St.-Petersburg State Polytechnical University, St. Petersburg, 195251 Russia A. E. Ivanov, St.-Petersburg State Polytechnical University, St. Petersburg, 195251 Russia V. T. Kim, St.-Petersburg State Polytechnical University, St. Petersburg, 195251 Russia V. A. Murzin, St. Petersburg Nuclear Physics Institute, Gatchina, 188300 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 2

Description:    A simple description has been proposed for the renormalization of the conduction band parameters in cuprates owing to the interaction of the current carriers with phonons. Kinks in the quasiparticle dispersion law in the optical phonon mode region (70 meV, compound Bi 2 Sr 2 CaCu 2 O 8 − x ) and data on the temperature dependence of the superconducting current density in YBa 2 Cu 3 O 7 have been analyzed. Ideas of new experiments have been discussed. Content Type Journal Article Category Condensed Matter Pages 105-108 DOI 10.1134/S0021364012140044 Authors M. V. Eremin, Institute of Physics, Kazan (Volga Region) Federal University, Kazan, 420008 Russia M. A. Malakhov, Institute of Physics, Kazan (Volga Region) Federal University, Kazan, 420008 Russia D. A. Sunyaev, Institute of Physics, Kazan (Volga Region) Federal University, Kazan, 420008 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 2

Description:    Spectral properties of LiFeAs superconductor are investigated within the LDA+DMFT method. Calculated distribution of the spectral weight in the k -space is in good agreement with angle-resolved photoemission (ARPES) spectra. Calculated effective electron mass enhancement factor m */ m ≈ 3 is close to the one estimated from comparison of density-functional theory results with ARPES spectra. Our results demonstrate that inclusion into consideration of dynamical Coulomb correlations between the electrons plays a key role in understanding of the spectral properties of LiFeAs. Content Type Journal Article Category Condensed Matter Pages 118-122 DOI 10.1134/S0021364012140111 Authors S. L. Skornyakov, Institute of Metal Physics, Ural Branch, Russian Academy of Sciences, Yekaterinburg, 620990 Russia D. Y. Novoselov, Institute of Metal Physics, Ural Branch, Russian Academy of Sciences, Yekaterinburg, 620990 Russia T. Gürel, Department of Physics, Namik Kemal University, 59030 Tekirdag, Turkey V. I. Anisimov, Institute of Metal Physics, Ural Branch, Russian Academy of Sciences, Yekaterinburg, 620990 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 2

Description:    We predict the insulator-metal-insulator transitions for the temperature and pressure of the lower mantle with the metal layer thickness Δ h ≈ 400 km at the depth of 1400–1800 km. The insulator-metal transition has the Mott-Hubbard origin, while the second transition from metal to insulator results from spin crossover of the Fe 2+ ions from high spin S = 2 to low spin S = 0 state. The conductivity in the metal layer may attain 250 S/m. The depth profile of the conductivity is also suggested. Content Type Journal Article Category Miscellaneous Pages 129-132 DOI 10.1134/S002136401214010X Authors S. G. Ovchinnikov, Kirensky Institute of Physics, Siberian Branch, Russian Academy of Sciences, Krasnoyarsk, 660036 Russia T. M. Ovchinnikova, Sukhachev Institute of Forest, Siberian Branch, Russian Academy of Sciences, Krasnoyarsk, 660036 Russia P. G. Dyad’kov, Trofimuk Institute of Petroleum-Gas Geology and Geophysics, Siberian Branch, Russian Academy of Sciences, Novosibirsk, 630090 Russia V. V. Plotkin, Trofimuk Institute of Petroleum-Gas Geology and Geophysics, Siberian Branch, Russian Academy of Sciences, Novosibirsk, 630090 Russia K. D. Litasov, Sobolev Institute of Geology and Mineralogy, Siberian Branch, Russian Academy of Sciences, Novosibirsk, 630090 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 2

Description:    Experimental studies of the phase diagram of Bose condensation in a system of spatially indirect dipolar excitons in GaAs/AlGaAs quantum wells are reviewed. The properties of spatially periodic patterns arising in the luminescence of the exciton Bose condensate in a ring-shaped potential trap and the coherence of the condensate luminescence are discussed. Content Type Journal Article Category Scientific Summaries Pages 138-147 DOI 10.1134/S0021364012140056 Authors A. V. Gorbunov, Institute of Solid State Physics, Russian Academy of Sciences, Chernogolovka, Moscow region, 142432 Russia V. B. Timofeev, Institute of Solid State Physics, Russian Academy of Sciences, Chernogolovka, Moscow region, 142432 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 2

Description:    Photoemission induced by vacuum ultraviolet resonance radiation of xenon atoms from the surface of a solid in vacuum and in the case of a target in contact with a gas has been experimentally studied. It has been demonstrated that the photoemission response increases strongly (up to an order of magnitude) under the adsorption (or implantation) of gas atoms into the target when vacuum ultraviolet radiation resonantly acts on these atoms. This is due to different mechanisms of photoemission from the surface of the solid in vacuum and from the surface in contact with the gas. The notion of activated resonant photoemission has been introduced. Content Type Journal Article Category Miscellaneous Pages 133-137 DOI 10.1134/S0021364012140032 Authors P. A. Bokhan, Rzhanov Institute of Semiconductor Physics, Siberian Branch, Russian Academy of Sciences, pr. akademika Lavrent’eva 13, Novosibirsk, 630090 Russia D. E. Zakrevsky, Rzhanov Institute of Semiconductor Physics, Siberian Branch, Russian Academy of Sciences, pr. akademika Lavrent’eva 13, Novosibirsk, 630090 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 2

Description:    The nature of the set of free fields that represent the system at the critical point has been revealed by studying the correlation functions of the degrees of freedom of the gauge supersymmetric Ising model on the cubic lattice. The same set of free fields represents the continuous supersymmetric Abelian gauge theory. Thus, the name of the lattice system is appropriate. Comparison with the two-dimensional Ising model is given. Content Type Journal Article Category Methods of Theoretical Physics Pages 123-128 DOI 10.1134/S0021364012140147 Authors S. N. Vergeles, Landau Institute for Theoretical Physics, Russian Academy of Sciences, Chernogolovka, Moscow region, 142432 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 2

Description:    The possibility of the generation of quasi-cw terahertz radiation by the optical rectification method for broad-band Fourier unlimited nanosecond laser pulses has been experimentally demonstrated. The broadband radiation of a LiF dye-center laser is used as a pump source of a nonlinear optical oscillator. The energy efficiency of terahertz optical frequency conversion in a periodically polarized lithium niobate crystal is 4 × 10 −9 at a pump power density of 7 MW/cm 2 . Content Type Journal Article Category Astrophysics and Cosmology Pages 94-97 DOI 10.1134/S0021364012140123 Authors A. N. Tuchak, Moscow State University, Moscow, 119991 Russia G. N. Gol’tsman, Moscow State Pedagogical University, ul. Malaya Pirogovskaya 1, Moscow, 119991 Russia G. Kh. Kitaeva, Moscow State University, Moscow, 119991 Russia A. N. Penin, Moscow State University, Moscow, 119991 Russia S. V. Seliverstov, Moscow State Pedagogical University, ul. Malaya Pirogovskaya 1, Moscow, 119991 Russia M. I. Finkel, Moscow State Pedagogical University, ul. Malaya Pirogovskaya 1, Moscow, 119991 Russia A. V. Shepelev, Gubkin State University of Oil and Gas, Leninskii pr. 65, Moscow, 119991 Russia P. V. Yakunin, Moscow State University, Moscow, 119991 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 2

Description:    Reelin-Disabled-1 (Dab1) signaling has a well-established role in regulating neuronal migration during brain development. Binding of Reelin to its receptors induces Dab1 tyrosine phosphorylation. Tyrosine-phosphorylated Dab1 recruits a wide range of SH2 domain-containing proteins and activates multiple signaling cascades, resulting in cytoskeleton remodeling and precise neuronal positioning. In this review, we summarize recent progress in the Reelin-Dab1 signaling field. We focus on Dab1 alternative splicing as a mechanism for modulating the Reelin signal in developing brain. We suggest that correct positioning of neurons in the developing brain is at least partly controlled by alternatively-spliced Dab1 isoforms that differ in the number and type of tyrosine phosphorylation motifs that they contain. We propose a model whereby different subsets of SH2 domain-containing proteins are activated by different Dab1 isoforms, resulting in coordinated migration of neurons. Content Type Journal Article Category Review Pages 1-11 DOI 10.1007/s00018-012-1171-6 Authors Zhihua Gao, Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada Roseline Godbout, Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The insulin signaling pathway regulates whole-body glucose homeostasis by transducing extracellular signals from the insulin receptor (IR) to downstream intracellular targets, thus coordinating a multitude of biological functions. Dysregulation of IR or its signal transduction is associated with insulin resistance, which may culminate in type 2 diabetes. Following initial stimulation of IR, insulin signaling diverges into different pathways, activating multiple substrates that have roles in various metabolic and cellular processes. The integration of multiple pathways arising from IR activation continues to expand as new IR substrates are identified and characterized. Accordingly, our review will focus on roles for IR substrates as they pertain to three primary areas: metabolism/glucose uptake, mitogenesis/growth, and aging/longevity. While IR functions in a seemingly pleiotropic manner in many cell types, through these three main roles in fat and skeletal muscle cells, IR multi-tasks to regulate whole-body glucose homeostasis to impact healthspan and lifespan. Content Type Journal Article Category Review Pages 1-20 DOI 10.1007/s00018-012-1176-1 Authors Latha Ramalingam, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA Eunjin Oh, Department of Pediatrics, Herman B Wells Center, Indiana University School of Medicine, Indianapolis, IN, USA Debbie C. Thurmond, Departments of Pediatrics, Biochemistry and Molecular Biology, and Cellular and Integrative Physiology, Herman B Wells Center, Indiana University School of Medicine, 635 Barnhill Drive MS 2031, Indianapolis, IN 46202, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The schizophrenia susceptibility gene, Rgs4 , is one of the most intensively studied regulators of G-protein signaling members, well known to be fundamental in regulating neurotransmission. However, little is known about its role in the developing nervous system. We have isolated zebrafish rgs4 and shown that it is transcribed in the developing nervous system. Rgs4 knockdown did not affect neuron number and patterning but resulted in locomotion defects and aberrant development of axons. This was confirmed using a selective Rgs4 inhibitor, CCG-4986. Rgs4 knockdown also attenuated the level of phosphorylated-Akt1, and injection of constitutively-activated AKT1 rescued the motility defects and axonal phenotypes in the spinal cord but not in the hindbrain and trigeminal neurons. Our in vivo analysis reveals a novel role for Rgs4 in regulating axonogenesis during embryogenesis, which is mediated by another schizophrenia-associated gene, Akt1 , in a region-specific manner. Content Type Journal Article Category Research article Pages 1-16 DOI 10.1007/s00018-012-1178-z Authors Yi-Chuan Cheng, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, 33383 Taiwan Paul J. Scotting, Children’s Brain Tumour Research Centre, Centre for Genetics and Genomics, Queen’s Medical Centre, University of Nottingham, Nottingham, NG7 2UH UK Li-Sung Hsu, Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, 40201 Taiwan Sheng-Jia Lin, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, 33383 Taiwan Hung-Yu Shih, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, 33383 Taiwan Fu-Yu Hsieh, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, 33383 Taiwan Hui-Lan Wu, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, 33383 Taiwan Chu-Li Tsao, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, 33383 Taiwan Chia-Jung Shen, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, 33383 Taiwan Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Posttranslational modifications such as phosphorylation are universally acknowledged regulators of protein function. Recently we characterised a striated muscle-specific isoform of the formin FHOD3 that displays distinct subcellular targeting and protein half-life compared to its non-muscle counterpart and which is dependent on phosphorylation by CK2 (formerly casein kinase 2). We now show that the two isoforms of FHOD3 are already expressed in the vertebrate embryonic heart. Analysis of CK2 alpha knockout mice showed that phosphorylation by CK2 is also required for proper targeting of muscle FHOD3 to the myofibrils in embryonic cardiomyocytes in situ. The localisation of muscle FHOD3 in the sarcomere varies depending on the maturation state, being either broader or restricted to the Z -disc proper in the adult heart. Following myofibril disassembly, such as that in dedifferentiating adult rat cardiomyocytes in culture, the expression of non-muscle FHOD3 is up-regulated, which is reversed once the myofibrils are reassembled. The shift in expression levels of different isoforms is accompanied by an increased co-localisation with p62, which is involved in autophagy, and affects the half-life of FHOD3. Phosphorylation of three amino acids in the C-terminus of FHOD3 by ROCK1 is sufficient for activation, which results in increased actin filament synthesis in cardiomyocytes and also a broader localisation pattern of FHOD3 in the myofibrils. ROCK1 can directly phosphorylate FHOD3, and FHOD3 seems to be the downstream mediator of the exaggerated actin filament formation phenotype that is induced in cardiomyocytes upon the overexpression of constitutively active ROCK1. We conclude that the expression of the muscle FHOD3 isoform is characteristic of the healthy mature heart and that two distinct phosphorylation events are crucial to regulate the activity of this isoform in thin filament assembly and maintenance. Content Type Journal Article Category Research article Pages 1-16 DOI 10.1007/s00018-012-1154-7 Authors Thomas Iskratsch, Muscle Cell Biology Section, The Randall Division of Cell and Molecular Biophysics and The Cardiovascular Division, BHF Research Excellence Centre, King’s College London, New Hunt’s House, Guy’s Campus, London, SE1 1UL UK Susan Reijntjes, Institute of Medical Sciences, University of Aberdeen, Scotland, UK Joseph Dwyer, Muscle Cell Biology Section, The Randall Division of Cell and Molecular Biophysics and The Cardiovascular Division, BHF Research Excellence Centre, King’s College London, New Hunt’s House, Guy’s Campus, London, SE1 1UL UK Paul Toselli, Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA Irene R. Dégano, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA Isabel Dominguez, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA Elisabeth Ehler, Muscle Cell Biology Section, The Randall Division of Cell and Molecular Biophysics and The Cardiovascular Division, BHF Research Excellence Centre, King’s College London, New Hunt’s House, Guy’s Campus, London, SE1 1UL UK Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The metal-insulator transition for the square, simple cubic, and body centered cubic lattices has been studied within the Hubbard model at half-filling taking into account nearest- and next-nearest-neighbor electron hopping. Both staggered antiferromagnetic and incommensurate magnetic states (spin-spiral wave) have been considered. The inclusion of the latter states for the three-dimensional lattices does not change the general pattern of the metal-insulator transition, but opens the fundamentally new possibility of the metal-insulator transition of the first order between the magnetically ordered states for the square lattice. Content Type Journal Article Category Condensed Matter Pages 171-175 DOI 10.1134/S002136401215012X Authors M. A. Timirgazin, Physical-Technical Institute, Ural Branch, Russian Academy of Sciences, Izhevsk, 426000 Russia A. K. Arzhnikov, Physical-Technical Institute, Ural Branch, Russian Academy of Sciences, Izhevsk, 426000 Russia V. Yu. Irkhin, Physical-Technical Institute, Ural Branch, Russian Academy of Sciences, Izhevsk, 426000 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 3

Description:    Precision measurements of the real and imaginary parts of the microwave surface impedance Z ac ( T ) = R ac ( T ) + iX ac ( T ) of the conducting ac layers of the k -(BEDT-TTF) 2 Cu[N(CN) 2 ]Br crystals in the temperature interval of 0.5 〈 T 〈 100 K have demonstrated a series of features: (i) the temperature course of the field penetration depth is close to linear Δλ ac ( T )∞Δ X ac ( T ) in the superconducting state at T T c ∼ 11.5 K; (ii) the curves R ac ( T ) = X ac ( T ) coincide at T c 〈 T 〈 40 K; (iii) the X ac ( T ) value at T 〉 40 K increases in comparison with R ac ( T ); (iv) the dependence R ac ( T ) at T 〉 40 K is nonmonotonic in thin crystals. These features of the impedance Z ac ( T ) with increasing T are interpreted in terms of (i) the d -type symmetry of the superconducting order parameter, (ii) normal skin effect, (iii) manifestations of the antiferromagnetic fluctuations, and (iv) the size effect. The electrodynamic parameters of k -(BEDT-TTF) 2 Cu[N(CN) 2 ]Br have been determined. Content Type Journal Article Category Condensed Matter Pages 184-187 DOI 10.1134/S0021364012150088 Authors N. V. Perunov, Institute of Solid State Physics, Russian Academy of Sciences, Chernogolovka, Moscow region, 142432 Russia A. F. Shevchun, Institute of Solid State Physics, Russian Academy of Sciences, Chernogolovka, Moscow region, 142432 Russia N. D. Kushch, Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka, Moscow region, 142432 Russia M. R. Trunin, Institute of Solid State Physics, Russian Academy of Sciences, Chernogolovka, Moscow region, 142432 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 3

Description:    The experimental conditions that facilitate the excitation of parametric decay instabilities upon the electron cyclotron resonance heating of a plasma at the second harmonic extraordinary wave in tokamaks and stellarators and, as a result, make anomalous absorption of microwave power possible have been analyzed. It has been shown that, in the case of a nonmonotonic radial profile of the plasma density, when the beam of electron cyclotron waves passes near the equatorial plane of a toroidal device, the parametric excitation of electron Bernstein waves, as well as the generation of ion Bernstein waves propagating from the parametric decay region to the nearest ion cyclotron harmonic, where they efficiently interact with ions, is possible. The proposed theoretical model can explain the anomalous generation of accelerated ions observed upon electron cyclotron heating in small and moderate toroidal facilities. Content Type Journal Article Category Plasma, Hydro- and Gas Dynamics Pages 164-170 DOI 10.1134/S002136401215009X Authors A. Yu. Popov, Ioffe Physical Technical Institute, Russian Academy of Sciences, Politekhnicheskaya ul. 26, St. Petersburg, 194021 Russia E. Z. Gusakov, Ioffe Physical Technical Institute, Russian Academy of Sciences, Politekhnicheskaya ul. 26, St. Petersburg, 194021 Russia A. N. Saveliev, Ioffe Physical Technical Institute, Russian Academy of Sciences, Politekhnicheskaya ul. 26, St. Petersburg, 194021 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 3

Description:    The connection of short-term neutron bursts near sea level with the electric and geomagnetic atmospheric fields during thunderstorms in 2009–2011 has been experimentally studied. The data from the cosmic-ray spectrograph named after Kuzmin, an electrostatic fluxmeter, and a three-component fluxgate magnetometer in Yakutsk have been analyzed. It has been shown that short-term (no longer than 4 min) neutron bursts are due to negative lightning discharges. The bursts are detected at the ground level 1–3 km below thunderstorm clouds. In this case, the neutron flux is about 4 × 10 −3 cm −2 s −1 . The minimum energy of the neutrons that are efficiently detected by the monitor is about 10 MeV. It has been found that short-term neutron bursts are detected when the electric field strength reaches a threshold value of −16 kV/m. Content Type Journal Article Category Miscellaneous Pages 188-191 DOI 10.1134/S0021364012150106 Authors S. A. Starodubtsev, Shafer Institute of Cosmophysical Research and Aeronomy, Siberian Branch, Russian Academy of Sciences, Yakutsk, 677980 Russia V. I. Kozlov, Shafer Institute of Cosmophysical Research and Aeronomy, Siberian Branch, Russian Academy of Sciences, Yakutsk, 677980 Russia A. A. Toropov, Shafer Institute of Cosmophysical Research and Aeronomy, Siberian Branch, Russian Academy of Sciences, Yakutsk, 677980 Russia V. A. Mullayarov, Shafer Institute of Cosmophysical Research and Aeronomy, Siberian Branch, Russian Academy of Sciences, Yakutsk, 677980 Russia V. G. Grigor’ev, Shafer Institute of Cosmophysical Research and Aeronomy, Siberian Branch, Russian Academy of Sciences, Yakutsk, 677980 Russia A. V. Moiseev, Shafer Institute of Cosmophysical Research and Aeronomy, Siberian Branch, Russian Academy of Sciences, Yakutsk, 677980 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 3

Description:    We have derived the so-called gap equation, which determines the upper critical magnetic field, perpendicular to conducting chains of a quasi-one-dimensional superconductor. By analyzing this equation at low temperatures, we have found that the calculated angular dependence of the upper critical magnetic field is qualitatively different than that in the so-called effective mass model. In particular, our theory predicts a non-analytical angular dependence of the upper critical magnetic field, H c 2 (0) − H c 2 (α) ∼ α 3/2 , when magnetic field is close to some special crystallographic axis and makes an angle α with it. We discuss possible experiments on the superconductor (DMET) 2 I 3 to discover this non-analytical dependence. Content Type Journal Article Category Condensed Matter Pages 176-180 DOI 10.1134/S0021364012150052 Authors A. G. Lebed, Department of Physics, University of Arizona, AZ 85721, Tucson, USA O. Sepper, Department of Physics, University of Arizona, AZ 85721, Tucson, USA Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 96 Journal Issue Volume 96, Number 3

Description:    Trichomes, originating from epidermal cells, are present on nearly all terrestrial plants. They exist in diverse forms, are readily accessible, and serve as an excellent model system for analyzing the molecular mechanisms in plant cell differentiation, including cell fate choices, cell cycle control, and cell morphogenesis. In Arabidopsis , two regulatory models have been identified that function in parallel in trichome formation; the activator–inhibitor model and the activator–depletion model. Cotton fiber, a similar unicellular structure, is controlled by some functional homologues of Arabidopsis trichome-patterning genes. Multicellular trichomes, as in tobacco and tomato, may form through a distinct pathway from unicellular trichomes. Recent research has shown that cell cycle control participates in trichome formation. In this review, we summarize the molecular mechanisms involved in the formation of unicellular and multicellular trichomes, and discuss the integration of the cell cycle in its initiation and morphogenesis. Content Type Journal Article Category Review Pages 1-12 DOI 10.1007/s00018-012-1147-6 Authors Changxian Yang, The Key Laboratory of Horticultural Plant Biology, Ministry of Education, Huazhong Agricultural University, Wuhan, 430070 China Zhibiao Ye, The Key Laboratory of Horticultural Plant Biology, Ministry of Education, Huazhong Agricultural University, Wuhan, 430070 China Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Haberlea rhodopensis is a resurrection plant with remarkable tolerance to desiccation. Haberlea exposed to drought stress, desiccation, and subsequent rehydration showed no signs of damage or severe oxidative stress compared to untreated control plants. Transcriptome analysis by next-generation sequencing revealed a drought-induced reprogramming, which redirected resources from growth towards cell protection. Repression of photosynthetic and growth-related genes during water deficiency was concomitant with induction of transcription factors (members of the NAC, NF-YA, MADS box, HSF, GRAS, and WRKY families) presumably acting as master switches of the genetic reprogramming, as well as with an upregulation of genes related to sugar metabolism, signaling, and genes encoding early light-inducible (ELIP), late embryogenesis abundant (LEA), and heat shock (HSP) proteins. At the same time, genes encoding other LEA, HSP, and stress protective proteins were constitutively expressed at high levels even in unstressed controls. Genes normally involved in tolerance to salinity, chilling, and pathogens were also highly induced, suggesting a possible cross-tolerance against a number of abiotic and biotic stress factors. A notable percentage of the genes highly regulated in dehydration and subsequent rehydration were novel, with no sequence homology to genes from other plant genomes. Additionally, an extensive antioxidant gene network was identified with several gene families possessing a greater number of antioxidant genes than most other species with sequenced genomes. Two of the transcripts most abundant during all conditions encoded catalases and five more catalases were induced in water-deficient samples. Using the pharmacological inhibitor 3-aminotriazole (AT) to compromise catalase activity resulted in increased sensitivity to desiccation. Metabolome analysis by GC or LC–MS revealed accumulation of sucrose, verbascose, spermidine, and γ-aminobutyric acid during drought, as well as particular secondary metabolites accumulating during rehydration. This observation, together with the complex antioxidant system and the constitutive expression of stress protective genes suggests that both constitutive and inducible mechanisms contribute to the extreme desiccation tolerance of H. rhodopensis . Content Type Journal Article Category Research article Pages 1-21 DOI 10.1007/s00018-012-1155-6 Authors Tsanko S. Gechev, Department of Plant Physiology and Plant Molecular Biology, University of Plovdiv, 24 Tsar Assen Str., Plovdiv, 4000 Bulgaria Maria Benina, Department of Plant Physiology and Plant Molecular Biology, University of Plovdiv, 24 Tsar Assen Str., Plovdiv, 4000 Bulgaria Toshihiro Obata, Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany Takayuki Tohge, Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany Neerakkal Sujeeth, Department of Plant Physiology and Plant Molecular Biology, University of Plovdiv, 24 Tsar Assen Str., Plovdiv, 4000 Bulgaria Ivan Minkov, Department of Plant Physiology and Plant Molecular Biology, University of Plovdiv, 24 Tsar Assen Str., Plovdiv, 4000 Bulgaria Jacques Hille, Molecular Biology of Plants, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands Mohamed-Ramzi Temanni, ServiceXS B.V., Plesmanlaan 1d, 2333 BZ Leiden, The Netherlands Andrew S. Marriott, Department of Chemistry, University of York, Heslington, York YO10 5DD, UK Ed Bergström, Department of Chemistry, University of York, Heslington, York YO10 5DD, UK Jane Thomas-Oates, Department of Chemistry, University of York, Heslington, York YO10 5DD, UK Carla Antonio, Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany Bernd Mueller-Roeber, Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany Jos H. M. Schippers, Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany Alisdair R. Fernie, Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany Valentina Toneva, Department of Plant Physiology and Plant Molecular Biology, University of Plovdiv, 24 Tsar Assen Str., Plovdiv, 4000 Bulgaria Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Since being discovered and intensively studied for over a decade, Smad ubiquitylation regulatory factor-1 (Smurf1) has been linked with several important biological pathways, including the bone morphogenetic protein pathway, the non-canonical Wnt pathway, and the mitogen-activated protein kinase pathway. Multiple functions of this ubiquitin ligase have been discovered in cell growth and morphogenesis, cell migration, cell polarity, and autophagy. Smurf1 is related to physiological manifestations in terms of age-dependent deficiency in bone formation and invasion of tumor cells. Smurf1-knockout mice have a significant phenotype in the skeletal system and considerable manifestations during embryonic development and neural outgrowth. In depth studying of Smurf1 will help us to understand the etiopathological mechanisms of related disorders. Here, we will summarize historical and recent studies on Smurf1, and discuss the E3 ligase-dependent and -independent functions of Smurf1. Moreover, intracellular regulations of Smurf1 and related physiological phenotypes will be described in this review. Content Type Journal Article Category Review Pages 1-13 DOI 10.1007/s00018-012-1170-7 Authors Yu Cao, State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, 100850 China Lingqiang Zhang, State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, 100850 China Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Hypoxic/ischemic injury remains the most dreaded cause of neurological disability and mortality. Despite the humbling experiences due to lack of promising therapy, our understanding of the complex cascades underlying the neuronal insult has led to advances in basic science research. One of the most noteworthy has been the effect of opioid receptors, especially the delta-opioid receptor (DOR), on hypoxic/ischemic neurons. Our recent studies, and those of others worldwide, present strong evidence that sheds light on DOR-mediated neuroprotection in the brain, especially in the cortex. The mechanisms of DOR neuroprotection are broadly categorized as: (1) stabilization of the ionic homeostasis, (2) inhibition of excitatory transmitter release, (3) attenuation of disrupted neuronal transmission, (4) increase in antioxidant capacity, (5) regulation of intracellular pathways—inhibition of apoptotic signals and activation of pro-survival signaling, (6) regulation of specific gene and protein expression, and (7) up-regulation of endogenous opioid release and/or DOR expression. Depending upon the severity and duration of hypoxic/ischemic insult, the release of endogenous opioids and DOR expression are regulated in response to the stress, and DOR signaling acts at multiple levels to confer neuronal tolerance to harmful insult. The phenomenon of DOR neuroprotection offers a potential clue for a promising target that may have significant clinical implications in our quest for neurotherapeutics. Content Type Journal Article Category Review Pages 1-13 DOI 10.1007/s00018-012-1167-2 Authors Xiaozhou He, The Third Clinical College of Suzhou University, Changzhou, Jiangsu, China Harleen K. Sandhu, The Vivian L Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, 77030 TX, USA Yilin Yang, The Third Clinical College of Suzhou University, Changzhou, Jiangsu, China Fei Hua, The Third Clinical College of Suzhou University, Changzhou, Jiangsu, China Nathalee Belser, The Vivian L Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, 77030 TX, USA Dong H. Kim, The Vivian L Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, 77030 TX, USA Ying Xia, The Vivian L Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, 77030 TX, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Although essential for energy production and cell fate decisions, the mechanisms that govern protein homeostasis, or proteostasis, in mitochondria are only recently beginning to emerge. Fresh experimental evidence has uncovered a role of molecular chaperones of the heat shock protein 90 (Hsp90) family in overseeing the protein folding environment in mitochondria. Initially implicated in protection against cell death, there is now evidence that Hsp90-directed protein quality control in mitochondria connects to hosts of cellular homeostatic networks that become prominently exploited in human cancer. Content Type Journal Article Category Review Pages 1-10 DOI 10.1007/s00018-012-1177-0 Authors Dario C. Altieri, Prostate Cancer Discovery and Development Program, The Wistar Institute Cancer Center, 3601 Spruce Street, Philadelphia, PA 19104, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    In mammals, one of the two X chromosomes of female cells is inactivated for dosage compensation between the sexes. X chromosome inactivation is initiated in early embryos by the noncoding Xist RNA. Subsequent chromatin modifications on the inactive X chromosome (Xi) lead to a remarkable stability of gene repression in somatic cell lineages. In mice, reactivation of genes on the Xi accompanies the establishment of pluripotent cells of the female blastocyst and the development of primordial germ cells. Xi reactivation also occurs when pluripotency is established during the reprogramming of somatic cells to induced pluripotent stem cells. The mechanism of Xi reactivation has attracted increasing interest for studying changes in epigenetic patterns and for improving methods of cell reprogramming. Here, we review recent advances in the understanding of Xi reactivation during development and reprogramming and illustrate potential clinical applications. Content Type Journal Article Category Review Pages 1-19 DOI 10.1007/s00018-012-1174-3 Authors Tatsuya Ohhata, Wellcome Trust and MRC Stem Cell Institute, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR UK Anton Wutz, Wellcome Trust and MRC Stem Cell Institute, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR UK Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Matricellular proteins interact with the extracellular matrix (ECM) and modulate cellular processes by binding to cell surface receptors and initiating intracellular signal transduction. Their association with the ECM and the ability of some members of this protein family to regulate cell motility have opened up new avenues of research to investigate their functions in normal and diseased cells. In this review, we summarize the research on CyrA, an ECM calmodulin-binding protein in Dictyostelium . CyrA is proteolytically cleaved into smaller EGF-like (EGFL) repeat containing cleavage products during development. The first EGFL repeat of CyrA binds to the cell surface and activates a novel signalling pathway that modulates cell motility in this model organism. The similarity of CyrA to the most well-characterized matricellular proteins in mammals allows it to be designated as the first matricellular protein identified in Dictyostelium . Content Type Journal Article Category Review Pages 1-9 DOI 10.1007/s00018-012-1068-4 Authors Robert J. Huber, Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, ON M5S 3G5, Canada Danton H. O’Day, Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, ON M5S 3G5, Canada Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The primary cilium protrudes from the cell surface and acts as a sensor for chemical and mechanical growth cues, with receptors for a number of growth factors (PDGFα, Hedgehog, Wnt, Notch) concentrated within the ciliary membrane. In normal tissues, the cilium assembles after cells exit mitosis and is resorbed as part of cell cycle re-entry. Although regulation of the cilium by cell cycle transitions has been appreciated for over 100 years, only recently have data emerged to indicate the cilium also exerts influence on the cell cycle. The resorption/protrusion cycle, regulated by proteins including Aurora-A, VHL, and GSK-3β, influences cell responsiveness to growth cues involving cilia-linked receptors; further, resorption liberates the ciliary basal body to differentiate into the centrosome, which performs discrete functions in S-, G2-, and M-phase. Besides these roles, the cilium provides a positional cue that regulates polarity of cell division, and thus directs cells towards fates of differentiation versus proliferation. In this review, we summarize the specific mechanisms mediating the cilia-cell cycle dialog. We then emphasize the examples of polycystic kidney disease (PKD), nephronopthisis (NPHP), and VHL-linked renal cysts as cases in which defects of ciliary function influence disease pathology, and may also condition response to treatment. Content Type Journal Article Category Review Pages 1-26 DOI 10.1007/s00018-012-1052-z Authors Junmin Pan, Protein Science Laboratory of the Ministry of Education, School of Life Sciences, Tsinghua University, Beijing, 100084 China Tamina Seeger-Nukpezah, Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA Erica A. Golemis, Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The gastrointestinal epithelium forms the boundary between the body and external environment. It effectively provides a selective permeable barrier that limits the permeation of luminal noxious molecules, such as pathogens, toxins, and antigens, while allowing the appropriate absorption of nutrients and water. This selective permeable barrier is achieved by intercellular tight junction (TJ) structures, which regulate paracellular permeability. Disruption of the intestinal TJ barrier, followed by permeation of luminal noxious molecules, induces a perturbation of the mucosal immune system and inflammation, and can act as a trigger for the development of intestinal and systemic diseases. In this context, much effort has been taken to understand the roles of extracellular factors, including cytokines, pathogens, and food factors, for the regulation of the intestinal TJ barrier. Here, I discuss the regulation of the intestinal TJ barrier together with its implications for the pathogenesis of diseases. Content Type Journal Article Category Review Pages 1-29 DOI 10.1007/s00018-012-1070-x Authors Takuya Suzuki, Department of Biofunctional Science and Technology, Graduate School of Biosphere Science, Hiroshima University, 1-4-4, Kagamiyama, Higashi-Hiroshima, 739-8528 Japan Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Monoamine oxidases (MAOs) are flavoproteins of the outer mitochondrial membrane that catalyze the oxidative deamination of biogenic and xenobiotic amines. In mammals there are two isoforms (MAO-A and MAO-B) that can be distinguished on the basis of their substrate specificity and their sensitivity towards specific inhibitors. Both isoforms are expressed in most tissues, but their expression in the central nervous system and their ability to metabolize monoaminergic neurotransmitters have focused MAO research on the functionality of the mature brain. MAO activities have been related to neurodegenerative diseases as well as to neurological and psychiatric disorders. More recently evidence has been accumulating indicating that MAO isoforms are expressed not only in adult mammals, but also before birth, and that defective MAO expression induces developmental abnormalities in particular of the brain. This review is aimed at summarizing and critically evaluating the new findings on the developmental functions of MAO isoforms during embryogenesis. Content Type Journal Article Category Review Pages 1-32 DOI 10.1007/s00018-012-1065-7 Authors Chi Chiu Wang, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin, Hong Kong Ellen Billett, School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS UK Astrid Borchert, Institute of Biochemistry, University Medicine Berlin-Charité, Oudenarder Str. 16, 13347 Berlin, Germany Hartmut Kuhn, Institute of Biochemistry, University Medicine Berlin-Charité, Oudenarder Str. 16, 13347 Berlin, Germany Christoph Ufer, Institute of Biochemistry, University Medicine Berlin-Charité, Oudenarder Str. 16, 13347 Berlin, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    In our tunneling investigation using Andreev superconductor-normal metal-superconductor contacts on LiFeAs single crystals we observed two reproducible independent subharmonic gap structures at dynamic conductance characteristics. From these results, we can derive the energy of the large superconducting gap Δ L = (2.5–3.4) meV and the small gap Δ S = (0.9–1) meV at T = 4.2 K for the T C local ≈ (10.5–14) K (the contact area critical temperature which deviation causes the variation of Δ L ). The BCS-ratio is found to be 2Δ L / k B T C = 4.6–5.6, whereas 2Δ S / k B T C ≪ 3.52 results from induced superconductivity in the bands with the small gap. Content Type Journal Article Category Condensed Matter Pages 537-543 DOI 10.1134/S0021364012100086 Authors S. A. Kuzmichev, Moscow State University, Moscow, 119991 Russia T. E. Shanygina, Moscow State University, Moscow, 119991 Russia I. V. Morozov, Moscow State University, Moscow, 119991 Russia A. I. Boltalin, Moscow State University, Moscow, 119991 Russia M. V. Roslova, Moscow State University, Moscow, 119991 Russia S. Wurmehl, IFW-Dresden, Institute for Solid State Research, D-01171 Dresden, Germany B. Büchner, IFW-Dresden, Institute for Solid State Research, D-01171 Dresden, Germany Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 95 Journal Issue Volume 95, Number 10

Description:    It has been shown that counterpropagating electromagnetic waves with different frequencies generate two lattices in a cubically nonlinear medium, one of which moves at a superluminal velocity. When weak radiation reflects from the superluminal lattice, the wavefront is quasi-conjugated with distortions owing to the Doppler frequency shift. These effects occur both in insulators with fast nonlinearity and in an electron-positron vacuum. Content Type Journal Article Category Optics and Laser Physics Pages 609-612 DOI 10.1134/S0021364012120132 Authors N. N. Rosanov, Vavilov State Optical Institute, Birzhevaya liniya 12, St. Petersburg, 199034 Russia Journal JETP Letters Online ISSN 1090-6487 Print ISSN 0021-3640 Journal Volume Volume 95 Journal Issue Volume 95, Number 12

Description:    Understanding the peopling history of Europe is crucial to comprehend the origins of modern populations. Of course, the analysis of current genetic data offers several explanations about human migration patterns which occurred on this continent, but it fails to explain precisely the impact of each demographic event. In this context, direct access to the DNA of ancient specimens allows the overcoming of recent demographic phenomena, which probably highly modified the constitution of the current European gene pool. In recent years, several DNA studies have been successfully conducted from ancient human remains thanks to the improvement of molecular techniques. They have brought new fundamental information on the peopling of Europe and allowed us to refine our understanding of European prehistory. In this review, we will detail all the ancient DNA studies performed to date on ancient European DNA from the Middle Paleolithic to the beginning of the protohistoric period. Content Type Journal Article Category Review Pages 1-15 DOI 10.1007/s00018-012-1180-5 Authors Marie Lacan, Laboratoire AMIS, CNRS UMR 5288, 37 Allées Jules Guesde, 31073 Toulouse cedex 3, France Christine Keyser, Laboratoire AMIS, CNRS UMR 5288, 37 Allées Jules Guesde, 31073 Toulouse cedex 3, France Eric Crubézy, Laboratoire AMIS, CNRS UMR 5288, 37 Allées Jules Guesde, 31073 Toulouse cedex 3, France Bertrand Ludes, Laboratoire AMIS, CNRS UMR 5288, 37 Allées Jules Guesde, 31073 Toulouse cedex 3, France Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Most tumor cells exhibit a glycolytic phenotype. Thus, inhibition of glycolysis might be of therapeutic value in antitumor treatment. Among the agents that can suppress glycolysis is citrate, a member of the Krebs cycle and an inhibitor of phosphofructokinase. Here, we show that citrate can trigger cell death in multiple cancer cell lines. The lethal effect of citrate was found to be related to the activation of apical caspases-8 and -2, rather than to the inhibition of cellular energy metabolism. Hence, increasing concentrations of citrate induced characteristic manifestations of apoptosis, such as caspase-3 activation, and poly-ADP-ribose polymerase cleavage, as well as the release of cytochrome c . Apoptosis induction did not involve the receptor-mediated pathway, since the processing of caspase-8 was not attenuated in cells deficient in Fas-associated protein with Death Domain. We propose that the activation of apical caspases by citrate could be explained by its kosmotropic properties. Caspase-8 is activated by proximity-induced dimerization, which might be facilitated by citrate through the stabilization of intermolecular interactions between the proteins. Content Type Journal Article Category Research article Pages 1-9 DOI 10.1007/s00018-012-1166-3 Authors Björn Kruspig, Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden Azadeh Nilchian, Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden Sten Orrenius, Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden Boris Zhivotovsky, Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden Vladimir Gogvadze, Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    We investigated the effects of bone morphogenetic proteins (BMPs) in determining the positional identity of neurons generated in vitro from mouse embryonic stem cells (ESCs), an aspect that has been neglected thus far. Classical embryological studies in lower vertebrates indicate that BMPs inhibit the default fate of pluripotent embryonic cells, which is both neural and anterior. Moreover, mammalian ESCs generate neurons more efficiently when cultured in a minimal medium containing BMP inhibitors. In this paper, we show that mouse ESCs produce, secrete, and respond to BMPs during in vitro neural differentiation. After neuralization in a minimal medium, differentiated ESCs show a gene expression profile consistent with a midbrain identity, as evaluated by the analysis of a number of markers of anterior–posterior and dorsoventral identity. We found that BMPs endogenously produced during neural differentiation mainly act by inhibiting the expression of a telencephalic gene profile, which was revealed by the treatment with Noggin or with other BMP inhibitors. To better characterize the effect of BMPs on positional fate, we compared the global gene expression profiles of differentiated ESCs with those of embryonic forebrain, midbrain, and hindbrain. Both Noggin and retinoic acid (RA) support neuronal differentiation of ESCs, but they show different effects on their positional identity: whereas RA supports the typical gene expression profile of hindbrain neurons, Noggin induces a profile characteristic of dorsal telencephalic neurons. Our findings show that endogenously produced BMPs affect the positional identity of the neurons that ESCs spontaneously generate when differentiating in vitro in a minimal medium. The data also support the existence of an intrinsic program of neuronal differentiation with dorsal telencephalic identity. Our method of ESC neuralization allows for fast differentiation of neural cells via the same signals found during in vivo embryonic development and for the acquisition of cortical identity by the inhibition of BMP alone. Content Type Journal Article Category Research Article Pages 1-17 DOI 10.1007/s00018-012-1182-3 Authors Michele Bertacchi, Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56100 Pisa, Italy Luca Pandolfini, Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56100 Pisa, Italy Elisa Murenu, CIBIO, Università di Trento, Trento, Italy Alessandro Viegi, Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56100 Pisa, Italy Simona Capsoni, Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56100 Pisa, Italy Alessandro Cellerino, Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56100 Pisa, Italy Andrea Messina, CIBIO, Università di Trento, Trento, Italy Simona Casarosa, CIBIO, Università di Trento, Trento, Italy Federico Cremisi, Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56100 Pisa, Italy Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The insulin-like growth factor-2 mRNA-binding proteins 1, 2, and 3 (IGF2BP1, IGF2BP2, IGF2BP3) belong to a conserved family of RNA-binding, oncofetal proteins. Several studies have shown that these proteins act in various important aspects of cell function, such as cell polarization, migration, morphology, metabolism, proliferation and differentiation. In this review, we discuss the IGF2BP family’s role in cancer biology and how this correlates with their proposed functions during embryogenesis. IGF2BPs are mainly expressed in the embryo, in contrast with comparatively lower or negotiable levels in adult tissues. IGF2BP1 and IGF2BP3 have been found to be re-expressed in several aggressive cancer types. Control of IGF2BPs’ expression is not well understood; however, let-7 microRNAs, β-catenin (CTNNB1) and MYC have been proposed to be involved in their regulation. In contrast to many other RNA-binding proteins, IGF2BPs are almost exclusively observed in the cytoplasm where they associate with target mRNAs in cytoplasmic ribonucleoprotein complexes (mRNPs). During development, IGF2BPs are required for proper nerve cell migration and morphological development, presumably involving the control of cytoskeletal remodeling and dynamics, respectively. Likewise, IGF2BPs modulate cell polarization, adhesion and migration in tumor-derived cells. Moreover, they are highly associated with cancer metastasis and the expression of oncogenic factors (KRAS, MYC and MDR1). However, a pro-metastatic role of IGF2BPs remains controversial due to the lack of ‘classical’ in vivo studies. Nonetheless, IGF2BPs could provide valuable targets in cancer treatment with many of their in vivo roles to be fully elucidated. Content Type Journal Article Category Review Pages 1-19 DOI 10.1007/s00018-012-1186-z Authors Jessica L. Bell, Section for Molecular Cell Biology, Institute of Molecular Medicine, Martin-Luther-University Halle, 06120 Halle, Germany Kristin Wächter, Section for Molecular Cell Biology, Institute of Molecular Medicine, Martin-Luther-University Halle, 06120 Halle, Germany Britta Mühleck, Section for Molecular Cell Biology, Institute of Molecular Medicine, Martin-Luther-University Halle, 06120 Halle, Germany Nikolaos Pazaitis, Section for Molecular Cell Biology, Institute of Molecular Medicine, Martin-Luther-University Halle, 06120 Halle, Germany Marcel Köhn, Section for Molecular Cell Biology, Institute of Molecular Medicine, Martin-Luther-University Halle, 06120 Halle, Germany Marcell Lederer, Section for Molecular Cell Biology, Institute of Molecular Medicine, Martin-Luther-University Halle, 06120 Halle, Germany Stefan Hüttelmaier, Section for Molecular Cell Biology, Institute of Molecular Medicine, Martin-Luther-University Halle, 06120 Halle, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Gram-negative bacteria can produce specific proteinaceous inhibitors to defend themselves against the lytic action of host lysozymes. So far, four different lysozyme inhibitor families have been identified. Here, we report the crystal structure of the Escherichia coli periplasmic lysozyme inhibitor of g-type lysozyme (PliG-Ec) in complex with Atlantic salmon g-type lysozyme (SalG) at a resolution of 0.95 Å, which is exceptionally high for a complex of two proteins. The structure reveals for the first time the mechanism of g-type lysozyme inhibition by the PliG family. The latter contains two specific conserved regions that are essential for its inhibitory activity. The inhibitory complex formation is based on a double ‘key-lock’ mechanism. The first key-lock element is formed by the insertion of two conserved PliG regions into the active site of the lysozyme. The second element is defined by a distinct pocket of PliG accommodating a lysozyme loop. Computational analysis indicates that this pocket represents a suitable site for small molecule binding, which opens an avenue for the development of novel antibacterial agents that suppress the inhibitory activity of PliG. Content Type Journal Article Category Research Article Pages 1-10 DOI 10.1007/s00018-012-1184-1 Authors S. Leysen, Laboratory for Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven, Herestraat 49 bus 822, 3000 Leuven, Belgium L. Vanderkelen, Laboratory of Food Microbiology, Leuven Food Science and Nutrition Research Centre (LFoRCe), Katholieke Universiteit Leuven, Kasteelpark Arenberg 22, 3001 Leuven, Belgium S. D. Weeks, Laboratory for Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven, Herestraat 49 bus 822, 3000 Leuven, Belgium C. W. Michiels, Laboratory of Food Microbiology, Leuven Food Science and Nutrition Research Centre (LFoRCe), Katholieke Universiteit Leuven, Kasteelpark Arenberg 22, 3001 Leuven, Belgium S. V. Strelkov, Laboratory for Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven, Herestraat 49 bus 822, 3000 Leuven, Belgium Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Cardiovascular disease is the foremost cause of morbidity and mortality in the Western world. Atherosclerosis followed by thrombosis (atherothrombosis) is the pathological process underlying most myocardial, cerebral, and peripheral vascular events. Atherothrombosis is a complex and heterogeneous inflammatory process that involves interactions between many cell types (including vascular smooth muscle cells, endothelial cells, macrophages, and platelets) and processes (including migration, proliferation, and activation). Despite a wealth of knowledge from many recent studies using knockout mouse and human genetic studies (GWAS and candidate approach) identifying genes and proteins directly involved in these processes, traditional cardiovascular risk factors (hyperlipidemia, hypertension, smoking, diabetes mellitus, sex, and age) remain the most useful predictor of disease. Eicosanoids (20 carbon polyunsaturated fatty acid derivatives of arachidonic acid and other essential fatty acids) are emerging as important regulators of cardiovascular disease processes. Drugs indirectly modulating these signals, including COX-1/COX-2 inhibitors, have proven to play major roles in the atherothrombotic process. However, the complexity of their roles and regulation by opposing eicosanoid signaling, have contributed to the lack of therapies directed at the eicosanoid receptors themselves. This is likely to change, as our understanding of the structure, signaling, and function of the eicosanoid receptors improves. Indeed, a major advance is emerging from the characterization of dysfunctional naturally occurring mutations of the eicosanoid receptors. In light of the proven and continuing importance of risk factors, we have elected to focus on the relationship between eicosanoids and cardiovascular risk factors. Content Type Journal Article Category Review Pages 1-20 DOI 10.1007/s00018-012-0982-9 Authors Scott Gleim, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, 300 George Street #795H, New Haven, CT 06511, USA Jeremiah Stitham, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, 300 George Street #795H, New Haven, CT 06511, USA Wai Ho Tang, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, 300 George Street #795H, New Haven, CT 06511, USA Kathleen A. Martin, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, 300 George Street #795H, New Haven, CT 06511, USA John Hwa, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, 300 George Street #795H, New Haven, CT 06511, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Age is an important risk for autoimmunity, and many autoimmune diseases preferentially occur in the second half of adulthood when immune competence has declined and thymic T cell generation has ceased. Many tolerance checkpoints have to fail for an autoimmune disease to develop, and several of those are susceptible to the immune aging process. Homeostatic T cell proliferation which is mainly responsible for T cell replenishment during adulthood can lead to the selection of T cells with increased affinity to self- or neoantigens and enhanced growth and survival properties. These cells can acquire a memory-like phenotype, in particular under lymphopenic conditions. Accumulation of end-differentiated effector T cells, either specific for self-antigen or for latent viruses, have a low activation threshold due to the expression of signaling and regulatory molecules and generate an inflammatory environment with their ability to be cytotoxic and to produce excessive amounts of cytokines and thereby inducing or amplifying autoimmune responses. Content Type Journal Article Category Multi-author review Pages 1-9 DOI 10.1007/s00018-012-0970-0 Authors Jörg J. Goronzy, Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, CCSR Building Room 2215, Mail Code 5166, 269 Campus Drive West, Stanford, CA 94305-5166, USA Cornelia M. Weyand, Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, CCSR Building Room 2215, Mail Code 5166, 269 Campus Drive West, Stanford, CA 94305-5166, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The human airway epithelium is a pseudostratified heterogenous layer comprised of ciliated, secretory, intermediate, and basal cells. As the stem/progenitor population of the airway epithelium, airway basal cells differentiate into ciliated and secretory cells to replenish the airway epithelium during physiological turnover and repair. Transcriptome analysis of airway basal cells revealed high expression of vascular endothelial growth factor A (VEGFA), a gene not typically associated with the function of this cell type. Using cultures of primary human airway basal cells, we demonstrate that basal cells express all of the three major isoforms of VEGFA (121, 165 and 189) but lack functional expression of the classical VEGFA receptors VEGFR1 and VEGFR2. The VEGFA is actively secreted by basal cells and while it appears to have no direct autocrine function on basal cell growth and proliferation, it functions in a paracrine manner to activate MAPK signaling cascades in endothelium via VEGFR2-dependent signaling pathways. Using a cytokine- and serum-free co-culture system of primary human airway basal cells and human endothelial cells revealed that basal cell-secreted VEGFA activated endothelium to express mediators that, in turn, stimulate and support basal cell proliferation and growth. These data demonstrate novel VEGFA-mediated cross-talk between airway basal cells and endothelium, the purpose of which is to modulate endothelial activation and in turn stimulate and sustain basal cell growth. Content Type Journal Article Category Research Article Pages 1-15 DOI 10.1007/s00018-012-0922-8 Authors Giacomo Curradi, Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 96, New York, NY 10065, USA Matthew S. Walters, Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 96, New York, NY 10065, USA Bi-Sen Ding, Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 96, New York, NY 10065, USA Shahin Rafii, Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 96, New York, NY 10065, USA Neil R. Hackett, Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 96, New York, NY 10065, USA Ronald G. Crystal, Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 96, New York, NY 10065, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The relatively homogenous clinical features and poor prognosis of chronic myelomonocytic leukemia (CMML) are associated with a molecular heterogeneity, with various mutations impacting several convergent pathways. Due to the restricted understanding of the mechanism involved in leukemogenesis, CMML still appears as a diagnostic and therapeutic undertaking, and poor prognosis of leukemia. Contrary to chronic myelogenous leukemia, BCR – ABL1 -positive, cytogenetic, and molecular abnormalities of CMML are not specific and not pathognomonic, confirming the different levels of heterogeneity of this disease. Various mutations can be associated with a common phenotype not distinct at the clinical level, further demonstrating that molecular probings are needed for choosing individual targeted therapies. Content Type Journal Article Category Review Pages 1-9 DOI 10.1007/s00018-012-0956-y Authors Jean-Noël Bastie, Faculté de Médecine, Inserm UMR 866, Université de Bourgogne, 7 bd Jeanne d’Arc, 21000 Dijon, France Romain Aucagne, Faculté de Médecine, Inserm UMR 866, Université de Bourgogne, 7 bd Jeanne d’Arc, 21000 Dijon, France Nathalie Droin, Inserm UMR 1009, IRCIV, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France Eric Solary, Inserm UMR 1009, IRCIV, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France Laurent Delva, Faculté de Médecine, Inserm UMR 866, Université de Bourgogne, 7 bd Jeanne d’Arc, 21000 Dijon, France Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The proteasome is a multi-catalytic protein complex whose primary function is the degradation of abnormal or foreign proteins. Upon exposure of cells to interferons (IFNs), the β1i/LMP2, β2i/MECL-1, and β5i/LMP7 subunits are induced and incorporated into newly synthesized immunoproteasomes (IP), which are thought to function solely as critical players in the optimization of the CD8 + T-cell response. However, the observation that IP are present in several non-immune tissues under normal conditions and/or following pathological events militates against the view that its role is limited to MHC class I presentation. In support of this concept, the recent use of genetic models deficient for β1i/LMP2, β2i/MECL-1, or β5i/LMP7 has uncovered unanticipated functions for IP in innate immunity and non-immune processes. Herein, we review recent data in an attempt to clarify the role of IP beyond MHC class I epitope presentation with emphasis on its involvement in the regulation of protein homeostasis, cell proliferation, and cytokine gene expression. Content Type Journal Article Category Review Pages 1-16 DOI 10.1007/s00018-012-0938-0 Authors Frédéric Ebstein, Institut für Biochemie, Charité-Universitätsmedizin Berlin Campus CVK, Oudenarderstr.16, 13347 Berlin, Germany Peter-Michael Kloetzel, Institut für Biochemie, Charité-Universitätsmedizin Berlin Campus CVK, Oudenarderstr.16, 13347 Berlin, Germany Elke Krüger, Institut für Biochemie, Charité-Universitätsmedizin Berlin Campus CVK, Oudenarderstr.16, 13347 Berlin, Germany Ulrike Seifert, Institut für Biochemie, Charité-Universitätsmedizin Berlin Campus CVK, Oudenarderstr.16, 13347 Berlin, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Metabolic engineering is the enabling science of development of efficient cell factories for the production of fuels, chemicals, pharmaceuticals, and food ingredients through microbial fermentations. The yeast Saccharomyces cerevisiae is a key cell factory already used for the production of a wide range of industrial products, and here we review ongoing work, particularly in industry, on using this organism for the production of butanol, which can be used as biofuel, and isoprenoids, which can find a wide range of applications including as pharmaceuticals and as biodiesel. We also look into how engineering of yeast can lead to improved uptake of sugars that are present in biomass hydrolyzates, and hereby allow for utilization of biomass as feedstock in the production of fuels and chemicals employing S. cerevisiae . Finally, we discuss the perspectives of how technologies from systems biology and synthetic biology can be used to advance metabolic engineering of yeast. Content Type Journal Article Category Review Pages 1-20 DOI 10.1007/s00018-012-0945-1 Authors Kuk-Ki Hong, Novo Nordisk Centre for Biosustainability, Department of Chemical and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden Jens Nielsen, Novo Nordisk Centre for Biosustainability, Department of Chemical and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Centrins are small, highly conserved members of the EF-hand superfamily of calcium-binding proteins that are found throughout eukaryotes. They play a major role in ensuring the duplication and appropriate functioning of the ciliary basal bodies in ciliated cells. They have also been localised to the centrosome, which is the major microtubule organising centre in animal somatic cells. We describe the identification, cloning and characterisation of centrins in multiple eukaryotic species. Although centrins have been implicated in centriole biogenesis, recent results have indicated that centrosome duplication can, in fact, occur in the absence of centrins. We discuss these data and the non-centrosomal functions that are emerging for the centrins. In particular, we discuss the involvement of centrins in nucleotide excision repair, a process that repairs the DNA lesions that are induced primarily by ultraviolet irradiation. We discuss how centrin may be involved in these diverse processes and contribute to nuclear and cytoplasmic events. Content Type Journal Article Category Review Pages 1-19 DOI 10.1007/s00018-012-0961-1 Authors Tiago J. Dantas, Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, University Road, Galway, Ireland Owen M. Daly, Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, University Road, Galway, Ireland Ciaran G. Morrison, Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, University Road, Galway, Ireland Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The pathobiology of pulmonary arterial hypertension (PAH) involves a remodeling process in distal pulmonary arteries, as well as vasoconstriction and in situ thrombosis, leading to an increase in pulmonary vascular resistance, right heart failure and death. Its etiology may be idiopathic, but PAH is also frequently associated with underlying conditions such as connective tissue diseases. During the past decade, more than welcome novel therapies have been developed and are in development, including those increasingly targeting the remodeling process. These therapeutic options modestly increase the patients’ long-term survival, now approaching 60% at 5 years. However, non-invasive tools for confirming PAH diagnosis, and assessing disease severity and response to therapy, are tragically lacking and would help to select the best treatment. After exclusion of other causes of pulmonary hypertension, a final diagnosis still relies on right heart catheterization, an invasive technique which cannot be repeated as often as an optimal follow-up might require. Similarly, other techniques and biomarkers used for assessing disease severity and response to treatment generally lack specificity and have significant limitations. In this review, imaging as well as current and future circulating biomarkers for diagnosis, prognosis, and follow-up are discussed. Content Type Journal Article Category Review Pages 1-27 DOI 10.1007/s00018-012-0950-4 Authors Marjorie Barrier, Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, QC G1V 4G5, Canada Jolyane Meloche, Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, QC G1V 4G5, Canada Maria Helena Jacob, Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, QC G1V 4G5, Canada Audrey Courboulin, Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, QC G1V 4G5, Canada Steeve Provencher, Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, QC G1V 4G5, Canada Sébastien Bonnet, Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, QC G1V 4G5, Canada Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Cell adhesion molecule 1 (CADM1), expressed by human lung mast cells (HLMCs), mediates their adhesion to airway smooth muscle (ASM), and contributes to ASM-dependent HLMC proliferation and survival. CADM1 is expressed in alternatively spliced isoforms, but those present in HLMCs and their function are not known. We cloned three functional and one cryptic non-functional isoform with alternative splicing between exons 7/11 and 1/2, respectively, from HLMCs and human MC lines (HMC-1 and LAD2). Differentiated HLMCs and LAD2 cells expressed the functional isoform SP4 containing exons 7/8/11 (~80% of clones), as well as SP1 (exons 7/8/9/11) and a novel SP6 (exons 7/8/9/10/11). In contrast, immature HMC-1 cells expressed only functional SP4. SP4 overexpression in HMC-1 cells and HLMCs augmented homotypic adhesion to a greater extent than SP1 in various conditions. In contrast, CADM1 downregulation abolished homotypic adhesion, indicating that CADM1 is the sole receptor mediating mast cell aggregation. CADM1-mediated adhesion was enhanced by the presence of cell survival factors. SP1 overexpression in HMC-1 cells compromised survival compared to SP4 overexpression or control. CADM1 downregulation resulted in reduced viability and decreased expression of the pro-survival protein Mcl-1 L , but not Blc-2 or Bcl-X L , and increased caspase-3/7 activity in both HMC-1 cells and HLMCs. This coincided with decreased basal Kit levels in HLMCs. In summary, human MCs express multiple CADM1 isoforms which exhibit differential regulation of survival and homotypic adhesion. The most highly expressed SP4 isoform is likely to contribute to MC aggregation and longevity in mastocytosis, and augment the pathophysiology of allergic diseases. Content Type Journal Article Category Research Article Pages 1-14 DOI 10.1007/s00018-012-0948-y Authors Elena P. Moiseeva, Department of Infection, Immunity and Inflammation, Institute for Lung Health, Clinical Sciences Wing, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP UK Mark L. Leyland, Department of Biochemistry, University of Leicester, Leicester, UK Peter Bradding, Department of Infection, Immunity and Inflammation, Institute for Lung Health, Clinical Sciences Wing, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP UK Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    A disintegrin and metalloproteinase10 (ADAM10) has been implicated as a major sheddase responsible for the ectodomain shedding of a number of important surface molecules including the amyloid precursor protein and cadherins. Despite a well-documented role of ADAM10 in health and disease, little is known about the regulation of this protease. To address this issue we conducted a split-ubiquitin yeast two-hybrid screen to identify membrane proteins that interact with ADAM10. The yeast experiments and co-immunoprecipitation studies in mammalian cell lines revealed tetraspanin15 (TSPAN15) to specifically associate with ADAM10. Overexpression of TSPAN15 or RNAi-mediated knockdown of TSPAN15 led to significant changes in the maturation process and surface expression of ADAM10. Expression of an endoplasmic reticulum (ER) retention mutant of TSPAN15 demonstrated an interaction with ADAM10 already in the ER. Pulse-chase experiments confirmed that TSPAN15 accelerates the ER-exit of the ADAM10–TSPAN15 complex and stabilizes the active form of ADAM10 at the cell surface. Importantly, TSPAN15 also showed the ability to mediate the regulation of ADAM10 protease activity exemplified by an increased shedding of N-cadherin and the amyloid precursor protein. In conclusion, our data show that TSPAN15 is a central modulator of ADAM10-mediated ectodomain shedding. Therapeutic manipulation of its expression levels may be an additional approach to specifically regulate the activity of the amyloid precursor protein alpha-secretase ADAM10. Content Type Journal Article Category Research Article Pages 1-14 DOI 10.1007/s00018-012-0960-2 Authors Johannes Prox, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, 24098 Kiel, Germany Michael Willenbrock, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, 24098 Kiel, Germany Silvio Weber, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, 24098 Kiel, Germany Tobias Lehmann, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, 24098 Kiel, Germany Dirk Schmidt-Arras, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, 24098 Kiel, Germany Ralf Schwanbeck, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, 24098 Kiel, Germany Paul Saftig, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, 24098 Kiel, Germany Michael Schwake, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, 24098 Kiel, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Oxidative stress and low-grade inflammation are the hallmarks of the aging process and are even more enhanced in many age-related degenerative diseases. Mitochondrial dysfunction and oxidative stress can provoke and potentiate inflammatory responses, but the mechanism has remained elusive. Recent studies indicate that oxidative stress can induce the assembly of multiprotein inflammatory complexes called the inflammasomes. Nod-like receptor protein 3 (NLRP3) is the major immune sensor for cellular stress signals, e.g., reactive oxygen species, ceramides, and cathepsin B. NLRP3 activation triggers the caspase-1-mediated maturation of the precursors of IL-1β and IL-18 cytokines. During aging, the autophagic clearance of mitochondria declines and dysfunctional mitochondria provoke chronic oxidative stress, which disturbs the cellular redox balance. Moreover, increased NF-κB signaling observed during aging could potentiate the expression of NLRP3 and cytokine proforms enhancing the priming of NLRP3 inflammasomes. Recent studies have demonstrated that NLRP3 activation is associated with several age-related diseases, e.g., the metabolic syndrome. We will review here the emerging field of inflammasomes in the appearance of the proinflammatory phenotype during the aging process and in age-related diseases. Content Type Journal Article Category Review Pages 1-15 DOI 10.1007/s00018-012-0962-0 Authors Antero Salminen, Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland Johanna Ojala, Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland Kai Kaarniranta, Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland Anu Kauppinen, Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Rapid signal propagation along vertebrate axons is facilitated by their insulation with myelin, a plasma membrane specialization of glial cells. The recent application of ‘omics’ approaches to the myelinating cells of the central nervous system, oligodendrocytes, revealed their mRNA signatures, enhanced our understanding of how myelination is regulated, and established that the protein composition of myelin is much more complex than previously thought. This review provides a meta-analysis of the 〉1,200 proteins thus far identified by mass spectrometry in biochemically purified central nervous system myelin. Contaminating proteins are surprisingly infrequent according to bioinformatic prediction of subcellular localization and comparison with the transcriptional profile of oligodendrocytes. The integration of datasets also allowed the subcategorization of the myelin proteome into functional groups comprising genes that are coregulated during oligodendroglial differentiation. An unexpectedly large number of myelin-related genes cause—when mutated in humans—hereditary diseases affecting the physiology of the white matter. Systematic approaches to oligodendrocytes and myelin thus provide valuable resources for the molecular dissection of developmental myelination, glia–axonal interactions, leukodystrophies, and demyelinating diseases. Content Type Journal Article Category Review Pages 1-16 DOI 10.1007/s00018-012-0958-9 Authors Patricia de Monasterio-Schrader, Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany Olaf Jahn, Proteomics Group, Max Planck Institute of Experimental Medicine, Göttingen, Germany Stefan Tenzer, Institute of Immunology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany Sven P. Wichert, Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany Julia Patzig, Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany Hauke B. Werner, Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Established views on the maintenance of immunological memory have been challenged recently by the description of memory plasma cells and memory T helper (Th) lymphocytes residing in the bone marrow (BM) in dedicated survival niches, resting in terms of proliferation and migration. While memory plasma cells are no longer reactive to antigen, memory Th lymphocytes are in a state of attentive rest, and can be reactivated fast and efficiently. Here, we discuss the signals controlling these resting states, which the memory lymphocytes receive from their microenvironment. Content Type Journal Article Category Multi-author review Pages 1-5 DOI 10.1007/s00018-012-0969-6 Authors Koji Tokoyoda, German Rheumatism Research Center Berlin, Chariteplatz 1, 10117 Berlin, Germany Andreas Radbruch, German Rheumatism Research Center Berlin, Chariteplatz 1, 10117 Berlin, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Tetraspanins regulate a variety of cellular functions. However, the general cellular mechanisms by which tetraspanins regulate these functions remain poorly understood. In this article we collected the observations that tetraspanins regulate the formation and/or development of various tubular structures of cell membrane. Because tetraspanins and their associated proteins (1) are localized at the tubular structures, such as the microvilli, adhesion zipper, foot processes, and penetration peg, and/or (2) regulate the morphogenesis of these membrane tubular structures, tetraspanins probably modulate various cellular functions through these membrane tubular structures. Some tetraspanins inhibit membrane tubule formation and/or extension, while others promote them. We predict that tetraspanins regulate the formation and/or development of various membrane tubular structures: (1) microvilli or nanovilli at the plasma membranes free of cell and matrix contacts, (2) membrane tubules at the plasma membrane of cell-matrix and cell-cell interfaces, and (3) membrane tubules at the intracellular membrane compartments. These different membrane tubular structures likely share a common morphogenetic mechanism that involves tetraspanins. Tetraspanins probably regulate the morphogenesis of membrane tubular structures by altering (1) the biophysical properties of the cell membrane such as curvature and/or (2) the membrane connections of cytoskeleton. Since membrane tubular structures are associated with cell functions such as adhesion, migration, and intercellular communication, in all of which tetraspanins are involved, the differential effects of tetraspanins on membrane tubular structures likely lead to the functional difference of tetraspanins. Content Type Journal Article Category Review Pages 1-10 DOI 10.1007/s00018-012-0954-0 Authors Xin A. Zhang, Department of Medicine, Vascular Biology and Cancer Centers, University of Tennessee Health Science Center, Cancer Research Building Room 220, 19 South Manassas Street, Memphis, TN 38163, USA Chao Huang, Department of Medicine, Vascular Biology and Cancer Centers, University of Tennessee Health Science Center, Cancer Research Building Room 220, 19 South Manassas Street, Memphis, TN 38163, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    MicroRNAs (miRNAs) are a family of small, non-coding RNAs that control gene expression at the post-transcriptional level by destabilizing and inhibiting translation of their target messenger RNAs. MiRNAs are involved in the regulation of a number of fundamental biological processes, and their dysregulation is thought to contribute to several disease processes. Emerging evidence suggests that miRNAs also play a critical role in protecting the heritable genome by contributing to the regulation of the DNA damage response. Consequently, much recent investigative effort has been directed towards an improved understanding of how miRNAs are regulated in response to DNA damage. In this review, we discuss the most recent findings regarding the regulation of miRNA expression and the functional roles of miRNAs in the DNA damage response. Content Type Journal Article Category Review Pages 1-12 DOI 10.1007/s00018-012-0959-8 Authors Cecil Han, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Guohui Wan, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Robert R. Langley, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Xinna Zhang, Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Xiongbin Lu, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Interkinetic nuclear migration (INM) is an oscillatory nuclear movement that is synchronized with the progression of the cell cycle. The efforts of several researchers, following the first report of INM in 1935, have revealed many of the molecular mechanisms of this fascinating phenomenon linking the timing of the cell cycle and nuclear positioning in tissue. Researchers are now faced with a more fundamental question: is INM important for tissue, particularly brain, development? In this review, I summarize the current understanding of the regulatory mechanisms governing INM, investigations involving several different tissues and species, and possible explanations for how nuclear movement affects cell-fate determination and tissue formation. Content Type Journal Article Category Review Pages 1-12 DOI 10.1007/s00018-012-0952-2 Authors Yoichi Kosodo, Department of Anatomy, Kawasaki Medical School, 577 Matsushima, Kurashiki, 701-0192 Japan Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The world of RNAs is much more complex than previously thought, and has rapidly emerged as one of the most actively researched topics in the life sciences. Recently, two findings in this field were reported and given special attention: promoter-associated RNAs (paRNAs), a novel class of RNAs with numerous potential functions; and promoter-targeted RNA-induced transcriptional gene regulation, a new regulatory mechanism to control transcription. In this review, we summarize the studies in these two areas, and outline the current understanding with respect to the potential biological functions of paRNAs, and the molecular mechanisms of promoter-targeted RNA-induced transcriptional gene silencing and activation. Additionally, we seek to integrate these two areas, as paRNAs may have potential biological links with promoter-targeted RNA-induced transcriptional gene regulation. Finally, we will discuss the significance of identifying paRNAs and the possible use of promoter-targeted RNAs in gene regulation and therapy. Content Type Journal Article Category Review Pages 1-10 DOI 10.1007/s00018-012-0953-1 Authors Bing-xue Yan, Icesnow Yanyan Bioscience Association, Beijing, 100094 China Jin-xia Ma, Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Barrier properties of tight junctions are determined by the claudin protein family. Many claudins seal this barrier, but others form paracellular channels. Among these, no claudins with general and clear-cut anion selectivity have yet been described, while for claudin-10a and claudin-4, only circumstantial or small anion selectivities have been shown. A claudin with unknown function and tissue distribution is claudin-17. We characterized claudin-17 by overexpression and knock-down in two renal cell lines. Overexpression in MDCK C7 cell layers caused a threefold increase in paracellular anion permeability and switched these cells from cation- to anion-selective. Knockdown in LLC-PK 1 cells indorsed the finding of claudin-17-based anion channels. Mutagenesis revealed that claudin-17 anion selectivity critically depends on a positive charge at position 65. Claudin-17 expression was found in two organs: marginal in brain but abundant in kidney, where expression was intense in proximal tubules and gradually decreased towards distal segments. As claudin-17 is predominantly expressed in proximal nephrons, which exhibit substantial, though molecularly not defined, paracellular chloride reabsorption, we suggest that claudin-17 has a unique physiological function in this process. In conclusion, claudin-17 forms channels within tight junctions with distinct anion preference. Content Type Journal Article Category Research Article Pages 1-14 DOI 10.1007/s00018-012-0949-x Authors Susanne M. Krug, Institute of Clinical Physiology, Campus Benjamin Franklin, Charité, Freie Universität and Humboldt Universität, Hindenburgdamm 30, 12203 Berlin, Germany Dorothee Günzel, Institute of Clinical Physiology, Campus Benjamin Franklin, Charité, Freie Universität and Humboldt Universität, Hindenburgdamm 30, 12203 Berlin, Germany Marcel P. Conrad, Institute of Clinical Physiology, Campus Benjamin Franklin, Charité, Freie Universität and Humboldt Universität, Hindenburgdamm 30, 12203 Berlin, Germany Rita Rosenthal, Institute of Clinical Physiology, Campus Benjamin Franklin, Charité, Freie Universität and Humboldt Universität, Hindenburgdamm 30, 12203 Berlin, Germany Anja Fromm, Institute of Clinical Physiology, Campus Benjamin Franklin, Charité, Freie Universität and Humboldt Universität, Hindenburgdamm 30, 12203 Berlin, Germany Salah Amasheh, Institute of Clinical Physiology, Campus Benjamin Franklin, Charité, Freie Universität and Humboldt Universität, Hindenburgdamm 30, 12203 Berlin, Germany Jörg D. Schulzke, Division of Nutritional Medicine, Department of Gastroenterology, Campus Benjamin Franklin, Charité, Freie Universität and Humboldt Universität, Hindenburgdamm 30, 12203 Berlin, Germany Michael Fromm, Institute of Clinical Physiology, Campus Benjamin Franklin, Charité, Freie Universität and Humboldt Universität, Hindenburgdamm 30, 12203 Berlin, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    In wound healing and development, large epithelial sheets migrate collectively, in defined directions, and maintain tight cell–cell adhesion. This type of movement ensures an essential function of epithelia, a barrier, which is lost when cells lose connection and move in isolation. Unless wounded, epithelial sheets in cultures normally do not have overall directional migration. Cell migration is mostly studied when cells are in isolation and in the absence of mature cell–cell adhesion; the mechanisms of the migration of epithelial sheets are less well understood. We used small electric fields (EFs) as a directional cue to instigate and guide migration of epithelial sheets. Significantly, cells in monolayer migrated far more efficiently and directionally than cells in isolation or smaller cell clusters. We demonstrated for the first time the group size-dependent directional migratory response in several types of epithelial cells. Gap junctions made a minimal contribution to the directional collective migration. Breaking down calcium-dependent cell–cell adhesion significantly reduced directional sheet migration. Furthermore, E-cadherin blocking antibodies abolished migration of cell sheets. Traction force analysis revealed an important role of forces that cells in the leading rows exert on the substratum. With EF, the traction forces of the leading edge cells coordinated in directional re-orientation. Our study thus identifies a novel mechanism—E-cadherin dependence and coordinated traction forces of leading cells in collective directional migration of large epithelial sheets. Content Type Journal Article Category Research Article Pages 1-11 DOI 10.1007/s00018-012-0951-3 Authors Li Li, Department of Dermatology, School of Medicine, Institute for Regenerative Cures, University of California at Davis, Suite 1630, 2921 Stockton Blvd., Room 1617, Sacramento, CA 95817, USA Robert Hartley, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD UK Bjoern Reiss, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD UK Yaohui Sun, Department of Dermatology, School of Medicine, Institute for Regenerative Cures, University of California at Davis, Suite 1630, 2921 Stockton Blvd., Room 1617, Sacramento, CA 95817, USA Jin Pu, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD UK Dan Wu, Department of Physics and Astronomy, University of Manitoba, Winnipeg, MB R3T 2N2, Canada Francis Lin, Department of Physics and Astronomy, University of Manitoba, Winnipeg, MB R3T 2N2, Canada Trung Hoang, Department of Biomedical Engineering, University of California at Davis, Davis, CA 95616, USA Soichiro Yamada, Department of Biomedical Engineering, University of California at Davis, Davis, CA 95616, USA Jianxin Jiang, State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042 China Min Zhao, Department of Dermatology, School of Medicine, Institute for Regenerative Cures, University of California at Davis, Suite 1630, 2921 Stockton Blvd., Room 1617, Sacramento, CA 95817, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Heart disease is one of the leading causes of death worldwide and the number of patients with the disease is likely to grow with the continual decline in health for most of the developed world. Heart transplantation is one of the only treatment options for heart failure due to an acute myocardial infarction, but limited donor supply and organ rejection limit its widespread use. Cellular cardiomyoplasty, or cellular implantation, combined with various tissue-engineering methods aims to regenerate functional heart tissue. This review highlights the numerous cell sources that have been used to regenerate the heart as well as cover the wide range of tissue-engineering strategies that have been devised to optimize the delivery of these cells. It will probably be a long time before an effective regenerative therapy can make a serious impact at the bedside. Content Type Journal Article Category Review Pages 1-22 DOI 10.1007/s00018-012-0942-4 Authors Andre Alcon, Yale University School of Medicine, Yale University, New Haven, CT, USA Esra Cagavi Bozkulak, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale Stem Cell Center, Yale School of Medicine, Yale University, 300 George Street, Suite 773A, New Haven, CT 06520, USA Yibing Qyang, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale Stem Cell Center, Yale School of Medicine, Yale University, 300 George Street, Suite 773A, New Haven, CT 06520, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Sex chromosome inactivation in male germ cells is a paradigm of epigenetic programming during sexual reproduction. Recent progress has revealed the underlying mechanisms of sex chromosome inactivation in male meiosis. The trigger of chromosome-wide silencing is activation of the DNA damage response (DDR) pathway, which is centered on the mediator of DNA damage checkpoint 1 (MDC1), a binding partner of phosphorylated histone H2AX (γH2AX). This DDR pathway shares features with the somatic DDR pathway recognizing DNA replication stress in the S phase. Additionally, it is likely to be distinct from the DDR pathway that recognizes meiosis-specific double-strand breaks. This review article extensively discusses the underlying mechanism of sex chromosome inactivation. Content Type Journal Article Category Review Pages 1-14 DOI 10.1007/s00018-012-0941-5 Authors Yosuke Ichijima, Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA Ho-Su Sin, Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA Satoshi H. Namekawa, Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Chromogranin A (CgA), a secretory protein expressed by many neuroendocrine cells, neurons, cardiomyocytes, and keratinocytes, is the precursor of various peptides that regulate the carbohydrate/lipid metabolism and the cardiovascular system. We have found that CgA, locally administered to injured mice, can accelerate keratinocyte proliferation and wound healing. This biological activity was abolished by the Asp 45 Glu mutation. CgA and its N-terminal fragments, but not the corresponding Asp 45 Glu mutants, could selectively recognize the αvβ6-integrin on keratinocytes (a cell-adhesion receptor that is up-regulated during wound healing) and regulate keratinocyte adhesion, proliferation, and migration. No binding was observed to other integrins such as αvβ3, αvβ5, αvβ8, α5β1, α1β1, α3β1, α6β4, α6β7 and α9β1. Structure–activity studies showed that the entire CgA 39–63 region is crucial for αvβ6 recognition ( K i  = 7 nM). This region contains an RGD site (residues CgA 43–45 ) followed by an amphipathic α-helix (residues CgA 47–63 ), both crucial for binding affinity and selectivity. These results suggest that the interaction of the RGD/α-helix motif of CgA with αvβ6 regulates keratinocyte physiology in wound healing. Content Type Journal Article Category Research Article Pages 1-13 DOI 10.1007/s00018-012-0955-z Authors Flavio Curnis, Division of Molecular Oncology and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy Anna Maria Gasparri, Division of Molecular Oncology and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy Renato Longhi, Istituto di Chimica del Riconoscimento Molecolare, CNR, 20131 Milan, Italy Barbara Colombo, Division of Molecular Oncology and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy Silvia D’Alessio, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy Fabio Pastorino, Laboratory of Oncology, Experimental Therapy Unit, G. Gaslini Children’s Hospital, 16148 Genoa, Italy Mirco Ponzoni, Laboratory of Oncology, Experimental Therapy Unit, G. Gaslini Children’s Hospital, 16148 Genoa, Italy Angelo Corti, Division of Molecular Oncology and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The cerebrospinal fluid (CSF) has attracted renewed interest as an active signaling milieu that regulates brain development, homeostasis, and disease. Advances in proteomics research have enabled an improved characterization of the CSF from development through adulthood, and key neurogenic signaling pathways that are transmitted via the CSF are now being elucidated. Due to its immediate contact with neural stem cells in the developing and adult brain, the CSF’s ability to swiftly distribute signals across vast distances in the central nervous system is opening avenues to novel and exciting therapeutic approaches. In this review, we will discuss the development of the choroid plexus-CSF system, and review the current literature on how the CSF actively regulates mammalian brain development, behavior, and responses to traumatic brain injury. Content Type Journal Article Category Review Pages 1-16 DOI 10.1007/s00018-012-0957-x Authors Mauro W. Zappaterra, Department of Physical Medicine and Rehabilitation, VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd, Los Angeles, CA 90073, USA Maria K. Lehtinen, Department of Pathology, Children’s Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    In addition to its central roles in protein quality control, regulation of cell cycle, intracellular signaling, DNA damage response and transcription regulation, the ubiquitin–proteasome system (UPS) plays specific roles in the nervous system, where it contributes to precise connectivity through development, and later assures functionality by regulating a wide spectrum of neuron-specific cellular processes. Aberrations in this system have been implicated in the etiology of neurodevelopmental and neurodegenerative diseases. In this review, we provide an updated view on the UPS and highlight recent findings concerning its role in normal and diseased nervous systems. We discuss the advantages of the model organism Caenorhabditis elegans as a tool to unravel the major unsolved questions concerning this biochemical pathway and its involvement in nervous system function and dysfunction, and expose the new possibilities, using state-of-the-art techniques, to assess UPS function using this model system. Content Type Journal Article Category Review Pages 1-25 DOI 10.1007/s00018-012-0946-0 Authors Márcio S. Baptista, Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal Carlos B. Duarte, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal Patrícia Maciel, Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    microRNAs (miRNAs) are small, stable RNA molecules that post-transcriptionally regulate gene expression in plants and animals by base pairing to partially complementary sequences on target mRNAs to inhibit protein synthesis. More than 250 miRNAs are reportedly expressed in the retina, and miRNA gene regulation has been shown to affect retinal development, function, and disease. Here we highlight recent advances in understanding the functional roles of vertebrate retinal miRNAs. Details are emerging about the physiological impact of specific miRNAs in the developing and mature retina, and we discuss a group of emerging technologies for studying miRNAs, which can be employed to yield a deeper understanding of retinal miRNA gene regulation. Content Type Journal Article Category Review Pages 1-12 DOI 10.1007/s00018-012-0976-7 Authors Thomas R. Sundermeier, Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106-4965, USA Krzysztof Palczewski, Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106-4965, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Homeostasis in the immune system encompasses the mechanisms governing maintenance of a functional and diverse pool of lymphocytes, thus guaranteeing immunity to pathogens while remaining self-tolerant. Antigen-naïve T cells rely on survival signals through contact with self-peptide-loaded major histocompatibility complex (MHC) molecules plus interleukin (IL)-7. Conversely, antigen-experienced (memory) T cells are typically MHC-independent and they survive and undergo periodic homeostatic proliferation through contact with both IL-7 and IL-15. Also, non-conventional γδ T cells rely on a mix of IL-7 and IL-15 for their homeostasis, whereas natural killer cells are mainly dependent on contact with IL-15. Homeostasis of CD4 + T regulatory cells is different in being chiefly regulated by contact with IL-2. Notably, increased levels of these cytokines cause expansion of responsive lymphocytes, such as found in lymphopenic hosts or following cytokine injection, whereas reduced cytokine levels cause a decline in cell numbers. Content Type Journal Article Category Multi-author review Pages 1-12 DOI 10.1007/s00018-012-0968-7 Authors Onur Boyman, Allergy Unit, Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland Carsten Krieg, Allergy Unit, Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland Dirk Homann, Departments of Pediatrics, Immunology and Microbiology, Barbara Davis Center, University of Colorado Denver, M20-3202D, 1775 Aurora Court, Aurora, CO 80010, USA Jonathan Sprent, Immunology Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The discovery of discontiguous tRNA genes triggered studies dissecting the process of tRNA splicing. As a result, we have gained detailed mechanistic knowledge on enzymatic removal of tRNA introns catalyzed by endonuclease and ligase proteins. In addition to the elucidation of tRNA processing, these studies facilitated the discovery of additional functions of RNA ligases such as RNA repair and non-conventional mRNA splicing events. Recently, the identification of a new type of RNA ligases in bacteria, archaea, and humans closed a long-standing gap in the field of tRNA processing. This review summarizes past and recent findings in the field of tRNA splicing with a focus on RNA ligation as it preferentially occurs in archaea and humans. In addition to providing an integrated view of the types and phyletic distribution of RNA ligase proteins known to date, this survey also aims at highlighting known and potential accessory biological functions of RNA ligases. Content Type Journal Article Category Review Pages 1-14 DOI 10.1007/s00018-012-0944-2 Authors Johannes Popow, Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Dr. Bohrgasse 3, 1030 Vienna, Austria Alexander Schleiffer, Bioinformatics Department, Research Institute of Molecular Pathology (IMP)–IMBA, Dr. Bohrgasse 7, 1030 Vienna, Austria Javier Martinez, Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Dr. Bohrgasse 3, 1030 Vienna, Austria Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The epidermis and its appendages, such as the hair follicle (HF), continually regenerate throughout postnatal mammalian life due to the activity of resident epithelial stem cells (SCs). The follicular SC niche, or the bulge, is composed of a heterogeneous population of self-renewing multipotent cells. Multiple intrinsic molecular mechanisms promote the transition of follicular SCs from quiescence to activation. In addition, numerous extrinsic cell types influence the activity and characteristics of bulge cells. Ultimately, the balance between these intrinsic and extrinsic mechanisms influences the function of bulge cells during homeostasis and tissue regeneration and likely contributes to skin tumorigenesis. Here, we review both the intrinsic and extrinsic factors that contribute to the skin SC niche. Content Type Journal Article Category Review Pages 1-10 DOI 10.1007/s00018-012-0943-3 Authors Jill Goldstein, Molecular Cell Biology, Genetics and Development Program, Yale University, 219 Prospect St., Box 208103, New Haven, CT 06520, USA Valerie Horsley, Department of Molecular, Cell and Developmental Biology, Yale University, 219 Prospect St., Box 208103, New Haven, CT 06520, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The non-coding microRNA (miRNA) is involved in the regulation of hepatitis C virus (HCV) infection and offers an alternative target for developing anti-HCV agent. In this study, we aim to identify novel cellular miRNAs that directly target the HCV genome with anti-HCV therapeutic potential. Bioinformatic analyses were performed to unveil liver-abundant miRNAs with predicted target sequences on HCV genome. Various cell-based systems confirmed that let-7b plays a negative role in HCV expression. In particular, let-7b suppressed HCV replicon activity and down-regulated HCV accumulation leading to reduced infectivity of HCVcc. Mutational analysis identified let-7b binding sites at the coding sequences of NS5B and 5′-UTR of HCV genome that were conserved among various HCV genotypes. We further demonstrated that the underlying mechanism for let-7b-mediated suppression of HCV RNA accumulation was not dependent on inhibition of HCV translation. Let-7b and IFNα-2a also elicited a synergistic inhibitory effect on HCV infection. Together, let-7b represents a novel cellular miRNA that targets the HCV genome and elicits anti-HCV activity. This study thereby sheds new insight into understanding the role of host miRNAs in HCV pathogenesis and to developing a potential anti-HCV therapeutic strategy. Content Type Journal Article Category Research Article Pages 1-13 DOI 10.1007/s00018-012-0940-6 Authors Ju-Chien Cheng, Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, 404 Taiwan, ROC Yung-Ju Yeh, Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, 404 Taiwan, ROC Ching-Ping Tseng, Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan, ROC Sheng-Da Hsu, Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, 300 Taiwan, ROC Yu-Ling Chang, Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, 404 Taiwan, ROC Naoya Sakamoto, Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan Hsien-Da Huang, Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, 300 Taiwan, ROC Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Microarray technology outgrew the detection of simple intermolecular interactions, as incubation of slides with living cells opened new vistas. Cell-based array technology permits simultaneous detection of several different cell surface molecules, allowing the complex characterization of cells with an amount of information that is hardly assessed by any other technique. Furthermore, binding of cells to printed antibodies or ligands may induce their activation, and consequently the outcome of these interactions, such as phosphorylation, gene expression, secretion of various products; differentiation, proliferation and apoptosis of the cells are also measurable on arrays. Moreover, since cells can be transfected with printed vectors, over- or under-expression of selected genes is also achievable simultaneously, creating a nice tool for assessing the function of a given gene. The enormously high-throughput cell-based microarray technology enables testing the effect of external stimuli on a scale that was earlier unthinkable. This review summarizes the possible applications of cell-based arrays. Content Type Journal Article Category Review Pages 1-9 DOI 10.1007/s00018-012-0947-z Authors Krisztián Papp, Immunology Research Group, Hungarian Academy of Sciences, MTA-ELTE, Pázmány P.s. 1/C, Budapest, 1117 Hungary Zoltán Szittner, Diagnosticum Ltd., Attila u. 126, Budapest, 1047 Hungary József Prechl, Immunology Research Group, Hungarian Academy of Sciences, MTA-ELTE, Pázmány P.s. 1/C, Budapest, 1117 Hungary Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Gap junction channels link cytoplasms of adjacent cells. Connexins, their constitutive proteins, are essential in cell homeostasis and are implicated in numerous physiological processes. Spermatogenesis is a sophisticated model of germ cell proliferation, differentiation, survival, and apoptosis, in which a connexin isotype, connexin 43, plays a crucial role as evidenced by genomic approaches based on gene deletion. The balance between cell proliferation/differentiation/apoptosis is a prerequisite for maintaining levels of spermatozoa essential for fertility and for limiting anarchic cell proliferation, a major risk of testis tumor. The present review highlights the emerging role of connexins in testis pathogenesis, focusing specifically on two intimately interconnected human testicular diseases (azoospermia with impaired spermatogenesis and testicular germ cell tumors), whose incidence increased during the last decades. This work proposes connexin 43 as a potential cancer diagnostic and prognostic marker, as well as a promising therapeutic target for testicular diseases. Content Type Journal Article Category Review Pages 1-14 DOI 10.1007/s00018-012-1121-3 Authors Daniel Chevallier, Department of Urology, Pasteur Hospital, Nice, France Diane Carette, UMR S775, University Paris Descartes, 45 rue des Saints Pères, Paris, 75006 France Dominique Segretain, UMR S775, University Paris Descartes, 45 rue des Saints Pères, Paris, 75006 France Jérome Gilleron, INSERM U 1065, Team 5 “Physiopathologic Control of Germ Cell Proliferation: Genomic and Non Genomic Mechanisms”, University Nice Sophia-Antipolis, C3M, 151 route Saint-Antoine de Ginestière BP 2 3194, Nice Cedex 3, 06204 France Georges Pointis, INSERM U 1065, Team 5 “Physiopathologic Control of Germ Cell Proliferation: Genomic and Non Genomic Mechanisms”, University Nice Sophia-Antipolis, C3M, 151 route Saint-Antoine de Ginestière BP 2 3194, Nice Cedex 3, 06204 France Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Sarcomas are a heterogeneous group of tumors with mesenchymal origins. Sarcomas are broadly classified into bone and soft tissue sarcomas with over 50 subtypes. Despite recent advances in sarcoma classification and treatment strategies, the prognosis of some aggressive sarcoma types remains poor due to treatment infectiveness and development of drug resistance. A better understanding of sarcoma pathobiology will significantly increase the potential for the development of therapeutics and treatment strategies. Recently, expressions of microRNAs (miRNA), a class of small non-coding RNAs, have been found to be deregulated in many sarcomas and are implicated in sarcoma pathobiology. Comprehensive understanding of gene regulatory networks mediated by miRNAs in each sarcoma type and the conservation of some shared/conserved miRNA-gene networks could be potentially investigated in the prevention, diagnosis, prognosis and as multi-modal treatment options in these cancers. In this review, we will discuss the current knowledge of miRNA–gene regulatory networks in various sarcoma types and give a perspective of the complex multilayer miRNA-mediated gene regulation in sarcomas. Content Type Journal Article Category Multi-author review Pages 1-15 DOI 10.1007/s00018-012-1127-x Authors Subbaya Subramanian, Department of Surgery, University of Minnesota, 11-212 Moos Tower (Mail Code: MMC 195), 515 Delaware St, S.E, Minneapolis, MN 55455, USA Reena V. Kartha, Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description: MicroRNA regulatory networks and human disease Content Type Journal Article Category Multi-author review Pages 1-3 DOI 10.1007/s00018-012-1123-1 Authors Yin-Yuan Mo, University of Mississippi Medical Center, Cancer Institute, Jackson, MS, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The molecular features that dominate the binding mode of agonists by a broadly tuned olfactory receptor are analyzed through a joint approach combining cell biology, calcium imaging, and molecular modeling. The odorant/receptor affinities, estimated through statistics accrued during molecular dynamics simulations, are in accordance with the experimental ranking. Although in many systems receptors recognize their target through a network of oriented interactions, such as H-bonding, the binding by broadly tuned olfactory receptors is dominated by non-polar terms. We show how such a feature allows chemicals belonging to different chemical families to similarly activate the receptors through compensations of interactions within the binding site. Content Type Journal Article Category Research article Pages 1-9 DOI 10.1007/s00018-012-1116-0 Authors Landry Charlier, Institut de Chimie de Nice, UMR CNRS, Université de Nice Sophia Antipolis 7272, 06108 Nice Cedex 2, France Jérémie Topin, Institut de Chimie de Nice, UMR CNRS, Université de Nice Sophia Antipolis 7272, 06108 Nice Cedex 2, France Catherine Ronin, Laboratoire de Neuroglycobiologie, GLM, CNRS, 31 Ch. J. Aiguier, 13402 Marseille, France Soo-Kyung Kim, Materials and Process Simulation Center (MC139-74), California Institute of Technology, 1200 E. California Blvd., Pasadena, CA 91125, USA William A. Goddard III, Materials and Process Simulation Center (MC139-74), California Institute of Technology, 1200 E. California Blvd., Pasadena, CA 91125, USA Roman Efremov, Laboratory of Biomolecular Modeling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, 117997 Moscow, Russia Jérôme Golebiowski, Institut de Chimie de Nice, UMR CNRS, Université de Nice Sophia Antipolis 7272, 06108 Nice Cedex 2, France Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Cardiac hypertrophy is an adaptive enlargement of the myocardium in response to altered stress or injury. The cellular responses of cardiomyocytes and non-cardiomyocytes to various signaling pathways should be tightly and delicately regulated to maintain cardiac homeostasis and prevent pathological cardiac hypertrophy. MicroRNAs (miRNAs) are endogenous, single-stranded, short non-coding RNAs that act as regulators of gene expression by promoting the degradation or inhibiting the translation of target mRNAs. Recent studies have revealed expression signatures of miRNAs associated with pathological cardiac hypertrophy and heart failure in humans and mouse models of heart diseases. Increasing evidence indicates that dysregulation of specific miRNAs could alter the cellular responses of cardiomyocytes and non-cardiomyocytes to specific signaling upon the pathological hemodynamic overload, leading to cardiac hypertrophy and heart failure. This review summarizes the cell-autonomous functions of cardiomyocyte miRNAs regulated by different pathways and the roles of non-cardiomyocyte miRNAs in cardiac hypertrophy. The therapeutic effects of a number of miRNAs in heart diseases are also discussed. Content Type Journal Article Category Multi-author review Pages 1-10 DOI 10.1007/s00018-012-1126-y Authors Jian Wang, State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, 20 Dongdajie, 100071 Beijing, China Xiao Yang, State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, 20 Dongdajie, 100071 Beijing, China Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Pentameric ligand-gated ion channel (pLGIC) receptors exhibit desensitization, the progressive reduction in ionic flux in the prolonged presence of agonist. Despite its pathophysiological importance and the fact that it was first described over half a century ago, surprisingly little is known about the structural basis of desensitization in this receptor family. Here, we explain how desensitization is defined using functional criteria. We then review recent progress into reconciling the structural and functional basis of this phenomenon. The extracellular–transmembrane domain interface is a key locus. Activation is well known to involve conformational changes at this interface, and several lines of evidence suggest that desensitization involves a distinct conformational change here that is incompatible with activation. However, major questions remain unresolved, including the structural basis of the desensitization-induced agonist affinity increase and the mechanism of pore closure during desensitization. Content Type Journal Article Category Review Pages 1-13 DOI 10.1007/s00018-012-1133-z Authors Angelo Keramidas, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia Joseph W. Lynch, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Tubulin cofactors (TBCs) participate in the folding, dimerization, and dissociation pathways of the tubulin dimer. Among them, TBCB and TBCE are two CAP-Gly domain-containing proteins that together efficiently interact with and dissociate the tubulin dimer. In the study reported here we showed that TBCB localizes at spindle and midzone microtubules during mitosis. Furthermore, the motif DEI/M-COO − present in TBCB, which is similar to the EEY/F-COO − element characteristic of EB proteins, CLIP-170, and α-tubulin, is required for TBCE–TBCB heterodimer formation and thus for tubulin dimer dissociation. This motif is responsible for TBCB autoinhibition, and our analysis suggests that TBCB is a monomer in solution. Mutants of TBCB lacking this motif are derepressed and induce microtubule depolymerization through an interaction with EB1 associated with microtubule tips. TBCB is also able to bind to the chaperonin complex CCT containing α-tubulin, suggesting that it could escort tubulin to facilitate its folding and dimerization, recycling or degradation. Content Type Journal Article Category Research article Pages 1-15 DOI 10.1007/s00018-012-1114-2 Authors Gerardo Carranza, Departamento de Biología Molecular, Facultad de Medicina, IFIMAV-Universidad de Cantabria, 39011 Santander, Spain Raquel Castaño, Departamento de Biología Molecular, Facultad de Medicina, IFIMAV-Universidad de Cantabria, 39011 Santander, Spain Mónica L. Fanarraga, Departamento de Biología Molecular, Facultad de Medicina, IFIMAV-Universidad de Cantabria, 39011 Santander, Spain Juan Carlos Villegas, Departamento de Anatomía y Biología Celular, Facultad de Medicina, IFIMAV-Universidad de Cantabria, 39011 Santander, Spain João Gonçalves, Centro de Química eBioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisbon, Portugal Helena Soares, Centro de Química eBioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisbon, Portugal Jesus Avila, Centro de Biología Molecular (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Cantoblanco, Madrid, Spain Marco Marenchino, Spectroscopy and NMR Unit, Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), Melchor Fdez. Almagro 3, 28029 Madrid, Spain Ramón Campos-Olivas, Spectroscopy and NMR Unit, Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), Melchor Fdez. Almagro 3, 28029 Madrid, Spain Guillermo Montoya, Macromolecular Crystallography Group, Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), Melchor Fdez. Almagro 3, 28029 Madrid, Spain Juan Carlos Zabala, Departamento de Biología Molecular, Facultad de Medicina, IFIMAV-Universidad de Cantabria, 39011 Santander, Spain Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Tumor cell migration is essential for invasion and dissemination from primary solid tumors and for the establishment of lethal secondary metastases at distant organs. In vivo and in vitro models enabled identification of different factors in the tumor microenvironment that regulate tumor progression and metastasis. However, the mechanisms by which tumor cells integrate these chemical and mechanical signals from multiple sources to navigate the complex microenvironment remain poorly understood. In this review, we discuss the factors that influence tumor cell migration with a focus on the migration of transformed carcinoma cells. We provide an overview of the experimental and computational methods that allow the investigation of tumor cell migration, and we highlight the benefits and shortcomings of the various assays. We emphasize that the chemical and mechanical stimulus paradigms are not independent and that crosstalk between them motivates the development of new assays capable of applying multiple, simultaneous stimuli and imaging the cellular migratory response in real-time. These next-generation assays will more closely mimic the in vivo microenvironment to provide new insights into tumor progression, inform techniques to control tumor cell migration, and render cancer more treatable. Content Type Journal Article Category Review Pages 1-22 DOI 10.1007/s00018-012-1115-1 Authors William J. Polacheck, Department of Mechanical Engineering, MIT, 77 Massachusetts Ave. Room NE47-315, Cambridge, MA 02139, USA Ioannis K. Zervantonakis, Department of Mechanical Engineering, MIT, 77 Massachusetts Ave. Room NE47-319, Cambridge, MA 02139, USA Roger D. Kamm, Departments of Mechanical Engineering and Biological Engineering, MIT, 77 Massachusetts Ave. Room NE47-321, Cambridge, MA 02139, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The emerging role of microRNAs (miRNAs) in the epigenetic regulation of many cellular processes has become recognized in both basic research and translational medicine as an important way that gene expression can be fine-tuned. Breast cancer is the most frequent cancer in women, with about one million new cases diagnosed each year worldwide. Starting with the early work of miRNA profiling, more effort has now been put on functions of miRNAs in normal mammary stem cells, breast cancer initiating cells and metastatic cells, and therapy-resistant cancer cells. Future translational studies may focus on identifying miRNA signatures as cancer biomarkers and developing miRNA-based targeted therapeutics. Content Type Journal Article Category Multi-author review Pages 1-13 DOI 10.1007/s00018-012-1128-9 Authors Huiping Liu, The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Integrin-mediated cytoskeletal tension supports growth-factor-induced proliferation, and disruption of the actin cytoskeleton in growth factor-stimulated cells prevents the re-expression of cyclin D and cell cycle re-entry from quiescence. In contrast to cells that enter the cell cycle from G0, cycling cells continuously express cyclin D, and are subject to major cell shape changes during the cell cycle. Here, we investigated the cell cycle requirements for cytoskeletal tension and cell spreading in cycling mammalian cells that enter G1-phase from mitosis. Disruption of the actin cytoskeleton at progressive time-points in G1-phase induced cell rounding, FA disassembly, and attenuated both integrin signaling and growth factor-induced p44/p42 mitogen-activated protein kinase activation. Although cyclin D expression was reduced, the expression of cyclin A and entry into S-phase were not affected. Moreover, expression of cyclin B1, progression through G2- and M-phase, and commitment to a new cell cycle occurred normally. In contrast, cell cycle progression was strongly prevented by inhibition of MAPK activity in G1-phase, whereas cell spreading, cytoskeletal organization, and integrin signaling were not impaired. MAPK inhibition also prevented cytoskeleton-independent cell cycle progression. Thus, these results uncouple the requirements for cell spreading and cytoskeletal organization from MAPK signaling, and show that cycling mammalian cells can proliferate independently of actin stress fibers, focal adhesions, or cell spreading, as long as a threshold level of MAPK activity is sustained. Content Type Journal Article Category Research Article Pages 1-15 DOI 10.1007/s00018-012-1130-2 Authors Coert Margadant, Department of Cell Biology, Faculty of Sciences, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands Lobke Cremers, Department of Cell Biology, Faculty of Sciences, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands Arnoud Sonnenberg, Department of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands Johannes Boonstra, Department of Cell Biology, Faculty of Sciences, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The efficient transport of blood and lymph relies on competent intraluminal valves that ensure unidirectional fluid flow through the vessels. In the lymphatic vessels, lack of luminal valves causes reflux of lymph and can lead to lymphedema, while dysfunction of venous valves is associated with venous hypertension, varicose veins, and thrombosis that can lead to edema and ulcerations. Despite their clinical importance, the mechanisms that regulate valve formation are poorly understood and have only recently begun to be characterized. Here, we discuss new findings regarding the development of venous and lymphatic valves that indicate the involvement of common molecular mechanisms in regulating valve formation in different vascular beds. Content Type Journal Article Category Review Pages 1-12 DOI 10.1007/s00018-012-1110-6 Authors Eleni Bazigou, Lymphatic Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London, WC2A 3LY UK Taija Makinen, Lymphatic Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London, WC2A 3LY UK Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The in vivo roles of meprin metalloproteases in pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human meprin α and β we employed TAILS (terminal amine isotopic labeling of substrates), a proteomics approach that enriches for N-terminal peptides of proteins and cleavage fragments. Of the 151 new extracellular substrates we identified, it was notable that ADAM10 (a disintegrin and metalloprotease domain-containing protein 10)—the constitutive α-secretase—is activated by meprin β through cleavage of the propeptide. To validate this cleavage event, we expressed recombinant proADAM10 and after preincubation with meprin β, this resulted in significantly elevated ADAM10 activity. Cellular expression in murine primary fibroblasts confirmed activation. Other novel substrates including extracellular matrix proteins, growth factors and inhibitors were validated by western analyses and enzyme activity assays with Edman sequencing confirming the exact cleavage sites identified by TAILS. Cleavages in vivo were confirmed by comparing wild-type and meprin −/− mice. Our finding of cystatin C, elafin and fetuin-A as substrates and natural inhibitors for meprins reveal new mechanisms in the regulation of protease activity important for understanding pathophysiological processes. Content Type Journal Article Category Research Article Pages 1-25 DOI 10.1007/s00018-012-1106-2 Authors Tamara Jefferson, Institute of Biochemistry, Christian-Albrechts-University, 24118 Kiel, Germany Ulrich auf dem Keller, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich, ETH Hoenggerberg, HPM D24, Zurich, Switzerland Caroline Bellac, Departments of Oral Biological and Medical Sciences and Biochemistry and Molecular Biology, Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada Verena V. Metz, Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University, Mainz, Germany Claudia Broder, Institute of Biochemistry, Christian-Albrechts-University, 24118 Kiel, Germany Jana Hedrich, Institute of Physiology and Pathophysiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany Anke Ohler, Cell and Matrix Biology, Johannes Gutenberg University, Mainz, Germany Wladislaw Maier, Institute of Pathobiochemistry, University Medical Center, Johannes Gutenberg-University, Mainz, Germany Viktor Magdolen, Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of Munich, Munich, Germany Erwin Sterchi, Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland Judith S. Bond, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA Arumugam Jayakumar, Department of Experimental Therapeutics, M.D. Anderson Cancer Center, The University of Texas, Houston, TX, USA Heiko Traupe, Department of Dermatology, University Hospital Münster, Münster, Germany Athena Chalaris, Institute of Biochemistry, Christian-Albrechts-University, 24118 Kiel, Germany Stefan Rose-John, Institute of Biochemistry, Christian-Albrechts-University, 24118 Kiel, Germany Claus U. Pietrzik, Institute of Pathobiochemistry, University Medical Center, Johannes Gutenberg-University, Mainz, Germany Rolf Postina, Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University, Mainz, Germany Christopher M. Overall, Departments of Oral Biological and Medical Sciences and Biochemistry and Molecular Biology, Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada Christoph Becker-Pauly, Institute of Biochemistry, Christian-Albrechts-University, 24118 Kiel, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Prion diseases are fatal transmissible neurodegenerative diseases, characterized by aggregation of the pathological form of prion protein, spongiform degeneration, and neuronal loss, and activation of astrocytes and microglia. Microglia can clear prion plaques, but on the other hand cause neuronal death via release of neurotoxic species. Elevated expression of the proinflammatory cytokine IL-1β has been observed in brains affected by several prion diseases, and IL-1R-deficiency significantly prolonged the onset of the neurodegeneration in mice. We show that microglial cells stimulated by prion protein (PrP) fibrils induced neuronal toxicity. Microglia and macrophages release IL-1β upon stimulation by PrP fibrils, which depends on the NLRP3 inflammasome. Activation of NLRP3 inflammasome by PrP fibrils requires depletion of intracellular K + , and requires phagocytosis of PrP fibrils and consecutive lysosome destabilization. Among the well-defined molecular forms of PrP, the strongest NLRP3 activation was observed by fibrils, followed by aggregates, while neither native monomeric nor oligomeric PrP were able to activate the NLRP3 inflammasome. Our results together with previous studies on IL-1R-deficient mice suggest the IL-1 signaling pathway as the perspective target for the therapy of prion disease. Content Type Journal Article Category Research article Pages 1-14 DOI 10.1007/s00018-012-1140-0 Authors Iva Hafner-Bratkovič, Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia Mojca Benčina, Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia Katherine A. Fitzgerald, Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, 55 Lake Avenue North, 01605 Worcester, MA, USA Douglas Golenbock, Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, 55 Lake Avenue North, 01605 Worcester, MA, USA Roman Jerala, Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Somatic cell reprogramming consists of the induction of a complex sequence of events that results in the modification of the developmental state of the cell. It is now routinely possible to reprogram fully differentiated cells back to pluripotent cells, and to transdifferentiate cells of a given type in cells of a totally different lineage origin. However, whether there are key initiating factors that are distinct from those that control stem-cell renewal and that can initiate the reprogramming process remains unknown. In contrast, what is clear is that, by modifying the epigenetic status of a cell, its reprogramming can be initiated. Here, we review the current literature that shows how the plasticity of a cell can be modulated by modifying its epigenetic status, and we discuss how epigenetic barriers can be removed, to induce an efficient reprogramming process. Content Type Journal Article Category Review Pages 1-12 DOI 10.1007/s00018-012-1137-8 Authors Frederic Lluis, Centre for Genomic Regulation (CRG) and UPF, Dr. Aiguader, 88, 08003 Barcelona, Spain Maria Pia Cosma, Centre for Genomic Regulation (CRG) and UPF, Dr. Aiguader, 88, 08003 Barcelona, Spain Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The double-stranded RNA binding domain (dsRBD) is a small protein domain of 65–70 amino acids adopting an αβββα fold, whose central property is to bind to double-stranded RNA (dsRNA). This domain is present in proteins implicated in many aspects of cellular life, including antiviral response, RNA editing, RNA processing, RNA transport and, last but not least, RNA silencing. Even though proteins containing dsRBDs can bind to very specific dsRNA targets in vivo, the binding of dsRBDs to dsRNA is commonly believed to be shape-dependent rather than sequence-specific. Interestingly, recent structural information on dsRNA recognition by dsRBDs opens the possibility that this domain performs a direct readout of RNA sequence in the minor groove, allowing a global reconsideration of the principles describing dsRNA recognition by dsRBDs. We review in this article the current structural and molecular knowledge on dsRBDs, emphasizing the intricate relationship between the amino acid sequence, the structure of the domain and its RNA recognition capacity. We especially focus on the molecular determinants of dsRNA recognition and describe how sequence discrimination can be achieved by this type of domain. Content Type Journal Article Category Review Pages 1-21 DOI 10.1007/s00018-012-1119-x Authors Grégoire Masliah, Institute of Molecular Biology and Biophysics, ETH Zurich, Schafmattstrasse 20, 8093 Zürich, Switzerland Pierre Barraud, Institute of Molecular Biology and Biophysics, ETH Zurich, Schafmattstrasse 20, 8093 Zürich, Switzerland Frédéric H. -T. Allain, Institute of Molecular Biology and Biophysics, ETH Zurich, Schafmattstrasse 20, 8093 Zürich, Switzerland Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Melanoblasts are a particular type of cell that displays extensive cellular proliferation during development to contribute to the skin. There are only a few melanoblast founders, initially located just dorsal to the neural tube, and they sequentially colonize the dermis, epidermis, and hair follicles. In each compartment, melanoblasts are exposed to a wide variety of developmental cues that regulate their expansion. The colonization of the dermis and epidermis by melanoblasts involves substantial proliferation to generate thousands of cells or more from a few founders within a week of development. This review addresses the cellular and molecular events occurring during melanoblast development. We focus on intrinsic and extrinsic factors that control melanoblast proliferation. We also present a robust mathematical model for estimating the doubling-time of dermal and epidermal melanoblasts for all coat color phenotypes from black to white. Content Type Journal Article Category Review Pages 1-13 DOI 10.1007/s00018-012-1112-4 Authors Lionel Larue, Institut Curie, Centre de Recherche, Developmental Genetics of Melanocytes, 91405 Orsay, France Florian de Vuyst, Centre de Mathématiques et de leurs applications, CNRS UMR 8536, Ecole Normale Supérieure de Cachan, 94235 Cachan cedex, France Véronique Delmas, Institut Curie, Centre de Recherche, Developmental Genetics of Melanocytes, 91405 Orsay, France Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    As master gene regulators, microRNAs are involved in diverse cellular pathways. It is well known that microRNAs are often dysregulated in many types of cancer and other human diseases. In cancer, microRNAs may function as oncogenes or tumor suppressors. Interestingly, recent evidence suggests that microRNA-mediated gene regulation interconnects with the Akt pathway, forming an Akt–microRNA regulatory network. MicroRNAs and Akt in this network work together to exert their cellular functions. Thus, a better understanding of this Akt–microRNA regulatory network is critical to successful targeting of the PI3K/Akt pathway for cancer therapy. We review recent advances in the understanding of how microRNAs affect Akt activity as well as how microRNAs are regulated through the Akt pathway. We also briefly discuss the clinical implication of gene regulation mediated through Akt-associated microRNAs. Content Type Journal Article Category Multi-author review Pages 1-12 DOI 10.1007/s00018-012-1129-8 Authors Min Xu, Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001 Jiangsu, People’s Republic of China Yin-Yuan Mo, Cancer Institute, University of Mississippi Medical Center, 2500 N State St, Guyton 2, Suite G651, Jackson, MS 39216-4505, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Inteins catalyze a post-translational modification known as protein splicing, where the intein removes itself from a precursor protein and concomitantly ligates the flanking protein sequences with a peptide bond. Over the past two decades, inteins have risen from a peculiarity to a rich source of applications in biotechnology, biomedicine, and protein chemistry. In this review, we focus on developments of intein-related research spanning the last 5 years, including the three different splicing mechanisms and their molecular underpinnings, the directed evolution of inteins towards improved splicing in exogenous protein contexts, as well as novel applications of inteins for cell biology and protein engineering, which were made possible by a clearer understanding of the protein splicing mechanism. Content Type Journal Article Category Review Pages 1-22 DOI 10.1007/s00018-012-1120-4 Authors Gerrit Volkmann, Institute of Biochemistry, University of Münster, Wilhelm-Klemm-Str. 2, 48149 Münster, Germany Henning D. Mootz, Institute of Biochemistry, University of Münster, Wilhelm-Klemm-Str. 2, 48149 Münster, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    When plants are subjected to high metal exposure, different plant species take different strategies in response to metal-induced stress. Largely, plants can be distinguished in four groups: metal-sensitive species, metal-resistant excluder species, metal-tolerant non-hyperaccumulator species, and metal-hypertolerant hyperaccumulator species, each having different molecular mechanisms to accomplish their resistance/tolerance to metal stress or reduce the negative consequences of metal toxicity. Plant responses to heavy metals are molecularly regulated in a process called metal homeostasis, which also includes regulation of the metal-induced reactive oxygen species (ROS) signaling pathway. ROS generation and signaling plays an important duel role in heavy metal detoxification and tolerance. In this review, we will compare the different molecular mechanisms of nutritional (Zn) and non-nutritional (Cd) metal homeostasis between metal-sensitive and metal-adapted species. We will also include the role of metal-induced ROS signal transduction in this comparison, with the aim to provide a comprehensive overview on how plants cope with Zn/Cd stress at the molecular level. Content Type Journal Article Category Multi-author review Pages 1-20 DOI 10.1007/s00018-012-1089-z Authors Ya-Fen Lin, Laboratory of Genetics, Wageningen University, Droevendaalsesteeg 1, 6708 PB Wageningen, The Netherlands Mark G. M. Aarts, Laboratory of Genetics, Wageningen University, Droevendaalsesteeg 1, 6708 PB Wageningen, The Netherlands Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Centrosomes are organelles involved in generating and organizing the interphase microtubule cytoskeleton, mitotic spindles and cilia. At the centrosome core are a pair of centrioles, structures that act as the duplicating elements of this organelle. Centrioles function to recruit and organize pericentriolar material which nucleates microtubules. While centrioles are relatively simple in construction, the mechanics of centriole biogenesis remain an important yet poorly understood process. More mysterious still are the regulatory mechanisms that oversee centriole assembly. The fidelity of centriole duplication is critical as defects in either the assembly or number of centrioles promote aneuploidy, primary microcephaly, birth defects, ciliopathies and tumorigenesis. In addition, some pathogens employ mechanisms to promote centriole overduplication to the detriment of the host cell. This review summarizes our current understanding of this important topic, highlighting the need for further study if new therapeutics are to be developed to treat diseases arising from defects of centrosome duplication. Content Type Journal Article Category Review Pages 1-14 DOI 10.1007/s00018-012-1102-6 Authors Christopher W. Brownlee, Department of Cellular and Molecular Medicine, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA Gregory C. Rogers, Department of Cellular and Molecular Medicine, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X