A mathematical model of the stoichiometric control of Smad complex formation in TGF-B signal transducion pathway

Cell fate in multicellular organism is regulated by the diffusible factor from surrounding cells in concentration-dependent manner. TGF-beta is a large protein family of the diffusible proteins secreted from a localized source. The signal of TGF-beta is transduced by Smad family transcription factor. Though it is well known that the stoichiometry of Smads in the transcriptional complex regulates the specificity of target genes of TGF-beta signal, little is known what the stoichiometry of Smads in the transcriptional complex is determined in TGF-beta signal transduction in concentration-dependent manner. To investigate the dynamics of Smad complex formation, we construct a two-compartment model for Smad complex formation in TGF-beta signal transduction. A simplified one-way oligomerization model, which ignores dissociation and well appropriate the full model under high expression levels of R- and Co-Smad, is constructed to analytically investigate the effect of the oligomerization of Smad. Our one-way model reveals that not only shuttling of the Smad from the cytoplasm to the nucleus but also the preferential accumulation of the heteromeric complex in oligomerization can contribute to the predominant production of the heteromeric complex of Smad including both R- and Co-Smad. It is also shown that oligomerization of Smad can contribute to the specificity of signal transduction. In endothelial cells, both Smad-1/5/8 and -2/3 pathways are activated by TGF-beta. The difference of the activity between the two pathways is amplified by trimerization but not by dimerization, suggesting possible importance of trimerization in maintaining the specificity of signal transduction

Optimal Phosphorylation Step Number of Intracellular Signal Transduction Pathway

Eukaryotic cells use signal transduction network to respond in specific ways to external signals from their environment. Several signal transduction pathway are composed of multi-step chemical reactions. We here theoretically study what determines the number of kinase phosphorylation steps composing of the intracellular signal transduction cascade. We examine a simple mathematical model for the association and phosphorylation process of kinases in the signal transduction cascade. We focus on the speed of signal transduction as the criterion for determining the optimal response. The present model first reveals that the initial expression level of kinase in each step of the cascade must be the same in the optimal response under the constraint of the constant total kinase concentration. The second conclusion is that the optimal step number of kinase cascade is primarily determined by the ratio of the target concentration of the final phosphorylated kinase in the cascade to that of input signal molecule, C/S. A multi-step phosphorylation can be optimal when the amplification of the final product concentration C relative to the input signal S is sufficiently large. This suggests that multi-step phosphorylation would have evolved to accelerate the speed of transduction of weak signals

A Mathematical Model for Apoptosome Assembly: The Optimal Cytochrome c/Apaf-1 Ratio

Apoptosis, a highly conserved form of cell suicide, is regulated by apoptotic signals and their transduction with caspases, a family of cystein proteases. Caspases are constantly expressed in the normal cells as inactive pro-enzymes. The activity of caspase is regulated by the proteolysis. Sequential proteolytic reactions of caspases are needed to execute apoptosis. Mitochondrial pathway is one of these apoptotic signal pathways, in which caspases are oligomerized into characteristic heptamer structure, called apoptosome, with caspase-9 that activate the effector caspases for apoptosis. To investigate the dynamics of signal transduction pathway regulated by oligomerization, we construct a mathematical model for Apaf-1 heptamer assembly process. The model first reveals that intermediate products can remain unconverted even after all assemble reactions are completed. The second result of the model is that the conversion efficiency of Apaf-1 heptamer assembly is maximized when the initial concentration of cytochrome c is equal to that of Apaf-1. When the concentration of cytochrome c is sufficiently larger or smaller than that of Apaf-1, the final Apaf-1 heptamer production is decreased, because intermediate Apaf-1 oligomers (tetramers and bigger oligomers), which themselves are unable to form active heptamer, accumulate too fast in the cells, choking a smooth production of Apaf-1 heptamer. Slow activation of Apaf-1 monomers and small oligomers increase the conversion efficiency. We also study the optimal number of subunits comprising an active oligomer that maximize the conversion efficiency in assembly process, and found that the tetramer is the optimum

Fluorescence kinetics of flavin adenine dinucleotide in different microenvironments

Fluorescence kinetics of flavin adenine dinucleotide was measured in a wide time and spectral range in different media, affecting its intra- end extramolecular interactions, and analyzed by a new method based on compressed sensing

Spin Currents Induced by Nonuniform Rashba-Type Spin-Orbit Field

We study the spin relaxation torque in nonmagnetic or ferromagnetic metals with nonuniform spin-orbit coupling within the Keldysh Green's function formalism. In non-magnet, the relaxation torque is shown to arise when the spin-orbit coupling is not uniform. In the absence of an external field, the spin current induced by the relaxation torque is proportional to the vector chirality of Rashba-type spin-orbit field (RSOF). In the presence of an external field, on the other hand, spin relaxation torque arises from the coupling of the external field and vector chirality of RSOF. Our result indicates that spin-sink or source effects are controlled by designing RSOF in junctions.Comment: 3 figure

Theoretical Study on Transport Properties of Normal Metal - Zigzag Graphene Nanoribbon - Normal Metal Junctions

We investigate transport properties of the junctions in which the graphene nanoribbon with the zigzag shaped edges consisting of the $N$ legs is sandwiched by the two normal metals by means of recursive Green's function method. The conductance and the transmission probabilities are found to have the remarkable properties depending on the parity of $N$. The singular behaviors close to E=0 with $E$ being the Fermi energy are demonstrated. The channel filtering is shown to occur in the case with $N=$ even.Comment: 4 pages, 5 figure

Ferroelectric Nanotubes

We report the independent invention of ferroelectric nanotubes from groups in several countries. Devices have been made with three different materials: lead zirconate-titanate PbZr1-xTixO3 (PZT); barium titanate BaTiO3; and strontium bismuth tantalate SrBi2Ta2O9 (SBT). Several different deposition techniques have been used successfully, including misted CSD (chemical solution deposition) and pore wetting. Ferroelectric hysteresis and high optical nonlinearity have been demonstrated. The structures are analyzed via SEM, TEM, XRD, AFM (piezo-mode), and SHG. Applications to trenching in Si dynamic random access memories, ink-jet printers, and photonic devices are discussed. Ferroelectric filled pores as small as 20 nm in diameter have been studied

Photoproduction of eta-mesons on the deuteron above S11(1535) in the presence of a narrow P11(1670) resonance

Incoherent photoproduction of eta-mesons on the deuteron is considered. The main attention is paid to the region above the S11(1535) resonance where rather narrow resonance like structure in the total cross section extracted for gamma n -> eta n has been reported. The corresponding experimental results are analyzed from the phenomenological standpoint within the model containing a baryon P11 with the mass about 1670 MeV and a width less than 30 MeV. This resonance was suggested in some recent works as a nonstrange member of the pentaquark antidecuplet with J^P=1/2^+. The calculation is also performed for the polarized and nonpolarized angular distributions of $\eta$ mesons. In addition, we present our predictions for the cross sections of the neutral kaons and double pion photoproduction, where the same narrow P11(1670) resonance is assumed to contribute through the decay into K^0 Lambda and pi Delta configuration.Comment: 11 pages, 5 figure

Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development

De novo establishment of DNA methylation is accomplished by DNMT3A and DNMT3B. Here, we analyze de novo DNA methylation in mouse embryonic fibroblasts (2i-MEFs) derived from DNA-hypomethylated 2i/L ES cells with genetic ablation of Dnmt3a or Dnmt3b. We identify 355 and 333 uniquely unmethylated genes in Dnmt3a and Dnmt3b knockout (KO) 2i-MEFs, respectively. We find that Dnmt3a is exclusively required for de novo methylation at both TSS regions and gene bodies of Polycomb group (PcG) target developmental genes, while Dnmt3b has a dominant role on the X chromosome. Consistent with this, tissue-specific DNA methylation at PcG target genes is substantially reduced in Dnmt3a KO embryos. Finally, we find that human patients with DNMT3 mutations exhibit reduced DNA methylation at regions that are hypomethylated in Dnmt3 KO 2i-MEFs. In conclusion, here we report a set of unique de novo DNA methylation target sites for both DNMT3 enzymes during mammalian development that overlap with hypomethylated sites in human patients

X-ray Astronomy in the Laboratory with a Miniature Compact Object Produced by Laser-Driven Implosion

Laboratory spectroscopy of non-thermal equilibrium plasmas photoionized by intense radiation is a key to understanding compact objects, such as black holes, based on astronomical observations. This paper describes an experiment to study photoionizing plasmas in laboratory under well-defined and genuine conditions. Photoionized plasma is here generated using a 0.5-keV Planckian x-ray source created by means of a laser-driven implosion. The measured x-ray spectrum from the photoionized silicon plasma resembles those observed from the binary stars Cygnus X-3 and Vela X-1 with the Chandra x-ray satellite. This demonstrates that an extreme radiation field was produced in the laboratory, however, the theoretical interpretation of the laboratory spectrum significantly contradicts the generally accepted explanations in x-ray astronomy. This model experiment offers a novel test bed for validation and verification of computational codes used in x-ray astronomy.Comment: 5 pages, 4 figures are included. This is the original submitted version of the manuscript to be published in Nature Physic