Redox signals at the ER-mitochondria interface control melanoma progression.

Reactive oxygen species (ROS) are emerging as important regulators of cancer growth and metastatic spread. However, how cells integrate redox signals to affect cancer progression is not fully understood. Mitochondria are cellular redox hubs, which are highly regulated by interactions with neighboring organelles. Here, we investigated how ROS at the endoplasmic reticulum (ER)-mitochondria interface are generated and translated to affect melanoma outcome. We show that TMX1 and TMX3 oxidoreductases, which promote ER-mitochondria communication, are upregulated in melanoma cells and patient samples. TMX knockdown altered mitochondrial organization, enhanced bioenergetics, and elevated mitochondrial- and NOX4-derived ROS. The TMX-knockdown-induced oxidative stress suppressed melanoma proliferation, migration, and xenograft tumor growth by inhibiting NFAT1. Furthermore, we identified NFAT1-positive and NFAT1-negative melanoma subgroups, wherein NFAT1 expression correlates with melanoma stage and metastatic potential. Integrative bioinformatics revealed that genes coding for mitochondrial- and redox-related proteins are under NFAT1 control and indicated that TMX1, TMX3, and NFAT1 are associated with poor disease outcome. Our study unravels a novel redox-controlled ER-mitochondria-NFAT1 signaling loop that regulates melanoma pathobiology and provides biomarkers indicative of aggressive disease

Improving Randomized Learning of Feedforward Neural Networks by Appropriate Generation of Random Parameters

In this work, a method of random parameters generation for randomized learning of a single-hidden-layer feedforward neural network is proposed. The method firstly, randomly selects the slope angles of the hidden neurons activation functions from an interval adjusted to the target function, then randomly rotates the activation functions, and finally distributes them across the input space. For complex target functions the proposed method gives better results than the approach commonly used in practice, where the random parameters are selected from the fixed interval. This is because it introduces the steepest fragments of the activation functions into the input hypercube, avoiding their saturation fragments

On Chip Implementation of a Pixel-Parallel Approach for Retinal Vessel Tree Extraction

Abstract-Retinal vessel tree extraction from angiography images play an important role not only in the medical domain, but also in biometric identification applications. From the image processing point of view, a lot of algorithms and strategies have been developed to deal with this topic. Although reliable results have been obtained, the main disadvantage in most of these proposals is still the high computation effort required. In this paper, a methodology to extract the retinal vessel tree has been developed, specially defined in terms of fine grain SIMD processing with the purpose of improving the computation time. The proposal has been implemented on the SIMD processor array chip SCAMP-3. The execution times for the main modules of the proposed algorithm have been included to show its capability

Physics Opportunities with the 12 GeV Upgrade at Jefferson Lab

This white paper summarizes the scientific opportunities for utilization of the upgraded 12 GeV Continuous Electron Beam Accelerator Facility (CEBAF) and associated experimental equipment at Jefferson Lab. It is based on the 52 proposals recommended for approval by the Jefferson Lab Program Advisory Committee.The upgraded facility will enable a new experimental program with substantial discovery potential to address important topics in nuclear, hadronic, and electroweak physics.Comment: 64 page

Surface Enhanced Second Harmonic Generation from Macrocycle, Catenane, and Rotaxane Thin Films: Experiments and Theory

Surface enhanced second harmonic generation (SE SHG) experiments on molecular structures, macrocycles, catenanes, and rotaxanes, deposited as monolayers and multilayers by vacuum sublimation on silver, are reported. The measurements show that the molecules form ordered thin films, where the highest degree of order is observed in the case of macrocycle monolayers and the lowest in the case of rotaxane multilayers. The second harmonic generation activity is interpreted in terms of electric field induced second harmonic (EFISH) generation where the electric field is created by the substrate silver atoms. The measured second order nonlinear optical susceptibility for a rotaxane thin film is compared with that obtained by considering only EFISH contribution to SHG intensity. The electric field on the surface of a silver layer is calculated by using the Delphi4 program for structures obtained with TINKER molecular mechanics/dynamics simulations. An excellent agreement is observed between the calculated and the measured SHG susceptibilities.

Expanding the set of rhodococcal Baeyer–Villiger monooxygenases by high-throughput cloning, expression and substrate screening

To expand the available set of Baeyer–Villiger monooxygenases (BVMOs), we have created expression constructs for producing 22 Type I BVMOs that are present in the genome of Rhodococcus jostii RHA1. Each BVMO has been probed with a large panel of potential substrates. Except for testing their substrate acceptance, also the enantioselectivity of some selected BVMOs was studied. The results provide insight into the biocatalytic potential of this collection of BVMOs and expand the biocatalytic repertoire known for BVMOs. This study also sheds light on the catalytic capacity of this large set of BVMOs that is present in this specific actinomycete. Furthermore, a comparative sequence analysis revealed a new BVMO-typifying sequence motif. This motif represents a useful tool for effective future genome mining efforts.

Time-odd components in the mean field of rotating superdeformed nuclei

Rotation-induced time-odd components in the nuclear mean field are analyzed using the Hartree-Fock cranking approach with effective interactions SIII, SkM*, and SkP. Identical dynamical moments ${{\cal J}^{(2)}}$ are obtained for pairs of superdeformed bands $^{151}$Tb(2)--$^{152}$Dy(1) and $^{150}$Gd(2)--$^{151}$Tb(1). The corresponding relative alignments strongly depend on which time-odd mean-field terms are taken into account in the Hartree-Fock equations.Comment: 23 pages, ReVTeX, 6 uuencoded postscript figures include

Exact Ampitude Ratio and Finite-Size Corrections for the M x N Square Lattice Ising Model The :

Let f, U and C represent, respectively, the free energy, the internal energy and the specific heat of the critical Ising model on the square M x N lattice with periodic boundary conditions. We find that N f and U are well-defined odd function of 1/N. We also find that ratios of subdominant (N^(-2 i - 1)) finite-size corrections amplitudes for the internal energy and the specific heat are constant. The free energy and the internal energy at the critical point are calculated asymtotically up to N^(-5) order, and the specific heat up to N^(-3) order.Comment: 18 pages, 4 figures, to be published in Phys. Rev. E 65, 1 February 200

Kinetics of antigen expression and epitope presentation during virus infection

Current knowledge about the dynamics of antigen presentation to T cells during viral infection is very poor despite being of fundamental importance to our understanding of anti-viral immunity. Here we use an advanced mass spectrometry method to simultaneously quantify the presentation of eight vaccinia virus peptide-MHC complexes (epitopes) on infected cells and the amounts of their source antigens at multiple times after infection. The results show a startling 1000-fold range in abundance as well as strikingly different kinetics across the epitopes monitored. The tight correlation between onset of protein expression and epitope display for most antigens provides the strongest support to date that antigen presentation is largely linked to translation and not later degradation of antigens. Finally, we show a complete disconnect between the epitope abundance and immunodominance hierarchy of these eight epitopes. This study highlights the complexity of viral antigen presentation by the host and demonstrates the weakness of simple models that assume total protein levels are directly linked to epitope presentation and immunogenicity.NHMRC (National Health and Medical Research Council of Australia