Computational Aspects of Protein Functionality

The purpose of this short article is to examine certain aspects of protein functionality with relation to some key organizing ideas. This is important from a computational viewpoint in order to take account of modelling both biological systems and knowledge of these systems. We look at some of the lexical dimensions of the function and how certain constructs can be related to underlying ideas. The pervasive computational metaphor is then discussed in relation to protein multifunctionality, and the specific case of von Willebrand factor as a ‘smart’ multifunctional protein is briefly considered. Some diagrammatic techniques are then introduced to better articulate protein function

On the Nesterov-Todd Direction in Semidefinite Programming

On the Nesterov-Todd Direction in Semidefinite Programmin

Tidal signals in ocean-bottom magnetic measurements of the Northwestern Pacific: observation versus prediction

Motional induction in the ocean by tides has long been observed by both land and satellite measurements of magnetic fields. While these signals are weak (∼10 nT) when compared to the main magnetic field, their persistent nature makes them important for consideration during geomagnetic field modelling. Previous studies have reported several discrepancies between observations and numerical predictions of the tidal magnetic signals and those studies were inconclusive of the source of the error. We address this issue by (1) analysing magnetometer data from ocean-bottom stations, where the low-noise and high-signal environment is most suitable for detecting the weak tidal magnetic signals, (2) by numerically predicting the magnetic field with a spatial resolution that is 16times higher than the previous studies and (3) by using four different models of upper-mantle conductivity. We use vector magnetic data from six ocean-bottom electromagnetic (OBEM) stations located in the Northwestern Pacific Ocean. The OBEM tidal amplitudes were derived using an iteratively re-weighted least-squares (IRLS) method and by limiting the analysis of lunar semidiurnal (M2), lunar elliptic semidinurnal (N2) and diurnal (O1) tidal modes to the night-time. Using a 3-D electromagnetic induction solver and the TPX07.2 tidal model, we predict the tidal magnetic signal. We use earth models with non-uniform oceans and four 1-D mantle sections underneath taken from Kuvshinov and Olsen, Shimizu etal. and Baba etal. to compare the effect of upper-mantle conductivity. We find that in general, the predictions and observations match within 10-70 per cent across all the stations for each of the tidal modes. The median normalized percent difference (NPD) between observed and predicted amplitudes for the tidal modes M2, N2 and O1 were 15 per cent, 47 per cent and 98 per cent, respectively, for all the stations and models. At the majority of stations, and for each of the tidal modes, the higher resolution (0.25°×0.25°) modelling gave amplitudes consistently closer to the observations than the lower resolution (1°×1°) modelling. The difference in lithospheric resistance east and west of the Izu-Bonin trench system seems to be affecting the model response and observations in the O1 tidal mode. This response is not seen in the M2 and N2 modes, thereby indicating that the O1 mode is more sensitive to lithospheric resistanc

Role of Interleukin 17 in arthritis chronicity through survival of synoviocytes via regulation of synoviolin expression

Background: The use of TNF inhibitors has been a major progress in the treatment of chronic inflammation. However, not all patients respond. In addition, response will be often lost when treatment is stopped. These clinical aspects indicate that other cytokines might be involved and we focus here on the role of IL-17. In addition, the chronic nature of joint inflammation may contribute to reduced response and enhanced chronicity. Therefore we studied the capacity of IL-17 to regulate synoviolin, an E3 ubiquitin ligase implicated in synovial hyperplasia in human rheumatoid arthritis (RA) FLS and in chronic reactivated streptococcal cell wall (SCW)-induced arthritis.<p></p> Methodology/Principal Findings: Chronic reactivated SCW-induced arthritis was examined in IL-17R deficient and wild-type mice. Synoviolin expression was analysed by real-time RT-PCR, Western Blot or immunostaining in RA FLS and tissue, and p53 assessed by Western Blot. Apoptosis was detected by annexin V/propidium iodide staining, SS DNA apoptosis ELISA kit or TUNEL staining and proliferation by PCNA staining. IL-17 receptor A (IL-17RA), IL-17 receptor C (IL-17-RC) or synoviolin inhibition were achieved by small interfering RNA (siRNA) or neutralizing antibodies. IL-17 induced sustained synoviolin expression in RA FLS. Sodium nitroprusside (SNP)-induced RA FLS apoptosis was associated with reduced synoviolin expression and was rescued by IL-17 treatment with a corresponding increase in synoviolin expression. IL-17RC or IL-17RA RNA interference increased SNP-induced apoptosis, and decreased IL-17-induced synoviolin. IL-17 rescued RA FLS from apoptosis induced by synoviolin knockdown. IL-17 and TNF had additive effects on synoviolin expression and protection against apoptosis induced by synoviolin knowndown. In IL-17R deficient mice, a decrease in arthritis severity was characterized by increased synovial apoptosis, reduced proliferation and a marked reduction in synoviolin expression. A distinct absence of synoviolin expressing germinal centres in IL-17R deficient mice contrasted with synoviolin positive B cells and Th17 cells in synovial germinal centre-like structures.<p></p> Conclusion/Significance: IL-17 induction of synoviolin may contribute at least in part to RA chronicity by prolonging the survival of RA FLS and immune cells in germinal centre reactions. These results extend the role of IL-17 to synovial hyperplasia.<p></p&gt

SeSAW: balancing sequence and structural information in protein functional mapping

Motivation: Functional similarity between proteins is evident at both the sequence and structure levels. SeSAW is a web-based program for identifying functionally or evolutionarily conserved motifs in protein structures by locating sequence and structural similarities, and quantifying these at the level of individual residues. Results can be visualized in 2D, as annotated alignments, or in 3D, as structural superpositions. An example is given for both an experimentally determined query structure and a homology model

Studies of Phase Turbulence in the One Dimensional Complex Ginzburg-Landau Equation

The phase-turbulent (PT) regime for the one dimensional complex Ginzburg-Landau equation (CGLE) is carefully studied, in the limit of large systems and long integration times, using an efficient new integration scheme. Particular attention is paid to solutions with a non-zero phase gradient. For fixed control parameters, solutions with conserved average phase gradient $\nu$ exist only for $|\nu|$ less than some upper limit. The transition from phase to defect-turbulence happens when this limit becomes zero. A Lyapunov analysis shows that the system becomes less and less chaotic for increasing values of the phase gradient. For high values of the phase gradient a family of non-chaotic solutions of the CGLE is found. These solutions consist of spatially periodic or aperiodic waves travelling with constant velocity. They typically have incommensurate velocities for phase and amplitude propagation, showing thereby a novel type of quasiperiodic behavior. The main features of these travelling wave solutions can be explained through a modified Kuramoto-Sivashinsky equation that rules the phase dynamics of the CGLE in the PT phase. The latter explains also the behavior of the maximal Lyapunov exponents of chaotic solutions.Comment: 16 pages, LaTeX (Version 2.09), 10 Postscript-figures included, submitted to Phys. Rev.

Sharper and Simpler Nonlinear Interpolants for Program Verification

Interpolation of jointly infeasible predicates plays important roles in various program verification techniques such as invariant synthesis and CEGAR. Intrigued by the recent result by Dai et al.\ that combines real algebraic geometry and SDP optimization in synthesis of polynomial interpolants, the current paper contributes its enhancement that yields sharper and simpler interpolants. The enhancement is made possible by: theoretical observations in real algebraic geometry; and our continued fraction-based algorithm that rounds off (potentially erroneous) numerical solutions of SDP solvers. Experiment results support our tool's effectiveness; we also demonstrate the benefit of sharp and simple interpolants in program verification examples

Inferring Multiple Graphical Structures

Gaussian Graphical Models provide a convenient framework for representing dependencies between variables. Recently, this tool has received a high interest for the discovery of biological networks. The literature focuses on the case where a single network is inferred from a set of measurements, but, as wetlab data is typically scarce, several assays, where the experimental conditions affect interactions, are usually merged to infer a single network. In this paper, we propose two approaches for estimating multiple related graphs, by rendering the closeness assumption into an empirical prior or group penalties. We provide quantitative results demonstrating the benefits of the proposed approaches. The methods presented in this paper are embeded in the R package 'simone' from version 1.0-0 and later

Mutually Penetrating Motion of Self-Organized 2D Patterns of Soliton-Like Structures

Results of numerical simulations of a recently derived most general dissipative-dispersive PDE describing evolution of a film flowing down an inclined plane are presented. They indicate that a novel complex type of spatiotemporal patterns can exist for strange attractors of nonequilibrium systems. It is suggested that real-life experiments satisfying the validity conditions of the theory are possible: the required sufficiently viscous liquids are readily available.Comment: minor corrections, 4 pages, LaTeX, 6 figures, mpeg simulations available upon or reques

Vascular changes in diabetic retinopathy-a longitudinal study in the Nile rat

Diabetic retinopathy is the most common microvascular complication of diabetes and is a major cause of blindness, but an understanding of the pathogenesis of the disease has been hampered by a lack of accurate animal models. Here, we explore the dynamics of retinal cellular changes in the Nile rat (Arvicanthis niloticus), a carbohydrate-sensitive model for type 2 diabetes. The early retinal changes in diabetic Nile rats included increased acellular capillaries and loss of pericytes that correlated linearly with the duration of diabetes. These vascular changes occurred in the presence of microglial infiltration but in the absence of retinal ganglion cell loss. After a prolonged duration of diabetes, the Nile rat also exhibits a spectrum of retinal lesions commonly seen in the human condition including vascular leakage, capillary non-perfusion, and neovascularization. Our longitudinal study documents a range and progression of retinal lesions in the diabetic Nile rat remarkably similar to those observed in human diabetic retinopathy, and suggests that this model will be valuable in identifying new therapeutic strategies