Metabolite biomarker discovery for metabolic diseases by flux analysis

Metabolites can serve as biomarkers and their identification has significant importance in the study of biochemical reaction and signalling networks. Incorporating metabolic and gene expression data to reveal biochemical networks is a considerable challenge, which attracts a lot of attention in recent research. In this paper, we propose a promising approach to identify metabolic biomarkers through integrating available biomedical data and disease-specific gene expression data. A Linear Programming (LP) based method is then utilized to determine flux variability intervals, therefore enabling the analysis of significant metabolic reactions. A statistical approach is also presented to uncover these metabolites. The identified metabolites are then verified by comparing with the results in the existing literature. The proposed approach here can also be applied to the discovery of potential novel biomarkers. © 2012 IEEE.published_or_final_versio

Discovery of metabolite biomarkers: flux analysis and reaction-reaction network approach

published_or_final_versio

Dual abrogation of Mnk and mTOR; a novel therapeutic approach for the treatment of aggressive cancers

Targeting the translational machinery has emerged as a promising therapeutic option for cancer treatment. Cancer cells require elevated protein synthesis for cell growth and exhibit augmented activity to meet the increased metabolic demand. Eukaryotic translation initiation factor 4E (eIF4E) is necessary for mRNA translation, its availability and phosphorylation are regulated by the PI3K/AKT/mTOR and Mnk1/2 pathways, respectively. The phosphorylated form of eIF4E drives the expression of oncogenic proteins including those involved in metastasis. This article will review the role of eIF4E in cancer, its regulation, and discuss the benefit of dual-inhibition of upstream pathways. The discernible interplay between the Mnk1/2 and mTOR signaling pathways provides a novel therapeutic opportunity to target aggressive migratory cancers through the development of hybrid molecules

Phase diagram of bismuth in the extreme quantum limit

Elemental bismuth provides a rare opportunity to explore the fate of a three-dimensional gas of highly mobile electrons confined to their lowest Landau level. Coulomb interaction, neglected in the band picture, is expected to become significant in this extreme quantum limit with poorly understood consequences. Here, we present a study of the angular-dependent Nernst effect in bismuth, which establishes the existence of ultraquantum field scales on top of its complex single-particle spectrum. Each time a Landau level crosses the Fermi level, the Nernst response sharply peaks. All such peaks are resolved by the experiment and their complex angular-dependence is in very good agreement with the theory. Beyond the quantum limit, we resolve additional Nernst peaks signaling a cascade of additional Landau sub-levels caused by electron interaction

Direct entropy determination and application to artificial spin ice

From thermodynamic origins, the concept of entropy has expanded to a range of statistical measures of uncertainty, which may still be thermodynamically significant. However, laboratory measurements of entropy continue to rely on direct measurements of heat. New technologies that can map out myriads of microscopic degrees of freedom suggest direct determination of configurational entropy by counting in systems where it is thermodynamically inaccessible, such as granular and colloidal materials, proteins and lithographically fabricated nanometre-scale arrays. Here, we demonstrate a conditional-probability technique to calculate entropy densities of translation-invariant states on lattices using limited configuration data on small clusters, and apply it to arrays of interacting nanometre-scale magnetic islands (artificial spin ice). Models for statistically disordered systems can be assessed by applying the method to relative entropy densities. For artificial spin ice, this analysis shows that nearest-neighbour correlations drive longer-range ones.Comment: 10 page

Analytical, Optimal, and Sparse Optimal Control of Traveling Wave Solutions to Reaction-Diffusion Systems

This work deals with the position control of selected patterns in reaction-diffusion systems. Exemplarily, the Schl\"{o}gl and FitzHugh-Nagumo model are discussed using three different approaches. First, an analytical solution is proposed. Second, the standard optimal control procedure is applied. The third approach extends standard optimal control to so-called sparse optimal control that results in very localized control signals and allows the analysis of second order optimality conditions.Comment: 22 pages, 3 figures, 2 table

Effective Conformal Theory and the Flat-Space Limit of AdS

We develop the idea of an effective conformal theory describing the low-lying spectrum of the dilatation operator in a CFT. Such an effective theory is useful when the spectrum contains a hierarchy in the dimension of operators, and a small parameter whose role is similar to that of 1/N in a large N gauge theory. These criteria insure that there is a regime where the dilatation operator is modified perturbatively. Global AdS is the natural framework for perturbations of the dilatation operator respecting conformal invariance, much as Minkowski space naturally describes Lorentz invariant perturbations of the Hamiltonian. Assuming that the lowest-dimension single-trace operator is a scalar, O, we consider the anomalous dimensions, gamma(n,l), of the double-trace operators of the form O (del^2)^n (del)^l O. Purely from the CFT we find that perturbative unitarity places a bound on these dimensions of |gamma(n,l)|<4. Non-renormalizable AdS interactions lead to violations of the bound at large values of n. We also consider the case that these interactions are generated by integrating out a heavy scalar field in AdS. We show that the presence of the heavy field "unitarizes" the growth in the anomalous dimensions, and leads to a resonance-like behavior in gamma(n,l) when n is close to the dimension of the CFT operator dual to the heavy field. Finally, we demonstrate that bulk flat-space S-matrix elements can be extracted from the large n behavior of the anomalous dimensions. This leads to a direct connection between the spectrum of anomalous dimensions in d-dimensional CFTs and flat-space S-matrix elements in d+1 dimensions. We comment on the emergence of flat-space locality from the CFT perspective.Comment: 46 pages, 2 figures. v2: JHEP published versio

The role of the right temporoparietal junction in perceptual conflict: detection or resolution?

The right temporoparietal junction (rTPJ) is a polysensory cortical area that plays a key role in perception and awareness. Neuroimaging evidence shows activation of rTPJ in intersensory and sensorimotor conflict situations, but it remains unclear whether this activity reflects detection or resolution of such conflicts. To address this question, we manipulated the relationship between touch and vision using the so-called mirror-box illusion. Participants' hands lay on either side of a mirror, which occluded their left hand and reflected their right hand, but created the illusion that they were looking directly at their left hand. The experimenter simultaneously touched either the middle (D3) or the ring finger (D4) of each hand. Participants judged, which finger was touched on their occluded left hand. The visual stimulus corresponding to the touch on the right hand was therefore either congruent (same finger as touch) or incongruent (different finger from touch) with the task-relevant touch on the left hand. Single-pulse transcranial magnetic stimulation (TMS) was delivered to the rTPJ immediately after touch. Accuracy in localizing the left touch was worse for D4 than for D3, particularly when visual stimulation was incongruent. However, following TMS, accuracy improved selectively for D4 in incongruent trials, suggesting that the effects of the conflicting visual information were reduced. These findings suggest a role of rTPJ in detecting, rather than resolving, intersensory conflict

Human Mas-related G protein-coupled receptors-X1 induce chemokine receptor 2 expression in rat dorsal root ganglia neurons and release of chemokine ligand 2 from the human LAD-2 mast cell line

Primate-specific Mas-related G protein-coupled receptors-X1 (MRGPR-X1) are highly enriched in dorsal root ganglia (DRG) neurons and induce acute pain. Herein, we analyzed effects of MRGPR-X1 on serum response factors (SRF) or nuclear factors of activated T cells (NFAT), which control expression of various markers of chronic pain. Using HEK293, DRG neuron-derived F11 cells and cultured rat DRG neurons recombinantly expressing human MRGPR-X1, we found activation of a SRF reporter gene construct and induction of the early growth response protein-1 via extracellular signal-regulated kinases-1/2 known to play a significant role in the development of inflammatory pain. Furthermore, we observed MRGPR-X1-induced up-regulation of the chemokine receptor 2 (CCR2) via NFAT, which is considered as a key event in the onset of neuropathic pain and, so far, has not yet been described for any endogenous neuropeptide. Up-regulation of CCR2 is often associated with increased release of its endogenous agonist chemokine ligand 2 (CCL2). We also found MRGPR-X1-promoted release of CCL2 in a human connective tissue mast cell line endogenously expressing MRGPR-X1. Thus, we provide first evidence to suggest that MRGPR-X1 induce expression of chronic pain markers in DRG neurons and propose a so far unidentified signaling circuit that enhances chemokine signaling by acting on two distinct yet functionally co-operating cell types. Given the important role of chemokine signaling in pain chronification, we propose that interruption of this signaling circuit might be a promising new strategy to alleviate chemokine-promoted pain

Cosmic rays and molecular clouds

This paper deals with the cosmic-ray penetration into molecular clouds and with the related gamma--ray emission. High energy cosmic rays interact with the dense gas and produce neutral pions which in turn decay into two gamma rays. This makes molecular clouds potential sources of gamma rays, especially if they are located in the vicinity of a powerful accelerator that injects cosmic rays in the interstellar medium. The amplitude and duration in time of the cosmic--ray overdensity around a given source depend on how quickly cosmic rays diffuse in the turbulent galactic magnetic field. For these reasons, gamma-ray observations of molecular clouds can be used both to locate the sources of cosmic rays and to constrain the properties of cosmic-ray diffusion in the Galaxy.Comment: To appear in the proceedings of the San Cugat Forum on Astrophysics 2012, 27 pages, 10 figure