Competitive pathways for peptide deamidation

Asparagine (Asn) residues spontaneously – yet non-enzymatically – deamidate to form aspartate under physiological conditions, causing time-dependent changes in the conformation of proteins, limiting their lifetime [1]. The 'molecular clocks' hypothesis [2], suggests that deamidation is a biological molecular timing mechanism that could be set to any desired time interval by genetic control of the protein structure and the immediate environment of the Asn residue. The fact that deamidation occurs over a wide range of biologically relevant time intervals suggests that different mechanisms may be at play. To date deamidation is believed to occur over a succinimide-mediated pathway [3]. A novel route leading to the succinimide intermediate via tautomerization of the Asn side chain amide functionality was recently proposed [4,5]. The current study introduces a new 'competing' route for the deamidation of asparagine residues. The aim is to comparatively analyze the feasibility of this new mechanism against the traditional succinimide route, taking into account the catalytic effect of the solvent environment. For this purpose, QM dynamics and meta-dynamics calculations were performed on a model peptide placed in a periodic water box. These results will identify the lowest energy pathway for asparagine deamidation and will serve as a stepping stone for QM/MM calculations of Asn deamidation in proteins

Quantum whistling in superfluid 4He

Fundamental considerations predict that macroscopic quantum systems such as superfluids and the electrons in superconductors will exhibit oscillatory motion when pushed through a small constriction. Here we report the observation of these oscillations between two reservoirs of superfluid 4He partitioned by an array of nanometer-sized apertures. They obey the Josephson frequency equation and are coherent amongst all the apertures. This discovery at the relatively high temperature of 2K (2000 times higher than related phenomena in 3He) may pave the way for a new class of practical rotation sensors of unprecedented precision.Comment: 6 pages, 3 figures, to be published in Natur

Kinetic Analysis of Discrete Path Sampling Stationary Point Databases

Analysing stationary point databases to extract phenomenological rate constants can become time-consuming for systems with large potential energy barriers. In the present contribution we analyse several different approaches to this problem. First, we show how the original rate constant prescription within the discrete path sampling approach can be rewritten in terms of committor probabilities. Two alternative formulations are then derived in which the steady-state assumption for intervening minima is removed, providing both a more accurate kinetic analysis, and a measure of whether a two-state description is appropriate. The first approach involves running additional short kinetic Monte Carlo (KMC) trajectories, which are used to calculate waiting times. Here we introduce `leapfrog' moves to second-neighbour minima, which prevent the KMC trajectory oscillating between structures separated by low barriers. In the second approach we successively remove minima from the intervening set, renormalising the branching probabilities and waiting times to preserve the mean first-passage times of interest. Regrouping the local minima appropriately is also shown to speed up the kinetic analysis dramatically at low temperatures. Applications are described where rates are extracted for databases containing tens of thousands of stationary points, with effective barriers that are several hundred times kT.Comment: 28 pages, 1 figure, 4 table

Classical orbital paramagnetism in non-equilibrium steady state

We report the results of our numerical simulation of classical-dissipative dynamics of a charged particle subjected to a non-markovian stochastic forcing. We find that the system develops a steady-state orbital magnetic moment in the presence of a static magnetic field. Very significantly, the sign of the orbital magnetic moment turns out to be {\it paramagnetic} for our choice of parameters, varied over a wide range. This is shown specifically for the case of classical dynamics driven by a Kubo-Anderson type non-markovian noise. Natural spatial boundary condition was imposed through (1) a soft (harmonic) confining potential, and (2) a hard potential, approximating a reflecting wall. There was no noticeable qualitative difference. What appears to be crucial to the orbital magnetic effect noticed here is the non-markovian property of the driving noise chosen. Experimental realization of this effect on the laboratory scale, and its possible implications are briefly discussed. We would like to emphasize that the above steady-state classical orbital paramagnetic moment complements, rather than contradicts the Bohr-van Leeuwen (BvL) theorem on the absence of classical orbital diamagnetism in thermodynamic equilibrium.Comment: 6 pages, 4 figures, Has appeared in Journal of Astrophysics and Astronomy special issue on 'Physics of Neutron Stars and Related Objects', celebrating the 75th birth-year of G. Srinivasa

Loss of histone macroH2A1 in hepatocellular carcinoma cells promotes paracrine-mediated chemoresistance and CD4+CD25+FoxP3+ regulatory T cells activation

Rationale: Loss of histone macroH2A1 induces appearance of cancer stem cells (CSCs)-like cells in hepatocellular carcinoma (HCC). How CSCs interact with the tumor microenvironment and the adaptive immune system is unclear. Methods: We screened aggressive human HCC for macroH2A1 and CD44 CSC marker expression. We also knocked down (KD) macroH2A1 in HCC cells, and performed integrated transcriptomic and secretomic analyses. Results: Human HCC showed low macroH2A1 and high CD44 expression compared to control tissues. MacroH2A1 KD CSC-like cells transferred paracrinally their chemoresistant properties to parental HCC cells. MacroH2A1 KD conditioned media transcriptionally reprogrammed parental HCC cells activated regulatory CD4+/CD25+/FoxP3+ T cells (Tregs). Conclusions: Loss of macroH2A1 in HCC cells drives cancer stem-cell propagation and evasion from immune surveillance

Building development and roads: implications for the distribution of stone curlews across the Brecks

Background: Substantial new housing and infrastructure development planned within England has the potential to conflict with the nature conservation interests of protected sites. The Breckland area of eastern England (the Brecks) is designated as a Special Protection Area for a number of bird species, including the stone curlew (for which it holds more than 60% of the UK total population). We explore the effect of buildings and roads on the spatial distribution of stone curlew nests across the Brecks in order to inform strategic development plans to avoid adverse effects on such European protected sites. Methodology: Using data across all years (and subsets of years) over the period 1988 – 2006 but restricted to habitat areas of arable land with suitable soils, we assessed nest density in relation to the distances to nearest settlements and to major roads. Measures of the local density of nearby buildings, roads and traffic levels were assessed using normal kernel distance-weighting functions. Quasi-Poisson generalised linear mixed models allowing for spatial auto-correlation were fitted. Results: Significantly lower densities of stone curlew nests were found at distances up to 1500m from settlements, and distances up to 1000m or more from major (trunk) roads. The best fitting models involved optimally distance-weighted variables for the extent of nearby buildings and the trunk road traffic levels. Significance : The results and predictions from this study of past data suggests there is cause for concern that future housing development and associated road infrastructure within the Breckland area could have negative impacts on the nesting stone curlew population. Given the strict legal protection afforded to the SPA the planning and conservation bodies have subsequently agreed precautionary restrictions on building development within the distances identified and used the modelling predictions to agree mitigation measures for proposed trunk road developments

Improved primary vertex finding for collider detectors

Primary vertex finding for collider experiments is studied. The efficiency and precision of finding interaction vertices can be improved by advanced clustering and classification methods, such as agglomerative clustering with fast pairwise nearest neighbor search, followed by Gaussian mixture model or k-means clustering.Comment: 12 pages, 10 figures, submitted to Nucl. Instrum. Meth.

Trapping Dynamics with Gated Traps: Stochastic Resonance-Like Phenomenon

We present a simple one-dimensional trapping model prompted by the problem of ion current across biological membranes. The trap is modeled mimicking the ionic channel membrane behaviour. Such voltage-sensitive channels are open or closed depending on the value taken by a potential. Here we have assumed that the external potential has two contributions: a determinist periodic and a stochastic one. Our model shows a resonant-like maximum when we plot the amplitude of the oscillations in the absorption current vs. noise intensity. The model was solved both numerically and using an analytic approximation and was found to be in good accord with numerical simulations.Comment: RevTex, 5 pgs, 3 figure

Inequivalent contact structures on Boothby-Wang 5-manifolds

We consider contact structures on simply-connected 5-manifolds which arise as circle bundles over simply-connected symplectic 4-manifolds and show that invariants from contact homology are related to the divisibility of the canonical class of the symplectic structure. As an application we find new examples of inequivalent contact structures in the same equivalence class of almost contact structures with non-zero first Chern class.Comment: 27 pages; to appear in Math. Zeitschrif