Benchmarking pKa prediction

Background: pKa values are a measure of the protonation of ionizable groups in proteins. Ionizable groups are involved in intra-protein, protein-solvent and protein-ligand interactions as well as solubility, protein folding and catalytic activity. The pKa shift of a group from its intrinsic value is determined by the perturbation of the residue by the environment and can be calculated from three-dimensional structural data. Results: Here we use a large dataset of experimentally-determined pKas to analyse the performance of different prediction techniques. Our work provides a benchmark of available software implementations: MCCE, MEAD, PROPKA and UHBD. Combinatorial and regression analysis is also used in an attempt to find a consensus approach towards pKa prediction. The tendency of individual programs to over- or underpredict the pKa value is related to the underlying methodology of the individual programs. Conclusion: Overall, PROPKA is more accurate than the other three programs. Key to developing accurate predictive software will be a complete sampling of conformations accessible to protein structures

Statistical deconvolution of enthalpic energetic contributions to MHC-peptide binding affinity

Background: MHC Class I molecules present antigenic peptides to cytotoxic T cells, which forms an integral part of the adaptive immune response. Peptides are bound within a groove formed by the MHC heavy chain. Previous approaches to MHC Class I-peptide binding prediction have largely concentrated on the peptide anchor residues located at the P2 and C-terminus positions. Results: A large dataset comprising MHC-peptide structural complexes was created by re-modelling pre-determined x-ray crystallographic structures. Static energetic analysis, following energy minimisation, was performed on the dataset in order to characterise interactions between bound peptides and the MHC Class I molecule, partitioning the interactions within the groove into van der Waals, electrostatic and total non-bonded energy contributions. Conclusion: The QSAR techniques of Genetic Function Approximation (GFA) and Genetic Partial Least Squares (G/PLS) algorithms were used to identify key interactions between the two molecules by comparing the calculated energy values with experimentally-determined BL50 data. Although the peptide termini binding interactions help ensure the stability of the MHC Class I-peptide complex, the central region of the peptide is also important in defining the specificity of the interaction. As thermodynamic studies indicate that peptide association and dissociation may be driven entropically, it may be necessary to incorporate entropic contributions into future calculations

Finding class C GPCR subtype-discriminating n-grams through feature selection

G protein-coupled receptors (GPCRs) are a large and heterogeneous superfamily of receptors that are key cell players for their role as extracellular signal transmitters. Class C GPCRs, in particular, are of great interest in pharmacology. The lack of knowledge about their full 3-D structure prompts the use of their primary amino acid sequences for the construction of robust classifiers, capable of discriminating their different subtypes. In this paper, we describe the use of feature selection techniques to build Support Vector Machine (SVM)-based classification models from selected receptor subsequences described as n-grams. We show that this approach to classification is useful for finding class C GPCR subtype-specific motifs.Peer ReviewedPostprint (author’s final draft

Diaphragm Disease: The Limitation of Laparoscopy and Assessment of the Small Bowel for Strictures Using a Ball Bearing

Diaphragm disease is a rare cause of intestinal obstruction that will be seen with increasing frequency with the widespread use of nonsteroidal anti-inflammatory drugs (NSAIDs). We present a case study of a patient with diaphragm disease where the diagnosis was not apparent at laparoscopy, and passage of a steel ball through the small intestine was required to identify all strictures present. A high index of suspicion, recognition of the limitations of conventional diagnostic aids, and the need to assess the full length of the small bowel are all important in the surgical management of this condition

Ising cubes with enhanced surface couplings

Using Monte Carlo techniques, Ising cubes with ferromagnetic nearest-neighbor interactions and enhanced couplings between surface spins are studied. In particular, at the surface transition, the corner magnetization shows non-universal, coupling-dependent critical behavior in the thermodynamic limit. Results on the critical exponent of the corner magnetization are compared to previous findings on two-dimensional Ising models with three intersecting defect lines.Comment: 4 pages, 2 figures included, submitted to Phys. Rev.

Detection of solar-like oscillations in relics of the Milky Way: Asteroseismology of K giants in M4 using data from the NASA K2 mission

Asteroseismic constraints on K giants make it possible to infer radii, masses and ages of tens of thousands of field stars. Tests against independent estimates of these properties are however scarce, especially in the metal-poor regime. Here, we report the detection of solar-like oscillations in eight stars belonging to the red-giant branch (RGB) and red-horizontal branch (RHB) of the globular cluster M4. The detections were made in photometric observations from the K2 Mission during its Campaign 2. Making use of independent constraints on the distance, we estimate masses of the eight stars by utilizing different combinations of seismic and non-seismic inputs. When introducing a correction to the ν scaling relation as suggested by stellar models, for RGB stars we find excellent agreement with the expected masses from isochrone fitting, and with a distance modulus derived using independent methods. The offset with respect to independent masses is lower, or comparable with, the uncertainties on the average RGB mass (4–10 per cent, depending on the combination of constraints used). Our results lend confidence to asteroseismic masses in the metal-poor regime. We note that a larger sample will be needed to allow more stringent tests to be made of systematic uncertainties in all the observables (both seismic and non-seismic), and to explore the properties of RHB stars, and of different populations in the cluster

Carnitine Acetyltransferase Mitigates Metabolic Inertia and Muscle Fatigue during Exercise

SummaryAcylcarnitine metabolites have gained attention as biomarkers of nutrient stress, but their physiological relevance and metabolic purpose remain poorly understood. Short-chain carnitine conjugates, including acetylcarnitine, derive from their corresponding acyl-CoA precursors via the action of carnitine acetyltransferase (CrAT), a bidirectional mitochondrial matrix enzyme. We show here that contractile activity reverses acetylcarnitine flux in muscle, from net production and efflux at rest to net uptake and consumption during exercise. Disruption of this switch in mice with muscle-specific CrAT deficiency resulted in acetyl-CoA deficit, perturbed energy charge, and diminished exercise tolerance, whereas acetylcarnitine supplementation produced opposite outcomes in a CrAT-dependent manner. Likewise, in exercise-trained compared to untrained humans, post-exercise phosphocreatine recovery rates were positively associated with CrAT activity and coincided with dramatic shifts in muscle acetylcarnitine dynamics. These findings show acetylcarnitine serves as a critical acetyl buffer for working muscles and provide insight into potential therapeutic strategies for combatting exercise intolerance

The bulk correlation length and the range of thermodynamic Casimir forces at Bose-Einstein condensation

The relation between the bulk correlation length and the decay length of thermodynamic Casimir forces is investigated microscopically in two three-dimensional systems undergoing Bose-Einstein condensation: the perfect Bose gas and the imperfect mean-field Bose gas. For each of these systems, both lengths diverge upon approaching the corresponding condensation point from the one-phase side, and are proportional to each other. We determine the proportionality factors and discuss their dependence on the boundary conditions. The values of the corresponding critical exponents for the decay length and the correlation length are the same, equal to 1/2 for the perfect gas, and 1 for the imperfect gas

A Phenomenological Analysis of Gluon Mass Effects in Inclusive Radiative Decays of the J/ψ\rm{J/\psi} and $\Upsilon

The shapes of the inclusive photon spectra in the processes \Jp \to \gamma X and \Up \to \gamma X have been analysed using all available experimental data. Relativistic, higher order QCD and gluon mass corrections were taken into account in the fitted functions. Only on including the gluon mass corrections, were consistent and acceptable fits obtained. Values of $0.721^{+0.016}_{-0.068}$ GeV and $1.18^{+0.09}_{-0.29}$ GeV were found for the effective gluon masses (corresponding to Born level diagrams) for the \Jp and \Up respectively. The width ratios \Gamma(V \to {\rm hadrons})/\Gamma(V \to \gamma+ {\rm hadrons}) V=\Jp, \Up were used to determine $\alpha_s(1.5 {\rm GeV})$ and $\alpha_s(4.9 {\rm GeV})$. Values consistent with the current world average $\alpha_s$ were obtained only when gluon mass correction factors, calculated using the fitted values of the effective gluon mass, were applied. A gluon mass $\simeq 1$ GeV, as suggested with these results, is consistent with previous analytical theoretical calculations and independent phenomenological estimates, as well as with a recent, more accurate, lattice calculation of the gluon propagator in the infra-red region.Comment: 50 pages, 11 figures, 15 table

The First Magnetic Fields

We review current ideas on the origin of galactic and extragalactic magnetic fields. We begin by summarizing observations of magnetic fields at cosmological redshifts and on cosmological scales. These observations translate into constraints on the strength and scale magnetic fields must have during the early stages of galaxy formation in order to seed the galactic dynamo. We examine mechanisms for the generation of magnetic fields that operate prior during inflation and during subsequent phase transitions such as electroweak symmetry breaking and the quark-hadron phase transition. The implications of strong primordial magnetic fields for the reionization epoch as well as the first generation of stars is discussed in detail. The exotic, early-Universe mechanisms are contrasted with astrophysical processes that generate fields after recombination. For example, a Biermann-type battery can operate in a proto-galaxy during the early stages of structure formation. Moreover, magnetic fields in either an early generation of stars or active galactic nuclei can be dispersed into the intergalactic medium.Comment: Accepted for publication in Space Science Reviews. Pdf can be also downloaded from http://canopus.cnu.ac.kr/ryu/cosmic-mag1.pd