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

Loss of hypothermic and anti-pyretic action of paracetamol in cyclooxygenase-1 knockout mice is indicative of inhibition of cyclooxygenase-1 variant enzymes

Paracetamol (acetaminophen), is a centrally-acting antipyretic analgesic drug, which can also lower body temperature. Despite a century of clinical use, its mechanism of pharmacological action has not been completely elucidated. Previously, we demonstrated significant attenuation in the paracetamol induced hypothermia in parallel with its inhibitory action on the synthesis of brain prostaglandin E₂ (PGE₂) in cyclooxygenase-1 (COX-1) knockout mice in comparison to wild-type mice. The above reported pharmacological actions by paracetamol were completely retained in COX-2 knockout mice. We thus concluded that the mechanism of hypothermic action of paracetamol is dependent on inhibition of a COX-1 gene-derived enzyme. In the current investigation, we provide further support for this notion by demonstrating that the paracetamol-induced hypothermia is not mediated through inhibition of COX-1 as neither the COX-1 selective inhibitor, SC560, nor the COX-1/COX-2 dual inhibitor, indomethacin, induced hypothermia at pharmacologically active doses in mice. In addition, using a COX-2-dependent and PGE₂-mediated model of endotoxin-induced fever, paracetamol induced anti-pyretic and hypothermic actions in COX-1 wild-type mice. These effects were fully or partially attenuated in COX-1 knockout mice after prophylactic or therapeutic administration, respectively. Therapeutically-administered paracetamol also reduced hypothalamic PGE₂ biosynthesis in febrile COX-1 wild-type mice, but not in febrile COX-1 knockout mice. In conclusion, we provide further evidence which suggests that the hypothermic and now anti-pyretic actions of paracetamol are mediated through inhibition of a COX-1 variant enzyme

Eating Habits in the Aasarakkovai

Human life is founded on virtue and common good of the society. Life is not commendable when one chooses to live recklessly just as he/she wants. One of the primary facets of Literatures of Ethics in Tamil is to foster meaningful values and adhere to them in life. Food customs indicate certain cultural formalities to be maintained as practice. This paper/thesis deals with a system of food customs that energize, develop cell-systems and cause good functioning of bodily organs as oriented by “Aasarakovai”

Female Psychology in Kathanayagi

In recent literary genres novels has got a unique identity. Novels describes about the  autobiography, historical studies, real life incidents and these are the story line of novels. Novels are written as an attempt to solve social problems and the problems faced by women. Psychology can be defined as how an individual react in the Society and not only that but also his learning ability, memory power and the loss of memory. The basic thing which is responsible for the creation of literature is human thoughts and feeling. They create literature based on their female experiences or of what they learn from circumstances and emotions play a vital role in the novels. Since the characters exhibit a volume of emotions, there is a spontaneous flow of psychological impacts. Tamil literary books and Tamil novels are the outcome of mixed human feelings in various situations. This essay is an abstract of various feeling and thoughts of human like guilty, emotions and the hidden thoughts, written by famous novelist Aandal Priyadharshini

Temporal evolution of magnetic molecular shocks II. Analytics of the steady state and semi-analytical construction of intermediate ages

In the first paper of this series (Paper I) we computed time dependent simulations of multifluid shocks with chemistry and a transverse magnetic field frozen in the ions, using an adaptive moving grid. In this paper, we present new analytical results on steady-state molecular shocks. Relationships between density and pressure in the neutral fluid are derived for the cold magnetic precursor, hot magnetic precursor, adiabatic shock front, and the following cooling layer. The compression ratio and temperature behind a fully dissociative adiabatic shock is also derived. To prove that these results may even hold for intermediate ages, we design a test to locally characterise the validity of the steady state equations in a time-dependent shock simulation. Applying this tool to the results of Paper I, we show that most of these shocks (all the stable ones) are indeed in a quasi-steady state at all times, i.e. : a given snapshot is composed of one or more truncated steady shock. Finally, we use this property to produce a construction method of any intermediate time of low velocity shocks (u < 20 km/s) with only a steady-state code. In particular, this method allows one to predict the occurrence of steady CJ-type shocks more accurately than previously proposed criteria.Comment: A&A in pres

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

Shocks in dense clouds. IV. Effects of grain-grain processing on molecular line emission

Grain-grain processing has been shown to be an indispensable ingredient of shock modelling in high density environments. For densities higher than \sim10^5 cm-3, shattering becomes a self-enhanced process that imposes severe chemical and dynamical consequences on the shock characteristics. Shattering is accompanied by the vaporization of grains, which can directly release SiO to the gas phase. Given that SiO rotational line radiation is used as a major tracer of shocks in dense clouds, it is crucial to understand the influence of vaporization on SiO line emission. We have developed a recipe for implementing the effects of shattering and vaporization into a 2-fluid shock model, resulting in a reduction of computation time by a factor \sim100 compared to a multi-fluid modelling approach. This implementation was combined with an LVG-based modelling of molecular line radiation transport. Using this model we calculated grids of shock models to explore the consequences of different dust-processing scenarios. Grain-grain processing is shown to have a strong influence on C-type shocks for a broad range of magnetic fields: they become hotter and thinner. The reduction in column density of shocked gas lowers the intensity of molecular lines, at the same time as higher peak temperatures increase the intensity of highly excited transitions compared to shocks without grain-grain processing. For OH the net effect is an increase in line intensities, while for CO and H2O it is the contrary. The intensity of H2 emission is decreased in low transitions and increased for highly excited lines. For all molecules, the highly excited lines become sensitive to the value of the magnetic field. Although vaporization increases the intensity of SiO rotational lines, this effect is weakened by the reduced shock width. The release of SiO early in the hot shock changes the excitation characteristics of SiO radiation.Comment: Published in Astronomy and Astrophysics (2013). 26 pages, 16 figures, 14 table

SiO line emission from C-type shock waves : interstellar jets and outflows

We study the production of SiO in the gas phase of molecular outflows, through the sputtering of Si--bearing material in refractory grain cores, which are taken to be olivine; we calculate also the rotational line spectrum of the SiO. The sputtering is driven by neutral particle impact on charged grains, in steady--state C-type shock waves, at the speed of ambipolar diffusion. The emission of the SiO molecule is calculated by means of an LVG code. A grid of models has been generated. We compare our results with those of an earlier study (Schilke et al. 1997). Improvements in the treatment of the coupling between the charged grains and the neutral fluid lead to narrower shock waves and lower fractions of Si being released into the gas phase. More realistic assumptions concerning the initial fractional abundance of O2 lead to SiO formation being delayed, so that it occurs in the cool, dense postshock flow. Good agreement is obtained with recent observations of SiO line intensities in the L1157 and L1448 molecular outflows. The inferred temperature, opacity, and SiO column density in the emission region differ significantly from those estimated by means of LVG `slab' models. The fractional abundance of SiO is deduced. Observed line profiles are wider than predicted and imply multiple, unresolved shock regions within the beam.Comment: 1 tex doc, 19 figure

Converts and Islamist Terrorism: An Introduction

Converts to Islam represent a small percentage of the Muslim community in Western countries. Yet when it comes to Islamist extremism and terrorism, research has suggested that converts are considerably overrepresented. This ICCT Policy Brief serves as an introduction to this topic by providing an overview of what is known about converts’ involvement in homegrown jihadism and the foreign fighter phenomenon. Notwithstanding considerable reservations about the quantity and quality of the available data, this Policy Brief finds support for the notion of convert overrepresentation in these activities. This is especially so in the case of foreign fighters. What little data was found on converts’ involvement in homegrown jihadism provided a more nuanced picture, emphasizing that overrepresentation may not be the norm in all Western countries and that it may be a relatively recent development. Numerous explanations for converts’ involvement in Islamist extremism and terrorism have been provided, running the gamut from structural-level explanations to distinctly personal motives. At present, however, a comprehensive, theoretically sound and empirically grounded understanding of how and why converts become involved in Islamist militancy is absent. The Policy Brief concludes by stressing the need to develop our understanding of this important yet under-researched topic.Security and Global Affair