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

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

A study of the agriculture, economy and settlement of North East Khorassan, Iran

Not availabl

Kinship and its consequences in the cooperatively breeding southern pied babbler Turdoides bicolor

Includes abstract.Includes bibliographical references (p. 119-132).Cooperative breeding occurs when more than two individuals help to raise offspring that are not their own, and has been the focus of empirical and theoretical research for over forty years. Of central importance to this work are the fitness costs and benefits of helping, and the factors limiting the reproduction of helpers. To understand these, the genetic relationship between individuals must be known. In this thesis, I use genetic and observational data to explore kinship between individuals in groups of wild Southern Pied Babblers Turdoides bicolor

Ages of Extragalactic Intermediate-Age Star Clusters

A dating technique for faint, distant star clusters observable in the local group of galaxies with the space telescope is discussed. Color-magnitude diagrams of Magellanic Cloud clusters are mentioned along with the metallicity of star clusters

Controlling inflammation: a fat chance?

The inflammatory response protects the body against infection and injury but can itself become deregulated with deleterious consequences to the host. It is now clear that several endogenous biochemical pathways activated during defense reactions can counterregulate inflammation. New experimental evidence adds resolvin E1 to this group of endogenous inhibitors and provides further rationale for the beneficial effects of dietary supplementation with fish oils. It also highlights an unexpected twist in the pharmacology of aspirin

Decomposition of NO studied by infrared emission and CO laser absorption

A diagnostic technique for monitoring the concentration of NO using absorption of CO laser radiation was developed and applied in a study of the decomposition kinetics of NO. Simultaneous measurements of infrared emission by NO at 5.3 microns were also made to validate the laser absorption technique. The data were obtained behind incident shocks in NO-N2O-Ar (or Kr) mixtures, with temperatures in the range 2400-4100 K. Rate constants for dominant reactions were inferred from comparisons with computer simulations of the reactive flow

On the hierarchical classification of G Protein-Coupled Receptors

Motivation: G protein-coupled receptors (GPCRs) play an important role in many physiological systems by transducing an extracellular signal into an intracellular response. Over 50% of all marketed drugs are targeted towards a GPCR. There is considerable interest in developing an algorithm that could effectively predict the function of a GPCR from its primary sequence. Such an algorithm is useful not only in identifying novel GPCR sequences but in characterizing the interrelationships between known GPCRs. Results: An alignment-free approach to GPCR classification has been developed using techniques drawn from data mining and proteochemometrics. A dataset of over 8000 sequences was constructed to train the algorithm. This represents one of the largest GPCR datasets currently available. A predictive algorithm was developed based upon the simplest reasonable numerical representation of the protein's physicochemical properties. A selective top-down approach was developed, which used a hierarchical classifier to assign sequences to subdivisions within the GPCR hierarchy. The predictive performance of the algorithm was assessed against several standard data mining classifiers and further validated against Support Vector Machine-based GPCR prediction servers. The selective top-down approach achieves significantly higher accuracy than standard data mining methods in almost all cases

The magnetic precursor of L1448-mm: Excitation differences between ion and neutral fluids

Shock modelling predicts an electron density enhancement within the magnetic precursor of C-shocks. Previous observations of SiO, H13CO+, HN13C and H13CN toward the young L1448-mm outflow showed an over-excitation of the ion fluid that was attributed to an electron density enhancement in the precursor. We re-visit this interpretation and test if it still holds when we consider different source morphologies and kinetic temperatures for the observed molecules, and also give some insight on the spatial extent of the electron density enhancement around L1448-mm. We estimate the opacities of H13CO+ and HN13C by observing the J=3\to2 lines of rarer isotopologues to confirm that the emission is optically thin. To model the excitation of the molecules, we use the large velocity gradient (LVG) approximation with updated collisional coefficients to i) re- analyse the observations toward the positions where the over-excitation of H13CO+ has previously been observed [i.e. toward L1448- mm at offsets (0,0) and (0,-10)], and ii) to investigate if the electron density enhancement is still required for the cases of extended and compact emission, and for kinetic temperatures of up to 400 K. We also report several lines of SiO, HN13C and H13CO+ toward new positions around this outflow, to investigate the spatial extent of the over-excitation of the ions in L1448-mm. From the isotopologue observations, we find that the emission of H13CO+ and HN13C from the precursor is optically thin if this emission is extended. Using the new collisional coefficients, an electron density enhancement is still needed to explain the excitation of H13CO+ for extended emission and for gas temperatures of\le 400 K toward L1448-mm (0,-10), and possibly also toward L1448-mm (0,0). For compact emission the data cannot be fitted. We do not find any evidence for the over-excitation of the ion fluid toward the newly observed positions around L1448-mm. The observed line emission of SiO, H13CO+ and HN13C toward L1448-mm (0,0) and (0,-10) is consistent with an electron density enhancement in the precursor component, if this emission is spatially extended. This is also true for the case of high gas temperatures (\le400 K) toward the (0,-10) offset. The electron density enhancement seems to be restricted to the southern, redshifted lobe of the L1448-mm outflow. Interferometric images of the line emission of these molecules are needed to confirm the spatial extent of the over-excitation of the ions and thus, of the electron density enhancement in the magnetic precursor of L1448-mm.Comment: Accepted for publication in A&A; 9 pages, 3 figure

Volcanology from Space: Interpreting Volcanic Processes Using Space-Borne Remote Sensing Imagery

No abstract availabl