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

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

Complex Langevin Equation and the Many-Fermion Problem

We study the utility of a complex Langevin (CL) equation as an alternative for the Monte Carlo (MC) procedure in the evaluation of expectation values occurring in fermionic many-body problems. We find that a CL approach is natural in cases where non-positive definite probability measures occur, and remains accurate even when the corresponding MC calculation develops a severe ``sign problem''. While the convergence of CL averages cannot be guaranteed in principle, we show how convergent results can be obtained in three examples ranging from simple one-dimensional integrals over quantum mechanical models to a schematic shell model path integral.Comment: 19 pages, 10 PS figures embedded in tex

Submillimeter Wave Astronomy Satellite mapping observations of water vapor around Sagittarius B2

Observations of the 1(10)-1(01) 556.936 GHz transition of ortho-water with the Submillimeter Wave Astronomy Satellite (SWAS) have revealed the presence of widespread emission and absorption by water vapor around the strong submillimeter continuum source Sagittarius B2. An incompletely-sampled spectral line map of a region of size 26 x 19 arcmin around Sgr B2 reveals three noteworthy features. First, absorption by foreground water vapor is detectable at local standard-of-rest (LSR) velocities in the range -100 to 0 km/s at almost every observed position. Second, spatially-extended emission by water is detectable at LSR velocities in the range 80 to 120 km/s at almost every observed position. This emission is attributable to the 180-pc molecular ring identified from previous observations of CO. The typical peak antenna temperature of 0.075 K for this component implies a typical water abundance of 1.2E-6 to 8E-6 relative to H2. Third, strong absorption by water is observed within 5 arcmin of Sgr B2 at LSR velocities in the range 60 to 82 km/s. An analysis of this absorption yields a H2O abundance ~ 2E-7 to 4E-7 relative to H2 if the absorbing water vapor is located within the core of Sgr B2 itself; or, alternatively, a water column density ~ 2.5E+16 to 4E+16 per cm2 if the water absorption originates in the warm, foreground layer of gas proposed previously as the origin of ammonia absorption observed toward Sgr B2.Comment: 29 pages (AASTeX), including 9 postscript figures, to appear in the Astrophysical Journa

Differential modulation of annexin I binding sites on monocytes and neutrophils.

Specific binding sites for the anti-inflammatory protein annexin I have been detected on the surface of human monocytes and polymorphonuclear leukocytes (PMN). These binding sites are proteinaceous in nature and are sensitive to cleavage by the proteolytic enzymes trypsin, collagenase, elastase and cathepsin G. When monocytes and PMN were isolated independently from peripheral blood, only the monocytes exhibited constitutive annexin I binding. However PMN acquired the capacity to bind annexin I following co-culture with monocytes. PMN incubation with sodium azide, but not protease inhibitors, partially blocked this process. A similar increase in annexin I binding capacity was also detected in PMN following adhesion to endothelial monolayers. We propose that a juxtacrine activation rather than a cleavage-mediated transfer is involved in this process. Removal of annexin I binding sites from monocytes with elastase rendered monocytes functionally insensitive to full length annexin I or to the annexin I-derived pharmacophore, peptide Ac2-26, assessed as suppression of the respiratory burst. These data indicate that the annexin I binding site on phagocytic cells may have an important function in the feedback control of the inflammatory response and their loss through cleavage could potentiate such responses

Multifluid, Magnetohydrodynamic Shock Waves with Grain Dynamics II. Dust and the Critical Speed for C Shocks

This is the second in a series of papers on the effects of dust on multifluid, MHD shock waves in weakly ionized molecular gas. We investigate the influence of dust on the critical shock speed, v_crit, above which C shocks cease to exist. Chernoff showed that v_crit cannot exceed the grain magnetosound speed, v_gms, if dust grains are dynamically well coupled to the magnetic field. We present numerical simulations of steady shocks where the grains may be well- or poorly coupled to the field. We use a time-dependent, multifluid MHD code that models the plasma as a system of interacting fluids: neutral particles, ions, electrons, and various ``dust fluids'' comprised of grains with different sizes and charges. Our simulations include grain inertia and grain charge fluctuations but to highlight the essential physics we assume adiabatic flow, single-size grains, and neglect the effects of chemistry. We show that the existence of a phase speed v_phi does not necessarily mean that C shocks will form for all shock speeds v_s less than v_phi. When the grains are weakly coupled to the field, steady, adiabatic shocks resemble shocks with no dust: the transition to J type flow occurs at v_crit = 2.76 v_nA, where v_nA is the neutral Alfven speed, and steady shocks with v_s > 2.76 v_nA are J shocks with magnetic precursors in the ion-electron fluid. When the grains are strongly coupled to the field, v_crit = min(2.76 v_nA, v_gms). Shocks with v_crit < v_s < v_gms have magnetic precursors in the ion-electron-dust fluid. Shocks with v_s > v_gms have no magnetic precursor in any fluid. We present time-dependent calculations to study the formation of steady multifluid shocks. The dynamics differ qualitatively depending on whether or not the grains and field are well coupled.Comment: 43 pages with 17 figures, aastex, accepted by The Astrophysical Journa

Massive expanding torus and fast outflow in planetary nebula NGC 6302

We present interferometric observations of $^{12}$CO and $^{13}$CO $J$=2$-$1 emission from the butterfly-shaped, young planetary nebula NGC 6302. The high angular resolution and high sensitivity achieved in our observations allow us to resolve the nebula into two distinct kinematic components: (1) a massive expanding torus seen almost edge-on and oriented in the North-South direction, roughly perpendicular to the optical nebula axis. The torus exhibits very complex and fragmentated structure; (2) high velocity molecular knots moving at high velocity, higher than 20 \kms, and located in the optical bipolar lobes. These knots show a linear position-velocity gradient (Hubble-like flow), which is characteristic of fast molecular outflow in young planetary nebulae. From the low but variable $^{12}$CO/$^{13}$CO $J$=2$-$1 line intensity ratio we conclude that the $^{12}$CO $J$=2$-$1 emission is optically thick over much of the nebula. Using the optically thinner line $^{13}$CO $J$=2$-$1 we estimate a total molecular gas mass of $\sim$ 0.1 M$_\odot$, comparable to the ionized gas mass; the total gas mass of the NGC 6302 nebula, including the massive ionized gas from photon dominated region, is found to be $\sim$ 0.5 M$_\odot$. From radiative transfer modelling we infer that the torus is seen at inclination angle of 75$^\circ$ with respect to the plane of the sky and expanding at velocity of 15 \kms. Comparison with recent observations of molecular gas in NGC 6302 is also discussed.Comment: 24 pages, 7 figures, accepted for publication in Astrophysical Journa