2,851 research outputs found
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 Eâ‚‚ (PGEâ‚‚) 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 PGEâ‚‚-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 PGEâ‚‚ 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
The Spatial Distribution of Atomic Carbon Emission in the Giant Molecular Cloud NGC 604-2
We have mapped a giant molecular cloud in the giant HII region NGC 604 in M33
in the 492 GHz ^3P_1 -- ^3P_0 transition of neutral atomic carbon using the
James Clerk Maxwell Telescope. We find the distribution of the [CI] emission to
be asymmetric with respect to the CO J=1--0 emission, with the peak of the [CI]
emission offset towards the direction of the center of the HII region. In
addition, the line ratio I_{[CI]}/I_{CO} is highest (~ 0.2) facing the HII
region and lowest (< 0.1) away from it. These asymmetries indicate an edge-on
morphology where the [CI] emission is strongest on the side of the cloud facing
the center of the HII region, and not detected at all on the opposite side This
suggests that the sources of the incident flux creating C from the dissociation
of CO are the massive stars of the HII region. The lowest line ratios are
similar to what is observed in Galactic molecular clouds, while the highest are
similar to starburst galaxies and other regions of intense star formation. The
column density ratio, N(C)/N(H_2) is a few times 10^{-6}, in general agreement
with models of photodissociation regions.Comment: Accepted for publication in ApJ. 8 pages, 5 figures, 3 table
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
The Ratio of Ortho- to Para-H2 in Photodissociation Regions
We discuss the ratio of ortho- to para-H2 in photodissociation regions
(PDRs). We draw attention to an apparent confusion in the literature between
the ortho-to-para ratio of molecules in FUV-pumped vibrationally excited
states, and the H2 ortho-to-para abundance ratio. These ratios are not the same
because the process of FUV-pumping of fluorescent H2 emission in PDRs occurs
via optically thick absorption lines. Thus, gas with an equilibrium ratio of
ortho- to para-H2 equal to 3 will yield FUV-pumped vibrationally excited
ortho-to-para ratios smaller than 3, because the ortho-H2 pumping rates are
preferentially reduced by optical depth effects. Indeed, if the ortho and para
pumping lines are on the ``square root'' part of the curve-of-growth, then the
expected ratio of ortho and para vibrational line strengths is the square root
of 3, ~ 1.7, close to the typically observed value. Thus, contrary to what has
sometimes been stated in the literature, most previous measurements of the
ratio of ortho- to para-H2 in vibrationally excited states are entirely
consistent with a total ortho-to-para ratio of 3, the equilibrium value for
temperatures greater than 200 K. We present an analysis and several detailed
models which illustrate the relationship between the total ratios of ortho- to
para-H2 and the vibrationally excited ortho-to-para ratios in PDRs. Recent
Infrared Space Observatory (ISO) measurements of pure rotational and
vibrational H2 emissions from the PDR in the star-forming region S140 provide
strong observational support for our conclusions.Comment: 23 pages (including 5 figures), LaTeX, uses aaspp4.sty, accepted for
publication in Ap
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