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- Nilsson, Johan, et al.
(författare)
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Paracetamol analogues conjugated by FAAH induce TRPV1-mediated antinociception without causing acute liver toxicity
- 2021
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 213
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Tidskriftsartikel (refereegranskat)abstract
- Paracetamol, one of the most widely used pain-relieving drugs, is deacetylated to 4-aminophenol (4-AP) that undergoes fatty acid amide hydrolase (FAAH)-dependent biotransformation into N-arachidonoylphenolamine (AM404), which mediates TRPV1-dependent antinociception in the brain of rodents. However, paracetamol is also converted to the liver-toxic metabolite N-acetyl-p-benzoquinone imine already at therapeutic doses, urging for safer paracetamol analogues. Primary amine analogues with chemical structures similar to paracetamol were evaluated for their propensity to undergo FAAH-dependent N-arachidonoyl conjugation into TRPV1 activators both in vitro and in vivo in rodents. The antinociceptive and antipyretic activity of paracetamol and primary amine analogues was examined with regard to FAAH and TRPV1 as well as if these analogues produced acute liver toxicity. 5-Amino-2-methoxyphenol (2) and 5-aminoindazole (3) displayed efficient target protein interactions with a dose-dependent antinociceptive effect in the mice formalin test, which in the second phase was dependent on FAAH and TRPV1. No hepatotoxicity of the FAAH substrates transformed into TRPV1 activators was observed. While paracetamol attenuates pyrexia via inhibition of brain cyclooxygenase, its antinociceptive FAAH substrate 4-AP was not antipyretic, suggesting separate mechanisms for the antipyretic and antinociceptive effect of paracetamol. Furthermore, compound 3 reduced fever without a brain cyclooxygenase inhibitory action. The data support our view that analgesics and antipyretics without liver toxicity can be derived from paracetamol. Thus, research into the molecular actions of paracetamol could pave the way for the discovery of analgesics and antipyretics with a better benefit-to-risk ratio.
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| 4. |
- Blomqvist, Anders, 1976-
(författare)
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A convex optimization approach to complexity constrained analytic interpolation with applications to ARMA estimation and robust control
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Analytical interpolation theory has several applications in systems and control. In particular, solutions of low degree, or more generally of low complexity, are of special interest since they allow for synthesis of simpler systems. The study of degree constrained analytic interpolation was initialized in the early 80's and during the past decade it has had significant progress. This thesis contributes in three different aspects to complexity constrained analytic interpolation: theory, numerical algorithms, and design paradigms. The contributions are closely related; shortcomings of previous design paradigms motivate development of the theory, which in turn calls for new robust and efficient numerical algorithms. Mainly two theoretical developments are studied in the thesis. Firstly, the spectral Kullback-Leibler approximation formulation is merged with simultaneous cepstral and covariance interpolation. For this formulation, both uniqueness of the solution, as well as smoothness with respect to data, is proven. Secondly, the theory is generalized to matrix-valued interpolation, but then only allowing for covariance-type interpolation conditions. Again, uniqueness and smoothness with respect to data is proven. Three algorithms are presented. Firstly, a refinement of a previous algorithm allowing for multiple as well as matrix-valued interpolation in an optimization framework is presented. Secondly, an algorithm capable of solving the boundary case, that is, with spectral zeros on the unit circle, is given. This also yields an inherent numerical robustness. Thirdly, a new algorithm treating the problem with both cepstral and covariance conditions is presented. Two design paradigms have sprung out of the complexity constrained analytical interpolation theory. Firstly, in robust control it enables low degree Hinf controller design. This is illustrated by a low degree controller design for a benchmark problem in MIMO sensitivity shaping. Also, a user support for the tuning of controllers within the design paradigm for the SISO case is presented. Secondly, in ARMA estimation it provides unique model estimates, which depend smoothly on the data as well as enables frequency weighting. For AR estimation, a covariance extension approach to frequency weighting is discussed, and an example is given as an illustration. For ARMA estimation, simultaneous cepstral and covariance matching is generalized to include prefiltering. An example indicates that this might yield asymptotically efficient estimates.
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| 6. |
- Chapman, Ben, et al.
(författare)
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To boldly go: individual differences in boldness influence migratory tendency.
- 2011
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Ingår i: Ecology Letters. - : Wiley. - 1461-023X. ; 14, s. 871-876
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Tidskriftsartikel (refereegranskat)abstract
- Ecology Letters (2011) ABSTRACT: Partial migration, whereby only a fraction of the population migrates, is thought to be the most common type of migration in the animal kingdom, and can have important ecological and evolutionary consequences. Despite this, the factors that influence which individuals migrate and which remain resident are poorly understood. Recent work has shown that consistent individual differences in personality traits in animals can be ecologically important, but field studies integrating personality traits with migratory behaviour are extremely rare. In this study, we investigate the influence of individual boldness, an important personality trait, upon the migratory propensity of roach, a freshwater fish, over two consecutive migration seasons. We assay and individually tag 460 roach and show that boldness influences migratory propensity, with bold individuals being more likely to migrate than shy fish. Our data suggest that an extremely widespread personality trait in animals can have significant ecological consequences via influencing individual-level migratory behaviour.
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| 7. |
- Dahl, Andreas, et al.
(författare)
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Traffic-generated emissions of ultrafine particles from pavement-tire interface
- 2006
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Ingår i: Atmospheric Environment. - : Elsevier. - 1352-2310 .- 1873-2844. ; 40:7, s. 1314-1323
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Tidskriftsartikel (refereegranskat)abstract
- In a road simulator study, a significant source of sub-micrometer fine particles produced by the road-tire interface was observed. Since the particle size distribution and source strength is dependent on the type of tire used, it is likely that these particles largely originate from the tires, and not the road pavement. The particles consisted most likely of mineral oils from the softening filler and fragments of the carbon-reinforcing filler material (soot agglomerates). This identification was based on transmission electron microscopy studies of collected ultrafine wear particles and on-line thermal treatment using a thermodesorber. The mean particle number diameters were between 15-50 nm, similar to those found in light duty vehicle (LDV) tail-pipe exhaust. A simple box model approach was used to estimate emission factors in the size interval 15-700 nm. The emission factors increased with increasing vehicle speed, and varied between 3.7 x 10(11) and 3.2 x 10(12) particles vehicle(-1) km(-1) at speeds of 50 and 70 km h(-1). This corresponds to between 0.1-1% of tail-pipe emissions in real-world emission studies at similar speeds from a fleet of LDV with 95% gasoline and 5% diesel-fueled cars. The emission factors for particles originating from the road-tire interface were, however, similar in magnitude to particle number emission factors from liquefied petroleum gas-powered vehicles derived in test bench studies in Australia 2005. Thus the road-tire interface may be a significant contributor to particle emissions from ultraclean vehicles. (c) 2005 Elsevier Ltd. All rights reserved.
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- Engblom, David, 1975-, et al.
(författare)
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Activation of prostanoid EP3 and EP4 receptor mRNA-expressing neurons in the rat parabrachial nucleus by intravenous injection of bacterial wall lipopolysaccharide
- 2001
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Ingår i: Journal of Comparative Neurology. - : Wiley. - 0021-9967 .- 1096-9861. ; 440:4, s. 378-386
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Tidskriftsartikel (refereegranskat)abstract
- Systemic inflammation activates central autonomic circuits, such as neurons in the pontine parabrachial nucleus. This activation may be the result of afferent signaling through the vagus nerve, but it may also depend on central prostaglandin-mediated mechanisms. Recently, we have shown that neurons in the parts of the parabrachial nucleus that are activated by immune challenge express prostaglandin receptors of the EP3 and EP4 subtypes, but it remains to be determined if the prostaglandin receptor-expressing neurons are identical to those that respond to immune stimuli. In the present study, bacterial wall lipopolysaccharide was injected intravenously in adult male rats and the expression of c-fos mRNA and of EP3 and EP4 receptor mRNA was examined with complementary RNA probes labeled with digoxigenin and radioisotopes, respectively. Large numbers of neurons in the external lateral parabrachial subnucleus, a major target of vagal-solitary tract efferents, expressed c-fos mRNA. Quantitative analysis showed that about 60% (range 40%–79%) of these neurons also expressed EP3 receptor mRNA. Conversely, slightly more than 50% (range 48%–63%) of the EP3 receptor-expressing neurons in the same subnucleus coexpressed c-fos mRNA. In contrast, few EP4 receptor-expressing neurons were c-fos positive, with the exception of a small population located in the superior lateral and dorsal lateral subnuclei. These findings show that immune challenge activates central autonomic neurons that could be the target of centrally produced prostaglandin E2, suggesting that synaptic signaling and paracrine mechanisms may interact on these neurons. J. Comp. Neurol. 440:378–386, 2001. © 2001 Wiley-Liss, Inc.
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| 10. |
- Engblom, David, et al.
(författare)
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Distribution of prostaglandin EP3 and EP4 receptor mRNA in the rat parabrachial nucleus
- 2000
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Ingår i: Neuroscience Letters. - : Elsevier Science B.V., Amsterdam.. - 0304-3940 .- 1872-7972. ; 281:2-3, s. 163-166
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Tidskriftsartikel (refereegranskat)abstract
- By using in situ hybridization, the distribution of mRNA for the PGE2 receptors EP3 and EP4 was examined in the rat parabrachial nucleus (PB), a major brain stem relay for autonomic and nociceptive processing. EP3 receptor mRNA was present in most subnuclei, with the densest labeling in the external lateral, dorsal lateral, superior lateral, central lateral and Kölliker–Fuse nuclei. EP4 receptor mRNA expressing cells had a more restricted distribution, largely being confined to the superior lateral and adjacent parts of the dorsal and central lateral nuclei in a pattern complementary to that for EP3 receptor mRNA. These findings suggest that EP3 and EP4 receptors in PB have distinct functional roles that include nociceptive processing, blood pressure regulation and feeding behavior.
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