bluuebunny/crossref_metadata_2025 huggingface dataset:
Authors: Appuhn Karl
Published: April 2008

The early modern period has aptly been called the “wooden age,” when timber, directly or indirectly, provided most of the material underpinnings of European and other societies. Most scholars who have been interested in wood as a historical problem have approached it from the perspective of historical geography or landscape. In this new book, Paul Warde analyzes the economic and political dimensions of timber in early modern Germany. Focusing on the relatively small Duchy of Württemberg in southwestern Germany, Warde uses timber as a way to both map out the material constraints of life in early modern communities, and to undertake an analysis of state development that moves away from abstract categories such as sovereignty and authority, and toward the concrete problems faced by rulers and bureaucrats as they sought to regulate crucial aspects of everyday life. In so doing, Warde seeks to situate local and regional communities within a well-defined ecological context so as to understand better the kinds of economic choices that early modern Europeans, like other pre-modern people, faced. This is something that environmental historians like to talk about at great length, even though they often neglect it in practice. To his credit, Warde puts his analysis where his mouth is.
Effects of matrix viscoelasticity on viscous and viscoelastic drop deformation in a shear flow
Authors: AGGARWAL NISHITH , SARKAR KAUSIK
Published: April 2008

The deformation of a Newtonian/viscoelastic drop suspended in a viscoelastic fluid is investigated using a three-dimensional front-tracking finite-difference method. The viscoelasticity is modelled using the Oldroyd-B constitutive equation. Matrix viscoelasticity affects the drop deformation and the inclination angle with the flow direction. Numerical predictions of these quantities are compared with previous experimental measurements using Boger fluids. The elastic and viscous stresses at the interface, polymer orientation, and the elastic and viscous forces in the domain are carefully investigated as they affect the drop response. Significant change in the drop inclination with increasing viscoelasticity is observed; this is explained in terms of the first normal stress difference. A non-monotonic change – a decrease followed by an increase – in the steady-state drop deformation is observed with increasing Deborah number (De) and explained in terms of the competition between increased localized polymer stretching at the drop tips and the decreased viscous stretching due to change in drop orientation angle. The transient drop orientation angle is found to evolve on the polymer relaxation time scale for highDe. The breakup of a viscous drop in a viscoelastic matrix is inhibited for smallDe, and promoted at higherDe. Polymeric to total viscosity ratio β was seen to affect the result through the combined parameter βDeindicating a dominant role of the first normal stress difference. A viscoelastic drop in a viscoelastic matrix with matched relaxation time experiences less deformation compared to the case when one of the phases is viscous; but the inclination angle assumes an intermediate value between two extreme cases. Increased drop phase viscoelasticity compared to matrix phase leads to decreased deformation.
A physically motivated approach for filtering acoustic waves from the equations governing compressible stratified flow
Authors: DURRAN DALE R.
Published: April 2008

An incompressibility approximation is formulated for isentropic motions in a compressible stratified fluid by defining a pseudo-density ρ* and enforcing mass conservation with respect to ρ* instead of the true density. Using this approach, sound waves will be eliminated from the governing equations provided ρ* is an explicit function of the space and time coordinates and of entropy. By construction, isentropic pressure perturbations have no influence on the pseudo-density.

A simple expression for ρ* is available for perfect gases that allows the approximate mass conservation relation to be combined with the unapproximated momentum and thermodynamic equations to yield a closed system with attractive energy conservation properties. The influence of pressure on the pseudo-density, along with the explicit (x,t) dependence of ρ* is determined entirely by the hydrostatically balanced reference state.

Scale analysis shows that the pseudo-incompressible approximation is applicable to motions for which ${\cal M})$2 ≪ min(1,${\cal R})$2, where ${\cal M})$ is the Mach number and ${\cal R}$ the Rossby number. This assumption is easy to satisfy for small-scale atmospheric motions in which the Earth's rotation may be neglected and is also satisfied for quasi-geostrophic synoptic-scale motions, but not planetary-scale waves. This scaling assumption can, however, be relaxed to allow the accurate representation of planetary-scale motions if the pressure in the time-evolving reference state is computed with sufficient accuracy that the large-scale components of the pseudo-incompressible pressure represent small corrections to the total pressure, in which case the full solution to both the pseudo-incompressible and reference-state equations has the potential to accurately model all non-acoustic atmospheric motions.
Measurements of the velocity field of a wing-tip vortex, wandering in grid turbulence
Authors: BAILEY S. C. C. , TAVOULARIS S.
Published: April 2008

Velocity measurements were performed in a wing-tip vortex wandering in free-stream turbulence using two four-wire hot-wire probes. Vortex wandering was well represented by a bi-normal probability density with increasing free-stream turbulence resulting in increased amplitude of wandering. The most dominant wavelength of wandering was found to remain unaffected by free-stream conditions. Two-point velocity measurements were used to reconstruct the vortex velocity profile in a frame of reference wandering with the vortex. Increasing turbulence intensity was found to increase the rate of decay of the vortex peak circumferential velocity while the radial location of this peak velocity remained unchanged. These results are consistent with several possible vortex decay mechanisms, including the stripping of vorticity by azimuthally aligned vortical structures, transfer of angular momentum from the vortex to these structures during their formation and the deformation and breakup of the vortex by strong free-stream eddies.
A stationary circular hydraulic jump, the limits of its existence and its gasdynamic analogue
Authors: KASIMOV ASLAN R.
Published: April 2008

We propose a theory of a steady circular hydraulic jump based on the shallow-water model obtained from the depth-averaged Navier–Stokes equations. The flow structure both upstream and downstream of the jump is determined by considering the flow over a plate of finite radius. The radius of the jump is found using the far-field conditions together with the jump conditions that include the effects of surface tension. We show that a steady circular hydraulic jump does not exist if the surface tension is above a certain critical value. The solution of the problem provides a basis for the hydrodynamic stability analysis of the hydraulic jump. An analogy between the hydraulic jump and a detonation wave is pointed out.
Global frequency selection in the observed time-mean wakes of circular cylinders
Authors: KHOR MOSES , SHERIDAN JOHN , THOMPSON MARK C. , HOURIGAN KERRY
Published: April 2008

Observations have been made of the time-mean velocity profile at midspan in the near-wake of circular cylinders at moderate Reynolds numbers between 600 and 4600, well beyond the Reynolds number of approximately 200 at which the wake becomes three-dimensional. The measured profiles are found to be represented quite accurately by a family of function profiles with known linear instability characteristics. The complex instability frequency is then determined as a function of wake position, using the function profiles. In general, the near wake undergoes a transition from convective to absolute instability; the distance downstream to the point of transition is found to increase over the Reynolds number range investigated. The emergence of a significant region of convective instability is consistent with the known appearance of Bloor–Gerrard vortices. The selected frequency of the wake instability is determined by the saddle-point criterion; the Strouhal numbers for Bénard–von Kármán vortex shedding are found to compare well with the values in the literature.
Studying Perception
Authors: Lagerspetz Olli
Published: April 2008

Empirical studies of perception must use the logic of everyday non-technical conceptions of perception as their unquestioned background. This is because the phenomena to be studied are defined and individuated on the basis of such basic understanding. Thus the methods of neurobiology exclude reductionist accounts from the outset, implicitly if not explicitly. It is further argued that the concepts of neural and mental representation, while not confused per se, presuppose a general picture where perception as a whole is viewed in the light of teleology. References are made to discussions by Bennett and Hacker, Paul Churchland, and Peter Winch.
What's Wrong With Megalopsychia?
Authors: Sarch Alexander
Published: April 2008

This paper looks at two accounts of Aristotle's views on the virtue of megalopsychia. The first, defended by Christopher Cordner, commits Aristotle to two claims about the virtuous person that might seem unpalatable to modern readers. The second account, defended by Roger Crisp, does not commit Aristotle to these claims. Some might count this as an advantage of Crisp's account. However, I argue that Cordner's account, not Crisp's, is actually the better interpretation of Aristotle. Nonetheless, this does not ultimately spell trouble for Aristotle, since, as I argue, the claims that Cordner's account commits Aristotle to are, on closer inspection, not really problematic.
The Complexity of Wittgenstein's Methods
Authors: Harré Rom
Published: April 2008

In claiming to draw out an inconsistency between Wittgenstein's declarations on method and his actual practice, John Cook argues that Wittgenstein retained a radical distinction between material things (bricks) and immaterial things (spooks). I argue that on the contrary Wittgenstein showed in detail how this dichotomy is to be rejected in favour of a spectrum of more or less ‘minded' beings, at one pole of which are persons as animated bodies. Discussing the grammar of ‘know', Cook claims that Wittgenstein depended on philosophers' distinctions rather than a surview of vernacular uses. I argue that it was the expression/description distinction that Wittgenstein used to make sense of the grammar of ‘know'.
Protein folding and misfolding: mechanism and principles
Authors: Englander S. Walter , Mayne Leland , Krishna Mallela M. G.
Published: April 2008

Two fundamentally different views of how proteins fold are now being debated. Do proteins fold through multiple unpredictable routes directed only by the energetically downhill nature of the folding landscape or do they fold through specific intermediates in a defined pathway that systematically puts predetermined pieces of the target native protein into place? It has now become possible to determine the structure of protein folding intermediates, evaluate their equilibrium and kinetic parameters, and establish their pathway relationships. Results obtained for many proteins have serendipitously revealed a new dimension of protein structure. Cooperative structural units of the native protein, called foldons, unfold and refold repeatedly even under native conditions. Much evidence obtained by hydrogen exchange and other methods now indicates that cooperative foldon units and not individual amino acids account for the unit steps in protein folding pathways. The formation of foldons and their ordered pathway assembly systematically puts native-like foldon building blocks into place, guided by a sequential stabilization mechanism in which prior native-like structure templates the formation of incoming foldons with complementary structure. Thus the same propensities and interactions that specify the final native state, encoded in the amino-acid sequence of every protein, determine the pathway for getting there. Experimental observations that have been interpreted differently, in terms of multiple independent pathways, appear to be due to chance misfolding errors that cause different population fractions to block at different pathway points, populate different pathway intermediates, and fold at different rates. This paper summarizes the experimental basis for these three determining principles and their consequences. Cooperative native-likefoldon unitsand thesequential stabilizationprocess together generate predetermined stepwise pathways. Optional misfoldingerrors are responsible for 3-state and heterogeneous kinetic folding.
Defaults and indeterminacy in temporal grammaticalization: The ‘perfect’ road to perfective
Authors: Schwenter Scott A. , Cacoullos Rena Torres
Published: April 2008

Adopting a grammaticalization path perspective on the envelope of variation, that is, the range of grammatical functions along the cross-linguistic perfect-to-perfective path, and employing the variationist comparative method, we compare use of the Present Perfect and Preterit in Mexican and Peninsular Spanish to identify the default past perfective form in each dialect. The linguistic conditioning of the variability provides evidence that the Present Perfect is becoming the default exponent of past perfective in Peninsular Spanish; in empirical terms, the default expression is the one appearing more frequently (combined effect of corrected mean and factor weight) in the most frequent and, crucially, the least specified contexts. The quantitative analysis of natural speech production—rather than elicited—data also suggests a different trajectory for perfect-to-perfective grammaticalization than the commonly assumed route via remoteness distinctions: the Present Perfect's shift from hodiernal to general perfective advances in temporally indeterminate past contexts.
Negative Correlation in Graphs and Matroids
Authors: SEMPLE CHARLES , WELSH DOMINIC
Published: April 2008

The following two conjectures arose in the work of Grimmett and Winkler, and Pemantle: the uniformly random forestFand the uniformly random connected subgraphCof a finite graphGhave the edge-negative association property. In other words, for all distinct edgeseandfofG, the probability thatF(respectively,C) containseconditioned on containingfis less than or equal to the probability thatF(respectively,C) containse. Grimmett and Winkler showed that the first conjecture is true for all simple graphs on 8 vertices and all graphs on 9 vertices with at most 18 edges. In this paper, we describe an infinite, nontrivial class of graphs and matroids for which a generalized version of both conjectures holds.
Cell-cycle synchronization of fibroblasts derived from transgenic cloned cattle ear skin: effects of serum starvation, roscovitine and contact inhibition
Authors: Sun XiuZhu , Wang ShuHui , Zhang YunHai , Wang HaiPing , Wang LiLi , Ying Liu , Li Rong , Li Ning
Published: April 2008

The purpose of the present study was to evaluate the effects of serum-starvation, contact-inhibition and roscovitine treatments on cell-cycle synchronization at the G0/G1 stage of ear skin fibroblasts isolated from transgenic cloned cattle. The developmental competence of re-cloned embryos was also examined. Our results showed that the proportion of G0/G1 cells from the serum-starved group at 3, 4 or 5 days was significantly higher compared with 1 or 2 days only (91.5, 91.7 and 93.5% versus 90.1 and 88.8%, respectively, p < 0.05); whilst there was no statistical difference among cells at 3, 4 or 5 days. For roscovitine-treated cells, the proportion of G0/G1 cells at 2, 3, 4 or 5 days was significantly higher than those treated for 1 day only (91.1, 90.1, 89.4 and 91.3% versus 86.51%, respectively, p < 0.05). The proportion of contact-inhibited G0/G1 cells rose significantly with treatment time, but was similar at 3, 4 and 5 days (89.4, 90.4, 91.4, 91.6 and 92.1%, respectively, p < 0.05). The efficiency of obtaining G0/G1 phase cells was lower when roscovitine treatment was employed to synchronize the cell cycle compared with the serum-starvation and contact-inhibition methods (89.7 versus 91.1% and 91.0%, p < 0.05). Moreover, obvious differences were observed in the rate of fused couplets and blastocysts (89.88 ± 2.70 versus 87.40 ± 5.13; 44.10 ± 8.62 versus 58.38 ± 13.28, respectively, p < 0.05), when nuclear transfer embryos were reconstructed using donors cells that had been serum starved or contact inhibited for 3 days. Our data indicate that 3 day treatment is feasible for harvesting sufficient G0/G1 cells to produce re-cloned transgenic bovine embryos, regardless of whether serum-starvation, contact-inhibition or roscovitine treatments are used as the synchronization methods.
In vitro development of non-enucleated rat oocytes following microinjection of a cumulus nucleus and chemical activation
Authors: Fujii Wataru , Funahashi Hiroaki
Published: April 2008

The present study examined in vitro development and the cytological status of non-enucleated rat oocytes after microinjection of cumulus nuclei and chemical activation. Oocyte–cumulus complexes were collected from gonadotropin-treated prepubertal female Wistar rats 14 h after human chorionic gonadotropin (hCG) injection. Cumulus nuclei were injected into ovulated oocytes and then stimulated in the presence of 5 mM SrCl2 for 20 min at various time points (0–3.5 h) after injection. Some of the reconstituted eggs were cultured to observe the pronuclear formation, cleavage, and blastocyst formation. The incidences of eggs forming at least one pronucleus or containing two pronuclei were not significantly different among the periods (82.4–83.5% and 43.4–51.9%, respectively). Nor did the incidences of eggs cleaving (86.7–97.7%) and developing to the blastocyst stage (0–3.5%) differ depending on when, after injection, stimulation began. When some of the reconstituted eggs were observed for cytological morphology 1–1.5 h after injection, 71.7% of the eggs caused premature chromatin condensation, but only 46.2% of them formed two spindles around each of maternal and somatic chromatins. However, the morphology of the somatic spindles differed from that of the spindles, which formed around the oocyte chromatins. Only 7.5% of the eggs contained the normal chromosomal number. In many reconstituted oocytes, before activation, an abnormal spindle formation was observed in the somatic chromatins. In conclusion, these results show that non-enucleated rat oocytes injected with cumulus nuclei can form pronuclei and cleave following chemical activation, whereas blastocyst formation is very limited, probably caused by abnormalities in the spindle formation and distribution of somatic chromatids.
Interaction between embryos and culture conditions duringin vitrodevelopment of bovine early embryos
Authors: Nagao Yoshikazu , Iijima Rumi , Saeki Kazuhiro
Published: April 2008

Various factors such as embryo density and substances in the medium can influence embryo developmentin vitro. These factors and the embryos probably interact with each other, however the interactions are not fully understood. To investigate the interactions, we examined the effects of the number of embryos, drop size, oxygen concentration and glucose and inorganic phosphate in the medium during protein-free culture of bovine IVM/IVF embryos. In Experiment 1, different numbers of embryos were cultured in a 50 μl drop of medium. The frequencies of blastocyst development in the groups with 25, 50 and 100 embryos per drop were higher than in the other groups. One, five and 25 embryos were cultured in different drop sizes (Experiment 2), a 50 µl drop of medium at different O2concentrations (Experiment 3) and a 50 µl drop of medium excluding glucose and/or inorganic phosphate (Experiment 4). In Experiment 2, the size of the medium drops did not improve blastocyst development. In Experiment 3, the highest frequency of blastocyst development for one, five and 25 embryos per drop was obtained at 1, 2.5 and 5% O2, respectively. In Experiment 4, blastocyst development for one and five embryos per drop were improved in the medium excluded inorganic phosphate. These results indicate that there is a cooperative interaction among embryos during culture and that this interaction may be mediated by reduction of toxic factors in the medium. At low embryo density, reduced oxygen concentration or the exclusion of inorganic phosphate enhanced blastocyst development.
Involvement of GABAAreceptor inBufo arenarumoocyte maturation
Authors: Toranzo G. Sánchez , Zelarayán L. , Bonilla F. , Oterino J. , Bühler M.I.
Published: April 2008

Amphibian oocytes meiotic arrest is released under the stimulus of progesterone; this hormone interacts with the oocyte surface and starts a cascade of events leading to the activation of a cytoplasmic maturation promoting factor (MPF) that induces germinal vesicle breakdown (GVBD), chromosome condensation and extrusion of the first polar body.

The aim of this work was to determine whether the activation of a GABAAreceptor is able to induce GVBD in fully grown denuded oocytes ofBufo arenarumand to analyse its possible participation in progesterone-induced maturation. We also evaluated the role of purines and phospholipids in the maturation process induced by a GABAAreceptor agonist such as muscimol.

Our results indicated that the activation of the GABAAreceptor by muscimol induces maturation in a dose- and time-dependent manner and that this activation is a genuine maturation that enables oocytes to form pronuclei. Assays with a receptor antagonist, picrotoxine, showed that the maturation induced by muscimol was inhibited. Treatment with picrotoxine, however, shows that the participation of GABAAreceptor in progesterone-induced maturation is not significant.

In addition, our results indicate that high intracellular levels of purines obtained by the use of db-AMPc and theophylline or the inhibition of the phosphatidylinositol 4,5-bisphosphate (PIP2hydrolysis by neomycin and PIP2turn over by LiCl, respectively, inhibited the maturation induced by muscimol. Treatment with H-7 indicated, however, that PKC activation is not necessary for GVBD induced by the GABAAreceptor agonist. Results suggest that the transduction pathway used by the GABAAreceptor to induce maturation is different from those used by progesterone.
In vitroageing of pig oocytes: effects of the histone deacetylase inhibitor trichostatin A
Authors: Ješeta M. , Petr J. , Krejčová T. , Chmelíková E. , Jílek F.
Published: April 2008

Afterin vitromaturation, the unfertilized pig oocytes underwent the process called ageing. This process involves typical events such as fragmentation, spontaneous parthenogenetic activation or lysis. Inhibition of histone deacetylase, using its specific inhibitor trichostatin A (TSA), significantly delayed the maturation of pig oocytes culturedin vitro. The ageing of oocytes matured under the effect of TSA is the same as the ageing in oocytes matured without TSA. The inhibition of histone deacetylase during oocyte ageing significantly reduced the percentage of fragmented oocytes (from 30% in untreated oocytes to 9% in oocytes aged under the effect of 100 nM of TSA). Oocytes maturedin vitroand subsequently aged for 1 day under the effects of TSA retained their developmental capacity. After parthenogenetic activation, a significantly higher portion (27% vs. 15%) of oocytes developed to the blastocyst stage after 24 h ageing under 100 nM TSA when compared with oocytes activated after 24 h ageing in a TSA-free medium. The parthenogenetic development in oocytes aged under TSA treatment is similar to the development of fresh oocytes (29% of blastocyst) artificially activated immediately afterin vitromaturation.
Congenital quadricuspid aortic valve in children
Authors: Di Pino Alfredo , Gitto Placido , Silvia Antonio , Bianca Innocenzo
Published: April 2008

Quadricuspid aortic valves are rare congenital anomalies, usually diagnosed in adult patients affected by severe aortic regurgitation. We have now encountered three such valves in children undergoing transthoracic echocardiography. All children were asymptomatic. The first child possessed a valve with two larger leaflets, and smaller leaflets of equal size. In the second child, 3 leaflets were of equal size, with 1 small accessory leaflet. The third child had a valve with four leaflets of approximately equal size. In one child, the aortic valve was functioning normally, and came to attention because of mitral valvar prolapse causing mild regurgitation. In the remaining two children, central mild aortic regurgitation was detected using colour flow analysis, and associated dilation of the aortic root was revealed by measurements of the cross-sectional images.
United States – Sunset Reviews of Anti-Dumping Measures on Oil Country Tubular Goods from Argentina: a cloudy sunset
Authors: GROSSMAN GENE M. , WAUTERS JASPER
Published: April 2008

We review the WTO Appellate Body report on United States – Sunset Reviews of Anti-Dumping Measures on Oil Country Tubular Goods from Argentina (WT/DS268/AB/R, 29 November 2004). This dispute is one of several that deals with sunset reviews of antidumping-duty orders. In its ruling, the AB reasserts a rigid distinction between mandatory and discretionary law, and sets a very high standard for Member challenges to laws or practices that allow for violations of WTO obligations but do not mandate such behavior. We argue that this ruling is unfortunate, because it diminishes scope of and incentives for ‘as-such’ challenges to laws and practices, which have a potentially useful role to play in the world trading system. The AB ruling also overlooks the purpose and objectives of sunset reviews – to ensure that duty orders are not extended when their removal would generate no harm to an import competing industry – by failing to impose sufficient discipline on their conduct. We argue that a sunset review requires an evaluation of competitive conditions in the industry and of the reasons and incentives for dumping, in order that the investigating authority can judge whether the removal of a duty order would lead to a continuation or recurrence of dumping and injury. The Appellate Body's rulings in this and other similar cases have the effect of relieving the investigating authority of this responsibility and thereby render the sunset review process virtually meaningless.
Measures Affecting the Cross-Border Supply of Gambling and Betting Services (DS 285)
Authors: IRWIN DOUGLAS A. , WEILER JOSEPH
Published: April 2008

The controversial gambling decision of the Appellate Body is mostly important because of examination of the nature of Access under Article XVI GATS, the relationship of that Article to Articles XIV and XVII GATS, and the parallels with Articles III, XI, and XX GATT. Notably, the Appellate Body took the position that an apparant internal regulatory measure, which, nonetheless, had equivalent effect to a zero quota, violated Article XVI GATS. A similar measure in the area of goods would have been examined under Article III GATT and require a showing of discrimination. The facts of the case would have allowed the decision to be based on Article XVII GATS. Most of this paper deals with this issue. We agree with this interpretation of Article XVI by the Appellate Body but are critical of its hermeneutics, suffering from a textual fetish and a policy phobia. Some other elements in the decision are also examined critically.
Foreword: After Afrofuturism
Authors: LEWIS GEORGE E.
Published: April 2008

Welcome to our special issue on Technology and Black Music in the Americas. As guest editor, I'd like to offer my personal thanks to all of our contributors, who are exploring relatively uncharted currents in the overall flow of black music technology. I'd also like to thank JSAM editor Ellie M. Hisama and assistant editor Benjamin Piekut for their tireless efforts, as well as their extraordinary abilities as editors to navigate quickly between leaf- and forest-level views.
Space‐based measurements of HCl: Intercomparison and historical context
Authors: Lary D. J. , Aulov O.
Published: April 2008

The peak in stratospheric HCl was reached in the late 1990s. Between 1998 and 2004 the stratospheric loading of HCl was relatively constant, with some month to month fluctuation; this was followed by a more pronounced decrease in HCl since 2004. We use probability distribution functions (PDFs) and scatter diagrams for validation and bias characterization of Aura Microwave Limb Sounder (MLS) HCl retrievals. Both these methods allow us to use large statistical samples and do not require correlative measurements to be colocated in space and time. The bias between the Halogen Occultation Experiment (HALOE) and Aura MLS is greatest above the 525 K (∼21 km) isentropic surface. The global average mean bias between Aura and the Atmospheric Chemistry Experiment (ACE) for January 2005 was 2% and between Aura MLS and HALOE was 14%. The widths of the PDFs are a measure of the spatial variability and measurement precision. The Aura MLS HCl PDFs are consistently wider than those for ACE and HALOE, this reflects the retrieval uncertainties. The median observation uncertainty for Aura MLS v1.51 HCl is 12%, and the median ACE v2.2 uncertainty is 8%. We also connect Aura MLS HCl with the heritage of HALOE HCl by using neural networks to learn the interinstrument biases and provide a seamless HCl record from the launch of the Upper Atmosphere Research Satellite (UARS) in 1991 to the present.
Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction
Authors: Christie M J
Published: April 2008

A large range of neuroadaptations develop in response to chronic opioid exposure and these are thought to be more or less critical for expression of the major features of opioid addiction: tolerance, withdrawal and processes that may contribute to compulsive use and relapse. This review considers these adaptations at different levels of organization in the nervous system including tolerance at the μ‐opioid receptor itself, cellular tolerance and withdrawal in opioid‐sensitive neurons, systems tolerance and withdrawal in opioid‐sensitive nerve networks, as well as synaptic plasticity in opioid sensitive nerve networks. Receptor tolerance appears to involve enhancement of mechanisms of receptor regulation, including desensitization and internalization. Adaptations causing cellular tolerance are more complex but several important processes have been identified including upregulation of cAMP/PKA and cAMP response element‐binding signalling and perhaps the mitogen activated PK cascades in opioid sensitive neurons that might not only influence tolerance and withdrawal but also synaptic plasticity during cycles of intoxication and withdrawal. The potential complexity of network, or systems adaptations that interact with opioid‐sensitive neurons is great but some candidate neuropeptide systems that interact with μ‐opioid sensitive neurons may play a role in tolerance and withdrawal, as might activation of glial signalling. Implication of synaptic forms of learning such as long term potentiation and long term depression in opioid addiction is still in its infancy but this ultimately has the potential to identify specific synapses that contribute to compulsive use and relapse.

British Journal of Pharmacology (2008) 154, 384–396; doi:10.1038/bjp.2008.100; published online 14 April 2008
Gonadotropins in doping: pharmacological basis and detection of illicit use
Authors: Stenman U‐H , Hotakainen K , Alfthan H
Published: April 2008

Parenteral administration of human chorionic gonadotropin (hCG) or luteinizing hormone (LH) stimulates the production of testosterone in males and these gonadotropins can therefore be used by athletes to enhance muscle strength. However, they are more expensive and less efficient than testosterone and anabolic steroids. Therefore their main use is probably to stimulate gonadal testosterone production during and after self‐administration of testosterone or anabolic steroids. A positive effect of hCG on muscle strength has not been demonstrated in women and elevated concentrations of hCG in females are often caused by pregnancy. The use of gonadotropins is therefore prohibited only in males but not in females. HCG occurs at low but measurable concentrations in plasma and urine of healthy males and can be measured by sensitive methods. However, the characteristics of the method to be used for doping control have not been defined. Virtually all commercially available hCG assays have been designed for determination of hCG in serum rather than urine, which is used for doping control. Methods based on mass spectrometric detection of fragments derived from hCG extracted from urine by immunoadsorption have been developed but their suitability for doping control remains to be determined. The concentrations of LH in serum and urine are variable and more then 10‐fold higher than those hCG. It is therefore difficult to detect illicit use of LH. The characteristics and reference values for hCG and LH assays used in doping control and the cutoff values need to be defined.

British Journal of Pharmacology (2008) 154, 569–583; doi:fn1; published online 14 April 2008
Antagonism of thromboxane receptors by diclofenac and lumiracoxib
Authors: Selg E , Buccellati C , Andersson M , Rovati G E , Ezinga M , Sala A , Larsson A‐K , Ambrosio E , Låstbom L , Capra V , Dahlén B , Ryrfeldt Å , Folco G C , Dahlén S‐E
Published: April 2008

British Journal of Pharmacology (2008) 153, 1763; doi:10.1038/bjp.2008.106
Discovery and biological characterization of a novel series of androgen receptor modulators
Authors: Zhou C , Wu G , Feng Y , Li Q , Su H , Mais D E , Zhu Y , Li N , Deng Y , Yang D , Wang M‐W
Published: April 2008

Background and purpose:

Selective androgen receptor modulators are of great value in the treatment of prostate cancer. The purpose of this study was to provide a preliminary characterization of a new class of non‐steroidal androgen receptor modulators discovered in a high‐throughput screening campaign.

Experimental approach:

Competitive receptor binding, luciferase‐based reporter methods, cell proliferation and in vivo assays were employed to evaluate an initial set of compounds from chemistry efforts.

Key results:

Forty‐nine analogues from the chemistry efforts showed high affinity binding to androgen receptors, agonist and/or antagonist activities in both CV‐1 and MDA‐MB‐453 transfection assays. A proliferation assay in LNCaP cells also exhibited this profile. A representative of these non‐steroidal compounds (compound 21) was devoid of activity at other nuclear receptors (oestrogen, progesterone, glucocorticoid and mineralocorticoid receptors) in the CV‐1 co‐transfection assay. At the same time, in an immature castrated rat model, it behaved as an androgen receptor antagonist against the growth of prostate, seminal vesicles and levator ani induced by exogenous androgen. Separation of compound 21 into its enantiomers showed that nearly all the androgen receptor modulating activity and binding resided in the dextrorotatory compound (23) while the laevorotatory isomer (22) possessed weak or little effect depending on the cell type studied.

Conclusions and implications:

These non‐steroidal compounds may represent a new class of androgen receptor modulators for the treatment of not only prostate cancer but other clinical conditions where androgens and androgen receptors are involved in the pathological processes.

British Journal of Pharmacology (2008) 154, 440–450; doi:10.1038/bjp.2008.107; published online 14 April 2008
The expression and function of Ca2+‐sensing receptors in rat mesenteric artery; comparative studies using a model of type II diabetes
Authors: Weston A H , Absi M , Harno E , Geraghty A R , Ward D T , Ruat M , Dodd R H , Dauban P , Edwards G
Published: April 2008

Background and purpose:

The extracellular calcium‐sensing receptor (CaR) in vascular endothelial cells activates endothelial intermediate‐conductance, calcium‐sensitive K+ channels (IKCa) indirectly leading to myocyte hyperpolarization. We determined whether CaR expression and function was modified in a rat model of type II diabetes.

Experimental approach:

Pressure myography, western blotting, sharp microelectrode and K+‐selective electrode recordings were used to investigate the functional expression of the CaR and IKCa in rat mesenteric arteries.

Key results:

Myocyte hyperpolarization to the CaR activator calindol was inhibited by Calhex 231. U46619‐induced vessel contraction elevated the extracellular [K+] around the myocytes, and inhibition of this ‘K+ cloud’ by iberiotoxin was needed to reveal calindol‐induced vasodilatations. These were antagonized by Calhex 231 and significantly smaller in Zucker diabetic fatty rat (ZDF) vessels than in Zucker lean (ZL) controls. Myocyte hyperpolarizations to calindol were also smaller in ZDF than in ZL arteries. In ZDF vessels, endothelial cell CaR protein expression was reduced; IKCa expression was also diminished, but IKCa‐generated hyperpolarizations mediated by 1‐EBIO were unaffected.

Conclusions and implications:

The reduced CaR‐mediated hyperpolarizing and vasodilator responses in ZDF arteries result from a decrease in CaR expression, rather than from a modification of IKCa channels. Detection of CaR‐mediated vasodilatation required the presence of iberiotoxin, suggesting a CaR contribution to vascular diameter, that is, inversely related to the degree of vasoconstriction. Compromise of the CaR pathway would favour the long‐term development of a higher basal vascular tone and could contribute to the vascular complications associated with type II diabetes.

British Journal of Pharmacology (2008) 154, 652–662; doi:10.1038/bjp.2008.108; published online 14 April 2008
The existence of a local 5‐hydroxytryptaminergic system in peripheral arteries
Authors: Ni W , Geddes T J , Priestley J R C , Szasz T , Kuhn D M , Watts S W
Published: April 2008

Background and purpose:

5‐HT is a vasoconstrictor exhibiting enhanced effects in systemic arteries from subjects with cardiovascular disease. The effect of endogenous 5‐HT on arteries is controversial, because the concentration of free circulating 5‐HT is low and a 5‐hydroxytryptaminergic system has not been identified in peripheral arteries. We hypothesized that a local 5‐hydroxytryptaminergic system (including 5‐HT synthesis, metabolism, uptake and release) with physiological function exists in peripheral arteries.

Experimental approach:

The presence of key components of a 5‐hydroxytryptaminergic system in rat aorta and superior mesenteric artery was examined using western blot analyses, immunohistochemistry and immunocytochemistry. The function of the rate‐limiting enzyme in 5‐HT biosynthesis, tryptophan hydroxylase (TPH), and 5‐HT transporter was tested by measuring enzyme activity and 5‐HT uptake, respectively. Isometric contraction of arterial strips was used to demonstrate the function of released endogenous 5‐HT in arterial tissues.

Key results:

mRNA for TPH‐1 was present in arteries, with low levels of TPH protein and TPH activity. Expression and function of MAO A (5‐HT metabolizing enzyme) was supported by immunohistochemistry, western analyses and the elevation of concentrations of 5‐hydroxyindoleacetic acid (5‐HT metabolite) after exposure to exogenous 5‐HT. The 5‐HT transporter was localized to the plasma membrane of freshly isolated aortic smooth muscle cells. Peripheral arteries actively took up 5‐HT in a time‐dependent and 5‐HT transporter‐dependent manner. The 5‐HT transporter substrate, (+)‐fenfluramine, released endogenous 5‐HT from peripheral arteries, which potentiated noradrenaline‐induced arterial contraction.

Conclusions and implications:

This study revealed the existence of a local 5‐hydroxytryptaminergic system in peripheral arteries.

British Journal of Pharmacology (2008) 154, 663–674; doi:10.1038/bjp.2008.111; published online 14 April 2008
Aldosterone and the autocrine modulation of potassium currents and oxidative stress in the diabetic rat heart
Authors: Shimoni Y , Chen K , Emmett T , Kargacin G
Published: April 2008

Background and purpose:

Aldosterone plays a major role in cardiac pathology. This study was designed to investigate the role of cardiac aldosterone in modulating K+ currents and oxidative stress in the streptozotocin‐induced diabetic rat heart.

Experimental approach:

Transient and sustained K+ currents were measured in ventricular myocytes by voltage clamp. Plasma and cellular aldosterone were measured by ELISA. Fluorescent dihydroethidium (DHE) was used to assess superoxide ions as markers of oxidative stress.

Key results:

The mineralocorticoid antagonist spironolactone (1 μM, 5–9 h) significantly augmented both K+ currents in diabetic males, with a concomitant shortening of the action potential but had no effect in myocytes from control males or from diabetic females. Effects of spironolactone were restored in ovariectomized diabetic females and abolished in orchidectomized diabetic males. The aldosterone synthase inhibitor FAD286 (1 μM, 5–9 h) significantly augmented K+ currents in cells from diabetic males, but not females. Spironolactone and FAD286 significantly reduced oxidative stress in cells from diabetic males. Plasma aldosterone content was elevated in diabetic males (relative to control), but not in females. Cellular aldosterone was also elevated, but not significantly. The elevation in aldosterone was only partly dependent on a concomitant increase in cellular angiotensin II.

Conclusions and implications:

A gender‐related, sex‐hormone‐dependent elevation in plasma and cardiac cell aldosterone contributed to oxidative stress and to attenuation of K+ currents in diabetic male rats. Aldosterone may thus contribute to diabetes‐associated cardiac arrhythmias. Aldosterone elevation was partly related to levels of angiotensin II, but residual, angiotensin II‐independent, aldosterone maintains functional relevance.

British Journal of Pharmacology (2008) 154, 675–687; doi:10.1038/bjp.2008.114; published online 14 April 2008
Bone morphogenetic protein signalling is required for the anti‐mitogenic effect of the proteasome inhibitor MG‐132 on colon cancer cells
Authors: Wu W K K , Sung J J Y , Wu Y C , Li Z J , Yu L , Cho C H
Published: April 2008

Background and purpose:

Inhibition of proteasome has been emerging as a promising approach in pathway‐directed cancer therapy. Bone morphogenetic protein (BMP) signalling, which is known to be regulated by the ubiquitin–proteasome pathway in osteoblasts, plays a crucial role in the suppression of gastrointestinal carcinogenesis. Here we sought to elucidate the anti‐mitogenic effect of a proteasome inhibitor in relation to BMP signalling in colon cancer.

Experimental approach:

The effects of the proteasome inhibitor MG‐132 on proliferation of SW1116 and HT‐29 colon cancer cells were determined by [3H]‐thymidine incorporation and colony‐formation assay. The involvement of BMP signalling in the action of MG‐132 was elucidated by western blot, real‐time PCR, immunofluorescence and RNA interference.

Key results:

MG‐132 significantly suppressed the proliferation of colon cancer SW1116 and HT‐29 cells. In this regard, MG‐132 activated BMP signalling and this was manifested as an increase in Smad1/5/8 phosphorylation and upregulation of p21Waf1/Cip1 and p27Kip1 expression. Knockdown of BMP receptor II abolished Smad1/5/8 phosphorylation, the induction of p21Waf1/Cip1 and p27Kip1 and inhibition of cell proliferation induced by MG‐132. Further analysis revealed that MG‐132 upregulated the expression of BMP1 and BMP2, which are secreted members of the BMP superfamily. Moreover, the expression of Smad6, an intracellular inhibitor of BMP signalling, was suppressed by MG‐132.

Conclusions and implications:

These findings suggest that inhibition of proteasome suppresses the proliferation of colon cancer cells via activation of BMP signalling. They also demonstrate a novel aspect of proteasome function in the regulation of colon cancer cell proliferation.

British Journal of Pharmacology (2008) 154, 632–638; doi:10.1038/bjp.2008.115; published online 14 April 2008
Cellular and molecular mechanisms responsible for the action of testosterone on human skeletal muscle. A basis for illegal performance enhancement
Authors: Kadi F
Published: April 2008

The popularity of testosterone among drug users is due to its powerful effects on muscle strength and mass. Important mechanisms behind the myotrophic effects of testosterone were uncovered both in athletes using steroids for several years and in short‐term controlled studies. Both long‐term and short‐term steroid usage accentuates the degree of fibre hypertrophy in human skeletal muscle by enhancing protein synthesis. A mechanism by which testosterone facilitates the hypertrophy of muscle fibres is the activation of satellite cells and the promotion of myonuclear accretion when existing myonuclei become unable to sustain further enhancement of protein synthesis. Interestingly, long‐term steroid usage also enhances the frequency of fibres with centrally located myonuclei, which implies the occurrence of a high regenerative activity. Under the action of testosterone, some daughter cells generated by satellite cell proliferation may escape differentiation and return to quiescence, which help to replenish the satellite cell reserve pool. However, whether long‐term steroid usage induces adverse effects of satellite cells remains unknown. Testosterone might also favour the commitment of pluripotent precursor cells into myotubes and inhibit adipogenic differentiation. The effects of testosterone on skeletal muscle are thought to be mediated via androgen receptors expressed in myonuclei and satellite cells. Some evidence also suggests the existence of an androgen‐receptor‐independent pathway. Clearly, testosterone abuse is associated with an intense recruitment of multiple myogenic pathways. This provides an unfair advantage over non‐drug users. The long‐term consequences on the regenerative capacity of skeletal muscle are unknown.

British Journal of Pharmacology (2008) 154, 522–528; doi:fn1; published online 14 April 2008