bluuebunny/crossref_metadata_2025 huggingface dataset:
On the motion of charged particles in a
sheared force-free magnetic field
Authors: VEKSTEIN G. E. , BOBROVA N. A. , BULANOV S. V.
Published: July 2002

This paper considers single-particle trajectories in a planar sheared force-free magnetic field. A specific feature of this magnetic configuration is the absence
of both gradient and curvature magnetic drifts, as well as a diamagnetic force along
field lines. Therefore, in the framework of the drift approximation, the motion of
the particle guiding centre does not feel the magnetic field's non-uniformity. Here
we discuss how the latter affects actual particle trajectories, making them quite
different from simple circular gyromotion even when the Larmor radius is small.
It is also shown how magnetic confinement ceases to work when the Larmor radius
becomes comparable to the spatial scale of the field variation.
Phonetic characteristics of an unexploded palatal implosive in Hendo
Authors: Demolin Didier , Ngonga-Ke-Mbembe Hubert , Soquet Alain
Published: July 2002

This paper describes the phonetic characteristics of an unexploded palatal implosive in Hendo, a Bantu language spoken in the Democratic Republic of Congo. This sound is an allophone of a palatal affricate implosive. Consideration of acoustic, aerodynamic and articulatory data obtained from various methods give a precise description of this sound.
Local scenes and dangerous crossroads: punk and theories of cultural hybridity
Authors: O'Connor Alan
Published: July 2002

Against theories of cultural hybridity and disembodied flows of recorded media, this article argues for the continued relevance of the concept of regional musical scenes. It takes as examples contemporary punk as it exists in four cities and shows that there are different local accents in Washington D.C., Austin, Texas, Toronto and Mexico City. The conclusion describes some aspects of the social organisation of cultural contacts between these scenes. The article is part of a larger project of multi-site ethnography of youth subculture and resistance to globalisation.
Control of an operator-assisted mobile robotic system
Authors: Chung Jae H.
Published: July 2002

In this paper, two different control methods are developed for an operator-assisted mobile robotic system for high load applications. For high load applications of mobile robots, an accurate tire model that considers wheel slip needs to be studied to achieve robustness of the system response. First, a simple operator-manipulator coordination system is developed based on explicit force control. Then, a position controller for the platform is designed to minimize the effect of wheel slip on control performance and integrated with the force controller for the operator-manipulator subsystem based on a motion coordination scheme. Then, a new type of human-robot coordination control method is developed, in which robust force control of the manipulator and impedance control of the mobile platform are integrated to achieve robust response and smooth interaction between the operator, the manipulator and the mobile platform. In simulation, the developed methods are compared for control performance on following the operator's motion intention.
An optimum robot path planning with payload constraints
Authors: Saramago Sezimaria F. P. , Ceccarelli Marco
Published: July 2002

This paper presents a general methodology for the off-line planning of optimal trajectory of robot manipulators by taking into account the grasping forces in the manipulator gripper. The mechanical energy of the actuators has been considered for the formulation of the objective function. The optimization problem has been formulated as subject to physical constraints, input torque/force constraints and payload constraints. The mathematical model takes into account the coupled nonlinear equations of manipulator motion. A numerical example shows the efficiency of the proposed procedure.
Nutrient fluxes in bulk precipitation, throughfall and stemflow in montane subtropical moist forest on Ailao Mountains in Yunnan, south-west China
Authors: Liu Wenyao , Fox John E. D. , Xu Zaifu
Published: July 2002

A study of nutrient movement through rainfall, throughfall and stemflow, as well as epiphytic bryophyte (moss and liverwort) biomass and its effect on nutrient composition of stemflow, was conducted for 2 y in subtropical montane moist forest (Lithocarpus–Castanopsis association) at Xujiaba, Ailao Mountain National Nature Reserve, Yunnan, south-west China. Base cation and fluxes were increased in throughfall, while NH4+-N and NO3--N were reduced relative to precipitation. Annual throughfall inputs of N, P, Ca and S were mainly from precipitation, while most K and two-thirds of Mg throughfall input was due to canopy leaching. Input of Na in the precipitation and throughfall was low in this forest. Net flux (throughfall flux minus bulk precipitation) and deposition ratios (ratio of throughfall flux to bulk precipitation flux) were in the low part of the range reported for other tropical montane rain forests. The throughfall data for this forest reveal generally low cycling rates for mineral elements. Abundant epiphytic bryophytes on bole bark affected the chemical composition of stemflow by selective uptake or release of elements. Relative to trees without epiphytic bryophytes, the annual amounts of total N, NH4+-N, Mg, Na and SO42--S were enhanced, while NO3--N, K, P and Ca were depleted in stemflow. Contributions of N from nitrogen-fixing organisms are likely to be constrained by low temperatures.
Phenology and stem-growth periodicity of tree species in Amazonian floodplain forests
Authors: Schöngart Jochen , Piedade Maria Teresa F. , Ludwigshausen Sabine , Horna Viviana , Worbes Martin
Published: July 2002

To study the impact of the annual long-term flooding (flood-pulse) on seasonal tree development in Amazonian floodplains, the phenology and growth in stem diameter of various tree species with different leaf-change patterns were observed over a period of 2 y. The trees of the functional ecotypes, evergreen, brevi-deciduous, deciduous and stem-succulent showed a periodic behaviour mainly triggered by the flood-pulse. Trees have high increment during the terrestrial phase. Flooding causes a shedding of some or all leaves leading to a cambial dormancy of about 2 mo and the formation of an annual ring. Studies carried out in tropical dry forests verify a strong relationship between the phenological development and the water status of the trees, strongly affected by seasonal drought. The comparison of the phenology and the diameter growth of the corresponding ecotypes in floodplain forest and a semi-deciduous forest in Venezuela shows a displacement of at least 2 mo in the periodicity, except for stem-succulent tree species. For stem-succulent trees it remains unclear which factors influence phenology and stem diameter growth.
The development of complex verb constructions in British Sign Language
Authors: MORGAN GARY , HERMAN ROSALIND , WOLL BENCIE
Published: July 2002

This study focuses on the mapping of events onto verb-argument structures in British Sign Language (BSL). The development of complex sentences in BSL is described in a group of 30 children, aged 3;2–12;0, using data from comprehension measures and elicited sentence production. The findings support two interpretations: firstly, in the mapping of concepts onto language, children acquiring BSL overgeneralize the use of argument structure related to perspective shifting;secondly, these overgeneralizations are predicted by the typological characteristics of the language and modality. Children under age 6;0, in attempting to produce sentences encoded through a perspective shift, begin by breaking down double-verb constructions (AB verbs) into components, producing only the part of the verb phrase which describes the perspective of the patient. There is also a prolonged period of development of non-manual features, with the full structure not seen in its adult form until after 9;0. The errors in the use of AB verbs and the subsequent protracted development of correct usage are explained in terms of the conceptual–linguistic interface.
Macroscopic models for melting derived from
averaging microscopic Stefan problems II:
Effect of varying geometry and composition
Authors: LACEY A. A. , HERRAIZ L. A.
Published: July 2002

A mushy region is assumed to consist of a fine mixture of two distinct phases separated by
free boundaries. A method of multiple scales, with restrictions on the form of the microscopic
free boundaries, is used to derive a macroscopic model for the mushy region. The final model
depends both on the microscopic structure and on how the free-boundary temperature varies
with curvature (Gibbs–Thomson effect), kinetic undercooling, or, for an alloy, composition.
The Definition of Motion in Avicenna's Physics
Authors: Hasnawi Ahmad
Published: July 2002

A part of chapter 1, Book II of the Physics of the šif¯' is dedicated to the aristotelian definition of motion (Physics III, 1, 201a10-11). The developments to which the treatment of this question gives rise are distinctive of the Avicennian style in his Physics. By assuming the notion of double entelechy, Avicenna is following the most classical exegetical tradition. However, by setting a correspondence between the double entelechy and the double notion of motion: 1) motion as an intermediary state, which can be ascribed to a moving object at any instant of its trajectory, and 2) motion as a traversal of a given distance, which cannot be ascribed to the moving object, but at the end-point of its trajectory, Avicenna gives a new content to a lieu commun of the exegetical tradition.
Selected papers from EUROCALL 2001: University of Nijmegen, The Netherlands
Authors: THOMPSON JUNE
Published: July 2002

EUROCALL 2001, held at the University of Nijmegen, The Netherlands,
included more than a hundred presentations. Out of these, twenty papers were submitted and
twelve of these were selected for inclusion in this issue of ReCALL containing the
Selected Papers. Due to space constraints a further two papers have been held in reserve for
the next issue. Additional material will be included in a CD-ROM to be produced by the
conference organisers. See http://www.kun.nl/eurocall/index2.html for details.
Narcy’s learning stages as the base for creating multimedia modules for L2 acquisition
Authors: BOULON JOLINE
Published: July 2002

Authoring systems can be a great advantage for teachers concerned with tools
created specifically for their learners. They allow the designer to conceive modules for a
precise public. The designer, often the teacher himself, can model his work on existing CD-ROMs
marketed for the general public, inserting information that is more specific to his own public.
For L2 acquisition, this solution can be satisfactory if the teacher’s main preoccupation
is to have learners work on the language at their own rhythm and in their own time. However,
there are a few oversights to this type of conception which need to be resolved: (1) teacher
access to the finished product, (2) student access to the different parts of the finished product,
and (3) pedagogical and didactic criteria. This paper concerned with all three oversights,
notably the last, concentrates on developing the characteristics of all four learning stages
described by Narcy (1997), while illustrating the different theoretical and practical
possibilities of incorporating these stages into modules created by teachers.
A REVIEW OF CHROMOSOME NUMBERS IN THE GENUS TILIA (TILIACEAE)
Authors: PIGOTT C. D.
Published: July 2002

Chromosome numbers for all 23 species of Tilia recognized by the author, and for several subspecies and hybrids, are reviewed. Counts or cytometric analyses for 14 species are reported for the first time; of these, eight species are diploid (2n=82): T. amurensis subsp. taquetii, T. chingiana, T. endochrysea, T. kiusiana, T. mandshurica, T. caroliniana, T. heterophylla and T. mexicana, five are tetraploid (2n=164): T. chinensis, T. henryana, T. miqueliana, T. mongolica and T. paucicostata, and one is octoploid (2n=328): T. nobilis. T. japonica, previously reported as diploid, is tetraploid in Japan (Hokkaidō) and in China. Three new combinations are created: T. amurensis Rupr. subsp. taquetii (C.K. Schneid.) Pigott, T. cordata Mill. subsp. sibirica (Bayer) Pigott and T. platyphyllos Scop. subsp. corinthiaca (Bosc ex K. Koch) Pigott.
Spinning into Europe: Britain, West Germany and the Netherlands – Uranium Enrichment and the Development of the Gas Centrifuge 1964–1970
Authors: Schrafstetter Susanna , Twigge Stephen
Published: July 2002

Based on recently released official documents, the article explores the role played by advanced technology in the Wilson government's efforts to join the Common Market. The analysis focuses on the development of the ultra-centrifuge process – a new technology to produce enriched uranium. The article shows that in restricting collaboration to the Netherlands and West Germany, the British government sought to undermine France's leading role in Europe and to undermine Franco-German relations. It also demonstrates that Britain was determined to establish a European solution to the question of uranium supply even if this led to serious frictions in the Anglo-American special relationship.
Structured inverse eigenvalue problems
Authors: Chu Moody T. , Golub Gene H.
Published: July 2002

An inverse eigenvalue problem concerns the reconstruction of a structured
matrix from prescribed spectral data. Such an inverse problem arises in many
applications where parameters of a certain physical system are to be determined
from the knowledge or expectation of its dynamical behaviour. Spectral
information is entailed because the dynamical behaviour is often governed by
the underlying natural frequencies and normal modes. Structural stipulation
is designated because the physical system is often subject to some feasibility
constraints. The spectral data involved may consist of complete or only partial
information on eigenvalues or eigenvectors. The structure embodied by the
matrices can take many forms. The objective of an inverse eigenvalue problem
is to construct a matrix that maintains both the specific structure as well as
the given spectral property. In this expository paper the emphasis is to provide
an overview of the vast scope of this intriguing problem, treating some of its
many applications, its mathematical properties, and a variety of numerical
techniques.
Black holes in stars and galaxies
Authors: CHARLES PHIL
Published: July 2002

For 200 years, black holes have been a solution looking for a problem. In the last two decades they have moved to become a real scientific phenomenon. Black holes exist both as stars in our own Galaxy (identifiable as members of binary stars that emit X-rays) and as the centres of energetic galaxies (‘active galactic nuclei’). The last decade has seen the first accurate mass measurements of these black holes, which lie in the range from five times the mass of our own Sun to many million times. We also have clear evidence for the way that black holes accrete material as their primary energy source. Furthermore, the presence of super-massive black holes has been established in some nearby galaxies, and in the centre of our own Galaxy, from their gravitational effect on nearby stars. Some observations show processes that occur very close to the black hole, where the field of gravity is strong enough to test General Relativity. Recent observations suggest the existence of intermediate mass black holes of an as yet unknown origin.
SUMMAC: a text summarization evaluation
Authors: MANI INDERJEET , KLEIN GARY , HOUSE DAVID , HIRSCHMAN LYNETTE , FIRMIN THERESE , SUNDHEIM BETH
Published: July 2002

The TIPSTER Text Summarization Evaluation (SUMMAC) has developed several new
extrinsic and intrinsic methods for evaluating summaries. It has established definitively that
automatic text summarization is very effective in relevance assessment tasks on news articles.
Summaries as short as 17% of full text length sped up decision-making by almost a factor
of 2 with no statistically significant degradation in accuracy. Analysis of feedback forms
filled in after each decision indicated that the intelligibility of present-day machine-generated
summaries is high. Systems that performed most accurately in the production of indicative
and informative topic-related summaries used term frequency and co-occurrence statistics,
and vocabulary overlap comparisons between text passages. However, in the absence of a
topic, these statistical methods do not appear to provide any additional leverage: in the case
of generic summaries, the systems were indistinguishable in accuracy. The paper discusses
some of the tradeoffs and challenges faced by the evaluation, and also lists some of the
lessons learned, impacts, and possible future directions. The evaluation methods used in the
SUMMAC evaluation are of interest to both summarization evaluation as well as evaluation
of other ‘output-related’ NLP technologies, where there may be many potentially acceptable
outputs, with no automatic way to compare them.
Word clustering and disambiguation based on co-occurrence data
Authors: LI HANG
Published: July 2002

We address the problem of clustering words (or constructing a thesaurus) based on co-occurrence
data, and conducting syntactic disambiguation by using the acquired word classes.
We view the clustering problem as that of estimating a class-based probability distribution
specifying the joint probabilities of word pairs. We propose an efficient algorithm based on the
Minimum Description Length (MDL) principle for estimating such a probability model. Our
clustering method is a natural extension of that proposed in Brown, Della Pietra, deSouza,
Lai and Mercer (1992). We next propose a syntactic disambiguation method which combines
the use of automatically constructed word classes and that of a hand-made thesaurus. The
overall disambiguation accuracy achieved by our method is 88.2%, which compares favorably
against the accuracies obtained by the state-of-the-art disambiguation methods.
Climate variability, vulnerability and effectiveness of farm-level adaptation options: the challenges and implications for food security in Southwestern Cameroon
Authors: Molua Ernest L.
Published: July 2002

The risks associated with increasing climate variability pose technological and economic challenges to societies which are dependent on agriculture for their livelihood. In Southwestern Cameroon the natural variability of rainfall and temperatures contribute to variability in agricultural production and food insecurity. This paper explores the impact of climate variability in Southwestern Cameroon on food availability. It examines farm household's vulnerability to food availability relating to climate, and reviews the interplay of climate, agriculture, and prospects for food security in the region. An econometric function directly relates farm income and precipitation, in order to statistically estimate the significance of farm-level adaptation methods. The results reveal that precipitation during growing and adaptation methods through changes in soil tillage and crop rotation practices have significant effects on farm returns. An essential precondition for food security and overall agricultural development in Southwestern Cameroon is a dynamic agricultural sector brought about both by steady increase in agricultural production and by greater efforts in farmer support, to enable farm households to take advantage of the opportunities and to minimize the negative impacts of climate variation on agriculture.
Thermal issues
Authors: Marsh Rob
Published: July 2002

Max Fordham's perceptive
comments (letters, arq 5/3) raise
many interesting points on
building physics and the
environmental performance of
buildings. Our article (arq 5/1)
summarizes a research project that
environmentally analyzed trends
in Danish housing design. The
results showed that the typical
design strategies advocated by
‘traditional’ low-energy and passive
housing design methods (large
glass areas and heavy thermal mass)
are not necessarily the most
optimal. Such strategies only take
account of the heating demand and
do not use modern life-cycle
analysis methodologies where the
environmental impact of the
building materials is also
integrated.
Why Are So Many Important Events Unpredictable? Self-Organized Criticality as the ‘Engine of History’
Authors: Brunk Gregory G.
Published: July 2002

The nonlinear dynamical process of self-organized criticality provides a new ‘theory of history’ that explains a number of unresolved anomalies: Why are the really big events in human history usually unpredictable? Why is it impossible to anticipate sudden political, economic, and social changes? Why do distributions of historical data almost always contain a few extreme events that seem to have had a different cause from all the rest? Why do so many of our ‘lessons of history’ fail to predict important future events? As people, organizations, and nations become increasingly sensitive to each other's behavior, trivial occurrences sometimes propagate into sudden changes. Such events are unpredictable because in the self-organized criticality environment that characterizes human history, the magnitude of a cause often is unrelated to the magnitude of its effect.
In Search of a Welfare Democracy
Authors: Fitzpatrick Tony
Published: July 2002

This article contributes to the growing literature concerning the necessity and desirability of democratising the UK welfare state. It takes a theoretical approach by exploring some of the key influences on contemporary debates: risk society, governmentality, the new social democracy and associational welfare. The article suggests that none of these supplies the theoretical foundations of a welfare democracy and that another approach must be found. It concludes that only by engaging with the debate concerning deliberative democracy can social policy find a way forward. The key is to emancipate social time through an alternative ethic to that of paid employment.
Inherited hypertrichoses
Authors: Garcia‐Cruz D , Figuera LE , Cantu JM
Published: July 2002

Hypertrichosis is a rare condition characterized by excessive growth of hair (terminal, vellus or lanugo) in areas of the body that are not predominantly androgen dependent, and it is independent of age, race or sex. It can be congenital, late‐onset, generalized, localized, inherited or acquired. More than 50 different OMIM entries related to hypertrichosis exist, few of them with a localized gene locus or with a candidate gene. The review of generalized hypertrichoses from a historical point of view, including a review of their clinical and genetic features, shows heterogeneity with at least nine different entities. A short analysis of other forms of hypertrichosis is presented.
Prognosis and work absence due to occupational contact dermatitis
Authors: Adisesh A. , Meyer J. D. , Cherry N. M.
Published: July 2002

The consequences of a diagnosis of occupational contact dermatitis (OCD) were investigated using cases available from the voluntary surveillance scheme, EPIDERM. Cases of OCD reported from November 1994 to September 1995 were identified and sampled to give at least 100 cases of allergic, irritant and mixed OCD reported by consultant dermatologists (344 cases) and occupational physicians (377 cases). A questionnaire was sent to the reporting physician to elicit further information. 512 completed questionnaires were returned, of which 510 were eligible for analysis. Among cases reported by dermatologists (n = 286) and occupational physicians (n = 224), 7% (6.3%) had been unemployed and 16.8% (20.1%) had taken sick leave. 3 factors independently predicted time off work in a logistic regression analysis: age OR = 1.25 (95% CI, 1.05–1.49), allergic dermatitis OR = 1.77 (95% CI, 1.13–2.79) and medicolegal assessment OR = 4.42 (95% CI, 2.20–8.89). Overall, 15.7% did not improve clinically between the first and last visit. Those who did not improve had been exposed to the agent for longer (mean 7.6 years) than those who did (5.3 years) (p = 0.09). In patients ≤ 45 years, those reported to be atopic failed to improve (25.4%) more often than those not atopic (13.4%) (p = 0.04). The substantial numbers (21%) with time off work and with persistent dermatitis suggest that OCD continues to have a significant impact on workers and their employers.
Quantification of hepatic thrombopoietin mRNA transcripts in patients with chronic liver diseases shows maintained gene expression in different etiologies of liver cirrhosis
Authors: Tacke Frank , Trautwein Christian , Zhao Shourong , Andreeff Michael , Manns Michael P. , Ganser Arnold , Schöffski Patrick
Published: July 2002

Background/Aims:

Platelet production is regulated by thrombopoietin (TPO), which is primarily synthesized in the liver. The TPO in patients with liver diseases could possibly be owing to impaired hepatic TPO production. As we reported previously, TPO serum levels are not decreased in patients with liver diseases compared with healthy controls and do not depend on the stage of cirrhosis or platelet count, but are highly elevated in patients with chronic virus hepatitis.

Methods:

To study possible mechanisms, we measured hepatic TPO mRNA levels in liver tissue samples from 31 liver cirrhosis patients by quantitative TaqMan real‐time RT–PCR and corresponding serum TPO concentrations by ELISA.

Results:

Median TPO serum levels were elevated in patients with viral hepatitis (n = 12) compared with patients with a biliary (n = 10), alcoholic (n = 6) or other (n = 3) disease etiology, while hepatic TPO mRNA levels did not differ. The TPO mRNA levels in patients with chronic liver diseases were not different from normal liver tissue sample. The TPO mRNA and TPO serum level did not correlate.

Conclusions:

We conclude that hepatic TPO gene expression appears to be maintained on a constitutive transcriptional level in patients with liver diseases and does not change dependent on disease etiology.
The highly selective CRF2 receptor antagonist K41498 binds to presynaptic CRF2 receptors in rat brain
Authors: Lawrence A J , Krstew E V , Dautzenberg F M , Rühmann A
Published: July 2002

Novel analogues of antisauvagine‐30 (aSvg‐30), a selective antagonist for CRF2 receptors, have been synthesized and characterized in vitro and in vivo.

The analogues were tested for their ability to compete for [125I‐Tyr0]Svg binding and to inhibit Svg‐stimulated adenylate cyclase activity in human embryonic kidney (HEK) 293 cells, permanently transfected with cDNA coding for the human CRF1 (hCRF1), hCRF2α and hCRF2β receptor. One analogue [D‐Phe11, His12, Nle17]Svg(11‐40), named K41498, showed high affinity binding to hCRF2α (Ki=0.66±0.03 nM) and hCRF2β (Ki=0.62±0.01 nM) but not the hCRF1 receptor (ki=425+50 nM) and decreased Svg‐stimulated cAMP accumulation in hCRF2 expressing cells. In conscious Wistar‐Kyoto rats, K41498 (1.84 μg, i.v.) antagonized the hypotensive response to systemic urocortin (1.4 μg, i.v.), but did not block the pressor response to centrally administered urocortin (2.35 μg, i.c.v.).

K41498 was subsequently radio‐iodinated, and in autoradiographic studies, specific (sensitive to rat urocortin, astressin and aSvg30, but insensitive to antalarmin) binding of 125I‐K41498 (100 pM) was detected in the heart and in selected brain regions including the nucleus tractus solitarius (NTS), spinal trigeminal nucleus, lateral septum and around the anterior and middle cerebral arteries.

Following unilateral nodose ganglionectomy, binding of 125I‐K41498 was reduced by 65% in the ipsilateral NTS, indicative of presynaptic CRF2 receptors on vagal afferent terminals.

These data demonstrate that K41498 is a useful tool to study native CRF2 receptors in the brain and periphery.

British Journal of Pharmacology (2002) 136, 896–904. doi:10.1038/sj.bjp.0704783
P2Y1 and P2Y2 receptors are coupled to the NO/cGMP pathway to vasodilate the rat arterial mesenteric bed
Authors: Buvinic Sonja , Briones René , Huidobro‐Toro J Pablo
Published: July 2002

To assess the role of nucleotide receptors in endothelial‐smooth muscle signalling, changes in perfusion pressure of the rat arterial mesenteric bed, the luminal output of nitric oxide (NO) and guanosine 3′,5′ cyclic monophosphate (cGMP) accumulation were measured after the perfusion of nucleotides.

The rank order of potency of ATP and analogues in causing relaxation of precontracted mesenteries was: 2‐MeSADP=2‐MeSATP>ADP>ATP=UDP=UTP>adenosine. The vasodilatation was coupled to a concentration–dependent rise in NO and cGMP production. MRS 2179 selectively blocked the 2‐MeSATP‐induced vasodilatation, the NO surge and the cGMP accumulation, but not the UTP or ATP vasorelaxation.

mRNA encoding for P2Y1, P2Y2 and P2Y6 receptors, but not the P2Y4 receptor, was detected in intact mesenteries by RT–PCR. After endothelium removal, only P2Y6 mRNA was found.

Endothelium removal or blockade of NO synthase obliterated the nucleotides‐induced dilatation, the NO rise and cGMP accumulation. Furthermore, 2‐MeSATP, ATP, UTP and UDP contracted endothelium‐denuded mesenteries, revealing additional muscular P2Y and P2X receptors.

Blockade of soluble guanylyl cyclase reduced the 2‐MeSATP and UTP‐induced vasodilatation and the accumulation of cGMP without interfering with NO production.

Blockade of phosphodiesterases with IBMX increased 15–20 fold the 2‐MeSATP and UTP‐induced rise in cGMP; sildenafil only doubled the cGMP accumulation. A linear correlation between the rise in NO and cGMP was found.

Endothelial P2Y1 and P2Y2 receptors coupled to the NO/cGMP cascade suggest that extracellular nucleotides are involved in endothelial‐smooth muscle signalling. Additional muscular P2Y and P2X receptors highlight the physiology of nucleotides in vascular regulation.

British Journal of Pharmacology (2002) 136, 847–856. doi:10.1038/sj.bjp.0704789
Attenuation of morphine tolerance after antisense oligonucleotide knock‐down of spinal mGluR1
Authors: Sharif Reza N , Osborne Michael , Coderre Terence J , Fundytus Marian E
Published: July 2002

Chronic systemic treatment of rats with morphine leads to the development of opioid tolerance. This study was designed to examine the effects of intrathecal (i.t.) infusion of a metabotropic glutamate receptor 1 (mGluR1) antisense oligonucleotide, concomitant with chronic morphine treatment, on the development of tolerance to morphine's antinociceptive effects.

All rats received chronic (6 day) s.c. administration of morphine to induce opioid tolerance. Additionally, rats were treated with either mGluR1 antisense (AS), missense (MIS) or artificial cerebrospinal fluid (ACSF) by i.t. infusion via chronically implanted i.t. catheters connected to osmotic mini‐pumps. The effects of acute i.t. or s.c. morphine on tail‐flick latencies were assessed prior to and following chronic s.c. morphine treatment for all chronic i.t. infusion groups. mGluR1 protein level in the spinal cord was determined by Western blot analysis for all treatments, assessing the efficiency of knock‐down with AS treatment.

Acute i.t. morphine dose‐dependently produced antinociception in the tail‐flick test in naïve rats. Systemic morphine‐treated rats administered i.t. ACSF or MIS developed tolerance to i.t. morphine. Chronic i.t. infusion with mGluR1 AS significantly reduced the development of tolerance to i.t. morphine.

In contrast to i.t. morphine, tolerance developed to the antinociceptive effects of s.c. morphine, in all i.t. infusion groups, including the mGluR1 AS group.

The spinal mGluR1 protein level was dramatically decreased after mGluR1 AS infusion when compared to control animals (naïve and ACSF‐treated animals).

These findings suggest that the spinal mGluR1 is involved in the development of tolerance to the antinociceptive effects of morphine. Selective blockade of mGluR1 may be beneficial in preventing the development of opioid analgesic tolerance.

British Journal of Pharmacology (2002) 136, 865–872. doi:10.1038/sj.bjp.0704792
New insights into heparin binding to vitronectin: studies with monoclonal antibodies
Authors: UNDERWOOD P. Anne , KIRKPATRICK Alan , MITCHELL Sue M.
Published: July 2002

Vitronectin is a plasma glycoprotein that binds to a variety of ligands. There is considerable debate regarding the dependency of these binding interactions upon the conformational status of vitronectin, the role of multimerization and how the binding of different ligands can change vitronectin's conformational state. We have developed a method of capturing vitronectin directly from fresh plasma using solid-phase monoclonal antibodies. Various biotin-labelled secondary monoclonal antibodies were used to quantify the bound vitronectin and to measure its degree of denaturation. Using these tools we demonstrated that one monoclonal antibody partially denatured vitronectin without direct multimerization. Treatment of vitronectin in plasma with soluble heparin produced a similar degree of denaturation. These results led to a proposed adaptation of the unfolding/refolding pathways for chemically denatured vitronectin originally presented by Zhuang and co-workers in 1996 [Zhuang, Blackburn and Peterson (1996) J. Biol. Chem. 271, 14323–14332 and Zhuang, Li, Williams, Wagner, Seiffert and Peterson (1996) J. Biol. Chem. 271, 14333–14343]. The adapted version allows for the production of a more stable partially unfolded intermediate, resulting from the binding of particular ligands. We also demonstrated that the avidity of heparin binding to vitronectin is governed by both the conformational state of the monomer and multimerization of the molecule.
Effects of l- and d-REKR amino acid-containing peptides on HIV and SIV envelope glycoprotein precursor maturation and HIV and SIV replication
Authors: BAHBOUHI Bouchaib , CHAZAL Nathalie , SEIDAH Nabil Georges , CHIVA Cristina , KOGAN Marcelo , ALBERICIO Fernando , GIRALT Ernest , BAHRAOUI Elmostafa
Published: July 2002

The aim of the present study was to evaluate the capacity of synthetic l- and d-peptides encompassing the HIV-1BRU gp160 REKR cleavage site to interfere with HIV and simian immuno-deficiency virus (SIV) replication and maturation of the envelope glycoprotein (Env) precursors. To facilitate their penetration into cells, a decanoyl (dec) group was added at the N-terminus. The sequences synthesized included dec5d or dec5l (decREKRV), dec9d or dec9l (decRVVQREKRV) and dec14d or dec14l (TKAKRRVVQREKRV). The peptide dec14d was also prepared with a chloromethane (cmk) group as C-terminus. Because l-peptides exhibit significant cytotoxicity starting at 35μM, further characterization was conducted mostly with d-peptides, which exhibited no cytotoxicity at concentrations higher than 70μM. The data show that only dec14d and dec14dcmk could inhibit HIV-1BRU, HIV-2ROD and SIVmac251 replication and their syncytium-inducing capacities. Whereas peptides dec5d and dec9d were inactive, dec14dcmk was at least twice as active as peptide dec14d. At the molecular level, our data show a direct correlation between anti-viral activity and the ability of the peptides to interfere with maturation of the Env precursors. Furthermore, we show that when tested in vitro the dec14d peptide inhibited PC7 with an inhibition constant Ki = 4.6μM, whereas the peptide dec14l preferentially inhibited furin with a Ki = 28μM. The fact that PC7 and furin are the major prohormone convertases reported to be expressed in T4 lymphocytes, the principal cell targets of HIV, suggests that they are involved in the maturation of HIV and SIV Env precursors.
UVB-mediated activation of p38 mitogen-activated protein kinase enhances resistance of normal human keratinocytes to apoptosis by stabilizing cytoplasmic p53
Authors: CHOUINARD Nadine , VALERIE Kristoffer , ROUABHIA Mahmoud , HUOT Jacques
Published: July 2002

Human keratinocytes respond to UV rays by developing a fast adaptive response that contributes to maintaining their functions and survival. We investigated the role of the mitogen-activated protein kinase pathways in transducing the UV signals in normal human keratinocytes. We found that UVA, UVB or UVC induced a marked and persistent activation of p38, whereas c-Jun N-terminal kinase or extracellular signal-regulated kinase were less or not activated respectively. Inhibition of p38 activity by expression of a dominant-negative mutant of p38 or with SB203580 impaired cell viability and led to an increase in UVB-induced apoptosis. This sensitization to apoptosis was independent of caspase activities. Inhibition of p38 did not sensitize transformed HaCaT keratinocytes to UVB-induced apoptosis. In normal keratinocytes, expression of a dominant-negative mutant of p53 increased UVB-induced cell death, pointing to a role for p53. In these cells, UVB triggered a p38-dependent phosphorylation of p53 on Ser-15. This phosphorylation was associated with an SB203580-sensitive accumulation of p53, even in the presence of a serine phosphatase inhibitor. Accumulated p53 was localized mainly in the cytoplasm, independently of CRM1 nuclear export. In HaCaT cells, p53 was localized exclusively in the nucleus and its distribution and level were not affected by UVB or p38 inhibition. However, UVB induced an SB203580-insensitive phosphorylation on Ser-15 of mutated p53. Overall, our results suggest that, in normal human keratinocytes, protection against UVB depends on p38-mediated phosphorylation and stabilization of p53 and is tightly associated with the cytoplasmic sequestration of wild-type p53. We conclude that the p38/p53 pathway plays a key role in the adaptive response of normal human keratinocytes against UV stress.
The chitinase 3-like protein human cartilage glycoprotein 39 (HC-gp39) stimulates proliferation of human connective-tissue cells and activates both extracellular signal-regulated kinase- and protein kinase B-mediated signalling pathways
Authors: RECKLIES Anneliese D. , WHITE Chantal , LING Hua
Published: July 2002

Human cartilage glycoprotein 39 (HC-gp39) is a glycoprotein secreted by articular chondrocytes, synoviocytes and macrophages. Increased levels of HC-gp39 have been demonstrated in synovial fluids of patients with rheumatoid or osteoarthritis. The increased secretion of HC-gp39 under physiological and pathological conditions with elevated connective-tissue turnover suggests its involvement in the homoeostasis of these tissues. We report here that HC-gp39 promotes the growth of human synovial cells as well as skin and fetal lung fibroblasts. A dose-dependent growth stimulation was observed when each of the fibroblastic cell lines was exposed to HC-gp39 in a concentration range from 0.1 to 2nM, which is similar to the effective dose of the well-characterized mitogen, insulin-like growth factor-1. At suboptimal concentrations, the two growth factors work in a synergistic fashion. The use of selective inhibitors of the mitogen-activated protein kinase and the protein kinase B (AKT) signalling pathways indicates that both are involved in mediating the mitogenic response to HC-gp39. Phosphorylation of both extracellular signal-regulated kinases 1/2 and AKT occurred in a dose- and time-dependent fashion upon addition of HC-gp39. Activation of these signalling pathways could also be demonstrated in human chondrocytes. Thus HC-gp39 initiates a signalling cascade in connective-tissue cells which leads to increased cell proliferation, suggesting that this protein could play a major role in the pathological conditions leading to tissue fibrosis.
A kinetic model of the co-operative binding of calcium and ADP to scallop (Argopecten irradians) heavy meromyosin
Authors: NYITRAI Miklós , SZENT-GYÖRGYI Andrew G. , GEEVES Michael A.
Published: July 2002

Analysis of the kinetics of ATP and ADP binding to scallop (Argopecten irradians) heavy meromyosin (HMM) showed that the only calcium-dependent process is the rate of ADP release. At physiological ionic strength calcium accelerated ADP release about 20-fold. Notably in the absence of calcium only one ADP bound HMM, with an affinity of 0.5–1μM. The second nucleotide site remained unoccupied at up to 50μM ADP yet could bind ATP rapidly. The calcium dependence of ADP-release rates showed that calcium binds co-operatively to scallop HMM with an affinity of 0.78μM and a Hill coefficient of 1.9. Detailed interpretation of the data suggests that HMM exists in equilibrium between the on and off states and that calcium and ADP modulate the equilibrium between the two states. The on state is favoured in the presence of calcium and in the absence of both calcium and nucleotide. The off state is favoured by ADP (or ADP·Pi) in the absence of calcium. A detailed co-operative model of the interaction of ADP and calcium with HMM is presented.
Leukotriene D4 induces association of active RhoA with phospholipase C-γ1 in intestinal epithelial cells
Authors: THODETI Charles Kumar , MASSOUMI Ramin , BINDSLEV Lene , SJÖLANDER Anita
Published: July 2002

It has been previously suggested that leukotriene-induced Ca2+ signalling is mediated through a Rho-dependent process, but neither direct activation of Rho nor a mechanism underlying such signalling has been reported. Accordingly, we used the Rhotekin binding assay to assess RhoA activation in intestinal epithelial cells and observed that RhoA was activated by leukotriene D4 (LTD4). We also found that, within 15s, activation of RhoA by LTD4 led to an increased association of RhoA with G-protein βγ (Gβγ) and phospholipase C-γ1 (PLC-γ1) in the plasma membrane, as evidenced by the results of co-immunoprecipitation, glutathione S-transferase (GST) pulldown assays, and confocal microscopy. Amounts of RhoA increased in both Gβ and PLC-γ1 immunoprecipitates within 15s of LTD4 treatment. An interaction between RhoA, Gβγ and PLC-γ1 is supported by our finding that a GST fusion protein of constitutively active RhoA (GST-RhoAV14) precipitated Gβγ and PLC-γ1 from cell lysates in an agonist-dependent manner. Such an association is also substantiated by our confocal immunofluorescence results, which revealed that LTD4 induction increased co-localization of constitutively active RhoA and PLC-γ1 to the plasma membrane of cells transfected with enhanced green fluorescent protein L63RhoA. Furthermore, microinjection of neutralizing RhoA antibodies, but not control antibodies, significantly reduced LTD4-induced Ca2+ mobilization. Our results are the first to demonstrate a LTD4-induced activation of RhoA and more importantly its association with PLC-γ1, which are essential for the PLC-γ1-mediated calcium mobilization.
Novel homodimeric and heterodimeric rat γ-hydroxybutyrate synthases that associate with the Golgi apparatus define a distinct subclass of aldo-keto reductase 7 family proteins
Authors: KELLY Vincent P. , SHERRATT Philip J. , CROUCH Dorothy H. , HAYES John D.
Published: July 2002

The aldo-keto reductase (AKR) 7 family is composed of the dimeric aflatoxin B1 aldehyde reductase (AFAR) isoenzymes. In the rat, two AFAR subunits exist, designated rAFAR1 and rAFAR2. Herein, we report the molecular cloning of rAFAR2, showing that it shares 76% sequence identity with rAFAR1. By contrast with rAFAR1, which comprises 327 amino acids, rAFAR2 contains 367 amino acids. The 40 extra residues in rAFAR2 are located at the N-terminus of the polypeptide as an Arg-rich domain that may form an amphipathic α-helical structure. Protein purification and Western blotting have shown that the two AFAR subunits are found in rat liver extracts as both homodimers and as a heterodimer. Reductase activity in rat liver towards 2-carboxybenzaldehyde (CBA) was resolved by anion-exchange chromatography into three peaks containing rAFAR1-1, rAFAR1-2 and rAFAR2-2 dimers. These isoenzymes are functionally distinct; with NADPH as cofactor, rAFAR1-1 has a low Km and high activity with CBA, whereas rAFAR2-2 exhibits a low Km and high activity towards succinic semialdehyde. These data suggest that rAFAR1-1 is a detoxication enzyme, while rAFAR2-2 serves to synthesize the endogenous neuromodulator γ-hydroxybutyrate (GHB). Subcellular fractionation of liver extracts showed that rAFAR1-1 was recovered in the cytosol whereas rAFAR2-2 was associated with the Golgi apparatus. The distinct subcellular localization of the rAFAR1 and rAFAR2 subunits was confirmed by immunocytochemistry in H4IIE cells. Association of rAFAR2-2 with the Golgi apparatus presumably facilitates secretion of GHB, and the novel N-terminal domain may either determine the targeting of the enzyme to the Golgi or regulate the secretory process. A murine AKR protein of 367 residues has been identified in expressed sequence tag databases that shares 91% sequence identity with rAFAR2 and contains the Arg-rich extended N-terminus of 40 amino acids. Further bioinformatic evidence is presented that full-length human AKR7A2 is composed of 359 amino acids and also possesses an additional N-terminal domain. On the basis of these observations, we conclude that AKR7 proteins can be divided into two subfamilies, one of which is a Golgi-associated GHB synthase with a unique, previously unrecognized, N-terminal domain that is absent from other AKR proteins.
Inhibition of peroxisome proliferator-activated receptor (PPAR)-mediated keratinocyte differentiation by lipoxygenase inhibitors
Authors: THUILLIER Philippe , BRASH Alan R. , KEHRER James P. , STIMMEL Julie B. , LEESNITZER Lisa M. , YANG Peiying , NEWMAN Robert A. , FISCHER Susan M.
Published: July 2002

Lipoxygenase (LOX) metabolites from arachidonic acid and linoleic acid have been implicated in atherosclerosis, inflammation, keratinocyte differentiation and tumour progression. We previously showed that peroxisome proliferator-activated receptors (PPARs) play a role in keratinocyte differentiation and that the PPARα ligand 8S-hydroxyeicosatetraenoic acid is important in this process. We hypothesized that blocking LOX activity would block PPAR-mediated keratinocyte differentiation. Three LOX inhibitors, nordihydroguaiaretic acid, quercetin and morin, were studied for their effects on primary keratinocyte differentiation and PPAR activity. All three LOX inhibitors blocked calcium-induced expression of the differentiation marker keratin 1. In addition, activity of a PPAR-responsive element was inhibited in the presence of all three inhibitors, and this effect was mediated primarily through PPARα and PPARγ. LOX inhibitors decreased the activity of a chimaeric PPAR-Gal4-ligand-binding domain reporter system and this effect was reversed by addition of PPAR ligands. Ligand-binding studies revealed that the LOX inhibitors bind directly to PPARs and demonstrate a novel mechanism for these inhibitors in altering PPAR-mediated gene expression.
A novel lactonohydrolase responsible for the detoxification of zearalenone: enzyme purification and gene cloning
Authors: TAKAHASHI-ANDO Naoko , KIMURA Makoto , KAKEYA Hideaki , OSADA Hiroyuki , YAMAGUCHI Isamu
Published: July 2002

Zearalenone (ZEN) is converted into a far less oestrogenic product by incubation with Clonostachys rosea IFO 7063. An alkaline hydrolase responsible for the detoxification was purified to homogeneity from the fungus by a combination of salt precipitation and column chromatography methods. The purified enzyme was homodimeric with a subunit molecular mass of 30kDa and contained an intra-subunit disulphide bridge. On the basis of the internal peptide sequences of the purified protein, we cloned the entire coding region of the gene (designated as zhd101) by PCR techniques. The ZEN degradation activity was detected in heterologous hosts (Schizosaccharomyces pombe and Escherichia coli) carrying the cloned gene. Zhd101 could be a promising genetic resource for in planta detoxification of the mycotoxin in important crops.