bluuebunny/crossref_metadata_2025 huggingface dataset:
Body pool and synthesis of ascorbic acid in adult sea lamprey (
Petromyzon marinus
): An agnathan fish with gulonolactone oxidase activity
Authors: Moreau Régis , Dabrowski Konrad
Published: July 2002

Although many vertebrates can synthesize ascorbic acid (vitamin C), it is still unclear from the evolutionary perspective when the ability to synthesize the vitamin first appeared in the animal kingdom and how frequently the trait has been lost. We report here ascorbic acid biosynthesis ability in sea lamprey (
Petromyzon marinus
) which represent the most ancient vertebrate lineage examined thus far for presence of gulonolactone oxidase, the enzyme catalyzing the terminal step in biosynthesis of vitamin C. This finding supports the view that the ancestors of living vertebrates were not scurvy prone and that the loss of gulonolactone oxidase activity subsequently occurred several times in vertebrate phylogeny. Adult sea lamprey allocate significant amounts of ascorbic acid to the gonads to guaranty high-quality gametes. Tissue stores of ascorbate were maintained by
de novo
synthesis (1.2–1.3 mg of ascorbic acid/300-g sea lamprey per day at 15°C) while sea lamprey fast during spawning migration. We estimate that the
in vivo
daily renewal rate of ascorbate is 4–5% of the whole-body ascorbate pool based on measurement of its biosynthesis and concentration in the whole animal.
On the electronic nature of low-barrier hydrogen bonds in enzymatic reactions
Authors: Schiøtt Birgit , Iversen Bo Brummerstedt , Madsen Georg Kent Hellerup , Larsen Finn Krebs , Bruice Thomas C.
Published: July 2002

The electronic nature of low-barrier hydrogen bonds (LBHBs) in enzymatic reactions is discussed based on combined low temperature neutron and x-ray diffraction experiments and on high levelab initiocalculations by using the model substrate benzoylacetone. This molecule has a LBHB, as the intramolecular hydrogen bond is described by a double-well potential with a small barrier for hydrogen transfer. From an “atoms in molecules” analysis of the electron density, it is found that the hydrogen atom is stabilized by covalent bonds to both oxygens. Large atomic partial charges on the hydrogen-bonded atoms are found experimentally and theoretically. Therefore, the hydrogen bond gains stabilization from both covalency and from the normal electrostatic interactions found for long, weak hydrogen bonds. Based on comparisons with other systems having short-strong hydrogen bonds or LBHBs, it is proposed that all short-strong and LBHB systems possess similar electronic features of the hydrogen-bonded region, namely polar covalent bonds between the hydrogen atom and both heteroatoms in question.
Mode of action of the
COR15a
gene on the freezing tolerance of
Arabidopsis thaliana
Authors: Steponkus Peter L. , Uemura Matsuo , Joseph Raymond A. , Gilmour Sarah J. , Thomashow Michael F.
Published: July 2002

Constitutive expression of the
co
ld-
r
egulated
COR15a
gene of
Arabidopsis thaliana
results in a significant increase in the survival of isolated protoplasts frozen over the range of −4.5 to −7°C. The increased freezing tolerance is the result of a decreased incidence of freeze-induced lamellar-to-hexagonal II phase transitions that occur in regions where the plasma membrane is brought into close apposition with the chloroplast envelope as a result of freeze-induced dehydration. Moreover, the mature polypeptide encoded by this gene, COR15am, increases the lamellar-to-hexagonal II phase transition temperature of dioleoylphosphatidylethanolamine and promotes formation of the lamellar phase in a lipid mixture composed of the major lipid species that comprise the chloroplast envelope. We propose that COR15am, which is located in the chloroplast stroma, defers freeze-induced formation of the hexagonal II phase to lower temperatures (lower hydrations) by altering the intrinsic curvature of the inner membrane of the chloroplast envelope.
Biochemical evolution II: Origin of life in tubular microstructures on weathered feldspar surfaces
Authors: Parsons Ian , Lee Martin R. , Smith Joseph V.
Published: July 2002

Mineral surfaces were important during the emergence of life on Earth because the assembly of the necessary complex biomolecules by random collisions in dilute aqueous solutions is implausible. Most silicate mineral surfaces are hydrophilic and organophobic and unsuitable for catalytic reactions, but some silica-rich surfaces of partly dealuminated feldspars and zeolites are organophilic and potentially catalytic. Weathered alkali feldspar crystals from granitic rocks at Shap, north west England, contain abundant tubular etch pits, typically 0.4–0.6 μm wide, forming an orthogonal honeycomb network in a surface zone 50 μm thick, with 2–3 × 10
6
intersections per mm
2
of crystal surface. Surviving metamorphic rocks demonstrate that granites and acidic surface water were present on the Earth’s surface by ∼3.8 Ga. By analogy with Shap granite, honeycombed feldspar has considerable potential as a natural catalytic surface for the start of biochemical evolution. Biomolecules should have become available by catalysis of amino acids, etc. The honeycomb would have provided access to various mineral inclusions in the feldspar, particularly apatite and oxides, which contain phosphorus and transition metals necessary for energetic life. The organized environment would have protected complex molecules from dispersion into dilute solutions, from hydrolysis, and from UV radiation. Sub-micrometer tubes in the honeycomb might have acted as rudimentary cell walls for proto-organisms, which ultimately evolved a lipid lid giving further shelter from the hostile outside environment. A lid would finally have become a complete cell wall permitting detachment and flotation in primordial “soup.” Etch features on weathered alkali feldspar from Shap match the shape of overlying soil bacteria.
Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase
Authors: Pasinelli Piera , Borchelt David R. , Houseweart Megan K. , Cleveland Don W. , Brown Robert H.
Published: July 2002

The mechanism by which mutations in the superoxide dismutase (SOD1) gene cause motor neuron degeneration in familial amyotrophic lateral sclerosis (ALS) is unknown. Recent reports that neuronal death in SOD1-familial ALS is apoptotic have not documented activation of cell death genes. We present evidence that the enzyme caspase-1 is activated in neurons expressing mutant SOD1 protein. Proteolytic processing characteristic of caspase-1 activation is seen both in spinal cords of transgenic ALS mice and neurally differentiated neuroblastoma (line N2a) cells with SOD1 mutations. This activation of caspase-1 is enhanced by oxidative challenge (xanthine/xanthine oxidase), which triggers cleavage and secretion of the interleukin 1β converting enzyme substrate, pro-interleukin 1β, and induces apoptosis. This N2a culture system should be an instructive
in vitro
model for further investigation of the proapoptotic properties of mutant SOD1.
A supersymmetric model for the evolution of the genetic code
Authors: Bashford J. D. , Tsohantjis I. , Jarvis P. D.
Published: July 2002

A model is presented for the structure and evolution of the eukaryotic and vertebrate mitochondrial genetic codes, based on the representation theory of the Lie superalgebra
A
(5,0) ≃
sl
(6/1). A key role is played by pyrimidine and purine exchange symmetries in codon quartets.
Activation of CD8+T lymphocytes through the T cell receptor turns on CD4 gene expression: Implications for HIV pathogenesis
Authors: Flamand Louis , Crowley Richard W. , Lusso Paolo , Colombini-Hatch Sandra , Margolis David M. , Gallo Robert C.
Published: July 2002

T cell activation through the T cell receptor is necessary to achieve a specific and effective immune response. We report here that stimulation of CD8+T cells through the T cell receptor complex leads tode novoexpression of the CD4 antigen on the cell surface that results in susceptibility of CD8+T cells to HIV infection. In addition, activation of peripheral blood mononuclear cells from HIV-infected individuals results in the appearance of double-positive CD4+/CD8+T cells, which become infected by endogenous HIV. HIV DNA sequences could be detected in uncultured and sorted mature CD3+CD8+T cells from HIV+individuals. These results suggest a new mechanism by which HIV could attack the immune system and may help to explain the CD8+T cell defects in AIDS patients.
The structure of the two amino-terminal domains of human ICAM-1 suggests how it functions as a rhinovirus receptor and as an LFA-1 integrin ligand
Authors: Bella Jordi , Kolatkar Prasanna R. , Marlor Christopher W. , Greve Jeffrey M. , Rossmann Michael G.
Published: July 2002

The normal function of human intercellular adhesion molecule-1 (ICAM-1) is to provide adhesion between endothelial cells and leukocytes after injury or stress. ICAM-1 binds to leukocyte function-associated antigen (LFA-1) or macrophage-1 antigen (Mac-1). However, ICAM-1 is also used as a receptor by the major group of human rhinoviruses and is a catalyst for the subsequent viral uncoating during cell entry. The three-dimensional atomic structure of the two amino-terminal domains (D1 and D2) of ICAM-1 has been determined to 2.2-Å resolution and fitted into a cryoelectron microscopy reconstruction of a rhinovirus–ICAM-1 complex. Rhinovirus attachment is confined to the BC, CD, DE, and FG loops of the amino-terminal Ig-like domain (D1) at the end distal to the cellular membrane. The loops are considerably different in structure to those of human ICAM-2 or murine ICAM-1, which do not bind rhinoviruses. There are extensive charge interactions between ICAM-1 and human rhinoviruses, which are mostly conserved in both major and minor receptor groups of rhinoviruses. The interaction of ICAMs with LFA-1 is known to be mediated by a divalent cation bound to the insertion (I)-domain on the α chain of LFA-1 and the carboxyl group of a conserved glutamic acid residue on ICAMs. Domain D1 has been docked with the known structure of the I-domain. The resultant model is consistent with mutational data and provides a structural framework for the adhesion between these molecules.
High gene density is conserved at syntenic loci of small and large grass genomes
Authors: Feuillet Catherine , Keller Beat
Published: July 2002

Comparative genomic analysis at the genetic-map level has shown extensive conservation of the gene order between the different grass genomes in many chromosomal regions. However, little is known about the gene organization in grass genomes at the microlevel. Comparison of gene-coding regions between maize, rice, and sorghum showed that the distance between the genes is correlated with the genome size. We have investigated the microcolinearity atLrkgene loci in the genomes of four grass species: wheat, barley, maize, and rice. TheLrkgenes, which encode receptor-like kinases, were found to be consistently associated with another type of receptor-like kinase (Tak) on chromosome groups 1 and 3 in Triticeae and on chromosomes homoeologous to Triticeae group 3 in the other grass genomes. On Triticeae chromosome group 1,TakandLrktogether with genes putatively encoding NBS/LRR proteins form a cluster of genes possibly involved in signal transduction. Comparison of the gene composition at orthologousLrkloci in wheat, barley, and rice revealed a maximal gene density of one gene per 4–5 kb, very similar to the gene density inArabidopsis thaliana.We conclude that small and large grass genomes contain regions that are highly enriched in genes with very little or no repetitive DNA. The comparison of the gene organization suggested various genome rearrangements during the evolution of the different grass species.
Femtosecond cluster studies of the solvated 7-azaindole excited state double-proton transfer
Authors: Folmer D. E. , Wisniewski E. S. , Hurley S. M. , Castleman A. W.
Published: July 2002

Presented here are femtosecond pump-probe studies on the water-solvated 7-azaindole dimer, a model DNA base pair. In particular, studies are presented that further elucidate the nature of the reactive and nonreactive dimers and also provide new insights establishing that the excited state double-proton transfer in the dimer occurs in a stepwise rather than a concerted manner. A major question addressed is whether the incorporation of a water molecule with the dimer results in the formation of species that are unable to undergo excited state double-proton transfer, as suggested by a recent study reported in the literature [Nakajima, A., Hirano, M., Hasumi, R., Kaya, K., Watanabe, H., Carter, C. C., Williamson, J. M. & Miller, T. (1997)
J. Phys. Chem.
101, 392–398]. In contrast to this earlier work, our present findings reveal that both reactive and nonreactive dimers can coexist in the molecular beam under the same experimental conditions and definitively show that the clustering of water does not induce the formation of the nonreactive dimer. Rather, when present with a species already determined to be a nonreactive dimer, the addition of water can actually facilitate the occurrence of the proton transfer reaction. Furthermore, on attaining a critical hydration number, the data for the nonreactive dimer suggest a solvation-induced conformational structure change leading to proton transfer on the photoexcited half of the 7-azaindole dimer.
The protein kinases of
Caenorhabditis elegans
: A model for signal transduction in multicellular organisms
Authors: Plowman Gregory D. , Sudarsanam Sucha , Bingham Jonathan , Whyte David , Hunter Tony
Published: July 2002

Caenorhabditis elegans
should soon be
the first multicellular organism whose complete genomic sequence has
been determined. This achievement provides a unique opportunity for a
comprehensive assessment of the signal transduction molecules required
for the existence of a multicellular animal. Although the worm
C.
elegans
may not much resemble humans, the molecules that regulate
signal transduction in these two organisms prove to be quite similar.
We focus here on the content and diversity of protein kinases present
in worms, together with an assessment of other classes of proteins that
regulate protein phosphorylation. By systematic analysis of the 19,099
predicted
C. elegans
proteins, and thorough analysis of the
finished and unfinished genomic sequences, we have identified 411 full
length protein kinases and 21 partial kinase fragments. We also
describe 82 additional proteins that are predicted to be structurally
similar to conventional protein kinases even though they share minimal
primary sequence identity. Finally, the richness of
phosphorylation-dependent signaling pathways in worms is further
supported with the identification of 185 protein phosphatases and 128
phosphoprotein-binding domains (SH2, PTB, STYX, SBF, 14-3-3, FHA, and
WW) in the worm genome.
Localization of Niemann–Pick C1 protein in astrocytes: Implications for neuronal degeneration in Niemann– Pick type C disease
Authors: Patel Shutish C. , Suresh Sundar , Kumar Ujendra , Hu C. Y. , Cooney Adele , Blanchette-Mackie E. Joan , Neufeld Edward B. , Patel Ramesh C. , Brady Roscoe O. , Patel Yogesh C. , Pentchev Peter G. , Ong Wei-Yi
Published: July 2002

Niemann–Pick type C disease (NP-C) is an inherited
neurovisceral lipid storage disorder characterized by progressive
neurodegeneration. Most cases of NP-C result from inactivating
mutations of
NPC1
, a recently identified member of a
family of genes encoding membrane-bound proteins containing putative
sterol sensing domains. By using a specific antipeptide antibody to
human NPC1, we have here investigated the cellular and subcellular
localization and regulation of NPC1. By light and electron microscopic
immunocytochemistry of monkey brain, NPC1 was expressed predominantly
in perisynaptic astrocytic glial processes. At a subcellular level,
NPC1 localized to vesicles with the morphological characteristics of
lysosomes and to sites near the plasma membrane. Analysis of the
temporal and spatial pattern of neurodegeneration in the NP-C mouse, a
spontaneous mutant model of human NP-C, by amino–cupric–silver
staining, showed that the terminal fields of axons and dendrites are
the earliest sites of degeneration that occur well before the
appearance of a neurological phenotype. Western blots of cultured human
fibroblasts and monkey brain homogenates revealed NPC1 as a 165-kDa
protein. NPC1 levels in cultured fibroblasts were unchanged by
incubation with low density lipoproteins or oxysterols but were
increased 2- to 3-fold by the drugs progesterone and U-18666A, which
block cholesterol transport out of lysosomes, and by the lysosomotropic
agent NH
4
Cl. These studies show that NPC1 in brain is
predominantly a glial protein present in astrocytic processes closely
associated with nerve terminals, the earliest site of degeneration in
NP-C. Given the vesicular localization of NPC1 and its proposed role in
mediating retroendocytic trafficking of cholesterol and other lysosomal
cargo, these results suggest that disruption of NPC1-mediated vesicular
trafficking in astrocytes may be linked to neuronal degeneration in
NP-C.
Functional integrity of mitochondrial genomes in human platelets and autopsied brain tissues from elderly patients with Alzheimer’s disease
Authors: Ito Sayaka , Ohta Shigeo , Nishimaki Kiyomi , Kagawa Yasuo , Soma Rika , Kuno Shin-ya , Komatsuzaki Yasuko , Mizusawa Hidehiro , Hayashi Jun-Ichi
Published: July 2002

To determine whether pathogenic mutations in mtDNA are involved in phenotypic expression of Alzheimer’s disease (AD), the transfer of mtDNA from elderly patients with AD into mtDNA-less (ρ
0
) HeLa cells was carried out by fusion of platelets or synaptosomal fractions of autopsied brain tissues with ρ
0
HeLa cells. The results showed that mtDNA in postmortem brain tissue survives for a long time without degradation and could be rescued in ρ
0
HeLa cells. Next, the cybrid clones repopulated with exogenously imported mtDNA from patients with AD were used for examination of respiratory enzyme activity and transfer of mtDNA with the pathogenic mutations that induce mitochondrial dysfunction. The presence of the mutated mtDNA was restricted to brain tissues and their cybrid clones that formed with synaptosomes as mtDNA donors, whereas no cybrid clones that isolated with platelets as mtDNA donors had detectable mutated mtDNA. However, biochemical analyses showed that all cybrid clones with mtDNA imported from platelets or brain tissues of patients with AD restored mitochondrial respiration activity to almost the same levels as those of cybrid clones with mtDNA from age-matched normal controls, suggesting functional integrity of mtDNA in both platelets and brain tissues of elderly patients with AD. These observations warrant the reassessment of the conventional concept that the accumulation of pathogenic mutations in mtDNA throughout the aging process is responsible for the decrease of mitochondrial respiration capacity with age and with the development of age-associated neurodegenerative diseases.
Ex vivo
evaluation of a Taylor-Couette flow, immobilized heparinase I device for clinical application
Authors: Ameer Guillermo A. , Barabino Gilda , Sasisekharan Ram , Harmon William , Cooney Charles L. , Langer Robert
Published: July 2002

Efficient and safe heparin anticoagulation has remained a problem for continuous renal replacement therapies and intermittent hemodialysis for patients with acute renal failure. To make heparin therapy safer for the patient with acute renal failure at high risk of bleeding, we have proposed regional heparinization of the circuit via an immobilized heparinase I filter. This study tested a device based on Taylor-Couette flow and simultaneous separation/reaction for efficacy and safety of heparin removal in a sheep model. Heparinase I was immobilized onto agarose beads via cyanogen bromide activation. The device, referred to as a vortex flow plasmapheretic reactor, consisted of two concentric cylinders, a priming volume of 45 ml, a microporous membrane for plasma separation, and an outer compartment where the immobilized heparinase I was fluidized separately from the blood cells. Manual white cell and platelet counts, hematocrit, total protein, and fibrinogen assays were performed. Heparin levels were indirectly measured via whole-blood recalcification times (WBRTs). The vortex flow plasmapheretic reactor maintained significantly higher heparin levels in the extracorporeal circuit than in the sheep (device inlet WBRTs were 1.5 times the device outlet WBRTs) with no hemolysis. The reactor treatment did not effect any physiologically significant changes in complete blood cell counts, platelets, and protein levels for up to 2 hr of operation. Furthermore, gross necropsy and histopathology did not show any significant abnormalities in the kidney, liver, heart, brain, and spleen.
Tid1/Rdh54 promotes colocalization of Rad51 and Dmc1 during meiotic recombination
Authors: Shinohara Miki , Gasior Stephen L. , Bishop Douglas K. , Shinohara Akira
Published: July 2002

Two RecA homologs, Rad51 and Dmc1, assemble as cytologically
visible complexes (foci) at the same sites on meiotic chromosomes. Time
course analysis confirms that co-foci appear and disappear as the
single predominant form. A large fraction of co-foci are eliminated in
a
red1
mutant, which is expected as a characteristic of
the interhomolog-specific recombination pathway. Previous studies
suggested that normal Dmc1 loading depends on Rad51. We show here that
a mutation in
TID1
/
RDH54
, encoding a
RAD54
homolog, reduces Rad51-Dmc1 colocalization
relative to WT. A
rad54
mutation, in contrast, has
relatively little effect on RecA homolog foci except when strains also
contain a
tid1
/
rdh54
mutation. The role
of Tid1/Rdh54 in coordinating RecA homolog assembly may be very
direct, because Tid1/Rdh54 is known to physically bind both Dmc1 and
Rad51. Also, Dmc1 foci appear early in a
tid1
/
rdh54
mutant. Thus, Tid1 may
normally act with Rad51 to promote ordered RecA homolog assembly by
blocking Dmc1 until Rad51 is present. Finally, whereas double-staining
foci predominate in WT nuclei, a subset of nuclei with expanded
chromatin exhibit individual Rad51 and Dmc1 foci side-by-side,
suggesting that a Rad51 homo-oligomer and a Dmc1 homo-oligomer assemble
next to one another at the site of a single double-strand break (DSB)
recombination intermediate.
Permeation and gating residues in serotonin transporter
Authors: Chen Jie-Guang , Rudnick Gary
Published: July 2002

The third transmembrane domain (TM3) of serotonin transporter (SERT) contains two isoleucine residues previously proposed to be involved in binding and transport of serotonin. When Ile-172 was replaced with cysteine, SERT became sensitive to inactivation by externally added [2-(trimethylammonium)ethyl]methanethio-sulfonate (MTSET). The disulfide product of this inactivation was not sensitive to reduction by externally added sulfhydryl compounds, but apparently reacted with intracellular reducing agents to spontaneously regenerate active SERT. The apparent accessibility of this residue to both external and cytoplasmic reagents is consistent with its localization near a serotonin binding site that is alternately exposed to both internal and external media. In another SERT mutant, I179C, transport also was inactivated by MTSET but substrate binding was resistant. External substrate bound to the inactivated I179C and enhanced its reactivation by free thiols. In norepinephrine transporter (NET), cysteine replacement of Ile-155 (corresponding to SERT Ile-179) also rendered the transporter sensitive to MTSET inactivation. In NET I155C, cocaine enhanced this inactivation, and the substrate, dopamine, apparently protected against inactivation. The characteristics of this protection suggest that dopamine was transported, converting NET to a form in which Ile-155 was occluded. The results support the proposal that TM3 of SERT and NET constitute part of the substrate permeation pathway, and that Ile-172 in SERT resides close to the substrate binding site. They also suggest that Ile-179 in SERT (and Ile-155 in NET) is in a conformationally sensitive part of TM3, which may act as part of an external gate.
Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry
Authors: McMillan Kirk , Adler Marc , Auld Douglas S. , Baldwin John J. , Blasko Eric , Browne Leslie J. , Chelsky Daniel , Davey David , Dolle Ronald E. , Eagen Keith A. , Erickson Shawn , Feldman Richard I. , Glaser Charles B. , Mallari Cornell , Morrissey Michael M. , Ohlmeyer Michael H. J. , Pan Gonghua , Parkinson John F. , Phillips Gary B. , Polokoff Mark A. , Sigal Nolan H. , Vergona Ronald , Whitlow Marc , Young Tish A. , Devlin James J.
Published: July 2002

Potent and selective inhibitors of inducible nitric oxide synthase (iNOS) (EC
1.14.13.39
) were identified in an encoded combinatorial chemical library that blocked human iNOS dimerization, and thereby NO production. In a cell-based iNOS assay (A-172 astrocytoma cells) the inhibitors had low-nanomolar IC
50
values and thus were >1,000-fold more potent than the substrate-based direct iNOS inhibitors 1400W and
N-
methyl-
l
-arginine. Biochemical studies confirmed that inhibitors caused accumulation of iNOS monomers in mouse macrophage RAW 264.7 cells. High affinity (
K
d
≈ 3 nM) of inhibitors for isolated iNOS monomers was confirmed by using a radioligand binding assay. Inhibitors were >1,000-fold selective for iNOS versus endothelial NOS dimerization in a cell-based assay. The crystal structure of inhibitor bound to the monomeric iNOS oxygenase domain revealed inhibitor–heme coordination and substantial perturbation of the substrate binding site and the dimerization interface, indicating that this small molecule acts by allosterically disrupting protein–protein interactions at the dimer interface. These results provide a mechanism-based approach to highly selective iNOS inhibition. Inhibitors were active
in vivo
, with ED
50
values of <2 mg/kg in a rat model of endotoxin-induced systemic iNOS induction. Thus, this class of dimerization inhibitors has broad therapeutic potential in iNOS-mediated pathologies.
Adjusting Social Inferences in Familiar and Unfamiliar Domains: The Generality of Response to Situational Pragmatics
Authors: Liu James H. , Pham Lien B. , Holyoak Keith J.
Published: July 2002

Two experiments investigated the influence of situational pragmatics on the selective use of specific instances and generalized knowledge structures to make social inferences. In Experiment 1, social inferences were made in an unfamiliar domain similar in structure to a typical situation of social greetings and address, but devoid of useful cues to social schemas. Participants were told that either one or another of the features of the situation was more pragmatically important for deriving inferences about appropriate social behaviour; consistent with predictions from a computational model of analogical mapping (ACME), they made reliable inferences based on analogies to specific instances, with the situational importance of relations guiding the selection of the optimal analogue. In Experiment 2, social inferences were examined in the more familiar domain of predicting social behavior between low and high status persons and between members of an ingroup and an outgroup in Japan. The availability of specific examples was varied, as was the perceived importance of status and group membership. The situation was isomorphic to that in the first experiment, except for the availability of generalized knowledge structures to guide inferences. Participants made relatively veridical inferences that were sensitive to variations in the pragmatic importance of dimensions. Provision of specific analogues had little impact on inferences, suggesting that participants were relying instead on more general and cross‐culturally applicable knowledge about adjusting social relations according to situational pragmatics.
Predictors of High School Achievement in a Hong Kong International School
Authors: Stewart Sunita Mahtani , Bond Michael H. , Deeds Osvelia , Westrick Jan , Wong C. M.
Published: July 2002

Asian students consistently achieve academically at higher rates than other students. This study reports on the prediction of grades by teenagers' values and autonomy expectations, and their mothers' reports on these variables. Fifty‐eight Western and 66 Asian juniors and seniors and their mothers were recruited from an international high school. Teenagers' value priority for Openness to Change and their autonomy expectations predicted academic achievement in the entire group of students, unpackaging the effect of culture on academic achievement. Mothers' value priorities and autonomy expectations did not associate with their teenagers' grades. Teenagers' value for Openness to Change emerged as a significant independent predictor in the combined group; however, the effect was stronger in Western than in Asian teenagers. This study provides unusual evidence for pancultural correlates of academic achievement.
IUPsyS — United Nations Activities
Authors: Sabourin Michel
Published: July 2002

In this column will be presented excerpts of the second part of the report of the Secretary General of the UN, Kofi Annan, that deals with ways of further enhancing the active participation of NGOs in the UN system. The first part was presented in the preceding column.
IUPsyS ‐ United Nations Activities
Authors: Sabourin Michel
Published: July 2002

At its 49th plenary meeting in July 1996, the Economic and Social Council (ECOSOC) reaffirmed the importance of the contributions of non‐governmental organizations to the work it accomplishes within the United Nations framework. It decided to recommend that the General Assembly examine the question of the participation of non‐governmental organizations in all areas of the work of the UN, including the General Assembly.

The following excerpts are taken from a recent report written by the Secretary General, Kofi Annan, for consideration at the fifty‐third session (that started in September 1998) of the General Assembly. In view of its length and its importance, we will present this report in two parts. The first part (this column) presents a thorough description of the actual work done by the NGOs within the UN system, and especially within those bodies of particular interest to the IUPsyS (UNICEF, UNESCO, WHO, etc…), while the second part (that will be presented in our next column) will look at ways of further enhancing the active participation of NGOs.

This report, which is presented in association with Item 58 (“Strengthening of the United Nations system”) of the provisional agenda of the General Assembly, comes at a time when the IUPsyS has just been officially granted a special consultative status with ECOSOC, as well as consultative status with the UN Department of Public Information, and is in the process of planning its actions and getting organized for an optimal contribution to the work of the United Nations.
Injecting drug use and knowledge and self‐report of hepatitis C among Australian gay and homosexually active men
Authors: Van de Ven Paul , Kippax Susan , Crawford June , Rodden Pamela
Published: July 2002

The aim of this study was to examine gay and homosexually active men's knowledge of hepatitis C, drug use, injecting practices and testing for hepatitis C. The data were from 3039 men who participated in the Male Call 96 national telephone survey of Australian gay and homosexually active men. Altogether, 9.9% of the men had ever injected and 4.4% had injected in the 6 months prior to data collection. Injecting drug use was more common among gay identified men and gay community attached men. Among the injecting drug users, 73.4% had injected before 25 years of age. There was a fair amount of uncertainty about hepatitis C although 41.3% of the men reported having been tested (higher at 64.2% among those who had ever injected). Sixty‐five men self‐reported a hepatitis C diagnosis, 17 with HIV co‐infection. In a multivariate model, self‐report of hepatitis C diagnosis was associated with being in the 30‐39 or 40‐49 years of age brackets, better knowledge of hepatitis C, HIV positivity and injecting drug use. Needs identified include education and support for both younger and older gay and homosexually active men within a health promotion framework of partnership, harm minimisation and community development.
Investigation of the inhibitory effects of HA‐1077 and Y‐32885 on the translocation of PKCβI, PKCβII and PKCζ in human neutrophils
Authors: Siomboing Xavier , Gressier Bernard , Dine Thierry , Brunet Claude , Luyckx Michel , Cazin Michelene , Cazin Jean-Claude
Published: July 2002

To transmit the information inside the cell, one possibility is the action of an enzyme called kinase that phosphorylates other proteins. To study these enzymes, chemical compound synthesis was needed to know the function and the mechanism of activation. The major difficulty is creating a specific molecule for one kinase. In this study, we test the action of Rho‐kinase inhibitors (HA‐1077 and Y‐32885) on protein kinase C (PKC) in the respiratory burst in the human polymorphonuclear neutrophils. We have shown that these compounds could inhibit the anion superoxide production. To prove their action on PKC, we have shown a decrease of binding of a specific ligand (phorbol‐12,13‐dibutyrate) with each inhibitor. During its activation, PKC was translocated from the cytoplasm to the plasmic membrane. We have also shown an inhibition of this translocation, proving an inhibition of PKC by HA‐1077 and Y‐32885.
Suppressive effects of anti‐allergic agent suplatast tosilate (IPD‐1151T) on the expression of co‐stimulatory molecules on mouse splenocytes in vivo
Authors: Kurokawa Masatsugu , Kawazu Kenta , Asano Kazuhito , Fumio Kokubu , Mita Akira , Adachi Mitsuru
Published: July 2002

The effects of IPD‐1151T on the expression of costimulatory molecules, CD40, CD80 and CD86, were investigated
in vivo using mice with allergic disorders. BALB/c mice were immunized intraperitoneally with two doses of dinitrophenylated ovalbumin (DNP‐OVA) at 1‐week intervals. These mice then were treated intraperitoneally with 100μg/kg of IPD1151T once a day for 14 days, starting 7 days after the first immunization. On day 21, some mice were challenged intraperitoneally with DNP‐OVA and the other mice were not challenged. All mice were autopsied on day 22 and assayed for immunoglobulin E, interleuken (IL)‐4 and IL‐5 productions following DNP‐OVA immunization. The intraperitoneal treatment with IPD‐1151T strongly suppressed immunoglobulin E contents in serum, which were enhanced by DNA‐OVA immunization. IPD‐1151T also caused a decrease in both IL‐4 and IL‐5 levels in splenic lymphocytes. We next examined the influence of IPD1151T on co‐stimulatory molecule expression on splenic lymphocytes. IPD‐1151T caused suppression of CD40 and CD86 expression; however, the treatments did not affect CD80 expression.
Hydrogen peroxide in breath condensate during a common cold
Authors: Jöbsis Rijn Q. , Schellekens Susanne L. , Fakkel-Kroesbergen Anoeska , Raatgeep Rolien H. C. , de Jongste Johan C.
Published: July 2002

Background: Hydrogen peroxide (H2O2) in exhaled air condensate is elevated in inflammatory disorders of the lower respiratory tract. It is unknown whether viral colds contribute
to exhaled H2O2.

Aim: To assess exhaled H2O2 during and after a common cold.

Methods: We examined H2O2 in the breath condensate of 20 normal subjects with acute symptoms of a common cold and after recovery 2 weeks later and, similarly, in 10 subjects without
infection. H2O2 was measured with a fluorimetric assay.

Results: At the time of infection exhaled H2O2 (median, ranges) was 0.20 μM (0.03‐1.2 μM), and this decreased to 0.09 μM (< 0.01‐0.40 μM) after recovery
(p = 0.006). There was no significant difference in lung function (forced vital capacity and forced expiratory volume in 1 sec) during and after colds. In the controls, exhaled H2O2 did not change over a 2‐week period.

Conclusions: H2O2 in exhaled air condensate is elevated during a common cold, and returns to normal within 2 weeks of recovery in healthy subjects. Hence, symptomatic upper respiratory tract infection may act as a confounder in studies of H2O2 as a marker of chronic lower airway inflammation.
Tumor necrosis factor, interleukin‐1 and interleukin‐8 mediate the nociceptive activity of the supernatant of LPS‐stimulated macrophages
Authors: Thomazzi S. M. , Ribeiro R. A. , Campos D. I. , Cunha F. Q. , Ferreira S. H.
Published: July 2002

It has been suggested that the supernatant of LPSstimulated macrophages (macrophage nociceptive factor, MNF) promotes nociception in mice. Intraperitoneal administration of MNF induced dose‐related writhing, which reached a plateau between 18 and 26 min after injection and decreased within 60 min. The release of MNF was inhibited by the pretreatment of the macrophages with cycloheximide, a protein synthesis inhibitor, or with the glucocorticoid dexamethasone. Cyclooxygenase inhibitors, such as indomethacin or paracetamol, had no effect. The MNF‐induced nociception was inhibited in a dose‐related manner by pretreatment of the animals with indomethacin, paracetamol or dexamethasone. Pretreatment of the animals with the sympatholytics guanethidine and atenolol partially reduced the MNF nociception, which was abolished by the combination of guanethidine or atenolol with indomethacin. The preincubation of MNF with antisera against TNF‐α, IL‐1 or IL‐8 partially inhibited its nociceptive effect. Intraperitoneal injection of a mixture of the recombinants cytokines TNF‐α, IL‐1 and IL‐8 mimicked MNF nociception. The individual injection of these cytokines was unable to induce the nociceptive effect. In conclusion, our data suggest that the nociceptive activity of the supernatant of LPSstimulated macrophages is explained by the presence of TNF‐α, IL‐1 and IL‐8, the nociceptive activity of which (in mice) seems to be due to the release of cyclooxygenase and sympathetic metabolites.
Prostaglandin E2 Affects Differently the Release of Inflammatory Mediators from Resident Macrophages by LPS and Muramyl Tripeptides
Authors: Dieter Peter , Hempel Ute , Kamionka Sabine , Kolada Angelika , Malessa Birgit , Fitzke Edith , Tran-Thi Thuy-Anh
Published: July 2002

LPS and MTP‐PE (liposome‐encapsulated N‐acetylmuramyl‐L‐alanyl‐D‐isoglutaminyl‐L‐alanine‐2‐:[1′,2′‐dipalmitoyl‐sni‐glycero‐3‐(hydroxy‐phosphoryl‐oxyl)] etylamide) induce in liver macrophages a synthesis and release of TNF‐α, nitric oxide and prostanoids. Both agents induce an expression of mRNA′s encoding TNF‐α, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)‐2, and of corresponding proteins. LPS and MTP‐PE induce a rapid activation of the extracellular regulated kinase (ERK) isoenzymes‐1 and ‐2. Inhibition of map kinase isoenzymes leads to a decreased release of TNF‐α, nitric oxide and prostaglandin (PG) E2 after both agents. The transcription factors NF‐κB and AP‐1 are strongly activated by LPS within 30 minutes. MTP‐PE induces a weak activation of both transcription factors only after 5 hours. Inhibition of NF‐κB inhibits the LPS‐ but not the MTP‐PE‐induced release of TNF‐α, nitric oxide and PGE2. PGE2 release after LPS is higher than after MTP‐PE. Exogenously added PGE2 inhibits the activation of map kinase and TNF‐α release by LPS, but not by MTP‐PE. Release of nitric oxide after LPS and MTP‐PE is enhanced after prior addition of PGE2. PGD2 is without any effect. MTP‐PE, but not LPS, induces a cytotoxicity of Kupffer cells against P815 tumor target cells. The MTP‐PE‐induced cytotoxicity is reduced by TNF‐α neutralizing antibodies, indicating the involvement of TNF‐α. Thus our results suggest that the different potencies of LPS and MTP‐PE as immunomodulators probably result from different actions on Kupffer cells, resulting in differences in the amounts and kinetics of released TNF‐α and PGE2, and that PGE2 plays an important regulatory role in the action of LPS, but not in the actions of MTP‐PE.
The Destructive Action of IL‐1α and IL‐1β in IDDM is a Multistage Process: Evidence and Confirmation by Apoptotic Studies, Induction of Intermediates and Electron Microscopy
Authors: Vassiliadis S. , Dragiotis V. , Protopapadakis E. , Athanassakis I. , Mitlianga P. , Konidaris K. , Papadopoulos G. K.
Published: July 2002

Using the rat β‐cell RIN‐5AH insulinoma line as a means for studying insulin‐dependent diabetes mellitus (IDDM), it is shown that interleukin‐1 (IL‐1) induces β‐cell damage initiated by early apoptotic signals. This action is demonstrated by DNA fragmentation, as assessed by specific BrdU labeling, surface expression of Fas and nitric oxide (NO) production. In addition, the interplay between NO and Fas is shown, while scanning electron microscopy (SEM) confirms apoptosis by revealing the degree and type of cellular damage which, in the case of IL‐1α, can be reversed by an inhibitor to NO synthesis. Apoptosis is also reconfirmed by transmission electron microscopy (TEM) by observing condensed nuclear chromatin after IL‐1 exposure. Thus, treatment of insulinoma cells with IL‐1α and IL‐1β seems to initiate a number of signals, including PKC activation as published previously, that ultimately lead to β‐cell destruction. Each IL‐1 isoform, however, definitely follows a different pathway of action.
Leguminous Lectins as Tools for Studying the Role of Sugar Residues in Leukocyte Recruitment
Authors: Alencar N. M. N. , Teixeira E. H. , Assreuy A. M. S. , Cavada B. S. , Flores C. A. , Ribeiro R. A.
Published: July 2002

The natural physiological ligands for selectins are oligosaccharides found in glycoprotein or glycolipid molecules in cell membranes. In order to study the role of sugar residues in the in vivo lectin anti‐inflammatory effect, we tested three leguminous lectins with different carbohydrate binding affinities in the peritonitis and paw oedema models induced by carrageenin in rats. L. sericeus lectin was more anti‐inflammatory than D. virgata lectin, the effects being reversed by their specific binding sugars (N‐acetylglucosamine and α‐methylmannoside, respectively). However, V. macrocarpa, a galactose‐specific lectin, was not anti‐inflammatory. The proposed anti‐inflammatory activity of lectins could be due to a blockage of neutrophil‐selectin carbohydrate ligands. Thus, according to the present data, we suggest an important role for N‐acetylglucosamine residue as the major ligand for selectins on rat neutrophil membranes.
Biomedical benefits of cannabinoids?
Authors: ASHTON C. H.
Published: July 2002

Cannabinoids appear to be of therapeutic value as antiemetics, antispasmodics, analgesics and appetite stimulants and may have potential uses in epilepsy, glaucoma and asthma. Scientific evidence for any of these indications, except for antiemetic effects, is extremely sparse and claims for clinical utility are largely based on anecdotal reports. Furthermore, the mechanisms of action of any of the therapeutic effects are unknown. This paper reviews the clinical trials which have been carried out with cannabinoids including Δ9‐tetrahydrocannabinol (THC) and synthetic cannabinoids such as nabilone and levonantradol, and discusses the advantages and adverse effects of cannabinoids in clinical use. The place of cannabinoids in modern medicine remains to be properly evaluated, but present evidence suggests that they could be valuable, particularly as adjuvants, for symptom control in a range of conditions for which standard drugs are not fully satisfactory.
Book and Media Reviews
Authors: COOK CHRIS
Published: July 2002

Book reviewed in this article:

Book reviews in this column will primarily be of titles focusing completely, or in part, on biological aspects of addiction. However, significant titles of general relevance to the addictions field will also be included, even if they are not “biological”, as will titles of general methodological and clinical relevance, even if they are not on “addictions”. Similar considerations will apply to other media (software, audio tapes and CDs, videos, etc). However, specific “addictions” software applications seem to be relatively uncommon and, as these items are rarely reviewed elsewhere, we will endeavour to include reviews of some of the older programmes that are still useful, as well as new titles that appear. I would appreciate suggestions of any items suitable for reviews, but especially software and other media of specific relevance to the addictions. Please contact: Professor Chris Cook, Kent Institute of Medicine and Health Sciences, University of Kent at Canterbury, Kent CT2 7NR, UK. Email: c.c.h.cook@ukc.ac.uk

Smoking in Adolescence: images and identities BARBARA LLOYD & KEVIN LUCAS

Drinking and Driving in Great Britain‐A Review. TRL Report 232 G. MAYCOCK

Educating Yourself about Alcohol and Drugs MARC SCHUKIT

Drugspeak. The Analysis of Drug Discourse JOHN BOOTH DAVIES

Clinical Handbook of Psychotropic Drugs 6th revised edition KALYNA Z. BEZCHLIBYNK‐BUTLER & J. JOEL JEFFRIES (Eds)

Addicted to Crime? J. R. HODGE, M. MCMURRAN & C. R. HOLLIN

Chaos and Intoxication ALAN DEAN

Loose Ends? SYDNEY BRENNER

Guidelines on the Practice of Ethics Committees in Medical Research Involving Human Subjects
Doxorubicin‐Based Chemotherapy for the Palliative Treatment of AdultPatients with Locally Advanced or Metastatic Soft‐Tissue Sarcoma:A Meta‐Analysis and Clinical Practice Guideline
Authors: Bramwell Vivien H. C. , Anderson Dale , Charette Manya L.
Published: July 2002

Purpose. To make recommendations for the use of doxorubicin‐based
chemotherapy in patients with soft‐tissue sarcoma.

Patients. The recommendations apply to patients with symptomatic
unresectable locally advanced or metastatic soft‐tissue sarcoma who are candidates for
palliative chemotherapy.

Methods. A systematic review of the published literature was combined
with a consensus process around the interpretation of the evidence in the context of
conventional practice to develop an evidence‐based practice guideline.

Results. Eight randomized trials comparing doxorubicin‐based combination
versus doxorubicin single‐agent chemotherapy were reviewed. Response rates and overall
survival were evaluated using pooled statistical analysis.The pooled response data in 2281
patients showed a slight trend favouring the combination therapy, although this did not reach
statistical significance (odds ratio (OR), 0.79; 95% confidence interval (CI), 0.60–1.05; p=0.10).
Survival data could only be abstracted from six studies involving 2097 patients, and showed
no significant advantage for combination therapy (OR, 0.84; 95% CI, 0.67–1.06; p=0.13).
Data on adverse effects could not be combined in a meta‐analysis; however nausea,
vomiting and myelosuppression were consistently more severe with combination
chemotherapy than with single‐agent chemotherapy.

Discussion. Single‐agent doxorubicin is an appropriate first‐line
chemotherapy option for advanced or metastatic soft‐tissue sarcoma. Some doxorubicin‐based
combination chemotherapy regimens, given in conventional doses, produce only marginal
increases in response rates, at the expense of increased adverse effects, and with no
improvements in overall survival. Future randomized clinical trials should compare new
regimens, whose activity has been established in single‐arm studies, with
single‐agent doxorubicin, and include quality of life as an outcome measure.