bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered states: Involvement of phosphorylated CagA in the induction of host cellular growth changes by
Helicobacter pylori
Authors: Segal E. D. , Cha J. , Lo J. , Falkow S. , Tompkins L. S.
Published: July 2002

Helicobacter pylori
, present in half of the world’s population, is a very successful pathogen. It can survive for decades in the human stomach with few obvious consequences to the host. However, it is also the cause of gastric diseases ranging from gastritis to ulcers to gastric cancer and has been classified a type 1 carcinogen by the World Health Organization. We have previously shown that phosphorylation of a 145-kDa protein and activation of signal transduction pathways are associated with the attachment of
H. pylori
to gastric cells. Here we identify the 145-kDa protein as the
H. pylori
CagA protein. We also show that CagA is necessary to induce a growth-factor-like phenotype (hummingbird) in host gastric cells similar to that induced by hepatocyte growth factor (HGF). Additionally, we identify a second cellular phenotype induced after attachment by
H. pylori,
which we call SFA (stress fiber associated). SFA is CagA independent and is produced by type I and type II
H. pylori
.
Disruption of the telomerase catalytic subunit gene from
Arabidopsis
inactivates telomerase and leads to a slow loss of telomeric DNA
Authors: Fitzgerald Matthew S. , Riha Karel , Gao Feng , Ren Shuxin , McKnight Thomas D. , Shippen Dorothy E.
Published: July 2002

Telomerase is an essential enzyme that maintains telomeres on eukaryotic chromosomes. In mammals, telomerase is required for the lifelong proliferative capacity of normal regenerative and reproductive tissues and for sustained growth in a dedifferentiated state. Although the importance of telomeres was first elucidated in plants 60 years ago, little is known about the role of telomeres and telomerase in plant growth and development. Here we report the cloning and characterization of the
Arabidopsis
telomerase reverse transcriptase (TERT) gene,
AtTERT. AtTERT
is predicted to encode a highly basic protein of 131 kDa that harbors the reverse transcriptase and telomerase-specific motifs common to all known TERT proteins.
AtTERT
mRNA is 10–20 times more abundant in callus, which has high levels of telomerase activity, versus leaves, which contain no detectable telomerase. Plants homozygous for a transfer DNA insertion into the
AtTERT
gene lack telomerase activity, confirming the identity and function of this gene. Because telomeres in wild-type
Arabidopsis
are short, the discovery that telomerase-null plants are viable for at least two generations was unexpected. In the absence of telomerase, telomeres decline by approximately 500 bp per generation, a rate 10 times slower than seen in telomerase-deficient mice. This gradual loss of telomeric DNA may reflect a reduced rate of nucleotide depletion per round of DNA replication, or the requirement for fewer cell divisions per organismal generation. Nevertheless, progressive telomere shortening in the mutants, however slow, ultimately should be lethal.
Molecular cloning and functional expression of gibberellin 2- oxidases, multifunctional enzymes involved in gibberellin deactivation
Authors: Thomas Stephen G. , Phillips Andrew L. , Hedden Peter
Published: July 2002

A major catabolic pathway for the gibberellins (GAs) is initiated by 2β-hydroxylation, a reaction catalyzed by 2-oxoglutarate-dependent dioxygenases. To isolate a GA 2β-hydroxylase cDNA clone we used functional screening of a cDNA library from developing cotyledons of runner bean (
Phaseolus coccineus
L.) with a highly sensitive tritium-release assay for enzyme activity. The encoded protein, obtained by heterologous expression in
Escherichia coli
, converted GA
9
to GA
51
(2β-hydroxyGA
9
) and GA
51
-catabolite, the latter produced from GA
51
by further oxidation at C-2. The enzyme thus is multifunctional and is best described as a GA 2-oxidase. The recombinant enzyme also 2β-hydroxylated other C
19
-GAs, although only GA
9
and GA
4
were converted to the corresponding catabolites. Three related cDNAs, corresponding to gene sequences present in
Arabidopsis thaliana
databases, also encoded functional GA 2-oxidases. Transcripts for two of the
Arabidopsis
genes were abundant in upper stems, flowers, and siliques, but the third transcript was not detected by Northern analysis. Transcript abundance for the two most highly expressed genes was lower in apices of the GA-deficient
ga1–2
mutant of
Arabidopsis
than in wild-type plants and increased after treatment of the mutant with GA
3
. This up-regulation of GA 2-oxidase gene expression by GA contrasts GA-induced down-regulation of genes encoding the biosynthetic enzymes GA 20-oxidase and GA 3β-hydroxylase. These mechanisms would serve to maintain the concentrations of biologically active GAs in plant tissues.
Miocene ungulates and terrestrial primary productivity: Where have all the browsers gone?
Authors: Janis Christine M. , Damuth John , Theodor Jessica M.
Published: July 2002

Progressive changes are observed in both the composition of mammal faunas and vegetation during the Miocene epoch [24–5 mega-annum (Ma)]. These changes are usually interpreted as a response to climatic changes. In the traditional view, forests or woodlands gradually gave way to more open habitats, with grazing (grass-eating) ungulate (hoofed) mammal species replacing the browsing (leafy-vegetation-eating) species as grasslands expanded. However, data from fossil assemblages in the Great Plains region of North America show that this faunal change was not a one-for-one replacement of browsers by grazers, as usually thought. Typical late early Miocene (17 Ma) fossil communities included extraordinarily high numbers of browsing ungulate species, comprising a fauna that cannot be directly analogized with any present-day community. Both maximum species richness of all ungulates and the proportion of browsers declined steadily in ungulate communities through the middle Miocene, to levels comparable to those of the present by the late Miocene. The resulting dramatic, cumulative loss of browsing species constitutes one of the strongest faunal signals of the late Tertiary (but was not a single “event”). We suggest that the early Miocene browser-rich communities may reflect higher levels of primary productivity in Miocene vegetation, compared with equivalent present-day vegetation types. The observed decline in species richness may represent a gradual decline in primary productivity, which would be consistent with one current hypothesis of a mid-Miocene decrease in atmospheric CO
2
concentrations from higher mid-Cenozoic values.
α-Galactosylceramide-activated Vα14 natural killer T cells mediate protection against murine malaria
Authors: Gonzalez-Aseguinolaza Gloria , de Oliveira Camila , Tomaska Margaret , Hong Seokmann , Bruna-Romero Oscar , Nakayama Toshinori , Taniguchi Masaru , Bendelac Albert , Van Kaer Luc , Koezuka Yasuhiko , Tsuji Moriya
Published: July 2002

Natural killer T (NKT) cells are a unique population of lymphocytes that coexpress a semiinvariant T cell and natural killer cell receptors, which are particularly abundant in the liver. To investigate the possible effect of these cells on the development of the liver stages of malaria parasites, a glycolipid, α-galactosylceramide (α-GalCer), known to selectively activate Vα14 NKT cells in the context of CD1d molecules, was administered to sporozoite-inoculated mice. The administration of α-GalCer resulted in rapid, strong antimalaria activity, inhibiting the development of the intrahepatocytic stages of the rodent malaria parasitesPlasmodium yoeliiandPlasmodium berghei. The antimalaria activity mediated by α-GalCer is stage-specific, since the course of blood-stage-induced infection was not inhibited by administration of this glycolipid. Furthermore, it was determined that IFN-γ is essential for the antimalaria activity mediated by the glycolipid. Taken together, our results provide the clear evidence that NKT cells can mediate protection against an intracellular microbial infection.
Benzo[
a
]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor
Authors: Shimizu Yasuhito , Nakatsuru Yoko , Ichinose Masao , Takahashi Yoshihisa , Kume Haruki , Mimura Junsei , Fujii-Kuriyama Yoshiaki , Ishikawa Takatoshi
Published: July 2002

The contribution of the aryl hydrocarbon receptor (AhR) in induction of a battery of xenobiotic-metabolizing enzymes has been studied extensively. However, no direct proof has been obtained that it plays a role in modulating carcinogenesis. To address the question of whether AhR is required for tumor induction, we have investigated the response of AhR-deficient mice to benzo[
a
]pyrene (B[
a
]P), a widely distributed environmental carcinogen. B[
a
]P treatment induced expression of the cytochrome P450 gene
Cyp1a1
in the skin and liver of AhR-positive mice bearing +/+ and +/− genotypes and did not induce expression of the cytochrome P450 gene
Cyp1a1
in AhR-null mice in either skin or liver. In contrast,
Cyp1a2
gene expression was positive in liver irrespective of the presence or absence of the AhR gene, or B[
a
]P treatment, although its inducibility was lost in the AhR(−/−) mouse. All AhR-positive male mice of both +/+ and +/− genotypes that received subcutaneous injection of B[
a
]P (2 mg) on the first and the eighth days had developed subcutaneous tumors at the site of injection at the end of the 18-week experiment. In contrast, no tumors were apparent in any of the AhR-deficient mice. Likewise, topical application of B[
a
]P (200 μg) at weekly intervals to the skin of female mice for 25 weeks produced skin tumors only in the AhR-positive mice. Thus the carcinogenic action of B[
a
]P may be determined primarily by AhR, a transcriptional regulator of the gene for CYP1A1. The results of the present study provide direct evidence that AhR is involved in carcinogenesis.
Tyrosine phosphorylation of theHelicobacter pyloriCagA antigen aftercag-driven host cell translocation
Authors: Stein Markus , Rappuoli Rino , Covacci Antonello
Published: July 2002

Helicobacter pyloristrains associated with severe tissue damage and inflammation possess a unique genetic locus,cag, containing 31 genes originating from a distant event of horizontal transfer and retained as a pathogenicity island. Thecagsystem is anHelicobacter-specific type IV secretion engine involved in cellular responses like induction of pedestals, secretion of IL-8, and phosphorylation of proteic targets. It has previously been reported that cocultivation of epithelial cells withHelicobacter pyloritriggers signal transduction and tyrosine phosphorylation of a 145-kDa putative host cell protein. Herein, we demonstrate that this protein is not derived from the host but rather is the bacterial immunodominant antigen CagA, a virulence factor commonly expressed in peptic ulcer disease and thought to be an orphan of a specific biological function. Thus, CagA is delivered into the epithelial cells by thecagtype IV secretion system where it is phosphorylated on tyrosine residues by an as yet unidentified host cell kinase and wired to eukaryotic signal transduction pathways and cytoskeletal plasticity.
Molecular computation: RNA solutions to chess problems
Authors: Faulhammer Dirk , Cukras Anthony R. , Lipton Richard J. , Landweber Laura F.
Published: July 2002

We have expanded the field of “DNA computers” to RNA and
present a general approach for the solution of satisfiability problems.
As an example, we consider a variant of the “Knight problem,”
which asks generally what configurations of knights can one place on an
n
×
n
chess board such that no knight is
attacking any other knight on the board. Using specific ribonuclease
digestion to manipulate strands of a 10-bit binary RNA library, we
developed a molecular algorithm and applied it to a 3 × 3
chessboard as a 9-bit instance of this problem. Here, the nine spaces
on the board correspond to nine “bits” or placeholders in a
combinatorial RNA library. We recovered a set of “winning”
molecules that describe solutions to this problem.
Importance of newly generated neurons in the adult olfactory bulb for odor discrimination
Authors: Gheusi Gilles , Cremer Harold , McLean Heather , Chazal Geneviève , Vincent Jean-Didier , Lledo Pierre-Marie
Published: July 2002

In adult rodents, neurons are continually generated in the subventricular zone of the forebrain, from where they migrate tangentially toward the olfactory bulb, the only known target for these neuronal precursors. Within the main olfactory bulb, they ascend radially into the granule and periglomerular cell layers, where they differentiate mainly into local interneurons. The functional consequences of this permanent generation and integration of new neurons into existing circuits are unknown. To address this question, we used neural cell adhesion molecule-deficient mice that have documented deficits in the migration of olfactory-bulb neuron precursors, leading to about 40% size reduction of this structure. Our anatomical study reveals that this reduction is restricted to the granule cell layer, a structure that contains exclusively γ-aminobutyric acid (GABA)ergic interneurons. Furthermore, mutant mice were subjected to experiments designed to examine the behavioral consequences of such anatomical alteration. We found that the specific reduction in the newly generated interneuron population resulted in an impairment of discrimination between odors. In contrast, both the detection thresholds for odors and short-term olfactory memory were unaltered, demonstrating that a critical number of bulbar granule cells is crucial only for odor discrimination but not for general olfactory functions.
Soluble CD14 enriched in colostrum and milk induces B cell growth and differentiation
Authors: Filipp Dominik , Alizadeh-Khiavi Kamel , Richardson Christopher , Palma Anthony , Paredes Nethnapha , Takeuchi Osamu , Akira Shizuo , Julius Michael
Published: July 2002

Induction of resting B cell growth and differentiation requires a complex series of temporally coordinated signals that are initiated on contact with activated helper T cells. These signals complement one another, each rendering the B cell susceptible to factors supporting progressive activation. Here, we demonstrate that soluble CD14 (sCD14) bypasses the physiological sequelae of events that limit B cell activation. B cell growth and differentiationin vitrois induced by both native and recombinant forms of sCD14 at nanomolar concentrations. sCD14-mediated cellular activation does not require membrane CD14 expression, depends on a region of CD14 that is not involved in lipopolysaccharide binding, and requires functional Toll-like receptor 4. Consistent with biological activity of sCD14in vitro, its administration to neonatal mice enhances Ig secretion. The results presented establish sCD14 as a naturally occurring soluble B cell mitogen of mammalian origin.
Dual modulation of cell survival and cell death by β
2
-adrenergic signaling in adult mouse cardiac myocytes
Authors: Zhu Wei-Zhong , Zheng Ming , Koch Walter J. , Lefkowitz Robert J. , Kobilka Brian K. , Xiao Rui-Ping
Published: July 2002

The goal of this study was to determine whether
β
1
-adrenergic receptor (AR) and β
2
-AR
differ in regulating cardiomyocyte survival and apoptosis and,
if so, to explore underlying mechanisms. One potential mechanism is
that cardiac β
2
-AR can activate both G
s
and
G
i
proteins, whereas cardiac β
1
-AR couples
only to G
s
. To avoid complicated crosstalk between β-AR
subtypes, we expressed β
1
-AR or β
2
-AR
individually in adult β
1
/β
2
-AR
double knockout mouse cardiac myocytes by using adenoviral gene
transfer. Stimulation of β
1
-AR, but not
β
2
-AR, markedly induced myocyte apoptosis, as
indicated by increased terminal deoxynucleotidyltransferase-mediated
UTP end labeling or Hoechst staining positive cells and DNA
fragmentation. In contrast, β
2
-AR (but not
β
1
-AR) stimulation elevated the activity of Akt, a
powerful survival signal; this effect was fully abolished by inhibiting
G
i
, G
β
γ
, or phosphoinositide 3
kinase (PI3K) with pertussis toxin, βARK-ct (a peptide inhibitor of
G
β
γ
), or LY294002, respectively. This
indicates that β
2
-AR activates Akt via a
G
i
-G
β
γ
-PI3K pathway. More
importantly, inhibition of the
G
i
-G
β
γ
-PI3K-Akt pathway
converts β
2
-AR signaling from survival to
apoptotic. Thus, stimulation of a single class of receptors,
β
2
-ARs, elicits concurrent apoptotic and survival
signals in cardiac myocytes. The survival effect appears to predominate
and is mediated by the
G
i
-G
β
γ
-PI3K-Akt signaling
pathway.
The crisis of ‘identity’ in high modernity
Authors: Bendle Mervyn F.
Published: July 2002

The concept of ‘identity’ is central to much contemporary sociology, reflecting a crisis that manifests itself in two ways. Firstly, there is a view that identity is both vital and problematic in this period of high modernity. Secondly, while this awareness is reflected in sociology, its accounts of identity are inconsistent, under‐theorized and incapable of bearing the analytical load required. As a result, there is an inherent contradiction between a valuing of identity as so fundamental as to be crucial to personal well‐being, and a theorization of ‘identity’ that sees it as something constructed, fluid, multiple, impermanent and fragmentary. The contemporary crisis of identity thus expresses itself as both a crisis of society, and a crisis of theory. This paper explores the diverse ways in which ‘identity’ is deployed before turning to case‐studies of its use by Anthony Giddens and Manuel Castells. This strategy demonstrates the widespread and diverse concern with identity before exploring how problematic it has become, even in the work of two of the world's leading sociologists.
Multiculturalism and Governing Neighbourhoods
Authors: Allen Judith , Cars Goran
Published: July 2002

Parekh's theory of multiculturalism offers a number of insights which are useful in analysing the role of neighbourhood governance in promoting social cohesion within culturally diverse small areas. The problems of neighbourhood governance are rooted in disjointed structural change across Europe over the past 25 years. In this context, the formation of a multicultural European polity risks creating a white European ethnicity which will institutionalise specific forms of racism within distressed neighbourhoods. At the same time, the shift from government to governance as a way to address the problems of governability in structurally reconstituted societies is associated with the top-down imposition of specific forms of neighbourhood governance which can then, unwittingly, become part of the institutionalisation of racism. Using Parekh's theory to construct a critique yields a set of principles which illuminate a number of key strategic elements which can be used practically in designing neighbourhood governance mechanisms and which illuminate the pre-occupations in the existing literature.
Bargaining, Coalitions and Local Expenditure
Authors: Gangopadhyay Partha , Nath Shyam
Published: July 2002

We extend the literature on local expenditure determination by showing that bargaining and grand coalition seem to facilitate collective decision-making in an assembly of elected councillors. We demonstrate that the solution of the game turns on the principle of equal relative concession. Based on limited experimentation, we assess the performance of local governments and find that group dominance frustrates local expenditure efficiency in urban localities of India.
Partnerships, Business Elites and Urban Politics: New Forms of Governance in an English City?
Authors: Bassett Keith
Published: July 2002

This paper begins with a review of the conditions which have led to a proliferation of partnership arrangements in English cities and the related emergence of new business elites with interests in urban policy-making. The paper reviews a series of recent studies of these phenomena and comments on the importance of local economic and political factors in explaining inter-urban variations. The paper then presents an analysis of political and policy change in Bristol in the post-war period, tracing the factors that have accounted for the recent, if tardy, rapprochement between the political and business sectors and the launching of a widening array of partnership initiatives. An attempt is then made to explain these developments using a number of different theoretical frameworks, in particular growth coalition theory, urban regime theory, and policy network analysis. The paper concludes with some comments on the relation between these trends and the suggestion that we are witnessing a transition from a Fordist to a post-Fordist mode of regulation in English cities.
New tools, new insights: Kohlberg’s moral judgement stages revisited
Authors: Dawson Theo Linda
Published: July 2002

In this paper, four sets of data, collected by four different research teams over a period of 30 years are examined. Common item equating, which yielded correlations from .94 to .97 across datasets, was employed to justify pooling the data for a new analysis. Probabilistic conjoint measurement (Rasch analysis) was used to model the results. The detailed analysis of these pooled data confirms results reported in previous research about the ordered acquisition of moral stages and the relationship between moral stages and age, education, and sex. New findings include: (1) empirical evidence that transitions between “childhood” and “adult” stages of development involve similar mechanisms; (2) support for the notion of stages as qualitatively distinct modes of reasoning that display properties consistent with a notion of structure d’ensemble; and (3) evidence of a stage between Kohlberg’s stages 3 and 4. Consistent with reports from earlier research, the relationship between age and moral development is curvilinear. The relationship between educational attainment and moral development is linear, suggesting that educational environments have an equivalent impact across the course of development. Older males have slightly higher scores than older females after age and education are taken into account (accounting for 0.3% of the variance in moral ability).
Contexts, functions, forms, and processes of collaborative everyday problem solving in older adulthood
Authors: Meegan Sean P. , Berg Cynthia A.
Published: July 2002

The present paper reviews the extant literature on collaborative everyday problem solving in older adulthood and explicates the contexts, functions, forms, and processes of collaboration in daily life. In this review, we examine collaboration as it occurs in the daily lives of older adults in addition to the specified intelligence-like tasks more typical of the current literature. Drawing from multiple literatures that have examined collaboration, including sociocultural perspectives within child development, life-span cognition, educational psychology, and social psychology, we illuminate the changing contexts of collaboration across the life span and examine the role of potential collaborators, the multiplicity of forms and functions of collaboration, and the social processes that may facilitate or hinder collaborative performance.
Goal Contents, Well-being, and Life Context During Transition to University: A Longitudinal Study
Authors: Salmela-Aro Katariina , Nurmi Jari-Erik
Published: July 2002

To examine the relationships between young adults’ goal contents, their life situation, experienced life events, and subjective well-being, 256 university students filled in the Little’s Personal Project Analysis (PPA), the revised Beck’s Depression Inventory (BDI), Rosenberg’s Self-esteem Scale (RSE), and a background questionnaire at the beginning of their studies. One year later, they also completed a life event scale (LES). Two years later, they again filled in the PPA, BDI, RSE, LES, and a background questionnaire. The results showed that an earlier life situation such as being married and having children was associated with interest in family-related goals, which again predicted subsequent transitions in this life domain. Moreover, goals that concern major age-graded developmental tasks, such as a future family, were found to predict high subjective well-being. In turn, high subjective well-being also predicted interest in these types of goals. By way of contrast, low self-esteem predicted interest in self-related goals, which again were associated with low well-being later on.
Adolescents’ Future Orientation in Time and Place: The Case of the Israeli Kibbutz
Authors: Seginer Rachel , Schlesinger Ronit
Published: July 2002

This study examined the effect of changing social circumstances on adolescents’ future orientation. Focusing on the recent kibbutz crisis, the future orientation of two cohorts of kibbutz and urban boys and girls ( N 438) who were high school seniors in 1984 and 1992 was analysed. Results partly supported cohort, gender, and cohort by setting effects in adolescents’ future orientation, indicating that: (1) the 1992 cohort invested more in constructing prospective domains pertaining to adulthood ( work and career, marriage and family) and less in military service; (2) the tendency of Israeli adolescents to construe a sex-typed future orientation was stable over time; and (3) that the 1992 kibbutz cohort increased its investment in work and career more than did the 1992 urban cohort. Results were explained in terms of the adaptability of adolescent future orientation to changing social circumstances, and in terms of Heckhausen’s (1977) principle of least necessary expenditure.
Staying in School Protects Boys with Poor Self-regulation in Childhood from Later Crime: A Longitudinal Study
Authors: Henry Bill , Caspi Avshalom , Moffitt Terrie E. , Harrington HonaLee , Silva Phil A.
Published: July 2002

Based on a theoretical model that emphasises the distinction between individual and contextual determinants of antisocial behaviour, the current study examined whether school attendance throughout adolescence acted as a protective factor for individuals at risk for criminal behaviour in early adulthood. Specifically, Lack of Control, an index of self-regulation which has previously been shown to predict later criminal behaviour, was expected to interact with early school leaving to predict self-reports and official records of criminal behaviour collected at age 21. Multivariate regression analyses revealed a significant three-way interaction between school attendance, self-regulation, and sex. Among males, after controlling for the effects of socioeconomic status and IQ, the main effects for Lack of Control and school attendance were found to be significant; additionally, the interaction between Lack of Control and school attendance was significant, indicating that the strength of the relation between Lack of Control and criminal outcomes was moderated by school attendance. The main effects for Lack of Control and school attendance were significant for females, but the interaction between Lack of Control and school attendance was not significant. The protective effect of school attendance among males could not be accounted for by differences in familial disruption or adolescent delinquency.
Practical Aspects of Discovery Pathology
Authors: Burkhardt John E. , Ryan Anne M. , Germann Paul-Georg
Published: July 2002

Pathologists are uniquely qualified to play a central role in driving drug discovery and development programs by: 1) establishing disease models to assess potential therapies, 2) characterizing modifications in the disease state in response to therapies, 3) characterizing toxicologic mechanisms and responses to drug candidates, and 4) facilitating multidisciplinary efforts to monitor for the clinical occurrence, progression, and reversibility of adverse events. Such nontraditional deployment of resources must, to be viable, produce benefits to the pharmaceutical industry comparable to those of more conventional activities such as delivery of data in nonclinical safety studies. Additionally, benefits must be tangible from standpoints such as timesavings or improved quality of research decisions, manifesting as either program acceleration or improved candidate survival.
Olfactory Epithelium as a Novel Toxic Target Following an Intravenous Administration of Vincristine to Mice
Authors: Kai Kiyonori , Satoh Hiroshi , Kashimoto Yoshinori , Kajimura Tetsuyo , Furuhama Kazuhisa
Published: July 2002

To delineate morphological characteristics of olfactory lesions induced by vincristine (VCR), a vinca alkaloid derivative with antitumor activity, male BALB/ c mice were given a single intravenous injection of 1.95 mg/kg, an estimated 10% lethal dose (designated as day 1). The animals were serially sacrificed on days 2, 3, 5, 10, 15 and 60, and the nasal mucosa was examined histopathologically. Cell death was noted in the olfactory epithelia adjacent to the respiratory epithelia from days 2 to 5. Inflammatory responses were not detected throughout the observation periods. Cell death was identified as apoptotic by the terminal deoxyribonucleotidy l transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) assay and electron microscopy. Mitotic figures and proliferating cell nuclear antigen (PCNA)-positive reactions were diffusely scattered in both the basal and sensory cells. On days 10 or after, no prominent histological abnormalities were noted in the olfactory epithelia, which suggests the aforementioned lesions were completely recovered. These results demonstrate that it is essential to perform histopathologica l evaluation of the nasal mucosa during an early preclinical stage for novel antitumor drugs, since olfactory lesions due to the certain compound s like VCR may not be detected by any other procedure.
Older Female Workers in Britain and its Regions
Authors: Collis Clive , Green Anne , Mallier Tony
Published: July 2002

In the context of demographic and workforce ageing, this paper examines the participation of older females in the labour market. While there has been increasing interest in lower employment rates amongst older males, little attention has been paid to older females. The paper reviews some of the determinants of female participation rates. It then moves on to explore issues and policies associated with education, training and learning; age discrimination and equal opportunities ; and pensions and benefits. In conclusion, a suggested research agenda - providing information to help guide the formulation and implementation of policy - is outlined.
Institutional Amnesia: A Paradox of the 'Information Age'?
Authors: Pollitt Christopher
Published: July 2002

It is one of the paradoxes of our age that, while new information technologies have provided us with the ability to store, retrieve, manipulate and communicate more data, faster than ever before, at the same time many of our public institutions seem to be losing their memories. Many texts have been written about 'organizational learning', but few about organizational forgetting. The core contention of this paper is that the phenomenon of organizational amnesia deserves attention, from scholars and practitioners alike. My aim, therefore, is to set out the character, causes and likely consequences of institutional memory loss in the contemporary public sector.
Petrol sniffing in Aboriginal communities: a review of interventions
Authors: MACLEAN SARAH J. , D'ABBS PETER H. N.
Published: July 2002

Petrol sniffing (and other forms of inhalant misuse) occur within some Aboriginal communities across Australia. However, there is little documented information about the nature and combination of interventions that are most effective in addressing it. This article reviews published and unpublished literature relevant to petrol sniffing in Australian Aboriginal communities. A range of strategies which have been trialled previously are discussed under the categories of primary, secondary and tertiary intervention. We have adopted Zinberg's schema of ‘drug’, ‘set’ and ‘setting’ in theorizing the mix of interventions most likely to reduce petrol sniffing. We argue that interventions should address as many as possible of these factors. Further, while no strategy is likely to succeed without strong support from local community members, governments also have an important role in addressing petrol sniffing. Consistent funding for strategies directly addressing petrol sniffing and co‐ordinated government responses to the broader needs of Aboriginal young people and their communities are critical.
Studies on the Biological Effects of Ozone: 10. Release of Factors from Ozonated Human Platelets
Authors: Valacchi G. , Bocci Velio
Published: July 2002

In a previous work we have shown that heparin, in the presence of ozone (O3), promotes a dose‐dependent platelet aggregation, while after Ca2+ chelation with citrate, platelet aggregation is almost negligible. These results led us to think that aggregation may enhance the release of platelet components. We have here shown that indeed significantly higher amount of platelet‐derived growth factor (PDGF), transforming growth factor β1 (TGF‐β1) and interleukin‐8(IL‐8) are released in a dose‐dependent manner after ozonation of heparinised platelet‐rich plasma samples. These findings may explain the enhanced healing of torpid ulcers in patients with chronic limbischemia treated with O3 autohaemoteraphy (O3‐AHT).
Alcohol Use in Adolescent Females: Correlates with Estradiol and Testosterone
Authors: Martin Catherine A. , Arch G. , III Mainous , Curry Thomas , Martin David
Published: July 2002

This study investigated if self‐reports of alcohol use correlated with estradiol and testosterone levels in adolescent females. Ninety‐four female senior high school student volunteers from 2 schools completed a questionnaire regarding alcohol use. Twenty cc of blood was assayed for estradiol, testosterone, progesterone, and FSH. Total estradiol levels were higher in females who reported current alcohol use (p ≤ .05), and females with higher levels of both testosterone and estradiol were more likely to be using alcohol currently (p ≤ 0.05). Hormonal relationships associated with adolescent alcohol use may be related to future health risks of alcohol use and/or increased risk of alcohol use.
Non‐specific nature of specific language impairment: a review of the literature with regard to concomitant motor impairments
Authors: Hill Elisabeth L.
Published: July 2002

In the light of emerging suggestions that language and motor deficits may co‐occur, the literature on specific language impairment (SLI) was reviewed to investigate the prevalence of co‐morbidity between SLI and poor limb motor skill in children diagnosed with language impairments. An extensive literature search was undertaken and the subsequent findings evaluated with particular reference to issues surrounding symptom co‐occurrence, as well as to theoretical and aetiological accounts of SLI. Clearly substantial co‐morbidity exists between SLI and poor motor skill, suggesting that SLI is not a specific disorder of language, but rather that children with SLI experience a broader range of difficulties, of which motor incoordination is one. Current theoretical explanations of SLI do not account fully for such wide‐ranging difficulties and it may be useful in the future to focus on a more detailed explanation in terms of shared cognitive processes or neuromaturational delay to understand further the nature of the disorder, to explain it theoretically and to deal with it practically.
The Saccharomyces cerevisiae Kinesin-related Motor Kar3p Acts at Preanaphase Spindle Poles to Limit the Number and Length of Cytoplasmic Microtubules
Authors: Saunders William , Hornack David , Lengyel Valerie , Deng Changchun
Published: July 2002

The Saccharomyces cerevisiae kinesin-related motor Kar3p, though known to be required for karyogamy, plays a poorly defined, nonessential role during vegetative growth. We have found evidence suggesting that Kar3p functions to limit the number and length of cytoplasmic microtubules in a cell cycle–specific manner. Deletion of KAR3 leads to a dramatic increase in cytoplasmic microtubules, a phenotype which is most pronounced from START through the onset of anaphase but less so during late anaphase in synchronized cultures. We have immunolocalized HA-tagged Kar3p to the spindle pole body region, and fittingly, Kar3p was not detected by late anaphase. A microtubule depolymerizing activity may be the major vegetative role for Kar3p. Addition of the microtubule polymerization inhibitors nocodazol or benomyl to the medium or deletion of the nonessential α-tubulin TUB3 gene can mostly correct the abnormal microtubule arrays and other growth defects of kar3 mutants, suggesting that these phenotypes result from excessive microtubule polymerization. Microtubule depolymerization may also be the mechanism by which Kar3p acts in opposition to the anaphase B motors Cin8p and Kip1p. A preanaphase spindle collapse phenotype of cin8 kip1 mutants, previously shown to involve Kar3p, is markedly delayed when microtubule depolymerization is inhibited by the tub2-150 mutation. These results suggest that the Kar3p motor may act to regulate the length and number of microtubules in the preanaphase spindle.
Dynamin at the Neck of Caveolae Mediates Their Budding to Form Transport Vesicles by GTP-driven Fission from the Plasma Membrane of Endothelium
Authors: Oh Phil , McIntosh Deirdre P. , Schnitzer Jan E.
Published: July 2002

The molecular mechanisms mediating cell surface trafficking of caveolae are unknown. Caveolae bud from plasma membranes to form free carrier vesicles through a “pinching off” or fission process requiring cytosol and driven by GTP hydrolysis (Schnitzer, J.E., P. Oh, and D.P. McIntosh. 1996. Science. 274:239–242). Here, we use several independent techniques and functional assays ranging from cell-free to intact cell systems to establish a function for dynamin in the formation of transport vesicles from the endothelial cell plasma membrane by mediating fission at the neck of caveolae. This caveolar fission requires interaction with cytosolic dynamin as well as its hydrolysis of GTP. Expression of dynamin in cytosol as well as purified recombinant dynamin alone supports GTP-induced caveolar fission in a cell-free assay whereas its removal from cytosol or the addition to the cytosol of specific antibodies for dynamin inhibits this fission. Overexpression of mutant dynamin lacking normal GTPase activity not only inhibits GTP-induced fission and budding of caveolae but also prevents caveolae-mediated internalization of cholera toxin B chain in intact and permeabilized endothelial cells. Analysis of endothelium in vivo by subcellular fractionation and immunomicroscopy shows that dynamin is concentrated on caveolae, primarily at the expected site of action, their necks. Thus, through its ability to oligomerize, dynamin appears to form a structural collar around the neck of caveolae that hydrolyzes GTP to mediate internalization via the fission of caveolae from the plasma membrane to form free transport vesicles.
PDMP Blocks Brefeldin A–induced Retrograde Membrane Transport from Golgi to ER: Evidence for Involvement of Calcium Homeostasis and Dissociation from Sphingolipid Metabolism
Authors: Kok Jan Willem , Babia Teresa , Filipeanu Catalin M. , Nelemans Adriaan , Egea Gustavo , Hoekstra Dick
Published: July 2002

In this study, we show that an inhibitor of sphingolipid biosynthesis, d,l-threo-1-phenyl-2- decanoylamino-3-morpholino-1-propanol (PDMP), inhibits brefeldin A (BFA)-induced retrograde membrane transport from Golgi to endoplasmic reticulum (ER). If BFA treatment was combined with or preceded by PDMP administration to cells, disappearance of discrete Golgi structures did not occur. However, when BFA was allowed to exert its effect before PDMP addition, PDMP could not “rescue” the Golgi compartment.

Evidence is presented showing that this action of PDMP is indirect, which means that the direct target is not sphingolipid metabolism at the Golgi apparatus. A fluorescent analogue of PDMP, 6-(N-[7-nitro-2,1,3-benzoxadiazol-4-yl]amino)hexanoyl-PDMP (C6-NBD-PDMP), did not localize in the Golgi apparatus. Moreover, the effect of PDMP on membrane flow did not correlate with impaired C6-NBD-sphingomyelin biosynthesis and was not mimicked by exogenous C6-ceramide addition or counteracted by exogenous C6-glucosylceramide addition. On the other hand, the PDMP effect was mimicked by the multidrug resistance protein inhibitor MK571.

The effect of PDMP on membrane transport correlated with modulation of calcium homeostasis, which occurred in a similar concentration range. PDMP released calcium from at least two independent calcium stores and blocked calcium influx induced by either extracellular ATP or thapsigargin. Thus, the biological effects of PDMP revealed a relation between three important physiological processes of multidrug resistance, calcium homeostasis, and membrane flow in the ER/ Golgi system.
Nexilin: A Novel Actin Filament-binding Protein Localized at Cell–Matrix Adherens Junction
Authors: Ohtsuka Toshihisa , Nakanishi Hiroyuki , Ikeda Wataru , Satoh Ayako , Momose Yumiko , Nishioka Hideo , Takai Yoshimi
Published: July 2002

We isolated two novel actin filament (F-actin)–binding proteins from rat brain and rat 3Y1 fibroblast. They were splicing variants, and we named brain big one b-nexilin and fibroblast small one s-nexilin. b-Nexilin purified from rat brain was a protein of 656 amino acids (aa) with a calculated molecular weight of 78,392, whereas s-nexilin, encoded by the cDNA isolated from rat 3Y1 cells by the reverse transcriptase-PCR method, was a protein of 606 aa with a calculated molecular weight of 71,942. b-Nexilin had two F-actin– binding domains (ABDs) at the NH2-terminal and middle regions, whereas s-nexilin had one ABD at the middle region because 64 aa residues were deleted and 14 aa residues were inserted in the first NH2-terminal ABD of b-nexilin, and thereby the first ABD lost its activity. b- and s-nexilins bound along the sides of F-actin, but only b-nexilin showed F-actin cross-linking activity. b-Nexilin was mainly expressed in brain and testis, whereas s-nexilin was mainly expressed in testis, spleen, and fibroblasts, such as rat 3Y1 and mouse Swiss 3T3 cells, but neither b- nor s-nexilin was detected in liver, kidney, or cultured epithelial cells. An immunofluorescence microscopic study revealed that s-nexilin was colocalized with vinculin, talin, and paxillin at cell– matrix adherens junction (AJ) and focal contacts, but not at cell–cell AJ, in 3Y1 cells. Overexpressed b- and s-nexilins were localized at focal contacts but not at cell–cell AJ. These results indicate that nexilin is a novel F-actin–binding protein localized at cell–matrix AJ.
Nervous System Defects of AnkyrinB (−/−) Mice Suggest Functional Overlap between the Cell Adhesion Molecule L1 and 440-kD AnkyrinB in Premyelinated Axons
Authors: Scotland Paula , Zhou Daixing , Benveniste Helene , Bennett Vann
Published: July 2002

The L1 CAM family of cell adhesion molecules and the ankyrin family of spectrin-binding proteins are candidates to collaborate in transcellular complexes used in diverse contexts in nervous systems of vertebrates and invertebrates. This report presents evidence for functional coupling between L1 and 440-kD ankyrinB in premyelinated axons in the mouse nervous system. L1 and 440-kD ankyrinB are colocalized in premyelinated axon tracts in the developing nervous system and are both down-regulated after myelination. AnkyrinB (−/−) mice exhibit a phenotype similar to, but more severe, than L1 (−/−) mice and share features of human patients with L1 mutations. AnkyrinB (−/−) mice exhibit hypoplasia of the corpus callosum and pyramidal tracts, dilated ventricles, and extensive degeneration of the optic nerve, and they die by postnatal day 21. AnkyrinB (−/−) mice have reduced L1 in premyelinated axons of long fiber tracts, including the corpus callosum, fimbria, and internal capsule in the brain, and pyramidal tracts and lateral columns of the spinal cord. L1 was evident in the optic nerve at postnatal day 1 but disappeared by postnatal day 7 in mutant mice while NCAM was unchanged. Optic nerve axons of ankyrinB (−/−) mice become dilated with diameters up to eightfold greater than normal, and they degenerated by day 20. These findings provide the first evidence for a role of ankyrinB in the nervous system and support an interaction between 440-kD ankyrinB and L1 that is essential for maintenance of premyelinated axons in vivo.
Vinexin: A Novel Vinculin-binding Protein with Multiple SH3 Domains Enhances Actin Cytoskeletal Organization
Authors: Kioka Noriyuki , Sakata Shohei , Kawauchi Takeshi , Amachi Teruo , Akiyama Steven K. , Okazaki Kenji , Yaen Christopher , Yamada Kenneth M. , Aota Shin-ichi
Published: July 2002

Using the yeast two-hybrid system and an in vitro binding assay, we have identified a novel protein termed vinexin as a vinculin-binding protein. By Northern blotting, we identified two types of vinexin mRNA that were 3 and 2 kb in length. Screening for full-length cDNA clones and sequencing indicated that the two mRNA encode 82- and 37-kD polypeptides termed vinexin α and β, respectively. Both forms of vinexin share a common carboxyl-terminal sequence containing three SH3 domains. The larger vinexin α contains an additional amino-terminal sequence. The interaction between vinexin and vinculin was mediated by two SH3 domains of vinexin and the proline-rich region of vinculin. When expressed, vinexin α and β localized to focal adhesions in NIH 3T3 fibroblasts, and to cell–cell junctions in epithelial LLC-PK1 cells. Furthermore, expression of vinexin increased focal adhesion size. Vinexin α also promoted upregulation of actin stress fiber formation. In addition, cell lines stably expressing vinexin β showed enhanced cell spreading on fibronectin. These data identify vinexin as a novel focal adhesion and cell– cell adhesion protein that binds via SH3 domains to the hinge region of vinculin, which can enhance actin cytoskeletal organization and cell spreading.
Direct Imaging of DNA in Living Cells Reveals the Dynamics of Chromosome Formation
Authors: Manders Erik M.M. , Kimura Hiroshi , Cook Peter R.
Published: July 2002

Individual chromosomes are not directly visible within the interphase nuclei of most somatic cells; they can only be seen during mitosis. We have developed a method that allows DNA strands to be observed directly in living cells, and we use it to analyze how mitotic chromosomes form. A fluorescent analogue (e.g., Cy5-dUTP) of the natural precursor, thymidine triphosphate, is introduced into cells, which are then grown on the heated stage of a confocal microscope. The analogue is incorporated by the endogenous enzymes into DNA. As the mechanisms for recognizing and removing the unusual residues do not prevent subsequent progress around the cell cycle, the now fluorescent DNA strands can be followed as they assemble into chromosomes, and segregate to daughters and granddaughters. Movies of such strands in living cells suggest that chromosome axes follow simple recognizable paths through their territories during G2 phase, and that late replicating regions maintain their relative positions as prophase chromosomes form. Quantitative analysis confirms that individual regions move little during this stage of chromosome condensation. As a result, the gross structure of an interphase chromosome territory is directly related to that of the prophase chromosome.