bluuebunny/crossref_metadata_2025 huggingface dataset:
Declines in mitochondrial respiration during cardiac reperfusion: Age-dependent inactivation of α-ketoglutarate dehydrogenase
Authors: Lucas David T. , Szweda Luke I.
Published: July 2002

We previously reported that cardiac reperfusion results in declines in mitochondrial NADH-linked respiration. The degree of inactivation increased with age and was paralleled by modification of protein by the lipid peroxidation product 4-hydroxy-2-nonenal. To gain insight into potential sites of oxidative damage, the present study was undertaken to identify specific mitochondrial protein(s) inactivated during ischemia and reperfusion and to determine which of these losses in activity are responsible for observed declines in mitochondrial respiration. Using a Langendorff rat heart perfusion protocol, we observed age-dependent inactivation of complex I during ischemia and complex IV and α-ketoglutarate dehydrogenase during reperfusion. Although losses in complex I and IV activities were found not to be of sufficient magnitude to cause declines in mitochondrial respiration, an age-related decrease in complex I activity during ischemia may predispose old animals to more severe oxidative damage during reperfusion. It was determined that inactivation of α-ketoglutarate dehydrogenase is responsible, in large part, for observed reperfusion-induced declines in NADH-linked respiration. α-Ketoglutarate dehydrogenase is highly susceptible to 4-hydroxy-2-nonenal inactivation
in vitro
. Thus, our results suggest a plausible mechanism for age-dependent, reperfusion-induced declines in mitochondrial function and identify α-ketoglutarate dehydrogenase as a likely site of free radical-mediated damage.
Silibinin decreases prostate-specific antigen with cell growth inhibition via G
1
arrest, leading to differentiation of prostate carcinoma cells: Implications for prostate cancer intervention
Authors: Zi Xiaolin , Agarwal Rajesh
Published: July 2002

Reduction in serum prostate-specific antigen (PSA) levels has been proposed as an endpoint biomarker for hormone-refractory human prostate cancer intervention. We examined whether a flavonoid antioxidant silibinin (an active constituent of milk thistle) decreases PSA levels in hormone-refractory human prostate carcinoma LNCaP cells and whether this effect has biological relevance. Silibinin treatment of cells grown in serum resulted in a significant decrease in both intracellular and secreted forms of PSA concomitant with a highly significant to complete inhibition of cell growth via a G
1
arrest in cell cycle progression. Treatment of cells grown in charcoal-stripped serum and 5α-dihydrotestosterone showed that the observed effects of silibinin are those involving androgen-stimulated PSA expression and cell growth. Silibinin-induced G
1
arrest was associated with a marked decrease in the kinase activity of cyclin-dependent kinases (CDKs) and associated cyclins because of a highly significant decrease in cyclin D1, CDK4, and CDK6 levels and an induction of Cip1/p21 and Kip1/p27 followed by their increased binding with CDK2. Silibinin treatment of cells did not result in apoptosis and changes in p53 and bcl2, suggesting that the observed increase in Cip1/p21 is a p53-independent effect that does not lead to an apoptotic cell death pathway. Conversely, silibinin treatment resulted in a significant neuroendocrine differentiation of LNCaP cells as an alternative pathway after Cip1/p21 induction and G
1
arrest. Together, these results suggest that silibinin could be a useful agent for the intervention of hormone-refractory human prostate cancer.
Informatic selection of a neural crest-melanocyte cDNA set for microarray analysis
Authors: Loftus S. K. , Chen Y. , Gooden G. , Ryan J. F. , Birznieks G. , Hilliard M. , Baxevanis A. D. , Bittner M. , Meltzer P. , Trent J. , Pavan W.
Published: July 2002

With cDNA microarrays, it is now possible to compare the expression of many genes simultaneously. To maximize the likelihood of finding genes whose expression is altered under the experimental conditions, it would be advantageous to be able to select clones for tissue-appropriate cDNA sets. We have taken advantage of the extensive sequence information in the dbEST expressed sequence tag (EST) database to identify a neural crest-derived melanocyte cDNA set for microarray analysis. Analysis of characterized genes with dbEST identified one library that contained ESTs representing 21 neural crest-expressed genes (library 198). The distribution of the ESTs corresponding to these genes was biased toward being derived from library 198. This is in contrast to the EST distribution profile for a set of control genes, characterized to be more ubiquitously expressed in multiple tissues (
P
< 1 × 10
−9
). From library 198, a subset of 852 clustered ESTs were selected that have a library distribution profile similar to that of the 21 neural crest-expressed genes. Microarray analysis demonstrated the majority of the neural crest-selected 852 ESTs (Mel1 array) were differentially expressed in melanoma cell lines compared with a non-neural crest kidney epithelial cell line (
P
< 1 × 10
−8
). This was not observed with an array of 1,238 ESTs that was selected without library origin bias (
P
= 0.204). This study presents an approach for selecting tissue-appropriate cDNAs that can be used to examine the expression profiles of developmental processes and diseases.
Interferons inhibit activation of STAT6 by interleukin 4 in human monocytes by inducingSOCS-1gene expression
Authors: Dickensheets Harold L. , Venkataraman Chandrasekar , Schindler Ulrike , Donnelly Raymond P.
Published: July 2002

Interferons (IFNs) inhibit induction by IL-4 of multiple genes in human monocytes. However, the mechanism by which IFNs mediate this inhibition has not been defined. IL-4 activates gene expression by inducing tyrosine phosphorylation, homodimerization, and nuclear translocation of the latent transcription factor, STAT6 (signal transducer and activator of transcription-6). STAT6-responsive elements are characteristically present in the promoters of IL-4-inducible genes. Because STAT6 activation is essential for IL-4-induced gene expression, we examined the ability of type I and type II IFNs to regulate activation of STAT6 by IL-4 in primary human monocytes. Pretreatment of monocytes with IFN-β or IFN-γ, but not IL-1, IL-2, macrophage colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, IL-6, or transforming growth factor β suppressed activation of STAT6 by IL-4. This inhibition was associated with decreased tyrosine phosphorylation and nuclear translocation of STAT6 and was not evident unless the cells were preincubated with IFN for at least 1 hr before IL-4 stimulation. Furthermore, inhibition by IFN could be blocked by cotreatment with actinomycin D and correlated temporally with induction of the JAK/STAT inhibitory gene,SOCS-1. Forced expression ofSOCS-1in a macrophage cell line, RAW264, markedly suppressed trans-activation of an IL-4-inducible reporter as well as IL-6- and IFN-γ-induced reporter gene activity. These findings demonstrate that IFNs inhibit IL-4-induced activation of STAT6 and STAT6-dependent gene expression, at least in part, by inducing expression ofSOCS-1.
Testing ancient RNA–protein interactions
Authors: Landweber Laura F.
Published: July 2002

The past decade in molecular biology has seen remarkable
advances in the study of the origin and early evolution of life. The
mathematical tools for analyzing DNA and protein sequences, coupled
with the availability of complete microbial genome sequences, provide
insight almost as far back as the age of the nucleic acids themselves.
Experimental evolution in the laboratory and especially
in
vitro
evolution of RNA provide insight into a hypothetical world
where RNA, or a close relative, may have debuted as a primary
functional and informational molecule. The ability to isolate new
functional RNAs from random sequences now ultimately makes the world of
possible primitive chemical interactions accessible even when the
molecules or reactions are no longer present in modern species. Thus we
can at last form direct experimental tests of specific models for the
origin of RNA–protein associations, such as those that influenced the
genetic code. This marks a turning point for probing the origin and
early history of life at the molecular level.
Schwann cell survival mediated by the signaling phospholipid lysophosphatidic acid
Authors: Weiner Joshua A. , Chun Jerold
Published: July 2002

Lysophosphatidic acid (LPA) is a bioactive phospholipid with properties of an extracellular growth factor for many cell lines, including those derived from neuroblastomas. However, the relevance of LPA signaling to the normal, developing nervous system is unknown, in part reflecting the previous unavailability of cloned receptor genes. Recent studies of the first such gene, encoding the G protein-coupled receptor LP
A1
/VZG-1 (lysophospholipid receptor A1/ventricular zone gene-1), revealed a major locus of expression in oligodendrocytes and Schwann cells (SCs) during development, suggesting an influence of LPA on these myelinating cells. Here we report that LPA (≥10 nM) is a potent survival factor for cultured neonatal SCs, with survival activity equaling the maximal effect of neuregulin, the major peptide SC survival factor. LPA activates a pharmacologically defined signaling pathway in SCs, involving G
i
and phosphoinositide 3-kinase. Moreover, LPA’s effect depends on Akt, a downstream kinase that can mediate phosphoinositide 3-kinase-dependent survival, as demonstrated by both Western blot and transfection analyses. Overexpression of functional epitope-tagged LP
A1
/VZG-1 protein decreases SC apoptosis in response to serum withdrawal. These data demonstrate a role for extracellular LPA and its receptor LP
A1
/VZG-1 in SC survival and, more broadly, implicate G protein-coupled receptor-mediated lysophospholipid signaling as a significant mechanism in neural development.
New patterns of centrifugally driven thermal convection
Authors: Jaletzky M. , Busse F. H.
Published: July 2002

An experimental study is described of convection driven by thermal buoyancy in the annular gap between two corotating coaxial cylinders, heated from the outside and cooled from the inside. Steady convection patterns of the hexaroll and of the knot type are observed in the case of high Prandtl number fluids, for which the Coriolis force is sufficiently small. Oblique rolls and phase turbulence in the form of irregular patterns of convection can also be observed in wide regions of the parameter space.
Uracil-DNA glycosylase–DNA substrate and product structures: Conformational strain promotes catalytic efficiency by coupled stereoelectronic effects
Authors: Parikh Sudip S. , Walcher Gunter , Jones Garry D. , Slupphaug Geir , Krokan Hans E. , Blackburn G. Michael , Tainer John A.
Published: July 2002

Enzymatic transformations of macromolecular substrates such as DNA repair enzyme/DNA transformations are commonly interpreted primarily by active-site functional-group chemistry that ignores their extensive interfaces. Yet human uracil–DNA glycosylase (UDG), an archetypical enzyme that initiates DNA base-excision repair, efficiently excises the damaged base uracil resulting from cytosine deamination even when active-site functional groups are deleted by mutagenesis. The 1.8-Å resolution substrate analogue and 2.0-Å resolution cleaved product cocrystal structures of UDG bound to double-stranded DNA suggest enzyme–DNA substrate-binding energy from the macromolecular interface is funneled into catalytic power at the active site. The architecturally stabilized closing of UDG enforces distortions of the uracil and deoxyribose in the flipped-out nucleotide substrate that are relieved by glycosylic bond cleavage in the product complex. This experimentally defined substrate stereochemistry implies the enzyme alters the orientation of three orthogonal electron orbitals to favor electron transpositions for glycosylic bond cleavage. By revealing the coupling of this anomeric effect to a delocalization of the glycosylic bond electrons into the uracil aromatic system, this structurally implicated mechanism resolves apparent paradoxes concerning the transpositions of electrons among orthogonal orbitals and the retention of catalytic efficiency despite mutational removal of active-site functional groups. These UDG/DNA structures and their implied dissociative excision chemistry suggest biology favors a chemistry for base-excision repair initiation that optimizes pathway coordination by product binding to avoid the release of cytotoxic and mutagenic intermediates. Similar excision chemistry may apply to other biological reaction pathways requiring the coordination of complex multistep chemical transformations.
Crosstalk pathway for inhibition of glucocorticoid-induced apoptosis by T cell receptor signaling
Authors: Jamieson Christina A. M. , Yamamoto Keith R.
Published: July 2002

Activation of the glucocorticoid receptor (GR) triggers apoptosis in T cells. However, activation of the T cell antigen receptor (TCR) blocks glucocorticoid-induced apoptosis, implying functional crosstalk between these two distinct signaling systems. By reconstructing or selectively blocking TCR-stimulated signaling pathways, we show here that TCR activation of the mitogen-activated protein kinase kinase/extracellular signal regulated kinase (MEK/ERK) cascade via Ras is necessary and sufficient to inhibit GR-mediated death in immortalized T and thymocyte cell lines and in primary T cells. Moreover, we found that activation of various pathway components (TCR, Ras, MEK1) altered the transcriptional regulatory activity of GR. In contrast, phosphatidylinositol 3-kinase and Akt, which down-regulate other lymphocyte apoptosis pathways, did not inhibit glucocorticoid-induced apoptosis. Our findings, which link signaling from the TCR cell surface receptor to that from the GR intracellular receptor, demonstrate the importance of the integration of signal transduction pathways in defining regulatory circuits. Because the TCR/Ras/MEK pathway has been shown previously to be essential for positive selection of thymocytes, the TCR/Ras/MEK signaling to GR crosstalk described herein may affect T cell development and homeostasis.
Spatial control of cell differentiation in
Myxococcus xanthus
Authors: Julien Bryan , Kaiser A. Dale , Garza Anthony
Published: July 2002

Myxococcus xanthus
develops species-specific multicellular fruiting bodies. Starting from a uniform mat of cells, some cells enter into nascent fruiting body aggregates, whereas other cells remain outside. The cells within the fruiting body differentiate from rods into spherical, heat-resistant spores, whereas the cells outside the aggregates, called peripheral cells, remain rod-shaped. Early developmentally regulated genes are expressed in peripheral cells as well as by cells in the fruiting bodies. By contrast, late developmental genes are only expressed by cells within the nascent fruiting bodies. The data show that peripheral cells begin to develop, but are unable to express genes that are switched on later than about 6 h after the start of development. All of the genes whose expression is limited to the fruiting body are dependent on C-signaling either directly or indirectly, whereas the genes that are equally expressed in peripheral rods and in fruiting body cells are not. One of the C-signal-dependent and spatially patterned operons is called
dev
, and the
dev
operon has been implicated in the process of sporulation. It is proposed that expression of certain genes, including those of the
dev
operon, is limited to the nascent fruiting body because fruiting body cells engage in a high level of C-signaling. Peripheral cells do less C-signaling than fruiting body cells, because they have a different spatial arrangement and are at lower density. As a consequence, peripheral cells fail to express the late genes necessary for spore differentiation.
Genome-wide expression profiling of mid-gestation placenta and embryo using a 15,000 mouse developmental cDNA microarray
Authors: Tanaka Tetsuya S. , Jaradat Saied A. , Lim Meng K. , Kargul George J. , Wang Xiaohong , Grahovac Marija J. , Pantano Serafino , Sano Yuri , Piao Yulan , Nagaraja Ramaiah , Doi Hirofumi , Wood William H. , Becker Kevin G. , Ko Minoru S. H.
Published: July 2002

cDNA microarray technology has been increasingly used to monitor global gene expression patterns in various tissues and cell types. However, applications to mammalian development have been hampered by the lack of appropriate cDNA collections, particularly for early developmental stages. To overcome this problem, a PCR-based cDNA library construction method was used to derive 52,374 expressed sequence tags from pre- and peri-implantation embryos, embryonic day (E) 12.5 female gonad/mesonephros, and newborn ovary. From these cDNA collections, a microarray representing 15,264 unique genes (78% novel and 22% known) was assembled. In initial applications, the divergence of placental and embryonic gene expression profiles was assessed. At stage E12.5 of development, based on triplicate experiments, 720 genes (6.5%) displayed statistically significant differences in expression between placenta and embryo. Among 289 more highly expressed in placenta, 61 placenta-specific genes encoded, for example, a novel prolactin-like protein. The number of genes highly expressed (and frequently specific) for placenta has thereby been increased 5-fold over the total previously reported, illustrating the potential of the microarrays for tissue-specific gene discovery and analysis of mammalian developmental programs.
Structural evidence for a programmed general base in the active site of a catalytic antibody
Authors: Golinelli-Pimpaneau Béatrice , Gonçalves Olivier , Dintinger Thierry , Blanchard Dominique , Knossow Marcel , Tellier Charles
Published: July 2002

The crystal structure of the complex of a catalytic antibody with its cationic hapten at 1.9-Å resolution demonstrates that the hapten amidinium group is stabilized through an ionic pair interaction with the carboxylate of a combining-site residue. The location of this carboxylate allows it to act as a general base in an allylic rearrangement. When compared with structures of other antibody complexes in which the positive moiety of the hapten is stabilized mostly by cation–π interactions, this structure shows that the amidinium moiety is a useful candidate to elicit a carboxylate in an antibody combining site at a predetermined location with respect to the hapten. More generally, this structure highlights the advantage of a bidentate hapten for the programmed positioning of a chemically reactive residue in an antibody through charge complementarity to the hapten.
Assessing climate impacts
Authors: Wohl Ellen E. , Pulwarty Roger S. , Zhang Jian Yun
Published: July 2002

Assessing climate impacts involves identifying sources and
characteristics of climate variability, and mitigating potential
negative impacts of that variability. Associated research focuses on
climate driving mechanisms, biosphere–hydrosphere responses and
mediation, and human responses. Examples of climate impacts come from
1998 flooding in the Yangtze River Basin and hurricanes in the
Caribbean and Central America. Although we have limited understanding
of the fundamental driving-response interactions associated with
climate variability, increasingly powerful measurement and modeling
techniques make assessing climate impacts a rapidly developing frontier
of science.
Ultrafast dynamics of many-body processes and fundamental quantum mechanical phenomena in semiconductors
Authors: Chemla Daniel S. , Shah Jagdeep
Published: July 2002

The large dielectric constant and small effective mass in a semiconductor allows a description of its electronic states in terms of envelope wavefunctions whose energy, time, and length scales are mesoscopic, i.e., halfway between those of atomic and those of condensed matter systems. This property makes it possible to demonstrate and investigate many quantum mechanical, many-body, and quantum kinetic phenomena with tabletop experiments that would be nearly impossible in other systems. This, along with the ability to custom-design semiconductor nanostructures, makes semiconductors an ideal laboratory for experimental investigations. We present an overview of some of the most exciting results obtained in semiconductors in recent years using the technique of ultrafast nonlinear optical spectrocopy. These results show that Coulomb correlation plays a major role in semiconductors and makes them behave more like a strongly interacting system than like an atomic system. The results provide insights into the physics of strongly interacting systems that are relevant to other condensed matter systems, but not easily accessible in other materials.
Hyperosmolality in the form of elevated NaCl but not urea causes DNA damage in murine kidney cells
Authors: Kültz Dietmar , Chakravarty Devulapalli
Published: July 2002

This study demonstrates, by using neutral comet assay and pulsed
field gel electrophoresis, that hyperosmotic stress causes DNA damage
in the form of double strand breaks (dsb). Different solutes increase
the rate of DNA dsb to different degrees at identical strengths of
hyperosmolality. Hyperosmolality in the form of elevated NaCl (HNa) is
most potent in this regard, whereas hyperosmolality in the form of
elevated urea (HU) does not cause DNA dsb. The amount of DNA dsb
increases significantly as early as 15 min after the onset of HNa. By
using neutral comet and DNA ladder assays, we show that this rapid
induction of DNA damage is not attributable to apoptosis. We
demonstrate that renal inner medullary cells are able to efficiently
repair hyperosmotic DNA damage within 48 h after exposure to
hyperosmolality. DNA repair correlates with cell survival and is
repressed by 25 μM LY294002, an inhibitor of DNA-activated protein
kinases. These results strongly suggest that the hyperosmotic stress
resistance of renal inner medullary cells is based not only on
adaptations that protect cellular proteins from osmotic damage but, in
addition, on adaptations that compensate DNA damage and maintain
genomic integrity.
Thoughts on the Meaning of Brain Electrical Activity
Authors: Pribram Karl H.
Published: July 2002

Recordings of electrical brain activity have provided a rich field of data. These data are harvested at at least two scales of inquiry: scalp recordings from humans have accessed cognitive aspects of the mind/brain relationship, and microelectrode recordings in animals have delineated circuits involved in sensory and motor processes. As yet, there are few studies that have attempted to reconcile the findings obtained at these different scales. It is such reconciliation that we are attempting in experiments performed in our Center for Brain Research and Informational Sciences. A progress report follows.
Bipolarity … or not? Some Conceptual Problems Relating to Bipolar Rating Scales
Authors: Yorke Mantz
Published: July 2002

Abstract Bipolar rating scales find considerable use in educational research, whether in formal instruments or as ad hoc scales produced by respondents (for example, in elicited repertory grids), and the data generated are often subjected to statistical analysis. This article examines the concept of bipolarity from primarily a linguistic perspective, taking particular inspiration from Lyons's contributions to the field and from the much earlier work of Ogden. It is argued that the conceptual quality of bipolar scales may be open to serious question, thus rendering statistical and qualitative analyses more problematic than many would prefer.
Psychological adjustment of adoptees in adulthood: Family environment and adoption-related correlates
Authors: Levy-Shiff Rachel
Published: July 2002

This longitudinal study explored psychological adjustment, evaluated in terms of self-concept and pathological symptomatology, in a nonclinical, community-based sample of adult adoptees and a matched control group of nonadoptees. Also explored was the role of adoption-related variables—age of placement of adoption, openness to adoption, and reunion with biological parents as well as family environment in predicting adjustment. Adoptees, as compared with nonadoptees, scored lower on self-concept but higher on pathological symptomatology. Likewise, they scored their families lower on all three dimensions of family environment—relationships, personal growth, and system maintenance. However, family environment variables were more predictive of adjustment in adoptees than in nonadoptees. Age of placement and openness to adoption were also associated with adoptees’ adjustment.
The impact of longitudinal studies on understanding development from young adulthood to old age
Authors: Schaie K. Warner
Published: July 2002

This essay considers progress in understanding adult development in the study of behaviour during the 20th century. It describes the influence of methodological advances including paradigmatic shifts from cross-sectional to longitudinal studies, advances in measurement, the impact of confirmatory factor analysis, and consideration of age as the dependent variable. A theoretical framework for understanding adult cognitive development is presented. Different types of longitudinal studies, the issue of structural invariance across age, sources of individual differences and the impact of cohort differences are discussed. Finally projections are made for future research.
Domain-specific constraints of conceptual development
Authors: Hatano Giyoo , Inagaki Kayoko
Published: July 2002

Although we have made much progress in understanding the growth of mind by shifting from Piagetian theory to a variety of views of conceptual development as the domain-specific construction of knowledge under constraints, the key notion of “constraints” is not yet well articulated. As a result, the views have not yet constituted a coherent theory that replaces Piagetian theory. In this article, after summarising “dominant” views of conceptual development, we reconceptualise the notion of “innate constraints”, more specifically as preferences and biases that serve as learning mechanisms, not as innate knowledge or representational contents. We then propose to expand the notion of “constraints” to include interactive, sociocultural constraints as well as internal, cognitive ones, which enable even young children to acquire knowledge in uniquely human ways. We believe that these formulations make the current views of conceptual development better specified and more comprehensive. Finally we offer our prospect for the future of conceptual development theories.
Determinants and Effectiveness of Children’s Coping with Political Violence
Authors: Punamäki Raija-Leena , Puhakka Taina
Published: July 2002

We examined how age and gender, and the intensity of political violence and stressful events influence children’s coping styles, and the effectiveness of coping. The participants were 185 Palestinian boys and girls of 10-13 years of age. Intensity of political violence was indicated by comparing a group tested before the Intifada ( N = 89) and a group during the Intifada ( N = 96). The results showed that older children used more emotional and cognitive coping, and a wider coping repertoire than younger ones. Boys used more Problem restructuring and behavioural coping than girls, who, for their part, used more emotional coping than boys. The more intensive the political violence was, the more Problem restructuring and the less Active fighting and Hostile confrontation children used. Further, during an intensively violent period of Intifada, children’s coping repertoire was narrow and involved little emotional and cognitive coping modes. Personal exposure to stressful events increased behavioural coping, Active fighting and Problem restructuring, and decreased emotional modes of coping. The effectiveness of coping styles in alleviating psychosocial problems varied according to the intensity of political violence. Problem restructuring, Active fighting, and behavioural coping were effective only during the Intifada, but not before the Intifada.
Children’s and Adults’ Reactions to a Schema-discrepant Event: A Developmental Analysis of Surprise
Authors: Schützwohl Achim , Reisenzein Rainer
Published: July 2002

Three studies investigated age-related differences in the surprise reaction. Study 1 revealed that children and seniors showed a more pronounced action delay in response to a simple, hedonically neutral surprising event than young adults that could not be attributed to a general slowing of information processing. Studies 2 and 3 provided evidence that these age-related differences in action delay between children and young adults were due to children’s greater difficulties to ”nd an explanation for the occurrence of the surprising event and to decide on its relevance for action. These results support the idea that the core mechanism of surprise is evolutionary-based and age-invariant, but its eliciting conditions and consequences depend on developmental changes of knowledge structures.
Social literacy and citizenship education in the school curriculum
Authors: Arthur James , Davison Jon
Published: July 2002

This article explores citizenship education's need to focus on both ‘political’ and ‘social’ literacy within a communitarian framework. The Crick Report (1998; see also Lahey, Crick and Porter, 1974), while recognizing that the social dimension of citizenship education was a precondition for both the civic and political dimensions, concentrated largely on ‘political’ literacy. This article examines the social dimension of citizenship education. Concern with the social dimension of the curriculum in schools is not a recent interest, but changes within society have accelerated the social demands made upon schools. At the very least, society expects schools to correct the behaviour of children and to teach them values which usually means insisting on ‘good’ behaviour. The social development of pupils has thus assumed a much greater place in the aspirations of schools. Programmes of personal and social education, together with citizenship education, invariably emphasize a range of social skills and these skills are introduced early and built upon throughout the years of schooling. An individual's sense and ability to make socially productive decisions do not develop by themselves; rather, they require knowledge, values and skills. Above all opportunities are required for children to experience social relations in such a way that they are able to operate critically within value‐laden discourses and thereby to become informed and ethically empowered, active citizens.
How would a well‐educated young citizen react to the Stephen Lawrence inquiry? An examination of the parameters of current models of citizenship education
Authors: Menter Ian , Walker Maggie
Published: July 2002

Taking as its starting point the murder of Stephen Lawrence and the failings which that case has demonstrated in justice and the judicial system in England, this article questions the extent to which current models of citizenship education address the reality of young people's lives. The critique focuses particularly on the proposed revisions to the English National Curriculum to be implemented in 2001. It is argued that unless citizenship education provides an opportunity to study the reality of contemporary experience, including the injustices and inequalities which continue to be features of that experience, it will be an ineffectual exercise. There are also severe dangers of the citizenship curriculum being overcrowded with factual knowledge at the expense of opportunities for experiencing democratic processes and playing a part in the formation of learners' identities. Some examples are given of effective work based on the principles outlined in the article. In conclusion, an agenda for research and curriculum development is described.
Mast cell tryptase and asthma
Authors: Zhang M-Q. , Timmerman H.
Published: July 2002

Recent physiological and pharmacological studies have indicated the potential importance of tryptase, the major protein component in mast cells, in inflammatory diseases (especially asthma). Being released at inflammatory sites after the activation of mast cells, tryptase is capable of causing bronchohyperresponsiveness and infiltration of eosinophils, neutrophils, etc. in animal airways. The mechanisms by which tryptase causes bronchoconstriction involve probably the potentiation of other chemical mediators such as histamine, production of bradykinin via the hydrolysis of kininogen, and cleavage of the bronchodilating peptides VIP (vasoactive intestinal peptide) and PHM (peptide histidine‐methionine). Tryptase has also been found to be a potent mitogen in vitro for airway smooth muscle cells and epithelial cells, implying its role in the hyperplasia of the asthmatic airways. The experimental data providing evidence for the above roles of tryptase are summarized in the present review, as well as the effects of tryptase inhibition in animal asthma models. The potential strategies for the development of anti‐asthmatic agents based on the inhibition of tryptase are discussed.
Comparison of Keratinocytes and Lymphocytes on Sulfur Mustard-Dependent Changes in Cell Yield and Viability
Authors: Moser Janet , Meier Henry L.
Published: July 2002

In comparing the effects of sulfur mustard (SM)-induced cell death in adult cultured normal human epidermal keratinocytes (NHEK) and peripheral blood lymphocytes (PBL), we observed an SM concentration-and time-dependent loss of NHEK and PBL viability as measured by propidium iodide exclusion. By this parameter alone, PBL appeared more susceptible to SM-induced cytotoxi-city than NHEK, as previously reported. However, therewas a concentration-and time-dependent loss of NHEK yield that was not observed in PBL. Keratinocyte yield was approximately 46% and 8% of control cells at 12 and 24 hours, respectively, following exposure to 0.3 mM SM. The decrease in NHEK yield was associated with an increase in trypan blue-stained fragments observed on slides. Fragments were not observed on slides of SM-exposed PBL cultures. These results suggest that SM causes fragmentation of cultured NHEK and subsequently results in a lower cell yield. The fragmented dead NHEK are not included in the total cell count when percent viability is determined by propidium iodide exclusion. Therefore, cytotoxicity of SM in NHEK is greater than that reflected by dye exclusion alone. Actual viable cell count, which considers both propidium iodide exclusion and cellyield, indicates NHEK are more susceptible than PBL to SM-induced cytotoxicity, contrary to previously published reports. Cell yield must be taken into account when using in vitro models to study not only viability, but also any quantitative biochemical changes induced by SM.
Court Appointed Experts in the Breast Implant Litigation: Current Developments and Historical Bases
Authors: Woodside Frank C. , Carpenter Robert A. , Hils M. Gabrielle , Erny Frederick M.
Published: July 2002

Recently, in the multidistrict breast implant litigation, Judge Pointer entered a series of orders relating to the establishment of a Federal Evidence Rule 706 science panel. In re: Silicone Gel Breast Implant Products Liability Litigation, MDL 926, CV92-P-10000-S (N.D. Ala.). Judge Pointer's Order No. 31 specifies that appointments are to be made on a national basis for potential use in all federal courts and as permitted in state courts. Federal Evidence Rule 706 gives a district court the authority to appoint experts to provide helpful testimony. The policy justification behind Rule 706 is to guarantee that the trier of fact has access to impartial experts. The parties to the litigation, however, must be informed of the court appointed experts' opinions in advance and be given the opportunity to depose and cross-examine any expert. Once those requirements are satisfied, all other aspects of appointing the experts are left to the sound discretion of the trial judge. In fact, bias or qualification of experts may not be considered when the Court appoints experts. Bias or qualification may affect not only the weight of the experts' opinions but also the admissibility of their testimony. Parties confronted with harmful testimony presented by court appointed experts may want to challenge the admissibility of that testimony. This is particularly true in multidistrict proceedings where the opinions issued by a science panel could affect multiple cases. Although Rule 706 has notbeen used with any frequency in the past, that could be changing as Rule 706 and court appointed experts are playing important roles in a number of recent high profile cases. Furthermore, when used properly Rule 706 poses little threat to the American trial system and the adversarial process. This article discusses Federal Evidence Rule 706, its history and structure, and several recent cases involving court appointed experts to demonstrate the development and impact that experts, particularly scientific experts, are having in modern courts.
Antisocial tendencies in alcohol‐dependent men and their relation to harman, salsolinol and dopamine
Authors: PODSCHUS JAN , DUFEU PETER , SCHMIDT LUTZ G. , SALLSTROM‐BAUM SIEDY , ROMMELSPACHER HANS
Published: July 2002

Abstract Plasma dopamine, β‐carbolines (norharman, harman) and isoquinolines ((R)‐ and (S)‐salsolinol) were examined for their relationship to antisocial tendencies in 138 drinking men with an alcohol dependence syndrome according to ICD‐10 criteria. Antisociality was assessed according to the following criteria: delinquency, involvement in fist‐fights and homelessness. The personality structure was documented by the Tridimensional Personality Questionnaire of Cloninger. An early age of onset of alcohol dependence and a high degree of ‘novelty seeking’ were associated with antisocial tendencies. Of the β‐carbolines and isoquinolines, harman and (S)‐salsolinol were significantly decreased among antisocial alcoholics. Norharman, (R)‐salsolinol and dopamine were not associated with antisocial personality. The contribution of endogenous alkaloids to the biological characterization of antisocial tendencies in alcoholics is described.
Predicting communicative competence at 2 and 3 years from pragmatic skills at 10 months
Authors: Smith Liane
Published: July 2002

It is proposed that children play an important part in determining the kinds of linguistic experience they receive, influencing their language environment by means of early pragmatic communication. These early behaviours may also be predictive of later communicative competence. As a preliminary investigation into the wider implications of children's potential influence over their linguistic environment, a study was undertaken which looked at infant pragmatic signalling systems and joint engagement skills, to establish whether these early interactive behaviours might be related to children's subsequent communicative development. During the course of the study, the frequency and distribution of early pragmatic behaviours in a random sample of 145 10‐month‐old infants were investigated, and their subsequent language development followed up at ages 24 and 36 months. The study examined (a) the predictive validity of specific pragmatic behaviours at age 10 months for language development at age 24 months and (b) the specificity and stability of profiles of communicative disability at 2 and 3 years. A subset of behaviours was identified which would have correctly predicted 82 4% of children found to have communicative difficulties at 24 months and 85 4% of those who did not. Predictive language profiles drawn up at age 24 months were substantially confirmed when the children were reassessed at age 36 months. It is proposed that specific early communicative behaviours may be predictive of a child's subsequent linguistic development. Additionally, 2‐year‐old children will be exhibiting certain patterns of language acquisition which may be significant for subsequent linguistic development. Implications for intervention are discussed.
Characterization of HIV-1 Vpr Nuclear Import: Analysis of Signals and Pathways
Authors: Jenkins Yonchu , McEntee Michele , Weis Karsten , Greene Warner C.
Published: July 2002

While the Vpr protein of HIV-1 has been implicated in import of the viral preintegration complex across the nuclear pore complex (NPC) of nondividing cellular hosts, the mechanism by which Vpr enters the nucleus remains unknown. We now demonstrate that Vpr contains two discrete nuclear targeting signals that use two different import pathways, both of which are distinct from the classical nuclear localization signal (NLS)- and the M9-dependent pathways. Vpr import does not appear to require Ran-mediated GTP hydrolysis and persists under conditions of low energy. Competition experiments further suggest that Vpr directly engages the NPC at two discrete sites. These sites appear to form distal components of a common import pathway used by NLS- and M9-containing proteins. Together, our data suggest that Vpr bypasses many of the soluble receptors involved in import of cellular cargoes. Rather, this viral protein appears to directly access the NPC, a property that may help to ensure the capacity of HIV to replicate in nondividing cellular hosts.
P53 Is Essential for Developmental Neuron Death as Regulated by the TrkA and p75 Neurotrophin Receptors
Authors: Aloyz Raquel S. , Bamji Shernaz X. , Pozniak Christine D. , Toma Jean G. , Atwal Jasvinder , Kaplan David R. , Miller Freda D.
Published: July 2002

Naturally occurring sympathetic neuron death is the result of two apoptotic signaling events: one normally suppressed by NGF/TrkA survival signals, and a second activated by the p75 neurotrophin receptor. Here we demonstrate that the p53 tumor suppressor protein, likely as induced by the MEKK-JNK pathway, is an essential component of both of these apoptotic signaling cascades. In cultured neonatal sympathetic neurons, p53 protein levels are elevated in response to both NGF withdrawal and p75NTR activation. NGF withdrawal also results in elevation of a known p53 target, the apoptotic protein Bax. Functional ablation of p53 using the adenovirus E1B55K protein inhibits neuronal apoptosis as induced by either NGF withdrawal or p75 activation. Direct stimulation of the MEKK-JNK pathway using activated MEKK1 has similar effects; p53 and Bax are increased and the subsequent neuronal apoptosis can be rescued by E1B55K. Expression of p53 in sympathetic neurons indicates that p53 functions downstream of JNK and upstream of Bax. Finally, when p53 levels are reduced or absent in p53+/− or p53−/− mice, naturally occurring sympathetic neuron death is inhibited. Thus, p53 is an essential common component of two receptor-mediated signal transduction cascades that converge on the MEKK-JNK pathway to regulate the developmental death of sympathetic neurons.
Myopalladin, a Novel 145-Kilodalton Sarcomeric Protein with Multiple Roles in Z-Disc and I-Band Protein Assemblies
Authors: Bang Marie-Louise , Mudry Ryan E. , McElhinny Abigail S. , Trombitás Karoly , Geach Adam J. , Yamasaki Rob , Sorimachi Hiroyuki , Granzier Henk , Gregorio Carol C. , Labeit Siegfried
Published: July 2002

We describe here a novel sarcomeric 145-kD protein, myopalladin, which tethers together the COOH-terminal Src homology 3 domains of nebulin and nebulette with the EF hand motifs of α-actinin in vertebrate Z-lines. Myopalladin's nebulin/nebulette and α-actinin–binding sites are contained in two distinct regions within its COOH-terminal 90-kD domain. Both sites are highly homologous with those found in palladin, a protein described recently required for actin cytoskeletal assembly (Parast, M.M., and C.A. Otey. 2000. J. Cell Biol. 150:643–656). This suggests that palladin and myopalladin may have conserved roles in stress fiber and Z-line assembly. The NH2-terminal region of myopalladin specifically binds to the cardiac ankyrin repeat protein (CARP), a nuclear protein involved in control of muscle gene expression. Immunofluorescence and immunoelectron microscopy studies revealed that myopalladin also colocalized with CARP in the central I-band of striated muscle sarcomeres. Overexpression of myopalladin's NH2-terminal CARP-binding region in live cardiac myocytes resulted in severe disruption of all sarcomeric components studied, suggesting that the myopalladin–CARP complex in the central I-band may have an important regulatory role in maintaining sarcomeric integrity. Our data also suggest that myopalladin may link regulatory mechanisms involved in Z-line structure (via α-actinin and nebulin/nebulette) to those involved in muscle gene expression (via CARP).
Neuronal survival induced by neurotrophins requires calmodulin
Authors: Egea Joaquim , Espinet Carme , Soler Rosa M. , Dolcet Xavier , Yuste Víctor J. , Encinas Mario , Iglesias Montserrat , Rocamora Nativitat , Comella Joan X.
Published: July 2002

It has been reported that phosphoinositide 3-kinase (PI 3-kinase) and its downstream target, protein kinase B (PKB), play a central role in the signaling of cell survival triggered by neurotrophins (NTs). In this report, we have analyzed the involvement of Ca2+ and calmodulin (CaM) in the activation of the PKB induced by NTs. We have found that reduction of intracellular Ca2+ concentration or functional blockade of CaM abolished NGF-induced activation of PKB in PC12 cells. Similar results were obtained in cultures of chicken spinal cord motoneurons treated with brain-derived neurotrophic factor (BDNF). Moreover, CaM inhibition prevented the cell survival triggered by NGF or BDNF. This effect was counteracted by the transient expression of constitutive active forms of the PKB, indicating that CaM regulates NT-induced cell survival through the activation of the PKB. We have investigated the mechanisms whereby CaM regulates the activation of the PKB, and we have found that CaM was necessary for the proper generation and/or accumulation of the products of the PI 3-kinase in intact cells.