bluuebunny/crossref_metadata_2025 huggingface dataset:
The histone deacetylase-3 complex contains nuclear receptor corepressors
Authors: Wen Yu-Der , Perissi Valentina , Staszewski Lena M. , Yang Wen-Ming , Krones Anna , Glass Christopher K. , Rosenfeld Michael G. , Seto Edward
Published: July 2002

Acetylation and deacetylation of nucleosomal histones have profound effects on gene transcription in all eukaryotes. In humans, three highly homologous class I and four class II histone deacetylase (HDAC) enzymes have been identified to date. The class I deacetylases HDAC1 and HDAC2 are components of multisubunit complexes, one of which could associate with the nuclear hormone receptor corepressor, N-CoR. N-CoR also interacts with class II deacetylases HDAC4, HDAC5, and HDAC7. In comparison with HDAC1 and HDAC2, HDAC3 remains relatively uncharacterized, and very few proteins have been shown to interact with HDAC3. Using an affinity purification approach, we isolated an enzymatically active HDAC3 complex that contained members of the nuclear receptor corepressor family. Deletion analysis of N-CoR revealed that HDAC3 binds multiple N-CoR regions
in vitro
and that all of these regions are required for maximal binding
in vivo
. The N-CoR domains that interact with HDAC3 are distinct from those that bind other HDACs. Transient overexpression of HDAC3 and microinjection of Abs against HDAC3 showed that a component of transcriptional repression mediated by N-CoR depends on HDAC3. Interestingly, data suggest that interaction with a region of N-CoR augments the deacetylase activity of HDAC3. These results provide a possible molecular mechanism for HDAC3 regulation and argue that N-CoR is a platform in which distinct domains can interact with most of the known HDACs.
The osmolyte xylitol reduces the salt concentration of airway surface liquid and may enhance bacterial killing
Authors: Zabner Joseph , Seiler Michael P. , Launspach Janice L. , Karp Philip H. , Kearney William R. , Look Dwight C. , Smith Jeffrey J. , Welsh Michael J.
Published: July 2002

The thin layer of airway surface liquid (ASL) contains
antimicrobial substances that kill the small numbers of bacteria that
are constantly being deposited in the lungs. An increase in ASL salt
concentration inhibits the activity of airway antimicrobial factors and
may partially explain the pathogenesis of cystic fibrosis (CF). We
tested the hypothesis that an osmolyte with a low transepithelial
permeability may lower the ASL salt concentration, thereby enhancing
innate immunity. We found that the five-carbon sugar xylitol has a low
transepithelial permeability, is poorly metabolized by several
bacteria, and can lower the ASL salt concentration in both CF and
non-CF airway epithelia
in vitro
. Furthermore, in a
double-blind, randomized, crossover study, xylitol sprayed for 4 days
into each nostril of normal volunteers significantly decreased the
number of nasal coagulase-negative
Staphylococcus
compared with saline control. Xylitol may be of value in decreasing ASL
salt concentration and enhancing the innate antimicrobial defense at
the airway surface.
Constitutive expression of the neuron-restrictive silencer factor (NRSF)/REST in differentiating neurons disrupts neuronal gene expression and causes axon pathfinding errors
in vivo
Authors: Paquette Alice J. , Perez Sharon E. , Anderson David J.
Published: July 2002

The neuron-restrictive silencer factor (NRSF; also known as REST
for repressor element-1 silencing transcription factor) is a
transcriptional repressor of multiple neuronal genes, but little is
known about its function
in vivo
. NRSF is normally
down-regulated upon neuronal differentiation. Constitutive expression
of NRSF in the developing spinal cord of chicken embryos caused
repression of two endogenous target genes, N-tubulin and
Ng-CAM, but did not prevent overt neurogenesis. Nevertheless,
commissural neurons that differentiated while constitutively expressing
NRSF showed a significantly increased frequency of axon guidance
errors. These data suggest that down-regulation of NRSF is necessary
for the proper development of at least some classes of neurons
in vivo
.
Mitochondrial carbonic anhydrase CA VB: Differences in tissue distribution and pattern of evolution from those of CA VA suggest distinct physiological roles
Authors: Shah Gul N. , Hewett-Emmett David , Grubb Jeffrey H. , Migas Mary C. , Fleming Robert E. , Waheed Abdul , Sly William S.
Published: July 2002

A cDNA for a second mouse mitochondrial carbonic anhydrase (CA) called CA VB was identified by homology to the previously characterized murine CA V, now called CA VA. The full-length cDNA encodes a 317-aa precursor that contains a 33-aa classical mitochondrial leader sequence. Comparison of products expressed from cDNAs for murine CA VB and CA VA in COS cells revealed that both expressed active CAs that localized in mitochondria, and showed comparable activities in crude extracts and in mitochondria isolated from transfected COS cells. Northern blot analyses of total RNAs from mouse tissues and Western blot analyses of mouse tissue homogenates showed differences in tissue-specific expression between CA VB and CA VA. CA VB was readily detected in most tissues, while CA VA expression was limited to liver, skeletal muscle, and kidney. The human orthologue of murine CA VB was recently reported also. Comparison of the CA domain sequence of human CA VB with that reported here shows that the CA domains of CA VB are much more highly conserved between mouse and human (95% identity) than the CA domains of mouse and human CA VAs (78% identity). Analysis of phylogenetic relationships between these and other available human and mouse CA isozyme sequences revealed that mammalian CA VB evolved much more slowly than CA VA, accepting amino acid substitutions at least 4.5 times more slowly since each evolved from its respective human–mouse ancestral gene around 90 million years ago. Both the differences in tissue distribution and the much greater evolutionary constraints on CA VB sequences suggest that CA VB and CA VA have evolved to assume different physiological roles.
Activated Cdc42/Rac reconstitutes FcɛRI-mediated Ca2+mobilization and degranulation in mutant RBL mast cells
Authors: Hong-Geller Elizabeth , Holowka David , Siraganian Reuben P. , Baird Barbara , Cerione Richard A.
Published: July 2002

Antigen stimulation of mast cells via FcɛRI, the high-affinity receptor for IgE, triggers a signaling cascade that requires Ca2+mobilization for exocytosis of secretory granules during an allergic response. This study investigates critical signaling components by using mutant RBL mast cells that are defective in antigen-stimulated phospholipase Cγ (PLCγ) activation, as well as other signaling activities downstream of stimulated tyrosine phosphorylation. We show that the expression of activated versions of the Cdc42 or Rac1 GTPase restores antigen-stimulated Ca2+mobilization necessary for degranulation in these mutant cells. Wild-type Cdc42 and Rac1, as well as activated Cdc42 containing effector domain mutations, all fail to restore antigen-stimulated signaling leading to exocytosis. Expression of oncogenic Dbl, a guanine nucleotide exchange factor for Cdc42 and Rac1, partially restores sustained Ca2+mobilization and degranulation, suggesting that activation of endogenous Cdc42 and/or Rac1 is impaired in the mutant cells. Overexpression of PLCγ1 with either activated Cdc42 or Rac1 synergistically stimulates degranulation, consistent with a critical defect in PLCγ activation in these cells. Thus, our results point to activation of Cdc42 and/or Rac1 playing an essential role in antigen stimulation of early events that culminate in mast cell degranulation.
The Fate of the Moros: A Cross‐cultural Exploration of Strategies in Complex and Dynamic Decision Making
Authors: Strohschneider Stefan , Güss Dominik
Published: July 2002

The ways in which people deal with complex and dynamic problems are shaped by their learning experiences within their culture as well as the functional constraints within which they have to operate. An experiment is described that explores the interaction of culture and ways of problem solving. University students from India and Germany had to work on one of two different versions of a computer‐simulated interactive complex problem. The anaylsis focuses on the strategic aspects of problem solving. Indian and German problem solvers clearly differed in their approach: German students used a more active and control‐oriented strategy and committed fewer strategic and tactical errors. The results form the basis of a discussion on the factors important in the development of problem‐solving expertise.
Globalising Kuala Lumpur and the Strategic Role of the Producer Services Sector
Authors: Morshidi Sirat
Published: July 2002

In the context of the international economy of the late 1970s, the Kuala Lumpur Structure Plan (1984) noted that the city's role as the commercial and financial centre of Malaysia would be maintained and enhanced. With intensifying globalisation processes in the 1990s and the coming of the new millennium, fresh approaches and innovative strategies relating to further tertiarisation in the urban economy have to be instituted. The paper argues that this sector has not yet distinctly disarticulated from that of goods production in or beyond the city limits. This raises a serious question whether producer services could support Kuala Lumpur's quest for 'world city' status by the year 2020.
Towards a Theory of Intraurban Hotel Location
Authors: Egan David J. , Nield Kevin
Published: July 2002

In his seminal paper on the urban land market, Alonso notes that when a purchaser acquires land, he acquires two goods (land and location) in one transaction, and a single payment is made for the combination. Thus it is possible to trade off a quantity of land against location, the principle underlying Alonso's bid-rent analysis. It is argued that the Alonso model of bid-rent analysis is still applicable to those types of economic activity which display a hierarchy of use in terms of distance from the city centre. The concern here is with hotel location, and we develop a model of the Alonso type which casts light upon the intraurban location decisions of hotels.
Urban Restructuring and Governance: North-South Differences in Europe and the EU URBAN Initiative
Authors: Chorianopoulos Ioannis
Published: July 2002

One of the highly emphasised dimensions of urban disparities in Europe is the north-south polarisation of growth trends. The paper discusses the relationship between the divergent urbanisation/industrialisation patterns in northern and southern Europe, which result in different forms of urban governance. It considers the distinct urban restructuring and governance mode in Spain, Greece and Portugal as a causal factor behind the lagging competitiveness of cities in southern Europe. This north-south pattern of urban governance heterogeneity is not addressed in the emerging EU urban policies aimed at tackling disparities and promoting economic competitiveness. Examples of six cities' governance responses to the EU URBAN initiative of the 1994-99 period are used to illustrate the argument.
The Effectiveness of Spline Urban Density Functions: An Empirical Investigation
Authors: Alperovich Gershon
Published: July 2002

Recent studies of population distribution in urban settings suggest that cubic-spline functions may be preferable to the conventional exponential form. It is contemplated that this specification is more suitable for untangling, discovering and depicting the complex density patterns of today's relatively dispersed urban areas. This paper examines the usefulness as well as the amenability of the cubic-spline function for describing and testing hypotheses on the processes underlying the determination of population densities in Tel Aviv-Yafo. The principal findings of the analysis are threefold. First, from the theoretical and empirical points of view the cubic-spline function is unlikely to be useful for testing hypotheses. Multicollinearity among distance variables renders the cubic-spline function without much practical merit for this purpose. Secondly, an exponential spline form which does not utilise high-order terms of distance is better suited for this purpose and should therefore be preferred to the cubic-spline. Thirdly, an alternative approach which employs an improved exponential form obtained by incorporating pertinent information on actual patterns of land-use development into the theoretically derived exponential form was highly supported by the data. Utilisation of the latter approach led to an increase in the explanatory power of the model from a mere 0.24 to a respectable 0.83. Indeed, the general lesson to be learned from the analysis is that utilisation of general functional forms cannot by itself correct for possible biases in sample selection, model specification or, for that matter, replace thorough understanding of the processes one is trying to model.
House and Land Prices in Sydney from 1931 to 1989
Authors: Abelson Peter
Published: July 2002

This paper describes and explains house and land prices in Sydney from 1931 to 1989. Throughout this period, house and land prices fell, generally exponentially, with distance to the CBD. However, the price gradients were not constant. Between 1931 and 1968 the gradients flattened. On the other hand, between the mid 1970s and 1989 they became steeper again. The changes in the gradients were caused mainly by changes in travel times and costs by road and rail. Real travel costs fell in the early period and rose later on. Other factors that affected the price gradients were changes in car ownership and the supply of urban services in the early period and gentrification of inner-city areas and the greater increase in housing supply on the urban fringe in the later period. The paper also shows how house size and environmental factors influenced house prices in the 1970s and 1980s.
Business Associations and the Politics of Urban Renewal: The Case of the Lower Don Valley, Sheffield
Authors: Raco Mike
Published: July 2002

Previous research has indicated that indigenous small business communities may be adversely affected by, and not well integrated into, the wider strategic objectives being pursued by regeneration agencies. At the same time, the ability of small business communities to contest damaging programmes of renewal has been characterised as being ineffective, because of the politically weak position of such communities and the cleavages within them. It has been suggested that this powerlessness has been compounded in recent times by new quango institutions of urban governance (such as Urban Development Corporations), which are accountable to central government and therefore effectively truncate local political challenges to their strategies and programmes. This paper addresses the theme of small business associations and their scope for localised political influence on a government quango by using the example of the redevelopment of the Lower Don Valley area of Sheffield. This was where a small business association developed and mounted a relatively successful, although limited, challenge to the redevelopment strategy of the Sheffield Development Corporation. The paper concludes that localised interests, if able to mobilise effectively and to adapt to changing circumstances, can influence elements of urban renewal schemes.
Patterns of Metropolitan Development: What Have We Learned?
Authors: Ingram Gregory K.
Published: July 2002

Urban development patterns in both industrial and developing countries with market-oriented economies show strong regularities consistent with basic urban location theory. Large metropolitan areas are converging to similarly decentralised structures with multiple sub-centres, decentralised manufacturing and more centralised service employment. Decentralisation is increasing the reliance on road-based urban transport for both passengers and freight. Land markets are strong determinants of decentralisation, and the development patterns of cities without land markets differ greatly from cities with even poorly functioning land markets. Demand patterns in urban housing are similar across cities, but supply-side impediments vary widely, resulting in a wide range of the ratio of housing prices to income. The efficiency of public infrastructure provision also varies widely across cities and across sectors within cities. Large metropolitan areas in low-income countries will continue to grow as these countries urbanise.
Construction Elasticities and Land Availability: A Two-stage Least-squares Model of Housing Supply Using the Variable Elasticity Approach
Authors: Pryce Gwilym
Published: July 2002

This paper uses data at English local authority district level to construct a simultaneous equation model of housing construction that compares elasticities of supply between two cross-sectional periods—1988 (boom) and 1992 (slump) — using the variable elasticity approach. Econometric issues raised by earlier supply studies are discussed and tested for. The paper also discusses the rationale for, and tests the existence of, a backward-bending supply relationship, and finds that supply is concave in both periods, and 'bends backwards' during the boom. Evidence of a structural break between boom and bust is found, producing average price elasticities of supply noticeably smaller in the boom (0.58) than in the slump (1.03), with considerable variation across disticts. Land supply elasticities are found to be more stable over time, and marginally greater in the boom (0.75) than in the slump (0.71). The paper also calculates second partial derivatives based on the whole demand-supply system to obtain estimates of the impact of land release on new house prices.
The Council Tenants' Forum: A Liminal Public Space between Lifeworld and System?
Authors: Jackson Neil
Published: July 2002

Towards the end of the 1980s, 'Bridgetown' local authority, having decentralised its housing administration, established a Council Tenants' Forum in one area, with tenants and councillors as voting members. The Tenants' Forum is a formal meeting open to the public and serviced by an area housing officer. In 1994 the council stated that the Tenants' Forum had "required tenants, councillors and officers to take on new roles" and that "the tenants' role has become in a truer sense that of a consumer with ability to accept or reject a service". As part of a PhD study working with the concept of a 'liminal public space' on the boundaries of 'system and lifeworld', looking at the democratic potential of the forum over a period of two years, this paper uses critical discourse analysis to examine one item of business that constituted a 'moment of crisis' during a forum meeting in 1995. The analysis reveals the inter-discursivity characteristic of the forum with consequent indeterminacy of subject positions/identities, and relationships between the members. The analysis indicates a redrawing of lifeworld-system boundaries or, alternatively, the workings of a lifeworld-system interface and the paper concludes by considering the implications of this for the democratic potential of this type of 'user participation'.
Finno-Ugrians of Russia: Vanishing Cultural Communities?
Authors: Lallukka Seppo
Published: July 2002

In 1990 a Mordvin scholar released an alarming forecast about the fate awaiting his people: provided that those adverse demographic trends that had established themselves over the course of the twentieth century continued, the last member of his million-strong nation would disappear by the year 2135. This statement was not the only one of its kind. During the final years of Soviet rule, the recently realized opportunity to speak out about the concerns of the non-Russian groups was being utilized speedily. Journalistic and scholarly reports on the various problems of Russia's minority groups, often painted in highly dramatic language, became common in both regional and central publications.
Reforming Motivation: How the structure of instruction affects students’ learning experiences
Authors: Yair Gad
Published: July 2002

Over the past decade, several US school and instructional reforms have sought ways to counter trends of mediocrity in education. These reforms are grounded in structural motivation theories which postulate that students' learning experiences are optimised when instruction is authentic, challenging, demands skills, and allows for student autonomy. This study set out to investigate empirically the effects of these four structural characteristics of instruction on students' learning experiences. Using a unique methodological design, the current investigation measures students' learning experiences with a confirmatory factor analysis. The four factors which emerged are next predicted with a series of structural variables. The results show that high quality learning experiences are indeed authentic, allow choice, and demand student skills. Boring and alienated experiences are produced when these instructional characteristics are absent. The findings suggest that the structures of instruction that disaffect students are overwhelmingly represented in students' daily school life; those that spark their hearts are not frequent enough to motivate students. They also imply that students do not have a general tendency to be emotionally depressed in school; rather, they perceive their experiences to be highly influenced by specific structural characteristics of instruction.
The acquisition of a theory of action and the dissociation between action intention and outcome intention in children aged 2-6 years
Authors: Bradmetz Joël , Amiotte-Suchet Helène
Published: July 2002

The aim of an action is linked to a desire, the choice of the action is linked to the subject’s beliefs about the world. Much data on the acquisition of a theory-of-mind by children evidence a lag in the conceptualisation of desires and beliefs. The authors assume that there is also a lag between the awareness and the recall of an outcome intention and of an action intention. Their central idea is the following: When an action fails, the outcome intention is frustrated and the associated action intention is deleted by a new action intention more in agreement with the expected outcome. This hypothesis was confirmed in a ” rst experiment when action intention and outcome intention verbalisations were clearly differentiated. A second experiment showed that the difficulties were not associated with an inadequate analysis of temporal markers. The hypothesis of a conceptual lag between binary and ternary structures, via the activation of more sophisticated computing in the latter case (according to Fodor, 1992), was theoretically attractive, but it was not possible to support it empirically in a third experiment. A fourth experiment compared an action intention item with a false belief item. A ”fth and a sixth experiment, both using a nonverbal design, confirmed the previous data. The six experiments were conducted with 310 children aged from 2;6 to 6;6 years.
Selection into long-term unemployment and its psychological consequences
Authors: Kokko Katja , Pulkkinen Lea , Puustinen Minna
Published: July 2002

The factors which predict a person’s long-term unemployment were studied within the framework of an emotional and behavioural regulation model consisting of two orthogonal dimensions: behavioural inhibition versus expression, and low versus high self-control of emotions (Pulkkinen, 1995, 1996). The participants were drawn from the ongoing Jyväskylä Longitudinal Study of Personality and Social Development, in which the same individuals have been followed up from age 8 ( n = 369) to 36 ( n = 311). In the present study, data collected at ages 8, 14, 27, and 36 were used. The findings showed that low self-control of emotions, especially aggression, at age 8 directly predicted long-term unemployment in adulthood, whereas behavioural inhibition (passive and anxious behaviour) predicted long-term unemployment indirectly (via poor educational attainment). Long-term unemployment in adulthood was related to an increased level of current psychological distress as measured by the presence of depressive symptoms and anxiety. Thus, the present study confirmed both the hypothesis concerning selection into unemployment, and the hypothesis concerning the psychological consequences of unemployment.
Sampling and generalisability in developmental research: Comparison of random and convenience samples of older adults
Authors: Hultsch David F. , MacDonald Stuart W.S. , Hunter Michael A. , Maitland Scott B. , Dixon Roger A.
Published: July 2002

Research in the developmental sciences is based largely on samples of convenience rather than samples drawn at random from the population. The important question of whether results observed in samples of convenience generalise to the larger population has not been studied directly. Because of demographic growth in the proportion of older adults in the population and increases in diversity across the lifespan, it is especially important to address this issue in aging adults. We compared the performance of older adults (65–100 years) on demographic and psychological measures for a random sample of community dwelling adults and two samples of convenience. Significant differences were observed on less than half the variables. When differences were present, participants in the convenience samples were advantaged compared to participants from the random sample. Differences were larger in some domains than others but remained small to moderate in magnitude. There were minimal differences in between-person variability and patterns of correlations among variables between the convenience and random samples. Results indicate the need for additional studies contrasting random and convenience samples to explore the parameters of external validity in psychological aging research.
Children’s Perceptions of Indebtedness: The Help-seeker’s Perspective
Authors: De Cooke Peggy A.
Published: July 2002

The present study examined age and ability differences in children’s evaluations of indebtedness in help-seeking. Second-, fourth-, and sixth-graders were separated into high-, medium-, and low-achievement groups. Children responded to two high-cost and two low-cost vignettes describing a hypothetical classroom help exchange between two peers. Second- and fourth-graders experienced difficulty in determining the extent of their indebtedness. Sixth-graders offered evaluations of indebtedness that varied systematically with helper cost. With the exception of the second-graders, low-achieving children did not differentiate their ratings across the cost conditions. In contrast, low-achieving second-graders and high-achieving sixth-graders rated the importance of reciprocation higher in the high-cost than in the low-cost condition. Children’s understanding of the norms guiding help-seeking interactions between peers is discussed.
Dose-dependent Induction of Glandular Stomach Preneoplastic and Neoplastic Lesions in Male F344 Rats Treated with Catechol Chronically
Authors: Hagiwara Akihiro , Takesada Yasuko , Tanaka Hikaru , Tamano Seiko , Hirose Masao , Ito Nobuyuki , Shirai Tomoyuki
Published: July 2002

The dose-dependence of catechol glandular stomach carcinogenesis was investigated in male F344 rats. Groups of 30 male animals were fed catechol at dietary levels of 0 (control), 0.1, 0.2, 0.4, and 0.8% for up to 104 weeks. Five rats of each group were killed at 34 weeks and the remaining animals were sacrificed at the termination, all undergoing histopathological examination. Moderate retardation of body weight increase was observed in the 0.8% group, but no adverse effects were found in terms of survival. Submucosal hyperplasias and adenomas of the pyloric glands developed in the 0.4 and 0.8% groups, only very minor changes being noted in the 0.1 and 0.2% groups at week 34. Incidences of adenocarcinom a development in the pylorus were 4% and 8% in 0.4% and 0.8% groups, respectively, and 0 in the 0.1% and 0.2% groups, at the termination. Adenomas and submucosal hyperplasias were found in nearly all animals fed 0.2% catechol or more, the incidences of those in 0.1% group being 0% and 56%, respectively. Serum gastrin levels were significantly increased in the 0.2, 0.4, and 0.8% groups at 34 weeks, and in all treated groups at the termination, at extents comparable with the induction of proliferative lesions in the pylorus.

The results thus demonstrated that dietary levels of 0.4% and 0.8% catechol long-term induce adenocarcinoma s in the pyloric glands, while 0.1 and 0.2% cause benign proliferative lesions, all accompanied by increase in serum gastrin levels. As a no-effect level could not be decided in the present study, further investigation of lower doses is needed to determine whether a threshold exists.
Peroxisome Proliferator-activated Receptors in Atherosclerosis and Inflammation—An Update
Authors: Elangbam Chandikumar S. , Tyler Ronald D. , Lightfoot Ruth M.
Published: July 2002

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor subfamily of transcription factors with pleiotropic effects on intra- and extracellular lipid metabolism, glucose homeostasis, cell proliferation, control of inflammation, and atherosclerosis. Three PPARs, namely α, δ, and γ have been identifi ed with distinct tissue distribution patterns and metabolic functions. PPAR- α is predominantly expressed in brown adipose tissue, liver, kidney, duodenum, heart, skeletal muscle, and vascular endothelial cells and is involved in the control of lipoprotein metabolism, fatty acid oxidation, and the cellular uptake of fatty acids. PPAR- γ is highly expressed in brown and white adipose tissues and, to lesser extent, in large intestine, retina, and some parts of the immune system, and plays a critical role in adipocyte differentiation and fat deposition. PPAR- δ shows a widespread tissue distribution but its regulation and functions are not yet known. Considerable evidence indicates that PPARs (PPAR- α and PPAR- γ ) have beneficial effects in infl ammatory diseases, including atherosclerosis, through regulation of cytokine production, adhesion molecule expression on the endothelial cells, fi brinolysis, and modulation of monocyte-derived macrophages. In this review, the general and specific roles of the PPAR isotypes and their implications in the control of vascular inflammation and atherosclerosis are discussed.
Is There a Local Business Community?
Authors: Curran James , Rutherfoord Robert , Smith Stephen Lloyd
Published: July 2002

This article reports a study of the attitudes of small business owners to the localities in which their businesses are located and local economic development. The views of the owners contrasted strongly with those of representatives of local business bodies and economic agencies. The findings indicate small business owners tend to be detached from the locality and from local economic initiatives. This appears to be due to historical trends that have reduced the role of small business in local political and economic processes and the logic(s) of business practice within the sectors analysed. This has occurred despite trends soliciting more private sector involvement in local economic initiatives.
Catalyzing Research Competitiveness: The Georgia Research Alliance
Authors: Lambright W. Henry
Published: July 2002

Virtually everywhere, there is governmental interest in developing and using science and technology as a tool for economic development and other public purposes. States within the United States look to advance vis-à-vis other states, just as nations seek to rise in competitiveness. What institutional mechanisms work? What research and other strategies are effective? The Georgia Research Alliance (GRA) represents an important model that appears successful. During the 1990s, key business executives, university presidents, and state government forged a research partnership - GRA. A non-profit entity, GRA played a catalytic role in getting state government, industry, and universities in a specific region to work in concert to hire scientific luminaries, attract federal research funds, and translate research into economic development. The dynamics of this catalytic entity are discussed using a life-cycle model of organizational development.
Cell adhesion molecules and hyaluronic acid as markers of inflammation, fibrosis and response to antiviral therapy in chronic hepatitis C patients
Authors: Granot Esther , Shouval Daniel , Ashur Yaffa
Published: July 2002

Objective: Cell adhesion molecules (intracellular adhesion molecule‐1 (ICAM‐1), vascular cell adhesion molecule‐1 (VCAM‐1)) and hyaluronic acid, markers of inflammation and fibrosis were monitored in hepatitis C patients to determine whether changes in plasma levels, during antiviral treatment, can predict long‐term response to therapy.

Methods: In 55 patients with chronic hepatitis C virus (HCV), 33 treated with interferon (IFN) and 22 treated with IFN + ribavirin, sera was collected prior to treatment, at 3 + 6 months of therapy and 6 months post‐treatment. Levels of ICAM‐1, VCAM‐1 and hyaluronic acid were correlated with alanine aminotransferase levels, HCV‐RNA‐polymerase chain reaction status and histological fibrosis scoring.

Results: A decrease in ICAM‐1 levels at 3 and 6 months of therapy, compared with pretreatment levels, was observed in responders to IFN + ribavirin therapy but this decrease in ICAM‐1 levels was not evident following cessation of treatment. Hyaluronic acid levels, in both treatment groups, did not differ significantly between responders and non‐responders. Hyaluronic acid levels did correlate, significantly, with degree of fibrosis whereas VCAM‐1 levels were marginally increased only in patients with moderate (grade III) fibrosis.

Conclusions: Monitoring of VCAM‐1 and hyaluronic acid, during antiviral therapy, does not differentiate between responders and non‐responders. A decrease in ICAM‐1 levels during IFN + ribavirin treatmment is associated with response to therapy, and its efficacy in predicting long‐term response should be further substantiated.
Inhalation toxicity of (1→3)‐β‐D glucan: recent advances
Authors: Fogelmark Birgitta , Sjöstrand Margareta , Williams David , Rylander Ragnar
Published: July 2002

To investigate the effects of (1→3)‐β‐D‐glucan after inhalation, animals were exposed to different forms of glucan and the number of lung lavage cells was determined 24 h after exposure. None of the different forms assayed caused any increase in cell numbers. In animals exposed to endotoxin, all types of cells were increased after 24 h. A simultaneous exposure to curdlan reduced this increase in a dose‐related fashion. The results suggest that (1→3)‐β‐D‐glucan‐related acute injury to the lung is induced by mechanisms other than those induced by inflammagenic agents such as endotoxin.
Local inflammation, lethality and cytokine release in mice injected with Bothrops atrox venom
Authors: Barros S. F. , Friedlanskaia I. , Petricevich V. L. , Kipnis T. L.
Published: July 2002

We have provided evidence that: (a) lethality of mice to crude Bothrops venom varies according the isogenic strain (A/J > C57Bl/6 > A/Sn > BALB/c > C3H/ HePas > DBA/2 > C3H/He); (b)BALB/c mice (LD50=100.0 μg) were injected i.p. with 50 μg of venom produced IL‐6, IL‐10, INF‐γ, TNF‐α and NO in the serum. In vitro the cells from the mice injected and challenged with the venom only released IL‐10 while peritoneal macrophages released IL‐10, INF‐γ and less amounts of IL‐6; (c) establishment of local inflammation and necrosis induced by the venom, coincides with the peaks of TNF‐α, IFN‐γ and NO and the damage was neutralized when the venom was incubated with a monoclonal antibody against a 60 kDa haemorrhagic factor. These results suggest that susceptibility to Bothrops a trox venom is genetically dependent but MHC independent; that IL‐6, IL10, TNF‐α, IFN‐γ and NO can be involved in the mediation of tissue damage; and that the major venom component inducers of the lesions are haemorrhagins.
Azathioprine in inflammatory bowel disease, a safe alternative?
Authors: Tanis A. A.
Published: July 2002

Azathioprine and its metabolite 6‐mercaptopurine are effective in the treatment of inflammatory bowel disease. They are mostly used for reduction of the use of steroids, maintenance therapy after remission induction by cyclosporin and treatment of fistulae in Crohn′s disease. Adverse effects occur in about 15% of patients. The main side effects are pancreatitis, allergic reactions, fever and bone marrow suppression. Symptoms, management and prevention are discussed. A blood monitoring schedule is suggested. Azathioprine and 6‐mercaptopurine seem to be safe in pregnancy. There may be a slight increased risk for developing a non‐Hodgkin′s lymphoma.
Preferred communication modes: prelinguistic and linguistic communication in non‐speaking preschool children with cerebral palsy
Authors: Falkman Kerstin W. , Sandberg Annika Dahlgren , Hjelmquist Erland
Published: July 2002

Seven non‐speaking preschool children with severe cerebral palsy, 5‐7 years of age, were studied with respect to the amount of prelinguistic versus linguistic modes of communication used in communicative interaction with a previously unknown adult. An attempt was also made to analyse this in relation to the childrens' physical, cognitive and linguistic capacities. No significant correlations were found, however. Given that all participants had reached preschool age and were of normal intelligence, the amount of linguistic communication used (12%) was much less than could be expected. Explanations for the results were suggested, including limited interaction possibilities with the environment due to motor dysfunction, which in turn might prevent development of linguistic skills necessary to take part in more complex communicative interaction later in life.
Unraveling the Role of Mitochondria During Oxidative Stress in Plants
Authors: Millar Harvey , Considine Michael J. , Day David A. , Whelan James
Published: July 2002

The sedentary habit of plants means that they must stand and fight environmental stresses that their mobile animal cousins can avoid. A range of these abiotic stresses initiate the production in plant cells of reactive oxygen and nitrogen species that ultimately lead to oxidative damage affecting the yield and quality of plant products. A complex network of enzyme systems, producing and quenching these reactive species operate in different organelles. It is the integration of these compartmented defense systems that coordinates an effective response to the various stresses. Future attempts to improve plant growth or yield must consider the complexity of inter‐organelle signaling and protein targeting if they are to be successful in producing plants with resistance to a broad range of stresses. Here we highlight the role of pre‐oxidant, anti‐oxidant, and post‐oxidant defense systems in plant mitochondria and the potential role of proteins targeted to both mitochondria and chloroplasts, in an integrated defense against oxidative damage in plants.
Postsynaptic Abnormalities at the Neuromuscular Junctions of Utrophin-deficient Mice
Authors: Deconinck Anne E. , Potter Allyson C. , Tinsley Jonathon M. , Wood Sarah J. , Vater Ruth , Young Carol , Metzinger Laurent , Vincent Angela , Slater Clarke R. , Davies Kay E.
Published: July 2002

Utrophin is a dystrophin-related cytoskeletal protein expressed in many tissues. It is thought to link F-actin in the internal cytoskeleton to a transmembrane protein complex similar to the dystrophin protein complex (DPC). At the adult neuromuscular junction (NMJ), utrophin is precisely colocalized with acetylcholine receptors (AChRs) and recent studies have suggested a role for utrophin in AChR cluster formation or maintenance during NMJ differentiation. We have disrupted utrophin expression by gene targeting in the mouse. Such mice have no utrophin detectable by Western blotting or immunocytochemistry. Utrophindeficient mice are healthy and show no signs of weakness. However, their NMJs have reduced numbers of AChRs (α-bungarotoxin [α-BgTx] binding reduced to ∼60% normal) and decreased postsynaptic folding, though only minimal electrophysiological changes. Utrophin is thus not essential for AChR clustering at the NMJ but may act as a component of the postsynaptic cytoskeleton, contributing to the development or maintenance of the postsynaptic folds. Defects of utrophin could underlie some forms of congenital myasthenic syndrome in which a reduction of postsynaptic folds is observed.
Ligation of Major Histocompatability Complex (MHC) Class I Molecules on Human T Cells Induces Cell Death through PI-3 Kinase–induced c-Jun NH2-terminal Kinase Activity: A Novel Apoptotic Pathway Distinct from Fas-induced Apoptosis
Authors: Skov Søren , Klausen Pia , Claesson Mogens H.
Published: July 2002

Ligation of major histocompatability complex class I (MHC-I) molecules expressed on T cells leads to both growth arrest and apoptosis. The aim of the current study was to investigate the intracellular signal pathways that mediate these effects.

MHC-I ligation of human Jurkat T cells induced a morphologically distinct form of apoptosis within 6 h. A specific caspase inhibitor, which inhibited Fas-induced apoptosis, did not affect apoptosis induced by MHC-I ligation. Furthermore, MHC-I–induced apoptosis did not involve cleavage and activation of the poly(ADP- ribose) polymerase (PARP) endonuclease or degradation of genomic DNA into the typical fragmentation ladder, both prominent events of Fas-induced apoptosis. These results suggest that MHC-I ligation of Jurkat T cells induce apoptosis through a signal pathway distinct from the Fas molecule.

In our search for other signal pathways leading to apoptosis, we found that the regulatory 85-kD subunit of the phosphoinositide-3 kinase (PI-3) kinase was tyrosine phosphorylated after ligation of MHC-I and the PI-3 kinase inhibitor wortmannin selectively blocked MHC-I–, but not Fas-induced, apoptosis. As the c-Jun NH2-terminal kinase (JNK) can be activated by PI-3 kinase activity, and has been shown to be involved in apoptosis of lymphocytes, we examined JNK activation after MHC-I ligation. Strong JNK activity was observed after MHC-I ligation and the activity was completely blocked by wortmannin. Inhibition of JNK activity, by transfecting cells with a dominant-negative JNKK– MKK4 construct, led to a strong reduction of apoptosis after MHC-I ligation. These results suggest a critical engagement of PI-3 kinase–induced JNK activity in apoptosis induced by MHC-I ligation.
The Human Polycomb Group Complex Associates with Pericentromeric Heterochromatin to Form a Novel Nuclear Domain
Authors: Saurin Andrew J. , Shiels Carol , Williamson Jill , Satijn David P.E. , Otte Arie P. , Sheer Denise , Freemont Paul S.
Published: July 2002

The Polycomb group (PcG) complex is a chromatin-associated multiprotein complex, involved in the stable repression of homeotic gene activity in Drosophila. Recently, a mammalian PcG complex has been identified with several PcG proteins implicated in the regulation of Hox gene expression. Although the mammalian PcG complex appears analogous to the complex in Drosophila, the molecular mechanisms and functions for the mammalian PcG complex remain unknown. Here we describe a detailed characterization of the human PcG complex in terms of cellular localization and chromosomal association. By using antibodies that specifically recognize three human PcG proteins— RING1, BMI1, and hPc2—we demonstrate in a number of human cell lines that the PcG complex forms a unique discrete nuclear structure that we term PcG bodies. PcG bodies are prominent novel nuclear structures with the larger PcG foci generally localized near the centromeres, as visualized with a kinetochore antibody marker. In both normal fetal and adult fibroblasts, PcG bodies are not randomly dispersed, but appear clustered into defined areas within the nucleus. We show in three different human cell lines that the PcG complex can tightly associate with large pericentromeric heterochromatin regions (1q12) on chromosome 1, and with related pericentromeric sequences on different chromosomes, providing evidence for a mammalian PcG–heterochromatin association. Furthermore, these heterochromatin-bound PcG complexes remain stably associated throughout mitosis, thereby allowing the potential inheritance of the PcG complex through successive cell divisions. We discuss these results in terms of the known function of the PcG complex as a transcriptional repression complex.
Development of Approaches to Improve Cell Survival in Myoblast Transfer Therapy
Authors: Qu Zhuqing , Balkir Levent , van Deutekom Judith C.T. , Robbins Paul D. , Pruchnic Ryan , Huard Johnny
Published: July 2002

Myoblast transplantation has been extensively studied as a gene complementation approach for genetic diseases such as Duchenne Muscular Dystrophy. This approach has been found capable of delivering dystrophin, the product missing in Duchenne Muscular Dystrophy muscle, and leading to an increase of strength in the dystrophic muscle. This approach, however, has been hindered by numerous limitations, including immunological problems, and low spread and poor survival of the injected myoblasts. We have investigated whether antiinflammatory treatment and use of different populations of skeletal muscle–derived cells may circumvent the poor survival of the injected myoblasts after implantation. We have observed that different populations of muscle-derived cells can be isolated from skeletal muscle based on their desmin immunoreactivity and differentiation capacity. Moreover, these cells acted differently when injected into muscle: 95% of the injected cells in some populations died within 48 h, while others richer in desmin-positive cells survived entirely. Since pure myoblasts obtained from isolated myofibers and myoblast cell lines also displayed a poor survival rate of the injected cells, we have concluded that the differential survival of the populations of muscle-derived cells is not only attributable to their content in desmin-positive cells. We have observed that the origin of the myogenic cells may influence their survival in the injected muscle. Finally, we have observed that myoblasts genetically engineered to express an inhibitor of the inflammatory cytokine, IL-1, can improve the survival rate of the injected myoblasts. Our results suggest that selection of specific muscle-derived cell populations or the control of inflammation can be used as an approach to improve cell survival after both myoblast transplantation and the myoblast-mediated ex vivo gene transfer approach.
Overexpression of VEGF in Testis and Epididymis Causes Infertility in Transgenic Mice: Evidence for Nonendothelial Targets for VEGF
Authors: Korpelainen Eija I. , Karkkainen Marika J. , Tenhunen Auri , Lakso Merja , Rauvala Heikki , Vierula Matti , Parvinen Martti , Alitalo Kari
Published: July 2002

Vascular endothelial growth factor (VEGF) is a key regulator of endothelial growth and permeability. However, VEGF may also target nonendothelial cells, as VEGF receptors and responsiveness have been detected for example in monocytes, and high concentrations of VEGF have been reported in human semen. In this work we present evidence that overexpression of VEGF in the testis and epididymis of transgenic mice under the mouse mammary tumor virus (MMTV) LTR promoter causes infertility. The testes of the transgenic mice exhibited spermatogenic arrest and increased capillary density. The ductus epididymidis was dilated, containing areas of epithelial hyperplasia. The number of subepithelial capillaries in the epididymis was also increased and these vessels were highly permeable as judged by the detection of extravasated fibrinogen products. Intriguingly, the expression of VEGF receptor-1 (VEGFR-1) was detected in certain spermatogenic cells in addition to vascular endothelium, and both VEGFR-1 and VEGFR-2 were also found in the Leydig cells of the testis. The infertility of the MMTV-VEGF male mice could thus result from VEGF acting on both endothelial and nonendothelial cells of the male genital tract. Taken together, these findings suggest that the VEGF transgene has nonendothelial target cells in the testis and that VEGF may regulate male fertility.