bluuebunny/crossref_metadata_2025 huggingface dataset:
Endogenous GABA Release Inhibits the Firing of Adult Gonadotropin-Releasing Hormone Neurons
Authors: Han Seong-Kyu , Todman Martin G. , Herbison Allan E.
Published: November 2003

The effect of endogenous γ-aminobutyric acid (GABA)A receptor-mediated signaling on the excitability of adult male and female GnRH neurons was examined using gramicidin perforated-patch electrophysiology in GnRH-LacZ and GnRH-GFP (green fluorescent protein) transgenic mouse models. In both lines of mice, approximately 80% of GnRH neurons (n = 42) responded to the selective GABAA receptor antagonist bicuculline (20 μm) with a rapid and reversible membrane depolarization and/or increase in firing rate. Approximately 16% of GnRH neurons gave no response, and two neurons were inhibited by bicuculline. The same depolarizing responses (78%) were obtained from adult gonadectomized GnRH-GFP mice. The depolarizing response to bicuculline persisted in the presence of tetrodotoxin, demonstrating that even action potential-independent GABA release was acting to reduce GnRH neuron membrane potential. These observations show that endogenous GABA signaling through the GABAA receptor exerts a powerful net inhibitory effect upon the excitability of mature GnRH neurons.
Ablation of specific expression domains reveals discrete functions of ectoderm- and endoderm-derived FGF8 during cardiovascular and pharyngeal development
Authors: Macatee Timothy L. , Hammond Benjamin P. , Arenkiel Benjamin R. , Francis Lily , Frank Deborah U. , Moon Anne M.
Published: November 2003

Fibroblast growth factor 8 (Fgf8) is expressed in many domains of the developing embryo. Globally decreased FGF8 signaling during murine embryogenesis results in a hypomorphic phenotype with a constellation of heart, outflow tract, great vessel and pharyngeal gland defects that phenocopies human deletion 22q11 syndromes, such as DiGeorge. We postulate that these Fgf8 hypomorphic phenotypes result from disruption of local FGF8 signaling from pharyngeal arch epithelia to mesenchymal cells populating and migrating through the third and fourth pharyngeal arches.

To test our hypothesis, and to determine whether the pharyngeal ectoderm and endoderm Fgf8 expression domains have discrete functional roles,we performed conditional mutagenesis of Fgf8 using novel Crerecombinase drivers to achieve domain-specific ablation of Fgf8gene function in the pharyngeal arch ectoderm and endoderm.

Remarkably, ablating FGF8 protein in the pharyngeal arch ectoderm causes failure of formation of the fourth pharyngeal arch artery that results in aortic arch and subclavian artery anomalies in 95% of mutants; these defects recapitulate the spectrum and frequency of vascular defects reported in Fgf8 hypomorphs. Surprisingly, no cardiac, outflow tract or glandular defects were found in ectodermal-domain mutants, indicating that ectodermally derived FGF8 has essential roles during pharyngeal arch vascular development distinct from those in cardiac, outflow tract and pharyngeal gland morphogenesis. By contrast, ablation of FGF8 in the third and fourth pharyngeal endoderm and ectoderm caused glandular defects and bicuspid aortic valve, which indicates that the FGF8 endodermal domain has discrete roles in pharyngeal and valvar development. These results support our hypotheses that local FGF8 signaling from the pharyngeal epithelia is required for pharyngeal vascular and glandular development, and that the pharyngeal ectodermal and endodermal domains of FGF8 have separate functions.
Initial state of theDrosophilaeye before dorsoventral specification is equivalent to ventral
Authors: Singh Amit , Choi Kwang-Wook
Published: November 2003

Dorsoventral (DV) patterning is crucial for eye development in invertebrates and higher animals. DV lineage restriction is the primary event in undifferentiated early eye primordia of Drosophila. In Drosophila eye disc, a dorsal-specific GATA family transcription factor pannier (pnr) controls Iroquois-Complex(Iro-C) genes to establish the dorsal eye fate whereas Lobe(L), which is involved in controlling a Notch ligand Serrate(Ser), is specifically required for ventral growth. However, fate of eye disc cells before the onset of dorsal expression of pnr and Iro-C is not known. We show that L/Ser are expressed in entire early eye disc before the expression of pnr and Iro-C is initiated in late first instar dorsal eye margin cells. Our evidence suggests that during embryogenesis pnr activity is not essential for eye development. We present evidence that loss of L or Serfunction prior to initiation of pnr expression results in elimination of the entire eye, whereas after the onset of pnr expression it results only in preferential loss of ventral half of eye. We demonstrate that dorsal eye disc cells also become L or Ser dependent when they are ventralized by removal of pnr or Iro-C gene function. Therefore, we propose that early state of the eye prior to DV lineage restriction is equivalent to ventral and requires L and Ser gene function.
Elevated ERK-MAP kinase activity protects the FOS family member FRA-1 against proteasomal degradation in colon carcinoma cells
Authors: Vial Emmanuel , Marshall Christopher J.
Published: November 2003

The AP-1 (activator protein-1) complex, which consists of proteins of the Fos and Jun families, is thought to play an important role in the balance between cell proliferation and apoptosis, the response to genotoxic stress and cell transformation. In cells containing oncogenic Ras, the major components of AP-1 are Fra-1 and c-Jun. Signalling from Ras to AP-1 is through the Raf/MEK[mitogen-activated protein (MAP) kinase kinase]/ERK (extracellular signal-regulated kinase) MAP kinase pathway as sustained activation of Raf1 or Mek1 modifies AP-1 composition and activity. To analyse the potential link between the ERK-MAPK pathway and AP-1 in colon cancer, in which RAS and BRAF mutations are frequent, we have studied the regulation of AP-1 in colon carcinoma cell lines. We show that c-JUN and FRA-1 expression is dependent on ERK activity and that different thresholds of ERK activity control the expression of FRA-1. A basal activity is required to induce transcription of the FRA-1 gene, but additional higher levels of activity stabilize FRA-1 against proteasome-dependent degradation. These results provide a clear-cut example that the magnitude of ERK signalling affects the cellular response. Although we find no contribution of FRA-1 towards cell proliferation of adherent tumour cells, the high levels of FRA-1 in cells where elevated ERK activity leads to protein stabilization provide survival signals for tumour cells removed from the extracellular matrix.
A novel cell-cell junction system: thecortex adhaerensmosaic of lens fiber cells
Authors: Straub Beate K. , Boda Judit , Kuhn Caecilia , Schnoelzer Martina , Korf Ulrike , Kempf Tore , Spring Herbert , Hatzfeld Mechthild , Franke Werner W.
Published: November 2003

The anucleate prismoid fiber cells of the eye lens are densely packed to form a tissue in which the plasma membranes and their associated cytoplasmic coat form a single giant cell-cell adhesive complex, the cortex adhaerens. Using biochemical and immunoprecipitation methods in various species (cow, pig, rat), in combination with immunolocalization microscopy, we have identified two different major kinds of cortical complex. In one, the transmembrane glycoproteins N-cadherin and cadherin-11 [which also occur in heterotypic (`mixed') complexes] are associated with α- and β-catenin, plakoglobin (proportions variable among species), p120ctn and vinculin. The other complex contains ezrin, periplakin, periaxin and desmoyokin (and so is called the EPPD complex), usually together with moesin, spectrin(s) and plectin. In sections through lens fiber tissue, the short sides of the lens fiber hexagons appear to be enriched in the cadherin-based complexes, whereas the EPPD complexes also occur on the long sides. Moreover, high resolution double-label fluorescence microscopy has revealed, on the short sides, a finer, almost regular mosaicism of blocks comprising the cadherin-based, catenin-containing complexes, alternating with patches formed by the EPPD complexes. The latter, a new type of junctional plaque ensemble of proteins hitherto known only from certain other cell types, must be added to the list of major lens cortex proteins. We here discuss its possible functional importance for the maintenance of lens structure and functions, notably clear and sharp vision.
Cell history determines the maintenance of transcriptional differences between left and right ventricular cardiomyocytes in the developing mouse heart
Authors: Kelly Robert G. , Lemonnier Marguerite , Zaffran Stephane , Munk Andrew , Buckingham Margaret E.
Published: November 2003

The molecular mechanisms that establish and maintain transcriptional differences between cardiomyocytes in the left and right ventricular chambers are unkown. We have previously analysed a myosin light chain 3f transgene containing an nlacZ reporter gene, which is transcribed in left but not right ventricular cardiomyocytes. In this report we examine the mechanisms involved in maintaining regionalised transgene expression. Primary cardiomyocytes prepared from left and right ventricular walls of transgenic mice were found to maintain transgene expression status in culture. However, similar cultures prepared from nontransgenic mice or rats show uniform expression after transient transfection of Mlc3f constructs, suggesting that the mechanism responsible for differential expression of the transgene between left and right ventricular cells does not operate on transiently introduced molecules. These data suggest that developmental cell history determines transgene expression status. Maintenance of transgene expression status is regulated by a cell-autonomous mechanism that is independent of DNA methylation, trichostatin A-sensitive histone deacetylation and miss-expression of transcription factors that are expressed in the left or right ventricles of the embryonic heart. Parallels between Mlc3f transgene repression in right ventricular cardiomyocytes and polycomb-mediated silencing in Drosophila suggest that Mlc3f regulatory sequences included on the transgene may contain a cellular memory module that is switched into an on or off state during early cardiogenesis. Epigenetic mechanisms may therefore be involved in maintaining patterning of the mammalian myocardium.
A finite element model of an idealized diarthrodial joint to investigate the effects of variation in the mechanical properties of the tissues
Authors: Dar F H , Aspden R M
Published: November 2003

The stiffness of articular cartilage increases dramatically with increasing rate of loading, and it has been hypothesized that increasing the stiffness of the subchondral bone may result in damaging stresses being generated in the articular cartilage. Despite the interdependence of these tissues in a joint, little is understood of the effect of such changes in one tissue on stresses generated in another. To investigate this, a parametric finite element model of an idealized joint was developed. The model incorporated layers representing articular cartilage, calcified cartilage, the subchondral bone plate and cancellous bone. Taguchi factorial design techniques, employing a two-level full-factorial and a four-level fractional factorial design, were used to vary the material properties and thicknesses of the layers over the wide range of values found in the literature. The effects on the maximum values of von Mises stress in each of the tissues are reported here. The stiffness of the cartilage was the main factor that determined the stress in the articular cartilage. This, and the thickness of the cartilage, also had the largest effect on the stresses in all the other tissues with the exception of the subchondral bone plate, in which stresses were dominated by its own stiffness. The stiffness of the underlying subchondral bone had no effect on the stresses generated in the cartilage. This study shows how stresses in the various tissues are affected by changes in their mechanical properties and thicknesses. It also demonstrates the benefits of a structured, systematic approach to investigating parameter variation in finite element models.
Various issues relating to computational fluid dynamics simulations of carotid bifurcation flow based on models reconstructed from three-dimensional ultrasound images
Authors: Augst A D , Barratt D C , Hughes A D , McG Thom S A , Xu X Y
Published: November 2003

Computational fluid dynamics (CFD) flow simulation techniques have the potential to enhance understanding of how haemodynamic factors are involved in atherosclerosis. Recently, three-dimensional ultrasound has emerged as an alternative to other three-dimensional imaging techniques, such as magnetic resonance angiography (MRA). The method can be used to generate accurate vascular geometry suitable for CFD simulations and can be coupled with Doppler ultrasound to provide physiologically realistic flow boundary conditions. However, there are various ways to utilize the flow data acquired, possibly leading to different results regarding both flow and wall shear stress patterns. A disadvantage of three-dimensional ultrasound for imaging the carotid bifurcation has been established as being the scanning limitation of the jawbone position. This may make artificial extensions of the internal and/or external carotid arteries necessary, which in turn may influence the predicted flow patterns. Flow simulations were carried out for three outflow calculation schemes as well as four geometries with different extensions to the carotid daughter vessels. It was found that variation of flow patterns was more strongly influenced by the outflow conditions than by the extensions of the daughter vessels. Consequently, it is recommended that for future CFD simulations of carotid flow using three-dimensional ultrasound data, the outflow boundary conditions should rely on the most accurate measurement available, and flow data recorded in the common and internal carotid are considered more reliable than data from the external carotid. Even though the extended lengths of the daughter vessels have insignificant effects on the predicted haemodynamic parameters, it would be a safer option to extend the internal carotid by approximately three times the diameter of the common carotid artery.
MASSIS: A Mass Spectrum Simulation System. 2: Procedures and Performance
Authors: Chen HaiFeng , Fan BoTao , Petitjean Michel , Panaye Annick , Doucet Jean-Pierre , Li Feng , Xia HaiRong , Yuan ShenGang
Published: November 2003

The use of the mass spectral simulation system, MASSIS, is reported and its performance has been evaluated. The search for substructures matching with fragments stored in four pivot databases was realised using the Ullmann algorithm. Special cleavage rules, such as the McLafferty rearrangement, the retro-Diels–Alder reaction, elimination of a neutral small molecule and oxygen migration, are processed through shortest path and depth-first search algorithms. For a search in the database of small fragments, the key step is to determine the tautomeric fragments; then a match can be obtained using a subgraph isomorphism algorithm. A string match is used to determine peak intensity. If the limited environment of an atom is the same as that found in the database of relationships between fragment and intensity, this intensity value is assigned to the query atom. Performance in a set of tests is very important in evaluating the system performance. A comparison of peaks with an intensity greater than 5% (relative) shows that our system has a very high performance figure (> 90%) for routine organic compounds.
Misleading Heuristics and Moderated Multiple Regression Models
Authors: Irwin Julie R. , McClelland Gary H.
Published: November 2003

Moderated multiple regression models allow the simple relationship between the dependent variable and an independent variable to depend on the level of another independent variable. The moderated relationship, often referred to as the interaction, is modeled by including a product term as an additional independent variable. Moderated relationships are central to marketing (e.g., Does the effect of promotion on sales depend on the market segment?). Multiple regression models not including a product term are widely used and well understood. The authors argue that researchers have derived from this simpler type of multiple regression several data analysis heuristics that, when inappropriately generalized to moderated multiple regression, can result in faulty interpretations of model coefficients and incorrect statistical analyses. Using theoretical arguments and constructed data sets, the authors describe these heuristics, discuss how they may easily be misapplied, and suggest some good practices for estimating, testing, and interpreting regression models that include moderated relationships.
Social Factors Influencing Export Initiation in Small and Medium-Sized Enterprises
Authors: Ellis Paul , Pecotich Anthony
Published: November 2003

The authors examine the influence of antecedent social ties on export behavior in an exploratory cross-case investigation of a sample of small and medium-sized exporters drawn from different industries. Data pertaining to 31 export market entries support the view that decision makers' cosmopolitanism has a significant influence on the initiation of exports.
Satisfaction, Repurchase Intent, and Repurchase Behavior: Investigating the Moderating Effect of Customer Characteristics
Authors: Mittal Vikas , Kamakura Wagner A.
Published: November 2003

Despite the claim that satisfaction ratings are linked to repurchase behavior, few attempts can be found that relate satisfaction ratings to actual repurchase behavior. This article fills this void by presenting a conceptual model for relating satisfaction ratings and repurchase behavior. The model is based on the premise that ratings observed in a typical customer satisfaction survey are error-prone measures of the customer's true satisfaction, and they may vary systematically on the basis of consumer characteristics. The authors apply the model to a large-scale study of 100,040 automotive customers. Results show that consumers with different characteristics have different thresholds such that, at the same level of rated satisfaction, repurchase rates are systematically different among different customer groups. The authors also find that the nature and extent of response bias in satisfaction ratings varies by customer characteristics. In one group, the response bias is so high that rated satisfaction is completely uncorrelated to repurchase behavior (r = 0). Furthermore, the authors find that, though nonlinear, the functional form relating rated satisfaction to repurchase intent is different from the one relating it to repurchase behavior. Although the functional form exhibits decreasing returns in the case of repurchase intent, it exhibits monotonically increasing returns in the case of repurchase behavior.
Truth or Consequences: An Analysis of Vaporware and New Product Announcements
Authors: Bayus Barry L. , Jain Sanjay , Rao Ambar G.
Published: November 2003

The software industry practice of announcing new products well in advance of actual market availability has led to allegations that firms are intentionally engaging in vaporware. The possible predatory and anticompetitive implications of this behavior recently surfaced in the antitrust case United States v. Microsoft Corporation. Taking the perspective that a new product announcement is a strategic signal among firms, the authors consider the possibility that intentional vaporware is a way to dissuade competitors from developing similar new products. An examination of empirical data for the software industry suggests that some firms use vaporware in a strategic manner. The authors then formulate and analyze the preannouncement and introduction timing decisions in a game-theoretic model of two competing firms. They find that vaporware can be a way for a dominant firm to signal its product development costs and that intentional vaporware can deter entry. The authors also show that there is a curvilinear relationship between development costs and announcement accuracy; that is, firms with high or very low product development costs make accurate product announcements, whereas firms with intermediate product development costs intentionally engage in vaporware. Empirical support for these theoretical results is also found in the software industry data. Finally, the authors discuss the beneficial and harmful consequences of vaporware and the associated implications.
Transaction Decoupling: How Price Bundling Affects the Decision to Consume
Authors: Soman Dilip , Gourville John T.
Published: November 2003

In today's marketplace, price bundling is widespread: Manufacturers and retailers routinely offer multiple products for a single, bundled price. Although the effects of price bundling on purchase behavior have been well researched, the effects of price bundling on postpurchase consumption behavior have received almost no attention. In this article, the authors build on the sunk cost literature (e.g., Thaler 1980 , 1985 ) and predict that price bundling leads to a disassociation or “decoupling” of transaction costs and benefits, thereby reducing attention to sunk costs and decreasing a consumer's likelihood of consuming a paid-for service (e.g., a theater performance). Four studies show this to be the case. In two lab studies, the authors show that having a bundled four-day ski pass as opposed to four one-day ski tickets decreases a person's likelihood of skiing on the final day of a four-day ski vacation. They replicate this result in a field study, showing that multiperformance ticket holders are more likely to forgo a given theatrical performance than are single-performance ticket holders, all else held constant. In a final study, the authors show that the decreased attention to sunk costs brought about by price bundling can be either cognitively driven (i.e., it is difficult to allocate a single payment across multiple benefits) or motivationally driven (i.e., there is an underlying desire to avoid consumption). Their findings have practical implications for managers interested in predicting or influencing actual product consumption.
Examining the Impact of Destructive Acts in Marketing Channel Relationships
Authors: Hibbard Jonathan D. , Kumar Nirmalya , Stern Louis W.
Published: November 2003

In virtually all marketing channel relationships, one of the parties eventually will engage in an action that another channel member considers potentially destructive for the relationship. How a particular channel member reacts to such an act has implications for the long-term viability and success of the relationship. On the basis of a large data set collected from both a focal supplier and its independent dealers, the authors classify dealers' responses to a supplier's destructive acts by extending the response typology of exit, voice, and loyalty, which is based on Hirschman's seminal writings on responses to decline in organizations and states. This study finds that dealers' reactions are influenced by several antecedent factors: perceived intensity of the supplier's destructive act, the attributions relative to the act, relationship quality before the act, and the level of interdependence between dealer and supplier. The results suggest that these more proximal dealer responses affect subsequent dealer performance and overall perceptions of relationship quality after an act. The authors draw several implications for both dealers and suppliers.
Cross-Functional Product Development Teams, Creativity, and the Innovativeness of New Consumer Products
Authors: Sethi Rajesh , Smith Daniel C. , Park C. Whan
Published: November 2003

Multiple studies have found that the primary determinant of new product failure is an absence of innovativeness—the extent to which a new product provides meaningfully unique benefits. Given the persistence of this finding and the growing use of cross-functional teams in new product development projects, the authors examine how innovativeness is affected by various characteristics of cross-functional teams and contextual influences on the team. On the basis of a study of 141 cross-functional product development teams, the authors find that innovativeness is positively related to the strength of superordinate identity in the team, encouragement to take risk, customers' influence, and active monitoring of the project by senior management. Beyond a moderate level, social cohesion among team members has a negative effect on innovativeness. The effect of superordinate identity on innovativeness is strengthened by encouragement to take risk and weakened by social cohesion. Functional diversity has no effect on innovativeness. The authors discuss managerial and research implications of the findings.
“Pie Sharing” in Complex Collaboration Contexts
Authors: Jap Sandy D.
Published: November 2003

Recently, there has been a growing interest in the development of collaborative relationships between organizations. Much attention has been given to how organizations “expand the pie” of benefits between them; however, there is little that addresses the ensuing issue: how organizations divide the expanded pie. The author examines the relational impact of pie sharing in complex collaboration contexts marked by uncertainty in resources and output, information asymmetries, intangible aspects, and noncomparable factors and processes. The author develops a conceptual framework that examines how the use of equity and equality sharing principles in conjunction with various resource and organizational conditions can be used to affect relational outcomes systematically. Survey results of 300 research and development managers, scientists, and engineers indicate that sharing principles can have a positive or negative effect on the relationship depending on the type of sharing principle used and the characteristics of the resources and organizations. In particular, sharing processes should be responsive to the goals of the collaboration. The results underscore the strategic nature of the sharing phenomenon as well as the importance of relational concerns in complex and uncertain interorganizational settings.
Choice Menus for Mass Customization: An Experimental Approach for Analyzing Customer Demand with an Application to a Web-Based Information Service
Authors: Liechty John , Ramaswamy Venkatram , Cohen Steven H.
Published: November 2003

Customers are now active collaborators in creating value. Companies are increasingly engaging in mass customization and offering consumers a “choiceboard” (or a menu of choices) of various features and options for configuring their own products and services. The authors discuss the use of experimental choice menus for assessing customers' preferences and price sensitivities for the variety of features and options that might be offered by a firm in its choiceboard. The proposed approach directly analyzes customers' portfolio of choices from each of several experimental menus by estimating the utility for each menu item as a function of its characteristics, its price, and other specific attributes such as multifeature discounts. The authors accommodate customer heterogeneity in the utilities, allow for correlation of the utilities across items, and incorporate constraints in menu choices. Various technical issues and methodological contributions are discussed. The authors illustrate the approach in a commercial application of a customized Web-based information service, which is typical of offerings in the information economy. To assess predictive performance, the authors compare the proposed approach with alternative traditional approaches. The authors conclude with a discussion of the types of insights that can be obtained from this approach to menu choices and the managerial implications of these findings.
Social Dimensions of Consumer Distinctiveness: The Influence of Social Status on Group Identity and Advertising Persuasion
Authors: Grier Sonya A. , Deshpandé Rohit
Published: November 2003

Consumer research using distinctiveness theory implies that targeted advertisements are most effective in contexts in which the targeted group is a numeric minority. The authors investigate the influence of group social status in addition to numeric status in a study of South African consumers. Results demonstrate that when social dimensions are incorporated, targeted advertisements can be effective even in contexts in which the targeted group is a numeric majority. Results also illustrate how consumer distinctiveness may exist at multiple levels of analysis. The authors discuss the implications of the results for understanding the influence of social context on consumer distinctiveness and responses to targeted marketing efforts.
Subscale Distance and Item Clustering Effects in Self-Administered Surveys: A New Metric
Authors: Bradlow Eric T. , Fitzsimons Gavan J.
Published: November 2003

The authors explore the effect of a form of question context on responses to a computer-mediated marketing research survey. As an increasing proportion of marketing research is conducted through computer interfaces, the pool of potential context effects is rapidly expanding. The authors conduct an experiment using a multi-item scale that consists of five dimensions and manipulate three such context effects: explicit item labeling, item presentation (alone/grouped), and subscale items presented contiguously or not. In a refined analysis of variance, the authors use a special one-dimensional case of the spatial and attribute-based distance metric proposed by Hoch, Bradlow, and Wansink (1999) to explain subscale variance, replacing the indicator variable for clustering used in a standard analysis of variance. This metric provides a scalar measure of how much variation exists in the order of presentation of items within a subscale (the subscale distance). This analysis indicates a significant decrease in subscale variance (increased reliability) with decreasing sub-scale distance but no-longer-significant effects due to labeling and grouping. The authors discuss implications of their findings for researchers conducting surveys in computer-mediated environments.
MYH9 spectrum of autosomal‐dominant giant platelet syndromes: Unexpected association with fibulin‐1 variant‐D inactivation
Authors: Toren Amos , Rozenfeld‐Granot Galit , Heath Karen E. , Amariglio Ninette , Rocca Bianca , Crosson John , Epstein Charles J. , Laghi Ferdinando , Landolfi Raffaele , Carlsson Lena E. , Argraves Scott , Bizzaro Nicola , Moxey‐Mims Marva , Brok‐Simoni Frida , Martignetti John A. , Greinacher Andreas , Rechavi Gideon
Published: November 2003

The autosomal‐dominant giant platelet syndromes (Fechtner, Epstein, and Sebastian platelet syndromes and May‐Hegglin anomaly) represent a group of disorders characterized by variable degrees of macrothrombocytopenia with further combinations of neutrophil inclusion bodies and Alport‐like syndrome manifestations, namely, deafness, renal disease, and eye abnormalities. The disease‐causing gene of these giant platelet syndromes was previously mapped by us to chromosome 22. Following their successful mapping, these syndromes were shown to represent a broad phenotypic spectrum of disorders caused by different mutations in the nonmuscle myosin heavy chain 9 gene (MYH9). In this study, we examined the potential role of another gene, fibulin‐1, encoding an extracellular matrix protein as a disease modifier. Eight unrelated families with autosomal‐dominant giant platelet syndromes were studied for DNA sequence mutations and expression of the four fibulin‐1 splice variants (A–D). A mutation in the splice acceptor site of fibulin‐1 exon 19 was found in affected individuals of the Israeli Fechtner family, whereas no MYH9 mutations were identified. Unexpectedly, fibulin‐1 variant D expression was absent in affected individuals from all eight families and coupled with expression of a putative antisense RNA. Transfection of the putative antisense RNA into H1299 cells abolished variant D expression. Based on the observation that only affected individuals lack variant D expression and demonstrate antisense RNA overexpression, we suggest that these autosomal‐dominant giant platelet syndromes are associated, and may be modified, by aberrant antisense gene regulation of the fibulin‐1 gene. Am. J. Hematol. 74:254–262, 2003. © 2003 Wiley‐Liss, Inc.
CD52 expression in hairy cell leukemia
Authors: Quigley Michael M. , Bethel Kelly J. , Sharpe Robert W. , Saven Alan
Published: November 2003

Hairy cell leukemia (HCL) is a rare chronic B‐cell lymphoproliferative disorder characterized by splenomegaly, pancytopenia, and circulating atypical lymphocytes with circumferential cytoplasmic projections. Although uncommon, HCL cases refractory to standard therapy occur, and effective alternatives are limited. There is evolving literature supporting monoclonal antibody therapy in the treatment of B‐cell lymphoid malignancies, including anti‐CD52 (Campath‐1H, alemtuzumab). We have examined nine cases of HCL and one case of HCL variant by flow cytometry for CD52 expression. All cases expressed CD52 antigen in 92–100% of the malignant cells. The demonstration of CD52 antigen expression on HCL cells provides the rationale for the use of alemtuzumab in refractory HCL. Am. J. Hematol. 74:227–230, 2003. © 2003 Wiley‐Liss, Inc.
Creation of the Chinese visible human data set
Authors: Zhang Shao‐Xiang , Heng Pheng‐Ann , Liu Zheng‐Jin , Tan Li‐Wen , Qiu Ming‐Guo , Li Qi‐Yu , Liao Rong‐Xia , Li Kai , Cui Gao‐Yu , Guo Yan‐Li , Yang Xiao‐Ping , Liu Guang‐Jiu , Shan Jing‐Lu , Liu Ji‐Jun , Zhang Wei‐Guo , Chen Xian‐Hong , Chen Jin‐Hua , Wang Jian , Chen Wei , Lu Ming , You Jian , Pang Xue‐Li , Xiao Hong , Xie Yong‐Ming
Published: November 2003

The United States Visible Human Project (VHP) created a digital image data set of complete human male (data acquisition finished in November 1994) and female (data acquisition finished in December 1995) cadavers in magnetic resonance imaging (MRI), computed tomography (CT), and anatomical (anatomic serial section) modes. VHP aroused worldwide enthusiasm for Visible Human Research (VHR), and the data set is being used in a variety of research and educational domains. The Visible Korean Human (VKH) male was produced in March 2001. To accelerate worldwide VHR and to promote virtual anatomy as a revolutionary break with conventional anatomy, more visible human data sets representative of different populations of the world are in demand. The Chinese Visible Human (CVH) male (created in October 2002) and female (created in February 2003) project achieved greater integrity of images, easier blood vessel identification, and were free of organic lesion (unlike the other visible human projects). We performed data acquisition, three‐dimensional (3D) reconstruction, and visualization with improved technology to create CVH male and female. CVH is the first volumetric data representing a complete normal adult human male and female of an Asian population. This article presents the history of Chinese Visible Human cadavers and the methods and technology used to produce the data set. Anat Rec (Part B: New Anat) 275B:190–195, 2003. © 2003 Wiley‐Liss, Inc.
Biology, ethics, and public policy: Deliberations at an unstable intersection
Authors: Zwanziger Lee L.
Published: November 2003

Biology, ethics, and politics intersect in many public policy issues. The unique features of the meeting point in each case are affected by changes in scientific and technological knowledge, moral analysis in a pluralistic society, and political relations. No one of the three can be ignored without repercussions. This essay, however, concentrates on ethics. The ethical dimension must allow for genuine differences in fundamental moral stance, which always persist alongside scientific developments. Two scientific/medical issues with considerable ethical and political implications are discussed: (1) application of human embryonic stem cell research in regenerative medicine and (2) neuroscientific reductionism in the context of behavioral research and moral responsibility. Public advisory committees and other governmental structures for pursuing public policy should not rely merely on cost‐benefit analysis to form policy, as if it were uniquely objective, but should also recognize the necessity of considering science and ethics together as two separate yet complementary foundations of policy. Minimizing the distinctness of the biological and ethical dimensions will make any conclusions unstable and their later implementation more difficult. Anat Rec (Part B: New Anat) 275B:185–189, 2003. © 2003 Wiley‐Liss, Inc.
Stereoselective metabolism of methadone N‐demethylation by cytochrome P4502B6 and 2C19
Authors: Gerber John G. , Rhodes Robert J. , Gal Joseph
Published: November 2003

Methadone is a clinically used opioid agonist that is oxidatively metabolized by cytochrome P450 (CYP) isoforms to a stable metabolite, EDDP. Methadone is a chiral drug administered as the racemic mixture of (R)‐(–)‐ and (S)‐(+)‐methadone, but (R)‐methadone is the active isomer. The cytochrome P450 (CYP) isoform involved in methadone's metabolism is thought to be CYP3A4, but human drug–drug interaction studies are not consistent with this. The ability of the common human drug‐metabolizing CYPs (obtained from baculovirus‐infected insect cell supersomes) to generate 2‐ethylidene‐1,5‐dimethyl‐3,3‐diphenylpyrrilidine (EDDP) from racemic methadone was examined and then determined if the CYP isoforms metabolized methadone stereoselectively. Only CYP2B6, 2C19, and 3A4 generated measurable EDDP from 1 μg/ml of racemic methadone. The hierarchy of EDDP generation was CYP2B6 > CYP2C19 ≥ CYP3A4. At 10 μg/ml of methadone, CYP2C9 and CYP2D6 also generated EDDP, but in at least 10‐fold lower quantities than CYP2B6. Michaelis‐Menten kinetic data demonstrated that CYP2B6 had the highest Vmax (44 ng/min/10pmol) and the lowest Km (12.6 μg/ml) for EDDP formation of all the CYP isoforms. In human liver microsomes with high and low CYP2B6 expression but equivalent CYP3A4 expression, high CYP2B6 expression microsomes generated twice the amount of EDDP from 10 μg/ml of methadone than low CYP2B6 expression microsomes. When stereoselective metabolism of racemic methadone by CYP2B6, 2C19, and 3A4 was examined using an enantiospecific methadone assay, CYP2B6 preferentially metabolized (S)‐methadone, CYP2C19 preferentially metabolized (R)‐methadone, and CYP3A4 showed no preference. These data suggest that multiple CYPs metabolized methadone but CYP2B6 had the highest Vmax/Km. In addition, only CYP2B6 and 2C19 showed stereoselective metabolism. Our data could explain why the plasma concentration ratio of R/S methadone is variable and why drugs that induce CYP2B6 such as nevirapine and efavirenz also induce methadone metabolism, while the CYP3A4 inducer rifabutin has no effect on methadone pharmacokinetics. Chirality 16:36–44, 2004. © 2003 Wiley‐Liss, Inc.
The role of environmental stochasticity in a toxic phytoplankton–non‐toxic phytoplankton–zooplankton system
Authors: Sarkar R. R. , Chattopadhayay J.
Published: November 2003

The effects of toxin producing plankton and environmental stochasticity are intriguing problems in marine plankton ecology. To observe the effect of stochastic fluctuation, a non‐toxic phytoplankton, toxic phytoplankton and zooplankton (NTP‐TPP‐Z) system with an assumption that the grazing pressure of zooplankton decreases due to toxic phytoplankton is proposed and analysed. The nature of the dynamics of the system is observed for both the deterministic model and the model with stochastic perturbation around the positive equilibrium. Exchange of stability is also observed for both the cases. To validate the analytical results, numerical experiments and field collected sample observations are also presented. We conclude that the deterministic extinction may be controlled by monitoring the intensity of white noise or artificial eutrophication. Copyright © 2003 John Wiley & Sons, Ltd.
Nucleophosmin/B23 is a proliferate shuttle protein associated with nuclear matrix
Authors: Yun Jing‐Ping , Chew Eng Ching , Liew Choong‐Tsek , Chan John Y.H. , Jin Mei‐Lin , Ding Ming‐Xiao , Fai Yam Hin , Li H.K. Richard , Liang Xiao‐Man , Wu Qiu‐Liang
Published: November 2003

It has become obvious that a better understanding and potential elucidation of the nucleolar phosphoprotein B23 involving in functional interrelationship between nuclear organization and gene expression. In present study, protein B23 expression were investigated in the regenerative hepatocytes at different periods (at days 0, 1, 2, 3, 4, 7) during liver regeneration after partial hepatectomy on the rats with immunohistochemistry and Western blot analysis. Another experiment was done with immunolabeling methods and two‐dimensional (2‐D) gel electrophoresis for identification of B23 in the regenerating hepatocytes and HepG2 cells (hepatoblastoma cell line) after sequential extraction with detergents, nuclease, and salt. The results showed that its expression in the hepatocytes had a locative move and quantitative change during the process of liver regeneration post‐operation. Its immunochemical localization in the hepatocytes during the process showed that it moved from nucleoli of the hepatocytes in the stationary stage to nucleoplasm, cytoplasm, mitotic spindles, and mitotic chromosomes of the hepatocytes in the regenerating livers. It was quantitatively increased progressively to peak level at day 3 post‐operation and declined gradually to normal level at day 7. It was detected in nuclear matrix protein (NMP) composition extracted from the regenerating hepatocytes and HepG2 cells and identified with isoelectric point (pI) value of 5.1 and molecular weight of 40 kDa. These results indicated that B23 was a proliferate shuttle protein involving in cell cycle and cell proliferation associated with nuclear matrix. © 2003 Wiley‐Liss, Inc.
Involvement of growth factors in thymic involution
Authors: García‐Suárez Olivia , Pérez‐Pérez Marta , Germanà Antonino , Esteban Isabel , Germanà Giovanni
Published: November 2003

The thymus undergoes an age‐dependent degenerative process which is mainly characterized by a progressive loss of lymphoid tissue. Thymic involution is particularly important in relation to immunosenescence and its various associated diseases; this fact has prompted many studies aimed at understanding the causes and mechanisms of thymic degeneration which may, ultimately, lead to the possibility of manipulating it. In this sense, one of the aspects which has deserved most attention is the thymic microenvironment, and more precisely, the many growth factors to which the cells present in the organ are exposed. Thus, the levels of several of such factors have been reported to undergo age‐dependent changes in the thymus, which may point at an influence on the regression of the organ. In this article we consider which growth factors and growth factor receptors occur in the vertebrate thymus. Then, focusing on those whose influences are better documented, i.e., neurotrophins, cytokines and IGFs, we discuss their potential role in the organ and the possibility of their being involved in thymic involution. Microsc. Res. Tech. 62:514–523, 2003. © 2003 Wiley‐Liss, Inc.
Aggregate content influences the Th1/Th2 immune response to influenza vaccine: Evidence from a mouse model
Authors: Babiuk Shawn , Skowronski Danuta M. , De Serres Gaston , HayGlass Kent , Brunham Robert C. , Babiuk Lorne
Published: November 2003

During the 2000–2001 season, a newly identified oculo‐respiratory syndrome (ORS) was detected across Canada as an adverse effect to one influenza vaccine. The implicated vaccine contained a higher than expected proportion of unsplit and aggregated influenza virions. Clinical and epidemiologic features of ORS were suggestive of type 2‐like influences on the immune response. We hypothesized that the implicated vaccine from the 2000–2001 season would induce greater Th2‐like polarization relative to the non‐implicated vaccine from the same season. Three groups consisting of eight mice each were either immunized with implicated vaccine, immunized with non‐implicated vaccine or not immunized. Antigen‐specific cellular responses were characterized based on the balance of Th2 (IL‐4, IL‐5) and Th1 (IFN‐γ) cytokines in vitro. We confirm that vaccine aggregates deviate the immune response to a greater Th2 cytokine pattern with potential implications for vaccine screening, safety, and efficacy. J. Med. Virol. 72:138–142, 2004. © 2004 Wiley‐Liss, Inc.
An application of fractional integration to a long temperature series
Authors: Gil‐Alana L. A.
Published: November 2003

Some recently proposed techniques of fractional integration are applied to a long UK temperature series. The tests are valid under general forms of serial correlation and do not require estimation of the fractional differencing parameter. The results show that central England temperatures have increased about 0.23 °C per 100 years in recent history. Attempting to summarize the conclusions for each of the months, we are left with the impression that the highest increase has occurred during the months from October to March. Copyright © 2003 Royal Meteorological Society
The derived demand for faculty research
Authors: Becker Elizabeth , Lindsay Cotton M. , Grizzle Gary
Published: November 2003

Estimation of the demands for many services supplied by government and charitable organizations are hampered by two practices common to the supply of these services. The suppliers often employ non‐price rationing of these services, and they price discriminate. The supply of college training, for example, is rationed on the basis of academic ability as well as willingness to pay, and more able students are typically quoted lower net prices (associated with scholarships) than less able students. This paper suggests a method for dealing with both practices in the analysis of cross‐sectional data. This methodology is used to investigate the question of why university faculty members are expected to do research as well as teach. One answer supported by our empirical work is that the customers (e.g., the students) demand it. Thus, controlling for price and non‐academic features, better students will choose to attend a university where more scholarly research is performed. Moreover, our empirical findings also support a strong negative link between faculty time devoted to teaching and the supply of research. Copyright © 2003 John Wiley & Sons, Ltd.