bluuebunny/crossref_metadata_2025_split huggingface dataset:
Luteinizing Hormone-Induced Connexin 43 Down-Regulation: Inhibition of Translation
Authors: Kalma Yael , Granot Irit , Galiani Dalia , Barash Amihai , Dekel Nava 
Published: December 2003

AbstractThe coordinated function of the different compartments of the follicle, the oocyte and the somatic cumulus/granulosa cells, is enabled by the presence of a network of cell-to-cell communication generated by gap junctions. Connexin 43 (Cx43) is the most abundant gap junction protein expressed by the ovarian follicle. The expression of Cx43 is subjected to the control of gonadotropins as follows: FSH up-regulates, whereas LH down-regulates its levels. The aim of this study was to explore the mechanism by which LH reduces the levels of Cx43 and to identify the signal transduction pathway involved in this process. The effect of LH was studied in vitro using isolated intact ovarian follicles. The possible mediators of LH-induced Cx43 down-regulation were examined by incubating the follicles with LH in the presence or absence of inhibitors of protein kinase A (PKA) and of MAPK signaling pathways. Our experiments revealed a 3-h half-life of Cx43 in both control and LH-treated follicles, suggesting that LH did not affect the rate of Cx43 degradation. We further demonstrated that the level of Cx43 mRNA was not significantly influenced by this gonadotropin. However, upon LH administration, [35S]methionine incorporation into Cx43 protein was remarkably reduced. The LH-induced arrest of Cx43 synthesis was counteracted by inhibitors of both the PKA and the MAPK cascades. We show herein that LH inhibits Cx43 expression by reducing its rate of translation and that this effect is mediated by both PKA and MAPK.
Insulin-Like Growth Factor-Induced Transcriptional Activity of the Skeletal α-Actin Gene Is Regulated by Signaling Mechanisms Linked to Voltage-Gated Calcium Channels during Myoblast Differentiation
Authors: Spangenburg Espen E. , Bowles Douglas K. , Booth Frank W. 
Published: December 2003

AbstractIGF-I activates signaling pathways that increase the expression of muscle-specific genes in differentiating myoblasts. Induction of skeletal α-actin expression occurs during differentiation through unknown mechanisms. The purpose of this investigation was to examine the mechanisms that IGF-I uses to induce skeletal α-actin gene expression in C2C12 myoblasts. IGF-I increased skeletal α-actin promoter activity by 107% compared with the control condition. Ni+ [T-type voltage-gated Ca2+ channel (VGCC) inhibitor] reduced basal-induced activation of the skeletal α-actin promoter by approximately 84%, and nifedipine (L-type VGCC inhibitor) inhibited IGF-I-induced activation of the skeletal α-actin promoter by 29–48%. IGF-I failed to increase skeletal α-actin promoter activity in differentiating dysgenic (lack functional L-type VGCC) myoblasts; 30 mm K+ and 30 mm K++IGF-I increased skeletal α-actin promoter activity by 162% and 76% compared with non-IGF-I or IGF-I-only conditions, respectively. IGF-I increased calcineurin activity, which was inhibited by cyclosporine A. Further, cyclosporine A inhibited K++IGF-I-induced activation of the skeletal α-actin promoter. Constitutively active calcineurin increased skeletal α-actin promoter activity by 154% and rescued the nifedipine-induced inhibition of L-type VGCC but failed to rescue the Ni+-inhibition of T-type VGCC. IGF-I-induced nuclear factor of activated T-cells transcriptional activity was not inhibited by nifedipine or Ni+. IGF-I failed to increase serum response factor transcriptional activity; however, serum response factor activity was reduced in the presence of Ni+. These data suggest that IGF-I-induced activation of the skeletal α-actin promoter is regulated by the L-type VGCC and calcineurin but independent of nuclear factor of activated T-cell transcriptional activity as C2C12 myoblasts differentiate into myotubes.
Fos and Jun Inhibit Estrogen-Induced Transcription of the Human Progesterone Receptor Gene through an Activator Protein-1 Site
Authors: Petz Larry N. , Ziegler Yvonne S. , Schultz Jennifer R. , Nardulli Ann M. 
Published: December 2003

AbstractThe progesterone receptor (PR) gene is activated by estrogen in normal reproductive tissues and in MCF-7 human breast cancer cells. Although it is typically thought that estrogen responsiveness is mediated through estrogen response elements (EREs), the human PR gene lacks a palindromic ERE sequence. We have identified an activating protein-1 (AP-1) site at +745 in the human PR gene that bound purified Fos and Jun and formed a complex with Fos/Jun heterodimers present in MCF-7 nuclear extracts. Surprisingly, mutating the +745 AP-1 site in the context of a 1.5-kb region of the PR gene significantly enhanced estrogen receptor (ER) α-mediated transactivation, suggesting that the wild-type +745 AP-1 site plays a role in inhibiting PR gene expression in the presence of hormone. In support of this idea, transient transfection assays demonstrated that increasing levels of Fos and Jun repressed transcription of a reporter plasmid containing the +745 AP-1 site. Fos levels were transiently increased, ERα levels were decreased, and Jun was dephosphorylated after MCF-7 cells were treated with estrogen. Chromatin immunoprecipitation assays demonstrated that Jun was associated with the +745 AP-1 site in the endogenous PR gene in the presence and in the absence of estrogen, but that ERα and Fos were only associated with the +745 AP-1 site after estrogen treatment of MCF-7 cells. Our studies suggest that the human PR gene is regulated by multiple transcription factors and that the differential binding of these dynamically regulated trans-acting factors influences gene expression.
The EZC-Prostate Model: Noninvasive Prostate Imaging in Living Mice
Authors: Xie Xiaoming , Luo Zheng , Slawin Kevin M. , Spencer David M. 
Published: December 2003

Abstract
Recently, progress in the development of prostate-specific promoters and high resolution imaging techniques has made real-time monitoring of transgenic expression possible, opening a vista of potentially important in vivo models of prostate disease. Herein, we describe a novel prostate reporter model, called the EZC-prostate model that permits both ex vivo and in vivo imaging of the prostate using a sensitive charge-coupled device. Firefly luciferase and enhanced green fluorescent protein were targeted to the prostate epithelium using the composite human kallikrein 2 (hK2)-based promoter, hK2-E3/P. In EZC-prostate mice, the ventral and dorsal/lateral prostate lobes were brilliant green under fluorescence microscopy, with expression localized to the secretory epithelium. In contrast, enhanced green fluorescent protein was undetectable in the anterior lobes of prostate, seminal vesicles, testes, liver, lung, and brain. The kinetics of luciferase activity in intact and castrated living mice monitored with the IVIS charge-coupled device-based imaging system confirmed that firefly luciferase expression was largely prostate restricted, increased with age up to 24 wk, and was androgen dependent. Decreases in reporter expression after 24 wk may reflect well known, age-related decreases in androgen signaling with age in humans. Ex vivo imaging of microdissected animals further confirmed that the luminescence detected in living mice emanated predominately from the prostate, with minor signals originating from the testes and cecum. These data demonstrate that the hK2-E3/P promoter directs strong prostate-specific expression in a transgenic mouse model. Multigenic models, generated by crosses with various hyperplastic and neoplastic prostate disease models, could potentially provide powerful new tools in longitudinal monitoring of changes in prostate size, androgen signaling, metastases, or response to novel therapies without sacrificing large cohorts of animals.
Characterization of a novel ZP3-independent sperm-binding ligand that facilitates sperm adhesion to the egg coat
Authors: Rodeheffer Carey , Shur Barry D. 
Published: December 2003

During mammalian fertilization, sperm adhere to the extracellular coat of the egg, or zona pellucida, in a species-specific manner. In mouse, evidence suggests that sperm recognize and bind to specific oligosaccharide ligands within the zona pellucida glycoprotein, ZP3, viaβ1,4-galactosyltransferase I (GalT I), a lectin-like receptor on the sperm surface. Although in vitro experiments using isolated gametes lend support to this model, recent in vivo studies of genetically altered mice question whether ZP3 and/or GalT I are solely responsible for sperm-egg binding. In this regard, sperm from GalT I-null mice bind poorly to ZP3 and fail to undergo a zona-induced acrosome reaction; however, they still bind to the ovulated egg coat in vitro.In this report, we characterize a novel ZP3- and GalT I-independent mechanism for sperm adhesion to the egg coat. Results show that the ovulated zona pellucida contains at least two distinct ligands for sperm binding: a ZP3-independent ligand that is peripherally associated with the egg coat and facilitates gamete adhesion; and a ZP3-dependent ligand that is present in the insoluble zona matrix and is recognized by sperm GalT I to facilitate acrosomal exocytosis. The ZP3-independent ligand is not a result of contamination by egg cortical granules, nor is it the mouse homolog of oviduct-specific glycoprotein. It behaves as a 250 kDa, WGA-reactive glycoprotein with a basic isoelectric point, distinguishing it from the acidic glycoproteins that form the insoluble matrix of the egg coat. When eluted from isoelectric focusing gels, the acidic matrix glycoproteins possess sperm-binding activity for wild-type sperm, but not for GalT I-null sperm,whereas the basic glycoprotein retains sperm-binding activity for both wild-type and GalT I-null sperm. Thus, GalT I-null sperm are able to resolve gamete recognition into at least two distinct binding events, leading to the characterization of a novel, peripherally associated, sperm-binding ligand on the ovulated zona pellucida.
The Dynamic Value of Hierarchy
Authors: Knott Anne Marie 
Published: December 2003

This study develops a dual-routines view of the dynamic value of hierarchy, and tests it against the implicit null hypothesis that hierarchy merely provides static advantages over markets. The view holds that hierarchical managers perform two roles that create value for firms in perpetuity—an administrative role of enforcing operational routine, and an entrepreneurial role of executing a metaroutine that continually revises operational routine to keep pace with changes in the environment. The test consists of a natural experiment comparing the behavior and performance of establishments that leave a franchise, “lose their hierarchical managers,” with those that remain. I find support for the view. In the absence of the franchisor, establishment behavior drifts from the operational routine, and establishments fail to adopt innovation. Both responses lead to significant decay in performance. Thus hierarchical managers are necessary to actively enforce routine, even after the routine been assimilated, and to introduce innovation, even in this unique setting of perfect incentives.
Performance Impacts of Information Technology: Is Actual Usage the Missing Link?
Authors: Devaraj Sarv , Kohli Rajiv 
Published: December 2003

The relationship between investment in information technology (IT) and its effect on organizational performance continues to interest academics and practitioners. In many cases, due to the nature of the research design employed, this stream of research has been unable to identify the impact of individual technologies on organizational performance. This study posits that the driver of IT impact is not the investment in the technology, but the actual usage of the technology. This proposition is tested in a longitudinal setting of a healthcare system comprising eight hospitals.Monthly data for a three–year period on various financial and nonfinancial measures of hospital performance and technology usage were analyzed. The data analysis provides evidence for the technology usage–performance link after controlling for various external factors. Technology usage was positively and significantly associated with measures of hospital revenue and quality, and this effect occurred after time lags. The analysis was triangulated using three measures of technology usage. The general support for the principal proposition of this paper that “actual usage” may be a key variable in explaining the impact of technology on performance suggests that omission of this variable may be a missing link in IT payoff analyses.
Overcoming Local Search Through Alliances and Mobility
Authors: Rosenkopf Lori , Almeida Paul 
Published: December 2003

Recent research suggests that, due to organizational and relational constraints, firms are limited contextually—both geographically and technologically—in their search for new knowledge. But distant contexts may offer ideas and insights that can be extremely useful to innovation through knowledge recombination. So how can firms reach beyond their existing contexts in their search for new knowledge? In this paper, we suggest that two mechanisms—alliances and the mobility of inventors—can serve as bridges to distant contexts and, thus, enable firms to overcome the constraints of contextually localized search. Through the analysis of patent citation patterns in the semiconductor industry, we first demonstrate both the geographic and technological localization of knowledge. We then explore if the formation of alliances and mobility of active inventors facilitate interfirm knowledge flows across contexts. We find that mobility is associated with interfirm knowledge flows regardless of geographic proximity and, in fact, the usefulness of alliances and mobility increases with technological distance. These findings suggest that firms can employ knowledge acquisition mechanisms to fill in the holes of their existing technological and geographic context.
Product Customization and Price Competition on the Internet
Authors: Dewan Rajiv , Jing Bing , Seidmann Abraham 
Published: December 2003

The Internet provides an unprecedented capability for sellers to learn about their customers and offer custom products at special prices. In addition, customization is more feasible today because of advances in manufacturing technologies that have improved sellers' manufacturing flexibility. We first develop a model of product customization and flexible pricing to incorporate the salient roles of the Internet and flexible manufacturing technologies in reducing the costs of designing and producing tailored consumer goods. We show how a monopoly seller may earn the highest profits by producing both standard and custom products and can raise prices for both types of products as customization and information collection technologies improve. Simultaneous adoption of customization in a duopoly reduces the differentiation between their standard products but does not intensify price competition. Compared with a two-facility monopolist, the duopoly may underinvest in customization. Consumer surplus improves after sellers adopt customization but does not monotonically increase as customization technologies advance. When firms face a fixed entry cost and adopt customization sequentially, the first entrant always achieves an advantage and may be able to deter subsequent entry by choosing its customization scope strategically.
Relaxed Most Negative Cycle and Most Positive Cut Canceling Algorithms for Minimum Cost Flow
Authors: Shigeno Maiko , Iwata Satoru , McCormick S. Thomas 
Published: December 2003

This paper presents two new scaling algorithms for the minimum cost network flow problem, one a primal cycle canceling algorithm, the other a dual cut canceling algorithm. Both algorithms scale a relaxed optimality parameter, and create a second, inner relaxation. The primal algorithm uses the inner relaxation to cancel a most negative node-disjoint family of cycles w.r.t. the scaled parameter, the dual algorithm uses it to cancel most positive cuts w.r.t. the scaled parameter. We show that in a network with n nodes and m arcs, both algorithms need to cancel only O(mn) objects per scaling phase. Furthermore, we show how to efficiently implement both algorithms to yield weakly polynomial running times that are as fast as any other cycle or cut canceling algorithms. Our algorithms have potential practical advantages compared to some other canceling algorithms as well. Along the way, we give a comprehensive survey of cycle and cut canceling algorithms for min-cost flow. We also clarify the formal duality between cycles and cuts.
Correlated Equilibrium in Quitting Games
Authors: Solan E. , Vohra R. V. 
Published: December 2003

A quitting game is a sequential game where each player has two actions: to continue or to quit. The game continues as long as all players decide to continue. The moment at least one player decides to quit, the game terminates. The terminal payoff depends on the subset of players who quit at the terminating stage. If the game continues forever, then the payoff for the players is some fixed-payoff vector. We prove that every quitting game admits a correlated uniform ε-equilibrium—a uniform ε-equilibrium in an extended game that includes a correlation device that sends one signal to each player before start of play.
Constraint Nondegeneracy in Variational Analysis
Authors: Robinson Stephen M. 
Published: December 2003

This paper studies the sensitivity analysis of variational conditions defined over perturbed systems of finitely many nonlinear inequalities or equations, subject to additional fixed polyhedral constraints. If the system of constraints obeys a certain property called nondegeneracy, we show how to construct a local diffeomorphism of the feasible set to its tangent cone. Moreover, this diffeomorphism varies smoothly as the perturbation parameter changes. The original variational condition is then locally equivalent to a variational inequality defined over this (polyhedral convex) tangent cone. This extends stability results already known for variational inequalities over polyhedral convex sets to a substantially more general case. We also show that existence, local uniqueness, and Lipschitz continuity, as well as B-differentiability of the solution, can all be predicted from a single affine variational inequality that is easily computable in terms of the data of the unperturbed problem at the point in question.
Markov Decision Processes with Slow Scale Periodic Decisions
Authors: Jacobson M. , Shimkin N. , Shwartz A. 
Published: December 2003

We consider a class of discrete time, dynamic decision-making models which we refer to as Periodically Time-Inhomogeneous Markov Decision Processes (PTMDPs). In these models, the decision-making horizon can be partitioned into intervals, called slow scale cycles, of N + 1 epochs. The transition law and reward function are time-homogeneous over the first N epochs of each slow scale cycle, but distinct at the final epoch. The motivation for such models is in applications where decisions of different nature are taken at different time scales, i.e., many “low-level” decisions are made between less frequent “high-level” ones. For the PTMDP model, we consider the problem of optimizing the expected discounted reward when rewards devalue by a discount factor λ at the beginning of each slow scale cycle. When N is large, initially stationary policies (i.s.p.'s) are natural candidates for optimal policies. Similar to turnpike policies, an initially stationary policy uses the same decision rule for some large number of epochs in each slow scale cycle, followed by a relatively short planning horizon of time-varying decision rules. In this paper, we characterize the form of the optimal value as a function of N, establish conditions ensuring the existence of near-optimal i.s.p.'s, and characterize their structure. Our analysis deals separately with the cases where the time-homogeneous part of the system has state-dependent and state-independent optimal average reward. As we illustrate, the results in these two distinct cases are qualitatively different.
Quality and Time-to-Market Trade-offs when There Are Multiple Product Generations
Authors: Morgan Leslie Olin , Morgan Ruskin M. , Moore William L. 
Published: December 2003

We extend previous work evaluating the quality versus time-to-market trade-off for a single product generation to the case of multiple generations. While a single generation framework is appropriate when either the technology is not extendable or when additional launch costs outweigh benefits, we find that it is important to recognize whether a technology is extendable and explicitly consider the potential for multiple generations. We evaluate the factors determining optimal development-cycle length and intensity using a forward-looking model that allows for multiple product generations. Comparisons are made with restricted versions of the model that reflect pure single generation and sequential single generation approaches. Against an active competitor, the multiple generation approach is much more profitable, with the greatest differences in fast-moving industries. More total time is spent in development when a multiple generation model is used. Further, this time is dedicated to the more frequent introduction of improved product generations—a “rapid inch-up” strategy—resulting in more, higher quality products over time. Factors affecting optimal time-to-market differ substantially for the single versus multiple generation approaches. A key difference is that faster rates of quality improvement lead to longer development cycles for the single and sequential single generation models, but shorter cycles with the forward-looking multiple generation model. With a single generation, variable costs have the biggest impact on cycle length (higher costs shorten cycles), but with multiple generations, fixed costs have the biggest impact on cycle length (higher costs lead to longer cycles).
Telephone Call Centers: Tutorial, Review, and Research Prospects
Authors: Gans Noah , Koole Ger , Mandelbaum Avishai 
Published: December 2003

Telephone call centers are an integral part of many businesses, and their economic role is significant and growing. They are also fascinating sociotechnical systems in which the behavior of customers and employees is closely intertwined with physical performance measures. In these environments traditional operational models are of great value—and at the same time fundamentally limited—in their ability to characterize system performance.We review the state of research on telephone call centers. We begin with a tutorial on how call centers function and proceed to survey academic research devoted to the management of their operations. We then outline important problems that have not been addressed and identify promising directions for future research.
Aggregation and Mixed Integer Rounding to Solve MIPs
Authors: Marchand Hugues , Wolsey Laurence A. 
Published: December 2003

In this paper, we discuss the use of mixed integer rounding (MIR) inequalities to solve mixed integer programs. MIR inequalities are essentially Gomory mixed integer cuts. However, as we wish to use problem structure, we insist that MIR inequalities be generated from constraints or simple aggregations of constraints of the original problem. This idea is motivated by the observation that several strong valid inequalities based on specific problem structure can be derived as MIR inequalities. Here we present and test a separation routine for such MIR inequalities that includes a heuristic row aggregation procedure to generate a single knapsack plus continuous variables constraint, complementation of variables, and finally the generation of an MIR inequality. Inserted in a branch-and-cut system, the results suggest that such a routine is a useful additional tool for tackling a variety of mixed integer programming problems.