bluuebunny/crossref_metadata_2025 huggingface dataset:
Medicinal plants in Suriname: hypotensive effect of Gossypium barbadense
Authors: Hasrat J A , Pieters L , Vlietinck A J
Published: March 2004

In traditional medicine Gossypium barbadense L. is used against hypertension. Looking for a scientific basis for this use, the blood-pressure-lowering effect of the decoction of the leaves was confirmed. Fraction II (frII) of the crude extract of G. barbadense showed a dose-dependent hypotensive effect in anaesthetized rats. In hexamethonium-treated rats, the blood-pressure-lowering effect of frII was almost abolished. A small decrease of the blood-pressure-lowering effect was followed by an increase in the blood pressure. Phentolamine antagonized the increase in blood pressure in hexamethoniumtreated rats. High doses of atropine (4 mg/rat) suppressed both depressor and heart effects. In-vitro experiments revealed that atropine did not antagonize the contraction of the ileum of the rat. Tripelennamine in a concentration of 100 μg could not influence the contraction either, whereas 300 μg did. In the guinea-pig ileum 10 μg tripelennamine did not reduce the contraction significantly.

In the mechanism of action of frII, acetylcholine receptors could be involved, but not histaminergic or adrenergic receptors. Although it is still not known which compound(s) in G. barbadense is (are) the active substance(s), the results obtained may explain the use of this plant in traditional medicine in Suriname.
Polymeric nanoparticles composed of fatty acids and polyvinylalcohol for topical application of sunscreens
Authors: Luppi B , Cerchiara T , Bigucci F , Basile R , Zecchi V
Published: March 2004

Benzophenone-3 (BZP) or oxybenzone is widely used in many cosmetic formulations, such as sunscreen lotions or emulsions, shampoos and hair sprays. The nature of the vehicle used can enhance or block the percutaneous absorption of UV filter. In this work, we hydrophobically modified polyvinylalcohol 10000 (PVA) with fatty acids (FAs) to obtain PVA-FA derivatives for the preparation of lipophilic polymeric nanoparticles able to prevent BZP movement towards the skin. Synthesized PVA-FA derivatives were confirmed by H1NMR. Nanoparticles loaded with BZP were prepared using a solvent extraction method. The particle size was monitored by means of dynamic light scattering measurements. In-vitro skin permeation studies were performed.
Distinct domains within Mash1 and Math1 are required for function in neuronal differentiation versus neuronal cell-type specification
Authors: Nakada Yuji , Hunsaker Thomas L. , Henke R. Michael , Johnson Jane E.
Published: March 2004

Many members of the basic helix-loop-helix (bHLH) family of transcription factors play pivotal roles in the development of a variety of tissues and organisms. We identify activities for the neural bHLH proteins Mash1 and Math1 in inducing neuronal differentiation, and in inducing the formation of distinct dorsal interneuron subtypes in the chick neural tube. Although both factors induce neuronal differentiation, each factor has a distinct activity in the type of dorsal interneuron that forms, with overexpression of Math1 increasing dI1 interneurons, and Mash1 increasing dI3 interneurons. Math1 and Mash1 function as transcriptional activators for both of these functions. Furthermore, we define discrete domains within the bHLH motif that are required for these different activities in neural development. Helix 1 of the Mash1 HLH domain is necessary for Mash1 to be able to promote neuronal differentiation, and is sufficient to confer this activity to the non-neural bHLH factor MyoD. In contrast, helix 2 of Math1, and both helix 1 and 2 of Mash1, are the domains required for the neuronal specification activities of these factors. The requirement for distinct domains within the HLH motif of Mash1 and Math1 for driving neuronal differentiation and cell-type specification probably reflects the importance of unique protein-protein interactions involved in these functions.
A zinc finger transcription factor, ZicL, is a direct activator ofBrachyuryin the notochord specification ofCiona intestinalis
Authors: Yagi Kasumi , Satou Yutaka , Satoh Nori
Published: March 2004

In ascidian embryos, Brachyury is expressed exclusively in blastomeres of the notochord lineage and play an essential role in the notochord cell differentiation. The genetic cascade leading to the transcriptional activation of Brachyury in A-line notochord cells of Ciona embryos begins with maternally provided β-catenin, which is essential for endodermal cell specification. β-catenin directly activates zygotic expression of a forkhead transcription factor gene, FoxD, at the 16-cell stage, which in turn somehow activates a zinc finger transcription factor gene, ZicL, at the 32-cell stage, and then Brachyury at the 64-cell stage. One of the key questions to be answered is whether ZicL functions as a direct activator of Brachyurytranscription, and this was addressed in the present study. A fusion protein was constructed in which a zinc finger domain of Ciona ZicL was connected to the C-terminus of GST. Extensive series of PCR-assisted binding site selection assays and electrophoretic mobility shift assays demonstrated that the most plausible recognition sequence of Ciona ZicL was CCCGCTGTG. We found the elements CACAGCTGG(complementary sequence: CCAGCTGTG) at -123 and CCAGCTGTG at -168 bp upstream of the putative transcription start site of Ci-Bra in a previously identified basal enhancer of this gene. In vitro binding assays indicated that the ZicL fusion protein binds to these elements efficiently. A fusion gene construct in which lacZ was fused with the upstream sequence of Ci-Bra showed the reporter gene expression exclusively in notochord cells when the construct was introduced into fertilized eggs. In contrast, fusion constructs with mutated ZicL-binding-elements failed to show the reporter expression. In addition,suppression of Ci-ZicL abolished the reporter gene expression, while ectopic and/or overexpression of Ci-ZicL resulted in ectopic reporter expression in non-notochord cells. These results provide evidence that ZicL directly activates Brachyury, leading to specification and subsequent differentiation of notochord cells.
DrosophilaHfp negatively regulatesdmycandstgto inhibit cell proliferation
Authors: Quinn Leonie M. , Dickins Ross A. , Coombe Michelle , Hime Gary R. , Bowtell David D. L. , Richardson Helena
Published: March 2004

Mammalian FIR has dual roles in pre-mRNA splicing and in negative transcriptional control of Myc. Here we show that Half pint (Hfp),the Drosophila orthologue of FIR, inhibits cell proliferation in Drosophila. We find that Hfp overexpression potently inhibits G1/S progression, while hfp mutants display ectopic cell cycles. Hfp negatively regulates dmyc expression and function, as reducing the dose of hfp increases levels of dmyc mRNA and rescues defective oogenesis in dmyc hypomorphic flies. The G2-delay in dmyc-overexpressing cells is suppressed by halving the dosage of hfp, indicating that Hfp is also rate-limiting for G2-M progression. Consistent with this, the cycle 14 G2-arrest of stg mutant embryos is rescued by the hfp mutant. Analysis of hfp mutant clones revealed elevated levels of Stg protein, but no change in the level of stg mRNA, suggesting that hfp negatively regulates Stg via a post-transcriptional mechanism. Finally, ectopic activation of the wingless pathway, which is known to negatively regulate dmycexpression in the wing, results in an accumulation of Hfp protein. Our findings indicate that Hfp provides a critical molecular link between the developmental patterning signals induced by the wingless pathway and dMyc-regulated cell growth and proliferation.
Neural crest survival and differentiation in zebrafish depends onmont blanc/tfap2agene function
Authors: Barrallo-Gimeno Alejandro , Holzschuh Jochen , Driever Wolfgang , Knapik Ela W.
Published: March 2004

Neural crest progenitor cells are the main contributors to craniofacial cartilage and connective tissue of the vertebrate head. These progenitor cells also give rise to the pigment, neuronal and glial cell lineages. To study the molecular basis of neural crest differentiation, we have cloned the gene disrupted in the mont blanc (mobm610) mutation,which affects all neural crest derivatives. Using a positional candidate cloning approach we identified an A to G transition within the 3′ splice site of the sixth intron of the tfap2a gene that abolishes the last exon encoding the crucial protein dimerization and DNA-binding domains. Neural crest induction and specification are not hindered in mobm610 mutant embryos, as revealed by normal expression of early neural crest specific genes such as snail2, foxd3and sox10. In addition, the initial stages of cranial neural crest migration appear undisturbed, while at a later phase the craniofacial primordia in pharyngeal arches two to seven fail to express their typical set of genes (sox9a, wnt5a, dlx2, hoxa2/b2). In mobm610 mutant embryos, the cell number of neuronal and glial derivatives of neural crest is greatly reduced, suggesting that tfap2a is required for their normal development. By tracing the fate of neural crest progenitors in live mont blanc(mobm610) embryos, we found that at 24 hpf neural crest cells migrate normally in the first pharyngeal arch while the preotic and postotic neural crest cells begin migration but fail to descend to the pharyngeal region of the head. TUNEL assay and Acridine Orange staining revealed that in the absence of tfap2a a subset of neural crest cells are unable to undergo terminal differentiation and die by apoptosis. Furthermore, surviving neural crest cells in tfap2a/mobm610 mutant embryos proliferate normally and later differentiate to individual derivatives. Our results indicate that tfap2a is essential to turn on the normal developmental program in arches 2-7 and in trunk neural crest. Thus, tfap2a does not appear to be involved in early specification and cell proliferation of neural crest, but it is a key regulator of an early differentiation phase and is required for cell survival in neural crest derived cell lineages.
PKA-R1 spatially restricts Oskar expression forDrosophilaembryonic patterning
Authors: Yoshida Shoko , Müller H-Arno J. , Wodarz Andreas , Ephrussi Anne
Published: March 2004

Targeting proteins to specific domains within the cell is central to the generation of polarity, which underlies many processes including cell fate specification and pattern formation during development. The anteroposterior and dorsoventral axes of the Drosophila melanogaster embryo are determined by the activities of localized maternal gene products. At the posterior pole of the oocyte, Oskar directs the assembly of the pole plasm,and is thus responsible for formation of abdomen and germline in the embryo. Tight restriction of oskar activity is achieved by mRNA localization,localization-dependent translation, anchoring of the RNA and protein, and stabilization of Oskar at the posterior pole. Here we report that the type 1 regulatory subunit of cAMP-dependent protein kinase (Pka-R1)is crucial for the restriction of Oskar protein to the oocyte posterior. Mutations in PKA-R1 cause premature and ectopic accumulation of Oskar protein throughout the oocyte. This phenotype is due to misregulation of PKA catalytic subunit activity and is suppressed by reducing catalytic subunit gene dosage. These data demonstrate that PKA mediates the spatial restriction of Oskar for anteroposterior patterning of the Drosophila embryo and that control of PKA activity by PKA-R1 is crucial in this process.
Ccm1is required for arterial morphogenesis: implications for the etiology of human cavernous malformations
Authors: Whitehead Kevin J. , Plummer Nicholas W. , Adams Jennifer A. , Marchuk Douglas A. , Li Dean Y.
Published: March 2004

Hemorrhagic stroke is a significant cause of morbidity and mortality in children, and is frequently associated with intracranial vascular malformations. One prevalent form of these vascular malformations, cerebral cavernous malformation, is characterized by thin-walled vascular cavities that hemorrhage and has been linked to loss-of-function mutations in CCM1. The neural and epithelial expression of CCM1 in adulthood suggests that cavernous malformations may be the result of primary neural defects. In this study, we generated mice lacking Ccm1 and demonstrate that Ccm1 is ubiquitously expressed early in embryogenesis and is essential for vascular development. Homozygous mutant embryos die in mid-gestation and the first detectable defects are exclusively vascular in nature. The precursor vessels of the brain become dilated starting at E8.5,reminiscent of the intracranial vascular defects observed in the human disease. In addition, there is marked enlargement and increased endothelial proliferation of the caudal dorsal aorta, as well as variable narrowing of the branchial arch arteries and proximal dorsal aorta. These vascular defects are not secondary to primary neural defects, as neural morphology and marker expression are normal even subsequent to the onset of vascular pathology. The defects in the vascular structure of embryos lacking Ccm1 are associated with early downregulation of artery-specific markers, including the Efnb2- and Notch-related genes. Finally, consistent with the murine data, we found that there is an analogous reduction in Notchgene expression in arterioles from humans with mutations in CCM1. Our studies suggest that cavernous malformations result from primary vascular rather than neural defects.
Kinetics of endocytosis and recycling of the GPI-anchored variant surface glycoprotein inTrypanosoma brucei
Authors: Engstler Markus , Thilo Lutz , Weise Frank , Grünfelder Christoph G. , Schwarz Heinz , Boshart Michael , Overath Peter
Published: March 2004

The dense coat of glycosylphosphatidylinositol (GPI)-anchored variant surface glycoprotein (VSG) covering parasitic African trypanosomes is essential for survival in mammalian hosts. VSG is internalised and recycled exclusively via a specialised part of the plasma membrane, the flagellar pocket. Direct measurement of the kinetics of VSG endocytosis and recycling shows that the VSG cell-surface pool is turned over within 12 minutes. Correspondingly, the turnover of the intracellular pool (9±4% of total VSG) requires only 1 minute, and this is an exceptionally high rate considering that endocytosis and exocytosis are limited to only 5% of the cell surface area. Kinetic 3D co-localisation analysis using biotinylated VSG and a panel of compartmental markers provides consistent evidence for the itinerary of VSG through the cell: VSG is endocytosed in large clathrin-coated vesicles, which bud from the flagellar pocket membrane at a rate of 6-7 vesicles per second, and is then delivered to RAB5-positive early endosomes. From there, VSG is recycled to RAB11-positive recycling endosomes at two stages, either directly or via RAB7-positive, late endosomes. Small clathrin-coated vesicles carrying fluid-phase cargo and being depleted of VSG bud from early and recycling endosomes. These vesicles are postulated to deliver their content to late endosomes and/or the lysosome. The recycling endosomes give rise to RAB11-positive exocytic carriers that fuse with the flagellar pocket and thereby return VSG to the cell surface. VSG recycling provides an interesting model for studies on the cellular trafficking and sorting of GPI-anchored proteins.
Parkinson's disease α-synuclein mutations exhibit defective axonal transport in cultured neurons
Authors: Saha Anirban R. , Hill Josephine , Utton Michelle A. , Asuni Ayodeji A. , Ackerley Steven , Grierson Andrew J. , Miller Christopher C. , Davies Alun M. , Buchman Vladimir L. , Anderton Brian H. , Hanger Diane P.
Published: March 2004

α-Synuclein is a major protein constituent of Lewy bodies and mutations in α-synuclein cause familial autosomal dominant Parkinson's disease. One explanation for the formation of perikaryal and neuritic aggregates of α-synuclein, which is a presynaptic protein, is that the mutations disrupt α-synuclein transport and lead to its proximal accumulation. We found that mutant forms of α-synuclein, either associated with Parkinson's disease (A30P or A53T) or mimicking defined serine, but not tyrosine, phosphorylation states exhibit reduced axonal transport following transfection into cultured neurons. Furthermore, transfection of A30P, but not wild-type, α-synuclein results in accumulation of the protein proximal to the cell body. We propose that the reduced axonal transport exhibited by the Parkinson's disease-associated α-synuclein mutants examined in this study might contribute to perikaryal accumulation of α-synuclein and hence Lewy body formation and neuritic abnormalities in diseased brain.
Regulation of human embryonic stem cell differentiation by BMP-2 and its antagonist noggin
Authors: Pera Martin F. , Andrade Jessica , Houssami Souheir , Reubinoff Benjamin , Trounson Alan , Stanley Edouard G. , Oostwaard Dorien Ward-van , Mummery Christine
Published: March 2004

Human embryonic stem cells differentiate spontaneously in vitro into a range of cell types, and they frequently give rise to cells with the properties of extra-embryonic endoderm. We show here that endogenous signaling by bone morphogenetic protein-2 controls the differentiation of embryonic stem cells into this lineage. Treatment of embryonic stem cell cultures with the bone morphogenetic protein antagonist noggin blocks this form of differentiation and induces the appearance of a novel cell type that can give rise to neural precursors. These findings indicate that bone morphogenetic protein-2 controls a key early commitment step in human embryonic stem cell differentiation, and show that the conservation of developmental mechanisms at the cellular level can be exploited in this system – in this case, to provide a facile route for the generation of neural precursors from pluripotent cells.
A peculiar internalization of claudins, tight junction-specific adhesion molecules, during the intercellular movement of epithelial cells
Authors: Matsuda Miho , Kubo Akiharu , Furuse Mikio , Tsukita Shoichiro
Published: March 2004

Tight junctions (TJs) seal the intercellular space of epithelial cells, while individual epithelial cells move against adjacent cells in cellular sheets. To observe TJs in live epithelial cellular sheets, green fluorescent protein (GFP) was fused to the N-terminus of claudin-3 (a major cell adhesion molecule of TJs), which was stably expressed at a level that was approximately 50% of that of endogenous claudin-3 in mouse Eph4 epithelial cells. Under confluent culture conditions, individual cells moved within cellular sheets, which was associated with the remodeling of TJs. However, during this remodeling, GFP-positive TJs did not lose their structural continuity. When TJs between two adjacent cells decreased in length during this remodeling, GFP-claudin-3 was frequently pinched off as a granular structure from GFP-positive TJs together with endogenous claudins. Co-culture experiments, as well as electron microscopy, revealed that the two apposed membranes of TJs were not detached, but co-endocytosed into one of the adjacent cells. Interestingly, other TJ components such as occludin, JAM and ZO-1 appeared to be dissociated from claudins before this endocytosis. The endocytosis of claudins was facilitated when the intercellular motility was upregulated by wounding the cellular sheets. These findings suggest that this peculiar internalization of claudins plays a crucial role in the remodeling of TJs, and that the fine regulation of this endocytosis is important for TJs to seal the intercellular space of epithelial cells that are moving against adjacent cells within cellular sheets.
TheDrosophilacentrosome-associated protein CP190 is essential for viability but not for cell division
Authors: Butcher R. D. J. , Chodagam S. , Basto R. , Wakefield J. G. , Henderson D. S. , Raff J. W. , Whitfield W. G. F.
Published: March 2004

The Drosophila CP190 and CP60 proteins interact with each other and shuttle between the nucleus in interphase and the centrosome in mitosis. Both proteins can bind directly to microtubules in vitro, and have been shown to associate with a specific pattern of loci on salivary gland polytene chromosomes, but their functions are unknown. Here we show that reducing the level of CP190 or CP60 by >90% in tissue culture cells does not significantly interfere with centrosome or microtubule organisation, with cell division, or with cell viability. However, CP190 is an essential protein, as flies homozygous for mutations in the Cp190 gene die at late pupal stages of development. In larval brains of Cp190 mutants, mitosis is not radically perturbed, and a mutated form of CP190 (CP190ΔM), that cannot bind to microtubules or associate with centrosomes, can rescue the lethality associated with mutations in the Cp190 gene. Thus, CP190 plays an essential role in flies that is independent of its association with centrosomes or microtubules.
Rac1-deficient macrophages exhibit defects in cell spreading and membrane ruffling but not migration
Authors: Wells Claire M. , Walmsley Marita , Ooi Steen , Tybulewicz Victor , Ridley Anne J.
Published: March 2004

Rac GTPases are activated by extracellular stimuli and contribute to cellular responses including cytoskeletal changes and cell migration. Dominant-negative Rac1 has been used to implicate Rac GTPases in these responses, but which of the three mammalian Rac isoforms it inhibits is not known. We show that mouse bone marrow-derived macrophages express Rac1, low levels of Rac2 but not Rac3. As Rac1-null mice die early in development, we have used mice with a loxP-flanked allele of Rac1 and the type I interferon-inducible Mx1-Cre transgene to address for the first time the specific role of Rac1 in cell motility. Bone marrow-derived macrophages isolated from mice treated with polyIC to induce interferon lack detectable Rac1, and there is no compensatory increase in Rac2 or Cdc42 expression. Rac1-deficient macrophages have an altered morphology: they are significantly more elongated than control cells and have a reduced adhesive area. Re-expression of Rac1 reverts the morphology to that of control cells. Loss of Rac1 reduces but does not completely prevent membrane ruffling in response to CSF-1. However, Rac1-deficient macrophages show normal migration and chemotaxis. Thus in macrophages Rac1 is primarily responsible for regulating cell morphology, contributes to membrane ruffling, but is not required for migration.
Newest findings on the oldest oncogene; how activated src does it
Authors: Frame Margaret C.
Published: March 2004

Oncogenic forms of the non-receptor tyrosine kinase Src alter cell structure, in particular the actin cytoskeleton and the adhesion networks that control cell migration, and also transmit signals that regulate proliferation and cell survival. Recent work indicates that they do so by influencing the RhoA-ROCK pathway that controls contractile actin filament assembly, the STAT family of transcription factors needed for transformation, and the Cbl ubiquitin ligase that controls Src protein levels. These studies also shed light on the role of focal adhesion kinase (FAK) downstream of v-Src and other signalling pathways in controlling migration, invasion and survival of transformed cells. Src directly phosphorylates integrins and can also modulate R-Ras activity. Moreover, it stimulates the E-cadherin regulator Hakai, interacts with and phosphorylates the novel podosome-linked adaptor protein Fish, and progressively phosphorylates the gap junction component connexion 43. A recurring theme is the identification of novel and important Src substrates that mediate key biological events associated with transformation.
Speed estimation and control in a belt-driven system for a web production process. Part 1: System modelling and validation
Authors: Makin E , Acarnley P
Published: March 2004

This paper develops a detailed mathematical model of a casting drum drive in a web production process. The drive uses a flat belt to connect the casting drum itself to a drive and a brake pulley. The model includes mechanical effects, such as creep and slip between the belt and pulleys, and its parameters are obtained by a combination of calculations and experimental tests. Experimental results from a laboratory-scale model of a commercial casting drum system are used to validate the model under steady-state and transient conditions. A companion paper describes the model's application in new controller strategies, which significantly reduce drum speed variations caused by web tension changes.
Knowledge Reuse for Innovation
Authors: Majchrzak Ann , Cooper Lynne P. , Neece Olivia E.
Published: March 2004

This study was conducted to better understand the knowledge reuse process when radical innovation (e.g., experiments to prepare for human exploration of Mars) is expected. The research involved detailing the knowledge reuse process in six case studies varying in degree of innovation. Across the six cases, a six-stage reuse-for-innovation process was identified consisting of three major actions: reconceptualize the problem and approach, including deciding to search for others' ideas to reuse; search-and-evaluate others' ideas to reuse; and develop the selected idea. Findings include (1) the need for an insurmountable gap in performance to stimulate the decision to reuse others' knowledge; (2) the critical importance of an adapter to bridge the idea source and recipient; (3) three layers of search-and-evaluate activities in which the first layer of scanning to find ideas to reuse and the last layer of detailed analysis of ideas are bridged by a layer of brief evaluations of ideas assessing the presence (or absence) of targeted information about each idea; and (4) the differential use of metaknowledge about each idea to facilitate proceeding through each search-and-evaluate layer. In addition, reusers in the more (versus less) innovative cases redefined problems at the outset in nontraditional ways using analogies and extensions, rather than accepting the preexisting problem definition; used a substantially broader search strategy with a greater variety of search methods; and worked more closely with adapters during the latter stages of the reuse process.
Modularity and Innovation in Complex Systems
Authors: Ethiraj Sendil K. , Levinthal Daniel
Published: March 2004

The problem of designing, coordinating, and managing complex systems has been central to the management and organization literature. Recent writings have tended to offer modularity as at least a partial solution to this design problem. However, little attention has been paid to the problem of identifying what constitutes an appropriate modularization of a complex system. We develop a formal simulation model that allows us to carefully examine the dynamics of innovation and performance in complex systems. The model points to the trade-off between the destabilizing effects of overly refined modularization and the modest levels of search and a premature fixation on inferior designs that can result from excessive levels of integration. The analysis highlights an asymmetry in this trade-off, with excessively refined modules leading to cycling behavior and a lack of performance improvement. We discuss the implications of these arguments for product and organization design.
Designing a Better Shopbot
Authors: Montgomery Alan L. , Hosanagar Kartik , Krishnan Ramayya , Clay Karen B.
Published: March 2004

A primary tool that consumers have for comparative shopping is the shopbot, which is short for shopping robot. These shopbots automatically search a large number of vendors for price and availability. Typically a shopbot searches a predefined set of vendors and reports all results, which can result in time-consuming searches that provide redundant or dominated alternatives. Our research demonstrates analytically how shopbot designs can be improved by developing a utility model of consumer purchasing behavior. This utility model considers the intrinsic value of the product and its attributes, the disutility from waiting, and the cognitive costs associated with evaluating the offers retrieved. We focus on the operational decisions made by the shopbot: which stores to search, how long to wait, and which offers to present to the user. To illustrate our model we calibrate the model to price and response time data collected at online bookstores over a six-month period. Using prior expectations about price and response time, we show how shopbots can substantially increase consumer utility by searching more intelligently and then selectively presenting offers.
Industry Risk and Market Integration
Authors: Carrieri Francesca , Errunza Vihang , Sarkissian Sergei
Published: March 2004

Traditionally, integration has been studied at the country level. With increasing economic integration, industrial reorganization, and blurring of national boundaries (e.g., European Union (EU)), it is important to investigate global integration at the industry level. We argue that country-level integration (segmentation) does not preclude industry-level segmentation (integration). Indeed, our results suggest that a country is integrated with (segmented from) the world capital markets only if most of her industries are integrated (segmented). We also show that although global industry risk is small, it can be priced for certain industries. Industries that are priced differently from either the world or domestic markets represent incremental opportunities for international diversification.
Closed-Loop Supply Chain Models with Product Remanufacturing
Authors: Savaskan R. Canan , Bhattacharya Shantanu , Van Wassenhove Luk N.
Published: March 2004

The importance of remanufacturing used products into new ones has been widely recognized in the literature and in practice. In this paper, we address the problem of choosing the appropriate reverse channel structure for the collection of used products from customers. Specifically, we consider a manufacturer who has three options for collecting such products: (1) she can collect them herself directly from the customers, (2) she can provide suitable incentives to an existing retailer (who already has a distribution channel) to induce the collection, or (3) she can subcontract the collection activity to a third party. Based on our observations in the industry, we model the three options described above as decentralized decision-making systems with the manufacturer being the Stackelberg leader. When considering decentralized channels, we find that ceteris paribus, the agent, who is closer to the customer (i.e., the retailer), is the most effective undertaker of product collection activity for the manufacturer. In addition, we show that simple coordination mechanisms can be designed such that the collection effort of the retailer and the supply chain profits are attained at the same level as in a centrally coordinated system.
The Allocation of Inventory Risk in a Supply Chain: Push, Pull, and Advance-Purchase Discount Contracts
Authors: Cachon Gérard P.
Published: March 2004

While every firm in a supply chain bears supply risk (the cost of insufficient supply), some firms may, even with wholesale price contracts, completely avoid inventory risk (the cost of unsold inventory). With a push contract there is a single wholesale price and the retailer, by ordering his entire supply before the selling season, bears all of the supply chain's inventory risk. A pull contract also has a single wholesale price, but the supplier bears the supply chain's inventory risk because only the supplier holds inventory while the retailer replenishes as needed during the season. (Examples include Vendor Managed Inventory with consignment and drop shipping.) An advance-purchase discount has two wholesale prices: a discounted price for inventory purchased before the season, and a regular price for replenishments during the selling season. Advance-purchase discounts allow for intermediate allocations of inventory risk: The retailer bears the risk on inventory ordered before the season while the supplier bears the risk on any production in excess of that amount. This research studies how the allocation of inventory risk (via these three types of wholesale price contracts) impacts supply chain efficiency (the ratio of the supply chain's profit to its maximum profit). It is found that the efficiency of a single wholesale price contract is considerably higher than previously thought as long as firms consider both push and pull contracts. In other words, the literature has exaggerated the value of implementing coordinating contracts (i.e., contracts that achieve 100% efficiency, such as buy-backs or revenue sharing) because coordinating contracts are compared against an inappropriate benchmark (often just a push contract). Furthermore, if firms also consider advance-purchase discounts, which are also simple to administer, then the coordination of the supply chain and the arbitrary allocation of its profit is possible. Several limitations of advance-purchase discounts are discussed.
Modeling the Benefits of Sharing Future Demand Information
Authors: Zhu Kaijie , Thonemann Ulrich W.
Published: March 2004

We analyze how sharing of future demand information (FDI) can help companies to lower cost. FDI is imperfect information on the customer demands of the upcoming period. We consider a supply chain with a single retailer and multiple customers, where customer demands are normally distributed and correlated. The retailer faces two decisions: With which customers should information be shared and how much should be ordered? We model the problem as a two-stage dynamic program, develop an optimal solution approach, and provide structural insights into the optimal extent of FDI sharing. We show that information cost and demand correlation are important factors for determining the optimal extent of FDI sharing. For a simplified version of the problem where only a single customer is contacted, we analyze how the optimal solution is affected by nonidentically distributed or nonuniformly correlated demands.
The Price of Robustness
Authors: Bertsimas Dimitris , Sim Melvyn
Published: March 2004

A robust approach to solving linear optimization problems with uncertain data was proposed in the early 1970s and has recently been extensively studied and extended. Under this approach, we are willing to accept a suboptimal solution for the nominal values of the data in order to ensure that the solution remains feasible and near optimal when the data changes. A concern with such an approach is that it might be too conservative. In this paper, we propose an approach that attempts to make this trade-off more attractive; that is, we investigate ways to decrease what we call the price of robustness. In particular, we flexibly adjust the level of conservatism of the robust solutions in terms of probabilistic bounds of constraint violations. An attractive aspect of our method is that the new robust formulation is also a linear optimization problem. Thus we naturally extend our methods to discrete optimization problems in a tractable way. We report numerical results for a portfolio optimization problem, a knapsack problem, and a problem from the Net Lib library.
Scheduling Multiple Parts in a Robotic Cell Served by a Dual-Gripper Robot
Authors: Sriskandarajah Chelliah , Drobouchevitch Inna , Sethi Suresh P. , Chandrasekaran Ramaswamy
Published: March 2004

A robotic cell—a manufacturing system widely used in industry—contains two or more robot-served machines, repetitively producing a number of part types. In this paper, we consider scheduling of operations in a bufferless dual-gripper robotic cell processing multiple part types. The processing constraints specify the cell to be a flowshop. The objective is to determine the robot move sequence and the sequence in which parts are to be processed so as to maximize the long-run average throughput rate for repetitive production of parts. We provide a framework to study the problem, and address the issues of problem complexity and solvability. Focusing on a particular class of robot move sequences, we identify all potentially optimal robot move sequences for the part-sequencing problem in a two-machine dual-gripper robot cell. In the case when the gripper switching time is sufficiently small, we specify the best robot move sequence in the class. We prove the problem of finding an optimal part sequence to be strongly NP-hard, even when the robot move sequence is specified. We provide a heuristic approach to solve the general two-machine problem and evaluate its performance on the set of randomly generated problem instances. We perform computations to estimate the productivity gain of using a dual-gripper robot in place of a single-gripper robot. Finally, we extend our results for the two-machine cell to solve an m-machine problem.
Overbooking with Substitutable Inventory Classes
Authors: Karaesmen Itir , van Ryzin Garrett
Published: March 2004

This paper considers an overbooking problem with multiple reservation and inventory classes, in which the multiple inventory classes may be used as substitutes to satisfy the demand of a given reservation class (perhaps at a cost). The problem is to jointly determine overbooking levels for the reservation classes, taking into account the substitution options. Such problems arise in a variety of revenue management contexts, including multicabin aircraft, back-to-back scheduled flights on the same leg, hotels with multiple room types, and mixed-vehicle car rental fleets. We model this problem as a two-period optimization problem. In the first period, reservations are accepted given only probabilistic knowledge of cancellations. In the second period, cancellations are realized and surviving customers are assigned to the various inventory classes to maximize the net benefit of assignments (e.g., minimize penalties). For this formulation, we show that the expected revenue function is submodular in the overbooking levels, which implies the natural property that the optimal overbooking level in one reservation class decreases with the number of reservations held in the other reservation classes. We then propose a stochastic gradient algorithm to find the joint optimal overbooking levels. We compare the decisions of the model to those produced by more naive heuristics on some examples motivated by airline applications. The results show that accounting for substitution when setting overbooking levels has a small, but still significant, impact on revenues and costs.
Centers in Connected Undirected Graphs: An Axiomatic Approach
Authors: Monsuur Herman , Storcken Ton
Published: March 2004

A center is a function that associates with every finite connected and undirected graph a nonempty subset of its vertices. These functions play an important role in networks such as social or interorganizational networks. Centers capture notions like: being a focal point of communication, being strategically located, ability and willingness to participate in strategic alliances, and the like. We focus on the conceptual issue of what makes a position in a graph a central one and investigate some possible concepts of centrality in relation to various properties. Characterizations of the uncovered center, the median, and degree center are presented, where each of these centers is defined for arbitrary connected undirected simple, and possibly cyclic, graphs.
Modeling of Pedestrian Delays with Pulsed Vehicular Traffic Flow
Authors: Guo Xiaoping , Dunne Michael C. , Black John A.
Published: March 2004

The phenomenon of the bunching of urban traffic is considered together with a mathematical model for the associated problem of the delay to pedestrians crossing a traffic stream. The approach used is also applicable to estimating delay to a single vehicle at a priority intersection and to merging vehicular traffic. Many pedestrian delay models include the assumption that successive vehicular headways are independent and identically distributed random variables. Such models may not be appropriate where vehicles form bunches—as occurs, for example, near traffic signals. Modeling of pedestrian delay is considered in two parts: the delay to pedestrians arriving during a vehicular bunch, and delay to those arriving during the random flow between bunches. These two parts are considered in combination to obtain overall delay.

Three field surveys were conducted in metropolitan Sydney. Useable data were obtained on 4,350 headways and 252 crossing pedestrians on major arterial roads. The field data were used to assess the validity and accuracy of the proposed model. They support the theoretical model and suggest that, under certain conditions, it provides a more accurate estimation of pedestrian delays downstream of traffic signals than do some existing models, such as Adams' (1936) model.
Ship Routing and Scheduling: Status and Perspectives
Authors: Christiansen Marielle , Fagerholt Kjetil , Ronen David
Published: March 2004

The objective of this paper is to review the current status of ship routing and scheduling. We focus on literature published during the last decade. Because routing and scheduling problems are closely related to many other fleet planning problems, we have divided this review into several parts. We start at the strategic fleet planning level and discuss the design of fleets and sea transport systems. We continue with the tactical and operational fleet planning level and consider problems that comprise various ship routing and scheduling aspects. Here, we separately discuss the different modes of operations: industrial, tramp, and liner shipping. Finally, we take a glimpse at naval applications and other related problems that do not naturally fall into these categories. The paper also presents some perspectives regarding future developments and use of optimization-based decision-support systems for ship routing and scheduling. Several of the trends indicate both accelerating needs for and benefits from such systems and, hopefully, this paper will stimulate further research in this area.
Dynamic Programming Approximations for a Stochastic Inventory Routing Problem
Authors: Kleywegt Anton J. , Nori Vijay S. , Savelsbergh Martin W. P.
Published: March 2004

This work is motivated by the need to solve the inventory routing problem when implementing a business practice called vendor managed inventory replenishment (VMI). With VMI, vendors monitor their customers′ inventories and decide when and how much inventory should be replenished at each customer. The inventory routing problem attempts to coordinate inventory replenishment and transportation in such a way that the cost is minimized over the long run. We formulate a Markov decision process model of the stochastic inventory routing problem and propose approximation methods to find good solutions with reasonable computational effort. We indicate how the proposed approach can be used for other Markov decision processes involving the control of multiple resources.
Deriving Link Travel-Time Distributions via Stochastic Speed Processes
Authors: Kharoufeh Jeffrey P. , Gautam Natarajan
Published: March 2004

We derive an analytical expression for the cumulative distribution function of travel time for a vehicle traversing a freeway link of arbitrary length. The vehicle's speed is assumed to be modulated by a random environment that can be modeled as a stochastic process. We first present a partial differential equation (PDE) describing the travel time distribution and obtain a solution in terms of Laplace transforms. Next, we present a numerical inversion algorithm to invert the transforms. The technique is demonstrated on two example problems. Numerical results indicate great promise for this approach to the link travel-time problem.
Anti-Xa Stability of Diluted Enoxaparin for Use in Pediatrics
Authors: Dager William E , Gosselin Robert C , King Jeffery H , Christensen Cinda L , Owings John T , Larkin Edward C
Published: March 2004

BACKGROUND

The use of enoxaparin in low-weight pediatric patients is becoming common practice. Anti-Xa stability of unit-dose syringes prepared after dilution beyond one day is presently unknown.

OBJECTIVE

To evaluate the anti-Xa stability of diluted enoxaparin stored in glass vials and tuberculin syringes.

METHODS

Four separate batches of enoxaparin were diluted with sterile water to a final concentration of 20 mg/mL (2000 IU/mL) and aliquoted into plastic 1-mL syringes containing 6 mg (0.3 mL) or maintained in the glass vial. Syringes were stored at room temperature or under refrigeration. The glass vial used for diluting was stored at room temperature. The anti-Xa activity was measured on the date of preparation to 4 weeks. Statistical comparisons determined whether differences in anti-Xa activity in diluted enoxaparin are affected by the storage medium or temperature. A paired t-test was used to determine any significant differences between the anti-Xa activity on date of preparation (baseline) and subsequent time periods, with p < 0.05 considered statistically significant.

RESULTS

The mean baseline anti-Xa activity was 2607 IU/mL (95% CI 2300 to 2914). No measurable decrease occurred in diluted enoxaparin anti-Xa activity in the glass vial maintained over the 4-week period. Compared with the glass vial, room temperature and refrigerated syringe samples had trending decreases of anti-Xa activity at weeks 3 and 4, but did not reach statistical significance.

CONCLUSIONS

A nonsignificant decrease in anti-Xa activity occurred starting at day 22 for the diluted enoxaparin in tuberculin syringes, regardless of storage temperature. Storage up to 4 weeks of diluted enoxaparin in glass or prefilled syringes does not result in a statistically significant loss of anticoagulant potential, as measured by anti-Xa activity.
Variability of Plasma Anti-Xa Activities with Different Lots of Enoxaparin
Authors: Gosselin Robert C , King Jeffery H , Janatpour Kim A , Dager William E , Larkin Edward C , Owings John T
Published: March 2004

BACKGROUND

Previous studies have indicated the variability of anti-Xa activity in different sources of heparin and the variability of different methods used for measuring anti-Xa activity. Manufacturers of low-molecular-weight heparins (LMWHs) determine each lot's anti-Xa activity against the World Health Organization standard, but little information is known about anti-Xa activity variation between lots of LMWH and the impact on reported anti-Xa activity in patient samples.

OBJECTIVE

To determine the variation of plasma anti-Xa activity in patients receiving enoxaparin when different lots of enoxaparin are used for test calibration.

METHODS

We obtained 7 lots of enoxaparin containing approximately 10 000 IU/mL and one lot containing approximately 15 000 IU/mL of anti-Xa activity. For each lot, a 2.0 anti-Xa IU/mL dilution was prepared and a calibration curve performed using a chromogenic method. To test the variation in reported results between the different calibration lots, 20 patient samples were tested. Nineteen patients receiving enoxaparin and one patient not receiving enoxaparin (negative control) were tested in a blinded fashion, and the changes in light absorbance recorded. Anti-Xa activity results from tested plasmas were then extrapolated from each enoxaparin lot calibration curve.

RESULTS

Using Student's paired t-test, there were statistically significant differences between the plasma anti-Xa activities generated from the various enoxaparin lots. In the range of 0.5–1.0 IU/mL of anti-Xa activity, 3 (4.2%) samples had a >0.2 IU/mL difference (maximum difference 0.33 IU/mL) in anti-Xa activity between 2 lots of enoxaparin. For samples that had supratherapeutic anti-Xa activities (1.0–1.5 IU/mL anti-Xa activity), there was a wider variation (>0.2 IU/mL) in anti-Xa activity, which may have resulted in a dosing change.

CONCLUSIONS

The statistical differences in plasma anti-Xa activities noted between enoxaparin lots are not clinically significant. However, anti-Xa activities in the upper therapeutic and supratherapeutic ranges (>1.0 IU/mL of anti-Xa activity) resulted in a deviation of >0.3 IU/mL in reported anti-Xa activity, which may result in dosing changes.