bluuebunny/crossref_metadata_2025 huggingface dataset:
Economic models for resource management and scheduling in Grid computing
Authors: Buyya Rajkumar , Abramson David , Giddy Jonathan , Stockinger Heinz
Published: January 2003

The accelerated development in peer‐to‐peer and Grid computing has positioned them as promising next‐generation computing platforms. They enable the creation of virtual enterprises for sharing resources distributed across the world. However, resource management, application development and usage models in these environments is a complex undertaking. This is due to the geographic distribution of resources that are owned by different organizations or peers. The resource owners of each of these resources have different usage or access policies and cost models, and varying loads and availability. In order to address complex resource management issues, we have proposed a computational economy framework for resource allocation and for regulating supply and demand in Grid computing environments. This framework provides mechanisms for optimizing resource provider and consumer objective functions through trading and brokering services. In a real world market, there exist various economic models for setting the price of services based on supply‐and‐demand and their value to the user. They include commodity market, posted price, tender and auction models. In this paper, we discuss the use of these models for interaction between Grid components to decide resource service value, and the necessary infrastructure to realize each model. In addition to usual services offered by Grid computing systems, we need an infrastructure to support interaction protocols, allocation mechanisms, currency, secure banking and enforcement services. We briefly discuss existing technologies that provide some of these services and show their usage in developing the Nimrod‐G grid resource broker. Furthermore, we demonstrate the effectiveness of some of the economic models in resource trading and scheduling using the Nimrod/G resource broker, with deadline and cost constrained scheduling for two different optimization strategies, on the World‐Wide Grid testbed that has resources distributed across five continents. Copyright © 2002 John Wiley & Sons, Ltd.
The Polder Computing Environment: a system for interactive distributed simulation
Authors: Iskra K. A. , Belleman R. G. , van Albada G. D. , Santoso J. , Sloot P. M. A. , Bal H. E. , Spoelder H. J. W. , Bubak M.
Published: January 2003

The paper provides an overview of an experimental, Grid‐like computing environment, Polder, and its components. Polder offers high‐performance computing and interactive simulation facilities to computational science. It was successfully implemented on a wide‐area cluster system, the Distributed ASCI Supercomputer. An important issue is an efficient management of resources, in particular multi‐level scheduling and migration of tasks that use PVM or sockets. The system can be applied to interactive simulation, where a cluster is used for high‐performance computations, while a dedicated immersive interactive environment (CAVE) offers visualization and user interaction. Design considerations for the construction of dynamic exploration environments using such a system are discussed, in particular the use of intelligent agents for coordination. A case study of simulatedabdominal vascular reconstruction is subsequently presented: the results of computed tomography or magnetic resonance imaging of a patient are displayed in CAVE, and a surgeon can evaluate the possible treatments by performing the surgeries virtually and analysing the resulting blood flow which is simulated using the lattice‐Boltzmann method. Copyright © 2002 John Wiley & Sons, Ltd.
Component‐based, problem‐solving environments for large‐scale scientific computing
Authors: Johnson Chris , Parker Steve , Weinstein David , Heffernan Sean
Published: January 2003

In this paper we discuss three scientific computing problem solving environments: SCIRun, BioPSE, and Uintah. We begin with an overview of the systems, describe their underlying software architectures, discuss implementation issues, and give examples of their use in computational science and engineering applications. We conclude by discussing future research and development plans for the three problem solving environments. Copyright © 2002 John Wiley & Sons, Ltd.
Application portals: practice and experience
Authors: Thomas Mary , Dahan Maytal , Mueller Kurt , Mock Steve , Mills Cathie , Regno Ray
Published: January 2003

The implementation of multiple Grid computing portals has led us to develop a methodology for Grid portal development that facilitates rapid prototyping and building of portals. Based on the National Partnership for Advanced Computational Infrastructure (NPACI) Grid Portal Toolkit (GridPort) and the NPACI HotPage, all portals inherit interactive Grid services, share a single account and login environment, and share the infrastructure required to support and provide services used by each portal. We have demonstrated that the GridPort software can be used in production application portal environments, that the software can be configured to extend multiple sites. In this paper, we describe our experiences gained in building Grid portals and developing software for the Grid. We describe the architecture and design of the portal system, Grid services and systems employed, as well as the unique features of the system. We present descriptions of several application portals and the driving design choices. Finally, we discuss the new and emerging architecture system that being studied based on the Web services architecture. Copyright © 2002 John Wiley & Sons, Ltd.
A comparison of concurrent programming and cooperative multithreading
Authors: Keen Aaron W. , Ishihara Takashi , Maris Justin T. , Li Tiejun , Fodor Eugene F. , Olsson Ronald A.
Published: January 2003

This paper presents a comparison of the cooperative multithreading model with the general concurrent programming model. It focuses on the execution time performance of a range of standard concurrent programming applications. The overall results are mixed. In some cases, programs written in the cooperative multithreading model outperform those written in the general concurrent programming model. The contributions of this paper are twofold. First, it presents a thorough analysis of the performances of applications in the different models, i.e. to explain the criteria that determine when a program in one model will outperform an equivalent program in the other. Second, it examines the tradeoffs in writing programs in the different programming styles. In some cases, better performance comes at the cost of more complicated code. Copyright © 2003 John Wiley & Sons, Ltd.
Object‐oriented distributed computing based on remote class reference
Authors: Huang Yan , Walker David W. , Rana Omer F.
Published: January 2003

Java RMI, Jini and CORBA provide effective mechanisms for implementing a distributed computing system. Recently many numeral libraries have been developed that take advantage of Java as an object‐oriented and portable language. The widely‐used client‐server method limits the extent to which the benefits of the object‐oriented approach can be exploited because of the difficulties arising when a remote object is the argument or return value of a remote or local method. In this paper this problem is solved by introducing a data object that stores the data structure of the remote object and related access methods. By using this data object, the client can easily instantiate a remote object, and use it as the argument or return value of either a local or remote method. Copyright © 2003 John Wiley & Sons, Ltd.
Improving the official specification of Java bytecode verification
Authors: Coglio Alessandro
Published: January 2003

Bytecode verification is the main mechanism to ensure type safety in the Java Virtual Machine. Inadequacies in its official specification may lead to incorrect implementations where security can be broken and/or certain legal programs are rejected. This paper provides a comprehensive analysis of the specification, along with concrete suggestions for improvement. Copyright © 2003 John Wiley & Sons, Ltd.
The utilization of the Purdue cognitive job analysis methodology
Authors: Wei June , Salvendy Gavriel
Published: January 2003

The objective of this article is to illustrate the utilization of the Purdue Cognitive Job and Task Analysis methodology, the Human Centered Cognitive Performance model based Purdue Cognitive Task Analysis Questionnaire, which not only analyzes jobs and tasks, but also provides a mechanism for improving cognitive job and task performance. Specifically, the utilization of this methodology can assist job evaluation, job design and job rotation, and personnel selection and training. © 2003 Wiley Periodicals, Inc. Hum Factors Man 13: 59–84, 2003.
Proprotein convertases regulate activity of prostate epithelial cell differentiation markers and are modulated in human prostate cancer cells
Authors: Uchida Katsunori , Chaudhary Lala R. , Sugimura Yoshiki , Adkisson Huston D. , Hruska Keith A.
Published: January 2003

Prostate derived factor (PDF) is a member of transforming growth factor‐β (TGF‐β) superfamily proteins involved in differentiation of the prostate epithelium. Proprotein convertases (PCs) such as furin are thought to mediate the processing of TGF‐β superfamily. In the present study, we demonstrated for the first time that human prostate cancer cell lines differentially synthesize and secret prostate derived factor (PDF), and that PDF secreted by LNCaP is processed by PCs. Exposure of LNCaP cells to the decanoyl‐Arg‐Val‐Lys‐Arg‐chloromethylketone (CMK), a synthetic furin‐like protease inhibitor, inhibited PDF processing and resulted in the loss of luminal cell phenotype and induction of basal cell phenotype in LNCaP cells as demonstrated by alternations in the expression of cytokeratins 8, 14, 18, and 19, markers of prostate epithelial cell differentiation. These results suggest that proprotein convertases may be involved in the regulation of prostate epithelial cell differentiation, and may be an important target of prostate cancer therapy. J. Cell. Biochem. 88: 394–399, 2003. © 2002 Wiley‐Liss, Inc.
Analogs of 1α,25‐dihydroxyvitamin D3 as pluripotent immunomodulators
Authors: van Etten Evelyne , Decallonne Brigitte , Verlinden Lieve , Verstuyf Annemieke , Bouillon Roger , Mathieu Chantal
Published: January 2003

The active form of vitamin D3, 1,25(OH)2D3, is known, besides its classical effects on calcium and bone, for its pronounced immunomodulatory effects that are exerted both on the antigen‐presenting cell level as well as directly on the T lymphocyte level. In animal models, these immune effects of 1,25(OH)2D3 are reflected by a strong potency to prevent onset and even recurrence of autoimmune diseases. A major limitation in using 1,25(OH)2D3 in clinical immune therapy are the adverse side effects on calcium and on bone. TX527 (19‐nor‐14,20‐bisepi‐23‐yne‐1,25(OH)2D3) is a structural 1,25(OH)2D3 analog showing reduced calcemic activity associated with enhanced in vitro and in vivo immunomodulating capacity compared to the mother‐molecule. Indeed, in vitro TX527 is more potent that 1,25(OH)2D3 in redirecting differentiation and maturation of dendritic cells and in inhibiting phytohemagglutinin‐stimulated T lymphocyte proliferation. In vivo, this enhanced potency of TX527 is confirmed by a stronger potential to prevent type 1 diabetes in nonobese diabetic (NOD) mice and to prolong the survival of syngeneic islets grafts, both alone and in combination with cyclosporine A, in overtly diabetic NOD mice. Moreover, these in vivo effects of TX527 are obtained without the adverse side effects observed for 1,25(OH)2D3 itself. We believe therefore that TX527 is a potentially interesting candidate to be considered for clinical intervention trails in autoimmune diseases. J. Cell. Biochem. 88: 223–226, 2003. © 2002 Wiley‐Liss, Inc.
Vitamin D and bone
Authors: Suda Tatsuo , Ueno Yutaka , Fujii Katsuyuki , Shinki Toshimasa
Published: January 2003

It is now well established that supraphysiological doses of 1α,25‐dihydroxyvitamin D3 [1α,25(OH)2D3] stimulate bone resorption. Recent studies have established that osteoblasts/stromal cells express receptor activator of NF‐κB ligand (RANKL) in response to several bone‐resorbing factors including 1α,25(OH)2D3 to support osteoclast differentiation from their precursors. Osteoclast precursors which express receptor activator of NF‐κB (RANK) recognize RANKL through cell‐to‐cell interaction with osteoblasts/stromal cells, and differentiate into osteoclasts in the presence of macrophage‐colony stimulating factor (M‐CSF). Osteoprotegerin (OPG) acts as a decoy receptor for RANKL. We also found that daily oral administration of 1α,25(OH)2D3 for 14 days to normocalcemic thyroparathyroidectomized (TPTX) rats constantly infused with parathyroid hormone (PTH) inhibited the PTH‐induced expression of RANKL and cathepsin K mRNA in bone. The inhibitory effect of 1α,25(OH)2D3 on the PTH‐induced expression of RANKL mRNA occurred only with physiological doses of the vitamin. Supraphysiological doses of 1α,25(OH)2D3 increased serum Ca and expression of RANKL in vivo in the presence of PTH. These results suggest that the bone‐resorbing activity of vitamin D does not occur at physiological dose levels in vivo. A certain range of physiological doses of 1α,25(OH)2D3 rather suppress the PTH‐induced bone resorption in vivo, supporting the concept that 1α,25(OH)2D3 or its derivatives are useful for the treatment of various metabolic bone diseases such as osteoporosis and secondary hyperparathyroidism. J. Cell. Biochem. 88: 259–266, 2003. © 2002 Wiley‐Liss, Inc.
Novel regulators of vitamin D action and metabolism: Lessons learned at the Los Angeles zoo
Authors: Adams J.S. , Chen H. , Chun R.F. , Nguyen L. , Wu S. , Ren S.‐Y. , Barsony J. , Gacad M.A.
Published: January 2003

We undertook an investigation of an outbreak of rachitic bone disease in the Emperor Tamarin New World primate colony at the Los Angeles Zoo in the mid‐1980s. The disease phenotype resembled that observed in humans with an inactivating mutation of the vitamin D receptor (VDR), hypocalcemia, high 1,25‐dihydroxyvitamin D (1,25‐(OH)2D) levels, and rickets in rapidly growing adolescent primates. In contrast to the human disease, the New World primate VDR was functionally normal in all respects. The proximate cause of vitamin D hormone resistance in New World primates was determined to be the constitutive overexpression of a heterogeneous nuclear ribonucleoprotein in the A family which we coined the vitamin D response element binding protein (VDRE‐BP). VDRE‐BP competed in trans with the VDR‐retinoid X receptor (RXR) for binding to the vitamin D response element. VDRE‐BP‐legislated resistance to 1,25‐(OH)2D was antagonized (i.e., compensated) by another set of constitutively overexpressed proteins, the hsp‐70‐related intracellular vitamin D binding proteins (IDBPs). IDBPs, present but expressed at much lower levels in Old World primates including man, exhibited a high capacity for 25‐hydroxylated vitamin D metabolites and functioned to traffic vitamin Ds to specific intracellular destinations to promote their action and metabolism. J. Cell. Biochem. 88: 308–314, 2003. © 2002 Wiley‐Liss, Inc.
Inhibition of prostate cancer growth by vitamin D: Regulation of target gene expression
Authors: Krishnan Aruna V. , Peehl Donna M. , Feldman David
Published: January 2003

Prostate cancer (PCa) cells express vitamin D receptors (VDR) and 1,25‐dihydroxyvitamin D3 (1,25(OH)2D3) inhibits the growth of epithelial cells derived from normal, benign prostate hyperplasia, and PCa as well as established PCa cell lines. The growth inhibitory effects of 1,25(OH)2D3 in cell cultures are modulated tissue by the presence and activities of the enzymes 25‐hydroxyvitamin D3 24‐hydroxylase which initiates the inactivation of 1,25(OH)2D3 and 25‐hydroxyvitamin D3 1α‐hydroxylase which catalyses its synthesis. In LNCaP human PCa cells 1,25(OH)2D3 exerts antiproliferative activity predominantly by cell cycle arrest through the induction of IGF binding protein‐3 (IGFBP‐3) expression which in turn increases the levels of the cell cycle inhibitor p21 leading to growth arrest. cDNA microarray analyses of primary prostatic epithelial and PCa cells reveal that 1,25(OH)2D3 regulates many target genes expanding the possible mechanisms of its anticancer activity and raising new potential therapeutic targets. Some of these target genes are involved in growth regulation, protection from oxidative stress, and cell–cell and cell–matrix interactions. A small clinical trial has shown that 1,25(OH)2D3 can slow the rate of prostate specific antigen (PSA) rise in PCa patients demonstrating proof of concept that 1,25(OH)2D3 exhibits therapeutic activity in men with PCa. Further investigation of the role of calcitriol and its analogs for the therapy or chemoprevention of PCa is currently being pursued. J. Cell. Biochem. 88: 363–371, 2003. © 2002 Wiley‐Liss, Inc.
Synthetic LXXLL peptide antagonize 1,25‐dihydroxyvitamin D3‐dependent transcription
Authors: Pike J. Wesley , Pathrose Peterman , Barmina Olga , Chang Ching‐Yi , McDonnell Donald P. , Yamamoto Hironori , Shevde Nirupama K.
Published: January 2003

The vitamin D receptor (VDR) is known to mediate the biological actions of 1,25‐dihydroxyvitamin D3 (1,25(OH)2D3) through its ability to regulate cellular programs of gene expression. We identified VDR‐ and retinoid X receptor (RXR)‐interacting LXXLL peptides using a mammalian two‐hybrid system and examined whether these molecules could block vitamin D and 9‐cis retinoic acid (9‐cis RA) response. Peptides were identified that were reactive to RXR alone as well as to both VDR and RXR. Peptide fusion proteins were then examined in MC3T3 E1 cells for their ability to block induction of the osteocalcin promoter by 1,25(OH)2D3 or stimulation of an RARE‐TK reporter by 9‐cis RA. Peptides that interacted with both VDR and RXR blocked 1,25(OH)2D3‐dependent transcription by up to 75%. Peptides that interacted with RXR blocked 9‐cis RA induced transcription. Two RXR‐interacting peptides, however, were also found to block 1,25(OH)2D3 response effectively. These studies support the idea that comodulator recruitment is essential for VDR‐ and RXR‐mediated gene expression and that RXR is required for 1,25(OH)2D3‐induced osteocalcin gene transcription. This approach may represent a novel means of assessing the contribution of RXR in various endogenous biological responses to 1,25(OH)2D3. J. Cell. Biochem. 88: 252–258, 2003. © 2002 Wiley‐Liss, Inc.
Molecular basis of the selective activity of vitamin D analogues
Authors: Carlberg Carsten
Published: January 2003

More than 2,000 synthetic analogues of the biological active form of vitamin D, 1α,25‐dihydroxyvitamin D3 (1α,25(OH)2D3), are presently known. Basically, all of them interfere with the molecular switch of nuclear 1α,25(OH)2D3 signaling, which is the complex of the vitamin D receptor (VDR), the retinoid X receptor (RXR), and a 1α,25(OH)2D3 response element (VDRE). Central element of this molecular switch is the ligand‐binding domain (LBD) of the VDR, which can be stabilized by a 1α,25(OH)2D3 analogue either in its agonistic, antagonistic, or non‐agonistic conformation. The positioning of helix 12 of the LBD is of most critical importance for these conformations. In each of the three conformations, the VDR performs different protein–protein interactions, which then result in a characteristic functional profile. Most 1α,25(OH)2D3 analogues have been identified as agonists, a few are antagonists (e.g., ZK159222 and TEI‐9647), and only Gemini and some of its derivatives act under restricted conditions as non‐agonists. The functional profile of some 1α,25(OH)2D3 analogues, such as EB1089 and Gemini, can be modulated by protein and DNA interaction partners of the VDR. This provides them with some selectivity for DNA‐dependent and ‐independent signaling pathways and VDRE structures. J. Cell. Biochem. 88: 274–281, 2003. © 2002 Wiley‐Liss, Inc.
Vitamin D: A millenium perspective
Authors: Holick Michael F.
Published: January 2003

Vitamin D is one of the oldest hormones that have been made in the earliest life forms for over 750 million years. Phytoplankton, zooplankton, and most plants and animals that are exposed to sunlight have the capacity to make vitamin D. Vitamin D is critically important for the development, growth, and maintenance of a healthy skeleton from birth until death. The major function of vitamin D is to maintain calcium homeostasis. It accomplishes this by increasing the efficiency of the intestine to absorb dietary calcium. When there is inadequate calcium in the diet to satisfy the body's calcium requirement, vitamin D communicates to the osteoblasts that signal osteoclast precursors to mature and dissolve the calcium stored in the bone. Vitamin D is metabolized in the liver and then in the kidney to 1,25‐dihydroxyvitamin D [1,25(OH)2D]. 1,25(OH)2D receptors (VDR) are present not only in the intestine and bone, but in a wide variety of other tissues, including the brain, heart, stomach, pancreas, activated T and B lymphocytes, skin, gonads, etc. 1,25(OH)2D is one of the most potent substances to inhibit proliferation of both normal and hyperproliferative cells and induce them to mature. It is also recognized that a wide variety of tissues, including colon, prostate, breast, and skin have the enzymatic machinery to produce 1,25(OH)2D. 1,25(OH)2D and its analogs have been developed for treating the hyperproliferative disease psoriasis. Vitamin D deficiency is a major unrecognized health problem. Not only does it cause rickets in children, osteomalacia and osteoporosis in adults, but may have long lasting effects. Chronic vitamin D deficiency may have serious adverse consequences, including increased risk of hypertension, multiple sclerosis, cancers of the colon, prostate, breast, and ovary, and type 1 diabetes. There needs to be a better appreciation of the importance of vitamin D for overall health and well being. J. Cell. Biochem. 88: 296–307, 2003. © 2002 Wiley‐Liss, Inc.
Vitamin D regulated keratinocyte differentiation: Role of coactivators
Authors: Bikle D.D. , Tu C.‐L. , Xie Z. , Oda Y.
Published: January 2003

1,25 Dihydroxyvitamin D (1,25(OH)2D) regulates the differentiation of keratinocytes. 1,25(OH)2D raises intracellular free calcium (Cai) as a necessary early step toward stimulating differentiation. 1,25(OH)2D induces the calcium sensing receptor (CaR) in keratinocytes and enhances the calcium response of these cells. Activation of the CaR by calcium increases intracellular free calcium by a mechanism involving phospholipase C (PLC) cleavage of phosphatidylinositolbisphosphate into inositoltrisphosphate (IP3) and diacylglycerol (DG). 1,25(OH)2D induces the family of PLCs. PLC‐γ1 has a DR6 VDRE in its promoter which binds and is activated by VDR/RAR rather than VDR/RXR. The involucrin gene, which encodes a critical component of the cornified envelope, contains a DR3 VDRE in its promoter that acts in conjunction with a nearby AP‐1 site. The sequential regulation of these genes is critical for the differentiation process. In undifferentiated keratinocytes, the VDR binds preferentially to the DRIP complex of coactivators. However, with differentiation DRIP 205 is no longer produced, and the VDR switches partners to the SRC family (SRC2 and 3). These studies suggest that at least part of the sequential activation of genes required during keratinocyte differentiation is regulated by the change (availability) of these different coactivator complexes. J. Cell. Biochem. 88: 290–295, 2003. © 2002 Wiley‐Liss, Inc.
Prostatic 25‐hydroxyvitamin D‐1α‐hydroxylase and its implication in prostate cancer
Authors: Chen Tai C. , Wang Lilin , Whitlatch Lyman W. , Flanagan John N. , Holick Michael F.
Published: January 2003

Evidence suggests that vitamin D may have a protective role for prostate cancer. 1α,25‐Dihydroxyvitamin D [1α,25(OH)2D] inhibits growth and induces differentiation of prostate cells. 25‐Hydroxyvitamin D‐1α‐hydroxylase [1α‐OHase], the enzyme that is responsible for the synthesis of 1α,25(OH)2D, is expressed in cultured prostate cells. We observed a marked decrease in 1α‐OHase activity in prostate cancer cells, suggesting some defect of the 1α‐OHase in these cells. To investigate whether the defect was due to dysregulation of the enzyme at the promoter level, a series of deletion constructs of the promoter was synthesized and incorporated upstream into the luciferase reporter gene. Two regions were identified with high basal activity in transfected normal prostate cell line (PZHPV‐7), −1100 bp (AN2), and −394 bp (AN5) upstream of ATG start site of the 1α‐OHase gene. When the reporter gene with either AN2 or AN5 was transfected into prostate cancer cell lines, we observed a lower basal promoter activity in PC‐3 cells and DU145 cells than that found in PZHPV‐7 cells for both constructs, and a loss of promoter activity in LNCaP cells. Thus, the results suggest that the defect in enzyme activity may result from the decreased promoter activity in prostate cancer cells. J. Cell. Biochem. 88: 315–322, 2003. © 2002 Wiley‐Liss, Inc.
Vitamin D regulation of the renin–angiotensin system
Authors: Li Yan Chun
Published: January 2003

The renin–angiotensin system (RAS) plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis. Epidemiological and clinical studies have long suggested an association of inadequate sunlight exposure or low serum 1,25‐dihydroxyvitamin D3 [1,25(OH)2D3] levels with high blood pressure and/or high plasma renin activity, but the mechanism is not understood. Our recent discovery that 1,25(OH)2D3 functions as a potent negative endocrine regulator of renin gene expression provides some insights into the mechanism. The concept of vitamin D regulation of blood pressure through the RAS opens a new avenue to our understanding of the physiological functions of the vitamin D endocrine system, and provides a basis for exploring the potential use of vitamin D analogues in prevention and treatment of hypertension. J. Cell. Biochem. 88: 327–331, 2003. © 2002 Wiley‐Liss, Inc.
Vitamin D and autoimmune diabetes
Authors: Zella Julia B. , DeLuca Hector F.
Published: January 2003

The biologically active form of vitamin D, 1,25(OH)2D3, is a potent modulator of the immune system as well as a regulator of bone and mineral metabolism. Vitamin D‐deficiency in infancy and vitamin D receptor gene polymorphisms may be risk factors for insulin‐dependent Diabetes mellitus (IDDM). 1,25(OH)2D3 and its analogs significantly repress the development of insulitis and diabetes in the non‐obese diabetic (NOD) mouse, a model of human IDDM. 1,25(OH)2D3 may modulate IDDM disease pathogenesis by repression of type I cytokines, inhibition of dendritic cell maturation, and upregulation of regulatory T cells. The function of vitamin D as a genetic and environmental determining factor for IDDM, the protective role of 1,25(OH)2D3 and its analogs in a mouse model of IDDM, and the possible mechanisms by which this protection occurs will be reviewed. J. Cell. Biochem. 88: 216–222, 2003. © 2002 Wiley‐Liss, Inc.
Rat cytochrome P450C24 (CYP24) does not metabolize 1,25‐dihydroxyvitamin D2 to calcitroic acid
Authors: Horst R.L. , Omdahl J.A. , Reddy S.
Published: January 2003

1α‐Hydroxy‐23 carboxy‐24,25,26,27‐tetranorvitamin D3 (calcitroic acid) is known to be the major water‐soluble metabolite produced during the deactivation of 1,25‐(OH)2D3. This deactivation process is carried out exclusively by the multicatalytic enzyme CYP24 and involves a series of oxidation reactions at C24 and C23 leading to side‐chain cleavage and, ultimately, formation of the calcitroic acid. Like 1,25‐(OH)2D3, 1α,25‐1,25‐(OH)2D2 is also known to undergo side‐chain oxidation and side‐chain cleavage to form calcitroic acid (Zimmerman et al. [2001]. 1,25‐(OH)2D2 differs from 1,25‐(OH)2D3 by the presence of a double bond at C22 and a methyl group at C24. To date, there have been no studies detailing the participation of CYP24 in the production of calcitroic acid from 1,25‐(OH)2D2. We, therefore, studied the metabolism of 1,25‐(OH)2D3 and 1,25‐(OH)2D2 using a purified rat CYP24 system. Lipid and aqueous‐soluble metabolites were prepared for characterization. Aqueous‐soluble metabolites were subjected to reverse‐phase high‐pressure liquid chromatography (HPLC) analysis. As expected, 1,23(OH)2‐24,25,26,27‐tetranor D and calcitroic acid were the major lipid and aqueous‐soluble metabolites, respectively, when 1,25‐(OH)2D3 was used as substrate. However, when 1,25‐(OH)2D2 was used as substrate, 1,24(R),25‐(OH)3D2 was the major lipid‐soluble metabolite with no evidence for the production of either 1,23(OH)2‐24,25,26,27‐tetranor D or calcitroic acid. Apparently, the CYP24 was able to 24‐hydroxylate 1,25‐(OH)2D2, but was unable to effect further changes, which would result in side‐chain cleavage. These data suggest that the presence of either the double bond at C22 or the C24 methyl group impedes the metabolism of 1,25‐(OH)2D2 to calcitroic acid by CYP24 and that enzymes other than CYP24 are required to effect this process. J. Cell. Biochem. 88: 282–285, 2003. Published 2002 Wiley‐Liss, Inc.
Intranuclear trafficking of transcription factors: Requirements for vitamin D‐mediated biological control of gene expression
Authors: Stein Gary S. , Lian Jane B. , Stein Janet L. , van Wijnen André J. , Montecino Martin , Javed Amjad , Pratap Jitesh , Choi Je , Zaidi S. Kaleem , Gutierrez Soraya , Harrington Kimberly , Shen Jiali , Young Daniel
Published: January 2003

The architecturally associated subnuclear organization of nucleic acids and cognate regulatory factors suggest functional interrelationships between nuclear structure and gene expression. Mechanisms that contribute to the spatial distribution of transcription factors within the three‐dimensional context of nuclear architecture control the sorting of regulatory information as well as the assembly and activities of sites within the nucleus that support gene expression. Vitamin D control of gene expression serves as a paradigm for experimentally addressing mechanisms that govern the intranuclear targeting of regulatory factors to nuclear domains where transcription of developmental and tissue‐specific genes occur. We will present an overview of molecular, cellular, genetic, and biochemical approaches that provide insight into the trafficking of regulatory factors that mediate vitamin D control of gene expression to transcriptionally active subnuclear sites. Examples will be presented that suggest modifications in the intranuclear targeting of transcription factors abrogate competency for vitamin D control of skeletal gene expression during development and fidelity of gene expression in tumor cells. J. Cell. Biochem. 88: 340–355, 2003. © 2002 Wiley‐Liss, Inc.
Inhibitors of vitamin D hydroxylases: Structure–activity relationships
Authors: Schuster Inge , Egger Helmut , Nussbaumer Peter , Kroemer Romano T.
Published: January 2003

Aiming at new drugs to efficiently treat diseases, in which either increased or decreased levels of active vitamin D are desirable, we have designed some 400 structurally different azole‐type inhibitors and examined their capacity to selectively block vitamin D metabolism by CYP24 or synthesis by CYP27B, in human keratinocytes. Based on resulting data, we built pharmacophore models of the active sites using commercial software. The overlay of potent selective compounds indicated similar docking modes in the two‐substrate pockets and allowed for identification of bioactive conformations. Superimposing these bioactive conformations with low energy conformers of 25(OH)D3 suggested that the substrate‐mimicked by strong inhibitors in size, shape and lipophilic character‐binds to both enzymes in 6s‐trans configuration. Pharmacophoric models implied a similar geometry of the substrate sites, nevertheless specific features of CYP24 and CYP27B could be defined. Bulky substituents in α‐position to the azole caused selectivity for CYP24, whereas bulky substituents in β‐position could result in selectivity for CYP27B. Moreover, studies with small sterically restricted inhibitors revealed a probable location of the 3‐OH‐group of 25(OH)D3 in CYP27B. In the absence of crystal structures, our inhibitors are valuable tools to model and understand the active sites of vitamin D hydroxylases, resulting in the design of powerful, selective therapeutics. J. Cell. Biochem. 88: 372–380, 2003. © 2002 Wiley‐Liss, Inc.
Positional information by rauber's sickle and a new look at the mechanisms of primitive streak initiation in avian blastoderms
Authors: Callebaut Marc , Van Nueten Emmy , Bortier Hilde , Harrisson Fernand
Published: January 2003

The present experimental in vitro study suggests that a primitive streak (PS) in avian blastoderms is induced by diffusion of morphogenetic substances emanating from Rauber's sickle. Indeed, even without direct contact between a quail Rauber's sickle and the reacting upper layer (by interposition of a vitelline membrane), a PS can be induced in the isolated area centralis or antisickle region of unincubated chicken blastoderms. The so‐formed PSs are localized below the vitelline membrane in the immediate neighborhood of the apposed Rauber's sickle material. This seems to indicate that Rauber's sickle organizes the formation of the avian PS according to the basic concept of “positional information.” The morphogenetic substances seem to have an effect only on the formation of a PS. Each part of Rauber's sickle seems to have, point by point, the same thickening and PS‐inducing effect on each corresponding part of the underlying upper layer (UL). By a mechanism of sliding over the basement membrane and fusion, this finally results in the formation of one single median PS. Our study shows that a PS can be induced in the total absence of hypoblast (sickle endoblast) or caudal marginal zone, by only the presence of Rauber's sickle material. In contrast, the differentiation of mesoblast into blood islands under the influence of Rauber's sickle and neural tissue development are impaired by the interposition of a vitelline membrane. The latter could be due to the absence of a normal interaction of Rauber's sickle‐derived sickle endoblast with endophyll and/or upper layer and the absence of cranial migration of the mesoblast. Thus, earlier studies and the present study indicate the existence of a temporospatially bound cascade of gastrulation and neurulation phenomena and blood island formation in the avian blastoderm, starting from Rauber's sickle, the primary major organizer with inducing, inhibiting, and dominating potencies. The latter not only plays a role by secretion of signaling molecules, but also influences development by its cell lineages (junctional endoblast and sickle endoblast). J. Morphol. 255:315–327, 2003. © 2003 Wiley‐Liss, Inc.
Microscopic anatomy of the orbital harderian gland in the common tree shrew (tupaia glis)
Authors: Pradidarcheep Wisuit , Asavapongpatana Somluk , Mingsakul Thaworn , Poonkhum Raksawan , Nilbu‐nga Somneuk , Somana Reon
Published: January 2003

The orbital Harderian gland of the common tree shrew (Tupaia glis) was investigated at the macroscopic and microscopic levels. In the glands of both sexes only one acinar cell type was found. The cell is characterized by the presence of numerous lipid vacuoles of variable size and by a small number of PAS‐positive, electron‐dense granules distributed throughout the cytoplasm, which are predominant at the basal portion of each acinar cell. The duct system is well developed within the gland. The content of lipid vacuoles within the acinar cells is secreted from the apical portions by exocytosis, indicating the exocrine function of the organ. Apart from the lipid vacuoles, both acinar and ductal luminal contents of the Harderian gland also contain accretion of electron‐dense materials. The vascularization within the Harderian gland is unique in that two capillary types (small fenestrated and irregular sinusoidal capillaries) could be demonstrated. The presence of fenestrated capillaries together with other morphological features (such as accumulation of the small electron‐dense granules at the basal pole and the presence of basolateral microvilli) near the basal portion of the acinar cells suggest that the Harderian gland in T. glis might also be involved in an endocrine function. J. Morphol. 255:328–336, 2003. © 2003 Wiley‐Liss, Inc.
Immunocytochemical and ultrastructural characterization of mammosomatotrope‐, growth hormone‐, and prolactin‐cells from the gilthead sea bream (sparus aurata l., teleostei): an ontogenic study
Authors: Villaplana Mariano , García Ayala Alfonsa , Hernández Maria Pilar García , Agulleiro Blanca
Published: January 2003

Growth hormone (GH), prolactin (PRL), and mammosomatotrope (MS) cells of gilthead sea bream, Sparus aurata, a teleost fish, were studied in specimens from hatching to 15 months (adults) using conventional electron microscopy and an immunogold method using anti‐tilapia GH sera and anti‐chum salmon PRL serum. MS cells, immunoreactive to both anti‐GH sera and anti‐PRL sera, had been first identified in fish in a previous study in newly hatched larvae and in older larvae and juvenile specimens of Sparus aurata by light microscopic immunocytochemistry. In the present work, MS cells reacted positively to immunogold label only in older larvae and juveniles and their secretory granules immunoreacted with both GH and PRL antisera or with only one of them. MS cells were ultrastructurally similar to the PRL cells, with which they coincided in time. This is the first report on the ultrastructural characterization of MS cells in fish. In adults, the secretory granules of GH cells (immunoreactive to anti‐GH serum) were mainly round, of variable size, and had a homogeneous, highly electron‐dense content. Irregularly shaped secretory granules were also present. PRL cells (immunoreactive to anti‐PRL serum) were usually observed in a follicular arrangement; they showed few, small, and mainly round secretory granules with a homogeneous and high or medium electron‐dense content. Some oval or elongated secretory granules were also observed. GH and PRL cells that showed involutive features were also found. In newly hatched larvae, GH, PRL, and MS cells could not be distinguished either by their ultrastructure or by the immunogold labeling of the secretory granules. In 1‐day‐old larvae, presumptive GH and PRL cells were observed according to their position in the pituitary gland. In 2‐day‐old larvae, a few cells showed some of the ultrastructural features described for GH and PRL cells of adults. During development, the number, size, and shape of the secretory granules in both cell types clearly increased and the organelles developed gradually. Some GH cells were found undergoing mitosis. J. Morphol. 255:347–357, 2003. © 2003 Wiley‐Liss, Inc.
Time asymptotics for the polyharmonic wave equation in waveguides
Authors: Lesky P. H.
Published: January 2003

Let Ω denote an unbounded domain in ℝn having the form Ω=ℝl×D with bounded cross‐section D⊂ℝn−l, and let m∈ℕ be fixed. This article considers solutions u to the scalar wave equation ∂u(t,x) +(−Δ)mu(t,x) = f(x)e−iωt satisfying the homogeneous Dirichlet boundary condition. The asymptotic behaviour of u as t→∞ is investigated. Depending on the choice of f ,ω and Ω, two cases occur: Either u shows resonance, which means that ∣u(t,x)∣→∞ as t→∞ for almost every x ∈ Ω, or u satisfies the principle of limiting amplitude. Furthermore, the resolvent of the spatial operators and the validity of the principle of limiting absorption are studied. Copyright © 2003 John Wiley & Sons, Ltd.
Asymptotic and spectral analysis of non‐selfadjoint operators generated by a filament model with a critical value of a boundary parameter
Authors: Shubov Marianna A.
Published: January 2003

We consider a class of non‐selfadjoint operators generated by the equation and the boundary conditions, which govern small vibrations of an ideal filament with non‐conservative boundary conditions at one end and a heavy load at the other end. The filament has a non‐constant density and is subject to a viscous damping with a non‐constant damping coefficient. The boundary conditions contain two arbitrary complex parameters. In our previous paper (Mathematical Methods in the Applied Sciences 2001; 24(15) : 1139–1169), we have derived the asymptotic approximations for the eigenvalues and eigenfunctions of the aforementioned non‐selfadjoint operators when the boundary parameters were arbitrary complex numbers except for one specific value of one of the parameters. We call this value the critical value of the boundary parameter. It has been shown (in Mathematical Methods in the Applied Sciences 2001; 24(15) : 1139–1169) that the entire set of the eigenvalues is located in a strip parallel to the real axis. The latter property is crucial for the proof of the fact that the set of the root vectors of the operator forms a Riesz basis in the state space of the system. In the present paper, we derive the asymptotics of the spectrum exactly in the case of the critical value of the boundary parameter. We show that in this case, the asymptotics of the eigenvalues is totally different, i.e. both the imaginary and real parts of eigenvalues tend to ∞as the number of an eigenvalue increases. We will show in our next paper, that as an indirect consequence of such a behaviour of the eigenvalues, the set of the root vectors of the corresponding operator is not uniformly minimal (let alone the Riesz basis property). Copyright © 2003 John Wiley & Sons, Ltd.
A new test of non‐inferiority for anti‐infective trials
Authors: Phillips Kem F.
Published: January 2003

This paper describes a new statistical test of non‐inferiority in clinical trials of anti‐infective medications. The test allows the inferiority limit, delta, to vary with the underlying success rates. The test is a simple modification of the standard fixed‐delta test, and its parameters can be adjusted to yield the fixed‐delta test, a test similar to the FDA's Points‐to‐Consider procedure, or a test with nearly constant power values over a range of success rates. The test satisfies the size and power criteria for a valid statistical test. The effects on the test of lowering success rates through stringent criteria or through error are discussed. Copyright © 2002 John Wiley & Sons, Ltd.
Non‐inferiority trials: the ‘at least as good as’ criterion
Authors: Laster Larry L. , Johnson Mary F.
Published: January 2003

To demonstrate in a clinical trial that a new or experimental therapy (et) is ‘at least as good as’ a standard therapy (st), a statistical test or confidence interval procedure must rule out clinical inferiority with a high probability. The term ‘at least as good as’ implies equivalent but not necessarily superior efficacy. As it is statistically impossible to demonstrate equivalence (that is, prove the null hypothesis of no difference), Blackwelder proposed a one‐sided significance test to reject the null hypothesis that standard therapy is better than experimental therapy by a clinically acceptable amount, δBW. In this paper, Blackwelder's approach is redefined in terms of the ratio of two means (RTrue=μet/μst) based on a continuous variate with higher values denoting greater improvement. The ratio‐based equivalents to Blackwelder's hypotheses will be shown. The ratio parameter has the benefit of being available as a dimensionless percentage, not tied to a specified difference in means. Thus, a study can be sized to assure, with high probability, that the experimental therapy is ‘at least’ (RLB×100) per cent ‘as effective as’ the standard therapy, where RLB is the selected lower bound on the percentage effectiveness. A practical rationale is given for defining non‐inferiority as a high fraction or percentage of the standard drug's efficacy, both in terms of statistical efficiency and medical relevance. For most typical ‘at least as good as’ applications (when RLB<RTrue ⩽1), the ratio formatted test of H0:RTrue⩽RLB is shown to be more efficient than Blackwelder's test of H0:μst ‐ μet ⩾ δBW, thereby requiring smaller sample sizes to detect the directionally based non‐null alternatives contained in H1:μet/μst>RLB or, equivalently, μst ‐ μet<δBW. Further, when RTrue= 1.0, tests of Blackwelder's hypotheses, their ratio‐based equivalents and conventional superiority can be evaluated for comparative efficiency. Testing H0:RTrue⩽RLB with single‐sided critical region of size α, versus H1:RTrue>RLB, is shown to be more efficient than excluding RLB from the lower limit of a 100(1–2α) per cent two‐sided symmetric confidence interval centred by R̂. Relevant examples will be presented. Copyright © 2003 John Wiley & Sons, Ltd.
Some fundamental issues with non‐inferiority testing in active controlled trials
Authors: James Hung H. M. , Wang Sue‐Jane , Tsong Yi , Lawrence John , O'Neil Robert T.
Published: January 2003

In an active controlled non‐inferiority trial without a placebo arm, it is often not entirely clear what the primary objective is. In many cases the considered goal is to demonstrate that the experimental treatment preserves at least some fraction of the effect of the active control. The active control effect is a parameter, the value of which is unknown. To test the hypothesis of effect preservation, the classical confidence interval approach requires specification of a non‐inferiority margin which is a function of the unknown active control effect. When the margin is estimated, it is also not clear what is the relevant type I error of making a false assertion about preservation of the active control effect. The statistical uncertainty of the estimated margin arguably needs to be incorporated in evaluation of the type I error. In this paper we discuss these fundamental issues. We show that the classical confidence interval approach cannot attain the target type I error exactly since this error varies as the sample size or as the values of the nuisance parameters in the active controlled trial change. In contrast, the preservation tests, as proposed in literature, can attain the target type I error rate exactly, regardless of the sample size and the values of the nuisance parameters, but can do so only at the price of several strong assumptions holding that may not be directly verifiable. One assumption is the constancy condition holding whereby the effect of the active control in the historical trial populations is assumed to carry to the population of the active control trial. When this condition is violated, both the confidence interval approach and the preservation test method may be problematic. Copyright © 2003 John Wiley & Sons, Ltd.
Rank‐based tests for non‐inferiority and equivalence hypotheses in multi‐centre clinical trials using mixed models
Authors: Rashid M.Mushfiqur
Published: January 2003

Rank‐based procedures for testing non‐inferiority and equivalence hypotheses for data (continuous) arising from multi‐centre clinical trials are developed using mixed models. The centres are presumed to be a random sample from the population of centres which might conceivably use the treatments under investigation, and the treatment effects are assumed to be fixed. It is assumed that there are no interactions between treatments and centres. Non‐inferiority and equivalence hypotheses are tested using rank (R) estimators. The R‐estimators are obtained by minimizing a combined dispersion function. The combined dispersion function is a sum of separate dispersion functions from each centre. Both the combined dispersion function and the centre‐specific dispersion functions are piecewise linear functions. As a result, the R‐estimates are expected to be less influenced by outliers. Large sample properties of the R‐estimators including efficiencies are developed. A small scale simulation study is conducted to compare the performances (empirical levels and powers) of the non‐parametric procedures and the normal theory based procedures. Published in 2003 by John Wiley & Sons, Ltd.