bluuebunny/crossref_metadata_2025 huggingface dataset:
AN OVERVIEW OF THE BLUEGENE/L SYSTEM SOFTWARE ORGANIZATION
Authors: ALMÁSI GEORGE , BELLOFATTO RALPH , BRUNHEROTO JOSÉ , CAŞCAVAL CĂLIN , CASTAÑOS JOSÉ G. , CRUMLEY PAUL , ERWAY C. CHRISTOPHER , LIEBER DEREK , MARTORELL XAVIER , MOREIRA JOSÉ E. , SAHOO RAMENDRA , SANOMIYA ALDA , CEZE LUIS , STRAUSS KARIN
Published: March 2004

BlueGene/L is a 65,536-compute node massively parallel supercomputer, built using system-on-a-chip integration and a cellular architecture. BlueGene/L represents a major challenge for parallel system software, particularly in the areas of scalability, maintainability, and usability. In this paper, we present the organization of the BlueGene/L system software, with emphasis on the features that address those challenges. The system software was developed in parallel with the hardware, relying on an architecturally accurate simulator of the machine. We validated this approach by demonstrating a working system software stack and high performance on real parallel applications just a few weeks after first hardware availability.
COST OPTIMALITY AND PREDICTABILITY OF PARALLEL PROGRAMMING WITH SKELETONS
Authors: BISCHOF HOLGER , GORLATCH SERGEI , KITZELMANN EMANUEL
Published: March 2004

Skeletons are reusable, parameterized program components with well-defined semantics and pre-packaged efficient parallel implementation. This paper develops a new, provably cost-optimal implementation of the DS (double-scan) skeleton for programming divide-and-conquer algorithms. Our implementation is based on a novel data structure called plist (pointed list); implementation's performance is estimated using an analytical model. We demonstrate the use of the DS skeleton for parallelizing a tridiagonal system solver and report experimental results for its MPI implementation on a Cray T3E and a Linux cluster: they confirm the performance improvement achieved by the cost-optimal implementation and demonstrate its good predictability by our performance model.
IMPROVING BANDWIDTH EFFICIENCY IN DISTRIBUTED VIDEO-ON-DEMAND ARCHITECTURES
Authors: CORES F. , RIPOLL A. , YANG X. Y. , QAZZAZ B. , SUPPI R. , HERNANDEZ P. , LUQUE E.
Published: March 2004

Distributed Video-on-Demand (DVoD) systems are proposed as a solution to the limited streaming capacity and null scalability of centralized systems. In a previous work, we proposed a fully distributed large-scale VoD architecture, called Double P-Tree, which has shown itself to be a good approach to the design of flexible and scalable DVoD systems. In this paper, we present relevant design aspects related to video mapping and traffic balancing in order to improve Double P-Tree architecture performance. Our simulation results demonstrate that these techniques yield a more efficient system and considerably increase its streaming capacity. The results also show the crucial importance of topology connectivity in improving multicasting performance in DVoD systems. Finally, a comparison among several DVoD architectures was performed using simulation, and the results show that the Double P-Tree architecture incorporating mapping and load balancing policies outperforms similar DVoD architectures.
A COMPARATIVE STUDY OF PROTOCOLS FOR EFFICIENT DATA PROPAGATION IN SMART DUST NETWORKS
Authors: CHATZIGIANNAKIS IOANNIS , DIMITRIOU TASSOS , MAVRONICOLAS MARIOS , NIKOLETSEAS SOTIRIS , SPIRAKIS PAUL
Published: March 2004

Smart Dust is comprised of a vast number of ultra-small fully autonomous computing and communication devices, with very restricted energy and computing capabilities, that co-operate to accomplish a large sensing task. Smart Dust can be very useful in practice i.e. in the local detection of a remote crucial event and the propagation of data reporting its realization to a control center. In this work, we have implemented and experimentally evaluated four protocols ( [Formula: see text], [Formula: see text] and two variations of [Formula: see text] which we here introduce ) for local detection and propagation in smart dust networks, under new, more general and realistic modelling assumptions. We comparatively study, by using extensive experiments, their behavior highlighting their relative advantages and disadvantages. All protocols are very successful. In the setting we considered here, [Formula: see text] seems to be faster while the [Formula: see text] based protocols are more energy efficient.
PARALLEL AGENT-BASED SIMULATION ON A CLUSTER OF WORKSTATIONS
Authors: Popov Konstantin , Rafea Mahmoud , Holmgren Fredrik , Brand Per , Vlassov Vladimir , Haridi Seif
Published: March 2004

We discuss a parallel implementation of an agent-based simulation. Our approach allows to adapt a sequential simulator for large-scale simulation on a cluster of workstations. We target discrete-time simulation models that capture the behavior of Web users and Web sites. Web users are connected with each other in a graph resembling the social network. Web sites are also connected in a similar graph. Users are stateful entities. At each time step, they exhibit certain behaviour such as visiting bookmarked sites, exchanging information about Web sites in the "word-of-mouth" style, and updating bookmarks. The real-world phenomena of emerged aggregated behavior of the Internet population is studied. The system distributes data among workstations, which allows large-scale simulations infeasible on a stand-alone computer. The model properties cause traffic between workstations proportional to partition sizes. Network latency is hidden by concurrent simulation of multiple users. The system is implemented in Mozart that provides multithreading, dataflow variables, component-based software development, and network-transparency. Currently we can simulate up to 106 Web users on 104 Web sites using a cluster of 16 computers, which takes few seconds per simulation step, and for a problem of the same size, parallel simulation offers speedups between 11 and 14.
TRIDIAGONAL SOLVERS WITH MULTIPLE RIGHT HAND SIDES ON k-DIMENSIONAL MESH AND TORUS INTERCONNECTION NETWORKS
Authors: SANTOS EUNICE E.
Published: March 2004

We consider the problem of designing optimal and efficient algorithms for solving tridiagonal linear systems with multiple right-hand side vectors on k-dimensional mesh and torus interconnection networks. We derive asymptotic upper and lower bounds for these solvers using odd-even cyclic reduction. We present various important bounds on execution time including general lower bounds which are independent of initial data assignment, and lower bounds based on classifying assignments via the proportion of initial data assigned amongst processors. Finally, different algorithms are designed in order to achieve running times that are within a small constant factor of the lower bounds provided.
PARALLEL ALGORITHMS FOR VEHICLE ROUTING PROBLEMS
Authors: GUPTA ARVIND , KRISHNAMURTI RAMESH
Published: March 2004

Vehicle routing problems involve the navigation of one or more vehicles through a network of locations. Locations have associated handling times as well as time windows during which they are active. The arcs connecting locations have time costs associated with them. In this paper, we consider two different problems in single vehicle routing. The first is to find least time cost routes between all pairs of nodes in a network for navigating vehicles; we call this the all pairs routing problem. We show that there is an O( log3n) time parallel algorithm using a polynomial number of processors for this problem on a CREW PRAM.

We next consider the problem in which a vehicle services all locations in a network. Here, locations can be passed through at any time but only serviced during their time window. The general problem is [Formula: see text] -complete under even fairly stringent restrictions but polynomial algorithms have been developed for some special cases. In particular, when the network is a line, there is no time cost in servicing a location, and all time windows are unbounded at either their lower or upper end, O(n2) algorithms have been developed. We show that under the same conditions, we can reduce this problem to the all pairs routing problem and therefore obtain an O( log3n) time parallel algorithm on a CREW PRAM.
PARALLEL SYNTENIC ALIGNMENTS
Authors: FUTAMURA NATSUHIKO , ALURU SRINIVAS , HUANG XIAOQIU
Published: March 2004

Given two genomic DNA sequences, the syntenic alignment problem is to compute an ordered list of subsequences for each sequence such that the corresponding subsequence pairs exhibit a high degree of similarity. Syntenic alignments are useful in comparing genomic DNA from related species and in identifying conserved genes. In this paper, we present a parallel algorithm for computing syntenic alignments that runs in [Formula: see text] time, where m and n are the respective lengths of the two genomic sequences, and p is the number of processors used. Our algorithm is time optimal with respect to the corresponding sequential algorithm and can use [Formula: see text] processors, where n is the length of the larger sequence. The space requirement of the algorithm is [Formula: see text] per processor. Using an implementation of this parallel algorithm, we report the alignment of a gene-rich region of human chromosome 12, namely 12p13 and its syntenic region in mouse chromosome 6 (both over 220,000 base pairs in length) in under 24 minutes on a 64-processor IBM xSeries cluster.
DEADLOCK-FREE ROUTING IN IRREGULAR NETWORKS USING PREFIX ROUTING
Authors: WU JIE , SHENG LI
Published: March 2004

We propose a deadlock-free routing scheme in irregular networks using prefix routing. Prefix routing is a special type of routing with a compact routing table associated with each node (processor). Basically, each outgoing channel of a node is assigned a special label and an outgoing channel is selected if its label is a prefix of the label of the destination node. Node and channel labeling in an irregular network is done through constructing a spanning tree. The routing process follows a two-phase process of going up and then down along the spanning tree, with a possible cross channel (shortcut) between two branches of the tree between two phases. We show that the proposed routing scheme is deadlock- and livelock-free. We also compare prefix routing with the existing up*/down* routing which has been widely used in irregular networks. Possible extensions are also discussed.
COMPLEXITY OF VERIFYING JAVA SHARED MEMORY EXECUTION
Authors: GONTMAKHER ALEX , POLYAKOV SERGEY , SCHUSTER ASSAF
Published: March 2004

This paper studies the problem of testing shared memory Java implementations to determine whether the memory behavior they provide is consistent. The complexity of the task is analyzed. The problem is defined as that of analyzing memory access traces. The study showed that the problem is NP-complete, both in the general case and in some particular cases in which the number of memory operations per thread, the number of write operations per variable, and the number of variables are restricted.
Sustainable Governance of Common-Pool Resources: Context, Methods, and Politics
Authors: Agrawal Arun
Published: March 2004

▪ Abstract  This paper presents a critical assessment of the field of common property. After discussing briefly the major findings and accomplishments of the scholarship on the commons, the paper pursues two strategies of critique. The first strategy of friendly critique accepts the basic assumptions of most writings on common property to show that scholars of commons have discovered far more variables that potentially affect resource management than is possible to analyze carefully. The paper identifies some potential means to address the problem of too many variables. The second line of critique proceeds differently. It asks how analyses of common property might change, and what they need to consider, if they loosen assumptions about sovereign selves and apolitical property rights institutions. My examination of these questions concludes this review with an emphasis on the need to (a) attend more carefully to processes of subject formation, and (b) investigate common property arrangements and associated subject positions with greater historical depth.
Context, Culture, and Structuration in the Languages of Australia
Authors: Evans Nicholas
Published: March 2004

▪ Abstract  Using Australian languages as examples, cultural selection is shown to shape linguistic structure through invisible hand processes that pattern the unintended outcomes (structures in the system of shared linguistic norms) of intentional actions (particular utterances by individual agents).

Examples of the emergence of culturally patterned structure through use are drawn from various levels: the semantics of the lexicon, grammaticalized kin-related categories, and culture-specific organizations of sociolinguistic diversity, such as moiety lects, “mother-in-law” registers, and triangular kin terms. These phenomena result from a complex of diachronic processes that adapt linguistic structures to culture-specific concepts and practices, such as ritualization and phonetic reduction of frequently used sequences, the input of shared cultural knowledge into pragmatic interpretation, semanticization of originally context-dependent inferences, and the input of linguistic ideologies into the systematization of lectal variants. Some of these processes, such as the emergence of subsection terminology and moiety lects, operate over speech communities that transcend any single language and can only be explained if the relevant processes take the multilingual speech community as their domain of operation.

Taken together, the cases considered here provide strong evidence against nativist assumptions that see linguistic structures simply as instantiations of biologically given “mentalese” concepts already present in the mind of every child and give evidence in favor of a view that sees individual language structures as also conditioned by historical processes, of which functional adaptation of various kinds is most important. They also illustrate how, in the domain of language, stable socially shared structures can emerge from the summed effects of many communicative micro-events by individual agents.
The Social Brain: Mind, Language, and Society in Evolutionary Perspective
Authors: Dunbar R.I.M.
Published: March 2004

▪ Abstract  The social brain (or Machiavellian Intelligence) hypothesis was proposed to explain primates' unusually large brains: It argues that the cognitive demands of living in complexly bonded social groups selected for increases in executive brain (principally neocortex). The evidence for this and alternative hypotheses is reviewed. Although there remain difficulties of interpretation, the bulk of the evidence comes down in favor of the social brain hypothesis. The extent to which the cognitive demands of bonding large intensely social groups involve aspects of social cognition, such as theory of mind, is explored. These findings are then related to the evolution of social group size, language, and culture within the hominid lineage.
Environmental Pollution in Urban Environments and Human Biology
Authors: Schell Lawrence M. , Denham Melinda
Published: March 2004

▪ Abstract  The biocultural approach of anthropologists is well suited to understand the interrelationship of urbanism and human biology. Urbanism is a social construction that has continuously changed and presented novel adaptive challenges to its residents. Urban living today involves several biological challenges, of which one is pollution. Using three different types of pollutants as examples, air pollution, lead, and noise, the impact of pollution on human biology (mortality, morbidity, reproduction, and development) can be seen. Chronic exposure to low levels of these pollutants has a small impact on the individual, but so many people are exposed to pollution that the effect species-wide is substantial. Also, disproportionate pollutant exposure by socioeconomically disadvantaged groups exacerbates risk of poor health and well being.
Maddening States
Authors: Aretxaga Begoña
Published: March 2004

▪ Abstract  Despite transformations in the character of the state in an age of globalization, news of its demise is certainly exaggerated. Even as operations of state (or state-like) power exceed the boundaries of the nation-state to be deployed by actors such as transnational nongovernmental organizations, private corporations, guerrilla groups, or narcotraffickers, the state form shows remarkable tenacity and adaptability. Invested with a kind of meta-capital, the state remains a crucial presence, a screen for political desires and identifications as well as fears. This review addresses recent academic reflection on the field of knowledge we call the state. It asks how the state becomes a social subject in everyday life, examining the subjective experience of state power and tracing its effects on territories, populations, and bodies. Finally, it considers the ways violence, sexuality, and desire work in the intimate spaces of state power.

Begoña Aretxaga's essay was left among her papers in an almost complete form at the time of her untimely death. A collective, consisting of James Brow, Charles Hale, Yael Navaro-Yahsin, Geeta Patel, Brandt Peterson, and Pauline Strong, worked to fill in citations, answer questions Begoña posed to herself, which were unresolved, and to lightly edit the final form of this essay. This piece has not been changed substantially. In an effort to keep to the form and spirit of Begoña's interrogations the essay stands as it was, without a literal conclusion. Perhaps a conclusion can be supplied by readers engaged in an ongoing analysis of contemporary political situations, to which Begoña's work speaks profoundly, as a legacy that this essay and her extended oeuvre bequeathed to us.
Anthropology, Inequality, and Disease: A Review
Authors: Nguyen Vinh-Kim , Peschard Karine
Published: March 2004

▪ Abstract  Anthropological approaches broaden and deepen our understanding of the finding that high levels of socioeconomic inequality correlate with worsened health outcomes across an entire society. Social scientists have debated whether such societies are unhealthy because of diminished social cohesion, psychobiological pathways, or the material environment. Anthropologists have questioned these mechanisms, emphasizing that fine-grained ethnographic studies reveal that social cohesion is locally and historically produced; psychobiological pathways involve complex, longitudinal biosocial dynamics suggesting causation cannot be viewed in purely biological terms; and material factors in health care need to be firmly situated within a broad geopolitical analysis. As a result, anthropological scholarship argues that this finding should be understood within a theoretical framework that avoids the pitfalls of methodological individualism, assumed universalism, and unidirectional causation. Rather, affliction must be understood as the embodiment of social hierarchy, a form of violence that for modern bodies is increasingly sublimated into differential disease rates and can be measured in terms of variances in morbidity and mortality between social groups. Ethnographies on the terrain of this neoliberal global health economy suggest that the violence of this inequality will continue to spiral as the exclusion of poorer societies from the global economy worsens their health—an illness poverty trap that, with few exceptions, has been greeted by a culture of indifference that is the hallmark of situations of extreme violence and terror. Studies of biocommodities and biomarkets index the processes by which those who are less well off trade in their long-term health for short-term gain, to the benefit of the long-term health of better-off individuals. Paradoxically, new biomedical technologies have served to heighten the commodification of the body, driving this trade in biological futures as well as organs and body parts.
The Anthropology of Welfare “Reform”: New Perspectives on U.S. Urban Poverty in the Post-Welfare Era
Authors: Morgen Sandra , Maskovsky Jeff
Published: March 2004

▪ Abstract  Anthropological research on welfare restructuring differs from most poverty research conducted by U.S. policy analysts and many other social scientists by its situating the study of welfare “reform” within an examination of the production of poverty and inequality at the center of the global system of advanced capitalism. In this review we examine urban poverty and welfare-state restructuring in relation to the ascent of neoliberalism, including the rise of market-oriented assumptions about social value, productivity, and investment that dominate civic life and public policy. We focus primarily, though not exclusively, on the United States. After a brief review of four theoretical frameworks that inform ethnographic research on welfare, we explore five approaches or themes in anthropological studies of welfare restructuring in the United States: (a) the ethnographic challenge to claims of policy success by documenting an unfolding crisis in social reproduction for the poor; (b) deconstructing the hegemonic discourse on welfare restructuring and juxtaposing it with the lived realities of impoverished households; (c) contesting and moving beyond the behaviorism of mainstream poverty research; (d) exploring the multiple perspectives of those differently situated within the welfare-state apparatus; and (e) theorizing the relationship between welfare restructuring and an eroding social citizenship of the poor. The analysis of gender, race, and, to a lesser extent, class is central to ethnographic research on welfare-state restructuring.
Complex Adaptive Systems
Authors: Lansing J. Stephen
Published: March 2004

▪ Abstract  The study of complex adaptive systems, a subset of nonlinear dynamical systems, has recently become a major focus of interdisciplinary research in the social and natural sciences. Nonlinear systems are ubiquitous; as mathematician Stanislaw Ulam observed, to speak of “nonlinear science” is like calling zoology the study of “nonelephant animals” (quoted in Campbell et al. 1985 , p. 374). The initial phase of research on nonlinear systems focused on deterministic chaos, but more recent studies have investigated the properties of self-organizing systems or anti-chaos. For mathematicians and physicists, the biggest surprise is that complexity lurks within extremely simple systems. For biologists, it is the idea that natural selection is not the sole source of order in the biological world. In the social sciences, it is suggested that emergence—the idea that complex global patterns with new properties can emerge from local interactions—could have a comparable impact.
Depletion of plasma membrane cholesterol dampens hydrostatic pressure and shear stress-induced mechanotransduction pathways in osteoblast cultures
Authors: Ferraro Jeffrey T. , Daneshmand Mani , Bizios Rena , Rizzo Victor
Published: March 2004

The preferential association of cholesterol and sphingolipids within plasma membranes forms organized compartments termed lipid rafts. Addition of caveolin proteins to this lipid milieu induces the formation of specialized invaginated plasma membrane structures called caveolae. Both lipid rafts and caveolae are purported to function in vesicular transport and cell signaling. We and others have shown that disassembly of rafts and caveolae through depletion of plasma membrane cholesterol mitigates mechanotransduction processes in endothelial cells. Because osteoblasts are subjected to fluid-mechanical forces, we hypothesize that cholesterol-rich plasma membrane microdomains also serve the mechanotransduction process in this cell type. Cultured human fetal osteoblasts were subjected to either sustained hydrostatic pressure or laminar shear stress using a pressure column or parallel-plate apparatus, respectively. We found that sustained hydrostatic pressure induced protein tyrosine phosphorylation, activation of extracellular signal-regulated kinase (ERK)1/2, and enhanced expression of c- fos in both time- and magnitude-dependent manners. Similar responses were observed in cells subjected to laminar shear stress. Both sustained hydrostatic pressure- and shear stress-induced signaling were significantly reduced in osteoblasts pre-exposed to either filipin or methyl-β-cyclodextrin. These mechanotransduction responses were restored on reconstitution of lipid rafts and caveolae, which suggests that cholesterol-rich plasma membrane microdomains participate in the mechanotransduction process in osteoblasts. In addition, mechanical force-induced phosphoproteins were localized within caveolin-containing membranes. These data support the concept that lipid rafts and caveolae serve a general function as cell surface mechanotransduction sites within the plasma membrane.
Modulation of epithelial tubule formation by Rho kinase
Authors: Eisen Randi , Ratcliffe Don R. , Ojakian George K.
Published: March 2004

We have developed a model system for studying integrin regulation of mammalian epithelial tubule formation. Application of collagen gel overlays to Madin-Darby canine kidney (MDCK) cells induced coordinated disassembly of junctional complexes that was accompanied by lamellipodia formation and cell rearrangement (termed epithelial remodeling). In this study, we present evidence that the Rho signal transduction pathway regulates epithelial remodeling and tubule formation. Incubation of MDCK cells with collagen gel overlays facilitated formation of migrating lamellipodia with membrane-associated actin. Inhibitors of myosin II and actin prevented lamellipodia formation, which suggests that actomyosin function was involved in regulation of epithelial remodeling. To determine this, changes in myosin II distribution, function, and phosphorylation were studied during epithelial tubule biogenesis. Myosin II colocalized with actin at the leading edge of lamellipodia thereby providing evidence that myosin is important in epithelial remodeling. This possibility is supported by observations that inhibition of Rho kinase, a regulator of myosin II function, alters formation of lamellipodia and results in attenuated epithelial tubule development. These data and those demonstrating myosin regulatory light-chain phosphorylation at the leading edge of lamellipodia strongly suggest that Rho kinase and myosin II are important modulators of epithelial remodeling. They support a hypothesis that the Rho signal transduction pathway plays a significant role in regulation of epithelial tubule formation.
Differential expression and targeting of endogenous Arf1 and Arf6 small GTPases in kidney epithelial cells in situ
Authors: El Annan Jaafar , Brown Dennis , Breton Sylvie , Bourgoin Sylvain , Ausiello Dennis A. , Marshansky Vladimir
Published: March 2004

ADP-ribosylation factors (Arfs) are small GTPases that regulate vesicular trafficking in exo- and endocytotic pathways. As a first step in understanding the role of Arfs in renal physiology, immunocytochemistry and Western blotting were performed to characterize the expression and targeting of Arf1 and Arf6 in epithelial cells in situ. Arf1 and Arf6 were associated with apical membranes and subapical vesicles in proximal tubules, where they colocalized with megalin. Arf1 was also apically expressed in the distal tubule, connecting segment, and collecting duct (CD). Arf1 was abundant in intercalated cells (IC) and colocalized with V-ATPase in A-IC (apical) and B-IC (apical and/or basolateral). In contrast, Arf6 was associated exclusively with basolateral membranes and vesicles in the CD. In the medulla, basolateral Arf6 was detectable mainly in A-IC. Expression in principal cells became weaker throughout the outer medulla, and Arf6 was not detectable in principal cells in the inner medulla. In some kidney epithelial cells Arf1 but not Arf6 was also targeted to a perinuclear patch, where it colocalized with TGN38, a marker of the trans-Golgi network. Quantitative Western blotting showed that expression of endogenous Arf1 was 26–180 times higher than Arf6. These data indicate that Arf GTPases are expressed and targeted in a cell- and membrane-specific pattern in kidney epithelial cells in situ. The results provide a framework on which to base and interpret future studies on the role of Arf GTPases in the multitude of cellular trafficking events that occur in renal tubular epithelial cells.
Changes in cellular composition of kidney collecting duct cells in rats with lithium-induced NDI
Authors: Christensen Birgitte Mønster , Marples David , Kim Young-Hee , Wang Weidong , Frøkiær Jørgen , Nielsen Søren
Published: March 2004

Lithium treatment for 4 wk caused severe polyuria, dramatic downregulation in aquaporin-2 (AQP-2) expression, and marked decrease in AQP-2 immunoreactivity with the appearance of a large number of cells without AQP-2 labeling in the collecting ducts after lithium treatment. Surprisingly, this was not all due to an increase in AQP-2-negative principal cells, because double immunolabeling revealed that the majority of the AQP-2-negative cells displayed [H+]ATPase labeling, which identified them as intercalated cells. Moreover, multiple [H+]ATPase-labeled cells were adjacent, which was never seen in control rats. Quantitation confirmed a significant decrease in the fraction of collecting duct cells that exhibited detectable AQP-2 labeling compared with control rats: in cortical collecting ducts, 40 ± 3.4 vs. 62 ± 1.8% of controls ( P < 0.05; n = 4) and in inner medullary collecting ducts, 58 ± 1.6 vs. 81 ± 1.3% of controls ( P < 0.05; n = 4). In parallel, a significant increase in the fraction of intercalated ([H+]ATPase-positive) cells was shown. Urine output, whole kidney AQP-2 expression, cellular organization, and the fractions of principal and intercalated cells in cortex and inner medulla returned to control levels after 4 wk on a lithium-free diet following 4 wk on a lithium-containing diet. In conclusion, lithium treatment not only decreased AQP-2 expression, but dramatically and reversibly reduced the fraction of principal cells and altered the cellular organization in collecting ducts. These effects are likely to be important in lithium-induced nephrogenic diabetes insipidus.
Caffeine sensitivity of native RyR channels from normal and malignant hyperthermic pigs: effects of a DHPR II–III loop peptide
Authors: Gallant Esther M. , Hart James , Eager Kevin , Curtis Suzanne , Dulhunty Angela F.
Published: March 2004

Enhanced sensitivity to caffeine is part of the standard tests for susceptibility to malignant hyperthermia (MH) in humans and pigs. The caffeine sensitivity of skeletal muscle contraction and Ca2+ release from the sarcoplasmic reticulum is enhanced, but surprisingly, the caffeine sensitivity of purified porcine ryanodine receptor Ca2+-release channels (RyRs) is not affected by the MH mutation (Arg615Cys). In contrast, we show here that native malignant hyperthermic pig RyRs (incorporated into lipid bilayers with RyR-associated lipids and proteins) were activated by caffeine at 100- to 1,000-fold lower concentrations than native normal pig RyRs. In addition, the results show that the mutant ryanodine receptor channels were less sensitive to high-affinity activation by a peptide (CS) that corresponds to a part of the II–III loop of the skeletal dihydropyridine receptor (DHPR). Furthermore, subactivating concentrations of peptide CS enhanced the response of normal pig and rabbit RyRs to caffeine. In contrast, the caffeine sensitivity of MH RyRs was not enhanced by the peptide. These novel results showed that in MH-susceptible pig muscles 1) the caffeine sensitivity of native RyRs was enhanced, 2) the sensitivity of RyRs to a skeletal II–III loop peptide was depressed, and 3) an interaction between the caffeine and peptide CS activation mechanisms seen in normal RyRs was lost.
Progressive dysregulation of transcription factors NF-κB and STAT1 in prostate cancer cells causes proangiogenic production of CXC chemokines
Authors: Shen Hui , Lentsch Alex B.
Published: March 2004

The CXC chemokine family includes members that possess angiogenic and angiostatic properties. Angiogenic CXC chemokines are produced by prostate cancer cells and contribute to prostate tumor growth. Production of angiostatic CXC chemokines by prostatic cells has not been previously studied. Here we show that normal prostate epithelial (PZ-HPV-7) cells produce low amounts of angiogenic CXC chemokines, whereas prostate cancer cells from primary (CA-HPV-10) and metastatic (PC-3) tumors produce progressively greater amounts. These effects were caused by progressive increases in activation of the transcription factor nuclear factor-κB in prostate cancer cells. Conversely, PZ-HPV-7 cells produced relatively high levels of angiostatic CXC chemokines, whereas CA-HPV-10 and PC-3 cells produced stepwise lower amounts. These effects were dependent on reduced activation of signal transduction and activator of transcription 1 (STAT1) in prostate cancer cells. These data suggest that there is progressive dysregulation of nuclear factor-κB and STAT1 in prostate cancer cells that leads to proangiogenic production of CXC chemokines.
Cytokine function of heat shock proteins
Authors: Tsan Min-Fu , Gao Baochong
Published: March 2004

Extensive work in the last 10 years has suggested that heat shock proteins (HSPs) may be potent activators of the innate immune system. It has been reported that Hsp60, Hsp70, Hsp90, and gp96 are capable of inducing the production of proinflammatory cytokines by the monocyte-macrophage system and the activation and maturation of dendritic cells (antigen-presenting cells) in a manner similar to the effects of lipopolysaccharide (LPS) and bacterial lipoprotein, e.g., via CD14/Toll-like receptor2 (TLR2) and CD14/TLR4 receptor complex-mediated signal transduction pathways. However, recent evidence suggests that the reported cytokine effects of HSPs may be due to the contaminating LPS and LPS-associated molecules. The reasons for previous failure to recognize the contaminant(s) as being responsible for the reported HSP cytokine effects include failure to use highly purified, low-LPS preparations of HSPs; failure to recognize the heat sensitivity of LPS; and failure to consider contaminant(s) other than LPS. Thus it is essential that efforts should be directed to conclusively determine whether the reported HSP cytokine effects are due to HSPs or to contaminant(s) present in the HSP preparations before further exploring the implication and therapeutic potential of the putative cytokine function of HSPs.
Angiotensin II-induced MMP-2 release from endothelial cells is mediated by TNF-α
Authors: Arenas Ivan A. , Xu Yi , Lopez-Jaramillo Patricio , Davidge Sandra T.
Published: March 2004

Angiotensin II (ANG II) has been etiologically linked to vascular disease; however, its role in the alterations of endothelial function that occur in vascular disorders is not completely understood. Matrix metalloproteinases (MMPs) and proinflammatory cytokines are involved in the pathological remodeling of blood vessels that occurs in vascular disease. In this study we evaluated the effects of ANG II on tumor necrosis factor (TNF)-α and MMP-2 production in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were stimulated with ANG II (0.1–10 μM) for 24 h, in the presence or absence of antagonists of ANG II type 1 (AT1R) and type 2 (AT2R) receptors, and the production and release of TNF-α and MMP-2 were assessed. ANG II increased TNF-α mRNA and protein expression and the release of bioactive TNF-α. Moreover, ANG II induced MMP-2 release and reduced the secretion of tissue inhibitor of MMP (TIMP)-2 from endothelial cells. To elucidate whether endogenous TNF-α could mediate the effects of ANG II on MMP-2 release, cells were pretreated with anti-TNF-α neutralizing antibodies or pentoxifylline (an inhibitor of TNF-α synthesis). TNF-α inhibition prevented the secretion of MMP-2 induced by ANG II. Furthermore, AT1R antagonism with candesartan prevented the formation of MMP-2 and TNF-α and the reduction of TIMP-2 induced by ANG II. These results indicate that ANG II, via AT1R, modulates the secretion of TNF-α and MMP-2 from endothelial cells and that TNF-α mediates the effects of ANG II on MMP-2 release.
Role for ICAT in β-catenin-dependent nuclear signaling and cadherin functions
Authors: Gottardi Cara J. , Gumbiner Barry M.
Published: March 2004

Inhibitor of β-catenin and TCF-4 (ICAT) is a 9-kDa polypeptide that inhibits β-catenin nuclear signaling by binding β-catenin and competing its interaction with the transcription factor TCF (T cell factor), but basic characterization of the endogenous protein and degree to which it alters other β-catenin functions is less well understood. At the subcellular level, we show that ICAT localizes to both cytoplasmic and nuclear compartments. In intestinal tissue, ICAT is upregulated in the mature, nondividing enterocyte population lining intestinal villi and is absent in the β-catenin/TCF signaling-active crypt region, suggesting that its protein levels may be inversely related with β-catenin signaling activity. However, ICAT protein levels are not altered by activation or inhibition of Wnt signaling in cultured cells, suggesting that ICAT expression is not a direct target of the Wnt/β-catenin pathway. In cells where β-catenin levels are elevated by Wnt, a fraction of this β-catenin pool is associated with ICAT, suggesting that ICAT may buffer the cell from increased levels of β-catenin. Distinct from TCF and cadherin, ICAT does not protect the soluble pool of β-catenin from degradation by the adenomatous polyposis coli containing “destruction complex.” Although ICAT inhibits β-catenin binding to the cadherin as well as TCF in vitro, stable overexpression of ICAT in Madin-Darby canine kidney (MDCK) epithelial cells shows no obvious alterations in the cadherin complex, suggesting that the ability of ICAT to inhibit β-catenin binding to the cadherin may be restricted in vivo. MDCK cells overexpressing ICAT do, however, exhibit enhanced cell scattering on hepatocyte growth factor treatment, suggesting a possible role in the regulation of dynamic rather than steady-state cell-cell adhesions. These findings confirm ICAT's primary role in β-catenin signaling inhibition and further suggest that ICAT may have consequences for cadherin-based adhesive function in certain circumstances, implying a broader role than previously described.
Contribution of PKC-dependent and -independent processes in temporal ERK regulation by ET-1, PDGF, and EGF in rat myometrial cells
Authors: Robin Philippe , Boulven Isaline , Bôle-Feysot Christine , Tanfin Zahra , Leiber Denis
Published: March 2004

Endothelin-1 (ET-1), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF) stimulated thymidine incorporation with different efficiency (PDGF ≫ EGF = ET-1) in rat myometrial cells. They also stimulated ERK activation, which culminated at 5 min and then declined to reach a plateau (at 45 min: EGF > 90%, PDGF = 50%, and ET-1 < 10% of maximum). Inhibition and downregulation of PKC demonstrated that ERK activation at 5 min involved PKCδ and -ζ for ET-1 and PKCα plus another PKC isoform for PDGF. By contrast, the EGF response did not involve PKC. Stimulation of Ras was more important with EGF than with PDGF, with ET-1 being the weakest activator. The simultaneous incubation of the cells with EGF and ET-1 potentiated the ERK activation at 5 min and mimicked the plateau phase obtained with PDGF. Under these conditions thymidine incorporation was comparable to that induced by PDGF. Taken together, our results indicated that the kinetic profile of ERK activation and its impact on cell proliferation can be modulated by the differential involvement of PKC isoforms and the amplitude of Ras activation.
Induction of early growth-response factor 1 by platelet-derived growth factor in human airway smooth muscle
Authors: Hjoberg Josephine , Le Louis , Imrich Amy , Subramaniam Venkat , Mathew Sheeba I. , Vallone Joseph , Haley Kathleen J. , Green Francis H. Y. , Shore Stephanie A. , Silverman Eric S.
Published: March 2004

Platelet-derived growth factors (PDGF) may contribute to the activation and growth of smooth muscle that is characteristic of airway remodeling in asthmatic patients. Early growth response 1 (EGR-1) is a transcription factor that is induced in several cell types by PDGF and may mediate some of the effects of PDGF. We show that human airway smooth muscle cells in cell culture express EGR-1 ∼1 h after addition of PDGF. Analysis of the EGR-1 promoter indicates that a serum response element located between 663 and 654 bp 5′ to the ATG start site is essential for this induction. Serum response factor, E26 transcription factor-like protein 1, and serum protein 1 bind to this region. PDGF causes phosphorylation of ERK1/2 and is temporally associated with E26 transcription factor-like protein 1 phosphorylation. Finally, the specific ERK1/2 inhibitor U-0126 abolishes PDGF-induced expression of EGR-1 in these cells. On the basis of these data, we speculated that EGR-1 would be increased in airway smooth muscle of asthmatic patients compared with nonasthmatic controls. Using immunohistochemistry, we found that EGR-1 protein was expressed in airway smooth muscle cells and epithelial cells of asthmatic patients and nonasthmatic controls; however, there was no significant difference in the intensity of staining between groups. EGR-1 was similarly expressed in the lungs of mice with and without ovalbumin-induced airway inflammation; however, there was no difference between groups by immunohistochemistry and quantitative PCR. Although EGR-1 is induced by PDGF in human airway smooth muscle cells in cell culture, the role of EGR-1 in airway remodeling and asthma remains to be established.
Delivery of CFTR by adenoviral vector to cystic fibrosis mouse lung in a model of chronicPseudomonas aeruginosalung infection
Authors: van Heeckeren Anna M. , Scaria Abraham , Schluchter Mark D. , Ferkol Thomas W. , Wadsworth Samuel , Davis Pamela B.
Published: March 2004

In cystic fibrosis (CF) there is an excessive inflammatory response to lung infections with Pseudomonas aeruginosa, which causes significant morbidity and mortality. Mice deficient in the cystic fibrosis conductance transmembrane regulator homolog ( Cftr) have exaggerated production of proinflammatory cytokines in epithelial lining fluid and increased mortality in response to chronic bronchopulmonary infection with mucoid P. aeruginosa, compared with infected wild-type littermates. Whether delivery of CFTR to CF airways by an adenoviral vector (Ad2/CFTR-16) decreases cytokine production and mortality in response to chronic bronchopulmonary infection with mucoid P. aeruginosa was tested. CF mice [stock Cftrtm1Unc-TgN(FABPCFTR)#Jaw] were anesthetized with isoflurane and inoculated intranasally with either Ad2/CFTR-16, diluent (sucrose), or empty vector (Ad2/EV). Two weeks later, mice were anesthetized with 2.5% Avertin and inoculated transtracheally with P. aeruginosa-laden agarose beads (PA M57–15). The cumulative 10-day survival of mice pretreated with Ad2/CFTR-16 was significantly higher compared with mice pretreated with sucrose but not significantly higher than mice pretreated with Ad2/EV. After adjusting for differences in experiment, we found weight loss at 3 days for mice treated with Ad2/CFTR-16 to be significantly less than for the sucrose- or Ad2/EV-treated groups. However, cytokine responses were similar in all groups 3 days after infection. In conclusion, the observed survival advantage of adenoviral delivery of CFTR to the CF lung may be due either to CFTR expression or possibly to proinflammatory effects of the adenoviral vector, or both.
Role of cGMP-dependent protein kinase in development of tolerance to nitric oxide in pulmonary veins of newborn lambs
Authors: Gao Yuansheng , Dhanakoti Srinivas , Trevino Earleen M. , Wang Xiaohua , Sander Fred C. , Portugal Ada D. , Raj J. Usha
Published: March 2004

Continuous exposure to nitrovasodilators and nitric oxide induces tolerance to their vasodilator effects in vascular smooth muscle. This study was done to determine the role of cGMP-dependent protein kinase (PKG) in the development of tolerance to nitric oxide. Isolated fourth-generation pulmonary veins of newborn lambs were studied. Incubation of veins for 20 h with DETA NONOate (DETA NO; a stable nitric oxide donor) significantly reduced their relaxation response to the nitric oxide donor and to β-phenyl-1, N2-etheno-8-bromo-cGMP (8-Br-PET-cGMP, a cell-permeable cGMP analog). Incubation with DETA NO significantly reduced PKG activity and protein and mRNA levels in the vessels. These effects were prevented by 1H-(1,2,4)oxadiazolo(4,3- a)quinoxalin-1-one (an inhibitor of soluble guanylyl cyclase) and Rp-8-Br-PET-cGMPS (an inhibitor of PKG). A decrease in PKG protein and mRNA levels was also observed after continuous exposure to cGMP analogs. The PKG inhibitor abrogated these effects. The decrease in cGMP-mediated relaxation and in PKG activity caused by continuous exposure to DETA NO was not affected by KT-5720, an inhibitor of cAMP-dependent protein kinase. Prolonged exposure to 8-Br-cAMP (a cell-permeable cAMP analog) did not affect PKG protein level in the veins. These results suggest that continuous exposure to nitric oxide or cGMP downregulates PKG by a PKG-dependent mechanism. Such a negative feedback mechanism may contribute to the development of tolerance to nitric oxide in pulmonary veins of newborn lambs.
Adaptation of the myoglobin knockout mouse to hypoxic stress
Authors: Schlieper Georg , Kim Jie-Hoon , Molojavyi Andrei , Jacoby Christoph , Laussmann Tim , Flögel Ulrich , Gödecke Axel , Schrader Jürgen
Published: March 2004

Myoglobin knockout (myo-/-) mice were previously reported to show no obvious phenotype but revealed several compensatory mechanisms that include increases in cardiac capillary density, coronary flow, and hemoglobin. The aim of this study was to investigate whether severe hypoxic stress can exhaust these compensatory mechanisms and whether this can be monitored on the gene and protein level. Myo-/- and wild-type (WT) mice were exposed to hypoxia (10% O2) for 2 wk. Thereafter hemodynamic parameters were investigated by invasive measurement combined with magnetic resonance imaging. Cardiac gene and protein expression were analyzed using cDNA arrays and two-dimensional gel electrophoresis plus mass spectrometry, respectively. Hematocrit levels increased from 44% (WT) and 48% (myo-/-) to 72% in both groups. Similar to WT controls, hypoxic myo-/- animals maintained stable cardiovascular function (mean arterial blood pressure 82.4 mmHg, ejection fraction 72.5%). Cardiac gene expression of hypoxic myo-/- mice differed significantly from WT controls in 17 genes (e.g., keratinocyte lipid binding protein +202%, cytochrome c oxidase Vb +41%). Interestingly, hypoxia inducible factor-1α remained unchanged in both groups. Proteome analysis revealed reduced levels of heart fatty acid-binding protein and heat shock protein 27 both in hypoxic myo-/- and WT mice. Our data thus demonstrate that myo-/- mice do not decompensate during hypoxic stress but are surprisingly well adapted. Changes in energy metabolism of fatty acids may contribute to the robustness of myoglobin-deficient mice.