bluuebunny/crossref_metadata_2025 huggingface dataset:
THERMODYNAMICS OF LOW-DENSITY ELECTRON GAS ON HIGHLY DISORDERED ONE-DIMENSIONAL HOST LATTICE
Authors: SLAVIN V. , SLUTSKIN A.
Published: November 2004

The low-temperature thermodynamics of a one-dimensional electron gas on a disordered lattice, which comes to existence when the inter-electron distances exceed noticeably the inter-site ones, has been studied. An efficient computer procedure, based on the presentation of the partition function as a product of random transfer-matrixes, has been developed for calculations of thermodynamic characteristics of the system under consideration. The lattice structures were varied from completely chaotic up to the strictly regular one. It has been established that for any degree of disorder the entropy and heat capacity of the system tend to zero linearly as the temperature is reduced. The conclusion about the gapless character of the elementary excitations spectrum has been made. An instability of one-dimensional electron gas on a disordered lattice has been revealed: under conditions of vanishingly small disordering of the lattice, the long-range order in the systems under consideration is broken by frustrations that are one-dimensional analogues of the frustrations in two- and three-dimensional spin glasses.
A FINITE STATE COMMA TAGGER
Authors: VAN DELDEN SEBASTIAN , GOMEZ FERNANDO
Published: November 2004

A method has been developed and implemented that assigns syntactic roles to commas. Text that has been tagged using a part-of-speech tagger serves as the input to the system. A set of Finite State Automata first assigns temporary syntactic roles to each comma in the sentence. A greedy learning algorithm is then used to determine the final syntactic roles of the commas. The system requires no training and is not domain specific. The performance of the system on numerous corpora is given and compared against a rule-based approach.
A LOGIC BASED APPROACH TO PLANNING FOR SPECIFYING A CLASS OF TEMPORALLY EXTENDED GOALS
Authors: NIYOGI RAJDEEP
Published: November 2004

Planning with temporally extended goals has recently been the focus of much attention to researchers in the planning community. We study a class of planning goals where in addition to a main goal there exist other goals, which we call auxiliary goals, that act as constraints to the main goal. Both these type of goals can, in general, be a temporally extended goal. Linear temporal logic (LTL) is inadequate for specification of the overall goals of this type, although, for some situations, it is capable of expressing them separately. A branching-time temporal logic, like CTL, on the other hand, can be used for specifying these goals. However, we are interested in situations where an auxiliary goal has to be satisfiable within a fixed bound. We show that CTL becomes inadequate for capturing these situations. We bring out an existing logic, called min-max CTL, and show how it can effectively be used for the planning purpose. We give a logical framework for expressing the overall planning goals. We propose a sound and complete planning procedure that incorporates a model checking technology. Doing so, we can answer such planning queries as plan existence at the onset besides producing an optimal plan (if any) in polynomial time.
CREATING A NEW SERVICE ON THE WEB
Authors: YAMAGUCHI HIROSHI , HUSHINO YUKIO , SUZUKI KENJI , RAMAMOORTHY CHITTOOR V.
Published: November 2004

Service functions are major component of every industry. The evolution of service functions have seen manually intensive tasks being replaced by a combination of mental and interactive tasks. As a part of this transformation, we have seen an increasing dependency on the high technology, actually information technology, mostly with computer-communications and the web. This high technology will finally replace the service functions by a combination of knowledge intensive, interactive and customer's individual tasks in the future. However, these knowledge intensive, interactive and customer's individual service functions could be enjoyable for the restricted person, due to the difficulties of the man (customers)-machine (PCs, web-server machines) interface and also the service providers are not able to obtain much more customer's individual and abstruse information for providing the customer's individual services, due to the customers' privacy problem. In this paper we focus on of knowledge intensive, interactive and customer's individual services in the future. We emphasize the importance of developing the mechanism of humanization for making these services enjoyable for anyone and the personalization for enjoyable the more individual services, and show some examples for these mechanisms in which humanization is realized by humanoid robots and personalization is realized by customers' privacy preserving scheme. We present a feedback system including the mechanism for humanization and personalization. By performing this feedback system, anyone who is not familiar to machines, can interact with machines like human-beings and can poll or report even though privacy related information anonymously to service providers. By periodically performing this feedback system, the customers' knowledge, information, suggestions and ideas can could be accumulated and the service providers could provide more individual services to customers, Once humanization and personalization mechanism are developed, by performing our feedback systems, we enhance customers' convenience and reduce the incidence of operation errors and thereby improve their productivity and quality of their life.
INCREMENTAL COORDINATION FOR TIME-BOUNDED AGENTS
Authors: MOUADDIB ABDEL-ILLAH
Published: November 2004

We address in this paper a problem of autonomous agents performing in a common environment where each agent has a goal to achieve before a given deadline. Each agent must determine a local plan and then react properly to the local plans of other agents before a given deadline. The solution presented consists in using progressive planning that adapts the detail of local plans according to local deadlines, and progressive negotiation that organizes conflicts between local plans into categories and solves them progressively from a mandatory category to an optional one. This structuration of conflicts in categories contributes in solving first, the most important conflicts in order to guarantee, when it is possible, the coordination of the mandatory part of the plan before the deadline. Our negotiation model is based on the modified PGP (Partial Global Planning) approach, named Partial Global Progressive Planning (PGPP), which is an incremental strategy to insert partial local plans progressively one by one. This strategy consists in discarding optional partial local plans of an agent when a deadline is exceeded or global consistency is violated. We show that this approach reduces the costs of detecting and solving conflicts. This approach can be seen as a step towards the application of contract-net type systems to real-world problems.
EIKONES — A LANGUAGE FOR IMAGE PROCESSING-ANALYSIS-PATTERN RECOGNITION
Authors: BOURBAKIS NIKOLAOS G. , ANDEL RICHARD
Published: November 2004

This paper presents a language for image processing-analysis called ElKONES. The language grammar is derived from the C language with extensions for efficient and flexible image processing. The EIKONES language provides to the user flexibility and friendliness for image processing which are not available in other image processing tools or conventional languages or function libraries. The basic idea behind EIKONES, is the consideration of the image processing algorithms as objects and the appropriate development of a formal grammar for its actual implementation. EIKONES provides a high level language for image processing with features such as learning capability, statistical and region analysis, object tracking. The way in which image operations are specified facilitates a natural language interface for use in a voice-activated system because multiple image operations are mapped to a single image word.
A METHODOLOGY FOR SCALING UP CLASSIFICATION ALGORITHMS
Authors: BOUTSINAS BASILIS , PRASSAS GEORGE , ANTZOULATOS GERASIMOS
Published: November 2004

Contrary to much of the research in machine learning where there is a concentration on problems with relatively small volume of data, one of the main challenges of the today's data mining systems is their ability to handle data that is substantially larger than available main memory on a single processor. In this paper, we present a distributed technique that consists in combining the partial results of different classifiers supplied, in parallel, with different subsets of data. It is, actually, a two-phase process. At first, a number of classifiers are trained, each with a different subset of the data. Then, the trained classifiers are used in the construction of a new training data set which has exactly the same format as, but is substantially smaller than, the initial one. The new data set is used to train the final classifier through an iterative process, which is guided by a threshold concerning the size of the data set and the achieved increase in accuracy. We present extensive empirical tests, which demonstrate that the proposed technique significantly reduces time complexity, usually at the expense of a lower accuracy, compared to a single classifier supplied with all the data.
AN EFFECTIVE NEURAL MODEL MECHANIZING HARD CAUSAL REASONING PROBLEMS WITH WTA and WTO NEURAL COMPUTATIONS
Authors: ROMDHANE LOTFI BEN , AYEB BECHIR
Published: November 2004

In this work, we develop a neural model to solve causal reasoning problems (said also abduction) in the open, independent and incompatibility classes. We model the reasoning process by a single and global energy function using cooperative and competitive neural computation. The update rules of the distinct connections of the network are derived from its energy function using gradient descent techniques. Simulation results reveal a good performance of the model.
MULTIMEDIA EXPERT SYSTEM FOR A NUCLEAR POWER PLANT ACCIDENT DIAGNOSIS USING A FUZZY INFERENCE METHOD
Authors: LEE MAL-REY , KANG HEAI-JO , KIM TAE EUN
Published: November 2004

The huge and complicated plants such as nuclear power stations are likely to cause the operators to make mistakes due to a variety of inexplicable reasons and symptoms in case of emergency. That's why the prevention system assisting the operators is being developed for. First of all, I suggest an improved fuzzy diagnosis. Secondly, I want to demonstrate that a classification system of nuclear plant's accident investigating the causes of accidents foresees possible problems, and maintains the reliability of the diagnostic reports in spite of improper working in part.

In the event of emergency in a nuclear plant, a lot of operational steps enable the operators to find out what caused the problems based on an emergent operating plan. Our system is able to classify their types within twenty to thirty seconds. As so, we expect the system to put down the accidents right after the rapid detection of the damage control-method concerned.
INVENTORY HEDGING AND OPTION MARKET MAKING
Authors: GIANNETTI ANTOINE , ZHONG RUI , WU LIXIN
Published: November 2004

In this paper, we develop an inventory-based approach to analyze the option market making activity. Indeed, we formulate and analytically solve the price-setting problem of a monopolistic option market maker facing exogenous public supply and demand first on a single exercise price (the "single option economy") and next on multiple exercise prices (the "multi-options economy"). While in the "single option economy" the familiar result that market maker inventory and price level are inversely related holds, the same is not necessarily true in the "multi-options economy". Additionally, we examine under which theoretical condition hedging is totally effective (i.e., the variance of the market maker hedged position is zero). Last but not least, our model is fully consistent with actual option market making practices, which consist in trading hedge portfolios to reduce risk. As such, our approach can be considered as a bridge between market microstructure and standard option pricing literature.
OPTIMAL STRATEGIES FOR THE ISSUANCES OF PUBLIC DEBT SECURITIES
Authors: ADAMO MASSIMILIANO , AMADORI ANNA LISA , BERNASCHI MASSIMO , CHIOMA CLAUDIA LA , MARIGO ALESSIA , PICCOLI BENEDETTO , SBARAGLIA SIMONE , UBOLDI ADAMO , VERGNI DAVIDE , FABBRI PAOLA , IACOVONI DAVIDE , NATALE FRANCESCO , SCALERA STEFANO , SPILOTRO LUCIA , VALLETTA ANTONELLA
Published: November 2004

We describe a model for the optimization of the issuances of Public Debt securities developed together with the Italian Ministry of Economy and Finance. The goal is to determine the composition of the portfolio issued every month which minimizes a specific "cost function". Mathematically speaking, this is a stochastic optimal control problem with strong constraints imposed by national regulations and the Maastricht treaty. The stochastic component of the problem is represented by the evolution of interest rates. At this time the optimizer employs classic Linear Programming techniques. However more sophisticated techniques based on Model Predictive Control strategies are under development.
BALAYAGE MONOTONOUS RISK MEASURES
Authors: LEITNER JOHANNES
Published: November 2004

We consider coherent risk measures satisfying the Fatou property which are monotonous with respect to balayage or dilatation. An equivalent condition ensuring balayage-monotonicity is given and a representation result is derived.
Vertebrate Dispersal of Seed Plants Through Time
Authors: Tiffney Bruce H.
Published: November 2004

▪ Abstract  Vertebrate dispersal of fruits and seeds is a common feature of many modern angiosperms and gymnosperms, yet the evolution and frequency of this feature in the fossil record remain unclear. Increasingly complex information suggests that (a) plants had the necessary morphological features for vertebrate dispersal by the Pennsylvanian, but possibly in the absence of clear vertebrate dispersal agents; (b) vertebrate herbivores first diversified in the Permian, and consistent dispersal relationships became possible; (c) the Mesozoic was dominated by large herbivorous dinosaurs, possible sources of diffuse, whole-plant dispersal; (d) simultaneously, several groups of small vertebrates, including lizards and, in the later Mesozoic, birds and mammals, could have established more specific vertebrate-plant associations, but supporting evidence is rudimentary; and (e) the diversification of small mammals and birds in the Tertiary established a consistent basis for organ-level interactions, allowing for the widespread occurrence of biotic dispersal in gymnosperms and angiosperms.
Bird Song: The Interface of Evolution and Mechanism
Authors: Podos Jeffrey , Huber Sarah K. , Taft Benjamin
Published: November 2004

▪ Abstract  Bird song provides an unusually impressive illustration of vertebrate behavioral diversification. Research on bird song evolution traditionally focuses on factors that enhance song diversity, such as cultural transmission and sexual selection. Recent advances in the study of proximate mechanisms of vocal behavior, however, provide opportunities for studying mechanistic constraints on song evolution. The main goal of this review is to examine, from both conceptual and empirical perspectives, how proximate mechanisms might temper patterns of song evolution. We provide an overview of the two “substrates” of song evolution, memes and vocal mechanisms. We argue that properties of vocal mechanisms (control, production, and ontogeny) constrain vocal potential and may thus limit pathways of meme evolution. We then consider how vocal mechanisms may constrain song evolution under five scenarios of drift and selection and examine four specific song traits for which mechanistic constraints appear to counter the diversifying effects of sexual selection. These examples illustrate the interplay between meme evolution as a diversifying influence and proximate limitations as a barrier to song divergence. We conclude by suggesting that vocal mechanisms not only constrain song evolution but also can facilitate the evolution of novel vocal features.
Evolutionary Trajectories and Biogeochemical Impacts of Marine Eukaryotic Phytoplankton
Authors: Katz Miriam E. , Finkel Zoe V. , Grzebyk Daniel , Knoll Andrew H. , Falkowski Paul G.
Published: November 2004

▪ Abstract  The evolutionary succession of marine photoautotrophs began with the origin of photosynthesis in the Archean Eon, perhaps as early as 3.8 billion years ago. Since that time, Earth's atmosphere, continents, and oceans have undergone substantial cyclic and secular physical, chemical, and biological changes that selected for different phytoplankton taxa. Early in the history of eukaryotic algae, between 1.6 and 1.2 billion years ago, an evolutionary schism gave rise to “green” (chlorophyll b–containing) and “red” (chlorophyll c–containing) plastid groups. Members of the “green” plastid line were important constituents of Neoproterozoic and Paleozoic oceans, and, ultimately, one green clade colonized land. By the mid-Mesozoic, the green line had become ecologically less important in the oceans. In its place, three groups of chlorophyll c–containing eukaryotes, the dinoflagellates, coccolithophorids, and diatoms, began evolutionary trajectories that have culminated in ecological dominance in the contemporary oceans. Breakup of the supercontinent Pangea, continental shelf flooding, and changes in ocean redox chemistry may all have contributed to this evolutionary transition. At the same time, the evolution of these modern eukaryotic taxa has influenced both the structure of marine food webs and global biogeochemical cycles.
Landscapes and Riverscapes: The Influence of Land Use on Stream Ecosystems
Authors: Allan J. David
Published: November 2004

▪ Abstract  Local habitat and biological diversity of streams and rivers are strongly influenced by landform and land use within the surrounding valley at multiple scales. However, empirical associations between land use and stream response only varyingly succeed in implicating pathways of influence. This is the case for a number of reasons, including (a) covariation of anthropogenic and natural gradients in the landscape; (b) the existence of multiple, scale-dependent mechanisms; (c) nonlinear responses; and (d) the difficulties of separating present-day from historical influences. Further research is needed that examines responses to land use under different management strategies and that employs response variables that have greater diagnostic value than many of the aggregated measures in current use.

In every respect, the valley rules the stream.

     H.B.N. Hynes (1975)
NATURAL HISTORY OF PLAGUE: Perspectives from More than a Century of Research
Authors: Gage Kenneth L. , Kosoy Michael Y.
Published: November 2004

▪ Abstract  For more than a century, scientists have investigated the natural history of plague, a highly fatal disease caused by infection with the gram-negative bacterium Yersinia pestis. Among their most important discoveries were the zoonotic nature of the disease and that plague exists in natural cycles involving transmission between rodent hosts and flea vectors. Other significant findings include those on the evolution of Y. pestis; geographic variation among plague strains; the dynamics and maintenance of transmission cycles; mechanisms by which fleas transmit Y. pestis; resistance and susceptibility among plague hosts; the structure and typology of natural foci; and how landscape features influence the focality, maintenance, and spread of the disease. The knowledge gained from these studies is essential for the development of effective prevention and control strategies.
EFFECTS OF PLANTS GENETICALLY MODIFIED FOR INSECT RESISTANCE ON NONTARGET ORGANISMS
Authors: O'Callaghan Maureen , Glare Travis R. , Burgess Elisabeth P.J. , Malone Louise A.
Published: November 2004

▪ Abstract  Insect resistance, based on Bacillus thuringiensis (Bt) endotoxins, is the second most widely used trait (after herbicide resistance) in commercial genetically modified (GM) crops. Other modifications for insect resistance, such as proteinase inhibitors and lectins, are also being used in many experimental crops. The extensive testing on nontarget plant-feeding insects and beneficial species that has accompanied the long-term and wide-scale use of Bt plants has not detected significant adverse effects. GM plants expressing other insect-resistant proteins that have a broader spectrum of activity have been tested on only a limited number of nontarget species. Little is known about the persistence of transgene-derived proteins in soil, with the exception of Bt endotoxins, which can persist in soil for several months. Bt plants appear to have little impact on soil biota such as earthworms, collembolans, and general soil microflora. Further research is required on the effects of GM plants on soil processes such as decomposition. Assessment of nontarget impacts is an essential part of the risk assessment process for insect-resistant GM plants.
THE MEVALONATE PATHWAY AND THE SYNTHESIS OF JUVENILE HORMONE IN INSECTS
Authors: Bellés Xavier , Martín David , Piulachs Maria-Dolors
Published: November 2004

▪ Abstract  The mevalonate pathway in insects has two important peculiarities, the absence of the sterol branch and the synthesis of juvenile hormone (JH), that may have influenced the mechanisms of regulation. The data available on these mechanisms indicate that cholesterol does not play a regulatory role and that JH modulates transcript levels of a number of genes of the mevalonate pathway or can influence the translatability and/or stability of the transcripts themselves. These data suggest that the mevalonate pathway in insects can best be interpreted in terms of coordinated regulation, in which regulators act in parallel to a number of enzymes, as occurs in the cholesterol-driven pathway in vertebrates.
rRNA Transcription in Escherichia coli
Authors: Paul Brian J. , Ross Wilma , Gaal Tamas , Gourse Richard L.
Published: November 2004

▪ Abstract  Ribosomal RNA transcription is the rate-limiting step in ribosome synthesis in bacteria and has been investigated intensely for over half a century. Multiple mechanisms ensure that rRNA synthesis rates are appropriate for the cell's particular growth condition. Recently, important advances have been made in our understanding of rRNA transcription initiation in Escherichia coli. These include (a) a model at the atomic level of the network of protein-DNA and protein-protein interactions that recruit RNA polymerase to rRNA promoters, accounting for their extraordinary strength; (b) discovery of the nonredundant roles of two small molecule effectors, ppGpp and the initiating NTP, in regulation of rRNA transcription initiation; and (c) identification of a new component of the transcription machinery, DksA, that is absolutely required for regulation of rRNA promoter activity. Together, these advances provide clues important for our molecular understanding not only of rRNA transcription, but also of transcription in general.
CHEMOKINES, SPHINGOSINE-1-PHOSPHATE, AND CELL MIGRATION IN SECONDARY LYMPHOID ORGANS
Authors: Cyster Jason G.
Published: November 2004

▪ Abstract  Secondary lymphoid organs serve as hubs for the adaptive immune system, bringing together antigen, antigen-presenting cells, and lymphocytes. Two families of G protein–coupled receptors play essential roles in lymphocyte migration through these organs: chemokine receptors and sphingosine-1-phosphate (S1P) receptors. Chemokines expressed by lymphoid stromal cells guide lymphocyte and dendritic cell movements during antigen surveillance and the initiation of adaptive immune responses. S1P receptor-1 is required for lymphocyte egress from thymus and secondary lymphoid organs and is downregulated by the immunosuppressive drug FTY720. Here, we review the steps associated with the initiation of adaptive immune responses in secondary lymphoid organs, highlighting the roles of chemokines and S1P.
The Silent Revolution: RNA Interference as Basic Biology, Research Tool, and Therapeutic
Authors: Dykxhoorn Derek M. , Lieberman Judy
Published: November 2004

RNA interference (RNAi) is an evolutionarily conserved mechanism for silencing gene expression. In primitive organisms, RNAi protects the genome from viruses and other insertable genetic elements and regulates gene expression during development. The antisense (guide) strand of short double-stranded RNAs is incorporated into an RNA-induced silencing complex that can either suppress protein expression or direct degradation of messenger RNAs that contain homologous sequence(s). The discovery that RNAi works in mammalian cells has sparked intense investigation into its role in normal mammalian cell function, its use as a tool to understand or screen for genes functioning in cellular pathways in healthy and diseased cells and animals, and its potential for therapeutic gene silencing. RNAi may provide an important new therapeutic modality for treating infection, cancer, neurodegenerative disease, and other illnesses, although in vivo delivery of small interfering RNAs into cells remains a significant obstacle.
Surgical Therapy for Metastatic Disease to the Liver
Authors: Bentrem David J. , DeMatteo Ronald P. , Blumgart Leslie H.
Published: November 2004

The liver is a common site of hematogenous metastasis. In the past, patients with liver metastases were often deemed inoperable, and medical therapy conferred only minor survival benefit. However, advances in surgical techniques and chemotherapeutic agents during the past two decades have led to effective treatments for selected patients with metastases to the liver. Up to ∼80% of the liver can be resected, and partial hepatectomy is now routinely performed with a perioperative mortality rate of <5%. Surgical resection of colorectal cancer metastatic to the liver results in a 5-year survival rate of 40%. These results are expected to improve even further with multimodality approaches that include newer chemotherapy regimens. Liver metastases from other primary tumors, such as neuroendocrine carcinoma and genitourinary tumors, are also treated effectively with liver resection. The indications for surgical treatment of liver metastases are broadening as a variety of novel therapies are being developed, including hepatic artery embolization, hepatic artery infusion of chemotherapy, and radiofrequency ablation.
BIOMARKERS IN PSYCHOTROPIC DRUG DEVELOPMENT: Integration of Data across Multiple Domains
Authors: Bieck Peter R. , Potter William Z.
Published: November 2004

▪ Abstract  This review focuses on the current status of biomarkers and/or approaches critical to assessing novel neuroscience targets with an emphasis on new paradigms and challenges in this field of research. The importance of biomarker data integration for psychotropic drug development is illustrated with examples for clinically used medications and investigational drugs. The question remains how to verify access to the brain. Early imaging studies including micro-PET can help to overcome this. However, in case of delayed tracer development or because of no feasible application of brain imaging effects of the molecule, using CSF as a matrix could fill this gap. Proteomic research using CSF will hopefully have a major impact on the development of treatments for psychiatric disorders.
CLINICAL DEVELOPMENT OF HISTONE DEACETYLASE INHIBITORS AS ANTICANCER AGENTS
Authors: Drummond Daryl C. , Noble Charles O. , Kirpotin Dmitri B. , Guo Zexiong , Scott Gary K. , Benz Christopher C.
Published: November 2004

▪ Abstract  Acetylation is a key posttranslational modification of many proteins responsible for regulating critical intracellular pathways. Although histones are the most thoroughly studied of acetylated protein substrates, histone acetyltransferases (HATs) and deacetylases (HDACs) are also responsible for modifying the activity of diverse types of nonhistone proteins, including transcription factors and signal transduction mediators. HDACs have emerged as uncredentialed molecular targets for the development of enzymatic inhibitors to treat human cancer, and six structurally distinct drug classes have been identified with in vivo bioavailability and intracellular capability to inhibit many of the known mammalian members representing the two general types of NAD+-independent yeast HDACs, Rpd3 (HDACs 1, 2, 3, 8) and Hda1 (HDACs 4, 5, 6, 7, 9a, 9b, 10). Initial clinical trials indicate that HDAC inhibitors from several different structural classes are very well tolerated and exhibit clinical activity against a variety of human malignancies; however, the molecular basis for their anticancer selectivity remains largely unknown. HDAC inhibitors have also shown preclinical promise when combined with other therapeutic agents, and innovative drug delivery strategies, including liposome encapsulation, may further enhance their clinical development and anticancer potential. An improved understanding of the mechanistic role of specific HDACs in human tumorigenesis, as well as the identification of more specific HDAC inhibitors, will likely accelerate the clinical development and broaden the future scope and utility of HDAC inhibitors for cancer treatment.
FAT CELLS: Afferent and Efferent Messages Define New Approaches to Treat Obesity
Authors: Lafontan Max
Published: November 2004

▪ Abstract  For a long time neural and endocrine messages were studied for their impact on adipocyte metabolism and control of storage/release of fatty acids. In fact, bidirectional communication exists between adipocytes and other tissues. Several molecules secreted from adipocytes are involved in fat cell signaling to other tissues. Adipocyte products could initiate antagonistic effects on target tissues. Fat cells produce peptides that can elicit insulin resistance, such as tumor necrosis factor-α and resistin, as well as hormones that can improve insulin resistance, such as leptin and adiponectin. Secretion of complement proteins, proinflammatory cytokines, procoagulant, and acute phase reactant proteins have also been observed in adipocytes. There is much to learn about how these signals function. It is unlikely that all the adipocyte's endocrine and paracrine signals have been identified. Putative pharmacological strategies aiming at modulation of afferent and efferent fat cell messages are reviewed and discussed.
HEPATIC FIBROSIS: Molecular Mechanisms and Drug Targets
Authors: Lotersztajn Sophie , Julien Boris , Teixeira-Clerc Fatima , Grenard Pascale , Mallat Ariane
Published: November 2004

▪ Abstract  Liver fibrosis is the common response to chronic liver injury, ultimately leading to cirrhosis and its complications, portal hypertension, liver failure, and hepatocellular carcinoma. Efficient and well-tolerated antifibrotic drugs are currently lacking, and current treatment of hepatic fibrosis is limited to withdrawal of the noxious agent. Efforts over the past decade have mainly focused on fibrogenic cells generating the scarring response, although promising data on inhibition of parenchymal injury and/or reduction of liver inflammation have also been obtained. A large number of approaches have been validated in culture studies and in animal models, and several clinical trials are underway or anticipated for a growing number of molecules. This review highlights recent advances in the molecular mechanisms of liver fibrosis and discusses mechanistically based strategies that have recently emerged.
EPOXIDE HYDROLASES: Mechanisms, Inhibitor Designs, and Biological Roles
Authors: Morisseau Christophe , Hammock Bruce D.
Published: November 2004

▪ Abstract  Organisms are exposed to epoxide-containing compounds from both exogenous and endogenous sources. In mammals, the hydration of these compounds by various epoxide hydrolases (EHs) can not only regulate their genotoxicity but also, for lipid-derived epoxides, their endogenous roles as chemical mediators. Recent findings suggest that the EHs as a family represent novel drug discovery targets for regulation of blood pressure, inflammation, cancer progression, and the onset of several other diseases. Knowledge of the EH mechanism provides a solid foundation for the rational design of inhibitors, and this review summarizes the current understanding of the catalytic mechanism of the EHs. Although the overall EH mechanism is now known, the molecular basis of substrate selectivity, possible allosteric regulation, and many fine details of the catalytic mechanism remain to be solved. Finally, recent development in the design of EH inhibitors and the EH biological role are discussed.
CYTOCHROME P450 ACTIVATION OF ARYLAMINES AND HETEROCYCLIC AMINES
Authors: Kim Donghak , Guengerich F. Peter
Published: November 2004

▪ Abstract  Arylamines and heterocyclic arylamines (HAAs) are of particular interest because of demonstrated carcinogenicity in animals and humans and the broad exposure to many of these compounds. The activation of these, and also some arylamine drugs, involves N-hydroxylation, usually by cytochrome P450 (P450). P450 1A2 plays a prominent role in these reactions. However, P450 1A1 and 1B1 and other P450s are also important in humans as well as experimental animals. Some arylamines (including drugs) are N-hydroxylated predominantly by P450s other than those in Family 1. Other oxygenases can also have roles. An important issue is extrapolation between species in predicting cancer risks, as shown by the low rates of HAA activation by rat P450 1A2 and low levels of P450 1A2 expression in some nonhuman primates.
INTRACELLULAR CALCIUM RELEASE AND CARDIAC DISEASE
Authors: Wehrens Xander H.T. , Lehnart Stephan E. , Marks Andrew R.
Published: November 2004

▪ Abstract  Intracellular calcium release channels are present on sarcoplasmic and endoplasmic reticuli (SR, ER) of all cell types. There are two classes of these channels: ryanodine receptors (RyR) and inositol 1,4,5-trisphosphate receptors (IP3R). RyRs are required for excitation-contraction (EC) coupling in striated (cardiac and skeletal) muscles. RyRs are made up of macromolecular signaling complexes that contain large cytoplasmic domains, which serve as scaffolds for proteins that regulate the function of the channel. These regulatory proteins include calstabin1/calstabin2 (FKBP12/FKBP12.6), a 12/12.6 kDa subunit that stabilizes the closed state of the channel and prevents aberrant calcium leak from the SR. Kinases and phosphatases are targeted to RyR2 channels and modulate RyR2 function in response to extracellular signals. In the classic fight or flight stress response, phosphorylation of RyR channels by protein kinase A reduces the affinity for calstabin and activates the channels leading to increased SR calcium release. In heart failure, a cardiac insult causes a mismatch between blood supply and metabolic demands of organs. The chronically activated fight or flight response leads to leaky channels, altered calcium signaling, and contractile dysfunction and cardiac arrhythmias.
PETER HOCHACHKA: Adventures in Biochemical Adaptation
Authors: Somero George N. , Suarez Raul K.
Published: November 2004

▪ Abstract  Peter Hochachka was one of the most creative forces in the field of comparative physiology during the past half-century. His career was truly an exploratory adventure, in both intellectual and geographic senses. His broad comparative studies of metabolism in organisms as diverse as trout, tunas, oysters, squid, turtles, locusts, hummingbirds, seals, and humans revealed the adaptable features of enzymes and metabolic pathways that provide the biochemical bases for diverse lifestyles and environments. In its combined breadth and depth, no other corpus of work better illustrates the principle of “unity in diversity” that marks comparative physiology. Through his publications, his stimulating mentorship, his broad editorial services, and his continuous—and highly infectious—enthusiasm for his field, Peter Hochachka served as one of the most influential leaders in the transformation of comparative physiology.
Personality Architecture: Within-Person Structures and Processes
Authors: Cervone Daniel
Published: November 2004

This chapter reviews theory and research on intraindividual personality structures and processes. Principles for modeling the architecture of personality, that is, the overall design and operating characteristics of intraindividual personality systems, are addressed. Research demonstrates that a focus on within-person structures and processes advances the understanding of two aspects of personality coherence: the functional relations among distinct elements of personality, and cross-situational coherence in personality functioning that results from interactions among enduring knowledge structures and dynamic appraisal processes. Also reviewed are recent conceptual and empirical advances, which demonstrate that the interindividual personality variables that summarize variability in the population are wholly insufficient for modeling intraindividual personality architecture.
Teams in Organizations: From Input-Process-Output Models to IMOI Models
Authors: Ilgen Daniel R. , Hollenbeck John R. , Johnson Michael , Jundt Dustin
Published: November 2004

This review examines research and theory relevant to work groups and teams typically embedded in organizations and existing over time, although many studies reviewed were conducted in other settings, including the laboratory. Research was organized around a two-dimensional system based on time and the nature of explanatory mechanisms that mediated between team inputs and outcomes. These mechanisms were affective, behavioral, cognitive, or some combination of the three. Recent theoretical and methodological work is discussed that has advanced our understanding of teams as complex, multilevel systems that function over time, tasks, and contexts. The state of both the empirical and theoretical work is compared as to its impact on present knowledge and future directions.
ADVANCES IN CANCER EPIDEMIOLOGY: Understanding Causal Mechanisms and the Evidence for Implementing Interventions
Authors: Schottenfeld David , Beebe-Dimmer Jennifer L.
Published: November 2004

▪ Abstract  In a worldwide population of 6 billion, in the year 2000, approximately 10 million cancers were diagnosed, and there were an estimated 6.2 million cancer deaths. Whereas the universality of cancer incidence and mortality is established, the burden of cancer by type or organ site is distributed unequally between developing and industrialized nations. Populations in developing countries are disproportionately affected by cancers in which infectious agents are causal. Our review of advances in cancer epidemiology underscores the complexity of pathogenic mechanisms mediated by chronic inflammation, obesity, and gene-environment interactions as in tobacco and alcohol carcinogenesis. Ultimately, the implementation of effective cancer control interventions that will serve to alleviate the cancer burden must integrate basic and applied research in the behavioral, social, biomedical, and population sciences.
PRIMARY PREVENTION OF DIABETES: What Can Be Done and How Much Can Be Prevented?
Authors: Schulze Matthias B. , Hu Frank B.
Published: November 2004

▪ Abstract  Although it is widely believed that type 2 diabetes mellitus is the result of a complex interplay between genetic and environmental factors, compelling evidence from epidemiologic studies indicates that the current worldwide diabetes epidemic is largely due to changes in diet and lifestyle. Prospective cohort studies and randomized clinical trials have demonstrated that type 2 diabetes can be prevented largely through moderate diet and lifestyle modifications. Excess adiposity is the most important risk factor for diabetes, and thus, maintaining a healthy body weight and avoiding weight gain during adulthood is the cornerstone of diabetes prevention. Increasing physical activity and reducing sedentary behaviors such as prolonged TV watching are important both for maintaining body weight and improving insulin sensitivity. There is increasing evidence that the quality of fat and carbohydrate plays a more important role than does the quantity, and thus, public health strategies should emphasize replacing saturated and trans fats with unsaturated fats and replacing refined grain products with whole grains. Recent studies have also suggested a potential role for coffee, dairy, nuts, magnesium, and calcium in preventing diabetes. Overall, a healthy diet, together with regular physical activity, maintenance of a healthy weight, moderate alcohol consumption, and avoidance of sedentary behaviors and smoking, could nearly eliminate type 2 diabetes. However, there is still a wide gap between what we know and what we practice in the field of public health; how to narrow that gap remains a major public health challenge.
CCR2-positive monocytes recruited to inflamed lungs downregulate local CCL2 chemokine levels
Authors: Maus Ulrich A. , Wellmann Sandra , Hampl Christine , Kuziel William A. , Srivastava Mrigank , Mack Matthias , Everhart M. Brett , Blackwell Timothy S. , Christman John W. , Schlöndorff Detlef , Bohle Rainer M. , Seeger Werner , Lohmeyer Jürgen
Published: November 2004

The CC chemokine ligand-2 (CCL2) and its receptor CCR2 are essential for monocyte trafficking under inflammatory conditions. However, the mechanisms that determine the intensity and duration of alveolar monocyte accumulation in response to CCL2 gradients in inflamed lungs have not been resolved. To determine the potential role of CCR2-expressing monocytes in regulating alveolar CCL2 levels, we compared leukocyte recruitment kinetics and alveolar CCL2 levels in wild-type and CCR2-deficient mice in response to intratracheal LPS challenge. In wild-type mice, LPS elicited a dose- and time-dependent alveolar monocyte accumulation accompanied by low CCL2 levels in bronchoalveolar lavage fluid (BALF). In contrast, LPS-treated CCR2-deficient mice lacked alveolar monocyte accumulation, which was accompanied by relatively high CCL2 levels in BALF. Similarly, wild-type mice that were treated systemically with the blocking anti-CCR2 antibody MC21 completely lacked LPS-induced alveolar monocyte trafficking that was associated with high CCL2 levels in BALF. Intratracheal application of anti-CCR2 antibody MC21 to locally block CCR2 on both resident and recruited cells did not affect LPS-induced alveolar monocyte trafficking but led to significantly increased BALF CCL2 levels. Reciprocally bone marrow-transplanted, LPS-treated wild-type and CCR2-deficient mice showed a strict inverse relationship between alveolar monocyte recruitment and BALF CCL2 levels. In addition, freshly isolated human and mouse monocytes were capable of integrating CCL2 in vitro. LPS-induced alveolar monocyte accumulation is accompanied by monocytic CCR2-dependent consumption of CCL2 levels in the lung. This feedback loop may limit the intensity of monocyte recruitment to inflamed lungs and play a role in the maintenance of homeostasis.
NF-κB activation and sustained IL-8 gene expression in primary cultures of cystic fibrosis airway epithelial cells stimulated withPseudomonas aeruginosa
Authors: Joseph Theresa , Look Dwight , Ferkol Thomas
Published: November 2004

The progression of lung disease in cystic fibrosis (CF) is characterized by an exuberant inflammatory response mounted by the respiratory epithelium that is further exacerbated by bacterial infection. Recent studies have demonstrated upregulation of nuclear factor-κB (NF-κB) in response to infection in genetically modified cell culture models, which is associated with expression of interleukin (IL)-8. Using human airway epithelial cells grown in primary culture, we examined in vitro activation of NF-κB in cells isolated from five CF (ΔF508/ΔF508) and three non-CF (NCF) patients in response to Pseudomonas aeruginosa. Immunofluorescence, gel-shift, and immunoblot assays demonstrated a rapid translocation of NF-κB subunits (p50 and p65) to the nucleus in both CF and NCF cell cultures. However, nuclear extracts from CF cells both before and following P. aeruginosa stimulation revealed elevated NF-κB activation compared with NCF cells. Additionally, elevated nuclear levels of the NF-κB inhibitor IκBα were detected in nuclei of CF cells after P. aeruginosa stimulation, but this increase was transient. There was no difference in IL-8 mRNA levels between CF and NCF cells early after stimulation, whereas expression was higher and sustained in CF cells at later times. Our results also demonstrated increased baseline translocation of NF-κB to nuclei of primary CF epithelial cell cultures, but intranuclear IκBα may initially block its effects following P. aeruginosa stimulation. Thus, IL-8 mRNA expression was prolonged after P. aeruginosa stimulation in CF epithelial cells, and this sustained IL-8 expression may contribute to the excessive inflammatory response in CF.
BMP4 inhibits proliferation and promotes myocyte differentiation of lung fibroblasts via Smad1 and JNK pathways
Authors: Jeffery Trina K. , Upton Paul D. , Trembath Richard C. , Morrell Nicholas W.
Published: November 2004

Fibroblast proliferation, differentiation, and migration contribute to the characteristic pulmonary vascular remodeling seen in primary pulmonary hypertension (PPH). The identification of mutations in the bone morphogenetic protein type II receptor (BMPRII) in PPH have led us to question what role BMPRII and its ligands play in pulmonary vascular remodeling. Thus, to further understand the functional significance of BMPRII in the pulmonary vasculature, we examined the expression of TGF-β superfamily receptors in human fetal lung fibroblasts (HFL) and investigated the role of BMP4 on cell cycle regulation, fibroblast proliferation, and differentiation. Furthermore, signaling pathways involved in these processes were examined. HFL expressed BMPRI and BMPRII mRNA and demonstrated specific I125-BMP4 binding sites. BMP4 inhibited [3H]thymidine incorporation and proliferation of HFL; protein expression was increased for the cell cycle inhibitor p21 and reduced for the positive regulators cyclin D and cdk2 by BMP4. BMP4 induced differentiation of HFL into a smooth muscle cell phenotype since protein expression of α-smooth muscle actin and smooth muscle myosin was increased. Furthermore, p38MAPK, ERK1/2, JNK, and Smad1 were phosphorylated by BMP4. Using specific MAPK inhibitors, a dominant negative Smad1 construct, and Smad1 siRNA, we found that the antiproliferative and prodifferentiation effects of BMP4 were Smad1 dependent with JNK also contributing to differentiation. Because failure of Smad phosphorylation is a major feature of BMPRII mutations, these results imply that BMPRII mutations may promote the expansion of fibroblasts resistant to the antiproliferative, prodifferentiation effects of BMPs and suggest a mechanism for the vascular obliteration seen in familial PPH.