bluuebunny/crossref_metadata_2025 huggingface dataset:
Multicast routing in datagram internetworks and extended LANs
Authors: Deering Stephen E. , Cheriton David R.
Published: July 2002

Multicasting, the transmission of a packet to a
group
of hosts, is an important service for improving the efficiency and robustness of distributed systems and applications. Although multicast capability is available and widely used in local area networks, when those LANs are interconnected by store-and-forward routers, the multicast service is usually not offered across the resulting
internetwork
. To address this limitation, we specify extensions to two common internetwork routing algorithms—distance-vector routing and link-state routing—to support low-delay datagram multicasting beyond a single LAN. We also describe modifications to the single-spanning-tree routing algorithm commonly used by link-layer bridges, to reduce the costs of multicasting in large extended LANs. Finally, we discuss how the use of multicast scope control and hierarchical multicast routing allows the multicast service to scale up to large internetworks.
Fast hashing of variable-length text strings
Authors: Pearson Peter K.
Published: July 2002

Using only a few simple and commonplace instructions, this algorithm efficiently maps variable-length text strings small integers.
A fast algorithm for optimal length-limited Huffman codes
Authors: Larmore Lawrence L. , Hirschberg Daniel S.
Published: July 2002

An
O
(
nL
)-time algorithm is introduced for constructing an optimal Huffman code for a weighted alphabet of size
n
, where each code string must have length no greater than
L
. The algorithm uses
O
(
n
) space.
Trafficking in Men: The Anthropology of Masculinity
Authors: Gutmann Matthew C.
Published: July 2002

Anthropology has always involved men talking to men about men, yet until fairly recently very few within the discipline had truly examined men as men. This chapter explores how anthropologists understand, utilize, and debate the category of masculinity by reviewing recent examinations of men as engendered and engendering subjects. Beginning with descriptions of four distinct ways in which masculinity is defined and treated in anthropology, special attention is paid to the relations of difference, inequality, and women to the anthropological study of masculinities, including the awkward avoidance of feminist theory on the part of many anthropologists who study manhood. Specific topics discussed include the diverse cultural economies of masculinity, the notion of cultural regions in relation to images of manhood, male friendship, machismo, masculine embodiment, violence, power, and sexual faultlines.
PLANT IN VITRO TRANSCRIPTION SYSTEMS
Authors: Sugiura Masahiro
Published: July 2002

▪ Abstract  In vitro transcription systems provide a powerful tool for detailed analysis of transcription reactions including initiation, elongation, and termination. Despite problems inherent to plant cells, efforts have been made to develop plant in vitro transcription systems in the past decade. These efforts have finally culminated in the development of reliable in vitro systems from suspension-cell cultures of both monocot and dicot plants. These systems can be useful in elucidating the specific mechanisms involved in the process of plant transcription and thus can potentially open a new era of transcription studies in plants.
Fidelity of Aminoacyl-tRNA Selection on the Ribosome: Kinetic and Structural Mechanisms
Authors: Rodnina Marina V. , Wintermeyer Wolfgang
Published: July 2002

▪ Abstract  The ribosome discriminates between correct and incorrect aminoacyl-tRNAs (aa-tRNAs), or their complexes with elongation factor Tu (EF-Tu) and GTP, according to the match between anticodon and mRNA codon in the A site. Selection takes place at two stages, prior to GTP hydrolysis (initial selection) and after GTP hydrolysis but before peptide bond formation (proofreading). In part, discrimination results from different rejection rates that are due to different stabilities of the respective codon-anticodon complexes. An important additional contribution is provided by induced fit, in that only correct codon recognition leads to acceleration of rate-limiting rearrangements that precede chemical steps. Recent elucidation of ribosome structures and mutational analyses suggest which residues of the decoding center may be involved in signaling formation of the correct codon-anticodon duplex to the functional centers of the ribosome. In utilizing induced fit for substrate discrimination, the ribosome resembles other nucleic acid–programmed polymerases.
Imaging Three-Dimensional Cardiac Function
Authors: O'Dell W. G. , McCulloch A. D.
Published: July 2002

▪ Abstract  The three-dimensional (3-D) nature of myocardial deformations is dependent on ventricular geometry, muscle fiber architecture, wall stresses, and myocardial-material properties. The imaging modalities of X-ray angiography, echocardiography, computed tomography, and magnetic resonance (MR) imaging (MRI) are described in the context of visualizing and quantifying cardiac mechanical function. The quantification of ventricular anatomy and cavity volumes is then reviewed, and surface reconstructions in three dimensions are demonstrated. The imaging of myocardial wall motion is discussed, with an emphasis on current MRI and tissue Doppler imaging techniques and their potential clinical applications. Calculation of 3-D regional strains from motion maps is reviewed and illustrated with clinical MRI tagging results. We conclude by presenting a promising technique to assess myocardial-fiber architecture, and we outline its potential applications, in conjunction with quantification of anatomy and regional strains, for the determination of myocardial stress and work distributions. The quantification of multiple components of 3-D cardiac function has potential for both fundamental-science and clinical applications.
A Decade of CLC Chloride Channels: Structure, Mechanism, and Many Unsettled Questions
Authors: Maduke Merritt , Miller Christopher , Mindell Joseph A.
Published: July 2002

▪ Abstract  ClC-type chloride channels are ubiquitous throughout the biological world. Expressed in nearly every cell type, these proteins have a host of biological functions. With nine distinct homologues known in eukaryotes, the ClCs represent the only molecularly defined family of chloride channels. ClC channels exhibit features of molecular architecture and gating mechanisms unprecedented in other types of ion channels. They form two-pore homodimers, and their voltage-dependence arises not from charged residues in the protein, but rather via coupling of gating to the movement of chloride ions within the pore. Because the functional characteristics of only a few ClC channels have been studied in detail, we are still learning which properties are general to the whole family. New approaches, including structural analyses, will be crucial to an understanding of ClC architecture and function.
ACTIN: General Principles from Studies in Yeast
Authors: Ayscough Kathryn R. , Drubin David G.
Published: July 2002

▪ Abstract  Three of the most important questions concerning actin function are: (a) How does actin structure relate to actin function? (b) How does each of the numerous proteins that interact with actin contribute to actin cytoskeleton function in vivo? (c) How are the activities of these proteins regulated? Powerful molecular genetics combined with well-established biochemical techniques make the yeast Saccharomyces cerevisiae an ideal organism for studies aimed at answering these questions.

The protein sequences and biochemical properties of actin and its interacting proteins and the pathways that regulate these interactions all appear to be conserved, indicating that principles elucidated from studies in yeast will apply to all eukaryotes. In this review, we highlight advances in our general understanding of actin properties, interactions with other proteins, and regulation of the actin cytoskeleton, derived from studies in the budding yeast S. cerevisiae.
NUCLEAR FUSION IN THE YEAST SACCHAROMYCES CEREVISIAE
Authors: Rose Mark D.
Published: July 2002

▪ Abstract  Karyogamy, or nuclear fusion, is the process during mating by which two haploid yeast nuclei fuse to produce a single diploid nucleus. Karyogamy occurs in two major steps: microtubule-dependent nuclear congression followed by fusion of the nuclear envelope membranes. Many of the proteins required for karyogamy have been discovered to act in related processes during mitotic growth. Accordingly, yeast karyogamy has become an important model system to investigate critical functions of the cytoplasmic microtubules and the microtubule organizing center, the nuclear envelope, and the endoplasmic reticulum.
INITIATION OF DNA REPLICATION IN EUKARYOTIC CELLS
Authors: Dutta Anindya , Bell Stephen P.
Published: July 2002

▪ Abstract  The recent identification of proteins that recognize origins of DNA replication and control the initiation of eukaryotic DNA replication has provided critical molecular tools to dissect this process. Dynamic changes in the assembly and disassembly of protein complexes at origins are important for the initiation of DNA replication and occur throughout the cell cycle. Herein, we review the key proteins required for the initiation of DNA replication, their involvement in the protein complex assembly at replication origins, and how the cell cycle machinery regulates this process.
Transport Between the Cell Nucleus and the Cytoplasm
Authors: Görlich Dirk , Kutay Ulrike
Published: July 2002

▪ Abstract  The compartmentation of eukaryotic cells requires all nuclear proteins to be imported from the cytoplasm, whereas, for example, transfer RNAs, messenger RNAs, and ribosomes are made in the nucleus and need to be exported to the cytoplasm. Nuclear import and export proceed through nuclear pore complexes and can occur along a great number of distinct pathways, many of which are mediated by importin β-related nuclear transport receptors. These receptors shuttle between nucleus and cytoplasm, and they bind transport substrates either directly or via adapter molecules. They all cooperate with the RanGTPase system to regulate the interactions with their cargoes. Another focus of our review is nuclear export of messenger RNA, which apparently largely relies on export mediators distinct from importin β-related factors. We discuss mechanistic aspects and the energetics of transport receptor function and describe a number of pathways in detail.
STROMATOLITES IN PRECAMBRIAN CARBONATES: Evolutionary Mileposts or Environmental Dipsticks?
Authors: Grotzinger John P. , Knoll Andrew H.
Published: July 2002

▪ Abstract  Stromatolites are attached, lithified sedimentary growth structures, accretionary away from a point or limited surface of initiation. Though the accretion process is commonly regarded to result from the sediment trapping or precipitation-inducing activities of microbial mats, little evidence of this process is preserved in most Precambrian stromatolites. The successful study and interpretation of stromatolites requires a process-based approach, oriented toward deconvolving the replacement textures of ancient stromatolites. The effects of diagenetic recrystallization first must be accounted for, followed by analysis of lamination textures and deduction of possible accretion mechanisms. Accretion hypotheses can be tested using numerical simulations based on modern stromatolite growth processes. Application of this approach has shown that stromatolites were originally formed largely through in situ precipitation of laminae during Archean and older Proterozoic times, but that younger Proterozoic stromatolites grew largely through the accretion of carbonate sediments, most likely through the physical process of microbial trapping and binding. This trend most likely reflects long-term evolution of the earth's environment rather than microbial communities.
Physical-Biological Coupling in Streams: The Pervasive Effects of Flow on Benthic Organisms
Authors: Hart David D. , Finelli Christopher M.
Published: July 2002

▪ Abstract  Flowing water has profound effects on a diverse array of ecological processes and patterns in streams and rivers. We propose a conceptual framework for investigating the multiple causal pathways by which flow influences benthic biota and focus particular attention on the local scales at which these organisms respond to flow. Flow (especially characteristics linked to the velocity field) can strongly affect habitat characteristics, dispersal, resource acquisition, competition, and predation; creative experiments will be needed to disentangle these complex interactions. Benthic organisms usually reside within the roughness layer, where the unique arrangement of sediment particles produces strongly sheared and highly three-dimensional flow patterns. Thus, accurate characterization of the local flow environments experienced by benthic organisms often requires the use of flow measurement technology with high spatial and temporal resolution. Because flow exhibits variation across a broad range of scales, it is also necessary to examine how organism-flow relationships at one scale are linked to those at others. Interdisciplinary approaches are needed in the study of physical-biological coupling; increased collaboration between ecologists and experts in fluid mechanics and hydraulic engineering is particularly desirable. A greater understanding of physical-biological coupling will not only yield deeper insights into the ecological organization of streams and rivers, it will also improve our ability to predict how flow alterations caused by various human activities affect these vital ecosystems.
Gene Flow and Introgression from Domesticated Plants into their Wild Relatives
Authors: Ellstrand Norman C. , Prentice Honor C. , Hancock James F.
Published: July 2002

▪ Abstract  Domesticated plant taxa cannot be regarded as evolutionarily discrete from their wild relatives. Most domesticated plant taxa mate with wild relatives somewhere in the world, and gene flow from crop taxa may have a substantial impact on the evolution of wild populations. In a literature review of the world's 13 most important food crops, we show that 12 of these crops hybridize with wild relatives in some part of their agricultural distribution. We use population genetic theory to predict the evolutionary consequences of gene flow from crops to wild plants and discuss two applied consequences of crop-to-wild gene flow–the evolution of aggressive weeds and the extinction of rare species. We suggest ways of assessing the likelihood of hybridization, introgression, and the potential for undesirable gene flow from crops into weeds or rare species.
Quasi-Replication and the Contract of Error: Lessons from Sex Ratios, Heritabilities and Fluctuating Asymmetry
Authors: Palmer A. Richard
Published: July 2002

▪ Abstract  Selective reporting—e.g., the preferential publication of results that are statistically significant, or consistent with theory or expectation—presents a challenge to meta-analysis and seriously undermines the quest for generalizations. Funnel graphs (scatterplots of effect size vs. sample size) help reveal the extent of selective reporting. They also allow the strength of biological effects to be judged easily, and they reaffirm the value of graphical presentations of data over statistical summaries.

Funnel graphs of published results, including: (a) sex-ratio variation in birds, (b) field estimates of heritabilities, and (c) relations between fluctuating asymmetry and individual attractiveness or fitness, suggest selective reporting is widespread and raise doubts about the true magnitude of these phenomena. Quasireplication—the “replication” of previous studies using different species or systems—has almost completely supplanted replicative research in ecology and evolution. Without incentives for formal replicative studies, which could come from changes to editorial policies, graduate training programs, and research funding priorities, the contract of error will continue to thwart attempts at robust generalizations.

“For as knowledges are now delivered, there is a kind of contract of error between the deliverer and the receiver: for he that delivereth knowledge desireth to deliver it in such a form as may be best believed, and not as may be best examined; and he that receiveth knowledge desireth rather present satisfaction than expectant inquiry; and so rather not to doubt than not to err: glory making the author not to lay open his weakness, and sloth making the disciple not to know his strength.”

     The Advancement of Learning, Francis Bacon, 1605 ( 8 :170–171)
BIOMASSETHANOL: Technical Progress, Opportunities, and Commercial Challenges
Authors: Wyman Charles E.
Published: July 2002

▪ Abstract  Ethanol made from lignocellulosic biomass sources, such as agricultural and forestry residues and herbaceous and woody crops, provides unique environmental, economic, and strategic benefits. Through sustained research funding, primarily by the U.S. Department of Energy, the estimated cost of biomass ethanol production has dropped from ∼$4.63/gallon in 1980 to ∼$1.22/gallon today, and it is now potentially competitive for blending with gasoline. Advances in pretreatment by acid-catalyzed hemicellulose hydrolysis and enzymes for cellulose breakdown coupled with recent development of genetically engineered bacteria that ferment all five sugars in biomass to ethanol at high yields have been the key to reducing costs. However, through continued advances in accessing the cellulose and hemicellulose fractions, the cost of biomass ethanol can be reduced to the point at which it is competitive as a pure fuel without subsidies. A major challenge to realizing the great benefits of biomass ethanol remains to substantially reduce the risk of commercializing first-of-a-kind technology, and greater emphasis on developing a fundamental understanding of the technology for biomass conversion to ethanol would reduce application costs and accelerate commercialization. Teaming of experts to cooperatively research key processing steps would be a particularly powerful and effective approach to meeting these needs.
A REVIEW OF TECHNICAL CHANGE IN ASSESSMENT OF CLIMATE POLICY
Authors: Azar Christian , Dowlatabadi Hadi
Published: July 2002

▪ Abstract  Climate policy is often discussed as a lever with which to bring about climate-friendly technical innovation and diffusion. However, quantitative policy assessments routinely treat technological change as a factor that is independent of policy. Stabilizing atmospheric concentrations of CO2 cannot be achieved through marginal changes in the way we supply and use energy. The only path to stabilization of climate over the next century that is consistent with widely accepted population and economic-growth scenarios involves substantial decoupling of energy services from carbon emissions. The required rate of structural and technical change for such a goal has been experienced only in the wake of economic and resource crises and for periods of a decade or less. Historic rates of structural and technical change averaged over a century are far from adequate for stabilizing climate. In this paper, we review technical changes in the energy system and a few instances in which energy economic models have begun to include technical change as an endogenous feature of their assessments. Finally, we consider the implications of considering endogenous technical change for critical climate policy questions, such as the cost of control and the appropriate timing of the emissions mitigation effort.
INDICATORS OFENERGYUSE ANDCARBONEMISSIONS: Explaining the Energy Economy Link
Authors: Schipper Lee , Unander Fridtjof , Murtishaw Scott , Ting Mike
Published: July 2002

▪ Abstract  This article reviews energy indicators, which are developed to describe the links between energy use and human activity in a disaggregated manner. After briefly reviewing a number of early and current efforts to develop indicators, we discuss the basic concepts of various indicators and the methodologies used to derive them. We also review the use of decomposition methods to aid in the analysis of trends in energy use and comparisons of uses between countries. Findings from our comparative and time-series analyses of several industrialized countries illustrate the application of these methods. Using simplified methods for estimating the carbon released in direct combustion of fossil fuels, and in electricity and heat production, energy indicators can be extended to carbon emissions. These carbon indicators can play an important role in aiding negotiations over carbon reduction targets and evaluating progress toward meeting abatement goals.
BIOLOGY AND USE OF THE WHITEFLY PARASITOIDENCARSIA FORMOSA
Authors: Hoddle M. S. , Van Driesche R. G. , Sanderson J. P.
Published: July 2002

▪ Abstract  Encarsia formosa is a parasitoid used worldwide for the biological control of whiteflies on vegetables and ornamental plants grown in greenhouses. Because of outstanding success in controlling Trialeurodes vaporariorum on tomatoes, the biology and behavior of this wasp have been intensively studied to identify attributes that contribute to successful biological control and how best to manipulate augmentative releases into greenhouses to suppress whitefly population growth. In this article, we review the biology of adult and immature E. formosa, population dynamics of whitefly-parasitoid interactions, and commercial use in greenhouses. Deficits in knowledge of aspects of E. formosa's biology and use are noted.
Blood Barriers of the Insect
Authors: Carlson Stanley D. , Juang Jyh-Lyh , Hilgers Susan L. , Garment Martin B.
Published: July 2002

▪ Abstract  The blood-brain barrier (BBB) ensures brain function in vertebrates and insects by maintaining ionic integrity of the neuronal bathing fluid. Without this barrier, paralysis and death ensue. The structural analogs of the BBB are occlusive (pleated-sheet) septate and tight junctions between perineurial cells, glia and perineurial cells, and possibly between glia. Immature Diptera have such septate junctions (without tight junctions) while both junctional types are found in the imago. Genetic and molecular biology of these junctions are discussed, namely tight (occludin) and pleated-sheet septate (neurexin IV). A temporal succession of blood barriers form in immature Diptera. The first barrier forms in the peripheral nervous system where pleated-sheet septate junctions bond cells of the nascent (embryonic) chordotonal organs in early neurogenesis. At the end of embryonic life, the central nervous system is fully vested with a blood-brain barrier. A blood-eye barrier arises in early pupal life. Future prospects in blood-barrier research are discussed.
Robert Legendre and Henri Werlé: Toward the Elucidation of Three-Dimensional Separation
Authors: Délery Jean M
Published: July 2002

▪ Abstract  The description and the physical understanding of three-dimensional separated flows are challenging problems mainly because of the use of inappropriate terms linked to the consideration of two-dimensional flows. This fact was realized in the early 1950s by Robert Legendre, who introduced the basic concepts of the Critical Point Theory to provide a rational definition of separation in three-dimensional flows. In parallel, demonstrative experiments were executed by Henri Werlé in the Onera water tunnel laboratory. From the close cooperation between these two scientists resulted the construction of a powerful theoretical tool allowing the elucidation of the structure of largely separated three-dimensional fields. The importance of their contribution to fluid mechanics is illustrated here by the consideration of basic configurations: flow past wings or elongated bodies, in front of obstacles, and behind a base. For each case, the flow organization is discussed by considering representative water tunnel visualizations and corresponding topological interpretations.
DRAGDUE TOLIFT: Concepts for Prediction and Reduction
Authors: Kroo Ilan
Published: July 2002

▪ Abstract  This article describes some of the fundamental ideas underlying methods for induced-drag prediction and reduction. A review of current analysis and design methods, including their development and common approximations, is followed by a survey of several approaches to lift-dependent drag reduction. Recent concepts for wing planform optimization, highly nonplanar surfaces, and various tip devices may lead to incremental but important gains in aircraft performance. Focusing on relatively high-aspect-ratio subsonic wings, the review suggests that opportunities for new concepts remain, but the greatest challenge lies in their integration with other aspects of the system.
LAGRANGIANINVESTIGATIONS OFTURBULENCE
Authors: Yeung P. K.
Published: July 2002

▪ Abstract  A Lagrangian description of turbulence has unique physical advantages that are especially important in studies of mixing and dispersion. We focus on fundamental aspects, using mainly data from direct numerical simulations capable of great detail and precision when specific accuracy requirements are met. Differences between time evolution in Eulerian and Lagrangian frames illustrate the dominance of advective transport. We examine basic results in Kolmogorov similarity, giving an estimate of an inertial-range universal constant and the grid resolution and Reynolds number needed to attain the requisite scaling range of time lags. The Lagrangian statistics of passive scalars are discussed in view of current efforts in model development, with differential diffusion between multiple scalars being characterized by shorter timescales. We also note the need for new data in more complex flows and in other applications where a Lagrangian viewpoint is especially useful.
MOLECULAR MECHANISMS OF BACTERIOCIN EVOLUTION
Authors: Riley Margaret A.
Published: July 2002

▪ Abstract  Microorganisms are engaged in a never-ending arms race. One consequence of this intense competition is the diversity of antimicrobial compounds that most species of bacteria produce. Surprisingly, little attention has been paid to the evolution of such extraordinary diversity. One class of antimicrobials, the bacteriocins, has received increasing attention because of the high levels of bacteriocin diversity observed and the use of bacteriocins as preservatives in the food industry and as antibiotics in the human health industry. However, little effort has been focused on evolutionary questions, such as what are the phylogenetic relationships among these toxins, what mechanisms are involved in their evolution, and how do microorganisms respond to such an arsenal of weapons? The focus of this review is to provide a detailed picture of our current understanding of the molecular mechanisms involved in the process of bacteriocin diversification.
ROLE OF CYTOKINES IN RHEUMATOID ARTHRITIS
Authors: Feldmann Marc , Brennan Fionula M. , Maini Ravinder N.
Published: July 2002

▪ Abstract  Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed that many proinflammatory cytokines such as TNFα, IL-1, IL-6, GM-CSF, and chemokines such as IL-8 are abundant in all patients regardless of therapy. This is compensated to some degree by the increased production of anti-inflammatory cytokines such as IL-10 and TGFβ and cytokine inhibitors such as IL-1ra and soluble TNF-R. However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNFα and IL-1 produced.

In rheumatoid joint cell cultures that spontaneously produce IL-1, TNFα was the major dominant regulator of IL-1. Subsequently, other proinflammatory cytokines were also inhibited if TNFα was neutralized, leading to the new concept that the proinflammatory cytokines were linked in a network with TNFα at its apex. This led to the hypothesis that TNFα was of major importance in rheumatoid arthritis and was a therapeutic target. This hypothesis has been successfully tested in animal models, of, for example, collagen-induced arthritis, and these studies have provided the rationale for clinical trials of anti-TNFα therapy in patients with long-standing rheumatoid arthritis. Several clinical trials using a chimeric anti-TNFα antibody have shown marked clinical benefit, verifying the hypothesis that TNFα is of major importance in rheumatoid arthritis. Retreatment studies have also shown benefit in repeated relapses, indicating that the disease remains TNFα dependent. Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.
Anti-TNFα Therapy of Rheumatoid Arthritis: What Have We Learned?
Authors: Feldmann Marc , Maini Ravinder N.
Published: July 2002

Rheumatoid arthritis (RA), a systemic disease, is characterized by a chronic inflammatory reaction in the synovium of joints and is associated with degeneration of cartilage and erosion of juxta-articular bone. Many pro-inflammatory cytokines including TNFα, chemokines, and growth factors are expressed in diseased joints. The rationale that TNFα played a central role in regulating these molecules, and their pathophysiological potential, was initially provided by the demonstration that anti-TNFα antibodies added to in vitro cultures of a representative population of cells derived from diseased joints inhibited the spontaneous production of IL-1 and other pro-inflammatory cytokines. Systemic administration of anti-TNFα antibody or sTNFR fusion protein to mouse models of RA was shown to be anti-inflammatory and joint protective. Clinical investigations in which the activcity of TNFα in RA patients was blocked with intravenously administered infliximab, a chimeric anti-TNFα monoclonal antibody (mAB), has provided evidence that TNF regulates IL-6, IL-8, MCP-1, and VEGF production, recruitment of immune and inflammatory cells into joints, angiogenesis, and reduction of blood levels of matrix metalloproteinases-1 and -3. Randomized, placebo-controlled, multi-center clinical trials of human TNFα inhibitors have demonstrated their consistent and remarkable efficacy in controlling signs and symptoms, with a favorable safety profile, in approximately two thirds of patients for up to 2 years, and their ability to retard joint damage. Infliximab (a mAB), and etanercept (a sTNF-R-Fc fusion protein) have been approved by regulatory authorities in the United States and Europe for treating RA, and they represent a significant new addition to available therapeutic options.
LEFT VENTRICULAR REMODELING AFTER ACUTE MYOCARDIAL INFARCTION
Authors: Pfeffer, M.D., Ph.D Marc A.
Published: July 2002

▪ Abstract  The loss of myocytes as a consequence of myocardial infarction results in a prompt reduction in regional wall motion and often leads to more protracted and progressive changes in ventricular architecture. The recognition that the process of ventricular enlargement following myocardial infarction is modifiable provided the initial rationale for the use of angiotensin-converting enzyme (ACE) inhibitors as therapy to prevent deterioration in ventricular size and function following infarction. Experimental and clinical studies have documented the effectiveness of this therapy in preventing this late enlargement following infarction. Increasing clinical evidence indicates that this new use of ACE inhibitor therapy in survivors of acute myocardial infarction will lead to an improvement in clinical outcome.
ROLE OF PHOSPHATIDYLINOSITOL-LINKED PROTEINS IN PAROXYSMAL NOCTURNAL HEMOGLOBINURIA PATHOGENESIS
Authors: Kinoshita, M.D Taroh , Inoue, M.D Norimitsu , Takeda, M.D Junji
Published: July 2002

▪ Abstract  Patients with paroxysmal nocturnal hemoglobinuria have one or more mutant hematopoietic stem cell clones deficient in glycosylphosphatidylinositol (GPI)-anchor synthesis owing to somatic mutations in the X-linked gene PIG-A. The progeny of mutant stem cells dominates the peripheral blood. The presence of a large number of GPI-anchor deficient, complement-sensitive erythrocytes leads to hemolytic anemia. The somatic mutations in PIG-A are small, various, and widely distributed in the coding regions and splice sites, indicating they occur randomly. Profiles of the mutations vary geographically, suggesting the presence of mutagen-induced mutations. The clonal dominance by the mutants does not seem to be solely due to the PIG-A mutation but may be caused either by autonomous expansion of the mutants due to a combination of the PIG-A mutation and some other genetic change(s) or by selection that preferentially suppresses normal stem cells.
Diagnosis and Treatment of Pre–Insulin Dependent Diabetes
Authors: Gottlieb P. A. , Eisenbarth G. S.
Published: July 2002

The development of genetic and serological markers of autoimmune Type I diabetes has allowed us to begin to identify subjects at risk for the development of Type I diabetes. Assessment of these variables can assign risk to subjects and permit the implementation of immune intervention trials in an attempt to alter the course of pre-diabetes. This review discusses relevant aspects of the genetics and diagnosis of pre-diabetes, and both current and future clinical trials that are attempting to prevent the full expression of clinical diabetes in these individuals.
New Considerations in the Treatment of Sickle Cell Disease
Authors: Reed W. , Vichinsky E. P.
Published: July 2002

The familial pattern of recurring pain and early death seen so often among those affected by sickle cell disease has been long recognized within African cultures, though its first clear description in Western medical literature did not appear until 1910 ( 1 ). Although most common in persons of African ancestry, the mutation giving rise to the sickle gene arose independently in several locations where malaria was prevalent ( 2 ), traveled with migrating populations, and is now widely distributed among regions and ethnic groups. Recognizing the qualitative abnormality of sickle hemoglobin as a prototype, Pauling & Castle established the notion of a molecular disease ( 3 ). Ironically, while the biochemistry and molecular biology of sickle cell disease has been intensively investigated, research into patient care has been limited in scope until recently. Prospective study of large patient groups diagnosed at birth is now providing insight into the disease's natural history and facilitating investigational treatments. Newborn diagnosis, combined with study of new drugs, cytokines, surgical procedures, and a more proactive utilization of transfusion is leading to greatly improved care and survival. Life expectancy is increasing ( 4 ) but adults are experiencing more complications of chronic organ dysfunction. A few patients have been cured by stem-cell transplantation, but difficult problems will continue to limit its application.
Progress Toward an HIV Vaccine
Authors: Letvin Norman L.
Published: July 2002

The development of an HIV vaccine is proving to be an unprecedented challenge. The difficulty in creating this vaccine arises from the enormous genetic variation of the virus and the unusual importance of cytotoxic T lymphocytes (CTL) in controlling its spread. Whereas traditional vaccine strategies are unlikely to confer safe and effective HIV protection, novel strategies for eliciting CTL have provided substantial clinical benefits in nonhuman primate model systems. These vaccine strategies, including plasmid DNA and live recombinant vectors, are currently being evaluated in human clinical trials.
Immune Checkpoints in Viral Latency
Authors: Redpath Stella , Angulo Ana , Gascoigne Nicholas R. J. , Ghazal Peter
Published: July 2002

▪ Abstract  The dynamics of the relationship between the immune system and latent viruses are highly complex. Latent viruses not only avoid elimination by the host's primary immune response, they also remain with the host for life in the presence of strong acquired immunity, often exhibiting periodic reactivation and recurrence from the latent state. The continual battle between reemergent infectious virus and immunological memory cells provides an essential virus-host regulatory loop in latency. In this review, we speculate on the critical importance of immune interference mechanisms by viruses contributing to the regulatory loop in viral homeostasis of latency. Central to the notion of viral homeostasis, we further invoke the concept of threshold limits in naive and memory states of immunity to account for the failure of the host to completely eradicate these intracellular parasites.
ARIA: A Neuromuscular Junction Neuregulin
Authors: Fischbach Gerald D. , Rosen Kenneth M.
Published: July 2002

▪ Abstract  Motor neurons influence the expression and the distribution of acetylcholine receptors in skeletal muscle. Molecules that mediate this carefully choreographed interaction have recently been identified. One of them, ARIA, is a polypeptide purified from chicken brain on the basis of its ability to stimulate the synthesis of muscle acetylcholine receptors. The predicted amino acid sequence suggests that ARIA is synthesized as a transmembrane precursor protein and that it is a member of a family of ligands that activate receptor tyrosine kinases related to the epidermal growth factor receptor. Certain features of the ligand family (the neuregulins) and their receptors (erbBs) are reviewed. Evidence that ARIA plays an important role at developing and mature neuromuscular junctions is discussed.
Cortical and Subcortical Contributions to Activity-Dependent Plasticity in Primate Somatosensory Cortex
Authors: Jones Edward G.
Published: July 2002

After manipulations of the periphery that reduce or enhance input to the somatosensory cortex, affected parts of the body representation will contract or expand, often over many millimeters. Various mechanisms, including divergence of preexisting connections, expression of latent synapses, and sprouting of new synapses, have been proposed to explain such phenomena, which probably underlie altered sensory experiences associated with limb amputation and peripheral nerve injury in humans. Putative cortical mechanisms have received the greatest emphasis but there is increasing evidence for substantial reorganization in subcortical structures, including the brainstem and thalamus, that may be of sufficient extent to account for or play a large part in representational plasticity in somatosensory cortex. Recent studies show that divergence of ascending connections is considerable and sufficient to ensure that small alterations in map topography at brainstem and thalamic levels will be amplified in the projection to the cortex. In the long term, slow, deafferentation-dependent transneuronal atrophy at brainstem, thalamic, and even cortical levels are operational in promoting reorganizational changes, and the extent to which surviving connections can maintain a map is a key to understanding differences between central and peripheral deafferentation.
Microtubule-Based Transport Systems in Neurons: The Roles of Kinesins and Dyneins
Authors: Goldstein Lawrence S. B. , Yang Zhaohuai
Published: July 2002

The large size and extreme polarization of neurons is crucial to their ability to communicate at long distances and to form the complex cellular networks of the nervous system. The size, shape, and compartmentalization of these specialized cells must be generated and supported by the cytoskeletal systems of intracellular transport. One of the major systems is the microtubule-based transport system along which kinesin and dynein motor proteins generate force and drive the traffic of many cellular components. This review describes our current understanding of the functions of kinesins and dyneins and how these motor proteins may be harnessed to generate some of the unique properties of neuronal cells.
MEASUREMENT OF SMALL ELECTRON-BEAM SPOTS
Authors: Tenenbaum Peter , Shintake Tsumoru
Published: July 2002

▪ Abstract  Measurements of transverse beam size are tremendously important to the performance of e+e− linear colliders. In this paper we review the traditional technologies used to make such measurements, such as profile monitors and wire scanners, and their limitations. We introduce a new technique for electron beam-size measurement: Compton-scattered laser light, which may be used as an unbreakable “wire” or in the form of an interferometer beam-size monitor (BSM). We describe the use of such an interferometer BSM, noting both the general issues related to its design and operation and the specific experiences with such an interferometer at the Final Focus Test Beam at SLAC. We conclude by considering the ultimate limitations of the laser-interferometer BSM.
CERULOPLASMIN METABOLISM AND FUNCTION
Authors: Hellman Nathan E. , Gitlin Jonathan D.
Published: July 2002

▪ Abstract  Ceruloplasmin is a serum ferroxidase that contains greater than 95% of the copper found in plasma. This protein is a member of the multicopper oxidase family, an evolutionarily conserved group of proteins that utilize copper to couple substrate oxidation with the four-electron reduction of oxygen to water. Despite the need for copper in ceruloplasmin function, this protein plays no essential role in the transport or metabolism of this metal. Aceruloplasminemia is a neurodegenerative disease resulting from inherited loss-of-function mutations in the ceruloplasmin gene. Characterization of this disorder revealed a critical physiological role for ceruloplasmin in determining the rate of iron efflux from cells with mobilizable iron stores and has provided new insights into human iron metabolism and nutrition.
CYTOCHROME P-450 3A4: Regulation and Role in Drug Metabolism
Authors: Guengerich F. Peter
Published: July 2002

▪ Abstract  Cytochrome P-450 (P-450) 3A4 is the most abundant P-450 expressed in human liver and small intestine. P-450 3A4 contributes to the metabolism of approximately half the drugs in use today, and variations in its catalytic activity are important in issues of bioavailability and drug-drug interactions. The gene is known to be inducible by barbiturates, glucocorticoids, and rifampicin in humans and in isolated hepatocytes, although the mechanism remains unclear. The 5′-untranslated region includes putative basal transcription element, hepatocyte nuclear factor, p53, AP-3, glucocorticoid regulatory element, pregnane X receptor, and estrogen receptor element sequences. Recently, the GRE element has been shown to act in a classic glucocorticoid response. Several issues remain to be resolved regarding the catalytic activity of the P-450 3A4 protein, including rate-limiting steps and the need for cytochrome b5, divalent cations, and acidic phospholipid systems for optimal activity. Another issue involves the basis of the homotropic and heterotropic cooperativity seen with the enzyme. The in vivo significance of these findings remains to be further established. In addition to more basic studies on P-450 3A4, several areas of practical interest to the pharmaceutical industry require development.
REDOX REGULATION OF c-Ha-ras AND OSTEOPONTIN SIGNALING IN VASCULAR SMOOTH MUSCLE CELLS: Implications in Chemical Atherogenesis
Authors: Ramos Kenneth S.
Published: July 2002

▪ Abstract  Reduction/oxidation (redox) reactions play a central role in the regulation of vascular cell functions. Recent studies in this laboratory have identified c-Ha-ras and osteopontin genes as critical molecular targets during oxidant-induced atherogenesis. This review focuses on the deregulation of gene transcription by redox-activated trans-acting factors after benzo(a)pyrene challenge and the modulation of extracellular matrix signaling in vascular smooth muscle cells by allylamine-induced oxidative injury. The induction of atherogenic vascular smooth muscle cell phenotypes by chemical injury exhibits remarkable parallels with those seen in other forms of atherogenesis.
Mitochondrial Targets of Drug Toxicity
Authors: Wallace K. B. , Starkov A. A.
Published: July 2002

Mitochondria have long been recognized as the generators of energy for the cell. Like any other power source, however, mitochondria are highly vulnerable to inhibition or uncoupling of the energy harnessing process and run a high risk for catastrophic damage to the cell. The exquisite structural and functional characteristics of mitochondria provide a number of primary targets for xenobiotic-induced bioenergetic failure. They also provide opportunities for selective delivery of drugs to the mitochondrion. In light of the large number of natural, commercial, pharmaceutical, and environmental chemicals that manifest their toxicity by interfering with mitochondrial bioenergetics, it is important to understand the underlying mechanisms. The significance is further underscored by the recent identification of bioenergetic control points for cell replication and differentiation and the realization that mitochondria play a determinant role in cell signaling and apoptotic modes of cell death.
Regulation, Function, and Tissue-Specific Expression of Cytochrome P450 CYP1B1
Authors: Murray Graeme I , Melvin William T , Greenlee William F , Burke M Danny
Published: July 2002

Cytochrome P450 CYP1B1 is a relatively recently identified member of the CYP1 gene family. The purpose of this commentary is to review the regulatory mechanisms, metabolic specificity, and tissue-specific expression of this cytochrome P450 and to highlight its unique properties. The regulation of CYP1B1 involves a variety of both transcriptional and post-transcriptional mechanisms. CYP1B1 can metabolize a range of toxic and carcinogenic chemicals in vitro but in some cases with a unique stereoselectivity. Estradiol 4-hydroxylation appears to be a characteristic reaction catalyzed by human CYP1B1. However, there are considerable species differences regarding the regulation, metabolic specificity, and tissue-specific expression of this P450. In humans CYP1B1 is overexpressed in tumor cells, and this has important implications for tumor development and progression and the development of anticancer drugs specifically activated by CYP1B1.
Structure, Function, and Inhibition of Chemokines
Authors: Fernandez Elias J. , Lolis Elias
Published: July 2002

Chemokines are the largest family of cytokines in human immunophysiology. These proteins are defined by four invariant cysteines and are categorized based on the sequence around the first two cysteines, which leads to two major and two minor subfamilies. Chemokines function by activating specific G protein–coupled receptors, which results in, among other functions, the migration of inflammatory and noninflammatory cells to the appropriate tissues or compartments within tissues. Some of these proteins and receptors have been implicated or shown to be involved in inflammation, autoimmune diseases, and infection by HIV-1. The three-dimensional structure of each monomer is virtually identical, but the quaternary structure of chemokines is different for each subfamily. Structure-function studies reveal several regions of chemokines to be involved in function, with the N-terminal region playing a dominant role. A number of proteins and small-molecule antagonists have been identified that inhibit chemokine activities. In this review, we discuss aspects of the structure, function, and inhibition of chemokines.
STATE-RESOLVED COLLISION-INDUCED ELECTRONIC TRANSITIONS
Authors: Dagdigian Paul J.
Published: July 2002

▪ Abstract  Laser and molecular beam techniques have enabled researchers to determine the rovibrational levels populated in collision-induced electronic transitions from specified initial levels of several diatomic molecules. As exemplified by the N2+– and CN–rare-gas systems, such measurements, in combination with theoretical calculations of cross sections for these state-to-state collisional processes, provide a means to understand in detail the dynamics of these electronic quenching and energy transfer processes. The present article reviews state-to-state studies of collision-induced electronic transitions. The various collision systems studied provide examples of both perturbation-assisted “gateways” between the initial and final electronic states and perturbation-independent transitions enabled by nonadiabatic mixing induced by the collision partner.