bluuebunny/crossref_metadata_2025 huggingface dataset:
KINETOCHORES AND THE CHECKPOINT MECHANISM THAT MONITORS FOR DEFECTS IN THE CHROMOSOME SEGREGATION MACHINERY
Authors: Skibbens Robert V. , Hieter Philip
Published: July 2002

▪ Abstract  Whether we consider the division of the simplest unicellular organisms into two daughter cells or the generation of haploid gametes by the most complex eukaryotes, no two processes secure the continuance of life more than the proper replication and segregation of the genetic material. The cell cycle, marked in part by the periodic rise and fall of cyclin-dependent kinase (CDK) activities, is the means by which these two processes are separated. DNA damage and mistakes in chromosome segregation are costly, so nature has further devised elaborate checkpoint mechanisms that halt cell cycle progression, allowing time for repairs or corrections. In this article, we review the mitotic checkpoint mechanism that responds to defects in the chromosome segregation machinery and arrests cells in mitosis prior to anaphase onset. At opposite ends of this pathway are the kinetochore, where many checkpoint proteins reside, and the anaphase-promoting complex (APC), the metaphase-to-interphase transition regulator. Throughout this review we focus on budding yeast but reference parallel processes found in other organisms.
Genetic Screening of Newborns
Authors: Levy Harvey L. , Albers Simone
Published: July 2002

Screening of newborn infants for genetic disease began over 35 years ago as a public health measure to prevent mental retardation in phenylketonuria (PKU). It was so successful that tests for several other genetic disorders were added. We review the current status of this screening, including discussions of the genetic disorders often covered and the results of newborn screening for them. We emphasize recent advances. These include expansion of coverage for genetic disorders with the new methodology of tandem mass spectrometry (MS-MS) and the introduction of molecular (DNA) testing to increase the specificity of testing for several disorders, thereby reducing false-positive rates. These and other advances have also produced issues of criteria for screening, missed cases, and appropriate use of stored newborn specimens.
Genome Organization, Function, and Imprinting in Prader-Willi and Angelman Syndromes
Authors: Nicholls Robert D. , Knepper Jessica L.
Published: July 2002

The chromosomal region, 15q11-q13, involved in Prader-Willi and Angelman syndromes (PWS and AS) represents a paradigm for understanding the relationships between genome structure, epigenetics, evolution, and function. The PWS/AS region is conserved in organization and function with the homologous mouse chromosome 7C region. However, the primate 4 Mb PWS/AS region is bounded by duplicons derived from an ancestral HERC2 gene and other sequences that may predispose to chromosome rearrangements. Within a 2 Mb imprinted domain, gene function depends on parental origin. Genetic evidence suggests that PWS arises from functional loss of several paternally expressed genes, including those that function as RNAs, and that AS results from loss of maternal UBE3A brain-specific expression. Imprinted expression is coordinately controlled in cis by an imprinting center (IC), a genetic element functional in germline and/or early postzygotic development that regulates the establishment of parental specific allelic differences in replication timing, DNA methylation, and chromatin structure.
T CELL ANTIGEN RECEPTOR SIGNAL TRANSDUCTION PATHWAYS
Authors: Cantrell Doreen
Published: July 2002

▪ Abstract  The T cell antigen receptor (TCR) regulates the activation and growth of T lymphocytes. The initial membrane proximal event triggered by the TCR is activation of protein tyrosine kinases with the resultant phosphorylation of cellular proteins. This biochemical response couples the TCR to a divergent array of signal transduction molecules including enzymes that regulate lipid metabolism, GTP binding proteins, serine/threonine kinases, and adapter molecules. The ultimate aim of studies of intracellular signaling mechanisms is to understand the functional consequences of a particular biochemical event for receptor function. The control of cytokine gene expression is one of the mechanisms that allows the TCR to control immune responses. Accordingly, one object of the present review is to discuss the role of the different TCR signal transduction pathways in linking the TCR to nuclear targets: the transcription factors that control the expression of cytokine genes.
JAKS AND STATS: Biological Implications
Authors: Leonard Warren J. , O'Shea John J.
Published: July 2002

▪ Abstract  Cytokines and interferons are molecules that play central roles in the regulation of a wide array of cellular functions in the lympho-hematopoietic system. These factors stimulate proliferation, differentiation, and survival signals, as well as specialized functions in host resistance to pathogens. Although cytokines are known to activate multiple signaling pathways that together mediate these important functions, one of these pathways, the Jak-STAT pathway, is the focus of this chapter. This pathway is triggered by both cytokines and interferons, and it very rapidly allows the transduction of an extracellular signal into the nucleus. The pathway uses a novel mechanism in which cytosolic latent transcription factors, known as signal transducers and activators of transcription (STATs), are tyrosine phosphorylated by Janus family tyrosine kinases (Jaks), allowing STAT protein dimerization and nuclear translocation. STATs then can modulate the expression of target genes. The basic biology of this system, including the range of known Jaks and STATs, is discussed, as are the defects in animals and humans lacking some of these signaling molecules.
THE DYNAMICS OF T CELL RECEPTOR SIGNALING: Complex Orchestration and the Key Roles of Tempo and Cooperation
Authors: Germain Ronald N. , Stefanová Irena
Published: July 2002

▪ Abstract  T cells constantly sample their environment using receptors (TCR) that possess both a germline-encoded low affinity for major histocompatibility complex (MHC) molecules and a highly diverse set of CDR3 regions contributing to a range of affinities for specific peptides bound to these MHC molecules. The decision of a T cell “to sense and to respond” with proliferation and effector activity rather than “to sense, live on, but not respond” is dependent on TCR interaction with a low number of specific foreign peptide:MHC molecule complexes recognized simultaneously with abundant self peptide-containing complexes. Interaction with self-complexes alone, on the other hand, generates a signal for survival without a full activation response. Current models for how this distinction is achieved are largely based on translating differences in receptor affinity for foreign versus self ligands into intracellular signals that differ in quality, intensity, and/or duration. A variety of rate-dependent mechanisms involving assembly of molecular oligomers and enzymatic modification of proteins underlie this differential signaling. Recent advances have been made in measuring TCR:ligand interactions, in understanding the biochemical origin of distinct proximal and distal signaling events resulting from TCR binding to various ligands, and in appreciating the role of feedback pathways. This new information can be synthesized into a model of how self and foreign ligand recognition each evoke the proper responses from T cells, how these two classes of signaling events interact, and how pathologic responses may arise as a result of the underlying properties of the system. The principles of signal spreading and stochastic resonance incorporated into this model reveal a striking similarity in mechanisms of decision-making among T cells, neurons, and bacteria.
IMMUNODOMINANCE IN MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I–RESTRICTED T LYMPHOCYTE RESPONSES
Authors: Yewdell Jonathan W. , Bennink Jack R.
Published: July 2002

▪ Abstract  Of the many thousands of peptides encoded by a complex foreign antigen that can potentially be presented to CD8+ T cells (TCD8+), only a small fraction induce measurable responses in association with any given major histocompatibility complex class I allele. To design vaccines that elicit optimal TCD8+responses, a thorough understanding of this phenomenon, known as immunodominance, is imperative. Here we review recent progress in unraveling the molecular and cellular basis for immunodominance. Of foremost importance is peptide binding to class I molecules; only ∼1/200 of potential determinants bind at greater than the threshold affinity (Kd> 500 nM) associated with immunogenicity. Limitations in the TCD8+repertoire render approximately half of these peptides nonimmunogenic, and inefficient antigen processing further thins the ranks by approximately four fifths. As a result, only ∼1/2000 of the peptides in a foreign antigen expressed by an appropriate antigen presenting cell achieve immunodominant status with a given class I allele. A roughly equal fraction of peptides have subdominant status, i.e. they induce weak-to-nondetectable primary TCD8+responses in the context of their natural antigen. Subdominant determinants may be expressed at or above levels of immunodominant determinants, at least on antigen presenting cells in vitro. The immunogenicity of subdominant determinants is often limited by immunodomination: suppression mediated by TCD8+specific for immunodominant determinants. Immunodomination is a central feature of TCD8+responses, as it even occurs among clones responding to the same immunodominant determinant. Little is known about how immunodominant and subdominant determinants are distinguished by the TCD8+repertoire, or how (and why) immunodomination occurs, but new tools are available to address these questions.
An Address System in the Vasculature of Normal Tissues and Tumors
Authors: Ruoslahti E. , Rajotte D.
Published: July 2002

The vasculature of individual tissues is highly specialized. The endothelium in lymphoid tissues expresses tissue-specific receptors for lymphocyte homing, and recent work utilizing phage homing has revealed an unprecedented degree of specialization in the vasculature of other normal tissues. In vivo screening of libraries of phage that displace random peptide sequences on their surfaces has yielded specific homing peptides for a large number of normal tissues. The tissue-specific endothelial molecules to which the phage peptides home may serve as receptors for metastasizing malignant cells. Probing of tumor vasculature has yielded peptides that home to endothelial receptors expressed selectively in angiogenic neovasculature. These receptors, and those specific for the vasculature of individual normal tissues, are likely to be useful in targeting therapies to specific sites.
The Bare Lymphocyte Syndrome and the Regulation of MHC Expression
Authors: Reith Walter , Mach Bernard
Published: July 2002

The bare lymphocyte syndrome (BLS) is a hereditary immunodeficiency resulting from the absence of major istocompatibility complex class II (MHCII) expression. Considering the central role of MHCII molecules in the development and activation of CD4+T cells, it is not surprising that the immune system of the patients is severely impaired. BLS is the prototype of a “disease of gene regulation.” The affected genes encode RFXANK, RFX5, RFXAP, and CIITA, four regulatory factors that are highly specific and essential for MHCII genes. The first three are subunits of RFX, a trimeric complex that binds to all MHCII promoters. CIITA is a non-DNA-binding coactivator that functions as the master control factor for MHCII expression. The study of RFX and CIITA has made major contributions to our comprehension of the molecular mechanisms controlling MHCII genes and has made this system into a textbook model for the regulation of gene expression.
Interleukin-18 Regulates Both Th1 and Th2 Responses
Authors: Nakanishi Kenji , Yoshimoto Tomohiro , Tsutsui Hiroko , Okamura Haruki
Published: July 2002

Although interleukin-18 is structurally homologous to IL-1 and its receptor belongs to the IL-1R/Toll-like receptor (TLR) superfamily, its function is quite different from that of IL-1. IL-18 is produced not only by types of immune cells but also by non-immune cells. In collaboration with IL-12, IL-18 stimulates Th1-mediated immune responses, which play a critical role in the host defense against infection with intracellular microbes through the induction of IFN-γ. However, the overproduction of IL-12 and IL-18 induces severe inflammatory disorders, suggesting that IL-18 is a potent proinflammatory cytokine that has pathophysiological roles in several inflammatory conditions. IL-18 mRNA is expressed in a wide range of cells including Kupffer cells, macrophages, T cells, B cells, dendritic cells, osteoblasts, keratinocytes, astrocytes, and microglias. Thus, the pathophysiological role of IL-18 has been extensively tested in the organs that contain these cells. Somewhat surprisingly, IL-18 alone can stimulate Th2 cytokine production as well as allergic inflammation. Therefore, the functions of IL-18 in vivo are very heterogeneous and complicated. In principle, IL-18 enhances the IL-12-driven Th1 immune responses, but it can also stimulate Th2 immune responses in the absence of IL-12.
Genetic Dissection of Immunity to Mycobacteria: The Human Model
Authors: Casanova Jean-Laurent , Abel Laurent
Published: July 2002

Humans are exposed to a variety of environmental mycobacteria (EM), and most children are inoculated with live Bacille Calmette-Guérin (BCG) vaccine. In addition, most of the world's population is occasionally exposed to human-borne mycobacterial species, which are less abundant but more virulent. Although rarely pathogenic, mildly virulent mycobacteria, including BCG and most EM, may cause a variety of clinical diseases. Mycobacterium tuberculosis, M. leprae, and EM M. ulcerans are more virulent, causing tuberculosis, leprosy, and Buruli ulcer, respectively. Remarkably, only a minority of individuals develop clinical disease, even if infected with virulent mycobacteria. The interindividual variability of clinical outcome is thought to result in part from variability in the human genes that control host defense. In this well-defined microbiological and clinical context, the principles of mouse immunology and the methods of human genetics can be combined to facilitate the genetic dissection of immunity to mycobacteria. The natural infections are unique to the human model, not being found in any of the animal models of experimental infection. We review current genetic knowledge concerning the simple and complex inheritance of predisposition to mycobacterial diseases in humans. Rare patients with Mendelian disorders have been found to be vulnerable to BCG, a few EM, and M. tuberculosis. Most cases of presumed Mendelian susceptibility to these and other mycobacterial species remain unexplained. In the general population leprosy and tuberculosis have been shown to be associated with certain human genetic polymorphisms and linked to certain chromosomal regions. The causal vulnerability genes themselves have yet to be identified and their pathogenic alleles immunologically validated. The studies carried out to date have been fruitful, initiating the genetic dissection of protective immunity against a variety of mycobacterial species in natural conditions of infection. The human model has potential uses beyond the study of mycobacterial infections and may well become a model of choice for the investigation of immunity to infectious agents.
CERAMIC SCINTILLATORS
Authors: Greskovich C. , Duclos S.
Published: July 2002

▪ Abstract  Scintillators are the primary radiation sensor in many applications such as medical diagnostics, medical radiographs, and industrial component inspection. Some of the limitations in the properties of single-crystal scintillators are discussed for imaging applications, and the advantages of a new class of polycrystalline ceramic scintillators are described in detail. After the important scintillator properties of transparency, X-ray stopping power, light output, primary speed, luminescent afterglow, and radiation damage are described, the processing and performance of ceramic scintillators (Y,Gd)2O3:Eu,Pr; Gd2O2S:Pr,Ce,F; and Gd3Ga5O12:Cr,Ce are discussed. Ceramic scintillator uses and trends are presented in light of issues related to their uses in advanced medical and industrial X-ray detectors for CT imaging applications. Finally, some of the challenges are given for successfully developing a polycrystalline ceramic scintillator for use in photon-counting applications.
NANOCRYSTALLINE DIAMOND FILMS
Authors: Gruen Dieter M.
Published: July 2002

▪ Abstract  The synthesis of nanocrystalline diamond films from carbon-containing noble gas plasmas is described. The nanocrystallinity is the result of new growth and nucleation mechanisms, which involve the insertion of C2, carbon dimer, into carbon-carbon and carbon-hydrogen bonds, resulting in hetereogeneous nucleation rates on the order 1010cm−2s−1. Extensive characterization studies led to the conclusion that phase-pure diamond is produced with a microstructure consisting of randomly oriented 3–15-nm crystallites.

By adjusting the noble gas/hydrogen ratio in the gas mixture, a continuous transition from micro- to nanocrystallinity is achieved. Up to 10% of the total carbon in the nanocrystalline films is located at 2 to 4 atom-wide grain boundaries. Because the grain boundary carbon is π-bonded, the mechanical, electrical, and optical properties of nanocrystalline diamond are profoundly altered.

Nanocrystalline diamond films are unique new materials with applications in fields as diverse as tribology, cold cathodes, corrosion resistance, electrochemical electrodes, and conformal coatings on MEMS devices.
Mechanisms Involved in Osteoblast Response to Implant Surface Morphology
Authors: Boyan Barbara D , Lohmann Christoph H , Dean David D , Sylvia Victor L , Cochran David L , Schwartz Zvi
Published: July 2002

▪ Abstract  Osteoblasts respond to surface topography with altered morphology, proliferation, and differentiation. The effects observed vary with cell culture model and the topographical features of the surface. In general, increased surface roughness is associated with decreased proliferation and increased differentiation. Cell responses to hormones, growth factors, and cytokines are altered as well, as is autocrine production of these factors. The cells interact with the surface via integrin receptors, and their expression is also surface roughness-dependent. Integrin binding to cell attachment proteins activates signal transduction cascades, including those mediated by protein kinase C and phospholipase A2. These signaling pathways are also used by regulatory factors, which results in synergistic responses. Prostaglandins are important mediators of the surface effects, and both constitutive and inducible cyclooxygenase are involved.
THE MOLECULAR BASIS OF X-LINKED SEVERE COMBINED IMMUNODEFICIENCY: Defective Cytokine Receptor Signaling
Authors: Leonard, M.D Warren J.
Published: July 2002

▪ Abstract  X-linked severe combined immunodeficiency (XSCID) is an inherited disease characterized by profoundly diminished cell-mediated and humoral immunity. XSCID was found to result from mutations in the interleukin-2 (IL-2) receptor γchain. Knowledge of the genetic defect has important implications for prenatal and postnatal diagnosis, carrier female identification, and the possibility of gene therapy. The fact that the phenotype and clinical manifestations in XSCID are more severe than the abnormalities found in humans or mice deficient in IL-2 led to the speculation and subsequent confirmation that the IL-2 receptor is not the only receptor to contain the γ chain. Instead, the γ chain is also a component of the receptors for IL-4, IL-7, IL- 9, and IL-15 and is now denoted as the common cytokine receptor γ chain, γc. The role of γcin signaling and lymphoid development and the implications of a shared receptor component are discussed.
CENSUS AND CONSENSUS IN BACTERIAL ECOSYSTEMS: The LuxR-LuxI Family of Quorum-Sensing Transcriptional Regulators
Authors: Fuqua Clay , Winans Stephen C. , Greenberg E. Peter
Published: July 2002

The importance of accurate demographic information is reflected in the United States Constitution, Article 1, which provides for a decennial census of this country's human population. Bacteria also conduct a census of their population and do so more frequently, more efficiently, and as far we know, with little if any of the political contentiousness caused by human demographers. Many examples have been found of particular bacterial genes, operons, or regulons that are expressed preferentially at high cell densities. Many of these are regulated by proteins related to the LuxR and LuxI proteins of Vibrio fischeri, and by a diffusible pheromone called an autoinducer. LuxR and LuxI and their cognate autoinducer (3-oxohexanoyl homoserine lactone, designated VAI-1) provide an important model to describe the functions of this family of proteins. LuxR is a VAI-1 receptor and a VAI-1–dependent transcriptional activator, and LuxI directs the synthesis of VAI-1. VAI-1 diffuses across the bacterial envelope, and intracellular concentrations of it are therefore strongly increased by nearby VAI-1–producing bacteria. Similar systems regulate pathogenesis factors in Pseudomonas aeruginosa and Erwinia spp., as well as Ti plasmid conjugal transfer in Agrobacterium tumefaciens, and many other genes in numerous genera of gram-negative bacteria. Genetic analyses of these systems have revealed a high degree of functional conservation, while also uncovering features that are unique to each.
Viruses and Interferons
Authors: Sen Ganes C.
Published: July 2002

▪ Abstract  The interferon system is the first line of defense against viral infection in mammals. This system is designed to block the spread of virus infection in the body, sometimes at the expense of accelerating the death of the infected cells. As expected of potent cytokines, in addition to their antiviral effects, interferons have profound effects on many aspects of cell physiology. All these actions of interferons are mediated by hundreds of interferon-induced proteins that are usually not synthesized in resting cells. Interferons induce their synthesis by activating the Jak-STAT pathways, a paradigm of cell signaling used by many cytokines and growth factors. Surprisingly, some of the same genes can also be induced directly by viruses and double-stranded RNA, a common viral by-product. Some of the interferon-induced proteins have novel biochemical properties and some are inactive as such but can be activated by double-stranded RNA produced during virus infection. Finally, almost all viruses have evolved mechanisms to evade the interferon system by partially blocking interferon synthesis or interferon action. Thus, in nature interferons and viruses maintain an equilibrium that allows regulated viral replication.
Apoptosis in Neural Development and Disease
Authors: Nijhawan Deepak , Honarpour Narimon , Wang Xiaodong
Published: July 2002

Cell death via apoptosis is a prominent feature in mammalian neural development. Recent studies into the basic mechanism of apoptosis have revealed biochemical pathways that control and execute apoptosis in mammalian cells. Protein factors in these pathways play important roles during development in regulating the balance between neuronal life and death. Additionally, mounting evidence indicates such pathways may also be activated during several neurodegenerative diseases, resulting in improper loss of neurons.
Signaling and Transcriptional Mechanisms in Pituitary Development
Authors: Dasen Jeremy S. , Rosenfeld Michael G.
Published: July 2002

▪ Abstract  During the development of the pituitary gland, distinct hormone-producing cell types arise from a common population of ectodermal progenitors, providing an instructive model system for elucidating the molecular mechanisms of patterning and cell type specification in mammalian organogenesis. Recent studies have established that the development of the pituitary occurs through multiple sequential steps, allowing the coordinate control of the commitment, early patterning, proliferation, and positional determination of pituitary cell lineages in response to extrinsic and intrinsic signals. The early phases of pituitary development appear to be mediated through the activities of multiple signaling gradients emanating from key organizing centers that give rise to temporally and spatially distinct patterns of transcription factor expression. The induction of these transcriptional mediators in turn acts to positionally organize specific pituitary cell lineages within an apparently uniform field of ectodermal progenitors. Ultimately, pituitary cell types have proven to be both specified and maintained through the combinatorial interactions of a series of cell-type-restricted transcription factors that dictate the cell autonomous programs of differentiation in response to the transient signaling events.
The Role of the Cerebellum in Voluntary Eye Movements
Authors: Robinson Farrel R , Fuchs Albert F
Published: July 2002

▪ Abstract  In general the cerebellum is crucial for the control but not the initiation of movement. Voluntary eye movements are particularly useful for investigating the specific mechanisms underlying cerebellar control because they are precise and their brain-stem circuitry is already well understood. Here we describe single-unit and inactivation data showing that the posterior vermis and the caudal fastigial nucleus, to which it projects, provide a signal during horizontal saccades to make them fast, accurate, and consistent. The caudal fastigial nucleus also is necessary for the recovery of saccadic accuracy after actual or simulated neural or muscular damage causes horizontal saccades to be dysmetric. Saccade-related activity in the interpositus nucleus is related to vertical saccades. Both the caudal fastigial nucleus and the flocculus/paraflocculus are necessary for the normal smooth eye movements that pursue a small moving spot. By using eye movements, we have begun to uncover basic principles that give us insight into how the cerebellum may control movement in general.
Molecular Mechanisms Regulating Hormone-Sensitive Lipase and Lipolysis
Authors: Holm Cecilia , Østerlund Torben , Laurell Henrik , Contreras Juan Antonio
Published: July 2002

Hormone-sensitive lipase, the rate-limiting enzyme of intracellular TG hydrolysis, is a major determinant of fatty acid mobilization in adipose tissue as well as other tissues. It plays a pivotal role in lipid metabolism, overall energy homeostasis, and, presumably, cellular events involving fatty acid signaling. Detailed knowledge about its structure and regulation may provide information regarding the pathogenesis of such human diseases as obesity and diabetes and may generate concepts for new treatments of these diseases. The current review summarizes the recent advances with regard to hormone-sensitive lipase structure and molecular mechanisms involved in regulating its activity and lipolysis in general. A summary of the current knowledge regarding regulation of expression, potential involvement in lipid disorders, and role in tissues other than adipose tissue is also provided.
HYDROXYLASEENZYMES OF THEVITAMIND PATHWAY: Expression, Function, and Regulation
Authors: Omdahl John L. , Morris Howard A. , May Brian K.
Published: July 2002

▪ Abstract  Vitamin D is a secosteroid that is metabolically activated and degraded through the actions of three cytochrome P450 hydroxylase enzymes. Bioactivation occurs through the sequential actions of cytochromes P450C25 and P450C1, resulting in synthesis of the pleiotropic hormone 1,25-dihydroxyvitamin D (1,25VD), which regulates over 60 genes whose actions include those associated with calcium homeostasis and immune responses as well as cellular growth, differentiation, and apoptosis. Inactivation of 1,25VD occurs by C23/C24 oxidation pathways that are catalyzed by the multifunctional cytochrome P450C24 enzyme. Both P450C1 and P450C24 are highly regulated enzymes whose differential expression is controlled in response to numerous cellular modulatory agents such as parathyroid hormone (PTH), calcitonin, interferon gamma, calcium, phosphorus, and pituitary hormones as well as the secosteroid hormone 1,25VD. Most thoroughly studied at the molecular level are the actions of PTH to upregulate P450C1 gene expression and 1,25VD to induce the expression of P450C24. The regulatory action of PTH is mediated through the protein kinase A pathway and involves the phosphorylation of transcription factors that function at the proximal promoter of the P450C1 gene. The upregulation of P450C24 by 1,25VD has both a rapid nongenomic and a slower genomic component that are functionally linked. The rapid response involves protein kinase C and mitogen-activated protein kinase (MAPK) pathways that direct the phosphorylation of nuclear transcription factors. The slower genomic actions are linked to the binding of 1,25VD to the vitamin D receptor (VDR) and the interaction of the VDR-1,25VD complex with its heterodimer partner retinoid-X-receptor and associated coactivators. The regulatory complex is assembled on vitamin D response elements in the proximal promoter of the P450C24 gene and functions to increase the transcription rate.
MOLECULAR DETERMINANTS OF DRUG BINDING AND ACTION ON L-TYPE CALCIUM CHANNELS
Authors: Hockerman Gregory H. , Peterson Blaise Z. , Johnson, and Barry D. , Catterall William A.
Published: July 2002

▪ Abstract  The crucial role of L-type Ca2+ channels in the initiation of cardiac and smooth muscle contraction has made them major therapeutic targets for the treatment of cardiovascular disease. L-type channels share a common pharmacological profile, including high-affinity voltage- and frequency-dependent block by the phenylalkylamines, the benz(othi)azepines, and the dihydropyridines. These drugs are thought to bind to three separate receptor sites on L-type Ca2+ channels that are allosterically linked. Results from different experimental approaches implicate the IIIS5, IIIS6, and IVS6 transmembrane segments of the α1 subunits of L-type Ca2+ channels in binding of all three classes of drugs. Site-directed mutagenesis has identified single amino acid residues within the IIIS5, IIIS6, and IVS6 transmembrane segments that are required for high-affinity binding of phenylalkylamines and/or dihydropyridines, providing further support for identification of these transmembrane segments as critical elements of the receptor sites for these two classes of drugs. The close proximity of the receptor sites for phenylalkylamines, benz(othi)azepines, and dihydropyridines raises the possibility that individual amino acid residues may be required for high-affinity binding of more than one of these ligands. Therefore, we suggest that phenylalkylamines and dihydropyridines bind to different faces of the IIIS6 and IVS6 transmembrane segments and, in some cases, bind to opposite sides of the side chains of the same amino acid residues. The results support the domain interface model for binding and channel modulation by these three classes of drugs.
Chlorinated Methanes and Liver Injury: Highlights of the Past 50 Years
Authors: Plaa Gabriel L.
Published: July 2002

The chlorinated methanes, particularly carbon tetrachloride and chloroform, are classic models of liver injury and have developed into important experimental hepatoxicants over the past 50 years. Hepatocellular steatosis and necrosis are features of the acute lesion. Mitochondria and the endoplasmic reticulum as target sites are discussed. The sympathetic nervous system, hepatic hemodynamic alterations, and role of free radicals and biotransformation are considered. With carbon tetrachloride, lipid peroxidation and covalent binding to hepatic constituents have been dominant themes over the years. Potentiation of chlorinated methane-induced liver injury by alcohols, aliphatic ketones, ketogenic compounds, and the pesticide chlordecone is discussed. A search for explanations for the potentiation phenomenon has led to the discovery of the role of tissue repair in the overall outcome of liver injury. Some final thoughts about future research are also presented.
ACTIVE CONTROL OF THE DYNAMICS OF ATOMS AND MOLECULES
Authors: Gordon Robert J. , Rice Stuart A.
Published: July 2002

▪ Abstract  There has been much progress in the control of chemical reactions since methods of active control were first proposed by Brumer & Shapiro and by Tannor & Rice ten years ago. This chapter reviews both theoretical and experimental advances in the field. Control schemes based on quantum mechanical interference between competing paths and the manipulation of wave packets with tailored laser pulses are discussed. The theory of optimal control, the limitations of control theory applied to many-body dynamics, and the effects of constraints on the trajectory of the controlled observable are presented. Experimental progress in controlling the population of specific quantum states, in manipulating the dynamics of bound wave packets, and in the control of chemical reactions are reviewed, and current problems in the field are summarized.
EXPLOSIVES DETECTION: A Challenge for Physical Chemistry
Authors: Steinfeld Jeffrey I. , Wormhoudt Jody
Published: July 2002

▪ Abstract  The detection of explosives, energetic materials, and their associated compounds for security screening, demining, detection of unexploded ordnance, and pollution monitoring is an active area of research. A wide variety of detection methods and an even wider range of physical chemistry issues are involved in this very challenging area. This review focuses on techniques such as optical and mass spectrometry and chromatography for detection of trace amounts of explosives with short response times. We also review techniques for detecting the decomposition fragments of these materials. Molecular data for explosive compounds are reviewed where available.
Endothelial Signal Integration in Vascular Assembly
Authors: Daniel Thomas O. , Abrahamson Dale
Published: July 2002

▪ Abstract  Regulated assembly of a highly specialized interconnecting network of vascular endothelial and supportive cells is fundamental to embryonic development and organogenesis, as well as to postnatal tissue repair in metazoans. This review advances an “endotheliocentric” model that defines tasks required of endothelial cells and describes molecular controls that regulate steps in activation, assembly, and maturation of new vessels. In addition to the classical assembly mechanisms—angiogenesis and vasculogenesis—endothelial cells are also recruited into vascular structures from the circulatory system in adult animals and from resident mesenchymally derived progenitors during organogenesis of kidney and other organs. Paracrine signaling cascades regulated by hypoxia initiate a sequentially coordinated series of endothelial responses, including matrix degradation, migration, proliferation, and morphogenetic remodeling. Surface receptors on committed endothelial lineage progenitors transduce cues from extracellular-matrix–associated proteins and cell-cell contact to direct migration, matrix attachment, proliferation, targeting and cell-cell assembly, and vessel maturation. Through their capacity to spatially segregate and temporally integrate a diverse range of extracellular signals, endothelial cells determine their migratory paths, cellular partners, and life-or-death responses to local cues.
THEROLE OFPOLYGALACTURONASE-INHIBITINGPROTEINS(PGIPS)INDEFENSEAGAINSTPATHOGENICFUNGI
Authors: De Lorenzo Giulia , D'Ovidio Renato , Cervone Felice
Published: July 2002

▪ Abstract  Polygalacturonase-inhibiting proteins (PGIPs) are extracellular plant proteins capable of inhibiting fungal endopolygalacturonases (PGs). Plants have evolved different PGIPs with specific recognition abilities against the many PGs produced by fungi. The genes encoding PGIPs are organized into families, and different members of each family may encode proteins with nearly identical characteristics but different specificities and regulation. PGIPs are typically induced by pathogen infection and stress-related signals. The recognition ability of PGIPs resides in their LRR (leucine-rich repeat) structure, where solvent-exposed residues in the β-strand/β-turn motifs of the LRRs are determinants of specificity. Manipulation of the primary structure of PGIPs is expected to generate more efficient PGIPs with novel recognition specificities to protect crop plants against pathogens.
Unions in Decline? What Has Changed and Why
Authors: Wallerstein Michael , Western Bruce
Published: July 2002

Between 1950 and 1980, labor markets grew increasingly organized in advanced industrial societies. Union membership in most countries expanded more rapidly than the labor force, centralized wage setting became more common, and union members became increasingly concentrated in a small number of large unions. Between 1980 and 1992, however, union density fell on average, and centralized wage setting grew increasingly rare. Only union concentration continued to increase in the 1980s. Existing theories of union organization and collective bargaining institutions are largely successful in explaining both the trends over time and much of the cross-national variation from 1950 to 1980, but they fail to account for the dramatic declines in union strength that some (but not all) countries have experienced since 1980.
Political Knowledge, Political Engagement, and Civic Education
Authors: Galston William A.
Published: July 2002

After decades of neglect, civic education is back on the agenda of political science in the United States. Despite huge increases in the formal educational attainment of the US population during the past 50 years, levels of political knowledge have barely budged. Today's college graduates know no more about politics than did high school graduates in 1950. Recent research indicates that levels of political knowledge affect the acceptance of democratic principles, attitudes toward specific issues, and political participation. There is evidence that political participation is in part a positional good and is shaped by relative as well as absolute levels of educational attainment. Contrary to findings from 30 years ago, recent research suggests that traditional classroom-based civic education can significantly raise political knowledge. Service learning—a combination of community-based civic experience and systematic classroom reflection on that experience—is a promising innovation, but program evaluations have yielded mixed results. Longstanding fears that private schools will not shape democratic citizens are not supported by the evidence.
THE SOCIAL STRUCTURE OF SCHOOLING
Authors: Dornbusch Sanford M. , Glasgow Kristan L. , Lin I-Chun
Published: July 2002

▪ Abstract  The term social structure refers to a relatively enduring pattern of social arrangements or interrelations within a particular society, organization, or group. This chapter reviews how the social structure of the larger society and the organizational structure of schools affect the educational process within American schools. The institutional context of schooling is first discussed. The ideology of mass education, social stratification, status attainment, credentialism, and the emphasis on ability differences are considered. The focus then shifts to the organizational structure of schools, beginning with a discussion of the external social context for school organization. Attention is given to professionalism and bureaucracy, institutional forms of organization, decentralized control, and community influences. Finally, the internal structure of school organization is considered: teachers' working conditions, status differences among students, and curriculum tracking. Throughout, the emphasis is on ways in which social structure influences what is taught in school, how it is taught, and what is learned.
KEY ISSUES IN THE DEVELOPMENT OF AGGRESSION AND VIOLENCE FROM CHILDHOOD TO EARLY ADULTHOOD
Authors: Loeber Rolf , Hay Dale
Published: July 2002

▪ Abstract  Different manifestations of aggression from childhood to early adulthood are reviewed to establish how early manifestations are related to later manifestations. Similarities and differences in manifestations of aggression between the two genders are noted. Developmental sequences and pathways from minor aggression to violence are highlighted. Long-term escalation is contrasted with short-term escalation at older ages. Although studies have emphasized high stability of aggression over time, data show that a substantial proportion of aggressive youth desist over time. Temperamental, emotional, and cognitive aspects of aggression are reviewed, either as precursors or co-occurring conditions to aggression. Selected processes in the realms of the family, peers, and neighborhoods are highlighted that are known to be associated with juvenile aggression. Cumulative, long-term causes are contrasted with short-term causes, and causes associated with desistance in aggression are reviewed.
WHAT'S ELEMENTARY ABOUT ASSOCIATIVE LEARNING?
Authors: Wasserman Edward A. , Miller Ralph R.
Published: July 2002

▪ Abstract  The scientific study of associative learning began nearly 100 years ago with the pioneering studies of Thorndike and Pavlov, and it continues today as an active area of research and theory. Associative learning should be the foundation for our understanding of other forms of behavior and cognition in human and nonhuman animals. The laws of associative learning are complex, and many modern theorists posit the involvement of attention, memory, and information processing in such basic conditioning phenomena as overshadowing and blocking, and the effects of stimulus preexposure on later conditioning. An unresolved problem for learning theory is distinguishing the formation of associations from their behavioral expression. This and other problems will occupy future generations of behavioral scientists interested in the experimental investigation of associative learning. Neuroscientists and cognitive scientists will both contribute to and benefit from that effort in the next 100 years of inquiry.
Decision Technology
Authors: Edwards W. , Fasolo B.
Published: July 2002

▪ Abstract  This review is about decision technology—the rules and tools that help us make wiser decisions. First, we review the three rules that are at the heart of most traditional decision technology—multi-attribute utility, Bayes' theorem, and subjective expected utility maximization. Since the inception of decision research, these rules have prescribed how we should infer values and probabilities and how we should combine them to make better decisions. We suggest how to make best use of all three rules in a comprehensive 19-step model. The remainder of the review explores recently developed tools of decision technology. It examines the characteristics and problems of decision-facilitating sites on the World Wide Web. Such sites now provide anyone who can use a personal computer with access to very sophisticated decision-aiding tools structured mainly to facilitate consumer decision making. It seems likely that the Web will be the mode by means of which decision tools will be distributed to lay users. But methods for doing such apparently simple things as winnowing 3000 options down to a more reasonable number, like 10, contain traps for unwary decision technologists. The review briefly examines Bayes nets and influence diagrams—judgment and decision-making tools that are available as computer programs. It very briefly summarizes the state of the art of eliciting probabilities from experts. It concludes that decision tools will be as important in the 21st century as spreadsheets were in the 20th.
ENVIRONMENTAL TOBACCO SMOKE:Health Effects and Policies to Reduce Exposure
Authors: Brownson Ross C. , Eriksen Michael P. , Davis Ronald M. , Warner Kenneth E.
Published: July 2002

▪ Abstract  The health hazards due to exposure to environmental tobacco smoke (ETS) are increasingly established. ETS contains thousands of chemicals including 43 known carcinogens. Known health effects of ETS exposure are lung cancer in nonsmokers, childhood disorders such as bronchitis, and perhaps, heart disease. Workplace exposure to ETS is widespread and is influenced strongly by the type of smoking policy in the workplace. To decrease ETS exposure, efforts to restrict public smoking have proliferated over the past decade. These restrictions have emanated from government as well as voluntary measures by various private industries. Bans on public smoking are effective in reducing nonsmokers' exposure to ETS. Workplace smoking bans also influence the intensity of smoking among employees and may increase quit smoking rates. In addition to the health benefits from smoke-free workplaces, there are likely cost savings to employers who implement such policies.
PREVENTION OF BICYCLE-RELATED INJURIES: Helmets, Education, and Legislation
Authors: Rivara Frederick P. , Thompson Diane C. , Patterson Matthew Q. , Thompson Robert S.
Published: July 2002

▪ Abstract  Efforts to reduce the toll of bicycle-related head injuries illustrate how the basic public health principles of surveillance, epidemiologic study, intervention, and evaluation can have a substantial impact on an injury problem, using a variety of injury-prevention strategies. Head injuries are the leading cause of serious morbidity and mortality from bicycle crashes. Helmets have been shown to reduce bicycle-related head injuries for cyclists of all ages involved in all types of crashes including those with motor vehicles. Helmet use has been promoted using educational campaigns, helmet subsidies, and legislation. Careful evaluation of these strategies has shown that these interventions increase helmet use and decrease the incidence of bicycle injuries. The model developed for the prevention of bicycle injuries is widely applicable to other injury problems.
A Review of Collaborative Partnerships as a Strategy for Improving Community Health
Authors: Roussos Stergios Tsai , Fawcett Stephen B.
Published: July 2002

▪ Abstract  Collaborative partnerships (people and organizations from multiple sectors working together in common purpose) are a prominent strategy for community health improvement. This review examines evidence about the effects of collaborative partnerships on (a) community and systems change (environmental changes), (b) community-wide behavior change, and (c) more distant population-level health outcomes. We also consider the conditions and factors that may determine whether collaborative partnerships are effective. The review concludes with specific recommendations designed to enhance research and practice and to set conditions for promoting community health.
Managed Care in Workers' Compensation Plans
Authors: Peele Pamela B , Tollerud David J
Published: July 2002

▪ Abstract  Workers' compensation plans have lagged behind most public and private health care plans in the adoption of managed care techniques. This is largely attributable to the underlying differences between workers' compensation and group health plans. Managed care techniques were developed within group health plans with the objective of health at the lowest cost. In workers' compensation, managed care must address a different objective—restoring a worker to health and productivity at the lowest cost. It is this fundamental difference that makes the application of managed care techniques to workers' compensation plans contentious and at times inappropriate. Research on the impact of managed care on the health and welfare of injured workers is sparse, and important questions remain about the appropriateness of care delivered under workers' compensation managed care plans. In this paper, we discuss the application of managed care to workers' compensation, and highlight the barriers to effective implementation.