bluuebunny/crossref_metadata_2025 huggingface dataset:
PROTEIN TARGETING TO THE THYLAKOID MEMBRANE
Authors: Schnell Danny J.
Published: July 2002

▪ Abstract  The assembly of the photosynthetic apparatus at the thylakoid begins with the targeting of proteins from their site of synthesis in the cytoplasm or stroma to the thylakoid membrane. Plastid-encoded proteins are targeted directly to the thylakoid during or after synthesis on plastid ribosomes. Nuclear-encoded proteins undergo a two-step targeting process requiring posttranslational import into the organelle from the cytoplasm and subsequent targeting to the thylakoid membrane. Recent investigations have revealed a single general import machinery at the envelope that mediates the direct transport of preproteins from the cytoplasm to the stroma. In contrast, at least four distinct pathways exist for the targeting of proteins to the thylakoid membrane. At least two of these systems are homologous to translocation systems that operate in bacteria and at the endoplasmic reticulum, indicating that elements of the targeting mechanisms have been conserved from the original prokaryotic endosymbiont.
ALKALOIDBIOSYNTHESIS INPLANTS: Biochemistry, Cell Biology, Molecular Regulation, and Metabolic Engineering Applications
Authors: Facchini Peter J
Published: July 2002

▪ Abstract  Recent advances in the cell, developmental, and molecular biology of alkaloid biosynthesis have heightened our appreciation for the complexity and importance of plant secondary pathways. Several biosynthetic genes involved in the formation of tropane, benzylisoquinoline, and terpenoid indole alkaloids have now been isolated. The early events of signal perception, the pathways of signal transduction, and the function of gene promoters have been studied in relation to the regulation of alkaloid metabolism. Enzymes involved in alkaloid biosynthesis are associated with diverse subcellular compartments including the cytosol, vacuole, tonoplast membrane, endoplasmic reticulum, chloroplast stroma, thylakoid membranes, and perhaps unique “biosynthetic” or transport vesicles. Localization studies have shown that sequential alkaloid biosynthetic enzymes can also occur in distinct cell types, suggesting the intercellular transport of pathway intermediates. Isolated genes have also been used to genetically alter the accumulation of specific alkaloids and other plant secondary metabolites. Metabolic modifications include increased indole alkaloid levels, altered tropane alkaloid accumulation, elevated serotonin synthesis, reduced indole glucosinolate production, redirected shikimate metabolism, and increased cell wall–bound tyramine formation. This review discusses the biochemistry, cell biology, molecular regulation, and metabolic engineering of alkaloid biosynthesis in plants.
ETA CARINAE AND ITS ENVIRONMENT
Authors: Davidson Kris , Humphreys Roberta M.
Published: July 2002

▪ Abstract  Eta Carinae (Eta) is one of the most remarkable of all well-studied stars and perhaps the most poorly understood. Observations with the Hubble Space Telescope and other modern instruments have solved a few of the mysteries concerning this object while opening a comparable number of new ones. In this review we first recount some essential background information concerning Eta, then we sketch most of the observational developments of the past few years, related to the star itself and to its ejecta. Throughout, we propose a series of specific unsolved observational and theoretical problems that seem especially interesting or important at this time.
Nucleic Acid Biotechnology
Authors: Roth Charles M. , Yarmush Martin L.
Published: July 2002

▪ Abstract  Driven by advances in the acquisition of genetic sequence information and the ability to manipulate small quantities of nucleic acid, a number of technologies are emerging that exploit nucleic acids for research, diagnostic, and therapeutic utility. In this review, we cover three technologies based on nucleic acids—DNA microarrays, antisense technology, and gene therapy—that are especially promising and may make a substantial impact in the laboratory and in the clinic during the coming years. For each of these areas, an overview of the current status and applications is provided, followed by a discussion of critical issues and challenges to be faced for further advancement of the technology; an emphasis is placed on quantitative and engineering aspects.
Biomechanics of Microcirculatory Blood Perfusion
Authors: Schmid-Schönbein Geert W.
Published: July 2002

▪ Abstract  The microcirculation represents a region of the circulation in which blood vessels are directly surrounded by the tissue and cells to which they supply nutrients and from which they collect metabolites. The cellular elements that make up the microcirculation have now been identified, and a large body of evidence has become available that provides molecular definitions of these elements. The blood flow is in a domain in which viscous stresses dominate, but the viscoelastic and active properties of cells lead to nonlinear problems. The ability of cells to actively control cytoplasmic mechanical properties and shape, as well as their membrane adhesion, leads to unique cell behavior in microvessels that has a direct influence on organ transport and function. There is also increasing evidence that the properties of the cells are in turn influenced by fluid shear stresses. These issues have greatly expanded the scope of microvascular analysis. The microcirculation is one of the sites in which diseases manifest themselves at an early stage. The application of biomechanical analysis of the microcirculation is starting to focus on diseases. The field is rich with problems of high significance.
THE STRUCTURAL AND FUNCTIONAL BASIS OF ANTIBODY CATALYSIS
Authors: Wade Herschel , Scanlan Thomas S.
Published: July 2002

▪ Abstract  Ten years have passed since the initial reports that antibodies could be programmed to have enzymatic activity by immunization with a transition-site analog. Much of the research over the last decade has focused on defining the scope and generality of antibody catalysis; however, during the past two years the first few crystal structures of catalytic antibody transition-state analogs have been reported. This review analyzes four such structures of catalytic antibodies that catalyze markedly different reactions, including ester hydrolysis, sulfide oxidation, and a pericyclic rearrangement. Structure-function relations for these catalysts are discussed and compared to the structure and function of natural enzymes, as well as the chemistry that occurs in solution.
LEFT-RIGHT ASYMMETRY IN ANIMAL DEVELOPMENT
Authors: B. Wood William
Published: July 2002

▪ Abstract  Most animal species exhibit left-right asymmetry in their body plans and show a strong bias for one handedness over the other. The mechanism of handedness choice, recognized as an intriguing problem over a century ago, is still a mystery. However, from recent advances in understanding when and how asymmetry arises in both invertebrates and vertebrates, developmental pathways for establishment and maintenance of left-right differences are beginning to take shape, and speculations can be made on the initial choice mechanism.
SYSTEMIN: A Polypeptide Signal for Plant Defensive Genes
Authors: Ryan Clarence A. , Pearce Gregory
Published: July 2002

▪ Abstract  Damage to leaves of several plant species by herbivores or by other mechanical wounding induces defense gene activation throughout the plants within hours. An 18-amino acid polypeptide, called systemin, has been isolated from tomato leaves that is a powerful inducer of over 15 defensive genes when supplied to the tomato plants at levels of fmol/plant. Systemin is readily transported from wound sites and is considered to be the primary systemic signal. The polypeptide is processed from a 200-amino acid precursor called prosystemin, analogous to polypeptide hormones in animals. However, the plant prohormone does not possess typical dibasic cleavage sites, nor does it contain a signal sequence or any typical membrane-spanning regions. The signal transduction pathway that mediates systemin signaling involves linolenic acid release from membranes and subsequent conversion to jasmonic acid, a potent activator of defense gene transcription. The pathway exhibits analogies to arachidonic acid/prostaglandin signaling in animals that leads to inflammatory and acute phase responses.
IO ON THE EVE OF THE GALILEO MISSION
Authors: Spencer John R. , Schneider Nicholas M.
Published: July 2002

▪ Abstract  Io, innermost of Jupiter's large moons, is one of the most unusual objects in the Solar System. Tidal heating of the interior produces a global heat flux 40 times the terrestrial value, producing intense volcanic activity and a global resurfacing rate averaging perhaps 1 cm yr−1. The volcanoes may erupt mostly silicate lavas, but the uppermost surface is dominated by sulfur compounds including SO2frost. The volcanoes and frost support a thin, patchy SO2atmosphere with peak pressure near 10−8bars. Self-sustaining bombardment of the surface and atmosphere by Io-derived plasma trapped in Jupiter's magnetosphere causes escape of material from Io (predominantly sulfur, oxygen, and sodium atoms, ions, and molecules) at a rate of about 103kg s−1. The resulting Jupiter-encircling torus of ionized sulfur and oxygen dominates the Jovian magnetosphere and, together with an extended cloud of neutral sodium, is readily observable from Earth.
Haldane's Rule
Authors: Orr H. Allen
Published: July 2002

Haldane's rule—the preferential sterility or inviability of hybrids of the heterogametic (XY) sex—characterizes speciation in all known animals. Over the past decade, an enormous amount of experimental and theoretical work has been devoted to explaining this pattern. This work has falsified several once-popular theories and, more important, has produced a strong consensus on the likely causes of Haldane's rule. Experiments show that the dominance theory, which posits that “speciation genes” act as partial recessives in hybrids, can explain Haldane's rule for hybrid inviability. Dominance likely also contributes to Haldane's rule for sterility. Recent experiments further show that faster evolution of hybrid male steriles plays an important role. Faster evolution of X-linked loci may also contribute, though the evidence here is weaker. Evolutionary geneticists now largely agree that the simultaneous action of these forces explains Haldane's rule.
Resistance of Hybrid Plants and Animals to Herbivores, Pathogens, and Parasites
Authors: Fritz Robert S. , Moulia Catherine , Newcombe George
Published: July 2002

▪ Abstract  Interspecific hybridization can disrupt normal resistance of plant and animal species to their parasites. Resistance to parasites is affected by hybridization in the following ways: no difference between hybrids and parentals, additivity, hybrid susceptibility, and dominance to susceptibility. Similar patterns were seen across host taxa. Responses of different parasite species vary widely to the same hybrid host, which indicates diverse genetic effects of interspecific hybridization on resistance. Differences between field and common garden or laboratory studies suggest that environmental factors in hybrid zones influence the patterns seen in the field. Based on recent studies of hybrid-parasite interactions, three avenues of future research will provide a more complete understanding of the roles of hybrids and the roles of parasites in host evolution. First, the relationship between inheritance of putative resistance mechanisms of hosts and responses of parasites needs study using analyses of recombinant progenies. Second, the interaction among environmental variation in hybrid zones, resistance mechanisms, responses of parasites, and the impact of parasites on host fitness needs experimental analysis using reciprocal transplant experiments in hybrid zones. Finally, the role of hybrids in the community structure and interactions of parasites needs study.
Accessory Pulsatile Organs: Evolutionary Innovations in Insects
Authors: Pass Günther
Published: July 2002

▪ Abstract  In addition to the dorsal vessel (“heart”), insects have accessory pulsatile organs (“auxiliary hearts”) that supply body appendages with hemolymph. They are indispensable in the open circulatory system for hemolymph exchange in antennae, long mouthparts, legs, wings, and abdominal appendages. This review deals with the great diversity in the functional morphology and the evolution of these accessory pulsatile organs. In primitive insects, hemolymph is supplied to antennae and cerci by arteries connected to the dorsal vessel. In higher insects, however, these arteries were decoupled and associated with autonomous pumps that entered their body plan as evolutionary innovations. To ensure hemolymph supply to legs, wings, and some other appendages, completely new accessory pulsatile organs evolved. The muscular components of these pulsatile organs and their elastic antagonists were recruited from various organ systems and assembled to new functional units. In general, it seems that the evolution of accessory pulsatile organs has been determined by developmental and spatial constraints imposed by other organ systems rather than by changes in circulatory demands.
ALTERNATIVE SPLICING OF PRE-mRNA: Developmental Consequences and Mechanisms of Regulation
Authors: Lopez A. Javier
Published: July 2002

▪ Abstract  Alternative splicing of pre-mRNAs is a powerful and versatile regulatory mechanism that can effect quantitative control of gene expression and functional diversification of proteins. It contributes to major developmental decisions and also to fine tuning of gene function. Genetic and biochemical approaches have identified cis-acting regulatory elements and trans-acting factors that control alternative splicing of specific pre-mRNAs. Both approaches are contributing to an understanding of their mode of action. Some alternative splicing decisions are controlled by specific factors whose expression is highly restricted during development, but others may be controlled by more modest variations in the levels of general factors acting cooperatively or antagonistically. Certain factors play active roles in both constitutive splicing and regulation of alternative splicing. Cooperative and antagonistic effects integrated at regulatory elements are likely to be important for specificity and for finely tuned differences in cell-type-specific alternative splicing patterns.
COURTSHIP INDROSOPHILA
Authors: Greenspan Ralph J. , Ferveur Jean-François
Published: July 2002

▪ Abstract  Courtship is a complex behavior in Drosophila that recruits a wide range of genes for its realization, including those concerning sex determination, ion channels, and circadian rhythms. Results from different experimental approaches—behavioral and genetic comparisons between species, analysis of mutants and mosaics, and identification of specific sensory stimuli—sketch the outlines of a set of pleiotropic genes acting on a distributed system in the brain to produce the species-specific sequence of responses and actions.
THE GENETICS OF PEROXISOME BIOGENESIS
Authors: Sacksteder Katherine A , Gould Stephen J
Published: July 2002

▪ Abstract  The segregation of metabolic functions within discrete organelles is a hallmark of eukaryotic cells. These compartments allow for the concentration of related metabolic functions, the separation of competing metabolic functions, and the formation of unique chemical microenvironments. However, such organization is not spontaneous and requires an array of genes that are dedicated to the assembly and maintenance of these structures. In this review we focus on the genetics of peroxisome biogenesis and on how defects in this process cause human disease.
Molecular Genetics of Hearing Loss
Authors: Petit Christine , Levilliers Jacqueline , Hardelin Jean-Pierre
Published: July 2002

▪ Abstract  Hereditary isolated hearing loss is genetically highly heterogeneous. Over 100 genes are predicted to cause this disorder in humans. Sixty loci have been reported and 24 genes underlying 28 deafness forms have been identified. The present epistemic stage in the realm consists in a preliminary characterization of the encoded proteins and the associated defective biological processes. Since for several of the deafness forms we still only have fuzzy notions of their pathogenesis, we here adopt a presentation of the various deafness forms based on the site of the primary defect: hair cell defects, nonsensory cell defects, and tectorial membrane anomalies. The various deafness forms so far studied appear as monogenic disorders. They are all rare with the exception of one, caused by mutations in the gene encoding the gap junction protein connexin26, which accounts for between one third to one half of the cases of prelingual inherited deafness in Caucasian populations.
Epithelial Cell Polarity and Cell Junctions inDrosophila
Authors: Tepass Ulrich , Tanentzapf Guy , Ward Robert , Fehon Richard
Published: July 2002

▪ Abstract  The polarized architecture of epithelial cells and tissues is a fundamental determinant of animal anatomy and physiology. Recent progress made in the genetic and molecular analysis of epithelial polarity and cellular junctions in Drosophila has led to the most detailed understanding of these processes in a whole animal model system to date. Asymmetry of the plasma membrane and the differentiation of membrane domains and cellular junctions are controlled by protein complexes that assemble around transmembrane proteins such as DE-cadherin, Crumbs, and Neurexin IV, or other cytoplasmic protein complexes that associate with the plasma membrane. Much remains to be learned of how these complexes assemble, establish their polarized distribution, and contribute to the asymmetric organization of epithelial cells.
THE IMPACT OF MICROBIAL GENOMICS ON ANTIMICROBIAL DRUG DEVELOPMENT
Authors: Tang Christoph M. , Moxon E. Richard
Published: July 2002

▪ Abstract  There is an urgent need to develop novel classes of antibiotics to counter the threat of the spread of multiply resistant bacterial pathogens. The availability of the complete genome sequence of many pathogenic microbes provides information on every potential drug target and is an invaluable resource in the search for novel compounds. Here, we review the approaches being taken to exploit the genome databases through a combination of bioinformatics, transcriptional analysis, and a further understanding of the molecular basis of the disease process. The emphasis is changing from compound screening to target hunting, as the latter offers flexible ways to design and optimize the next generation of broad-spectrum antibiotics.
RECOGNITION BY γ/δ T CELLS
Authors: Chien Yueh-hsiu , Jores Rita , Crowley Michael P.
Published: July 2002

▪ Abstract  In contrast with the study of αβ T cells, that of γδ T cells is relatively recent and stems from the discovery of their rearranged genes, rather than from any knowledge of their biological function. Thus, experiments designed to characterize their specificity and function have drawn heavily on our knowledge of αβ T cells. During the past few years, many studies, especially with mice lacking either αβ or γδ T cells, have demonstrated that γδ T cells can contribute to immune competence, but they do so in a way that is distinct from αβ T cells. It is also evident that γδ T cells may not recognize antigen the same way as do αβ T cells. Analysis of three protein antigens—the murine MHC class II IEk, the nonclassical MHC T10/T22, and the Herpes virus glycoprotein gI—indicates that γδ T cell recognition does not require antigen processing and that the proteins are recognized directly. In all three cases, recognition by these T cell clones involves neither peptides bound to these proteins nor peptides derived from them. Moreover, a group of small phosphate-containing nonpeptide compounds derived from mycobacterial extracts has been found to stimulate a major population of human peripheral γδ T cells in a T cell receptor (TCR)-dependent manner. This indicates that γδ T cells can respond to ligands that are different from those of α β T cells.

Analysis of complementarity determining region (CDR3) length distributions of γ and δ chains indicates that they are more similar to those of immunoglobulins than to TCR α and β. This further supports the idea that γδ and αβ T cells recognize antigens differently and suggests that γδ T cells may be more like immunoglobulins in their recognition properties. γδ T cells share many cell surface proteins with αβ T cells and are able to secrete lymphokines and express cytolytic activities in response to antigenic stimulation. These, together with the results cited above, indicate that γδ T cells can mediate cellular immune functions without a requirement for antigen processing. Thus, pathogens, damaged tissues, or even B and T cells can be recognized directly, and cellular immune responses can be initiated without a requirement for antigen degradation or specialized antigen-presenting cells. This would give γδ T cells greater flexibility than the more classical type of αβ T cell–mediated cellular immunity.
Cellular Interactions in Thymocyte Development
Authors: Anderson Graham , Moore Nel C. , Owen John J. T. , Jenkinson Eric J.
Published: July 2002

Interactions between stromal cells and thymocytes play a crucial role in T cell development. The thymic stroma is complex and consists of epithelial cells derived from the pharyngeal region during development, together with macrophages and dendritic cells of bone marrow origin. In addition, fibroblasts and matrix molecules permeate the whole framework. It is now apparent that these individual stromal components play specialized roles at different stages of T cell differentiation. Thus, at the early CD4−8−stage of development, T cell precursors require fibroblast as well as epithelial cell interactions. Later, at the CD4+8+stage, as well as providing low avidity TCR/MHC-peptide interactions, thymic epithelial cells have been shown to possess unique properties essential for positive selection. Dendritic cells, on the other hand, are probably efficient mediators of negative selection, but they may not be solely responsible for this activity.

Alongside the functional roles of stromal cells, considerable progress is being made in unraveling the nature of the signaling pathways involved in T cell development. Identification of the pre-T cell receptor (pre-TCR) and associated signaling molecules marks an important advance in understanding the mechanisms that control gene rearrangement and allelic exclusion. In addition, a better understanding of the signaling pathways that lead to positive selection on the one hand and negative selection on the other is beginning to emerge.

Many issues remain unresolved, and some are discussed in this review. What, for example, is the nature of the chemotactic factor(s) that attract stem cells to the thymus? What is the molecular basis of the essential interactions between early thymocytes and fibroblasts, and early thymocytes and epithelial cells? What is special about cortical epithelial cells in supporting positive selection? These and other issues are ripe for analysis and can now be approached using a combination of modern molecular and cellular techniques.
INDUCTION OF TH1 AND TH2 CD4+T CELL RESPONSES:The Alternative Approaches
Authors: Constant Stephanie L. , Bottomly Kim
Published: July 2002

▪ Abstract  T helper lymphocytes can be divided into two distinct subsets of effector cells based on their functional capabilities and the profile of cytokines they produce. The Th1 subset of CD4+T cells secretes cytokines usually associated with inflammation, such as IFN-γ and TNF and induces cell-mediated immune responses. The Th2 subset produces cytokines such as IL-4 and IL-5 that help B cells to proliferate and differentiate and is associated with humoral-type immune responses. The selective differentiation of either subset is established during priming and can be significantly influenced by a variety of factors. One of these factors, the cytokine environment, has been put forward as the major variable influencing Th development and is already well reviewed by others. Instead, in the current review, we focus on some of the alternative approaches for skewing Th1/Th2 responses. Specifically, we discuss the effects on Th priming of (a) using altered peptide ligands as antigens, (b) varying the dose of antigen, and (c) altering costimulatory signals. The potential importance of each of these variables to influence immune responses to pathogens in vivo is discussed throughout.
THE REGULATION OF CD4 AND CD8 CORECEPTOR GENE EXPRESSION DURING T CELL DEVELOPMENT
Authors: Ellmeier Wilfried , Sawada Shinichiro , Littman Dan R.
Published: July 2002

▪ Abstract  The two major subsets of T lymphocytes in the peripheral immune system, the helper and cytotoxic T cells, are defined by their expression of either the CD4 or the CD8 glycoproteins, respectively. Expression of these molecules, which serve as coreceptors by interacting specifically with either MHC class II or class I molecules, also defines discrete stages of T cell development within the thymus. Thus, CD4+and CD8+single-positive (SP) thymocytes arise from common progenitor double positive (DP) cells that express both CD4 and CD8, during a process known as positive selection. The molecular mechanisms underlying the developmental choice toward the helper or cytotoxic lineage remain poorly understood. Because regulation of coreceptor gene expression appears to be coupled to the phenotypic choice of the differentiating T cell, it is likely that shared signaling pathways direct CD4 and CD8 transcription and the development of an uncommited DP thymocyte toward either the helper or cytotoxic lineage. Therefore, an understanding of how CD4 and CD8 expression is regulated will not only provide insights into transcriptional control mechanisms in T cells, but may also result in the identification of molecular factors that are involved in lineage choices during T cell development. In this review, we summarize recent progress that has been made toward an understanding of how CD4 and CD8 gene expression is regulated.
Multiple Roles for the Major Histocompatibility Complex Class I– Related Receptor FcRn
Authors: Ghetie Victor , Ward E. Sally
Published: July 2002

Multiple functions have recently been identified for the neonatal Fc receptor FcRn. In addition, a human homolog of the rodent forms of FcRn has been identified and characterized. This major histocompatibility complex class I-related receptor plays a role in the passive delivery of immunoglobulin (Ig)Gs from mother to young and the regulation of serum IgG levels. In addition, FcRn expression in tissues such as liver, mammary gland, and adult intestine suggests that it may modulate IgG transport at these sites. These diverse functions are apparently brought about by the ability of FcRn to bind IgGs and transport them within and across cells. However, the molecular details as to how FcRn traffics within cells have yet to be fully understood, although in vitro systems have been developed for this purpose. The molecular nature of the FcRn-IgG interaction has been studied extensively and encompasses residues located at the CH2-CH3 domain interface of the Fc region of IgG. These Fc amino acids are highly conserved in rodents and man and interact with residues primarily located on the α2 domain of FcRn. Thus, it is now possible to engineer IgGs with altered affinities for FcRn, and this has relevance to the modulation of IgG serum half-life and maternofetal IgG transport for therapeutic applications.
Multiple Viral Strategies of HTLV-1 for Dysregulation of Cell Growth Control
Authors: Yoshida Mitsuaki
Published: July 2002

The human T cell leukemia virus-1 (HTLV-1) is a retrovirus that causes adult T cell leukemia (ATL) and neurological disorder, the tropical spastic paraparesis (HAM/TSP). The pathogenesis apparently results from the pleiotropic function of Tax protein, which is a key regulator of viral replication. Tax exerts (a) trans-activation and -repression of transcription of different sets of cellular genes through binding to groups of transcription factors and coactivators, (b) dysregulation of cell cycle through binding to inhibitors of CDK4/6, and (c) inhibition of some tumor suppressor proteins. These effects on a wide variety of cellular targets seem to cooperate in promoting cell proliferation. This is an effective viral strategy to amplify its proviral genome through replication of infected cells; ultimately it results in cell transformation and leukemogenesis.
T Cell Response in Experimental Autoimmune Encephalomyelitis (EAE): Role of Self and Cross-Reactive Antigens in Shaping, Tuning, and Regulating the Autopathogenic T Cell Repertoire
Authors: Kuchroo Vijay K. , Anderson Ana C. , Waldner Hanspeter , Munder Markus , Bettelli Estelle , Nicholson Lindsay B.
Published: July 2002

T cells that can respond to self-antigens are present in the peripheral immune repertoire of all healthy individuals. Recently we have found that unmanipulated SJL mice that are highly susceptible to EAE also maintain a very high frequency of T cells responding to an encephalitogenic epitope of a myelin antigen proteolipid protein (PLP) 139-151 in the peripheral repertoire. This is not due to lack of expression of myelin antigens in the thymus resulting in escape of PLP 139-151 reactive cells from central tolerance, but is due to expression of a splice variant of PLP named DM20, which lacks the residues 116-150. In spite of this high frequency, the PLP 139-151 reactive cells remain undifferentiated in the periphery and do not induce spontaneous EAE. In contrast, SJL TCR transgenic mice expressing a receptor derived from a pathogenic T cell clone do develop spontaneous disease. This may be because in normal mice, autoreactive cells are kept in check by an alternate PLP 139-151 reactive nonpathogenic repertoire, which maintains a balance that keeps them healthy. If this is the case, selective activation of one repertoire or the other may alter susceptibility to autoimmune disease. Since T cells are generally cross-reactive, besides responding to nonself-antigens, they also maintain significant responses to self-antigens. Based on the PLP 139-151 system, we propose a model in which activation with foreign antigens can result in the generation of pathogenic memory T cells that mediate autoimmunity. We also outline circumstances under which activation of self-reactive T cells with foreign antigens can generate selective tolerance and thus generate protective/regulatory memory against self while still maintaining significant responses against foreign antigens. This provides a mechanism by which the fidelity and specificity of the immune system against foreign antigens is improved without increasing the potential for developing an autoimmune disease.
CHEMICAL FORCE MICROSCOPY
Authors: Noy Aleksandr , Vezenov Dmitri V. , Lieber Charles M.
Published: July 2002

▪ Abstract  Atomic force microscopy is an imaging tool used widely in fundamental research, although it has, like other scanned probe microscopies, provided only limited information about the chemical nature of systems studied. Modification of force microscope probe tips by covalent linking of organic monolayers that terminate in well-defined functional groups enables direct probing of molecular interactions and imaging with chemical sensitivity. This new chemical force microscopy technique has been used to probe adhesion and frictional forces between distinct chemical groups in organic and aqueous solvents. Contact mechanics provide a framework to model the adhesive forces and to estimate the number of interacting molecular groups. In general, measured adhesive and frictional forces follow trends expected from the strengths of the molecular interactions, although solvation also plays an important role. Knowledge of these forces provides a basis for rationally interpretable mapping of a variety of chemical functionalities and processes such as protonation and ionization.
IMAGING AND CONTROL OF DOMAIN STRUCTURES IN FERROELECTRIC THIN FILMS VIA SCANNING FORCE MICROSCOPY
Authors: Gruverman Alexei , Auciello Orlando , Tokumoto Hiroshi
Published: July 2002

▪ Abstract  Scanning force microscopy (SFM) is becoming a powerful technique with great potential both for imaging and for control of domain structures in ferroelectric materials at the nanometer scale. Application of SFM to visualization of domain structures in ferroelectric thin films is described. Imaging methods of ferroelectric domains are based on the detection of surface charges in the noncontact mode of SFM and on the measurement of the piezoelectric response of a ferroelectric film to an external field applied by the tip in the SFM contact mode. This latter mode can be used for nondestructive evaluation of local ferroelectric and piezoelectric properties and for manipulation of domains of less than 50 nm in diameter. The effect of the film thickness and crystallinity on the imaging resolution is discussed. Scanning force microscopy is shown to be a technique well suited for nanoscale investigation of switching processes and electrical degradation effects in ferroelectric thin films.
CATHODIC ARC DEPOSITION OF FILMS
Authors: Brown Ian G.
Published: July 2002

▪ Abstract  Cathodic arc deposition is a plasma-based technology for the fabrication of films. The process can be carried out either at high vacuum or in a low pressure gaseous environment, and films can be formed for example of metals, ceramics, diamond-like carbon, some semiconductors and superconductors, and more. The plasma stream can be filtered to remove microdroplet contamination, and the ion energy can be controlled by substrate bias, thereby transforming the straightforward deposition method into hybrids with other surface modification processes such as ion beam–assisted deposition, ion beam mixing, and ion implantation. The method provides a versatile and powerful plasma tool for the synthesis of novel and technically important surfaces.
Holographic Polymer-Dispersed Liquid Crystals (H-PDLCs)
Authors: Bunning T. J. , Natarajan L. V. , Tondiglia V. P. , Sutherland R. L.
Published: July 2002

▪ Abstract  The formation of switchable holographic gratings from polymer-dispersed liquid crystals (H-PDLCs) allows for the development of switchable transmissive and reflective diffractive optics. These structures are created by the coherent interference of laser radiation within a syrup containing photoreactive monomer, initiator, and liquid crystal. Local differences in photopolymerization rates induce phase separation of discrete LC domains to occur periodically commensurate with the period of the interference pattern. These spatially periodic gratings of nano-scale sized LC domains can be formed on grating length scales ranging from 100 nm to microns depending on the optics of fabrication. True Bragg gratings are formed with spacings typically less than 1 μm. Owing to the refractive profile generated by this periodic two-phase structure, diffraction of light occurs. Electrical switching of the average director orientation within the LC domains results in a modulation of diffracted radiation. This technology serves as the basis for the fabrication of switchable diffractive optical elements. We review the current state-of-the-art of H-PDLC technology including the materials used to date, the resulting electro-optical properties, the importance of grating formation dynamic measurements, and structure/property relationships developed using solid state morphology techniques.
Cellular and Molecular Abnormalities in the Vascular Endothelium of Diabetes Mellitus
Authors: King George L. , Shiba Teruo , Oliver Javier , Inoguchi Toyoshi , Bursell Sven-Erik
Published: July 2002

▪ Abstract  Diabetic vascular complications affect both micro- and macrovasculature, primarily in the retina, renal glomeruli, and multiple sites in the macrovessels. This review presents a summary of the abnormal function found in vivo and in cultured vascular cells exposed to elevated levels of glucose. We also discuss the various biochemical hypotheses that have been proposed to explain the adverse effects of hyperglycemia on vascular cells.
THE MODERN VERSION OF ADULT RESPIRATORY DISTRESS SYNDROME
Authors: Demling, M.D Robert H.
Published: July 2002

▪ Abstract  Adult respiratory distress syndrome (ARDS) remains a highly lethal complication of autodestructive inflammation. This syndrome originally referred to a single organ failure but is now considered a component, usually the first, of the multisystem organ failure syndrome (MOFS). Cytokines, neutrophils, and endothelial adherence molecules initiate the disease process, with cell injury caused by oxidants and proteases released from inflammatory cells. ARDS, if progressive, will result in pulmonary fibrosis. Improved ventilatory support techniques have not been shown to decrease mortality. Pharmacologic manipulation of the inflammatory response is a more promising method of controlling the disease process.
DIABETES CONTROL AND COMPLICATIONS
Authors: Crofford, M.D Oscar B.
Published: July 2002

▪ Abstract  The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive treatment of patients with insulin-dependent diabetes mellitus (IDDM) can substantially reduce the onset and progression of diabetic retinopathy, nephropathy, and neuropathy. The major risk associated with intensive treatment is recurrent hypoglycemia. Implementation of intensive treatment recommendations is difficult but should be considered and probably recommended to most patients with IDDM. If intensive treatment is impractical, any improvement in glycemic control is probably beneficial. Improved glycemic control should be recommended to most patients with non-insulin-dependent diabetes mellitus (NIDDM). The use of insulin in patients with NIDDM is controversial, especially in patients who are overweight, overeating, and minimally symptomatic.
BORDERLINE HYPOTHYROIDISM AND DEPRESSION
Authors: Haggerty Jr. John J. , Prange Jr. Arthur J.
Published: July 2002

▪ Abstract  This review defines subclinical hypothyroidism and examines its influence on the occurrence and course of major depression. Recommendations are presented for the identification and treatment of patients with coexisting mood disorders and borderline thyroid failure.
VOLTAGE-GATED ION CHANNELOPATHIES: Inherited Disorders Caused by Abnormal Sodium, Chloride, and Calcium Regulation in Skeletal Muscle
Authors: Hoffman, Ph.D Eric P.
Published: July 2002

▪ Abstract  The pathological genetic defects in the inherited myotonias and periodic paralyses were recently elucidated using molecular genetic studies. These disorders are usually transmitted as a dominant trait from an affected parent to a child. The many clinical symptoms include cold-induced uncontrollable contraction of muscle, potassium-induced contraction and paralysis, myotonia with dramatic muscular hypertrophy, muscle stiffness, and insulin-induced paralysis (in males). Horses afflicted with the disorder can suddenly collapse, despite an impressive physique. In the past three years, these clinically defined disorders have been shown to share a common etiology: subtle defects of ion channels in the muscle-fiber membrane. Although the specific ion channel involved varies depending on the disease, most patients have single amino acid changes in the channel proteins, with both normal and mutant channels present in each muscle fiber. For each patient, we can now establish a precise molecular diagnosis in the face of overlapping clinical symptoms and begin specific pharmacological treatment based on the primary problem. These studies have also provided insight into basic muscle biology and emphasize the careful regulation of ions in muscle excitation.
THE VASCULAR BIOLOGY OF NITRIC OXIDE AND ITS ROLE IN ATHEROGENESIS
Authors: Lloyd-Jones, M.D Donald M. , Bloch, M.D Kenneth D.
Published: July 2002

▪ Abstract  Nitric oxide (NO), the biologically active component of endothelium-derived relaxing factor, has critical roles in the maintenance of vascular homeostasis. Decreased endothelial NO production, as a result of endothelial dysfunction, occurs in the early phases of atherosclerosis. NO appears to inhibit atherogenesis by inhibiting leukocyte and platelet activation and by inhibiting smooth muscle cell proliferation. Endothelial denudation is a prominent feature of vascular injury associated with percutaneous angioplasty, and decreased NO production appears to contribute to the restenosis process. Manipulation of the NO/cGMP signal transduction system may provide novel therapeutic approaches for limiting atherogenesis and neointimal proliferation in the future.
Advances in the Medical Treatment of Epilepsy
Authors: Bazil Carl W. , Pedley Timothy A.
Published: July 2002

Treatment options for epilepsy, especially using antiepileptic drugs, have increased substantially in the past five years. Since 1993, four novel antiepileptic drugs have been approved and marketed in the United States: felbamate, gabapentin, lamotrigine, and topiramate. Two others, tiagabine and vigabatrin, are likely to be approved in the near future. For many patients, these agents offer the realistic promise of improved seizure control, often with fewer adverse effects and less significant drug interactions compared with older agents. In addition, fosphenytoin, a water-soluble phenytoin prodrug with a number of advantages over intravenous phenytoin, has been released. There are new administration options for carbamazepine, diazepam, and valproic acid. For drug-resistant or -intolerant patients, there has been renewed interest in alternative therapies, especially the ketogenic diet. Taken together, these represent significant therapeutic advances that are benefiting patients with epilepsy. At the same time, improved understanding of the basic mechanisms of epileptogenesis, and of the cellular and molecular actions of available antiepileptic drugs, creates a framework for designing unique therapeutic strategies that are targeted at key sites of vulnerability involved in the development and maintenance of the epileptic state.
Diagnosis and Management of Congenital Adrenal Hyperplasia
Authors: New Maria I.
Published: July 2002

Congenital adrenal hyperplasia is a family of inborn errors of steroidogenesis, each characterized by a specific enzyme deficiency that impairs cortisol production by the adrenal cortex, and can lead to sexual ambiguity in both genetic males and females. The enzymes most often affected are 21-hydroxylase, 11β-hydroxylase, and 3β-hydroxysteroid dehydrogenase, and less often, 17α-hydroxylase/17, 20-lyase and cholesterol desmolase. Decreased production of cortisol results in increased pituitary secretion of adrenocorticotropic hormone. The elevated adrenocorticotropic hormone stimulates both the accumulation of precursor steroids in the impeded pathways and excessive steroid synthesis in other adrenal biosynthetic pathways unaffected by the enzyme deficiency. Correct identification of the enzyme affected is achieved by the observation of clinical syndromes reflecting distinct hormonal patterns, and it is measured quantitatively as low levels of cortisol and other adrenal steroids, as well as increased levels of steroids proximal to the blocked step. Many of the corresponding genes for the described enzymes have been isolated and characterized, and specific mutations causing many cases of congenital adrenal hyperplasia have been identified. These advances have important implications for early prenatal diagnosis and prenatal treatment.
How Can Physicians Keep Up-to-Date?
Authors: Laine, MD, MPH Christine , Weinberg, MD, MSc David S.
Published: July 2002

Keeping one's personal fund of knowledge current is one of the most formidable challenges that physicians face. This article considers a few strategies that may help physicians as they struggle to keep their knowledge up-to-date. Physicians need to develop their own goals for staying current, systematically and periodically search the literature for high-quality material relevant to the topics on their agendas, become facile with critical appraisal of the literature, and schedule time for reading. One of the responsibilities of any professional is to maintain expertise, and this responsibility is probably nowhere more critical, or more difficult, than in the profession of medicine.
The Role of Protein Traffic in the Progression of Renal Diseases
Authors: Ruggenenti Piero , Remuzzi Giuseppe
Published: July 2002

Progression to irreversible renal parenchymal damage and end-stage renal disease is the final common pathway of chronic proteinuric nephropathies and is relatively independent of the type of initial insult. In animals, a reduction in nephron mass exposes the remaining nephrons to adaptive hemodynamic changes that are intended to sustain renal function but may be detrimental in the long term. High glomerular capillary pressure impairs glomerular permeability to proteins, which are then filtered in excessive quantities and reach the lumen of the proximal tubule. The secondary process of reabsorption of filtered proteins can contribute substantially to renal interstitial injury by activating intracellular events, including upregulation of vasoactive and inflammatory genes. The corresponding molecules formed in excessive amounts by the renal tubules cause an interstitial inflammatory reaction that normally precedes renal scarring and correlates with declining function. In several clinical studies, the increase in urinary protein excretion correlated with the tendency of the renal disease to progress more than it correlated with the underlying renal disease itself. Whenever urinary protein excretion is reduced, the decline in the glomerular filtration rate (GFR) slows or stops. Thus, to the extent that angiotensin-converting enzyme inhibitors lower the rate of urinary protein excretion, they effectively limit the progressive decline in GFR. If treatment is sufficiently prolonged, the GFR decline can be effectively halted or reversed, even in patients with remarkably severe disease, and remission is now achievable in some patients.
Current Treatment Strategies for Chronic Hepatitis B and C
Authors: Lin Otto S. , Keeffe Emmet B.
Published: July 2002

▪ Abstract  For chronic hepatitis B, treatment with a 4-month course of interferon alfa-2b can achieve hepatitis B e antigen seroconversion, normalization of aminotrans-ferase levels, reduced hepatic inflammation, and possibly reduced progression to cirrhosis and improvement in survival in 20%–30% of patients. Similar results can be achieved with a 12-month course of lamivudine, with response rates increasing to 40%–65% after 3 years of therapy. Interferon can also be used in early cirrhotic patients, and lamivudine can be used in advanced cirrhotics and immunosuppressed patients. Combination interferon and lamivudine therapy does not confer additional benefits. For chronic hepatitis C, the combination of interferon alfa-2b and ribavirin is the treatment of choice, offering superior sustained response rates (40%) compared with interferon alone (15%). Therapy should be administered for 12 months to patients with genotype 1 virus but for only 6 months to patients with genotypes 2 and 3. Patients experiencing relapse after 6 months of interferon monotherapy can be re-treated with interferon and ribavirin or high-dose interferon, with 45%–56% sustained response rates. However, relatively few patients who are prior nonresponders to interferon monotherapy will have sustained response to further interferon-based treatments, including combination therapy with ribavirin. Successful therapy not only leads to the eradication of viral RNA but also may delay progression to cirrhosis and hepatocellular carcinoma. Interferon combined with polyethylene glycol (PEG), shows promise as an improved formulation of interferon with yet higher sustained response rates.