bluuebunny/crossref_metadata_2025 huggingface dataset:
THE INTERLEUKIN-12/INTERLEUKIN-12-RECEPTOR SYSTEM: Role in Normal and Pathologic Immune Responses
Authors: Gately Maurice K. , Renzetti Louis M. , Magram Jeanne , Stern Alvin S. , Adorini Luciano , Gubler Ueli , Presky David H.
Published: July 2002

▪ Abstract  Interleukin-12 (IL-12) is a heterodimeric cytokine that plays a central role in promoting type 1 T helper cell (Th1) responses and, hence, cell-mediated immunity. Its activities are mediated through a high-affinity receptor composed of two subunits, designated β1 and β2. Of these two subunits, β2 is more restricted in its distribution, and regulation of its expression is likely a central mechanism by which IL-12 responsiveness is controlled. Studies with neutralizing anti-IL-12 antibodies and IL-12-deficient mice have suggested that endogenous IL-12 plays an important role in the normal host defense against infection by a variety of intracellular pathogens. However, IL-12 appears also to play a central role in the genesis of some forms of immunopathology. Inhibition of IL-12 synthesis or activity may be beneficial in diseases associated with pathologic Th1 responses, such as multiple sclerosis or Crohn's disease. On the other hand, administration of recombinant IL-12 may have utility in the treatment of diseases associated with pathologic Th2 responses such as allergic disorders and asthma.
DISCOVERING THE ORIGINS OF IMMUNOLOGICAL COMPETENCE
Authors: Miller Jacques F. A. P.
Published: July 2002

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▪ Abstract  Work done in the late 1950s and in the 1960s revealed the role of the thymus in virus-induced leukemia in mice. Thymectomizing mice at birth to test whether the virus first multiplied in thymus tissue and then spread elsewhere ultimately led to the conclusion that the thymus was essential to the normal development of the immune system. Subsequent testing to try to understand how the thymus contributes to the pool of immunocompetent lymphocytes opened a new chapter in immunology and required a reappraisal of many immunological phenomena and an understanding of the molecular interactions that take place during cell-to-cell interactions.
CHEMOKINE RECEPTORS AS HIV-1 CORECEPTORS: Roles in Viral Entry, Tropism, and Disease
Authors: Berger Edward A. , Murphy Philip M. , Farber Joshua M.
Published: July 2002

▪ Abstract  In addition to CD4, the human immunodeficiency virus (HIV) requires a coreceptor for entry into target cells. The chemokine receptors CXCR4 and CCR5, members of the G protein-coupled receptor superfamily, have been identified as the principal coreceptors for T cell line-tropic and macrophage-tropic HIV-1 isolates, respectively. The updated coreceptor repertoire includes numerous members, mostly chemokine receptors and related orphans. These discoveries provide a new framework for understanding critical features of the basic biology of HIV-1, including the selective tropism of individual viral variants for different CD4+target cells and the membrane fusion mechanism governing virus entry. The coreceptors also provide molecular perspectives on central puzzles of HIV-1 disease, including the selective transmission of macrophage-tropic variants, the appearance of T cell line-tropic variants in many infected persons during progression to AIDS, and differing susceptibilities of individuals to infection and disease progression. Genetic findings have yielded major insights into the in vivo roles of individual coreceptors and their ligands; of particular importance is the discovery of an inactivating mutation in the CCR5 gene which, in homozygous form, confers strong resistance to HIV-1 infection. Beyond providing new perspectives on fundamental aspects of HIV-1 transmission and pathogenesis, the coreceptors suggest new avenues for developing novel therapeutic and preventative strategies to combat the AIDS epidemic.
Discovering the Role of the Major Histocompatibility Complex in the Immune Response
Authors: McDevitt Hugh O.
Published: July 2002

[Formula: see text] The discovery that genes in the major histocompatibility complex (MHC) play an important role in the immune response depended on the chance interaction of several unrelated events. The first, and most important, was the decision by Michael Sela to synthesize a series of branched, multichain, synthetic polypeptides based on a backbone of poly-l-lysine. The prototype compound, (T,G)-A–L, was tipped with short random sequences of tyrosine and glutamic acid. This resulted in a restricted range of antigenic determinants composed of only two or three amino acids with a variable length—ideal for binding to the peptide binding groove of MHC class II molecules.

The second was the decision by John Humphrey to immunize various strains of rabbits with this synthetic polypeptide. Two of these rabbit strains showed very large quantitative differences in antibody response to (T,G)-A–L. In transferring this system to inbred mouse strains, the third bit of good fortune was the availability at the National Institute of Medical Research, in Mill Hill (London), of the CBA (H2k) and C57 (H2b) strains. The H2bhaplotype is the only one mediating a uniform high antibody response to (T,G)-A–L. The fourth critical ingredient was the availability of numerous congenic and H2 recombinant inbred strains of mice produced earlier by Snell, Stimpfling, Shreffler, and Klein. A search for congenic pairs of mice expressing the responder and nonresponder H2 haplotypes on the same background revealed that these strains responded as a function of their H2 haplotype, not of their inbred background. Extensive studies in a variety of inbred strains carrying recombinant H2 haplotypes, as well as a four-point linkage cross, mapped immune response to (T,G)A–L within the murine MHC, between the K and Ss loci.

The demonstration that stimulation in the mixed lymphocyte reaction (MLR) mapped to the same region quickly led to attempts to produce antisera in congenic H2 recombinant strain combinations. These antisera identified I-region associated (Ia) antigens. Immunoprecipitation and blocking studies showed that the gene products controlling specific immune responses, the mixed lymphocyte reaction, and the structure of Ia antigens were one and the same—now designated as the I-A MHC class II molecules. These antisera and inbred strains enabled Unanue to demonstrate the peptide binding function of class II MHC molecules.
SEMICONDUCTOR WAFER BONDING
Authors: Gösele U. , Tong Q.-Y.
Published: July 2002

▪ Abstract  When mirror-polished, flat, and clean wafers of almost any material are brought into contact at room temperature, they are locally attracted to each other by van der Waals forces and adhere or bond. This phenomenon is referred to as wafer bonding. The most prominent applications of wafer bonding are silicon-on-insulator (SOI) devices, silicon-based sensors and actuators, as well as optical devices. The basics of wafer-bonding technology are described, including microcleanroom approaches, prevention of interface bubbles, bonding of III-V compounds, low-temperature bonding, ultra-high vacuum bonding, thinning methods such as smart-cut procedures, and twist wafer bonding for compliant substrates. Wafer bonding allows a new degree of freedom in design and fabrication of material combinations that previously would have been excluded because these material combinations cannot be realized by the conventional approach of epitaxial growth.
TWO-DIMENSIONAL DOPANT PROFILING BY SCANNING CAPACITANCE MICROSCOPY
Authors: Williams C. C.
Published: July 2002

▪ Abstract  The scanning capacitance microscope (SCM) provides a direct method for mapping the dopant distribution in a semiconductor device on a 10 nm scale. This capability is critical for the development, optimization, and understanding of future ULSI processes and devices. The basic elements of the SCM and its application to nanometer scale metal oxide semiconductor (MOS) capacitor measurements are described. Experimental SCM methods are reviewed. Basic measurements show that nanometer scale capacitance-voltage relations are understood. High-quality probe tips and surfaces are critical for obtaining accurate measurements of two-dimensional dopant profiles. Quantitative modeling of SCM measurement is described for converting raw SCM data to dopant density. An inverse modeling method is presented. Direct comparison between secondary ion mass spectroscopy (SIMS) and SCM-measured dopant profiles are made. Quantitative junction measurements and models are discussed and images of small transistors are presented.
Ultrathin Diffusion Barriers/Liners for Gigascale Copper Metallization
Authors: Kaloyeros A. E. , Eisenbraun E.
Published: July 2002

▪ Abstract  The transition to copper-based interconnects for sub-quarter-micron device technologies has generated significant challenges in the identification and development of the robust material and process technologies required to form reliable multilevel metallization interconnects. In particular, a critical need exists for the identification and development of diffusion barrier/adhesion promoter liner materials that provide excellent performance in preventing the diffusion and intermixing of copper with the adjacent dielectric and semiconductor regions of the computer chip. This review summarizes key technology trends in interconnect metallization, with emphasis on ultrathin liner materials, predominant diffusion mechanisms in liner materials, and most promising candidate liners for copper metallization. Key results are presented from the development of physical vapor deposition and chemical vapor deposition processes for binary refractory metal nitrides, such as tantalum nitride and tungsten nitride, and amorphous ternary liners, including the titanium-silicon-nitrogen, tantalum-silicon-nitrogen, and tungsten-silicon-nitrogen systems. The applicability of these materials as diffusion barriers in copper-based interconnects is reviewed and assessed, particularly in terms of driving failure mechanisms and performance metrics.
Design and Synthesis of Energetic Materials
Authors: Fried Laurence E , Manaa M Riad , Pagoria Philip F , Simpson Randall L.
Published: July 2002

▪ Abstract  Energetic materials are chemical compounds or mixtures that store significant quantities of energy. In this review, we explore recent approaches to property prediction and new material synthesis. We show how the successful design of new energetic materials with tailored properties is becoming a practical reality.
THE PRESENT USE OF ELECTROCONVULSIVE THERAPY
Authors: Weiner, M.D R.D. , Krystal, M.D A.D.
Published: July 2002

▪ Abstract  Physicians attempting to treat certain severe mental disorders have recently shown renewed interest in electroconvulsive therapy (ECT). A number of technical innovations have made ECT safer, as well as more effective. These innovations include oxygenation, muscular relaxation, unilateral nondominant electrode placement, use of brief-pulse stimuli, titrated stimulus dosing, electroencephalographic (EEG) monitoring, determination of seizure adequacy, and pharmacologic enhancement of treatment response.
ENDOTHELIAL-LEUKOCYTE ADHESION MOLECULES IN HUMAN DISEASE
Authors: Bevilacqua, M.D., Ph.D Michael P. , Nelson, Ph.D Richard M. , Mannori, M.D., Ph.D Gianna , Cecconi, M.D Oliviero
Published: July 2002

▪ Abstract  An effective host response to infection or tissue damage requires focal accumulation of leukocytes. Leukocyte adhesion to the vessel wall, a key step in this process, depends on the ordered expression of specific endothelial cell surface molecules. The endothelial molecules that support adhesion include selectins that recognize leukocyte cell surface glycoconjugates as well as members of the immunoglobulin superfamily that interact with leukocyte integrins. Although inflammation can occur with minimal damage to the vessel wall and surrounding tissues, control mechanisms sometimes appear to fail, and the inflammatory response itself becomes a significant clinical problem. In this review, we discuss endothelial-leukocyte adhesion molecules with particular emphasis on their expression and function in human disease. Pathophysiological processes presented include atherosclerosis, ischemia-reperfusion injury, acute lung injury, rheumatoid arthritis, and graft rejection. A more detailed description of the discovery and characterization of the key molecules appears in the antecedent article entitled “Endothelial-Leukocyte Adhesion Molecules” ( 1 ).
XENOTRANSPLANTATION
Authors: Steele, M.D David J. R. , Auchincloss Hugh
Published: July 2002

▪ Abstract  The need for an alternative source of donor organs, together with the expansion of scientific data in this field, has focused attention on xenotransplantation as a possible alternative to allotransplantation in the treatment of patients with end-stage disease of vital organs. However, xenotransplantation is rarely successful. Not only are the immunological barriers to the acceptance of xenogeneic tissue more powerful than those seen in allotransplantation, but the potential for the transmission of xenograft-associated zoonoses to the human host at the time of transplantation is also present. In addition, data on the physiological performance of the xenograft in the human environment are lacking, although a few functioning xenografts have been shown to be capable of supporting human life.

Although progress has been made in clarifying some of the barriers to xenotransplantation and in defining appropriate therapeutic interventions, including interventions aimed at the removal of natural antibody and at the limitation of complement activation, xenotransplantation is not yet a viable alternative to allotransplantation in the clinical setting.
THE NUCLEAR HORMONE RECEPTOR GENE SUPERFAMILY
Authors: Ribeiro, M.D Ralff C. J. , Kushner, Ph.D Peter J. , Baxter, M.D John D.
Published: July 2002

▪ Abstract  The nuclear hormone receptor gene superfamily encodes structurally related proteins that regulate transcription of target genes. These macromolecules include receptors for steroid and thyroid hormones, vitamins, and other proteins for which no ligands have been found. These receptors have modular domains. The DNA-binding domain directs the receptors to bind specific DNA sequences as monomers, homodimers, or heterodimers. The ligand-binding domain responds to binding of the cognate hormone; this domain and the amino terminal domain interact with other transcription factors. Nuclear receptor-specific actions are derived from a combination of diverse elements, including availability of ligand, receptors, and nonreceptor factors; target-site structure; interactions with other proteins, such as the general transcription factors; and influences of other signaling pathways. These interactions result in ligand-regulated and ligand-independent effects on initiation of transcription of the target genes. Understanding the mechanisms of nuclear receptor action will enhance our knowledge of transcription and hormone influences on disease and facilitate the design of drugs with greater therapeutic value.
HYPERTENSION IN PREGNANCY: Current Concepts of Preeclampsia
Authors: Witlin, DO Andrea G. , Sibai, MD Baha M.
Published: July 2002

▪ Abstract  Hypertensive disorders (gestational hypertension, preeclampsia, chronic hypertension, superimposed preeclampsia) are the most common medical complications of pregnancy and constitute a major cause of maternal and perinatal morbidity and mortality. Prediction of those women destined to develop preeclampsia remains elusive. The benefits of calcium supplementation for prevention of preeclampsia are encouraging; however, the definitive study is not yet complete. Aspirin therapy for low-risk women has not been helpful; results of therapy for high-risk women are pending. More experience is being gained with antihypertensive therapy and expectant management in severe preeclampsia. Conservative management of severe preeclampsia, when performed in a tertiary care center, may benefit a select group of women and their fetuses.
Role of Telomerase in Cell Senescence and Oncogenesis
Authors: Urquidi Virginia , Tarin David , Goodison Steve
Published: July 2002

The ends of linear chromosomes are capped by specialized nucleoprotein structures termed telomeres. Telomeres comprise tracts of noncoding hexanucleotide repeat sequences that, in combination with specific proteins, protect against degradation, rearrangement, and chromosomal fusion events. Due to the polarity of conventional DNA synthesis, a net loss of telomeric sequences occurs at each cell division. It has been proposed that this cumulative telomeric erosion is a limiting factor in replicative capacity and elicits a signal for the onset of cellular senescence. To proliferate beyond the senescent checkpoint, cells must restore telomere length. This can be achieved by telomerase, an enzyme with reverse-transcriptase activity. This enzyme is absent in differentiated somatic tissues, but telomerase reactivation has been detected in most tumors. Much investigative effort is focusing on telomere dynamics with a view to possible manipulation of cellular proliferative potential. In this article, we review the role of telomeres and telomerase in senescence and tumor progression, and we discuss the potential use of telomerase in diagnosis and treatment.
The Pathophysiology of Asthma
Authors: Maddox Lee , Schwartz David A.
Published: July 2002

▪ Abstract  Asthma is a chronic disorder of the airways that is characterized by reversible airflow obstruction and airway inflammation, persistent airway hyperreactivity, and airway remodeling. The etiology of asthma is complex and multifactorial. Recent advances have demonstrated the importance of genetics in the development of asthma, particularly atopic asthma. Environmental stimuli, particularly early childhood infections, have also been associated with the development of asthma. Most current data seem to suggest that these factors drive the development of a Th-2 lymphocyte–predominant immune response, which has been associated with atopy and IgE-mediated inflammation. The concept of reversible airflow obstruction has also recently been challenged. It is now clear that chronic airway changes occur, which may contribute to progressive airflow obstruction. We discuss the important influence of genetic and environmental factors on the emergence of the asthmatic phenotype. The significance of Th-1 and Th-2 lymphocyte–mediated immunity are discussed, and the inflammatory processes leading to chronic airway inflammation are detailed.
LIVE ATTENUATED VARICELLA VACCINE
Authors: Arvin Ann M. , Gershon Anne A
Published: July 2002

Varicella-zoster virus (VZV) is a ubiquitous human pathogen that causes varicella, commonly called chicken pox; establishes latency; and reactivates as herpes zoster, referred to as shingles. A live attenuated varicella vaccine, derived from the Oka strain of VZV has clinical efficacy for the prevention of varicella. The vaccine induces persistent immunity to VZV in healthy children and adults. Immunization against VZV also has the potential to lower the risk of reactivation of latent virus. The varicella vaccine may eventually reduce or eliminate herpes zoster, which is a serious problem for elderly and immunocompromised individuals.
SAFE HAVEN: The Cell Biology of Nonfusogenic Pathogen Vacuoles
Authors: Sinai Anthony P. , Joiner Keith A.
Published: July 2002

▪ Abstract  Our understanding of both membrane traffic in mammalian cells and the cell biology of infection with intracellular pathogens has increased dramatically in recent years. In this review, we discuss the cell biology of the host-microbe interaction for four intracellular pathogens: Chlamydia spp., Legionella pneumophila, Mycobacterium spp., and the protozoan parasite Toxoplasma gondii. All of these organisms reside in vacuoles inside cells that have restricted fusion with host organelles of the endocytic cascade. Despite this restricted fusion, the vacuoles surrounding each pathogen display novel interactions with other host cell organelles. In addition to the effect of infection on host membrane traffic, we focus on these novel interactions and relate them where possible to nutrient acquisition by the intracellular organisms.
Regulation of Carbon Catabolism inBacillusSpecies
Authors: Stülke J. , Hillen W.
Published: July 2002

▪ Abstract  The gram-positive bacterium Bacillus subtilisis capable of using numerous carbohydrates as single sources of carbon and energy. In this review, we discuss the mechanisms of carbon catabolism and its regulation. Like many other bacteria, B. subtilis uses glucose as the most preferred source of carbon and energy. Expression of genes involved in catabolism of many other substrates depends on their presence (induction) and the absence of carbon sources that can be well metabolized (catabolite repression). Induction is achieved by different mechanisms, with antitermination apparently more common in B. subtilis than in other bacteria. Catabolite repression is regulated in a completely different way than in enteric bacteria. The components mediating carbon catabolite repression in B. subtilis are also found in many other gram-positive bacteria of low GC content.
Big Bacteria
Authors: Schulz Heide N. , Jørgensen Bo Barker
Published: July 2002

▪ Abstract  A small number of prokaryotic species have a unique physiology or ecology related to their development of unusually large size. The biomass of bacteria varies over more than 10 orders of magnitude, from the 0.2 μm wide nanobacteria to the largest cells of the colorless sulfur bacteria, Thiomargarita namibiensis, with a diameter of 750 μm. All bacteria, including those that swim around in the environment, obtain their food molecules by molecular diffusion. Only the fastest and largest swimmers known, Thiovulum majus, are able to significantly increase their food supply by motility and by actively creating an advective flow through the entire population. Diffusion limitation generally restricts the maximal size of prokaryotic cells and provides a selective advantage for μm-sized cells at the normally low substrate concentrations in the environment. The largest heterotrophic bacteria, the 80 × 600 μm large Epulopiscium sp. from the gut of tropical fish, are presumably living in a very nutrient-rich medium. Many large bacteria contain numerous inclusions in the cells that reduce the volume of active cytoplasm. The most striking examples of competitive advantage from large cell size are found among the colorless sulfur bacteria that oxidize hydrogen sulfide to sulfate with oxygen or nitrate. The several-cm-long filamentous species can penetrate up through the ca 500-μm-thick diffusive boundary layer and may thereby reach into water containing their electron acceptor, oxygen or nitrate. By their ability to store vast quantities of both nitrate and elemental sulfur in the cells, these bacteria have become independent of the coexistence of their substrates. In fact, a close relative, T. namibiensis, can probably respire in the sulfidic mud for several months before again filling up their large vacuoles with nitrate.
CREB AND MEMORY
Authors: Silva Alcino J. , Kogan Jeffrey H. , Frankland Paul W. , Kida Satoshi
Published: July 2002

▪ Abstract  The cAMP responsive element binding protein (CREB) is a nuclear protein that modulates the transcription of genes with cAMP responsive elements in their promoters. Increases in the concentration of either calcium or cAMP can trigger the phosphorylation and activation of CREB. This transcription factor is a component of intracellular signaling events that regulate a wide range of biological functions, from spermatogenesis to circadian rhythms and memory. Here we review the key features of CREB-dependent transcription, as well as the involvement of CREB in memory formation. Evidence from Aplysia, Drosophila, mice, and rats shows that CREB-dependent transcription is required for the cellular events underlying long-term but not short-term memory. While the work in Aplysia and Drosophila only involved CREB function in very simple forms of conditioning, genetic and pharmacological studies in mice and rats demonstrate that CREB is required for a variety of complex forms of memory, including spatial and social learning, thus indicating that CREB may be a universal modulator of processes required for memory formation.
GENE DISCOVERY INDROSOPHILA: New Insights for Learning and Memory
Authors: Dubnau Josh , Tully Tim
Published: July 2002

▪ Abstract  Genetic approaches have been used to investigate increasingly complex biological systems. Here we review the current state of genetic analysis of learning and memory in the fruitfly, Drosophila melanogaster. Emerging findings support two main themes. First, discovery and manipulation of genes involved with behavioral plasticity in genetically accessible systems such as D. melanogaster enables dissection of the biochemical, cellular, anatomical, and behavioral pathways of learning and memory. Second, because core cellular mechanisms of simple forms of learning are evolutionarily conserved, biological pathways discovered in invertebrates are likely to be conserved in vertebrate systems as well.
COMPUTATIONAL NEUROIMAGING OF HUMAN VISUAL CORTEX
Authors: Wandell Brian A.
Published: July 2002

▪ Abstract  Functional magnetic resonance imaging is a new neuroimaging method for probing the intact, alert, human brain. With this tool, brain activity that has been hidden can now be measured. Recent advances in measuring and understanding human neural responses underlying motion, color, and pattern perception are reviewed. In individual human brains, we can now identify the positions of several retinotopically organized visual areas; measure retinotopic organization within these areas; identify the location of a motion-sensitive region in individual brains; measure responses associated with contrast, color, and motion; and measure effects of attentional modulation on visually evoked responses. By framing experiments and analyses as questions about visual computation, these neuroimaging measurements can be coupled closely with those from other basic vision-science methods.
The Developmental Biology of Brain Tumors
Authors: Wechsler-Reya Robert , Scott Matthew P.
Published: July 2002

▪ Abstract  Tumors of the central nervous system (CNS) can be devastating because they often affect children, are difficult to treat, and frequently cause mental impairment or death. New insights into the causes and potential treatment of CNS tumors have come from discovering connections with genes that control cell growth, differentiation, and death during normal development. Links between tumorigenesis and normal development are illustrated by three common CNS tumors: retinoblastoma, glioblastoma, and medulloblastoma. For example, the retinoblastoma (Rb) tumor suppressor protein is crucial for control of normal neuronal differentiation and apoptosis. Excessive activity of the epidermal growth factor receptor and loss of the phosphatase PTEN are associated with glioblastoma, and both genes are required for normal growth and development. The membrane protein Patched1 (Ptc1), which controls cell fate in many tissues, regulates cell growth in the cerebellum, and reduced Ptc1 function contributes to medulloblastoma. Just as elucidating the mechanisms that control normal development can lead to the identification of new cancer-related genes and signaling pathways, studies of tumor biology can increase our understanding of normal development. Learning that Ptc1 is a medulloblastoma tumor suppressor led directly to the identification of the Ptc1 ligand, Sonic hedgehog, as a powerful mitogen for cerebellar granule cell precursors. Much remains to be learned about the genetic events that lead to brain tumors and how each event regulates cell cycle progression, apoptosis, and differentiation. The prospects for beneficial work at the boundary between oncology and developmental biology are great.
Activation, Deactivation, and Adaptation in Vertebrate Photoreceptor Cells
Authors: Burns Marie E , Baylor Denis A
Published: July 2002

▪ Abstract  Visual transduction captures widespread interest because its G-protein signaling motif recurs throughout nature yet is uniquely accessible for study in the photoreceptor cells. The light-activated currents generated at the photoreceptor outer segment provide an easily observed real-time measure of the output of the signaling cascade, and the ease of obtaining pure samples of outer segments in reasonable quantity facilitates biochemical experiments. A quiet revolution in the study of the mechanism has occurred during the past decade with the advent of gene-targeting techniques. These have made it possible to observe how transduction is perturbed by the deletion, overexpression, or mutation of specific components of the transduction apparatus.
LASER TRAPPING OF RADIOACTIVE ATOMS
Authors: Sprouse G. D. , Orozco L. A.
Published: July 2002

▪ Abstract  Light forces acting on radioactive atoms confine them in cold samples of large phase space density. We describe the processes of radioactive atom production, reduction of their velocity, and capture. The trapped atoms form excellent sources for the study of atomic parity non-conservation, β decay and α decay asymmetries, and other weak interactions.
COMPARATIVE NUTRITIONOF IRON AND COPPER
Authors: Winzerling Joy J. , Law  and John H.
Published: July 2002

▪ Abstract  The suggestion from nutritional studies with mammals of a link between iron and copper metabolism has been reinforced by recent investigations with yeast cells. Iron must be in the reduced ferrous (FeII) state for uptake by yeast cells, and reoxidation to ferric (FeIII) by a copper oxidase is part of the transport process. Thus, yeast cells deficient in copper are unable to absorb iron. In an analogous way, animals deficient in copper appear to be unable to move FeII out of cells, probably because it cannot be oxidized to FeIII. Invertebrate animals use copper and iron in ways very similar to vertebrates, with some notable exceptions. In the cases where vertebrates and invertebrates are similar, the latter may be useful models for vertebrate metabolism. In cases where they differ (e.g. predominance of serum ferritin in insects, oxygen transport by a copper protein in many arthropods, central importance of phenoloxidase, a copper enzyme in arthropods), the differences may represent processes that are exaggerated in invertebrates and thus more amenable to study in these organisms. On the other hand, they may represent processes unique to invertebrates, thus providing novel information on species diversity.
Human Body Composition: Advances in Models and Methods
Authors: B. Heymsfield Steven , Wang ZiMian , Baumgartner Richard N. , Ross Robert
Published: July 2002

▪ Abstract  The field of human body composition research is reaching a mature stage in its development: The three interconnected areas that define body composition research—models and their rules, methodology, and biological effects—are well-defined and are actively investigated by scientists in diverse disciplines from many different nations; and methods are available for measuring all major atomic, molecular, cellular, and tissue-system level body composition components in research, clinical, and epidemiological settings. This review summarizes main body composition research concepts, examines new component-measurement methodologies, and identifies potential areas of future research.
Calcium in Pregnancy and Lactation
Authors: Prentice Ann
Published: July 2002

Pregnancy and lactation are periods of high calcium requirement. This review highlights recent advances in our understanding of calcium and bone metabolism during human pregnancy and lactation and discusses the findings in relation to the calcium nutrition of the mother. The evidence indicates that pregnancy and lactation are characterized by physiological adaptive processes that are independent of maternal calcium intake and that provide the calcium necessary for fetal growth and breast-milk production without requiring an increase in maternal calcium intake. There are firm data that demonstrate that a low calcium intake during lactation does not lead to impaired lactational performance or to exaggerated bone loss. However, more research is required to define whether a low calcium intake prior to or during pregnancy can have deleterious effects on reproductive and lactational performance, and on the long-term health of the mother and child.
SARCOPENIA, WEIGHT LOSS, AND NUTRITIONAL FRAILTY IN THE ELDERLY
Authors: Bales Connie W. , Ritchie Christine S.
Published: July 2002

▪ Abstract  The progression of the aging process leads to a decreased margin of homeostatic reserve and a reduced ability to accommodate metabolic challenges, including nutritional stress. Nutritional frailty refers to the disability that occurs in old age owing to rapid, unintentional loss of body weight and loss of lean body mass (sarcopenia). Sarcopenia, a loss of muscle mass and strength, contributes to functional impairment. Weight loss is commonly due to a reduction in food intake; its possible etiology includes a host of physiological and nonphysiological causes. The release of cytokines during chronic disease may also be an important determinant of frailty. In addition to being anorectic, cytokines also contribute to lipolysis, muscle protein breakdown, and nitrogen loss. Whereas the multiple causes of nutritional frailty are not completely understood, clinical interventions for weight loss, sarcopenia, and cytokine alterations have been used with modest success.
Interindividual Variability in Inhibition and Induction of Cytochrome P450 Enzymes
Authors: Lin Jiunn H , Lu Anthony YH
Published: July 2002

Drug interactions have always been a major concern in medicine for clinicians and patients. Inhibition and induction of cytochrome P450 (CYP) enzymes are probably the most common causes for documented drug interactions. Today, many pharmaceutical companies are predicting potential interactions of new drug candidates. Can in vivo drug interactions be predicted accurately from in vitro metabolic studies? Should the prediction be qualitative or quantitative? Although some scientists believe that quantitative prediction of drug interactions is possible, others are less optimistic and believe that quantitative prediction would be very difficult. There are many factors that contribute to our inability to quantitatively predict drug interactions. One of the major complicating factors is the large interindividual variability in response to enzyme inhibition and induction. This review examines the sources that are responsible for the interindividual variability in inhibition and induction of cytochrome P450 enzymes.
Molecular Targets of Lithium Action
Authors: Phiel Christopher J , Klein Peter S
Published: July 2002

Lithium is highly effective in the treatment of bipolar disorder and also has multiple effects on embryonic development, glycogen synthesis, hematopoiesis, and other processes. However, the mechanism of lithium action is still unclear. A number of enzymes have been proposed as potential targets of lithium action, including inositol monophosphatase, a family of structurally related phosphomonoesterases, and the protein kinase glycogen synthase kinase-3. These potential targets are widely expressed, require metal ions for catalysis, and are generally inhibited by lithium in an uncompetitive manner, most likely by displacing a divalent cation. Thus, the challenge is to determine which target, if any, is responsible for a given response to lithium in cells. Comparison of lithium effects with genetic disruption of putative target molecules has helped to validate these targets, and the use of alternative inhibitors of a given target can also lend strong support for or against a proposed mechanism of lithium action. In this review, lithium sensitive enzymes are discussed, and a number of criteria are proposed to evaluate which of these enzymes are involved in the response to lithium in a given setting.
QUANTITATIVE OPTICAL SPECTROSCOPY FOR TISSUE DIAGNOSIS
Authors: Richards-Kortum Rebecca , Sevick-Muraca Eva
Published: July 2002

▪ Abstract  The interaction of light within tissue has been used to recognize disease since the mid-1800s. The recent developments of small light sources, detectors, and fiber optic probes provide opportunities to quantitatively measure these interactions, which yield information for diagnosis at the biochemical, structural, or (patho)physiological level within intact tissues. However, because of the strong scattering properties of tissues, the reemitted optical signal is often influenced by changes in biochemistry (as detected by these spectroscopic approaches) and by physiological and pathophysiological changes in tissue scattering. One challenge of biomedical optics is to uncouple the signals influenced by biochemistry, which themselves provide specificity for identifying diseased states, from those influenced by tissue scattering, which are typically unspecific to a pathology. In this review, we describe optical interactions pursued for biomedical applications (fluorescence, fluorescence lifetime, phosphorescence, and Raman from cells, cultures, and tissues) and then provide a descriptive framework for light interaction based upon tissue absorption and scattering properties. Finally, we review important endogenous and exogenous biological chromophores and describe current work to employ these signals for detection and diagnosis of disease.
AB INITIO DYNAMICS OF SURFACE CHEMISTRY
Authors: Radeke Michelle R. , Carter Emily A.
Published: July 2002

▪ Abstract  We review the young field of ab initio molecular dynamics applied to molecule-surface reactions. The techniques of ab initio molecular dynamics include methods that use an analytic potential energy function fit to ab initio data and those that are fully ab initio. In this review, we focus on the insights provided by ab initio–based molecular dynamics that are currently unavailable from experimental studies and discuss current techniques and limitations. As an example of how different aspects of a problem can be tackled with state-of-the-art theoretical tools, we consider the well-studied case of H2desorption and adsorption from the Si(100)-2 × 1 surface.
REACTIONS OFTRANSITIONMETALCLUSTERS WITHSMALLMOLECULES
Authors: Knickelbein Mark B.
Published: July 2002

▪ Abstract  Atoms and small molecules react with transition metal clusters in ways that are analogous to the physisorption and chemisorption reactions observed on the corresponding extended metal surface. However, often underlying these similarities are size-dependent variations in the reaction mechanisms and rates, the interpretation of which requires a detailed understanding of the structures of both the bare metal cluster substrates and the cluster-molecule complexes. Although polyatomic transition metal clusters cannot be characterized by the traditional methods of molecular spectroscopy, the combination of other physical and chemical probes can provide qualitative and semiquantitative structural information. These techniques, when combined with equilibrium geometries calculated using ab initio or semiempirical methods, provide a detailed picture of the structural origin of metal cluster reactivity and its variation with size.
FROMFOLDINGTHEORIES TOFOLDINGPROTEINS: A Review and Assessment of Simulation Studies of Protein Folding and Unfolding
Authors: Shea Joan-Emma , Brooks III Charles L
Published: July 2002

▪ Abstract  Beginning with simplified lattice and continuum “minimalist” models and progressing to detailed atomic models, simulation studies have augmented and directed development of the modern landscape perspective of protein folding. In this review we discuss aspects of detailed atomic simulation methods applied to studies of protein folding free energy surfaces, using biased-sampling free energy methods and temperature-induced protein unfolding. We review studies from each on systems of particular experimental interest and assess the strengths and weaknesses of each approach in the context of “exact” results for both free energies and kinetics of a minimalist model for a beta-barrel protein. We illustrate in detail how each approach is implemented and discuss analysis methods that have been developed as components of these studies. We describe key insights into the relationship between protein topology and the folding mechanism emerging from folding free energy surface calculations. We further describe the determination of detailed “pathways” and models of folding transition states that have resulted from unfolding studies. Our assessment of the two methods suggests that both can provide, often complementary, details of folding mechanism and thermodynamics, but this success relies on (a) adequate sampling of diverse conformational regions for the biased-sampling free energy approach and (b) many trajectories at multiple temperatures for unfolding studies. Furthermore, we find that temperature-induced unfolding provides representatives of folding trajectories only when the topology and sequence (energy) provide a relatively funneled landscape and “off-pathway” intermediates do not exist.
ENTEROGLUCAGON
Authors: Holst J. J.
Published: July 2002

▪ Abstract  The gene encoding proglucagon, the biosynthetic precursor of glucagon, is expressed not only in the pancreatic islets but also in endocrine cells of the gastrointestinal mucosa. The proglucagon (PG)-derived peptides from the gut include glicentin (corresponding to PG 1–69); smaller amounts of oxyntomodulin (PG 33–69) and glicentin-related pancreatic polypeptide (GRPP, PG 1–30); glucagon-like peptide-1 (GLP-1, PG 78–107 amide); intervening peptide-2 (IP-2, PG 111–122 amide); and glucagon-like peptide-2 (GLP-2, PG 126–158). All are secreted into the blood in response to ingestion of carbohydrates and lipids. Only oxyntomodulin and GLP-1 have proven biological activity; oxyntomodulin possibly because it interacts (but with lower potency) with GLP-1 and glucagon receptors. GLP-1 is the most potent insulinotropic hormone known and functions as an incretin hormone. It also inhibits glucagon secretion and, therefore, lowers blood glucose. This effect is preserved in patients with non-insulin-dependent diabetes mellitus, in whom infusions of GLP-1 may completely normalize blood glucose. However, GLP-1 also potently inhibits gastrointestinal secretion and motility, and its physiological functions include mediation of the “ileal-brake” effect, i.e. the inhibition of upper gastrointestinal functions elicited by the presence of unabsorbed nutrients in the ileum. As such it may serve to regulate food intake.
SYNCHRONOUS ACTIVITY IN THE VISUAL SYSTEM
Authors: Usrey W. Martin , Reid R. Clay
Published: July 2002

▪ Abstract  Synchronous activity among ensembles of neurons is a robust phenomenon observed in many regions of the brain. With the increased use of multielectrode recording techniques, synchronous firing of ensembles of neurons has been found at all levels in the mammalian visual pathway, from the retina to the extrastriate cortex. Here we distinguish three categories of synchrony in the visual system, (a) synchrony from anatomical divergence, (b) stimulus-dependent synchrony, and (c) emergent synchrony (oscillations). Although all three categories have been well documented, their functional significance remains uncertain. We discuss several lines of evidence both for and against a role for synchrony in visual processing: the perceptual consequences of synchronous activity, its ability to carry information, and the transmission of synchronous neural events to subsequent stages of processing.
The Gastrins: Their Production and Biological Activities
Authors: Dockray G J , Varro A , Dimaline R , Wang T
Published: July 2002

▪ Abstract  Gastric epithelial organization and function are controlled and maintained by a variety of endocrine and paracrine mediators. Peptides encoded by the gastrin gene are an important part of this system because targeted deletion of the gene, or of the gastrin-CCKB receptor gene, leads to decreased numbers of parietal cells and decreased gastric acid secretion. Recent studies indicate that the gastrin precursor, preprogastrin, gives rise to a variety of products, each with a distinctive spectrum of biological activity. The conversion of progastrin to smaller peptides is regulated by multiple mechanisms including prohormone phosphorylation and secretory vesicle pH. Progastrin itself stimulates colonic epithelial proliferation; biosynthetic intermediates (Gly-gastrins) stimulate colonic epithelial proliferation and gastric epithelial differentiation; and C-terminally amidated gastrins stimulate colonic proliferation, gastric epithelial proliferation and differentiation, and acid secretion. The effects of progastrin-derived peptides on gastric epithelial function are mediated in part by release of paracrine factors that include histamine, epidermal growth factor (EGF)–receptor ligands, and Reg. The importance of the appropriate regulation of this system is shown by the observation that prolonged moderate hypergastrinemia in transgenic mice leads to remodelling of the gastric epithelium, and in the presence of Helicobacter, to gastric cancer.
Antifreeze and Ice Nucleator Proteins in Terrestrial Arthropods
Authors: Duman John G
Published: July 2002

▪ Abstract  Terrestrial arthropods survive subzero temperatures by becoming either freeze tolerant (survive body fluid freezing) or freeze avoiding (prevent body fluid freezing). Protein ice nucleators (PINs), which limit supercooling and induce freezing, and antifreeze proteins (AFPs), which function to prevent freezing, can have roles in both freeze tolerance and avoidance. Many freeze-tolerant insects produce hemolymph PINs, which induce freezing at high subzero temperatures thereby inhibiting lethal intracellular freezing. Some freeze-tolerant species have AFPs that function as cryoprotectants to prevent freeze damage. Although the mechanism of this cryoprotection is not known, it may involve recrystallization inhibition and perhaps stabilization of the cell membrane. Freeze-avoiding species must prevent inoculative freezing initiated by external ice across the cuticle and extend supercooling abilities. Some insects remove PINs in the winter to promote supercooling, whereas others have selected against surfaces with ice-nucleating abilities on an evolutionary time scale. However, many freeze-avoiding species do have proteins with ice-nucleating activity, and these proteins must be masked in winter. In the beetle Dendroides canadensis, AFPs in the hemolymph and gut inhibit ice nucleators. Also, hemolymph AFPs and those associated with the layer of epidermal cells under the cuticle inhibit inoculative freezing. Two different insect AFPs have been characterized. One type from the beetles D. canadensis and Tenebrio molitor consists of 12- and 13-mer repeating units with disulfide bridges occurring at least every six residues. The spruce budworm AFP lacks regular repeat units. Both have much higher activities than any known AFPs.
Molecular Analysis of Mammalian Circadian Rhythms
Authors: Reppert Steven M , Weaver David R
Published: July 2002

▪ Abstract  In mammals, a master circadian “clock” resides in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN clock is composed of multiple, single-cell circadian oscillators, which, when synchronized, generate coordinated circadian outputs that regulate overt rhythms. Eight clock genes have been cloned that are involved in interacting transcriptional-/translational-feedback loops that compose the molecular clockwork. The daily light-dark cycle ultimately impinges on the control of two clock genes that reset the core clock mechanism in the SCN. Clock-controlled genes are also generated by the central clock mechanism, but their protein products transduce downstream effects. Peripheral oscillators are controlled by the SCN and provide local control of overt rhythm expression. Greater understanding of the cellular and molecular mechanisms of the SCN clockwork provides opportunities for pharmacological manipulation of circadian timing.