bluuebunny/crossref_metadata_2025 huggingface dataset:
Mass Loss from Cool Stars: Impact on the Evolution of Stars and Stellar Populations
Authors: Willson Lee Anne
Published: July 2002

▪ Abstract  This review emphasizes the mass loss processes that affect the fates of single stars with initial masses between one and nine solar masses. Just one epoch of mass loss has been clearly demonstrated to be important for these stars; that is the episode that ends their evolution up the asymptotic giant branch. Quite a clear picture of this evolutionary stage is emerging from current studies. Mass loss rates increase precipitously as stars evolve toward greater luminosity and radius and decreased effective temperature. As a result, empirical relationships between mass loss rates and stellar parameters are determined mostly by selection effects and tell us which stars are losing mass rather than how stars lose mass. After detailed theoretical models are found to match observational constraints, the models may be used to extrapolate to populations not available for study nearby, such as young stars with low metallicity. The fates of stars are found to depend on both their initial masses and their initial metallicities; a larger proportion of low-metallicity stars should end up with core masses reaching the Chandrasekhar limit, giving rise to Type 1.5 supernovae, and the remnant white dwarfs of low-Z populations will be both fewer and more massive than those in Population I. There are also clear indications that some stars lose one to several tenths of a solar mass during the helium core flash, but neither models nor observations reveal any details of this process yet. The observational and theoretical bases for a variety of mass loss formulae in current use are also reviewed in this article, and the relations are compared in a series of figures.
FROM CHEMISTRY TO BIOCHEMISTRY TO CATALYSIS TO MOVEMENT
Authors: Jencks William P.
Published: July 2002

Mechanisms of chemical reactions can often be predicted by determining the dependence of the lifetime of reaction intermediates on the structure of the reactants. When there is no lifetime in the presence of another reactant or catalyst the reaction proceeds through an enforced concerted mechanism.

Noncovalent binding interactions between enzymes and their substrates provide a major contribution to catalysis by decreasing entropy and by destabilizing the ground state relative to the transition state, as well as by covalent and noncovalent chemical interactions with the substrate.

Movement in biological systems, such as muscle contraction and the active transport of ions, is generally brought about through a series of alternating chemical and vectorial steps that involve a series of changes in the specificity for catalysis of the chemical and vectorial reactions. These changes divide the overall reaction into segments so that neither the chemical nor the vectorial reaction will be completed unless the other is also completed.
MCM Proteins in DNA Replication
Authors: Tye Bik K.
Published: July 2002

▪ Abstract  The MCM proteins are essential replication initiation factors originally identified as proteins required for minichromosome maintenance in Saccharomyces cerevisiae. The best known among them are a family of six structurally related proteins, MCM2–7, which are evolutionally conserved in all eukaryotes. The MCM2–7 proteins form a hexameric complex. This complex is a key component of the prereplication complex that assembles at replication origins during early G1 phase. New evidence suggests that the MCM2–7 proteins may be involved not only in the initiation but also in the elongation of DNA replication. Orchestration of the functional interactions between the MCM2–7 proteins and other components of the prereplication complex by cell cycle–dependent protein kinases results in initiation of DNA synthesis once every cell cycle.
Micro- and Nanomechanics of the Cochlear Outer Hair Cell
Authors: Brownell W. E. , Spector A. A. , Raphael R. M. , Popel A. S.
Published: July 2002

▪ Abstract  Outer hair cell electromotility is crucial for the amplification, sharp frequency selectivity, and nonlinearities of the mammalian cochlea. Current modeling efforts based on morphological, physiological, and biophysical observations reveal transmembrane potential gradients and membrane tension as key independent variables controlling the passive and active mechanics of the cell. The cell's mechanics has been modeled on the microscale using a continuum approach formulated in terms of effective (cellular level) mechanical and electric properties. Another modeling approach is nanostructural and is based on the molecular organization of the cell's membranes and cytoskeleton. It considers interactions between the components of the composite cell wall and the molecular elements within each of its components. The methods and techniques utilized to increase our understanding of the central role outer hair cell mechanics plays in hearing are also relevant to broader research questions in cell mechanics, cell motility, and cell transduction.
Image-Guided Acoustic Therapy
Authors: Vaezy Shahram , Andrew Marilee , Kaczkowski Peter , Crum Lawrence
Published: July 2002

▪ Abstract  The potential role of therapeutic ultrasound in medicine is promising. Currently, medical devices are being developed that utilize high-intensity focused ultrasound as a noninvasive method to treat tumors and to stop bleeding (hemostasis). The primary advantage of ultrasound that lends the technique so readily to use in noninvasive therapy is its ability to penetrate deep into the body and deliver to a specific site thermal or mechanical energy with submillimeter accuracy. Realizing the full potential of acoustic therapy, however, requires precise targeting and monitoring. Fortunately, several imaging modalities can be utilized for this purpose, thus leading to the concept of image-guided acoustic therapy. This article presents a review of high-intensity focused ultrasound therapy, including its mechanisms of action, the imaging modalities used for guidance and monitoring, some current applications, and the requirements and technology associated with this exciting and promising field.
SOLID-STATE NUCLEAR MAGNETIC RESONANCE INVESTIGATION OF PROTEIN AND POLYPEPTIDE STRUCTURE
Authors: Fu Riqiang , Cross Timothy A.
Published: July 2002

▪ Abstract  Solid-state nuclear magnetic resonance (NMR) is rapidly emerging as a successful and important technique for protein and peptide structural elucidation from samples in anisotropic environments. Because of the diversity of nuclei and nuclear spin interactions that can be observed, and because of the broad range of sample conditions that can be studied by solid-state NMR, the potential for gaining structural constraints is great. Structural constraints in the form of orientational, distance, and torsional constraints can be obtained on proteins in crystalline, liquid-crystalline, or amorphous preparations. Great progress in the past few years has been made in developing techniques for obtaining these constraints, and now it has also been clearly demonstrated that these constraints can be assembled into uniquely defined three-dimensional structures at high resolution. Although much progress toward the development of solid-state NMR as a routine structural tool has been documented, the future is even brighter with the continued development of the experiments, of NMR hardware, and of the molecular biological methods for the preparation of labeled samples.
RNA Folds: Insights from Recent Crystal Structures
Authors: Ferré-D'Amaré Adrian R. , Doudna Jennifer A.
Published: July 2002

An RNA fold is the result of packing together two or more coaxial helical stacks. To date, four RNA folds have been determined at near-atomic resolution by X-ray crystallography: transfer RNA, the hammerhead ribozyme, the P4–P6 domain of the Tetrahymena group I intron, and the hepatitis delta virus ribozyme. All four folds result in RNAs that are considerably more compact than isolated A-form duplexes. These structures illustrate, to varying degrees, three modes of fold stabilization: association of complementary molecular surfaces, stabilization of close RNA packing by binding of cations, and stabilization through pseudoknotting.
Unnatural Ligands for Engineered Proteins: New Tools for Chemical Genetics
Authors: Bishop Anthony , Buzko Oleksandr , Heyeck-Dumas Stephanie , Jung Ilyoung , Kraybill Brian , Liu Yi , Shah Kavita , Ulrich Scott , Witucki Laurie , Yang Feng , Zhang Chao , Shokat Kevan M.
Published: July 2002

▪ Abstract  Small molecules that modulate the activity of biological signaling molecules can be powerful probes of signal transduction pathways. Highly specific molecules with high affinity are difficult to identify because of the conserved nature of many protein active sites. A newly developed approach to discovery of such small molecules that relies on protein engineering and chemical synthesis has yielded powerful tools for the study of a wide variety of proteins involved in signal transduction (G-proteins, protein kinases, 7-transmembrane receptors, nuclear hormone receptors, and others). Such chemical genetic tools combine the advantages of traditional genetics and the unparalleled temporal control over protein function afforded by small molecule inhibitors/activators that act at diffusion controlled rates with targets.
Hydrogen Bonding, Base Stacking, and Steric Effects in DNA Replication
Authors: Kool Eric T.
Published: July 2002

▪ Abstract  Understanding the mechanisms by which genetic information is replicated is important both to basic knowledge of biological organisms and to many useful applications in biomedical research and biotechnology. One of the main functions of a DNA polymerase enzyme is to help DNA recognize itself with high specificity when a strand is being copied. Recent studies have shed new light on the question of what physical forces cause a polymerase enzyme to insert a nucleotide into a strand of DNA and to choose the correct nucleotide over the incorrect ones. This is discussed in the light of three main forces that govern DNA recognition: base stacking, Watson-Crick hydrogen bonding, and steric interactions. These factors are studied with natural and structurally altered DNA nucleosides.
MANAGEMENT OF THE SPOTTED OWL: A Case History in Conservation Biology
Authors: Noon Barry R. , McKelvey Kevin S.
Published: July 2002

▪ Abstract  Official conservation efforts for the northern spotted owl began in the United States in 1975 when it was declared “threatened” in the state of Oregon; efforts continued in a sporadic and unsystematic way through the 1980s. In 1989 the Interagency Scientific Committee (ISC) was established by Congress and charged with the development of a scientifically defensible conservation strategy covering the entire range of the northern spotted owl, which includes parts of the states of Oregon, Washington, and California. The ISC collated all spotted owl research and approached questions concerning the need for a conservation strategy and the efficacy of potential reserve designs as testable hypotheses. Because the hypothesis tests were based on incomplete data and highly stylized population models, uncertainty concerning the conclusions of the ISC remained. Subsequent research focused on answering those uncertainties, and here we revisit the ISC's conclusions, asking which if any of them have been invalidated. The ISC's major conclusions have remained robust: he population of spotted owls is declining due to reductions in old growth habitat. Subsequent trend-analyses confirmed the levels of population decline calculated by the ISC and in addition concluded that the rate of decline was accelerating. The ISC's response to these conclusions was to recommend the establishment of an extensive network of large reserves. Subsequent research and more detailed computer modeling have confirmed the conceptual validity of this conservation plan but suggest that optimistic assumptions led the ISC to propose a minimal reserve structure. Current federal management plans in the Pacific Northwest propose more habitat than the ISC envisioned, providing a greater likelihood of persistence.
THE ROLE OF INTRODUCED SPECIES IN THE DEGRADATION OF ISLAND ECOSYSTEMS: A Case History of Guam
Authors: Fritts Thomas H. , Rodda Gordon H.
Published: July 2002

▪ Abstract  The accidental introduction of the brown treesnake (Boiga irregularis) on Guam around 1950 induced a cascade of extirpations that may be unprecedented among historical extinction events in taxonomic scope and severity. Birds, bats, and reptiles were affected, and by 1990 most forested areas on Guam retained only three native vertebrates, all of which were small lizards. Of the hypotheses to account for the severity of this extinction event, we find some support for the importance of lack of coevolution between introduced predator and prey, availability of alternate prey, extraordinary predatory capabilities of the snake, and vulnerabilities of the Guam ecosystem. In addition, there were important interactions among these factors, especially the presence of introduced prey (possessing coevolutionary experience) that were thus able to maintain their populations and provide alternate prey to the introduced predator while it was driving the native prey species to extinction. This complex of vulnerabilities is common on oceanic islands.
The Kinship Theory of Genomic Imprinting
Authors: Haig David
Published: July 2002

▪ Abstract  The inclusive fitness effect attributable to an allele can be divided into an effect on matrilineal kin when the allele is maternally derived and an effect on patrilineal kin when paternally derived. However, the allele is not subject to selection on its effects on patrilineal kin when maternally derived nor on its effects on matrilineal kin when paternally derived. As a result, natural selection may favor alleles with effects that differ, depending on the allele's parental origin. At autosomal loci, this process is predicted to lead to the silencing of alleles when inherited from one or the other parent. At X-linked loci subject to random X inactivation, the process is predicted to lead to quantitative differences of expression between maternal and paternal alleles but not to complete silencing of one allele. The implications of this theory and some challenges to the theory are reviewed.
BIOLOGY OF THE MANTISPIDAE
Authors: Redborg Kurt E.
Published: July 2002

▪ Abstract  Members of the Neuropteran family Mantispidae, subfamily Mantispinae, are predators in the egg sacs of spiders, draining egg contents through a piercing/sucking tube formed by modified mandibles and maxillae. First-instar mantispids use two strategies to locate spider eggs: Larvae may burrow directly through the silk of egg sacs they find, or they may board and be carried by female spiders prior to sac production, entering the sac as it is being constructed. Mantispids that board spiders usually adopt positions on or near the pedicel; some species may enter the spider's book lungs. Larvae maintain themselves aboard spiders by feeding on spider blood. Transfers of larvae from spider to spider are possible during spider mating or cannibalism. All of the major groups of hunting spiders are attacked by spider-boarding mantispids; the egg sacs of web-building species are also entered by egg-sac penetrators.
Insect Pest Management in Tropical Asian Irrigated Rice
Authors: Matteson P. C.
Published: July 2002

▪ Abstract  Abundant natural enemies in tropical Asian irrigated rice usually prevent significant insect pest problems. Integrated pest management (IPM) extension education of depth and quality is required to discourage unnecessary insecticide use that upsets this natural balance, and to empower farmers as expert managers of a healthy paddy ecosystem. Farmers' skill and collaboration will be particularly important for sustainable exploitation of the potential of new, higher-yielding and pestresistant rices. IPM “technology transfer” through training and visit (T&V) extension systems failed, although mass media campaigns encouraging farmer participatory research can reduce insecticide use. The “farmer first” approach of participatory nonformal education in farmer field schools, followed by community IPM activities emphasizing farmer-training-farmer and research by farmers, has had greater success in achieving IPM implementation. Extension challenges are a key topic for rice IPM research, and new pest management technology must promote, rather than endanger, ecological balance in rice paddies.
Phylogenetic System and Zoogeography of the Plecoptera
Authors: Zwick Peter
Published: July 2002

▪ Abstract  Information about the phylogenetic relationships of Plecoptera is summarized. The few characters supporting monophyly of the order are outlined. Several characters of possible significance for the search for the closest relatives of the stoneflies are discussed, but the sister-group of the order remains unknown. Numerous characters supporting the presently recognized phylogenetic system of Plecoptera are presented, alternative classifications are discussed, and suggestions for future studies are made. Notes on zoogeography are appended. The order as such is old (Permian fossils), but phylogenetic relationships and global distribution patterns suggest that evolution of the extant suborders started with the breakup of Pangaea. There is evidence of extensive recent speciation in all parts of the world.
INSECTBIODEMOGRAPHY
Authors: Carey James R.
Published: July 2002

▪ Abstract  Biodemography is an emerging subdiscipline of classical demography that brings life table techniques, mortality models, experimental systems, and comparative methods to bear on questions concerned with the fundamental determinants of mortality, longevity, aging, and life span. It is important to entomology because it provides a secure and comprehensive actuarial foundation for life table and mortality analysis, it suggests new possibilities for the use of model insect systems in the study of aging and mortality dynamics, and it integrates an interdisciplinary perspective on demographic concepts and actuarial techniques into the entomological literature. This paper describes the major life table formulae and mortality models used to analyze the actuarial properties of insects; summarizes the literature on adult insect life span, including a discussion of basic concepts; identifies the major correlates of extended longevity; and suggests new ideas for using demographic concepts in both basic and applied entomology.
TURBULENT FLOW OVER HILLS AND WAVES
Authors: Belcher S. E. , Hunt J. C. R.
Published: July 2002

▪ Abstract  This is a review of the mechanisms that control neutrally stable turbulent boundary-layer flow over hills and waves, their relative magnitudes, and how they exert their greatest effects in different regions of the flow. We compare calculations based on various analytical and computational models with each other and with relevant experimental data. We discuss practical applications of these studies.
CELLULARFLUIDMECHANICS
Authors: Kamm Roger D.
Published: July 2002

▪ Abstract  The coupling of fluid dynamics and biology at the level of the cell is an intensive area of investigation because of its critical role in normal physiology and disease. Microcirculatory flow has been a focus for years, owing to the complexity of cell-cell or cell-glycocalyx interactions. Noncirculating cells, particularly those that comprise the walls of the circulatory system, experience and respond biologically to fluid dynamic stresses. In this article, we review the more recent studies of circulating cells, with an emphasis on the role of the glycocalyx on red-cell motion in small capillaries and on the deformation of leukocytes passing through the microcirculation. We also discuss flows in the vicinity of noncirculating cells, the influence of fluid dynamic shear stress on cell biology, and diffusion in the lipid bi-layer, all in the context of the important fluid-dynamic phenomena.
SHIP WAKES AND THEIR RADAR IMAGES
Authors: Reed Arthur M. , Milgram Jerome H.
Published: July 2002

▪ Abstract  Remote observations of a surface ship wake using synthetic aperture radar (SAR) show distinct features such as a dark trailing centerline region, bright V-images aligned at some angle to the ship's path, and, sometimes, either the transverse or the diverging waves of the Kelvin-wave pattern. The dark region of relatively low radar backscatter is usually associated with a region that is relatively lacking in short wave components, whereas the bright line feature suggests a region of enhanced radar return within the apparent angular confines of the ship's usual Kelvin-wave pattern. This review provides a survey of remotely sensed wake images, the systems that have collected these images, and an overview of the theory of Kelvin wakes—a primary source of the phenomena that cause the dark centerline and bright V-images—with example predictions. The review concludes with a survey of the phenomena that cause the dark centerline returns and some example predictions of the radar reflectivity across these dark centerline returns.
MAMMALS THAT BREAK THE RULES: Genetics of Marsupials and Monotremes
Authors: Graves Jennifer A. Marshall
Published: July 2002

▪ Abstract  Marsupials and monotremes, the mammals most distantly related to placental mammals, share essentially the same genome but show major variations in chromosome organization and function. Rules established for the mammalian genome by studies of human and mouse do not always apply to these distantly related mammals, and we must make new and more general laws. Some examples are contradictions to our assumption of frequent genome reshuffling in vertebrate evolution, Ohno's Law of X chromosome conservation, the Lyon Hypothesis of X chromosome inactivation, sex chromosome pairing, several explanations of Haldane's Rule, and the theory that the mammalian Y chromosome contains a male-specific gene with a direct dominant action on sex determination. Significantly, it is not always the marsupials and monotremes (usually considered the weird mammals) that are exceptional. In many features, it appears that humans and, particularly, mice are the weird mammals that break more general mammalian, or even vertebrate rules.
Human Genetics on the Web
Authors: Guttmacher Alan E.
Published: July 2002

Use of the World Wide Web (“the web”) and our knowledge of human genetics are both currently expanding rapidly. By allowing swift, universal, and free access to data, the web has already played an important role in human genetics research. It has also begun to change the way that information is shared in clinical genetics and, to a lesser degree, affect how education in human genetics occurs. There are scores of web sites helpful to those interested in either research or clinical aspects of human genetics. The web and related communication technologies should continue to play increasingly important roles in human genetics.
MECHANISMS OF MHC CLASS I–RESTRICTED ANTIGEN PROCESSING
Authors: Pamer Eric , Cresswell Peter
Published: July 2002

▪ Abstract  Classical class I molecules assemble in the endoplasmic reticulum (ER) with peptides mostly generated from cytosolic proteins by the proteasome. The activity of the proteasome can be modulated by a variety of accessory protein complexes. A subset of the proteasome β-subunits (LMP2, LMP7, and MECL-1) and one of the accessory complexes, PA28, are upregulated by γ-interferon and affect the generation of peptides to promote more efficient antigen recognition. The peptides are translocated into the ER by the transporter associated with antigen processing (TAP). A transient complex containing a class I heavy chain–β2microglobulin (β2m) dimer is assembled onto the TAP molecule by successive interactions with the ER chaperones calnexin and calreticulin and a specialized molecule, tapasin. Peptide binding releases the class I–β2m dimer for transport to the cell surface, while lack of binding results in proteasome-mediated degradation. The products of certain nonclassical MHC-linked class I genes bind peptides in a similar way. A homologous set of β2m-associated membrane glycoproteins, the CD1 molecules, appears to bind lipid-based ligands within the endocytic pathway.
THE IMMUNOGENETICS OF HUMAN INFECTIOUS DISEASES
Authors: Hill Adrian V. S.
Published: July 2002

▪ Abstract  Twin and adoptee studies have indicated that host genetic factors are major determinants of susceptibility to infectious diseases in humans. Twin studies have also found high heritabilities for many humoral and cellular immune responses to pathogen antigens, with most of the genetic component mapping outside of the major histocompatibility complex. Candidate gene studies have implicated several immunogenetic polymorphisms in human infectious diseases. HLA variation has been associated with susceptibility or resistance to malaria, tuberculosis, leprosy, AIDS, and hepatitis virus persistence. Variation in the tumor necrosis factor gene promoter has also been associated with several infectious diseases. Chemokine receptor polymorphism affects both susceptibility to HIV-1 infection and the rate of progression to AIDS. Inactivating mutations of the γ-interferon receptor lead to increased susceptibility to atypical mycobacteria and disseminated BCG infection in homozygous children. The active form of vitamin D has immunomodulatory effects, and allelic variants of the vitamin D receptor appear to be associated with differential susceptibility to several infectious diseases. NRAMP1, a macrophage gene identified by positional cloning of its murine homologue, has been implicated in susceptibility to tuberculosis in Africans. Whole genome linkage analysis of multi-case families is now being used to map and identify new loci affecting susceptibility to infectious diseases. It is likely that susceptibility to most microorganisms is determined by a large number of polymorphic genes, and identification of these should provide insights into protective and pathogenic mechanisms in infectious diseases.
SUPERTWISTED NEMATIC (STN) LIQUID CRYSTAL DISPLAYS
Authors: Scheffer Terry , Nehring Jürgen
Published: July 2002

▪ Abstract  Passive matrix, supertwisted nematic (STN) displays are well established as small- and medium-sized matrix displays and are presently being used in half of the notebook-sized computers. STN screens are being considered as desk-top CRT monitor replacements because their simpler construction allows them to be manufactured in larger sizes and at lower cost than active matrix LCDs. This chapter describes the fundamental physics behind STN operation, reviews the many device and materials developments that have improved STN performance, and points out likely future trends.
ISOTROPIC NEGATIVE THERMAL EXPANSION
Authors: Sleight Arthur W.
Published: July 2002

▪ Abstract  Materials that contract on heating are unusual and have important applications. Materials showing such negative thermal expansion behavior are usually anisotropic and usually exhibit this behavior over only a small temperature range. The zirconium tungstate family is unique in showing strong negative thermal expansion over a broad temperature range.
ELECTROPHORETIC DEPOSITION OF MATERIALS
Authors: Van der Biest Omer O. , Vandeperre Luc J.
Published: July 2002

▪ Abstract  The electrophoretic deposition of materials is reviewed. Numerous applications of electrophoretic deposition are described, including production of coatings, free-standing objects, and laminated or graded materials, infiltration of porous materials, and fabrication of woven fiber preforms. The preparation of electrophoretic suspensions is discussed as are a number of mechanisms of deposition that have been proposed elsewhere. In discussing the kinetics of the process, primary attention is given to the relation between the evolution of the current and the electric field strength.
KELVIN PROBE FORCE MICROSCOPY OF MOLECULAR SURFACES
Authors: Fujihira Masamichi
Published: July 2002

▪ Abstract  The electrostatic force microscope is one of many specialized tip sensors used in near-field microscopy. This type of microscope is realized by applying a voltage on a conducting AFM tip. It can be used to image samples that present a distribution of electrical properties on inhomogeneous materials as well as on nanostructures. This microscopy technique has been used to probe phase separation, chemical recognition, molecular orientation, and photo-induced charge separation in molecular photodiodes in Langmuir-Blodgett films.
Mechanical Behavior of Metallic Foams
Authors: Gibson L. J.
Published: July 2002

▪ Abstract  Metallic foams have a combination of properties that make them attractive for a number of engineering applications, including lightweight structural sandwich panels, energy absorption devices, and heat sinks. For many potential applications an understanding of the mechanical behavior of these foams is essential. Recently, there has been substantial progress in identifying the mechanisms of deformation and failure in metallic foams. Here, we summarize the current understanding of the elastic moduli, uniaxial strength, yield criterion, creep, and fatigue of metallic foams.
Low Dielectric Constant Materials for ULSI Interconnects
Authors: Morgen Michael , Ryan E. Todd , Zhao Jie-Hua , Hu Chuan , Cho Taiheui , Ho Paul S.
Published: July 2002

▪ Abstract  As integrated circuit (IC) dimensions continue to decrease, RC delay, crosstalk noise, and power dissipation of the interconnect structure become limiting factors for ultra-large-scale integration of integrated circuits. Materials with low dielectric constant are being developed to replace silicon dioxide as interlevel dielectrics. In this review, the general requirements for process integration and material properties of low-k dielectrics are first discussed. The discussion is focused on the challenge in developing materials with low dielectric constant but strong thermomechanical properties. This is followed by a description of the material characterization techniques, including several recently developed for porous materials. Finally, the material characteristics of candidate low-k dielectrics will be discussed to illustrate their structure-property relations.
THALASSEMIA: Pathophysiology of Red Cell Changes
Authors: Schrier, M.D Stanley L.
Published: July 2002

▪ Abstract  The thalassemias are extremely heterogeneous in terms of their clinical severity, and their underlying pathophysiology relates directly to the extent of accumulation of excess unmatched globin chains: α in βthalassemia and βin the αthalassemias. However, the accumulation of each separate globin chain affects red cell membrane material properties and the state of red cell hydration very differently. These observations presumably account for the varying extent of ineffective erythropoiesis and peripheral blood hemolysis in the major variants of thalassemia.
MECHANISM OF EPILEPSY
Authors: Shin, M.D Cheolsu , McNamara, M.D James O.
Published: July 2002

▪ Abstract  Epilepsy is a collection of diverse disorders that together affect approximately 1% of the general population. Current therapies are largely symptomatic and are aimed at controlling seizures in affected individuals. This review focuses on emerging insights into mechanisms underlying the most common form of epilepsy—complex partial epilepsy—and also addresses progress in molecular genetic approaches. Such developments will hopefully lead to more effective therapies.
BROWN ADIPOSE TISSUE, β3-ADRENERGIC RECEPTORS, AND OBESITY
Authors: Lowell, MD, PhD B. B. , Flier, MD J. S.
Published: July 2002

▪ Abstract  Brown adipose tissue is distinguished by its unique capacity for uncoupled mitochondrial respiration, which is highly regulated by sympathetic nerve activity. Because of this, energy expenditure in brown fat is capable of ranging over many orders of magnitude. The fact that the function of brown adipose tissue is impaired in obese rodents and that transgenic mice with decreased brown fat develop obesity demonstrates the importance of brown fat in maintaining nutritional homeostasis. However, the role of brown fat in humans is less clear. β3-Adrenergic receptors are found on brown adipocytes, and treatment with β3-selective agonists markedly increases energy expenditure and decreases obesity in rodents. Whether β3-selective agonists will be effective anti-obesity agents in humans is presently under investigation.
MARKERS FOR PREDICTING THE DEVELOPMENT OF ACUTE RESPIRATORY DISTRESS SYNDROME
Authors: Connelly, MD Kevin G. , Repine, MD John E.
Published: July 2002

▪ Abstract  The acute respiratory distress syndrome (ARDS) is a relatively common, inflammatory lung disorder that is associated with major morbidity and high mortality. The pathogenesis of ARDS is complex, and unfortunately, the development of ARDS in an individual patient is difficult to anticipate. In this chapter, we outline the rationale for why accurately predicting the development of ARDS would be valuable. We also review the accumulated data on approaches for predicting ARDS and discuss the potential difficulties in establishing predictive markers.
The Role of Glutamatergic Neurotransmission in the Pathophysiology of Alcoholism
Authors: Tsai Guochuan , Coyle Joseph T.
Published: July 2002

Recent evidence suggests that ethanol abuse produces its diverse effects on the brain to a substantial degree by disrupting the function of the major excitatory neurotransmitter, glutamate. Ethanol, at concentrations associated with behavioral effects in humans, inhibits the N-methyl-d-aspartate (NMDA) receptor, which mediates the post-synaptic excitatory effects of glutamate. Tolerance to ethanol results in up-regulation of the NMDA receptor so that abrupt withdrawal produces a hyperexcitable state that leads to seizures, delerium tremens, and excitotoxic neuronal death. Ethanol's inhibition of the NMDA receptor in the fetal brain likely contributes to the CNS manifestations of fetal alcohol syndrome. Therapeutic strategies aimed at correcting glutamatergic dysregulation in alcoholism need to be explored.
Infection Genomics:Nramp1as a Major Determinant of Natural Resistance to Intracellular Infections
Authors: Skamene, MD, PhD Emil , Schurr, PhD Erwin , Gros, PhD Philippe
Published: July 2002

The scope of the tuberculosis (TB) epidemic in the world today is enormous, with about 30 million active cases. Current research into preventing the spread of TB is focused on development of new drugs to inactivate Mycobacterium tuberculosis, the causative agent of TB, as well as on identifying the critical steps of host defense to infection with Mycobacteria, which might also yield therapeutic targets. Our infection genomics approach toward the latter strategy has been to isolate and characterize a mouse gene, Bcg (Nramp1), which controls natural susceptibility to infection with Mycobacteria, as well as Salmonella and Leishmania. Through comparative genomics, we have identified the homologous human NRAMP1 gene, alleles of which are now being used for tests of linkage with TB and leprosy.
Gene Expression Profiling of Lymphoid Malignancies
Authors: Staudt Louis M.
Published: July 2002

▪ Abstract  Comprehensive gene expression profiling using DNA microarrays is providing a molecular classification of cancer into disease categories that are homogeneous with respect to pathogenesis and clinical behavior. Gene expression profiling revealed that diffuse large B cell lymphoma (DLBCL) consists of at least two molecularly distinct diseases that are derived from distinct stages of B cell differentiation and have strikingly different clinical outcomes. By contrast, chronic lymphocytic leukemia (CLL) was found to be a single disease defined by a characteristic gene expression signature. Nonetheless, gene expression profiling distinguished two clinically divergent CLL subtypes and provided evidence that signaling through the B cell antigen receptor may play a role in the clinically aggressive subtype. Gene expression analysis also illuminated the mechanism of lymphomagenesis caused by BCL-6 translocations and provided evidence that the NF-κB signaling pathway is a new molecular therapeutic target in DLBCL.
INTRACELLULAR ANTIBODIES (INTRABODIES) FOR GENE THERAPY OF INFECTIOUS DISEASES
Authors: Rondon Isaac J. , Marasco Wayne A.
Published: July 2002

▪ Abstract  Intracellular antibodies (intrabodies) represent a new class of neutralizing molecules with a potential use in gene therapy. Intrabodies are engineered single-chain antibodies in which the variable domain of the heavy chain is joined to the variable domain of the light chain through a peptide linker, preserving the affinity of the parent antibody. Intrabodies are expressed inside cells and directed to different subcellular compartments where they can exert their function more effectively. The effects of intrabodies have been investigated using structural, regulatory, and enzymatic proteins of the human immunodeficiency virus (HIV-1) as targets. These intrabodies have demonstrated their versatility by controlling early as well as late events of the viral life cycle. In this article, we review studies of the use of intrabodies as research tools and therapeutic agents against HIV-1.
MICROBIAL ALDOLASES AND TRANSKETOLASES: New Biocatalytic Approaches to Simple and Complex Sugars
Authors: Takayama Shuichi , McGarvey Glenn J. , Wong Chi-Huey
Published: July 2002

▪ Abstract  Enzymes have become exceedingly valuable tools in organic synthesis as the reactions they catalyze generally proceed under mild conditions and in high stereo- and regioselectivity. Advances in microbiology and genetic engineering have greatly increased the availability of various enzymes. One of the most useful applications of enzyme-catalyzed chemical transformations is in the synthesis of water-soluble, polyfunctional organic molecules such as carbohydrates. As the pivotal roles that carbohydrates play in biological processes become more evident, access to these compounds becomes increasingly important. This review gives a brief overview of the use of aldolases and transketolases in the synthesis of sugars, sugar analogs, and related compounds.
TOUR DE PACLITAXEL: Biocatalysis for Semisynthesis
Authors: Patel Ramesh N.
Published: July 2002

▪ Abstract  In collaboration with the National Cancer Institute, Bristol-Myers Squibb has developed paclitaxel for treatment of various cancers; it has been approved by the Food and Drug Administration for the treatment of ovarian and metastatic breast cancer. Originally paclitaxel was isolated and purified from the bark of Pacific yew trees. This source of paclitaxel was considered to be economically and ecologically unsuitable as it required the destruction of the yew trees. This review article describes alternate methods for the production of paclitaxel, specifically, a semisynthetic approach and the application of biocatalysis in enabling the semisynthesis of paclitaxel. Three novel enzymes were discovered in our laboratory that converted the variety of taxanes to a single molecule, namely 10-deacetylbaccatin III (paclitaxel without C-13 side chain and C-10 acetate), a precursor for paclitaxel semisynthesis. These enzymes are C-13 taxolase (catalyzes the cleavage of C-13 side chain of various taxanes), C-10 deacetylase (catalyzes the cleavage of C-10 acetate of various taxanes), and C-7 xylosidase (catalyzes the cleavage of C-7 xylose from various xylosyltaxanes). Using a biocatalytic approach, paclitaxel and a variety of taxane in extracts of a variety of Taxus cultivars were converted to a 10-deacetylbaccatin III. The concentration of 10-deacetylbaccatin III was increased by 5.5- to 24-fold in the extracts treated with the enzymes, depending upon the type of Taxus cultivars used. Biocatalytic processes have also been described for the preparation of C-13 paclitaxel side chain synthons. The chemical coupling of 10-deacetylbaccatin III or baccatin III to C-13 paclitaxel side chain has been summarized to prepare paclitaxel by semisynthesis.
In Vivo Genetic Analysis of Bacterial Virulence
Authors: Chiang Su L. , Mekalanos John J. , Holden David W.
Published: July 2002

▪ Abstract  In vitro assays contribute greatly to our understanding of bacterial pathogenesis, but they frequently cannot replicate the complex environment encountered by pathogens during infection. The information gained from such studies is therefore limited. In vivo models, on the other hand, can be difficult to use, and this has to some extent diminished the incentive to perform studies in living animals. However, several recently developed techniques permit in vivo examination of many genes simultaneously. Most of these methods fall into two broad classes: in vivo expression technology and signature-tagged mutagenesis. In vivo expression technology is a promoter-trap strategy designed to identify genes whose expression is induced in a specific environment, typically that encountered in a host. Signature-tagged mutagenesis uses comparative hybridization to isolate mutants unable to survive specified environmental conditions and has been used to identify genes critical for survival in the host. Both approaches have so far been used exclusively for investigating pathogen-host interactions, but they should be easily adaptable to the study of other processes.
Anthrax
Authors: Mock Michèle , Fouet Agnès
Published: July 2002

▪ Abstract  Bacillus anthracis was shown to be the etiological agent of anthrax by R. Koch and L. Pasteur at the end of the nineteenth century. The concepts on which medical microbiology are based arose from their work on this bacterium. The link between plasmids and major virulence factors of B. anthracis was not discovered until the 1980s. The three toxin components are organized in two A-B type toxins, and the bacilli are covered by an antiphagocytic polyglutamic capsule. Structure-function analysis of the toxins indicated that the common B-domain binds to a ubiquitous cell receptor and forms a heptamer after proteolytic activation. One enzyme moiety is an adenylate cyclase and the other is a Zn2+metalloprotease, which is able to cleave MAPKKs. The capsule covers an S-layer sequentially composed of two distinct proteins. Knowledge of the toxins facilitates the design of safer veterinary vaccines. Spore-structure analysis could contribute to the improvement of human nonliving vaccines. The phylogeny of B. anthracis within the Bacillus cereus group is also reviewed.
GENETIC AND ENVIRONMENTAL INFLUENCES ON HUMAN BEHAVIORAL DIFFERENCES
Authors: McGue Matt , Bouchard Thomas J.
Published: July 2002

▪ Abstract  Human behavioral genetic research aimed at characterizing the existence and nature of genetic and environmental influences on individual differences in cognitive ability, personality and interests, and psychopathology is reviewed. Twin and adoption studies indicate that most behavioral characteristics are heritable. Nonetheless, efforts to identify the genes influencing behavior have produced a limited number of confirmed linkages or associations. Behavioral genetic research also documents the importance of environmental factors, but contrary to the expectations of many behavioral scientists, the relevant environmental factors appear to be those that are not shared by reared together relatives. The observation of genotype-environment correlational processes and the hypothesized existence of genotype-environment interaction effects serve to distinguish behavioral traits from the medical and physiological phenotypes studied by human geneticists. Behavioral genetic research supports the heritability, not the genetic determination, of behavior.
INDUCIBLE GENE EXPRESSION IN THE NERVOUS SYSTEM OF TRANSGENIC MICE
Authors: Gingrich Jeffrey R. , Roder John
Published: July 2002

▪ Abstract  Gene function during mammalian development is often studied by making irreversible changes to the genome. This approach has a major drawback in that the function of the gene in question must be deduced from the phenotype of animals that have been deficient for the product of the disrupted gene throughout ontogeny. Compensation for the loss of the gene product could yield an apparently unaltered phenotype. Alternatively, the changes in the regulation of other genes could yield a misleading phenotype. If the genetic manipulation results in embryonic or neonatal lethality, gene function at later stages of development cannot be analyzed. It would thus be highly advantageous if the expression of a particular gene could be restricted both temporally and spatially through the use of an inducible genetic system. This paper describes the various inducible genetic expression systems developed for use in mammalian cells, with particular emphasis on their application in the nervous system of transgenic mice.
Stopping Time: The Genetics of Fly and Mouse Circadian Clocks
Authors: Allada Ravi , Emery Patrick , Takahashi Joseph S. , Rosbash Michael
Published: July 2002

▪ Abstract  Forward genetic analyses in flies and mice have uncovered conserved transcriptional feedback loops at the heart of circadian pacemakers. Conserved mechanisms of posttranslational regulation, most notably phosphorylation, appear to be important for timing feedback. Transcript analyses have indicated that circadian clocks are not restricted to neurons but are found in several tissues. Comparisons between flies and mice highlight important differences in molecular circuitry and circadian organization. Future studies of pacemaker mechanisms and their control of physiology and behavior will likely continue to rely on forward genetics.
Localization and Globalization in Conscious Vision
Authors: Zeki S.
Published: July 2002

▪ Abstract  The primate visual brain consists of many separate, functionally specialized processing systems, each consisting of several apparently hierarchical stages or nodes. The evidence reviewed here leads me to speculate (a) that the processing systems are autonomous with respect to one another, (b) that activity at each node reaches a perceptual end point at a different time, resulting in a perceptual asynchrony in vision, and (c) that, consequently, activity at each node generates a microconsciousness. Visual consciousness is therefore distributed in space and time, with the universal organizing principle of abstraction applied separately within each processing system. The consequence of spatially and temporally distributed microconsciousnesses is that their integration is a multistage, nonhierarchical process that may involve a neural “glue.”
RESPONSIVENESS OF SELENOPROTEINS TO DIETARY SELENIUM,
Authors: Allan Christian B. , Lacourciere Gerard M. , Stadtman Thressa C.
Published: July 2002

Selenocysteine-containing enzymes that have been identified in mammals include the glutathione peroxidase family (GPX1, GPX2, GPX3, and GPX4), one or more iodothyronine deiodinases and two thioredixin reductases. Selenoprotein P, a glycoprotein that contains 10 selenocysteine residues per 43 kDa polypeptide and selenoprotein W, a 10 kDa muscle protein, are unidentified as to function. Levels of all of these selenocysteine-containing proteins in various tissues are affected to different extents by selenium availability. Increased amounts of selenoproteins observed in response to selenium supplementation were shown in several studies to correlate with increases in the corresponding mRNA levels. In general, selenoprotein levels in brain are less sensitive to dietary selenium fluctuation than the corresponding selenoprotein levels in other tissues.