bluuebunny/crossref_metadata_2025 huggingface dataset:
MOLECULAR-FUNCTIONAL STUDIES OF ADAPTIVE GENETIC VARIATION IN PROKARYOTES AND EUKARYOTES
Authors: Watt Ward B , Dean Antony M
Published: July 2002

▪ Abstract  Knowledge of both prokaryotic and eukaryotic organisms is essential to the study of molecular evolution. Their common ancestry mandates that their molecular functions share many aspects of adaptation and constraint, yet their differences in size, ploidy, and structural complexity also give rise to divergent evolutionary options. We explore the interplay of adaptation, constraint, and neutrality in their evolution by the use of genetic variants to probe molecular function in context of molecular structure, metabolic organization, and phenotype-environment interactions. Case studies ranging from bacteria to butterflies, flies, and vertebrates emphasize, among other points:

a. the importance of moving from initial recording of evolutionary pattern variation to studying the processes underlying the patterns, by experiment, reconstructive inference, or both; b. the complementarity, not conflict, of finding different performance and fitness impacts of natural variants in prokaryotes or eukaryotes, depending on the nature and magnitude of the variants, their locations and roles in pathways, the nature of molecular function affected, and the resulting organismal phenotype-environment interactions leading to selection or its absence; c. the importance of adaptive functional interaction of different kinds of variants, as in gene expression variants versus variants altering polypeptide properties, or interaction of changes in enzymes' active sites with complementary changes elsewhere that adjust catalytic function in different ways, or coadaptation of different steps' properties in pathways; d. the power afforded by combining structural and functional analyses of variants with study of the variants' phenotype-environment interactions to understand how molecular changes affect (or fail to affect) adaptive mechanisms “in the wild.”

Comparative study of prokaryotes and eukaryotes in this multifaceted way promises to deliver both new insights into evolution and a host of new and productive questions about it.
COMPLEX TRAIT ANALYSIS IN THE MOUSE: The Strengths, The Limitations and The Promise Yet To Come
Authors: Moore Karen J , Nagle Deborah L
Published: July 2002

▪ Abstract  In 1990, David Baltimore predicted that the 1990s would be the decade of the mouse ( 1 ). This certainly proved to be true: The mouse has contributed immensely to biological research through transgenic, embryonic stem cell (ES) knockout, and classical genetic technologies. But its usefulness as a model organism is by no means over; indeed it is still rising to its peak: The mouse as a model mammalian organism still has much to offer. This article reviews use of the mouse to dissect complex genetic traits using quantitative trait analysis, with a particular emphasis on medically important diseases.
Methods for Genotyping Single Nucleotide Polymorphisms
Authors: Kwok Pui-Yan
Published: July 2002

One of the fruits of the Human Genome Project is the discovery of millions of DNA sequence variants in the human genome. The majority of these variants are single nucleotide polymorphisms (SNPs). A dense set of SNP markers opens up the possibility of studying the genetic basis of complex diseases by population approaches. In all study designs, a large number of individuals must be genotyped with a large number of markers. In this review, the current status of SNP genotyping is discussed in terms of the mechanisms of allelic discrimination, the reaction formats, and the detection modalities. A number of genotyping methods currently in use are described to illustrate the approaches being taken. Although no single genotyping method is ideally suited for all applications, a number of good genotyping methods are available to meet the needs of many study designs. The challenges for SNP genotyping in the near future include increasing the speed of assay development, reducing the cost of the assays, and performing multiple assays in parallel. Judging from the accelerated pace of new method development, it is hopeful that an ideal SNP genotyping method will be developed soon.
REDOX REGULATION OF CELLULAR ACTIVATION
Authors: Nakamura Hajime , Nakamura Kazuhiro , Yodoi Junji
Published: July 2002

▪ Abstract  Growing evidence has indicated that cellular reduction/oxidation (redox) status regulates various aspects of cellular function. Oxidative stress can elicit positive responses such as cellular proliferation or activation, as well as negative responses such as growth inhibition or cell death. Cellular redox status is maintained by intracellular redox-regulating molecules, including thioredoxin (TRX). TRX is a small multifunctional protein that has a redox-active disulfide/dithiol within the conserved active site sequence: Cys-Gly-Pro-Cys. Adult T cell leukemia–derived factor (ADF), which we originally defined as an IL-2 receptor α-chain/Tac inducer produced by human T cell lymphotrophic virus-I (HTLV-I)–transformed T cells, has been identified as human TRX. TRX/ADF is a stress-inducible protein secreted from cells. TRX/ADF has both intracellular and extracellular functions as one of the key regulators of signaling in the cellular responses against various stresses. Extracellularly, TRX/ADF shows a cytoprotective activity against oxidative stress–induced apoptosis and a growth-promoting effect as an autocrine growth factor. Intracellularly, TRX/ADF is involved in the regulation of protein-protein or protein–nucleic acid interactions through the reduction/oxidation of protein cysteine residues. For example, TRX/ADF translocates from the cytosol into the nucleus by a variety of cellular stresses, to regulate the expression of various genes through the redox factor-1 (Ref-1)/APEX. Further studies to clarify the regulatory roles of TRX/ADF and its target molecules may elucidate the intracellular signaling pathways in the responses against various stresses. The concept of “redox regulation” is emerging as an understanding of the novel mechanisms in the pathogenesis of several disorders, including viral infections, immunodeficiency, malignant transformation, and degenerative disease.
CD81 (TAPA-1): A MOLECULE INVOLVED IN SIGNAL TRANSDUCTION AND CELL ADHESION IN THE IMMUNE SYSTEM
Authors: Levy Shoshana , Todd Scott C. , Maecker Holden T.
Published: July 2002

▪ Abstract  CD81 (TAPA-1) is a widely expressed cell-surface protein involved in an astonishing variety of biologic responses. It has been cloned independently several times for different functional effects and is reported to influence adhesion, morphology, activation, proliferation, and differentiation of B, T, and other cells. On B cells CD81 is part of a complex with CD21, CD19, and Leu13. This complex reduces the threshold for B cell activation via the B cell receptor by bridging Ag specific recognition and CD21-mediated complement recognition. Similarly on T cells CD81 associates with CD4 and CD8 and provides a costimulatory signal with CD3. In fetal thymic organ culture, mAb to CD81 block maturation of CD4−CD8−thymocytes, and expression of CD81 on CHO cells endows those cells with the ability to support T cell maturation. However, CD81-deficient mice express normal numbers and subsets of T cells. These mice do exhibit diminished antibody responses to protein antigens. CD81 is also physically and functionally associated with several integrins. Anti-CD81 can activate integrin α4β1(VLA-4) on B cells, facilitating their adhesion to tonsilar interfollicular stroma. Similarly, anti-CD81 can activate αLβ2 (LFA-1) on human thymocytes. CD81 can also affect cognate B-T cell interactions because anti-CD81 increases IL-4 synthesis by T cells responding to antigen presented by B cells but not by monocytes. The tetraspanin superfamily (or TM4SF) includes CD81, CD9, CD37, CD53, CD63, CD82, CD151, and an increasing number of additional proteins. Like CD81, several tetraspanins are involved in cell adhesion, motility, and metastasis, as well as cell activation and signal transduction.
SELECTION OF THE T CELL REPERTOIRE
Authors: Sebzda Eric , Mariathasan Sanjeev , Ohteki Toshiaki , Jones Russell , Bachmann Martin F. , Ohashi Pamela S.
Published: July 2002

▪ Abstract  Advances in gene technology have allowed the manipulation of molecular interactions that shape the T cell repertoire. Although recognized as fundamental aspects of T lymphocyte development, only recently have the mechanisms governing positive and negative selection been examined at a molecular level. Positive selection refers to the active process of rescuing MHC-restricted thymocytes from programmed cell death. Negative selection refers to the deletion or inactivation of potentially autoreactive thymocytes. This review focuses on interactions during thymocyte maturation that define the T cell repertoire, with an emphasis placed on current literature within this field.
Signaling and Transcription in T Helper Development
Authors: Murphy Kenneth M. , Ouyang Wenjun , Farrar J. David , Yang Jianfei , Ranganath Sheila , Asnagli Helene , Afkarian Maryam , Murphy Theresa L.
Published: July 2002

The recognition of polarized T cell subsets defined by cytokine production was followed by a search to define the factors controlling this phenomenon. Suitable in vitro systems allowed the development of cytokine “recipes” that induced rapid polarization of naïve T cells into Th1 or Th2 populations. The next phase of work over the past several years has begun to define the intracellular processes set into motion during Th1/Th2 development, particularly by the strongly polarizing cytokines IL-12 and IL-4. Although somewhat incomplete, what has emerged is a richly detailed tapestry of signaling and transcription, controlling an important T cell developmental switch. In addition several new mediators of control have emerged, including IL-18, the intriguing Th2-selective T1/ST2 product, and heterogeneity in dendritic cells capable of directing cytokine-independent Th development.
Phosphorylation Meets Ubiquitination: The Control of NF-κB Activity
Authors: Karin Michael , Ben-Neriah Yinon
Published: July 2002

NF-κB (nuclear factor-κB) is a collective name for inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif. NF-κB is found in essentially all cell types and is involved in activation of an exceptionally large number of genes in response to infections, inflammation, and other stressful situations requiring rapid reprogramming of gene expression. NF-κB is normally sequestered in the cytoplasm of nonstimulated cells and consequently must be translocated into the nucleus to function. The subcellular location of NF-κB is controlled by a family of inhibitory proteins, IκBs, which bind NF-κB and mask its nuclear localization signal, thereby preventing nuclear uptake. Exposure of cells to a variety of extracellular stimuli leads to the rapid phosphorylation, ubiquitination, and ultimately proteolytic degradation of IκB, which frees NF-κB to translocate to the nucleus where it regulates gene transcription. NF-κB activation represents a paradigm for controlling the function of a regulatory protein via ubiquitination-dependent proteolysis, as an integral part of a phosphorylationbased signaling cascade. Recently, considerable progress has been made in understanding the details of the signaling pathways that regulate NF-κB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-α and interleukin-1. The multisubunit IκB kinase (IKK) responsible for inducible IκB phosphorylation is the point of convergence for most NF-κB–activating stimuli. IKK contains two catalytic subunits, IKKα and IKKβ, both of which are able to correctly phosphorylate IκB. Gene knockout studies have shed light on the very different physiological functions of IKKα and IKKβ. After phosphorylation, the IKK phosphoacceptor sites on IκB serve as an essential part of a specific recognition site for E3RSIκB/β-TrCP, an SCF-type E3 ubiquitin ligase, thereby explaining how IKK controls IκB ubiquitination and degradation. A variety of other signaling events, including phosphorylation of NF-κB, hyperphosphorylation of IKK, induction of IκB synthesis, and the processing of NF-κB precursors, provide additional mechanisms that modulate the level and duration of NF-κB activity.
Activating Receptors and Coreceptors Involved in Human Natural Killer Cell-Mediated Cytolysis
Authors: Moretta Alessandro , Bottino Cristina , Vitale Massimo , Pende Daniela , Cantoni Claudia , Mingari Maria Cristina , Biassoni Roberto , Moretta Lorenzo
Published: July 2002

Natural killer cells can discriminate between normal cells and cells that do not express adequate amounts of major histocompatibility complex (MHC) class I molecules. The discovery, both in mouse and in human, of MHC-specific inhibitory receptors clarified the molecular basis of this important NK cell function. However, the triggering receptors responsible for positive NK cell stimulation remained elusive until recently. Some of these receptors have now been identified in humans, thus shedding some light on the molecular mechanisms involved in NK cell activation during the process of natural cytotoxicity. Three novel, NK-specific, triggering surface molecules (NKp46, NKp30, and NKp44) have been identified. They represent the first members of a novel emerging group of receptors collectively termed natural cytotoxicity receptors (NCR). Monoclonal antibodies (mAbs) to NCR block to differing extents the NK-mediated lysis of various tumors. Moreover, lysis of certain tumors can be virtually abrogated by the simultaneous masking of the three NCRs. There is a coordinated surface expression of the three NCRs, their surface density varying in different individuals and also in the NK cells isolated from a given individual. A direct correlation exists between the surface density of NCR and the ability of NK cells to kill various tumors. NKp46 is the only NCR involved in human NK-mediated killing of murine target cells. Accordingly, a homologue of NKp46 has been detected in mouse. Molecular cloning of NCR revealed novel members of the Ig superfamily displaying a low degree of similarity to each other and to known human molecules. NCRs are coupled to different signal transducing adaptor proteins, including CD3ζ, Fc∍RIγ, and KARAP/DAP12. Another triggering NK receptor is NKG2D. It appears to play either a complementary or a synergistic role with NCRs. Thus, the triggering of NK cells in the process of tumor cell lysis may often depend on the concerted action of NCR and NKG2D. In some instances, however, it may uniquely depend upon the activity of NCR or NKG2D only. Strict NKG2D-dependency can be appreciated using clones that, in spite of their NCRdullphenotype, efficiently lyse certain epithelial tumors or leukemic cell lines. Other triggering surface molecules including 2B4 and the novel NKp80 appear to function as coreceptors rather than as true receptors. Indeed, they can induce natural cytotoxicity only when co-engaged with a triggering receptor. While an altered expression or function of NCR or NKG2D is being explored as a possible cause of immunological disorders, 2B4 dysfunction has already been associated with a severe form of immunodeficiency. Indeed, in patients with the X-linked lymphoproliferative disease, the inability to control Epstein-Barr virus infections may be consequent to a major dysfunction of 2B4 that exerts inhibitory instead of activating functions.
Interleukin-10 and the Interleukin-10 Receptor
Authors: Moore Kevin W. , de Waal Malefyt Rene , Coffman Robert L. , O'Garra Anne
Published: July 2002

Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.
PROCESSING AND CHARACTERIZATION OF PIEZOELECTRIC MATERIALS AND INTEGRATION INTO MICROELECTROMECHANICAL SYSTEMS
Authors: Polla Dennis L. , Francis Lorraine F.
Published: July 2002

▪ Abstract  Piezoelectric materials have been integrated with silicon microelectromechanical systems (MEMS) in both microsensor and microactuator applications. Thin-film materials selection and processing routes are reviewed. Some recent and emerging applications of piezoelectric MEMS are presented including acoustic emission microsensors, vibration monitors, molecular recognition biosensors, precision positioners, micropumps, and linear stepper motors.
MODERN RESONANT X-RAY STUDIES OF ALLOYS: Local Order and Displacements
Authors: Ice G. E. , Sparks C. J.
Published: July 2002

▪ Abstract  The recent availability of intense synchrotron sources with selectable X-ray energies permits high-precision measurements of chemically specific atomic-pair correlations in solid-solution alloys. Short-range chemical order can be accurately measured to identify one atom in a 100 for 10 or more shells, even in alloys with elements nearby in the periodic table, and chemically specific static displacements can be measured with 0.0001 nm resolution. This new information tests theoretical models of alloy phase stability and structure and gives new insights into the physical properties of alloys.
Photoinitiated Polymerization of Biomaterials
Authors: Fisher John P , Dean David , Engel Paul S , Mikos Antonios G
Published: July 2002

▪ Abstract  Photoinitiated polymerization and polymer crosslinking are viable strategies for biomaterial synthesis because of the mild temperatures and neutral pH environments in which these reactions typically take place. This review summarizes the relevant theories as well as current status of photoinitiated polymerizations in biomaterials. Photoinitiation, photoinitiated polymerization, and photoinitiators are discussed with consideration toward the biological nature of the intended application. Recent investigations into biomaterials, including hydrogels, biodegradable materials, and hard tissue resorbable scaffolds are presented. Lastly, studies of cell interactions with photoinitiated biomaterials are discussed. The work herein illustrates the potential use of photoinitiated polymerization in the development of novel biomaterials for tissue engineering.
THE TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
Authors: Goldfarb, M.D Lev G. , Brown, M.D Paul
Published: July 2002

▪ Abstract  The human transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of rapidly progressive disorders characterized by a spectrum of clinical abnormalities that include cognitive impairment, ataxia, myoclonus, and visual, pyramidal, and extrapyramidal signs. They share a spongiform (vacuolar) degeneration and variable amyloid plaque formation. Examples of TSEs are kuru, an infectious disease; Creutzfeldt-Jakob disease (CJD), which may take an infectious, genetic, or sporadic form; and Gerstmann-Sträussler-Scheinker disease (GSS) and fatal familial insomnia (FFI), rare familial disorders. With the exception of FFI, all of these disorders have been experimentally transmitted to nonhuman primates and laboratory rodents. The pathogenic PrP protein accumulating in the brain of TSE patients is a protease-resistant and insoluble product of a precursor protein molecule of unknown function that is encoded by the PRNP gene on chromosome 20. Different mutations in this gene are responsible for various phenotypes of TSE in its familial form, and a polymorphism at codon 129 controls susceptibility to the infectious and perhaps sporadic forms of disease. TSEs are transmissible amyloidoses in which the host-encoded protein has the propensity to acquire a beta-sheet conformation and produce amyloid; the accumulation of amyloid eventually destroys the neurons and induces the deadly disease.
Chemokines and Chemokine Receptors: Biology and Clinical Relevance in Inflammation and AIDS
Authors: Locati, MD Massimo , Murphy, MD Philip M.
Published: July 2002

Chemokines constitute a large family of chemotactic cytokines that act at G protein-coupled receptors to regulate diverse biological processes, including leukocyte trafficking, angiogenesis, hematopoiesis, and organogenesis. They are believed to be both beneficial in host defense against infectious agents and harmful in diseases marked by pathologic inflammation; however, actual clinical roles in these areas have not yet been established. Recently, unexpected ways have been discovered in which medically important pathogens, including HIV-1, exploit or subvert the chemokine system. These and other recent results suggest that targeting specific chemokines and chemokine receptors may have therapeutic utility in both inflammation and infectious disease.
Genetics of Psychiatric Disease
Authors: Berrettini Wade H.
Published: July 2002

▪ Abstract  Genetic epidemiologic studies reveal that relatives of bipolar (BIP) probands are at increased risk for recurrent unipolar (RUP), BIP, and schizoaffective (SA) disorders, while relatives of schizophrenia (SZ) probands are at increased risk for SZ, SA, and RUP disorders. The overlap in familial risk may reflect shared genetic susceptibility. Recent genetic linkage studies have defined confirmed susceptibility loci for BIP disorder for multiple regions of the human genome, including 4p16, 12q24, 18p11.2, 18q22, 21q21, 22q11–13, and Xq26. Studies of SZ kindreds have yielded robust evidence for susceptibility at 18p11.2 and 22q11–13, both of which are implicated in susceptibility to BIP disorder. Similarly, confirmed SZ vulnerability loci have been mapped for 6p24, 8p and 13q32. Strong statistical evidence for a 13q32 BIP susceptibility locus has been reported. Thus, both family and molecular studies of these disorders suggest shared genetic susceptibility. These two group of disorders may not be so distinct as current nosology suggests.
Liver Transplants from Living Related Donors
Authors: Samstein Benjamin , Emond Jean
Published: July 2002

▪ Abstract  Liver transplantation from living related donors was unthinkable until recently, when the safety of modern hepatic surgery became widely appreciated. The first step was the successful demonstration that parts of livers could be transplanted. This technique, termed reduced-size liver transplantation, evolved into reliable procedures to allow parents to donate small parts of their livers to small children. More recently, right hepatectomy, in which up to 70% of the liver is resected for donation, has been performed in adults. As the demand for liver transplantation continues to increase, the development of ethically sound, medically and surgically optimal programs for routine use of living donors has become essential. This chapter provides a broad overview of the evolution and current state of liver transplantation with living donors.
THYMINE METABOLISM AND THYMINELESS DEATH IN PROKARYOTES AND EUKARYOTES
Authors: Ahmad S. I. , Kirk S. H. , Eisenstark A.
Published: July 2002

▪ Abstract  For many years it has been known that thymine auxotrophic microorganisms undergo cell death in response to thymine starvation [thymineless death (TLD)]. This effect is unusual in that deprivation of many other nutritional requirements has a biostatic, but not lethal, effect. Studies of numerous microbes have indicated that thymine starvation has both direct and indirect effects. The direct effects involve both single- and double-strand DNA breaks. The former may be repaired effectively, but the latter lead to cell death. DNA damaged by thymine starvation is a substrate for DNA repair processes, in particular recombinational repair. Mutations in recBCD recombinational repair genes increase sensitivity to thymineless death, whereas mutations in RecF repair protein genes enhance the recovery process. This suggests that the RecF repair pathway may be critical to cell death, perhaps because it increases the occurrence of double-strand DNA breaks with unique DNA configurations at lesion sites. Indirect effects in bacteria include elimination of plasmids, loss of transforming ability, filamentation, changes in the pool sizes of various nucleotides and nucleosides and in their excretion, and phage induction. Yeast cells show effects similar to those of bacteria upon thymine starvation, although there are some unique features. The mode of action of certain anticancer drugs and antibiotics is based on the interruption of thymidylate metabolism and provides a major impetus for further studies on TLD. There are similarities between TLD of bacteria and death of eukaryotic cells. Also, bacteria have “survival” genes other than thy (thymidylate synthetase), and this raises the question of whether there is a relationship between the two. A model is presented for a molecular basis of TLD.
Wolbachia Pipientis: Microbial Manipulator of Arthropod Reproduction
Authors: Stouthamer R. , Breeuwer J. A. J. , Hurst G. D. D.
Published: July 2002

▪ Abstract  The α-proteobacterium Wolbachia pipientis is a very common cytoplasmic symbiont of insects, crustaceans, mites, and filarial nematodes. To enhance its transmission, W. pipientis has evolved a large scale of host manipulations: parthenogenesis induction, feminization, and male killing. W. pipientis's most common effect is a crossing incompatibility between infected males and uninfected females. Little is known about the genetics and biochemistry of these symbionts because of their fastidious requirements. The affinity of W. pipientis for the microtubules associated with the early divisions in eggs may explain some of their effects. Such inherited microorganisms are thought to have been major factors in the evolution of sex determination, eusociality, and speciation. W. pipientis isolates are also of interest as vectors for the modification of wild insect populations, in the improvement of parasitoid wasps in biological pest control, and as a new method for interfering with diseases caused by filarial nematodes.
Molecular Aspects of Parasite-Vector and Vector-Host Interactions in Leishmaniasis
Authors: Sacks David , Kamhawi Shaden
Published: July 2002

▪ Abstract  Leishmania-sand fly interactions are reviewed in the context of the potential barriers to the complete development of the parasite that exist within the midgut environment of phlebotomine flies and the molecular adaptations that the parasite has evolved that permit the development of transmissible infections to proceed. Cell surface and secreted phosphoglycans protect the parasite from the proteolytic activities of the blood-fed midgut, mediate attachment to the gut wall in order to maintain infection during excretion of the bloodmeal, and contribute to the formation of a biological plug in the anterior gut that may promote transmission by bite. The importance of vector saliva in modulating the host response to transmitted parasites is also reviewed.
FUNCTION-RELATED PLASTICITY IN HYPOTHALAMUS
Authors: Hatton Glenn I.
Published: July 2002

▪ Abstract  Physiological activation of the magnocellular hypothalamo-neurohypophysial system induces a coordinated astrocytic withdrawal from between the magnocellular somata and the parallel-projecting dendrites of the supraoptic nucleus. Neural lobe astrocytes release engulfed axons and retract from their usual positions along the basal lamina. Occurring on a minutes-to-hours time scale, these changes are accompanied by increased direct apposition of both somatic and dendritic membrane, the formation of dendritic bundles, the appearance of novel multiple synapses in both the somatic and dendritic zones, and increased neural occupation of the perivascular basal lamina. Reversal, albeit with varying time courses, is achieved by removing the activating stimuli. Additionally, activation results in interneuronal coupling increases that are capable of being modulated synaptically via second messenger–dependent mechanisms. These changes appear to play important roles in control and coordination of oxytocin and vasopressin release during such conditions as lactation and dehydration.
HUMAN AUTOIMMUNE NEUROPATHIES
Authors: Ho T. W. , McKhann G. M. , Griffin J. W.
Published: July 2002

▪ Abstract  Peripheral nerve diseases are among the most prevalent disorders of the nervous system. Because of the accessibility of the peripheral nervous system (PNS) to direct physiological and pathological study, neuropathies have traditionally played a unique role in developing our understanding of basic mechanism of nervous system injury and repair. At present they are providing new insight into the mechanisms of immune injury to the nervous system. A rapidly growing catalogue of PNS disorders are now suspected to be immune-mediated, and in the best understood of these disorders, the molecular and cellular targets of immune attack are known, and the pathophysiology follows directly from the specific immune injury. This review summarizes the immunologically relevant features of the PNS, then considers selected immune-mediated neuropathies, focusing on pathogenetic mechanisms. Finally, the PNS is providing a testing ground for new immunotherapies and approaches to protection and regeneration, including the use of trophic factors. The current status of treatment and implications for future approaches is reviewed.
ZINC AND BRAIN INJURY
Authors: Choi Dennis W. , Koh Jae Y.
Published: July 2002

▪ Abstract  Zinc is an essential catalytic or structural element of many proteins, and a signaling messenger that is released by neural activity at many central excitatory synapses. Growing evidence suggests that zinc may also be a key mediator and modulator of the neuronal death associated with transient global ischemia and sustained seizures, as well as perhaps other neurological disease states. Manipulations aimed at reducing extracellular zinc accumulation, or cellular vulnerability to toxic zinc exposure, may provide a novel therapeutic approach toward ameliorating pathological neuronal death in these settings.
MUTANT GENES IN FAMILIAL ALZHEIMER'S DISEASE AND TRANSGENIC MODELS
Authors: Price Donald L. , Sisodia Sangram S.
Published: July 2002

▪ Abstract  The most common cause of dementia occurring in mid- to late-life is Alzheimer's disease (AD). Some cases of AD, particularly those of early onset, are familial and inherited as autosomal dominant disorders linked to the presence of mutant genes that encode the amyloid precursor protein (APP) or the presenilins (PS1 or PS2). These mutant gene products cause dysfunction/death of vulnerable populations of nerve cells important in memory, higher cognitive processes, and behavior. AD affects 7–10% of individuals >65 years of age and perhaps 40% of individuals >80 years of age. For the late-onset cases, the principal risk factors are age and apolipoprotein (apoE) allele type, with apoE4 allele being a susceptibility factor. In this review, we briefly discuss the clinical syndrome of AD and the neurobiology/neuropathology of the disease and then focus attention on mutant genes linked to autosomal dominant familial AD (FAD), the biology of the proteins encoded by these genes, and the recent exciting progress in investigations of genetically engineered animal models that express these mutant genes and develop some features of AD.
BIRDSONG AND HUMAN SPEECH: Common Themes and Mechanisms
Authors: Doupe Allison J. , Kuhl Patricia K.
Published: July 2002

▪ Abstract  Human speech and birdsong have numerous parallels. Both humans and songbirds learn their complex vocalizations early in life, exhibiting a strong dependence on hearing the adults they will imitate, as well as themselves as they practice, and a waning of this dependence as they mature. Innate predispositions for perceiving and learning the correct sounds exist in both groups, although more evidence of innate descriptions of species-specific signals exists in songbirds, where numerous species of vocal learners have been compared. Humans also share with songbirds an early phase of learning that is primarily perceptual, which then serves to guide later vocal production. Both humans and songbirds have evolved a complex hierarchy of specialized forebrain areas in which motor and auditory centers interact closely, and which control the lower vocal motor areas also found in nonlearners. In both these vocal learners, however, how auditory feedback of self is processed in these brain areas is surprisingly unclear. Finally, humans and songbirds have similar critical periods for vocal learning, with a much greater ability to learn early in life. In both groups, the capacity for late vocal learning may be decreased by the act of learning itself, as well as by biological factors such as the hormones of puberty. Although some features of birdsong and speech are clearly not analogous, such as the capacity of language for meaning, abstraction, and flexible associations, there are striking similarities in how sensory experience is internalized and used to shape vocal outputs, and how learning is enhanced during a critical period of development. Similar neural mechanisms may therefore be involved.
PDZ Domains and the Organization of Supramolecular Complexes
Authors: Sheng Morgan , Sala Carlo
Published: July 2002

▪ Abstract  PDZ domains are modular protein interaction domains that bind in a sequence-specific fashion to short C-terminal peptides or internal peptides that fold in a β-finger. The diversity of PDZ binding specificities can be explained by variable amino acids lining the peptide-binding groove of the PDZ domain. Abundantly represented in Caenorhabditis elegans, Drosophila melanogaster, and mammalian genomes, PDZ domains are frequently found in multiple copies or are associated with other protein-binding motifs in multidomain scaffold proteins. PDZ-containing proteins are typically involved in the assembly of supramolecular complexes that perform localized signaling functions at particular subcellular locations. Organization around a PDZ-based scaffold allows the stable localization of interacting proteins and enhances the rate and fidelity of signal transduction within the complex. Some PDZ-containing proteins are more dynamically regulated in distribution and may also be involved in the trafficking of interacting proteins within the cell.
The Vanilloid Receptor: A Molecular Gateway to the Pain Pathway
Authors: Caterina Michael J , Julius David
Published: July 2002

▪ Abstract  The detection of painful stimuli occurs primarily at the peripheral terminals of specialized sensory neurons called nociceptors. These small-diameter neurons transduce signals of a chemical, mechanical, or thermal nature into action potentials and transmit this information to the central nervous system, ultimately eliciting a perception of pain or discomfort. Little is known about the proteins that detect noxious stimuli, especially those of a physical nature. Here we review recent advances in the molecular characterization of the capsaicin (vanilloid) receptor, an excitatory ion channel expressed by nociceptors, which contributes to the detection and integration of pain-producing chemical and thermal stimuli. The analysis of vanilloid receptor gene knockout mice confirms the involvement of this channel in pain sensation, as well as in hypersensitivity to noxious stimuli following tissue injury. At the same time, these studies demonstrate the existence of redundant mechanisms for the sensation of heat-evoked pain.
HADRONIC FORM FACTORS AND PERTURBATIVE QCD
Authors: Sterman George , Stoler Paul
Published: July 2002

▪ Abstract  The electromagnetic form factors of hadrons at large momentum transfer have been the subject of intense theoretical and experimental scrutiny over the past two decades, yet there is still not a universally accepted framework for their description. This review is a synopsis of their current status. The basic theoretical approaches to form factors at large momentum transfer are developed, emphasizing the valence quark and Feynman (soft) pictures. The discussion includes the relation of these descriptions to the parton model, as well as the roles of factorization, evolution, Sudakov resummation and QCD sum rules. This is followed by a discussion of the experimental status of pion and nucleon elastic form factors and resonance production amplitudes in the light of recent data; the successes and shortcomings of various theoretical proposals are highlighted.
COLLECTIVE FLOW IN HEAVY-ION COLLISIONS
Authors: Reisdorf W. , Ritter H. G.
Published: July 2002

▪ Abstract  We provide an overview of collective flow phenomena observed in heavy ion collisions from the Fermi energy range up to CERN Super Proton Synchrotron (SPS) energies. We summarize the experimental data in terms of the various observed aspects of flow, namely directed flow in the reaction plane, elliptic flow in- and out-of-plane, and azimuthally symmetric radial flow originating from the expansion of the hot and compressed reaction zone. Also reviewed are the theoretical concepts developed to simulate the complex reactions with the aim of extracting fundamental properties of hot and compressed nuclear matter.
PENGUIN DECAYS OFBMESONS
Authors: Lingel Karen , Skwarnicki Tomasz , Smith James G.
Published: July 2002

▪ Abstract  Penguin, or loop, decays of B mesons induce effective flavor-changing neutral currents, which are forbidden at tree level in the standard model. These decays give special insight into the CKM matrix and are sensitive to non–standard-model effects. In this review, we give a historical and theoretical introduction to penguins and a description of the various types of penguin processes: electromagnetic, electroweak, and gluonic. We review the experimental searches for penguin decays, including the measurements of the electromagnetic penguins b → sγ and B → K*γ and gluonic penguins B → Kπ, B+→ ωK+and B → η′K, and their implications for the standard model and new physics. We conclude by exploring the future prospects for penguin physics.
HORMONAL REGULATION OF HUMAN MUSCLE PROTEIN METABOLISM
Authors: Rooyackers Olav E. , Nair K. Sreekumaran
Published: July 2002

▪ Abstract  A continuous turnover of protein (synthesis and breakdown) maintains the functional integrity and quality of skeletal muscle. Hormones are important regulators of this remodeling process. Anabolic hormones stimulate human muscle growth mainly by increasing protein synthesis (growth hormone, insulin-like growth factors, and testosterone) or by decreasing protein breakdown (insulin). Unlike in growing animals, insulin's main anabolic effect on muscle protein in adult humans is an inhibition of protein breakdown. Protein synthesis is stimulated only in the presence of a high amino acid supply. A combination of the stress hormones (glucagon, glucocorticoids, and catecholamines) cause muscle catabolism, but the effects of the individual hormones on human muscle and their mechanisms of action remain to be clearly defined. Although thyroid hormone is essential during growth, both an excess and a deficiency cause muscle wasting by yet unknown mechanisms. A greater understanding of the regulation of human muscle protein metabolism is essential to elucidate mechanisms of muscle wasting.
Why Do We Eat? A Neural Systems Approach
Authors: Levine Allen S. , Billington Charles J.
Published: July 2002

▪ Abstract  Neuroregulators found at various brain sites are involved in controlling food intake, a behavior that occurs for many reasons. Different neuroregulators may affect different stimuli that impact eating behavior. For example, neuropeptide Y may initiate feeding for energy needs, opioid peptides may provide the rewarding aspects of eating, and corticotropin releasing factor may affect stress-induced eating. We know that the neural networks regulating feeding also impact other components of energy balance. Neuropeptide Y not only increases eating, it also decreases energy expenditure in brown fat and increases enzymatic activity associated with fat storage in white fat, resulting in a more obese animal. What the sites of action are of these neuroregulators and how they interact with regulators at other sites are of utmost importance. Different regions of the brain, together with the periphery, communicate via signals acting in coordinated fashion, which leads to the final outcome: eating less or more and expending less or more energy.
REGULATION OF MAMMALIAN ACETYL-COENZYME A CARBOXYLASE
Authors: Kim Ki-Han
Published: July 2002

▪ Abstract  Long-chain fatty acids are involved in all aspects of cellular structure and function. For controlling amounts of fatty acids, cells are endowed with two acetyl-coenzyme A carboxylase (ACC) systems. ACC-α is the rate-limiting enzyme in the biogenesis of long-chain fatty acids, and ACC-β is believed to control mitochondrial fatty acid oxidation. These two isoforms of ACC control the amount of fatty acids in the cells. Phosphorylation and dephosphorylation of ACC-α cause enzyme inactivation and activation, respectively, and serve as the enzyme's short-term regulatory mechanism. Covalently modified enzymes become more sensitive toward cellular metabolites. In addition, many hormones and nutrients affect gene expression. The gene products formed are heterogeneous and tissue specific. The ACC-β gene is located on human chromosome 12; the cDNA for this gene has just been cloned. The gene for the α-isoform is located on human chromosome 17. The catalytic core of the β-isoform is homologous to that of the α-isoform, except for an additional peptide of about 150 amino acids at the N terminus. This extra peptide sequence makes the β-form about 10,000 daltons larger, and it is thought to be involved in the unique role that has been assigned to this enzyme. The detailed control mechanisms for the β-isoform are not known.
DIETARY FRUCTANS
Authors: Roberfroid M. B. , Delzenne N. M.
Published: July 2002

▪ Abstract  Fructan is a general term used for any carbohydrate in which one or more fructosyl-fructose link constitutes the majority of osidic bonds. This review focuses on the fate of inulin-type fructans (namely native chicory inulin, oligofructose produced by the partial enzymatic hydrolysis of chicory inulin, and synthetic fructans produced by enzymatic synthesis from sucrose) in the gastrointestinal tract, as well as on their systemic physiological effects on mineral absorption, carbohydrate and lipid metabolism, hormone balance, and nitrogen homeostasis. The scientific evidence for the functional claims of inulin-type fructans is discussed, as well as their potential application in risk reduction of disease, namely constipation, infectious diarrhea, cancer, osteoporosis, atherosclerotic cardiovascular disease, obesity, and non-insulin dependent diabetes.
PSYCHOSOCIAL CORRELATES OF DIETARY INTAKE: Advancing Dietary Intervention
Authors: Baranowski Tom , Cullen Karen Weber , Baranowski Janice
Published: July 2002

▪ Abstract  Psychosocial variables that predict dietary behavior become important targets for change in nutrition education programs. Psychosocial variables in models with higher predictability provide more effective levers to promote healthy dietary change. A review of the literature on models with psychosocial variables predicting dietary fat and fruit and vegetable consumption revealed generally low predictiveness, R2 < 0.3 (where R2 is the squared multiple correlation of the statistical model). No single theory provided models that regularly out-predicted others. When models predicted narrower categories of behavior (e.g. milk or salad consumption), predictiveness tended to be higher. Substantial problems were revealed in the psychometrics of both the independent and dependent variables. Little theory-based research has been conducted with adolescents, and the few studies done with children had low predictiveness. In order to increase the predictiveness of models, future research should combine variables from several theories, attend to the psychometrics of all variables, and incorporate variables that moderate the relationship of psychosocial to dietary behavior (e.g. genetics of taste, stage in the life course). Refinements on current research would include longitudinal designs and use of non–self-report methods of dietary behavior to supplement the self-report methods. Improved understanding of dietary behavior should lead to more effective dietary behavior change interventions.
Iron Transport
Authors: Wessling-Resnick Marianne
Published: July 2002

Iron homeostasis is maintained by regulating its absorption: Under conditions of deficiency, assimilation is enhanced but iron uptake is otherwise limited to prevent toxicity due to overload. Iron deficiency remains the most important micronutrient deficiency worldwide, but increasing awareness of the genetic basis for iron-loading diseases points to iron overload as a major public health issue as well. Recent identification of mutant alleles causing iron uptake disorders in mice and humans provides new insights into the mechanisms involved in iron transport and its regulation. This article summarizes these discoveries and discusses their impact on our current understanding of iron transport and its regulation.
Cellular Copper Transport and Metabolism
Authors: Harris Edward D.
Published: July 2002

The transport and cellular metabolism of Cu depends on a series of membrane proteins and smaller soluble peptides that comprise a functionally integrated system for maintaining cellular Cu homeostasis. Inward transport across the plasma membrane appears to be a function of integral membrane proteins that form the channels that select Cu ions for passage. Two membrane-bound Cu-transporting ATPase enzymes, ATP7A and ATP7B, the products of the Menkes and Wilson disease genes, respectively, catalyze an ATP-dependent transfer of Cu to intracellular compartments or expel Cu from the cell. ATP7A and ATP7B work in concert with a series of smaller peptides, the copper chaperones, that exchange Cu at the ATPase sites or incorporate the Cu directly into the structure of Cu-dependent enzymes such as cytochrome c oxidase and Cu, Zn superoxide dismutase. These mechanisms come into play in response to a high influx of Cu or during the course of normal Cu metabolism.