bluuebunny/crossref_metadata_2025 huggingface dataset:
ATP-Binding Cassette Transporters in Bacteria
Authors: Davidson Amy L. , Chen Jue
Published: June 2004

▪ Abstract  ATP-binding cassette (ABC) transporters couple ATP hydrolysis to the uptake and efflux of solutes across the cell membrane in bacteria and eukaryotic cells. In bacteria, these transporters are important virulence factors because they play roles in nutrient uptake and in secretion of toxins and antimicrobial agents. In humans, many diseases, such as cystic fibrosis, hyperinsulinemia, and macular dystrophy, are traced to defects in ABC transporters. Recent advances in structural determination and functional analysis of bacterial ABC transporters, reviewed herein, have greatly increased our understanding of the molecular mechanism of transport in this transport superfamily.
The Sir2 Family of Protein Deacetylases
Authors: Blander Gil , Guarente Leonard
Published: June 2004

▪ Abstract  The yeast SIR protein complex has been implicated in transcription silencing and suppression of recombination. The Sir complex represses transcription at telomeres, mating-type loci, and ribosomal DNA. Unlike SIR3 and SIR4, the SIR2 gene is highly conserved in organisms ranging from archaea to humans. Interestingly, Sir2 is active as an NAD+-dependent deacetylase, which is broadly conserved from bacteria to higher eukaryotes. In this review, we discuss the role of NAD+, the unusual products of the deacetylation reaction, the Sir2 structure, and the Sir2 chemical inhibitors and activators that were recently identified. We summarize the current knowledge of the Sir2 homologs from different organisms, and finally we discuss the role of Sir2 in caloric restriction and aging.
Cytochrome C-Mediated Apoptosis
Authors: Jiang Xuejun , Wang Xiaodong
Published: June 2004

▪ Abstract  Apoptosis, or programmed cell death, is involved in development, elimination of damaged cells, and maintenance of cell homeostasis. Deregulation of apoptosis may cause diseases, such as cancers, immune diseases, and neurodegenerative disorders. Apoptosis is executed by a subfamily of cysteine proteases known as caspases. In mammalian cells, a major caspase activation pathway is the cytochrome c-initiated pathway. In this pathway, a variety of apoptotic stimuli cause cytochrome c release from mitochondria, which in turn induces a series of biochemical reactions that result in caspase activation and subsequent cell death. In this review, we focus on the recent progress in understanding the biochemical mechanisms and regulation of the pathway, the roles of the pathway in physiology and disease, and their potential therapeutic values.
Directed Evolution of Nucleic Acid Enzymes
Authors: Joyce Gerald F.
Published: June 2004

▪ Abstract  Just as Darwinian evolution in nature has led to the development of many sophisticated enzymes, Darwinian evolution in vitro has proven to be a powerful approach for obtaining similar results in the laboratory. This review focuses on the development of nucleic acid enzymes starting from a population of random-sequence RNA or DNA molecules. In order to illustrate the principles and practice of in vitro evolution, two especially well-studied categories of catalytic nucleic acid are considered: RNA enzymes that catalyze the template-directed ligation of RNA and DNA enzymes that catalyze the cleavage of RNA. The former reaction, which involves attack of a 2′- or 3′-hydroxyl on the α-phosphate of a 5′-triphosphate, is more difficult. It requires a comparatively larger catalytic motif, containing more nucleotides than can be sampled exhaustively within a starting population of random-sequence RNAs. The latter reaction involves deprotonation of the 2′-hydroxyl adjacent to the cleavage site, resulting in cleaved products that bear a 2′,3′-cyclic phosphate and 5′-hydroxyl. The difficulty of this reaction, and therefore the complexity of the corresponding DNA enzyme, depends on whether a catalytic cofactor, such as a divalent metal cation or small molecule, is present in the reaction mixture.
Molecular Mechanisms of Mammalian DNA Repair and the DNA Damage Checkpoints
Authors: Sancar Aziz , Lindsey-Boltz Laura A. , Ünsal-Kaçmaz Keziban , Linn Stuart
Published: June 2004

▪ Abstract  DNA damage is a relatively common event in the life of a cell and may lead to mutation, cancer, and cellular or organismic death. Damage to DNA induces several cellular responses that enable the cell either to eliminate or cope with the damage or to activate a programmed cell death process, presumably to eliminate cells with potentially catastrophic mutations. These DNA damage response reactions include: (a) removal of DNA damage and restoration of the continuity of the DNA duplex; (b) activation of a DNA damage checkpoint, which arrests cell cycle progression so as to allow for repair and prevention of the transmission of damaged or incompletely replicated chromosomes; (c) transcriptional response, which causes changes in the transcription profile that may be beneficial to the cell; and (d) apoptosis, which eliminates heavily damaged or seriously deregulated cells. DNA repair mechanisms include direct repair, base excision repair, nucleotide excision repair, double-strand break repair, and cross-link repair. The DNA damage checkpoints employ damage sensor proteins, such as ATM, ATR, the Rad17-RFC complex, and the 9-1-1 complex, to detect DNA damage and to initiate signal transduction cascades that employ Chk1 and Chk2 Ser/Thr kinases and Cdc25 phosphatases. The signal transducers activate p53 and inactivate cyclin-dependent kinases to inhibit cell cycle progression from G1 to S (the G1/S checkpoint), DNA replication (the intra-S checkpoint), or G2 to mitosis (the G2/M checkpoint). In this review the molecular mechanisms of DNA repair and the DNA damage checkpoints in mammalian cells are analyzed.
Return of the GDI: The GoLoco Motif in Cell Division
Authors: Willard Francis S. , Kimple Randall J. , Siderovski David P.
Published: June 2004

▪ Abstract  The GoLoco motif is a 19-amino-acid sequence with guanine nucleotide dissociation inhibitor activity against G-alpha subunits of the adenylyl-cyclase-inhibitory subclass. The GoLoco motif is present as an independent element within multidomain signaling regulators, such as Loco, RGS12, RGS14, and Rap1GAP, as well as in tandem arrays in proteins, such as AGS3, G18, LGN, Pcp-2/L7, and Partner of Inscuteable (Pins/Rapsynoid). Here we discuss the biochemical mechanisms of GoLoco motif action on G-alpha subunits in light of the recent crystal structure of G-alpha-i1 bound to the RGS14 GoLoco motif. Currently, there is sparse evidence for GoLoco motif regulation of canonical G-protein–coupled receptor signaling. Rather, studies of asymmetric cell division in Drosophila and Caenorhabditis elegans, as well as mammalian mitosis, implicate GoLoco proteins, such as Pins, GPR-1/GPR-2, LGN, and RGS14, in mitotic spindle organization and force generation. We discuss potential mechanisms by which GoLoco/Gα complexes might modulate spindle dynamics.
Intermediate Filaments: Molecular Structure, Assembly Mechanism, and Integration Into Functionally Distinct Intracellular Scaffolds
Authors: Herrmann Harald , Aebi Ueli
Published: June 2004

▪ Abstract  The superfamily of intermediate filament (IF) proteins contains at least 65 distinct proteins in man, which all assemble into ∼10 nm wide filaments and are principal structural elements both in the nucleus and the cytoplasm with essential scaffolding functions in metazoan cells. At present, we have only circumstantial evidence of how the highly divergent primary sequences of IF proteins lead to the formation of seemingly similar polymers and how this correlates with their function in individual cells and tissues. Point mutations in IF proteins, particularly in lamins, have been demonstrated to lead to severe, inheritable multi-systemic diseases, thus underlining their importance at several functional levels. Recent structural work has now begun to shed some light onto the complex fine tuning of structure and function in these fibrous, coiled coil forming multidomain proteins and their contribution to cellular physiology and gene regulation.
Crawling Toward a Unified Model of Cell Motility: Spatial and Temporal Regulation of Actin Dynamics
Authors: Rafelski Susanne M. , Theriot Julie A.
Published: June 2004

▪ Abstract  Crawling cells of various morphologies displace themselves in their biological environments by a similar overall mechanism of protrusion through actin assembly at the front coordinated with retraction at the rear. Different cell types organize very distinct protruding structures, yet they do so through conserved biochemical mechanisms to regulate actin polymerization dynamics and vary the mechanical properties of these structures. The moving cell must spatially and temporally regulate the biochemical interactions of its protein components to exert control over higher-order dynamic structures created by these proteins and global cellular responses four or more orders of magnitude larger in scale and longer in time than the individual protein-protein interactions that comprise them. To fulfill its biological role, a cell globally responds with high sensitivity to a local perturbation or signal and coordinates its many intracellular actin-based functional structures with the physical environment it experiences to produce directed movement. This review attempts to codify some unifying principles for cell motility that span organizational scales from single protein polymer filaments to whole crawling cells.
Using Protein Folding Rates to Test Protein Folding Theories
Authors: Gillespie Blake , Plaxco Kevin W.
Published: June 2004

▪ Abstract  The fastest simple, kinetically two-state protein folds a million times more rapidly than the slowest. Here we review many recent theories of protein folding kinetics in terms of their ability to qualitatively rationalize, if not quantitatively predict, this fundamental experimental observation.
Novel Lipid Modifications of Secreted Protein Signals
Authors: Mann Randall K. , Beachy Philip A.
Published: June 2004

▪ Abstract  Secreted signaling proteins function in a diverse array of essential patterning events during metazoan development, ranging from embryonic segmentation in insects to neural tube differentiation in vertebrates. These proteins generally are expressed in a localized manner, and they may elicit distinct concentration-dependent responses in the cells of surrounding tissues and structures, thus functioning as morphogens that specify the pattern of cellular responses by their tissue distribution. Given the importance of signal distribution, it is notable that the Hedgehog (Hh) and Wnt proteins, two of the most important families of such signals, are known to be covalently modified by lipid moieties, the membrane-anchoring properties of which are not consistent with passive models of protein mobilization within tissues. This review focuses on the mechanisms underlying biogenesis of the mature Hh proteins, which are dually modified by cholesteryl and palmitoyl adducts, as well as on the relationship between Hh proteins and the self-splicing proteins (i.e., proteins containing inteins) and the Hh-like proteins of nematodes. We further discuss the cellular mechanisms that have evolved to handle lipidated Hh proteins in the spatial deployment of the signal in developing tissues and the more recent findings that implicate palmitate modification as an important feature of Wnt signaling proteins.
The Excitement of Discovery
Authors: Rich Alexander
Published: June 2004

I had the good luck to start research at the dawn of molecular biology when it was possible to ask fundamental questions about the nature of the nucleic acids and how information is transferred in living systems. The search for answers led me into many different areas, often with the question of how molecular structure leads to biological function. Early work in this period provided some of the roots supporting the current explosive developments in life sciences. Here I give a brief account of my development, describe some contributions, and provide a hint of the exhilaration in discovering new things. Most of all, I had the good fortune to have inspiring teachers, stimulating colleagues, and excellent students.
Nuclear Magnetic Resonance Spectroscopy of High-Molecular-Weight Proteins
Authors: Tugarinov Vitali , Hwang Peter M. , Kay Lewis E.
Published: June 2004

▪ Abstract  Recent developments in NMR spectroscopy, which include new experiments that increase the lifetimes of NMR signals or that precisely define the orientation of internuclear bond vectors with respect to a common molecular frame, have significantly increased the size of proteins for which quantitative structural and dynamic information can be obtained. These experiments have, in turn, benefited from new labeling strategies that continue to drive the field. The utility of the new methodology is illustrated by considering applications to malate synthase G, a 723 residue enzyme, which is the largest single polypeptide chain for which chemical shift assignments have been obtained to date. New experiments developed specifically to address the complexity and low sensitivity of spectra recorded on this protein are presented. A discussion of the chemical information that is readily available from studies of systems in the 100 kDa mol wt range is included. Prospects for membrane protein structure determination are discussed briefly in the context of an application to an Escherichia coli enzyme, PagP, localized to the outer membrane of gram-negative bacteria.
Protein Modification by SUMO
Authors: Johnson Erica S.
Published: June 2004

▪ Abstract  Small ubiquitin-related modifier (SUMO) family proteins function by becoming covalently attached to other proteins as post-translational modifications. SUMO modifies many proteins that participate in diverse cellular processes, including transcriptional regulation, nuclear transport, maintenance of genome integrity, and signal transduction. Reversible attachment of SUMO is controlled by an enzyme pathway that is analogous to the ubiquitin pathway. The functional consequences of SUMO attachment vary greatly from substrate to substrate, and in many cases are not understood at the molecular level. Frequently SUMO alters interactions of substrates with other proteins or with DNA, but SUMO can also act by blocking ubiquitin attachment sites. An unusual feature of SUMO modification is that, for most substrates, only a small fraction of the substrate is sumoylated at any given time. This review discusses our current understanding of how SUMO conjugation is controlled, as well as the roles of SUMO in a number of biological processes.
Inositol 1,4,5-Trisphosphate Receptors as Signal Integrators
Authors: Patterson Randen L. , Boehning Darren , Snyder Solomon H.
Published: June 2004

▪ Abstract  The inositol 1,4,5 trisphosphate (IP3) receptor (IP3R) is a Ca2+ release channel that responds to the second messenger IP3. Exquisite modulation of intracellular Ca2+ release via IP3Rs is achieved by the ability of IP3R to integrate signals from numerous small molecules and proteins including nucleotides, kinases, and phosphatases, as well as nonenzyme proteins. Because the ion conduction pore composes only ∼5% of the IP3R, the great bulk of this large protein contains recognition sites for these substances. Through these regulatory mechanisms, IP3R modulates diverse cellular functions, which include, but are not limited to, contraction/excitation, secretion, gene expression, and cellular growth. We review the unique properties of the IP3R that facilitate cell-type and stimulus-dependent control of function, with special emphasis on protein-binding partners.
REGULATION OF CATIONIC AMINO ACID TRANSPORT: The Story of the CAT-1 Transporter
Authors: Hatzoglou Maria , Fernandez James , Yaman Ibrahim , Closs Ellen
Published: June 2004

▪ Abstract  The discovery of the function of the receptor for the ecotropic retrovirus as a membrane transporter for the essential amino acids lysine and arginine was a landmark finding in the field of molecular nutrition. This finding indicated that cationic amino acid transporters (CATs) act pathologically as viral receptors. The importance of this transporter was further supported by knockout mice that were not viable after birth. CAT-1 was the first amino acid transporter to be cloned; several other CATs were later characterized biochemically and molecularly. These transporters mediate the bidirectional transport of cationic amino acids, thus supporting important metabolic functions, such as synthesis of proteins, nitric oxide (NO) synthesis, polyamine biosynthesis, and interorgan amino acid flow. This review briefly describes the advances in the regulation of cationic amino acid transport, focusing on the molecular mechanisms that regulate the CAT-1 transporter. Of particular interest to this review is the regulation of CAT-1 by nutritional stresses, such as amino acid availability. The studies that are reviewed conclude that the CAT-1 gene is essential for cell survival during stress because it allows cells to resume growth as soon as amino acids become available.
BIOACTIVE COMPOUNDS IN NUTRITION AND HEALTH-RESEARCH METHODOLOGIES FOR ESTABLISHING BIOLOGICAL FUNCTION: The Antioxidant and Anti-inflammatory Effects of Flavonoids on Atherosclerosis
Authors: Kris-Etherton P.M. , Lefevre M. , Beecher G.R. , Gross M.D. , Keen C.L. , Etherton T.D.
Published: June 2004

▪ Abstract  Identifying bioactive compounds and establishing their health effects are active areas of scientific inquiry. There are exciting prospects that select bioactive compounds will reduce the risk of many diseases, including chronic diseases such as cardiovascular disease. Recent findings have established that cardiovascular disease is a disease of inflammation, and consequently is amenable to intervention via molecules that have anti-inflammatory effects. In addition, research demonstrating adverse effects of oxidants on atherogenesis raises the possibility that antioxidants can confer cardioprotective effects. This review provides an overview of research approaches that can be used to unravel the biology and health effects of bioactive compounds. Because of the number of bioactive compounds and the diversity of likely biological effects, numerous and diverse experimental approaches must be taken to increase our understanding of the biology of bioactive compounds. Recognizing the complexity of this biology, sophisticated experimental designs and analytical methodologies must be employed to advance the field. The discovery of novel health effects of bioactive compounds will provide the scientific basis for future efforts to use biotechnology to modify/fortify foods and food components as a means to improve public health.
DIETARY n-6 AND n-3 FATTY ACID BALANCE AND CARDIOVASCULAR HEALTH
Authors: Wijendran Vasuki , Hayes K.C.
Published: June 2004

▪ Abstract  Epidemiological and clinical studies have established that the n-6 fatty acid, linoleic acid (LA), and the n-3 fatty acids, linolenic acid (LNA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) collectively protect against coronary heart disease (CHD). LA is the major dietary fatty acid regulating low-density lipoprotein (LDL)-C metabolism by downregulating LDL-C production and enhancing its clearance. Further, the available mass of LA is a critical factor determining the hyperlipemic effects of other dietary fat components, such as saturated and trans fatty acids, as well as cholesterol. By contrast, n-3 fatty acids, especially EPA and DHA, are potent antiarryhthmic agents. EPA and DHA also improve vascular endothelial function and help lower blood pressure, platelet sensitivity, and the serum triglyceride level. The distinct functions of these two families make the balance between dietary n-6 and n-3 fatty acids an important consideration influencing cardiovascular health. Based on published literature describing practical dietary intakes, we suggest that consumption of ∼6% en LA, 0.75% en LNA, and 0.25% en EPA + DHA represents adequate and achievable intakes for most healthy adults. This corresponds to an n-6/n-3 ratio of ∼6:1. However, the absolute mass of essential fatty acids consumed, rather than their n-6/n-3 ratio, should be the first consideration when contemplating lifelong dietary habits affecting cardiovascular benefit from their intake.
DEVELOPMENTAL ASPECTS AND FACTORS INFLUENCING THE SYNTHESIS AND STATUS OF ASCORBIC ACID IN THE PIG
Authors: Mahan D.C. , Ching S. , Dabrowski K.
Published: June 2004

▪ Abstract  Ascorbic acid synthesis in the pig occurs at mid-pregnancy, but activity of the enzyme l-gulono-γ-lactone oxidase (GLO) declines thereafter during gestation and remains low when the pig nurses the sow. During late gestation the ascorbic acid concentration in the fetus increases, but serum and liver ascorbic acid concentration in the sow declines without affecting the dam's liver GLO activity. It is presumed that as gestation progresses an increased amount of maternal ascorbic acid is transferred to the fetus and to the mammary gland. Colostrum and milk are rich sources of the vitamin and supply the nursing pig with ascorbic acid. The available data suggest that high amounts of ascorbic acid appear to suppress liver GLO activity in the pig. Upon weaning, when exogenous vitamin C is generally not provided, liver GLO activity and serum ascorbic acid increases. During the initial periods postweaning, some reports have indicated growth benefits of supplemental vitamin C. Body tissues differ in their concentrations of ascorbic acid, but tissues of high metabolic need generally have greater concentrations. The corpus luteum in the female, the testis in the male, and the adrenal glands in all pigs contain greater concentrations of the vitamin. Knockout genes preventing ascorbic acid synthesis in pigs have demonstrated poor skeletal and collagen formation and poor antioxidant protection. Under periods of stress ascorbic acid declines in the adrenal, but the pig rapidly recovers to its resting state once the stressor agent is removed. Although there are periods when supplemental vitamin C has been shown to promote pig performance (e.g., during high environmental stress and early postweaning), supplemental vitamin C has not been shown to routinely enhance pig performance.
EXTRACELLULAR THIOLS AND THIOL/DISULFIDE REDOX IN METABOLISM
Authors: Moriarty-Craige Siobhan E. , Jones Dean P.
Published: June 2004

▪ Abstract  Many proteins present on cell surfaces and located in extracellular fluids contain cysteine and methionine residues that are subject to oxidation. These proteins, which include transporters, receptors, and enzymes, respond to variations in the extracellular thiol/disulfide redox environment. Changes in activity of these proteins can alter the ability of organs to function normally and influence processes such as nutritional absorption, secretory function, neurotransmission, and susceptibility to toxicants. In addition, extracellular redox can regulate tissue homeostasis through effects on cell proliferation, differentiation, apoptosis, and immune function. Consequently, extracellular redox can have important influences on health status and disease states and thus could be a target for nutritional interventions.
IRON, FERRITIN, AND NUTRITION
Authors: Theil Elizabeth C.
Published: June 2004

▪ Abstract  Ferritin, a major form of endogenous iron in food legumes such as soybeans, is a novel and natural alternative for iron supplementation strategies where effectiveness is limited by acceptability, cost, or undesirable side effects. A member of the nonheme iron group of dietary iron sources, ferritin is a complex with Fe3+ iron in a mineral (thousands of iron atoms inside a protein cage) protected from complexation. Ferritin illustrates the wide range of chemical and biological properties among nonheme iron sources. The wide range of nonheme iron receptors matched to the structure of the iron complexes that occurs in microorganisms may, by analogy, exist in humans. An understanding of the chemistry and biology of each type of dietary iron source (ferritin, heme, Fe2+ ion, etc.), and of the interactions dependent on food sources, genes, and gender, is required to design diets that will eradicate global iron deficiency in the twenty-first century.
NEW INSIGHTS INTO ERYTHROPOIESIS: The Roles of Folate, Vitamin B12, and Iron
Authors: Koury Mark J. , Ponka Prem
Published: June 2004

▪ Abstract  Erythropoiesis is the process in which new erythrocytes are produced. These new erythrocytes replace the oldest erythrocytes (normally about one percent) that are phagocytosed and destroyed each day. Folate, vitamin B12, and iron have crucial roles in erythropoiesis. Erythroblasts require folate and vitamin B12 for proliferation during their differentiation. Deficiency of folate or vitamin B12 inhibits purine and thymidylate syntheses, impairs DNA synthesis, and causes erythroblast apoptosis, resulting in anemia from ineffective erythropoiesis. Erythroblasts require large amounts of iron for hemoglobin synthesis. Large amounts of iron are recycled daily with hemoglobin breakdown from destroyed old erythrocytes. Many recently identified proteins are involved in absorption, storage, and cellular export of nonheme iron and in erythroblast uptake and utilization of iron. Erythroblast heme levels regulate uptake of iron and globin synthesis such that iron deficiency causes anemia by retarded production rates with smaller, less hemoglobinized erythrocytes.
MAMMALIAN ZINC TRANSPORTERS
Authors: Liuzzi Juan P. , Cousins Robert J.
Published: June 2004

▪ Abstract  New insights into mammalian zinc metabolism have been acquired through the identification and characterization of zinc transporters. These proteins all have transmembrane domains, and are encoded by two solute-linked carrier (SLC) gene families: ZnT (SLC30) and Zip (SLC39). There are at least 9 ZnT and 15 Zip transporters in human cells. They appear to have opposite roles in cellular zinc homeostasis. ZnT transporters reduce intracellular zinc availability by promoting zinc efflux from cells or into intracellular vesicles, while Zip transporters increase intracellular zinc availability by promoting extracellular zinc uptake and, perhaps, vesicular zinc release into the cytoplasm. Both the ZnT and Zip transporter families exhibit unique tissue-specific expression, differential responsiveness to dietary zinc deficiency and excess, and differential responsiveness to physiologic stimuli via hormones and cytokines.
AMERICA'S OBESITY: Conflicting Public Policies, Industrial Economic Development, and Unintended Human Consequences
Authors: Tillotson James E.
Published: June 2004

▪ Abstract  The chapter reviews the historical development and interactions of U.S. agricultural, economic, nutrition, and development policies relating to the creation of the commercial environment of social, economic, technological, and political factors that favor the development of American obesity.
VITAMIN B12 DEFICIENCY AS A WORLDWIDE PROBLEM
Authors: Stabler Sally P. , Allen Robert H.
Published: June 2004

▪ Abstract  Pernicious anemia is a common cause of megaloblastic anemia throughout the world and especially in persons of European or African descent. Dietary deficiency of vitamin B12 due to vegetarianism is increasing and causes hyperhomocysteinemia. The breast-fed infant of a vitamin B12–deficient mother is at risk for severe developmental abnormalities, growth failure, and anemia. Elevated methylmalonic acid and/or total homocysteine are sensitive indicators of vitamin B12–deficient diets and correlate with clinical abnormalities. Dietary vitamin B12 deficiency is a severe problem in the Indian subcontinent, Mexico, Central and South America, and selected areas in Africa. Dietary vitamin B12 deficiency is not prevalent in Asia, except in vegetarians. Areas for research include intermittent vitamin B12 supplement dosing and better measurements of the bioavailability of B12 in fermented vegetarian foods and algae.
REPROGRAMMING OF THE IMMUNE SYSTEM DURING ZINC DEFICIENCY
Authors: Fraker Pamela J. , King Louis E.
Published: June 2004

▪ Abstract  Thymic atrophy, lymphopenia, and compromised cell- and antibody-mediated responses that cause increased rates of infections of longer duration are the immunological hallmarks of zinc deficiency (ZD) in humans and higher animals. As the deficiency advances, a reprogramming of the immune system occurs, beginning with the activation of the stress axis and chronic production of glucocorticoids that accelerate apoptosis among pre-B and -T cells. This reduces lymphopoiesis and causes atrophy of the thymus. In contrast, myelopoiesis is preserved, thereby providing protection for the first line of immune defense or innate immunity. Changes in gene expression for cytokines, DNA repair enzymes, zinc transporters, signaling molecules, etc., suggest that cells of the immune system are attempting to adapt to the stress of suboptimal zinc. Better understanding of the molecular and cellular changes made in response to inadequate zinc should lead to the development of immunotherapeutic interventions.
ISOFLAVONES IN SOY INFANT FORMULA: A Review of Evidence for Endocrine and Other Activity in Infants
Authors: Chen Aimin , Rogan Walter J.
Published: June 2004

▪ Abstract  Soy infant formulas are widely used, but few studies have evaluated long-term safety or examined specific forms of toxicity, such as to the endocrine or immune systems. This review focuses on newer experimental studies of the effects on estrogen activity, immune function, and thyroid economy of genistein and daidzein, two isoflavones in soy infant formula, and existing human studies of soy formula use. In order to judge the likelihood that an endpoint seen in laboratory studies might occur in soy-fed infants, we examined the doses and the resulting serum or plasma concentrations from the laboratory studies and compared them with doses and concentrations seen in soy-fed infants. We also summarized the estimates of the potency of the isoflavone compounds relative to estradiol. Given the scarcity and inconsistency of existing human data and the substantial laboratory evidence of hormonal and other activity at doses relevant to the soy-fed infant, we conclude that more clinical and epidemiological study is warranted.
Cell mechanics and mechanotransduction: pathways, probes, and physiology
Authors: Huang Hayden , Kamm Roger D. , Lee Richard T.
Published: June 2004

Cells face not only a complex biochemical environment but also a diverse biomechanical environment. How cells respond to variations in mechanical forces is critical in homeostasis and many diseases. The mechanisms by which mechanical forces lead to eventual biochemical and molecular responses remain undefined, and unraveling this mystery will undoubtedly provide new insight into strengthening bone, growing cartilage, improving cardiac contractility, and constructing tissues for artificial organs. In this article we review the physical bases underlying the mechanotransduction process, techniques used to apply controlled mechanical stresses on living cells and tissues to probe mechanotransduction, and some of the important lessons that we are learning from mechanical stimulation of cells with precisely controlled forces.
The Tau Gene Locus and Frontotemporal Dementia
Authors: Pickering-Brown Stuart
Published: June 2004

Frontotemporal lobar degeneration (FTLD) has become an increasingly recognised form of dementia. It has been demonstrated that a proportion of cases of FTLD result from mutations in the tau gene on chromosome 17. A pathological hallmark in the brains from patients with tau mutations is an accumulation of insoluble tau within neurons and glia that is considered neurotoxic. However, there are reports of families with FTLD linked to the tau locus on chromosome 17 in which no mutations have been found, and these families lack any accumulation of insoluble tau. Recently, two new tau mutations have been described that also appear to cause disease in the absence of any tau accumulation. The role of the tau locus and tau accumulation in contributing to the neurodegenerative process in chromosome-17-linked families without mutations and in families with tau mutations without insoluble tau is discussed.
Epidemiology of Frontotemporal Lobar Degeneration
Authors: Ikeda Manabu , Ishikawa Tomohisa , Tanabe Hirotaka
Published: June 2004

A few epidemiologic studies have dealt with the prevalence of frontotemporal lobar degeneration (FTLD), including Pick’s disease. The aim of this study was to review the epidemiologic studies of FTLD in western countries and to compare them with those in Japan. A community-based study of early-onset dementia in London revealed that 12% of cases with frontotemporal dementia (FTD) fulfilled the Lund-Manchester criteria in contrast to 34% of cases with Alzheimer’s disease (AD) in a sample of 185 cases. The Cambridge Group has recently examined the prevalence of early-onset dementia in a community-based study. Of 108 cases, 15.7% had FTLD and 25% had AD. FTLD included 13 FTD cases, and 2 each with semantic dementia (SD) and nonfluent progressive aphasia (PA). Almost one third of cases with FTLD (29%) had a positive family history. Of our consecutive 330 outpatients with dementia (hospital setting without age limitation), 42 (12.7%) had FTLD and 215 (65.1%) had AD. In our series of patients, 22 FTD, 15 SD and 5 PA cases were identified. There was no family history in all subtypes of FTLD. Epidemiologic studies, both community-based and hospital-based, demonstrate that FTLD is a more common cause of early-onset dementia than previously recognized. Regarding the subtypes of FTLD, in Japan, compared with the data from the UK, FTD is less common, SD may be more common and PA is equally common. The reason for this discrepancy is supposed to be mainly based on the role of heredity.
Recognition of Emotion in the Frontal and Temporal Variants of Frontotemporal Dementia
Authors: Rosen Howard J. , Pace-Savitsky Katherine , Perry Richard J. , Kramer Joel H. , Miller Bruce L. , Levenson Robert W.
Published: June 2004

Recent studies have suggested that the frontal and temporal variants of frontotemporal dementia (fvFTD and tvFTD) are both associated with impairments in emotional processing. However, the degree and type of emotional processing deficits in the two syndromes have not been previously compared. We used the Florida Affect Battery to examine recognition of facial expressions of emotion in fvFTD and tvFTD patients who have no evidence of visual perceptual difficulties for faces. In general, both groups were impaired at recognizing emotions compared with age-matched controls. In tvFTD, this deficit was limited to emotions with a negative valence (sadness, anger, fear), while fvFTD patients showed impairment for positive valence (happiness) as well. These results suggest that damage to frontal lobe regions in FTD may lead to more profound impairment in recognition of emotion than when damage is more limited to the temporal lobe.
Right and Left Medial Orbitofrontal Volumes Show an Opposite Relationship to Agreeableness in FTD
Authors: Rankin Katherine P. , Rosen Howard J. , Kramer Joel H. , Schauer Guido F. , Weiner Michael W. , Schuff Norbert , Miller Bruce L.
Published: June 2004

Recent investigations of the neuroanatomy of complex social behaviors suggest that the underlying brain circuits involve multiple cortical and subcortical structures. The neuroanatomic origins of agreeableness have not yet been clearly elucidated. However, frontotemporal dementia (FTD) patients can evidence dramatic alterations in agreeableness arising from frontal and temporal lobe damage. Based on previous research, we hypothesized that agreeableness would be negatively correlated with left medial orbitofrontal cortex size and positively correlated with right amygdala volume. First-degree relatives of 27 FTD patients (diagnosed according to the Lund-Manchester criteria) were asked to fill out the NEO-Five Factor Inventory to assess the patients’ current level of agreeableness, a construct comprised of the facets trust, straightforwardness, altruism, compliance, modesty, and tender-mindedness. These patients underwent T1-weighted MRI imaging, and gray matter volumes for right and left orbitofrontal lobes and amygdalas were derived via segmentation and region of interest tracing, normalizing for total intracranial volume. Regression analysis revealed that 38% of the variance in the NEO agreeableness score was predicted by a model in which right orbitofrontal volume (β = 0.731) was positively correlated with agreeableness, and left orbitofrontal lobe volume (β = –0.638) was negatively correlated with agreeableness (p < 0.01). Contrary to our hypothesis, amygdala volume did not significantly predict agreeableness. This finding partly replicates a previous study that used a different measure of social functioning, the Interpersonal Adjective Scale, to delineate a left frontal-right amygdala circuit for agreeableness. These data support the hypothesis that regulation of agreeableness arises from a balanced, mutually inhibitory circuit involving both hemispheres.
Hippocampal Sclerosis and Ubiquitin-Positive Inclusions in Dementia Lacking Distinctive Histopathology
Authors: Josephs Keith A. , Jones A.G. , Dickson Dennis W.
Published: June 2004

The aim of this study was to determine the frequency of ubiquitin-positive inclusions (UPI) in dementia lacking distinctive histology (DLDH), and their relationship to other pathologic features, such as hippocampal sclerosis (HpScl), as well as genetic factors. Routine and immunohistochemical studies were carried out in a consecutive series of 29 cases of DLDH. 83% of the cases had UPI, while HpScl was demonstrated in 76%. There was no significant correlation among pathologic features or between pathologic features and genetic factors. The high prevalence of UPI demonstrated in this study implies that DLDH is similar to motor neuron disease inclusion dementia. The high prevalence of HpScl may be the cause of some of the clinical features observed in patients with frontotemporal lobar degeneration.
Total and Phosphorylated Tau Proteins: Evaluation as Core Biomarker Candidates in Frontotemporal Dementia
Authors: Hampel Harald , Teipel Stefan J.
Published: June 2004

An ever increasing number of patients with neurodegenerative disorders calls for the evaluation of potential diagnostic markers that allow an early diagnosis and an early initiation of specific therapy. Clinical diagnosis of Alzheimer’s disease (AD), the most common neurodegenerative disorder, reaches 80–90% accuracy upon autopsy in specialized clinical centers. Diagnosis of AD in early clinical or preclinical stages is far less accurate, as is the differential diagnosis between AD and other primary dementias, such as frontotemporal dementia (FTD). Microtubule-associated tau protein is abnormally phosphorylated in AD and aggregates as paired helical filaments in neurofibrillary tangles. Recently, immunoassays have been developed detecting tau phosphorylated at specific epitopes in cerebrospinal fluid (CSF). Four years of clinical research consistently demonstrate that CSF phosphorylated tau (p-tau) is highly increased in AD compared to healthy controls and may differentiate AD from its most relevant differential diagnoses. Tau phosphorylated at threonine 231 (p-tau231) shows excellent differentiation between AD and FTD, whereas serine 181 (p-tau181) enhances accurate differentiation between AD and dementia with Lewy bodies. Moreover, p-tau231 levels decline with disease progression, correlating with cognitive performance at baseline. Total tau (t-tau) is regarded as a general marker of neurodegeneration for evaluation in future population-based studies. p-tau231 and p-tau181 yield excellent discrimination between AD and non-AD dementias including FTD, exceeding the differential diagnostic and prognostic accuracy of t-tau. Therefore, p-tau is a core biological marker candidate for future evaluation in large national and international multicenter networks.
Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia: Current Status and Challenges
Authors: Izraeli Shai , Waldman Dalia
Published: June 2004

The pace of disappearance of leukemic blasts in response to therapy has long been recognized as the most important prognostic factor in childhood acute lymphoblastic leukemia (ALL). Recent technological advancements enable detection of submicroscopic leukemic cells. The extent of reduction in the level of minimal residual disease (MRD) during the first phase of therapy can be exploited for improved risk classification of children with ALL. Current prospective studies test the hypothesis that tailoring treatment to the level of MRD will improve patients’ outcome.
Detection of Minimal Residual Disease in Acute Myelogenous Leukemia
Authors: Raanani P. , Ben-Bassat I.
Published: June 2004

Acute myelogenous leukemia (AML) is considered to be in complete remission when fewer than 5% of the cells in bone marrow are blasts. Nevertheless, approximately two thirds of patients relapse due to persisting leukemic blasts. The persistence of these cells, below the threshold of morphological detection, is termed minimal residual disease (MRD) and various methods are used for its detection. These methods include classical cytogenetics, fluorescence in situ hybridization, qualitative and quantitative RT-PCR and multiparametric flow cytometry. Currently, less than half of the AML patients have a specific marker detectable by RT-PCR techniques. The major specific molecular markers are involvement of the MLL gene with up to 50 different partners and partial tandem duplications, the core binding factor leukemias with AML1/ETO and CBFβ/MYH11 rearrangements, PML/RARα in acute promyelocytic leukemia, internal tandem duplications and mutations of FLT3 and some other rare translocations. In addition, several other genes show abnormal expression levels in AML, including the Wilms tumor gene, the PRAME gene and Ig/TCR rearrangements. Most of these genetic abnormalities can be detected by qualitative but more importantly by quantitative RT-PCR. The kinetics of disappearance of molecular markers in AML differs between the various types of leukemias, although at least a 2 log reduction of transcript after induction chemotherapy is necessary for long-term remission in all types. Conversely, the change of PCR from negativity to positivity is highly predictive of relapse. Whereas in acute lymphoblastic leukemia, multiparametric flow cytometry is an established method for MRD detection, this is less so in AML. The reason is the absence of well-characterized leukemia-specific antigens and the existence of phenotypic changes at relapse. On the other hand, this method is convenient due to its simplicity and universal applicability. In conclusion, several methods can be used for MRD detection in AML patients; each has its pros and cons. Several issues still remain to be settled including the choice of the best method and the timing for MRD monitoring and above all the practical clinical implications of MRD in the various types of AML.
Clinical Implications of Minimal Residual Disease Monitoring for Stem Cell Transplantation after Reduced Intensity and Nonmyeloablative Conditioning
Authors: Shimoni Avichai , Nagler Arnon
Published: June 2004

Allogeneic stem cell transplantation (SCT) is a potentially curative therapy for a variety of hematological malignancies; however, relapse and treatment-related toxicities are major obstacles to cure. Nonmyeloablative and reduced-intensity conditioning regimens were designed not to eradicate the malignancy completely, but rather to be immunosuppressive enough to allow engraftment, and to serve as a platform for additional cellular immunotherapy. Minimal residual disease (MRD) typically persists after SCT, and is gradually eliminated with different kinetics typical of each disease. Significant progress has been achieved with technologies for MRD assessment. Quantitative PCR tests are very sensitive in detecting tumor-associated transcripts, allowing serial monitoring. Threshold levels have been established for some malignancies, above which relapse is imminent. Persistent negative tests, a low level or a decreasing MRD level are consistent with continuous remission, whereas high-level MRD or increasing levels predict an incipient relapse. Patients at high risk of relapse are candidates for additional cellular or targeted therapy. Immunotherapy is more effective for MRD than at frank relapse. Timing and dosing of therapy are not yet well established and depend on aggressiveness of the disease, type of conditioning, level and kinetics of MRD.
Cancer and Mental Disorders in a National Community Sample: Findings from the National Comorbidity Survey
Authors: Honda Keiko , Goodwin Renee D.
Published: June 2004

Objective: To determine the association between cancer (past 12 months) and mental disorders (past 12 months) among community-dwelling adults. Methods: Data were drawn from the National Comorbidity Survey (n = 5,877), a representative household sample of adults aged 15–54 years in the United States. Multiple logistic regression analyses were used to determine the association between cancer and mental disorders, adjusting for differences in sociodemographic characteristics. Results: Cancer was significantly associated with increased rates of major depression [odds ratio (OR) = 3.6, 95% confidence interval (CI) = 1.4–8.8], drug dependence (OR = 3.6, 95% CI = 1.3–9.8), simple phobia (OR = 2.5, 95% CI = 1.0–6.2) and agoraphobia (OR = 3.3, 95% CI = 1.0–10.4). These associations persisted after adjusting for major sociodemographic factors, and sex plays a significant role in the association between cancer diagnosis and mental disorder, with cancer diagnosis having a stronger influence on major depression and drug dependence in men than in women. Conclusions: Clinicians and community health workers working with cancer survivors need to be not only alert for signs of clinical depression but also of co-occurring drug dependence and certain anxiety disorders so that appropriate referrals to mental health professionals can be made.
A Comparative Study on the Effects of Naltrexone and Loratadine on Uremic Pruritus
Authors: Legroux-Crespel Emmanuelle , Clèdes Jacques , Misery Laurent
Published: June 2004

Background: Two recent studies have provided opposite results on the efficacy of naltrexone on uremic pruritus. We have performed a third study. Objective: To compare the efficacy and tolerance of naltrexone and loratadine in uremic pruritus. Patients/Methods: Among 296 hemodialyzed patients, 65 suffered from uremic pruritus. Fifty-two patients participated in the study. The patients were treated for 2 weeks with naltrexone (50 mg/day; 26 patients) or loratadine (10 mg/day; 26 patients), after a washout of 48 h. Pruritus intensity was scored by a visual analogue scale (VAS). Adverse events were carefully searched for. The two groups were statistically equivalent. Results: There was no significant difference in the mean VAS scores after treatment, but naltrexone allowed a dramatic decrease in VAS scores (Δ >3/10) in 7 patients. Adverse events (mainly nausea and sleep disturbances) were observed in 10/26 patients. Conclusions: Naltrexone is effective only in a subset of patients. Adverse events are very frequent. The differences of efficacy and tolerance between patients might be due to metabolism. Naltrexone might be considered as a second-line treatment.