bluuebunny/crossref_metadata_2025 huggingface dataset:
MODERN THOUGHTS ON AN ANCYENT MARINERE: Function, Evolution, Regulation
Authors: Hartl Daniel L. , Lohe Allan R. , Lozovskaya Elena R.
Published: July 2002

▪ Abstract  The mariner/Tc1 superfamily of transposable elements is one of the most diverse and widespread Class II transposable elements. Within the larger assemblage, the mariner-like elements (MLEs) and the Tc1-like elements (TLEs) are distinct families differing characteristically in the composition of the “D,D(35)E” cation-binding domain. Based on levels of sequence similarity, the elements in each family can be subdivided further into several smaller subfamilies. MLEs and TLEs both have an extraordinarily wide host range. They are abundant in insect genomes and other invertebrates and are found even in some vertebrate species including, in the case of mariner, humans, in which one element on chromosome 17p has been implicated as a hotspot of recombination. In spite of the extraordinary evolutionary success of the elements, virtually nothing is known about their mode of regulation within genomes. There is abundant evidence that the elements are disseminated to naive host genomes by horizontal transmission, and there is a substantial base of evidence for inference about the subsequent population dynamics. Studies of engineered mariner elements and induced mutations in the transposase have identified two mechanisms that may be operative in mariner regulation. One mechanism is overproduction inhibition, in which excessive wild-type transposase reduces the rate of excision of a target element. A second mechanism is dominant-negative complementation, in which certain mutant transposase proteins antagonize the activity of the wild-type transposase. The latter process may help explain why the vast majority of MLEs in nature undergo “vertical inactivation” by multiple mutations and, eventually, stochastic loss. There is also evidence that mariner/Tc1 elements can be mobilized in hybrid dysgenesis; in particular, certain dysgenic crosses in Drosophila virilis result in mobilization of a TLE designated Paris as well as the mobilization of other unrelated transposable elements.
HUMAN CYTOTOXIC T LYMPHOCYTE RESPONSES TO EPSTEIN-BARR VIRUS INFECTION
Authors: Rickinson Alan B. , Moss Denis J.
Published: July 2002

▪ Abstract  Epstein-Barr virus (EBV) provides one of the most informative systems with which to study cytotoxic T lymphocyte (CTL) responses in humans. The virus establishes a highly immunogenic growth-transforming infection of B lymphocytes, associated with the coordinate expression of six virus-coded nuclear antigens (EBNAs 1, 2, 3A, 3B, 3C, -LP) and two latent membrane proteins (LMPs 1 and 2). This elicits both primary and memory CT8+CTL responses that are markedly skewed toward HLA allele-specific epitopes drawn from the EBNA3A, 3B, 3C subset of latent proteins, with reactivities to other antigens being generally much less frequent. This heirarchy of immunodominance among the different latent proteins may at least partly reflect their differential accessibility to the HLA class I–processing pathway. Furthermore, CTLs to some of the immunodominant epitopes involve highly conserved T cell receptor (TCR) usage, a level of focusing which evidence suggests could have immunopathological consequences from cross-reactive recognition of other target structures. EBV is associated with a range of human tumors, and there is increasing interest in the possibility of targeting such malignancies using virus-specific CTLs. The dramatic reversal of EBV-driven lymphoproliferations in bone marrow transplant patients following CTL infusion demonstrates the potential of this approach, and here we discuss prospects for its extension to other EBV-positive tumors in which the immunodominant EBNA3A, 3B, 3C proteins are not expressed.
T CELL MEMORY
Authors: Dutton R. W. , Bradley L. M. , Swain S. L.
Published: July 2002

▪ Abstract  Immunological memory can be defined as the faster and stronger response of an animal that follows reexposure to the same antigen. By this definition, it is an operational property of the whole animal or the immune system. Memory cells express a different pattern of cell surface markers, and they respond in several ways that are functionally different from those of naive cells. Murine memory cells are CD44 high and low in the expression of activation markers such as CD25 (IL-2R), whereas human memory cells are CD45RA−, CD45RO+. In contrast to naive cells, memory cells secrete a full range of T cell cytokines and can be polarized to secrete particular restricted patterns of secretion for both CD4 and CD8 T cells. The requirements for the activation of memory cells for proliferation and cytokine production are not quite as strict as those of naive cells, but costimulation in the broad sense is required for optimum responses and for responses to suboptimum antigen concentrations. It would appear that memory cells can persist in the absence of antigenic stimulation and persist as nondividing cells. Reencounter with the same antigen can expand the population to a new, stable, higher level and generate a separate population of CD44 high effectors that may be required for protection, while competition from other antigens can drive it down to a lower stable level. It is unclear how or where memory cells arise, but once generated they have different pathways of recirculation and homing.
Accessing Complexity: The Dynamics of Virus-Specific T Cell Responses
Authors: Doherty Peter C. , Christensen Jan P.
Published: July 2002

The cellular dynamics of the immune system are complex and difficult to measure. Access to this problematic area has been greatly enhanced by the recent development of tetrameric complexes of MHC class I glycoprotein + peptide (tetramers) for the direct staining of freshly isolated, antigen-specific CD8+T cells. Analysis to date with both naturally acquired and experimentally induced infections has established that the numbers of virus-specific CD8+T cells present during both the acute and memory phases of the host response are more than tenfold in excess of previously suspected values. The levels are such that the virus-specific CD8+set is readily detected in the human peripheral blood lymphocyte compartment, particularly during persistent infections. Experimentally, it is now possible to measure the extent of cycling for tetramer+CD8+T cells during the acute and memory phases of the host response to viruses. Dissection of the phenotypic, functional, and molecular diversity of CD8+T cell populations has been greatly facilitated. It is hoped it will also soon be possible to analyze CD4+T cell populations in this way. Though these are early days and there is an enormous amount to be done, our perceptions of the shape of virus-specific cell-mediated immunity are changing rapidly.
RANK-L and RANK: T Cells, Bone Loss, and Mammalian Evolution
Authors: Theill Lars E. , Boyle William J. , Penninger Josef M.
Published: July 2002

TNF and TNFR family proteins play important roles in the control of cell death, proliferation, autoimmunity, the function of immune cells, or the organogenesis of lymphoid organs. Recently, novel members of this large family have been identified that have critical functions in immunity and that couple lymphoid cells with other organ systems such as bone morphogenesis and mammary gland formation in pregnancy. The TNF-family molecule RANK-L (RANK-L, TRANCE, ODF) and its receptor RANK are key regulators of bone remodeling, and they are essential for the development and activation of osteoclasts. Intriguingly, RANK-L/RANK interactions also regulate T cell/dendritic cell communications, dendritic cell survival, and lymph node formation; T cell–derived RANK-L can mediate bone loss in arthritis and periodontal disease. Moreover, RANK-L and RANK are expressed in mammary gland epithelial cells, and they control the development of a lactating mammary gland during pregnancy and the propagation of mammalian species. Modulation of these systems provides us with a unique opportunity to design novel therapeutics to inhibit bone loss in arthritis, periodontal disease, and osteoporosis.
Harnessing the Power of the Placebo Effect and Renaming It “Remembered Wellness”
Authors: Benson, M.D Herbert , Friedman, Ph.D Richard
Published: July 2002

▪ Abstract  The placebo effect yields beneficial clinical results in 60–90% of diseases that include angina pectoris, bronchial asthma, herpes simplex, and duodenal ulcer. Three components bring forth the placebo effect: (a) positive beliefs and expectations on the part of the patient; (b) positive beliefs and expectations on the part of the physician or health care professional; and (c) a good relationship between the two parties. Because of the heavily negative connotations of the very words “placebo effect,” the term should be replaced by “remembered wellness.” Remembered wellness has been one of medicine's most potent assets and it should not be belittled or ridiculed. Unlike most other treatments, it is safe and inexpensive and has withstood the test of time.
Bacterial Vaginosis
Authors: Sobel Jack D.
Published: July 2002

▪ Abstract  Bacterial vaginosis represents a unique upheaval of the complex vaginal bacterial flora with disappearance of lactobacilli and overgrowth of Gardnerella vaginalis and resident anaerobic vaginal bacteria. Little progress has occurred in identifying causal factors, although the pathophysiology of this syndrome is better understood. Although symptoms are easily recognizable, obstetric and gynecologic complications continue to increase in number. Bacterial vaginosis is far more than a nuisance infection. Problems with diagnosis continue to dominate clinical practice, although new tests have been introduced. Therapeutic options have increased, although recurrent disease remains common, and management of this common complication constitutes a major challenge.
Advances in the Treatment of Lupus Nephritis
Authors: Zimmerman Robert , Radhakrishnan Jai , Valeri Anthony , Appel Gerald
Published: July 2002

▪ Abstract  Systemic lupus erythematosus (SLE) is an autoimmune disease that leads to the formation and deposition of immune complexes throughout the body, which are pathogenic for the disease. Different forms of glomerulonephritis can occur in patients with SLE and can contribute significantly to the associated morbidity and, ultimately, mortality from the disease. Over the past two decades, there have been significant strides in our understanding of the disease and in treatments that attempt to control the formation and deposition of anti-DNA auto-antibodies and immune complexes, as well as the subsequent inflammatory cascade mediated through various cellular and humoral pathways leading to progressive renal damage and end-stage renal disease. In this chapter, we review the current understanding of the pathogenesis and treatment of lupus nephritis in its various stages and discuss the experimental and human data regarding some of the potential newer forms of therapy. We discuss data regarding the use of steroids, azathioprine, cyclophosphamide, cyclosporine A, mycophenolate mofetil, gammaglobulin, plasmapheresis, LJP 394, flaxseed oil, bindarit, anti-CD40 ligand, and CTLA4Ig.
WHAT SIZE SHOULD A BACTERIUM BE? A Question of Scale
Authors: Koch Arthur L.
Published: July 2002

There are living prokaryotes (Bacteria and Archaea) that have cell sizes that range from 0.02–400 μm3. Over this tremendous range, various abilities to cope with the environment are needed. This review attempts to formulate some of the problems and some of the solutions. The smallest size for a free-living organism is suggested to be largely set by the catalytic efficiency of enzymes and protein synthetic machinery. Because of fluctuations in the environment, cells must maintain machinery to cope with various catastrophes; these mechanisms increase the minimum size of the cell. On the other hand, the largest cell is reasonably assumed to be limited by the ability of diffusion to bring nutrients to the appropriate part of the cell and to dispose of waste products. To explore the limitation imposed by diffusion, analysis is developed of diffusion processes through stirred and unstirred media, diffusion through media that contains obstacles, and the effect of size and shape.
Clostridial Toxins as Therapeutic Agents: Benefits of Nature's Most Toxic Proteins
Authors: Johnson Eric A.
Published: July 2002

▪ Abstract  Toxins are increasingly being used as valuable tools for analysis of cellular physiology, and some are used medicinally for treatment of human diseases. In particular, botulinum toxin, the most poisonous biological substance known, is used for treatment of a myriad of human neuromuscular disorders characterized by involuntary muscle contractions. Since approval of type-A botulinum toxin by the US Food and Drug Administration in December 1989 for three disorders (strabismus, blepharospasm, and hemifacial spasm), the number of indications being treated has increased greatly to include numerous focal dystonias, spasticity, tremors, cosmetic applications, migraine and tension headaches, and other maladies. Many of these diseases were previously refractory to pharmacological and surgical treatments. The remarkable therapeutic utility of botulinum toxin lies in its ability to specifically and potently inhibit involuntary muscle activity for an extended duration. The clostridia produce more protein toxins than any other bacterial genus and are a rich reservoir of toxins for research and medicinal uses. Research is underway to use clostridial toxins or toxin domains for drug delivery, prevention of food poisoning, and the treatment of cancer and other diseases. The remarkable success of botulinum toxin as a therapeutic agent has created a new field of investigation in microbiology.
Antigenic Variation at the Infected Red Cell Surface in Malaria
Authors: Kyes Sue , Horrocks Paul , Newbold Chris
Published: July 2002

▪ Abstract  Many pathogens that either rely on an insect vector to complete their life cycle (e.g., Trypanosoma spp. and Borrelia spp.) or exist in a unique ecological niche where transmission from host to host is sporadic (e.g., Neisseria spp.) have evolved strategies to maintain infection of their mammalian hosts for long periods of time in order to ensure their survival. Because they have to survive in the face of a fully functional immune system, a common feature of many of these organisms is their development of sophisticated strategies for immune evasion. For the above organisms and for malaria parasites of the genus Plasmodium, a common theme is the ability to undergo clonal antigenic variation. In all cases, surface molecules that are important targets of the humoral immune response are encoded in the genome as multicopy, nonallelic gene families. Antigenic variation is accomplished by the successive expression of members of these gene families that show little or no immunological cross-reactivity. In the case of malaria parasites, however, some of the molecules that undergo antigenic variation are also major virulence factors, adding an additional level of complication to the host-parasite interaction. In this review, we cover the history of antigenic variation in malaria and then summarize the more recent data with particular emphasis on Plasmodium falciparum, the etiological agent of the most severe form of human malaria.
CLONED POTASSIUM CHANNELS FROM EUKARYOTES AND PROKARYOTES
Authors: Jan Lily Yeh , Jan Yuh Nung
Published: July 2002

▪ Abstract  Potassium channels contribute to the excitability of neurons and signaling in the nervous system. They arise from multiple gene families including one for voltage-gated potassium channels and one for inwardly rectifying potassium channels. Features of potassium permeation, channel gating and regulation, and subunit interaction have been analyzed. Potassium channels of similar design have been found in animals ranging from jellyfish to humans, as well as in plants, yeast, and bacteria. Structural similarities are evident for the pore-forming α subunits and for the β subunits, which could potentially regulate channel activity according to the level of energy and/or reducing power of the cell.
TWO-PARTICLECORRELATIONS INRELATIVISTICHEAVY-IONCOLLISIONS
Authors: Heinz Ulrich , Jacak Barbara V.
Published: July 2002

▪ Abstract  Two-particle momentum correlations between pairs of identical particles produced in relativistic heavy-ion reactions can be analyzed to extract the space-time structure of the collision fireball. We review recent progress in the application of this method, based on newly developed theoretical tools and new high-quality data from heavy-ion collision experiments. Implications for our understanding of the collision dynamics and for the search for the quark-gluon plasma are discussed.
EMERGING ISSUES IN MICROBIOLOGICAL FOOD SAFETY
Authors: Meng J. , Doyle M. P.
Published: July 2002

▪ Abstract  Many microorganisms previously unrecognized as food-borne or harmful are emerging as human pathogens transmitted by food. This is a result of recent acquisition of key virulence factors, detection by newly developed isolation procedures, or astute detective-like laboratory skills of microbiologists. Six microbial pathogens, including Shiga toxin-producing Escherichia coli, Listeria monocytogenes, Arcobacter butzleri, Helicobacter pylori, Cryptosporidium parvum, and Cyclospora, have become recognized as significant causes of human illness. Although the ecology and epidemiology of illness caused by some of these pathogens have not been fully elucidated, food has the potential of being an important vehicle in their dissemination. Existing technologies and new approaches such as irradiation and hazard analysis critical control point (HACCP) programs are useful tools in the control of food-borne hazards. However, because of ever-changing products, processes, food-handling practices, societal habits, and pathogens, emerging food-borne diseases will continue to be an important public health concern.
CYCLIC AMP SIGNALING AND GENE REGULATION
Authors: Daniel Philip B. , Walker William H. , Habener Joel F.
Published: July 2002

▪ Abstract  Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger produced in cells in response to hormones and nutrients. The production of cAMP is dependent upon the actions of many different proteins that affect its synthesis and degradation. An important function of cAMP is to activate the phosphorylating enzyme, protein kinase A. The key roles of cAMP and protein kinase A in the phosphorylation and regulation of enzyme substrates involved in intermediary metabolism are well known. A newly discovered role for protein kinase A is in the phosphorylation and activation of transcription factors that are critical for the control of the transcription of genes in response to elevated levels of cAMP.
THE MOLECULAR BIOLOGY OF METAL ION TRANSPORT INSACCHAROMYCES CEREVISIAE
Authors: Eide David J.
Published: July 2002

▪ Abstract  Transition metals such as iron, copper, manganese, and zinc are essential nutrients. The yeast Saccharomyces cerevisiae is an ideal organism for deciphering the mechanism and regulation of metal ion transport. Recent studies of yeast have shown that accumulation of any single metal ion is mediated by two or more substrate-specific transport systems. High-affinity systems are active in metal-limited cells, whereas low-affinity systems play the predominant roles when the substrate is more abundant. Metal ion uptake systems of cells are tightly controlled, and both transcriptional and posttranscriptional regulatory mechanisms have been identified. Most importantly, studies of S. cerevisiae have identified a large number of genes that function in metal ion transport and have illuminated the existence and importance of gene families that play related roles in these processes in mammals.
DIETARYREGULATION OFEXPRESSION OFGLUCOSE-6-PHOSPHATEDEHYDROGENASE
Authors: Salati Lisa M , Amir-Ahmady Batoul
Published: July 2002

▪ Abstract  The family of enzymes involved in lipogenesis is a model system for understanding how a cell adapts to dietary energy in the form of carbohydrate versus energy in the form of triacylglycerol. Glucose-6-phosphate dehydrogenase (G6PD) is unique in this group of enzymes in that it participates in multiple metabolic pathways: reductive biosynthesis, including lipogenesis; protection from oxidative stress; and cellular growth. G6PD activity is enhanced by dietary carbohydrates and is inhibited by dietary polyunsaturated fats. These changes in G6PD activity are a consequence of changes in the expression of the G6PD gene. Nutrients can regulate the expression of genes at both transcriptional and posttranscriptional steps. Most lipogenic enzymes undergo large changes in the rate of gene transcription in response to dietary changes; however, G6PD is regulated at a step subsequent to transcription. This step is involved in the rate of synthesis of the mature mRNA in the nucleus, specifically regulation of the efficiency of splicing of the nascent G6PD transcript. Understanding the mechanisms by which nutrients alter nuclear posttranscriptional events will help uncover new information on the breadth of mechanisms involved in gene regulation.
What Are Preschool Children Eating? A Review of Dietary Assessment
Authors: Serdula Mary K , Alexander Maria P , Scanlon Kelley S , Bowman Barbara A
Published: July 2002

Accurate assessment of dietary intake among preschool-aged children is important for clinical care and research, for nutrition monitoring and evaluating nutrition interventions, and for epidemiologic research. We identified 25 studies published between January 1976 and August 2000 that evaluated the validity of food recalls (n = 12), food frequency questionnaires (n = 9), food records (n = 2), or other methods (n = 2). We identified four studies that evaluated the reproducibility of food frequency questionnaires. Validity studies varied in validation standard and study design, making comparisons between studies difficult. In general, food frequency questionnaires overestimated total energy intake and were better at ranking, than quantifying, nutrient intake. Compared with the validation standard, food recalls both overestimated and underestimated energy intake. When choosing a method to estimate diet, both purpose of the assessment and practicality of the method must be considered, in addition to the validity and reproducibility reported in the scientific literature.
THEROLE OFVITAMINAINMAMMALIANREPRODUCTION ANDEMBRYONICDEVELOPMENT
Authors: Clagett-Dame Margaret , DeLuca Hector F.
Published: July 2002

▪ Abstract  Since the late 1980s, there has been an explosion of information on the molecular mechanisms and functions of vitamin A. This review focuses on the essential role of vitamin A in female reproduction and embryonic development and the metabolism of vitamin A (retinol) that results in these functions. Evidence strongly supports that in situ–generated all-trans retinoic acid (atRA) is the functional form of vitamin A in female reproduction and embryonic development. This is supported by the ability to reverse most reproductive and developmental blocks found in vitamin A deficiency with atRA, the block in embryonic development that occurs in retinaldehyde dehydrogenase type 2 null mutant mice, and the essential roles of the retinoic acid receptors, at least in embryogenesis.

Early studies of embryos from marginally vitamin A–deficient (VAD) pregnant rats revealed a collection of defects called the vitamin A–deficiency syndrome. The manipulation of all-trans retinoic acid (atRA) levels in the diet of VAD female rats undergoing a reproduction cycle has proved to be an important new tool in deciphering the points of atRA function in early embryos and has provided a means to generate large numbers of embryos at later stages of development with the vitamin A–deficiency syndrome. The essentiality of the retinoid receptors in mediating the activity of atRA is exemplified by the many compound null mutant embryos that now recapitulate both the original vitamin A–deficiency syndrome and exhibit a host of new defects, many of which can also be observed in the VAD-atRA-supported rat embryo model and in retinaldehyde dehydrogenase type 2 (RALDH2) mutant mice. A major task for the future is to elucidate the atRA-dependent pathways that are normally operational in vitamin A–sufficient animals and that are perturbed in deficiency, thus leading to the characteristic VAD phenotypes described above.
BIOCHEMICAL, CELLULAR, AND PHARMACOLOGICAL ASPECTS OF THE MULTIDRUG TRANSPORTER
Authors: Ambudkar Suresh V. , Dey Saibal , Hrycyna Christine A. , Ramachandra Muralidhara , Pastan Ira , Gottesman Michael M.
Published: July 2002

▪ Abstract  Considerable evidence has accumulated indicating that the multidrug transporter or P-glycoprotein plays a role in the development of simultaneous resistance to multiple cytotoxic drugs in cancer cells. In recent years, various approaches such as mutational analyses and biochemical and pharmacological characterization have yielded significant information about the relationship of structure and function of P-glycoprotein. However, there is still considerable controversy about the mechanism of action of this efflux pump and its function in normal cells. This review summarizes current research on the structure-function analysis of P-glycoprotein, its mechanism of action, and facts and speculations about its normal physiological role.
Drug Discovery in the Next Millennium
Authors: Ohlstein Eliot H. , Ruffolo Jr Robert R. , Elliott John D.
Published: July 2002

Selection and validation of novel molecular targets have become of paramount importance in light of the plethora of new potential therapeutic drug targets that have emerged from human gene sequencing. In response to this revolution within the pharmaceutical industry, the development of high-throughput methods in both biology and chemistry has been necessitated. This review addresses these technological advances as well as several new areas that have been created by necessity to deal with this new paradigm, such as bioinformatics, cheminformatics, and functional genomics. With many of these key components of future drug discovery now in place, it is possible to map out a critical path for this process that will be used into the new millennium.
Pharmacogenomics: Unlocking the Human Genome for Better Drug Therapy
Authors: McLeod Howard L , Evans William E
Published: July 2002

There is great heterogeneity in the way humans respond to medications, often requiring empirical strategies to find the appropriate drug therapy for each patient (the “art” of medicine). Over the past 50 years, there has been great progress in understanding the molecular basis of drug action and in elucidating genetic determinants of disease pathogenesis and drug response. Pharmacogenomics is the burgeoning field of investigation that aims to further elucidate the inherited nature of interindividual differences in drug disposition and effects, with the ultimate goal of providing a stronger scientific basis for selecting the optimal drug therapy and dosages for each patient. These genetic insights should also lead to mechanism-based approaches to the discovery and development of new medications. This review highlights the current status of work in this field and addresses strategies that hold promise for future advances in pharmacogenomics.
Molecular Basis of Environmentally Induced Birth Defects
Authors: Finnell Richard H. , Waes Janée Gelineau-van , Eudy James D. , Rosenquist Thomas H.
Published: July 2002

Exposure of the developing conceptus to selected environmental agents can lead to deleterious and often times lethal birth defects. These malformations result in serious emotional and financial consequences to families and societies worldwide. As we continue to progress technologically, we face challenges from the introduction of new pharmacological agents and chemical compounds into the environment. This results in a concomitant need to more fully understand the relationship between in utero exposure to environmental teratogens and the risk of congenital malformations. The goal of this review is to provide a current perspective of the major concepts related to the molecular basis of environmentally induced birth defects. Starting with a discussion of commonly occurring birth defects, we consider important fundamental facets of embryonic development, teratology, and gene-environment interactions. The review then summarizes our current understanding of the molecular mechanisms involved in selected birth defects following exposure to pharmacological compounds, including thalidomide, retinoids, and valproic acid. Understanding these signaling pathways may lead to the development of safer pharmaceutical compounds and a reduction in the number of infants born with preventable birth defects.
MOLECULAR ELECTRONIC SPECTRAL BROADENING IN LIQUIDS AND GLASSES
Authors: Myers Anne B.
Published: July 2002

▪ Abstract  The magnitudes, time scales, and underlying mechanisms responsible for broadening the electronic spectra of molecules in liquid solutions and glasses are reviewed. The emphasis is on experimental results from hole-burning, single-molecule, photon echo, and resonance Raman and fluorescence studies. The influence of the time scale of the measurement in distinguishing between homogeneous broadening (electronic dephasing) and inhomogeneous broadening is discussed, and the role of coupling of solvent phonons to the solute's electronic transition is stressed.
INWARD RECTIFIER POTASSIUM CHANNELS
Authors: Nichols C. G. , Lopatin A. N.
Published: July 2002

▪ Abstract  The past three years have seen remarkable progress in research on the molecular basis of inward rectification, with significant implications for basic understanding and pharmacological manipulation of cellular excitability. Expression cloning of the first inward rectifier K channel (Kir) genes provided the necessary breakthrough that has led to isolation of a family of related clones encoding channels with the essential functional properties of classical inward rectifiers, ATP-sensitive K channels, and muscarinic receptor-activated K channels. High-level expression of cloned channels led to the discovery that classical inward so-called anomalous rectification is caused by voltage-dependent block of the channel by polyamines and Mg2+ ions, and it is now clear that a similar mechanism results in inward rectification of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-kainate receptor channels. Knowledge of the primary structures of Kir channels and the ability to mutate them also has led to the determination of many of the structural requirements of inward rectification.
Lung Development and Function in Preterm Infants in the Surfactant Treatment Era
Authors: Jobe Alan H. , Ikegami Machiko
Published: July 2002

▪ Abstract  Mortality of infants of <1-kg birth weight has decreased because of surfactant treatments, antenatal glucocorticoid treatments, and new ventilation strategies. However, many of these infants develop a chronic lung disease characterized by an arrest of lung development and interference with alveolarization. Antenatal glucocorticoids can induce early lung maturation clinically, but new information from transgenic and other experimental models indicates that traditional explanations for glucocorticoid effects on the developing lung are inadequate. These very preterm infants have lungs with small lung gas volumes and delicate lung tissue that are susceptible to injury with the initiation of ventilation and subsequent ventilation. Antenatal proinflammatory exposures are frequent in very preterm infants, and postnatal injury is associated with elevations of proinflammatory cytokines in the lungs. One hypothesis is that proinflammatory cytokines can promote or interfere with lung development as well as promote lung injury. Mechanisms of lung injury being characterized in the adult lung may have unique characteristics in the developing lung.
Intracellular Transport Mechanisms of Signal Transducers
Authors: Dorn Gerald W. , Mochly-Rosen Daria
Published: July 2002

▪ Abstract  Recent discoveries have revolutionized our conceptions of enzyme-substrate specificity in signal transduction pathways. Protein kinases A and C are localized to discreet subcellular regions, and this localization changes in an isozyme-specific manner upon activation, a process referred to as translocation. The mechanisms for translocation involve interactions of soluble kinases with membrane-bound anchor proteins that recognize individual kinase isoenzymes and their state of activation. Recently, modulation of kinase-anchor protein interactions has been used to specifically regulate, positively or negatively, the activity of C kinase isozymes. Also described in this review is a role for the Rab family of small G proteins in regulating subcellular protein trafficking. The pathophysiological significance of disrupted subcellular protein transport in cell signaling and the potential therapeutic utility of targeted regulation of these events are in the process of being characterized.
FUNGAL TRANSMISSION OF PLANT VIRUSES
Authors: Campbell R. N.
Published: July 2002

▪ Abstract  Thirty soilborne viruses or virus-like agents are transmitted by five species of fungal vectors. Ten polyhedral viruses, of which nine are in the family Tombusviridae, are acquired in the in vitro manner and do not occur within the resting spores of their vectors, Olpidium brassicae and O. bornovanus. Fungal vectors for other viruses in the family should be sought even though tombusviruses are reputed to be soil transmitted without a vector. Eighteen rod-shaped viruses belonging to the furo- and bymovirus groups and to an unclassified group are acquired in the in vivo manner and survive within the resting spores of their vector, O. brassicae, Polymyxa graminis, P. betae, and Spongospora subterranea. The viral coat protein has an essential role in in vitro transmission. With in vivo transmission a site in the coat protein-read through protein (CP-RT) of beet necrotic yellow vein furovirus determines vector transmissibility as does a site in a similar 98-kDa polyprotein of barley mild mosaic bymovirus. The mechanisms by which virions move (or are moved) into and out of the protoplasm of zoospores or of thalli needs study.
Epidemiology of Wheat Leaf and Stem Rust in the Central Great Plains of the USA
Authors: Eversmeyer M. G. , Kramer C. L.
Published: July 2002

Wheat (Triticum aestivum L) is grown throughout the grasslands from southern Mexico into the prairie provinces of Canada, a distance of nearly 4200 km. The total area seeded to wheat varies considerably each year; however, from 28 to 32 million ha are planted in the Great Plains of the United States alone. Generally in the central Great Plains, an area from central Texas through central Nebraska, 15 million ha are seeded to winter wheat each year. A wide range of environmental conditions exist throughout this area that may affect the development and final severity of wheat leaf rust (caused by Puccinia triticina L), stripe rust (caused by P. striiformis), and stem rust (caused by P. graminis Pers. f. sp tritici) epidemics and the subsequent reduction in wheat yields. Variation in severity of rust epidemics in this area depends on differences in crop maturity at the time of infection by primary inoculum, host resistance used, and environmental conditions. The interrelationships among time, host, pathogen and environment are complex, and studying the interactions is very difficult. Historically, cultivars with new or different leaf rust resistance genes become ineffective after several years of large-scale production within the Great Plains, and then cultivars carrying new or different resistance genes must be developed and released into production. This is the typical “boom and bust” cycle of the cereal rust resistance genes in the central Great Plains.
DIVERSITY OF THEBURKHOLDERIA CEPACIACOMPLEX ANDIMPLICATIONS FORRISKASSESSMENT OFBIOLOGICALCONTROLSTRAINS
Authors: Parke Jennifer L. , Gurian-Sherman Doug
Published: July 2002

▪ Abstract  The Burkholderia cepacia complex (Bcc) consists of several species of closely related and extremely versatile gram-negative bacteria found naturally in soil, water, and the rhizosphere of plants. Strains of Bcc have been used in biological control of plant diseases and bioremediation, while some strains are plant pathogens or opportunistic pathogens of humans with cystic fibrosis. The ecological versatility of these bacteria is likely due to their unusually large genomes, which are often comprised of several (typically two or three) large replicons, as well as their ability to use a large array of compounds as sole carbon sources. The original species B. cepacia has been split into eight genetic species (genomovars), including five named species, but taxonomic distinctions have not enabled biological control strains to be clearly distinguished from human pathogenic strains. This has led to a reassessment of the risk of several strains registered by the U.S. Environmental Protection Agency for biological control. We review the biology of Bcc bacteria, especially how our growing knowledge of Bcc ecology and pathogenicity might be used in risk assessment. The capability of this bacterial complex to cause disease in plants and humans, as well as to control plant diseases, affords a rare opportunity to explore traits that may function in all three environments.
MOLECULAR DETERMINANTS OF RHIZOSPHERE COLONIZATION BY PSEUDOMONAS
Authors: Lugtenberg Ben J. J. , Dekkers Linda , Bloemberg Guido V.
Published: July 2002

▪ Abstract  Rhizosphere colonization is one of the first steps in the pathogenesis of soilborne microorganisms. It can also be crucial for the action of microbial inoculants used as biofertilizers, biopesticides, phytostimulators, and bioremediators. Pseudomonas, one of the best root colonizers, is therefore used as a model root colonizer. This review focuses on (a) the temporal-spatial description of root-colonizing bacteria as visualized by confocal laser scanning microscopal analysis of autofluorescent microorganisms, and (b) bacterial genes and traits involved in root colonization. The results show a strong parallel between traits used for the colonization of roots and of animal tissues, indicating the general importance of such a study. Finally, we identify several noteworthy areas for future research.
Parenting and its Effects on Children: On Reading and Misreading Behavior Genetics
Authors: Maccoby Eleanor E.
Published: July 2002

There is clear evidence that parents can and do influence children. There is equally clear evidence that children’s genetic makeup affects their own behavioral characteristics, and also influences the way they are treated by their parents. Twin and adoption studies provide a sound basis for estimating the strength of genetic effects, although heritability estimates for a given trait vary widely across samples, and no one estimate can be considered definitive. This chapter argues that knowing only the strength of genetic factors, however, is not a sufficient basis for estimating environmental ones and indeed, that attempts to do so can systematically underestimate parenting effects. Children’s genetic predispositions and their parents’ childrearing regimes are seen to be closely interwoven, and the ways in which they function jointly to affect children’s development are explored.
Mass Media Effects on Violent Behavior
Authors: Felson Richard B.
Published: July 2002

The literature on the effect of exposure to media violence (including exposure to violent pornography) on aggressive behavior is critically reviewed. Evidence and theoretical arguments regarding short-term and long-term effects are discussed. Three points are emphasized: 1. Exposure to violence in laboratory and field experiments is as likely to affect nonaggressive antisocial behavior as it does aggressive behavior. The pattern is consistent with a sponsor effect rather than a modeling effect: an experimenter who shows violent films creates a permissive atmosphere; 2. the message that is learned from the media about when it is legitimate to use violence is not much different from the message learned from other sources, with the exception that illegitimate violence is more likely to be punished in media presentations; 3. the fact that violent criminals tend to be versatile—they commit nonviolent crimes as well—is inconsistent with explanations that emphasize proviolence socialization (from the media or other sources). I conclude that exposure to television violence probably does have a small effect on violent behavior for some viewers, possibly because the media directs viewer's attention to novel forms of violent behavior that they would not otherwise consider.
The Choice-Within-Constraints New Institutionalism and Implications for Sociology
Authors: Ingram Paul , Clay Karen
Published: July 2002

The variant of new institutionalism that is our focus is a pan-disciplinary theory that asserts that actors pursue their interests by making choices within institutional constraints. We organize our review of the theory around its behavioral assumptions, the operation of institutional forms, and processes of institutional change. At each stage, we give particular attention to the potential contributions of sociology to the theory. The behavioral assumptions of the theory amount to bounded rationality and imply transaction costs, which, in the absence of institutions, may frustrate collective ends. The principle weakness of these behavioral assumptions is a failure to treat preferences as endogenous. We categorize the institutions that arise in response to transaction costs as to whether they are public or private in their source and centralized or decentralized in their making. In detailing the resulting categories of institutional forms, we identify key interdependencies across the public/private and centralized/decentralized dimensions. The new institutionalism is in particular need of better theory about private decentralized institutions, and theorists could turn to embeddedness theory and cognitive new-institutional theory as a source of help on this topic. The dominant view of institutional change is that it is evolutionary, driven by organizational competition, and framed by individual beliefs and shared understandings. Sociology can refine the change theory by adding better explanations of the behavior of organizations, and of the processes by which institutional alternatives come to be viewed as acceptable or unacceptable.
Efficacy and Safety of Ezetimibe Coadministered With Atorvastatin or Simvastatin in Patients With Homozygous Familial Hypercholesterolemia
Authors: Gagné Claude , Gaudet Daniel , Bruckert Eric
Published: July 2002

Background

—

Patients with homozygous familial hypercholesterolemia (HoFH) have a high incidence of cardiovascular morbidity and mortality from premature atherosclerosis, and the efficacy of pharmacological therapy has been limited. We evaluated the efficacy, safety, and tolerability of ezetimibe, a novel cholesterol absorption inhibitor, in a multicenter, double-blind, randomized trial of HoFH patients receiving atorvastatin or simvastatin.

Methods and Results

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Fifty patients with a diagnosis of HoFH on the National Cholesterol Education Program Step 1 or stricter diet and taking open-label atorvastatin 40 mg/d or simvastatin 40 mg/d (statin-40) with (n=25) or without (n=25) concomitant LDL apheresis were randomized to 1 of 3 double-blind treatments: atorvastatin or simvastatin 80 mg/d (statin-80, n=17); ezetimibe 10 mg/d plus atorvastatin or simvastatin 40 mg/d (n=16); or ezetimibe 10 mg/d plus atorvastatin or simvastatin 80 mg/d (n=17) for 12 weeks. The primary end point was mean percentage change in LDL cholesterol (LDL-C) from statin-40 baseline to the end point for patients receiving statins alone (statin-80) versus patients receiving ezetimibe plus atorvastatin or simvastatin at either dose (ezetimibe plus statin-40/80). Ezetimibe plus statin-40/80 significantly reduced LDL-C levels compared with statin-80 (−20.7% versus −6.7%,
P
=0.007). In the high-dose statin cohorts, ezetimibe plus statin-80 reduced LDL-C by an additional 20.5% (
P
=0.0001) versus statin-80. Similar significant reductions in LDL-C concentrations were observed for patients with genotype-confirmed HoFH (n=35). Ezetimibe was safe and well tolerated.

Conclusions

—

Ezetimibe coadministered with atorvastatin or simvastatin in patients with HoFH produced clinically important LDL-C reductions compared with best current therapy. Ezetimibe provides a new, complementary pharmacological approach for this high-risk population.
Overexpression of Interleukin-10 by Activated T Lymphocytes Inhibits Atherosclerosis in LDL Receptor–Deficient Mice by Altering Lymphocyte and Macrophage Phenotypes
Authors: Pinderski Laura J. , Fischbein Michael P. , Subbanagounder Ganesamoorthy , Fishbein Michael C. , Kubo Nobuhiko , Cheroutre Hilde , Curtiss Linda K. , Berliner Judith A. , Boisvert William A.
Published: July 2002

Previous studies demonstrated that interleukin-10 (IL-10) overexpression decreases formation of early fatty-streak lesions in mice independent of lipoprotein levels. The present studies, using bone marrow transplantation, demonstrate that overexpression of IL-10 by T cells inhibits advanced atherosclerotic lesions in LDL receptor–null mice fed an atherogenic diet. In mice receiving bone marrow from the IL-10 transgenic mice compared with those receiving wild-type marrow, there was a 47% decrease in lesion size and a marked decrease in lesion complexity with an 80% reduction in the necrotic core. Accumulation of cholesterol and phospholipid oxidation products in the aorta was decreased by 50% to 80%, unrelated to plasma lipid or IL-10 levels. Our studies also provide insight into the mechanism of the IL-10–mediated decrease in lesion size. Although a strong influence toward a Th1 phenotype has previously been demonstrated in atherosclerotic models, T lymphocytes in the IL-10 transgenic (Tg) group revealed a marked shift to a Th2 phenotype, with decreased IFN-γ production and an increase in IL-10. Evaluation of specific immunoglobulin subclasses demonstrated a preponderance of IgG
1
isotype, characteristic of a Th2 influence on B cell immunoglobulin class-switching in the IL-10 Tg group. A major finding of these studies was altered monocyte/macrophage function in the IL-10 Tg group. Monocytes showed a decrease in activation resulting in decreased expression of IFN-γ. Furthermore, macrophage foam cells within lesions of the IL-10 Tg group exhibited markedly decreased apoptosis. These studies demonstrate that T lymphocyte IL-10 can influence the function of other immune cells to reduce the development of advanced atherosclerotic lesions in mice.
Trust and Cooperation Through Agent-specific Punishments
Authors: McGillivray Fiona , Smith Alastair
Published: July 2002

Using the infinitely repeated prisoners' dilemma game as a modeling platform, we examine how domestic political institutions affect the ability of nations to trust and cooperate with each other. We propose a strategy, the agent-specific grim trigger, in which national leaders direct punishments for past defections at the leader of the nation responsible rather than at the nation itself. Leaders refuse to cooperate with those leaders who have cheated them in the past. However, by being prepared to cooperate with new leaders, cooperation can be restored. The focus of punishment on specific agents of the people (leaders), rather than the nation itself, means that citizens want to remove leaders who defect. Hence, domestically accountable leaders pay audience costs for failing to cooperate. These costs make accountable leaders more trustworthy and foster greater cooperation. In contrast, when replacing leaders is difficult, cooperation is less robust; and once cooperation falters, agent-specific punishment policies often lead to prolonged hostilities and periods of acrimonious relations between states.