bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of activity during early postnatal development on motor unit size
Authors: Vrbová G , Lowrie M B
Published: November 2004

At early stages of neuromuscular development, motor unit territory is expanded, with each muscle fibre being supplied by several axons. During postnatal development, some synapses are eliminated, motor unit size decreases, and the adult distribution of motor unit sizes emerges. This process depends on activity, since it proceeds more rapidly when the nerve is activated and is slower when activity is reduced. Here we studied whether, in addition to influencing the rate of retraction of motor unit territory, activity during the critical period of development affects the final outcome of the distribution of motor unit sizes. The sciatic nerve of 8- to 12-day-old rats was stimulated daily. One week later the tension of the extensor digitorum longus muscle and that of its individual motor units was recorded. The sizes of individual motor units were calculated and compared with those from animals that received no stimulation. The distribution of motor unit sizes from stimulated muscles was not significantly different from those from control muscles. Therefore, we conclude that although activity increases the rate at which motor units attain their adult size, it does not influence the final outcome of motor unit size distribution.Key words: motor unit, electrical stimulation, postnatal development, polyneuronal elimination.
ENTROPY OF HORIZONS, COMPLEX PATHS AND QUANTUM TUNNELLING
Authors: PADMANABHAN T.
Published: November 2004

In any spacetime, it is possible to have a family of observers following a congruence of timelike curves such that they do not have access to part of the spacetime. This lack of information suggests associating a (congruence dependent) notion of entropy with the horizon that blocks the information from these observers. While the blockage of information is absolute in classical physics, quantum mechanics will allow tunnelling across the horizon. This process can be analyzed in a simple, yet general, manner and we show that the probability for a system with energy E to tunnel across the horizon is P(E)∝ exp [-(2π/κ)E) where κ is the surface gravity of the horizon. If the surface gravity changes due to the leakage of energy through the horizon, then one can associate an entropy S(M) with the horizon where dS=[2π/κ(M)]dM and M is the active gravitational mass of the system. The implications are discussed.
THE EFFECT OF VERY LOW ENERGY SOLAR NEUTRINOS ON THE MSW MECHANISM
Authors: ESPOSITO S.
Published: November 2004

We study some implications on standard matter oscillations of solar neutrinos induced by a background of extremely low energy thermal neutrinos trapped inside the Sun by means of coherent refractive interactions. Possible experimental tests are envisaged and current data on solar neutrinos detected at Earth are briefly discussed.
D-INSTANTON SUMS FOR MATTER HYPERMULTIPLETS
Authors: KETOV SERGEI V. , SANTILLAN OSVALDO P. , ZORIN ANDREI G.
Published: November 2004

We calculate some nonperturbative (D-instanton) quantum corrections to the moduli space metric of several (n>1) identical matter hypermultiplets for the type-IIA superstrings compactified on a Calabi–Yau threefold, near conifold singularities. We find a nontrivial deformation of the (real) 4n-dimensional hypermultiplet moduli space metric due to the infinite number of D-instantons, under the assumption of n tri-holomorphic commuting isometries of the metric, in the hyper-Kähler limit (i.e. in the absence of gravitational corrections).
LONG MEMORY IN STOCK TRADING
Authors: LEONIDOV ANDREI
Published: November 2004

Using a relationship between the moments of the probability distribution of times between the two consecutive trades (intertrade time distribution) and the moments of the distribution of a daily number of trades, we show that the underlying point process is essentially non-Markovian. A detailed analysis of all trades in the EESR stock on the Moscow International Currency Exchange in the period January 2003–September 2003, including correlation between intertrade time intervals is presented. A power-law decay of the correlation function provides an additional evidence of the long-memory nature of the series of times of trades. A data set including all trades in Siemens, Commerzbank and Karstadt stocks traded on the Xetra electronic stock exchange of Deutsche Boerse in October 2002 is also considered.
A History of Clinical Psychology as a Profession in America (and a Glimpse at Its Future)
Authors: Benjamin Ludy T.
Published: November 2004

Clinical psychology emerged as a profession in the United States in the 1890s with studies conducted by psychologists with patients in the mental asylums of that time, and with the founding of Witmer's psychological clinic, where he treated children with learning and behavioral problems. This chapter traces the history of clinical psychology as a profession, from the focus on assessment at the turn of the twentieth century to the provision of psychotherapy that would come to dominate the field after World War II. It concludes with a discussion of some of the contemporary concerns in the profession and how those might impact the future practice of clinical psychologists.
Cognitive Vulnerability to Emotional Disorders
Authors: Mathews Andrew , MacLeod Colin
Published: November 2004

A review of recent research on cognitive processing indicates that biases in attention, memory, and interpretation, as well as repetitive negative thoughts, are common across emotional disorders, although they vary in form according to type of disorder. Current cognitive models emphasize specific forms of biased processing, such as variations in the focus of attention or habitual interpretative styles that contribute to the risk of developing particular disorders. As well as predicting risk of emotional disorders, new studies haveprovided evidence of a causal relationship between processing bias and vulnerability. Beyond merely demonstrating the existence of biased processing, research is thus beginning to explore the cognitive causes of emotional vulnerability, and their modification.
Stress and Depression
Authors: Hammen Constance
Published: November 2004

Improved methods of assessment and research design have established a robust and causal association between stressful life events and major depressive episodes. The chapter reviews these developments briefly and attempts to identify gaps in the field and new directions in recent research. There are notable shortcomings in several important topics: measurement and evaluation of chronic stress and depression; exploration of potentially different processes of stress and depression associated with first-onset versus recurrent episodes; possible gender differences in exposure and reactivity to stressors; testing kindling/sensitization processes; longitudinal tests of diathesis-stress models; and understanding biological stress processes associated with naturally occurring stress and depressive outcomes. There is growing interest in moving away from unidirectional models of the stress-depression association, toward recognition of the effects of contexts and personal characteristics on the occurrence of stressors, and on the likelihood of progressive and dynamic relationships between stress and depression over time—including effects of childhood and lifetime stress exposure on later reactivity to stress.
The Evolutionary Ecology of Novel Plant-Pathogen Interactions
Authors: Parker Ingrid M. , Gilbert Gregory S.
Published: November 2004

▪ Abstract  Novel plant-pathogen combinations occur whenever pathogen or plant species are introduced to regions outside their native range. Whether a pathogen is able to acquire a new host depends on the genetic compatibility between the two, through either preadaptation of the pathogen or subsequent evolutionary change. The ecological outcome of the novel interaction—for example, a spreading disease epidemic or the extinction of an incipient plant invasion—depends on the life history of the pathogen, opportunities for rapid evolution of virulence or resistance, and the presence of a suitable environment. We review recent work on the biology of pathogen virulence and host resistance, their mechanisms, and their costs. We then explore factors influencing the ecological and evolutionary dynamics of novel plant-pathogen interactions, using that evolutionary ecology framework to provide insight into three important practical applications: emerging diseases, biological invasions, and biological control.
Mutualisms and Aquatic Community Structure: The Enemy of My Enemy Is My Friend
Authors: Hay Mark E. , Parker John D. , Burkepile Deron E. , Caudill Christopher C. , Wilson Alan E. , Hallinan Zachary P. , Chequer Alexander D.
Published: November 2004

▪ Abstract  Mutualisms occur when interactions between species produce reciprocal benefits. However, the outcome of these interactions frequently shifts from positive, to neutral, to negative, depending on the environmental and community context, and indirect effects commonly produce unexpected mutualisms that have community-wide consequences. The dynamic, and context dependent, nature of mutualisms can transform consumers, competitors, and parasites into mutualists, even while they consume, compete with, or parasitize their partner species. These dynamic, and often diffuse, mutualisms strongly affect community organization and ecosystem processes, but the historic focus on pairwise interactions decoupled from their more complex community context has obscured their importance. In aquatic systems, mutualisms commonly support ecosystem-defining foundation species, underlie energy and nutrient dynamics within and between ecosystems, and provide mechanisms by which species can rapidly adjust to ecological variance. Mutualism is as important as competition, predation, and physical disturbance in determining community structure, and its impact needs to be adequately incorporated into community theory.
Are Diseases Increasing in the Ocean?
Authors: Lafferty Kevin D. , Porter James W. , Ford Susan E.
Published: November 2004

▪ Abstract  Many factors (climate warming, pollution, harvesting, introduced species) can contribute to disease outbreaks in marine life. Concomitant increases in each of these makes it difficult to attribute recent changes in disease occurrence or severity to any one factor. For example, the increase in disease of Caribbean coral is postulated to be a result of climate change and introduction of terrestrial pathogens. Indirect evidence exists that (a) warming increased disease in turtles; (b) protection, pollution, and terrestrial pathogens increased mammal disease; (c) aquaculture increased disease in mollusks; and (d) release from overfished predators increased sea urchin disease. In contrast, fishing and pollution may have reduced disease in fishes. In other taxa (e.g., sea grasses, crustaceans, sharks), there is little evidence that disease has changed over time. The diversity of patterns suggests there are many ways that environmental change can interact with disease in the ocean.
ECOLOGY OF INTERACTIONS BETWEEN WEEDS AND ARTHROPODS
Authors: Norris Robert F. , Kogan Marcos
Published: November 2004

▪ Abstract  Weeds and arthropods interact in agricultural systems. Weeds can directly serve as food sources or provide other ecosystem resources for herbivorous arthropods, and indirectly serve carnivorous (beneficial) arthropods by providing food and shelter to their prey. Weeds can serve as alternative hosts for pest and beneficial arthropods when their preferred crop host is absent. Herbivory on crops by pest arthropods reduces the competitive ability of crop plants, leading to increased weed growth. Interactions between weeds and arthropods have several implications to integrated pest management (IPM). Pest and beneficial arthropod populations can be maintained in the absence of crop hosts. This statement also applies to all other pests that use weeds as a food source, including pathogens, nematodes, mollusks, and vertebrates. Weeds outside crop fields that maintain overwintering populations of arthropod pests are the major reason for the development of area-wide IPM programs for certain mobile arthropod pests. Weeds can serve as a source of increased diversity in agroecosystems. Increased diversity has been the rationale for enhancing biological control of arthropod pests through habitat management. The consequences of such approaches are difficult to predict on a multispecies IPM basis.
FOLSOMIA CANDIDA(COLLEMBOLA): A “Standard” Soil Arthropod
Authors: Fountain Michelle T. , Hopkin Steve P.
Published: November 2004

▪ Abstract  Folsomia candida Willem 1902, a member of the order Collembola (colloquially called springtails), is a common and widespread arthropod that occurs in soils throughout the world. The species is parthenogenetic and is easy to maintain in the laboratory on a diet of granulated dry yeast. F. candida has been used as a “standard” test organism for more than 40 years for estimating the effects of pesticides and environmental pollutants on nontarget soil arthropods. However, it has also been employed as a model for the investigation of numerous other phenomena such as cold tolerance, quality as a prey item, and effects of microarthropod grazing on pathogenic fungi and mycorrhizae of plant roots. In this comprehensive review, aspects of the life history, ecology, and ecotoxicology of F. candida are covered. We focus on the recent literature, especially studies that have examined the effects of soil pollutants on reproduction in F. candida using the protocol published by the International Standards Organization in 1999.
CHEMICAL ECOLOGY OF LOCUSTS AND RELATED ACRIDIDS
Authors: Hassanali Ahmed , Njagi Peter G.N. , Bashir Magzoub Omer
Published: November 2004

▪ Abstract  The results and insights from recent research on the chemical ecology of polymorphic acridids are reviewed. Many of the new findings come from studies on the desert locust, Schistocerca gregaria, which has continued to be the primary research insect in most laboratories. Earlier confusion between stimuli associated with phase change and social cohesion has been resolved. The roles of chemotactile and olfactory cues together with tactile and visual stimuli in key locust processes, comprising gregarization, social cohesion, synchronous maturation, mating, oviposition, and maternal transfer of gregarious character, are better understood. Some of the key pheromones of the gregarious phase have been characterized. Chemical communication is also shown to be important in the life style of the solitarious phase. The behavioral pattern and responses of this phase reflect a strong propensity of the species to exploit opportunities under appropriate conditions to form or join the crowd and to gregarize. Outstanding questions are highlighted.
THE EVOLUTION OF COTTON PEST MANAGEMENT PRACTICES IN CHINA
Authors: Wu K.M. , Guo Y.Y.
Published: November 2004

▪ Abstract  The development of cotton pest management practices in China has followed a pattern seen for many crops that rely heavily on insecticides. Helicoverpa armigera resistance to chemical pesticides resulted in the unprecedented pest densities of the early 1990s. Transgenic cotton that expresses a gene derived from the bacterium Bacillus thuringiensis (Bt) has been deployed for combating H. armigera since 1997. The pest management tactics associated with Bt cotton have resulted in a drastic reduction in insecticide use, which usually results in a significant increase in populations of beneficial insects and thus contributes to the improvement of the natural control of some pests. Risk assessment analyses show that the natural refuges derived from the mixed-planting system of cotton, corn, soybean, and peanut on small-scale, single-family-owned farms play an important function in delaying evolution of cotton bollworm resistance, and that no trend toward Bt cotton resistance has been apparent despite intensive planting of Bt cotton over the past several years.
ECOLOGICAL, BEHAVIORAL, AND BIOCHEMICAL ASPECTS OF INSECT HYDROCARBONS
Authors: Howard Ralph W. , Blomquist Gary J.
Published: November 2004

▪ Abstract  This review covers selected literature from 1982 to the present on some of the ecological, behavioral, and biochemical aspects of hydrocarbon use by insects and other arthropods. Major ecological and behavioral topics are species- and gender-recognition, nestmate recognition, task-specific cues, dominance and fertility cues, chemical mimicry, and primer pheromones. Major biochemical topics include chain length regulation, mechanism of hydrocarbon formation, timing of hydrocarbon synthesis and transport, and biosynthesis of volatile hydrocarbon pheromones of Lepidoptera and Coleoptera. In addition, a section is devoted to future research needs in this rapidly growing area of science.
BIOLOGY AND MANAGEMENT OF INSECT PESTS IN NORTH AMERICAN INTENSIVELY MANAGED HARDWOOD FOREST SYSTEMS,
Authors: Coyle David R. , Nebeker T. Evan , Hart Elwood R. , Mattson William J.
Published: November 2004

▪ Abstract  Increasing demand for wood and wood products is putting stress on traditional forest production areas, leading to long-term economic and environmental concerns. Intensively managed hardwood forest systems (IMHFS), grown using conventional agricultural as well as forestry methods, can help alleviate potential problems in natural forest production areas. Although IMHFS can produce more biomass per hectare per year than natural forests, the ecologically simplified, monocultural systems may greatly increase the crop's susceptibility to pests. Species in the genera Populus and Salix comprise the greatest acreage in IMHFS in North America, but other species, including Liquidambar styraciflua and Platanus occidentalis, are also important. We discuss life histories, realized and potential damage, and management options for the most economically influential pests that affect these hardwood species. The substantial inherent challenges associated with pest management in the monocultural environments created by IMHFS are reviewed. Finally, we discuss ways to design IMHFS that may reduce their susceptibility to pests, increase their growth and productivity potential, and create a more sustainable environment.
MOSQUITO BEHAVIOR AND VECTOR CONTROL
Authors: Pates Helen , Curtis Christopher
Published: November 2004

▪ Abstract  Effective indoor residual spraying against malaria vectors depends on whether mosquitoes rest indoors (i.e., endophilic behavior). This varies among species and is affected by insecticidal irritancy. Exophilic behavior has evolved in certain populations exposed to prolonged spraying programs. Optimum effectiveness of insecticide-treated nets presumably depends on vectors biting at hours when most people are in bed. Time of biting varies among different malaria vector species, but so far there is inconclusive evidence for these evolving so as to avoid bednets. Use of an untreated net diverts extra biting to someone in the same room who is without a net. Understanding choice of oviposition sites and dispersal behavior is important for the design of successful larval control programs including those using predatory mosquito larvae. Prospects for genetic control by sterile males or genes rendering mosquitoes harmless to humans will depend on competitive mating behavior. These methods are hampered by the immigration of monogamous, already-mated females.
TSETSE GENETICS: Contributions to Biology, Systematics, and Control of Tsetse Flies
Authors: Gooding R.H. , Krafsur E.S.
Published: November 2004

▪ Abstract  Tsetse flies (Diptera: Glossinidae) constitute a small, ancient taxon of exclusively hematophagous insects that reproduce slowly and viviparously. Because tsetse flies are the only vectors of pathogenic African trypanosomes, they are a potent and constant threat to humans and livestock over much of sub-Saharan Africa. Despite their low fecundity, tsetse flies demonstrate great resilience, which makes population suppression expensive, transient, and beyond the capacities of private and public sectors to accomplish, except over small areas. Nevertheless, control measures that include genetic methods are under consideration at national and supranational levels. There is a pressing need for sufficient laboratory cultures of tsetse flies and financial support to carry out genetic research. Here we review tsetse genetics from organismal and population points of view and identify some research needs.
Mitochondria of Protists
Authors: Gray Michael W. , Lang B. Franz , Burger Gertraud
Published: November 2004

▪ Abstract  Over the past several decades, our knowledge of the origin and evolution of mitochondria has been greatly advanced by determination of complete mitochondrial genome sequences. Among the most informative mitochondrial genomes have been those of protists (primarily unicellular eukaryotes), some of which harbor the most gene-rich and most eubacteria-like mitochondrial DNAs (mtDNAs) known. Comparison of mtDNA sequence data has provided insights into the radically diverse trends in mitochondrial genome evolution exhibited by different phylogenetically coherent groupings of eukaryotes, and has allowed us to pinpoint specific protist relatives of the multicellular eukaryotic lineages (animals, plants, and fungi). This comparative genomics approach has also revealed unique and fascinating aspects of mitochondrial gene expression, highlighting the mitochondrion as an evolutionary playground par excellence.
Genetic Analyses from Ancient DNA
Authors: Pääbo Svante , Poinar Hendrik , Serre David , Jaenicke-Després Viviane , Hebler Juliane , Rohland Nadin , Kuch Melanie , Krause Johannes , Vigilant Linda , Hofreiter Michael
Published: November 2004

▪ Abstract  About 20 years ago, DNA sequences were separately described from the quagga (a type of zebra) and an ancient Egyptian individual. What made these DNA sequences exceptional was that they were derived from 140- and 2400-year-old specimens. However, ancient DNA research, defined broadly as the retrieval of DNA sequences from museum specimens, archaeological finds, fossil remains, and other unusual sources of DNA, only really became feasible with the advent of techniques for the enzymatic amplification of specific DNA sequences. Today, reports of analyses of specimens hundreds, thousands, and even millions of years old are almost commonplace. But can all these results be believed? In this paper, we critically assess the state of ancient DNA research. In particular, we discuss the precautions and criteria necessary to ascertain to the greatest extent possible that results represent authentic ancient DNA sequences. We also highlight some significant results and areas of promising future research.
Metagenomics: Genomic Analysis of Microbial Communities
Authors: Riesenfeld Christian S. , Schloss Patrick D. , Handelsman Jo
Published: November 2004

▪ Abstract  Uncultured microorganisms comprise the majority of the planet's biological diversity. Microorganisms represent two of the three domains of life and contain vast diversity that is the product of an estimated 3.8 billion years of evolution. In many environments, as many as 99% of the microorganisms cannot be cultured by standard techniques, and the uncultured fraction includes diverse organisms that are only distantly related to the cultured ones. Therefore, culture-independent methods are essential to understand the genetic diversity, population structure, and ecological roles of the majority of microorganisms. Metagenomics, or the culture-independent genomic analysis of an assemblage of microorganisms, has potential to answer fundamental questions in microbial ecology. This review describes progress toward understanding the biology of uncultured Bacteria, Archaea, and viruses through metagenomic analyses.
Mobile Group II Introns
Authors: Lambowitz Alan M. , Zimmerly Steven
Published: November 2004

▪ Abstract  Mobile group II introns, found in bacterial and organellar genomes, are both catalytic RNAs and retrotransposable elements. They use an extraordinary mobility mechanism in which the excised intron RNA reverse splices directly into a DNA target site and is then reverse transcribed by the intron-encoded protein. After DNA insertion, the introns remove themselves by protein-assisted, autocatalytic RNA splicing, thereby minimizing host damage. Here we discuss the experimental basis for our current understanding of group II intron mobility mechanisms, beginning with genetic observations in yeast mitochondria, and culminating with a detailed understanding of molecular mechanisms shared by organellar and bacterial group II introns. We also discuss recently discovered links between group II intron mobility and DNA replication, new insights into group II intron evolution arising from bacterial genome sequencing, and the evolutionary relationship between group II introns and both eukaryotic spliceosomal introns and non-LTR-retrotransposons. Finally, we describe the development of mobile group II introns into gene-targeting vectors, “targetrons,” which have programmable target specificity.
Prion Genetics: New Rules for a New Kind of Gene
Authors: Wickner Reed B. , Edskes Herman K. , Ross Eric D. , Pierce Michael M. , Baxa Ulrich , Brachmann Andreas , Shewmaker Frank
Published: November 2004

▪ Abstract  Just as nucleic acids can carry out enzymatic reactions, proteins can be genes. These heritable infectious proteins (prions) follow unique genetic rules that enable their identification: reversible curing, inducible “spontaneous generation,” and phenotype surprises. Most prions are based on self-propagating amyloids, depend heavily on chaperones, show strain phenomena and, like other infectious elements, show species barriers to transmission. A recently identified prion is based on obligatory self-activation of an enzyme in trans. Although prions can be detrimental, they may also be beneficial to their hosts.
Mechanisms of Pattern Formation in Plant Embryogenesis
Authors: Willemsen Viola , Scheres Ben
Published: November 2004

▪ Abstract  Many of the patterning mechanisms in plants were discovered while studying postembryonic processes and resemble mechanisms operating during animal development. The emergent role of the plant hormone auxin, however, seems to represent a plant-specific solution to multicellular patterning. This review summarizes our knowledge on how diverse mechanisms that were first dissected at the postembryonic level are now beginning to provide an understanding of plant embryogenesis.
Light Signal Transduction in Higher Plants
Authors: Chen Meng , Chory Joanne , Fankhauser Christian
Published: November 2004

▪ Abstract  Plants utilize several families of photoreceptors to fine-tune growth and development over a large range of environmental conditions. The UV-A/blue light sensing phototropins mediate several light responses enabling optimization of photosynthetic yields. The initial event occurring upon photon capture is a conformational change of the photoreceptor that activates its protein kinase activity. The UV-A/blue light sensing cryptochromes and the red/far-red sensing phytochromes coordinately control seedling establishment, entrainment of the circadian clock, and the transition from vegetative to reproductive growth. In addition, the phytochromes control seed germination and shade-avoidance responses. The molecular mechanisms involved include light-regulated subcellular localization of the photoreceptors, a large reorganization of the transcriptional program, and light-regulated proteolytic degradation of several photoreceptors and signaling components.
Chlamydomonas reinhardtii in the Landscape of Pigments
Authors: Grossman Arthur R. , Lohr Martin , Im Chung Soon
Published: November 2004

▪ Abstract  This review focuses on the biosynthesis of pigments in the unicellular alga Chlamydomonas reinhardtii and their physiological and regulatory functions in the context of information gathered from studies of other photosynthetic organisms. C. reinhardtii is serving as an important model organism for studies of photosynthesis and the pigments associated with the photosynthetic apparatus. Despite extensive information pertaining to the biosynthetic pathways critical for making chlorophylls and carotenoids, we are just beginning to understand the control of these pathways, the coordination between pigment and apoprotein synthesis, and the interactions between the activities of these pathways and those for other important cellular metabolites branching from these pathways. Other exciting areas relating to pigment function are also emerging: the role of intermediates of pigment biosynthesis as messengers that coordinate metabolism in the chloroplast with nuclear gene activity, and the identification of photoreceptors and their participation in critical cellular processes including phototaxis, gametogenesis, and the biogenesis of the photosynthetic machinery. These areas of research have become especially attractive for intensive development with the application of potent molecular and genomic tools currently being applied to studies of C. reinhardtii.
Repair and Genetic Consequences of Endogenous DNA Base Damage in Mammalian Cells
Authors: Barnes Deborah E. , Lindahl Tomas
Published: November 2004

▪ Abstract  Living organisms dependent on water and oxygen for their existence face the major challenge of faithfully maintaining their genetic material under a constant attack from spontaneous hydrolysis and active oxygen species and from other intracellular metabolites that can modify DNA bases. Repair of endogenous DNA base damage by the ubiquitous base-excision repair pathway largely accounts for the significant turnover of DNA even in nonreplicating cells, and must be sufficiently accurate and efficient to preserve genome stability compatible with long-term cellular viability. The size of the mammalian genome has necessitated an increased complexity of repair and diversification of key enzymes, as revealed by gene knock-out mouse models. The genetic instability characteristic of cancer cells may be due, in part, to mutations in genes whose products normally function to ensure DNA integrity.
Closing Mitosis: The Functions of the Cdc14 Phosphatase and Its Regulation
Authors: Stegmeier Frank , Amon Angelika
Published: November 2004

▪ Abstract  Completion of the cell cycle requires the temporal and spatial coordination of chromosome segregation with mitotic spindle disassembly and cytokinesis. In budding yeast, the protein phosphatase Cdc14 is a key regulator of these late mitotic events. Here, we review the functions of Cdc14 and how this phosphatase is regulated to accomplish the coupling of mitotic processes. We also discuss the function and regulation of Cdc14 in other eukaryotes, emphasizing conserved features.
MARGINAL ZONE B CELLS
Authors: Pillai Shiv , Cariappa Annaiah , Moran Stewart T.
Published: November 2004

▪ Abstract  Our views regarding the origins and functions of splenic marginal zone B cells have changed considerably over the past few years. Perspectives regarding the development and function of these cells vary considerably between investigators studying human and rodent immunology. Marginal zone B cells are now recognized to constitute a distinct naive B lymphoid lineage. Considerable progress has been made regarding the mechanisms involved in marginal zone B cell development in the mouse. Many of the molecular events that participate in the retention of this lineage of B cells in the marginal zone have been identified. Here, we discuss the functions of these cells in both innate and adaptive immunity. We also attempt to reconcile differing viewpoints regarding the generation and function of marginal zone B cells in rodents and primates.
Application of Microbial Genomic Science to Advanced Therapeutics
Authors: Fraser Claire M. , Rappuoli Rino
Published: November 2004

Since the publication of the first complete microbial genome sequence of Haemophilus influenzae in 1995, more than 200 additional microbial genome sequences have become available in the public domain. Approximately 40% of these represent important human pathogens. Comparative in silico methods, along with large-scale approaches such as transcriptomics and proteomics, are beginning to reveal insights into new virulence genes, pathogen-host interactions, and the molecular basis of host specificity. Sequence data are also starting to accumulate from multiple isolates or strains of a single pathogen, and this type of data has proven to be quite valuable in providing new insights into the genetic variability that is present in a particular species as well as in facilitating correlations between genotype and phenotype. Ultimately, a major goal of genome-enabled infectious disease research is the development of novel diagnostics, therapeutics, and vaccines.
Gene-Environment Interactions in Asthma and Other Respiratory Diseases
Authors: Kleeberger Steven R. , Peden David
Published: November 2004

It is generally agreed that many lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) have polygenic inheritance, and that the association of a specific genotype or genotypes with the disease is likely to vary between populations. Furthermore, it is recognized that the etiology of many lung diseases involves a complex interplay between genetic background and exposure to multiple environmental stimuli, and understanding the mechanisms through which genes and environment interact represents a major challenge for pulmonary researchers. We discuss experimental approaches and challenges that must be overcome to identify disease genes for asthma, COPD and chronic bronchitis, and occupational lung diseases. In particular, common polymorphisms in CD14, glutathione S-transferase, and tumor necrosis factor alpha have been found to be important in gene-environment interaction and asthma pathogenesis. An understanding of gene-environment interactions in complex lung diseases is essential to the development of new strategies for lung disease prevention and treatment.
Therapeutic Intervention and Targets for Sepsis
Authors: Rice Todd W. , Bernard Gordon R.
Published: November 2004

Sepsis syndrome, a systemic response to infection, can beget devastating outcomes even in previously normal individuals. Recent research in septic patients has led to the discovery that early goal-directed resuscitation guided by continuous monitoring of mixed venous hemoglobin saturation, along with moderate doses of corticosteroids, can reduce mortality. An improved understanding of the complex interaction between the inflammatory and coagulant systems in sepsis pathophysiology has resulted in novel treatments, such as recombinant human activated protein C, which improves survival in patients with severe sepsis and a high risk of death. However, despite an increased understanding of the complex pathophysiology of this syndrome and the discovery of new, effective treatments, severe sepsis still results in significant morbidity and mortality. Consequently, investigations continue into additional therapeutic agents directed against novel targets. Following a review of recent advances in sepsis treatment, we briefly discuss a few of the new, promising therapeutic strategies currently being investigated.
DNA Repair Defects in Stem Cell Function and Aging
Authors: Park Youngji , Gerson Stanton L.
Published: November 2004

Cellular DNA is under constant challenge by exogenous and endogenous genotoxic stress, which results in both transient and accumulated DNA damage and genomic instability. All cells are equipped with DNA damage response pathways that trigger DNA repair, cell cycle arrest, and, if need be, apoptosis, to eliminate DNA damage or damaged cells. The consequences of these processes for stem cells can be profound: diminution in stem cell pools, or, because of altered gene expression, an increased chance for stem cell differentiation or malignant transformation. Furthermore, a number of DNA repair abnormalities are linked to premature aging syndromes, and these are associated with defects in the stem cell population. The specific DNA repair systems for which there are data regarding the impact of repair defects on stem cell function include O6-alkylguanine DNA alkyltransferase, nucleotide excision repair, base excision repair, mismatch repair, non-homologous DNA end-joining Fanconi's anemia protein complex, and homologous recombination. It has recently become clear that deficiencies of these processes are associated not only with cancer and/or aging but also with stem cell defects. This discovery raises the possibility of a link between aging and stem cell dysfunction. In this review, we provide evidence for a link between DNA repair systems and the maintenance and longevity of stem cells.
Severe Acute Respiratory Syndrome (SARS): A Year in Review
Authors: Skowronski Danuta M. , Astell Caroline , Brunham Robert C. , Low Donald E. , Petric Martin , Roper Rachel L. , Talbot Pierre J. , Tam Theresa , Babiuk Lorne
Published: November 2004

Severe acute respiratory syndrome (SARS) emerged from China as an untreatable and rapidly spreading respiratory illness of unknown etiology. Following point source exposure in February 2003, more than a dozen guests infected at a Hong Kong hotel seeded multi-country outbreaks that persisted through the spring of 2003. The World Health Organization responded by invoking traditional public health measures and advanced technologies to control the illness and contain the cause. A novel coronavirus was implicated and its entire genome was sequenced by mid-April 2003. The urgency of responding to this threat focused scientific endeavor and stimulated global collaboration. Through real-time application of accumulating knowledge, the world proved capable of arresting the first pandemic threat of the twenty-first century, despite early respiratory-borne spread and global susceptibility. This review synthesizes lessons learned from this remarkable achievement. These lessons can be applied to re-emergence of SARS or to the next pandemic threat to arise.
ACTIONS OF ADENOSINE AT ITS RECEPTORS IN THE CNS: Insights from Knockouts and Drugs
Authors: Fredholm Bertil B. , Chen Jiang-Fan , Masino Susan A. , Vaugeois Jean-Marie
Published: November 2004

▪ Abstract  Adenosine and its receptors have been the topic of many recent reviews ( 1 – 26 ). These reviews provide a good summary of much of the relevant literature—including the older literature. We have, therefore, chosen to focus the present review on the insights gained from recent studies on genetically modified mice, particularly with respect to the function of adenosine receptors and their potential as therapeutic targets. The information gained from studies of drug effects is discussed in this context, and discrepancies between genetic and pharmacological results are highlighted.
PLEIOTROPIC EFFECTS OF STATINS
Authors: Liao James K. , Laufs Ulrich
Published: November 2004

▪ Abstract  Statins are potent inhibitors of cholesterol biosynthesis. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. However, the overall benefits observed with statins appear to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. Indeed, recent studies indicate that some of the cholesterol-independent or “pleiotropic” effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Furthermore, statins have beneficial extrahepatic effects on the immune system, CNS, and bone. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the pleiotropic effects of statins.
GLUTATHIONE TRANSFERASES
Authors: Hayes John D. , Flanagan Jack U. , Jowsey Ian R.
Published: November 2004

▪ Abstract  This review describes the three mammalian glutathione transferase (GST) families, namely cytosolic, mitochondrial, and microsomal GST, the latter now designated MAPEG. Besides detoxifying electrophilic xenobiotics, such as chemical carcinogens, environmental pollutants, and antitumor agents, these transferases inactivate endogenous α,β-unsaturated aldehydes, quinones, epoxides, and hydroperoxides formed as secondary metabolites during oxidative stress. These enzymes are also intimately involved in the biosynthesis of leukotrienes, prostaglandins, testosterone, and progesterone, as well as the degradation of tyrosine. Among their substrates, GSTs conjugate the signaling molecules 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and 4-hydroxynonenal with glutathione, and consequently they antagonize expression of genes trans-activated by the peroxisome proliferator-activated receptor γ (PPARγ) and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Through metabolism of 15d-PGJ2, GST may enhance gene expression driven by nuclear factor-κB (NF-κB). Cytosolic human GST exhibit genetic polymorphisms and this variation can increase susceptibility to carcinogenesis and inflammatory disease. Polymorphisms in human MAPEG are associated with alterations in lung function and increased risk of myocardial infarction and stroke. Targeted disruption of murine genes has demonstrated that cytosolic GST isoenzymes are broadly cytoprotective, whereas MAPEG proteins have proinflammatory activities. Furthermore, knockout of mouse GSTA4 and GSTZ1 leads to overexpression of transferases in the Alpha, Mu, and Pi classes, an observation suggesting they are part of an adaptive mechanism that responds to endogenous chemical cues such as 4-hydroxynonenal and tyrosine degradation products. Consistent with this hypothesis, the promoters of cytosolic GST and MAPEG genes contain antioxidant response elements through which they are transcriptionally activated during exposure to Michael reaction acceptors and oxidative stress.
NEONICOTINOID INSECTICIDE TOXICOLOGY: Mechanisms of Selective Action
Authors: Tomizawa Motohiro , Casida John E.
Published: November 2004

▪ Abstract  The neonicotinoids, the newest major class of insecticides, have outstanding potency and systemic action for crop protection against piercing-sucking pests, and they are highly effective for flea control on cats and dogs. Their common names are acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. They generally have low toxicity to mammals (acute and chronic), birds, and fish. Biotransformations involve some activation reactions but largely detoxification mechanisms. In contrast to nicotine, epibatidine, and other ammonium or iminium nicotinoids, which are mostly protonated at physiological pH, the neonicotinoids are not protonated and have an electronegative nitro or cyano pharmacophore. Agonist recognition by the nicotinic receptor involves cation-π interaction for nicotinoids in mammals and possibly a cationic subsite for interaction with the nitro or cyano substituent of neonicotinoids in insects. The low affinity of neonicotinoids for vertebrate relative to insect nicotinic receptors is a major factor in their favorable toxicological profile.
NON-MICHAELIS-MENTEN KINETICS IN CYTOCHROME P450-CATALYZED REACTIONS
Authors: Atkins William M.
Published: November 2004

▪ Abstract  The cytochrome P450 monooxygenases (CYPs) are the dominant enzyme system responsible for xenobiotic detoxification and drug metabolism. Several CYP isoforms exhibit non-Michaelis-Menten, or “atypical,” steady state kinetic patterns. The allosteric kinetics confound prediction of drug metabolism and drug-drug interactions, and they challenge the theoretical paradigms of allosterism. Both homotropic and heterotropic ligand effects are now widely documented. It is becoming apparent that multiple ligands can simultaneously bind within the active sites of individual CYPs, and the kinetic parameters change with ligand occupancy. In fact, the functional effect of any specific ligand as an activator or inhibitor can be substrate dependent. Divergent approaches, including kinetic modeling and X-ray crystallography, are providing new information about how multiple ligand binding yields complex CYP kinetics.
CYTOCHROME P450: Nature's Most Versatile Biological Catalyst
Authors: Coon Minor J.
Published: November 2004

▪ Abstract  The author describes studies that led to the resolution and reconstitution of the cytochrome P450 enzyme system in microsomal membranes. The review indicates how purification and characterization of the cytochromes led to rigorous evidence for multiple isoforms of the oxygenases with distinct chemical and physical properties and different but somewhat overlapping substrate specificities. Present knowledge of the individual steps in the P450 and reductase reaction cycles is summarized, including evidence for the generation of multiple functional oxidants that may contribute to the exceptional diversity of the reactions catalyzed.
TYROSINE KINASE INHIBITORS AND THE DAWN OF MOLECULAR CANCER THERAPEUTICS
Authors: Tibes Raoul , Trent Jonathan , Kurzrock Razelle
Published: November 2004

▪ Abstract  The clinical application of tyrosine kinase inhibitors for cancer treatment represents a therapeutic breakthrough. The rationale for developing these compounds rests on the observation that tyrosine kinase enzymes are critical components of the cellular signaling apparatus and are regularly mutated or otherwise deregulated in human malignancies. Novel tyrosine kinase inhibitors are designed to exploit the molecular differences between tumor cells and normal tissues. Herein, we will review the current state-of-the-art using agents that target as prototypes Bcr-Abl, platelet-derived growth factor receptor (PDGFR), KIT (stem cell factor receptor), and epidermal growth factor receptor (EGFR). These compounds are remarkably effective in treating diverse cancers that are highly resistant to conventional treatment, including various forms of leukemia, hypereosinophilic syndrome, mast cell disease, sarcomas, and lung cancer. It is now clear that the molecular defects underlying cancer can be targeted with designer drugs that yield striking salutary effects with minimal toxicity.
QUANTUM CHAOS MEETS COHERENT CONTROL
Authors: Gong Jiangbin , Brumer Paul
Published: November 2004

▪ Abstract  Coherent control of atomic and molecular processes has been a rapidly developing field. Applications of coherent control to large and complex molecular systems are expected to encounter the effects of chaos in the underlying classical dynamics, i.e., quantum chaos. Hence, recent work has focused on examining control in model chaotic systems. This work is reviewed, with an emphasis on a variety of new quantum phenomena that are of interest to both areas of quantum chaos and coherent control.
LIGAND CONTROL OF COREGULATOR RECRUITMENT TO NUCLEAR RECEPTORS
Authors: Nettles Kendall W. , Greene Geoffrey L.
Published: November 2004

▪ Abstract  Nuclear receptors modulate transcription through ligand-mediated recruitment of transcriptional coregulator proteins. The structural connection between ligand and coregulator is mediated by a molecular switch, made up of the most carboxy-terminal helix in the ligand-binding domain, helix 12. The dynamics of this switch are thought to underlie ligand specificity of nuclear receptor signaling, but the details of this control mechanism have remained elusive. This review highlights recent structural work on how the ligand controls this molecular switch and the modulation of this signaling pathway by receptor subtype and dimer partner.