bluuebunny/crossref_metadata_2025 huggingface dataset:
New Strategies for Protein Crystal Growth
Authors: Wiencek J. M.
Published: July 2002

▪ Abstract  Protein crystallization is the most difficult and time-consuming step in the determination of a protein’s atomic structure. As X-ray diffraction becomes a commonly available tool in structural biology, the necessity for rational methodologies and protocols to produce single, high-quality protein crystals has come to the forefront. The basics of protein crystallization conform to the classical understanding of crystallization of small molecules. Understanding the effect of solution variables such as pH, temperature, pressure, and ionicity on protein solubility allows the proper evaluation of the degree of supersaturation present in protein crystallization experiments. Physicochemical measurements such as laser light scattering, X-ray scattering, X-ray diffraction, and atomic force microscopy provide a clearer picture of protein crystal nucleation and growth. This ever deepening knowledge base is generating rational methods to produce protein crystals as well as means to improve the diffraction quality of such protein crystals. Yet, much remains unclear, and the protein crystallization research community will be quite active for many years to come.
CYTOCHROME C OXIDASE: Structure and Spectroscopy
Authors: Michel H. , Behr J. , Harrenga A. , Kannt A.
Published: July 2002

▪ Abstract  Cytochrome c oxidase, the terminal enzyme of the respiratory chains of mitochondria and aerobic bacteria, catalyzes electron transfer from cytochrome c to molecular oxygen, reducing the latter to water. Electron transfer is coupled to proton translocation across the membrane, resulting in a proton and charge gradient that is then employed by the F0F1-ATPase to synthesize ATP.

Over the last years, substantial progress has been made in our understanding of the structure and function of this enzyme. Spectroscopic techniques such as EPR, absorbance and resonance Raman spectroscopy, in combination with site-directed mutagenesis work, have been successfully applied to elucidate the nature of the cofactors and their ligands, to identify key residues involved in proton transfer, and to gain insight into the catalytic cycle and the structures of its intermediates. Recently, the crystal structures of a bacterial and a mitochondrial cytochrome c oxidase have been determined. In this review, we provide an overview of the crystal structures, summarize recent spectroscopic work, and combine structural and spectroscopic data in discussing mechanistic aspects of the enzyme. For the latter, we focus on the structure of the oxygen intermediates, proton-transfer pathways, and the much-debated issue of how electron transfer in the enzyme might be coupled to proton translocation.
Atomic Force Microscopy in the Study of Macromolecular Crystal Growth
Authors: McPherson A. , Malkin A. J. , Kuznetsov Yu. G.
Published: July 2002

▪ Abstract  Atomic force microscopy (AFM) has been used to study protein, nucleic acid, and virus crystals in situ, in their mother liquors, as they grow. From sequential AFM images taken at brief intervals over many hours, or even days, the mechanisms and kinetics of the growth process can be defined. The appearance of both two- and three-dimensional nuclei on crystal surfaces have been visualized, defect structures of crystals were clearly evident, and defect densities of crystals were also determined. The incorporation of a wide range of impurities, ranging in size from molecules to microns or larger microcrystals, and even foreign particles were visually recorded. From these observations and measurements, a more complex understanding of the detailed character of macromolecular crystals is emerging, one that reveals levels of complexity previously unsuspected. The unique features of these crystals, apparently in AFM images, undoubtedly influence the diffraction properties of the crystals and the quality of the molecular images obtained by X-ray crystallography.
LIGHT CONTROL OF PLANT DEVELOPMENT
Authors: Fankhauser Christian , Chory Joanne
Published: July 2002

▪ Abstract  To grow and develop optimally, all organisms need to perceive and process information from both their biotic and abiotic surroundings. A particularly important environmental cue is light, to which organisms respond in many different ways. Because they are photosynthetic and non-motile, plants need to be especially plastic in response to their light environment. The diverse responses of plants to light require sophisticated sensing of its intensity, direction, duration, and wavelength. The action spectra of light responses provided assays to identify three photoreceptor systems absorbing in the red/far-red, blue/near-ultraviolet, and ultraviolet spectral ranges. Following absorption of light, photoreceptors interact with other signal transduction elements, which eventually leads to many molecular and morphological responses. While a complete signal transduction cascade is not known yet, molecular genetic studies using the model plant Arabidopsis have led to substantial progress in dissecting the signal transduction network. Important gains have been made in determining the function of the photoreceptors, the terminal response pathways, and the intervening signal transduction components.
FORMATION AND FUNCTION OF SPEMANN'S ORGANIZER
Authors: Harland Richard , Gerhart John
Published: July 2002

▪ Abstract  The organizer is formed in an equatorial sector of the blastula stage amphibian embryo by cells that have responded to two maternal agents: a general meso-endoderm inducer (involving the TFG-β signaling pathway) and a dorsal modifier (probably involving the Wnt signaling pathway). The meso-endoderm inducer is secreted by most vegetal cells, those containing maternal materials that had been localized in the vegetal hemisphere of the oocyte during oogenesis. As a consequence of the inducer's distribution and action, the competence domains of prospective ectoderm, mesoderm, and endoderm are established in an animal-to-vegetal order in the blastula. The dorsal modifier signal is secreted by a sector of cells of the animal and vegetal hemispheres on one side of the blastula. These cells contain maternal materials transported there in the first cell cycle from the vegetal pole of the egg along microtubules aligned by cortical rotation. The Nieuwkoop center is the region of blastula cells secreting both maternal signals, and hence specifying the organizer in an equatorial sector. Final steps of organizer formation at the late blastula or early gastrula stage may involve locally secreted zygotic signals as well. At the gastrula stage, the organizer secretes a variety of zygotic proteins that act as antagonists to various members of the BMP and Wnt families of ligands, which are secreted by cells of the competence domains surrounding the organizer. BMPs and Wnts favor ventral development, and cells near the organizer are protected from these agents by the organizer's inducers. The nearby cells are derepressed in their inherent capacity for dorsal development, which is apparent in the neural induction of the ectoderm, dorsalization of the mesoderm, and anteriorization of the endoderm. The organizer also engages in extensive specialized morphogenesis, which brings it within range of responsive cell groups. It also self-differentiates to a variety of axial tissues of the body.
Structural Basis for the Interaction of Tubulin with Proteins and Drugs that Affect Microtubule Dynamics
Authors: Downing Kenneth H.
Published: July 2002

▪ Abstract  The microtubule cytoskeleton is a highly regulated system. At different times in the cell cycle and positions within the organism, microtubules can be very stable or highly dynamic. Stability and dynamics are regulated by interaction with a large number of proteins that themselves may change at specific points in the cell cycle. Exogenous ligands can disrupt the normal processes by either increasing or decreasing microtubule stability and inhibiting their dynamic behavior. The recent determination of the structure of tubulin, the main component of microtubules, makes it possible now to begin to understand the details of these interactions. We review here the structure of the tubulin dimer, with particular regard to how proteins and drugs may bind and modulate microtubule dynamics.
Boundaries in Development: Formation and Function
Authors: Irvine Kenneth D. , Rauskolb Cordelia
Published: July 2002

▪ Abstract  Developing organisms may contain billions of cells destined to differentiate in numerous different ways. One strategy organisms use to simplify the orchestration of development is the separation of cell populations into distinct functional units. Our expanding knowledge of boundary formation and function in different systems is beginning to reveal general principles of this process. Fields of cells are subdivided by the interpretation of morphogen gradients, and these subdivisions are then maintained and refined by local cell-cell interactions. Sharp and stable separation between cell populations requires special mechanisms to keep cells segregated, which in many cases appear to involve the regulation of cell affinity. Once cell populations become distinct, specialized cells are often induced along the borders between them. These boundary cells can then influence the patterning of surrounding cells, which can result in progressively finer subdivisions of a tissue. Much has been learned about the signaling pathways that establish boundaries, but a key challenge for the future remains to elucidate the cellular and molecular mechanisms that actually keep cell populations separated.
TEMPERATURES IN PROTOPLANETARY DISKS
Authors: Boss Alan P.
Published: July 2002

▪ Abstract  Observations of suspected planet-forming disks provide estimates of protoplanetary disk masses, surface temperatures, and the rate at which mass is infalling onto the disks. Analyses of primitive meteorites and comets and their components constrain the solar nebula's temperature at the locations and times where those components were formed. Theoretical models of disks undergoing the accretion of mass from an infalling cloud envelope predict disk temperatures in good agreement with these constraints: a moderately warm (500–1500 K) inner disk, surrounded by a cool (50–150 K) outer disk. These models have important implications for the depletion of volatiles in the inner Solar System, for mechanisms of disk evolution, and for the orbital distances at which terrestrial and gas giant planets form.
IMPACT CRATER COLLAPSE
Authors: Melosh H. J. , Ivanov B. A.
Published: July 2002

▪ Abstract  The detailed morphology of impact craters is now believed to be mainly caused by the collapse of a geometrically simple, bowl-shaped “transient crater.” The transient crater forms immediately after the impact. In small craters, those less than approximately 15 km diameter on the Moon, the steepest part of the rim collapses into the crater bowl to produce a lens of broken rock in an otherwise unmodified transient crater. Such craters are called “simple” and have a depth-to-diameter ratio near 1:5. Large craters collapse more spectacularly, giving rise to central peaks, wall terraces, and internal rings in still larger craters. These are called “complex” craters. The transition between simple and complex craters depends on 1/g, suggesting that the collapse occurs when a strength threshold is exceeded. The apparent strength, however, is very low: only a few bars, and with little or no internal friction. This behavior requires a mechanism for temporary strength degradation in the rocks surrounding the impact site. Several models for this process, including acoustic fluidization and shock weakening, have been considered by recent investigations. Acoustic fluidization, in particular, appears to produce results in good agreement with observations, although better understanding is still needed.
FOREST CANOPIES: Methods, Hypotheses, and Future Directions
Authors: Lowman Margaret D. , Wittman Philip K.
Published: July 2002

▪ Abstract  Forest canopies contain a major portion of the diversity of organisms on Earth and constitute the bulk of photosynthetically active foliage and biomass in forest ecosystems. For these reasons, canopy research has become integral to the management of forest ecosystems, and to our better understanding of global change. Ecological research in forest canopies is relatively recent and has been primarily descriptive in scope. The development of new methods of canopy access has enabled scientists to conduct more quantified research in tree crowns. Studies of sessile organisms, mobile organisms, and canopy interactions and processes have emerged as subdisciplines of canopy biology, each requiring different methods for collecting data. Canopy biology is beginning to shift from a descriptive autecology of individuals to a more complex ecosystem approach, although some types of field work are still limited by access.

Questions currently addressed in canopy research are extremely diverse but emphasize comparisons with respect to spatial and temporal variation. Spatial scales range from leaves (e.g. quantifying the number of mites on individual phylloplanes) to trees (e.g. measuring photosynthesis between sun and shade leaves), to forest stands (e.g. measuring turbulence above the canopy), and entire landscapes (e.g. comparing mammals between different forest types). Temporal variation is of particular significance in tropical forest canopies, where populations of organisms and their resources have diurnal, seasonal, or even annual periodicity. As the methods for canopy access improve, more rigorous hypotheses-driven field studies remain a future priority of this newly coalesced discipline.
Global Amphibian Declines: A Problem in Applied Ecology
Authors: Alford Ross A. , Richards Stephen J.
Published: July 2002

▪ Abstract  Declines and losses of amphibian populations are a global problem with complex local causes. These may include ultraviolet radiation, predation, habitat modification, environmental acidity and toxicants, diseases, changes in climate or weather patterns, and interactions among these factors. Understanding the extent of the problem and its nature requires an understanding of how local factors affect the dynamics of local populations. Hypotheses about population behavior must be tested against appropriate null hypotheses. We generated null hypotheses for the behavior of amphibian populations using a model, and we used them to test hypotheses about the behavior of 85 time series taken from the literature. Our results suggest that most amphibian populations should decrease more often than they increase, due to highly variable recruitment and less variable adult mortality. During the period covered by our data (1951–1997), more amphibian populations decreased than our model predicted. However, there was no indication that the proportion of populations decreasing changed over time. In addition, our review of the literature suggests that many if not most amphibians exist in metapopulations. Understanding the dynamics of amphibian populations will require an integration of studies on and within local populations and at the metapopulation level.
ENERGY AND RESOURCE CONSTRAINTS ON INTENSIVE AGRICULTURAL PRODUCTION
Authors: Naylor Rosamond L.
Published: July 2002

▪ Abstract  This review explores the potential energy, soil, and water constraints on highly productive agricultural systems. It focuses on the process of agricultural intensification during the past 50 years, and it shows that multiple constraints—as opposed to a single constraint, such as energy—are needed to assess the future sustainability of intensive agricultural production. Recent studies documenting changes in total factor productivity based on long-term experimental trials and field surveys are discussed in detail. The results of these studies are worrisome; they indicate that degradation in soil quality and in the overall natural resource base may threaten the long-run viability of several of the world's most intensive agricultural systems. Other studies are reviewed that support a more optimistic view of resource availability and the ability of improved technology and management to overcome these physical constraints. However, the combined evidence suggests that the increase in agricultural prices required to induce the necessary changes in technology could be devastating to low-income households. Most of the world's poor consume more agricultural output than they produce, and they spend up to 80% of their incomes on food.
CODES OF ENVIRONMENTAL MANAGEMENT PRACTICE: Assessing Their Potential as a Tool for Change
Authors: Nash Jennifer , Ehrenfeld John
Published: July 2002

Codes of environmental management practice emerged as a tool of environmental policy in the late 1980s. Industry and other groups have developed codes for two purposes: to change the environmental behavior of participating firms and to increase public confidence in industry's commitment to environmental protection. This review examines five codes of environmental management practice: Responsible Care, the International Chamber of Commerce's Business Charter for Sustainable Development, ISO 14000, the CERES Principles, and The Natural Step. The first three codes have been drafted and promoted primarily by industry; the others have been developed by non-industry groups. These codes have spurred participating firms to introduce new practices, including the institution of environmental management systems, public environmental reporting, and community advisory panels. The extent to which codes are introducing a process of cultural change is considered in terms of four dimensions: new consciousness, norms, organization, and tools.
THEPOTENTIAL OFBIOMASSFUELS INTHECONTEXT OFGLOBALCLIMATECHANGE: Focus on Transportation Fuels
Authors: Kheshgi Haroon S. , Prince Roger C. , Marland Gregg
Published: July 2002

▪ Abstract  An ultimate limit on the extent that biomass fuels can be used to displace fossil transportation fuels, and their associated emissions of CO2, will be the land area available to produce the fuels and the efficiencies by which solar radiation can be converted to useable fuels. Currently, the Brazil cane-ethanol system captures 33% of the primary energy content in harvested cane in the form of ethanol. The US corn-ethanol system captures 54% of the primary energy of harvested corn kernels in the form of ethanol. If ethanol is used to substitute for gasoline, avoided fossil fuel CO2emissions would equal those of the substituted amount minus fossil emissions incurred in producing the cane- or corn-ethanol. In this case, avoided emissions are estimated to be 29% of harvested cane and 14% of harvested corn primary energy. Unless these efficiencies are substantially improved, the displacement of CO2emissions from transportation fuels in the United States is unlikely to reach 10% using domestic biofuels. Candidate technologies for improving these efficiencies include fermentation of cellulosic biomass and conversion of biomass into electricity, hydrogen, or alcohols for use in electric drive-train vehicles.
PROTECTING AGRICULTURAL CROPS FROM THE EFFECTS OF TROPOSPHERIC OZONE EXPOSURE: Reconciling Science and Standard Setting in the United States, Europe, and Asia
Authors: Mauzerall Denise L. , Wang Xiaoping
Published: July 2002

▪ Abstract  Ozone (O3) is well documented as the air pollutant most damaging to agricultural crops and other plants. Most crops in developed countries are grown in summer when O3 concentrations are elevated and frequently are sufficiently high to reduce yields. This article examines the difficulties in scientifically determining the reduction in yield that results from the exposure of agricultural crops to surface O3 and then transforming that knowledge into efficient and effective regulatory standards. The different approaches taken by the United States and Europe in addressing this issue as well as the few studies that have been conducted to date in developing countries are examined and summarized. Extensive research was conducted in the United States during the 1980s but has not been continued. During the 1990s, the European community forged ahead with scientific research and innovative proposals for air-quality standards. These efforts included the development of a “critical level” (CL) for O3 based on a cumulative exposure above a cutoff concentration below which only an acceptable level of harm is incurred. Current research focuses on estimating O3 dosage to plants and incorporating this metric into regulatory standards. The US regulatory community can learn from current European scientific research and regulatory strategies, which argue strongly for a separate secondary standard for O3 to protect vegetation. Increasing impacts of O3 on crops are likely in developing countries as they continue to industrialize and their emissions of air pollutants increase. More research is needed on surface O3 concentrations in developing countries, on their projected increase, and on the sensitivity that crop cultivars used in developing countries have to O3. The threat of reduced agricultural yields due to increasing O3 concentrations may encourage developing countries to increase their energy efficiency and to use different energy sources. This could simultaneously achieve a local benefit through improved regional air quality and a global benefit through a reduction in the emission of greenhouse gases.
RISK-SPREADING AND BET-HEDGING IN INSECT POPULATION BIOLOGY
Authors: Hopper Keith R.
Published: July 2002

▪ Abstract  In evolutionary ecology, risk-spreading (i.e. bet-hedging) is the idea that unpredictably variable environments favor genotypes with lower variance in fitness at the cost of lower arithmetic mean fitness. Variance in fitness can be reduced by physiology or behavior that spreads risk of encountering an unfavorable environment over time or space. Such risk-spreading can be achieved by a single phenotype that avoids risks (conservative risk-spreading) or by phenotypic variation expressed by a single genotype (diversified risk-spreading). Across these categories, three types of risk-spreading can be usefully distinguished: temporal, metapopulation, and within-generation. Theory suggests that temporal and metapopulation risk-spreading may work under a broad range of population sizes, but within-generation risk-spreading appears to work only when populations are small. Although genetic polymorphisms have sometimes been treated as risk-spreading, the underlying mechanisms are different, and they often require different conditions for their evolution and thus are better treated separately. I review the types of evidence that could be used to test for risk-spreading and discuss evidence for risk-spreading in facultative diapause, migration polyphenism, spatial distribution of oviposition, egg size, and other miscellaneous traits. Although risk-spreading theory is voluminous and well developed in some ways, rarely has it been used to generate detailed, testable hypotheses about the evolution of risk-spreading. Furthermore, although there is evidence for risk-spreading, particularly in facultative diapause, I have been unable to find any definitive tests with unequivocal results showing that risk-spreading has been a major factor in the evolution of insect behaviors or life histories. To advance our understanding of risk-spreading in the wild, we need (a) explicit empirical models that predict levels of diversifying risk-spreading for several insect populations in several environments that vary in uncertainty, and (b) tests of these models using measurements of phenotypes and their fitnesses over several generations in each environment.
The Population Biology of Oak Gall Wasps (Hymenoptera: Cynipidae)
Authors: Stone Graham N. , Schönrogge Karsten , Atkinson Rachel J. , Bellido David , Pujade-Villar Juli
Published: July 2002

▪ Abstract  Oak gall wasps (Hymenoptera: Cynipidae, Cynipini) are characterized by possession of complex cyclically parthenogenetic life cycles and the ability to induce a wide diversity of highly complex species- and generation-specific galls on oaks and other Fagaceae. The galls support species-rich, closed communities of inquilines and parasitoids that have become a model system in community ecology. We review recent advances in the ecology of oak cynipids, with particular emphasis on life cycle characteristics and the dynamics of the interactions between host plants, gall wasps, and natural enemies. We assess the importance of gall traits in structuring oak cynipid communities and summarize the evidence for bottom-up and top-down effects across trophic levels. We identify major unanswered questions and suggest approaches for the future.
CONVECTION IN MUSHY LAYERS
Authors: Worster M. Grae
Published: July 2002

▪ Abstract  As a molten alloy or any multi-component liquid is cooled and solidified the growing solid phase usually forms a porous matrix through which the residual liquid can flow. The reactive two-phase medium comprising the solid matrix and residual liquid is called a mushy layer. Buoyancy forces, owing primarily to compositional depletion as one or more of the components of the alloy are extracted to form the solid phase, can drive convection in the layer. In this review, I present an account of various studies of buoyancy-driven convection in mushy layers, paying particular attention to the complex interactions between solidification and flow that lead to novel styles of convective behavior, including focusing of the flow to produce chimneys: narrow, vertical channels devoid of solid. I define an ‘ideal’ mushy layer and argue that chimneys are an inevitable consequence of convection in ideal mushy layers. The absence of chimneys in certain laboratory experiments is explained in terms of nonideal effects.
FLOW CONTROL WITH NONCIRCULAR JETS
Authors: Gutmark E. J. , Grinstein F. F.
Published: July 2002

▪ Abstract  Noncircular jets have been the topic of extensive research in the last fifteen years. These jets were identified as an efficient technique of passive flow control that allows significant improvements of performance in various practical systems at a relatively low cost because noncircular jets rely solely on changes in the geometry of the nozzle. The applications of noncircular jets discussed in this review include improved large- and small-scale mixing in low- and high-speed flows, and enhanced combustor performance, by improving combustion efficiency, reducing combustion instabilities and undesired emissions. Additional applications include noise suppression, heat transfer, and thrust vector control (TVC).

The flow patterns associated with noncircular jets involve mechanisms of vortex evolution and interaction, flow instabilities, and fine-scale turbulence augmentation. Stability theory identified the effects of initial momentum thickness distribution, aspect ratio, and radius of curvature on the initial flow evolution. Experiments revealed complex vortex evolution and interaction related to self-induction and interaction between azimuthal and axial vortices, which lead to axis switching in the mean flow field. Numerical simulations described the details and clarified mechanisms of vorticity dynamics and effects of heat release and reaction on noncircular jet behavior.

The research on noncircular jets has also led to technology transfer. A topic that started as an academic curiosity—an interesting flow phenomenon—subsequently has had various industrial applications. The investigations reviewed include experimental, theoretical, numerical, and technological aspects of the subject.
Passive Scalars in Turbulent Flows
Authors: Warhaft Z.
Published: July 2002

▪ Abstract  Passive scalar behavior is important in turbulent mixing, combustion, and pollution and provides impetus for the study of turbulence itself. The conceptual framework of the subject, strongly influenced by the Kolmogorov cascade phenomenology, is undergoing a drastic reinterpretation as empirical evidence shows that local isotropy, both at the inertial and dissipation scales, is violated. New results of the complex morphology of the scalar field are reviewed, and they are related to the intermittency problem. Recent work on other aspects of passive scalar behavior—its spectrum, probability density function, flux, and variance—is also addressed.
PROGRAMMED TRANSLATIONAL FRAMESHIFTING
Authors: Farabaugh P. J.
Published: July 2002

▪ Abstract  Errors that alter the reading frame occur extremely rarely during translation, yet some genes have evolved sequences that efficiently induce frameshifting. These sequences, termed programmed frameshift sites, manipulate the translational apparatus to promote non-canonical decoding.

Frameshifts are mechanistically diverse. Most cause a −1 shift of frames; the first such site was discovered in a metazoan retrovirus, but they are now known to be dispersed quite widely among evolutionarily diverse species. +1 frameshift sites are much less common, but again dispersed widely. The rarest form are the translational hop sites which program the ribosome to bypass a region of several dozen nucleotides. Each of these types of events are stimulated by distinct mechanisms. All of the events share a common phenomenology in which the programmed frameshift site causes the ribosome to pause during elongation so that the kinetically unfavorable alternative decoding event can occur. During this pause most frameshifts occur because one or more ribosome-bound tRNAs slip between cognate or near-cognate codons. However, even this generalization is not entirely consistent, since some frameshifts occur without slippage. Because of their similarity to rarer translational errors, programmed frameshift sites provide a tool with which to probe the mechanism of frame maintenance.
Mammalian DNA Mismatch Repair
Authors: Buermeyer Andrew B. , Deschênes Suzanne M. , Baker Sean M. , Liskay R. Michael
Published: July 2002

▪ Abstract  DNA mismatch repair (MMR) is one of multiple replication, repair, and recombination processes that are required to maintain genomic stability in prokaryotes and eukaryotes. In the wake of the discoveries that hereditary nonpolyposis colorectal cancer (HNPCC) and other human cancers are associated with mutations in MMR genes, intensive efforts are under way to elucidate the biochemical functions of mammalian MutS and MutL homologs, and the consequences of defects in these genes. Genetic studies in cultured mammalian cells and mice are proving to be instrumental in defining the relationship between the functions of MMR in mutation and tumor avoidance. Furthermore, these approaches have raised awareness that MMR homologs contribute to DNA damage surveillance, transcription-coupled repair, and recombinogenic and meiotic processes.
Immunotoxins: An Update
Authors: Thrush Gerald R. , Lark Laura R. , Clinchy Birgitta C. , Vitetta Ellen S.
Published: July 2002

The use of immunotoxins (ITs) in the therapy of cancer, graft-vs-host disease (GvHD), autoimmune diseases, and AIDS has been ongoing for the past two decades. ITs contain a targeting moiety for delivery and a toxic moiety for cytotoxicity. Theoretically, one molecule of a toxin, routed to the appropriate cellular compartment, will be lethal to a cell. Newly developed MoAbs, toxins, and molecular biological technologies have enabled researchers to construct ITs that can effectively kill many different cell types. In fact, phase I/II clinical trials have given promising results. Although nonspecific toxicity and immunogenicity still limit the use of IT therapy, these agents hold enormous promise in an optimal setting to treat minimal disease.
T Cell Activation and the Cytoskeleton
Authors: Acuto Oreste , Cantrell Doreen
Published: July 2002

Ligation of the T cell antigen receptor (TCR) stimulates protein tyrosine kinases (PTKs), which regulate intracellular calcium and control the activity of protein kinase C (PKC) isozymes. PTKs activated by antigen receptors and costimulatory molecules also couple to phosphatidylinositol-3 kinase (PI3K) and control the activity of Ras- and Rho-family GTPases. T cell signal transduction is triggered physiologically by antigen in the context of antigen presenting cells (APC). The formation of stable and prolonged contacts between T cells and APCs is not neccessary to initiate T cell signaling but is required for effective T cell proliferation and differentiation. The stabilization of the T cell/ APC conjugate is regulated by intracellular signals induced by antigen receptors and costimulators. These coordinate the regulation of the actin and microtubule cytoskeleton and organize a specialized signaling zone that allows sustained TCR signaling.
Molecular Genetics of Allergic Diseases
Authors: Ono Santa Jeremy
Published: July 2002

Allergic diseases affect approximately one third of the general population. This class of disease, characterized by elevated serum IgE levels and hypersensitivity to normally innocuous antigen, can manifest in practically any mucosal tissue or as a systemic response. A few examples of serious allergic diseases include asthma, dermatitis, bee sting allergy, food allergy, conjunctivitis, and severe systemic anaphylaxis. Taken together, allergic diseases constitute one of the major problems of modern day medicine. A considerable portion of the healthcare budget is expended in the treatment of allergic disease, and morbidity rates of inner city asthmatics are rising steadily. Due to the enormity of the problem, there has been a worldwide effort to identify factors that contribute to the etiology of allergic diseases. Epidemiologic studies of multigeneration families and large numbers of twins clearly indicate a strong genetic component to atopic diseases. At least two independently segregating diseasesusceptibility genes are thought to come together with environmental factors to result in allergic inflammation in a particular tissue. On the basis of the strong genetic studies, multiple groups have attempted to identify disease-susceptibility genes via either a candidate gene approach or by genome-wide scans. Both of these approaches have implicated multiple regions in the human and mouse genomes, which are currently being evaluated as harboring putative atopy genes.
E Protein Function in Lymphocyte Development
Authors: Quong Melanie W. , Romanow William J. , Murre Cornelis
Published: July 2002

Lymphocytes arise from hematopoietic stem cells through the coordinated action of transcription factors. The E proteins (E12, E47, HEB and E2-2) have emerged as key regulators of both B and T lymphocyte differentiation. This review summarizes the current data and examines the various functions of E proteins and their antagonists, Id2 and Id3, throughout lymphoid maturation. Beyond an established role in B and T lineage commitment, E proteins continue to be essential at subsequent stages of development. E protein activity regulates the expression of surrogate and antigen receptor genes, promotes Ig and TCR rearrangements, and coordinates cell survival and proliferation with developmental progression in response to TCR signaling. Finally, this review also discusses the role of E47 as a tumor suppressor.
Protein Kinase Cθ in T Cell Activation
Authors: Isakov Noah , Altman Amnon
Published: July 2002

The novel protein kinase C (PKC) isoform, PKCθ, is selectively expressed in T lymphocytes and is a sine qua non for T cell antigen receptor (TCR)-triggered activation of mature T cells. Productive engagement of T cells by antigen-presenting cells (APCs) results in recruitment of PKCθ to the T cell–APC contact area—the immunological synapse—where it interacts with several signaling molecules to induce activation signals essential for productive T cell activation and IL-2 production. The transcription factors NF-κB and AP-1 are the primary physiological targets of PKCθ, and efficient activation of these transcription factors by PKCθ requires integration of TCR and CD28 costimulatory signals. PKCθ cooperates with the protein Ser/Thr phosphatase, calcineurin, in transducing signals leading to activation of JNK, NFAT, and the IL-2 gene. PKCθ also promotes T cell cycle progression and regulates programmed T cell death. The exact mode of regulation and immediate downstream substrates of PKCθ are still largely unknown. Identification of these molecules and determination of their mode of operation with respect to the function of PKCθ will provide essential information on the mechanism of T cell activation. The selective expression of PKCθ in T cells and its essential role in mature T cell activation establish it as an attractive drug target for immunosuppression in transplantation and autoimmune diseases.
Phagocytosis of Microbes: Complexity in Action
Authors: Underhill David M. , Ozinsky Adrian
Published: July 2002

The phagocytic response of innate immune cells such as macrophages is defined by the activation of complex signaling networks that are stimulated by microbial contact. Many individual proteins have been demonstrated to participate in phagocytosis, and the application of high-throughput tools has indicated that many more remain to be described. In this review, we examine this complexity and describe how during recognition, multiple receptors are simultaneously engaged to mediate internalization, activate microbial killing, and induce the production of inflammatory cytokines and chemokines. Many signaling molecules perform multiple functions during phagocytosis, and these molecules are likely to be key regulators of the process. Indeed, pathogenic microorganisms target many of these molecules in their attempts to evade destruction.
THE ROLE OF METASTABLE STATES IN POLYMER PHASE TRANSITIONS: Concepts, Principles, and Experimental Observations
Authors: Cheng Stephen Z. D. , Keller Andrew
Published: July 2002

▪ Abstract  Polymer phases can be described in the same way as phases in other condensed matter using a number density operator and its correlation functions. This description requires the understanding of symmetry operations and order at different atomic and molecular levels. Statistical mechanics provides a link between the microscopic description of the structure and motion and the macroscopic thermodynamic properties. Within the limits of the laws of thermodynamics, polymers exhibit a rich variety of phase transition behaviors. By definition, a first-order phase transition describes a transformation that involves a sudden change of thermodynamic properties at its transition temperature, whereas higher-order phase transitions are classified as critical phenomena. Of special interest is the role of metastability in phase and phase transition behaviors. Although a metastable state possesses a local free energy minimum, it is not at the global equilibrium. Furthermore, metastable states can also be associated with phase sizes. Metastable behavior is also observed in phase transformations that are impeded by kinetic limitations along the pathway to thermodynamic equilibrium. This is illustrated in structural and morphological investigations of crystallization and mesophase transitions, liquid-liquid phase separation, vitrification, and gel formation, as well as combinations of transformation processes. In these cases, the metastable state often becomes the dominant state for the entire system and is observed over a range of time and size scales. This review describes the general principles of metastability in polymer phases and phase transitions and provides illustrations from current experimental works in selected areas.
The Electronic Structure of Semiconductor Nanocrystals
Authors: Efros Al. L. , Rosen M.
Published: July 2002

▪ Abstract  We review the rapid progress made in our understanding of the crystal properties of semiconductors and nanocrystals focussing on theoretical results obtained within the multiband effective mass approximation. A comparison with experiment shows these results are valid for nanocrystals down 22–26 Å in diameter. The effect of the electron-hole Coulomb interaction on the optical spectra is analyzed. A theory of the quantum–size levels in wide gap (CdSe) and narrow gap semiconductors (InAs) is presented that describes the absorption spectra of these semiconductors well. A great enhancement of the electron-hole exchange interaction leads to the formation of the optically forbidden Dark Exciton in nanocrystals, which strongly affects their photoluminescence. A theory of the band-edge exciton fine structure is presented and applied to the study of the PL in CdSe nanocrystals. The effect of doping on nanocrystal spectra is considered. The enhancement of the short–range spin-spin interaction in Mn-doped nanocrystals leads to a giant splitting of the electron and hole spin sublevels.
ORAL TOLERANCE FOR THE TREATMENT OF AUTOIMMUNE DISEASES
Authors: Weiner, MD Howard L.
Published: July 2002

▪ Abstract  Orally administered autoantigens suppress autoimmunity in animal models, including experimental allergic encephalomyelitis, collagen and adjuvant-induced arthritis, uveitis, and diabetes in the non-obese diabetic mouse. Low doses of oral antigen induce antigen-specific regulatory T-cells in the gut, which act by releasing inhibitory cytokines such as transforming growth factor-β, interleukin-4, and interleukin-10 at the target organ. Thus, one can suppress inflammation at a target organ by orally administering an antigen derived from the site of inflammation, even if it is not the target of the autoimmune response. Initial human trials of orally administered antigen have shown positive findings in patients with multiple sclerosis and rheumatoid arthritis. A double-blind, placebo-controlled, phase III multi-center trial of oral myelin in 515 relapsing-remitting multiple sclerosis patients is in progress, as are phase II clinical trials investigating the oral administration of type II collagen in rheumatoid arthritis, S-antigen in uveitis, and insulin in type I diabetes.
How to Screen for Colon Cancer
Authors: Lieberman David
Published: July 2002

The biology of colorectal cancer provides a unique opportunity for early detection and prevention. There is now evidence that screening of asymptomatic average-risk individuals over 50 years of age can reduce mortality resulting from colorectal cancer. New recommendations from the US Preventive Services Task Force endorse screening with fecal occult blood tests or sigmoidoscopy. The best method for population screening remains uncertain. The cost of screening is an important issue in the development of public policy. This review discusses the various screening options, examines the “downstream” effects of screening, and reviews the anticipated costs and effectiveness. Ultimately, the effectiveness of any screening program depends on patient compliance. Further research is needed to determine the best methods of enhancing patient adherence to a screening program.
Homocysteine and Cardiovascular Disease
Authors: Refsum H. , Ueland P. M. , Nygård O. , Vollset S. E.
Published: July 2002

An elevated level of total homocysteine (tHcy) in blood, denoted hyperhomocysteinemia, is emerging as a prevalent and strong risk factor for atherosclerotic vascular disease in the coronary, cerebral, and peripheral vessels, and for arterial and venous thromboembolism. The basis for these conclusions is data from about 80 clinical and epidemiological studies including more than 10,000 patients. Elevated tHcy confers a graded risk with no threshold, is independent of but may enhance the effect of the conventional risk factors, and seems to be a particularly strong predictor of cardiovascular mortality. Hyperhomocysteinemia is attributed to commonly occurring genetic and acquired factors including deficiencies of folate and vitamin B12. Supplementation with B-vitamins, in particular with folic acid, is an efficient, safe, and inexpensive means to reduce an elevated tHcy level. Studies are now in progress to establish whether such therapy will reduce cardiovascular risk.
Immunologic Therapy of Multiple Sclerosis
Authors: Arnason, MD Barry G. W.
Published: July 2002

Three interferon β preparations (Betaseron®, Avonex®, and Rebif®) have shown efficacy in the treatment of relapsing-remitting multiple sclerosis (MS). Attack frequency is reduced by 30% and major attacks to an even greater extent. Accumulating disease burden as measured by annual T2-weighted magnetic resonance imaging is markedly lessened, and disease activity as measured by serial gadolinium-enhanced MRI scanning is reduced by over 80%. A fourth preparation, Copaxone®, a basic copolymer of four amino acids, lessens MS attack frequency by 30% and also lessens disease activity as measured by gadolinium-enhanced MRI. Betaseron® lessens accumulation of disability in MS patients with secondary progressive disease regardless of the severity of disability at the time treatment is commenced. MS is now a treatable disease.
The Prognostic Significance of Altered Cyclin-Dependent Kinase Inhibitors in Human Cancer
Authors: Tsihlias, MD, FRCSC J. , Kapusta, MD, FRCPC L. , Slingerland, MD, FRCPC, PhD J.
Published: July 2002

Progression through the cell cycle is governed by cyclin-dependent kinases (cdks), whose activity is inhibited by the cdk inhibitors. Cyclins, cdks, and cdk inhibitors are frequently deregulated in cancers. This chapter reviews the prognostic significance of alterations in cdk inhibitors. Loss of p27 protein provides independent prognostic information in breast, prostate, colon, and gastric carcinomas, and immunohistochemical (IHC) staining for p27 may eventually become part of routine histopathologic processing of cancers. Loss of IHC staining for p21 may be prognostic in certain cancers but conflicting results are reported in breast cancer. Reports on homozygous deletion of p16 and p15 genes suggest the value of larger, prospective studies with standardized treatment protocols to definitively establish the prognostic utility of p15/p16 deletions in acute leukemias. Larger trials and the development of a consensus on methods for deletion analysis, IHC staining, and tumor scoring will be needed to move these molecular assays from bench to bedside.
Natural History and Preventative Treatment of Recurrent Mood Disorders
Authors: Frank, PhD Ellen , Thase, MD Michael E.
Published: July 2002

This chapter focuses on recent developments in our understanding of the etiology, epidemiology, and treatment of recurrent mood disorders. It addresses the changing relationship between endogenous and exogenous factors over time in the etiology of mood episodes. In the area of epidemiology, the chapter presents new information on the prevalence of various subtypes and male/female differences in lifetime risk. Complications of the mood disorders, such as suicide, and important comorbidities, including alcoholism and substance abuse, are discussed. In the area of treatment, the life-long nature of many of the mood disorders is described, as is the consequent role of the primary care physician in their management. The evidence for the efficacy of the depression-specific psychotherapies, cognitive therapy and interpersonal therapy, is reviewed. Current issues in the pharmacotherapy of mood disorders are discussed, including the relative efficacy of the older antidepressants versus the newer selective serotonin reuptake inhibitors (SSRIs) and the treatment of various subtypes of mood disorders, including dysthymia, chronic depression, and atypical depression. Finally, the chapter describes recent advances in the treatment of bipolar disorder.
Carotid Artery Dissection
Authors: Stapf C. , Elkind M. S. V. , Mohr J. P.
Published: July 2002

Among the large variety of cerebrovascular syndromes, carotid artery dissections remain often under-recognized. Many patients present with minor or transient symptoms, some with local pain only, and some are asymptomatic. A useful rule is that the coincidence of any local pain in neck or face with an ipsilateral Horner’s syndrome preceding transient or persistent retinal or cerebral ischemic symptoms should alert physicians—notably those treating emergencies—to rule out an underlying dissection of the ipsilateral carotid artery. In most cases the extracranial part of the carotid artery is affected; therefore, this review will focus on this main subgroup of patients. We review the pathological anatomy, as well as possible underlying causes, clinical features, diagnostic tools, differential diagnosis, treatment options, and outcome data.