ALBERT

Notes: Abstract Physical detection of antigen-specific CD4 T cells has revealed features of the in vivo immune response that were not appreciated from in vitro studies. In vivo, antigen is initially presented to naive CD4 T cells exclusively by dendritic cells within the T cell areas of secondary lymphoid tissues. Anatomic constraints make it likely that these dendritic cells acquire the antigen at the site where it enters the body. Inflammation enhances in vivo T cell activation by stimulating dendritic cells to migrate to the T cell areas and display stable peptide-MHC complexes and costimulatory ligands. Once stimulated by a dendritic cell, antigen-specific CD4 T cells produce IL-2 but proliferate in an IL-2-independent fashion. Inflammatory signals induce chemokine receptors on activated T cells that direct their migration into the B cell areas to interact with antigen-specific B cells. Most of the activated T cells then die within the lymphoid tissues. However, in the presence of inflammation, a population of memory T cells survives. This population is composed of two functional classes. One recirculates through nonlymphoid tissues and is capable of immediate effector lymphokine production. The other recirculates through lymph nodes and quickly acquires the capacity to produce effector lymphokines if stimulated. Therefore, antigenic stimulation in the presence of inflammation produces an increased number of specific T cells capable of producing effector lymphokines throughout the body.

Notes: Abstract Rheumatoid arthritis (RA), a systemic disease, is characterized by a chronic inflammatory reaction in the synovium of joints and is associated with degeneration of cartilage and erosion of juxta-articular bone. Many pro-inflammatory cytokines including TNFalpha, chemokines, and growth factors are expressed in diseased joints. The rationale that TNFalpha played a central role in regulating these molecules, and their pathophysiological potential, was initially provided by the demonstration that anti-TNFalpha antibodies added to in vitro cultures of a representative population of cells derived from diseased joints inhibited the spontaneous production of IL-1 and other pro-inflammatory cytokines. Systemic administration of anti-TNFalpha antibody or sTNFR fusion protein to mouse models of RA was shown to be anti-inflammatory and joint protective. Clinical investigations in which the activcity of TNFalpha in RA patients was blocked with intravenously administered infliximab, a chimeric anti-TNFalpha monoclonal antibody (mAB), has provided evidence that TNF regulates IL-6, IL-8, MCP-1, and VEGF production, recruitment of immune and inflammatory cells into joints, angiogenesis, and reduction of blood levels of matrix metalloproteinases-1 and -3. Randomized, placebo-controlled, multi-center clinical trials of human TNFalpha inhibitors have demonstrated their consistent and remarkable efficacy in controlling signs and symptoms, with a favorable safety profile, in approximately two thirds of patients for up to 2 years, and their ability to retard joint damage. Infliximab (a mAB), and etanercept (a sTNF-R-Fc fusion protein) have been approved by regulatory authorities in the United States and Europe for treating RA, and they represent a significant new addition to available therapeutic options.

Notes: Abstract Natural killer cells can discriminate between normal cells and cells that do not express adequate amounts of major histocompatibility complex (MHC) class I molecules. The discovery, both in mouse and in human, of MHC-specific inhibitory receptors clarified the molecular basis of this important NK cell function. However, the triggering receptors responsible for positive NK cell stimulation remained elusive until recently. Some of these receptors have now been identified in humans, thus shedding some light on the molecular mechanisms involved in NK cell activation during the process of natural cytotoxicity. Three novel, NK-specific, triggering surface molecules (NKp46, NKp30, and NKp44) have been identified. They represent the first members of a novel emerging group of receptors collectively termed natural cytotoxicity receptors (NCR). Monoclonal antibodies (mAbs) to NCR block to differing extents the NK-mediated lysis of various tumors. Moreover, lysis of certain tumors can be virtually abrogated by the simultaneous masking of the three NCRs. There is a coordinated surface expression of the three NCRs, their surface density varying in different individuals and also in the NK cells isolated from a given individual. A direct correlation exists between the surface density of NCR and the ability of NK cells to kill various tumors. NKp46 is the only NCR involved in human NK-mediated killing of murine target cells. Accordingly, a homologue of NKp46 has been detected in mouse. Molecular cloning of NCR revealed novel members of the Ig superfamily displaying a low degree of similarity to each other and to known human molecules. NCRs are coupled to different signal transducing adaptor proteins, including CD3zeta, FcRIgamma, and KARAP/DAP12. Another triggering NK receptor is NKG2D. It appears to play either a complementary or a synergistic role with NCRs. Thus, the triggering of NK cells in the process of tumor cell lysis may often depend on the concerted action of NCR and NKG2D. In some instances, however, it may uniquely depend upon the activity of NCR or NKG2D only. Strict NKG2D-dependency can be appreciated using clones that, in spite of their NCRdull phenotype, efficiently lyse certain epithelial tumors or leukemic cell lines. Other triggering surface molecules including 2B4 and the novel NKp80 appear to function as coreceptors rather than as true receptors. Indeed, they can induce natural cytotoxicity only when co-engaged with a triggering receptor. While an altered expression or function of NCR or NKG2D is being explored as a possible cause of immunological disorders, 2B4 dysfunction has already been associated with a severe form of immunodeficiency. Indeed, in patients with the X-linked lymphoproliferative disease, the inability to control Epstein-Barr virus infections may be consequent to a major dysfunction of 2B4 that exerts inhibitory instead of activating functions.

Notes: Abstract Elevation of intracellular free Ca2+ is one of the key triggering signals for T-cell activation by antigen. A remarkable variety of Ca2+ signals in T cells, ranging from infrequent spikes to sustained oscillations and plateaus, derives from the interactions of multiple Ca2+ sources and sinks in the cell. Following engagement of the T cell receptor, intracellular channels (IP3 and ryanodine receptors) release Ca2+ from intracellular stores, and by depleting the stores trigger prolonged Ca2+ influx through store-operated Ca2+ (CRAC) channels in the plasma membrane. The amplitude and dynamics of the Ca2+ signal are shaped by several mechanisms, including K+ channels and membrane potential, slow modulation of the plasma membrane Ca2+-ATPase, and mitochondria that buffer Ca2+ and prevent the inactivation of CRAC channels. Ca2+ signals have a number of downstream targets occurring on multiple time scales. At short times, Ca2+ signals help to stabilize contacts between T cells and antigen-presenting cells through changes in motility and cytoskeletal reorganization. Over periods of minutes to hours, the amplitude, duration, and kinetic signature of Ca2+ signals increase the efficiency and specificity of gene activation events. The complexity of Ca2+ signals contains a wealth of information that may help to instruct lymphocytes to choose between alternate fates in response to antigenic stimulation.

Notes: Abstract B cell development is a highly regulated process whereby functional peripheral subsets are produced from hematopoietic stem cells, in the fetal liver before birth and in the bone marrow afterward. Here we review progress in understanding some aspects of this process in the mouse bone marrow, focusing on delineation of the earliest stages of commitment, on pre-B cell receptor selection, and B cell tolerance during the immature-to-mature B cell transition. Then we note some of the distinctions in hematopoiesis and pre-B selection between fetal liver and adult bone marrow, drawing a connection from fetal development to B-1/CD5+ B cells. Finally, focusing on CD5+ cells, we consider the forces that influence the generation and maintenance of this distinctive peripheral B cell population, enriched for natural autoreactive specificities that are encoded by particular germline VH-VL combinations.

Notes: Abstract CD8 T cells respond to viral infections but also participate in defense against bacterial and protozoal infections. In the last few years, as new methods to accurately quantify and characterize pathogen-specific CD8 T cells have become available, our understanding of in vivo T cell responses has increased dramatically. Pathogen-specific T cells, once thought to be quite rare following infection, are now known to be present at very high frequencies, particularly in peripheral, nonlymphoid tissues. With the ability to visualize in vivo CD8 T cell responses has come the recognition that T cell expansion is programmed and, to a great extent, independent of antigen concentrations. Comparison of CD8 T cell responses to different pathogens also highlights the intricate relationship between microbially induced innate inflammatory responses and the kinetics, magnitude, and character of long-term T cell responses. This review describes recent progress in some of the major murine models of CD8 T cell-mediated immunity to viral, bacterial, and protozoal infection.

Notes: Abstract A functional immune system requires the selection of T lymphocytes expressing receptors that are major histocompatibility complex restricted but tolerant to self-antigens. This selection occurs predominantly in the thymus, where lymphocyte precursors first assemble a surface receptor. In this review we summarize the current state of the field regarding the natural ligands and molecular factors required for positive and negative selection and discuss a model for how these disparate outcomes can be signaled via the same receptor. We also discuss emerging data on the selection of regulatory T cells. Such cells require a high-affinity interaction with self-antigens, yet differentiate into regulatory cells instead of being eliminated.

Notes: Abstract In the absence of antiretroviral treatment, HIV-1 establishes a chronic, progressive infection of the human immune system that invariably, over the course of years, leads to its destruction and fatal immunodeficiency. Paradoxically, while viral replication is extensive throughout the course of infection, deterioration of conventional measures of immunity is slow, including the characteristic loss of CD4+ T cells that is thought to play a key role in the development of immunodeficiency. This conundrum suggests that CD4+ T cell-directed viral cytopathicity alone cannot explain the course of disease. Indeed, recent advances now indicate that HIV-1 pathogenesis is likely to result from a complex interplay between the virus and the immune system, particularly the mechanisms responsible for T cell homeostasis and regeneration. We review these data and present a model of HIV-1 pathogenesis in which the protracted loss of CD4+ T cells results from early viral destruction of selected memory T cell populations, followed by a combination of profound increases in overall memory T cell turnover, damage to the thymus and other lymphoid tissues, and physiological limitations in peripheral CD4+ T cell renewal.

Notes: Abstract IL-13 was first recognized for its effects on B cells and monocytes, where it upregulated class II expression, promoted IgE class switching and inhibited inflammatory cytokine production. It was also thought to be functionally redundant with IL-4. However, studies conducted with knockout mice, neutralizing antibodies, and novel antagonists demonstrate that IL-13 possesses several unique effector functions that distinguish it from IL-4. Resistance to most gastrointestinal nematodes is mediated by type-2 cytokine responses, in which IL-13 plays a dominant role. By regulating cell-mediated immunity, IL-13 modulates resistance to intracellular organisms including Leishmania major, Leishmania mexicana, and Listeria monocytogenes. In the lung, IL-13 is the central mediator of allergic asthma, where it regulates eosinophilic inflammation, mucus secretion, and airway hyperresponsiveness. Manipulation of IL-13 effector function may also prove useful in the treatment of some cancers like B-cell chronic lymphocytic leukemia and Hodgkin's disease, where IL-13 modulates apoptosis or tumor cell growth. IL-13 can also inhibit tumor immunosurveillance. As such, inhibitors of IL-13 might be effective as cancer immunotherapeutics by boosting type-1-associated anti-tumor defenses. Finally, IL-13 was revealed as a potent mediator of tissue fibrosis in both schistosomiasis and asthma, which indicates that it is a key regulator of the extracellular matrix. The mechanisms that regulate IL-13 production and/or function have also been investigated, and IL-4, IL-12, IL-18, IFN-gamma, IL-10, TGF-beta, TNF-alpha, and the IL-4/IL-13 receptor complex play important roles. This review highlights the effector functions of IL-13 and describes multiple pathways for modulating its activity in vivo.

Notes: Abstract Collectins and ficolins, present in plasma and on mucosal surfaces, are humoral molecules of the innate immune systems, which recognize pathogen-associated molecular patterns. The human collectins, mannan-binding lectin (MBL) and surfactant protein A and D (SP-A and SP-D), are oligomeric proteins composed of carbohydrate-recognition domains (CRDs) attached to collagenous regions and are thus structurally similar to the ficolins, L-ficolin, M-ficolin, and H-ficolin. However, they make use of different CRD structures: C-type lectin domains for the collectins and fibrinogen-like domains for the ficolins. Upon recognition of the infectious agent, MBL and the ficolins initiate the lectin pathway of complement activation through attached serine proteases (MASPs), whereas SP-A and SP-D rely on other effector mechanisms: direct opsonization, neutralization, and agglutination. This limits the infection and concurrently orchestrates the subsequent adaptive immune response. Deficiencies of the proteins may predispose to infections or other complications, e.g., reperfusion injuries or autoimmune diseases. Structure, function, clinical implications, and phylogeny are reviewed.

Notes: Abstract The T helper lymphocyte is responsible for orchestrating the appropriate immune response to a wide variety of pathogens. The recognition of the polarized T helper cell subsets Th1 and Th2 has led to an understanding of the role of these cells in coordinating a variety of immune responses, both in responses to pathogens and in autoimmune and allergic disease. Here, we discuss the mechanisms that control lineage commitment to the Th1 phenotype. What has recently emerged is a rich understanding of the cytokines, receptors, signal transduction pathways, and transcription factors involved in Th1 differentiation. Although the picture is still incomplete, the basic pathways leading to Th1 differentiation can now be understood in in vitro and a number of infection and disease models.

Notes: Abstract Dendritic cells (DCs) have several functions in innate and adaptive immunity. In addition, there is increasing evidence that DCs in situ induce antigen-specific unresponsiveness or tolerance in central lymphoid organs and in the periphery. In the thymus DCs generate tolerance by deleting self-reactive T cells. In peripheral lymphoid organs DCs also induce tolerance to antigens captured by receptors that mediate efficient uptake of proteins and dying cells. Uptake by these receptors leads to the constitutive presentation of antigens on major histocompatibility complex (MHC) class I and II products. In the steady state the targeting of DC antigen capture receptors with low doses of antigens leads to deletion of the corresponding T cells and unresponsiveness to antigenic rechallenge with strong adjuvants. In contrast, if a stimulus for DC maturation is coadministered with the antigen, the mice develop immunity, including interferon-gamma-secreting effector T cells and memory T cells. There is also new evidence that DCs can contribute to the expansion and differentiation of T cells that regulate or suppress other immune T cells. One possibility is that distinct developmental stages and subsets of DCs and T cells can account for the different pathways to peripheral tolerance, such as deletion or suppression. We suggest that several clinical situations, including autoimmunity and certain infectious diseases, can be influenced by the antigen-specific tolerogenic role of DCs.

Notes: Abstract B cell chronic lymphocytic leukemia (B-CLL) is an accumulative disease of slowly proliferating CD5+ B lymphocytes that develops in the aging population. Whereas some patients with B-CLL have an indolent course and die after many years from unrelated causes, others progress very rapidly and succumb within a few years from this currently incurable leukemia. Over the past decade studies of the structure and function of the B cell antigen receptor (BCR) used by these leukemic cells have helped redefine the nature of this disease. In this review we summarize and reinterpret several aspects of these BCR-related studies and how they might relate to the disease. In particular, we address the ability of antigens to select out and drive B cell clones from the normal state to overt leukemic cells by binding to BCRs that are relatively unique and characteristic of B-CLL cells. The differential capacity of some B-CLL cases to continue to transduce signals through the BCR during the leukemic phase and the consequences for the in vivo biology of the leukemic clone is also considered. Finally, we discuss current and emerging views of the cellular origin of B-CLL cells and the differentiation pathways down which we believe these cells progress.

Notes: Abstract Tolerance to beta cell autoantigens represents a fragile equilibrium. Autoreactive T cells specific to these autoantigens are present in most normal individuals but are kept under control by a number of peripheral tolerance mechanisms, among which CD4+ CD25+ CD62L+ T cell-mediated regulation probably plays a central role. The equilibrium may be disrupted by inappropriate activation of autoantigen-specific T cells, notably following to local inflammation that enhances the expression of the various molecules contributing to antigen recognition by T cells. Even when T cell activation finally overrides regulation, stimulation of regulatory cells by CD3 antibodies may reset the control of autoimmunity. Other procedures may also lead to disease prevention. These procedures are essentially focused on Th2 cytokines, whether used systemically or produced by Th2 cells after specific stimulation by autoantigens. Protection can also be obtained by NK T cell stimulation. Administration of beta cell antigens or CD3 antibodies is now being tested in clinical trials in prediabetics and/or recently diagnosed diabetes.

Notes: Abstract Since the description of the first mouse knockout for an IgG Fc receptor seven years ago, considerable progress has been made in defining the in vivo functions of these receptors in diverse biological systems. The role of activating FcgammaRs in providing a critical link between ligands and effector cells in type II and type III inflammation is now well established and has led to a fundamental revision of the significance of these receptors in initiating cellular responses in host defense, in determining the efficacy of therapeutic antibodies, and in pathological autoimmune conditions. Considerable progress has been made in the last two years on the in vivo regulation of these responses, through the appreciation of the importance of balancing activation responses with inhibitory signaling. The inhibitory FcR functions in the maintenance of peripheral tolerance, in regulating the threshold of activation responses, and ultimately in terminating IgG mediated effector stimulation. The consequences of deleting the inhibitory arm of this system are thus manifested in both the afferent and efferent immune responses. The hyperresponsive state that results leads to greatly magnified effector responses by cytotoxic antibodies and immune complexes and can culminate in autoimmunity and autoimmune disease when modified by environmental or genetic factors. FcgammaRs offer a paradigm for the biological significance of balancing activation and inhibitory signaling in the expanding family of activation/inhibitory receptor pairs found in the immune system.

Notes: Abstract The adaptive immune response is initiated by the interaction of T cell antigen receptors with major histocompatibility complex molecule-peptide complexes in the nanometer scale gap between a T cell and an antigen-presenting cell, referred to as an immunological synapse. In this review we focus on the concept of immunological synapse formation as it relates to membrane structure, T cell polarity, signaling pathways, and the antigen-presenting cell. Membrane domains provide an organizational principle for compartmentalization within the immunological synapse. T cell polarization by chemokines increases T cell sensitivity to antigen. The current model is that signaling and formation of the immunological synapse are tightly interwoven in mature T cells. We also extend this model to natural killer cell activation, where the inhibitory NK synapse provides a striking example in which inhibition of signaling leaves the synapse in its nascent, inverted state. The APC may also play an active role in immunological synapse formation, particularly for activation of naive T cells.

Notes: Abstract A broad array of biological responses, including cell polarization, movement, immune and inflammatory responses, and prevention of HIV-1 infection, are triggered by the chemokines, a family of structurally related chemoattractant proteins that bind to specific seven-transmembrane receptors linked to G proteins. Here we discuss one of the early signaling pathways activated by chemokines, the JAK/STAT pathway. Through this pathway, and possibly in conjunction with other signaling pathways, the chemokines promote changes in cellular morphology, collectively known as polarization, required for chemotactic responses. The polarized cell expresses the chemokine receptors at the leading cell edge, to which they are conveyed by rafts, a cholesterol-enriched membrane fraction fundamental to the lateral organization of the plasma membrane. Finally, the mechanisms through which the chemokines promote their effect are discussed in the context of the prevention of HIV-1 infection.

Notes: Abstract The T cell compartment of adaptive immunity provides vertebrates with the potential to survey for and respond specifically to an incredible diversity of antigens. The T cell repertoire must be carefully regulated to prevent unwanted responses to self. In the periphery, one important level of regulation is the action of costimulatory signals in concert with T cell antigen-receptor (TCR) signals to promote full T cell activation. The past few years have revealed that costimulation is quite complex, involving an integration of activating signals and inhibitory signals from CD28 and CTLA-4 molecules, respectively, with TCR signals to determine the outcome of a T cell's encounter with antigen. Newly emerging data suggest that inhibitory signals mediated by CTLA-4 not only can determine whether T cells become activated, but also can play a role in regulating the clonal representation in a polyclonal response. This review primarily focuses on the cellular and molecular mechanisms of regulation by CTLA-4 and its manipulation as a strategy for tumor immunotherapy.

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

Notes: Abstract Apoptotic cell death plays a critical role in the development and functioning of the immune system. During differentiation, apoptosis weeds out lymphocytes lacking useful antigen receptors and those expressing dangerous ones. Lymphocyte death is also involved in limiting the magnitude and duration of immune responses to infection. In this review, we describe the role of the Bcl-2 protein family, and to a lesser extent that of death receptors (members of the tumor necrosis factor receptor family with a death domain), in the control of lymphoid and myeloid cell survival. We also consider the pathogenic consequences of failure of apoptosis in the immune system.

Notes: Abstract Plasma cells are terminally differentiated final effectors of the humoral immune response. Plasma cells that result from antigen activation of B-1 and marginal zone B cells provide the first, rapid response to antigen. Plasma cells that develop after a germinal center reaction provide higher-affinity antibody and often survive many months in the bone marrow. Transcription factors Bcl-6 and Pax5, which are required for germinal center B cells, block plasmacytic differentiation and repress Blimp-1 and XBP-1, respectively. When Bcl-6-dependent repression of Blimp-1 is relieved, Blimp-1 ensures that plasmacytic development is irreversible by repressing BCL-6 and PAX5. In plasma cells, Blimp-1, XBP-1, IRF4, and other regulators cause cessation of cell cycle, decrease signaling from the B cell receptor and communication with T cells, inhibit isotype switching and somatic hypermutation, downregulate CXCR5, and induce copious immunoglobulin synthesis and secretion. Thus, commitment to plasmacytic differentiation involves inhibition of activities associated with earlier B cell developmental stages as well as expression of the plasma cell phenotype.

Notes: Abstract The innate immune system in drosophila and mammals senses the invasion of microorganisms using the family of Toll receptors, stimulation of which initiates a range of host defense mechanisms. In drosophila antimicrobial responses rely on two signaling pathways: the Toll pathway and the IMD pathway. In mammals there are at least 10 members of the Toll-like receptor (TLR) family that recognize specific components conserved among microorganisms. Activation of the TLRs leads not only to the induction of inflammatory responses but also to the development of antigen-specific adaptive immunity. The TLR-induced inflammatory response is dependent on a common signaling pathway that is mediated by the adaptor molecule MyD88. However, there is evidence for additional pathways that mediate TLR ligand-specific biological responses.

Notes: Abstract A novel lymphocyte lineage, Valpha14 natural killer T (NKT) cells, is now well established as distinct from conventional alphabeta T cells. Valpha14 NKT cells express a single invariant Valpha14 antigen receptor that is essential for their development. Successful identification of a specific ligand, alpha-galactosylceramide(alpha-GalCer), and the establishment of gene-manipulated mice with selective loss of Valpha14 NKT cells helped elucidate the remarkable functional diversity of Valpha14 NKT cells in various immune responses such as host defense by mediating anti-nonself innate immune reaction, homeostatic regulation of anti-self responses, and antitumor immunity.

Notes: Abstract The Human Genome Project transformed the quest of more than 50 years to understand the major histocompatibility complex (Mhc). The sequence of the Mhc from human and mouse, together with a large amount of sequence and mapping information from several other species, allows us to draw general conclusions about the organization and origin of this crucial part of the immune system. The Mhc is a mosaic of stretches formed by conserved and nonconserved genes. Surprisingly, of the ~3.6-Mb Mhc, the stretches that encode the class I and class II genes, which epitomize the Mhc, are the least conserved part, whereas the ~1.7-Mb stretches that encode at least 115 other genes are highly conserved. We summarize the available data to answer the questions (a) What is the Mhc? and (b) How can we define it in a general, not species-specific, way? Knowing what is essential and what is incidental helps us understand the fundamentals of the Mhc, and defining the species differences makes the model organisms more useful.

Notes: Abstract This review describes the contribution of noncytolytic mechanisms to the control of viral infections with a particular emphasis on the role of cytokines in these processes. It has long been known that most cell types in the body respond to an incoming viral infection by rapidly secreting antiviral cytokines such as interferon alpha/beta (IFN-alpha/beta). After binding to specific receptors on the surface of infected cells, IFN-alpha/beta has the potential to trigger the activation of multiple noncytolytic intracellular antiviral pathways that can target many steps in the viral life cycle, thereby limiting the amplification and spread of the virus and attenuating the infection. Clearance of established viral infections, however, requires additional functions of the immune response. The accepted dogma is that complete clearance of intracellular viruses by the immune response depends on the destruction of infected cells by the effector cells of the innate and adaptive immune system [natural killer (NK) cells and cytotoxic T cells (CTLs)]. This notion, however, has been recently challenged by experimental evidence showing that much of the antiviral potential of these cells reflects their ability to produce antiviral cytokines such as IFN-gamma and tumor necrosis factor (TNF)-alpha at the site of the infection. Indeed, these cytokines can purge viruses from infected cells noncytopathically as long as the cell is able to activate antiviral mechanisms and the virus is sensitive to them. Importantly, the same cytokines also control viral infections indirectly, by modulating the induction, amplification, recruitment, and effector functions of the immune response and by upregulating antigen processing and display of viral epitopes at the surface of infected cells. In keeping with these concepts, it is not surprising that a number of viruses encode proteins that have the potential to inhibit the antiviral activity of cytokines.

Notes: Abstract Recent advances in the understanding of T cell activation have led to new therapeutic approaches in the treatment of immunological disorders. One attractive target of intervention has been the blockade of T cell costimulatory pathways, which result in more selective effects on only those T cells that have encountered specific antigen. In fact, in some instances, costimulatory pathway antagonists can induce antigen-specific tolerance that prevents the progression of autoimmune diseases and organ graft rejection. In this review, we summarize the current understanding of these complex costimulatory pathways including the individual roles of the CD28, CTLA-4, B7-1 (CD80), and B7-2 (CD86) molecules. We present evidence that suggests that multiple mechanisms contribute to CD28/B7-mediated T cell costimulation in disease settings that include expansion of activated pathogenic T cells, differentiation of Th1/Th2 cells, and the migration of T cells into target tissues. Additionally, the negative regulatory role of CTLA-4 in autoimmune diseases and graft rejection supports a dynamic but complex process of immune regulation that is prominent in the control of self-reactivity. This is most apparent in regulation of the CD4+CD25+CTLA-4+ immunoregulatory T cells that control multiple autoimmune diseases. The implications of these complexities and the potential for use of these therapies in clinical immune intervention are discussed.

Notes: Abstract The bare lymphocyte syndrome (BLS) is a hereditary immunodeficiency resulting from the absence of major istocompatibility complex class II (MHCII) expression. Considering the central role of MHCII molecules in the development and activation of CD4+ T cells, it is not surprising that the immune system of the patients is severely impaired. BLS is the prototype of a "disease of gene regulation." The affected genes encode RFXANK, RFX5, RFXAP, and CIITA, four regulatory factors that are highly specific and essential for MHCII genes. The first three are subunits of RFX, a trimeric complex that binds to all MHCII promoters. CIITA is a non-DNA-binding coactivator that functions as the master control factor for MHCII expression. The study of RFX and CIITA has made major contributions to our comprehension of the molecular mechanisms controlling MHCII genes and has made this system into a textbook model for the regulation of gene expression.

Notes: Abstract The human T cell leukemia virus-1 (HTLV-1) is a retrovirus that causes adult T cell leukemia (ATL) and neurological disorder, the tropical spastic paraparesis (HAM/TSP). The pathogenesis apparently results from the pleiotropic function of Tax protein, which is a key regulator of viral replication. Tax exerts (a) trans-activation and -repression of transcription of different sets of cellular genes through binding to groups of transcription factors and coactivators, (b) dysregulation of cell cycle through binding to inhibitors of CDK4/6, and (c) inhibition of some tumor suppressor proteins. These effects on a wide variety of cellular targets seem to cooperate in promoting cell proliferation. This is an effective viral strategy to amplify its proviral genome through replication of infected cells; ultimately it results in cell transformation and leukemogenesis.

Notes: Abstract Helicobacter pylori is a gram negative, spiral, microaerophylic bacterium that infects the stomach of more than 50% of the human population worldwide. It is mostly acquired during childhood and, if not treated, persists chronically, causing chronic gastritis, peptic ulcer disease, and in some individuals, gastric adenocarcinoma and gastric B cell lymphoma. The current therapy, based on the use of a proton-pump inhibitor and antibiotics, is efficacious but faces problems such as patient compliance, antibiotic resistance, and possible recurrence of infection. The development of an efficacious vaccine against H. pylori would thus offer several advantages. Various approaches have been followed in the development of vaccines against H. pylori, most of which have been based on the use of selected antigens known to be involved in the pathogenesis of the infection, such as urease, the vacuolating cytotoxin (VacA), the cytotoxin-associated antigen (CagA), the neutrophil-activating protein (NAP), and others, and intended to confer protection prophylactically and/or therapeutically in animal models of infection. However, very little is known of the natural history of H. pylori infection and of the kinetics of the induced immune responses. Several lines of evidence suggest that H. pylori infection is accompanied by a pronounced Th1-type CD4+ T cell response. It appears, however, that after immunization, the antigen-specific response is predominantly polarized toward a Th2-type response, with production of cytokines that can inhibit the activation of Th1 cells and of macrophages, and the production of proinflammatory cytokines. The exact effector mechanisms of protection induced after immunization are still poorly understood. The next couple of years will be crucial for the development of vaccines against H. pylori. Several trials are foreseen in humans, and expectations are that most of the questions being asked now on the host-microbe interactions will be answered.

Notes: Abstract My work on basic and clinical immunology has focused on the regulation of the human immune response and how its dysregulation can lead to immunodeficiency, autoimmune, and malignant disorders. The early focus in our laboratory was on pathogenic mechanisms underlying hypogammaglobulinemia. Our demonstration of active suppression by human suppressor T cells changed thinking about the pathogenesis of certain immunodeficiency disorders. Recently we have focused on the cytokines interleukin-2 (IL-2) and IL-15, which have competitive functions in adaptive immune responses. IL-2 is necessary to destroy self-reactive lymphocytes and thus favors peripheral tolerance to self-antigens, whereas IL-15 favors the persistence of lymphocytes involved in the memory and effector responses to invading pathogens but risks the development of inflammatory autoimmune diseases. Our murine anti-Tac monoclonal antibody exploits these differences, as does a humanized form (daclizumab) now approved for the prevention of renal allograft rejection. New forms of therapy directed at IL-2 and IL-15 receptors may be effective against certain neoplastic diseases and autoimmune disorders and in the prevention of allograft rejection.

Notes: Abstract BAFF, a member of the TNF family, is a fundamental survival factor for transitional and mature B cells. BAFF overexpression leads to an expanded B cell compartment and autoimmunity in mice, and elevated amounts of BAFF can be found in the serum of autoimmune patients. APRIL is a related factor that shares receptors with BAFF yet appears to play a different biological role. The BAFF system provides not only potential insight into the development of autoreactive B cells but a relatively simple paradigm to begin considering the balancing act between survival, growth, and death that affects all cells.

Notes: Abstract T cell anergy is a tolerance mechanism in which the lymphocyte is intrinsically functionally inactivated following an antigen encounter, but remains alive for an extended period of time in a hyporesponsive state. Models of T cell anergy affecting both CD4+ and CD8+ cells fall into two broad categories. One, clonal anergy, is principally a growth arrest state, whereas the other, adaptive tolerance or in vivo anergy, represents a more generalized inhibition of proliferation and effector functions. The former arises from incomplete T cell activation, is mostly observed in previously activated T cells, is maintained by a block in the Ras/MAP kinase pathway, can be reversed by IL-2 or anti-OX40 signaling, and usually does not result in the inhibition of effector functions. The latter is most often initiated in naive T cells in vivo by stimulation in an environment deficient in costimulation or high in coinhibition. Adaptive tolerance can be induced in the thymus or in the periphery. The cells proliferate and differentiate to varying degrees and then downregulate both functions in the face of persistent antigen. The state involves an early block in tyrosine kinase activation, which predominantly inhibits calcium mobilization, and an independent mechanism that blocks signaling through the IL-2 receptor. Adaptive tolerance reverses in the absence of antigen. Aspects of both of the anergic states are found in regulatory T cells, possibly preventing them from dominating initial immune responses to foreign antigens and shutting down such responses prematurely.

Notes: Abstract The cells of both the adaptive and innate immune systems express a dizzying array of receptors that transduce and integrate an enormous amount of information about the environment that allows the cells to mount effective immune responses. Over the past several years, significant advances have been made in elucidating the molecular details of signal cascades initiated by the engagement of immune cell receptors by their ligands. Recent evidence indicates that immune receptors and components of their signaling cascades are spatially organized and that this spatial organization plays a central role in the initiation and regulation of signaling. A key organizing element for signaling receptors appears to be cholesterol- and sphingolipid-rich plasma membrane microdomains termed lipid rafts. Research into the molecular basis of the spatial segregation and organization of signaling receptors provided by rafts is adding fundamentally to our understanding of the initiation and prolongation of signals in the immune system.

Notes: Abstract Allergic individuals exposed to minute quantities of allergen experience an immediate response. Immediate hypersensitivity reflects the permanent sensitization of mucosal mast cells by allergen-specific IgE antibodies bound to their high-affinity receptors (FcepsilonRI). A combination of factors contributes to such long-lasting sensitization of the mast cells. They include the homing of mast cells to mucosal tissues, the local synthesis of IgE, the induction of FcepsilonRI expression on mast cells by IgE, the consequent downregulation of FcgammaR (through an insufficiency of the common gamma-chains), and the exceptionally slow dissociation of IgE from FcepsilonRI. To understand the mechanism of the immediate hypersensitivity phenomenon, we need explanations of why IgE antibodies are synthesized in preference to IgG in mucosal tissues and why the IgE is so tenaciously retained on mast cell-surface receptors. There is now compelling evidence that the microenvironment of mucosal tissues of allergic disease favors class switching to IgE; and the exceptionally high affinity of IgE for FcepsilonRI can now be interpreted in terms of the recently determined crystal structures of IgE-FcepsilonRI and IgG-FcgammaR complexes. The rate of local IgE synthesis can easily compensate for the rate of the antibody dissociation from its receptors on mucosal mast cells. Effective mechanisms ensure that allergic reactions are confined to mucosal tissues, thereby minimizing the risk of systemic anaphylaxis.

Notes: Abstract Over the past decade, key protein interactions contributing to T cell antigen recognition have been characterized in molecular detail. These have included interactions involving the T cell antigen receptor (TCR) itself, its coreceptors CD4 and CD8, the accessory molecule CD2, and the costimulatory receptors CD28 and CTLA-4. A clear view is emerging of how these molecules interact with their ligands at the cell-cell interface. Structural and binding studies have confirmed that the proteins span small but comparable distances and that, overall, they interact very weakly. However, there have been important surprises as well: that TCR interactions with peptide-MHC are topologically constrained and characterized by considerable conformational flexibility at the binding interface; that coreceptors engage peptide-MHC with extraordinarily fast kinetics and at angles apparently precluding direct interactions with the TCR bound to the same peptide-MHC; that the structural mechanisms allowing recognition by costimulatory and accessory molecules to be weak and yet specific are very heterogeneous; and that because of differences in both binding affinity and stoichiometry, there is enormous variation in the stability of the various costimulatory receptor/ligand complexes. These studies provide the necessary framework for exploring how these molecular interactions initiate T cell activation.

Notes: Abstract Stem cell biology is scientifically, clinically, and politically a current topic. The hematopoietic stem cell, the common ancestor of all types of blood cells, is one of the best-characterized stem cells in the body and the only stem cell that is clinically applied in the treatment of diseases such as breast cancer, leukemias, and congenital immunodeficiencies. Multicolor cell sorting enables the purification not only of hematopoietic stem cells, but also of their downstream progenitors such as common lymphoid progenitors and common myeloid progenitors. Recent genetic approaches including gene chip technology have been used to elucidate the gene expression profile of hematopoietic stem cells and other progenitors. Although the mechanisms that control self-renewal and lineage commitment of hematopoietic stem cells are still ambiguous, recent rapid advances in understanding the biological nature of hematopoietic stem and progenitor cells have broadened the potential application of these cells in the treatment of diseases.

Notes: Abstract Our understanding of the X-linked lymphoproliferative syndrome (XLP) has advanced significantly in the last two years. The gene that is altered in the condition (SAP/SH2D1A) has been cloned and its protein crystal structure solved. At least two sets of target molecules for this small SH2 domain-containing protein have been identified: A family of hematopoietic cell surface receptors, i.e. the SLAM family, and a second molecule, which is a phosphorylated adapter. A SAP-like protein, EAT-2, has also been found to interact with this family of surface receptors. Several lines of evidence, including structural studies and analyses of missense mutations in XLP patients, support the notion that SAP/SH2D1A is a natural inhibitor of SH2-domain-dependent interactions with members of the SLAM family. However, details of its role in signaling mechanisms are yet to be unravelled. Further analyses of the SAP/SH2D1A gene in XLP patients have made it clear that the development of dys-gammaglobulinemia and B cell lymphoma can occur without evidence of prior EBV infection. Moreover, preliminary results of virus infections of a mouse in which the SAP/SH2D1A gene has been disrupted suggest that EBV infection is not per se critical for the development of XLP phenotypes. It appears therefore that the SAP/SH2D1A gene controls signaling via the SLAM family of surface receptors and thus may play a fundamental role in T cell and APC interactions during viral infections.

Notes: Abstract There is great heterogeneity in the way humans respond to medications, often requiring empirical strategies to find the appropriate drug therapy for each patient (the "art" of medicine). Over the past 50 years, there has been great progress in understanding the molecular basis of drug action and in elucidating genetic determinants of disease pathogenesis and drug response. Pharmacogenomics is the burgeoning field of investigation that aims to further elucidate the inherited nature of interindividual differences in drug disposition and effects, with the ultimate goal of providing a stronger scientific basis for selecting the optimal drug therapy and dosages for each patient. These genetic insights should also lead to mechanism-based approaches to the discovery and development of new medications. This review highlights the current status of work in this field and addresses strategies that hold promise for future advances in pharmacogenomics.

Notes: Abstract Phenobarbital (PB) response elements are composed of various nuclear receptor (NR)-binding sites. A 51-bp distal element PB-responsive enhancer module (PBREM) conserved in the PB-inducible CYP2B genes contains two NR-binding direct repeat (DR)-4 motifs. Responding to PB exposure in liver, the NR constitutive active receptor (CAR) translocates to the nucleus, forms a dimer with the retinoid X receptor (RXR), and activates PBREM via binding to DR-4 motifs. For CYP3A genes, a common NR site [DR-3 or everted repeat (ER)-6] is present in proximal promoter regions. In addition, the distal element called the xenobiotic responsive module (XREM) is found in human CYP3A4 genes, which contain both DR-3 and ER-6 motifs. Pregnane X receptor (PXR) could bind to all of these sites and, upon PB induction, a PXR:RXR heterodimer could transactivate XREM. These response elements and NRs are functionally versatile, and capable of responding to distinct but overlapping groups of xenochemicals.

Notes: Abstract Nitric oxide (NO), a simple free radical gas, elicits a surprisingly wide range of physiological and pathophysiological effects. NO interacts with soluble guanylate cyclase to evoke many of these effects. However, NO can also interact with molecular oxygen and superoxide radicals to produce reactive nitrogen species that can modify a number of macromolecules including proteins, lipids, and nucleic acids. NO can also interact directly with transition metals. Here, we have reviewed the non-3',5'-cyclic-guanosine-monophosphate-mediated effects of NO including modifications of proteins, lipids, and nucleic acids.

Notes: Abstract L-Arginine (2-amino-5-guanidinovaleric acid) is the precursor of nitric oxide, an endogenous messenger molecule involved in a variety of endothelium-mediated physiological effects in the vascular system. Acute and chronic administration of L-arginine has been shown to improve endothelial function in animal models of hypercholesterolemia and atherosclerosis. L-Arginine also improves endothelium-dependent vasodilation in humans with hypercholesterolemia and atherosclerosis. The responsiveness to L-arginine depends on the specific cardiovascular disease studied, the vessel segment, and morphology of the artery. The pharmacokinetics of L-arginine have recently been investigated. Side effects are rare and mostly mild and dose dependent. The mechanism of action of L-arginine may involve nitric oxide synthase substrate provision, especially in patients with elevated levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine. Endocrine effects and unspecific reactions may contribute to L-arginine-induced vasodilation after higher doses. Several long-term studies have been performed that show that chronic oral administration of L-arginine or intermittent infusion therapy with L-arginine can improve clinical symptoms of cardiovascular disease in man.

Notes: Abstract Cells are constantly under threat from the cytotoxic and mutagenic effects of DNA damaging agents. These agents can either be exogenous or formed within cells. Environmental DNA-damaging agents include UV light and ionizing radiation, as well as a variety of chemicals encountered in foodstuffs, or as air- and water-borne agents. Endogenous damaging agents include methylating species and the reactive oxygen species that arise during respiration. Although diverse responses are elicited in cells following DNA damage, this review focuses on three aspects: DNA repair mechanisms, cell cycle checkpoints, and apoptosis. Because the areas of nucleotide excision repair and mismatch repair have been covered extensively in recent reviews (1, 2, 3, 4, 5, 6), we restrict our coverage of the DNA repair field to base excision repair and DNA double-strand break repair.

Notes: Abstract Cytochrome P450 CYP1B1 is a relatively recently identified member of the CYP1 gene family. The purpose of this commentary is to review the regulatory mechanisms, metabolic specificity, and tissue-specific expression of this cytochrome P450 and to highlight its unique properties. The regulation of CYP1B1 involves a variety of both transcriptional and post-transcriptional mechanisms. CYP1B1 can metabolize a range of toxic and carcinogenic chemicals in vitro but in some cases with a unique stereoselectivity. Estradiol 4-hydroxylation appears to be a characteristic reaction catalyzed by human CYP1B1. However, there are considerable species differences regarding the regulation, metabolic specificity, and tissue-specific expression of this P450. In humans CYP1B1 is overexpressed in tumor cells, and this has important implications for tumor development and progression and the development of anticancer drugs specifically activated by CYP1B1.

Notes: Abstract This article reviews current knowledge of the metabolism of drugs that contain fluorine. The strategic value of fluorine substitution in drug design is discussed in terms of chemical structure and basic concepts in drug metabolism and drug toxicity.

Notes: Abstract Substantial epidemiologic data support a role for vitamin D in cancer prevention. However, dose-limiting hypercalcemic effects have proved a major obstacle to the development of natural vitamin D as a cancer chemopreventive. Structure-activity studies have sought to disassociate the toxicities and chemopreventive activities of vitamin D, and a number of synthetic deltanoids (vitamin D analogs) have shown considerable promise in this regard. Several such compounds have chemopreventive efficacy in preclinical studies, as does natural vitamin D. Data supporting further development of agents of this class include in vitro and in vivo evidence of antiproliferative, proapoptotic, prodifferentiating and antiangiogenic activities. Ongoing studies are aimed at further defining the molecular mechanisms through which vitamin D and synthetic deltanoids affect gene expression and cellular fate. Additional efforts are focused on establishing the chemopreventive index (efficacy vs toxicity) of each synthetic deltanoid.

Notes: Abstract Calmodulin (CaM) is an essential protein that serves as a ubiquitous intracellular receptor for Ca2+. The Ca2+/CaM complex initiates a plethora of signaling cascades that culminate in alteration of cellular functions. Among the many Ca2+/CaM-binding proteins to be discovered, the multifunctional protein kinases CaMKI, II, and IV play pivotal roles. Our review focuses on this class of CaM kinases to illustrate the structural and biochemical basis for Ca2+/CaM interaction with and regulation of its target enzymes. Gene transcription has been chosen as the functional endpoint to illustrate the recent advances in Ca2+/CaM-mediated signal transduction mechanisms.

Notes: Abstract Originally known for its regulation of reproductive functions, estradiol, a lipophilic hormone that can easily cross plasma membranes as well as the blood-brain barrier, maintains brain systems subserving arousal, attention, mood, and cognition. In addition, both synthetic and natural estrogens exert neurotrophic and neuroprotective effects. There is increasing evidence that estrogen actions are mediated by nongenomic as well as direct and indirect genomic pathways. Although in vitro models have provided the most extensive evidence for neurotrophic and neuroprotective actions to date, there are also in vivo studies that support these actions.

Notes: Abstract Drug interactions have always been a major concern in medicine for clinicians and patients. Inhibition and induction of cytochrome P450 (CYP) enzymes are probably the most common causes for documented drug interactions. Today, many pharmaceutical companies are predicting potential interactions of new drug candidates. Can in vivo drug interactions be predicted accurately from in vitro metabolic studies? Should the prediction be qualitative or quantitative? Although some scientists believe that quantitative prediction of drug interactions is possible, others are less optimistic and believe that quantitative prediction would be very difficult. There are many factors that contribute to our inability to quantitatively predict drug interactions. One of the major complicating factors is the large interindividual variability in response to enzyme inhibition and induction. This review examines the sources that are responsible for the interindividual variability in inhibition and induction of cytochrome P450 enzymes.

Notes: Abstract G protein-coupled receptors (GPCRs) represent a major class of proteins in the genome of many species, including humans. In addition to the mapping of a number of human disorders to regions of the genome containing GPCRs, a growing body of literature has documented frequently occurring variations (i.e. polymorphisms) in GPCR loci. In this article, we use a domain-based approach to systematically examine examples of genetic variation in the coding and noncoding regions of GPCR loci. Data to date indicate that residues in GPCRs are involved in ligand binding and coupling to G proteins and that regulation can be altered by polymorphisms. Studies of GPCR polymorphisms have also uncovered the functional importance of residues not previously implicated from other approaches that are involved in the function of GPCRs. We predict that studies of GPCR polymorphisms will have a significant impact on medicine and pharmacology, in particular, by providing new means to subclassify patients in terms of both diagnosis and treatment.

Notes: Abstract The resurgence of tuberculosis worldwide has intensified research efforts directed at examining the host defense and pathogenic mechanisms operative in Mycobacterium tuberculosis infection. This review summarizes our current understanding of the host immune response, with emphasis on the roles of macrophages, T cells, and the cytokine/chemokine network in engendering protective immunity. Specifically, we summarize studies addressing the ability of the organism to survive within macrophages by controlling phagolysosome fusion. The recent studies on Toll-like receptors and the impact on the innate response to M. tuberculosis are discussed. We also focus on the induction, specificity, and effector functions of CD4+ and CD8+ T cells, and the roles of cytokines and chemokines in the induction and effector functions of the immune response. Presentation of mycobacterial antigens by MHC class I, class II, and CD1 as well as the implications of these molecules sampling various compartments of the cell for presentation to T cells are discussed. Increased attention to this disease and the integration of animal models and human studies have afforded us a greater understanding of tuberculosis and the steps necessary to combat this infection. The pace of this research must be maintained if we are to realize an effective vaccine in the next decades.

Notes: Abstract Although interleukin-18 is structurally homologous to IL-1 and its receptor belongs to the IL-1R/Toll-like receptor (TLR) superfamily, its function is quite different from that of IL-1. IL-18 is produced not only by types of immune cells but also by non-immune cells. In collaboration with IL-12, IL-18 stimulates Th1-mediated immune responses, which play a critical role in the host defense against infection with intracellular microbes through the induction of IFN-gamma. However, the overproduction of IL-12 and IL-18 induces severe inflammatory disorders, suggesting that IL-18 is a potent proinflammatory cytokine that has pathophysiological roles in several inflammatory conditions. IL-18 mRNA is expressed in a wide range of cells including Kupffer cells, macrophages, T cells, B cells, dendritic cells, osteoblasts, keratinocytes, astrocytes, and microglias. Thus, the pathophysiological role of IL-18 has been extensively tested in the organs that contain these cells. Somewhat surprisingly, IL-18 alone can stimulate Th2 cytokine production as well as allergic inflammation. Therefore, the functions of IL-18 in vivo are very heterogeneous and complicated. In principle, IL-18 enhances the IL-12-driven Th1 immune responses, but it can also stimulate Th2 immune responses in the absence of IL-12.

Notes: Abstract Interferon regulatory factors (IRFs) constitute a family of transcription factors that commonly possess a novel helix-turn-helix DNA-binding motif. Following the initial identification of two structurally related members, IRF-1 and IRF-2, seven additional members have now been reported. In addition, virally encoded IRFs, which may interfere with cellular IRFs, have also been identified. Thus far, intensive functional analyses have been done on IRF-1, revealing a remarkable functional diversity of this transcription factor in the regulation of cellular response in host defense. Indeed, IRF-1 selectively modulates different sets of genes, depending on the cell type and/or the nature of cellular stimuli, in order to evoke appropriate responses in each. More recently, much attention has also been focused on other IRF family members. Their functional roles, through interactions with their own or other members of the family of transcription factors, are becoming clearer in the regulation of host defense, such as innate and adaptive immune responses and oncogenesis.

Notes: Abstract Regulation of tyrosine phosphorylation is a critical control point for integration of environmental signals into cellular responses. This regulation is mediated by the reciprocal actions of protein tyrosine kinases and phosphatases. CD45, the first and prototypic receptor-like protein tyrosine phosphatase, is expressed on all nucleated hematopoietic cells and plays a central role in this process. Studies of CD45 mutant cell lines, CD45-deficient mice, and CD45-deficient humans initially demonstrated the essential role of CD45 in antigen receptor signal transduction and lymphocyte development. It is now known that CD45 also modulates signals emanating from integrin and cytokine receptors. Recent work has focused on regulation of CD45 expression and alternative splicing, isoform-specific differences in signal transduction, and regulation of phosphatase activity. From these studies, a model is emerging in which CD45 affects cellular responses by controlling the relative threshold of sensitivity to external stimuli. Perturbation of this function may contribute to autoimmunity, immunodeficiency, and malignancy. Moreover, recent advances suggest that modulation of CD45 function can have therapeutic benefit in many disease states.

Notes: Abstract The IgA receptor family comprises a number of surface receptors including the polymeric Ig receptor involved in epithelial transport of IgA/IgM, the myeloid specific IgA Fc receptor (FcalphaRI or CD89), the Fcalpha/muR, and at least two alternative IgA receptors. These are the asialoglycoprotein receptor and the transferrin receptor, which have been implicated in IgA catabolism, and tissue IgA deposition. In this reviewwe focus on the biology of FcalphaRI (CD89). FcalphaRI is expressed on neutrophils, eosinophils, monocytes/macrophages, dendritic cells, and Kupffer cells. This receptor represents a heterogeneously glycosylated transmembrane protein that binds both IgA subclasses with low affinity. A single gene encoding FcalphaRI has been isolated, which is located within the leukocyte receptor cluster on chromosome 19. The FcalphaRI alpha chain lacks canonical signal transduction domains but can associate with the FcR gamma-chain that bears an activation motif (ITAM) in the cytoplasmic domain, allowing activatory functions. FcalphaRI expressed alone mediates endocytosis and recyling of IgA. No FcalphaRI homologue has been defined in the mouse, and progress in defining the in vivo role of FcalphaRI has been made using human FcalphaRI transgenic (Tg) mice. FcalphaRI-Tg mice demonstrated FcalphaRI expression on Kupffer cells and so defined a key role for the receptor in mucosal defense. The receptor functions as a second line of antibacterial defense involving serum IgA rather than secretory IgA. Studies in FcalphaRI-Tg mice, furthermore, defined an essential role for soluble FcalphaRI in the development of IgA nephropathy by formation of circulating IgA-FcalphaRI complexes. Finally, recent work points out a role for human IgA in treatment of infectious and neoplastic diseases.

Notes: Abstract Large DNA viruses defend against hostile assault executed by the host immune system by producing an array of gene products that systematically sabotage key components of the inflammatory response. Poxviruses target many of the primary mediators of innate immunity including interferons, tumor necrosis factors, interleukins, complement, and chemokines. Poxviruses also manipulate a variety of intracellular signal transduction pathways such as the apoptotic response. Many of the poxvirus genes that disrupt these pathways have been hijacked directly from the host immune system, while others have demonstrated no clear resemblance to any known host genes. Nonetheless, the immunological targets and the diversity of strategies used by poxviruses to disrupt these host pathways have provided important insights into diverse aspects of immunology, virology, and inflammation. Furthermore, because of their anti-inflammatory nature, many of these poxvirus proteins hold promise as potential therapeutic agents for acute or chronic inflammatory conditions.

Notes: Abstract At least nine closely related isoforms of adenylyl cyclases (ACs), the enzymes responsible for the synthesis of cyclic AMP (cAMP) from ATP, have been cloned and characterized in mammals. Depending on the properties and the relative levels of the isoforms expressed in a tissue or a cell type at a specific time, extracellular signals received through the G-protein-coupled receptors can be differentially integrated. The present review deals with various aspects of such regulations, emphasizing the role of calcium/calmodulin in activating AC1 and AC8 in the central nervous system, the potential inhibitory effect of calcium on AC5 and AC6, and the changes in the expression pattern of the isoforms during development. A particular emphasis is given to the role of cAMP during drug and ethanol dependency and to some experimental limitations (pitfalls in the interpretation of cellular transfection, scarcity of the invalidation models, existence of complex macromolecular structures, etc).

Notes: Abstract The neurohypophysial hormone arginine vasopressin (AVP) is a cyclic nonpeptide whose actions are mediated by the stimulation of specific G protein-coupled membrane receptors pharmacologically classified into V1-vascular (V1R), V2-renal (V2R) and V3-pituitary (V3R) AVP receptor subtypes. The random screening of chemical compounds and optimization of lead compounds recently resulted in the development of orally active nonpeptide AVP receptor antagonists. Potential therapeutic uses of AVP receptor antagonists include (a) the blockade of V1-vascular AVP receptors in arterial hypertension, congestive heart failure, and peripheral vascular disease; (b) the blockade of V2-renal AVP receptors in the syndrome of inappropriate vasopressin secretion, congestive heart failure, liver cirrhosis, nephrotic syndrome and any state of excessive retention of free water and subsequent dilutional hyponatremia; (c) the blockade of V3-pituitary AVP receptors in adrenocorticotropin-secreting tumors. The pharmacological and clinical profile of orally active nonpeptide vasopressin receptor antagonists is reviewed here.

Notes: Abstract In spite of its proven heuristic value, the dopamine hypothesis of schizophrenia is now yielding to a multifactorial view, in which the other monoamines as well as glutamate and GABA are included, with a focus on neurotransmitter interactions in complex neurocircuits. The primary lesion(s) in schizophrenia does not necessarily involve any of these neurotransmitters directly but could deal with a more general defect, such as a faulty connectivity of developmental origin. Nevertheless, a precise identification of neurotransmitter aberrations in schizophrenia will probably provide clues for a better understanding of the disease and for the development of new treatment and prevention strategies.

Notes: Abstract The mammalian thioredoxins are a family of small (approximately 12 kDa) redox proteins that undergo NADPH-dependent reduction by thioredoxin reductase and in turn reduce oxidized cysteine groups on proteins. The two main thioredoxins are thioredoxin-1, a cytosolic and nuclear form, and thioredoxin-2, a mitochondrial form. Thioredoxin-1 has been studied more. It performs many biological actions including the supply of reducing equivalents to thioredoxin peroxidases and ribonucleotide reductase, the regulation of transcription factor activity, and the regulation of enzyme activity by heterodimer formation. Thioredoxin-1 stimulates cell growth and is an inhibitor of apoptosis. Thioredoxins may play a role in a variety of human diseases including cancer. An increased level of thioredoxin-1 is found in many human tumors, where it is associated with aggressive tumor growth. Drugs are being developed that inhibit thioredoxin and that have antitumor activity.

Notes: Abstract Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are two Ca2+ messengers derived from NAD and NADP, respectively. Although NAADP is a linear molecule, structurally distinct from the cyclic cADPR, it is synthesized by similar enzymes, ADP-ribosyl cyclase and its homolog, CD38. The crystal structure of the cyclase has been solved and its active site identified. These two novel nucleotides have now been shown to be involved in a wide range of cellular functions including: cell cycle regulation in Euglena, a protist; gene expression in plants; and in animal systems, from fertilization to neurotransmitter release and long-term depression in brain. A battery of pharmacological reagents have been developed, providing valuable tools for elucidating the physiological functions of these two novel Ca2+ messengers. This article reviews these recent results and explores the implications of the existence of multiple Ca2+ messengers and Ca2+ stores in cells.

Notes: Abstract Antisense oligonucleotides have been used for more than a decade to downregulate gene expression. Phosphodiester oligonucleotides are nuclease sensitive, and the more nuclease-resistant phosphorothioate oligonucleotides are now in common use in the laboratory and have entered clinical trials. However, these molecules are highly bioactive and may inhibit gene expression by more than one mechanism. Although some dramatic successes have been demonstrated, it can still be difficult to properly interpret experimental data derived from the use of this class of oligonucleotide. This review discusses some of these issues with particular reference to a major area of current interest-inhibition of bcl-2 expression in tumor cells.

Notes: Abstract Natural killer cells express inhibitory receptors specific for MHC class I proteins and stimulatory receptors with diverse specificities. The MHC-specific receptors discriminate among different MHC class I alleles and are expressed in a variegated, overlapping fashion, such that each NK cell expresses several inhibitory and stimulatory receptors. Evidence suggests that individual developing NK cells initiate expression of inhibitory receptor genes in a sequential, cumulative, and stochastic fashion. Superimposed on the receptor acquisition process are multiple education mechanisms, which act to coordinate the stimulatory and inhibitory specificities of developing NK cells. One process influences the complement of receptors expressed by individual NK cells. Other mechanisms may prevent NK cell autoaggression even when the developing NK cell fails to express self-MHC-specific inhibitory receptors. Together, these mechanisms ensure a self-tolerant and maximally discriminating NK cell population. Like NK cells, a fraction of memory phenotype CD8+ T cells, as well as other T cell subsets, express inhibitory class I-specific receptors in a variegated, overlapping fashion. The characteristics of these cells suggest that inhibitory receptor expression may be a response to prior antigenic stimulation as well as to poorly defined additional signals. A unifying hypothesis is that both NK cells and certain T cell subsets initiate expression of inhibitory receptors in response to stimulation.

Notes: Abstract This review summarizes the general parameters of cell- and antibody-mediated immune protection and the basic mechanisms responsible for what we call immunological memory. From this basis, the various successes and difficulties of vaccines are evaluated with respect to the role of antigen in maintaining protective immunity. Based on the fact that in humans during the first 12-48 months maternal antibodies from milk and serum protect against classical acute childhood and other infections, the concept is developed that maternal antibodies attenuate most infections of babies and infants and turn them into effective vaccines. If this "natural vaccination" under passive protective conditions does not occur, acute childhood diseases may be severe, unless infants are actively vaccinated with conventional vaccines early enough, i.e., in synchronization with the immune system's maturation. Although vaccines are available against the classical childhood diseases, they are not available for many seemingly milder childhood infections such as gastrointestinal and respiratory infections; these may eventually trigger immunopathological diseases. These changing balances between humans and infections caused by changes in nursing habits but also in hygiene levels may well be involved in changing disease patterns including increased frequencies of certain autoimmune and degenerative diseases.

Notes: Abstract Given the vast number of genetic and epigenetic changes associated with carcinogenesis, it is clear that tumors express many neoantigens. A central question in cancer immunology is whether recognition of tumor antigens by the immune system leads to activation (i.e., surveillance) or tolerance. Paradoxically, while strong evidence exists that specific immune surveillance systems operate at early stages of tumorigenesis, established tumors primarily induce immune tolerance. A unifying hypothesis posits that the fundamental processes of cancer progression, namely tissue invasion and metastasis, are inherently proinflammatory and thus activating for innate and adaptive antitumor immunity. To elude immune surveillance, tumors must develop mechanisms that block the elaboration and sensing of proinflammatory danger signals, thereby shifting the balance from activation to tolerance induction. Elucidation of these mechanisms provides new strategies for cancer immunotherapy.

Notes: Abstract This paper contains recollections of some of the people and events that influenced the development of toxicology as an academic discipline. It also describes my experiences in pharmacology at the University of Chicago and the University of Kansas Medical Center and concludes with speculation concerning the future of toxicology. Moderation in all things/Ne quid nimis. -Terence in Andria

Notes: Abstract The mechanisms of general anesthesia in the central nervous system are finally yielding to molecular examination. As a result of research during the past several decades, a group of ligand-gated ion channels have emerged as plausible targets for general anesthetics. Molecular biology techniques have greatly accelerated attempts to classify ligand-gated ion channel sensitivity to general anesthetics, and have identified the sites of receptor subunits critical for anesthetic modulation using chimeric and mutated receptors. The experimental data have facilitated the construction of tenable molecular models for anesthetic binding sites, which in turn allows structural predictions to be tested. In vivo significance of a putative anesthetic target can now be examined by targeted gene manipulations in mice. In this review, we summarize from a molecular perspective recent advances in our understanding of mechanisms of action of general anesthetics on ligand-gated ion channels.

Notes: Abstract DNA topoisomerases are double-edged swords. They are essential for many vital functions of DNA during normal cell growth. However, they are also highly vulnerable under various physiological and nonphysiological stresses because of their delicate act on breaking and rejoining DNA. These stresses (e.g. exposure to topoisomerase poisons, acidic pH, and oxidative stresses) can convert DNA topoisomerases into DNA-breaking nucleases, resulting in cell death and/or genomic instability. The importance of topoisomerase-mediated DNA cleavage in tumor cell death and carcinogenesis has been recognized. This review focuses on recent findings concerning the molecular mechanisms of the stress responses to topoisomerase-mediated DNA damage. The involvement of ubiquitin/26S proteasome and SUMO/UBC9 in these processes, as well as the role of topoisomerase cleavable complexes in apoptotic cell death are discussed.

Notes: Abstract In the future, biomarkers will play an increasingly important role in all phases of drug development, including regulatory review. However, only a few of these biomarkers will become established well enough to serve in regulatory decision making as surrogate endpoints, thereby substituting for traditional clinical endpoints. Even generally accepted surrogate endpoints are unlikely to capture all the therapeutic benefits and potential adverse effects a drug will have in a diverse patient population. Accordingly, combinations of biomarkers probably will be needed to provide a more complete characterization of the spectrum of pharmacologic response. In the future, pharmacogenomic approaches, including those based on differential expression of gene arrays, will provide panels of relevant biomarkers that can be expected to transform the drug development process.

Notes: Abstract Considerable recent progress has been made in the field of ab initio protein structure prediction, as witnessed by the third Critical Assessment of Structure Prediction (CASP3). In spite of this progress, much work remains, for the field has yet to produce consistently reliable ab initio structure prediction protocols. In this work, we review the features of current ab initio protocols in an attempt to highlight the foundations of recent progress in the field and suggest promising directions for future work.

Notes: Abstract Species and tissue-specific isozymes of phosphorylase display differences in regulatory properties consistent with their distinct roles in particular organisms and tissues. In this review, we compare crystallographic structures of regulated and unregulated phosphorylases, including maltodextrin phosphorylase (MalP) from Escherichia coli, glycogen phosphorylase from yeast, and mammalian isozymes from muscle and liver tissues. Mutagenesis and functional studies supplement the structural work and provide insights into the structural basis for allosteric control mechanisms. MalP, a simple, unregulated enzyme, is contrasted with the more complicated yeast and mammalian phosphorylases that have evolved regulatory sites onto the basic catalytic architecture. The human liver and muscle isozymes show differences structurally in their means of invoking allosteric activation. Phosphorylation, though common to both the yeast and mammalian enzymes, occurs at different sites and activates the enzymes by surprisingly different mechanisms.

Notes: Abstract Computer modeling has been developed and widely applied in studying molecules of biological interest. The force field is the cornerstone of computer simulations, and many force fields have been developed and successfully applied in these simulations. Two interesting areas are (a) studying enzyme catalytic mechanisms using a combination of quantum mechanics and molecular mechanics, and (b) studying macromolecular dynamics and interactions using molecular dynamics (MD) and free energy (FE) calculation methods. Enzyme catalysis involves forming and breaking of covalent bonds and requires the use of quantum mechanics. Noncovalent interactions appear ubiquitously in biology, but here we confine ourselves to review only noncovalent interactions between protein and protein, protein and ligand, and protein and nucleic acids.

Notes: Abstract Molecular chaperones are required to assist folding of a subset of proteins in Escherichia coli. We describe a conceptual framework for understanding how the GroEL-GroES system assists misfolded proteins to reach their native states. The architecture of GroEL consists of double toroids stacked back-to-back. However, most of the fundamentals of the GroEL action can be described in terms of the single ring. A key idea in our framework is that, with coordinated ATP hydrolysis and GroES binding, GroEL participates actively by repeatedly unfolding the substrate protein (SP), provided that it is trapped in one of the misfolded states. We conjecture that the unfolding of SP becomes possible because a stretching force is transmitted to the SP when the GroEL particle undergoes allosteric transitions. Force-induced unfolding of the SP puts it on a higher free-energy point in the multidimensional energy landscape from which the SP can either reach the native conformation with some probability or be trapped in one of the competing basins of attraction (i.e., the SP undergoes kinetic partitioning). The model shows, in a natural way, that the time scales in the dynamics of the allosteric transitions are intimately coupled to folding rates of the SP. Several scenarios for chaperonin-assisted folding emerge depending on the interplay of the time scales governing the cycle. Further refinement of this framework may be necessary because single molecule experiments indicate that there is a great dispersion in the time scales governing the dynamics of the chaperonin cycle.

Notes: Abstract The mammalian thioredoxins are a family of small (approximately 12 kDa) redox proteins that undergo NADPH-dependent reduction by thioredoxin reductase and in turn reduce oxidized cysteine groups on proteins. The two main thioredoxins are thioredoxin-1, a cytosolic and nuclear form, and thioredoxin-2, a mitochondrial form. Thioredoxin-1 has been studied more. It performs many biological actions including the supply of reducing equivalents to thioredoxin peroxidases and ribonucleotide reductase, the regulation of transcription factor activity, and the regulation of enzyme activity by heterodimer formation. Thioredoxin-1 stimulates cell growth and is an inhibitor of apoptosis. Thioredoxins may play a role in a variety of human diseases including cancer. An increased level of thioredoxin-1 is found in many human tumors, where it is associated with aggressive tumor growth. Drugs are being developed that inhibit thioredoxin and that have antitumor activity.

Notes: Abstract Mass spectrometry has provided a powerful method for monitoring hydrogen exchange of protein backbone amides with deuterium from solvent. In comparison to popular NMR approaches, mass spectrometry has the advantages of higher sensitivity, wider coverage of sequence, and the ability to analyze larger proteins. Proteolytic fragmentation of proteins following the exchange reaction provides moderate structural resolution, in some cases enabling measurements from single amides. The technique has provided new insight into protein-protein and protein-ligand interfaces, as well as conformational changes during protein folding or denaturation. In addition, recent studies illustrate the utility of hydrogen exchange mass spectrometry toward detecting protein motions relevant to allostery, covalent modifications, and enzyme function.

Notes: Abstract Cations are bound to nucleic acids in a solvated state. High-resolution X-ray diffraction studies of oligonucleotides provide a detailed view of Mg2+, and occasionally other ions bound to DNA. In a survey of several such structures, certain general observations emerge. First, cations bind preferentially to the guanine base in the major groove or to phosphate group oxygen atoms. Second, cations interact with DNA most frequently via water molecules in their primary solvation shell, direct ion-DNA contacts being only rarely observed. Thus, the solvated ions should be viewed as hydrogen bond donors in addition to point charges. Finally, ion interaction sites are readily exchangeable: The same site may be occupied by any ion, including spermine, as well as by a water molecule.

Notes: Abstract Although protein function is thought to depend on flexibility, precisely how the dynamics of the molecule and its environment contribute to catalytic mechanisms is unclear. We review experimental and computational work relating to enzyme dynamics and function, including the role of solvent. The evidence suggests that fast motions on the 100 ps timescale, and any motions coupled to these, are not required for enzyme function. Proteins where the function is electron transfer, proton tunneling, or ligand binding may have different dynamical dependencies from those for enzymes, and enzymes with large turnover numbers may have different dynamical dependencies from those that turn over more slowly. The timescale differences between the fastest anharmonic fluctuations and the barrier-crossing rate point to the need to develop methods to resolve the range of motions present in enzymes on different time- and lengthscales.

Notes: Abstract The OB-fold domain is a compact structural motif frequently used for nucleic acid recognition. Structural comparison of all OB-fold/nucleic acid complexes solved to date confirms the low degree of sequence similarity among members of this family while highlighting several structural sequence determinants common to most of these OB-folds. Loops connecting the secondary structural elements in the OB-fold core are extremely variable in length and in functional detail. However, certain features of ligand binding are conserved among OB-fold complexes, including the location of the binding surface, the polarity of the nucleic acid with respect to the OB-fold, and particular nucleic acid-protein interactions commonly used for recognition of single-stranded and unusually structured nucleic acids. Intriguingly, the observation of shared nucleic acid polarity may shed light on the longstanding question concerning OB-fold origins, indicating that it is unlikely that members of this family arose via convergent evolution.

Notes: Abstract Understanding the action of enzymes on an atomistic level is one of the important aims of modern biophysics. This review describes the state of the art in addressing this challenge by simulating enzymatic reactions. It considers different modeling methods including the empirical valence bond (EVB) and more standard molecular orbital quantum mechanics/molecular mechanics (QM/MM) methods. The importance of proper configurational averaging of QM/MM energies is emphasized, pointing out that at present such averages are performed most effectively by the EVB method. It is clarified that all properly conducted simulation studies have identified electrostatic preorganization effects as the source of enzyme catalysis. It is argued that the ability to simulate enzymatic reactions also provides the chance to examine the importance of nonelectrostatic contributions and the validity of the corresponding proposals. In fact, simulation studies have indicated that prominent proposals such as desolvation, steric strain, near attack conformation, entropy traps, and coherent dynamics do not account for a major part of the catalytic power of enzymes. Finally, it is pointed out that although some of the issues are likely to remain controversial for some time, computer modeling approaches can provide a powerful tool for understanding enzyme catalysis.

Notes: Abstract A number of novel chemical methods for studying biological systems have recently been developed that provide a means of addressing biological questions not easily studied with other techniques. In this review, examples that highlight the development and use of such chemical approaches are discussed. Specifically, strategies for modulating protein activity or protein-protein interactions using small molecules are presented. In addition, methods for generating and utilizing novel biomolecules (proteins, oligonucleotides, oligosaccharides, and second messengers) are examined.

Notes: Abstract The phosphoinositide 3-kinase (PI3K) family of enzymes is recruited upon growth factor receptor activation and produces 3' phosphoinositide lipids. The lipid products of PI3K act as second messengers by binding to and activating diverse cellular target proteins. These events constitute the start of a complex signaling cascade, which ultimately results in the mediation of cellular activities such as proliferation, differentiation, chemotaxis, survival, trafficking, and glucose homeostasis. Therefore, PI3Ks play a central role in many cellular functions. The factors that determine which cellular function is mediated are complex and may be partly attributed to the diversity that exists at each level of the PI3K signaling cascade, such as the type of stimulus, the isoform of PI3K, or the nature of the second messenger lipids. Numerous studies have helped to elucidate some of the key factors that determine cell fate in the context of PI3K signaling. For example, the past two years has seen the publication of many transgenic and knockout mouse studies where either PI3K or its signaling components are deregulated. These models have helped to build a picture of the role of PI3K in physiology and indeed there have been a number of surprises. This review uses such models as a framework to build a profile of PI3K function within both the cell and the organism and focuses, in particular, on the role of PI3K in cell regulation, immunity, and development. The evidence for the role of deregulated PI3K signaling in diseases such as cancer and diabetes is reviewed.

Notes: Abstract Seed development requires coordinated expression of embryo and endosperm and has contributions from both sporophytic and male and female gametophytic genes. Genetic and molecular analyses in recent years have started to illuminate how products of these multiple genes interact to initiate seed development. Imprinting or differential expression of paternal and maternal genes seems to be involved in controlling seed development, presumably by controlling gene expression in developing endosperm. Epigenetic processes such as chromatin remodeling and DNA methylation affect imprinting of key seed-specific genes; however, the identity of many of these genes remains unknown. The discovery of FIS genes has illuminated control of autonomous endosperm development, a component of apomixis, which is an important developmental and agronomic trait. FIS genes are targets of imprinting, and the genes they control in developing endosperm are also regulated by DNA methylation and chromatin remodeling genes. These results define some exciting future areas of research in seed development.

Notes: Abstract Fifteen years ago, we had a model of peroxisome biogenesis that involved growth and division of preexisting peroxisomes. Today, thanks to genetically tractable model organisms and Chinese hamster ovary cells, 23 PEX genes have been cloned that encode the machinery ("peroxins") required to assemble the organelle. Membrane assembly and maintenance requires three of these (peroxins 3, 16, and 19) and may occur without the import of the matrix (lumen) enzymes. Matrix protein import follows a branched pathway of soluble recycling receptors, with one branch for each class of peroxisome targeting sequence (two are well characterized), and a common trunk for all. At least one of these receptors, Pex5p, enters and exits peroxisomes as it functions. Proliferation of the organelle is regulated by Pex11p. Peroxisome biogenesis is remarkably conserved among eukaryotes. A group of fatal, inherited neuropathologies are recognized as peroxisome biogenesis diseases; the responsible genes are orthologs of yeast or Chinese hamster ovary peroxins. Future studies must address the mechanism by which folded, oligomeric enzymes enter the organelle, how the peroxisome divides, and how it segregates at cell division. Most pex mutants contain largely empty membrane "ghosts" of peroxisomes; a few mutants apparently lacking peroxisomes entirely have led some to propose the de novo formation of the organelle. However, there is evidence for residual peroxisome membrane vesicles ("protoperoxisomes") in some of these, and the preponderance of data supports the continuity of the peroxisome compartment in space and time and between generations of cells.

Notes: Abstract Novel therapeutic strategies can be envisioned based on altering the expression level of target genes involved in cellular processes and disease progression; however, our ability to efficiently manipulate gene expression is limited. Non-viralbased gene therapy provides a relatively safe approach to increase or decrease the expression of a specific gene using DNA or antisense sequences; however, synthetic systems are required to direct plasmids and oligonucleotides to a specific tissue and to enhance cellular uptake and intracellular trafficking. Numerous materials are being developed that interact with DNA to enhance its properties (e.g. stability, charge density) and thus direct its biodistribution and facilitate cellular interactions. The development of synthetic delivery systems to manipulate gene expression efficiently is a powerful tool that will ultimately lead to novel therapeutic strategies for the treatment of numerous disorders.

Notes: Abstract The use of energetic particles (ions and atoms) has become increasingly important in physical vapor deposition techniques. These deposition processes can be divided in two main classes: ion beam-assisted deposition and energetic condensation (or deposition). This review focuses on the latter, i.e. processes in which the actual depositing species have energies that far exceed ordinary thermal energies, namely energies greater than 20 eV. The phenomenology of the effect of these high-energy particles on the growth of thin films is first broadly presented, and then specific examples of film deposition are given. The examples drawn here are of films that have been prepared by metal plasma immersion implantation and deposition. The observed microstructures and functional properties of these films are discussed in terms of processing conditions.

Notes: Abstract All materials intended for application in humans as biomaterials, medical devices, or prostheses undergo tissue responses when implanted into living tissue. This review first describes fundamental aspects of tissue responses to materials, which are commonly described as the tissue response continuum. These actions involve fundamental aspects of tissue responses including injury, inflammatory and wound healing responses, foreign body reactions, and fibrous encapsulation of the biomaterial, medical device, or prosthesis. The second part of this review describes the in vivo evaluation of tissue responses to biomaterials, medical devices, and prostheses to determine intended performance characteristics and safety or biocompatibility considerations. While fundamental aspects of tissue responses to materials are important from research and development perspectives, the in vivo evaluation of tissue responses to these materials is important for performance, safety, and regulatory reasons.

Notes: Abstract A review of the field of photorefractive liquid crystals is presented. The first reports of photorefractive liquid crystals occurred in 1994, and the performance of these materials has dramatically improved since that time. Liquid crystalline materials have proven to be highly versatile, showing photorefractive character under a wide range of conditions. For example, new composites based on high-molar-mass liquid crystals are now capable of forming volume (Bragg) gratings with high photorefractive gain coefficients of 〉600 cm-1. Formation times for photorefractive Bragg gratings of 15 ms with applied fields of only 0.1 V/mum have been reported. Low-molar-mass liquid crystals continue to be developed and show their largest photorefractive character in the thin (Raman-Nath) grating regime. Composites of nonmesogenic polymers and liquid crystals are also discussed. The experiments and theoretical work that have been used to characterize these materials are reviewed.

Notes: Abstract The field of biomaterials has recently been focused on the design of intelligent materials. Toward this goal, materials have been developed that can provide specific bioactive signals to control the biological environment around them during the process of materials integration and wound healing. In addition, materials have been developed that can respond to changes in their environment, such as a change in pH or cell-associated enzymatic activity. In designing such novel biomaterials, researchers have sought not merely to create bio-inert materials, but rather materials that can respond to the cellular environment around them to improve device integration and tissue regeneration.

Notes: Abstract Recently there have been significant advances in understanding the magnetic properties of epitaxial ferrite films that are not found in bulk ferrites. Much effort has been expended on trying to achieve bulk properties in thin films for a wide range of applications. From a fundamental science perspective, epitaxial thin films and heterostructures have provided model systems in which novel phenomena, such as modified super-exchange interactions, nearly ideal exchange coupling, and perpendicular exchange coupling, have been observed. These magnetic phenomena and other anomalous magnetic properties are interesting in their own right and are highlighted here.

Notes: Abstract Energetic materials are chemical compounds or mixtures that store significant quantities of energy. In this review, we explore recent approaches to property prediction and new material synthesis. We show how the successful design of new energetic materials with tailored properties is becoming a practical reality.

Notes: Abstract We summarize developments in the construction of synthetic cells made from polymers, with a particular focus on mimicking the structure and behavior of blood cells. Two basic themes emerge-the use of block copolymers to make polmer vesicles and the functionalization of colloidal or polymeric microspheres with cell-like adhesive properties. Both platforms provide a means for building the complex hierarchy that is characteristic of biological cells, while also incorporating novel and perhaps superior properties of material strength, specific targeting, and controlled release.

Notes: Abstract Materials research has been applied successfully to the study of archaeological ceramics for the last fifty years. To learn about our history and the human condition is not just to analyze and preserve the objects but also to investigate and understand the knowledge and skills used to produce and use them. Many researchers have probed the limits and methods of such studies, always mindful that a glimpse at ancient reality lies in the details of time and place, context of finds, and experimentally produced data, usually compared with standards that were collected in an equivalent ethnographic setting or that were fabricated in a laboratory in order to elucidate the critical questions in a technology that could be understood in no other way. The basis of most studies of ancient technology has been established as microstructure; composition and firing; methods and sequence of manufacture; differentiation of use; use-wear and post-depositional processes; technological variability that can be interpreted as a pattern of stasis or innovation, which can be related to cultural continuity or change; and interpretation that can involve technology, subsistence trade, organization, and symbolic group- and self-definition.

Notes: Abstract The hydrogen economy is fast approaching as petroleum reserves are rapidly consumed. The fuel cell promises to deliver clean and efficient power by combining hydrogen and oxygen in a simple electrochemical device that directly converts chemical energy to electrical energy. Hydrogen, the most plentiful element available, can be extracted from water by electrolysis. One can imagine capturing energy from the sun and wind and/or from the depths of the earth to provide the necessary power for electrolysis. Alternative energy sources such as these are the promise for the future, but for now they are not feasible for power needs across the globe. A transitional solution is required to convert certain hydrocarbon fuels to hydrogen. These fuels must be available through existing infrastructures such as the natural gas pipeline. The present review discusses the catalyst and adsorbent technologies under development for the extraction of hydrogen from natural gas to meet the requirements for the proton exchange membrane (PEM) fuel cell. The primary market is for residential applications, where pipeline natural gas will be the source of H2 used to power the home. Other applications including the reforming of methanol for portable power applications such as laptop computers, cellular phones, and personnel digital equipment are also discussed. Processing natural gas containing sulfur requires many materials, for example, adsorbents for desulfurization, and heterogeneous catalysts for reforming (either autothermal or steam reforming) water gas shift, preferential oxidation of CO, and anode tail gas combustion. All these technologies are discussed for natural gas and to a limited extent for reforming methanol.

Notes: Abstract Chemical reactivity at heterophase interfaces is reviewed with a special focus on metal-oxide and oxide-oxide interfaces. Equilibrium chemistry of interfaces is discussed in terms of processes at the macroscopic and atomic level. The dependency on thermodynamic and crystallographic variables is described and illustrated by experimental results. Any reaction-related motion of an interface is associated with numerous transport and reaction steps that include not only atom transfer across the interface, chemical reactions between species and defects and phase transitions, but also steps accommodating lattice mismatch and volume changes. Faceting and morphology evolution of interfaces are included in the considerations.

Notes: Abstract The performance of the oxide-ion electrolyte of a solid oxide fuel cell (SOFC) is critical to the development of an intermediate-temperature system. Although yttria-stabilized zirconia is the electrolyte used in SOFCs under commercial development, other candidate materials are now available, and there remains a strong motivation to search for new, improved oxide-ion electrolytes. The leading contenders are discussed not only with respect to their oxide-ion conductivity, but also with respect to mechanical and chemical compatibility with the electrodes and the working environment at each electrode.

Notes: Abstract The main obstacles to greater commercialization of polymer electrolyte fuel cells are mostly related to the low-proton conductivity at low-relative humidity of the known ionomeric membranes, to their high methanol permeability and poor mechanical properties above ~130oC. A possible solution for these problems has been found in the development of composite membranes, where particles of suitable fillers are dispersed in the ionomer matrix. The preparation methods for obtaining composite membranes are described, and recent work dealing with composite ionomeric membranes containing silica, heteropolyacids, layered metal phosphates, and phosphonates is reviewed. Finally, new strategies for the preparation of nano-composite membranes and for the filling of porous polymeric membranes with highly conductive zirconium phosphonates are described. The expected influence of size and orientation of these particles on membrane properties, such as conductivity and permeability to methanol, is also discussed.

Notes: Abstract Solid oxide fuel cells operating at temperatures below 800oC require the use of supported thin film solid electrolytes. A variety of processing methods are reviewed that can deliver electrolyte films with satisfactory performance. These include vapor phase, sol-gel, and powder methods such as colloidal deposition. An important consideration is that a number of these processing methods may not meet the low cost required by commercialization. The most cost-effective methods are considered to be simple powder methods combined with co-firing.

Notes: Abstract Methanol oxidation in the cathode compartment of the fuel cell, which occurs during the oxygen-reduction reaction on Pt-based cathodes, constitutes a significant performance loss in the direct methanol fuel cells. Over the past decade, four types of methanol-resistant oxygen-reduction catalysts have been developed to circumvent this problem. Among these, transition-metal chalcogenides, and in particular RuSe, have shown effective selectivity to oxygen-reduction reaction in the presence of methanol. These catalysts not only can enhance the performance of the conventional direct methanol fuel cells but also could provide a route to develop mixed-reactants direct methanol fuel cells, which could be highly cost-effective in comparison with the conventional direct methanol fuel cells. This article is a brief update on the preparation, characterization, and implications of methanol-resistant oxygen-reduction catalysts.

Notes: Abstract After a brief survey of fuel cell types, attention is focused on material requirements for SOFC and PEMFC stacks, with an introductory section on materials technology for reformers. Materials cost and processing, together with durability issues, are emphasized as these now dominate materials selection processes for prototype stack units. In addition to optimizing the cell components, increasing attention is being given to the composition and processing of the bipolar plate component as the weight and volume of the relevant material has a major influence on the overall power density and cost of the fuel cell stack. It is concluded that the introduction of alternative materials/processes that would enable PEMFC stacks to operate at 150-200oC, and IT-SOFC stacks to operate at 500-700oC, would have a major impact on the successful commercialization of fuel cell technology.

Notes: Abstract This paper presents a review of atomic-scale defects (planar defects and dislocations) analysis using atom probe (AP) and field ion microscopy (FIM). A large part of the discussion is dedicated to the first atomic-scale observation of a Cottrell atmosphere by a three-dimensional atom probe method (3DAP). The nanoscale boron segregation to line dislocations and planar defects in a B2-ordered FeAl (40 at.%Al) is imaged in three dimensions of the real space. The boron-enriched Cottrell atmosphere is imaged in the close vicinity of an edge 001〉 dislocation as a rod 3 nm in diameter, around to the dislocation line.

Notes: Abstract Rotation curves of spiral galaxies are the major tool for determining the distribution of mass in spiral galaxies. They provide fundamental information for understanding the dynamics, evolution, and formation of spiral galaxies. We describe various methods to derive rotation curves and review the results obtained. We discuss the basic characteristics of observed rotation curves in relation to various galaxy properties, such as Hubble type, structure, activity, and environment.