ALBERT

Notes: In this essay, I make four points about the operation of the immune system. First, thanks to the innate immune system's regulation of the main costimulatory molecules CD80 and CD86, the immune system rarely mistakes a pathogen for a self-antigen. Second, the adaptive immune system consisting of T lymphocytes and B lymphocytes can mistake self for non-self because adaptive immunity is selected in single somatic cells. Third, the adaptive immune system of T lymphocytes and B lymphocytes is always referential to self, as it is selected on self-ligands; it persists in the periphery on self-ligands; and at least for T cells, it is dependent on self-ligands to be able to mount a response. Fourth, it is becoming clear that regulatory or suppressor T cells are our main defense against autoimmunity, as my first boss, Richard Gershon, had predicted. These cells recognize antigen as do all T cells, but they secrete the immunoregulatory cytokines IL-10 and TGFbeta.

Notes: Abstract A reciprocal regulation exists between the central nervous and immune systems through which the CNS signals the immune system via hormonal and neuronal pathways and the immune system signals the CNS through cytokines. The primary hormonal pathway by which the CNS regulates the immune system is the hypothalamic-pituitary-adrenal axis, through the hormones of the neuroendocrine stress response. The sympathetic nervous system regulates the function of the immune system primarily via adrenergic neurotransmitters released through neuronal routes. Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate immune responses in inflammatory disease. Glucocorticoids are the main effector end point of this neuroendocrine system and, through the glucocorticoid receptor, have multiple effects on immune cells and molecules. This review focuses on the regulation of the immune response via the neuroendocrine system. Particular details are presented on the effects of interruptions of this regulatory loop at multiple levels in predisposition and expression of immune diseases and on mechanisms of glucocorticoid effects on immune cells and molecules.

Notes: Abstract KIR genes have evolved in primates to generate a diverse family of receptors with unique structures that enable them to recognize MHC-class I molecules with locus and allele-specificity. Their combinatorial expression creates a repertoire of NK cells that surveys the expression of almost every MHC molecule independently, thus antagonizing the spread of pathogens and tumors that subvert innate and adaptive defense by selectively downregulating certain MHC class I molecules. The genes encoding KIR that recognize classical MHC molecules have diversified rapidly in human and primates; this contrasts with conservation of immunoglobulin- and lectin-like receptors for nonclassical MHC molecules. As a result of the variable KIR-gene content in the genome and the polymorphism of the HLA system, dissimilar numbers and qualities of KIR:HLA pairs function in different humans. This diversity likely contributes variability to the function of NK cells and T-lymphocytes by modulating innate and adaptive immune responses to specific challenges.

Notes: Abstract Engagement of the T cell antigen receptor (TCR) leads to a complex series of molecular changes at the plasma membrane, in the cytoplasm, and at the nucleus that lead ultimately to T cell effector function. Activation at the TCR of a set of protein tyrosine kinases (PTKs) is an early event in this process. This chapter reviews some of the critical substrates of these PTKs, the adapter proteins that, following phosphorylation on tyrosine residues, serve as binding sites for many of the critical effector enzymes and other adapter proteins required for T cell activation. The role of these adapters in binding various proteins, the interaction of adapters with plasma membrane microdomains, and the function of adapter proteins in control of the cytoskeleton are discussed.

Notes: Abstract Typical immune responses lead to prominent clonal expansion of antigen-specific T and B cells followed by differentiation into effector cells. Most effector cells die at the end of the immune response but some of these cells survive and form long-lived memory cells. The factors controlling the formation and survival of memory T cells are reviewed.

Notes: Abstract Unmethylated CpG motifs are prevalent in bacterial but not vertebrate genomic DNAs. Oligodeoxynucleotides (ODN) containing CpG motifs activate host defense mechanisms leading to innate and acquired immune responses. The recognition of CpG motifs requires Toll-like receptor (TLR) 9, which triggers alterations in cellular redox balance and the induction of cell signaling pathways including the mitogen activated protein kinases (MAPKs) and NFkappaB. Cells that express TLR-9, which include plasmacytoid dendritic cells (PDCs) and B cells, produce Th1-like proinflammatory cytokines, interferons, and chemokines. Certain CpG motifs (CpG-A) are especially potent at activating NK cells and inducing IFN-alpha production by PDCs, while other motifs (CpG-B) are especially potent B cell activators. CpG-induced activation of innate immunity protects against lethal challenge with a wide variety of pathogens, and has therapeutic activity in murine models of cancer and allergy. CpG ODN also enhance the development of acquired immune responses for prophylactic and therapeutic vaccination.

Notes: Abstract MAP kinases are among the most ancient signal transduction pathways and are widely used throughout evolution in many physiological processes. In mammalian species, MAP kinases are involved in all aspects of immune responses, from the initiation phase of innate immunity, to activation of adaptive immunity, and to cell death when immune function is complete. In this review, we summarize recent progress in understanding the function and regulation of MAP kinase pathways in these phases of immune responses.

Notes: Abstract Class switch recombination (CSR) and somatic hypermutation (SHM) have been considered to be mediated by different molecular mechanisms because both target DNAs and DNA modification products are quite distinct. However, involvement of activation-induced cytidine deaminase (AID) in both CSR and SHM has revealed that the two genetic alteration mechanisms are surprisingly similar. Accumulating data led us to propose the following scenario: AID is likely to be an RNA editing enzyme that modifies an unknown pre-mRNA to generate mRNA encoding a nicking endonuclease specific to the stem-loop structure. Transcription of the S and V regions, which contain palindromic sequences, leads to transient denaturation, forming the stem-loop structure that is cleaved by the AID-regulated endonuclease. Cleaved single-strand tails will be processed by error-prone DNA polymerase-mediated gap-filling or exonuclease-mediated resection. Mismatched bases will be corrected or fixed by mismatch repair enzymes. CSR ends are then ligated by the NHEJ system while SHM nicks are repaired by another ligation system.

Notes: Abstract Virtually all of the measurable cell-mediated cytotoxicity delivered by cytotoxic T lymphocytes and natural killer cells comes from either the granule exocytosis pathway or the Fas pathway. The granule exocytosis pathway utilizes perforin to traffic the granzymes to appropriate locations in target cells, where they cleave critical substrates that initiate DNA fragmentation and apoptosis; granzymes A and B induce death via alternate, nonoverlapping pathways. The Fas/FasL system is responsible for activation-induced cell death but also plays an important role in lymphocyte-mediated killing under certain circumstances. The interplay between these two cytotoxic systems provides opportunities for therapeutic interventions to control autoimmune diseases and graft vs. host disease, but oversuppression of these pathways may also lead to increased viral susceptibility and/or decreased tumor cell killing.

Notes: Abstract Gene-chips contain thousands of nucleotide sequences that allow simultaneous analysis of the complex mixture of RNAs transcribed in cells. Like these gene-chips, major histocompatibility complex (MHC) class I molecules display a large array of peptides on the cell surface for probing by the CD8+ T cell repertoire. The peptide mixture represents fragments of most, if not all, intracellular proteins. The antigen processing machinery accomplishes the daunting task of sampling these proteins and cleaving them into the precise set of peptides displayed by MHC I molecules. It has long been believed that antigenic peptides arose as by-products of normal protein turnover. Recent evidence, however, suggests that the primary source of peptides is newly synthesized proteins that arise from conventional as well as cryptic translational reading frames. It is increasingly clear that for many peptides the C-terminus is generated in the cytoplasm, and N-terminal trimming occurs in the endoplasmic reticulum in an MHC I-dependent manner. Nature's gene-chips are thus both parsimonious and elegant.

Notes: Abstract Dendritic cells take up antigens in peripheral tissues, process them into proteolytic peptides, and load these peptides onto major histocompatibility complex (MHC) class I and II molecules. Dendritic cells then migrate to secondary lymphoid organs and become competent to present antigens to T lymphocytes, thus initiating antigen-specific immune responses, or immunological tolerance. Antigen presentation in dendritic cells is finely regulated: antigen uptake, intracellular transport and degradation, and the traffic of MHC molecules are different in dendritic cells as compared to other antigen-presenting cells. These specializations account for dendritic cells' unique role in the initiation of immune responses and the induction of tolerance.

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

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

Notes: Abstract The rapid and devastating spread of the AIDS epidemic in the developing world as well as the difficulties associated with delivering antiretroviral drugs in affected countries underscore the urgent need for the development of a safe and effective AIDS vaccine. In this review, we discuss recent advances in our understanding of the cellular and humoral immune responses to human immunodeficiency virus type 1 (HIV-1) infection. We then describe vaccine strategies that have been explored and discuss the evidence suggesting that cellular immune responses elicited by novel vaccine modalities may attenuate clinical disease caused by HIV-1.

Notes: Abstract T cells that can respond to self-antigens are present in the peripheral immune repertoire of all healthy individuals. Recently we have found that unmanipulated SJL mice that are highly susceptible to EAE also maintain a very high frequency of T cells responding to an encephalitogenic epitope of a myelin antigen proteolipid protein (PLP) 139-151 in the peripheral repertoire. This is not due to lack of expression of myelin antigens in the thymus resulting in escape of PLP 139-151 reactive cells from central tolerance, but is due to expression of a splice variant of PLP named DM20, which lacks the residues 116-150. In spite of this high frequency, the PLP 139-151 reactive cells remain undifferentiated in the periphery and do not induce spontaneous EAE. In contrast, SJL TCR transgenic mice expressing a receptor derived from a pathogenic T cell clone do develop spontaneous disease. This may be because in normal mice, autoreactive cells are kept in check by an alternate PLP 139-151 reactive nonpathogenic repertoire, which maintains a balance that keeps them healthy. If this is the case, selective activation of one repertoire or the other may alter susceptibility to autoimmune disease. Since T cells are generally cross-reactive, besides responding to nonself-antigens, they also maintain significant responses to self-antigens. Based on the PLP 139-151 system, we propose a model in which activation with foreign antigens can result in the generation of pathogenic memory T cells that mediate autoimmunity. We also outline circumstances under which activation of self-reactive T cells with foreign antigens can generate selective tolerance and thus generate protective/regulatory memory against self while still maintaining significant responses against foreign antigens. This provides a mechanism by which the fidelity and specificity of the immune system against foreign antigens is improved without increasing the potential for developing an autoimmune disease.

Notes: Abstract Whether B-1a (CD5+) cells are a distinct lineage derived from committed fetal/neonatal precursors or arise from follicular B-2 cells in response to BCR ligation and other, unknown signals remains controversial. Recent evidence indicates that B-1a cells can derive from adult precursors expressing an appropriate specificity when the (self-) antigen is present. Antibody specificity determines whether a B cell expressing immunoglobulin transgenes has a B-2, B-1a or marginal zone (MZ) phenotype. MZ cells share many phenotypic characteristics of B-1 cells and, like them, appear to develop in response to T independent type 2 antigens. Because fetal-derived B cell progenitors fail to express terminal deoxynucleotidyl transferase (TdT) and for other reasons, they are likely to express a repertoire that allows selection into the B-1a population. As it is selected by self-antigen, the B-1 repertoire tends to be autoreactive. This potentially dangerous repertoire is also useful, as B-1 cells are essential for resistance to several pathogens and they play an important role in mucosal immunity. The CD5 molecule can function as a negative regulator of BCR signaling that may help prevent inappropriate activation of autoreactive B-1a cells.

Notes: Abstract The development of the immune system and the host response to microbial infection rely on the activation and silencing of numerous, differentially expressed genes. Since the mid-1980s, a primary goal has been to identify transcription factors that regulate specific genes and specific immunological processes. More recently, there has been a growing appreciation of the role of chromatin structure in gene regulation. Before most activators of a gene access their binding sites, a transition from a condensed to a decondensed chromatin structure appears to take place. The activation of transcription is then accompanied by the remodeling of specific nucleosomes. Conversely, the acquisition of a more condensed chromatin structure is often associated with gene silencing. Chromatin structure is a particularly significant contributor to gene regulation because it is likely to be a major determinant of cell identity and cell memory. That is, the propagation of decondensed chromatin at specific loci through DNA replication and cell division helps a cell remember which genes are expressed constitutively in that cell type or are poised for expression upon exposure to a stimulus. Here we review recent progress toward understanding the role of chromatin in the immune system. The interleukin-4 gene serves as a primary model for exploring the events involved in the acquisition and heritable maintenance of a decondensed chromatin structure. Studies of the interleukin-12 p40 and interferon-beta genes are then reviewed for insight into the mechanisms by which the remodeling of specific nucleosomes in the vicinity of a promoter can contribute to rapid activation following cell stimulation. Finally, basic principles of gene silencing are discussed.

Notes: Abstract Immune cells are activated as a result of productive interactions between ligands and various receptors known as immunoreceptors. These receptors function by recruiting cytoplasmic protein tyrosine kinases, which trigger a unique phosphorylation signal leading to cell activation. In the recent past, there has been increasing interest in elucidating the processes involved in the negative regulation of immunoreceptor-mediated signal transduction. Evidence is accumulating that immunoreceptor signaling is inhibited by complex and highly regulated mechanisms that involve receptors, protein tyrosine kinases, protein tyrosine phosphatases, lipid phosphatases, ubiquitin ligases, and inhibitory adaptor molecules. Genetic evidence indicates that this inhibitory machinery is crucial for normal immune cell homeostasis.

Notes: Abstract The phagocytic response of innate immune cells such as macrophages is defined by the activation of complex signaling networks that are stimulated by microbial contact. Many individual proteins have been demonstrated to participate in phagocytosis, and the application of high-throughput tools has indicated that many more remain to be described. In this review, we examine this complexity and describe how during recognition, multiple receptors are simultaneously engaged to mediate internalization, activate microbial killing, and induce the production of inflammatory cytokines and chemokines. Many signaling molecules perform multiple functions during phagocytosis, and these molecules are likely to be key regulators of the process. Indeed, pathogenic microorganisms target many of these molecules in their attempts to evade destruction.

Notes: Abstract T cell activation is dependent upon signals delivered through the antigen-specific T cell receptor and accessory receptors on the T cell. A primary costimulatory signal is delivered through the CD28 receptor after engagement of its ligands, B7-1 (CD80) or B7-2 (CD86). Engagement of CTLA-4 (CD152) by the same B7-1 or B7-2 ligands results in attenuation of T cells responses. Recently, molecular homologs of CD28 and CTLA-4 receptors and their B7-like ligands have been identified. ICOS is a CD28-like costimulatory receptor with a unique B7-like ligand. PD-1 is an inhibitory receptor, with two B7-like ligands. Additional members of B7 and CD28 gene families have been proposed. Integration of signals through this family of costimulatory and inhibitory receptors and their ligands is critical for activation of immune responses and tolerance. Understanding these pathways will allow development of new strategies for therapeutic intervention in immune-mediated diseases.

Notes: Abstract The innate immune system is a universal and ancient form of host defense against infection. Innate immune recognition relies on a limited number of germline-encoded receptors. These receptors evolved to recognize conserved products of microbial metabolism produced by microbial pathogens, but not by the host. Recognition of these molecular structures allows the immune system to distinguish infectious nonself from noninfectious self. Toll-like receptors play a major role in pathogen recognition and initiation of inflammatory and immune responses. Stimulation of Toll-like receptors by microbial products leads to the activation of signaling pathways that result in the induction of antimicrobial genes and inflammatory cytokines. In addition, stimulation of Toll-like receptors triggers dendritic cell maturation and results in the induction of costimulatory molecules and increased antigen-presenting capacity. Thus, microbial recognition by Toll-like receptors helps to direct adaptive immune responses to antigens derived from microbial pathogens.

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

Notes: Abstract Heat shock proteins are abundant soluble intracellular proteins, present in all cells. Members of the heat shock protein family bind peptides including antigenic peptides generated within cells. Heat shock proteins also interact with antigen presenting cells through CD91 and other receptors, eliciting a cascade of events including re-presentation of heat shock protein-chaperoned peptides by MHC, translocation of NFkappaB into the nuclei and maturation of dendritic cells. These consequences point to a key role of heat shock proteins in fundamental immunological phenomena such as activation of antigen presenting cells, indirect presentation (or cross-priming), and chaperoning of peptides during antigen presentation. Heat shock proteins appear to have been involved in innate immune responses since the emergence of phagocytes in early multicellular organisms and to have been commandeered for adaptive immune responses with the advent of specificity. These properties of heat shock proteins also allow them to be used for immunotherapy of cancers and infections in novel ways.

Notes: Abstract In recent years the status of the inflammatory bowel diseases (IBDs) as canonical autoimmune diseases has risen steadily with the recognition that these diseases are, at their crux, abnormalities in mucosal responses to normally harmless antigens in the mucosal microflora and therefore responses to antigens that by their proximity and persistence are equivalent to self-antigens. This new paradigm is in no small measure traceable to the advent of multiple models of mucosal inflammation whose very existence is indicative of the fact that many types of immune imbalance can lead to loss of tolerance for mucosal antigens and thus inflammation centered in the gastrointestinal tract. We analyze the immunology of the IBDs through the lens of the murine models, first by drawing attention to their common features and then by considering individual models at a level of detail necessary to reveal their individual capacities to provide insight into IBD pathogenesis. What emerges is that murine models of mucosal inflammation have given us a road map that allows us to begin to define the immunology of the IBDs in all its complexity and to find unexpected ways to treat these diseases.

Notes: Abstract Humans are exposed to a variety of environmental mycobacteria (EM), and most children are inoculated with live Bacille Calmette-Guerin (BCG) vaccine. In addition, most of the world's population is occasionally exposed to human-borne mycobacterial species, which are less abundant but more virulent. Although rarely pathogenic, mildly virulent mycobacteria, including BCG and most EM, may cause a variety of clinical diseases. Mycobacterium tuberculosis, M. leprae, and EM M. ulcerans are more virulent, causing tuberculosis, leprosy, and Buruli ulcer, respectively. Remarkably, only a minority of individuals develop clinical disease, even if infected with virulent mycobacteria. The interindividual variability of clinical outcome is thought to result in part from variability in the human genes that control host defense. In this well-defined microbiological and clinical context, the principles of mouse immunology and the methods of human genetics can be combined to facilitate the genetic dissection of immunity to mycobacteria. The natural infections are unique to the human model, not being found in any of the animal models of experimental infection. We review current genetic knowledge concerning the simple and complex inheritance of predisposition to mycobacterial diseases in humans. Rare patients with Mendelian disorders have been found to be vulnerable to BCG, a few EM, and M. tuberculosis. Most cases of presumed Mendelian susceptibility to these and other mycobacterial species remain unexplained. In the general population leprosy and tuberculosis have been shown to be associated with certain human genetic polymorphisms and linked to certain chromosomal regions. The causal vulnerability genes themselves have yet to be identified and their pathogenic alleles immunologically validated. The studies carried out to date have been fruitful, initiating the genetic dissection of protective immunity against a variety of mycobacterial species in natural conditions of infection. The human model has potential uses beyond the study of mycobacterial infections and may well become a model of choice for the investigation of immunity to infectious agents.

Notes: Abstract In contrast to T cell receptors, signal transducing cell surface membrane molecules involved in the regulation of responses by cells of the innate immune system employ structures that are encoded in the genome rather than generated by somatic recombination and that recognize either classical MHC-I molecules or their structural relatives (such as MICA, RAE-1, or H-60). Considerable progress has recently been made in our understanding of molecular recognition by such molecules based on the determination of their three-dimensional structure, either in isolation or in complex with their MHC-I ligands. Those best studied are the receptors that are expressed on natural killer (NK) cells, but others are found on populations of T cells and other hematopoietic cells. These molecules fall into two major structural classes, those of the immunoglobulin superfamily (KIRs and LIRs) and of the C-type lectin-like family (Ly49, NKG2D, and CD94/NKG2). Here we summarize, in a functional context, the structures of the murine and human molecules that have recently been determined, with emphasis on how they bind different regions of their MHC-I ligands, and how this allows the discrimination of tumor or virus-infected cells from normal cells of the host.

Notes: Abstract Cytokines play a critical role in orchestrating and perpetuating inflammation in asthmatic airways and several specific cytokine and chemokine inhibitors are now in development for the treatment of asthma. Inhibition of IL-4 with soluble IL-4 receptors has shown promising early results in asthma. Anti-IL-5 antibody is very effective at inhibiting peripheral blood and airway eosinophils but does not appear to be effective in symptomatic asthma. Inhibitory cytokines, such as IL-10, interferons, and IL-12 are less promising because systemic delivery produces intolerable side effects. Inhibition of TNF-alpha may be useful in severe asthma. Many chemokines are involved in the inflammatory response of asthma, and small-molecule inhibitors of chemokine receptors are in development. CCR3 antagonists are now in clinical development for the treatment of asthma. Because so many cytokines are involved in asthma, drugs that inhibit the synthesis of multiple cytokines may prove to be more useful. Several such classes of drug are now in clinical development, and the risk of side effects with these nonspecific inhibitors may be reduced by the inhaled route of delivery.

Notes: Abstract Foods produced through agricultural biotechnology are reaching the consumer marketplace. These novel foods should be assessed for their safety, including their potential allergenicity. Agricultural biotechnology involves the introduction of novel proteins into the modified foods, and proteins can be allergenic. The potential allergenicity of the introduced proteins can be evaluated by focusing on the source of the gene, the homology of the newly introduced protein to known allergens, the reactivity of the novel protein with IgE antibodies from the serum of individuals with known allergies to the source of the transferred DNA or to materials that are broadly related to the source of the transferred DNA, the resistance of the novel protein to pepsin, and the immunoreactivity of the novel protein in appropriate animal models. Additional factors, such as the level of expression of the novel protein in the modified food and expression in the edible portion of the food, may also yield valuable insights. Applying such criteria provides a reasonable approach to determining whether or not the novel protein is likely to become an allergen.

Notes: Abstract Pharmacogenomics requires the integration and analysis of genomic, molecular, cellular, and clinical data, and it thus offers a remarkable set of challenges to biomedical informatics. These include infrastructural challenges such as the creation of data models and databases for storing these data, the integration of these data with external databases, the extraction of information from natural language text, and the protection of databases with sensitive information. There are also scientific challenges in creating tools to support gene expression analysis, three-dimensional structural analysis, and comparative genomic analysis. In this review, we summarize the current uses of informatics within pharmacogenomics and show how the technical challenges that remain for biomedical informatics are typical of those that will be confronted in the postgenomic era.

Notes: Abstract Efficacy has been defined in receptor pharmacology as a proportionality factor denoting the amount of physiological response a given ligand imparts to a biological system for a given amount of receptor occupancy. While first defined in terms of response, the concept can be expanded to a wide variety of G protein-coupled receptor (GPCR) behaviors, which includes pleiotropic interaction with multiple G proteins, internalization, oligomerization, desensitization, and interaction with membrane auxilliary proteins. Thus, there can be numerous types of efficacy, and different ligands can have a range of efficacies for different receptor behaviors. This review discusses the use of the efficacy concept in GPCR models based on the thermodynamic linkage theory and also in terms of the protein ensemble theory, in which macroaffinity of ligands for an ensemble of receptor microstates produces a new ligand-bound ensemble. The pharmacological characteristics of the ligand emerge from the intersection of the ligand-bound ensemble with the various ensembles defining pharmacological receptor behaviors. Receptor behaviors discussed are activation of G proteins; ability to be phosphorylated, desensitized, and internalized; formation of dimers and oligomers; and the interaction with auxiliary membrane and cytosolic proteins. The concepts of ligand-specific receptor conformation and conditional efficacy are also discussed in the context of ligand control of physiological response.

Notes: Abstract Chemokines are the largest family of cytokines in human immunophysiology. These proteins are defined by four invariant cysteines and are categorized based on the sequence around the first two cysteines, which leads to two major and two minor subfamilies. Chemokines function by activating specific G protein-coupled receptors, which results in, among other functions, the migration of inflammatory and noninflammatory cells to the appropriate tissues or compartments within tissues. Some of these proteins and receptors have been implicated or shown to be involved in inflammation, autoimmune diseases, and infection by HIV-1. The three-dimensional structure of each monomer is virtually identical, but the quaternary structure of chemokines is different for each subfamily. Structure-function studies reveal several regions of chemokines to be involved in function, with the N-terminal region playing a dominant role. A number of proteins and small-molecule antagonists have been identified that inhibit chemokine activities. In this review, we discuss aspects of the structure, function, and inhibition of chemokines.

Notes: Abstract S-nitrosothiols are biological metabolites of nitric oxide. It has often been suggested that they represent a more stable metabolite of nitric oxide that can either be stored, or transported, although the evidence for this is sparse. There are many unanswered questions concerning how S-nitrosothiols are formed, how they are metabolized and how they elicit biological responses. These questions are highlighted by the fact that the known chemistry of nitric oxide, thiols, and S-nitrosothiols cannot serve to explain their proposed biological activities. This review attempts to highlight the gulf between our chemical understanding of S-nitrosothiols and the proposed biological activities of these compounds with respect to guanylyl cyclase-independent nitric oxide bioactivity and also the control of vascular tone.

Notes: Abstract Early NMR structural studies of serum lipoproteins were based on 1H, 13C, 31P, and 2H studies of lipid components. From the early studies information on composition, lipid chain dynamics and order parameters, and monolayer organization resulted. More recently, selective or complete isotopic labeling techniques, combined with multidimensional NMR spectroscopy, have resulted in structural information of apoprotein fragments. Finally, use of heteronuclear three- and four-dimensional experiments have yielded solution structures and protein-lipid interactions of intact apolipoproteins C-I, C-II, and A-I.

Notes: Abstract During the course of their biological function, proteins undergo different types of structural rearrangements ranging from local to large-scale conformational changes. These changes are usually triggered by their interactions with small-molecular-weight ligands or other macromolecules. Because binding interactions occur at specific sites and involve only a small number of residues, a chain of cooperative interactions is necessary for the propagation of binding signals to distal locations within the protein structure. This process requires an uneven structural distribution of protein stability and cooperativity as revealed by NMR-detected hydrogen/deuterium exchange experiments under native conditions. The distribution of stabilizing interactions does not only provide the architectural foundation to the three-dimensional structure of a protein, but it also provides the required framework for functional cooperativity. In this review, the statistical thermodynamic linkage between protein stability, functional cooperativity, and ligand binding is discussed.

Notes: Abstract We determined the high-resolution structures of large and small ribosomal subunits from mesophilic and thermophilic bacteria and compared them with those of the thermophilic ribosome and the halophilic large subunit. We confirmed that the elements involved in intersubunit contacts and in substrate binding are inherently flexible and that a common ribosomal strategy is to utilize this conformational variability for optimizing its functional efficiency and minimizing nonproductive interactions. Under close-to-physiological conditions, these elements maintain well-ordered characteristic conformations. In unbound subunits, the features creating intersubunit bridges within associated ribosomes lie on the interface surface, and the features that bind factors and substrates reach toward the binding site only when conditions are ripe.

Notes: Abstract Chromatin fibers are dynamic macromolecular assemblages that are intimately involved in nuclear function. This review focuses on recent advances centered on the molecular mechanisms and determinants of chromatin fiber dynamics in solution. Major points of emphasis are the functions of the core histone tail domains, linker histones, and a new class of proteins that assemble supramolecular chromatin structures. The discussion of important structural issues is set against a background of possible functional significance.

Notes: Abstract The review deals with recent advances in magnetic resonance spectroscopy (hf EPR and NMR) of paramagnetic metal centers in biological macromolecules. In the first half of our chapter, we present an overview of recent technical developments in the NMR of paramagnetic bio-macromolecules. These are illustrated by a variety of examples deriving mainly from the spectroscopy of metalloproteins and their complexes. The second half focuses on recent developments in high-frequency EPR spectroscopy and the application of the technique to copper, iron, and manganese proteins. Special attention is given to the work on single crystals of copper proteins.

Notes: Abstract A large number of protein toxins having enzymatically active A- and B-moieties that bind to cell surface receptors must be endocytosed before the A-moiety is translocated into the cytosol where it exerts its cytotoxic action. The accumulated information about the most well-studied toxins has provided a detailed picture of how they exploit the membrane trafficking systems of cells, and studies of toxin trafficking have revealed the existance of new pathways. The complexity of different endocytic mechanisms, as well as the multiple routes between endosomes and the Golgi apparatus and retrogradely to the endoplasmic reticulum (ER), are being unravelled by investigations of how toxins gain access to their targets. With increasing information about the internalization and intracellular trafficking of these opportunistic toxins, new avenues have been opened for their application in areas of medicine such as drug delivery and therapy.

Notes: Abstract Co-option occurs when natural selection finds new uses for existing traits, including genes, organs, and other body structures. Genes can be co-opted to generate developmental and physiological novelties by changing their patterns of regulation, by changing the functions of the proteins they encode, or both. This often involves gene duplication followed by specialization of the resulting paralogous genes into particular functions. A major role for gene co-option in the evolution of development has long been assumed, and many recent comparative developmental and genomic studies have lent support to this idea. Although there is relatively less known about the molecular basis of co-option events involving developmental pathways, much can be drawn from well-studied examples of the co-option of structural proteins. Here, we summarize several case studies of both structural gene and developmental genetic circuit co-option and discuss how co-option may underlie major episodes of adaptive change in multicellular organisms. We also examine the phenomenon of intraspecific variability in gene expression patterns, which we propose to be one form of material for the co-option process. We integrate this information with recent models of gene family evolution to provide a framework for understanding the origin of co-optive evolution and the mechanisms by which natural selection promotes evolutionary novelty by inventing new uses for the genetic toolkit.

Notes: Abstract In flowering plants, pollen grains germinate to form pollen tubes that transport male gametes (sperm cells) to the egg cell in the embryo sac during sexual reproduction. Pollen tube biology is complex, presenting parallels with axon guidance and moving cell systems in animals. Pollen tube cells elongate on an active extracellular matrix in the style, ultimately guided by stylar and embryo sac signals. A well-documented recognition system occurs between pollen grains and the stigma in sporophytic self-incompatibility, where both receptor kinases in the stigma and their peptide ligands from pollen are now known. Complex mechanisms act to precisely target the sperm cells into the embryo sac. These events initiate double fertilization in which the two sperm cells from one pollen tube fuse to produce distinctly different products: one with the egg to produce the zygote and embryo and the other with the central cell to produce the endosperm.

Notes: Abstract The Arabidopsis genome sequence has revealed that plants contain a much larger complement of receptor kinase genes than other organisms. Early analysis of these genes revealed involvement in a diverse array of developmental and defense functions that included gametophyte development, pollen-pistil interactions, shoot apical meristem equilibrium, hormone perception, and cell morphogenesis. Amino acid sequence motifs and binding studies indicate that the ectodomains are capable of binding, either directly or indirectly, various classes of molecules including proteins, carbohydrates, and steroids. Genetic and biochemical approaches have begun to identify other components of several signal transduction pathways. Some receptor-like kinases (RLKs) appear to function with coreceptors lacking kinase domains, and genome analysis suggests this might be true for many RLKs. The KAPP protein phosphatase functions as a negative regulator of at least two RLK systems, and in vitro studies suggest it could be a common component of more. Whether plant signaling systems display a modularity similar to animal systems remains to be determined. Future efforts will reveal unknown functions of other RLKs and elucidate the relationships among their signaling networks.

Notes: Abstract Eukaryotic cells use actin polymerization to change shape, move, and internalize extracellular materials by phagocytosis and endocytosis, and to form contractile structures. In addition, several pathogens have evolved to use host cell actin assembly for attachment, internalization, and cell-to-cell spread. Although cells possess multiple mechanisms for initiating actin polymerization, attention in the past five years has focused on the regulation of actin nucleation-the formation of new actin filaments from actin monomers. The Arp2/3 complex and the multiple nucleation-promoting factors (NPFs) that regulate its activity comprise the only known cellular actin-nucleating factors and may represent a universal machine, conserved across eukaryotic phyla, that nucleates new actin filaments for various cellular structures with numerous functions. This review focuses on our current understanding of the mechanism of actin nucleation by the Arp2/3 complex and NPFs and how these factors work with other cytoskeletal proteins to generate structurally and functionally diverse actin arrays in cells.

Notes: Abstract Membrane fusion is a fundamental biochemical reaction and the final step in all vesicular trafficking events. It is crucial for the transfer of proteins and lipids between different compartments and for exo- and endocytic traffic of signaling molecules and receptors. It leads to the reconstruction of organelles such as the Golgi or the nuclear envelope, which decay into fragments during mitosis. Hence, controlled membrane fusion reactions are indispensible for the compartmental organization of eukaryotic cells; for their communication with the environment via hormones, neurotransmitters, growth factors, and receptors; and for the integration of cells into multicellular organisms. Intracellular pathogenic bacteria, such as Mycobacteria or Salmonellae, have developed means to control fusion reactions in their host cells. They persist in phagosomes whose fusion with lysosomes they actively suppress-a means to ensure survival inside host cells. The past decade has witnessed rapid progress in the elucidation of parts of the molecular machinery involved in these membrane fusion reactions. Whereas some elements of the fusion apparatus are remarkably similar in several compartments, there is an equally striking divergence of others. The purpose of this review is to highlight common features of different fusion reactions and the concepts that emerged from them but also to stress the differences and challenge parts of the current hypotheses. This review covers only the endoplasmic fusion reactions mentioned above, i.e., reactions initiated by contacts of membranes with their cytoplasmic faces. Ectoplasmic fusion events, which depend on an initial contact of the fusion partners via the membrane surfaces exposed to the surrounding medium are not discussed, nor are topics such as the entry of enveloped viruses, formation of syncytia, gamete fusion, or vesicle scission (a fusion reaction that leads to the fission of, e.g., transport vesicles).

Notes: Abstract Golgi inheritance proceeds via sequential biogenesis and partitioning phases. Although little is known about Golgi growth and replication (biogenesis), ultrastructural and fluorescence analyses have provided a detailed, though still controversial, perspective of Golgi partitioning during mitosis in mammalian cells. Partitioning requires the fragmentation of the juxtanuclear ribbon of interconnected Golgi stacks into a multitude of tubulovesicular clusters. This process is choreographed by a cohort of mitotic kinases and an inhibition of heterotypic and homotypic Golgi membrane-fusion events. Our model posits that accurate partitioning occurs early in mitosis by the equilibration of Golgi components on either side of the metaphase plate. Disseminated Golgi components then coalesce to regenerate Golgi stacks during telophase. Semi-intact cell and cell-free assays have accurately recreated these processes and allowed their molecular dissection. This review attempts to integrate recent findings to depict a more coherent, synthetic molecular picture of mitotic Golgi fragmentation and reassembly. Of particular importance is the emerging concept of a highly regulated and dynamic Golgi structural matrix or template that interfaces with cargo receptors, Golgi enzymes, Rab-GTPases, and SNAREs to tightly couple biosynthetic transport to Golgi architecture. This structural framework may be instructive for Golgi biogenesis and may encode sufficient information to ensure accurate Golgi inheritance, thereby helping to resolve some of the current discrepancies between different workers.

Notes: Abstract Methods of density functional theory in statistical mechanics have been applied extensively over the past 15 years to problems in the equilibrium and dynamic properties of materials. They allow the incorporation of microscopic atomic and molecular forces at a much lower computational cost than direct simulation. This review discusses recent advances in the calculation of density functionals for materials, with particular emphasis on fluids at walls and in porous media, on crystal nucleation and growth from the melt, and on complex fluids and biomolecules. The extension of equilibrium density functional methods to approximate theories of phase transition dynamics is emphasized.

Notes: Abstract We review progress made in quantitatively ascertaining the various statistical correlation functions that are fundamental to determining the material properties of specific classes of disordered materials. Topics covered include the definitions of the correlation functions, a unified theoretical means of representing and computing the different statistical descriptors, structural characterization from two-dimensional and three-dimensional images of materials, scalar order metrics and particle packings, and reconstruction techniques.

Notes: Abstract The paper is about cellular automaton models in materials science. It gives an introduction to the fundamentals of cellular automata and reviews applications, particularly for those that predict recrystallization phenomena. Cellular automata for recrystallization are typically discrete in time, physical space, and orientation space and often use quantities such as dislocation density and crystal orientation as state variables. Cellular automata can be defined on a regular or nonregular two- or three-dimensional lattice considering the first, second, and third neighbor shell for the calculation of the local driving forces. The kinetic transformation rules are usually formulated to map a linearized symmetric rate equation for sharp grain boundary segment motion. While deterministic cellular automata directly perform cell switches by sweeping the corresponding set of neighbor cells in accord with the underlying rate equation, probabilistic cellular automata calculate the switching probability of each lattice point and make the actual decision about a switching event by evaluating the local switching probability using a Monte Carlo step. Switches are in a cellular automaton algorithm generally performed as a function of the previous state of a lattice point and the state of the neighboring lattice points. The transformation rules can be scaled in terms of time and space using, for instance, the ratio of the local and the maximum possible grain boundary mobility, the local crystallographic texture, the ratio of the local and the maximum-occurring driving forces, or appropriate scaling measures derived from a real initial specimen. The cell state update in a cellular automaton is made in synchrony for all cells. The review deals, in particular, with the prediction of the kinetics, microstructure, and texture of recrystallization. Couplings between cellular automata and crystal plasticity finite element models are also discussed.

Notes: Abstract The phase-field method has recently emerged as a powerful computational approach to modeling and predicting mesoscale morphological and microstructure evolution in materials. It describes a microstructure using a set of conserved and nonconserved field variables that are continuous across the interfacial regions. The temporal and spatial evolution of the field variables is governed by the Cahn-Hilliard nonlinear diffusion equation and the Allen-Cahn relaxation equation. With the fundamental thermodynamic and kinetic information as the input, the phase-field method is able to predict the evolution of arbitrary morphologies and complex microstructures without explicitly tracking the positions of interfaces. This paper briefly reviews the recent advances in developing phase-field models for various materials processes including solidification, solid-state structural phase transformations, grain growth and coarsening, domain evolution in thin films, pattern formation on surfaces, dislocation microstructures, crack propagation, and electromigration.

Notes: Abstract An overview of the phase-field method for modeling solidification is presented, together with several example results. Using a phase-field variable and a corresponding governing equation to describe the state (solid or liquid) in a material as a function of position and time, the diffusion equations for heat and solute can be solved without tracking the liquid-solid interface. The interfacial regions between liquid and solid involve smooth but highly localized variations of the phase-field variable. The method has been applied to a wide variety of problems including dendritic growth in pure materials; dendritic, eutectic, and peritectic growth in alloys; and solute trapping during rapid solidification.

Notes: Abstract A fracture mechanics framework has been developed for predicting crack initiation and growth in full-scale components and structures from test specimen data. Much knowledge has also been gained about the mechanisms by which fracture occurs in a variety of materials. However, the development of quantitative connections between models of the physical processes of fracture and macroscale measures of fracture resistance is still at an early stage. A key difficulty is that fracture spans several length scales from the atomistic to the macroscopic scale. In this paper, some analyses are reviewed that use micromechanical modeling to predict fracture toughness from the physics of separation and plastic flow processes. Attention is confined to fracture by cleavage in metal crystals, under both monotonic and cyclic loading conditions. The role of models at the dislocation size scale in bridging the gap between atomistic and continuum descriptions is highlighted.

Notes: Abstract Various methods for calculating the free energies of fluids, solids, and discrete spin systems are reviewed with particular emphasis on applications relevant in materials science. First, traditional methodologies based on harmonic approximations and thermodynamic integration are examined to highlight the workings of these very useful and robust techniques. Several newer and more specialized strategies are then discussed to provide a snapshot of current practices. Our aim here is to compare and contrast several related techniques and to provide an assessment of their relative strengths.

Notes: Abstract Computation is one of the centerpieces of both the physical and biological sciences. A key thrust in computational science is the explicit mechanistic simulation of the spatiotemporal evolution of materials ranging from macromolecules to intermetallic alloys. However, our ability to simulate such systems is in the end always limited in both the spatial extent of the systems that are considered, as well as the duration of the time that can be simulated. As a result, a variety of efforts have been put forth that aim to finesse these challenges in both space and time through new techniques in which constraint is exploited to reduce the overall computational burden. The aim of this review is to describe in general terms some of the key ideas that have been set forth in both the materials and biological setting and to speculate on future developments along these lines. We begin by developing general ideas on the exploitation of constraint as a systematic tool for degree of freedom thinning. These ideas are then applied to case studies ranging from the plastic deformation of solids to the interactions of proteins and DNA.

Notes: Abstract Atomistic aspects of dynamic fracture in a variety of brittle crystalline, amorphous, nanophase, and nanocomposite materials are reviewed. Molecular dynamics (MD) simulations, ranging from a million to 1.5 billion atoms, are performed on massively parallel computers using highly efficient multiresolution algorithms. These simulations shed new light on (a) branching, deflection, and arrest of cracks; (b) growth of nanoscale pores ahead of the crack and how pores coalesce with the crack to cause fracture; and (c) the influence of these mechanisms on the morphology of fracture surfaces. Recent advances in novel multiscale simulation schemes combining quantum mechanical, molecular dynamics, and finite-element approaches and the use of these hybrid approaches in the study of crack propagation are also discussed.

Notes: Abstract The Kuiper Belt consists of a large number of small, solid bodies in heliocentric orbit beyond Neptune. Discovered as recently as 1992, the Kuiper Belt objects (KBOs) are thought to hold the keys to understanding the early solar system, as well as the origin of outer solar system objects, such as the short-period comets and the Pluto-Charon binary. The KBOs are probably best viewed as aged relics of the Sun's accretion disk. Dynamical structures in the Kuiper Belt provide evidence for processes operative in the earliest days of the solar system, including a phase of planetary migration and a clearing phase, in which substantial mass was lost from the disk. Dust is produced to this day by collisions between KBOs. In its youth, the Kuiper Belt may have compared to the dust rings observed now around such stars as GG Tau and HR 4796A. This review presents the basic physical parameters of the KBOs and makes connections with the disks observed around nearby stars.

Notes: Abstract The gamma ray burst phenomenon is reviewed from a theoretical point of view, with emphasis on the fireball shock scenario of the prompt emission and the longer wavelength afterglow. Recent progress and issues are discussed, including spectral-temporal evolution, localizations, jets, spectral lines, environmental and cosmological aspects, as well as some prospects for future experiments in both electromagnetic and nonelectromagnetic channels.

Notes: Abstract Modified Newtonian dynamics (MOND) is an empirically motivated modification of Newtonian gravity or inertia suggested by Milgrom as an alternative to cosmic dark matter. The basic idea is that at accelerations below ao= 10-8 cm/s2=cHo/6 the effective gravitational attraction approaches , where gn is the usual Newtonian acceleration. This simple algorithm yields flat rotation curves for spiral galaxies and a mass-rotation velocity relation of the form MV4 that forms the basis for the observed luminosity-rotation velocity relation-the Tully-Fisher law. We review the phenomenological success of MOND on scales ranging from dwarf spheroidal galaxies to superclusters and demonstrate that the evidence for dark matter can be equally well interpreted as evidence for MOND. We discuss the possible physical basis for an acceleration-based modification of Newtonian dynamics as well as the extention of MOND to cosmology and structure formation.

Notes: Abstract Although we have a general understanding of the manner in which individual stars form, our understanding of how binary stars form is far from complete. This is in large part due to the fact that the star formation process happens very quickly and in regions of the Galaxy that are difficult to study observationally. We review the theoretical models that have been developed in an effort to explain how binaries form. Several proposed mechanisms appear to be quite promising, but none is completely satisfactory.

Notes: Abstract Study of radio supernovae over the past 20 years includes two dozen detected objects and more than 100 upper limits. From this work it is possible to identify classes of radio properties, demonstrate conformance to and deviations from existing models, estimate the density and structure of the circumstellar material and, by inference, the evolution of the presupernova stellar wind, and reveal the last stages of stellar evolution before explosion. It is also possible to detect ionized hydrogen along the line of sight, to demonstrate binary properties of the stellar system, and to show clumpiness of the circumstellar material. More speculatively, it may be possible to provide distance estimates to radio supernovae. Over the past four years the afterglow of gamma-ray bursters has occasionally been detected in the radio, as well in other wavelengths bands. In particular, the interesting and unusual gamma-ray burst GRB980425, thought to be related to SN1998bw, is a possible link between supernovae and gamma-ray bursters. Analyzing the extensive radio emission data avaliable for SN1998bw, one can describe its time evolution within the well-established framework available for the analysis of radio emission from supernovae. This allows relatively detailed description of a number of physical properties of the object. The radio emission can best be explained as the interaction of a mildly relativistic (Gamma~ 1.6) shock with a dense preexplosion stellar wind-established circumstellar medium that is highly structured both azimuthally, in clumps or filaments, and radially, with observed density enhancements. Because of its unusual characteristics for a Type Ib/c supernova, the relation of SN1998bw to GRB980425 is strengthened and suggests that at least some classes of GRBs originate in massive star explosions. Thus, employing the formalism for describing the radio emission from supernovae and following the link through SN1998bw/GRB980425, it is possible to model the gross properties of the radio and optical/infrared emission from the half-dozen GRBs with extensive radio observations. From this we conclude that at least some members of the "slow-soft" class of GRBs can be attributed to the explosion of a massive star in a dense, highly structured circumstellar medium that was presumably established by the preexplosion stellar system.

Notes: Abstract The Sunyaev-Zel'dovich effect (SZE) provides a unique way to map the large-scale structure of the universe as traced by massive clusters of galaxies. As a spectral distortion of the cosmic microwave background, the SZE is insensitive to the redshift of the galaxy cluster, making it well-suited for studies of clusters at all redshifts, and especially at reasonably high redshifts (z〉 1) where the abundance of clusters is critically dependent on the underlying cosmology. Recent high signal-to-noise detections of the SZE have enabled interesting constraints on the Hubble constant and on the matter density of the universe using small samples of galaxy clusters. Upcoming SZE surveys are expected to find hundreds to thousands of new galaxy clusters, with a mass selection function that is remarkably uniform with redshift. In this review we provide an overview of the SZE and its use for cosmological studies, with emphasis on the cosmology that can, in principle, be extracted from SZE survey yields. We discuss the observational and theoretical challenges that must be met before precise cosmological constraints can be extracted from the survey yields.

Notes: Abstract The coupling of fluid dynamics and biology at the level of the cell is an intensive area of investigation because of its critical role in normal physiology and disease. Microcirculatory flow has been a focus for years, owing to the complexity of cell-cell or cell-glycocalyx interactions. Noncirculating cells, particularly those that comprise the walls of the circulatory system, experience and respond biologically to fluid dynamic stresses. In this article, we review the more recent studies of circulating cells, with an emphasis on the role of the glycocalyx on red-cell motion in small capillaries and on the deformation of leukocytes passing through the microcirculation. We also discuss flows in the vicinity of noncirculating cells, the influence of fluid dynamic shear stress on cell biology, and diffusion in the lipid bi-layer, all in the context of the important fluid-dynamic phenomena.

Notes: Abstract Recent progress in modeling and simulation of the flow of nematic liquid crystals is presented. The Leslie-Ericksen (LE) theory has been successful in elucidating the flow of low molar-mass nematics. The theoretical framework for the flow of polymeric nematic liquid crystals is still evolving; extensions of the Doi theory capture qualitative features of the flow of polymeric nematics in simple geometries, but these theories have not been shown to predict texture development in flow. Mesoscopic theories for textured materials based on spatial averaging capture only some qualitative features of nonrectilinear liquid-crystalline polymer flow. Interfacial effects in liquid-crystalline systems have begun to receive attention in the context of interfacial viscoelasticity and the dynamics of dispersed liquid-crystalline polymers in immiscible blends.

Notes: Abstract We examine situations in which two droplets of the same liquid may come into apparent contact without coalescing or in which a droplet that normally wets a surface may deform against it without actually wetting it. The focus of this review is on cases driven by hydrodynamic lubrication, the lubricant provided either by surface motion or by evaporation.

Notes: Abstract The current understanding of boundary-layer receptivity to external acoustic and vortical disturbances is reviewed. Recent advances in theoretical modeling, numerical simulations, and experiments are discussed. It is shown that aspects of the theory have been validated and that the mechanisms by which freestream disturbances provide the initial conditions for unstable waves are better understood. Challenges remain, however, particularly with respect to freestream turbulence.

Notes: Abstract Because the cost of large-eddy simulations (LES) of wall-bounded flows that resolve all the important eddies depends strongly on the Reynolds number, methods to bypass the wall layer are required to perform high-Reynolds-number LES at a reasonable cost. In this paper the available methodologies are reviewed, and their ranges of applicability are highlighted. Various unresolved issues in wall-layer modeling are presented, mostly in the context of engineering applications.

Notes: Abstract The Richtmyer-Meshkov instability arises when a shock wave interacts with an interface separating two different fluids. It combines compressible phenomena, such as shock interaction and refraction, with hydrodynamic instability, including nonlinear growth and subsequent transition to turbulence, across a wide range of Mach numbers. This review focuses on the basic physical processes underlying the onset and development of the Richtmyer-Meshkov instability in simple geometries. It examines the principal theoretical results along with their experimental and numerical validation. It also discusses the different experimental approaches and techniques and how they can be used to resolve outstanding issues in this field.

Notes: Abstract There has been limited corroboration to date for McClintock's vision of gene regulation by transposable elements (TEs), although her proposition on the origin of species by TE-induced complex chromosome reorganizations in combination with gene mutations, i.e., the involvement of both factors in relatively sudden formations of species in many plant and animal genera, has been more promising. Moreover, resolution is in sight for several seemingly contradictory phenomena such as the endless reshuffling of chromosome structures and gene sequences versus synteny and the constancy of living fossils (or stasis in general). Recent wide-ranging investigations have confirmed and enlarged the number of earlier cases of TE target site selection (hot spots for TE integration), implying preestablished rather than accidental chromosome rearrangements for nonhomologous recombination of host DNA. The possibility of a partly predetermined generation of biodiversity and new species is discussed. The views of several leading transposon experts on the rather abrupt origin of new species have not been synthesized into the macroevolutionary theory of the punctuated equilibrium school of paleontology inferred from thoroughly consistent features of the fossil record.

Notes: Abstract Genome sequencing and structural genomics projects are providing new insights into the evolutionary history ofprote in domains. As methods for sequence and structure comparison improve, more distantly related domains are shown to be homologous. Thus there is a need for domain families to be classified within a hierarchy similar to Linnaeus' Systema Naturae, the classification of species. With such a hierarchy in mind, we discuss the evolution of domains, their combination into proteins, and evidence as to the likely origin of protein domains. We also discuss when and how analysis of domains can be used to understand details of protein function. Unconventional features of domain evolution such as intragenomic competition, domain insertion, horizontal gene transfer, and convergent evolution are seen as analogs of organismal evolutionary events. These parallels illustrate how the concept of domains can be applied to provide insights into evolutionary biology.