ALBERT

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: Astrophysics has been an important part of my personal and scientific life three times. The first was in 1938 when I did work on stellar energy production. The second was a joyful period nearly 30 years later when that work was rewarded with the Nobel Prize in physics. And the third has lasted over the time since my retirement in 1975 during which Gerry Brown and I have had a very satisfactory collaboration exploring various aspects of supernovae and, more recently, binary pairs.

Notizen: The first law of theoretical physics, the Newtonian law of gravitation, relies on the concept of action at a distance. The success of this law led to the concept being applied to electricity and magnetism, which were next to be explored in depth. Here the action at a distance had a limited success and ultimately had to be abandoned in favor of the increasingly more popular field theory. Nevertheless, in the 1940s, an attempt was made to revive the concept of action at a distance in a relativistically invariant way by Wheeler & Feynman (1945, 1949). It inspired a series of investigations in both electrodynamics and gravity in which the field concept was not used but the interaction was described as taking place directly between particles. As it impinged very intimately on cosmology, Hoyle was keenly interested in it. This review discusses the work by Hoyle, the author, and others on the development of electrodynamics and gravitation as direct particle theories. In this review, the author discusses how the work was started and went through stages of increasing sophistication, e.g., extending the Wheeler-Feynman electrodynamics to curved spacetime, its consequences in different cosmologies, and the issues arising from its quantization. The resolution of ultraviolet divergences in quantum electrodynamics is also briefly discussed. The parallel development of a Machian theory of gravitation followed the lead from electrodynamics. In both theories one sees a strong link between the large-scale structure of the universe and local physics, as might be expected from an action-at-a-distance framework.

Notizen: Targeted laboratory astrophysics measurements are being conducted to address the needs of X-ray astronomy. The measurements are producing large sets of reliable atomic data, which include ionization and recombination cross sections for charge balance calculations, as well as line lists, excitation cross sections, and dielectronic recombination rates for interpreting X-ray line formation. Additional experiments focus on resolving specific puzzles posed by astrophysical observations, as well as on calibrating existing and developing new X-ray line diagnostics. We discuss the types of data produced and illustrate how the laboratory measurements support such missions as ASCA, EUVE, Chandra, XMM, and ASTRO-E2.

Notizen: Abstract Recent small-scale turbulence observations allow the mixing regimes in lakes, reservoirs, and other enclosed basins to be categorized into the turbulent surface and bottom boundary layers as well as the comparably quiet interior. The surface layer consists of an energetic wave-affected thin zone at the very top and a law-of-the-wall layer right below, where the classical logarithmic-layer characteristic applies on average. Short-term current and dissipation profiles, however, deviate strongly from any steady state. In contrast, the quasi-steady bottom boundary layer behaves almost perfectly as a logarithmic layer, although periodic seiching modifies the structure in the details. The interior stratified turbulence is extremely weak, even though much of the mechanical energy is contained in baroclinic basin-scale seiching and Kelvin waves or inertial currents (large lakes). The transformation of large-scale motions to turbulence occurs mainly in the bottom boundary and not in the interior, where the local shear remains weak and the Richardson numbers are generally large.

Notizen: Abstract We review the most important theoretical and numerical results obtained in the realm of shell models for the energy-turbulent cascade. We mainly focus here on those results that had or will have some impact on the fluid-dynamics community. In particular, we address the problem of small-scale intermittency by discussing energy-helicity interactions, energy-dissipation multifractality, and universality of intermittency, i.e., independence of anomalous scaling exponents from large-scale forcing and boundary conditions. A multifractal-based description of multiscale and multitime correlation functions in turbulence is also presented. Finally, we also briefly review the analytical difficulties, and hopes, of calculating anomalous exponents.

Notizen: Abstract Cyclooxygenases-1 and -2 (COX-1 and COX-2, also known as prostaglandin H2 synthases-1 and -2) catalyze the committed step in prostaglandin synthesis. COX-1 and -2 are of particular interest because they are the major targets of nonsteroidal antiinflammatory drugs (NSAIDs) including aspirin, ibuprofen, and the new COX-2-selective inhibitors. Inhibition of the COXs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs reduces the incidence of fatal thrombotic events, as well as the development of colon cancer and Alzheimer's disease. In this review, we examine how the structures of COXs relate mechanistically to cyclooxygenase and peroxidase catalysis and how alternative fatty acid substrates bind within the COX active site. We further examine how NSAIDs interact with COXs and how differences in the structure of COX-2 result in enhanced selectivity toward COX-2 inhibitors.

Notizen: Abstract Since mid-1990, with cloning and identification of several families of natural killer (NK) receptors, research on NK cells began to receive appreciable attention. Determination of structures of NK cell surface receptors and their ligand complexes led to a fast growth in our understanding of the activation and ligand recognition by these receptors as well as their function in innate immunity. Functionally, NK cell surface receptors are divided into two groups, the inhibitory and the activating receptors. Structurally, they belong to either the immunoglobulin (Ig)-like receptor superfamily or the C-type lectin-like receptor (CTLR) superfamily. Their ligands are either members of class I major histocompatibility complexes (MHC) or homologs of class I MHC molecules. The inhibitory form of NK receptors provides the protective immunity through recognizing class I MHC molecules with self-peptides on healthy host cells. The activating, or the noninhibitory, NK receptors mediate the killing of tumor or virally infected cells through their specific ligand recognition. The structures of activating and inhibitory NK cell surface receptors and their complexes with the ligands determined to date, including killer immunoglobulin-like receptors (KIRs) and their complexes with HLA molecules, CD94, Ly49A, and its complex with H-2Dd, and NKG2D receptors and their complexes with class I MHC homologs, are reviewed here.

Notizen: Abstract Recent years have witnessed a renaissance of fluorescence microscopy techniques and applications, from live-animal multiphoton confocal microscopy to single-molecule fluorescence spectroscopy and imaging in living cells. These achievements have been made possible not so much because of improvements in microscope design, but rather because of development of new detectors, accessible continuous wave and pulsed laser sources, sophisticated multiparameter analysis on one hand, and the development of new probes and labeling chemistries on the other. This review tracks the lineage of ideas and the evolution of thinking that have led to the actual developments, and presents a comprehensive overview of the field, with emphasis put on our laboratory's interest in single-molecule microscopy and spectroscopy.

Notizen: Abstract The lamba integrase, or tyrosine-based family of site-specific recombinases, plays an important role in a variety of biological processes by inserting, excising, and inverting DNA segments. Flp, encoded by the yeast 2-mum plasmid, is the best-characterized eukaryotic member of this family and is responsible for maintaining the copy number of this plasmid. Over the past several years, structural and biochemical studies have shed light on the details of a common catalytic scheme utilized by these enzymes with interesting variations under different biological contexts. The emergence of new Flp structures and solution data provides insights not only into its unique mechanism of active site assembly and activity regulation but also into the specific contributions of certain protein residues to catalysis.

Notizen: Abstract The past decade has witnessed increasingly detailed insights into the structural mechanism of the bacteriorhodopsin photocycle. Concurrently, there has been much progress within our knowledge pertaining to the lipids of the purple membrane, including the discovery of new lipids and the overall effort to localize and identify each lipid within the purple membrane. Therefore, there is a need to classify this information to generalize the findings. We discuss the properties and roles of haloarchaeal lipids and present the structural data as individual case studies. Lipid-protein interactions are discussed in the context of structure-function relationships. A brief discussion of the possibility that bacteriorhodopsin functions as a light-driven inward hydroxide pump rather than an outward proton pump is also presented.

Notizen: Abstract G protein-coupled receptors (GPCRs) are integral membrane proteins that respond to environmental signals and initiate signal transduction pathways activating cellular processes. Rhodopsin is a GPCR found in rod cells in retina where it functions as a photopigment. Its molecular structure is known from cryo-electron microscopic and X-ray crystallographic studies, and this has reshaped many structure/function questions important in vision science. In addition, this first GPCR structure has provided a structural template for studies of other GPCRs, including many known drug targets. After presenting an overview of the major structural elements of rhodopsin, recent literature covering the use of the rhodopsin structure in analyzing other GPCRs will be summarized. Use of the rhodopsin structural model to understand the structure and function of other GPCRs provides strong evidence validating the structural model.

Notizen: Abstract The coupling of high-performance mass spectrometry instrumentation with highly efficient chromatographic and electrophoretic separations has enabled rapid qualitative and quantitative analysis of thousands of proteins from minute samples of biological materials. Here, we review recent progress in the development and application of mass spectrometry-based techniques for the qualitative and quantitative analysis of global proteome samples derived from whole cells, tissues, or organisms. Techniques such as multidimensional peptide and protein separations coupled with mass spectrometry, accurate mass measurement of peptides from global proteome digests, and mass spectrometric characterization of intact proteins hold great promise for characterization of highly complex protein mixtures. Advances in chemical tagging and isotope labeling techniques have enabled quantitative analysis of proteomes, and highly specific isolation strategies have been developed aimed at selective analysis of posttranslationally modified proteins.

Notizen: Abstract The use of low-energy electron microscopy (LEEM) to study reversible surface phase transitions is reviewed. Representative experiments are described that highlight the key advantages of LEEM: the ability to image surfaces in situ, at elevated temperature, with good spatial and temporal resolution. With these capabilities, the evolution of individual surface features-domains, facets, islands, steps, etc.-can be measured. Real-time and real-space imaging make LEEM a powerful tool for characterizing the thermodynamics and kinetics that govern surface phase transformations.

Notizen: Abstract Anhydrous proton-conducting polymers usually consist of a more or less inert polymer matrix that is swollen with an appropriate proton solvent (in most cases, phosphoric acid). An outline of the different materials is provided, with a focus on PBI/H3PO4 blends that are currently most suitable for fuel cell applications. Also discussed are alternative concepts for fully polymeric materials, which establish proton conductivity as an intrinsic property using amphoteric heterocycles such as imidazole as a proton solvent. The development of some of the first polymers is described, and the fundamental relations between their material properties and conductivity are discussed. Closely related to this relatively new concept are mechanistic investigations focusing on intermolecular proton transfer and diffusion of (protonated) solvent molecules, the contributions of both transport processes to conductivity, and the dependence of these ratios on composition, charge carrier density, etc. Although the development of fully polymeric proton conductors is inseparably related to mechanistic considerations, relatively little attention has been paid to these concepts in the field of conventional membranes (hydrated ionomers, H3PO4-based materials). Consequently, their general relevance is emphasized, and according investigations are summarized to provide a more comprehensive picture of proton transport processes within proton exchange membranes.

Notizen: Abstract The need to operate polymer electrolyte membrane (PEM) fuel cells at temperatures above 100oC, where the amount of water in the membrane is restricted, has provided much of the motivation for understanding the mechanisms of proton conduction at low degrees of hydration. Although experiments have not provided any direct information, numerous theoretical investigations have begun to provide the basis for understanding the mechanisms of proton conduction in these nano-phase-separated materials. Both the hydrated morphology and the nature of the confined water in the hydrophilic domains influence proton dissociation from the acidic sites (i.e., -SO3H), transfer to the water environment, and transport through the membrane. The following molecular processes are discussed in connection to their role in the conduction of protons in sulfonic acid-based polymer electrolyte membranes (PEMs): (a) local chemistry of the hydrophilic side chains; its effect on the dissociation of the proton and eventual stabilization (separation) of the proton in the water; (b) the presence of neighboring sulfonic acid groups on proton transfer; and (c) the effect of the distribution of the sulfonate groups on the transport of protons in the channels/pores of the membrane.

Notizen: Abstract The structural and chemical parameters determining the formation and mobility of protonic defects in oxides are discussed, and the paramount role of high-molar volume, coordination numbers, and symmetry are emphasized. Symmetry also relates to the structural and chemical matching of the acceptor dopant. Y-doped BaZrO3-based oxides are demonstrated to combine high stability with high proton conductivity that exceeds the conductivity of the best oxide ion conductors at temperatures below about 700oC. The unfavorably high grain boundary impedances and brittleness of ceramics have been reduced by forming solid solutions with small amounts of BaCeO3, and an initial fuel cell test has demonstrated that proton-conducting electrolytes based on Y-doped BaZrO3 provide alternatives for separator materials in solid oxide fuel cells (SOFCs). These materials have the potential to operate at lower temperatures compared with those of conventional SOFCs, and the appearance of chemical water diffusion across the electrolyte at typical operation temperatures (T = 500-800oC) allows the use of dry methane as a fuel.

Notizen: Abstract Recently, a number of papers about direct oxidation of methane and hydrocarbon in solid oxide fuel cells (SOFC) at relatively low temperatures (about 700oC) have been published. Even though the conversion of almost dry CH4 at 1000oC on ceramic anodes was demonstrated more than 10 years ago, the reports about high-current densities for methane oxidation at such low temperatures are indeed surprising. Several papers indicate that a catalytic effect (due to the mixed ionic and electronic conductivity) of CeO2-x is partially responsible for this effect. However, this seems to contradict previous reports, and thus this issue deserves further analysis.

Notizen: Abstract The emphasis in this short review is to describe the materials issues involved in the development of present thermal barrier coatings and the advances necessary for the next generation, higher temperature capability coatings.

Notizen: Abstract Several recent experimental and numerical investigations have contributed to the improved understanding of the electrochemical mechanisms taking place at solid oxide fuel cell (SOFC) cathodes and yielded valuable information on the relationships between alterable parameters (geometry/material) and the cathodic polarization resistance. Efforts to reduce the polarization resistance in SOFCs can benefit from these results, and some important aspects of the corresponding studies are reviewed. Experimental results, particularly measurements using geometrically well-defined Sr-doped LaMnO3 (LSM) cathodes, are discussed. In regard to simulations, the different levels of sophistication used in SOFC electrode modeling studies are summarized and compared. Exemplary simulations of mixed conducting cathodes that show the capabilities and limits of different modeling levels are described.

Notizen: Abstract This account reviews the discovery, synthesis, properties, and the latest research advances of carbon nanotubes developed over the past 12 years. Because of their remarkable electronic and mechanical properties, carbon nanotubes are unique and exciting. The field has been developed rapidly, and the number of publications per year is increasing almost exponentially. Various technological applications are likely to arise using nanotubes for fabrication of flat panel displays, gas storage devices, toxic gas sensors, Li+ batteries, robust and lightweight composites, conducting paints, electronic nanodevices, etc. Further experimental and theoretical research is still necessary so that novel technologies will become a reality in the early twenty-first century.

Notizen: Stellar clusters are born embedded within giant molecular clouds (GMCs) and during their formation and early evolution are often only visible at infrared wavelengths, being heavily obscured by dust. Over the past 15 years advances in infrared detection capabilities have enabled the first systematic studies of embedded clusters in galactic molecular clouds. In this article we review the current state of empirical knowledge concerning these extremely young protocluster systems. From a survey of the literature we compile the first extensive catalog of galactic embedded clusters. We use the catalog to construct the mass function and estimate the birthrate for embedded clusters within ~2 kpc of the sun. We find that the embedded cluster birthrate exceeds that of visible open clusters by an order of magnitude or more indicating a high infant mortality rate for protocluster systems. Less than 4-7% of embedded clusters survive emergence from molecular clouds to become bound clusters of Pleiades age. The vast majority (90%) of stars that form in embedded clusters form in rich clusters of 100 or more members with masses in excess of 50 Mo. Moreover, observations of nearby cloud complexes indicate that embedded clusters account for a significant (70-90%) fraction of all stars formed in GMCs. We review the role of embedded clusters in investigating the nature of the initial mass function (IMF) that, in one nearby example, has been measured over the entire range of stellar and substellar mass, from OB stars to substellar objects near the deuterium burning limit. We also review the role embedded clusters play in the investigation of circumstellar disk evolution and the important constraints they provide for understanding the origin of planetary systems. Finally, we discuss current ideas concerning the origin and dynamical evolution of embedded clusters and the implications for the formation of bound open clusters.

Notizen: In this contribution, a review is presented on the ample data obtained on post-AGB stars, both on the central stars and their circumstellar material. The fast evolutionary phase is characterized by a rapid change in the properties of the objects, but the variety is so large that there is yet no clear consensus on how the detailed studies of individual objects are linked together by evolutionary channels. The absence of strong molecular veiling in the photospheres of the central stars, together with a spread in intrinsic metallicity make post-AGB stars very useful in constraining AGB chemical evolutionary models. We discuss the surprisingly wide variety of chemical signatures observed. The onset in the creation process of the panoply of structures and shapes observed in planetary nebulae occurs during the short post-AGB evolution, but the physical nature of the processes involved is still badly understood. In the rapidly growing field of circumstellar mineralogy, post-AGB stars have their story to tell and also the molecular envelope changes significantly due to dilution and hardening of the stellar radiation. The real-time evolution of some objects suffering a late thermal flash is reviewed and their possible link to other hydrogen-deficient objects is discussed. Any review on stellar evolution has a section on binaries and this contribution is no exception because binaries make up a significant fraction of the post-AGB stars known to date.

Notizen: Abstract Full-scale icing experiments and, therefore, certification time and cost can be significantly reduced by developing calculation methods to evaluate the aircraft and system performance for a wide range of icing conditions. This article summarizes calculation methods for icing that include ice accretion, ice system performance, and icing effects on aircraft.

Notizen: Abstract Drag reduction in wall-bounded flows can be achieved by transverse motions imposed by passive means, e.g., riblets, or by external forcing, such as wall oscillation or transverse traveling-wave excitation. In this article, we review possible physical mechanisms responsible for turbulent drag reduction and corresponding near-wall flow modification.

Notizen: Abstract In this review we describe the aerodynamic problems that must be addressed in order to design a successful small aerial vehicle. The effects of Reynolds number and aspect ratio (AR) on the design and performance of fixed-wing vehicles are described. The boundary-layer behavior on airfoils is especially important in the design of vehicles in this flight regime. The results of a number of experimental boundary-layer studies, including the influence of laminar separation bubbles, are discussed. Several examples of small unmanned aerial vehicles (UAVs) in this regime are described. Also, a brief survey of analytical models for oscillating and flapping-wing propulsion is presented. These range from the earliest examples where quasi-steady, attached flow is assumed, to those that account for the unsteady shed vortex wake as well as flow separation and aeroelastic behavior of a flapping wing. Experiments that complemented the analysis and led to the design of a successful ornithopter are also described.

Notizen: Abstract The issue of the physical mechanism(s) that control the efficiency with which the density field in stably stratified fluid is mixed by turbulent processes has remained enigmatic. Similarly enigmatic has been an explanation of the numerical value of ~0.2, which is observed to characterize this efficiency experimentally. We review recent work on the turbulence transition in stratified parallel flows that demonstrates that this value is not only numerically predictable but also that it is expected to be a nonmonotonic function of the Richardson number that characterizes preturbulent stratification strength. This value of the mixing efficiency appears to be characteristic of the late-time behavior of the turbulent flow that develops after an initially laminar shear flow has undergone the transition to turbulence through an intermediate instability of Kelvin-Helmholtz type.

Notizen: Abstract It is classically assumed that the far field of a round turbulent jet discharging into quiescent fluid has a unique behavior characterized only by its momentum flux. However, there is now considerable evidence that different discharge conditions at the jet nozzle exit can give rise to very different far-field flows. Perhaps the most striking examples of these are the bifurcating and blooming jets produced by appropriate combinations of controlled axial and circumferential excitations at the nozzle exit. With the right excitations, a jet can be made to divide into two separate jets (bifurcating jet), each of which carries half the axial momentum and spreads in a manner similar to a single jet. Trifurcating jets can also be produced. Other excitations can produce blooming jets, in which the jet explodes into a shower of vortex rings, producing a far-field flow that is quite unlike a normal unexcited jet. Bifurcating and blooming jets exhibit much greater mixing than normal jets, suggesting possible applications in flow control. This article summarizes our work on bifurcating and blooming jets, which began with our discovery of them in the early 1980s and continued through the mid- 1990s. One of us (D.E.P.) continued exploration of flow control using excited jets, first at the McDonnell Douglas Corporation, and more recently at the Georgia Institute of Technology. The key to flow control is the manipulation of the large vortical structures in the near field of the jet. Ultimately this work, and that of others, led to full-scale testing of jet engine exhaust mixing control. There it was shown that the jet temperature downstream of the engine can be very significantly reduced by application of well-designed and easily implemented excitation at the engine discharge, thereby solving problems encountered during ground operations. Related jet control work by other investigators is included in this review.

Notizen: Abstract The recent progress in three-dimensional boundary-layer stability and transition is reviewed. The material focuses on the crossflow instability that leads to transition on swept wings and rotating disks. Following a brief overview of instability mechanisms and the crossflow problem, a summary of the important findings of the 1990s is given.

Notizen: Abstract The observation of liquid-liquid immiscibility in cholesterol-phospholipid mixtures in monolayers and bilayers has opened a broad field of research into their physical chemistry. Some mixtures exhibit multiple immiscibilities. This unusual property has led to a thermodynamic model of "condensed complexes." These complexes are the consequence of an exothermic, reversible reaction between cholesterol and phospholipids. In this quantitative model the complexes are sometimes concentrated in a separate liquid phase. The phase separation into a complex-rich phase depends on membrane composition and intensive variables such as temperature. The properties of defined cholesterol-phospholipid mixtures provide a conceptual foundation for the exploration of a number of aspects of the biophysics and biochemistry of animal cell membranes.

Notizen: Abstract Combinatorial methods provide a means for accelerating the discovery of fuel cell catalysts. The first example of parallel fuel cell catalysts screening was an indirect method that used fluorescent chemosensors to detect changes in pH in proximity to electrocatalyst spots. Serial direct electrochemical methods have been developed that use voltammetry, chronoamperometry, and scanning electrochemical microscopy. An array fuel cell screens catalysts simultaneously, using high-performance fuel cell components. Heuristic models based on mechanistic and spectroscopic studies provide guidance for library development, and detailed studies of discovered catalysts can help to refine these models. The remaining challenges are the development of high throughput synthetic methods that can enable the use of discovery level and focus level screening. Until these synthetic methods are developed, a greater emphasis should be placed on smaller libraries with design of experiment strategies leveraged with informatics and data mining.

Notizen: Abstract The past 10 years have witnessed a tremendous acceleration in research devoted to non-fluorinated polymer membranes, both as competitive alternatives to commercial perfluorosulfonic acid membranes operating in the same temperature range and with the objective of extending the range of operation of polymer fuel cells toward those more generally occupied by phosphoric acid fuel cells. Important requirements are adequate membrane mechanical strength at levels of functionalization (generally sulfonation) and hydration allowing high proton conductivity, and stability in the aggressive environment of a working fuel cell, in particular thermohydrolytic and chemical stability. This review provides an overview of progress made in the development of proton-conducting hydrocarbon and heterocyclic-based polymers for proton exchange and direct methanol fuel cells and describes the various approaches made to polymer modification/synthesis and salient properties of the materials formed, including those relating to proton transport and proton conductivity, e.g., water diffusion and electro-osmotic drag. The microstructure, deduced from small angle X-ray and neutron diffraction measurements of representative non-fluorinated polymers is compared with that of perfluorosulfonic acid membranes. Different degradation mechanisms and aging processes that can result in chemical and morphological alteration are considered, and recent characterization of membrane-electrode assemblies (MEAs) in direct methanol and hydrogen-air (oxygen) fuel cells completes this review of the state of the art. While several types of non-fluorinated polymer membrane have demonstrated lifetimes of 500-4000 h, only a limited number of systems exist that hold promise for long-term operation above 100oC.1

Notizen: Abstract The use of chemical potential diagrams to examine interface chemistry is discussed in terms of the chemical reactions among oxides and associated interdiffusion across the interface. The driving force for both processes can be determined from the chemical potential values. The geometrical features of the chemical potential diagrams can be related to the valence stability of binary oxides and the stabilization energy of double oxides from the constituent oxides. The materials compatibility in solid oxide fuel cell materials is discussed with a focus on a lanthanum manganite cathode and a yttria-stabilized zirconia (YSZ) electrolyte. Emphasis is placed on the valence numbers of manganese in the fluorite solid solution and the perovskite oxides, which have been derived by thermodynamic analysis of the magnitude of the stabilization energy/interaction parameters as a function of ionic size for respective valence numbers. The change of manganese valence on La2Zr2O7 formation and Mn dissolution in YSZ are discussed in relation with the oxygen evolution/adsorption process. Oxygen flow associated with electrochemical reactions exhibits markedly different features depending on the direction of the polarization, which can lead to drastic changes in the interface chemistry (precipitation or interdiffusion).

Notizen: The galaxies of the Local Group serve as important laboratories for understanding the physics of massive stars. Here I discuss what is involved in identifying various kinds of massive stars in nearby galaxies: the hydrogen-burning O-type stars and their evolved He-burning evolutionary descendants, the luminous blue variables, red supergiants, and Wolf-Rayet stars. Primarily I review what our knowledge of the massive star population in nearby galaxies has taught us about stellar evolution and star formation. I show that the current generation of stellar evolutionary models do well at matching some of the observed features and provide a look at the sort of new observational data that will provide a benchmark against which new models can be evaluated.

Notizen: We review the origin, evolution, and physical nature of hot gas in elliptical galaxies and associated galaxy groups. Unanticipated recent X-ray observations with Chandra and XMM indicate much less cooling than previously expected. Consequently, many long-held assumptions must be reexamined or discarded and new approaches must be explored. Chief among these are the role of heating by active galactic nuclei, the influence of radio lobes on the hot gas, details of the cooling process, possible relation between the hot and colder gas in elliptical galaxies, and the complexities of stellar enrichment of the hot gas.

Notizen: This review surveys the observed properties of interstellar dust grains: the wavelength-dependent extinction of starlight, including absorption features, from UV to infrared; optical luminescence; infrared emission; microwave emission; optical, UV, and X-ray scattering by dust; and polarization of starlight and of infrared emission. The relationship between presolar grains in meteorites and the interstellar grain population is discussed. Candidate grain materials and abundance constraints are considered. A dust model consisting of amorphous silicate grains, graphite grains, and polycyclic aromatic hydrocarbons is compared with observed emission and scattering. Some issues concerning evolution of interstellar dust are discussed.

Notizen: Giant planets have now been discovered around other stars, and it is only a matter of time until Earth-sized planets are detected. Whether any of these planets are suitable for life depends on their volatile abundances, especially water, and on their climates. Only planets within the liquid-water habitable zone (HZ) can support life on their surfaces and, thus, can be analyzed remotely to determine whether they are inhabited. Fortunately, current models predict that HZs are relatively wide around main-sequence stars not too different from our sun. This conclusion is based on studies of how our own planet has evolved over time. Earth's climate has remained conducive to life for the past 3.5 billion years or more, despite a large increase in solar luminosity, probably because of previous higher concentrations of CO2 and/or CH4. Both these gases are involved in negative feedback loops that help to stabilize the climate. In addition to these topics, we also briefly discuss the rise of atmospheric O2 and O3, along with their possible significance as indicators of life on other planets.

Notizen: Photoionized clouds are ubiquitous. They define the endpoints of stellar evolution (H II regions and planetary nebulae), constitute the interstellar and intergalactic media, and are found in high redshift quasars and star-forming galaxies. The spectra of these objects are dominated by emission lines that are sensitive to details of the emitting gas. These details include the microscopic atomic processes that cause the gas to glow; the density, composition, and temperature of the gas; and the radiation field of the central continuum source. Large-scale numerical codes that incorporate all the needed physics and predict the observed spectrum have become essential tools in understanding these objects. This article reviews the current status of the numerical simulations of emitting gas, with particular emphasis on photoionized clouds and the underlying simplicity that governs these nebulae; the types of questions that can be addressed by today's codes; and the big questions that remain unanswered.

Notizen: The status of our current understanding of angular momentum transport in accretion disks is reviewed. The last decade has seen a dramatic increase both in the recognition of key physical processes and in our ability to carry through direct numerical simulations of turbulent flow. Magnetic fields have at once powerful and subtle influences on the behavior of (sufficiently) ionized gas, rendering them directly unstable to free energy gradients. Outwardly descreasing angular velocity profiles are unstable. The breakdown of Keplerian rotation into MHD turbulence may be studied in some numerical detail, and key transport coefficients may be evaluated. Chandra observations of the Galactic Center support the existence of low luminosity accretion, which may ultimately prove amenable to global three-dimensional numerical simulation.

Notizen: Abstract The more violent impacts of water waves on walls create velocities and pressures having magnitudes much larger than those associated with the propagation of ordinary waves under gravity. Insight into these effects has been gained by irrotational-flow computations and by investigating the role of entrained and trapped air in wave impacts. This review focuses on the results of theoretical work, making particular note of the value of considering pressure impulse, and highlights the aspects that are poorly understood.

Notizen: Abstract The modern study of a crowd as a flowing continuum is a recent development. Distinct from a classical fluid because of the property that a crowd has the capacity to think, interesting new physical ideas are involved in its study. An appealing property of a crowd in motion is that the nonlinear, time-dependent, simultaneous equations representing a crowd are conformably mappable. This property makes many interesting applications analytically tractable. In this review examples are given in which the theory has been used to provide possible assistance in the annual Muslim Hajj, to understand the Battle of Agincourt, and, surprisingly, to locate barriers that actually increase the flow of pedestrians above that when there are no barriers present. Modern developments may help prevent some of the approximately two thousand deaths that annually occur in accidents owing to crowding.The field of crowd motion, that is, the field of "thinking fluids," is an intriguing area of research with great promise.

Notizen: Abstract The recent avalanche of research activity in the field of granular matter has yielded much progress. The use of state-of-the-art (and other) computational and experimental methods has led to the discovery of new states and patterns and enabled detailed tests of theories and models. The application of statistical mechanical methods and phenomenology has contributed to the understanding of the microscopic a nd macroscopic properties of granular systems. Some previously open problems seem to be solved. Fluidized granular systems (rapid granular flows), recently referred to as granular gases, are often modeled by hydrodynamic equations of motion, some of which are based on systematic expansions applied to the pertinent Boltzmann equation. The undeniable success of granular hydrodynamics is somewhat surprising in view of the lack of scale separation in these systems and the neglect of certain correlations in most derivations of the hydrodynamic equations. Microstructures have been recognized as key features of granular gases; explanations for their existence have been proposed, and many of their properties elucidated. Granular-gas multistability can often be traced back to microstructure dynamics. In spite of these and other impressive advances, this field still poses serious challenges.

Notizen: Abstract Recent advances in achieving textbook multigrid efficiency for fluid simulations are presented. Textbook multigrid efficiency is defined as attaining the solution to the governing system of equations in a computational work that is a small multiple of the operation counts associated with discretizing the system. Strategies are reviewed to attain this efficiency by exploiting the factorizability properties inherent to a range of fluid simulations, including the compressible Navier-Stokes equations. Factorizability is used to separate the elliptic and hyperbolic factors contributing to the target system; each of the factors can then be treated individually and optimally. Boundary regions and discontinuities are addressed with separate (local) treatments. New formulations and recent calculations demonstrating the attainment of textbook efficiency for aerodynamic simulations are shown.

Notizen: Abstract Comparative physiology has proven a powerful approach to our understanding of how animals function under hypoxic conditions and to identifying potential adaptations to environmental oxygen levels. This review considers the potential for using a similar comparative approach with functional genomics to understand the genetic basis of such physiological processes and evolutionary adaptations. Comparative functional genomics is currently limited by genome data, which are available for only a few model organisms. However, comparative studies between model organisms of the same species having slightly different genomes (e.g., in-bred strains of laboratory rodents, transgenic mice, and consomic rats) demonstrate the types of results, as well as the analytical challenges, that are possible if comparative functional genomics is applied to more species. Results from wild and domestic animal studies suggest new models to investigate physiological and evolutionary responses to oxygen levels with functional genomics.

Notizen: Abstract Helicobacter pylori is a neutralophilic, gram-negative, ureolytic organism that is able to colonize the human stomach but does not survive in a defined medium with a pH 〈4.0 unless urea is present. In order to live in the gastric environment, it has developed a repertoire of acid resistance mechanisms that can be classified into time-independent, acute, and chronic responses. Time-independent acid resistance depends on the structure of the organism's inner and outer membrane proteins that have a high isoelectric point, thereby reducing their proton permeability. Acute acid resistance depends on the constitutive synthesis of a neutral pH optimum urease that is an oligomeric Ni2+-containing heterodimer of UreA and UreB subunits. Gastric juice urea is able to rapidly access intrabacterial urease when the periplasmic pH falls below ~6.2 owing to pH-gating of a urea channel, UreI. This results in the formation of NH3, which then neutralizes the bacterial periplasm to provide a pH of ~6.2 and an inner membrane potential of -101 mV, giving a proton motive force of ~-200 mV. UreI is a six-transmembrane segment protein, with homology to the amiS genes of the amidase gene cluster and to UreI of Helicobacter hepaticus and Streptococcus salivarius. Expression of these UreI proteins in Xenopus oocytes has shown that UreI of H. pylori and H. hepaticus can transport urea only at acidic pH, whereas that of S. salivarius is open at both neutral and acidic pH. Site-directed mutagenesis and chimeric analysis have identified amino acids implicated in maintaining the closed state of the channel at neutral pH and other amino acids that play a structural role in channel function. Deletion of ureI abolishes the ability of the organism to survive in acid and also to colonize the mouse or gerbil stomach. However, if acid secretion is inhibited in gerbils, the deletion mutants do colonize but are eradicated when acid secretion is allowed to return, showing that UreI is essential for gastric survival and that the habitat of H. pylori at the gastric surface must fall to pH 3.5 or below. The chronic response is from increased Ni2+ insertion into the apo-enzyme, which results in a threefold increase in urease, which is also dependent on expression of UreI. This allows the organism to live in either gastric fundus or gastric antrum depending on the level of acidity at the gastric surface. There are other effects of acid on transcript stability that may alter levels of protein synthesis in acid. Incubation of the organism at acidic pH also results in regulation of expression of a variety of genes, such as some outer membrane proteins, that constitutes an acid tolerance response. Understanding of these acid resistance and tolerance responses should provide novel eradication therapies for this carcinogenic gastric pathogen.

Notizen: Abstract Gene therapy as a treatment modality for pulmonary disorders has attracted significant interest over the past decade. Since the initiation of the first clinical trials for cystic fibrosis lung disease using recombinant adenovirus in the early 1990s, the field has encountered numerous obstacles including vector inflammation, inefficient delivery, and vector production. Despite these obstacles, enthusiasm for lung gene therapy remains high. In part, this enthusiasm is fueled through the diligence of numerous researchers whose studies continue to reveal great potential of new gene transfer vectors that demonstrate increased tropism for airway epithelia. Several newly identified serotypes of adeno-associated virus have demonstrated substantial promise in animal models and will likely surface soon in clinical trials. Furthermore, an increased understanding of vector biology has also led to the development of new technologies to enhance the efficiency and selectivity of gene delivery to the lung. Although the promise of gene therapy to the lung has yet to be realized, the recent concentrated efforts in the field that focus on the basic virology of vector development will undoubtedly reap great rewards over the next decade in treating lung diseases.

Notizen: Abstract Understanding of the functions and regulation of the phenotype of the alveolar type I epithelial cell has lagged behind studies of its neighbor the type II cell because of lack of cell-specific molecular markers. The recent identification of several proteins expressed by type I cells indicates that these cells may play important roles in regulation of cell proliferation, ion transport and water flow, metabolism of peptides, modulation of macrophage functions, and signaling events in the peripheral lung. Cell systems and reagents are available to characterize type I cell biology in detail, an important goal given that the cells provide the extensive surface that facilitates gas exchange in the intact animal.

Notizen: Abstract Maintenance of membrane lipid asymmetry is a dynamic process that influences many events over the lifespan of the cell. With few exceptions, most cells restrict the bulk of the aminophospholipids to the inner membrane leaflet by means of specific transporters. Working in concert with each other, these proteins correct for sporadic incursions of the aminophospholipids to the outer membrane leaflet as a result of bilayer imbalances created by various cellular events. A shift in the relative contribution in each of these activities can result in sustained exposure of the aminophospholipids at the cell surface, which allows capture of the cells by phagocytes before the integrity of the plasma membrane is compromised. The absence of an efficient recognition and elimination mechanism can result in uncontrolled and persistent presentation of self-antigens to the immune system, with development of autoimmune syndromes. To prevent this, phagocytes have developed a diverse array of distinct and redundant receptor systems that drive the postphagocytic events along pathways that facilitate cross-talk between the homeostatic and the immune systems. In this work, we review the basis for the proposed mechanism(s) by which apoptotic ligands appear on the target cell surface and the phagocyte receptors that recognize these moieties.

Notizen: Abstract Rhodopsin is a retinal photoreceptor protein of bipartite structure consisting of the transmembrane protein opsin and a light-sensitive chromophore 11-cis-retinal, linked to opsin via a protonated Schiff base. Studies on rhodopsin have unveiled many structural and functional features that are common to a large and pharmacologically important group of proteins from the G protein-coupled receptor (GPCR) superfamily, of which rhodopsin is the best-studied member. In this work, we focus on structural features of rhodopsin as revealed by many biochemical and structural investigations. In particular, the high-resolution structure of bovine rhodopsin provides a template for understanding how GPCRs work. We describe the sensitivity and complexity of rhodopsin that lead to its important role in vision.

Notizen: In this brief, autobiographical account, I trace the development of my intellectual and theoretical interests, especially as they relate to culture. How can we account for culture's being learned by individuals and yet apparently shared by members of a community? How do cultures as shared within communities change and evolve? How does what we know about languages, themselves a kind of cultural tradition, contribute to understanding culture and cultural evolution? Are processes of cultural and linguistic evolution analogous to those in the evolution of biological species and, if so, in what ways? How, also, do genetically based behavioral proclivities manifest themselves in social arenas that are structured by language and culture?

Notizen: During the Mississippian period (a.d. 1000-1500) the southeastern United States witnessed a broadscale fluorescence of polities characterized by impressive earthwork construction, rich mortuary offerings, and intensified agriculture. Research on the nature of complexity in these so-called chiefdoms has been an enduring issue in North American archaeology, even as this research has undergone several paradigmatic shifts. This study focuses on the primary dimensions of the archaeological record used to describe and explain variation in Mississippian complexity-polity scale, settlement and landscape, the organization of labor, mortuary ritual and ideology, and tribute and feasting. Changing perspectives toward the organization of complexity and power have become increasingly pronounced in each of these categories.

Notizen: Using Australian languages as examples, cultural selection is shown to shape linguistic structure through invisible hand processes that pattern the unintended outcomes (structures in the system of shared linguistic norms) of intentional actions (particular utterances by individual agents). Examples of the emergence of culturally patterned structure through use are drawn from various levels: the semantics of the lexicon, grammaticalized kin-related categories, and culture-specific organizations of sociolinguistic diversity, such as moiety lects, "mother-in-law" registers, and triangular kin terms. These phenomena result from a complex of diachronic processes that adapt linguistic structures to culture-specific concepts and practices, such as ritualization and phonetic reduction of frequently used sequences, the input of shared cultural knowledge into pragmatic interpretation, semanticization of originally context-dependent inferences, and the input of linguistic ideologies into the systematization of lectal variants. Some of these processes, such as the emergence of subsection terminology and moiety lects, operate over speech communities that transcend any single language and can only be explained if the relevant processes take the multilingual speech community as their domain of operation. Taken together, the cases considered here provide strong evidence against nativist assumptions that see linguistic structures simply as instantiations of biologically given "mentalese" concepts already present in the mind of every child and give evidence in favor of a view that sees individual language structures as also conditioned by historical processes, of which functional adaptation of various kinds is most important. They also illustrate how, in the domain of language, stable socially shared structures can emerge from the summed effects of many communicative micro-events by individual agents.

Notizen: This review examines the convergence of recent anthropological interests in gender, labor, and globalization. Attention to gender and gender inequality offers a productive strategy for the analysis of globalizing processes and their local variations and contestations. Contemporary ethnographic research explores multiple dimensions of labor and gender inequalities in the global economy: gendered patterns of labor recruitment and discipline, the transnational mobility and commodification of reproductive labor, and the gendered effects of international structural adjustment programs, among others. New and continuing research explores the diverse meanings and practices that produce a gendered global labor force, incorporating the perspectives of men and women, masculinities and femininities, and examines how these processes of gender and labor inequality articulate with other structures of subordination (such as ethnicity and nationality) to shape lived experiences of work and livelihood, exploitation and struggle, around the world.

Notizen: Abstract Theoretical calculations, based on both the chemical and isotopic composition of sedimentary rocks, indicate that atmospheric O2 has varied appreciably over Phanerozoic time, with a notable excursion during the Permo-Carboniferous reaching levels as high as 35% O2. This agrees with measurements of the carbon isotopic composition of fossil plants together with experiments and calculations on the effect of O2 on photosynthetic carbon isotope fractionation. The principal cause of the excursion was the rise of large vascular land plants and the consequent increased global burial of organic matter. Higher levels of O2 are consistent with the presence of Permo-Carboniferous giant insects, and preliminary experiments indicate that insect body size can increase with elevated O2. Higher O2 also may have caused more extensive, possibly catastrophic, wildfires. To check this, realistic burning experiments are needed to examine the effects of elevated O2 on fire behavior.

Notizen: Abstract Plants and animals exploit the soil for food and shelter and, in the process, affect it in many different ways. For example, uprooted trees may break up bedrock, transport soil downslope, increase the heterogeneity of soil respiration rates, and inhibit soil horizonation. In this contribution, we review previously published papers that provide insights into the process of bioturbation. We focus particularly on studies that allow us to place bioturbation within a quantitative framework that links the form of hillslopes with the processes of sediment transport and soil production. Using geometrical relationships and data from others' work, we derive simple sediment flux equations for tree throw and root growth and decay.

Notizen: Abstract A review of crocodylian phylogeny reveals a more complex history than might have been anticipated from a direct reading of the fossil record without consideration of phylogenetic relationships. The three main extant crocodylian lineages-Gavialoidea, Alligatoroidea, Crocodyloidea-are known from fossils in the Late Cretaceous, and the group is found nearly worldwide during the Cenozoic. Some groups have distributions that are best explained by the crossing of marine barriers during the Tertiary. Early Tertiary crocodylian faunas are phylogenetically composite, and clades tend to be morphologically uniform and geographically widespread. Later in the Tertiary, Old World crocodylian faunas are more endemic. Crocodylian phylogeneticists face numerous challenges, the most important being the phylogenetic relationships and time of divergence of the two living gharials (Gavialis gangeticus and Tomistoma schlegelii), the relationships among living true crocodiles (Crocodylus), and the relationships among caimans.

Notizen: Abstract We present preliminary evidence for a ~10,000-year earthquake record from two major fault systems based on sediment cores collected along the continental margins of western North America. New stratigraphic evidence from Cascadia demonstrates that 13 earthquakes ruptured the entire margin from Vancouver Island to at least the California border since the eruption of the Mazama ash 7700 years ago. The 13 events above this prominent stratigraphic marker have an average repeat time of 600 years, and the youngest event ~300 years ago coincides with the coastal record. We also extend the record of past earthquakes to the base of the Holocene (at least 9800 years ago), during which 18 events correlate along the same region. The sequence of Holocene events in Cascadia appears to contain a repeating pattern of events, a tantalizing first look at what may be the long-term behavior of a major fault system. The northern California margin cores show a cyclic record of turbidite beds that may represent Holocene earthquakes on the northern segment of the San Andreas Fault. Preliminary results are in reasonably good agreement with onshore paleoseismic data that indicate an age for the penultimate event in the mid-1600s at several sites and the most likely age for the third event of ~AD 1300.

Notizen: Abstract The issue of whether pain is represented by specific neural elements or by patterned activity within a convergent somatosensory subsystem has been debated for over a century. The gate control theory introduced in 1965 denied central specificity, and since then most authors have endorsed convergent wide-dynamic-range neurons. Recent functional and anatomical findings provide compelling support for a new perspective that views pain in humans as a homeostatic emotion that integrates both specific labeled lines and convergent somatic activity.

Notizen: Abstract Behavioral, anatomical, and physiological approaches can be integrated in the study of sound localization in barn owls. Space representation in owls provides a useful example for discussion of place and ensemble coding. Selectivity for space is broad and ambiguous in low-order neurons. Parallel pathways for binaural cues and for different frequency bands converge on high-order space-specific neurons, which encode space more precisely. An ensemble of broadly tuned place-coding neurons may converge on a single high-order neuron to create an improved labeled line. Thus, the two coding schemes are not alternate methods. Owls can localize sounds by using either the isomorphic map of auditory space in the midbrain or forebrain neural networks in which space is not mapped.

Notizen: Abstract Breathing is a vital behavior that is particularly amenable to experimental investigation. We review recent progress on three problems of broad interest. (i) Where and how is respiratory rhythm generated? The preBotzinger Complex is a critical site, whereas pacemaker neurons may not be essential. The possibility that coupled oscillators are involved is considered. (ii) What are the mechanisms that underlie the plasticity necessary for adaptive changes in breathing? Serotonin-dependent long-term facilitation following intermittent hypoxia is an important example of such plasticity, and a model that can account for this adaptive behavior is discussed. (iii) Where and how are the regulated variables CO2 and pH sensed? These sensors are essential if breathing is to be appropriate for metabolism. Neurons with appropriate chemosensitivity are spread throughout the brainstem; their individual properties and collective role are just beginning to be understood.

Notizen: Abstract Many neurodegenerative diseases, including Alzheimer's and Parkinson's and the transmissible spongiform encephalopathies (prion diseases), are characterized at autopsy by neuronal loss and protein aggregates that are typically fibrillar. A convergence of evidence strongly suggests that protein aggregation is neurotoxic and not a product of cell death. However, the identity of the neurotoxic aggregate and the mechanism by which it disables and eventually kills a neuron are unknown. Both biophysical studies aimed at elucidating the precise mechanism of in vitro aggregation and animal modeling studies support the emerging notion that an ordered prefibrillar oligomer, or protofibril, may be responsible for cell death and that the fibrillar form that is typically observed at autopsy may actually be neuroprotective. A subpopulation of protofibrils may function as pathogenic amyloid pores. An analogous mechanism may explain the neurotoxicity of the prion protein; recent data demonstrates that the disease-associated, infectious form of the prion protein differs from the neurotoxic species. This review focuses on recent experimental studies aimed at identification and characterization of the neurotoxic protein aggregates.

Notizen: Abstract Neurotrophins are a family of growth factors critical for the development and functioning of the nervous system. Although originally identified as neuronal survival factors, neurotrophins elicit many biological effects, ranging from proliferation to synaptic modulation to axonal pathfinding. Recent data indicate that the nature of the signaling cascades activated by neurotrophins, and the biological responses that ensue, are specified not only by the ligand itself but also by the temporal pattern and spatial location of stimulation. Studies on neurotrophin signaling have revealed variations in the Ras/MAP kinase, PI3 kinase, and phospholipase C pathways, which transmit spatial and temporal information. The anatomy of neurons makes them particularly appropriate for studying how the location and tempo of stimulation determine the signal cascades that are activated by receptor tyrosine kinases such as the Trk receptors. These signaling variations may represent a general mechanism eliciting specificity in growth factor responses.