ALBERT

Notes: Work done in the late 1950s and in the 1960s revealed the role of the thymus in virus-induced leukemia in mice. Thymectomizing mice at birth to test whether the virus first multiplied in thymus tissue and then spread elsewhere ultimately led to the conclusion that the thymus was essential to the normal development of the immune system. Subsequent testing to try to understand how the thymus contributes to the pool of immunocompetent lymphocytes opened a new chapter in immunology and required a reappraisal of many immunological phenomena and an understanding of the molecular interactions that take place during cell-to-cell interactions.

Notes: Abstract Interleukin-15 (IL-15) is a 14- to 15-kDa member of the 4 alpha-helix bundle family of cytokines. IL-15 expression is controlled at the levels of transcription, translation, and intracellular trafficking. In particular, IL-15 protein is posttranscriptionally regulated by multiple controlling elements that impede translation, including 12 upstream AUGs of the 5' UTR, 2 unusual signal peptides, and the C-terminus of the mature protein. IL-15 uses two distinct receptor and signaling pathways. In T and NK cells the IL-15 receptor includes IL-2/15Rbeta and gammac, subunits, which are shared with IL-2, and an IL-15-specific receptor subunit, IL-15Ralpha. Mast cells respond to IL-15 with a receptor system that does not share elements with the IL-2 receptor but uses a novel 60- to 65-kDa IL-15RX subunit. In mast cells IL-15 signaling involves Jak2/STAT5 activation rather than the Jak1/Jak3 and STAT5/STAT3 system used in activated T cells. In addition to its other functional activities in immune and nonimmune cells, IL-15 plays a pivotal role in the development, survival, and function of NK cells. Abnormalities of IL-15 expression have been described in patients with rheumatoid arthritis or inflammatory bowel disease and in diseases associated with the retroviruses HIV and HTLV-I. New approaches directed toward IL-15, its receptor, or its signaling pathway may be of value in the therapy of these disorders.

Notes: Abstract Natural killer (NK) cells are populations of lymphocytes that can be activated to mediate significant levels of cytotoxic activity and produce high levels of certain cytokines and chemokines. NK cells respond to and are important in defense against a number of different infectious agents. The first indications for this function came from the observations that virus-induced interferons alpha/beta (IFN-alpha and -beta) are potent inducers of NK cell-mediated cytotoxicity, and that NK cells are important contributors to innate defense against viral infections. In addition to IFN-alpha/beta, a wide range of other innate cytokines can mediate biological functions regulating the NK cell responses of cytotoxicity, proliferation, and gamma interferon (IFN-gamma) production. Certain, but not all, viral infections induce interleukin 12 (IL-12) to elicit NK cell IFN-gamma production and antiviral mechanisms. However, high levels of IFN-alpha/beta appear to be unique and/or uniquely dominant in the context of viral infections and act to regulate other innate responses, including induction of NK cell proliferation in vivo and overall negative regulation of IL-12 production. A detailed picture is developing of particular innate cytokines activating NK cell responses and their consorted effects in providing unique endogenous milieus promoting downstream adaptive responses, most beneficial in defense against viral infections.

Notes: Abstract Four members of the tumor necrosis factor (TNF) ligand family, TNF-alpha, LT-alpha, LT-beta, and LIGHT, interact with four receptors of the TNF/nerve growth factor family, the p55 TNF receptor (CD120a), the p75 TNF receptor (CD120b), the lymphotoxin beta receptor (LTbetaR), and herpes virus entry mediator (HVEM) to control a wide range of innate and adaptive immune response functions. Of these, the most thoroughly studied are cell death induction and regulation of the inflammatory process. Fas/Apo1 (CD95), a receptor of the TNF receptor family activated by a distinct ligand, induces death in cells through mechanisms shared with CD120a. The last four years have seen a proliferation in knowledge of the proteins participating in the signaling by the TNF system and CD95. The downstream signaling molecules identified so far-caspases, phospholipases, the three known mitogen activated protein (MAP) kinase pathways, and the NF-kappaB activation cascade-mediate the effects of other inducers as well. However, the molecules that initiate these signaling events, including the death domain- and TNF receptor associated factor (TRAF) domain-containing adapter proteins and the signaling enzymes associated with them, are largely unique to the TNF/nerve growth factor receptor family.

Notes: Abstract Exciting breakthroughs in the last two years have begun to elucidate the structural basis of cellular immune recognition. Crystal structures have been determined for full-length and truncated forms of alphabeta T cell receptor (TCR) heterodimers, both alone and in complex with their peptide-MHC (pMHC) ligands or with anti-TCR antibodies. In addition, a truncated CD8 coreceptor has been visualized with a pMHC. Aided in large part by the substantial body of knowledge accumulated over the last 25 years on antibody structure, a number of general conclusions about TCR structure and its recognition of antigen can already be derived from the relatively few TCR structures that have been determined. Small, but important, variations between TCR and antibody structures bear on their functional differences as well as on their specific antigen recognition requirements. As observed in antibodies, canonical CDR loop structures are already emerging for some of the TCR CDR loops. Highly similar docking orientations of the TCR Valpha domains in the TCR/pMHC complex appear to play a primary role in dictating orientation, but the Vbeta positions diverge widely. Similar TCR contact positions, but whose exact amino acid content can vary, coupled with relatively poor interface shape complementarity, may explain the flexibility and short half-lives of many TCR interactions with pMHC. Here we summarize the current state of this field, and suggest that the knowledge gap between the three-dimensional structure and the signaling function of the TCR can be bridged through a synthesis of molecular biological and biophysical techniques.

Notes: Abstract In B lymphocytes, a signaling complex that contributes to cell fate decisions is the B cell antigen receptor (BCR). Data from knockout experiments in cell lines and mice have revealed distinct functions for the intracellular protein tyrosine kinases (Lyn, Syk, Btk) in BCR signaling and B cell development. Combinations of intracellular signaling pathways downstream of these PTKs determine the quality and quantity of BCR signaling. For example, concerted actions of the PLC-gamma2 and PI3-K pathways are required for proper calcium responses. Similarly, the regulation of ERK and JNK responses involves both PLC-gamma2 and GTPases pathways. Since the immune response in vivo is regulated by alteration of these signaling outcomes, achieving a precise understanding of intracellular molecular events leading to B lymphocyte proliferation, deletion, anergy, receptor editing, and survival still remains a challenge for the future.

Notes: Abstract Phagocytosis of pathogens by macrophages initiates the innate immune response, which in turn orchestrates the adaptive response. In order to discriminate between infectious agents and self, macrophages have evolved a restricted number of phagocytic receptors, like the mannose receptor, that recognize conserved motifs on pathogens. Pathogens are also phagocytosed by complement receptors after relatively nonspecific opsonization with complement and by Fc receptors after specific opsonization with antibodies. All these receptors induce rearrangements in the actin cytoskeleton that lead to the internalization of the particle. However, important differences in the molecular mechanisms underlying phagocytosis by different receptors are now being appreciated. These include differences in the cytoskeletal elements that mediate ingestion, differences in vacuole maturation, and differences in inflammatory responses. Infectious agents, such as M. tuberculosis, Legionella pneumophila, and Salmonella typhimurium, enter macrophages via heterogeneous pathways and modify vacuolar maturation in a manner that favors their survival. Macrophages also play an important role in the recognition and clearance of apoptotic cells; a notable feature of this process is the absence of an inflammatory response.

Notes: Abstract The immune system relies on cell death to maintain lymphoid homeostasis and avoid disease. Recent evidence has indicated that the caspase family of cysteine proteases is a central effector in apoptotic cell death and is absolutely responsible for many of the morphological features of apoptosis. Cell death, however, can occur through caspase-independent and caspase-dependent pathways. In the case of cells that are irreversibly neglected or damaged, death occurs even in the absence of caspase activity. In contrast, healthy cells require caspase activation to undergo cell death induced by surface receptors. This review summarizes the current understanding of these two pathways of cell death in the immune system.

Notes: Abstract An RNA fold is the result of packing together two or more coaxial helical stacks. To date, four RNA folds have been determined at near-atomic resolution by X-ray crystallography: transfer RNA, the hammerhead ribozyme, the P4-P6 domain of the Tetrahymena group I intron, and the hepatitis delta virus ribozyme. All four folds result in RNAs that are considerably more compact than isolated A-form duplexes. These structures illustrate, to varying degrees, three modes of fold stabilization: association of complementary molecular surfaces, stabilization of close RNA packing by binding of cations, and stabilization through pseudoknotting.

Notes: Abstract The F0F1 ATP synthase is a large multisubunit complex that couples translocation of protons down an electrochemical gradient to the synthesis of ATP. Recent advances in structural analyses have led to the demonstration that the enzyme utilizes a rotational catalytic mechanism. Kinetic and biochemical evidence is consistent with the expected equal participation of the three catalytic sites in the alpha3beta3 hexamer, which operate in sequential, cooperative reaction pathways. The rotation of the core gamma subunit plays critical roles in establishing the conformation of the sites and the cooperative interactions. Mutational analyses have shown that the rotor subunits are responsible for coupling and in doing so transmit specific conformational information between transport and catalysis.

Notes: Abstract Solid-state nuclear magnetic resonance (NMR) is rapidly emerging as a successful and important technique for protein and peptide structural elucidation from samples in anisotropic environments. Because of the diversity of nuclei and nuclear spin interactions that can be observed, and because of the broad range of sample conditions that can be studied by solid-state NMR, the potential for gaining structural constraints is great. Structural constraints in the form of orientational, distance, and torsional constraints can be obtained on proteins in crystalline, liquid-crystalline, or amorphous preparations. Great progress in the past few years has been made in developing techniques for obtaining these constraints, and now it has also been clearly demonstrated that these constraints can be assembled into uniquely defined three-dimensional structures at high resolution. Although much progress toward the development of solid-state NMR as a routine structural tool has been documented, the future is even brighter with the continued development of the experiments, of NMR hardware, and of the molecular biological methods for the preparation of labeled samples.

Notes: Abstract Stably folded membrane proteins reside in a free energy minimum determined by the interactions of the peptide chains with each other, the lipid bilayer hydrocarbon core, the bilayer interface, and with water. The prediction of three-dimensional structure from sequence requires a detailed understanding of these interactions. Progress toward this objective is summarized in this review by means of a thermodynamic framework for describing membrane protein folding and stability. The framework includes a coherent thermodynamic formalism for determining and describing the energetics of peptide-bilayer interactions and a review of the properties of the environment of membrane proteins-the bilayer milieu. Using a four-step thermodynamic cycle as a guide, advances in three main aspects of membrane protein folding energetics are discussed: protein binding and folding in bilayer interfaces, transmembrane helix insertion, and helix-helix interactions. The concepts of membrane protein stability that emerge provide insights to fundamental issues of protein folding.

Notes: Abstract Bacteriorhodopsin is the best understood ion transport protein and has become a paradigm for membrane proteins in general and transporters in particular. Models up to 2.5 A resolution of bacteriorhodopsin's structure have been published during the last three years and are basic for understanding its function. Thus one focus of this review is to summarize and to compare these models in detail. Another focus is to follow the protein through its catalytic cycle in summarizing more recent developments. We focus on literature published since 1995; a comprehensive series of reviews was published in 1995 (112).

Notes: Abstract In Dictyostelium amoebae, cell-type differentiation, spatial patterning, and morphogenesis are controlled by a combination of cell-autonomous mechanisms and intercellular signaling. A chemotactic aggregation of ~105 cells leads to the formation of a multicellular organism. Cell-type differentiation and cell sorting result in a small number of defined cell types organized along an anteroposterior axis. Finally, a mature fruiting body is created by the terminal differentiation of stalk and spore cells. Analysis of the regulatory program demonstrates a role for several molecules, including GSK-3, signal transducers and activators of transcription (STAT) factors, and cAMP-dependent protein kinase (PKA), that control spatial patterning in metazoans. Unexpectedly, two component systems containing histidine kinases and response regulators also play essential roles in controlling Dictyostelium development. This review focuses on the role of cAMP, which functions intracellularly to mediate the activity of PKA, an essential component in aggregation, cell-type specification, and terminal differentiation. Cytoplasmic cAMP levels are controlled through both the regulated activation of adenylyl cyclases and the degradation by a phosphodiesterase containing a two-component system response regulator. Extracellular cAMP regulates G-protein-dependent and -independent pathways to control aggregation as well as the activity of GSK-3 and the transcription factors GBF and STATa during multicellular development. The integration of these pathways with others regulated by the morphogen DIF-1 to control cell fate decisions are discussed.

Notes: Abstract I present the general picture of how galactic magnetic fields grow in disks according to the alpha-Omega dynamo theory. Emphasis is placed on following the lines of force during the dynamo process. The dynamo equation is presented together with a simple growing solution for the galactic disk. Then I take up the various critical questions that have been raised concerning the galactic dynamo theory. These are (1) the importance of the escape of flux from the disk in order for the magnetic field to grow; (2) the physics of turbulent diffusion and its mixing of field lines together so that the rms field is possibly greater than the mean field; (3) whether magnetic reconnection plays a role in the galactic dynamo; (4) whether small-scale fields can grow large enough to swamp the dynamo. Then I discuss the possible seed fields from which the dynamo starts and their relation to the primordial hypothesis. Finally I take up the question of the final evolution of the galactic field after the alpha effect saturates. My conclusion is that all these problems warrant attention but none of them seem to be serious enough to cast any real doubt on the dynamo as the most likely generator of galactic fields.

Notes: Abstract Advances in wide-angle astrometric measurements of three to four orders of magnitude in the last thirty years have resulted in a redefinition of the fundamental astronomical reference frame. This new frame, the International Celestial Reference Frame (ICRF), is based on the radio positions of 212 compact extragalactic radio sources. The ICRF defines the direction of the axes of the International Celestial Reference System (ICRS) with a precision of approximately 20 muas. At optical wavelengths, the Hipparcos catalog is the realization of this frame. The precision with which the ICRF is now determined requires that the ICRS models for precession, nutation, and others, be revised. Increases in the precision of measurements from astrometric space missions will further improve the celestial reference frame and may require its redefinition within the next ten years. These improvements will again challenge the models for the celestial reference system.

Notes: Abstract The physical conditions in molecular clouds control the nature and rate of star formation, with consequences for planet formation and galaxy evolution. The focus of this review is on the conditions that characterize regions of star formation in our Galaxy. A review of the tools and tracers for probing physical conditions includes summaries of generally applicable results. Further discussion distinguishes between the formation of low-mass stars in relative isolation and formation in a clustered environment. Evolutionary scenarios and theoretical predictions are more developed for isolated star formation, and observational tests are beginning to interact strongly with the theory. Observers have identified dense cores collapsing to form individual stars or binaries, and analysis of some of these cores support theoretical models of collapse. Stars of both low and high mass form in clustered environments, but massive stars form almost exclusively in clusters. The theoretical understanding of such regions is considerably less developed, but observations are providing the ground rules within which theory must operate. The richest and most massive star clusters form in massive, dense, turbulent cores, which provide models for star formation in other galaxies.

Notes: Abstract Far-ultraviolet radiation is a ubiquitous, if unanticipated, phenomenon in elliptical galaxies and early-type spiral bulges. It is the most variable photometric feature associated with old stellar populations. Recent observational and theoretical evidence shows that it is produced mainly by low-mass, small-envelope, helium-burning stars in extreme horizontal branch and subsequent phases of evolution. These are probably descendants of the dominant, metal rich population of the galaxies. Their lifetime UV outputs are remarkably sensitive to their physical properties and hence to the age and the helium and metal abundances of their parents. UV spectra are therefore exceptionally promising diagnostics of old stellar populations, although their calibration requires a much improved understanding of giant branch mass loss, helium enrichment, and atmospheric diffusion.

Notes: Abstract Nuclear magnetic resonance (NMR) measurements of flowing materials are reviewed with emphasis on applications to multiphase flows. After a brief presentation of NMR physics, experimental considerations related to flow measurements are discussed. Both imaging and non-imaging NMR as well as topics such as Earth's field NMR and rapid imaging are covered. Specific topics that follow are tagging and time-of-flight, phase measurement of velocity, diffusion, turbulence, and calibration and validations. Finally, recent applications are reviewed in the areas of sedimentation, suspension flows in Couette and pipe geometries, rheometers and viscometers, liquid-liquid multiphase flows, porous media flow, granular flows, and turbulence.

Notes: Abstract In this review, we describe the dynamics and thermodynamics of liquid and vapor flow through hot fractured rock. Such flows occur in geothermal reservoirs and have important implications for geothermal power generation; we describe both forced flows associated with liquid injection into such systems, and natural convective flows associated with the vertical heat transfer through such systems. First we focus on permeable media and describe the heat transfer of single-phase liquid or vapor flow through a medium of different temperature. Then we consider the dynamics and thermodynamics of a liquid front as it advances into a superheated region and boils. The morphological stability of such an interface is discussed, and we describe conditions under which the interface breaks down to form a two-phase zone between the liquid and vapor. We next examine the heat transfer and boiling in gravity-driven flows advancing through a superheated permeable rock, identifying that at large times such currents asymptote to a family of similarity solutions. In the second part of the review, we describe the analogous heat transfer and boiling processes associated with liquid flow along a fracture embedded in an impermeable rock. We describe some simple asymptotic solutions for the temperature distribution in the bounding rock, which reveal that in the fracture, a two-phase boiling region develops between the purely liquid and purely vapor zones. Model predictions are successfully tested with laboratory experiments. In the final section of the review, we briefly discuss natural convective flows, illustrating how single-phase and two-phase convective regions interact and in some cases produce instability.

Notes: Abstract This review deals primarily with the bifurcation, stability, and evolution of gravity and capillary-gravity waves. Recent results on the bifurcation of various types of capillary-gravity waves, including two-dimensional solitary waves at the minimum of the dispersion curve, are reviewed. A survey of various mechanisms (including the most recent ones) to explain the frequency downshift phenomenon is provided. Recent significant results are given on "horseshoe" patterns, which are three-dimensional structures observable on the sea surface under the action of wind or in wave tank experiments. The so-called short-crested waves are then discussed. Finally, the importance of surface tension effects on steep waves is studied.

Notes: Abstract We survey the newly developed Hilbert spectral analysis method and its applications to Stokes waves, nonlinear wave evolution processes, the spectral form of the random wave field, and turbulence. Our emphasis is on the inadequacy of presently available methods in nonlinear and nonstationary data analysis. Hilbert spectral analysis is here proposed as an alternative. This new method provides not only a more precise definition of particular events in time-frequency space than wavelet analysis, but also more physically meaningful interpretations of the underlying dynamic processes.

Notes: Abstract A decade of research on adaptive mutation has revealed a plethora of mutagenic mechanisms that may be important in evolution. The DNA synthesis associated with recombination could be an important source of spontaneous mutation in cells that are not proliferating. The movement of insertion elements can be responsive to environmental conditions. Insertion elements not only activate and inactivate genes, they also provide sequence homology that allows large-scale genomic rearrangements. Some conjugative plasmids can recombine with their host's chromosome, and may acquire chromosomal genes that could then spread through the population and even to other species. Finally, a subpopulation of transient hypermutators could be a source of multiple variant alleles, providing a mechanism for rapid evolution under adverse conditions.

Notes: Abstract Lentiviruses are associated with chronic diseases of the hematological and neurological systems in animals and man. In particular, human immunodeficiency virus type 1 (HIV-1) is the etiological agent of the global AIDS epidemic. The genomes of lentiviruses are complex, encoding a number of regulatory and accessory proteins not found in other retroviruses. This complexity is reflected in their replication cycle, which reveals intricate regulatory pathways and unique mechanisms for viral persistence. In this review, we highlight some of these unique features for HIV-1, with particular focus on the transcriptional and posttranscriptional control of gene expression. Although our understanding of the biology of HIV-1 is far from complete, the knowledge gained thus far has already led to novel strategies for both virus intervention and exploiting the lentiviruses for therapeutic applications.

Notes: Abstract The stability of mRNA in prokaryotes depends on multiple factors and it has not yet been possible to describe the process of mRNA degradation in terms of a unique pathway. However, important advances have been made in the past 10 years with the characterization of the cis-acting RNA elements and the trans-acting cellular proteins that control mRNA decay. The trans-acting proteins are mainly four nucleases, two endo- (RNase E and RNase III) and two exonucleases (PNPase and RNase II), and poly(A) polymerase. RNase E and PNPase are found in a multienzyme complex called the degradosome. In addition to the host nucleases, phage T4 encodes a specific endonuclease called RegB. The cis-acting elements that protect mRNA from degradation are stable stem-loops at the 5' end of the transcript and terminators or REP sequences at their 3' end. The rate-limiting step in mRNA decay is usually an initial endonucleolytic cleavage that often occurs at the 5' extremity. This initial step is followed by directional 3' to 5' degradation by the two exonucleases. Several examples, reviewed here, indicate that mRNA degradation is an important step at which gene expression can be controlled. This regulation can be either global, as in the case of growth rate-dependent control, or specific, in response to changes in the environmental conditions.

Notes: Abstract Due to the increase of human migrations, the appearance of emerging and reemerging endemies, growing antibiotic resistance, and climatic changes, infectious diseases most probably constitute the major challenge for medicine in the next century. The advent of molecular methods of pathogen characterization has considerably improved our knowledge of the epidemiology of these diseases. However, the use of concepts of evolutionary genetics for interpreting "molecular epidemiology" data remains limited, although the application of such methods would broaden considerably the scope of this field of research, and allow epidemiologic and taxonomic approaches to be ascertained on a much firmer basis. In turn, pathogens, hosts, and vectors provide fascinating models for basic research. The artificial character of the border between "basic" and "applied" research is especially apparent with regard to the "integrated genetic epidemiology of infectious diseases" concept. The goal of this chapter is to evaluate the respective impact, on the transmission and pathogenicity of infectious diseases, of the host's, the pathogen's, and the vector's (for vector-borne diseases) genetic diversity, and the interactions between these three parameters (coevolution phenomena).

Notes: Abstract In the past few years great progress has been made in identifying and characterizing plant photoreceptors active in the blue/UV-A regions of the spectrum. These photoreceptors include cryptochrome 1 and cryptochrome 2, which are similar in structure and chromophore composition to the prokaryotic DNA photolyases. However, they have a C-terminal extension that is not present in photolyases and lack photolyase activity. They are involved in regulation of cell elongation and in many other processes, including interfacing with circadian rhythms and activating gene transcription. Animal cryptochromes that play a photoreceptor role in circadian rhythms have also been characterized. Phototropin, the protein product of the NPH1 gene in Arabidopsis, likely serves as the photoreceptor for phototropism and appears to have no other role. A plasma membrane protein, it serves as photoreceptor, kinase, and substrate for light-activated phosphorylation. The carotenoid zeaxanthin may serve as the chromophore for a photoreceptor involved in blue-light-activated stomatal opening. The properties of these photoreceptors and some of the downstream events they are known to activate are discussed.

Notes: Abstract Cell proliferation and cell death must be closely regulated to maintain the integrity of the immune system during the lifetime of multicellular organisms. Proliferative expansion of lymphoid cells is required for effective immune responses against invading microorganisms. However, following infection eradication, expanded effector cells must be eliminated to prevent non-adaptive accumulation of cells. Therefore, higher vertebrates have developed an extensive network of signal transduction pathways that allow integration of cell survival and cell death stimuli. This network functions to ensure the controlled activation and expansion of cells during an immune response and the deletion of lymphoid cells that are no longer needed at the end of an immune response. Extracellular signals appear to control both mechanisms. Ultimate responses are integrated through cell surface receptors that are linked to intracellular signaling cascades. These signal transduction pathways converge to regulate cell fate at both transcriptional and post-transcriptional levels. In this review, the role of pathways triggered by TNFR-related molecules that determine the fate of lymphoid cells during development and activation is summarized.

Notes: Abstract Endoderm, one of the three principal germ layers, contributes to all organs of the alimentary tract. For simplicity, this review divides formation of endodermal organs into four fundamental steps: (a) formation of endoderm during gastrulation, (b) morphogenesis of a gut tube from a sheet of cells, (c) budding of organ domains from the tube, and (d) differentiation of organ-specific cell types within the growing buds. We discuss possible mechanisms that regulate how undifferentiated endoderm becomes specified into a myriad of cell types that populate the respiratory and gastrointestinal tracts.

Notes: Abstract At a certain stage in their life cycle, plants switch from vegetative to reproductive development. This transition is regulated by multiple developmental and environmental cues. These ensure that the plant switches to flowering at a time when sufficient internal resources have been accumulated and the environmental conditions are favorable. The use of a molecular genetic approach in Arabidopsis has resulted in the identification and cloning of many of the genes involved in regulating floral transition. The current view on the molecular function of these genes, their division into different genetic pathways, and how the pathways interact in a complex regulatory network are summarized.

Notes: Abstract The [PSI+] factor of the yeast Saccharomyces cerevisiae is an epigenetic regulator of translation termination. More than three decades ago, genetic analysis of the transmission of [PSI+] revealed a complex and often contradictory series of observations. However, many of these discrepancies may now be reconciled by a revolutionary hypothesis: protein conformation-based inheritance (the prion hypothesis). This model predicts that a single protein can stably exist in at least two distinct physical states, each associated with a different phenotype. Propagation of one of these traits is achieved by a self-perpetuating change in the protein from one form to the other. Mounting genetic and biochemical evidence suggests that the determinant of [PSI+] is the nuclear encoded Sup35p, a component of the translation termination complex. Here we review the series of experiments supporting the yeast prion hypothesis and provide another look at the 30 years of work preceding this theory in light of our current state of knowledge.

Notes: Abstract Cotranslational protein translocation across and integration into the membrane of the endoplasmic reticulum (ER) occur at sites termed translocons. Translocons are composed of several ER membrane proteins that associate to form an aqueous pore through which secretory proteins and lumenal domains of membrane proteins pass from the cytoplasm to the ER lumen. These sites are not passive holes in the bilayer, but instead are quite dynamic both structurally and functionally. Translocons cycle between ribosome-bound and ribosome-free states, and convert between translocation and integration modes of operation. These changes in functional state are accompanied by structural rearrangements that alter translocon conformation, composition, and interactions with ligands such as the ribosome and BiP. Recent studies have revealed that the translocon is a complex and sophisticated molecular machine that regulates the movement of polypeptides through the bilayer, apparently in both directions as well as laterally into the bilayer, all while maintaining the membrane permeability barrier.

Notes: Abstract Synaptic vesicles, which have been a paradigm for the fusion of a vesicle with its target membrane, also serve as a model for understanding the formation of a vesicle from its donor membrane. Synaptic vesicles, which are formed and recycled at the periphery of the neuron, contain a highly restricted set of neuronal proteins. Insight into the trafficking of synaptic vesicle proteins has come from studying not only neurons but also neuroendocrine cells, which form synaptic-like microvesicles (SLMVs). Formation and recycling of synaptic vesicles/SLMVs takes place from the early endosome and the plasma membrane. The cytoplasmic machinery of synaptic vesicle/SLMV formation and recycling has been studied by a variety of experimental approaches, in particular using cell-free systems. This has revealed distinct machineries for membrane budding and fission. Budding is mediated by clathrin and clathrin adaptors, whereas fission is mediated by dynamin and its interacting protein SH3p4, a lysophosphatidic acid acyl transferase.

Notes: Abstract I was born and educated in Canada, obtaining my PhD in experimental nuclear physics. When I learned that technetium had been found in stellar spectra, I taught myself some astrophysics and began to study stellar nucleosynthesis. This is an account of those studies and of the pathway through much of theoretical astrophysics and planetary physics that was a natural outgrowth of the pursuit of nucleosynthesis problems. I also discuss my experiences in government service and in academia, in organization of conferences, in governmental advising, and in academic administration. In particular, I emphasize the logical connections among the various scientific themes that I have pursued.

Notes: Abstract We present a review of nucleosynthesis in AGB stars outlining the development of theoretical models and their relationship to observations. We focus on the new high resolution codes with improved opacities, which recently succeeded in accounting for the third dredge-up. This opens the possibility of understanding low luminosity C stars (enriched in s-elements) as the normal outcome of AGB evolution, characterized by production of 12C and neutron-rich nuclei in the He intershell and by mass loss from strong stellar winds. Neutron captures in AGB stars are driven by two reactions: 13C(alpha,n)16O, which provides the bulk of the neutron flux at low neutron densities (Nn〈= 107 n/cm3), and 22Ne(alpha,n)25Mg, which is mildly activated at higher temperatures and mainly affects the production of s-nuclei depending on reaction branchings. The first reaction is now known to occur in the radiative interpulse phase, immediately below the region previously homogenized by third dredge-up. The second reaction occurs during the convective thermal pulses. The resulting nucleosynthesis phenomena are rather complex and rule out any analytical approximation (exponential distribution of neutron fluences). Nucleosynthesis in AGB stars, modeled at different metallicities, account for several observational constraints, coming from a wide spectrum of sources: evolved red giants rich in s-elements, unevolved stars at different metallicities, presolar grains recovered from meteorites, and the abundances of s-process isotopes in the solar system. In particular, a good reproduction of the solar system main component is obtained as a result of Galactic chemical evolution that mixes the outputs of AGB stars of different stellar generations, born with different metallicities and producing different patterns of s-process nuclei. The main solar s-process pattern is thus not considered to be the result of a standard archetypal s-process occurring in all stars. Concerning the 13C neutron source, its synthesis requires penetration of small amounts of protons below the convective envelope, where they are captured by the abundant 12C forming a 13C-rich pocket. This penetration cannot be modeled in current evolutionary codes, but is treated as a free parameter. Future hydrodynamical studies of time dependent mixing will be required to attack this problem. Evidence of other insufficiencies in the current mixing algorithms is common throughout the evolution of low and intermediate mass stars, as is shown by the inadequacy of stellar models in reproducing the observations of CNO isotopes in red giants and in circumstellar dust grains. These observations require some circulation of matter between the bottom of convective envelopes and regions close to the H-burning shell (cool bottom processing). AGB stars are also discussed in the light of their possible contribution to the inventory of short-lived radioactivities that were found to be alive in the early solar system. We show that the pollution of the protosolar nebula by a close-by AGB star may account for concordant abundances of 26Al, 41Ca, 60Fe, and 107Pd. The AGB star must have undergone a very small neutron exposure, and be of small initial mass ( ). There is a shortage of 26Al in such models, that however remains within the large uncertainties of crucial reaction rates. The net 26Al production problem requires further investigation.

Notes: Abstract Because of mean distortion, most turbulent flows are anisotropic. Two-point descriptions, forming the heart of this review of anisotropic models, capture the continuum of anisotropically structured turbulent scales and, moreover, allow exact treatment of the linear terms representing mean distortion, only needing closure assumptions for the nonlinear part of the model. The rapid-distortion limit, in which nonlinear terms are neglected, is the main subject of Section 2, while Section 3 introduces nonlinearity. It is shown that, even with significant nonlinearity, many features of turbulence can, at least qualitatively, be understood using linear theory alone, e.g. the directionality of velocity fluctuations and correlation lengths induced by strong mean shear near a wall or straining by duct flow, whereas some, e.g. wave resonances in rotating turbulence, involve a subtle combination of linear and nonlinear terms. The importance of linear effects is reflected in the triadic models of Section 3, which contain no approximations of the linear terms and whose anisotropic nonlinear closures are heavily dependent on linear theory. Despite being fundamentally less satisfactory (because they involve additional ad hoc hypotheses to compensate for the lack of two-point information), one-point models dominate industrial calculations because they are robust, well-established, and computationally relatively cheap. Although there are too many spectral degrees of freedom for a one-point model to reproduce two-point results in all circumstances, two-point theories-in particular RDT-have been exploited to develop new one-point models, as discussed in Section 4. Given the significant limitation of classical two-point models to homogeneous turbulence, some inhomogeneous extensions are described in Section 5.

Notes: Abstract Natural ventilation of buildings is the flow generated by temperature differences and by the wind. The governing feature of this flow is the exchange between an interior space and the external ambient. Although the wind may often appear to be the dominant driving mechanism, in many circumstances temperature variations play a controlling feature on the ventilation since the directional buoyancy force has a large influence on the flow patterns within the space and on the nature of the exchange with the outside. Two forms of ventilation are discussed: mixing ventilation, in which the interior is at an approximately uniform temperature, and displacement ventilation, where there is strong internal stratification. The dynamics of these buoyancy-driven flows are considered, and the effects of wind on them are examined. The aim behind this work is to give designers rules and intuition on how air moves within a building; the research reveals a fascinating branch of fluid mechanics.

Notes: Abstract We discuss the thickness of the liquid layer entrained by a solid drawn out of a bath, focusing on the case where the solid is a fiber or a wire. Slow withdrawals out of a pure or a complex fluid are described as well as quick coatings. We specify the general laws of entrainment and stress the cases where the fiber curvature plays a role. We finally give an overview on the further evolution of the coated film.

Notes: Abstract A review of planetary-entry gas dynamics is presented. Evolution of a blunt-body flowfield from a free molecular flow environment to a continuum environment is described. Simulations of near-wake flow phenomena, important for defining aerobrake payload environments, are also discussed. Some topics to be highlighted include aerodynamic coefficient predictions with emphasis on high-temperature gas effects; surface heating and temperature predictions for thermal protection system (TPS) design in a high-temperature, thermochemical nonequilibrium environment; and thermochemical models required for numerical flow simulation. Recent applications involving atmospheric entry into Jupiter (Galileo), Mars (Pathfinder and Global Surveyor), and a planned mission in which dust from the tail of a comet will be returned to Earth (Stardust) will provide context for this discussion.

Notes: Abstract A conserved mRNA degradation system, referred to as mRNA surveillance, exists in eukaryotic cells to degrade aberrant mRNAs. A defining aspect of aberrant transcripts is that the spatial relationship between the termination codon and specific downstream sequence information has been altered. A key, yet unknown, feature of the mRNA surveillance system is how this spatial relationship is assessed in individual transcripts. Two views have emerged to describe how discrimination between proper and improper termination might occur. In the first view, a surveillance complex assembles onto the mRNA after translation termination, and scans the mRNA in a 3' to 5' direction for a limited distance. If specific downstream sequence information is encountered during this scanning, then the surveillance complex targets the transcript for rapid decay. An alternate view suggests that the downstream sequence information influences how translation termination occurs. This view encompasses several ideas including: (a) The architecture of the mRNP can alter the rate of key steps in translation termination; (b) the discrimination between a proper and improper termination occurs via an internal, Upf1-dependent, timing mechanism; and (c) proper termination results in the restructuring of the mRNP to a form that promotes mRNA stability. This proposed model for mRNA surveillance is similar to other systems of kinetic proofreading that monitor the accuracy of other biogenic processes such as translation and spliceosome assembly.

Notes: Abstract French genetics had unusual beginnings. There are clear indications that the French biological establishment resisted Mendelian genetics strenuously from about 1910 to 1940. From about 1930 to 1950 several unconventional research programs with a strongly physiological orientation paved the way for the full entrance of French biology into genetics after World War II. This review examines some salient features of this history to clarify the strengths, weaknesses, and distinctive features of French genetics until about 1965. We suggest that after that date French genetics slowly merged into the international mainstream as genetics has become a largely molecular discipline.

Notes: Abstract Retrotransposons are mobile genetic elements that transpose through reverse transcription of an RNA intermediate. Retrotransposons are ubiquitous in plants and play a major role in plant gene and genome evolution. In many cases, retrotransposons comprise over 50% of nuclear DNA content, a situation that can arise in just a few million years. Plant retrotransposons are structurally and functionally similar to the retrotransposons and retroviruses that are found in other eukaryotic organisms. However, there are important differences in the genomic organization of retrotransposons in plants compared to some other eukaryotes, including their often-high copy numbers, their extensively heterogeneous populations, and their chromosomal dispersion patterns. Recent studies are providing valuable insights into the mechanisms involved in regulating the expression and transposition of retrotransposons. This review describes the structure, genomic organization, expression, regulation, and evolution of retrotransposons, and discusses both their contributions to plant genome evolution and their use as genetic tools in plant biology.

Notes: Abstract Many cellular processes require a balance between protein synthesis and protein degradation. The vacuole/lysosome is the main site of protein and organellar turnover within the cell due to its ability to sequester numerous hydrolases within a membrane-enclosed compartment. Several mechanisms are used to deliver substrates, as well as resident hydrolases, to this organelle. The delivery processes involve dynamic rearrangements of membrane. In addition, continual adjustments are made to respond to changes in environmental conditions. In this review, we focus on recent progress made in analyzing these delivery processes at a molecular level. The identification of protein components involved in the recognition, sequestration, and transport events has begun to provide information about this important area of eukaryotic cell physiology.

Notes: Abstract Organelle transport has been proposed to proceed in two steps: long-range transport along microtubules and local delivery via actin filaments. This model is supported by recent studies of pigment transport in several cell types and transport in neurons, and in several cases, class V myosin has been implicated as the actin-based motor. Mutations in mice (dilute) and yeast (myo2) have also implicated this class of myosin in organelle transport, and genetic interactions in yeast have indicated that a kinesin-related protein (Smy1p) plays a supporting role. This link between members of two different motor superfamilies has now taken a surprising turn: There is evidence for a physical interaction between class V myosins and kinesin or Smy1p in both mice and yeast.

Notes: Abstract The neural crest is a transient population of multipotent precursor cells named for its site of origin at the crest of the closing neural folds in vertebrate embryos. Following neural tube closure, these cells become migratory and populate diverse regions throughout the embryo where they give rise to most of the neurons and support cells of the peripheral nervous system (PNS), pigment cells, smooth muscle, craniofacial cartilage, and bone. Because of its remarkable ability to generate such diverse derivatives, the neural crest has fascinated developmental biologists for over one hundred years. A great deal has been learned about the migratory pathways neural crest cells follow and the signals that may trigger their differentiation, but until recently comparatively little was known about earlier steps in neural crest development. In the past few years progress has been made in understanding these earlier events, including how the precursors of these multipotent cells are specified in the early embryo and the mechanisms by which they become migratory. In this review, we first examine the mechanisms underlying neural crest induction, paying particular attention to a number of growth factor and transcription factor families that have been implicated in this process. We also discuss when and how the fate of neural crest precursors may diverge from those of nearby neural and epidermal populations. Finally, we review recent advances in our understanding of how neural crest cells become migratory and address the process of neural crest diversification.

Notes: Abstract Ubiquitous among eukaryotes, the ADF/cofilins are essential proteins responsible for the high turnover rates of actin filaments in vivo. In vertebrates, ADF and cofilin are products of different genes. Both bind to F-actin cooperatively and induce a twist in the actin filament that results in the loss of the phalloidin-binding site. This conformational change may be responsible for the enhancement of the off rate of subunits at the minus end of ADF/cofilin-decorated filaments and for the weak filament-severing activity. Binding of ADF/cofilin is competitive with tropomyosin. Other regulatory mechanisms in animal cells include binding of phosphoinositides, phosphorylation by LIM kinases on a single serine, and changes in pH. Although vertebrate ADF/cofilins contain a nuclear localization sequence, they are usually concentrated in regions containing dynamic actin pools, such as the leading edge of migrating cells and neuronal growth cones. ADF/cofilins are essential for cytokinesis, phagocytosis, fluid phase endocytosis, and other cellular processes dependent upon actin dynamics.

Notes: Abstract The Drosophila phototransduction cascade has emerged as an attractive paradigm for understanding the molecular mechanisms underlying visual transduction, as well as other G protein-coupled signaling cascades that are activated and terminated with great rapidity. A large collection of mutants affecting the fly visual cascade have been isolated, and the nature and function of many of the affected gene products have been identified. Virtually all of the proteins, including those that were initially classified as novel, are highly related to vertebrate homologs. Recently, it has become apparent that most of the proteins central to Drosophila phototransduction are coupled into a supramolecular signaling complex, signalplex, through association with a PDZ-containing scaffold protein. The characterization of this complex has led to a re-evaluation of the mechanisms underlying the activation and deactivation of the phototransduction cascade.

Notes: Abstract Caspase activation plays a central role in the execution of apoptosis. The key components of the biochemical pathways of caspase activation have been recently elucidated. In this review, we focus on the two most well-studied pathways of caspase activation: the cell surface death receptor pathway and the mitochondria-initiated pathway. In the cell surface death receptor pathway, activation of caspase-8 following its recruitment to the death-inducing signaling complex (DISC) is the critical event that transmits the death signal. This event is regulated at several different levels by various viral and mammalian proteins. Activated caspase-8 can activate downstream caspases by direct cleavage or indirectly by cleaving Bid and inducing cytochrome c release from the mitochondria. In the mitochondrial-initiated pathway, caspase activation is triggered by the formation of a multimeric Apaf-1/cytochrome c complex that is fully functional in recruiting and activating procaspase-9. Activated caspase-9 will then cleave and activate downstream caspases such as caspase-3, -6, and -7. This pathway is regulated at several steps, including the release of cytochrome c from the mitochondria, the binding and hydrolysis of dATP/ATP by Apaf-1, and the inhibition of caspase activation by the proteins that belong to the inhibitors of apoptosis (IAP).

Notes: Abstract Actin-related proteins (Arps) participate in a diverse array of cellular processes. They modulate assembly of conventional actin, contribute to microtubule-based motility catalyzed by dynein, and serve as integral components of large protein complexes required for gene expression. We highlight here recent work aimed at understanding the roles played by Arps in each of these processes.

Notes: Abstract Protein degradation is deployed to modulate the steady-state abundance of proteins and to switch cellular regulatory circuits from one state to another by abrupt elimination of control proteins. In eukaryotes, the bulk of the protein degradation that occurs in the cytoplasm and nucleus is carried out by the 26S proteasome. In turn, most proteins are thought to be targeted to the 26S proteasome by covalent attachment of a multiubiquitin chain. Ubiquitination of proteins requires a multienzyme system. A key component of ubiquitination pathways, the ubiquitin ligase, controls both the specificity and timing of substrate ubiquitination. This review is focused on a conserved ubiquitin ligase complex known as SCF that plays a key role in marking a variety of regulatory proteins for destruction by the 26S proteasome.

Notes: Abstract The formation of the vertebrate nervous system is initiated at gastrula stages of development, when signals from a specialized cluster of cells (the organizer) trigger neural development in the ectoderm. This process, termed neural induction, was first described in 1924 and stemmed from experiments on amphibia (Spemann & Mangold 1924). In recent years, the molecular mechanisms underlying neural induction in the amphibian have been elucidated. Surprisingly, neuralizing agents secreted by the organizer do not act via receptor-mediated signaling events; rather, these factors antagonize local epidermal inducers within the cells of the dorsal ectoderm and function to uncover the latent neural fate of these cells. Many of the recent advances in our understanding of vertebrate neural induction come from studies on the frog, Xenopus laevis. It is now clear that a blockade of signaling of the bone morphogenetic proteins (BMPs) during gastrula stages is sufficient to initiate neuralization of the ectoderm in this species. Thus this review first details our current understanding of neural induction, using the amphibian as a model. We then use data emerging from other systems to examine the extent to which the Xenopus studies can be applied to other vertebrate species. The initiation of the neurectoderm-specific gene expression program and subsequent steps in patterning and neuronal development are only touched on here. We focus primarily on the initial establishment of the neural fate in the vertebrate gastrula ectoderm.

Notes: Abstract Clathrin-based systems are responsible for a large portion of vesicular traffic originating from the plasma membrane and the trans-Golgi network that reaches the endosomal compartment. The assembly of cytosolic clathrin forms the scaffold required for the local deformation of the membrane and for the formation of coated pits and vesicles. In this process, clathrin interacts in a coordinated fashion with a large number of protein partners. A subset designated clathrin adaptors links integral membrane proteins to the clathrin coat, a process that results in the recruitment of specific cargo proteins to the budding vesicle. This review focuses on the most recent advances dealing with the molecular basis for sorting by clathrin adaptors.

Notes: Abstract Gravitational lenses can provide crucial information on the geometry of the Universe, on the cosmological scenario of formation of its structures as well as on the history of its components with look-back time. In this review, I focus on the most recent results obtained during the last five years from the analysis of the weak lensing regime. The potential of weak lensing as a probe of dark matter and the study of the coupling between light and mass on scales of clusters of galaxies, large-scale structures and galaxies is discussed first. Then I present the impact of weak lensing for the study of distant galaxies and of the population of lensed sources as a function of redshift. Finally, I discuss the potential of weak lensing to constrain the cosmological parameters, either from pure geometrical effects observed in peculiar lenses, or from the coupling of weak lensing with the CMB.

Notes: Abstract Black holes of stellar mass and neutron stars in binary systems are first detected as hard X-ray sources using high-energy space telescopes. Relativistic jets in some of these compact sources are found by means of multiwavelength observations with ground-based telescopes. The X-ray emission probes the inner accretion disk and immediate surroundings of the compact object, whereas the synchrotron emission from the jets is observed in the radio and infrared bands, and in the future could be detected at even shorter wavelengths. Black-hole X-ray binaries with relativistic jets mimic, on a much smaller scale, many of the phenomena seen in quasars and are thus called microquasars. Because of their proximity, their study opens the way for a better understanding of the relativistic jets seen elsewhere in the Universe. From the observation of two-sided moving jets it is inferred that the ejecta in microquasars move with relativistic speeds similar to those believed to be present in quasars. The simultaneous multiwavelength approach to microquasars reveals in short timescales the close connection between instabilities in the accretion disk seen in the X-rays, and the ejection of relativistic clouds of plasma observed as synchrotron emission at longer wavelengths. Besides contributing to a deeper understanding of accretion disks and jets, microquasars may serve in the future to determine the distances of jet sources using constraints from special relativity, and the spin of black holes using general relativity.

Notes: Abstract Quasar (QSO) elemental abundances provide unique probes of high-redshift star formation and galaxy evolution. There is growing evidence from both the emission and intrinsic absorption lines that QSO environments have roughly solar or higher metallicities out to redshifts 〉4. The range is not well known, but solar to a few times solar metallicity appears to be typical. There is also evidence for higher metallicities in more luminous objects and for generally enhanced N/C and Fe/alpha abundances compared with solar ratios. These results identify QSOs with vigorous, high-redshift star formation-consistent with the early evolution of massive galactic nuclei or dense protogalactic clumps. However, the QSOs offer new constraints. For example, (a) most of the enrichment and star formation must occur before the QSOs "turn on" or become observable, on time scales of 1 Gyr at least at the highest redshifts. (b) The tentative result for enhanced Fe/alpha suggests that the first local star formation began at least ~1 Gyr before the QSO epoch. (c) The star formation must ultimately be extensive to reach high metallicities; that is, a substantial fraction of the local gas must be converted into stars and stellar remnants. The exact fraction depends on the shape of the initial mass function (IMF). (d) The highest derived metallicities require IMFs that are weighted slightly more toward massive stars than in the solar neighborhood. (e) High metallicities also require deep gravitational potentials. By analogy with the well-known mass-metallicity relation among low-redshift galaxies, metal-rich QSOs should reside in galaxies (or protogalaxies) that are minimally as massive (or as tightly bound) as our own Milky Way.

Notes: Abstract This article reviews the transport properties of coherent vortices in rotating barotropic flows. It is shown that vortices induce regular Lagrangian motion inside their cores and are highly impermeable to inward and outward particle fluxes. Passive tracers can be trapped inside vortex cores for long times and are transported by the vortex motion over large distances. Absolute dispersion in vortex-dominated flows is discussed by studying particle dynamics in 2D turbulence, point-vortex systems, and subsurface float trajectories in the ocean. Finally, it is shown that anticyclonic coherent vortices in cyclonically rotating reference frames can concentrate heavy impurities (e.g. dust grains) in their cores. This process may play an important role in the formation of planetesimals in the early solar nebula.

Notes: Abstract The current state of the art in computational aerodynamics for whole-body aircraft flowfield simulations is described. Recent advances in geometry modeling, surface and volume grid generation, and flow simulation algorithms have led to accurate flowfield predictions for increasingly complex and realistic configurations. As a result, computational aerodynamics has emerged as a crucial enabling technology for the design and development of flight vehicles. Examples illustrating the current capability for the prediction of transport and fighter aircraft flowfields are presented. Unfortunately, accurate modeling of turbulence remains a major difficulty in the analysis of viscosity-dominated flows. In the future, inverse design methods, multidisciplinary design optimization methods, artificial intelligence technology, and massively parallel computer technology will be incorporated into computational aerodynamics, opening up greater opportunities for improved product design at substantially reduced costs.

Notes: Abstract An overview of preconditioning for the steady-state compressible inviscid fluid dynamic equations is presented. Extensions to the Navier-Stokes equations are also considered. These preconditioners are necessary for many algorithms in order to have the correct behavior at low speeds and to converge to the solution of the incompressible equations as the Mach number goes to zero. In addition, the preconditioning accelerates the convergence to a steady state for problems in which a significant portion of the flow is low speed. This low speed preconditioner can be combined with Jacobi and line preconditioners to damp high frequencies at all speeds. This is necessary for use with multigrid methods. Such combined methods are also better at accelerating problems with high aspect ratios. Details of the implementation are presented including several different variants for the preconditioning matrix.

Notes: Abstract The paper reviews striking features of swirling flows-collapse, swirl generation, vortex breakdown, hysteresis, and axisymmetry breaking-and the mechanisms involved with the help of conical similarity solutions of the Navier-Stokes equations. The strong accumulation of axial and angular momenta, observed in tornadoes and flows over delta wings, corresponds to collapse, i.e. the singularity development in these solutions. Bifurcation of swirl explains the threshold character of swirl development in capillary and electrovortex flows. Analytical solutions for fold catastrophes and hysteresis reveal why there are so few stable states and why the jump transitions between the states occur-features typical of tornadoes, of flows over delta wings, and in vortex devices. Finally, the divergent instability explains such effects as the splitting of a tornado and the development of spiral branches in tree and near-wall swirling flows.

Notes: Abstract I was pleased to receive the invitation to write this prefatory chapter. In doing so, I join a number of physiologists whose work and writings I have often admired. There are two aspects of my experience in physiology that I discuss here. The first concerns my own research accomplishments. The second is my role in developing three departments of physiology and fostering the careers of others. While I take pleasure in the former, the overall contribution of the latter was undoubtedly greater.

Notes: Abstract The main contributors to increases in [Ca2+]i and tension are the entry of Ca2+ through voltage-dependent channels opened by depolarization or during action potential (AP) or slow-wave discharge, and Ca2+ release from store sites in the cell by the action of IP3 or by Ca2+-induced Ca2+-release (CICR). The entry of Ca2+ during an AP triggers CICR from up to 20 or more subplasmalemmal store sites (seen as hot spots, using fluorescent indicators); Ca2+ waves then spread from these hot spots, which results in a rise in [Ca2+]i throughout the cell. Spontaneous transient releases of store Ca2+, previously detected as spontaneous transient outward currents (STOCs), are seen as sparks when fluorescent indicators are used. Sparks occur at certain preferred locations-frequent discharge sites (FDSs)-and these and hot spots may represent aggregations of sarcoplasmic reticulum scattered throughout the cytoplasm. Activation of receptors for excitatory signal molecules generally depolarizes the cell while it increases the production of IP3 (causing calcium store release) and diacylglycerols (which activate protein kinases). Activation of receptors for inhibitory signal molecules increases the activity of protein kinases through increases in cAMP or cGMP and often hyperpolarizes the cell. Other receptors link to tyrosine kinases, which trigger signal cascades interacting with trimeric G-protein systems.

Notes: Abstract Angina pectoris often results from ischemic episodes that excite chemosensitive and mechanoreceptive receptors in the heart. Ischemic episodes release a collage of chemicals, including adenosine and bradykinin, that excites the receptors of the sympathetic and vagal afferent pathways. Sympathetic afferent fibers from the heart enter the upper thoracic spinal cord and synapse on cells of origin of ascending pathways. This review focuses on the spinothalamic tract, but other pathways are excited as well. Excitation of spinothalamic tract cells in the upper thoracic and lower cervical segments, except C7 and C8 segments, contributes to the anginal pain experienced in the chest and arm. Cardiac vagal afferent fibers synapse in the nucleus tractus solitarius of the medulla and then descend to excite upper cervical spinothalamic tract cells. This innervation contributes to the anginal pain experienced in the neck and jaw. The spinothalamic tract projects to the medial and lateral thalamus and, based on positron emission tomography studies, activates several cortical areas, including the anterior cingulate gyrus (BA 24 and 25), the lateral basal frontal cortex, and the mesiofrontal cortex.

Notes: Abstract Secreted by the heart, more specifically by atrial cardiomyocytes under normal conditions but also by ventricular myocytes during cardiac hypertrophy, natriuretic peptides are now considered important hormones in the control of blood pressure and salt and water excretion. Studies on natriuretic peptide secretagogues and their mechanisms of action have been complicated by hemodynamic changes and contractions to which the atria are constantly subjected. It now appears that atrial stretch through mechano-sensitive ion channels, adrenergic stimulation via alpha1A-adrenergic receptors, and endothelin via its ETA receptor subtype are major triggering agents of natriuretic peptide release. With several other stimuli, such as angiotensin II and beta-adrenergic agents, modulation of natriuretic peptide release appears to be linked to local generation of prostaglandins. In all cases, intracellular calcium homeostasis, controlled by several ion channels, is considered a key element in the regulation of natriuretic peptide secretion.

Notes: Abstract This review surveys a wide range of cellular and molecular approaches to strengthening the injured or weakened heart, focusing on strategies to replace dysfunctional, necrotic, or apoptotic cardiomyocytes with new cells of mesodermal origin. A variety of cell types, including myogenic cell lines, adult skeletal myoblasts, immortalized atrial cells, embryonic and adult cardiomyocytes, embryonic stem cells, teratoma cells, genetically altered fibroblasts, smooth muscle cells, and bone marrow-derived cells have all been proposed as useful cells in cardiac repair and may have the capacity to perform cardiac work. We focus on the implantation of mesodermally derived cells, the best developed of the options. We review the developmental and cell biology that have stimulated these studies, examine the limitations of current knowledge, and identify challenges for the future, which we believe are considerable.

Notes: Abstract Subcellularly localized Ca2+ signals in cardiac and skeletal muscle have recently been identified as elementary Ca2+ signaling events. The signals, termed Ca2+ sparks and Ca2+ quarks, represent openings of Ca2+ release channels located in the membrane of the sarcoplasmic reticulum (SR). In cardiac muscle, the revolutionary discovery of Ca2+ sparks has allowed the development of a fundamentally different concept for the amplification of Ca2+ signals by Ca2+-induced Ca2+ release. In such a system, a graded amplification of the triggering Ca2+ signal entering the myocyte via L-type Ca2+ channels is accomplished by a recruitment process whereby individual SR Ca2+ release units are locally controlled by L-type Ca2+ channels. In skeletal muscle, the initial SR Ca2+ release is governed by voltage-sensors but subsequently activates additional Ca2+ sparks by Ca2+-induced Ca2+ release from the SR. Results from studies on elementary Ca2+ release events will improve our knowledge of muscle Ca2+ signaling at all levels of complexity, from the molecule to normal cellular function, and from the regulation of cardiac and skeletal muscle force to the pathophysiology of excitation-contraction coupling.

Notes: Abstract Krebs cycle intermediates such as succinate, citrate, and alpha-ketoglutarate are transferred across plasma membranes of cells by secondary active transporters that couple the downhill movement of sodium to the concentrative uptake of substrate. Several transporters have been identified in isolated membrane vesicles and cells based on their functional properties, suggesting the existence of at least three or more Na+/dicarboxylate cotransporter proteins in a given species. Recently, several cDNAs, called NaDC-1, coding for the low-affinity Na+/dicarboxylate cotransporters have been isolated from rabbit, human, and rat kidney. The Na+/dicarboxylate cotransporters are part of a distinct gene family that includes the renal and intestinal Na+/sulfate cotransporters. Other members of this family include a Na+- and Li+-dependent dicarboxylate transporter from Xenopus intestine and a putative Na+/dicarboxylate cotransporter from rat intestine. The current model of secondary structure in NaDC-1 contains 11 transmembrane domains and an extracellular N-glycosylated carboxy terminus.

Notes: Figure 1 Figure 1 A broad reflection on some of the major surprises to anthropological theory occasioned by the history, and in a number of instances the tenacity, of indigenous cultures in the twentieth century. We are not leaving the century with the same ideas that got us there. Contrary to the inherited notions of progressive development, whether of the political left or right, the surviving victims of imperial capitalism neither became all alike nor just like us. Contrary to the "despondency theory" of mid-century, the logical and historical precursor of dependency theory, surviving indigenous peoples aim to take cultural responsibility for what has been done to them. Across large parts of northern North America, even hunters and gatherers live, largely by hunting and gathering. The Eskimo are still there, and they are still Eskimo. Around the world the peoples give the lie to received theoretical oppositions between tradition and change, indigenous culture and modernity, townsmen and tribesmen, and other cliches of the received anthropological wisdom. Reports of the death of indigenous cultures-as of the demise of anthropology-have been exaggerated.

Notes: Abstract Ingested nutrients and nonnutrients are presented as determinants in human evolution. The amount and quality of energy, including fat, various foods supply are important criteria in governing selection. Oxidative stress associated with respiration of energy is a factor in the etiology of dietary diseases, such as cardiovascular disease and cancer, and in aging. Evolutionary trends such as gains in brain and body sizes, greater ingestion of long-chain polyunsaturated fatty acids and cholesterol, heating of fatty food, and greater longevity increased oxidative stress while greater reliance on animals foods and less on plants decreased ingestion of exogenous antioxidants. The hypothesis that selection for nonnutrient ingestive behaviors was a compensatory mechanism for increasing antioxidants is presented within the context of a four-factor model on the origins of human medicine.

Notes: Abstract The interaction of nutritional status with political structure in prehistoric New World societies is examined through bioarchaeological analysis. Overall, a general correlation is seen between political complexity and patterns of morbidity among various subsegments of the population. This relationship is strongest among egalitarian societies, in which few differences exist, and state-level societies, in which differences are readily apparent and appear to widen over time. At intermediate levels of political complexity, a less consistent picture emerges; various explanations are considered as to why the dietary differences predicted by the ethnohistorical and archaeological records are not reflected in the osteological record. Also addressed are patterns of differences in access to nutritional resources by gender at the various levels of political organization, as well as patterns of access between rural and urban centers. Future directions of study are suggested.

Notes: Abstract This article reviews some of the major archeological research and resulting current debates that center around the nature of the formation of Islamic society in the Maghreb and the Iberian Peninsula from the seventh century AD through the later Middle Ages. Over the last two decades, archeology has played an increasingly important role in working out the details of how this great cultural transformation occurred and has led to considerable revision of historical interpretations of the medieval period in the western Mediterranean region. On a more general anthropological level, research in both regions presents a remarkable potential to contribute to the literature on the archeology of ethnicity, and to research into the impact of changing religion and ideology on such diverse areas of human activity as household organization, gender relations, settlement location and spatial organization, and ceramic production and distribution.

Notes: Abstract War is a fraught subject. Those who study it often fight about it. This chapter examines the current state of the study of war, described and analyzed by anthropologists and nonanthropologists who employ concepts like culture in writing about the future of war. Warfare seems bound to keep us revisiting certain aspects of the past. At the same time, nothing induces change quite like conflict. Does war have a future? The preponderance of evidence-biological, archeological, ethnological-suggests that it does. But not all anthropologists agree. This in and of itself represents one of a series of gaps that begs further consideration.

Notes: Abstract To better understand both the shared and special features of human growth, this article explores the evolution of growth patterns of mammals in general and primates in particular. Special attention is paid to several competing hypotheses concerning the adaptive value of the juvenile stage to the life history of the social mammals. One hypothesis claims that all social mammals have a juvenile stage of life, but although most primate species are social, not all primates show a juvenile stage of life history. There is also controversy over whether the adolescent growth spurt is a uniquely human feature. On the basis of empirical observations and evolutionary considerations, I conclude that the human adolescent growth spurt in stature and skeletal maturation is species specific, not found in any other primate species. Finally, data and theory are used to advance a philosophy of human growth. An acceptable philosophy must acknowledge the mammalian and primate foundations for the human pattern of growth. But a robust philosophy of human growth must also account for the ecology to which the human species, indeed any species, is adapted. Accordingly, a philosophy of human growth must allow for the evolution of variations on common themes and of new stages of growth that may be unique to the human species.

Notes: Abstract The professionalization of archaeology in the late nineteenth century was linked to the growth of antiquities markets and the development of museums as institutions of education and social reproduction. Professional archaeologists moved into the universities in large numbers after World War II and then increasingly into the private sector after the mid-1970s. In the United States, archaeologists currently confront a highly segmented labor market with significant wage and benefits differentials, and increasing numbers face marginal employment. At the same time, descendant communities and government regulations are transforming the ways by which archaeologists have traditionally conducted their investigations.

Notes: Abstract This paper provides an overview of the main approaches to the discursive analysis of racist utterances. Moreover, we discuss the notions of racism and race historically and from the point of view of different cultures and languages. We restrict ourselves to the discourse analytical concepts and methodologies, which vary greatly, both in theory and in analysis. We present one example and analyze it in detail as an illustration of the linguistic tools that help make hidden and latent meanings transparent.

Notes: Abstract Humans' relationships with animals, increasingly the subject of controversy, have long been of interest to those whose primary aim has been the better understanding of humans' relationships with other humans. Since this topic was last reviewed here, human-animal relationships have undergone considerable reexamination, reflecting key trends in the history of social analysis, including concerns with connections between anthropology and colonialism and with the construction of race, class, and gender identities. There have been many attempts to integrate structuralist or symbolic approaches with those focused on environmental, political, and economic dimensions. Human-animal relationships are now much more likely to be considered in dynamic terms, and consequently, there has been much interdisciplinary exchange between anthropologists and historians. Some research directly engages moral and political concerns about animals, but it is likely that sociocultural research on human-animal relationships will continue to be as much, if not more, about humans.

Notes: Abstract Apocalypticism and millennialism are the dark and light sides of a historical sensibility transfixed by the possibility of imminent catastrophe, cosmic redemption, spiritual transformation, and a new world order. This essay briefly surveys work by anthropologists and like-minded scholars that focuses directly on endtime movements. It then reviews at more length a varied literature focusing on American apocalypticisms and millennialisms. Turning to contemporary America, we survey the ways in which an apocalyptic/millennial sensibility-as a mode of attention, mode of knowing, and voice-has come to inhabit and structure modern American life across a wide range of registers.

Notes: Abstract With the concept of environment as its organizing motif, this review focuses on two general fields of anthropological environmental research: ecological anthropology and the anthropology of environmentalism. Analysis of the complementary political and human ecology research programs is structured around four theoretical and methodological areas: transformations in the ecological paradigm, levels of analysis and articulation, the use of history, and the reemergence of space. Ethnographic analyses of the social forces of environmentalism point to civil society as an emerging and important protagonist with regard to environmental issues, and these social forces are reviewed within the categories of environmental movements, rights, territories, and discourses. A final prospective section looks at contemporary urban, viral, virtual, and warfare environments and postulates that the combination of empirical and political approaches can provide for anthropology an expanded role, one that has strong bioethical implications, in environmental debates and issues.