ALBERT

Notes: Abstract Protein kinase C homology-1 and -2, FYVE, and pleckstrin homology domains are ubiquitous in eukaryotic signal transduction and membrane-trafficking proteins. These domains regulate subcellular localization and protein function by binding to lipid ligands embedded in cell membranes. Structural and biochemical analysis of these domains has shown that their molecular mechanisms of membrane binding depend on a combination of specific and nonspecific interactions with membrane lipids. In vivo studies of green fluorescent protein fusions have highlighted the key roles of these domains in regulating protein localization to plasma and internal membranes in cells.

Notes: Abstract Although the force fields and interaction energies that control protein behavior can be inferred indirectly from equilibrium and kinetic measurements, recent developments have made it possible to quantify directly (a) the ranges, magnitudes, and time dependence of the interaction energies and forces between biological materials; (b) the mechanical properties of isolated proteins; and (c) the strength of single receptor-ligand bonds. This review describes recent results obtained by using the atomic force microscope, optical tweezers, the surface force apparatus, and micropipette aspiration to quantify short-range protein-ligand interactions and the long-range, nonspecific forces that together control protein behavior. The examples presented illustrate the power of force measurements to quantify directly the force fields and energies that control protein behavior.

Notes: Abstract Cys2His2 zinc fingers are one of the most common DNA-binding motifs found in eukaryotic transcription factors. These proteins typically contain several fingers that make tandem contacts along the DNA. Each finger has a conserved betabetaalpha structure, and amino acids on the surface of the alpha-helix contact bases in the major groove. This simple, modular structure of zinc finger proteins, and the wide variety of DNA sequences they can recognize, make them an attractive framework for attempts to design novel DNA-binding proteins. Several studies have selected fingers with new specificities, and there clearly are recurring patterns in the observed side chain-base interactions. However, the structural details of recognition are intricate enough that there are no general rules (a "recognition code") that would allow the design of an optimal protein for any desired target site. Construction of multifinger proteins is also complicated by interactions between neighboring fingers and the effect of the intervening linker. This review analyzes DNA recognition by Cys2His2 zinc fingers and summarizes progress in generating proteins with novel specificities from fingers selected by phage display.

Notes: Abstract The majority of soluble and membrane-bound proteins in modern cells are symmetrical oligomeric complexes with two or more subunits. The evolutionary selection of symmetrical oligomeric complexes is driven by functional, genetic, and physicochemical needs. Large proteins are selected for specific morphological functions, such as formation of rings, containers, and filaments, and for cooperative functions, such as allosteric regulation and multivalent binding. Large proteins are also more stable against denaturation and have a reduced surface area exposed to solvent when compared with many individual, smaller proteins. Large proteins are constructed as oligomers for reasons of error control in synthesis, coding efficiency, and regulation of assembly. Symmetrical oligomers are favored because of stability and finite control of assembly. Several functions limit symmetry, such as interaction with DNA or membranes, and directional motion. Symmetry is broken or modified in many forms: quasisymmetry, in which identical subunits adopt similar but different conformations; pleomorphism, in which identical subunits form different complexes; pseudosymmetry, in which different molecules form approximately symmetrical complexes; and symmetry mismatch, in which oligomers of different symmetries interact along their respective symmetry axes. Asymmetry is also observed at several levels. Nearly all complexes show local asymmetry at the level of side chain conformation. Several complexes have reciprocating mechanisms in which the complex is asymmetric, but, over time, all subunits cycle through the same set of conformations. Global asymmetry is only rarely observed. Evolution of oligomeric complexes may favor the formation of dimers over complexes with higher cyclic symmetry, through a mechanism of prepositioned pairs of interacting residues. However, examples have been found for all of the crystallographic point groups, demonstrating that functional need can drive the evolution of any symmetry.

Notes: Abstract A fundamental perspective can be achieved by targeting single cells for analysis with the goal of deconvoluting complex biological functions. However, single-cell studies have their own difficulties, such as minute volumes and sample amounts. Quantitative chemical analysis of single cells has emerged as a powerful new area in recent years due to several technological advancements. The development of microelectrodes has allowed the measurement of redox-active species as a function of cellular dynamics. This miniaturization trend is also evident in the separation sciences with the application of small column separations to single cells. Desorption ionization methods with mass spectrometric detection have shown single-cell capability owing to numerous technological developments. Finally, fluorescence imaging has also progressed to the point where single-cell dynamics can be probed by native fluorescence utilizing either single or multiple photon excitation. The results of these studies are reviewed with an emphasis on the quantitation of single-cell dynamics.

Notes: Abstract Vancomycin is the archetype among naturally occurring compounds known as glycopeptide antibiotics. Because it is a vital therapeutic agent used worldwide for the treatment of infections with gram-positive bacteria, emerging bacterial resistance to vancomycin is a major public health threat. Recent investigations into the mechanisms of action of glycopeptide antibiotics are driven by a need to understand their detailed mechanism of action so that new agents can be developed to overcome resistance. These investigations have revealed that glycopeptide antibiotics exhibit a rich array of complex cooperative phenomena when they bind target ligands, making them valuable model systems for the study of molecular recognition.

Notes: Abstract Comparative modeling predicts the three-dimensional structure of a given protein sequence (target) based primarily on its alignment to one or more proteins of known structure (templates). The prediction process consists of fold assignment, target-template alignment, model building, and model evaluation. The number of protein sequences that can be modeled and the accuracy of the predictions are increasing steadily because of the growth in the number of known protein structures and because of the improvements in the modeling software. Further advances are necessary in recognizing weak sequence-structure similarities, aligning sequences with structures, modeling of rigid body shifts, distortions, loops and side chains, as well as detecting errors in a model. Despite these problems, it is currently possible to model with useful accuracy significant parts of approximately one third of all known protein sequences. The use of individual comparative models in biology is already rewarding and increasingly widespread. A major new challenge for comparative modeling is the integration of it with the torrents of data from genome sequencing projects as well as from functional and structural genomics. In particular, there is a need to develop an automated, rapid, robust, sensitive, and accurate comparative modeling pipeline applicable to whole genomes. Such large-scale modeling is likely to encourage new kinds of applications for the many resulting models, based on their large number and completeness at the level of the family, organism, or functional network.

Notes: Abstract In order to solve the immensely difficult protein-folding problem, it will be necessary to characterize the barriers that slow folding and the intermediate structures that promote it. Although protein-folding intermediates are not accessible to the usual structural studies, hydrogen exchange (HX) methods have been able to detect and characterize intermediates in both kinetic and equilibrium modes-as transient kinetic folding intermediates on a subsecond time scale, as labile equilibrium molten globule intermediates under destabilizing conditions, and as infinitesimally populated intermediates in the high free-energy folding landscape under native conditions. Available results consistently indicate that protein-folding landscapes are dominated by a small number of discrete, metastable, native-like partially unfolded forms (PUFs). The PUFs appear to be produced, one from another, by the unfolding and refolding of the protein's intrinsically cooperative secondary structural elements, which can spontaneously create stepwise unfolding and refolding pathways. Kinetic experiments identify three kinds of barrier processes: (a) an initial intrinsic search-nucleation-collapse process that prepares the chain for intermediate formation by pinning it into a condensed coarsely native-like topology; (b) smaller search-dependent barriers that put the secondary structural units into place; and (c) optional error-dependent misfold-reorganization barriers that can cause slow folding, intermediate accumulation, and folding heterogeneity. These conclusions provide a coherent explanation for the grossly disparate folding behavior of different globular proteins in terms of distinct folding pathways.

Notes: Abstract This review describes how kinetic experiments using techniques with dramatically improved time resolution have contributed to understanding mechanisms in protein folding. Optical triggering with nanosecond laser pulses has made it possible to study the fastest-folding proteins as well as fundamental processes in folding for the first time. These include formation of alpha-helices, beta-sheets, and contacts between residues distant in sequence, as well as overall collapse of the polypeptide chain. Improvements in the time resolution of mixing experiments and the use of dynamic nuclear magnetic resonance methods have also allowed kinetic studies of proteins that fold too fast (〉 103 s-1) to be observed by conventional methods. Simple statistical mechanical models have been extremely useful in interpreting the experimental results. One of the surprises is that models originally developed for explaining the fast kinetics of secondary structure formation in isolated peptides are also successful in calculating folding rates of single domain proteins from their native three-dimensional structure.

Notes: Abstract ClC-type chloride channels are ubiquitous throughout the biological world. Expressed in nearly every cell type, these proteins have a host of biological functions. With nine distinct homologues known in eukaryotes, the ClCs represent the only molecularly defined family of chloride channels. ClC channels exhibit features of molecular architecture and gating mechanisms unprecedented in other types of ion channels. They form two-pore homodimers, and their voltage-dependence arises not from charged residues in the protein, but rather via coupling of gating to the movement of chloride ions within the pore. Because the functional characteristics of only a few ClC channels have been studied in detail, we are still learning which properties are general to the whole family. New approaches, including structural analyses, will be crucial to an understanding of ClC architecture and function.

Notes: Abstract In the past decade, a general design for sequence-specific minor groove ligands has evolved, based on the natural products distamycin and netropsin. By utilizing a basic set of design rules for connecting pyrrole, imidazole, and hydroxypyrrole modules, new ligands can be prepared to target almost any sequence of interest with both high affinity and specificity. In this review we present the design rules with a brief history of how they evolved. The structural basis for sequence-specific recognition is explained, together with developments that allow linking of recognition modules that enable targeting of long DNA sequences. Examples of the affinity and specificity that can be achieved with a number of variations on the basic design are given. Recently these molecules have been used to compete with proteins both in vitro and in vivo, and a brief description of the experimental results are given.

Notes: Abstract Photosystem II uses visible light to drive the oxidation of water, resulting in bioactivated electrons and protons, with the production of molecular oxygen as a byproduct. This water-splitting reaction is carried out by a manganese cluster/tyrosine radical ensemble, the oxygen-evolving complex. Although conventional continuous-wave, perpendicular-polarization electron paramagnetic resonance (EPR) spectroscopy has significantly advanced our knowledge of the structure and function of the oxygen-evolving complex, significant additional information can be obtained with the application of additional EPR methodologies. Specifically, parallel-polarization EPR spectroscopy can be used to obtain highly resolved EPR spectra of integer spin Mn species, and pulsed EPR spectroscopy with electron spin echo-based sequences, such as electron spin echo envelope modulation and electron spin echo-electron nuclear double resonance, can be used to measure weak interactions obscured in continuous-wave spectroscopy by inhomogeneous broadening.

Notes: Abstract The ability to manipulate, stretch and twist biomolecules opens the way to an understanding of their structural transitions. We review some of the recently discovered stress-induced structural transitions in DNA as well as the application of single molecule manipulation techniques to DNA unzipping and to the study of protein folding/unfolding transitions.

Notes: Abstract The genomes of higher cells consist of double-helical DNA, a densely charged polyelectrolyte of immense length. The intrinsic physical properties of DNA, as well as the properties of its complexes with proteins and ions, are therefore of fundamental interest in understanding the functions of DNA as an informational macromolecule. Because individual DNA molecules often exceed 1 cm in length, it is clear that DNA bending, folding, and interaction with nuclear proteins are necessary for packaging genomes in small volumes and for integrating the nucleotide sequence information that guides genetic readout. This review first focuses on recent experiments exploring how the shape of the densely charged DNA polymer and asymmetries in its surrounding counterion distribution mutually influence one another. Attention is then turned to experiments seeking to discover the degree to which asymmetric phosphate neutralization can lead to DNA bending in protein-DNA complexes. It is argued that electrostatic effects play crucial roles in the intrinsic, sequence-dependent shape of DNA and in DNA shapes induced by protein binding.

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

Notes: Abstract We review how motile cells regulate actin filament assembly at their leading edge. Activation of cell surface receptors generates signals (including activated Rho family GTPases) that converge on integrating proteins of the WASp family (WASp, N-WASP, and Scar/WAVE). WASP family proteins stimulate Arp2/3 complex to nucleate actin filaments, which grow at a fixed 70o angle from the side of pre-existing actin filaments. These filaments push the membrane forward as they grow at their barbed ends. Arp2/3 complex is incorporated into the network, and new filaments are capped rapidly, so that activated Arp2/3 complex must be supplied continuously to keep the network growing. Hydrolysis of ATP bound to polymerized actin followed by phosphate dissociation marks older filaments for depolymerization by ADF/cofilins. Profilin catalyzes exchange of ADP for ATP, recycling actin back to a pool of unpolymerized monomers bound to profilin and thymosin-beta4 that is poised for rapid elongation of new barbed ends.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Notes: The effect of force on the thermodynamics and kinetics of reactions is described. The key parameters are the difference in end-to-end distance between reactant and product for thermodynamics, and the distance to the transition state for kinetics. I focus the review on experimental results on force unfolding of RNA. Methods to measure Gibbs free energies and kinetics for reversible and irreversible reactions are described. The use of the worm-like-chain model to calculate the effects of force on thermodynamics and kinetics is illustrated with simple models. The main purpose of the review is to describe the simple experiments that have been done so far, and to encourage more people to enter a field that is new and full of opportunities.

Notes: Abstract ROSAT observations indicate that approximately half of all nearby groups of galaxies contain spatially extended X-ray emission. The radial extent of the X-ray emission is typically 50-500 h-1100 kpc or approximately 10-50% of the virial radius of the group. Diffuse X-ray emission is generally restricted to groups that contain at least one early-type galaxy. X-ray spectroscopy suggests the emission mechanism is most likely a combination of thermal bremsstrahlung and line emission. This interpretation requires that the entire volume of groups be filled with a hot, low-density gas known as the intragroup medium. ROSAT and ASCA observations indicate that the temperature of the diffuse gas in groups ranges from approximately 0.3 keV to 2 keV. Higher temperature groups tend to follow the correlations found for rich clusters between X-ray luminosity, temperature, and velocity dispersion. However, groups with temperatures below approximately 1 keV appear to fall off the cluster LX-T relationship (and possibly the LX-sigma and sigma-T cluster relationships, although evidence for these latter departures is at the present time not very strong). Deviations from the cluster LX-T relationship are consistent with preheating of the intragroup medium by an early generation of stars and supernovae. There is now considerable evidence that most X-ray groups are real, physical systems and not chance superpositions or large-scale filaments viewed edge-on. Assuming the intragroup gas is in hydrostatic equilibrium, X-ray observations can be used to estimate the masses of individual systems. ROSAT observations indicate that the typical mass of an X-ray group is ~1013 h-1100 M out to the radius to which X-ray emission is currently detected. The observed baryonic masses of groups are a small fraction of the X-ray determined masses, which implies that groups are dominated by dark matter. On scales of the virial radius, the dominant baryonic component in groups is likely the intragroup medium.

Notes: Abstract The brown dwarfs occupy the gap between the least massive star and the most massive planet. They begin as dimly stellar in appearance and experience fusion (of at least deuterium) in their interiors. But they are never able to stabilize their luminosity or temperature and grow ever fainter and cooler with time. For that reason, they can be viewed as a constituent of baryonic "dark matter." Indeed, we currently have a hard time directly seeing an old brown dwarf beyond 100 pc. After 20 years of searching and false starts, the first confirmed brown dwarfs were announced in 1995. This was due to a combination of increased sensitivity, better search strategies, and new means of distinguishing substellar from stellar objects. Since then, a great deal of progress has been made on the observational front. We are now in a position to say a substantial amount about actual brown dwarfs. We have a rough idea of how many of them occur as solitary objects and how many are found in binary systems. We have obtained the first glimpse of atmospheres intermediate in temperature between stars and planets, in which dust formation is a crucial process. This has led to the proposal of the first new spectral classes in several decades and the need for new diagnostics for classification and setting the temperature scale. The first hints on the substellar mass function are in hand, although all current masses depend on models. It appears that numerically, brown dwarfs may well be almost as common as stars (though they appear not to contain a dynamically interesting amount of mass).

Notes: Abstract The discovery of counterparts in X-ray and optical to radio wavelengths has revolutionized the study of gamma-ray bursts, until recently the most enigmatic of astrophysical phenomena. We now know that gamma-ray bursts are the biggest explosions in nature, caused by the ejection of ultrarelativistic matter from a powerful energy source and its subsequent collision with its environment. We have just begun to uncover a connection between supernovae and gamma-ray bursts, and are finally constraining the properties of the ultimate source of gamma-ray burst energy. We review here the observations that have led to this breakthrough in the field; we describe the basic theory of the fireball model and discuss the theoretical understanding that has been gained from interpreting the new wealth of data on gamma-ray bursts.

Notes: Abstract Broad emission lines hold fundamental clues about the kinematics and structure of the central regions in AGN. In this article we review the most robust line profile properties and correlations emerging from the best data available. We identify fundamental differences between the profiles of radio-quiet and radio-loud sources as well as differences between the high- and low-ionization lines, especially in the radio-quiet majority of AGN. An Eigenvector 1 correlation space involving FWHM Hbeta, W(FeIIopt)/W(Hbeta), and the soft X-ray spectral index provides optimal discrimination between all principal AGN types (from narrow-line Seyfert 1 to radio galaxies). Both optical and radio continuum luminosities appear to be uncorrelated with the E1 parameters. We identify two populations of radio-quiet AGN: Population A sources (with FWHM(Hbeta) 4000 km s-1, generally strong FeII emission and a soft X-ray excess) show almost no parameter space overlap with radio-loud sources. Population B shows optical properties largely indistinguishable from radio-loud sources, including usually weak FeII emission, FWHM(Hbeta) 4000 km s-1 and lack of a soft X-ray excess. There is growing evidence that a fundamental parameter underlying Eigenvector 1 may be the luminosity-to-mass ratio of the active nucleus (L/M), with source orientation playing a concomitant role.

Notes: Abstract The first millisecond X-ray variability phenomena from accreting compact objects have recently been discovered with the Rossi X-ray Timing Explorer. Three new phenomena are observed from low-mass X-ray binaries containing low-magnetic-field neutron stars: millisecond pulsations, burst oscillations, and kilohertz quasi-periodic oscillations. Models for these new phenomena involve the neutron star spin and orbital motion close around the neutron star, and rely explicitly on our understanding of strong gravity and dense matter. I review the observations of these new neutron-star phenomena and some possibly related phenomena in black-hole candidates, and describe the attempts to use these observations to perform measurements of fundamental physical interest in these systems.

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

Notes: Abstract The search for evidence of extraterrestrial intelligence is placed in the broader astronomical context of the search for extrasolar planets and biomarkers of primitive life elsewhere in the universe. A decision tree of possible search strategies is presented as well as a brief history of the search for extraterrestrial intelligence (SETI) projects since 1960. The characteristics of 14 SETI projects currently operating on telescopes are discussed and compared using one of many possible figures of merit. Plans for SETI searches in the immediate and more distant future are outlined. Plans for success, the significance of null results, and some opinions on deliberate transmission of signals (as well as listening) are also included. SETI results to date are negative, but in reality, not much searching has yet been done.

Notes: Abstract Dusty circumstellar disks in orbit around main-sequence stars were discovered in 1983 by the infrared astronomical satellite. It was the first time material that was not another star had been seen in orbit around a main-sequence star other than our Sun. Since that time, analyses of data from the infrared astronomical satellite, the infrared space observatory, and ground-based telescopes have enabled astronomers to paint a picture of dusty disks around numerous main-sequence and post-main-sequence stars. This review describes, primarily in an evolutionary framework, the properties of some dusty disks orbiting, first, pre-main-sequence stars, then main-sequence and post-main-sequence stars, and ending with white dwarfs.

Notes: Abstract The cosmic infrared background records much of the radiant energy released by processes of structure formation that have occurred since the decoupling of matter and radiation following the Big Bang. In the past few years, data from the Cosmic Background Explorer (COBE) mission provided the first measurements of this background, with additional constraints coming from studies of the attenuation of TeV gamma-rays. At the same time, there has been rapid progress in resolving a significant fraction of this background with the deep galaxy counts at infrared wavelengths from the Infrared Space Observatory (ISO) instruments and at submillimeter wavelengths from the Submillimeter Common User Bolometer Array (SCUBA) instrument. This article reviews the measurements of the infrared background and sources contributing to it and discusses the implications for past and present cosmic processes.

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

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

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

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

Notes: 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.

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

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

Notes: 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.

Notes: 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.

Notes: Turbulence affects the structure and motions of nearly all temperature and density regimes in the interstellar gas. This two-part review summarizes the observations, theory, and simulations of interstellar turbulence and their implications for many fields of astrophysics. The first part begins with diagnostics for turbulence that have been applied to the cool interstellar medium and highlights their main results. The energy sources for interstellar turbulence are then summarized along with numerical estimates for their power input. Supernovae and superbubbles dominate the total power, but many other sources spanning a large range of scales, from swing-amplified gravitational instabilities to cosmic ray streaming, all contribute in some way. Turbulence theory is considered in detail, including the basic fluid equations, solenoidal and compressible modes, global inviscid quadratic invariants, scaling arguments for the power spectrum, phenomenological models for the scaling of higher-order structure functions, the direction and locality of energy transfer and cascade, velocity probability distributions, and turbulent pressure. We emphasize expected differences between incompressible and compressible turbulence. Theories of magnetic turbulence on scales smaller than the collision mean free path are included, as are theories of magnetohydrodynamic turbulence and their various proposals for power spectra. Numerical simulations of interstellar turbulence are reviewed. Models have reproduced the basic features of the observed scaling relations, predicted fast decay rates for supersonic MHD turbulence, and derived probability distribution functions for density. Thermal instabilities and thermal phases have a new interpretation in a supersonically turbulent medium. Large-scale models with various combinations of self-gravity, magnetic fields, supernovae, and star formation are beginning to resemble the observed interstellar medium in morphology and statistical properties. The role of self-gravity in turbulent gas evolution is clarified, leading to new paradigms for the formation of star clusters, the stellar mass function, the origin of stellar rotation and binary stars, and the effects of magnetic fields. The review ends with a reflection on the progress that has been made in our understanding of the interstellar medium and offers a list of outstanding problems.

Notes: Observation of cooling neutron stars can potentially provide information about the states of matter at supernuclear densities. We review physical properties important for cooling such as neutrino emission processes and superfluidity in the stellar interior, surface envelopes of light elements owing to accretion of matter, and strong surface magnetic fields. The neutrino processes include the modified Urca process and the direct Urca process for nucleons and exotic states of matter, such as a pion condensate, kaon condensate, or quark matter. The dependence of theoretical cooling curves on physical input and observations of thermal radiation from isolated neutron stars are described. The comparison of observation and theory leads to a unified interpretation in terms of three characteristic types of neutron stars: high-mass stars, which cool primarily by some version of the direct Urca process; low-mass stars, which cool via slower processes; and medium-mass stars, which have an intermediate behavior. The related problem of thermal states of transiently accreting neutron stars with deep crustal burning of accreted matter is discussed in connection with observations of soft X-ray transients. Observations imply that some stars cool more rapidly than can be explained on the basis of nonsuperfluid neutron star models cooling via the modified Urca process, whereas other star cool less rapidly. We describe possible theoretical models that are consistent with observations.

Notes: This chapter reviews the properties of faint IR-selected field galaxies and the extremely red color-selected populations in particular. These populations are a mix of passively evolving stellar systems and heavily obscured star-forming galaxies. The star-forming component appears to constitute 20-50% of the population depending on the magnitude and color cuts employed. The remaining objects are a mix of passively evolving ellipticals and early-type disk galaxies. The passively evolving red galaxies are strongly clustered in space and are likely the high-mass high-luminosity end of the elliptical galaxy progenitor population at redshifts between one and two. These galaxies have masses and space densities that appear to be in conflict with late-forming hierarchical galaxy-formation models. The red galaxies appear to be a population that is distinct from the moderately star-forming Lyman-Break galaxies but may be related to the starburst population at z 〉 2 seen in deep submillimeter surveys.

Notes: I was born in 1914 in Amsterdam. I grew up there, filling my teenage years with activities as an amateur astronomer. I later studied at Leiden University and volunteered at Leiden Observatory. From 1938 to 1945, I was assistant at the Kapteyn Institute in Groningen, including during the war years 1940-1945, returning to Leiden in October 1945. After prolonged stays at Yerkes Observatory in 1947-1948 and 1952, and participation in Leiden's astrometric Kenya expedition in 1949-1950, I became associate professor at Yerkes Observatory in the fall of 1953. In 1957, I returned to the Kapteyn Institute and soon became involved in the creation of ESO, of which I became scientific director in 1968 and director general from 1970 to 1974. In 1975, I joined Leiden Observatory again, staying until my retirement in 1981, and since then I have enjoyed the hospitality of the Kapteyn Institute. I was president of the IAU from 1976 to 1979. From 1982 to 1989, I was chairman of the Scientific Programs Selection Committee for the European Space Agency's satellite, Hipparcos. My principal research interests have been in galactic structure and star formation, with emphasis on stellar associations. In addition to my astronomical interests, I have researched and published on Dutch village history.

Notes: The Universe is in transition. At early times, galactic evolution was dominated by hierarchical clustering and merging, processes that are violent and rapid. In the far future, evolution will mostly be secular-the slow rearrangement of energy and mass that results from interactions involving collective phenomena such as bars, oval disks, spiral structure, and triaxial dark halos. Both processes are important now. This review discusses internal secular evolution, concentrating on one important consequence, the buildup of dense central components in disk galaxies that look like classical, merger-built bulges but that were made slowly out of disk gas. We call these pseudobulges. We begin with an "existence proof"-a review of how bars rearrange disk gas into outer rings, inner rings, and stuff dumped onto the center. The results of numerical simulations correspond closely to the morphology of barred galaxies. In the simulations, gas is transported to small radii, where it reaches high densities and plausibly feeds star formation. In the observations, many barred and oval galaxies have dense central concentrations of gas and star formation. Optical colors and spectra often imply young stellar populations. So the formation of pseudobulges is well supported by theory and observations. It is embedded in a broader evolution picture that accounts for much of the richness observed in galaxy structure. If secular processes built dense central components that masquerade as bulges, how can we distinguish them from merger-built bulges? Observations show that pseudobulges retain a memory of their disky origin. That is, they have one or more characteristics of disks: (a) flatter shapes than those of classical bulges, (b) correspondingly large ratios of ordered to random velocities, (c) small velocity dispersions sigma with respect to the Faber-Jackson correlation between sigma and bulge lumi nosity, (d) spiral structure or nuclear bars in the "bulge" part of the light profile, (e) nearly exponential brightness profiles, and ( f ) starbursts. All these structures occur preferentially in barred and oval galaxies, where secular evolution should be most rapid. So the cleanest examples of pseudobulges are recognizable. Are their formation timescales plausible? We use measurements of central gas densities and star-formation rates to show that pseudobulges of the observed densities form on timescales of a few billion years. Thus a large variety of observational and theoretical results lead to a new picture of galaxy evolution that complements hierarchical clustering and merging. Secular evolution consists of more than the aging of stellar populations. Every galaxy is dynamically evolving.

Notes: Abundance variations within globular clusters (GCs), and of GC stars with respect to field stars, are important diagnostics of a variety of physical phenomena, related to the evolution of individual stars, mass transfer in binary systems, and chemical evolution in high density environments. The broad astrophysical implications of GCs as building blocks of our knowledge of the Universe make a full understanding of their history and evolution basic in a variety of astrophysical fields. We review the current status of the research in this field, comparing the abundances in GCs with those obtained for field stars, discussing in depth the evidence for H-burning at high temperatures in GC stars, describing the process of self-enrichment in GCs with particular reference to the case of the most massive Galactic GC (omega Cen), and discussing various classes of cluster stars with abundance anomalies. Whereas the overall pattern might appear very complex at first sight, exciting new scenarios are opening where the interplay between GC dynamical and chemical properties are closely linked with each other.

Notes: Important physical processes on the Sun, and especially in sunspots, occur on spatial scales at or below the limiting resolution of current solar telescopes. Over the past decade, using a number of new techniques, high-resolution observations have begun to reveal the complex thermal and magnetic structure of a sunspot, along with associated flows and oscillations. During this time remarkable advances in computing power have allowed significant progress in our theoretical understanding of the dynamical processes, such as magnetoconvection, taking place within a sunspot. In this review we summarize the latest observational results and theoretical interpretations of the fine structure in sunspots. A number of projects underway to build new solar telescopes or upgrade existing ones, along with several promising new theoretical ideas, ensure that there will be significant advances in sunspot research over the coming decade.

Notes: Impulsive reconnection dynamics is characterized not only by fast growth but also by a sudden change in the time derivative of the growth rate. I review recent developments in the theory and simulation of forced impulsive reconnection based on the equations of resistive and Hall magnetohydrodynamics (MHD). Impulsive reconnection can be realized in resistive as well as Hall MHD by the imposition of suitable boundary conditions. However, compared with resistive MHD, Hall MHD reconnection is distinguished by qualitatively different magnetic field and electron and ion signatures in the reconnection layer. Furthermore, nonlinear reconnection rates in Hall MHD are weakly dependent on the Lundquist number. I discuss applications of the physics of impulsive reconnection to substorms in the Earth's magnetotail and solar flares.

Notes: Abstract Interest in novel forms of marine propulsion and maneuvering has sparked a number of studies on unsteadily operating propulsors. We review recent experimental and theoretical work identifying the principal mechanism for producing propulsive and transient forces in oscillating flexible bodies and fins in water, the formation and control of large-scale vortices. Connection with studies on live fish is made, explaining the observed outstanding fish agility.

Notes: Abstract This review pertains to the body of work dealing with internal recirculating flows generated by the motion of one or more of the containing walls. These flows are not only technologically important, they are of great scientific interest because they display almost all fluid mechanical phenomena in the simplest of geometrical settings. Thus corner eddies, longitudinal vortices, nonuniqueness, transition, and turbulence all occur naturally and can be studied in the same closed geometry. This facilitates the comparison of results from experiment, analysis, and computation over the whole range of Reynolds numbers. Considerable progress has been made in recent years in the understanding of three-dimensional flows and in the study of turbulence. The use of direct numerical simulation appears very promising.

Notes: Abstract The idealized interactions of shock waves with homogeneous and isotropic turbulence, homogeneous sheared turbulence, turbulent jets, shear layers, turbulent wake flows, and two-dimensional boundary layers have been reviewed. The interaction between a shock wave and turbulence is mutual. A shock wave exhibits substantial unsteadiness and deformation as a result of the interaction, whereas the characteristic velocity, timescales and length scales of turbulence change considerably. The outcomes of the interaction depend on the strength, orientation, location, and shape of the shock wave, as well as the flow geometry and boundary conditions. The state of turbulence and the compressibility of the incoming flow are two additional parameters that also affect the interaction.

Notes: Abstract Sonoluminescence, the transduction of sound into light, is a phenomenon that pushes fluid mechanics beyond its limit. An initial state with long wavelength and low Mach number, such as is realized for a gas bubble driven by an audible sound field, spontaneously focuses the energy density so as to generate supersonic motion and a different phase of matter, from which are then emitted picosecond flashes of broad-band UV light. Although the most rational picture of sonoluminescence involves the creation of a "cold" dense plasma by an imploding shock wave, neither the imploding shock nor the plasma has been directly observed. Attempts to attack sonoluminescence from the perspective of continuum mechanics have led to interesting issues related to bubble shape oscillations, shock shape instabilities, and shock propagation through nonideal media, and chemical hydrodynamics. The limits of energy focusing that can be achieved from collapsing bubbles in the far-off equilibrium motion of fluids have yet to be determined either experimentally or theoretically.

Notes: Abstract We review the dynamics of stably stratified flows in the regime in which the Froude number is considered small and the Rossby number is of order one or greater. In particular we emphasize the nonpropagating component of the flow field, as opposed to the internal wave component. Examples of such flows range from the later stages of decay of turbulent flows to mesoscale meteorological flows. Results from theoretical analyses, laboratory experiments, and numerical simulations are presented. The limiting form of the equations of motion appears to describe the laboratory experiments and numerical simulations rather well. There are similarities with the dynamics of two-dimensional flows, but three-dimensional effects are clearly important. A number of remaining open issues are discussed.

Notes: Abstract In the framework of the classical gas dynamics, no steady flow is induced in a gas without an external force, such as gravity, by the effect of a temperature field. In a rarefied gas, on the other hand, the temperature field of a gas (often in combination with a solid boundary) plays an important role in inducing a steady flow. In the present article, we introduce various kinds of flows induced by the temperature effect and discuss their physical mechanisms. These flows vanish in the continuum limit (the limit where the mean free path of the gas molecules tends to zero), but it has been found recently that they, strangely, affect the behavior of a gas in this limit. This interesting effect, called a ghost effect, is also discussed.

Notes: Abstract Fluid mechanics research related to fire is reviewed with a focus on canonical flows, multiphysics coupling aspects, and experimental and numerical techniques. Fire is a low-speed, chemically reacting flow in which buoyancy plays an important role. Fire research has focused on two canonical flows, the reacting boundary layer and the reacting free plume. There is rich, multilateral, bidirectional coupling among fluid mechanics and scalar transport, combustion, and radiation. There is only a limited experimental fluid mechanics database for fire owing to measurement difficulties in the harsh environment and to the focus within the fire community on thermal/chemical consequences. Increasingly, computational fluid dynamics techniques are being used to provide engineering guidance on thermal/chemical consequences and to study fire phenomenology.

Notes: Abstract Models are considered for rotating flows over sills, through straits, and along coasts where the variation in geometry in the flow direction is slow but otherwise unrestricted. In addition to the (rotation-modified) free surface waves of nonrotating open channel hydraulics, with their predominantly vertical signature, slow Rossby or vorticity waves are possible when the background potential vorticity varies. In all but the simplest cases the conservation of energy and momentum fluxes is no longer sufficient to determine the flow behavior. Various additional modeling assumptions are reviewed, and time-dependent finite-amplitude and weakly nonlinear theories that include long Rossby wave dynamics are summarized.

Notes: Abstract This review begins with the classical foundations of relative dispersion in Kolmogorov's similarity scaling. Analysis of the special cases of isotropic and homogeneous scalar fields is then used to establish most simply the connection with turbulent mixing. The importance of the two-particle acceleration covariance in relative dispersion is demonstrated from the kinematics of the motion of particle-pairs. A summary of the development of two-particle Lagrangian stochastic models is given, with emphasis on the assumptions and constraints involved, and on predictions of the scalar variance field for inhomogeneous sources. Two-point closures and kinematic simulation are also reviewed in the context of their prediction of the Richardson constant and other fundamental constants. In the absence of reliable field data, direct numerical simulations and laboratory measurements seem most likely to provide suitable data with which to test the assumptions and predictions of these theories.

Notes: Abstract The current understanding of the average flow properties of packed beds and particle suspensions, in which inertia plays a significant role on the particle length scale, is examined. The features of inertial suspensions posing challenges to theoriticians include the nonlinear and unsteady nature of the governing equations, the inability to superimpose solutions, the prevalence of hydrodynamic instabilities, and the existence of particle-particle collisions. We discuss two special cases of inertial suspensions, for which detailed kinetic theories have been developed: (a) particles in a gas, and (b) spherical, high-Reynolds number bubbles in liquid. Subsequently, we review recent applications of computational fluid dynamics to simulate the motion in particle suspensions with both inertia and vorticity in the continueous phase. The synthesis of these analytical and numerical techniques is a promising approach to address the many challenges of modelling inertial suspensions.

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

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

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

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

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

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

Notes: Abstract 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.

Notes: 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.

Notes: Coating is the process of applying thin liquid layers to a substrate, often a moving web. Complex coating processes can be approached through examination of their fluid mechanical components. The flow elements reviewed in this article include the boundary layer along a moving wall, the dynamic wetting line, withdrawal from a pool, flow metered by a narrow channel, die flow, flow on an incline, the freely falling liquid curtain, premetered coating with a small gap, and flow after coating. Although some flow elements are well studied and understood, others require additional investigation. Genuinely predictive modeling of complex coating processes is not yet possible and coating practice remains largely empirical. Nonetheless, coating science is sufficiently advanced that physical insights and mathematical models greatly benefit design and practice.

Notes: Since Leibovich's comprehensive review of Langmuir circulation in 1983 there have been substantial advances in modeling (notably the construction of Large Eddy Simulation models) and in observations using novel techniques that together have led to a radical change in understanding the phenomena. It is now regarded as one of the several turbulent processes driven by wind and waves in the upper layers of large bodies of water, influential in producing and maintaining the uniform surface mixed layer and in driving dispersion.

Notes: Early concepts in shock wave drag reduction enabled modern aeronautical systems, and continuing research progress in this arena is crucial for significant improvements in long haul transports and various military platforms and weapons. The research area is rich in concepts/approaches, but many of these have not progressed into the realm of application. This is due in part to a lack of knowledge on the part of the fluids research community concerning the multidisciplinary "real-world" design space/metrics and a consequent lack of the requisite breadth and depth of research information required to evaluate/apply the concept. The article reviews the extant wave drag reduction approaches that are (a) well understood/applied, (b) under active study/indicate considerable promise, and (c) those in the nascent stage only.

Notes: Almost all vessels carrying fluids within the body are flexible, and interactions between an internal flow and wall deformation often underlie a vessel's biological function or dysfunction. Such interactions can involve a rich range of fluid-mechanical phenomena, including nonlinear pressure-drop/flow-rate relations, self-excited oscillations of single-phase flow at high Reynolds number and capillary-elastic instabilities of two-phase flow at low Reynolds number. We review recent advances in understanding the fundamental mechanics of flexible-tube flows, and discuss physiological applications spanning the cardiovascular system (involving wave propagation and flow-induced instabilities of blood vessels), the respiratory system (involving phonation, the closure and reopening of liquid-lined airways, and Marangoni flows on flexible surfaces), and elsewhere in the body (involving active peristaltic transport driven by fluid-structure/muscle interactions).

Notes: We review the use of ray models for internal waves, particularly formulations for calculating wave amplitudes along the ray. These are expressed in spatial, wave number, and phase-space coordinates. The choice of formulation affects not only the difficulty of the calculations for rays and caustics but also the degree to which the waves satisfy slowly varying assumptions. We describe several examples taken from atmospheric and oceanic applications that illustrate the variety of options for ray models.

Notes: The characterization of blood flow is important for understanding the function of the cardiovascular system under normal and diseased conditions, designing cardiovascular devices, and diagnosing and treating congenital and acquired cardiovascular disease. Experimental methods, especially magnetic resonance imaging techniques can be used to noninvasively quantify blood flow for diagnosing cardiovascular disease, researching disease mechanisms, and validating assumptions and predictions of mathematical models. Computational methods can be used to simulate blood flow and vessel dynamics, test hypotheses of disease formation under controlled conditions, and evaluate devices that have not yet been built and treatments that have not yet been implemented. In this article we review experimental and computational methods for quantifying blood flow velocity and pressure fields in human arteries. We place particular emphasis on providing an introduction to the physics and applications of magnetic resonance imaging, and surveying lumped parameter, one-dimensional, and three-dimensional numerical methods used to model blood flow.

Notes: We review the experimental evidence on turbulent flows over rough walls. Two parameters are important: the roughness Reynolds number ks+ , which measures the effect of the roughness on the buffer layer, and the ratio of the boundary layer thickness to the roughness height, which determines whether a logarithmic layer survives. The behavior of transitionally rough surfaces with low ks+ depends a lot on their geometry. Riblets and other drag-reducing cases belong to this regime. In flows with delta/k 〈 50, the effect of the roughness extends across the boundary layer, and is also variable. There is little left of the original wall-flow dynamics in these flows, which can perhaps be better described as flows over obstacles. We also review the evidence for the phenomenon of d-roughness. The theoretical arguments are sound, but the experimental evidence is inconclusive. Finally, we discuss some ideas on how rough walls can be modeled without the detailed computation of the flow around the roughness elements themselves.

Notes: We review artificial boundary conditions (BCs) for simulation of inflow, outflow, and far-field (radiation) problems, with an emphasis on techniques suitable for compressible turbulent shear flows. BCs based on linearization near the boundary are usually appropriate for inflow and radiation problems. A variety of accurate techniques have been developed for this case, but some robustness and implementation issues remain. At an outflow boundary, the linearized BCs are usually not accurate enough. Various ad hoc models have been proposed for the nonlinear case, including absorbing layers and fringe methods. We discuss these techniques and suggest directions for future modeling efforts.

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

Notes: Abstract We review the physical properties of phosphatidylinositol 4,5-bisphosphate (PIP2) that determine both its specific interactions with protein domains of known structure and its nonspecific electrostatic sequestration by unstructured domains. Several investigators have postulated the existence of distinct pools of PIP2 within the cell to account for the myriad functions of this lipid. Recent experimental work indicates certain regions of the plasma membrane-membrane ruffles and nascent phagosomes-do indeed concentrate PIP2. We consider two mechanisms that could account for this phenomenon: local synthesis and electrostatic sequestration. We conclude by considering the hypothesis that proteins such as MARCKS bind a significant fraction of the PIP2 in a cell, helping to sequester it in lateral membrane domains, then release this lipid in response to local signals such as an increased concentration of Ca++/calmodulin or activation of protein kinase C.

Notes: Abstract The first crystal structures of intact T cell receptors (TCRs) bound to class I peptide-MHC (pMHCs) antigens were determined in 1996. Since then, further structures of class I TCR/pMHC complexes have explored the degree of structural variability in the TCR-pMHC system and the structural basis for positive and negative selection. The recent determination of class II and allogeneic class I TCR/pMHC structures, as well as those of accessory molecules (e.g., CD3), has pushed our knowledge of TCR/pMHC interactions into new realms, shedding light on clinical pathologies, such as graft rejection and graft-versus-host disease. Furthermore, the determination of coreceptor structures lays the foundation for a more comprehensive structural description of the supramolecular TCR signaling events and those assemblies that arise in the immunological synapse. While these telling photodocumentaries of the TCR/pMHC interaction are composed mainly from static crystal structures, a full description of the biological snapshots in T cell signaling requires additional analytical methods that record the dynamics of the process. To this end, surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), and ultracentrifugation (UC) have furnished both affinities and kinetics of the TCR/pMHC association. In the past year, structural, biochemical, and molecular biological data describing TCR/pMHC interactions have sublimely coalesced into a burgeoning well of understanding that promises to deliver further insights into T cell recognition. The coming years will, through a more intimate union of structural and kinetic data, allow many pressing questions to be addressed, such as how TCR/pMHC ligation is affected by coreceptor binding and what is the mechanism of TCR signaling in both early and late stages of T cell engagement with antigen-presenting cells.

Notes: Abstract The structures of an increasing number of channels and other alpha-helical membrane proteins have been determined recently, including the KcsA potassium channel, the MscL mechanosensitive channel, and the AQP1 and GlpF members of the aquaporin family. In this chapter, the orientation and packing characteristics of bilayer-spanning helices are surveyed in integral membrane proteins. In the case of channels, alpha-helices create the sealed barrier that separates the hydrocarbon region of the bilayer from the permeation pathway for solutes. The helices surrounding the permeation pathway tend to be rather steeply tilted relative to the membrane normal and are consistently arranged in a right-handed bundle. The helical framework further provides a supporting scaffold for nonmembrane-spanning structures associated with channel selectivity. Although structural details remain scarce, the conformational changes associated with gating transitions between closed and open states of channels are reviewed, emphasizing the potential roles of helix-helix interactions in this process.

Notes: Abstract Using luminescent lanthanides, instead of conventional fluorophores, as donor molecules in resonance energy transfer measurements offers many technical advantages and opens up a wide range of new applications. Advantages include farther measurable distances (~100 A) with greater accuracy, insensitivity to incomplete labeling, and the ability to use generic relatively large labels, when necessary. Applications highlighted include the study of ion channels in living cells, protein-protein interaction in cells, DNA-protein complexes, and high-throughput screening assays to measure peptide dimerization associated with DNA transcription factors and ligand-receptor interactions.

Notes: Abstract Cryo-electron microscopy (cryo-EM) of biological molecules in single-particle (i.e., unordered, nonaggregated) form is a new approach to the study of molecular assemblies, which are often too large and flexible to be amenable to X-ray crystallography. New insights into biological function on the molecular level are expected from cryo-EM applied to the study of such complexes "trapped" at different stages of their conformational changes and dynamical interactions. Important molecular machines involved in the fundamental processes of transcription, mRNA splicing, and translation are examples for successful applications of the new technique, combined with structural knowledge gained by conventional techniques of structure determination, such as X-ray crystallography and NMR.

Notes: 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.

Notes: 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.

Notes: 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.

Notes: 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.

Notes: 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.

Notes: 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.

Notes: 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.

Notes: Residual dipolar couplings (RDCs) have recently emerged as a new tool in nuclear magnetic resonance (NMR) with which to study macromolecular structure and function in a solution environment. RDCs are complementary to the more conventional use of NOEs to provide structural information. While NOEs are local-distance restraints, RDCs provide long-range orientational information. RDCs are now widely utilized in structure calculations. Increasingly, they are being used in novel applications to address complex issues in structural biology such as the accurate determination of the global structure of oligonucleotides and the relative orientation of protein domains. This review briefly describes the theory and methods for obtaining RDCs and then describes the range of biological applications where RDCs have been used.