ALBERT

Notes: Abstract Owing to the rapid development of in vivo applications for non-viral gene delivery vectors, it is necessary to have a better understanding of how the structure-activity relationships of these lipid-DNA complexes are affected by their environment. Indeed, research in gene therapy first focused on in vitro cell culture studies to determine the mechanisms involved in the delivery of DNA into the cell. New biophysical techniques such as electron microscopy and X-ray diffraction have been developed to discern the structure of the lipid-DNA complex. However, further studies have revealed discrepancies between optimal lipid-DNA formulations for in vitro transfection and for in vivo administration of these vectors. Furthermore, some immune stimulatory effects have been associated with in vivo lipid-DNA administration. This review summarizes the current state of knowledge on in vitro and in vivo lipid-DNA complex transfections. New prospects of vectors for in vivo gene transfer are also discussed.

Notes: Abstract Hundreds of acetyltransferases exist. All use a common acetyl donor-acetyl coenzyme A-and each exhibits remarkable specificity for acetyl acceptors, which include small molecules and proteins. Analysis of the primary sequences of these enzymes indicates that they can be sorted into several superfamilies. This review covers the three-dimensional structures of members of one of these superfamilies, now referred to in the literature as the GCN5-related N-acetyltransferases (GNAT), reflecting the importance of one functional category, the histone acetyltransferases. Despite the diversity of substrate specificities, members of the GNAT superfamily demonstrate remarkable similarity in protein topology and mode of acetyl coenzyme A binding, likely reflecting a conserved catalytic mechanism.

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 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 I have had a very fortunate career in astronomy, benefiting greatly from numerous accidents of fate. I grew up in Cincinnati, Ohio, served in the US Army Air Force in World War II, and had all my further education at the University of Chicago, from PhB in the College to PhD in astronomy and astrophysics. There, as a postdoc at Princeton University, and as a young faculty member at Caltech and Mount Wilson and Palomar Observatories, I had excellent teachers and mentors. I have done research primarily on gaseous nebulae and active galactic nuclei, but also made a few early contributions on stellar interiors and the heating in the outer layers of the Sun. The major part of my scientific career was at the University of Wisconsin and Lick Observatory, but I also had three productive years at the Institute for Advanced Study.

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 This review deals with the winds from "normal" hot stars such as O-stars, B- and A-supergiants, and Central Stars of Planetary Nebulae with O-type spectra. The advanced diagnostic methods of stellar winds, including an assessment of the accuracy of the determinations of global stellar wind parameters (terminal velocities, mass-loss rates, wind momenta, and energies), are introduced and scaling relations as a function of stellar parameters are provided. Observational results are interpreted in the framework of the stationary, one-dimensional (1-D) theory of line-driven winds. Systematic effects caused by nonhomogeneous structures, time dependence, and deviations from spherical symmetry are discussed. The review finishes with a brief description of the role of stellar winds as extragalactic distance indicators and as tracers of the chemical composition of galaxies at high redshift.

Notes: Abstract The active control of sound waves has become an extraordinarily large and vigorous area of academic research and technological development. In this paper we describe the physical principles underlying the control of sound and review their application in a wide range of contexts. One scenario involves the control of noise from a primary source by the introduction of secondary sources, and this technique is described for fields in ducts, in free space, in enclosures (with particular reference to aircraft cabins), and for turbomachinery. A second scenario involves the use of the active control of sound to eliminate large-scale oscillations in more complicated flows, in which part of an unstable feedback cycle is mediated via acoustic waves. Successful applications of this idea include the control of combustion instabilities and compressor surge.

Notes: Abstract This article reviews some aspects of the roles that laboratory experiments have played in the study of orographic effects in the Earth's atmosphere and oceans. The review focuses on, but is not restricted to, physical systems for which the effects of both background stratification and rotation are important. In the past, such laboratory studies have been largely decoupled from attempts to make quantitative comparisons with the results of numerical-model studies or observations from field programs. Rather, they have been used mostly in the important task of better understanding the physics of rotating and stratified flows. Furthermore, most laboratory experiments concerned with the effects of orography on either homogeneous or stratified rotating fluids have considered laminar flows, whereas their counterpart flows in the atmosphere and ocean are turbulent. We argue that laboratory investigations are likely to be more useful in addressing critical environmental problems if the studies are more closely allied with numerical-modeling efforts. The latter, in turn, should be tied to field projects, with the overall objective of improving our ability to predict the behavior of natural systems. In this same spirit, we conclude that far more attention should be given to the laboratory simulation of the turbulent characteristics of natural flows. The availability of rapidly developing technology to acquire and analyze laboratory data provides the capability necessary to support the increasingly important roles that laboratory experiments can play in understanding and predicting the behavior of our natural environment.

Notes: Abstract We concentrate on the rich effects that surface tension has on free and forced surface waves for linear, nonlinear, and especially strongly nonlinear waves close to or at breaking or their limiting form. These effects are discussed in the context of standing gravity and gravity-capillary waves, Faraday waves, and parasitic capillary waves. Focus is primarily on post-1989 research. Regarding standing waves, new waveforms and the large effect that small capillarity can have are considered. Faraday waves are discussed principally with regard to viscous effects, hysteresis, and limit cycles; nonlinear waveforms of low mode numbers; contact-line effects and surfactants; breaking and subharmonics; and drop ejection. Pattern formation and chaotic and nonlinear dynamics of Faraday waves are mentioned only briefly. Gravity and gravity-capillary wave generation of parasitic capillaries and dissipation are considered at length. We conclude with our view on the direction of future research in these areas.

Notes: Abstract Passive scalar behavior is important in turbulent mixing, combustion, and pollution and provides impetus for the study of turbulence itself. The conceptual framework of the subject, strongly influenced by the Kolmogorov cascade phenomenology, is undergoing a drastic reinterpretation as empirical evidence shows that local isotropy, both at the inertial and dissipation scales, is violated. New results of the complex morphology of the scalar field are reviewed, and they are related to the intermittency problem. Recent work on other aspects of passive scalar behavior-its spectrum, probability density function, flux, and variance-is also addressed.

Notes: Abstract A vapor explosion results from the rapid and intense heat transfer that may follow contact between a hot liquid and a cold, more volatile one. Because it can happen during severe-accident sequences of a nuclear power plan, that is, when a large part of the core is molten, vapor explosions have been widely studied. The different sequences of a vapor explosion are presented, including premixing, triggering, propagation, and expansion. Typical experimental results are also analyzed to understand the involved physics. Then the different physics involved in the sequences are addressed, as well as the present experimental program.

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 Electrokinetic forces are emerging as a powerful means to drive microfluidic systems with flow channel cross-sectional dimensions in the tens of micrometers and flow rates in the nanoliter per second range. These systems provide many advantages such as improved analysis speed, improved reproducibility, greatly reduced reagent consumption, and the ability to perform multiple operations in an integrated fashion. Planar microfabrication methods are used to make these analysis chips in materials such as glass or polymers. Many applications of this technology have been demonstrated, such as DNA separations, enzyme assays, immunoassays, and PCR amplification integrated with microfluidic assays. Further development of this technology is expected to yield higher levels of functionality of sample throughput on a single microfluidic analysis chip.

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 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 Small molecules that modulate the activity of biological signaling molecules can be powerful probes of signal transduction pathways. Highly specific molecules with high affinity are difficult to identify because of the conserved nature of many protein active sites. A newly developed approach to discovery of such small molecules that relies on protein engineering and chemical synthesis has yielded powerful tools for the study of a wide variety of proteins involved in signal transduction (G-proteins, protein kinases, 7-transmembrane receptors, nuclear hormone receptors, and others). Such chemical genetic tools combine the advantages of traditional genetics and the unparalleled temporal control over protein function afforded by small molecule inhibitors/activators that act at diffusion controlled rates with targets.

Notes: Abstract The common envelope phase of binary star evolution plays an essential role in the formation of short period systems containing a compact object. In this process, significant mass and angular momentum are lost, transforming a wide progenitor system into a close remnant binary. The pathways leading to this phase and the outcomes are described. Emphasis is placed on the conditions that are required for survival of the binary according to the results of three-dimensional hydrodynamics calculations. The evolution of high-mass systems containing neutron stars is discussed, including double neutron stars, binary pulsars, Thorne-Zytkow objects, and high- and low-mass X-ray binaries.

Notes: Abstract In this article we first review the main physical effects to be considered in the building of evolutionary models of rotating stars on the Upper Main-Sequence (MS). The internal rotation law evolves as a result of contraction and expansion, meridional circulation, diffusion processes, and mass loss. In turn, differential rotation and mixing exert a feedback on circulation and diffusion, so that a consistent treatment is necessary. We review recent results on the evolution of internal rotation and the surface rotational velocities for stars on the Upper MS, for red giants, supergiants, and W-R stars. A fast rotation enhances the mass loss by stellar winds and, conversely, high mass loss removes a lot of angular momentum. The problem of the breakup or Omega-limit is critically examined in connection with the origin of Be and LBV stars. The effects of rotation on the tracks in the HR diagram, the lifetimes, the isochrones, the blue-to-red supergiant ratios, the formation of Wolf-Rayet stars, and the chemical abundances in massive stars as well as in red giants and AGB stars are reviewed in relation to recent observations for stars in the Galaxy and Magellanic Clouds. The effects of rotation on the final stages and on the chemical yields are examined, along with the constraints placed by the periods of pulsars. On the whole, this review points out that stellar evolution is not only a function of mass M and metallicity Z, but of angular velocity Omega as well.

Notes: Abstract Our understanding of the evolution of organic molecules, and their voyage from molecular clouds to the early solar system and Earth, has changed dramatically. Incorporating recent observational results from the ground and space, as well as laboratory simulation experiments and new methods for theoretical modeling, this review recapitulates the inventory and distribution of organic molecules in different environments. The evolution, survival, transport, and transformation of organics is monitored, from molecular clouds and the diffuse interstellar medium to their incorporation into solar system material such as comets and meteorites. We constrain gas phase and grain surface formation pathways to organic molecules in dense interstellar clouds, using recent observations with the Infrared Space Observatory (ISO) and ground-based radiotelescopes. The main spectroscopic evidence for carbonaceous compounds in the diffuse interstellar medium is discussed (UV bump at 2200 A, diffuse interstellar bands, extended red emission, and infrared absorption and emission bands). We critically review the signatures and unsolved problemsrelated to the main organic components suggested to be present in the diffuse gas, such as polycyclic aromatic hydrocarbons (PAHs), fullerenes, diamonds, and carbonaceous solids. We also briefly discuss the circumstellar formation of organics around late-typestars. In the solar system, space missions to comet Halley and observations of the bright comets Hyakutake and Hale-Bopp have recently allowed a reexamination of the organic chemistry of dust and volatiles in long-period comets. We review the advances in this area and also discuss progress being made in elucidating the complex organic inventory of carbonaceous meteorites. The knowledge of organic chemistry in molecular clouds, comets, and meteorites and their common link provides constraints for the processes that lead to the origin, evolution, and distribution of life in the Galaxy.

Notes: Abstract More than a decade ago the IRAS satellite opened the realm of external galaxies for studies in the 10 to 100 mum band and discovered emission from tens of thousands of normal and active galaxies. With the 1995-1998 mission of the Infrared Space Observatory1, the next major steps in extragalactic infrared astronomy became possible: detailed imaging, spectroscopy, and spectrophotometry of many galaxies detected by IRAS, as well as deep surveys in the mid- and far-IR. The spectroscopic data reveal a wealth of detail about the nature of the energy source(s) and about the physical conditions in galaxies. ISO's surveys for the first time explore the infrared emission of distant, high-redshift galaxies. ISO's main theme in extragalactic astronomy is the role of star formation in the activity and evolution of galaxies.

Notes: Abstract The relationship between flow in the arteries, particularly the wall shear stresses, and the sites where atherosclerosis develops has motivated much of the research on arterial flow in recent decades. It is now well accepted that it is sites where shear stresses are low, or change rapidly in time or space, that are most vulnerable. These conditions are likely to prevail at places where the vessel is curved; bifurcates; has a junction, a side branch, or other sudden change in flow geometry; and when the flow is unsteady. These flows, often but not always involving flow separation or secondary motions, are also the most difficult ones in fluid mechanics to analyze or compute. In this article we review the modeling studies and experiments on steady and unsteady, two-and three-dimensional flows in arteries, and in arterial geometries most relevant in the context of atherosclerosis. These include studies of normal vessels-to identify, on the basis of the fluid mechanics, lesion foci-and stenotic vessels, to model and measure flow in vessels after the lesions have evolved into plaques sufficiently large to significantly modify the flow. We also discuss recent work that elucidates many of the pathways by which mechanical forces, primarily the wall shear stresses, are transduced to effect changes in the arterial wall at the cellular, subcellular, and genetic level.

Notes: Abstract New developments have occurred in recent years in the field of dynamo theory. The increase in computer capacity has permitted simulations of convection-driven dynamos in rotating spherical fluid shells in parameter ranges much closer to those of the Earth's core than has been possible before. The progress in handling flows of liquid sodium in large containers, on the other hand, has opened opportunities for realizations of homogeneous dynamos in the laboratory. These developments will lead to a deeper understanding of the origin of magnetic fields in planets and in stars.

Notes: Abstract The single-point statistics of turbulence in the 'roughness sub-layer' occupied by the plant canopy and the air layer just above it differ significantly from those in the surface layer. The mean velocity profile is inflected, second moments are strongly inhomogeneous with height, skewnesses are large, and second-moment budgets are far from local equilibrium. Velocity moments scale with single length and time scales throughout the layer rather than depending on height. Large coherent structures control turbulence dynamics. Sweeps rather than ejections dominate eddy fluxes and a typical large eddy consists of a pair of counter-rotating streamwise vortices, the downdraft between the vortex pair generating the sweep. Comparison with the statistics and instability modes of the plane mixing layer shows that the latter rather than the boundary layer is the appropriate model for canopy flow and that the dominant large eddies are the result of an inviscid instability of the inflected mean velocity profile. Aerodynamic drag on the foliage is the cause both of the unstable inflected velocity profile and of a 'spectral short cut' mechanism that removes energy from large eddies and diverts it to fine scales, where it is rapidly dissipated, bypassing the inertial eddy-cascade. Total dissipation rates are very large in the canopy as a result of the fine-scale shear layers that develop around the foliage.

Notes: Abstract Lava flows are gravity currents of partially molten rock that cool as they flow, in some cases melting the surface over which they flow but in all cases gradually solidifying until they come to rest. They present a wide range of flow regimes from turbulent channel flows at moderate Reynolds numbers to extremely viscous or plastic, creeping flows, and even brittle rheology may play a role once some solid has formed. The cooling is governed by the coupling of heat transport in the flowing lava with transfer from the lava surface into the surrounding atmosphere or water or into the underlying solid, and it leads to large changes in rheology. Instabilities, mostly resulting from cooling, lead to flow branching, surface folding, rifting, and fracturing, and they contribute to the distinctive styles and surface appearances of different classes of flows. Theoretical and laboratory models have complemented field studies in developing the current understanding of lava flows, motivated by the extensive roles they play in the development of planetary crusts and ore deposits and by the immediate hazards posed to people and property. However, much remains to be learned about the mechanics governing creeping, turbulent, and transitional flows in the presence of large rheology change on cooling and particularly about the advance of flow fronts, flow instabilities, and the development of flow morphology. I introduce the dynamical problems involved in the study of lava flows and review modeling approaches.

Notes: Abstract Predicting the motion of bubbles in dispersed flows is a key problem in fluid mechanics that has a bearing on a wide range of applications from oceanography to chemical engineering. In this review we synthesize the recent progress made in describing bubble motion in inhomogeneous flow. A trident approach consisting of experimental, analytical, and numerical work has given a clearer description of the hydrodynamic forces experienced by isolated bubbles moving either in inviscid flows or in slightly viscous laminar flows. A significant part of the paper is devoted to a discussion of drag, added-mass force, and shear-induced lift experienced by spheroidal bubbles moving in inertially dominated, time-dependent, rotational, nonuniform flows. The important influence of surfactants and shape distortion on bubble motion in a quiescent liquid is highlighted. Examples of bubble motion in inhomogeneous flows combining several of the effects mentioned above are discussed.

Notes: Abstract This review summarizes results for Rayleigh-Benard convection that have been obtained over the past decade or so. It concentrates on convection in compressed gases and gas mixtures with Prandtl numbers near one and smaller. In addition to the classical problem of a horizontal stationary fluid layer heated from below, it also briefly covers convection in such a layer with rotation about a vertical axis, with inclination, and with modulation of the vertical acceleration.

Notes: Abstract During the last decade, the understanding of fine features of the structure and evolution of stars has become possible as a result of enormous progress made in the acquisition of high-quality observational and experimental data, and of new developments and refinements in the theoretical description of stellar plasmas. The confrontation of high-quality observations with sophisticated stellar models has allowed many aspects of the theory to be validated, and several characteristics of stars relevant to Galactic evolution and cosmology to be inferred. This paper is a review of the results of recent studies undertaken in the context of the Hipparcos mission, taking benefit of the high-quality astrometric data it has provided. Successes are discussed, as well as the problems that have arisen and suggestions proposed to solve them. Future observational and theoretical developments expected and required in the field are also presented.

Notes: Abstract Because calibrated light curves of type Ia supernovae have become a major tool to determine the local expansion rate of the universe and also its geometrical structure, considerable attention has been given to models of these events over the past couple of years. There are good reasons to believe that perhaps most type Ia supernovae are the explosions of white dwarfs that have approached the Chandrasekhar mass, , and are disrupted by thermonuclear fusion of carbon and oxygen. However, the mechanism whereby such accreting carbon-oxygen white dwarfs explode continues to be uncertain. Recent progress in modeling type Ia supernovae as well as several of the still open questions are addressed in this review. Although the main emphasis is on studies of the explosion mechanism itself and on the related physical processes, including the physics of turbulent nuclear combustion in degenerate stars, we also discuss observational constraints.

Notes: Abstract Since the discovery of the first bona-fide brown dwarfs and extra-solar planets in 1995, the field of low-mass stars and substellar objects has progressed considerably, both from theoretical and observational viewpoints. Recent developments in the physics entering the modeling of these objects have led to significant improvements in the theory and to a better understanding of these objects' mechanical and thermal properties. This theory can now be confronted with observations directly in various observational diagrams (color-color, color-magnitude, mass-magnitude, mass-spectral type), a stringent and unavoidable constraint that became possible only recently with the generation of synthetic spectra. In this paper we present the current state-of-the-art general theory of low-mass stars and sub stellar objects, from one solar mass to one Jupiter mass, regarding primarily their interior structure and evolution. This review is a natural complement to the previous review by Allard et al (1997) on the atmosphere of low-mass stars and brown dwarfs. Special attention is devoted to the comparison of the theory with various available observations. The contribution of low-mass stellar and sub stellar objects to the Galactic mass budget is also analyzed.

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 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 An overview of the near and far-field breakup and atomization of a liquid jet by a high speed annular gas jet is presented. The various regimes of liquid jet breakup are discussed in the parameter space of the liquid Reynolds number, the aerodynamic Weber number, and the ratio of the momentum fluxes between the gas and the liquid streams. Recent measurements of the gas-liquid interfacial instabilities are reviewed and used to analyze the underlying physical mechanisms involved in the primary breakup of the liquid jet. This process is shown to consist of the periodic stripping of liquid sheets, or ligaments, which subsequently break up into smaller lumps or drops. Models to predict the liquid shedding frequency, as well as the global parameters of the spray such as the liquid core length and spray spreading angle are discussed and compared with the experiments. The role of the secondary liquid breakup on the far-field atomization of the liquid jet is also considered, and an attempt is made to apply the classical turbulent breakup concepts to explain qualitatively the measurement of the far-field droplet size distribution and its dependence on the liquid to gas mass and momentum flux ratios. Models for the droplet breakup frequency in the far-field region of the jet, and for the daughter-size probability density function, which account for the effect of the liquid loading on the local turbulent dissipation rate in the gas, are discussed in the context of the statistical description of the spray in the far field. The striking effect of the addition of swirl in the gas stream is also examined.

Notes: Abstract Recent developments in the study of buoyancy-driven convection, magnetoconvection, and convection-driven dynamos in rapidly rotating spherical systems, with application to the fluid parts of the metallic cores of the Earth and other planets and satellites, are reviewed. While the fluid motions driven by convection generate and sustain magnetic fields by magnetohydrodynamic dynamo processes, the pattern and strength of the convective motions that control dynamo action are critically influenced by the combined and inseparable effects of rotation, magnetic fields, and spherical geometry. Emphasis is placed on the key dynamic feature of rotating spherical magnetohydrodynamics-the interaction between the Coriolis and Lorentz forces and the resulting effect on convection and magnetohydrodynamic processes. It is shown that the small value of the Ekman number, a result of rapid rotation and small viscosity in the fluid parts of planetary cores, causes severe difficulties in modeling planetary dynamos. There exist huge disparities, as a direct consequence of a small Ekman number, in the spatial, temporal, and amplitude scales of a convection-driven dynamo. The use of hyperviscosity removes these difficulties, but at the same time it alters the key dynamics in a fundamental and undesirable way. A convection-driven dynamo solution in rotating spherical systems at a sufficiently small Ekman number that is dynamically relevant to planetary fluid cores is yet to be achieved and remains a great challenge.

Notes: Abstract We review the research on a wide variety of topics using data obtained with the 200-inch Hale telescope. Using state-of-the-art spectrographs, photometers, spectrometers and infrared detectors, the Palomar astronomers investigated the spectra of stars, interstellar matter, AGNs and quasars in great detail. Spectral resolutions ranged from 1000 A for broad-band photometry to 0.04 A using interferometric techniques.

Notes: Abstract Astronomical studies in the extreme ultraviolet (EUV) band of the spectrum were dismissed during the early years of space astronomy as impossible, primarily because of the mistaken view that radiation in this band would be absorbed by the interstellar medium. Observations in the 1980s from sounding rockets and limited duration orbital spacecraft began to show the potential of this field and led to the deployment of two spacecraft devoted to EUV astronomy: the UK Wide Field Camera and the Extreme Ultraviolet Explorer. The instrumentation in these missions, although quite limited in comparison with instrumentation in other fields of space astronomy, provided unique and far-reaching results. These included new information on solar system topics, stellar chromospheres and corona, white dwarf astrophysics, cataclysmic variables, the interstellar medium, galaxies, and clusters of galaxies. We summarize these findings herein.

Notes: Abstract This review emphasizes the mass loss processes that affect the fates of single stars with initial masses between one and nine solar masses. Just one epoch of mass loss has been clearly demonstrated to be important for these stars; that is the episode that ends their evolution up the asymptotic giant branch. Quite a clear picture of this evolutionary stage is emerging from current studies. Mass loss rates increase precipitously as stars evolve toward greater luminosity and radius and decreased effective temperature. As a result, empirical relationships between mass loss rates and stellar parameters are determined mostly by selection effects and tell us which stars are losing mass rather than how stars lose mass. After detailed theoretical models are found to match observational constraints, the models may be used to extrapolate to populations not available for study nearby, such as young stars with low metallicity. The fates of stars are found to depend on both their initial masses and their initial metallicities; a larger proportion of low-metallicity stars should end up with core masses reaching the Chandrasekhar limit, giving rise to Type 1.5 supernovae, and the remnant white dwarfs of low-Z populations will be both fewer and more massive than those in Population I. There are also clear indications that some stars lose one to several tenths of a solar mass during the helium core flash, but neither models nor observations reveal any details of this process yet. The observational and theoretical bases for a variety of mass loss formulae in current use are also reviewed in this article, and the relations are compared in a series of figures.

Notes: Abstract The Hubble space telescope observations of the northern Hubble deep field, and more recently its counterpart in the south, provide detections and photometry for stars and field galaxies to the faintest levels currently achievable, reaching magnitudes V~ 30. Since 1995, the northern Hubble deep field has been the focus of deep surveys at nearly all wavelengths. These observations have revealed many properties of high redshift galaxies and have contributed to important data on the stellar mass function in the Galactic halo.

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 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 Granular materials segregate. Small differences in either size or density lead to flow-induced segregation, a complex phenomenon without parallel in fluids. Modeling of mixing and segregation processes requires the confluence of several tools, including continuum and discrete descriptions (particle dynamics, Monte Carlo simulations, cellular automata computations) and, often, considerable geometrical insight. None of these viewpoints, however, is wholly satisfactory by itself. Moreover, continuum and discrete descriptions of granular flows are regime dependent, and this fact may require adopting different subviewpoints. This review organizes a body of knowledge that forms-albeit imperfectly-the beginnings of an expandable continuum framework for the description of mixing and segregation of granular materials. We focus primarily on noncohesive particles, possibly differing in size, density, shape, etc. We present segregation mechanisms and models for size and density segregation and introduce chaotic advection, which appears in noncircular tumblers. Chaotic advection interacts in nontrivial ways with segregation in granular materials and leads to unique equilibrium structures that serve as a prototype for systems displaying organization in the midst of disorder.

Notes: Abstract Relationships between small and large scales of motion in turbulent flows are of much interest in large-eddy simulation of turbulence, in which small scales are not explicitly resolved and must be modeled. This paper reviews models that are based on scale-invariance properties of high-Reynolds-number turbulence in the inertial range. The review starts with the Smagorinsky model, but the focus is on dynamic and similarity subgrid models and on evaluating how well these models reproduce the true impact of the small scales on large-scale physics and how they perform in numerical simulations. Various criteria to evaluate the model performance are discussed, including the so-called a posteriori and a priori studies based on direct numerical simulation and experimental data. Issues are addressed mainly in the context of canonical, incompressible flows, but extensions to scalar-transport, compressible, and reacting flows are also mentioned. Other recent modeling approaches are briefly introduced.

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 This survey of the current status of research into Earth's orbitally forced paleoclimatic record summarizes recent developments in the theory of Earth's orbital parameters, and reviews how various techniques of data collection and analysis have fared in the search and recovery of orbital signals in ancient stratigraphy. The emerging significance of the quasi-periodicity of Earth's orbital variations as a principal tool in the analysis of orbitally forced stratigraphy is discussed in detail. Five case studies are presented that illustrate new directions in research: (a) time series analysis of discontinuous strata; (b) measurement of ultra-high resolution stratigraphic signals; (c) new perspectives on the 100 kyr Pleistocene glaciation problem; (d) stratigraphic evidence for solar system resonance modes; and (e) evaluating Phanerozoic length of day from orbitally forced stratigraphy.

Notes: Abstract Theories of scaling apply wherever similarity exists across many scales. This similarity may be found in geometry and in dynamical processes. Universality arises when the qualitative character of a system is sufficient to quantitatively predict its essential features, such as the exponents that characterize scaling laws. Within geomorphology, two areas where the concepts of scaling and universality have found application are the geometry of river networks and the statistical structure of topography. We begin this review with a pedagogical presentation of scaling and universality. We then describe recent progress made in applying these ideas to networks and topography. This overview leads to a synthesis that attempts a classification of surface and network properties based on generic mechanisms and geometric constraints. We also briefly review how scaling and universality have been applied to related problems in sedimentology-specifically, the origin of stromatolites and the relation of the statistical properties of submarine-canyon topography to the size distribution of turbidite deposits. Throughout the review, our intention is to elucidate not only the problems that can be solved using these concepts, but also those that cannot.

Notes: Abstract This chapter reviews the experimental properties of shears bands. The most puzzling characteristic of these structures is the emergence of rotational-like behavior while the nucleus retains a small quadrupole deformation. Regardless of the details of particular theoretical models, it can be shown that the most important degree of freedom in describing the shears mechanism is the shears angle. It is then possible to develop a semiclassical description of the shears mechanism, in which the nature (multipole order) of the interaction between valence protons and neutrons constituting the shears "blades" may be derived and the dynamics of the system described. We discuss the competition between the shears mechanism and collective rotation and mention the connection to "magnetic rotation." Directions for future theoretical and experimental efforts are suggested.

Notes: Abstract Properties of charged particles confined in ion traps can be determined to high accuracy. The ability to capture stable and unstable isotopes in such traps with high efficiency has led to a series of measurements of gross properties of nuclei. These recent high-accuracy measurements, along with the enabling technological developments and propects for the field, are presented.

Notes: Abstract The standard model of electroweak interactions has had great success in describing the observed data over the past three decades. The precision of experimental measurements affords tests of the standard model at the quantum loop level beyond leading order. Despite this success, it is important to continue confronting experimental measurements with the standard model's predictions because any deviation would signal new physics. As a fundamental parameter of the standard model, the mass of the W boson, MW, is of particular importance. Aside from being an important test of the model itself, a precision measurement of MW can be used to constrain the mass of the Higgs boson, MH. In this article, we review the principal experimental techniques for determining MW and discuss their combination into a single precision MW measurement. We conclude by briefly discussing future prospects for precision measurements of the W boson mass.

Notes: Abstract Random matrix theory is a powerful way to describe universal correlations of eigenvalues of complex systems. It also may serve as a schematic model for disorder in quantum systems. In this review, we discuss both types of applications of chiral random matrix theory to the QCD partition function. We show that constraints imposed by chiral symmetry and its spontaneous breaking determine the structure of low-energy effective partition functions for the Dirac spectrum. We thus derive exact results for the low-lying eigenvalues of the QCD Dirac operator. We argue that the statistical properties of these eigenvalues are universal and can be described by a random matrix theory with the global symmetries of the QCD partition function. The total number of such eigenvalues increases with the square root of the Euclidean four-volume. The spectral density for larger eigenvalues (but still well below a typical hadronic mass scale) also follows from the same low-energy effective partition function. The validity of the random matrix approach has been confirmed by many lattice QCD simulations in a wide parameter range. Stimulated by the success of the chiral random matrix theory in the description of universal properties of the Dirac eigenvalues, the random matrix model is extended to nonzero temperature and chemical potential. In this way we obtain qualitative results for the QCD phase diagram and the spectrum of the QCD Dirac operator. We discuss the nature of the quenched approximation and analyze quenched Dirac spectra at nonzero baryon density in terms of an effective partition function. Relations with other fields are also discussed.

Notes: Abstract The faithful segregation of genetic information requires highly orchestrated changes of chromosome structure during the mitotic cell cycle. The linkage between duplicated sister DNAs is established during S phase and maintained throughout G2 phase (cohesion). In early mitosis, dramatic structural changes occur to produce metaphase chromosomes, each consisting of a pair of compacted sister chromatids (condensation). At anaphase onset, a signal is produced to disrupt the linkage between sister chromatids (separation), allowing them to be pulled apart to opposite poles of the cell. This review discusses our current understanding of the three stages of large-scale structural changes of chromosomes in eukaryotic cells. Recent genetic and biochemical studies have identified key components involved in these processes and started to uncover hitherto unexpected functional links between mitotic chromosome dynamics and other important chromosome functions.

Notes: Abstract An unconventional mechanism for retaining improperly folded glycoproteins and facilitating acquisition of their native tertiary and quaternary structures operates in the endoplasmic reticulum. Recognition of folding glycoproteins by two resident lectins, membrane-bound calnexin and its soluble homolog, calreticulin, is mediated by protein-linked monoglucosylated oligosaccharides. These oligosaccharides contain glucose (Glc), mannose (Man), and N-acetylglucosamine (GlcNAc) in the general form Glc1Man7-9GlcNAc2. They are formed by glucosidase I- and II-catalyzed partial deglucosylation of the oligosaccharide transferred from dolichol diphosphate derivatives to Asn residues in nascent polypeptide chains (Glc3Man9GlcNAc2). Further deglucosylation of the oligosaccharides by glucosidase II liberates glycoproteins from their calnexin/calreticulin anchors. Monoglucosylated glycans are then recreated by the UDP-Glc:glycoprotein glucosyltransferase (GT), and thus recognized again by the lectins, only when linked to improperly folded protein moieties, as GT behaves as a sensor of glycoprotein conformations. The deglucosylation-reglucosylation cycle continues until proper folding is achieved. The lectin-monoglucosylated oligosaccharide interaction is one of the alternative ways by which cells retain improperly folded glycoproteins in the endoplasmic reticulum. Although it decreases the folding rate, it increases folding efficiency, prevents premature glycoprotein oligomerization and degradation, and suppresses formation of nonnative disulfide bonds by hindering aggregation and thus allowing interaction of protein moieties of folding glycoproteins with classical chaperones and other proteins that assist in folding.

Notes: Abstract Non-avian dinosaur reproductive and parenting behaviors were mostly similar to those of extant archosaurs. Non-avian dinosaurs were probably sexually dimorphic and some may have engaged in hierarchical rituals. Non-avian coelurosaurs (e.g. Troodontidae, Oviraptorosauria) had two active oviducts, each of which produced single eggs on a daily or greater time scale. The eggs of non-coelurosaurian dinosaurs (e.g. Ornithischia, Sauropoda) were incubated in soils, whereas the eggs of non-avian coelurosaurs (e.g. Troodon, Oviraptor) were incubated with a combination of soil and direct parental contact. Parental attention to the young was variable, ranging from protection from predators to possible parental feeding of nest-bound hatchlings. Semi-altricial hadrosaur hatchlings exited their respective nests near the time of their first linear doubling. Some reproductive behaviors, once thought exclusive to Aves, arose first in non-avian dinosaurs. The success of the Dinosauria may be related to reproductive strategies.

Notes: Abstract Synthetic aperture radar interferometry (InSAR) from Earth-orbiting spacecraft provides a new tool to map global topography and deformation of the Earth's surface. Radar images taken from slightly different viewing directions allow the construction of digital elevation models of meter-scale accuracy. These data sets aid in the analysis and interpretation of tectonic and volcanic landscapes. If the Earth's surface deformed between two radar image acquisitions, a map of the surface displacement with tens-of-meters resolution and subcentimeter accuracy can be constructed. This review gives a basic overview of InSAR for Earth scientists and presents a selection of geologic applications that demonstrate the unique capabilities of InSAR for mapping the topography and deformation of the Earth.

Notes: Abstract Vredefort, Sudbury, and Chicxulub are the largest known terrestrial impact structures. All have been cited as multi-ring basins. The available data indicate that all have some form of multiple-ring attributes, most commonly structural features. Chicxulub, however, is the only example with morphological ring features. There are also commonalities in the structural and lithological features of Vredefort and Sudbury, and it is possible to construct a generalized compilation of the character of 200-300 km diameter impact basins on Earth. It is not clear, however, that any of these structures had the original morphological characteristics of large lunar multi-ring basins. Additional data and synthesis are required to fully characterize these structures in order to realize their potential to constrain large-scale cratering processes. If this is not sufficient incentive for further studies (the environmental effects of Chicxulub aside), the Vredefort, Sudbury, and Chicxulub impact events are also the reason for the existence of world-class mineral and hydrocarbon deposits.

Notes: Abstract The mantle plume hypothesis was proposed thirty years ago by Jason Morgan to explain hotspot volcanoes such as Hawaii. A thermal diapir (or plume) rises from the thermal boundary layer at the base of the mantle and produces a chain of volcanoes as a plate moves on top of it. The idea is very attractive, but direct evidence for actual plumes is weak, and many questions remain unanswered. With the great improvement of seismic imagery in the past ten years, new prospects have arisen. Mantle plumes are expected to be rather narrow, and their detection by seismic techniques requires specific developments as well as dedicated field experiments. Regional travel-time tomography has provided good evidence for plumes in the upper mantle beneath a few hotspots (Yellowstone, Massif Central, Iceland). Beneath Hawaii and Iceland, the plume can be detected in the transition zone because it deflects the seismic discontinuities at 410 and 660 km depths. In the lower mantle, plumes are very difficult to detect, so specific methods have been worked out for this purpose. There are hints of a plume beneath the weak Bowie hotspot, as well as intriguing observations for Hawaii. Beneath Iceland, high-resolution tomography has just revealed a wide and meandering plume-like structure extending from the core-mantle boundary up to the surface. Among the many phenomena that seem to take place in the lowermost mantle (or D"), there are also signs there of the presence of plumes. In this article I review the main results obtained so far from these studies and discuss their implications for plume dynamics. Seismic imaging of mantle plumes is still in its infancy but should soon become a turbulent teenager.

Notes: Abstract There has been considerable controversy concerning the role of chemical weathering in the regulation of the atmospheric partial pressure of carbon dioxide, and thus the strength of the greenhouse effect and global climate. Arguments center on the sensitivity of chemical weathering to climatic factors, especially temperature. Laboratory studies reveal a strong dependence of mineral dissolution on temperature, but the expression of this dependence in the field is often obscured by other environmental factors that co-vary with temperature. In the field, the clearest correlation is between chemical erosion rates and runoff, indicating an important dependence on the intensity of the hydrological cycle. Numerical models and interpretation of the geologic record reveal that chemical weathering has played a substantial role in both maintaining climatic stability over the eons as well as driving climatic swings in response to tectonic and paleogeographic factors.

Notes: Abstract Epizonal base and precious metal deposits makeup a range of familiar deposit styles including porphyry copper-gold, epithermal veins and stockworks, carbonate-replacement deposits, and polymetallic volcanic rock-hosted (VHMS) deposits. They occur along convergent plate margins and are invariably associated directly with active faults and volcanism. They are complex in form, variable in their characteristics at all scales, and highly localized in the earth's crust. More than a century of detailed research has provided an extensive base of observational data characterizing these deposits, from their regional setting to the fluid and isotope chemistry of mineral deposition. This has led to a broad understanding of the large-scale hydrothermal systems within which they form. Low salinity vapor, released by magma crystallization and dispersed into vigorously convecting groundwater systems, is recognized as a principal source of metals and the gases that control redox conditions within systems. The temperature and pressure of the ambient fluid anywhere within these systems is close to its vapor-liquid phase boundary, and mineral deposition is a consequence of short timescale perturbations generated by localized release of crustal stress. However, a review of occurrence data raises questions about ore formation that are not addressed by traditional genetic models. For example, what are the origins of banding in epithermal veins, and what controls the frequency of oscillatory lamination? What controls where the phenomenon of mineralization occurs, and why are some porphyry deposits, for example, so much larger than others? The distinctive, self-organized characteristics of epizonal deposits are shown to be the result of repetitive coupling of fracture dilation consequent on brittle failure, phase separation ("boiling"), and heat transfer between fluid and host rock. Process coupling substantially increases solute concentrations and triggers fast, far-from-equilibrium depositional processes. Since these coupled processes lead to localized transient changes in fluid characteristics, paragenetic, isotope, and fluid inclusion data relate to conditions at the site of deposition and only indirectly to the characteristics of the larger-scale hydrothermal system and its longer-term behavior. The metal concentrations (i.e. grade) of deposits and their internal variation is directly related to the geometry of the fracture array at the deposit scale, whereas finer-scale oscillatory fabrics in ores may be a result of molecular scale processes. Giant deposits are relatively rare and develop where efficient metal deposition is spatially focused by repetitive brittle failure in active fault arrays. Some brief case histories are provided for epithermal, replacement, and porphyry mineralization. These highlight how rock competency contrasts and feedback between processes, rather than any single component of a hydrothermal system, govern the size of individual deposits. In turn, the recognition of the probabilistic nature of mineralization provides a firmer foundation through which exploration investment and risk management decisions can be made.

Notes: Abstract The synoptic coverage offered by satellites provides unparalleled opportunities for monitoring active volcanoes, and opens new avenues of scientific inquiry. Thermal infrared radiation can be used to monitor levels of activity, which is useful for automated eruption detection and for studying the emplacement of lava flows. Satellite radars can observe volcanoes through clouds or at night, and provide high-resolution topographic data. In favorable conditions, radar inteferometery can be used to measure ground deformation associated with eruptive activity on a centimetric scale. Clouds from explosive eruptions present a pressing hazard to aviation; therefore, techniques are being developed to assess eruption cloud height and to discriminate between ash and meterological clouds. The multitude of sensors to be launched on future generations of space platforms promises to greatly enhance volcanological studies, but a satellite dedicated to volcanology is needed to meet requirements of aviation safety and volcano monitoring.

Notes: Abstract A review of the geologic history of the Himalayan-Tibetan orogen suggests that at least 1400 km of north-south shortening has been absorbed by the orogen since the onset of the Indo-Asian collision at about 70 Ma. Significant crustal shortening, which leads to eventual construction of the Cenozoic Tibetan plateau, began more or less synchronously in the Eocene (50-40 Ma) in the Tethyan Himalaya in the south, and in the Kunlun Shan and the Qilian Shan some 1000-1400 km in the north. The Paleozoic and Mesozoic tectonic histories in the Himalayan-Tibetan orogen exerted a strong control over the Cenozoic strain history and strain distribution. The presence of widespread Triassic flysch complex in the Songpan-Ganzi-Hoh Xil and the Qiangtang terranes can be spatially correlated with Cenozoic volcanism and thrusting in central Tibet. The marked difference in seismic properties of the crust and the upper mantle between southern and central Tibet is a manifestation of both Mesozoic and Cenozoic tectonics. The former, however, has played a decisive role in localizing Tertiary contractional deformation, which in turn leads to the release of free water into the upper mantle and the lower crust of central Tibet, causing partial melting in the mantle lithosphere and the crust.

Notes: Abstract Twenty years after the Viking Mission, Mars is again being scrutinized in the light of a flood of information from spacecraft missions to Mars, the Hubble Space Telescope, and the SNC meteorites. This review provides an overview of the current understanding of Mars, especially in light of the data being returned from the Mars Global Surveyor Mission. Mars does not now have a global magnetic field, but the presence of crustal anomalies indicates that a global field existed early in Martian history. The topography, geodetic figure, and gravitational field are known to high precision. The northern hemisphere is lower and has a thinner and stronger crust than the southern hemisphere. The global weather and the thermal structure of the atmosphere have been monitored for more than a year. Surface-atmosphere interaction has been investigated by observations of surface features, polar caps, atmospheric dust, and condensate clouds. The surface has been imaged at very high resolution and spectral measures have been obtained to quantify surface characteristics and geologic processes. Many questions remain unanswered, especially about the earliest period of Mars' history.

Notes: Abstract Substantial volumes of methane gas are trapped below the seafloor and in permafrost by an ice-like solid called clathrate hydrate. Global estimates of the methane in clathrate hydrate may exceed 1016 kg, which represents one of the largest sources of hydrocarbon on Earth. Speculations about large releases of methane from clathrate hydrate have raised serious but unresolved questions about its possible role in climate change. Progress in our understanding of clathrate hydrate has been made through integrated geophysical and geochemical surveys of known clathrate occurrences. Details from these surveys have motivated new investigations of the physical, chemical, and biological processes that contribute to growth and breakdown of clathrate hydrate in natural settings. In this article, I give an overview of recent advances and future challenges.

Notes: Abstract As volcanoes grow, they become ever heavier. Unlike mountains exhumed by erosion of rocks that generally were lithified at depth, volcanoes typically are built of poorly consolidated rocks that may be further weakened by hydrothermal alteration. The substrates upon which volcanoes rest, moreover, are often sediments lithified by no more than the weight of the volcanic overburden. It is not surprising, therefore, that volcanic deformation includes-and in the long term is often dominated by-spreading motions that translate subsidence near volcanic summits to outward horizontal displacements around the flanks and peripheries. We review examples of volcanic spreading and go on to derive approximate expressions for the time volcanoes require to deform by spreading on weak substrates. We also demonstrate that shear stresses that drive low-angle thrust faulting from beneath volcanic constructs have maxima at volcanic peripheries, just where such faults are seen to emerge. Finally, we establish a theoretical basis for experimentally derived scalings that delineate volcanoes that spread from those that do not.

Notes: Abstract We review recent progress in our understanding of the physics of black holes. In particular, we discuss the ideas from string theory that explain the entropy of black holes from a counting of microstates of the hole, and the related derivation of unitary Hawking radiation from such holes.

Notes: Abstract We review the current status of the field of rare kaon decays. The study of rare kaon decays has played a key role in the development of the standard model, and the field continues to have significant impact. The two areas of greatest import are the search for physics beyond the standard model and the determination of fundamental standard-model parameters. Due to the exquisite sensitivity of rare kaon decay experiments, searches for new physics can probe very high mass scales. Studies of the Kpinu modes in particular, where the first event has recently been seen, will permit tests of the standard-model picture of quark mixing and CP violation.

Notes: Abstract The neutral B mesons, B0 and Bs0, can oscillate between their particle and antiparticle states owing to flavor-changing weak interactions. In recent years, techniques to detect these oscillations as a function of the meson's decay time have been developed. This article reviews the physics of flavor oscillations and summarizes theoretical predictions. The many observations that demonstrate the time dependence of oscillations are presented along with a combined measurement of its frequency, Deltamd = 0.484 +- 0.015 ps-1. The attempts to measure the Bs0 oscillation frequency, both directly and indirectly, are then summarized, currently resulting in a limit of Deltams〉 14.6 ps-1 (95% CL). Finally, values for the CKM elements |Vtd| = (3.6 +- 0.4) x 10-3 and |Vts/Vtd| 〉 4.7 (95% CL) are extracted.

Notes: Abstract Circadian rhythms are oscillations in the biochemical, physiological, and behavioral functions of organisms that occur with a periodicity of approximately 24 h. They are generated by a molecular clock that is synchronized with the solar day by environmental photic input. The cryptochromes are the mammalian circadian photoreceptors. They absorb light and transmit the electromagnetic signal to the molecular clock using a pterin and flavin adenine dinucleotide (FAD) as chromophore/cofactors, and are evolutionarily conserved and structurally related to the DNA repair enzyme photolyase. Humans and mice have two cryptochrome genes, CRY1 and CRY2, that are differentially expressed in the retina relative to the opsin-based visual photoreceptors. CRY1 is highly expressed with circadian periodicity in the mammalian circadian pacemaker, the suprachiasmatic nucleus (SCN). Mutant mice lacking either Cry1 or Cry2 have impaired light induction of the clock gene mPer1 and have abnormally short or long intrinsic periods, respectively. The double mutant has normal vision but is defective in mPer1 induction by light and lacks molecular and behavioral rhythmicity in constant darkness. Thus, cryptochromes are photoreceptors and central components of the molecular clock. Genetic evidence also shows that cryptochromes are circadian photoreceptors in Drosophila and Arabidopsis, raising the possibility that they may be universal circadian photoreceptors. Research on cryptochromes may provide new understanding of human diseases such as seasonal affective disorder and delayed sleep phase syndrome.

Notes: Abstract This review summarizes the progress made in our understanding of peroxisome biogenesis in the last few years, during which the functional roles of many of the 23 peroxins (proteins involved in peroxisomal protein import and peroxisome biogenesis) have become clearer. Previous reviews in the field have focussed on the metabolic functions of peroxisomes (1, 2), aspects of import/biogenesis (3, 4, 5, 6, 7), the role of peroxins in human disease (2, 8), and involvement of the endoplasmic reticulum in peroxisome membrane biogenesis (9, 10, 11) as well as the degradation of this organelle (5, 12). This review refers to some of the earlier work for the sake of introduction and continuity but deals primarily with the more recent progress. The principal areas of progress are the identification of new peroxins, definition of protein-protein interactions among peroxins leading to the recognition of complexes involved in peroxisomal protein import, insight into the biogenesis of peroxisomal membrane proteins, and, of most importance, the elucidation of the role of many conserved peroxins in human disease. Given the rapid progress in the field, this review also highlights some of the unanswered questions that remain to be tackled.

Notes: Abstract Helicases are motor proteins that couple the hydrolysis of nucleoside triphosphate (NTPase) to nucleic acid unwinding. The hexameric helicases have a characteristic ring-shaped structure, and all, except the eukaryotic minichromosomal maintenance (MCM) helicase, are homohexamers. Most of the 12 known hexameric helicases play a role in DNA replication, recombination, and transcription. A human genetic disorder, Bloom's syndrome, is associated with a defect in one member of the class of hexameric helicases. Significant progress has been made in understanding the biochemical properties, structures, and interactions of these helicases with DNA and nucleotides. Cooperativity in nucleotide binding was observed in many, and sequential NTPase catalysis has been observed in two proteins, gp4 of bacteriophage T7 and rho of Escherichia coli. The crystal structures of the oligomeric T7 gp4 helicase and the hexamer of RepA helicase show structural features that substantiate the observed cooperativity, and both are consistent with nucleotide binding at the subunit interface. Models are presented that show how sequential NTP hydrolysis can lead to unidirectional and processive translocation. Possible unwinding mechanisms based on the DNA exclusion model are proposed here, termed the wedge, torsional, and helix-destabilizing models.

Notes: Abstract The initiation of DNA replication in eukaryotic cells is tightly controlled to ensure that the genome is faithfully duplicated once each cell cycle. Genetic and biochemical studies in several model systems indicate that initiation is mediated by a common set of proteins, present in all eukaryotic species, and that the activities of these proteins are regulated during the cell cycle by specific protein kinases. Here we review the properties of the initiation proteins, their interactions with each other, and with origins of DNA replication. We also describe recent advances in understanding how the regulatory protein kinases control the progress of the initiation reaction. Finally, we describe the checkpoint mechanisms that function to preserve the integrity of the genome when the normal course of genome duplication is perturbed by factors that damage the DNA or inhibit DNA synthesis.

Notes: Abstract The cytochrome bc complexes represent a phylogenetically diverse group of complexes of electron-transferring membrane proteins, most familiarly represented by the mitochondrial and bacterial bc1 complexes and the chloroplast and cyanobacterial b6f complex. All these complexes couple electron transfer to proton translocation across a closed lipid bilayer membrane, conserving the free energy released by the oxidation-reduction process in the form of an electrochemical proton gradient across the membrane. Recent exciting developments include the application of site-directed mutagenesis to define the role of conserved residues, and the emergence over the past five years of X-ray structures for several mitochondrial complexes, and for two important domains of the b6f complex.

Notes: Abstract The surface-sensitive optical technique of surface plasmon resonance (SPR) imaging is used to characterize ultrathin organic and biopolymer films at metal interfaces in a spatially resolved manner. Because of its high surface sensitivity and its ability to measure in real time the interaction of unlabeled biological molecules with arrays of surface-bound species, SPR imaging has the potential to become a powerful tool in biomolecular investigations. Recently, SPR imaging has been successfully implemented in the characterization of supported lipid bilayer films, the monitoring of antibody-antigen interactions at surfaces, and the study of DNA hybridization adsorption. The following is included in this review: (a) an introduction to the principles of surface plasmon resonance, (b) the details of SPR imaging instrumental design, (c) a short discussion concerning resolution, sensitivity, and quantitation in SPR imaging, (d) the details of DNA array fabrication on chemically modified gold surfaces, and (e) two examples that demonstrate the application of the SPR imaging technique to the study of protein-DNA interactions.

Notes: Abstract This article provides a review of recent studies of the properties of unsolvated (and partially solvated) peptides and proteins. The methods used to produce vapor-phase peptide and protein ions are described along with some of the techniques used to study them, such as H/D exchange, blackbody infrared radiative dissociation, and ion mobility measurements. Studies of unsolvated peptides and proteins provide information about their intrinsic intramolecular interactions. The topics covered include the role of zwitterions and salt bridges in the vapor phase, Coulomb interactions in multiply charged ions, the unfolding and refolding of vapor-phase proteins, and the stability of unsolvated helices and sheets. Finally, dehydration and rehydration studies of proteins in the vapor phase are described. These can provide exquisitely detailed information about hydration interactions, such as the enthalpy and entropy changes associated with adsorbing individual water molecules.

Notes: Abstract Dynamic processes in crystalline solids are reflected in the atomic displacement amplitudes determined, together with the atomic coordinates, by crystal structure analysis. The interpretation of such amplitudes poses two severe problems: (a) The relative phases of the atomic displacements are lost; and (b) the amplitudes may reflect disorder in the structure and systematic error in the diffraction experiment in addition to motion, but the three contributions cannot be separated on the basis of measurements at a single temperature. Several approximate ways to solve these problems, e.g. rigid-body and segmented-rigid-body analysis, are reviewed together with their limitations. A more recent approach that represents a significant advance with respect to both difficulties is also described: Crystal structures are determined over a range of temperatures; the mean square amplitude quantities are interpreted by taking explicit account of their temperature dependence, i.e. by exploiting the difference in behavior of a microscopic oscillator in the low-temperature, quantum regime and in the high-temperature, classical regime. A distinction between low-frequency and high-frequency motion, disorder, and systematic error becomes possible with this model; this is illustrated with the help of case studies.

Notes: Abstract Ice particles found within polar stratospheric clouds (PSCs) and upper tropospheric cirrus clouds can dramatically impact the chemistry and climate of the Earth's atmosphere. The formation of PSCs and the subsequent chemical reactions that occur on their surfaces are key components of the massive ozone hole observed each spring over Antarctica. Cirrus clouds also provide surfaces for heterogeneous reactions and significantly modify the Earth's climate by changing the visible and infrared radiation fluxes. Although the role of ice particles in climate and chemistry is well recognized, the exact mechanisms of cloud formation are still unknown, and thus it is difficult to predict how anthropogenic activities will change cloud abundances in the future. This article focuses on the nucleation, chemistry, and microphysical properties of ice particles composing PSCs and cirrus clouds. A general overview of the current state of research is presented along with some unresolved issues facing scientists in the future.

Notes: Abstract This article considers early work from the author's laboratory on muscarinic receptor specificity, subtypes, and conformational variability, with the use of nuclear magnetic resonance in pharmacology and the conformational variants of dihydrofolate reductase and general questions of receptors. It also considers some current approaches to drug development and receptor function, particularly as influenced by increasing knowledge of three-dimensional structure of receptors.

Notes: Abstract The Laboratory of Chemical Pharmacology (LCP) began in 1950 as the Section of Pharmacology within the National Heart Institute, the National Institutes of Health. Its first chief was Bernard B. Brodie, considered by many to be one of the fathers of modern pharmacology. Since its inception, LCP has made many significant contributions to the fields of pharmacology and toxicology. LCP was among the first to study (a) the effects of drugs on the turnover of serotonin and norepineprine in brain and other tissues, (b) the absorption of drugs from the gastrointestinal tract and their passage across the blood-brain barrier, (c) the oxidation and reduction of drugs and other foreign compounds by liver microsomal enzymes (later known as the cytochrome P450 enzymes) and inhibitors and inducers of these enzymes, (d) the formation of toxic chemically reactive metabolites of drugs and other foreign compounds, and (e) mechanisms of immunological responses. Approximately 300 scientists worked in LCP during its existence, and they and their collaborators published more than 1,300 papers. This is a short history of the people who worked in it and of their contributions to biomedical sciences.

Notes: Abstract The chlorinated methanes, particularly carbon tetrachloride and chloroform, are classic models of liver injury and have developed into important experimental hepatoxicants over the past 50 years. Hepatocellular steatosis and necrosis are features of the acute lesion. Mitochondria and the endoplasmic reticulum as target sites are discussed. The sympathetic nervous system, hepatic hemodynamic alterations, and role of free radicals and biotransformation are considered. With carbon tetrachloride, lipid peroxidation and covalent binding to hepatic constituents have been dominant themes over the years. Potentiation of chlorinated methane-induced liver injury by alcohols, aliphatic ketones, ketogenic compounds, and the pesticide chlordecone is discussed. A search for explanations for the potentiation phenomenon has led to the discovery of the role of tissue repair in the overall outcome of liver injury. Some final thoughts about future research are also presented.

Notes: Abstract We propose a framework for considering the role of pharmacokinetic/ pharmacodynamic modeling in drug development and an appraisal of its current and potential impact on that activity. After some introduction, definitions, and background information on drug development, we discuss subject-matter models that underlie pharmacokinetic/pharmacodynamic modeling and show how they determine appropriate statistical models. We discuss the broad role modeling can play in drug development, enhancing primarily the "learning" steps, i.e. acquiring the information needed for the label and for planning efficient confirmatory clinical trials. Examples of past applications of modeling to drug development are presented in tabular form, followed by a discussion of some practical issues in application. Modeling will not reach its potential utility until it is manifest as a visible and separate work unit within a drug development program. We suggest that that work unit is the "in numero" study: a protocol-driven exercise designed to extract additional information, and/or answer a specific drug-development question, through an integrated model-based (meta-) analysis of existent raw data, often pooled across separate (clinical) studies.

Notes: Abstract Selection and validation of novel molecular targets have become of paramount importance in light of the plethora of new potential therapeutic drug targets that have emerged from human gene sequencing. In response to this revolution within the pharmaceutical industry, the development of high-throughput methods in both biology and chemistry has been necessitated. This review addresses these technological advances as well as several new areas that have been created by necessity to deal with this new paradigm, such as bioinformatics, cheminformatics, and functional genomics. With many of these key components of future drug discovery now in place, it is possible to map out a critical path for this process that will be used into the new millennium.

Notes: Abstract High-throughput gene sequencing has revolutionized the process used to identify novel molecular targets for drug discovery. Thousands of new gene sequences have been generated but only a limited number of these can be converted into validated targets likely to be involved in disease. We describe here some of the approaches used at SmithKline Beecham to select and validate novel targets. These include the identification of selective tissue gene product expression, such as for cathepsin K, a novel osteoclast-specific cysteine protease. We also describe the discovery and functional characterization of novel members of the G-protein coupled receptor superfamily and their pairing with natural ligands. Lastly, we discuss the promises of gene microarrays and proteomics, developing technologies that allow the parallel analyses of tissue expression patterns of thousands of genes or proteins, respectively.

Notes: Abstract Computer simulation of clinical trials has evolved over the past two decades from a simple instructive game to "full" simulation models yielding pharmacologically sound, realistic trial outcomes. The need to make drug development more efficient and informative and the awareness that many industries make extensive use of simulation in product development have advanced considerably the use of simulation of clinical trials in pharmaceutical product development over the past decade. The structural and stochastic components of trial simulation models are explained as a prelude to a listing of representative simulation projects, reflecting investigative applications of statistical methods, trial design comparisons, and full simulation of new drugs being developed. Lessons learned from these projects are reviewed in the context of their current impact and potential for influencing the future of drug development.

Notes: Abstract Technological advances continue to be a central driving force in the acceleration of the drug discovery process. Combinatorial chemistry methods, developed over the past 15 years, represent a paradigm shift in drug discovery. Initially viewed as a curiosity by the pharmaceutical industry, combinatorial chemistry is now recognized as an essential tool that decreases the time of discovery and increases the throughput of chemical screening by as much as 1000-fold. The use of parallel array synthesis approaches and mixture-based combinatorial libraries for drug discovery is reviewed.

Notes: Abstract Regulator of G protein signaling (RGS) proteins are responsible for the rapid turnoff of G protein-coupled receptor signaling pathways. The major mechanism whereby RGS proteins negatively regulate G proteins is via the GTPase activating protein activity of their RGS domain. Structural and mutational analyses have characterized the RGS/Galpha interaction in detail, explaining the molecular mechanisms of the GTPase activating protein activity of RGS proteins. More than 20 RGS proteins have been isolated, and there are indications that specific RGS proteins regulate specific G protein-coupled receptor pathways. This specificity is probably created by a combination of cell type-specific expression, tissue distribution, intracellular localization, posttranslational modifications, and domains other than the RGS domain that link them to other signaling pathways. In this review we discuss what has been learned so far about the role of RGS proteins in regulating G protein-coupled receptor signaling and point out areas that may be fruitful for future research.

Notes: Abstract Cloning of multiple opioid receptors has presented opportunities to investigate the mechanisms of multiple opioid receptor signaling and the regulation of these signals. The subsequent identification of receptor gene structures has also provided opportunities to study the regulation of receptor gene expression and to manipulate the concentration of the gene products in vivo. Thus, in the current review, we examine recent advances in the delineation basis for the multiple opioid receptor signaling, and their regulation at multiple levels. We discuss the use of receptor knockout animals to investigate the function and the pharmacology of these multiple opioid receptors. The reasons and basis for the multiple opioid receptor are addressed.