ALBERT

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

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

Notes: Abstract Active transport requires the alternation of substrate uptake and release with a switch in the access of the substrate binding site to the two sides of the membrane. Both the transfer and switch aspects of the photocycle have been subjects of magnetic resonance studies in bacteriorhodopsin. The results for ion transfer indicate that the Schiff base of the chromophore is hydrogen bonded before, during, and after its deprotonation. This suggests that the initial complex counterion of the Schiff base decomposes in such a way that the Schiff base carries its immediate hydrogen-bonding partner with it as it rotates during the first half of the photocycle. If so, bacteriorhodopsin acts as an inward-directed hydroxide pump rather than as an outward-directed proton pump. The studies of the access switch explore both protein-based and chromophore-based mechanisms. Combined with evidence from functional studies of mutants and other forms of spectroscopy, the results suggest that maintaining access to the extracellular side of the protein after photoisomerization involves twisting of the chromophore and that the decisive switch in access to the cytoplasmic side results from relaxation of the chromophore when the constraints on the Schiff base are released by decomposition of the complex counterion.

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

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

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

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

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

Notes: Abstract The recent report of the crystal structure of rhodopsin provides insights concerning structure-activity relationships in visual pigments and related G protein-coupled receptors (GPCRs). The seven transmembrane helices of rhodopsin are interrupted or kinked at multiple sites. An extensive network of interhelical interactions stabilizes the ground state of the receptor. The ligand-binding pocket of rhodopsin is remarkably compact, and several chromophore-protein interactions were not predicted from mutagenesis or spectroscopic studies. The helix movement model of receptor activation, which likely applies to all GPCRs of the rhodopsin family, is supported by several structural elements that suggest how light-induced conformational changes in the ligand-binding pocket are transmitted to the cytoplasmic surface. The cytoplasmic domain of the receptor includes a helical domain extending from the seventh transmembrane segment parallel to the bilayer surface. The cytoplasmic surface appears to be approximately large enough to bind to the transducin heterotrimer in a one-to-one complex. The structural basis for several unique biophysical properties of rhodopsin, including its extremely low dark noise level and high quantum efficiency, can now be addressed using a combination of structural biology and various spectroscopic methods. Future high-resolution structural studies of rhodopsin and other GPCRs will form the basis to elucidate the detailed molecular mechanism of GPCR-mediated signal transduction.

Notes: Abstract Integrins are a structurally elaborate family of heterodimers that mediate divalent cation-dependent cell adhesion in a wide range of biological contexts. The inserted (I) domain binds ligand in the subset of integrins in which it is present. Its structure has been determined in two alternative conformations, termed open and closed. In striking similarity to signaling G proteins, rearrangement of a Mg2+-binding site is linked to large conformational movements in distant backbone regions. Mutations have been used to stabilize either the closed or open structures. These show that the snapshots of the open conformation seen only in the presence of a ligand or a ligand mimetic represent a high-affinity, ligand-binding conformation, whereas those of the closed conformation correspond to a low-affinity conformation. The C-terminal alpha-helix moves 10 A down the side of the domain in the open conformation. Locking in the conformation of the preceding loop is sufficient to increase affinity for ligand 9000-fold. This C-terminal "bell-rope" provides a mechanism for linkage to conformational movements in other domains. The transition from the closed to open conformation has been implicated in fast (〈1 s) regulation of integrin affinity in response to activation signals from inside the cell. Recent integrin structures and functional studies reveal interactions between beta-propeller, I, and I-like domains in the headpiece, and a critical role for integrin EGF domains in the stalk region. These studies suggest that the headpiece of the integrin faces down toward the membrane in the inactive conformation and extends upward in a "switchblade"-like opening motion upon activation. These long-range structural rearrangements of the entire integrin molecule involving multiple interdomain contacts appear closely linked to conformational changes in the I domain, which result in increased affinity and competence for ligand binding.

Notes: Abstract The amyloid precursor protein and the proteases cleaving this protein are important players in the pathogenesis of Alzheimer's disease via the generation of the amyloid peptide. Physiologically, the amyloid precursor protein is implied in axonal vesicular trafficking and the proteases are implicated in developmentally important signaling pathways, most significantly those involving regulated intramembrane proteolysis or RIP. We discuss the cell biology behind the amyloid and tangle hypothesis for Alzheimer's disease, drawing on the many links to the fields of cell biology and developmental biology that have been established in the recent years.

Notes: Abstract The type III mechanism of protein secretion is a pathogenic strategy shared by a number of gram-negative pathogens of plants and animals that has evolved in order to inject virulence proteins into the cytosol of target eukaryotic cells. The pathogens of the Yersinia genus represent a model system where much progress has been made in understanding this secretion pathway. Herein, we review what has been recently learned in yersiniae about the various environmental signals that induce type III secretion, how the synthesis of secretion substrates is regulated, and how such a diverse group of proteins is recognized as a substrate for secretion.

Notes: Abstract The host cytoskeleton plays important roles in the entry, replication, and egress of viruses. An assortment of viruses hijack cellular motor proteins to move on microtubules toward the cell interior during the entry process; others reverse this transport during egress to move assembling virus particles toward the plasma membrane. Polymerization of actin filaments is sometimes used to propel viruses from cell to cell, while many viruses induce the destruction of select cytoskeletal filaments apparently to effect efficient egress. Indeed, the tactics used by any given virus to achieve its infectious life cycle are certain to involve multiple cytoskeletal interactions. Understanding these interactions, and their orchestration during viral infections, is providing unexpected insights into basic virology, viral pathogenesis, and the biology of the cytoskeleton.

Notes: Abstract Spindle microtubules interact with mitotic chromosomes, binding to their kinetochores to generate forces that are important for accurate chromosome segregation. Motor enzymes localized both at kinetochores and spindle poles help to form the biologically significant attachments between spindle fibers and their cargo, but microtubule-associated proteins without motor activity contribute to these junctions in important ways. This review examines the molecules necessary for chromosome-microtubule interaction in a range of well-studied organisms, using biological diversity to identify the factors that are essential for organized chromosome movement. We conclude that microtubule dynamics and the proteins that control them are likely to be more important for mitosis than the current enthusiasm for motor enzymes would suggest.

Notes: Abstract Chlamydiae, bacterial obligate intracellular pathogens, are the etiologic agents of several human diseases. A large part of the chlamydial intracellular survival strategy involves the formation of a unique organelle called the inclusion that provides a protected site within which they replicate. The chlamydial inclusion is effectively isolated from endocytic pathways but is fusogenic with a subset of exocytic vesicles that deliver sphingomyelin from the Golgi apparatus to the plasma membrane. A combination of host and parasite functions contribute to the biogenesis of this compartment. Establishment of the mature inclusion is accompanied by the insertion of multiple chlamydial proteins, suggesting that chlamydiae actively modify the inclusion to define its interactions with the eukaryotic host cell. Despite being sequestered within a membrane-bound vacuole, chlamydiae clearly communicate with and manipulate the host cell from within this privileged intracellular niche.

Notes: Abstract Epithelial morphogenesis comprises the various processes by which epithelia contribute to organ formation and body shape. These complex and diverse events play a central role in animal development and regeneration. Recently, the characterization of some of the molecular mechanisms involved in epithelial morphogenesis has provided an abundance of new information on the role and regulation of the cytoskeleton, cell-cell adhesion, and cell-matrix adhesion in these processes. In this review, we discuss our current understanding of the molecular mechanisms driving cell shape changes, cell intercalation, fusion of epithelia, ingression, egression, and cell migration. Our discussion is mostly focused on results from Drosophila and mammalian tissue culture but also draws on the insights gained from other organisms.

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

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

Notes: Abstract Cosmic microwave background (CMB) temperature anisotropies have and will continue to revolutionize our understanding of cosmology. The recent discovery of the previously predicted acoustic peaks in the power spectrum has established a working cosmological model: a critical density universe consisting of mainly dark matter and dark energy, which formed its structure through gravitational instability from quantum fluctuations during an inflationary epoch. Future observations should test this model and measure its key cosmological parameters with unprecedented precision. The phenomenology and cosmological implications of the acoustic peaks are developed in detail. Beyond the peaks, the yet to be detected secondary anisotropies and polarization present opportunities to study the physics of inflation and the dark energy. The analysis techniques devised to extract cosmological information from voluminous CMB data sets are outlined, given their increasing importance in experimental cosmology as a whole.

Notes: Abstract Considerable progress has been made over the past decade in the study of the evolutionary trends of the population of galaxy clusters in the Universe. In this review we focus on observations in the X-ray band. X-ray surveys with the ROSAT satellite, supplemented by follow-up studies with ASCA and Beppo-SAX, have allowed an assessment of the evolution of the space density of clusters out to z= 1 and the evolution of the physical properties of the intracluster medium out to z= 0.5. With the advent of Chandra and Newton-XMM and their unprecedented sensitivity and angular resolution, these studies have been extended beyond redshift unity and have revealed the complexity of the thermodynamical structure of clusters. The properties of the intracluster gas are significantly affected by nongravitational processes including star formation and Active Galactic Nuclei (AGN) activity. Convincing evidence has emerged for modest evolution of both the bulk of the X-ray cluster population and their thermodynamical properties since redshift unity. Such an observational scenario is consistent with hierarchical models of structure formation in a flat low-density universe with Omegam= 0.3 and sigma8= 0.7-0.8 for the normalization of the power spectrum. Basic methodologies for construction of X-ray-selected cluster samples are reviewed, and implications of cluster evolution for cosmological models are discussed.

Notes: Abstract Giant planet research has moved from the study of a handful of solar system objects to that of a class of bodies with dozens of known members. Since the original 1995 discovery of the first extrasolar giant planets (EGPs), the total number of known examples has increased to ~80 (circa November 2001). Current theoretical studies of giant planets emphasize predicted observable properties, such as luminosity, effective temperature, radius, external gravity field, atmospheric composition, and emergent spectra as a function of mass and age. This review focuses on the general theory of hydrogen-rich giant planets; smaller giant planets with the mass and composition of Uranus and Neptune are not covered. We discuss the status of the theory of the nonideal thermodynamics of hydrogen and hydrogen-helium mixtures under the conditions found in giant-planet interiors, and the experimental constraints on it. We provide an overview of observations of extrasolar giant planets and our own giant planets by which the theory can be validated.

Notes: Abstract Magnetic fields in the intercluster medium have been measured using a variety of techniques, including studies of synchrotron relic and halo radio sources within clusters, studies of inverse Compton X-ray emission from clusters, surveys of Faraday rotation measures of polarized radio sources both within and behind clusters, and studies of cluster cold fronts in X-ray images. These measurements imply that most cluster atmospheres are substantially magnetized, with typical field strengths of order 1 muGauss with high areal filling factors out to Mpc radii. There is likely to be considerable variation in field strengths and topologies both within and between clusters, especially when comparing dynamically relaxed clusters to those that have recently undergone a merger. In some locations, such as the cores of cooling flow clusters, the magnetic fields reach levels of 10-40 muG and may be dynamically important. In all clusters the magnetic fields have a significant effect on energy transport in the intracluster medium. We also review current theories on the origin of cluster magnetic fields.

Notes: Abstract David Crighton, a greatly admired figure in fluid mechanics, Head of the Department of Applied Mathematics and Theoretical Physics at Cambridge, and Master of Jesus College, Cambridge, died at the peak of his career. He had made important contributions to the theory of waves generated by unsteady flow. Crighton's work was always characterized by the application of rigorous mathematical approximations to fluid mechanical idealizations of practically relevant problems. At the time of his death, he was certainly the most influential British applied mathematical figure, and his former collaborators and students form a strong school that continues his special style of mathematical application. Rigorous analysis of well-posed aeroacoustical problems was transformed by David Crighton.

Notes: Abstract Cavitation in vortical structures is a common, albeit complex, problem in engineering applications. Cavitating vortical structures can be found on the blade surfaces, in the clearance passages, and at the hubs of various types of turbomachinery. Cavitating microvortices at the trailing edge of attached sheet cavitation can be highly erosive. Cavitating hub vortices in the draft tubes of hydroturbines can cause major surges and power swings. There is also mounting evidence that vortex cavitation is a dominant factor in the inception process in a broad range of turbulent flows. Most research has focused on the inception process, with limited attention paid to developed vortex cavitation. Wave-like disturbances on the surfaces of vapor cores are an important feature. Vortex core instabilities in microvortices are found to be important factors in the erosion mechanisms associated with sheet/cloud cavitation. Under certain circumstances, intense sound at discrete frequencies can result from a coupling between tip vortex disturbances and oscillating sheet cavitation. Vortex breakdown phenomena that have some commonalities are also noted, as are some differences with vortex breakdown in fully wetted flow. Simple vortex models can sometimes be used to describe the cavitation process in complex turbulent flows such as bluff body wakes and in plug valves. Although a vortex model for cavitation in jets does not exist, the mechanism of inception appears to be related to the process of vortex pairing. The pairing process can produce negative peaks in pressure that can exceed the rms value by a factor of ten, sometimes exceeding the dynamic pressure by a factor of two. A new and important issue is that cavitation is not only induced in vortical structures but is also a mechanism for vorticity generation.

Notes: Abstract Microstructure in an immiscible polymer blend consists of the size, shape, and orientation of the phases. Blends exhibit many interesting behaviors, including enhanced elasticity at small strains, drop-size hysteresis, enhanced shear thinning, and stress relaxation curves whose shapes are sensitive to deformation history. These behaviors are directly related to changes in the microstructure, which result from phase deformation, coalescence, retraction, and different types of breakup. These phenomena are reviewed, together with models that describe them. Rheological measurements can probe the microstructure because microstructure contributes directly to stress through interfacial tension. Rheo-optical experiments also provide important insights. Droplet theories explain most of the phenomena for Newtonian phases at low concentrations. Behaviors at high volume fractions or with strongly non-Newtonian phases are less well understood.

Notes: Abstract Recent advances in the computational modeling of molecular conformational and orientational effects in the flow of viscoelastic fluids are described. These advances involve the coupling of molecular models for the underlying microstructure of macromolecules with the macroscopic equations of change. The kinetic theory for polymeric liquids is described along with the most useful micromechanical models for computing the fluid flow of polymeric liquids. Three levels of description are covered for the computation of molecular orientation effects: methods for molecular models for which closed-form, continuum-like evolution equations for average quantities describing molecular conformations can be obtained, hybrid methods that involve coupling direct solution of the Fokker-Planck equation describing the distribution function for molecular orientations with the equations of change, and hybrid methods that couple stochastic simulations of individual molecule trajectories with the macroscopic equations of change. Illustrative results for rheometric flows (flows with homogeneous, fixed kinematics) and complex flows are given.

Notes: Abstract The El Nino variability in the equatorial Tropical Pacific is characterized by sea-surface temperature anomalies and associated changes in the atmospheric circulation. Through an enormous monitoring effort over the last decades, the relevant time scales and spatial patterns are fairly well documented. In the meantime, a hierarchy of models has been developed to understand the physics of this phenomenon and to make predictions of future variability. In this review, the robust and relevant details of the observations, the fluid mechanical "building blocks," the theory of the deterministic part of the variability, and the impact of small-scale ("noise") and remote ("external") processes are evaluated.

Notes: Abstract Cryptococcus neoformans is a pathogenic fungus that primarily afflicts immunocompromised patients, infecting the central nervous system to cause meningoencephalitis that is uniformly fatal if untreated. C. neoformans is a basidiomycetous fungus with a defined sexual cycle that has been linked to differentiation and virulence. Recent advances in classical and molecular genetic approaches have allowed molecular descriptions of the pathways that control cell type and virulence. An ongoing genome sequencing project promises to reveal much about the evolution of this human fungal pathogen into three distinct varieties or species. C. neoformans shares features with both model ascomycetous yeasts (Saccharomyces cerevisiae, Schizosaccharomyces pombe) and basidiomycetous pathogens and mushrooms (Ustilago maydis, Coprinus cinereus, Schizophyllum commune), yet ongoing studies reveal unique features associated with virulence and the arrangement of the mating type locus. These advances have catapulted C. neoformans to center stage as a model of both fungal pathogenesis and the interesting approaches to life that the kingdom of fungi has adopted.

Notes: Abstract An unusual feature of the Diptera is that homologous chromosomes are intimately synapsed in somatic cells. At a number of loci in Drosophila, this pairing can significantly influence gene expression. Such influences were first detected within the bithorax complex (BX-C) by E.B. Lewis, who coined the term transvection to describe them. Most cases of transvection involve the action of enhancers in trans. At several loci deletion of the promoter greatly increases this action in trans, suggesting that enhancers are normally tethered in cis by the promoter region. Transvection can also occur by the action of silencers in trans or by the spreading of position effect variegation from rearrangements having heterochromatic breakpoints to paired unrearranged chromosomes. Although not demonstrated, other cases of transvection may involve the production of joint RNAs by trans-splicing. Several cases of transvection require Zeste, a DNA-binding protein that is thought to facilitate homolog interactions by self-aggregation. Genes showing transvection can differ greatly in their response to pairing disruption. In several cases, transvection appears to require intimate synapsis of homologs. However, in at least one case (transvection of the iab-5,6,7 region of the BX-C), transvection is independent of synapsis within and surrounding the interacting gene. The latter example suggests that transvection could well occur in organisms that lack somatic pairing. In support of this, transvection-like phenomena have been described in a number of different organisms, including plants, fungi, and mammals.

Notes: Abstract DNA checkpoints play a significant role in cancer pathology, perhaps most notably in maintaining genome stability. This review summarizes the genetic and molecular mechanisms of checkpoint activation in response to DNA damage. The major checkpoint proteins common to all eukaryotes are identified and discussed, together with how the checkpoint proteins interact to induce arrest within each cell cycle phase. Also discussed are the molecular signals that activate checkpoint responses, including single-strand DNA, double-strand breaks, and aberrant replication forks. We address the connection between checkpoint proteins and damage repair mechanisms, how cells recover from an arrest response, and additional roles that checkpoint proteins play in DNA metabolism. Finally, the connection between checkpoint gene mutation and genomic instability is considered.

Notes: Abstract Long-term potentiation (LTP) is the predominant experimental model for the synaptic plasticity mechanisms thought to underlie learning and memory. This review is focused on the contributions of genetics to the understanding of the role of LTP in learning and memory. These studies have used a combination of genetics, molecular biology, neurophysiology, and psychology to demonstrate that molecular mechanisms of synaptic plasticity are critical for learning and memory. Because of the large scope of this literature, we focus primarily on genetic studies of hippocampal-dependent learning. Altogether, these findings not only demonstrate a role for plasticity in learning, they also lay down the foundations for the new field of molecular and cellular cognition.

Notes: Abstract The compilation of a dense gene map and eventually a whole genome sequence (WGS) of the domestic cat holds considerable value for human genome annotation, for veterinary medicine, and for insight into the evolution of genome organization among mammals. Human association and veterinary studies of the cat, its domestic breeds, and its charismatic wild relatives of the family Felidae have rendered the species a powerful model for human hereditary diseases, for infectious disease agents, for adaptive evolutionary divergence, for conservation genetics, and for forensic applications. Here we review the advantages, rationale, and present strategy of a feline genome project, and we describe the disease models, comparative genomics, and biological applications posed by the full resolution of the cat's genome.

Notes: Abstract A moment estimator of theta, the coancestry coefficient for alleles within a population, was described by Weir & Cockerham in 1984 (100) and is still widely cited. The estimate is used by population geneticists to characterize population structure, by ecologists to estimate migration rates, by animal breeders to describe genetic variation, and by forensic scientists to quantify the strength of matching DNA profiles. This review extends the work of Weir & Cockerham by allowing different levels of coancestry for different populations, and by allowing non-zero coancestries between pairs of populations. All estimates are relative to the average value of theta between pairs of populations. Moment estimates for within- and between-population theta values are likely to have large sampling variances, although these may be reduced by combining information over loci. Variances also decrease with the numbers of alleles at a locus, and with the numbers of populations sampled. This review also extends the work of Weir & Cockerham by employing maximum likelihood methods under the assumption that allele frequencies follow the normal distribution over populations. For the case of equal theta values within populations and zero theta values between populations, the maximum likelihood estimate is the same as that given by Robertson & Hill in 1984 (70). The review concludes by relating functions of theta values to times of population divergence under a pure drift model.

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

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

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

Notes: Abstract Fungal pathogens of plants or animals invade their hosts either by secretion of lytic enzymes, exerting force, or by a combination of both. Although many fungi are thought to rely mostly on lysis of the host tissue, some plant pathogenic fungi differentiate complex infection cells that develop enormous turgor pressure, which in turn is translated into force used for invasion. In order to understand mechanisms of fungal infection in detail, methods have been developed that indirectly or directly measure turgor pressure and force. In this article, these methods are described and critically discussed, and their importance in analysis of fungal infection are outlined.

Notes: Abstract The field of computational cell biology has emerged within the past 5 years because of the need to apply disciplined computational approaches to build and test complex hypotheses on the interacting structural, physical, and chemical features that underlie intracellular processes. To meet this need, newly developed software tools allow cell biologists and biophysicists to build models and generate simulations from them. The construction of general-purpose computational approaches is especially challenging if the spatial complexity of cellular systems is to be explicitly treated. This review surveys some of the existing efforts in this field with special emphasis on a system being developed in the authors' laboratory, Virtual Cell. The theories behind both stochastic and deterministic simulations are discussed. Examples of respective applications to cell biological problems in RNA trafficking and neuronal calcium dynamics are provided to illustrate these ideas.

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

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

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

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

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

Notes: Abstract Bacterial pathogens utilize several strategies to modulate the organization of the actin cytoskeleton. Some bacterial toxins catalyze the covalent modification of actin or the Rho GTPases, which are involved in the control of the actin cytoskeleton. Other bacteria produce toxins that act as guanine nucleotide exchange factors or GTPase-activating proteins to modulate the nucleotide state of the Rho GTPases. This latter group of toxins provides a temporal modulation of the actin cytoskeleton. A third group of bacterial toxins act as adenylate cyclases, which directly elevate intracellular cAMP to supra-physiological levels. Each class of toxins gives the bacterial pathogen a selective advantage in modulating host cell resistance to infection.

Notes: Abstract The mammalian cell continuously adjusts its sterol content by regulating levels of key sterol synthetic enzymes and levels of LDL receptors that mediate uptake of cholesterol-laden particles. Control is brought about by sterol-regulated transcription of relevant genes and by regulated degradation of the committed step enzyme HMG-CoA reductase (HMGR). Current work has revealed that proteolysis is at the heart of each of these mechanistically distinct axes. Transcriptional control is effected by regulated cleavage of the membrane-bound transcription factor sterol regulatory element binding protein (SREBP), and HMGR degradation is brought about by ubiquitin-mediated degradation. In each case, ongoing cell biological processes are being harnessed to bring about regulation. The secretory pathway plays a central role in allowing sterol-mediated control of transcription. The constitutively active endoplasmic reticulum (ER) quality control apparatus is employed to bring about regulated destruction of HMGR. This review describes the methods and results of various studies to understand the mechanisms and molecules involved in these distinct but interrelated aspects of sterol regulation and the intriguing similarities that appear to exist at the levels of protein sequence and cell biology.

Notes: Abstract Multiferroic magnetoelectrics are materials that are both ferromagnetic and ferroelectric in the same phase. As a result, they have a spontaneous magnetization that can be switched by an applied magnetic field and a spontaneous polarization that can be switched by an applied electric field. In this paper we show that density functional theory has been invaluable both in explaining the properties of known magnetically ordered ferroelectric materials, and in predicting the occurrence of new ones. Density functional calculations have shown that, in general, the transition metal d electrons essential for magnetism reduce the tendency for off-center ferroelectric distortion. Consequently, an additional electronic or structural driving force must be present for ferromagnetism and ferroelectricity to occur simultaneously.

Notes: Abstract Vacancies and self-interstitial defects in silicon are here investigated by means of semi-empirical quantum molecular dynamics simulations performed within the tight-binding model. We extensively discuss the process of formation and migration of native point defects and investigate their interaction and clustering phenomena. The formation of larger stable structures is further studied by combining tight-binding and Monte Carlo simulations. Tight-binding simulation results provide a global picture for defect-induced microstructure evolution in bulk silicon. These results are consistent with state-of-the-art experimental data and elucidate many relevant atomic-scale mechanisms.

Notes: Abstract I fled with my parents from Hitler's Austria to Australia and studied physics at Sydney University. I obtained my Ph.D. in quantum electrodynamics with Rudolf Peierls at Birmingham University and came to Cornell to work with Hans Bethe. I have stayed at Cornell ever since, and I have essentially had only a single job in my whole life, but have switched fields quite often. I worked in nuclear astrophysics and in late-stellar evolution, estimated the Initial Mass Function for star formation and the metal enrichment of the interstellar medium. I suggested black hole accretion as the energy source for quasars, worked on molecule formation on dust grain surfaces, and was involved in 21-cm studies of gas clouds and disk galaxies. I collaborated with my wife on the neurobiology of the neuromuscular junction and with one of my daughters on the epidemiology of tuberculosis.

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

Notes: Abstract Radio astronomy has provided evidence for the presence of ionized atmospheres around almost all classes of nondegenerate stars. Magnetically confined coronae dominate in the cool half of the Hertzsprung-Russell diagram. Their radio emission is predominantly of nonthermal origin and has been identified as gyrosynchrotron radiation from mildly relativistic electrons, apart from some coherent emission mechanisms. Ionized winds are found in hot stars and in red giants. They are detected through their thermal, optically thick radiation, but synchrotron emission has been found in many systems as well. The latter is emitted presumably by shock-accelerated electrons in weak magnetic fields in the outer wind regions. Radio emission is also frequently detected in pre-main sequence stars and protostars and has recently been discovered in brown dwarfs. This review summarizes the radio view of the atmospheres of nondegenerate stars, focusing on energy release physics in cool coronal stars, wind phenomenology in hot stars and cool giants, and emission observed from young and forming stars. Eines habe ich in einem langen Leben gelernt, namlich, dass unsere ganze Wissenschaft, an den Dingen gemessen, von kindlicher Primitivitat ist-und doch ist es das Kostlichste, was wir haben. One thing I have learned in a long life: that all our science, measured against reality, is primitive and childlike-and yet it is the most precious thing we have. A. Einstein 1951, in a letter to H. Muhsam, Einstein Archive 36-610

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

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

Notes: Abstract This essay is based on the G.K. Batchelor Memorial Lecture that I delivered in May 2000 at the Institute for Theoretical Physics (ITP), Santa Barbara, where two parallel programs on Turbulence and Astrophysical Turbulence were in progress. It focuses on George Batchelor's major contributions to the theory of turbulence, particularly during the postwar years when the emphasis was on the statistical theory of homogeneous turbulence. In all, his contributions span the period 1946-1992 and are for the most part concerned with the Kolmogorov theory of the small scales of motion, the decay of homogeneous turbulence, turbulent diffusion of a passive scalar field, magnetohydrodynamic turbulence, rapid distortion theory, two-dimensional turbulence, and buoyancy-driven turbulence.

Notes: Abstract Turbulent flows driven by thermal buoyancy are featured by phenomena that pose a special challenge to conventional one-point closure models. Inherent unsteadiness, energy nonequilibrium, counter-gradient diffusion, strong pressure fluctuations, and lack of universal scaling, all believed to be associated with distinct large-scale coherent eddy structures, are hardly tractable by Reynolds-type averaging. Second-moment closures, though inadequate for providing information on eddy structure, offer better prospects than eddy-viscosity models for capturing at least some of the phenomena. For some configurations (e.g., with heating from below), unsteady computational solutions of ensemble-averaged equations, using a one-point closure as the subscale model, may be unavoidable for accurate prediction of flow details and wall heat transfer. This article reviews the rationale and some specific modeling issues related to buoyant flows within the realm of one-point closures. The inadequacy of isotropic eddy-diffusivity models is discussed first, followed by the rationale of the second-moment modeling and its term-by-term scrutiny based on direct numerical simulations (DNS). Algebraic models based on a rational truncation of the differential second-moment closure are proposed as the minimum closure level for complex flows. These closures are also recommended as subscale models for transient statistical modeling (T-RANS) and very large eddy simulations (VLES). Examples of applications illustrate some recent achievements.

Notes: Abstract Remote observations of a surface ship wake using synthetic aperture radar (SAR) show distinct features such as a dark trailing centerline region, bright V-images aligned at some angle to the ship's path, and, sometimes, either the transverse or the diverging waves of the Kelvin-wave pattern. The dark region of relatively low radar backscatter is usually associated with a region that is relatively lacking in short wave components, whereas the bright line feature suggests a region of enhanced radar return within the apparent angular confines of the ship's usual Kelvin-wave pattern. This review provides a survey of remotely sensed wake images, the systems that have collected these images, and an overview of the theory of Kelvin wakes-a primary source of the phenomena that cause the dark centerline and bright V-images-with example predictions. The review concludes with a survey of the phenomena that cause the dark centerline returns and some example predictions of the radar reflectivity across these dark centerline returns.

Notes: Abstract We review the mechanisms of steepening and breaking for internal gravity waves in a continuous density stratification. After discussing the instability of a plane wave of arbitrary amplitude in an infinite medium at rest, we consider the steepening effects of wave reflection on a sloping boundary and propagation in a shear flow. The final process of breaking into small-scale turbulence is then presented. The influence of those processes upon the fluid medium by mean flow changes is discussed. The specific properties of wave turbulence, induced by wave-wave interactions and breaking, are illustrated by comparative studies of oceanic and atmospheric observations, as well as laboratory and numerical experiments. We then review the different attempts at a statistical description of internal gravity wave fields, whether weakly or strongly interacting.

Notes: In order to understand both the past and future directions of research in evolutionary biology we need to begin by understanding in what way these programs of research differ from the model of most scientific work. The study of evolutionary processes and, in particular, the genetics of the evolutionary process must confront special difficulties in both the conceptual and the methodological aspects of research. On the conceptual side, unlike for molecular, cellular, and developmental biology, there is no basic mechanism that evolutionists are attempting to elucidate. There is no single cause of the evolutionary change in the properties of members of a species. Natural selection may be involved but so are random events, patterns of migration and interbreeding, mutational events, and horizontal transfer of genes across species boundaries. The change in each character of each species is a consequence of a particular mixture of these causal pathways.

Notes: Abstract Fish species have diverse breeding behaviors that make them valuable for testing theories on genetic mating systems and reproductive tactics. Here we review genetic appraisals of paternity and maternity in wild fish populations. Behavioral phenomena quantified by genetic markers in various species include patterns of multiple mating by both sexes; frequent cuckoldry by males and rare cuckoldry by females in nest-tending species; additional routes to surrogate parentage via nest piracy and egg-thievery; egg mimicry by nest-tending males; brood parasitism by helper males in cooperative breeders; clutch mixing in oral brooders; kinship in schooling fry of broadcast spawners; sperm storage by dams in female-pregnant species; and sex-role reversal, polyandry, and strong sexual selection on females in some male-pregnant species. Additional phenomena addressed by genetic parentage analyses in fishes include clustered mutations, filial cannibalism, and local population size. All results are discussed in the context of relevant behavioral and evolutionary theory.

Notes: Abstract Recombination can be a dominant force in shaping genomes and associated phenotypes. To better understand the impact of recombination on genomic evolution, we need to be able to identify recombination in aligned sequences. We review bioinformatic approaches for detecting recombination and measuring recombination rates. We also examine the impact of recombination on the reconstruction of evolutionary histories and the estimation of population genetic parameters. Finally, we review the role of recombination in the evolutionary history of bacteria, viruses, and human mitochondria. We conclude by highlighting a number of areas for future development of tools to help quantify the role of recombination in genomic evolution.

Notes: Abstract Spirochetes are a medically important and ecologically significant group of motile bacteria with a distinct morphology. Outermost is a membrane sheath, and within this sheath is the protoplasmic cell cylinder and subterminally attached periplasmic flagella. Here we address specific and unique aspects of their motility and chemotaxis. For spirochetes, translational motility requires asymmetrical rotation of the two internally located flagellar bundles. Consequently, they have swimming modalities that are more complex than the well-studied paradigms. In addition, coordinated flagellar rotation likely involves an efficient and novel signaling mechanism. This signal would be transmitted over the length of the cell, which in some cases is over 100-fold greater than the cell diameter. Finally, many spirochetes, including Treponema, Borrelia, and Leptospira, are highly invasive pathogens. Motility is likely to play a major role in the disease process. This review summarizes the progress in the genetics of motility and chemotaxis of spirochetes, and points to new directions for future experimentation.

Notes: Abstract The plant life cycle alternates between a diploid sporophyte generation and a haploid gametophyte generation. The angiosperm female gametophyte is critical to the reproductive process. It is the structure within which egg cell production and fertilization take place. In addition, the female gametophyte plays a role in pollen tube guidance, the induction of seed development, and the maternal control of seed development. Genetic analysis in Arabidopsis has uncovered mutations that affect female gametophyte development and function. Mutants defective in almost all stages of development have been identified, and analysis of these mutants is beginning to reveal features of the female gametophyte developmental program. Other mutations that affect female gametophyte function have uncovered regulatory genes required for the induction of endosperm development. From these studies, we are beginning to understand the regulatory networks involved in female gametophyte development and function. Further investigation of the female gametophyte will require complementary approaches including expression-based approaches to obtain a complete profile of the genes functioning within this critical structure.

Notes: Abstract The idea that the ancestors of modern cells were RNA cells (ribocytes) can be investigated by asking whether all essential cellular functions might be performed by RNAs. This requires isolating suitable molecules by selection-amplification when the predicted molecules are presently extinct. In fact, RNAs with many properties required during a period in which RNA was the major macromolecular agent in cells (an RNA world) have been selected in modern experiments. There is, accordingly, reason to inquire how such a ribocyte might appear, based on the properties of the RNAs that composed it. Combining the intrinsic qualities of RNA with the fundamental characteristics of selection from randomized sequence pools, one predicts ribocytes with a cell cycle measured (roughly) in weeks. Such cells likely had a rapidly varying genome, composed of many small genetic and catalytic elements made of tens of ribonucleotides. There are substantial arguments that, at the mid-RNA era, a subset of these nucleotides are reproducibly available and resemble the modern four. Such cells are predicted to evolve rapidly. Instead of modifying preexisting genes, ribocytes frequently draw new functions from an internal pool containing zeptomoles (〈1 attomole) of predominantly inactive random sequences.

Notes: Abstract The prospect of specifically controlling gene activities in vivo has become a defining hallmark of many model organisms of biological research. Where once the aim was to gain control over gene activities using endogenous control elements, new technologies have emerged that owe their remarkable specificity to heterologous components derived from evolutionarily distant species. This review highlights inducible transcriptional systems and site-specific recombination. Their quantitative and qualitative characteristics are discussed, with examples of how recent developments have expanded the spectrum of cells and organisms that are now accessible to genetic dissection of unprecedented precision. Transgenesis has already converted the mouse into a prime model for mammalian genetics. Combined with the new approaches of conditional activation or inactivation of genes, this model has opened up new horizons for the analysis of gene function in mammals.

Notes: Abstract Because the level of DNA superhelicity varies with the cellular energy charge, it can change rapidly in response to a wide variety of altered nutritional and environmental conditions. This is a global alteration, affecting the entire chromosome and the expression levels of all operons whose promoters are sensitive to superhelicity. In this way, the global pattern of gene expression may be dynamically tuned to changing needs of the cell under a wide variety of circumstances. In this article, we propose a model in which chromosomal superhelicity serves as a global regulator of gene expression in Escherichia coli, tuning expression patterns across multiple operons, regulons, and stimulons to suit the growth state of the cell. This model is illustrated by the DNA supercoiling-dependent mechanisms that coordinate basal expression levels of operons of the ilv regulon both with one another and with cellular growth conditions.

Notes: Abstract In this review, we describe the pathway for generating meiotic crossovers in Drosophila melanogaster females and how these events ensure the segregation of homologous chromosomes. As appears to be common to meiosis in most organisms, recombination is initiated with a double-strand break (DSB). The interesting differences between organisms appear to be associated with what chromosomal events are required for DSBs to form. In Drosophila females, the synaptonemal complex is required for most DSB formation. The repair of these breaks requires several DSB repair genes, some of which are meiosis-specific, and defects at this stage can have effects downstream on oocyte development. This has been suggested to result from a checkpoint-like signaling between the oocyte nucleus and gene products regulating oogenesis. Crossovers result from genetically controlled modifications to the DSB repair pathway. Finally, segregation of chromosomes joined by a chiasma requires a bipolar spindle. At least two kinesin motor proteins are required for the assembly of this bipolar spindle, and while the meiotic spindle lacks traditional centrosomes, some centrosome components are found at the spindle poles.

Notes: Abstract Influenza A viruses contain genomes composed of eight separate segments of negative-sense RNA. Circulating human strains are notorious for their tendency to accumulate mutations from one year to the next and cause recurrent epidemics. However, the segmented nature of the genome also allows for the exchange of entire genes between different viral strains. The ability to manipulate influenza gene segments in various combinations in the laboratory has contributed to its being one of the best characterized viruses, and studies on influenza have provided key contributions toward the understanding of various aspects of virology in general. However, the genetic plasticity of influenza viruses also has serious potential implications regarding vaccine design, pathogenicity, and the capacity for novel viruses to emerge from natural reservoirs and cause global pandemics.

Notes: Abstract Spontaneous mutations are derived from various sources, including errors made during replication of undamaged template DNA, mutagenic nucleotide substrates, and endogenous DNA lesions. These sources vary in their frequencies and resultant mutations, and are differently affected by the DNA sequence, DNA transactions, and cellular metabolism. Organisms possess a variety of cellular functions to suppress spontaneous mutagenesis, and the specificity and effectiveness of each function strongly affect the pattern of spontaneous mutations. Base substitutions and single-base frameshifts, two major classes of spontaneous mutations, occur non-randomly throughout the genome. Within target DNA sequences there are hotspots for particular types of spontaneous mutations; outside of the hotspots, spontaneous mutations occur more randomly and much less frequently. Hotspot mutations are attributable more to endogenous DNA lesions than to replication errors. Recently, a novel class of mutagenic pathway that depends on short inverted repeats was identified as another important source of hotspot mutagenesis.

Notes: Abstract Introns are removed from precursor messenger RNAs in the cell nucleus by a large ribonucleoprotein complex called the spliceosome. The spliceosome contains five subcomplexes called snRNPs, each with one RNA and several protein components. Interactions of the snRNPs with each other and the intron are highly dynamic, changing in an ordered progression throughout the splicing process. This allosteric cascade of interactions is programmed into the RNA and protein components of the spliceosome, and is driven by a family of DExD/H-box RNA-dependent ATPases. The dependence of cascade progression on multiple intron-recognition events likely serves to enforce the accuracy of splicing. Here, the progression of the allosteric cascade from the first recognition event to the first catalytic step of splicing is reviewed.

Notes: Abstract Dosage compensation in mammals is achieved by the transcriptional inactivation of one X chromosome in female cells. From the time X chromosome inactivation was initially described, it was clear that several mechanisms must be precisely integrated to achieve correct regulation of this complex process. X-inactivation appears to be triggered upon differentiation, suggesting its regulation by developmental cues. Whereas any number of X chromosomes greater than one is silenced, only one X chromosome remains active. Silencing on the inactive X chromosome coincides with the acquisition of a multitude of chromatin modifications, resulting in the formation of extraordinarily stable facultative heterochromatin that is faithfully propagated through subsequent cell divisions. The integration of all these processes requires a region of the X chromosome known as the X-inactivation center, which contains the Xist gene and its cis-regulatory elements. Xist encodes an RNA molecule that plays critical roles in the choice of which X chromosome remains active, and in the initial spread and establishment of silencing on the inactive X chromosome. We are now on the threshold of discovering the factors that regulate and interact with Xist to control X-inactivation, and closer to an understanding of the molecular mechanisms that underlie this complex process.

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

Notes: Abstract Much of our knowledge of the actin cytoskeleton has been derived from biochemical and cell biological approaches, through which actin-binding proteins have been identified and their in vitro interactions with actin have been characterized. The study of actin-binding proteins (ABPs) in genetic model systems has become increasingly important for validating and extending our understanding of how these proteins function. New ABPs have been identified through genetic screens, and genetic results have informed the interpretation of in vitro experiments. In this review, we describe the molecular and ultrastructural characteristics of the actin cytoskeleton in the Drosophila ovary, and discuss recent genetic analyses of actin-binding proteins that are required for oogenesis.

Notes: Abstract Although initially recognized as a handy tool to reduce gene expression, RNA silencing, triggered by double-stranded RNA molecules, is now recognized as a mechanism for cellular protection and cleansing: It defends the genome against molecular parasites such as viruses and transposons, while removing abundant but aberrant nonfunctional messenger RNAs. The underlying mechanisms in distinct gene silencing phenomena in different genetic systems, such as cosuppression in plants and RNAi in animals, are very similar. There are common RNA intermediates, and similar genes are required in RNA silencing pathways in protozoa, plants, fungi, and animals, thus indicating an ancient pathway. This chapter gives an overview of both biochemical and genetic approaches leading to the current understanding of the molecular mechanism of RNA silencing and its probable biological function.

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

Notes: Abstract Nearly twenty years after the first high-resolution crystal structures of specific protein-DNA complexes were determined, the stereo-chemical basis for protein-DNA recognition remains an active area of investigation. One outstanding question is, how are proteins able to detect noncontacted sequences in their binding sites? The papillomavirus E2 proteins represent a particularly suitable group of proteins in which to examine the mechanisms of "indirect readout." Coordinated structural and thermodynamic studies of the E2-DNA interaction conducted over the past five years are summarized in this review. The data support a model in which the electrostatic properties of the individual E2 proteins correlate with their affinities for intrinsically flexible or rigidly prebent DNA targets.

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

Notes: Abstract Autoinhibitory domains are regions of proteins that negatively regulate the function of other domains via intramolecular interactions. Autoinhibition is a potent regulatory mechanism that provides tight "on-site" repression. The discovery of autoinhibition generates valuable clues to how a protein is regulated within a biological context. Mechanisms that counteract the autoinhibition, including proteolysis, post-translational modifications, as well as addition of proteins or small molecules in trans, often represent central regulatory pathways. In this review, we document the diversity of instances in which autoinhibition acts in cell regulation. Seven well-characterized examples (e.g., sigma70, Ets-1, ERM, SNARE and WASP proteins, SREBP, Src) are covered in detail. Over thirty additional examples are listed. We present experimental approaches to characterize autoinhibitory domains and discuss the implications of this widespread phenomenon for biological regulation in both the normal and diseased states.

Notes: Abstract In Caenorhabditis elegans the timing of many developmental events is regulated by heterochronic genes. Such genes orchestrate the timing of cell divisions and fates appropriate for the developmental stage of an organism. Analyses of heterochronic mutations in the nematode C. elegans have revealed a genetic pathway that controls the timing of post-embryonic cell divisions and fates. Two of the genes in this pathway encode small regulatory RNAs. The 22 nucleotide (nt) RNAs downregulate the expression of protein-coding mRNAs of target heterochronic genes. Analogous variations in the timing of appearance of particular features have been noted among closely related species, suggesting that such explicit control of developmental timing may not be exclusive to C. elegans. In fact, some of the genes that globally pattern the temporal progression of C. elegans development, including one of the tiny RNA genes, are conserved and temporally regulated across much of animal phylogeny, suggesting that the molecular mechanisms of temporal control are ancient and universal. A very large family of tiny RNA genes called microRNAs, which are similar in structure to the heterochronic regulatory RNAs, have been detected in diverse animal species and are likely to be present in most metazoans. Functions of the newly discovered microRNAs are not yet known. Other examples of temporal programs during growth include the exquisitely choreographed temporal sequences of developmental fates in neurogenesis in Drosophila and the sequential programs of epidermal coloration in insect wing patterning. An interesting possibility is that microRNAs mediate transitions on a variety of time scales to pattern the activities of particular target protein-coding genes and in turn generate sets of cells over a period of time. Plasticity in these microRNA genes or their targets may lead to changes in relative developmental timing between related species, or heterochronic change. Instead of inventing new gene functions, even subtle changes in temporal expression of pre-existing control genes can result in speciation by altering the time at which they function.

Notes: Abstract Signaling between cells is a widely used mechanism by which cell fate and tissue patterning is determined in development. We review the mechanisms by which signaling between cells is regulated so that a cell receives the right amount of signal, at the right time, to achieve its intended developmental fate and position. In nearly all cases, we find that the supply of signal factor (ligand) is the limiting step in initiating a signaling process. Ligand supply is regulated by the transcription and localization of RNA, the spread of ligand from a source, and by inhibitors that operate at several different levels. We emphasize the different regulatory strategies that operate for threshold as opposed to concentration-dependent (morphogen) signaling. Threshold signaling is extensively regulated by feedback mechanisms. Morphogen signaling is regulated quantitatively by receptor loading and transduction flow.

Notes: Abstract Cells monitor the physiological load placed on their endoplasmic reticulum (ER) and respond to perturbations in ER function by a process known as the unfolded protein response (UPR). In metazoans the UPR has a transcriptional component that up-regulates expression of genes that enhance the capacity of the organelle to deal with the load of client proteins and a translational component that insures tight coupling between protein biosynthesis on the cytoplasmic side and folding in the ER lumen. Together, these two components adapt the secretory apparatus to physiological load and protect cells from the consequences of protein malfolding.

Notes: Abstract The vasculature is one of the most important and complex organs in the mammalian body. The first functional organ to form during embryonic development, the intricately branched network of endothelial and supporting periendothelial cells is essential for the transportation of oxygen and nutrients to and the removal of waste products from the tissues. Serious disruptions in the formation of the vascular network are lethal early in post-implantation development, while the maintenance of vessel integrity and the control of vessel physiology and hemodynamics have important consequences throughout embryonic and adult life. A full understanding of the signaling pathways of vascular development is important not just for understanding normal development but because of the importance of reactivation of angiogenic pathways in disease states. Clinically there is a need to develop therapies to promote new blood vessel formation in situations of severe tissue ischemia, such as coronary heart disease. In addition, there is considerable interest in developing angiogenic inhibitors to block the new vessel growth that solid tumors promote in host tissue to enhance their own growth. Already studies on the signaling pathways of normal vascular development have provided new targets for therapeutic intervention in both situations. Further understanding of the complexities of the pathways should help refine such strategies.

Notes: Abstract The actin cytoskeleton plays a major role in morphological development of neurons and in structural changes of adult neurons. This article reviews the myriad functions of actin and myosin in axon initiation, growth, guidance and branching, in morphogenesis of dendrites and dendritic spines, in synapse formation and stability, and in axon and dendrite retraction. Evidence is presented that signaling pathways involving the Rho family of small GTPases are key regulators of actin polymerization and myosin function in the context of different aspects of neuronal morphogenesis. These studies support an emerging theme: Different aspects of neuronal morphogenesis may involve regulation of common core signaling pathways, in particular the Rho GTPases.

Notes: Abstract Striated muscle is an intricate, efficient, and precise machine that contains complex interconnected cytoskeletal networks critical for its contractile activity. The individual units of the sarcomere, the basic contractile unit of myofibrils, include the thin, thick, titin, and nebulin filaments. These filament systems have been investigated intensely for some time, but the details of their functions, as well as how they are connected to other cytoskeletal elements, are just beginning to be elucidated. These investigations have advanced significantly in recent years through the identification of novel sarcomeric and sarcomeric-associated proteins and their subsequent functional analyses in model systems. Mutations in these cytoskeletal components account for a large percentage of human myopathies, and thus insight into the normal functions of these proteins has provided a much needed mechanistic understanding of these disorders. In this review, we highlight the components of striated muscle cytoarchitecture with respect to their interactions, dynamics, links to signaling pathways, and functions. The exciting conclusion is that the striated muscle cytoskeleton, an exquisitely tuned, dynamic molecular machine, is capable of responding to subtle changes in cellular physiology.

Notes: Abstract Chromatin remodeling in plants has usually been discussed in relation to aspects of genome defense such as transgene silencing and the resetting of transposon activity. The role of remodeling in controlling development has been less emphasized, although well established in animal systems. This is because cell fate in plants is often held to be entirely specified on the basis of position, apparently excluding any significant role for cell ancestry and chromatin remodeling. We argue that chromatin remodeling is used to confer mitotically heritable cell fates at late stages in pattern formation. Several examples in which chromatin remodeling factors are used to confer a memory of transient events in plant development are discussed. Because the precise biochemical functions of most remodeling factors are obscure, and little is known of plant chromatin structure, the underlying mechanisms remain poorly understood.

Notes: Abstract Embryological and genetic studies of mouse, bird, zebrafish, and frog embryos are providing new insights into the regulatory functions of the myogenic regulatory factors, MyoD, Myf5, Myogenin, and MRF4, and the transcriptional and signaling mechanisms that control their expression during the specification and differentiation of muscle progenitors. Myf5 and MyoD genes have genetically redundant, but developmentally distinct regulatory functions in the specification and the differentiation of somite and head muscle progenitor lineages. Myogenin and MRF4 have later functions in muscle differentiation, and Pax and Hox genes coordinate the migration and specification of somite progenitors at sites of hypaxial and limb muscle formation in the embryo body. Transcription enhancers that control Myf5 and MyoD activation in muscle progenitors and maintain their expression during muscle differentiation have been identified by transgenic analysis. In epaxial, hypaxial, limb, and head muscle progenitors, Myf5 is controlled by lineage-specific transcription enhancers, providing evidence that multiple mechanisms control progenitor specification at different sites of myogenesis in the embryo. Developmental signaling ligands and their signal transduction effectors function both interactively and independently to control Myf5 and MyoD activation in muscle progenitor lineages, likely through direct regulation of their transcription enhancers. Future investigations of the signaling and transcriptional mechanisms that control Myf5 and MyoD in the muscle progenitor lineages of different vertebrate embryos can be expected to provide a detailed understanding of the developmental and evolutionary mechanisms for anatomical muscles formation in vertebrates. This knowledge will be a foundation for development of stem cell therapies to repair diseased and damaged muscles.

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

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

Notes: Abstract We review the recent progress in our understanding of the mechanical and electrical properties of carbon nanotubes, emphasizing the theoretical aspects. Nanotubes are the strongest materials known, but the ultimate limits of their strength have yet to be reached experimentally. Modeling of nanotube-reinforced composites indicates that the addition of small numbers of nanotubes may lead to a dramatic increase in the modulus, with only minimal crosslinking. Deformations in nanotube structures lead to novel structural transformations, some of which have clear electrical signatures that can be utilized in nanoscale sensors and devices. Chemical reactivity of nanotube walls is facilitated by strain, which can be used in processing and functionalization. Scanning tunneling microscopy and spectroscopy have provided a wealth of information about the structure and electronic properties of nanotubes, especially when coupled with appropriate theoretical models. Nanotubes are exceptional ballistic conductors, which can be used in a variety of nanodevices that can operate at room temperature. The quantum transport through nanotube structures is reviewed at some depth, and the critical roles played by band structure, one-dimensional confinement, and coupling to nanoscale contacts are emphasized. Because disorder or point defect-induced scattering is effectively averaged over the circumference of the nanotube, electrons can propagate ballistically over hundreds of nanometers. However, severe deformations or highly resistive contacts isolate nanotube segments and lead to the formation of quantum dots, which exhibit Coulomb blockade effects, even at room temperature. Metal-nanotube and nanotube-nanotube contacts range from highly transmissive to very resistive, depending on the symmetry of two structures, the charge transfer, and the detailed rehybridization of the wave functions. The progress in terms of nanotube applications has been extraordinarily rapid, as evidenced by the development of several nanotube-based prototypical devices, including memory and logic circuits, chemical sensors, electron emitters and electromechanical actuators.

Notes: Abstract Polymers offer a wide spectrum of possibilities for materials applications, in part because of the chemical complexity and variability of the constituent molecules, and in part because they can be blended together with other organic as well as inorganic components. The majority of applications of polymeric materials is based on their excellent mechanical properties, which arise from the long-chain nature of the constituents. Microscopically, this means that polymeric materials are able to respond to external forces in a broad frequency range, i.e., with a broad range of relaxation processes. Computer simulation methods are ideally suited to help to understand these processes and the structural properties that lead to them and to further our ability to predict materials properties and behavior. However, the broad range of timescales and underlying structure prohibits any one single simulation method from capturing all of these processes. This manuscript provides an overview of some of the more popular computational models and methods used today in the field of molecular and mesoscale simulation of polymeric materials, ranging from molecular models and methods that treat electronic degrees of freedom to mesoscopic field theoretic methods.

Notes: Abstract Computational mechanics comprises all types of computer modeling of the mechanical behavior of materials. In this contribution we concentrate on new developments in modeling based on the finite element method (FEM), especially deformation analyses based on numerical homogenization techniques (self-consistent embedding procedure, matricity model), simulations of real microstructural cut-outs, damage analyses of artificial and real microstructures, and multiscale modeling aspects. The limit flow stresses for transverse loading of metal matrix composites reinforced with continuous fibers and for uniaxial loading of spherical particle reinforced metal matrix composites are investigated by recently developed embedded cell models in conjunction with the finite element method. A fiber of circular cross section or a spherical particle is surrounded by a metal matrix, which is again embedded in the composite material, with the mechanical behavior to be determined iteratively in a self-consistent manner. Stress-strain curves have been calculated for a number of metal matrix composites with the embedded cell method and verified with literature data of a particle reinforced Ag/58vol.%Ni composite and for a transversely loaded uniaxially fiber reinforced Al/46vol.%B composite. Good agreement has been obtained between experiment and calculation, and the embedded cell model is thus found to well represent metal matrix composites with randomly arranged inclusions. Systematic studies of the mechanical behavior of fiber- and particle-reinforced composites with plane strain and axisymmetric embedded cell models are carried out to determine the influence of fiber or particle volume fraction and matrix strain-hardening ability on composite strengthening levels. Results for random inclusion arrangements obtained with self-consistent embedded cell models are compared with strengthening levels for regular inclusion arrangements from conventional unit cell models. It is found that with increasing inclusion volume fractions pronounced differences in composite strengthening exist between all models. Finally, closed-form expressions are derived to predict composite strengthening for regular fiber arrangements and for realistic random fiber or particle arrangements as a function of matrix hardening and particle volume fraction. The impact of the results on effectively designing technically relevant metal matrix composites reinforced by randomly arranged strong inclusions is emphasized. Atomistic modeling such as Monte Carlo (MC) simulations and molecular dynamics (MD) methods, dislocation theoretical modeling, and continuum mechanical methods are applied in order to provide insight into the mechanical behavior of materials. Simulations are presented graphically in a systematic manner for different material systems and are compared with experimental results. Finally, it will be shown that the results can be used to predict the future behavior of materials presently in service and even to design new materials.

Notes: Abstract The formation and evolution of galaxies is one of the great outstanding problems of astrophysics. Within the broad context of hierachical structure formation, we have only a crude picture of how galaxies like our own came into existence. A detailed physical picture where individual stellar populations can be associated with (tagged to) elements of the protocloud is far beyond our current understanding. Important clues have begun to emerge from both the Galaxy (near-field cosmology) and the high redshift universe (far-field cosmology). Here we focus on the fossil evidence provided by the Galaxy. Detailed studies of the Galaxy lie at the core of understanding the complex processes involved in baryon dissipation. This is a necessary first step toward achieving a successful theory of galaxy formation.

Notes: Abstract In this paper we review the properties of Lyman-break galaxies, namely starburst galaxies at high redshifts, approximately in the range 2.5 〈z〈 5, identified by the colors of their far ultraviolet spectral energy distribution around the 912 A Lyman continuum discontinuity. The properties of forming galaxies in the young universe are very important to constrain the history of galaxy evolution and the formation of the Hubble sequence, and until recently, they have remained largely unexplored. The Lyman-break technique has broken an impasse in the exploration of galaxies at high redshift that lasted for about two decades, and within a few years has yielded large and well-controlled samples of star-forming, but otherwise normal, galaxies at z〉 2.5, including ~1000 spectroscopic redshifts and another few thousands of robust candidates. This dataset has allowed us an unprecedented look at fundamental properties of galaxies at 20% of the Hubble time or less. In this paper, we discuss the nature of the Lyman-break galaxies and their properties, including star-formation rate, stellar and total mass, chemical abundance, morphology, and interstellar medium (ISM) kinematics, and outline their contribution to the stellar content of the universe and their connection to the galaxies observed in the present-day universe. We also discuss what the properties of these galaxies, in particular their spatial clustering, imply about the mechanisms of galaxy formation and about the relationship between the underlying distribution of dark matter and the activity of star formation.

Notes: Abstract Some applications of the study of outdoor acoustics and sets of data for sound-level spectra obtained close to the ground are described. Measurements and models of ground effects arising from the interaction between sound traveling directly from source to receiver and sound reflected from the ground are emphasized. Details are given concerning the influences of porosity, layering, small-scale surface roughness, and tall vegetation. Areas of related current and future research are outlined.

Notes: Abstract A Lagrangian description of turbulence has unique physical advantages that are especially important in studies of mixing and dispersion. We focus on fundamental aspects, using mainly data from direct numerical simulations capable of great detail and precision when specific accuracy requirements are met. Differences between time evolution in Eulerian and Lagrangian frames illustrate the dominance of advective transport. We examine basic results in Kolmogorov similarity, giving an estimate of an inertial-range universal constant and the grid resolution and Reynolds number needed to attain the requisite scaling range of time lags. The Lagrangian statistics of passive scalars are discussed in view of current efforts in model development, with differential diffusion between multiple scalars being characterized by shorter timescales. We also note the need for new data in more complex flows and in other applications where a Lagrangian viewpoint is especially useful.

Notes: Abstract In this review we describe the discovery and development of understanding of the so-called elliptical instability. This is the name given to the linear instability mechanism that tends to break up regions of elliptical streamlines in a rotating flow. The instability is discussed in the three different contexts-an unbounded strained vortex, a localized strained vortex, and a triaxial ellipsoid-where it was originally discovered and then rediscovered. These make it clear that the instability is one of parametric resonance where a normal mode, or pair of normal modes, of the undistorted rotating flow resonates with the underlying strain field. The effects of additional physics on the instability process are examined before its nonlinear evolution is discussed. Various applications of the instability in nature are then reviewed.

Notes: Abstract Filament-stretching rheometers are devices for measuring the extensional viscosity of moderately viscous non-Newtonian fluids such as polymer solutions. In these devices, a cylindrical liquid bridge is initially formed between two circular end-plates. The plates are then moved apart in a prescribed manner such that the fluid sample is subjected to a strong extensional deformation. Asymptotic analysis and numerical computation show that the resulting kinematics closely approximate those of an ideal homogeneous uniaxial elongation. The evolution in the tensile stress (measured mechanically) and the molecular conformation (measured optically) can be followed as functions of the rate of stretching and the total strain imposed. The resulting rheological measurements are a sensitive discriminant of molecularly based constitutive equations proposed for complex fluids. The dynamical response of the elongating filament is also coupled to the extensional rheology of the polymeric test fluid, and this can lead to complex viscoelastic-flow instabilities such as filament necking and rupture or elastic peeling from the rigid end-plates.

Notes: Abstract The evolution of a synthetic (zero-net mass flux) jet and the flow mechanisms of its interaction with a cross flow are reviewed. An isolated synthetic jet is produced by the interactions of a train of vortices that are typically formed by alternating momentary ejection and suction of fluid across an orifice such that the net mass flux is zero. A unique feature of these jets is that they are formed entirely from the working fluid of the flow system in which they are deployed and, thus, can transfer linear momentum to the flow system without net mass injection across the flow boundary. Synthetic jets can be produced over a broad range of length and timescale, and their unique attributes make them attractive fluidic actuators for a number of flow control applications. The interaction of synthetic jets with an external cross flow over the surface in which they are mounted can displace the local streamlines and induce an apparent or virtual change in the shape of the surface, thereby effecting flow changes on length scales that are one to two orders of magnitude larger than the characteristic scale of the jets. This control approach emphasizes an actuation frequency that is high enough so that the interaction domain between the actuator and the cross flow is virtually invariant on the global timescale of the flow, and therefore, global effects such as changes in aerodynamic forces are effectively decoupled from the operating frequency of the actuators.

Notes: Abstract In the past few years, in vivo technologies have emerged that, due to their efficiency and simplicity, may one day replace standard genetic engineering techniques. Constructs can be made on plasmids or directly on the Escherichia coli chromosome from PCR products or synthetic oligonucleotides by homologous recombination. This is possible because bacteriophage-encoded recombination functions efficiently recombine sequences with homologies as short as 35 to 50 base pairs. This technology, termed recombineering, is providing new ways to modify genes and segments of the chromosome. This review describes not only recombineering and its applications, but also summarizes homologous recombination in E. coli and early uses of homologous recombination to modify the bacterial chromosome. Finally, based on the premise that phage-mediated recombination functions act at replication forks, specific molecular models are proposed.

Notes: Abstract The molecular mechanisms for the transduction of light and chemical signals in animals are fairly well understood. In contrast, the processes by which the senses of touch, balance, hearing, and proprioception are transduced are still largely unknown. Biochemical approaches to identify transduction components are difficult to use with mechanosensory systems, but genetic approaches are proving more successful. Genetic research in several organisms has demonstrated the importance of cytoskeletal, extracellular, and membrane components for sensory mechanotransduction. In particular, researchers have identified channel proteins in the DEG/ENaC and TRP families that are necessary for signaling in a variety of mechanosensory cells. Proof that these proteins are components of the transduction channel, however, is incomplete.