ALBERT

Notes: Abstract NMR spin relaxation spectroscopy is a powerful approach for characterizing intramolecular and overall rotational motions in proteins. This review describes experimental methods for measuring laboratory frame spin relaxation rate constants by high-resolution solution-state NMR spectroscopy, together with theoretical approaches for interpreting spin relaxation data in order to quantify protein conformational dynamics on picosecond-nanosecond time scales. Recent applications of these techniques to proteins are surveyed, and investigations of the contribution of conformational chain entropy to protein function are highlighted. Insights into the dynamical properties of proteins obtained from NMR spin relaxation spectroscopy are compared with results derived from other experimental and theoretical techniques.

Notes: Abstract The fusion of vesicles with target membranes is controlled by a complex network of protein-protein and protein-lipid interactions. Structures of the SNARE complex, synaptotagmin III, nSec1, domains of the NSF chaperone and its adaptor SNAP, and Rab3 and some of its effectors provide the framework for developing molecular models of vesicle fusion and for designing experiments to test these models.

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

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

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

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

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

Notes: Abstract Proteins are designed to function in environments crowded by cosolutes, but most studies of protein equilibria are conducted in dilute solution. While there is no doubt that crowding changes protein equilibria, interpretations of the changes remain controversial. This review combines experimental observations on the effect of small uncharged cosolutes (mostly sugars) on protein stability with a discussion of the thermodynamics of cosolute-induced nonideality and critical assessments of the most commonly applied interpretations. Despite the controversy surrounding the most appropriate manner for interpreting these effects of thermodynamic nonideality arising from the presence of small cosolutes, experimental advantage may still be taken of the ability of the cosolute effect to promote not only protein stabilization but also protein self-association and complex formation between dissimilar reactants. This phenomenon clearly has potential ramifications in the cell, where the crowded environment could well induce the same effects.

Notes: Abstract Nuclear receptors (NRs) form a superfamily of ligand-inducible transcription factors composed of several domains. Recent structural studies focused on domain E, which harbors the ligand-binding site and the ligand-dependent transcription activation function AF-2. Structures of single representatives in an increasing number of various complexes as well as new structures of further NRs addressed issues such as discrimination of ligands, superagonism, isotype specificity, and partial agonism. Until today, one unique transcriptionally active form of domain E was determined; however, divergent tertiary structures of apo-forms and transcriptionally inactive forms are known. Thus, recent results link the transformation of NRs upon ligand binding to principles of protein folding. Furthermore, the ensemble of NR structures, including those of DNA-binding domains, provides one of the foundations for the understanding of interactions with transcription intermediary factors up to the characterization of the link between NR complexes and the basal transcriptional machinery at the structural level.

Notes: Abstract Microtubules are polymers that are essential for, among other functions, cell transport and cell division in all eukaryotes. The regulation of the microtubule system includes transcription of different tubulin isotypes, folding of alpha/beta-tubulin heterodimers, post-translation modification of tubulin, and nucleotide-based microtubule dynamics, as well as interaction with numerous microtubule-associated proteins that are themselves regulated. The result is the precise temporal and spatial pattern of microtubules that is observed throughout the cell cycle. The recent high-resolution analysis of the structure of tubulin and the microtubule has brought new insight to the study of microtubule function and regulation, as well as the mode of action of antimitotic drugs that disrupt normal microtubule behavior. The combination of structural, genetic, biochemical, and biophysical data should soon give us a fuller understanding of the exquisite details in the regulation of the microtubule cytoskeleton.

Notes: Abstract The past few years have seen exciting advances in understanding the structure and function of catalytic RNA. Crystal structures of several ribozymes have provided detailed insight into the folds of RNA molecules. Models of other biologically important RNAs have been constructed based on structural, phylogenetic, and biochemical data. However, many questions regarding the catalytic mechanisms of ribozymes remain. This review compares the structures and possible catalytic mechanisms of four small self-cleaving RNAs: the hammerhead, hairpin, hepatitis delta virus, and in vitro-selected lead-dependent ribozymes. The organization of these small catalysts is contrasted to that of larger ribozymes, such as the group I intron.

Notes: Abstract The bacterial pathogen Salmonella enterica has evolved a very sophisticated functional interface with its vertebrate hosts. At the center of this interface is a specialized organelle, the type III secretion system, that directs the translocation of bacterial proteins into the host cell. Salmonella spp. encode two such systems that deliver a remarkable array of bacterial proteins capable of modulating a variety of cellular functions, including actin cytoskeleton dynamics, nuclear responses, and endocytic trafficking. Many of these bacterial proteins operate by faithful mimicry of host proteins, in some cases representing the result of extensive molecular tinkering and convergent evolution. The coordinated action of these type III secreted proteins secures the replication and survival of the bacteria avoiding overt damage to the host. The study of this remarkable pathogen is not only illuminating general paradigms in microbial pathogenesis but is also providing valuable insight into host cell functions.

Notes: Abstract Vertebrate limb buds are embryonic structures for which much molecular and cellular data are known regarding the mechanisms that control pattern formation during development. Specialized regions of the developing limb bud, such as the zone of polarizing activity (ZPA), the apical ectodermal ridge (AER), and the non-ridge ectoderm, direct and coordinate the development of the limb bud along the anterior-posterior (AP), dorsal-ventral (DV), and proximal-distal (PD) axes, giving rise to a stereotyped pattern of elements well conserved among tetrapods. In recent years, specific gene functions have been shown to mediate the organizing and patterning activities of the ZPA, the AER, and the non-ridge ectoderm. The analysis of these gene functions has revealed the existence of complex interactions between signaling pathways operated by secreted factors of the HH, TGF-beta/BMP, WNT, and FGF superfamilies, which interact with many other genetic networks to control limb positioning, outgrowth, and patterning. The study of limb development has helped to establish paradigms for the analysis of pattern formation in many other embryonic structures and organs.

Notes: Abstract Cells in the immune and nervous systems communicate through informational synapses. The two-dimensional chemistry underlying the process of synapse formation is beginning to be explored using fluorescence imaging and mechanical techniques. Early analysis of two-dimensional kinetic rates (kon and koff) and equilibrium constants (Kd) provides a number of biological insights. First, there are two regimes for adhesion-one disordered with slow kon and the other self-ordered with 104-fold faster kon. Despite huge variation in two-dimensional kon, the two-dimensional koff is like koff in solution, and two-dimensional koff is more closely related to intrinsic properties of the interaction than the two-dimensional kon. Thus difference in koff can be used to set signaling thresholds. Early signaling complexes are compartmentalized to generate synergistic signaling domains. Immune antigen receptor components have a role in neural synapse editing. This suggests significant parallels in informational synapse formation based on common two-dimensional chemistry and signaling strategies.

Notes: Abstract Pollen tubes and root hairs are highly elongated, cylindrically shaped cells whose polarized growth permits them to explore the environment for the benefit of the entire plant. Root hairs create an enormous surface area for the uptake of water and nutrients, whereas pollen tubes deliver the sperm cells to the ovule for fertilization. These cells grow exclusively at the apex and at prodigious rates (in excess of 200 nm/s for pollen tubes). Underlying this rapid growth are polarized ion gradients and fluxes, turnover of cytoskeletal elements (actin microfilaments), and exocytosis and endocytosis of membrane vesicles. Intracellular gradients of calcium and protons are spatially localized at the growing apex; inward fluxes of these ions are apically directed. These gradients and fluxes oscillate with the same frequency as the oscillations in growth rate but not with the same phase. Actin microfilaments, which together with myosin generate reverse fountain streaming, undergo rapid turnover in the apical domain, possibly being regulated by key actin-binding proteins, e.g., profilin, villin, and ADF/cofilin, in concert with the ion gradients. Exocytosis of vesicles at the apex, also dependent on the ion gradients, provides precursor material for the continuously expanding cell wall of the growing cell. Elucidation of the interactions and of the dynamics of these different components is providing unique insight into the mechanisms of polarized growth.

Notes: Abstract Developing organisms may contain billions of cells destined to differentiate in numerous different ways. One strategy organisms use to simplify the orchestration of development is the separation of cell populations into distinct functional units. Our expanding knowledge of boundary formation and function in different systems is beginning to reveal general principles of this process. Fields of cells are subdivided by the interpretation of morphogen gradients, and these subdivisions are then maintained and refined by local cell-cell interactions. Sharp and stable separation between cell populations requires special mechanisms to keep cells segregated, which in many cases appear to involve the regulation of cell affinity. Once cell populations become distinct, specialized cells are often induced along the borders between them. These boundary cells can then influence the patterning of surrounding cells, which can result in progressively finer subdivisions of a tissue. Much has been learned about the signaling pathways that establish boundaries, but a key challenge for the future remains to elucidate the cellular and molecular mechanisms that actually keep cell populations separated.

Notes: Abstract We focus on new observational capabilities (Yohkoh, SoHO, TRACE), observations, modeling approaches, and insights into physical processes of the solar corona. The most impressive new results and problems discussed in this article can be appreciated from the movies available on the Annual Reviews website and at http://www.lmsal.com/pub/araa/araa.html . "The Sun is new each day." Heraclites (ca 530-475 BC) "Everything flows." Heraclites (ca 530-475 BC)

Notes: Abstract This review takes a critical look at the cosmological scenario at the turn of the century by examining the available cosmological models in the light of the present observational evidence. The center stage is held by the big bang models, which are collectively referred to here as standard cosmology (SC) and its extensions. SC itself is characterized by a seven parameter set of models based on Einstein's general theory of relativity. The seven parameters are H0, OmegaB, OmegaDM, OmegaLambda, OmegaR (describing the background universe, and A, n (specifying the amplitude and power law index of initial fluctuation spectrum). The extended SC includes extrapolations of the SC to earlier epochs when the mean energies of the particles were greater than about 100 GeV. The strength of the SC is seen to lie in its successful prediction of the expansion of the universe, the abundance of light nuclei, and the spectrum and anisotropies of the cosmic microwave background (CMBR). The SC has led to a whole class of theories of structure formation, which are, in principle, testable observationally. The subject of twentieth century cosmology gained considerably from occasional ideas different from the SC; some of these are briefly outlined and placed in historical perspective. Currently there is only one alternative cosmology, the quasi steady state cosmology (QSSC), that has been developed to a stage where it can be compared with observations and also with the SC. Although the SC does appear quite successful, there are still many unresolved issues that keep the cosmological scene fairly open.

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

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

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

Notes: Abstract The development of cancer requires multiple genetic alterations perturbing distinct cellular pathways. In human cancers, these alterations often arise owing to mutations in tumor-suppressor genes whose normal function is to either inhibit the proliferation, apoptosis, or differentiation of cells, or maintain their genomic integrity. Mouse models for tumor suppressors frequently provide definitive evidence for the antitumorigenic functions of these genes. In addition, animal models permit the identification of previously unsuspected roles of these genes in development and differentiation. The availability of null and tissue-specific mouse mutants for tumor-suppressor genes has greatly facilitated our understanding of the mechanisms leading to cancer. In this review, we describe mouse models for tumor-suppressor genes.

Notes: Abstract Chromatin boundaries and insulators are transcriptional regulatory elements that modulate interactions between enhancers and promoters and protect genes from silencing effects by the adjacent chromatin. Originally discovered in Drosophila, insulators have now been found in a variety of organisms, ranging from yeast to humans. They have been found interspersed with regulatory sequences in complex genes and at the boundaries between active and inactive chromatin. Insulators might modulate transcription by organizing the chromatin fiber within the nucleus through the establishment of higher-order domains of chromatin structure.

Notes: Abstract Double-strand breaks and other lesions in DNA can stimulate homologous genetic recombination in two quite different ways: by promoting recombination near the break (roughly within a kb) or far from the break. Recent emphasis on the repair aspect of recombination has focused attention on DNA interactions and recombination near breaks. Here I review evidence for recombination far from DNA breaks in bacteria and fungi and discuss mechanisms by which this can occur. These mechanisms include entry of a traveling entity ("recombination machine") at a break, formation of long heteroduplex DNA, priming of DNA replication by a broken end, and induction of recombination potential in trans. Special emphasis is placed on contrasting views of how the RecBCD enzyme of Escherichia coli promotes recombination far (tens of kb) from a double-strand break. The occurrence of recombination far from DNA breaks and of correlated recombination events far apart suggests that "action at a distance" during recombination is a widespread feature among diverse organisms.

Notes: Abstract Recombination is a major source of genetic variability in retroviruses. Each viral particle contains two single-stranded genomic RNAs. Recombination mostly results from a switch in template between these two RNAs during reverse transcription. Here we emphasize the main mechanisms underlying recombination that are emerging from recent advances in biochemical and cell culture techniques. Increasing evidence supporting the involvement of RNA secondary structures now complements the predominant role classically attributed to enzyme pausing during reverse transcription. Finally, the implications of recombination on the dynamics of emergence of genomic aberrations in retroviruses are discussed.

Notes: Abstract A central aspect of cellular function is the proper regulation of nucleocytoplasmic transport. In recent years, significant progress has been made in identifying and characterizing the essential components of the transport machinery. Despite these advances, some facets of this process are still unclear. Furthermore, recent work has uncovered novel molecules and mechanisms of nuclear transport. This review focuses on the unresolved and novel aspects of nuclear transport and explores issues in tRNA, snRNA, and mRNA export that highlight the diversity of nuclear transport mechanisms.

Notes: Abstract Phenotypic variation for quantitative traits results from the segregation of alleles at multiple quantitative trait loci (QTL) with effects that are sensitive to the genetic, sexual, and external environments. Major challenges for biology in the post-genome era are to map the molecular polymorphisms responsible for variation in medically, agriculturally, and evolutionarily important complex traits; and to determine their gene frequencies and their homozygous, heterozygous, epistatic, and pleiotropic effects in multiple environments. The ease with which QTL can be mapped to genomic intervals bounded by molecular markers belies the difficulty in matching the QTL to a genetic locus. The latter requires high-resolution recombination or linkage disequilibrium mapping to nominate putative candidate genes, followed by genetic and/or functional complementation and gene expression analyses. Complete genome sequences and improved technologies for polymorphism detection will greatly advance the genetic dissection of quantitative traits in model organisms, which will open avenues for exploration of homologous QTL in related taxa.

Notes: Abstract Translational control is a prevalent means of gene regulation during Drosophila oogenesis and embryogenesis. Multiple maternal mRNAs are localized within the oocyte, and this localization is often coupled to their translational regulation. Subsequently, translational control allows maternally deposited mRNAs to direct the early stages of embryonic development. In this review we outline some general mechanisms of translational regulation and mRNA localization that have been uncovered in various model systems. Then we focus on the posttranscriptional regulation of four maternal transcripts in Drosophila that are localized during oogenesis and are critical for embryonic patterning: bicoid (bcd), nanos (nos), oskar (osk), and gurken (grk). Cis- and trans-acting factors required for the localization and translational control of these mRNAs are discussed along with potential mechanisms for their regulation.

Notes: Abstract Although coevolution is complicated, in that the interacting species evolve in response to each other, such evolutionary dynamics are amenable to mathematical modeling. In this article, we briefly review models and data on coevolution between plants and the pathogens and herbivores that attack them. We focus on "arms races," in which trait values in the plant and its enemies escalate to more and more extreme values. Untested key assumptions in many of the models are the relationships between costs and benefits of resistance in the plant and the level of resistance, as well as how costs of virulence or detoxification ability in the enemy change with levels of these traits. A preliminary assessment of these assumptions finds only mixed support for the models. What is needed are models that are more closely tailored to particular plant-enemy interactions, as well as experiments that are expressly designed to test existing models.

Notes: Abstract Calmodulin, a small, ubiquitous Ca2+-binding protein, regulates a wide variety of proteins and processes in all eukaryotes. CMD1, the single gene encoding calmodulin in S. cerevisiae, is essential, and this review discusses studies that identified many of calmodulin's physiological targets and their functions in yeast cells. Calmodulin performs essential roles in mitosis, through its regulation of Nuf1p/Spc110p, a component of the spindle pole body, and in bud growth, by binding Myo2p, an unconventional class V myosin required for polarized secretion. Surprisingly, mutant calmodulins that fail to bind Ca2+ can perform these essential functions. Calmodulin is also required for endocytosis in yeast and participates in Ca2+-dependent, stress-activated signaling pathways through its regulation of a protein phosphatase, calcineurin, and the protein kinases, Cmk1p and Cmk2p. Thus, calmodulin performs important physiological functions in yeast cells in both its Ca2+-bound and Ca2+-free form.

Notes: Abstract The development of molecular markers and genomic resources has facilitated the isolation of genes responsible for rare monogenic epilepsies in human and mouse. Many of the identified genes encode ion channels or other components of neuronal signaling. The electrophysiological properties of mutant alleles indicate that neuronal hyperexcitability is one cellular mechanism underlying seizures. Genetic heterogeneity and allelic variability are hallmarks of human epilepsy. For example, mutations in three different sodium channel genes can produce the same syndrome, GEFS+, while individuals with the same allele can experience different types of seizures. Haploinsufficiency for the sodium channel SCN1A has been demonstrated by the severe infantile epilepsy and cognitive deficits in heterozygotes for de novo null mutations. Large-scale patient screening is in progress to determine whether less severe alleles of the genes responsible for monogenic epilepsy may contribute to the common types of epilepsy in the human population. The development of pharmaceuticals directed towards specific epilepsy genotypes can be anticipated, and the introduction of patient mutations into the mouse genome will provide models for testing these targeted therapies.

Notes: Abstract Hereditary isolated hearing loss is genetically highly heterogeneous. Over 100 genes are predicted to cause this disorder in humans. Sixty loci have been reported and 24 genes underlying 28 deafness forms have been identified. The present epistemic stage in the realm consists in a preliminary characterization of the encoded proteins and the associated defective biological processes. Since for several of the deafness forms we still only have fuzzy notions of their pathogenesis, we here adopt a presentation of the various deafness forms based on the site of the primary defect: hair cell defects, nonsensory cell defects, and tectorial membrane anomalies. The various deafness forms so far studied appear as monogenic disorders. They are all rare with the exception of one, caused by mutations in the gene encoding the gap junction protein connexin26, which accounts for between one third to one half of the cases of prelingual inherited deafness in Caucasian populations.

Notes: Abstract The separation of sister chromatids at the metaphase to anaphase transition is one of the most dramatic of all cellular events and is a crucial aspect of all sexual and asexual reproduction. The molecular basis for this process has until recently remained obscure. New research has identified proteins that hold sisters together while they are aligned on the metaphase plate. It has also shed insight into the mechanisms that dissolve sister chromatid cohesion during both mitosis and meiosis. These findings promise to provide insights into defects in chromosome segregation that occur in cancer cells and into the pathological pathways by which aneuploidy arises during meiosis.

Notes: Abstract The polarized architecture of epithelial cells and tissues is a fundamental determinant of animal anatomy and physiology. Recent progress made in the genetic and molecular analysis of epithelial polarity and cellular junctions in Drosophila has led to the most detailed understanding of these processes in a whole animal model system to date. Asymmetry of the plasma membrane and the differentiation of membrane domains and cellular junctions are controlled by protein complexes that assemble around transmembrane proteins such as DE-cadherin, Crumbs, and Neurexin IV, or other cytoplasmic protein complexes that associate with the plasma membrane. Much remains to be learned of how these complexes assemble, establish their polarized distribution, and contribute to the asymmetric organization of epithelial cells.

Notes: Abstract Human population genetics has entered a new era of public interest, of controversy, and of ethical problems. Population genetics raises novel ethical problems because both the individuals and the populations being studied are, in effect, "subjects" of the research. Those populations are collectively subject to possible benefits and harms from the research and have interests, somewhat different from those of the individuals, that must be considered from both ethical and practical standpoints. The chapter first describes the new setting for research in human population genetics. It then examines the most controversial ethical issue in population genetics-whether researchers must obtain the informed consent of both the individual subjects and the group as a collectivity. Other vexing issues, including special problems caused by researchers' commercial interests, confidentiality, control over research uses and materials, and return of information to the population are also considered.

Notes: Figure 1 G. LEDYARD STEBBINS Reproduction from Original Negative by Ansel Adams, Courtesy UCR/California Museum of Photography, Sweeney/Rubin Ansel Adams FIAT LUX Collection, University of California at Riverside. Figure 1 G. LEDYARD STEBBINS Reproduction from Original Negative by Ansel Adams, Courtesy UCR/Californ... More than any other individual, Stebbins synthesized knowledge from a disparate set of areas that included plant genetics, systematics, and evolution. This work culminated in 1950 with the appearance of his magnum opus, Variation and Evolution in Plants. This book gave plant evolution a coherent framework that was compatible with that emerging from the work of Theodosius Dobzhansky, Ernst Mayr, G. G. Simpson, and Julian Huxley, and others associated with establishing the synthetic theory of evolution. For this work he is regarded as the botanical "architect" of the evolutionary synthesis.

Notes: Abstract Genetic screens in Drosophila melanogaster have helped elucidate the process of axis formation during early embryogenesis. Axis formation in the D. melanogaster embryo involves the use of two fundamentally different mechanisms for generating morphogenetic activity: patterning the anteroposterior axis by diffusion of a transcription factor within the syncytial embryo and specification of the dorsoventral axis through a signal transduction cascade. Identification of Drosophila genes involved in axis formation provides a launch-pad for comparative studies that examine the evolution of axis specification in different insects. Additionally, there is similarity between axial patterning mechanisms elucidated genetically in Drosophila and those demonstrated for chordates such as Xenopus. In this review we examine the postfertilization mechanisms underlying axis specification in Drosophila. Comparative data are then used to ask whether aspects of axis formation might be derived or ancestral.

Notes: Abstract Quorum sensing is an example of community behavior prevalent among diverse bacterial species. The term "quorum sensing" describes the ability of a microorganism to perceive and respond to microbial population density, usually relying on the production and subsequent response to diffusible signal molecules. A significant number of gram-negative bacteria produce acylated homoserine lactones (acyl-HSLs) as signal molecules that function in quorum sensing. Bacteria that produce acyl-HSLs can respond to the local concentration of the signaling molecules, and high population densities foster the accumulation of inducing levels of acyl-HSLs. Depending upon the bacterial species, the physiological processes regulated by quorum sensing are extremely diverse, ranging from bioluminescence to swarming motility. Acyl-HSL quorum sensing has become a paradigm for intercellular signaling mechanisms. A flurry of research over the past decade has led to significant understanding of many aspects of quorum sensing including the synthesis of acyl-HSLs, the receptors that recognize the acyl-HSL signal and transduce this information to the level of gene expression, and the interaction of these receptors with the transcriptional machinery. Recent studies have begun to integrate acyl-HSL quorum sensing into global regulatory networks and establish its role in developing and maintaining the structure of bacterial communities.

Notes: Abstract L1 retrotransposons comprise 17% of the human genome. Although most L1s are inactive, some elements remain capable of retrotransposition. L1 elements have a long evolutionary history dating to the beginnings of eukaryotic existence. Although many aspects of their retrotransposition mechanism remain poorly understood, they likely integrate into genomic DNA by a process called target primed reverse transcription. L1s have shaped mammalian genomes through a number of mechanisms. First, they have greatly expanded the genome both by their own retrotransposition and by providing the machinery necessary for the retrotransposition of other mobile elements, such as Alus. Second, they have shuffled non-L1 sequence throughout the genome by a process termed transduction. Third, they have affected gene expression by a number of mechanisms. For instance, they occasionally insert into genes and cause disease both in humans and in mice. L1 elements have proven useful as phylogenetic markers and may find other practical applications in gene discovery following insertional mutagenesis in mice and in the delivery of therapeutic genes.

Notes: Abstract Early studies of animal mitochondrial DNA (mtDNA) assumed that nucleotide sequence variation was neutral. Recent analyses of sequences from a variety of taxa have brought the validity of this assumption into question. Here we review analytical methods used to test for neutrality and evidence for nonneutral evolution of animal mtDNA. Evaluations of mitochondrial haplotypes in different nuclear backgrounds identified differences in performance, typically favoring coevolved mitochondrial and nuclear genomes. Experimental manipulations also indicated that certain haplotypes have an advantage over others; however, biotic and historical effects and cyto-nuclear interactions make it difficult to assess the relative importance of nonneutral factors. Statistical analyses of sequences have been used to argue for nonneutrality of mtDNA; however, rejection of neutral patterns in the published literature is common but not predominant. Patterns of replacement and synonymous substitutions within and between species identified a trend toward an excess of replacement mutations within species. This pattern has been viewed as support for the existence of mildly deleterious mutations within species; however, other alternative explanations that can produce similar patterns cannot be eliminated.

Notes: Abstract Structural models of site-specific recombinases from the lambda integrase family of enzymes have in the last four years provided an important new perspective on the three-dimensional nature of the recombination pathway. Members of this family, which include the bacteriophage P1 Cre recombinase, bacteriophage lambda integrase, the yeast Flp recombinase, and the bacterial XerCD recombinases, exchange strands between DNA substrates in a stepwise process. One pair of strands is exchanged to form a Holliday junction intermediate, and the second pair of strands is exchanged during resolution of the junction to products. Crystal structures of reaction intermediates in the Cre-loxP site-specific recombination system, together with recent biochemical studies in the field, support a "strand swapping" model for recombination that does not require branch migration of the Holliday junction intermediate in order to test homology between recombining sites.

Notes: Abstract On laboratory time scales, the energy landscape of a weak bond along a dissociation pathway is fully explored through Brownian-thermal excitations, and energy barriers become encoded in a dissociation time that varies with applied force. Probed with ramps of force over an enormous range of rates (force/time), this kinetic profile is transformed into a dynamic spectrum of bond rupture force as a function of loading rate. On a logarithmic scale in loading rate, the force spectrum provides an easy-to-read map of the prominent energy barriers traversed along the force-driven pathway and exposes the differences in energy between barriers. In this way, the method of dynamic force spectroscopy (DFS) is being used to probe the complex relation between force-lifetime-and chemistry in single molecular bonds. Most important, DFS probes the inner world of molecular interactions to reveal barriers that are difficult or impossible to detect in assays of near equilibrium dissociation but that determine bond lifetime and strength under rapid detachment. To use an ultrasensitive force probe as a spectroscopic tool, we need to understand the physics of bond dissociation under force, the impact of experimental technique on the measurement of detachment force (bond strength), the consequences of complex interactions in macromolecular bonds, and effects of multiply-bonded attachments.

Notes: Abstract Understanding the mechanisms by which genetic information is replicated is important both to basic knowledge of biological organisms and to many useful applications in biomedical research and biotechnology. One of the main functions of a DNA polymerase enzyme is to help DNA recognize itself with high specificity when a strand is being copied. Recent studies have shed new light on the question of what physical forces cause a polymerase enzyme to insert a nucleotide into a strand of DNA and to choose the correct nucleotide over the incorrect ones. This is discussed in the light of three main forces that govern DNA recognition: base stacking, Watson-Crick hydrogen bonding, and steric interactions. These factors are studied with natural and structurally altered DNA nucleosides.

Notes: Abstract Enzymes of the mitochondrial respiratory chain serve as proton pumps, using the energy made available from electron transfer reactions to transport protons across the inner mitochondrial membrane and create an electrochemical gradient used for the production of ATP. The ATP synthase enzyme is reversible and can also serve as a proton pump by coupling ATP hydrolysis to proton translocation. Each of the respiratory enzymes uses a different strategy for performing proton pumping. In this work, the strategies are described and the structural bases for the action of these proteins are discussed in light of recent crystal structures of several respiratory enzymes. The mechanisms and efficiency of proton translocation are also analyzed in terms of the thermodynamics of the substrate transformations catalyzed by these enzymes.

Notes: Abstract Atomic resolution structure determinations of proteins by X-ray crystallography are formidable multidisciplinary undertakings, requiring protein construct design, expression and purification, crystallization trials, phase determination, and model building. Modern mass spectrometric methods can greatly facilitate these obligate tasks. Thus, mass spectrometry can be used to verify that the desired protein construct has been correctly expressed, to define compact domains in the target protein, to assess the components contained within the protein crystals, and to screen for successful incorporation of seleno-methionine and other heavy metal reagents used for phasing. In addition, mass spectrometry can be used to address issues of modeling, topology, and side-chain proximity. Here, we demonstrate how rational use of mass spectrometry assists and expedites high resolution X-ray structure determination through each stage of the process of protein crystallography.

Notes: Abstract Understanding the precise role of photosystem II as an element of oxygenic photosynthesis requires knowledge of the molecular structure of this membrane protein complex. The past few years have been particularly exciting because the structural era of the plant photosystem II has begun. Although the atomic structure has yet to be determined, the map obtained at 6 A resolution by electron crystallography allows assignment of the key reaction center subunits with their associated pigment molecules. In the following, we first review the structural details that have recently emerged and then discuss the primary and secondary photochemical reaction pathways. Finally, in an attempt to establish the evolutionary link between the oxygenic and the anoxygenic photosynthesis, a framework structure common to all photosynthetic reaction centers has been defined, and the implications have been described.

Notes: Abstract This review focuses on recent advances in understanding protein folding kinetics in the context of nucleation theory. We present basic concepts such as nucleation, folding nucleus, and transition state ensemble and then discuss recent advances and challenges in theoretical understanding of several key aspects of protein folding kinetics. We cover recent topology-based approaches as well as evolutionary studies and molecular dynamics approaches to determine protein folding nucleus and analyze other aspects of folding kinetics. Finally, we briefly discuss successful all-atom Monte-Carlo simulations of protein folding and conclude with a brief outlook for the future.

Notes: Abstract Oligosaccharides play a crucial role in many of the recognition, signaling, and adhesion events that take place at the surface of cells. Abnormalities in the synthesis or presentation of these carbohydrates can lead to misfolded and inactive proteins, as well as to several debilitating disease states. However, their diverse structures, which are the key to their function, have hampered studies by biologists and chemists alike. This review presents an overview of techniques for examining and manipulating cell surface oligosaccharides through genetic, enzymatic, and chemical strategies.

Notes: Abstract Thrombospondins are secreted, multidomain macromolecules that act as regulators of cell interactions in vertebrates. Gene knockout mice constructed for two members of this family demonstrate roles in the organization and homeostasis of multiple tissues, with particularly significant activities in the regulation of angiogenesis. This review discusses the functions of thrombospondins with regard to their cellular mechanisms of action and highlights recent advances in understanding how multifactorial molecular interactions, at the cell surface and within extracellular matrix, produce cell-type-specific effects on cell behavior and the organization of matrix and tissues.

Notes: Abstract Multipotent stem cells are clonal cells that self-renew as well as differentiate to regenerate adult tissues. Whereas stem cells and their fates are known by unique genetic marker studies, the fate and function of these cells are best studied by their prospective isolation. This review is about the properties of various highly purified tissue-specific multipotent stem cells and purified oligolineage progenitors. We contend that unless the stem or progenitor cells in question have been purified to near homogeneity, one cannot know whether their generation of expected (or unexpected) progeny is a property of a known cell type. It is interesting that in the hematopoietic system the only long-term self-renewing cells in the stem and progenitors pool are the hematopoietic stem cells. This fact is discussed in the context of normal and leukemic hematopoiesis.

Notes: Abstract Mouse embryonic stem cells are continuous cell lines derived directly from the fetal founder tissue of the preimplantation embryo. They can be expanded in culture while retaining the functional attributes of pluripotent early embryo cells. In particular, they can participate fully in fetal development when reintroduced into the embryo. The capacity for multilineage differentiation is reproduced in culture where embryonic stem cells can produce a wide range of well-defined cell types. This has stimulated interest in the isolation of analogous cells of human origin. Such human pluripotent stem cells could constitute a renewable source of more differentiated cells that could be employed to replace diseased or damaged tissue by cellular transplantation. In this review, the relationships between mouse embryonic stem cells, resident pluripotent cells in the embryo, and human embryo-derived cell lines are evaluated, and the prospects and challenges of embryo stem cell research are considered. This review is dedicated to Rosa Beddington FRS, a great developmental biologist, a wonderful colleague, and an inspirational advocate of human stem cell research.

Notes: Abstract The matrix metalloproteinases (MMPs) constitute a multigene family of over 25 secreted and cell surface enzymes that process or degrade numerous pericellular substrates. Their targets include other proteinases, proteinase inhibitors, clotting factors, chemotactic molecules, latent growth factors, growth factor-binding proteins, cell surface receptors, cell-cell adhesion molecules, and virtually all structural extracellular matrix proteins. Thus MMPs are able to regulate many biologic processes and are closely regulated themselves. We review recent advances that help to explain how MMPs work, how they are controlled, and how they influence biologic behavior. These advances shed light on how the structure and function of the MMPs are related and on how their transcription, secretion, activation, inhibition, localization, and clearance are controlled. MMPs participate in numerous normal and abnormal processes, and there are new insights into the key substrates and mechanisms responsible for regulating some of these processes in vivo. Our knowledge in the field of MMP biology is rapidly expanding, yet we still do not fully understand how these enzymes regulate most processes of development, homeostasis, and disease.

Notes: Abstract There has recently been considerable progress in understanding the regulation of clathrin-coated vesicle (CCV) formation and function. These advances are due to the determination of the structure of a number of CCV coat components at molecular resolution and the identification of novel regulatory proteins that control CCV formation in the cell. In addition, pathways of (a) phosphorylation, (b) receptor signaling, and (c) lipid modification that influence CCV formation, as well as the interaction between the cytoskeleton and CCV transport pathways are becoming better defined. It is evident that although clathrin coat assembly drives CCV formation, this fundamental reaction is modified by different regulatory proteins, depending on where CCVs are forming in the cell. This regulatory difference likely reflects the distinct biological roles of CCVs at the plasma membrane and trans-Golgi network, as well as the distinct properties of these membranes themselves. Tissue-specific functions of CCVs require even more-specialized regulation and defects in these pathways can now be correlated with human diseases.

Notes: Abstract A distinctive and essential feature of the vertebrate body is a pronounced left-right asymmetry of internal organs and the central nervous system. Remarkably, the direction of left-right asymmetry is consistent among all normal individuals in a species and, for many organs, is also conserved across species, despite the normal health of individuals with mirror-image anatomy. The mechanisms that determine stereotypic left-right asymmetry have fascinated biologists for over a century. Only recently, however, has our understanding of the left-right patterning been pushed forward by links to specific genes and proteins. Here we examine the molecular biology of the three principal steps in left-right determination: breaking bilateral symmetry, propagation and reinforcement of pattern, and the translation of pattern into asymmetric organ morphogenesis.

Notes: Abstract Circadian rhythms are found in most eukaryotes and some prokaryotes. The mechanism by which organisms maintain these roughly 24-h rhythms in the absence of environmental stimuli has long been a mystery and has recently been the subject of intense research. In the past few years, we have seen explosive progress in the understanding of the molecular basis of circadian rhythms in model systems ranging from cyanobacteria to mammals. This review attempts to outline these primarily genetic and biochemical findings and encompasses work done in cyanobacteria, Neurospora, higher plants, Drosophila, and rodents. Although actual clock components do not seem to be conserved between kingdoms, central clock mechanisms are conserved. Somewhat paradoxically, clock components that are conserved between species can be used in diverse ways. The different uses of common components may reflect the important role that the circadian clock plays in adaptation of species to particular environmental niches.

Notes: Abstract The synthesis of the two currently used superhard materials, diamond and cubic boron nitride, is briefly described with indications of the factors influencing the quality of the crystals obtained. The physics of hardness is discussed and the importance of covalent bonding and fixed atomic positions in the crystal structure, which determine high hardness values, is outlined. The materials investigated to date are described and new potentially superhard materials are presented. No material that is thermodynamically stable under ambient conditions and composed of light (small) atoms will have a hardness greater than that of diamond. Materials with hardness values similar to that of cubic boron nitride (cBN) can be obtained. However, increasing the capabilities of the high-pressure devices could lead to the production of better quality cBN compacts without binders.

Notes: Abstract A review of the field of photorefractive liquid crystals is presented. The first reports of photorefractive liquid crystals occurred in 1994, and the performance of these materials has dramatically improved since that time. Liquid crystalline materials have proven to be highly versatile, showing photorefractive character under a wide range of conditions. For example, new composites based on high-molar-mass liquid crystals are now capable of forming volume (Bragg) gratings with high photorefractive gain coefficients of 〉600 cm-1. Formation times for photorefractive Bragg gratings of 15 ms with applied fields of only 0.1 V/mum have been reported. Low-molar-mass liquid crystals continue to be developed and show their largest photorefractive character in the thin (Raman-Nath) grating regime. Composites of nonmesogenic polymers and liquid crystals are also discussed. The experiments and theoretical work that have been used to characterize these materials are reviewed.

Notes: Abstract The field of biomaterials has recently been focused on the design of intelligent materials. Toward this goal, materials have been developed that can provide specific bioactive signals to control the biological environment around them during the process of materials integration and wound healing. In addition, materials have been developed that can respond to changes in their environment, such as a change in pH or cell-associated enzymatic activity. In designing such novel biomaterials, researchers have sought not merely to create bio-inert materials, but rather materials that can respond to the cellular environment around them to improve device integration and tissue regeneration.

Notes: Abstract A two-part review of research concerning block copolymer thin films is presented. The first section summarizes experimental and theoretical studies of the fundamental physics of these systems, concentrating upon the forces that govern film morphology. The role of film thickness and surface energetics on the morphology of compositionally symmetric, amorphous diblock copolymer films is emphasized, including considerations of boundary condition symmetry, so-called hybrid structures, and surface chemical expression. Discussions of compositionally asymmetric systems and emerging research areas, e.g., liquid-crystalline and A-B-C triblock systems, are also included. In the second section, technological applications of block copolymer films, e.g., as lithographic masks and photonic materials, are considered. Particular attention is paid to means by which microphase domain order and orientation can be controlled, including exploitation of thickness and surface effects, the application of external fields, and the use of patterned substrates.

Notes: Abstract The Orion Nebula (M 42) is one of the best studied objects in the sky. The advent of multi-wavelength investigations and quantitative high resolution imaging has produced a rapid improvement in our knowledge of what is widely considered the prototype H II region and young galactic cluster. Perhaps uniquely among this class of object, we have a good three dimensional picture of the nebula, which is a thin blister of ionized gas on the front of a giant molecular cloud, and the extremely dense associated cluster. The same processes that produce the nebula also render visible the circumstellar material surrounding many of the pre-main sequence low mass stars, while other circumstellar clouds are seen in silhouette against the nebula. The process of photoevaporation of ionized gas not only determines the structure of the nebula that we see, but is also destroying the circumstellar clouds, presenting a fundamental conundrum about why these clouds still exist.

Notes: Abstract Distant type Ia supernovae (SNe Ia) appear fainter than their local counterparts. Independent of what explanation will eventually be found to be correct, this implies a significant change in how we see the distant universe and what we understand of these stellar explosions. The observational characteristics of nearby SNe Ia show some differences from event to event. Despite their considerable range in observed peak luminosity, they can be normalized by their light-curve shape. Through this normalization, SNe Ia can be used as exquisite distance indicators. The Hubble diagram of nearby SNe Ia, demonstrating the linear cosmic expansion at small scales, is the simplest observational proof for the standard character of these objects. Compared with Friedmann models of the universe, the distant SNe are too faint even for a freely coasting, "empty" universe, barring other influences that could dim the events. This result is independent of the absolute calibration of the peak luminosity, which is needed to derive the Hubble constant. Possible noncosmological explanations could be gray dust, with properties that do not change the color of the objects significantly, evolution of the explosions, or deamplification by gravitational lensing. Current indications are that none of these alternatives alone can explain the dimness of the distant SNe. The intrinsic colors of the distant SNe Ia are typically bluer when compared with the local sample. This in itself makes the dust hypothesis less likely. On the other hand, it could be a signature of evolutionary trends that could influence the peak luminosity. This trend is contrary to the observations in the local sample, where bluer objects typically are more luminous. However, current lack of understanding of the explosion physics and the radiation transport of SNe Ia encumbers any investigation of evolutionary changes. Any change in the peak luminosity of SNe Ia must be inferred from indirect observations, such as light-curve shape, colors, and spectral evolution. At the moment, many of the distant SNe do not have the required data set for a detailed investigation of these parameters. The near-uniform light-curve and spectral evolution of SNe Ia can be used as accurate cosmic clocks to demonstrate the time dilation as predicted from expanding world models. The test has been performed through both photometry and spectroscopy, and is fully consistent with the predictions. The supernova (SN) results can be reconciled only with cosmological models that provide some form of acceleration. The simplest such models either include the cosmological constant or refer to a decaying particle field ("quintessence"). Combined with recent measurements of the cosmic microwave background that indicate a flat geometry of the universe, and low-matter density, as derived from bulk flows and the evolution of galaxy clusters, the SNe define a fairly narrow likelihood region for OmegaM and OmegaLambda. With these new values for the cosmological parameters, the long-standing problem of the dynamical age of the universe appears to be solved. On the other hand, the size of the acceleration, if interpreted as a cosmological constant, is in clear contradiction to predictions from particle theories. In addition, we live in a very privileged period when matter density and the cosmological constant are equal contributors to the cosmic expansion.

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

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

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

Notes: Abstract The inner few parsecs at the Galactic Center have come under intense scrutiny in recent years, in part due to the exciting broad-band observations of this region, but also because of the growing interest from theorists motivated to study the physics of black hole accretion, magnetized gas dynamics, and unusual star formation. The Galactic Center is now known to contain arguably the most compelling supermassive black hole candidate, weighing in at a little over 2.6 million suns. Its interaction with the nearby environment, comprised of clusters of evolved and young stars, a molecular dusty ring, ionized gas streamers, diffuse hot gas, and a hypernova remnant, is providing a wealth of accretion phenomenology and high-energy processes for detailed modeling. In this review, we summarize the latest observational results and focus on the physical interpretation of the most intriguing object in this region-the compact radio source Sgr A*, thought to be the radiative manifestation of the supermassive black hole.

Notes: Abstract The field of optical and infrared (IR) interferometry has seen rapid technical and scientific progress over the past few years. A number of instruments capable of precise visibility measurements have been built, and closure-phase imaging with multitelescope arrays has been demonstrated. Astronomical results from these instruments include measurements of stellar diameters and their wavelength dependence, limb darkening, stellar surface structure, and distances of Cepheids and of Nova Cygni 1992. Precise stellar masses have been obtained from interferometric observations of spectroscopic binaries, and circumstellar disks and shells have been resolved. Searches for substellar companions and extrasolar planets with interferometric astrometry will begin soon. Nulling interferometry will enable studies of exozodiacal disks from the ground and the detection and characterization of terrestrial extrasolar planets from space. These developments are reviewed, as well as progress in some key technological areas.

Notes: Abstract Since the first radio astronomy observations in the 1930s, the angular resolution of radio telescopes has improved from tens of degrees to better than one thousandth of a second of arc. This advancement has been the result of technological innovations such as stable, sensitive, short-wavelength radio receivers, digital correlators, atomic clocks, and high-speed tape recorders, as well as the development of sophisticated image processing algorithms implemented on inexpensive, fast, digital computers.

Notes: Abstract Outflow activity is associated with all stages of early stellar evolution, from deeply embedded protostellar objects to visible young stars. Herbig-Haro (HH) objects are the optical manifestations of this powerful mass loss. Analysis of HH flows, and in particular of the subset of highly collimated HH jets, provides indirect but important insights into the nature of the accretion and mass-loss processes that govern the formation of stars. The recent recognition that HH flows may attain parsec-scale dimensions opens up the possibility of partially reconstructing the mass-ejection history of the newly born driving sources and, therefore, their mass-accretion history. Furthermore, HH flows are astrophysical laboratories for the analysis of shock structures, of hydrodynamics in collimated flows, and of their interaction with the surrounding environment. HH flows may be an important source of turbulence in molecular clouds. Recent technological developments have enabled detailed observations of outflows from young stars at near-infrared, mid-infrared, submillimeter, millimeter, and centimeter wavelengths, providing a comprehensive picture of the outflow phenomenon of young stars.

Notes: Abstract An optical technique is described that is often used nowadays to measure surface pressures on wind tunnel models and flight vehicles. The technique uses luminescent coatings, which are painted on the model surface, excited by light of appropriate wavelength, and imaged with digital cameras. The intensity of the emitted light is inversely proportional to the surface pressure. Hence, the surface pressures can be measured efficiently and affordably with a high spatial resolution. The theory and chemistry of how such coatings work and the parameters that affect them are presented. The required hardware and software are described, with emphasis on the different measurement systems and procedures. The various error sources are discussed, and correction schemes that can be used to minimize them are presented. Sample results, covering a wide range of conditions and applications, are presented and discussed.

Notes: Abstract Early work of Ricardo is described, in which squish is used in flat-head engines to generate turbulence levels comparable to those in overhead-valve engines, leading to rapid flame propagation, and suppressing knock. Work by NACA before World War II is described, in which turbulence levels were measured in overhead-valve engines, indicating indirectly that surprisingly high levels were achieved just before ignition, possibly due to a tumble instability. Finally, work of Obukhov of 30 years ago is described, in which instabilities of tumbling flow are investigated in ellipsoids crudely modeling the engine cylinder as the piston rises; this suggests that there is an instability leading to intense small-scale motion just before ignition. Suggestions for further work are given.

Notes: Abstract Polymer melts exhibit extrusion instabilities at sufficiently high levels of stress, and they appear to exhibit wall slip. I explore the evidence for slip, the possible mechanisms of slip, and the relation between slip and extrusion instabilities.

Notes: Abstract Junction flows occur when a boundary layer encounters an obstacle attached to the same surface. Physical phenomena that have been observed for blunt and streamlined obstacles are discussed for both laminar and turbulent approaching boundary layers. The pressure gradients around an obstacle produce a three-dimensional separation with horseshoe vortices that wrap around the obstacle. Except for very low Reynolds number laminar flows, these vortices are highly unsteady and are responsible for high turbulence intensities, high surface pressure fluctuations and heat transfer rates, and erosion scour in the nose region of the obstacle. Calculation methods are also reviewed; methods that capture the large-scale chaotic vortical motions should be used for computations. Some work on the control, modification, or elimination of such vortices is also reviewed.

Notes: Abstract This article describes some of the fundamental ideas underlying methods for induced-drag prediction and reduction. A review of current analysis and design methods, including their development and common approximations, is followed by a survey of several approaches to lift-dependent drag reduction. Recent concepts for wing planform optimization, highly nonplanar surfaces, and various tip devices may lead to incremental but important gains in aircraft performance. Focusing on relatively high-aspect-ratio subsonic wings, the review suggests that opportunities for new concepts remain, but the greatest challenge lies in their integration with other aspects of the system.

Notes: Abstract Spilling breakers receive much less attention from casual observers of the ocean surface than their more dramatic and powerful plunging counterparts. However, spilling breakers probably occur more frequently than plunging breakers and are important contributors to turbulence, spray, and bubble generation at the water surface. Recent research has concentrated primarily on relatively weak and/or short-wavelength spillers whose crests are strongly affected by surface tension forces both during wave steepening and the resulting turbulent free-surface flow. When surface tension forces are dominant, the free surface does not overturn or splash during the breaking process but undergoes some unique and interesting motions. In this review, recent research contributions are discussed and placed in the context of spilling behavior over a wide range of wavelengths and breaking intensities.

Notes: Abstract The compression system instabilities known as surge and rotating stall are natural limits to the performance of all compressors and are especially troubling in gas turbine engines. In the last 15 years, rapid progress has been made in understanding this complex problem through the application of control technology; in particular, system identification techniques have proven to be useful. New findings include the roles of compressibility and nonlinearity in the stall-inception process. These findings have been used to implement feedback control schemes that have achieved increased stability in a variety of compressors and engines. Approaches fall into one of two categories: (a) operating range extension through active damping of linear disturbances, or (b) manipulation of the nonlinear system dynamics to maintain the operating point close to the instability boundary in the presence of disturbances seen in operation.

Notes: Abstract Fungal viruses are considered unconventional because they lack an extracellular route of infection and persistently infect their hosts, often in the absence of apparent symptoms. Because mycoviruses are limited to intracellular modes of transmission, they can be considered as intrinsic fungal genetic elements. Such long-term genetic interactions, even involving apparently asymptomatic mycoviruses, are likely to have an impact on fungal ecology and evolution. One of the clearest examples supporting this view is the phenomenon of hypovirulence (virulence attenuation) observed for strains of the chestnut blight fungus, Cryphonectria parasitica, harboring members of the virus family Hypoviridae. The goal of this chapter is to document recent advances in hypovirus molecular genetics and to provide examples of how that progress is leading to the identification of virus-encoded determinants responsible for altering fungal host phenotype, insights into essential and dispensable elements of hypovirus replication, revelations concerning the role of G-protein signaling in fungal pathogenesis, and new avenues for enhancing biological control potential.

Notes: Abstract Cytokinesis creates two daughter cells endowed with a complete set of chromosomes and cytoplasmic organelles. This conceptually simple event is mediated by a complex and dynamic interplay between the microtubules of the mitotic spindle, the actomyosin cytoskeleton, and membrane fusion events. For many decades the study of cytokinesis was driven by morphological studies on specimens amenable to physical manipulation. The studies led to great insights into the cellular structures that orchestrate cell division, but the underlying molecular machinery was largely unknown. Molecular and genetic approaches have now allowed the initial steps in the development of a molecular understanding of this fundamental event in the life of a cell. This review provides an overview of the literature on cytokinesis with a particular emphasis on the molecular pathways involved in the division of animal cells.

Notes: Abstract A number of novel chemical methods for studying biological systems have recently been developed that provide a means of addressing biological questions not easily studied with other techniques. In this review, examples that highlight the development and use of such chemical approaches are discussed. Specifically, strategies for modulating protein activity or protein-protein interactions using small molecules are presented. In addition, methods for generating and utilizing novel biomolecules (proteins, oligonucleotides, oligosaccharides, and second messengers) are examined.

Notes: Abstract The phosphoinositide 3-kinase (PI3K) family of enzymes is recruited upon growth factor receptor activation and produces 3' phosphoinositide lipids. The lipid products of PI3K act as second messengers by binding to and activating diverse cellular target proteins. These events constitute the start of a complex signaling cascade, which ultimately results in the mediation of cellular activities such as proliferation, differentiation, chemotaxis, survival, trafficking, and glucose homeostasis. Therefore, PI3Ks play a central role in many cellular functions. The factors that determine which cellular function is mediated are complex and may be partly attributed to the diversity that exists at each level of the PI3K signaling cascade, such as the type of stimulus, the isoform of PI3K, or the nature of the second messenger lipids. Numerous studies have helped to elucidate some of the key factors that determine cell fate in the context of PI3K signaling. For example, the past two years has seen the publication of many transgenic and knockout mouse studies where either PI3K or its signaling components are deregulated. These models have helped to build a picture of the role of PI3K in physiology and indeed there have been a number of surprises. This review uses such models as a framework to build a profile of PI3K function within both the cell and the organism and focuses, in particular, on the role of PI3K in cell regulation, immunity, and development. The evidence for the role of deregulated PI3K signaling in diseases such as cancer and diabetes is reviewed.

Notes: Abstract Seed development requires coordinated expression of embryo and endosperm and has contributions from both sporophytic and male and female gametophytic genes. Genetic and molecular analyses in recent years have started to illuminate how products of these multiple genes interact to initiate seed development. Imprinting or differential expression of paternal and maternal genes seems to be involved in controlling seed development, presumably by controlling gene expression in developing endosperm. Epigenetic processes such as chromatin remodeling and DNA methylation affect imprinting of key seed-specific genes; however, the identity of many of these genes remains unknown. The discovery of FIS genes has illuminated control of autonomous endosperm development, a component of apomixis, which is an important developmental and agronomic trait. FIS genes are targets of imprinting, and the genes they control in developing endosperm are also regulated by DNA methylation and chromatin remodeling genes. These results define some exciting future areas of research in seed development.

Notes: Abstract This review provides a synthesis that combines data from classical experimentation and recent advances in our understanding of early eye development. Emphasis is placed on the events that underlie and direct neural retina formation and lens induction. Understanding these events represents a longstanding problem in developmental biology. Early interest can be attributed to the curiosity generated by the relatively frequent occurrence of disorders such as cyclopia and anophthalmia, in which dramatic changes in eye development are readily observed. However, it was the advent of experimental embryology at the turn of the century that transformed curiosity into active investigation. Pioneered by investigators such as Spemann and Adelmann, these embryological manipulations have left a profound legacy. Questions about early eye development first addressed using tissue manipulations remain topical as we try to understand the molecular basis of this process.

Notes: Abstract The localization of mRNAs is used by various types of polarized cells to locally translate specific proteins, which restricts their distribution to a particular sub-region of the cytoplasm. This mechanism of protein sorting is involved in major biological processes such as asymmetric cell division, oogenesis, cellular motility, and synapse formation. With the finding of localized mRNAs in the yeast Saccharomyces cerevisiae, it is now possible to benefit from the powerful yeast laboratory tools to explore the molecular basis of RNA localization. Because mRNA transport and localization in yeast share many features with RNA localization in higher eukaryotes, including the formation of a large ribonucleoprotein (RNP) localization complex, the requirement of a polarized cytoskeleton and molecular motors, and the role of nuclear RNA-binding proteins in cytoplasmic localization, the yeast can be used as a paradigm for unraveling the molecular aspects of this process. This review summarizes the current knowledge on RNP transport and localization in yeast.

Notes: Abstract In vertebrates, the paraxial mesoderm corresponds to the bilateral strips of mesodermal tissue flanking the notochord and neural tube and which are delimited laterally by the intermediate mesoderm and the lateral plate. The paraxial mesoderm comprises the head or cephalic mesoderm anteriorly and the somitic region throughout the trunk and the tail of the vertebrates. Soon after gastrulation, the somitic region of vertebrates starts to become segmented into paired blocks of mesoderm, termed somites. This process lasts until the number of somites characteristic of the species is reached. The somites later give rise to all skeletal muscles of the body, the axial skeleton, and part of the dermis. In this review I discuss the processes involved in the formation of the paraxial mesoderm and its segmentation into somites in vertebrates.

Notes: Abstract The intracellular localization of mRNA, a common mechanism for targeting proteins to specific regions of the cell, probably occurs in most if not all polarized cell types. Many of the best characterized localized mRNAs are found in oocytes and early embryos, where they function as localized determinants that control axis formation and the development of the germline. However, mRNA localization has also been shown to play an important role in somatic cells, such as neurons, where it may be involved in learning and memory. mRNAs can be localized by a variety of mechanisms including local protection from degradation, diffusion to a localized anchor, and active transport, and we consider the evidence for each of these processes, before discussing the cis-acting elements that direct the localization of specific mRNAs and the trans-acting factors that bind them.

Notes: Abstract The replicated copies of each chromosome, the sister chromatids, are attached prior to their segregation in mitosis and meiosis. This association or cohesion is critical for each sister chromatid to bind to microtubules from opposite spindle poles and thus segregate away from each other at anaphase of mitosis or meiosis II. The cohesin protein complex is essential for cohesion in both mitosis and meiosis, and cleavage of one of the subunits is sufficient for loss of cohesion at anaphase. The localization of the cohesin complex and other cohesion proteins permits evaluation of the positions of sister-chromatid associations within the chromosome structure, as well as the relationship between cohesion and condensation. Recently, two key riddles in the mechanism of meiotic chromosome segregation have yielded to molecular answers. First, analysis of the cohesin complex in meiosis provides molecular support for the long-standing hypothesis that sister-chromatid cohesion links homologs in meiosis I by stabilizing chiasmata. Second, the isolation of the monopolin protein that controls kinetochore behavior in meiosis I defines a functional basis by which sister kinetochores are directed toward the same pole in meiosis I.

Notes: Abstract Fifteen years ago, we had a model of peroxisome biogenesis that involved growth and division of preexisting peroxisomes. Today, thanks to genetically tractable model organisms and Chinese hamster ovary cells, 23 PEX genes have been cloned that encode the machinery ("peroxins") required to assemble the organelle. Membrane assembly and maintenance requires three of these (peroxins 3, 16, and 19) and may occur without the import of the matrix (lumen) enzymes. Matrix protein import follows a branched pathway of soluble recycling receptors, with one branch for each class of peroxisome targeting sequence (two are well characterized), and a common trunk for all. At least one of these receptors, Pex5p, enters and exits peroxisomes as it functions. Proliferation of the organelle is regulated by Pex11p. Peroxisome biogenesis is remarkably conserved among eukaryotes. A group of fatal, inherited neuropathologies are recognized as peroxisome biogenesis diseases; the responsible genes are orthologs of yeast or Chinese hamster ovary peroxins. Future studies must address the mechanism by which folded, oligomeric enzymes enter the organelle, how the peroxisome divides, and how it segregates at cell division. Most pex mutants contain largely empty membrane "ghosts" of peroxisomes; a few mutants apparently lacking peroxisomes entirely have led some to propose the de novo formation of the organelle. However, there is evidence for residual peroxisome membrane vesicles ("protoperoxisomes") in some of these, and the preponderance of data supports the continuity of the peroxisome compartment in space and time and between generations of cells.

Notes: Abstract Novel therapeutic strategies can be envisioned based on altering the expression level of target genes involved in cellular processes and disease progression; however, our ability to efficiently manipulate gene expression is limited. Non-viralbased gene therapy provides a relatively safe approach to increase or decrease the expression of a specific gene using DNA or antisense sequences; however, synthetic systems are required to direct plasmids and oligonucleotides to a specific tissue and to enhance cellular uptake and intracellular trafficking. Numerous materials are being developed that interact with DNA to enhance its properties (e.g. stability, charge density) and thus direct its biodistribution and facilitate cellular interactions. The development of synthetic delivery systems to manipulate gene expression efficiently is a powerful tool that will ultimately lead to novel therapeutic strategies for the treatment of numerous disorders.

Notes: Abstract Continuing increases in the areal density of hard disk drives will be limited by thermal instability of the thin film medium. Patterned media, in which data are stored in an array of single-domain magnetic particles, have been suggested as a means to overcome this limitation and to enable recording densities of up to 150 Gbit cm-2 (1 Tbit inch-2) to be achieved. However, the implementation of patterned media requires fabrication of sub-50-nm features over large areas and the design of recording systems that differ substantially from those used in conventional hard drives. This review describes patterned media, including the fabrication of arrays of small magnetic particles and their magnetic properties, such as domain structure, reversal mechanisms, thermal stability, and interactions. The practical implementation of patterned media recording schemes is assessed.

Notes: Abstract Energetic materials are chemical compounds or mixtures that store significant quantities of energy. In this review, we explore recent approaches to property prediction and new material synthesis. We show how the successful design of new energetic materials with tailored properties is becoming a practical reality.

Notes: Abstract We summarize developments in the construction of synthetic cells made from polymers, with a particular focus on mimicking the structure and behavior of blood cells. Two basic themes emerge-the use of block copolymers to make polmer vesicles and the functionalization of colloidal or polymeric microspheres with cell-like adhesive properties. Both platforms provide a means for building the complex hierarchy that is characteristic of biological cells, while also incorporating novel and perhaps superior properties of material strength, specific targeting, and controlled release.

Notes: Abstract Materials research has been applied successfully to the study of archaeological ceramics for the last fifty years. To learn about our history and the human condition is not just to analyze and preserve the objects but also to investigate and understand the knowledge and skills used to produce and use them. Many researchers have probed the limits and methods of such studies, always mindful that a glimpse at ancient reality lies in the details of time and place, context of finds, and experimentally produced data, usually compared with standards that were collected in an equivalent ethnographic setting or that were fabricated in a laboratory in order to elucidate the critical questions in a technology that could be understood in no other way. The basis of most studies of ancient technology has been established as microstructure; composition and firing; methods and sequence of manufacture; differentiation of use; use-wear and post-depositional processes; technological variability that can be interpreted as a pattern of stasis or innovation, which can be related to cultural continuity or change; and interpretation that can involve technology, subsistence trade, organization, and symbolic group- and self-definition.

Notes: Abstract This review summarizes recent experimental studies of instabilities in free-surface flows driven by thermocapillarity. Two broad classes are considered, depending upon whether the imposed temperature gradient is perpendicular (Marangoni-convection instability) or parallel (thermocapillary-convection instability) to the free surface. Both steady and time-dependent instabilites are reviewed in experiments employing both large- and small-aspect-ratio geometries of various symmetries.

Notes: Abstract We consider the manner in which a container filled with viscous fluid adjusts to changes in its rotation rate. We begin with homogeneous flows involving small departures in rotation rate from an initial state of solid-body rotation in an axisymmetric container. This is followed by a summary of other more recent developments, including weakly and fully nonlinear calculations and comparison with experiment and the question of spin-down. The question of "spin-over" is addressed, followed by a brief synopsis of free-surface effects, and a discussion of nonaxisymmetric spin-up. The second part of the review focuses on the effects of stratification on the spin-up process. Linearized (low Rossby number) spin-up within a cylindrical container is described. Thereafter, both experimental and nonlinear computational results are described and compared. The final section focuses on stratified spin-up and spin-down in conical geometries, and a number of comparisons between theory and experiment are given.

Notes: Abstract Recent studies of the morphodynamics of the coastal region are reviewed. Emphasis is given to idealized models that consider a morphological pattern in isolation from the others, to obtain indications on the physical processes controlling its appearance and development. In particular, attention focuses on morphodynamic stability analyses that allow understanding of the behavior of morphological features that are repetitive in both space and time. Indeed rhythmic patterns are commonly observed both in the continental shelf far from the coast and in the near-shore region.

Notes: Abstract This review highlights the differences between the aerodynamics of high-speed trains and other types of transportation vehicles. The emphasis is on modern, high-speed trains, including magnetic levitation (Maglev) trains. Some of the key differences are derived from the fact that trains operate near the ground or a track, have much greater length-to-diameter ratios than other vehicles, pass close to each other and to trackside structures, are more subject to crosswinds, and operate in tunnels with entry and exit events. The coverage includes experimental techniques and results and analytical and numerical methods, concentrating on the most recent information available.

Notes: Abstract The interaction of a flexible structure with a flowing fluid in which it is submersed or by which it is surrounded gives rise to a rich variety of physical phenomena with applications in many fields of engineering, for example, the stability and response of aircraft wings, the flow of blood through arteries, the response of bridges and tall buildings to winds, the vibration of turbine and compressor blades, and the oscillation of heat exchangers. To understand these phenomena we need to model both the structure and the fluid. However, in keeping with the overall theme of this volume, the emphasis here is on the fluid models. Also, the applications are largely drawn from aerospace engineering although the methods and fundamental physical phenomena have much wider applications. In the present article, we emphasize recent developments and future challenges. To provide a context for these, the article begins with a description of the various physical models for a fluid undergoing time-dependent motion, then moves to a discussion of the distinction between linear and nonlinear models, time-linearized models and their solution in either the time or frequency domains, and various methods for treating nonlinear models, including time marching, harmonic balance, and systems identification. We conclude with an extended treatment of the modal character of time-dependent flows and the construction of reduced-order models based on an expansion in terms of fluid modes. The emphasis is on the enhanced physical understanding and dramatic reductions in computational cost made possible by reduced-order models, time linearization, and methodologies drawn from dynamical system theory.

Notes: Abstract Shelterbelts or windbreaks were used for centuries to reduce wind speed, to control heat and moisture transfer and pollutant diffusion, to improve climate and environment, and to increase crop yields; but only within the last few decades have systematic studies considered the aerodynamics and shelter mechanisms of shelterbelts and windbreaks. This review examines recent modeling and numerical simulation studies as well as the mechanisms that control flow and turbulence around shelterbelts and windbreaks. We compare numerical simulations with experimental data and explain the relationships between sheltering effects and the structure of shelterbelts and windbreaks. We discuss how and why the desired effects are achieved by using numerical analysis. This chapter begins with the derivation of a general equation set for porous shelterbelts and windbreaks; the numerical model and simulation procedure are developed; unseparated and separated flows are predicted and characterized; the momentum budget and shelter mechanisms are analyzed; the effects of wind direction, density, width, and three dimensionality of shelterbelt structure on flow and turbulence are systematically described. Recent modeling and simulation of heat flux and evapotranspiration are also summarized. Finally, we discuss the use of high-performance distributed and parallel computing as well as clusters of networked workstations to enhance performance of the model applied to simulations of shelterbelts and windbreaks.

Notes: Abstract Over the years, the evolutionary importance of natural hybridization has been a contentious issue. At one extreme is the relatively common view of hybridization as an evolutionarily unimportant process. A less common perspective, but one that has gained support over the past decade, is that of hybridization as a relatively widespread and potentially creative evolutionary process. Indeed, studies documenting the production of hybrid genotypes exhibiting a wide range of fitnesses have become increasingly common. In this review, we examine the genetic basis of such variation in hybrid fitness. In particular, we assess the genetic architecture of hybrid inferiority (both sterility and inviability). We then extend our discussion to the genetic basis of increased fitness in certain hybrid genotypes. The available evidence argues that hybrid inferiority is the result of widespread negative epistasis in a hybrid genetic background. In contrast, increased hybrid fitness can be most readily explained through the segregation of additive genetic factors, with epistasis playing a more limited role.

Notes: Abstract The eugenics movement was initiated by Sir Francis Galton, a Victorian scientist. Galton's career can be divided into two parts. During the first, Galton was engaged in African exploration, travel writing, geography, and meteorology. The second part began after he read the Origin of Species by his cousin Charles Darwin. The book convinced Galton that humanity could be improved through selective breeding. During this part of his career he was interested in the factors that determine what he called human "talent and character" and its hereditary basis. Consequently, he delved into anthropometrics and psychology and played a major role in the development of fingerprinting. He also founded the field of biometrics, inventing such familiar statistical procedures as correlation and regression analysis. He constructed his own theory of inheritance in which nature and not nurture played the leading role. He actively began to promote eugenics and soon gained important converts.