ALBERT

Notes: Abstract A young man adrift, I was rescued by Paul Gast, a college classmate, and sent off to Columbia's Lamont Geological Observatory as a summer intern. As it turns out, I am still there. During this 47-year sojourn, I have been a participant in the enormous expansion of the field of isotope geochemistry. I experienced the golden age when so many plums awaited picking that we, the pioneers, gorged ourselves with exciting discovery. Being at what is now called Lamont-Doherty Earth Observatory put me at the center of many of the developments that changed forever the Earth Sciences. It also made me part of the great challenge associated with the drive to replace the exploitative mode that characterized the Industrial Revolution with what is often referred to as the sustainable mode. In the following pages I recount my path from confused youth to the globe-encircling oceanic "conveyor belt."

Notes: Abstract The 1990s saw a resurgence in the windpower industry, with installed grid-connected capacity expanding more than five-fold between 1990 and 2000. Most of this increase occurred in Europe, where governmental policies aimed at developing domestic energy supplies and reducing pollutant emissions provided a sheltered market for renewable energy generation. The 1990s were also marked by a return to large, megawatt-sized wind turbines, a reduction and consolidation of wind turbine manufacturers, and increased interest in offshore windpower. This article reviews recent trends in the windpower industry, including some of the fundamental engineering principles of wind turbine design. Technological impediments and advances are discussed in the context of changes in the global electricity markets and environmental performance.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Notes: Abstract HIV protease inhibitors, as components of combination antiretroviral drug regimens, have substantially reduced the morbidity and mortality associated with HIV infection. They selectively block the action of the virus-encoded protease and stop the virus from replicating. In general, these drugs have poor systemic bioavailability and must be dosed with respect to meals for optimal absorption. Protease inhibitor-containing regimens require ingestion of a large number of capsules, are costly, and produce or are susceptible to metabolic drug interactions. Simultaneous administration of two protease inhibitors takes advantage of beneficial pharmacokinetic interactions and may circumvent many of the drugs' undesirable pharmacologic properties. For example, ritonavir increases saquinavir concentrations at steady state by up to 30-fold, allowing reduction of saquinavir dose and dosing frequency. Ritonavir decreases the systemic clearance of indinavir and overcomes the deleterious effect of food on indinavir bioavailability. These benefits reflect inhibition of presystemic clearance and first-pass metabolism, as well as inhibition of systemic clearance mediated by hepatic cytochrome P450 3A4. Several dual protease inhibitor combination regimens have shown great promise in clinical trials and are now recommended as components of salvage therapy for HIV-infected patients.

Notes: Abstract Recently, the selectin family of glycoprotein adhesion molecules (P-selectin, E-selectin, and L-selectin) has been implicated in the pathogenesis of a number of inflammatory disease states. The selectins modulate the early adhesive interactions between circulating neutrophils and the endothelium. Both P-selectin and E-selectin can be expressed on the surface of endothelial cells following stimulation by a number of inflammatory mediators. In contrast, L-selectin is constitutively expressed on the surface of neutrophils at very high levels. In addition, neutrophils also express ligands for the endothelial selectins, including the carbohydrate sialyl Lewisx and the high-affinity ligand P-selectin glycoprotein ligand 1, which facilitate neutrophil-endothelial interactions. Selectins have been extensively investigated in ischemia/reperfusion injury states. The study of selectin involvement in ischemia/ reperfusion injury has been facilitated by the development of highly specific selectin antagonists, including monoclonal antibodies, carbohydrates, small molecule inhibitors, and soluble forms of P-selectin glycoprotein ligand 1. This article reviews the results of current studies of selectin antagonists in experimental models of ischemia/ reperfusion injury.

Notes: Abstract 5-ht6 receptors are the latest serotonin receptors to be identified by molecular cloning. Their high affinity for a wide range of drugs used in psychiatry, coupled with their intriguing distribution in the brain, has stimulated significant interest. Antisense oligonucleotides, antipeptide antibodies, selective radioligands, knockout mice, and selective antagonists of the 5-ht6 receptor have recently become available. Surprisingly, 5-ht6 receptors appear to regulate cholinergic neurotransmission in the brain, rather than the expected interaction as modulators of dopaminergic transmission. This interaction predicts a possible role for 5-ht6 receptor antagonists in the treatment of learning and memory disorders. Furthermore, polymorphisms in the sequence of the 5-ht6 receptor gene may provide a genetic tool to further our understanding of the differential responses of patients to antipsychotic medications.

Notes: Abstract A potentially powerful approach to drug delivery in the treatment of disease involves the use of cells to introduce genes encoding therapeutic proteins into the body. Candidate genes for delivery include those encoding secreted factors that could have broad applications ranging from treatment of inherited single-gene deficiencies to acquired disorders of the vasculature or cancer. Myoblasts, the proliferative cell type of skeletal muscle tissues, are potent tools for stable delivery of a gene of interest into the body, as they become an integral part of the muscle into which they are injected, in close proximity to the circulation. The recent development of improved tetracycline-inducible retroviral vectors allows for fine control of recombinant gene expression levels. The combination of ex vivo gene transfer using myoblasts and regulatable retroviral vectors provides a powerful toolbox with which to develop gene therapies for a number of human diseases.

Notes: Abstract Determining the potential toxicity of compounds early in the drug discovery process can be extremely beneficial in terms of both time and money conservation. Because of the speed of modern chemical synthesis and screening, to accurately evaluate the large number of compounds being produced, toxicology assays must have both high-fidelity and high-throughput capabilities. In addition, assays must be performed using limited amounts of compound. In the past decade, several new and innovative techniques have been developed that not only allow for high-throughput screening but can also provide detailed information concerning the molecular mechanisms behind toxic effects. Techniques such as hybridization microarrays, real-time polymerase chain reaction, and large-scale sequencing are some of the methods that have been or are starting to be used routinely in pharmaceutical companies. This review examines the contributions of these and related techniques toward toxicity evaluation of potential drug candidates and their future role in the discovery of new therapeutics.

Notes: Abstract Mitochondria have long been recognized as the generators of energy for the cell. Like any other power source, however, mitochondria are highly vulnerable to inhibition or uncoupling of the energy harnessing process and run a high risk for catastrophic damage to the cell. The exquisite structural and functional characteristics of mitochondria provide a number of primary targets for xenobiotic-induced bioenergetic failure. They also provide opportunities for selective delivery of drugs to the mitochondrion. In light of the large number of natural, commercial, pharmaceutical, and environmental chemicals that manifest their toxicity by interfering with mitochondrial bioenergetics, it is important to understand the underlying mechanisms. The significance is further underscored by the recent identification of bioenergetic control points for cell replication and differentiation and the realization that mitochondria play a determinant role in cell signaling and apoptotic modes of cell death.

Notes: Abstract nAChRs are pentameric transmembrane proteins into the superfamily of ligand-gated ion channels that includes the 5HT3, glycine, GABAA, and GABAC receptors. Electron microscopy, affinity labeling, and mutagenesis experiments, together with secondary structure predictions and measurements, suggest an all-beta folding of the N-terminal extracellular domain, with the connecting loops contributing to the ACh binding pocket and to the subunit interfaces that mediate the allosteric transitions between conformational states. The ion channel consists of two distinct elements symmetrically organized along the fivefold axis of the molecule: a barrel of five M2 helices, and on the cytoplasmic side five loops contributing to the selectivity filter. The allosteric transitions of the protein underlying the physiological ACh-evoked activation and desensitization possibly involve rigid body motion of the extracellular domain of each subunit, linked to a global reorganization of the transmembrane domain responsible for channel gating.

Notes: Abstract Low molecular weight G proteins of the Rho subfamily are regulators of actin cytoskeletal organization. In contrast to the heterotrimeric G proteins, the small GTPases are not directly activated through ligand binding to G protein-coupled receptors (GPCRs). However, a subset of GPCRs, including those for lysophosphatidic acid and thrombin, induce stress fibers, focal adhesions, and cell rounding through Rho-dependent pathways. C3 exoenzyme has been a useful tool for demonstrating Rho involvement in these and other responses, including Ca2+ sensitization of smooth muscle contraction, cell migration, transformation, and serum response element-mediated gene expression. Most of the GPCRs that induce Rho-dependent responses can activate Gq, but this is not a sufficient signal. Recent data demonstrate that Galpha12/13 can induce Rho-dependent responses. Furthermore, Galpha12/13 can bind and activate Rho-specific guanine nucleotide exchange factors, providing a mechanism by which GPCRs that couple to Galpha12/13 could activate Rho and its downstream responses.

Notes: Abstract Peroxisome proliferators (PPs) are a large class of structurally dissimilar chemicals that have diverse effects in rodents and humans. Most, if not all, of the diverse effects of PPs are mediated by three members of the nuclear receptor superfamily called peroxisome proliferator-activated receptors (PPARs). In this review, we define the molecular mechanisms of PPs, including PPAR binding specificity, alteration of gene expression through binding to DNA response elements, and cross talk with other signaling pathways. We discuss the roles of PPARs in growth promotion in rodent hepatocarcinogenesis and potential therapeutic effects, including suppression of cancer growth and inflammation.

Notes: Abstract There are seven P2X receptor cDNAs currently known. Six homomeric (P2X1, P2X2, P2X3, P2X4, P2X5, P2X7) and three heteromeric (P2X2/P2X3, P2X4/P2X6, P2X1/P2X5) P2X receptor channels have been characterized in heterologous expression systems. Homomeric P2X1 and P2X3 receptors are readily distinguishable by their rapid desensitization, the agonist action of alphabetamethyleneATP, and the block by 2',3'-O-(2,4,6-trinitrophenyl)-ATP. P2X2 receptors are unique among homomeric forms in their potentiation by low pH. Homomeric P2X4 receptors are much less sensitive to antagonism by suramin and pyridoxal 5-phosphate-6-azo-2',4'-disulfonic acid. Homomeric P2X7 receptors are the only form in which 2',3'-O-(4-benzoylbenzoyl)-ATP is more potent than ATP. The heteromeric P2X2/P2X3 receptor resembles P2X2 in slow desensitization kinetics and potentiation by low pH and is similar to P2X3 with respect to agonism by alphabetamethyleneATP and block by 2',3'-O-(2,4,6-trinitrophenyl)-ATP. Other agonists, antagonists, and ions that can be used to differentiate among the receptors are discussed.

Notes: Abstract The 14-3-3 proteins are a family of conserved regulatory molecules expressed in all eukaryotic cells. A striking feature of the 14-3-3 proteins is their ability to bind a multitude of functionally diverse signaling proteins, including kinases, phosphatases, and transmembrane receptors. This plethora of interacting proteins allows 14-3-3 to play important roles in a wide range of vital regulatory processes, such as mitogenic signal transduction, apoptotic cell death, and cell cycle control. In this review, we examine the structural basis for 14-3-3-ligand interactions, proposed functions of 14-3-3 in various signaling pathways, and emerging views of mechanisms that regulate 14-3-3 actions.

Notes: Abstract In vertebrates, the glucuronidation of small lipophilic agents is catalyzed by the endoplasmic reticulum UDP-glucuronosyltransferases (UGTs). This metabolic pathway leads to the formation of water-soluble metabolites originating from normal dietary processes, cellular catabolism, or exposure to drugs and xenobiotics. This classic detoxification process, which led to the discovery nearly 50 years ago of the cosubstrate UDP-glucuronic acid (19), is now known to be carried out by 15 human UGTs. Characterization of the individual gene products using cDNA expression experiments has led to the identification of over 350 individual compounds that serve as substrates for this superfamily of proteins. This data, coupled with the introduction of sophisticated RNA detection techniques designed to elucidate patterns of gene expression of the UGT superfamily in human liver and extrahepatic tissues of the gastrointestinal tract, has aided in understanding the contribution of glucuronidation toward epithelial first-pass metabolism. In addition, characterization of the UGT1A locus and genetic studies directed at understanding the role of bilirubin glucuronidation and the biochemical basis of the clinical symptoms found in unconjugated hyperbilirubinemia have uncovered the structural gene polymorphisms associated with Crigler-Najjar's and Gilbert's syndrome. The role of the UGTs in metabolism and different disease states in humans is the topic of this review.

Notes: Abstract Over the past decade, PAS domains have been identified in dozens of signal transduction molecules and various forms have been found in animals, plants, and prokaryotes. In this review, we summarize this rapidly expanding research area by providing a detailed description of three signal transduction pathways that utilize PAS protein heterodimers to drive their transcriptional output. It is hoped that these model pathways can provide a framework for use in understanding the biology of the less well-understood members of this emerging superfamily, as well as of those to be characterized in the days to come. We use this review to develop the idea that most eukaryotic PAS proteins can be classified by functional similarities, as well as by predicted phylogenetic relationships. We focus on the alpha-class proteins, which often act as sensors of environmental signals, and the beta-class proteins, which typically act as broad-spectrum partners that target these heterodimers to their genomic targets.

Notes: Abstract Civilization's advances during the twentieth century are closely bound with an unprecedented rise of energy consumption in general, and of hydrocarbons and electricity in particular. Substantial improvements of all key nineteenth-century energy techniques and introduction of new extraction and transportation means and new prime movers resulted in widespread diffusion of labor-saving and comfort-providing conversions and in substantially declining energy prices. Although modern societies could not exist without large and incessant flows of energy, there are no simple linear relationships between the inputs of fossil fuels and electricity and a nation's economic performance and social accomplishments. International comparisons show a variety of consumption patterns and a continuing large disparity between affluent and modernizing nations. The necessity of minimizing environmental impacts of energy use, particularly those with potentially worrisome global effects, is perhaps the greatest challenge resulting from the twentieth century's energy advances.

Notes: Abstract Phosphorus has a number of indispensable biochemical roles, but it does not have a rapid global cycle akin to the circulations of C or N. Natural mobilization of the element, a part of the grand geotectonic denudation-uplift cycle, is slow, and low solubility of phosphates and their rapid transformation to insoluble forms make the element commonly the growth-limiting nutrient, particularly in aquatic ecosystems. Human activities have intensified releases of P. By the year 2000 the global mobilization of the nutrient has roughly tripled compared to its natural flows: Increased soil erosion and runoff from fields, recycling of crop residues and manures, discharges of urban and industrial wastes, and above all, applications of inorganic fertilizers (15 million tonnes P/year) are the major causes of this increase. Global food production is now highly dependent on the continuing use of phosphates, which account for 50-60% of all P supply; although crops use the nutrient with relatively high efficiency, lost P that reaches water is commonly the main cause of eutrophication. This undesirable process affects fresh and ocean waters in many parts of the world. More efficient fertilization can lower nonpoint P losses. Although P in sewage can be effectively controlled, such measures are often not taken, and elevated P is common in treated wastewater whose N was lowered by denitrification. Long-term prospects of inorganic P supply and its environmental consequences remain a matter of concern.

Notes: Abstract Various applications using carbon dioxide (CO2) have developed within the last decade and, if current trends continue, the CO2 technology platform could emerge as the most commonly used solvent in the twenty-first century. An environmentally friendly platform that is wrapped in a successful business format with apparent implications for people and their communities is most likely to endure. Does the CO2 technology platform meet the criteria for becoming a sustainable enterprise? Utilizing CO2 as an alternative solvent in conventional processes has the potential to favorably impact the environment and our communities. There are, however, several barriers to adopting CO2-based applications. Several concepts as well as obstacles to adopting the carbon dioxide technology platform are highlighted in this chapter.

Notes: Abstract An ultimate limit on the extent that biomass fuels can be used to displace fossil transportation fuels, and their associated emissions of CO2, will be the land area available to produce the fuels and the efficiencies by which solar radiation can be converted to useable fuels. Currently, the Brazil cane-ethanol system captures 33% of the primary energy content in harvested cane in the form of ethanol. The US corn-ethanol system captures 54% of the primary energy of harvested corn kernels in the form of ethanol. If ethanol is used to substitute for gasoline, avoided fossil fuel CO2 emissions would equal those of the substituted amount minus fossil emissions incurred in producing the cane- or corn-ethanol. In this case, avoided emissions are estimated to be 29% of harvested cane and 14% of harvested corn primary energy. Unless these efficiencies are substantially improved, the displacement of CO2 emissions from transportation fuels in the United States is unlikely to reach 10% using domestic biofuels. Candidate technologies for improving these efficiencies include fermentation of cellulosic biomass and conversion of biomass into electricity, hydrogen, or alcohols for use in electric drive-train vehicles.

Notes: Abstract The first phase of promoting renewable energy in Europe is coming to an end. The timetable of the European Commission's Single Electricity Market (SEM) Directive has been the key recent driver of change within European energy and electricity markets. As mainland European countries have been forced to restructure their electricity industries and reappraise their renewable energy policies, they have been impressed by the results of the England and Wales Renewable Non-Fossil Fuel Obligation (NFFO). The NFFO is a mechanism for promoting renewable energy that has a competitive basis. However, the United Kingdom is in the process of creating a new policy. As new renewable energy policies have been discussed or put in place in mainland European countries, so these have influenced those of the United Kingdom. Renewable energy policies throughout Europe are converging. This paper analyzes the history behind these changes and underlines the lessons to be learned.

Notes: Abstract Geoengineering is the intentional large-scale manipulation of the environment, particularly manipulation that is intended to reduce undesired anthropogenic climate change. The post-war rise of climate and weather modification and the history of U.S. assessments of the CO2-climate problem is reviewed. Proposals to engineer the climate are shown to be an integral element of this history. Climate engineering is reviewed with an emphasis on recent developments, including low-mass space-based scattering systems for altering the planetary albedo, simulation of the climate's response to albedo modification, and new findings on iron fertilization in oceanic ecosystems. There is a continuum of human responses to the climate problem that vary in resemblance to hard geoengineering schemes such as space-based mirrors. The distinction between geoengineering and mitigation is therefore fuzzy. A definition is advanced that clarifies the distinction between geoengineering and industrial carbon management. Assessment of geoengineering is reviewed under various framings including economics, risk, politics, and environmental ethics. Finally, arguments are presented for the importance of explicit debate about the implications of countervailing measures such as geoengineering.

Notes: Abstract Industrial symbiosis, as part of the emerging field of industrial ecology, demands resolute attention to the flow of materials and energy through local and regional economies. Industrial symbiosis engages traditionally separate industries in a collective approach to competitive advantage involving physical exchange of materials, energy, water, and/or by-products. The keys to industrial symbiosis are collaboration and the synergistic possibilities offered by geographic proximity. This paper reviews the small industrial symbiosis literature and some antecedents, as well as early efforts to develop eco-industrial parks as concrete realizations of the industrial symbiosis concept. Review of the projects is organized around a taxonomy of five different material exchange types. Input-output matching, stakeholder processes, and materials budgeting appear to be useful tools in advancing eco-industrial park development. Evolutionary approaches to industrial symbosis are found to be important in creating the level of cooperation needed for multi-party exchanges.

Notes: Abstract Fossil fuels account for about 80% of energy consumption in Asia. Because of its abundance and easy recoverability, especially in India and China, coal will remain the fuel of choice in the foreseeable future. If current trends continue, sulfur dioxide emissions from Asia may soon equal the emissions from North America and Europe combined. These trends portend a variety of local, regional, and global environmental impacts. Acid rain damages human health, ecosystems, and built surfaces. Many ecosystems will be unable to absorb these increased acidic depositions, leading to irreversible ecosystem damage with far-reaching implications for health, forestry, agriculture, fisheries, and tourism. RAINS-ASIA is a scenario-generating tool used to estimate the extent of damages caused by acid rain and to review the costs and impacts of alternatives to provide a look into the future. Its use extends from national-, regional-, and city-scale evaluation and inputs for cost-effective options analyses, to international negotiations on transboundary pollution.

Notes: Abstract Over the past 25 years more than 20 major studies have examined the technological potential to improve the fuel economy of passenger cars and light trucks in the United States. The majority have used technology/cost analysis, a combination of analytical methods from the disciplines of economics and automotive engineering. In this review we describe the key elements of this methodology, discuss critical issues responsible for the often widely divergent estimates produced by different studies, review the history of this methodology's use, and present results from six recent assessments. Whereas early studies tended to confine their scope to the potential of proven technology over a 10-year time period, more recent studies have focused on advanced technologies, raising questions about how best to include the likelihood of technological change. The review concludes with recommendations for further research.

Notes: Abstract The notion of capacity development (CD) has been receiving increasing attention as a way to assist the South in its environmental management. Consequently, there has been an exploration of various facets of the capacity issue in the literature and an incorporation of CD in environmental programs of donor agencies. Yet, many of these discussions have remained rather broad, and efforts to develop environmental capacity have shown only limited success. Based on an examination of the capacity needs for environmental management in agriculture and industry, and for dealing with climate change, this review suggests that strengthening domestic capabilities for policy research and innovation as well as for managing technological change may be particularly critical to allow for adaptation of policies and technologies for local conditions and needs. Examination of innovative local experiments on environmental management in developing countries can also provide useful lessons on how to develop and utilize capacity that works under the constrained conditions often found in developing countries. Furthermore, it is important to stress that improving the environment in developing countries also requires capacity in the North to examine and reorient Northern policies that impact the environment, as well as capacity for the environment, in the poorer parts of the world. Ultimately, though, the development of sustainable and appropriate capacity for the environment will require not merely donor-driven programs but a systematic effort driven by Southern governments and organizations.

Notes: Abstract Water vapor is the dominant greenhouse gas, the most important gaseous source of infrared opacity in the atmosphere. As the concentrations of other greenhouse gases, particularly carbon dioxide, increase because of human activity, it is centrally important to predict how the water vapor distribution will be affected. To the extent that water vapor concentrations increase in a warmer world, the climatic effects of the other greenhouse gases will be amplified. Models of the Earth's climate indicate that this is an important positive feedback that increases the sensitivity of surface temperatures to carbon dioxide by nearly a factor of two when considered in isolation from other feedbacks, and possibly by as much as a factor of three or more when interactions with other feedbacks are considered. Critics of this consensus have attempted to provide reasons why modeling results are overestimating the strength of this feedback. Our uncertainty concerning climate sensitivity is disturbing. The range most often quoted for the equilibrium global mean surface temperature response to a doubling of CO2 concentrations in the atmosphere is 1.5oC to 4.5oC. If the Earth lies near the upper bound of this sensitivity range, climate changes in the twenty-first century will be profound. The range in sensitivity is primarily due to differing assumptions about how the Earth's cloud distribution is maintained; all the models on which these estimates are based possess strong water vapor feedback. If this feedback is, in fact, substantially weaker than predicted in current models, sensitivities in the upper half of this range would be much less likely, a conclusion that would clearly have important policy implications. In this review, we describe the background behind the prevailing view on water vapor feedback and some of the arguments raised by its critics, and attempt to explain why these arguments have not modified the consensus within the climate research community.

Notes: Abstract Theoretical considerations and empirical data suggest that existing technologies and procedures can improve indoor environments in a manner that significantly increases productivity and health. The existing literature contains moderate to strong evidence that characteristics of buildings and indoor environments significantly influence rates of communicable respiratory illness, allergy and asthma symptoms, sick building symptoms, and worker performance. Whereas there is considerable uncertainty in the estimates of the magnitudes of productivity gains that may be obtained by providing better indoor environments, the projected gains are very large. For the United States, the estimated potential annual savings and productivity gains are $6 to $14 billion from reduced respiratory disease, $1 to $4 billion from reduced allergies and asthma, $10 to $30 billion from reduced sick building syndrome symptoms, and $20 to $160 billion from direct improvements in worker performance that are unrelated to health. Productivity gains that are quantified and demonstrated could serve as a strong stimulus for energy efficiency measures that simultaneously improve the indoor environment.

Notes: Abstract Low environmental damage is one of the main justifications for continued efforts to reduce energy consumption and to shift to cleaner sources such as solar energy, especially now that supply security has slipped from public consciousness. In recent years there has been much progress in the analysis of environmental damages, in particular thanks to the ExternE (External Costs of Energy) Project of the European Commission. This paper presents a summary of the methodology and key results for the external costs of the major energy technologies. Even though the uncertainties are large, the results provide substantial evidence that the classic air pollutants (particles, NOx and SOx) from fossil fuels impose significant public health costs, comparable to the cost of global warming from CO2 emissions.

Notes: Abstract Current guidelines for green buildings are cursory and inadequate for specifying materials and designing ventilation systems to ensure a healthful indoor environment, i.e. a "healthy building," by design. Public perception, cultural preferences, litigation trends, current codes and regulations, and rapid introduction of new building materials and commercial products, as well as the prevailing design-build practices, pose challenges to systems integration in the design, construction and operation phases of modern buildings. We are on the verge of a paradigm shift in ventilation design thinking. In the past, thermal properties of air within a zone determined heating, ventilating, and air-conditioning specifications. In the future, occupant-specific and highly responsive systems will become the norm. Natural ventilation, displacement ventilation, and microzoning with subfloor plenums, along with the use of point-of-source heat control and point-of-use sensors, will evolve to create a "smart," responsive ventilation-building dynamic system. Advanced ventilation design tools such as the modeling of computational fluid dynamics (CFD) will be used routinely. CFD will be integrated into air quality and risk assessment models.

Notes: Abstract Indian megacities are among the most polluted in the world. Air concentrations of a number of air pollutants are much higher than levels recommended by the World Health Organization. In this paper, we focus on Mumbai and Delhi to characterize salient issues in health risks from particulate air (PM10) pollution in Indian cities. We perform a synthesis of the literature for all elements of the causal chain of health risks-sources, exposure, and health effects-and provide estimates of source strengths, exposure levels, and health risks from air pollution in Indian cities. We also analyze the factors that lead to uncertainty in these quantities and provide an overall assessment of the state of scientific knowledge on air pollution in urban India.

Notes: Abstract Chromosome segregation during mitosis and meiosis is driven by a complex superstructure called the spindle. Microtubules are the primary structural component of spindles, and spindle assembly and function are intimately linked to the intrinsic dynamics of microtubules. This review summarizes spindle structure and highlights recent findings regarding the mechanisms and molecules involved in organizing microtubules into spindles. In addition, mechanisms for chromosome movement and segregation are discussed.

Notes: Abstract DNA replication fidelity is a key determinant of genome stability and is central to the evolution of species and to the origins of human diseases. Here we review our current understanding of replication fidelity, with emphasis on structural and biochemical studies of DNA polymerases that provide new insights into the importance of hydrogen bonding, base pair geometry, and substrate-induced conformational changes to fidelity. These studies also reveal polymerase interactions with the DNA minor groove at and upstream of the active site that influence nucleotide selectivity, the efficiency of exonucleolytic proofreading, and the rate of forming errors via strand misalignments. We highlight common features that are relevant to the fidelity of any DNA synthesis reaction, and consider why fidelity varies depending on the enzymes, the error, and the local sequence environment.

Notes: Abstract Hemagglutinin (HA) is the receptor-binding and membrane fusion glycoprotein of influenza virus and the target for infectivity-neutralizing antibodies. The structures of three conformations of the ectodomain of the 1968 Hong Kong influenza virus HA have been determined by X-ray crystallography: the single-chain precursor, HA0; the metastable neutral-pH conformation found on virus, and the fusion pH-induced conformation. These structures provide a framework for designing and interpreting the results of experiments on the activity of HA in receptor binding, the generation of emerging and reemerging epidemics, and membrane fusion during viral entry. Structures of HA in complex with sialic acid receptor analogs, together with binding experiments, provide details of these low-affinity interactions in terms of the sialic acid substituents recognized and the HA residues involved in recognition. Neutralizing antibody-binding sites surround the receptor-binding pocket on the membrane-distal surface of HA, and the structures of the complexes between neutralizing monoclonal Fabs and HA indicate possible neutralization mechanisms. Cleavage of the biosynthetic precursor HA0 at a prominent loop in its structure primes HA for subsequent activation of membrane fusion at endosomal pH (Figure 1). Priming involves insertion of the fusion peptide into a charged pocket in the precursor; activation requires its extrusion towards the fusion target membrane, as the N terminus of a newly formed trimeric coiled coil, and repositioning of the C-terminal membrane anchor near the fusion peptide at the same end of a rod-shaped molecule. Comparison of this new HA conformation, which has been formed for membrane fusion, with the structures determined for other virus fusion glycoproteins suggests that these molecules are all in the fusion-activated conformation and that the juxtaposition of the membrane anchor and fusion peptide, a recurring feature, is involved in the fusion mechanism. Extension of these comparisons to the soluble N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) protein complex of vesicle fusion allows a similar conclusion. Figure 1 Three conformations of the hemagglutinin trimer. (a) Uncleaved precursor R329Q HA0 (82). Circled 1 marks cleavage sites, residues 323 of HA1 to 12 of HA2 sites, and adjacent cavities in each monomer. Oligosaccharides are shown as balls and sticks; oligosaccharide at Asn-22 of HA1 is labeled as 22. (b) Cleaved BHA (3). Receptor-binding sites marked with circled 2 (4). (c) Low-pH-induced conformation of thermolysin-solubilized TBHA2 (104); HA2, shaded; HA1, unshaded. Disulfide bonds are black lines. Figure prepared with MOLSCRIPT (202). Figure 1 Three conformations of the hemagglutinin trimer. (a) Uncleaved precursor R329Q HA0 (82). Circ...

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 Most prokaryotic signal-transduction systems and a few eukaryotic pathways use phosphotransfer schemes involving two conserved components, a histidine protein kinase and a response regulator protein. The histidine protein kinase, which is regulated by environmental stimuli, autophosphorylates at a histidine residue, creating a high-energy phosphoryl group that is subsequently transferred to an aspartate residue in the response regulator protein. Phosphorylation induces a conformational change in the regulatory domain that results in activation of an associated domain that effects the response. The basic scheme is highly adaptable, and numerous variations have provided optimization within specific signaling systems. The domains of two-component proteins are modular and can be integrated into proteins and pathways in a variety of ways, but the core structures and activities are maintained. Thus detailed analyses of a relatively small number of representative proteins provide a foundation for understanding this large family of signaling proteins.

Notes: Abstract Platelet-activating factor (PAF) is a phospholipid with potent, diverse physiological actions, particularly as a mediator of inflammation. The synthesis, transport, and degradation of PAF are tightly regulated, and the biochemical basis for many of these processes has been elucidated in recent years. Many of the actions of PAF can be mimicked by structurally related phospholipids that are derived from nonenzymatic oxidation, because such compounds can bind to the PAF receptor. This process circumvents much of the biochemical control and presumably is regulated primarily by the rate of degradation, which is catalyzed by PAF acetylhydrolase. The isolation of cDNA clones encoding most of the key proteins involved in regulating PAF has allowed substantial recent progress and will facilitate studies to determine the structural basis for substrate specificity and the precise role of PAF in physiological events.

Notes: Abstract The process of mRNA turnover is a critical component of the regulation of gene expression. In the past few years a discrete set of pathways for the degradation of polyadenylated mRNAs in eukaryotic cells have been described. A major pathway of mRNA degradation in yeast occurs by deadenylation of the mRNA, which leads to a decapping reaction, thereby exposing the mRNA to rapid 5' to 3' exonucleolytic degradation. A critical step in this pathway is decapping, since it effectively terminates the existence of the mRNA and is the site of numerous control inputs. In this review, we discuss the properties of the decapping enzyme and how its activity is regulated to give rise to differential mRNA turnover. A key point is that decapping appears to be controlled by access of the enzyme to the cap structure in a competition with the translation initiation complex. Strikingly, several proteins required for mRNA decapping show interactions with the translation machinery and suggest possible mechanisms for the triggering of mRNA decapping.

Notes: Abstract Clathrin was discovered nearly 25 years ago. Since then, a large number of other proteins that participate in the process by which clathrin-coated vesicles retrieve synaptic membranes or take up endocytic receptors have been identified. The functional relationships among these disparate components remain, in many cases, obscure. High-resolution structures of parts of clathrin, determined by X-ray crystallography, and lower-resolution images of assembled coats, determined by electron cryomicroscopy, now provide the information necessary to integrate various lines of evidence and to design experiments that test specific mechanistic notions. This review summarizes and illustrates the recent structural results and outlines what is known about coated-vesicle assembly in the context of this information.

Notes: Abstract Following graduate training, which was disrupted by my changing schools and serving in the Navy in World War II, I arrived in Berkeley in 1948 as an instructor in the Biochemistry Department. Despite numerous academic reorganizations and a host of struggles over the University-imposed Loyalty Oath, dismissal of a faculty member because of political affiliations, free speech for students, and my resistance to mandatory retirement, I survived with the help of great graduate students, postdoctoral fellows, undergraduates, superb research assistants, and a supportive wife. Studies on structure of tobacco mosaic virus led to our investigating an ultracentrifuge anomaly and the construction of a synthetic boundary cell. In turn, this resulted in about 15 years of research on the ultracentrifuge and its application to the study of biological macromolecules. Among the latter, the discovery of large ribonucleoprotein complexes, now known as ribosomes, and chromatophores in photosynthetic microorganisms attracted the most attention. But it was the development of the photoelectric absorption optical system and the incorporation of the Rayleigh interferometer onto the ultracentrifuge that had the greatest impact on our further research. These tools, when applied to our initial research on E. coli aspartate transcarbamoylase (ATCase), led to the discovery of distinct subunits for catalysis and regulation and the global conformational change in the enzyme associated with its role in regulation. For almost 35 years we have been using the techniques of protein chemistry and molecular biology in studies of structural and conformational changes in the enzyme, the genes encoding the different polypeptides, subunit interactions, and assembly of the enzyme from six catalytic and six regulatory chains. Hybrids constructed from inactive mutants were used to demonstrate shared active sites requiring the joint participation of amino acid residues from adjoining polypeptide chains. ATCase is still being studied as a model for understanding allostery as a regulatory mechanism. Circularly permuted polypeptide chains are being used to study the folding and assembly pathways, and the recently determined crystal structure of the active nonallosteric catalytic subunit has led to new questions regarding the activated form of ATCase.

Notes: Abstract Apoptosis, a physiological process for killing cells, is critical for the normal development and function of multicellular organisms. Abnormalities in cell death control can contribute to a variety of diseases, including cancer, autoimmunity, and degenerative disorders. Signaling for apoptosis occurs through multiple independent pathways that are initiated either from triggering events within the cell or from outside the cell, for instance, by ligation of death receptors. All apoptosis signaling pathways converge on a common machinery of cell destruction that is activated by a family of cysteine proteases (caspases) that cleave proteins at aspartate residues. Dismantling and removal of doomed cells is accomplished by proteolysis of vital cellular constituents, DNA degradation, and phagocytosis by neighboring cells. This article reviews current knowledge of apoptosis signaling, lists several pressing questions, and presents a novel model to explain the biochemical and functional interactions between components of the cell death regulatory machinery.

Notes: Abstract Translational bypassing joins the information found within two disparate open reading frames into a single polypeptide chain. The underlying mechanism centers on the decoding properties of peptidyl-transfer RNA (tRNA) and involves three stages: take-off, scanning, and landing. In take-off, the peptidyl-tRNA/messenger RNA (mRNA) complex in the P site of the ribosome dissociates, and the mRNA begins to move through the ribosome. In scanning, the peptidyl-tRNA probes the mRNA sliding through the decoding center. In landing, the peptidyl-tRNA re-pairs with a codon with which it can form a stable interaction. Although few examples of genes are known that rely on translational bypassing to couple open reading frames, ribosomes appear to have an innate capacity for bypassing. This suggests that the strategy of translational bypassing may be more common than presently appreciated. The best characterized example of this phenomenon is T4 gene 60, in which a complex set of signals stimulates bypassing of 50 nucleotides between the two open reading frames. In this review, we focus on the bypassing mechanism of gene 60 in terms of take-off, scanning, and landing.

Notes: Abstract Protein splicing is a form of posttranslational processing that consists of the excision of an intervening polypeptide sequence, the intein, from a protein, accompanied by the concomitant joining of the flanking polypeptide sequences, the exteins, by a peptide bond. It requires neither cofactors nor auxiliary enzymes and involves a series of four intramolecular reactions, the first three of which occur at a single catalytic center of the intein. Protein splicing can be modulated by mutation and converted to highly specific self-cleavage and protein ligation reactions that are useful protein engineering tools. Some of the reactions characteristic of protein splicing also occur in other forms of protein autoprocessing, ranging from peptide bond cleavage to conjugation with nonprotein moieties. These mechanistic similarities may be the result of convergent evolution, but in at least one case-hedgehog protein autoprocessing-there is definitely a close evolutionary relationship to protein splicing.

Notes: Abstract Aminoacyl-tRNAs are substrates for translation and are pivotal in determining how the genetic code is interpreted as amino acids. The function of aminoacyl-tRNA synthesis is to precisely match amino acids with tRNAs containing the corresponding anticodon. This is primarily achieved by the direct attachment of an amino acid to the corresponding tRNA by an aminoacyl-tRNA synthetase, although intrinsic proofreading and extrinsic editing are also essential in several cases. Recent studies of aminoacyl-tRNA synthesis, mainly prompted by the advent of whole genome sequencing and the availability of a vast body of structural data, have led to an expanded and more detailed picture of how aminoacyl-tRNAs are synthesized. This article reviews current knowledge of the biochemical, structural, and evolutionary facets of aminoacyl-tRNA synthesis.

Notes: Abstract Antibody molecules elicited with rationally designed transition-state analogs catalyze numerous reactions, including many that cannot be achieved by standard chemical methods. Although relatively primitive when compared with natural enzymes, these catalysts are valuable tools for probing the origins and evolution of biological catalysis. Mechanistic and structural analyses of representative antibody catalysts, generated with a variety of strategies for several different reaction types, suggest that their modest efficiency is a consequence of imperfect hapten design and indirect selection. Development of improved transition-state analogs, refinements in immunization and screening protocols, and elaboration of general strategies for augmenting the efficiency of first-generation catalytic antibodies are identified as evident, but difficult, challenges for this field. Rising to these challenges and more successfully integrating programmable design with the selective forces of biology will enhance our understanding of enzymatic catalysis. Further, it should yield useful protein catalysts for an enhanced range of practical applications in chemistry and biology.

Notes: Abstract Helical membrane protein folding and oligomerization can be usefully conceptualized as involving two energetically distinct stages-the formation and subsequent side-to-side association of independently stable transbilayer helices. The interactions of helices with the bilayer, with prosthetic groups, and with each other are examined in the context of recent evidence. We conclude that the two-stage concept remains useful as an approach to simplifying discussions of stability, as a framework for folding concepts, and as a basis for understanding membrane protein evolution.

Notes: Abstract In just a few short years, the chemical ligation of unprotected peptide segments in aqueous solution has established itself as the most practical method for the total synthesis of native proteins. A wide range of proteins has been prepared. These synthetic molecules have led to the elucidation of gene function, to the discovery of novel biology, and to the determination of new three-dimensional protein structures by both NMR and X-ray crystallography. The facile access to novel analogs provided by chemical protein synthesis has led to original insights into the molecular basis of protein function in a number of systems. Chemical protein synthesis has also enabled the systematic development of proteins with enhanced potency and specificity as candidate therapeutic agents.

Notes: Abstract This paper reviews the available data and models on energy and material flows through the world's 25 largest cities. Throughput is categorized as stored, transformed, or passive for the major flow modes. The aggregate, fuel, food, water, and air cycles are all examined. Emphasis is placed on atmospheric pathways because the data are abundant. Relevant models of urban energy and material flows, demography, and atmospheric chemistry are discussed. Earth system-level loops from cities to neighboring ecosystems are identified. Megacities are somewhat independent of their immediate environment for food, fuel, and aggregate inputs, but all are constrained by their regional environment for supplying water and absorbing wastes. We elaborate on analogies with biological metabolism and ecosystem succession as useful conceptual frameworks for addressing urban ecological problems. We conclude that whereas data are numerous for some individual cities, cross-cutting compilations are lacking in biogeochemical analysis and modeling. Synthesis of the existing information will be a crucial first step. Cross-cutting field research and integrated, multidisciplinary simulations will be necessary.

Notes: Abstract It is commonly assumed that biomass fuel cycles based on renewable harvesting of wood or agricultural wastes are greenhouse-gas (GHG) neutral because the combusted carbon in the form of CO2 is soon taken up by regrowing vegetation. Thus, the two fifths or more of the world's households relying on such fuels are generally not thought to play a significant role in GHG emissions, except where the wood or other biomass they use is not harvested renewably. This review examines this assumption using an emissions database of CO2, CO, CH4, NMHC, N2O, and total suspended particulate emissions from a range of household stoves in common use in India using six biomass fuels, kerosene, liquefied petroleum gas, and biogas. Because typical biomass stoves are thermally inefficient and divert substantial fuel carbon to products of incomplete combustion, their global warming commitment (GWC) per meal is high. Depending on time horizons and which GHGs are measured, the GWC of a meal cooked on a biomass stove can actually exceed that of the fossil fuels, even if based on renewably harvested fuel. Biogas, being based on a renewable fuel and, because it is a gas, being combusted with high efficiency in simple devices, has by far the lowest GWC emitted at the stove per meal and is indicative of the advantage that upgraded fuels made from biomass have in moving toward sustainable development goals. There are a number of policy implications of this work, including revelation of a range of win-win opportunities for international investment in rural energy development that would achieve cost-effective GHG reduction as well as substantial local benefits.

Notes: Abstract We assess the environmental health impact and policy implications of the widespread addition of methyl tert-butyl ether (MTBE) as a chemical that is used as an oxygenate to much of the gasoline supply in the United States. Initial concerns about short-term and long-term adverse health consequences following the substantial increase in MTBE use in the winter of 1992-1993 have been supplemented by the discovery in 1996 of what is now relatively widespread contamination of groundwater. We identify 14 governmental initiatives during the 10-year period 1989-1999 in which the potential adverse consequences of MTBE were considered and a nearly identical research agenda was proposed. The lessons from the ongoing MTBE episode show that: (a) research should precede rather than follow environmental health policy decisions; (b) the extent of potential human and environmental exposure should be an important criterion in determining the amount of information needed before making an environmental policy decision; (c) a better understanding of nonspecific human symptoms associated with environmental exposures is needed; (d) the boundaries between the US Environmental Protection Agency program offices should be as porous as the boundaries between environmental media; (e) the US Environmental Protection Agency needs to focus more on public health rather than on legal approaches to environmental management; (f) it is more difficult to remove a chemical once it is in commerce than it is to prevent its use; (g) resolution of uncertainty is best accomplished through research rather than through repetitive review; and (h) better tools are needed to evaluate risk/risk trade-offs. The ongoing replacement of MTBE by other, less well studied oxygenates such as tertiary amyl methyl ether indicates that these environmental public policy lessons have not been learned.

Notes: Abstract Meeting the growing demand for personal mobility and transport of goods in a sustainable way presents a wide range of interrelated engineering and public policy challenges. This chapter reviews some of the technical options being developed for mitigating the local and global environmental impact of road vehicles, made possible using developments in the materials and combustion sciences, sensor technologies, catalysis, and information processing. Although the improved technical performance of these options can be quantified, the likelihood of commercial success is harder to predict. This review considers factors that may support the adoption of innovative vehicle technologies, recognizing that the ubiquity of existing solutions and infrastructures will make any change process complex.

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 Tyrosine phosphorylation is one of the key covalent modifications that occurs in multicellular organisms as a result of intercellular communication during embryogenesis and maintenance of adult tissues. The enzymes that carry out this modification are the protein tyrosine kinases (PTKs), which catalyze the transfer of the gamma phosphate of ATP to tyrosine residues on protein substrates. Phosphorylation of tyrosine residues modulates enzymatic activity and creates binding sites for the recruitment of downstream signaling proteins. Two classes of PTKs are present in cells: the transmembrane receptor PTKs and the nonreceptor PTKs. Because PTKs are critical components of cellular signaling pathways, their catalytic activity is strictly regulated. Over the past several years, high-resolution structural studies of PTKs have provided a molecular basis for understanding the mechanisms by which receptor and nonreceptor PTKs are regulated. This review will highlight the important results that have emerged from these structural studies.

Notes: Abstract The prostaglandin endoperoxide H synthases-1 and 2 (PGHS-1 and PGHS-2; also cyclooxygenases-1 and 2, COX-1 and COX-2) catalyze the committed step in prostaglandin synthesis. PGHS-1 and 2 are of particular interest because they are the major targets of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, ibuprofen, and the new COX-2 inhibitors. Inhibition of the PGHSs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs reduces fatal thrombotic events, as well as the development of colon cancer and Alzheimer's disease. In this review, we examine how the structures of these enzymes relate mechanistically to cyclooxygenase and peroxidase catalysis, and how differences in the structure of PGHS-2 confer on this isozyme differential sensitivity to COX-2 inhibitors. We further examine the evidence for independent signaling by PGHS-1 and PGHS-2, and the complex mechanisms for regulation of PGHS-2 gene expression.

Notes: Abstract Homotypic (self) fusion of yeast vacuoles, which is essential for the low copy number of this organelle, uses catalytic elements similar to those used in heterotypic vesicular trafficking reactions between different organelles throughout nature. The study of vacuole inheritance has benefited from the ease of vacuole isolation, the availability of the yeast genome sequence and numerous mutants, and from a rapid, quantitative in vitro assay of fusion. The soluble proteins and small molecules that support fusion are being defined, conserved membrane proteins that catalyze the reaction have been identified, and the vacuole membrane has been solubilized and reconstituted into fusion-competent proteoliposomes, allowing the eventual purification of all needed factors. Studies of homotypic vacuole fusion have suggested a modified paradigm of membrane fusion in which integral membrane proteins termed "SNAREs" can form stable complexes in cis (when on the same membrane) as well as in trans (when anchored to opposing membranes). Chaperones (NSF/Sec18p, LMA1, and alpha-SNAP/Sec17p) disassemble cis-SNARE complexes to prepare for the docking of organelles rather than to drive fusion. The specificity of organelle docking resides in a cascade of trans-interactions (involving Rab-like GTPases), "tethering factors," and trans-SNARE pairing. Fusion itself, the mixing of the membrane bilayers and the organelle contents, is triggered by calcium signaling.

Notes: Abstract The sequestration and delivery of cytoplasmic material to the yeast vacuole and mammalian lysosome require the dynamic mobilization of cellular membranes and specialized protein machinery. Under nutrient deprivation conditions, double-membrane vesicles form around bulk cytoplasmic cargo destined for degradation and recycling in the vacuole/lysosome. A similar process functions to remove excess organelles under vegetative conditions in which they are no longer needed. Biochemical, morphological, and molecular genetic studies in yeasts and mammalian cells have begun to elucidate the molecular details of this autophagy process. In addition, the overlap of macroautophagy with the process of pexophagy and with the biosynthetic cytoplasm-to-vacuole targeting pathway, which delivers the resident vacuolar hydrolase aminopeptidase I, indicates that these three pathways are related mechanistically. Identification and characterization of the autophagic/cytoplasm-to-vacuole protein-targeting components have revealed the essential roles for various functional classes of proteins, including a novel protein conjugation system and the machinery for vesicle formation and fusion.

Notes: Abstract Three lines of evidence have converged on a multiprotein Mediator complex as a conserved interface between gene-specific regulatory proteins and the general transcription apparatus of eukaryotes. Mediator was discovered as an activity required for transcriptional activation in a reconstituted system from yeast. Upon resolution to homogeneity, the activity proved to reside in a 20-protein complex, which could exist in a free state or in a complex with RNA polymerase II, termed holoenzyme. A second line of evidence came from screens in yeast for mutations affecting transcription. Two-thirds of Mediator subunits are encoded by genes revealed by these screens. Five of the genetically defined subunits, termed Srbs, were characterized as interacting with the C-terminal domain of RNA polymerase II in vivo, and were shown to bind polymerase in vitro. A third line of evidence has come recently from studies in mammalian transcription systems. Mammalian counterparts of yeast Mediator were shown to interact with transcriptional activator proteins and to play an essential role in transcriptional regulation. Mediator evidently integrates and transduces positive and negative regulatory information from enhancers and operators to promoters. It functions directly through RNA polymerase II, modulating its activity in promoter-dependent transcription. Details of the Mediator mechanism remain obscure. Additional outstanding questions include the patterns of promoter-specificity of the various Mediator subunits, the possible cell-type-specificity of Mediator subunit composition, and the full structures of both free Mediator and RNA polymerase II holoenzyme.

Notes: Abstract GTPase-activating proteins (GAPs) regulate heterotrimeric G proteins by increasing the rates at which their alpha subunits hydrolyze bound GTP and thus return to the inactive state. G protein GAPs act allosterically on Galpha subunits, in contrast to GAPs for the Ras-like monomeric GTP-binding proteins. Although they do not contribute directly to the chemistry of GTP hydrolysis, G protein GAPs can accelerate hydrolysis 〉2000-fold. G protein GAPs include both effector proteins (phospholipase C-beta, p115RhoGEF) and a growing family of regulators of G protein signaling (RGS proteins) that are found throughout the animal and fungal kingdoms. GAP activity can sharpen the termination of a signal upon removal of stimulus, attenuate a signal either as a feedback inhibitor or in response to a second input, promote regulatory association of other proteins, or redirect signaling within a G protein signaling network. GAPs are regulated by various controls of their cellular concentrations, by complex interactions with Gbetagamma or with Gbeta5 through an endogenous Ggamma-like domain, and by interaction with multiple other proteins.

Notes: Abstract Multistep chemical reactions are increasingly seen as important in a growing number of complex biotransformations. Covalently attached prosthetic groups or swinging arms, and their associated protein domains, are essential to the mechanisms of active-site coupling and substrate channeling in a number of the multifunctional enzyme systems responsible. The protein domains, for which the posttranslational machinery in the cell is highly specific, are crucially important, contributing to the processes of molecular recognition that define and protect the substrates and the catalytic intermediates. The domains have novel folds and move by virtue of conformationally flexible linker regions that tether them to other components of their respective multienzyme complexes. Structural and mechanistic imperatives are becoming apparent as the assembly pathways and the coupling of multistep reactions catalyzed by these dauntingly complex molecular machines are unraveled.

Notes: Abstract Although it has long been recognized that dynamics in supercooled liquids might be spatially heterogeneous, only in the past few years has clear evidence emerged to support this view. As a liquid is cooled far below its melting point, dynamics in some regions of the sample can be orders of magnitude faster than dynamics in other regions only a few nanometers away. In this review, the experimental work that characterizes this heterogeneity is described. In particular, the following questions are addressed: How large are the heterogeneities? How long do they last? How much do dynamics vary between the fastest and slowest regions? Why do these heterogeneities arise? The answers to these questions influence practical applications of glass-forming materials, including polymers, metallic glasses, and pharmaceuticals.

Notes: Abstract Rotational tunneling of small molecular groups has been the subject of considerable theoretical and experimental activity for several decades. Much of this activity has been driven by the promise of exploiting the extreme sensitivity of quantum tunneling to interatomic potentials, but until recently, there was no straightforward means by which quantitative information about these potentials could be extracted. This review explains how a quantitative method, suitable for general application, was developed. It then goes on to show how this has been used to understand tunneling systems for which no previous satisfactory explanation had been found. The application of the methodology, and its results, to other disciplines is discussed.

Notes: Abstract Infrared (IR) spectroscopy is widely used to identify molecular adsorbates that form on metals in the course of surface chemical reactions. Because IR spectroscopy is one of the few surface-sensitive probes that provide molecule-specific information without perturbing the chemisorbed state, there is great interest in extracting as much structural information from the spectra as possible. The various ways IR spectroscopy is used to determine the structure of molecular adsorbates, from strictly qualitative interpretations based on symmetry selection rules to the use of ab initio electronic structure calculations to predict the IR spectrum of a chemisorbed molecule, are reviewed.

Notes: Abstract New electron spin resonance (ESR) technologies have been developed, which have led to new and improved applications. (a) The development of two-dimensional Fourier transform (FT) ESR required spectrometers providing intense pi/2 microwave pulses of very short (3-5 ns) duration, wide bandwidths, and very short dead times. It has enabled studies that resolve sophisticated details of molecular dynamics in complex fluids. (b) Methods that produce multiple quantum coherences by pulsed ESR now enable accurate measurements of large distances (〉12A). (c) One of the most important advances has been the extension of ESR to high magnetic fields and high frequencies. This has benefited from the utilization of quasi-optical methods, especially above 150 GHz. The greatly improved orientational resolution and the faster "snapshot" of motions that are provided by ESR at high frequencies enhance studies of molecular dynamics. The use of both high and lower frequencies enables one to unravel faster and slower modes from the complex dynamics of fluids and macromolecules. (d) The development of FT-ESR imaging required substantial pulsed field gradients lasting only 50-100 ns. ESR imaging is effective in studying diffusion in fluids. Areas for further development are also described.

Notes: Abstract The power and effectiveness of clinical pharmacology are about to be transformed with a speed that earlier in this decade could not have been foreseen even by the most astute visionaries. In the very near future, we will have at our disposal the reference DNA sequence for the entire human genome, estimated to contain approximately 3.5 billion bp. At the same time, the science of whole genome sequencing is fostering the computational science of bioinformatics needed to develop practical applications for pharmacology and toxicology. Indeed, it is likely that pharmacology, toxicology, bioinformatics, and genomics will merge into a new branch of medical science for studying and developing pharmaceuticals from molecule to bedside.

Notes: Abstract Cytosolic sulfotransferase catalyzes sulfoconjugation of relatively small lipophilic endobiotics and xenobiotics. At least 44 cytosolic sulfotransferases have been identified from mammals, and based on their amino acid sequences, these forms are shown to constitute five different families. In humans, 10 sulfotransferase genes have been identified and shown to localize on at least five different chromosomes. The enzymatic properties characterized in the recombinant forms indicate the association of their substrate specificity with metabolisms of such nonpeptide hormones as estrogen, corticoid, and thyroxine, although most forms are also active on the sulfation of various xenobiotics. Genetic polymorphisms are observed on such human sulfotransferases as ST1A2, ST1A3, and ST2A3.

Notes: Abstract The application of rapid methods currently used for screening discovery drug candidates for metabolism and pharmacokinetic characteristics is discussed. General considerations are given for screening in this context, including the criteria for good screens, the use of counterscreens, the proper sequencing of screens, ambiguity in the interpretation of results, strategies for false positives and negatives, and the special difficulties encountered in drug metabolism and pharmacokinetic screening. Detailed descriptions of the present status of screening are provided for absorption potential, blood-brain barrier penetration, inhibition and induction of cytochrome P450, pharmacokinetics, biotransformation, and computer modeling. Although none of the systems currently employed for drug metabolism and pharmacokinetic screening can be considered truly high-throughput, several of them are rapid enough to be a practical part of the screening paradigm for modern, fast-moving discovery programs.

Notes: Abstract The standard description of the vibrational and rotational motion of polyatomic molecules, as expressed by the distortable rotor/harmonic oscillator approximation, provides an adequate description of the molecular quantum states only in regions of low total state density. When the total state density is large, exceeding 100 states/cm-1, the vibrational dynamics are "dissipative" and the fundamental process of intramolecular vibrational energy redistribution is operative. The presence of intramolecular vibrational energy redistribution leads to molecular quantum states of a qualitatively different nature. With respect to a normal-mode vibrational basis, these quantum states are "highly mixed" in their vibrational character and represent nuclear motion that is a combination of all the normal-mode motions. This review describes frequency domain spectroscopy techniques designed to probe the vibrational, rotational, and structural composition of these eigenstates. Recent work that investigates spectroscopy between highly mixed states is also reviewed.

Notes: Abstract The vibrational relaxation of noble gas-halogen van der Waals clusters has been fertile territory for the development of experimental and theoretical tools for state-to-state dynamics studies. Proceeding through the various combinations of noble gas atoms and halogen molecules, one goes from "simple" direct vibrational predissociation, through sequential relaxation pathways, to the statistical intramolecular vibrational relaxation limit. In some cases the vibrational processes dominate, in others electronically nonadiabatic processes, including chemical reactions, interfere. Thus the noble gas-halogen species provide test cases for most of the dynamical processes available to more "normal" molecules. This review discusses the current state-of-the-art for such studies and points to important problems that remain to be solved.

Notes: Abstract This review examines the use of self-assembly in the fabrication of ceramic mesostructures, emphasizing the use of amphiphilic surfactants and block copolymers. The association between this area of research and biomimetics is discussed, linking developments in synthetic self-assembly with biomineralization. The fabrication of hierarchical structures through the use of simultaneous processing is shown to be a necessary condition for applications of this new technology.

Notes: Abstract Femtosecond visible and infrared analogues of multiple-pulse nuclear magnetic resonance techniques provide novel snapshot probes into the structure and electronic and vibrational dynamics of complex molecular assemblies such as photosynthetic antennae, proteins, and hydrogen-bonded liquids. A classical-oscillator description of these spectroscopies in terms of interacting quasiparticles (rather than transitions among global eigenstates) is developed and sets the stage for designing new pulse sequences and inverting the multidimensional signals to yield molecular structures. Considerable computational advantages and a clear physical insight into the origin of the response and the relevant coherence sizes are provided by a real-space analysis of the underlying coherence-transfer pathways in Liouville space.

Notes: Abstract Thermionic emission is discussed as a long time (microseconds) decay mode of energy-rich large molecules, metallic and metcar clusters, and fullerenes. We review what is known and consider the many experiments, systems, and theoretical and computational studies that still need to be done. We conclude with a wish list for future work. Particular attention is given to the experimental signatures, such as the dependence on the mode of energy acquisition, and theoretical indications of a not-quite-statistical delayed ionization and to the competition of electron emission with other decay modes, such as fragmentation or radiative cooling. Coupling of the electronic and nuclear modes can be a bottleneck and quite long time-delayed ionization can be observed, as in the decay of high Rydberg states probed by ZEKE spectroscopy, before the onset of complete energy partitioning.

Notes: Abstract Theoretical aspects of dynamical processes at metal surfaces are reviewed. Experimental challenges to theory are presented and progress toward meeting these challenges is appraised. Topics include adsorbate vibrational energy flow, inelastic molecule-surface scattering, adsorption, transient mobility, dissociation, desorption, photochemistry, and electron-induced chemistry at metal surfaces. Experimental examples cited illustrate the richness of dynamical phenomena to be understood and the necessity of developing multidimensional, beyond Born-Oppenheimer, formulations of adsorbate dynamics. Classical mechanical and quantum mechanical treatments of dynamics are contrasted. The importance of including phonon and electron-hole pair dissipation in theories of adsorbate dynamics is emphasized, and strategies for doing this in classical and quantum treatments are presented.

Notes: Abstract This review summarizes and assesses recent theoretical and experimental advances, with special emphasis on the effective interaction between charge-stabilized colloids, in the bulk or in confined geometries, and on the ambiguities of defining an effective charge of the colloidal particles. Some consideration is given to the often neglected discrete solvent effects.

Notes: Abstract Calculation of chemical reaction dynamics is central to theoretical chemistry. The majority of calculations use either classical mechanics, which is computationally inexpensive but misses quantum effects, such as tunneling and interference, or quantum mechanics, which is computationally expensive and often conceptually opaque. An appealing middle ground is the use of semiclassical mechanics. Indeed, since the early 1970s there has been great interest in using semiclassical methods to calculate reaction probabilities. However, despite the elegance of classical S-matrix theory, numerical results on even the simplest reactive systems remained out of reach. Recently, with advances both in correlation function formulations of reactive scattering as well as in semiclassical methods, it has become possible for the first time to calculate reaction probabilities semiclassically. The correlation function methods are contrasted with recent flux-based methods, which, although providing somewhat more compact expressions for the cumulative reactive probability, are less compatible with semiclassical implementation.

Notes: Abstract Quantum Monte Carlo methods have recently made it possible to calculate the electronic structure of relatively large molecular systems with very high accuracy. These large systems range from positron complexes [NH2,Ps] with ~10 electrons to C20 isomers with 120 electrons, to silicon crystal structures of 250 atoms and 1000 valence electrons. The techniques for such calculations and a sampling of applications are reviewed.

Notes: Abstract The growth and evolution of strained epitaxial Ge on a Si(001) surface provides a rich system for exploring the behavior of strongly interacting nanocrystals. In the temperature regime above 500oC, there are two different (metastable) shapes of defect-free nanocrystals, termed pyramids and domes, that dominate the system depending on the temperature of the substrate during growth and the amount of Ge deposited. In contrast to the usual case considered in nucleation theory, the relaxation of the strain energy at the surface of the nanocrystals makes those surfaces stabilizing, i.e. the surface contribution to the free energy of the Ge nanocrystals is negative. Given that the edges of the nanocrystals are destabilizing (positive free energy), the interaction of the surfaces and edges of the nanocrystals in an ensemble renders an internal free energy for the system that has a local minimum with respect to the size (volume) of the nanocrystal. At finite temperatures, this free energy yields a size distribution with a characteristic centroid, width, and skewness for each nanocrystal shape. The smaller pyramids transform into domes when they grow to the point where they can surmount a kinetic energy barrier between the two structures. However, the Ge nanocrystals also effectively repel one another strongly via the strain fields that are produced in the Si substrate. This repulsive interaction makes the ensemble of Ge nanocrystals a highly nonideal thermodynamic system and, in turn, makes the free energies of the nanocrystals a function of their number density, or equivalently a function of the amount of Ge deposited. The interplay of the stabilizing effect of the nanocrystal surfaces and the destabilizing influence of their repulsive interactions yields a complex behavior for the nanocrystal-size distributions that can nonetheless be modeled using simple thermodynamic expressions.

Notes: Abstract Recent high-pressure studies reveal a wealth of new information about the behavior of molecular materials subjected to pressures well into the multimegabar range (several hundred gigapascal), corresponding to compressions in excess of an order of magnitude. Under such conditions, bonding patterns established for molecular systems near ambient conditions change dramatically, causing profound effects on numerous physical and chemical properties and leading to the formation of new classes of materials. Representative systems are examined to illustrate key phenomena, including the evolution of structure and bonding with compression; pressure-induced phase transitions and chemical reactions; pressure-tuning of vibrational dynamics, quantum effects, and excited electronic states; and novel states of electronic and magnetic order. Examples are taken from simple elemental molecules (e.g. homonuclear diatomics), simple heteronuclear species, hydrogen-bonded systems (including H2O), simple molecular mixtures, and selected larger, more complex molecules. There are many implications that span the sciences.

Notes: Abstract A nostalgic account is given of my scientific odyssey, recalling early encounters, some fateful, some just fun, with mentors, methods, and molecules. These include stories of my student years at Stanford, pursuing chemical kinetics with Harold Johnston; graduate study at Harvard, doing molecular spectroscopy with Bright Wilson; and fledgling faculty years at Berkeley, launching molecular beam studies of reaction dynamics. A few vignettes from my "ever after " era on the Harvard faculty emphasize thematic motivations or methods inviting further exploration. An Appendix provides a concise listing of colleagues in research and the topics we have pursued.

Notes: Abstract It would often be useful in computer simulations to use a simple description of solvation effects, instead of explicitly representing the individual solvent molecules. Continuum dielectric models often work well in describing the thermodynamic aspects of aqueous solvation, and approximations to such models that avoid the need to solve the Poisson equation are attractive because of their computational efficiency. Here we give an overview of one such approximation, the generalized Born model, which is simple and fast enough to be used for molecular dynamics simulations of proteins and nucleic acids. We discuss its strengths and weaknesses, both for its fidelity to the underlying continuum model and for its ability to replace explicit consideration of solvent molecules in macromolecular simulations. We focus particularly on versions of the generalized Born model that have a pair-wise analytical form, and therefore fit most naturally into conventional molecular mechanics calculations.

Notes: Abstract Explicitly time-dependent implementations of optical frequency modulation spectroscopy have been recently applied to a wide range of problems in chemical physics. We provide a brief description of the methodology, with an emphasis on its intrinsic advantages for interrogating transient species. Several examples highlight the application of the technique to high-resolution absorption spectra of free radicals, rate measurements for gas-phase reactions, and Doppler spectroscopy of the gas-phase products of photoinitiated reactions.