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  • Articles  (56,611)
  • Springer  (32,702)
  • American Association for the Advancement of Science  (22,342)
  • Oxford University Press  (1,020)
  • Annual Reviews  (547)
  • Blackwell Publishing Ltd
  • 2005-2009  (56,611)
  • Chemistry and Pharmacology  (56,611)
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  • Articles  (56,611)
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  • 1
    Electronic Resource
    Electronic Resource
    APPLICATIONS OF DNA MICROARRAYS IN BIOLOGY (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 53-82 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: DNA microarrays have enabled biology researchers to conduct large-scale quantitative experiments. This capacity has produced qualitative changes in the breadth of hypotheses that can be explored. In what has become the dominant mode of use, changes in the transcription rate of nearly all the genes in a genome, taking place in a particular tissue or cell type, can be measured in disease states, during development, and in response to intentional experimental perturbations, such as gene disruptions and drug treatments. The response patterns have helped illuminate mechanisms of disease and identify disease subphenotypes, predict disease progression, assign function to previously unannotated genes, group genes into functional pathways, and predict activities of new compounds. Directed at the genome sequence itself, microarrays have been used to identify novel genes, binding sites of transcription factors, changes in DNA copy number, and variations from a baseline sequence, such as in emerging strains of pathogens or complex mutations in disease-causing human genes. They also serve as a general demultiplexing tool to sort spatially the sequence-tagged products of highly parallel reactions performed in solution. A brief review of microarray platform technology options, and of the process steps involved in complete experiment workflows, is included.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.74.082803.133212
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  • 2
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 355-383 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Nods are cytosolic proteins that contain a nucleotide-binding oligomerization domain (NOD). These proteins include key regulators of apoptosis and pathogen resistance in mammals and plants. A large number of Nods contain leucine-rich repeats (LRRs), hence referred to as NOD-LRR proteins. Genetic variation in several NOD-LRR proteins, including human Nod2, Cryopyrin, and CIITA, as well as mouse Naip5, is associated with inflammatory disease or increased susceptibility to microbial infections. Nod1, Nod2, Cryopyrin, and Ipaf have been implicated in protective immune responses against pathogens. Together with Toll-like receptors, Nod1 and Nod2 appear to play important roles in innate and acquired immunity as sensors of bacterial components. Specifically, Nod1 and Nod2 participate in the signaling events triggered by host recognition of specific motifs in bacterial peptidoglycan and, upon activation, induce the production of proinflammatory mediators. Naip5 is involved in host resistance to Legionella pneumophila through cell autonomous mechanisms, whereas CIITA plays a critical role in antigen presentation and development of antigen-specific T lymphocytes. Thus, NOD-LRR proteins appear to be involved in a diverse array of processes required for host immune reactions against pathogens.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.74.082803.133347
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  • 3
    Electronic Resource
    Electronic Resource
    COPPER-ZINC SUPEROXIDE DISMUTASE AND AMYOTROPHIC LATERAL SCLEROSIS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 563-593 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Copper-zinc superoxide dismutase (CuZnSOD, SOD1 protein) is an abundant copper- and zinc-containing protein that is present in the cytosol, nucleus, peroxisomes, and mitochondrial intermembrane space of human cells. Its primary function is to act as an antioxidant enzyme, lowering the steady-state concentration of superoxide, but when mutated, it can also cause disease. Over 100 different mutations have been identified in the sod1 genes of patients diagnosed with the familial form of amyotrophic lateral sclerosis (fALS). These mutations result in a highly diverse group of mutant proteins, some of them very similar to and others enormously different from wild-type SOD1. Despite their differences in properties, each member of this diverse set of mutant proteins causes the same clinical disease, presenting a challenge in formulating hypotheses as to what causes SOD1-associated fALS. In this review, we draw together and summarize information from many laboratories about the characteristics of the individual mutant SOD1 proteins in vivo and in vitro in the hope that it will aid investigators in their search for the cause(s) of SOD1-associated fALS.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.72.121801.161647
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  • 4
    Electronic Resource
    Electronic Resource
    EUKARYOTIC TRANSLESION SYNTHESIS DNA POLYMERASES: Specificity of Structure and Function (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 317-353 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: This review focuses on eukaryotic translesion synthesis (TLS) DNA polymerases, and the emphasis is on Saccharomyces cerevisiae and human Y-family polymerases (Pols) ??, ?’, ?”, and Rev1, as well as on Pol?
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.74.082803.133250
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  • 5
    Electronic Resource
    Electronic Resource
    STRUCTURE AND PHYSIOLOGIC FUNCTION OF THE LOW-DENSITY LIPOPROTEIN RECEPTOR (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 535-562 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The low-density lipoprotein receptor (LDLR) is responsible for uptake of cholesterol-carrying lipoprotein particles into cells. The receptor binds lipoprotein particles at the cell surface and releases them in the low-pH environment of the endosome. The focus of the current review is on biochemical and structural studies of the LDLR and its ligands, emphasizing how structural features of the receptor dictate the binding of low-density lipoprotein (LDL) and beta-migrating forms of very low-density lipoprotein (?‚-VLDL) particles, how the receptor releases bound ligands at low pH, and how the cytoplasmic tail of the LDLR interfaces with the endocytic machinery.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.74.082803.133354
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  • 6
    Electronic Resource
    Electronic Resource
    DNA MISMATCH REPAIR (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 681-710 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: DNA mismatch repair (MMR) is an evolutionarily conserved process that corrects mismatches generated during DNA replication and escape proofreading. MMR proteins also participate in many other DNA transactions, such that inactivation of MMR can have wide-ranging biological consequences, which can be either beneficial or detrimental. We begin this review by briefly considering the multiple functions of MMR proteins and the consequences of impaired function. We then focus on the biochemical mechanism of MMR replication errors. Emphasis is on structure-function studies of MMR proteins, on how mismatches are recognized, on the process by which the newly replicated strand is identified, and on excision of the replication error.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.74.082803.133243
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  • 7
    Electronic Resource
    Electronic Resource
    STRUCTURE AND FUNCTION OF FATTY ACID AMIDE HYDROLASE (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 411-432 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Fatty acid amide hydrolase (FAAH) is a mammalian integral membrane enzyme that degrades the fatty acid amide family of endogenous signaling lipids, which includes the endogenous cannabinoid anandamide and the sleep-inducing substance oleamide. FAAH belongs to a large and diverse class of enzymes referred to as the amidase signature (AS) family. Investigations into the structure and function of FAAH, in combination with complementary studies of other AS enzymes, have engendered provocative molecular models to explain how this enzyme integrates into cell membranes and terminates fatty acid amide signaling in vivo. These studies, as well as their biological and therapeutic implications, are the subject of this review
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.74.082803.133450
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  • 8
    Electronic Resource
    Electronic Resource
    STRUCTURAL INSIGHTS INTO TRANSLATIONAL FIDELITY (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 129-177 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The underlying basis for the accuracy of protein synthesis has been the subject of over four decades of investigation. Recent biochemical and structural data make it possible to understand at least in outline the structural basis for tRNA selection, in which codon recognition by cognate tRNA results in the hydrolysis of GTP by EF-Tu over 75??A?? away. The ribosome recognizes the geometry of codon-anticodon base pairing at the first two positions but monitors the third, or wobble position, less stringently. Part of the additional binding energy of cognate tRNA is used to induce conformational changes in the ribosome that stabilize a transition state for GTP hydrolysis by EF-Tu and subsequently result in accelerated accommodation of tRNA into the peptidyl transferase center. The transition state for GTP hydrolysis is characterized, amongf other things, by a distorted tRNA. This picture explains a large body of data on the effect of antibiotics and mutations on translational fidelity. However, many fundamental questions remain, such as the mechanism of activation of GTP hydrolysis by EF-Tu, and the relationship between decoding and frameshifting.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.74.061903.155440
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  • 9
    Electronic Resource
    Electronic Resource
    MONITORING ENERGY BALANCE: Metabolites of Fatty Acid Synthesis as Hypothalamic Sensors (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 515-534 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Because energy balance is important for survival, a system is required to monitor energy status and to make appropriate adjustments in energy intake and energy expenditure. In higher animals, a centrally located system has evolved to accomplish this task. When caloric intake exceeds expenditure, the surplus is channeled into energy storage pathways, primarily the synthesis of fatty acids, which are converted into fat and stored in adipose tissue. Thus, metabolic flux through the pathway of fatty acid synthesis, located in the lipogenic tissues, reflects the "energy status" of the animal. The enzymatic machinery of this pathway is also expressed in the brain, notably the hypothalamus. In the hypothalamus, intermediates in this pathway appear to serve as energy sensors that signal higher brain centers to produce appropriate responses, e.g., altered food intake and energy expenditure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.074027
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  • 10
    Electronic Resource
    Electronic Resource
    EUKARYOTIC CYTOSINE METHYLTRANSFERASES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 481-514 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Large-genome eukaryotes use heritable cytosine methylation to silence promoters, especially those associated with transposons and imprinted genes. Cytosine methylation does not reinforce or replace ancestral gene regulation pathways but instead endows methylated genomes with the ability to repress specific promoters in a manner that is buffered against changes in the internal and external environment. Recent studies have shown that the targeting of de novo methylation depends on multiple inputs; these include the interaction of repeated sequences, local states of histone lysine methylation, small RNAs and components of the RNAi pathway, and divergent and catalytically inert cytosine methyltransferase homologues that have acquired regulatory roles. There are multiple families of DNA (cytosine-5) methyltransferases in eukaryotes, and each family appears to be controlled by different regulatory inputs. Sequence-specific DNA-binding proteins, which regulate most aspects of gene expression, do not appear to be involved in the establishment or maintenance of genomic methylation patterns.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.74.010904.153721
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  • 11
    Electronic Resource
    Electronic Resource
    ULTRAFAST CHEMISTRY: Using Time-Resolved Vibrational Spectroscopy for Interrogation of Structural Dynamics (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 337-367 
    Details
    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: Time-resolved infrared (IR) and Raman spectroscopy elucidates molecular structure evolution during ultrafast chemical reactions. Following vibrational marker modes in real time provides direct insight into the structural dynamics, as is evidenced in studies on intramolecular hydrogen transfer, bimolecular proton transfer, electron transfer, hydrogen bonding during solvation dynamics, bond fission in organometallic compounds and heme proteins, cis-trans isomerization in retinal proteins, and transformations in photochromic switch pairs. Femtosecond IR spectroscopy monitors the site-specific interactions in hydrogen bonds. Conversion between excited electronic states can be followed for intramolecular electron transfer by inspection of the fingerprint IR- or Raman-active vibrations in conjunction with quantum chemical calculations. Excess internal vibrational energy, generated either by optical excitation or by internal conversion from the electronic excited state to the ground state, is observable through transient frequency shifts of IR-active vibrations and through nonequilibrium populations as deduced by Raman resonances.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physchem.56.092503.141314
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  • 12
    Electronic Resource
    Electronic Resource
    FEMTOSECOND LASER PHOTOELECTRON SPECTROSCOPY ON ATOMS AND SMALL MOLECULES: Prototype Studies in Quantum Control (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 25-56 
    Details
    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: We review prototype studies in the area of quantum control with femtosecond lasers. We restrict this discussion to atoms and diatomics under gas-phase collision-free conditions to allow for a comparison between theory and experiment. Both the perturbative regime and the nonperturbative regime of the light-matter interaction are addressed. To that end, atomic/molecular beam techniques are combined together with femtosecond laser techniques and energy-resolved photoelectron spectroscopy and ion detection. Highly detailed information on the laser-induced quantum dynamics is extracted with the help of kinetic energy-resolved photoelectron spectroscopy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physchem.56.092503.141315
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  • 13
    Electronic Resource
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    TRANSPORT SPECTROSCOPY OF CHEMICAL NANOSTRUCTURES: The Case of Metallic Single-Walled Carbon Nanotubes (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 475-490 
    Details
    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: Transport spectroscopy, a technique based on current-voltage measurements of individual nanostructures in a three-terminal transistor geometry, has emerged as a powerful new tool to investigate the electronic properties of chemically derived nanostructures. In this review, we discuss the utility of this approach using the recent studies of single-nanotube transistors as an example. Specifically, we discuss how transport measurements can be used to gain detailed insight into the electronic motion in metallic single-walled carbon nanotubes in several distinct regimes, depending on the coupling strength of the contacts to the nanotubes. Measurements of nanotube devices in these different conductance regimes have enabled a detailed analysis of the transport properties, including the experimental determination of all Hartree-Fock parameters that govern the electronic structure of metallic nanotubes and the demonstration of Fabry-Perot resonators based on the interference of electron waves.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physchem.56.092503.141226
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  • 14
    Electronic Resource
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    RYDBERG WAVEPACKETS IN MOLECULES: From Observation to Control (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 91-117 
    Details
    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: Significant advances in laser technology have led to an increasing interest in the time evolution of Rydberg wavepackets as a means to understanding, and ultimately controlling, quantum phenomena. Rydberg wavepackets in molecules are particularly interesting as they possess many of the dynamical complications of large molecules, such as nonadiabatic coupling between the various degrees of freedom, yet they remain tractable experimentally and theoretically. This review explains in detail how the method of interfering wavepackets can be applied to observe and control Rydberg wavepackets in molecules; it discusses the achievements to date and the possibilities for the future.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physchem.55.091602.094428
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  • 15
    Electronic Resource
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    PROBING TRANSIENT MOLECULAR STRUCTURES IN PHOTOCHEMICAL PROCESSES USING LASER-INITIATED TIME-RESOLVED X-RAY ABSORPTION SPECTROSCOPY (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 221-254 
    Details
    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: Molecular structures during chemical processes are crucial for predicting molecular reactivity and reaction mechanisms. Using a laser pulse as an internal clock for starting fundamental chemical processes, molecular structural dynamics can be characterized by coherent vibrational motions and by incoherent transitions between different intermediate states. Recent developments in pulsed X-ray facilities allow structural determination of discrete excited states and reaction intermediates using laser-initiated time-resolved X-ray absorption spectroscopy (LITR-XAS). Moreover, femtosecond X-ray sources have begun making significant contributions in monitoring coherent molecular motions. This review summarizes recent developments in the field, including technical and scientific challenges as well as several examples involving excited state molecular structure and electronic configuration determinations. Future applications of this technique with high time resolution will enable visualization of fundamental chemical events in many systems and further our understanding in photochemistry.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physchem.56.092503.141310
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  • 16
    Electronic Resource
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    FAT CELLS: Afferent and Efferent Messages Define New Approaches to Treat Obesity (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 119-146 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: For a long time neural and endocrine messages were studied for their impact on adipocyte metabolism and control of storage/release of fatty acids. In fact, bidirectional communication exists between adipocytes and other tissues. Several molecules secreted from adipocytes are involved in fat cell signaling to other tissues. Adipocyte products could initiate antagonistic effects on target tissues. Fat cells produce peptides that can elicit insulin resistance, such as tumor necrosis factor-ʼ̛ and resistin, as well as hormones that can improve insulin resistance, such as leptin and adiponectin. Secretion of complement proteins, proinflammatory cytokines, procoagulant, and acute phase reactant proteins have also been observed in adipocytes. There is much to learn about how these signals function. It is unlikely that all the adipocyte's endocrine and paracrine signals have been identified. Putative pharmacological strategies aiming at modulation of afferent and efferent fat cell messages are reviewed and discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095843
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  • 17
    Electronic Resource
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    NATURAL HEALTH PRODUCTS AND DRUG DISPOSITION * (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 203-226 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Botanicals such as herbal products (HPs) and nutraceuticals (NCs) are often regarded as low risk because of their long history of human use. Anecdotal and literature reports of adverse drug events (ADEs) and clinical studies with HPs are increasing, but many of the reports are incomplete and contradictory. These reports need to identify confounding factors and explain contradictory findings if they are to help health care professionals or patients understand what risks are involved. HPs are complex botanicals, not single-active ingredient (SAI) products. Studies can be confounded by different manufacturing processes and formulations, including cosmetics and food supplements; environment; chemotypes; misidentification or adulteration; and factors associated with the patient or user population such as use, total drug load, and genetics. Future studies need to be conducted with characterized product that includes all commercially available related products. Clinical trials should be relevant to the user population and take into account the confounding factors that may influence the interpretation of the findings.
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    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095950
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  • 18
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    EPOXIDE HYDROLASES: Mechanisms, Inhibitor Designs, and Biological Roles (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 311-333 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Organisms are exposed to epoxide-containing compounds from both exogenous and endogenous sources. In mammals, the hydration of these compounds by various epoxide hydrolases (EHs) can not only regulate their genotoxicity but also, for lipid-derived epoxides, their endogenous roles as chemical mediators. Recent findings suggest that the EHs as a family represent novel drug discovery targets for regulation of blood pressure, inflammation, cancer progression, and the onset of several other diseases. Knowledge of the EH mechanism provides a solid foundation for the rational design of inhibitors, and this review summarizes the current understanding of the catalytic mechanism of the EHs. Although the overall EH mechanism is now known, the molecular basis of substrate selectivity, possible allosteric regulation, and many fine details of the catalytic mechanism remain to be solved. Finally, recent development in the design of EH inhibitors and the EH biological role are discussed.
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    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095920
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  • 19
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    NUCLEAR AND MITOCHONDRIAL COMPARTMENTATION OF OXIDATIVE STRESS AND REDOX SIGNALING (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 215-234 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: New methods to measure thiol oxidation show that redox compartmentation functions as a mechanism for specificity in redox signaling and oxidative stress. Redox Western analysis and redox-sensitive green fluorescent proteins provide means to quantify thiol/disulfide redox changes in specific subcellular compartments. Analyses using these techniques show that the relative redox states from most reducing to most oxidizing are mitochondria 〉 nuclei 〉 cytoplasm 〉 endoplasmic reticulum 〉 extracellular space. Mitochondrial thiols are an important target of oxidant-induced apoptosis and necrosis and are especially vulnerable to oxidation because of the relatively alkaline pH. Maintenance of a relatively reduced nuclear redox state is critical for transcription factor binding in transcriptional activation in response to oxidative stress. The new methods are applicable to a broad range of experimental systems and their use will provide improved understanding of the pharmacologic and toxicologic actions of drugs and toxicants.
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    URL: http://dx.doi.org/10.1146/annurev.pharmtox.46.120604.141122
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  • 20
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    CYTOCHROME P450: Nature's Most Versatile Biological Catalyst (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 1-25 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The author describes studies that led to the resolution and reconstitution of the cytochrome P450 enzyme system in microsomal membranes. The review indicates how purification and characterization of the cytochromes led to rigorous evidence for multiple isoforms of the oxygenases with distinct chemical and physical properties and different but somewhat overlapping substrate specificities. Present knowledge of the individual steps in the P450 and reductase reaction cycles is summarized, including evidence for the generation of multiple functional oxidants that may contribute to the exceptional diversity of the reactions catalyzed.
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    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.100030
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  • 21
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    GLUTATHIONE TRANSFERASES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 51-88 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: This review describes the three mammalian glutathione transferase (GST) families, namely cytosolic, mitochondrial, and microsomal GST, the latter now designated MAPEG. Besides detoxifying electrophilic xenobiotics, such as chemical carcinogens, environmental pollutants, and antitumor agents, these transferases inactivate endogenous ʼ̛,?‚-unsaturated aldehydes, quinones, epoxides, and hydroperoxides formed as secondary metabolites during oxidative stress. These enzymes are also intimately involved in the biosynthesis of leukotrienes, prostaglandins, testosterone, and progesterone, as well as the degradation of tyrosine. Among their substrates, GSTs conjugate the signaling molecules 15-deoxy-??12,14-prostaglandin J2 (15d-PGJ2) and 4-hydroxynonenal with glutathione, and consequently they antagonize expression of genes trans-activated by the peroxisome proliferator-activated receptor ?? (PPAR??) and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Through metabolism of 15d-PGJ2, GST may enhance gene expression driven by nuclear factor-?”B (NF-?”B). Cytosolic human GST exhibit genetic polymorphisms and this variation can increase susceptibility to carcinogenesis and inflammatory disease. Polymorphisms in human MAPEG are associated with alterations in lung function and increased risk of myocardial infarction and stroke. Targeted disruption of murine genes has demonstrated that cytosolic GST isoenzymes are broadly cytoprotective, whereas MAPEG proteins have proinflammatory activities. Furthermore, knockout of mouse GSTA4 and GSTZ1 leads to overexpression of transferases in the Alpha, Mu, and Pi classes, an observation suggesting they are part of an adaptive mechanism that responds to endogenous chemical cues such as 4-hydroxynonenal and tyrosine degradation products. Consistent with this hypothesis, the promoters of cytosolic GST and MAPEG genes contain antioxidant response elements through which they are transcriptionally activated during exposure to Michael reaction acceptors and oxidative stress.
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    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095857
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  • 22
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    THE ROLE OF METABOLIC ACTIVATION IN DRUG-INDUCED HEPATOTOXICITY (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 177-202 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The importance of reactive metabolites in the pathogenesis of drug-induced toxicity has been a focus of research interest since pioneering investigations in the 1950s revealed the link between toxic metabolites and chemical carcinogenesis. There is now a great deal of evidence that shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, but how these toxic species initiate and propagate tissue damage is still poorly understood. This review summarizes the evidence for reactive metabolite formation from hepatotoxic drugs, such as acetaminophen, tamoxifen, diclofenac, and troglitazone, and the current hypotheses of how this leads to liver injury. Several hepatic proteins can be modified by reactive metabolites, but this in general equates poorly with the extent of toxicity. Much more important may be the identification of the critical proteins modified by these toxic species and how this alters their function. It is also important to note that the toxicity of reactive metabolites may be mediated by noncovalent binding mechanisms, which may also have profound effects on normal liver physiology. Technological developments in the wake of the genomic revolution now provide unprecedented power to characterize and quantify covalent modification of individual target proteins and their functional consequences; such information should dramatically improve our understanding of drug-induced hepatotoxic reactions.
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    NON-MICHAELIS-MENTEN KINETICS IN CYTOCHROME P450-CATALYZED REACTIONS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 291-310 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The cytochrome P450 monooxygenases (CYPs) are the dominant enzyme system responsible for xenobiotic detoxification and drug metabolism. Several CYP isoforms exhibit non-Michaelis-Menten, or "atypical," steady state kinetic patterns. The allosteric kinetics confound prediction of drug metabolism and drug-drug interactions, and they challenge the theoretical paradigms of allosterism. Both homotropic and heterotropic ligand effects are now widely documented. It is becoming apparent that multiple ligands can simultaneously bind within the active sites of individual CYPs, and the kinetic parameters change with ligand occupancy. In fact, the functional effect of any specific ligand as an activator or inhibitor can be substrate dependent. Divergent approaches, including kinetic modeling and X-ray crystallography, are providing new information about how multiple ligand binding yields complex CYP kinetics.
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    NITROXYL (HNO): Chemistry, Biochemistry, and Pharmacology (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 335-355 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Recent discoveries of novel and potentially important biological activity have spurred interest in the chemistry and biochemistry of nitroxyl (HNO). It has become clear that, among all the nitrogen oxides, HNO is unique in its chemistry and biology. Currently, the intimate chemical details of the biological actions of HNO are not well understood. Moreover, many of the previously accepted chemical properties of HNO have been recently revised, thus requiring reevaluation of possible mechanisms of biological action. Herein, we review these developments in HNO chemistry and biology.
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    ACTIONS OF ADENOSINE AT ITS RECEPTORS IN THE CNS: Insights from Knockouts and Drugs (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 385-412 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Adenosine and its receptors have been the topic of many recent reviews ( 1Đ??26 ). These reviews provide a good summary of much of the relevant literatureĐ??including the older literature. We have, therefore, chosen to focus the present review on the insights gained from recent studies on genetically modified mice, particularly with respect to the function of adenosine receptors and their potential as therapeutic targets. The information gained from studies of drug effects is discussed in this context, and discrepancies between genetic and pharmacological results are highlighted.
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    PROTEASOME INHIBITION IN MULTIPLE MYELOMA: Therapeutic Implication (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 465-476 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Normal cellular functioning requires processing of proteins regulating cell cycle, growth, and apoptosis. The ubiquitin-proteasome pathway (UBP) modulates intracellular protein degradation. Specifically, the 26S proteasome is a multienzyme protease that degrades misfolded or redundant proteins; conversely, blockade of the proteasomal degradation pathways results in accumulation of unwanted proteins and cell death. Because cancer cells are more highly proliferative than normal cells, their rate of protein translation and degradation is also higher. This notion led to the development of proteasome inhibitors as therapeutics in cancer. The FDA recently approved the first proteasome inhibitor bortezomib (VelcadeĐ?„), formerly known as PS-341, for the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). Ongoing studies are examining other novel proteasome inhibitors, in addition to bortezomib, for the treatment of MM and other cancers.
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    MOLECULAR MECHANISMS OF RESISTANCE IN ANTIMALARIAL CHEMOTHERAPY: The Unmet Challenge (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 565-585 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The enormous public health problem posed by malaria has been substantially worsened in recent years by the emergence and worldwide spread of drug-resistant parasites. The utility of two major therapies, chloroquine and the synergistic combination of pyrimethamine/sulfadoxine, is now seriously compromised. Although several genetic mechanisms have been described, the major source of drug resistance appears to be point mutations in protein target genes. Clinically significant resistance to these agents requires the accumulation of multiple mutations, which genetic studies of parasite populations suggest arise focally and sweep through the population. Efforts to circumvent resistance range from the use of combination therapy with existing agents to laboratory studies directed toward discovering novel targets and therapies. The prevention and management of drug resistance are among the most important practical problems of tropical medicine and public health. Leonard J. Bruce-Chwatt, 1972
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    THE CARDIAC FIBROBLAST: Therapeutic Target in Myocardial Remodeling and Failure (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 657-687 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Cardiac fibroblasts play a central role in the maintenance of extracellular matrix in the normal heart and as mediators of inflammatory and fibrotic myocardial remodeling in the injured and failing heart. In this review, we evaluate the cardiac fibroblast as a therapeutic target in heart disease. Unique features of cardiac fibroblast cell biology are discussed in relation to normal and pathophysiological cardiac function. The contribution of cardiac fibrosis as an independent risk factor in the outcome of heart failure is considered. Candidate drug therapies that derive benefit from actions on cardiac fibroblasts are summarized, including inhibitors of angiotensin-aldosterone systems, endothelin receptor antagonists, statins, anticytokine therapies, matrix metalloproteinase inhibitors, and novel antifibrotic/anti-inflammatory agents. These findings point the way to future challenges in cardiac fibroblast biology and pharmacotherapy.
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    HUMAN FLAVIN-CONTAINING MONOOXYGENASES (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 65-100 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: This review summarizes recent information concerning the pharmacological and toxicological significance of the human flavin-containing monooxygenase (FMO, EC 1.14.13.8). The human FMO oxygenates nucleophilic heteroatom-containing chemicals and drugs and generally converts them into harmless, polar, readily excreted metabolites. Sometimes, however, FMO bioactivates chemicals into reactive materials that can cause toxicity. Most of the interindividual differences of FMO are due to genetic variability and allelic variation, and splicing variants may contribute to interindividual and interethnic variability observed for FMO-mediated metabolism. In contrast to cytochrome P450 (CYP), FMO is not easily induced nor readily inhibited, and potential adverse drug-drug interactions are minimized for drugs prominently metabolized by FMO. These properties may provide advantages in drug design and discovery, and by incorporating FMO detoxication pathways into drug candidates, more drug-like materials may be forthcoming. Although exhaustive examples are not available, physiological factors can influence FMO function, and this may have implications for the clinical significance of FMO and a role in human disease.
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    PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS: How Their Effects on Macrophages Can Lead to the Development of a New Drug Therapy Against Atherosclerosis (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 1-39 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Peroxisome proliferator-activated receptors (PPARs) alpha (ʼ̛), beta/delta (?‚/??), and gamma (??) are members of the nuclear receptor superfamily, which also includes the estrogen, androgen, and glucocorticoid receptors. Recent evidence suggests that PPARs regulate genes involved in lipid metabolism, glucose homeostasis, and inflammation in various tissues; however, the mechanisms involved are not completely understood. Anti-diabetic drugs, called glitazones, can selectively activate PPAR??, and hypolipidemic drugs, called fibrates, can weakly activate PPARʼ̛. Both classes of drugs can decrease insulin resistance and dyslipidemias, which also makes them attractive for treating the metabolic syndrome. The metabolic syndrome exhibits a constellation of risk factors for atherosclerosis that include obesity, insulin resistance, dyslipidemias, and hypertension. Interestingly, all three PPARs are present in macrophages and can therefore have a profound effect on several disease processes, including atherosclerosis. Macrophages are key players in atherosclerotic lesion development. Currently, the first line of defense in reducing the risk of atherosclerosis is aimed at lowering low-density lipoproteins (LDL) and raising high-density lipoproteins (HDL), but a large percentage of patients on statins still succumb to coronary artery disease. However, with the development of drugs selectively activating PPARs, a new arsenal of drugs specifically targeting to the macrophage/foam cell may potentially have a profound impact on how we treat cardiovascular disease.
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    THE REGULATION AND PHARMACOLOGY OF ENDOTHELIAL NITRIC OXIDE SYNTHASE (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 235-276 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Nitric oxide (NO) is a small, diffusible, lipophilic free radical gas that mediates significant and diverse signaling functions in nearly every organ system in the body. The endothelial isoform of nitric oxide synthase (eNOS) is a key source of NO found in the cardiovascular system. This review summarizes the pharmacology of NO and the cellular regulation of endothelial NOS (eNOS). The molecular intricacies of the chemistry of NO and the enzymology of NOSs are discussed, followed by a review of the biological activities of NO. This information is then used to develop a more global picture of the pharmacological control of NO synthesis by NOSs in both physiologic conditions and pathophysiologic states.
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    CYTOCHROME P450 AND XENOBIOTIC RECEPTOR HUMANIZED MICE * (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 41-64 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Most xenobiotics that enter the body are subjected to metabolism that functions primarily to facilitate their elimination. Metabolism of certain xenobiotics can also result in the production of electrophilic derivatives that can cause cell toxicity and transformation. Many xenobiotics can also activate receptors that in turn induce the expression of genes encoding xenobiotic-metabolizing enzymes and xenobiotic transporters. However, there are marked species differences in the way mammals respond to xenobiotics, which are due in large part to molecular differences in receptors and xenobiotic-metabolizing enzymes. This presents a problem in extrapolating data obtained with rodent model systems to humans. There are also polymorphisms in xenobiotic-metabolizing enzymes that can impact drug therapy and cancer susceptibility. In an effort to generate more reliable in vivo systems to study and predict human response to xenobiotics, humanized mice are under development.
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    PROLINE HYDROXYLATION AND GENE EXPRESSION (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 115-128 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Hypoxia-inducible factor (HIF) is a master transcriptional regulator of hypoxia-inducible genes and consists of a labile ʼ̛ subunit (such as HIF1ʼ̛) and a stable subunit (such as HIF1?‚ or ARNT). In the presence of oxygen, HIFʼ̛ family members are hydroxylated on one of two conserved prolyl residues by members of the egg-laying-defective nine (EGLN) family. Prolyl hydroxylation generates a binding site for a ubiquitin ligase complex containing the von Hippel-Lindau (VHL) tumor suppressor protein, which results in HIFʼ̛ destruction. In addition, the HIFʼ̛ transcriptional activation function is modulated further by asparagine hydroxylation by FIH (factor-inhibiting HIF), which affects recruitment of the coactivators p300 and CBP. These findings provide new mechanistic insights into oxygen sensing by metazoans and are the first examples of protein hydroxylation being used in intracellular signaling. The existence of three human EGLN family members, as well as other putative hydroxylases, raises the possibility that this signal is used in other contexts by other proteins.
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    THE MAMMALIAN UNFOLDED PROTEIN RESPONSE (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 739-789 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: In the endoplasmic reticulum (ER), secretory and transmembrane proteins fold into their native conformation and undergo posttranslational modifications important for their activity and structure. When protein folding in the ER is inhibited, signal transduction pathways, which increase the biosynthetic capacity and decrease the biosynthetic burden of the ER to maintain the homeostasis of this organelle, are activated. These pathways are called the unfolded protein response (UPR). In this review, we briefly summarize principles of protein folding and molecular chaperone function important for a mechanistic understanding of UPR-signaling events. We then discuss mechanisms of signal transduction employed by the UPR in mammals and our current understanding of the remodeling of cellular processes by the UPR. Finally, we summarize data that demonstrate that UPR signaling feeds into decision making in other processes previously thought to be unrelated to ER function, e.g., eukaryotic starvation responses and differentiation programs.
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    STRUCTURAL STUDIES BY ELECTRON TOMOGRAPHY: From Cells to Molecules (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 833-865 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Electron tomography (ET) is uniquely suited to obtain three-dimensional reconstructions of pleomorphic structures, such as cells, organelles or supramolecular assemblies. Although the principles of ET have been known for decades, its use has gathered momentum only in recent years, thanks to technological advances and its combination with improved specimen preparation techniques. The rapid freezing/freeze-substitution preparation is applicable to whole cells and tissues, and it is the method of choice for ET investigations of cellular ultrastructure. The frozen-hydrated preparation provides the best possible structural preservation and allows the imaging of molecules, complexes, and supramolecular assemblies in their native state and their natural environment. Devoid of staining and chemical fixation artifacts, cryo-ET provides a faithful representation of both the surface and internal structure of molecules. In combination with advanced computational methods, such as molecular identification based on pattern recognition techniques, cryo-ET is currently the most promising approach to comprehensively map macromolecular architecture inside cellular tomograms.
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    ORIGINS OF THE GENETIC CODE: The Escaped Triplet Theory (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 179-198 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: There is very significant evidence that cognate codons and/or anticodons are unexpectedly frequent in RNA-binding sites for seven of eight biological amino acids that have been tested. This suggests that a substantial fraction of the genetic code has a stereochemical basis, the triplets having escaped from their original function in amino acidĐ??binding sites to become modern codons and anticodons. We explicitly show that this stereochemical basis is consistent with subsequent optimization of the code to minimize the effect of coding mistakes on protein structure. These data also strengthen the argument for invention of the genetic code in an RNA world and for the RNA world itself.
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    FROM PROTEIN SYNTHESIS TO GENETIC INSERTION (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 1-28 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: In 1946, 14C-cyanide made its appearance as an offshoot of the Atomic Energy Program. Our colleague Robert Loftfield built it into 14C-alanine by the Strecker synthesis, and a lusty program directed toward uncovering the unknown mechanism of protein synthesis grew out of this beginning. The necessity for an undiscovered series of steps and enzymes was soon evident. A cell free system was developed, and a succession of components necessary for this new pathway tumbled out. ATP dependence, amino acid activation, the ribosome as the site of polypeptide formation, discovery of tRNA as the translation molecule linking the gene and protein sequence, and GTP as the essential energy ingredient in peptide chain extension all appeared from our laboratory within the next decade. A little later the AP4N family, whose functions remain imperfectly defined, of intracellular molecules was discovered. Isolation of specific species of RNA became a high priority, and we sequenced a small segment of the 3' end of the Rous sarcoma virus, just inside the poly(A) tail, at the same time the Gilbert group at Harvard was sequencing the 5' end. The sequence identity and polarity of the two ends suggested a circular intermediate in replication and predicted correctly that a synthetic antisense oligonucleotide targeted against this sequence might be a specific inhibitor of replication. More recently, we have evolved a technique that appears to achieve a trinucleotide insertion into tissue culture cells bearing a specific ??508 mRNA triplet deletion, resulting in phenotypic reversion in the tissue culture.
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    THE STRUCTURE AND FUNCTION OF SMC AND KLEISIN COMPLEXES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 595-648 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Protein complexes consisting of structural maintenance of chromosomes (SMC) and kleisin subunits are crucial for the faithful segregation of chromosomes during cell proliferation in prokaryotes and eukaryotes. Two of the best-studied SMC complexes are cohesin and condensin. Cohesin is required to hold sister chromatids together, which allows their biorientation on the mitotic spindle. Cleavage of cohesin's kleisin subunit by the separase protease then triggers the movement of sister chromatids into opposite halves of the cell during anaphase. Condensin is required to organize mitotic chromosomes into coherent structures that prevent them from getting tangled up during segregation. Here we describe the discovery of SMC complexes and discuss recent advances in determining how members of this ancient protein family may function at a mechanistic level.
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    THE BIOCHEMISTRY OF PARKINSON'S DISEASE * (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 29-52 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Several genes have been identified for monogenic disorders that variably resemble Parkinson's disease. Dominant mutations in the gene encoding ʼ̛-synuclein enhance the propensity of this protein to aggregate. As a consequence, these patients have a widespread disease with protein inclusion bodies in several brain areas. In contrast, mutations in several recessive genes (parkin, DJ-1, and PINK1) produce neuronal cell loss but generally without protein aggregation pathology. Progress has been made in understanding some of the mechanisms of toxicity: Parkin is an E3 ubiquitin ligase and DJ-1 and PINK1 appear to protect against mitochondrial damage. However, we have not yet fully resolved how the recessive genes relate to ʼ̛-synuclein, or whether they represent different ways to induce a similar phenotype.
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    NONTEMPLATE-DEPENDENT POLYMERIZATION PROCESSES: Polyhydroxyalkanoate Synthases as a Paradigm 1 (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 433-480 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: This review focuses on nontemplate-dependent polymerases that use water-soluble substrates and convert them into water-insoluble polymers that form granules or inclusions within the cell. The initial part of the review summarizes briefly the current knowledge of polymer formation catalyzed by starch and glycogen synthases, polyphosphate kinase (a polymerase), cyanophycin synthetases, and rubber synthases. Specifically, our current understanding of their mechanisms of initiation, elongation (including granule formation), termination, remodeling, and polymer reutilization will be presented. General underlying principles that govern these types of polymerization reactions will be enumerated as a paradigm for all nontemplate-dependent polymerizations. The bulk of the review then focuses on polyhydroxyalkanoate (PHA) synthases that generate polyoxoesters. These enzymes are of interest as they generate biodegradable polymers. Our current knowledge of PHA production and utilization in vitro and in vivo as well as the contribution of many proteins to these processes will be reviewed.
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    PROTEIN FAMILIES AND THEIR EVOLUTIONĐ??A STRUCTURAL PERSPECTIVE (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 867-900 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: We can now assign about two thirds of the sequences from completed genomes to as few as 1400 domain families for which structures are known and thus more ancient evolutionary relationships established. About 200 of these domain families are common to all kingdoms of life and account for nearly 50% of domain structure annotations in the genomes. Some of these domain families have been very extensively duplicated within a genome and combined with different domain partners giving rise to different multidomain proteins. The ways in which these domain combinations evolve tend to be specific to the organism so that less than 15% of the protein families found within a genome appear to be common to all kingdoms of life. Recent analyses of completed genomes, exploiting the structural data, have revealed the extent to which duplication of these domains and modifications of their functions can expand the functional repertoire of the organism, contributing to increasing complexity.
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    MEMBRANE-ASSOCIATED GUANYLATE KINASES REGULATE ADHESION AND PLASTICITY AT CELL JUNCTIONS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 219-245 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Tissue development, differentiation, and physiology require specialized cellular adhesion and signal transduction at sites of cell-cell contact. Scaffolding proteins that tether adhesion molecules, receptors, and intracellular signaling enzymes organize macromolecular protein complexes at cellular junctions to integrate these functions. One family of such scaffolding proteins is the large group of membrane-associated guanylate kinases (MAGUKs). Genetic studies have highlighted critical roles for MAGUK proteins in the development and physiology of numerous tissues from a variety of metazoan organisms. Mutation of Drosophila discs large (dlg) disrupts epithelial septate junctions and causes overgrowth of imaginal discs. Similarly, mutation of lin-2, a related MAGUK in Caenorhabditis elegans, blocks vulval development, and mutation of the postsynaptic density protein PSD-95 impairs synaptic plasticity in mammalian brain. These diverse roles are explained by recent biochemical and structural analyses of MAGUKs, which demonstrate their capacity to assemble well-definedĐ??yet adaptableĐ??protein complexes at cellular junctions.
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    REGULATION OF PROTEIN FUNCTION BY GLYCOSAMINOGLYCANSĐ??AS EXEMPLIFIED BY CHEMOKINES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 385-410 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Immune modulators such as cytokines and growth factors exert their biological activity through high-affinity interactions with cell-surface receptors, thereby activating specific signaling pathways. However, many of these molecules also participate in low-affinity interactions with another class of molecules, referred to as proteoglycans. Proteoglycans consist of a protein core to which glycosaminoglycan (GAG) chains are attached. The GAGs are long, linear, sulfated, and highly charged heterogeneous polysaccharides that are expressed throughout the body in different forms, depending on the developmental or pathological state of the organ/organism. They participate in many biological functions, including organogenesis and growth control, cell adhesion, signaling, inflammation, tumorigenesis, and interactions with pathogens. Recently, it was demonstrated that certain chemokines require interactions with GAGs for their in vivo function. The GAG interaction is thought to provide a mechanism for retaining chemokines on cell surfaces, facilitating the formation of chemokine gradients. These gradients serve as directional cues to guide the migration of the appropriate cells in the context of their inflammatory, developmental, and homeostatic functions. In this review, we discuss GAGs and their interaction with proteins, with a special emphasis on the chemokine system.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.72.121801.161747
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 199-217 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The importance of small, noncoding RNAs that act as regulators of transcription, of RNA modification or stability, and of mRNA translation is becoming increasingly apparent. Here we discuss current knowledge of regulatory RNA function and review how the RNAs have been identified in a variety of organisms. Many of the regulatory RNAs act through base-pairing interactions with target RNAs. The base-pairing RNAs can be grouped into two general classes: those that are encoded on the opposite strand of their target RNAs such that they contain perfect complementarity with their targets, and those that are encoded at separate locations on the chromosome and have imperfect base-pairing potential with their targets. Other regulatory RNAs act by modifying protein activity, in some cases by mimicking the structures of other RNA or DNA molecules.
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    STRUCTURE, FUNCTION, AND FORMATION OF BIOLOGICAL IRON-SULFUR CLUSTERS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 247-281 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Iron-sulfur [Fe-S] clusters are ubiquitous and evolutionary ancient prosthetic groups that are required to sustain fundamental life processes. Owing to their remarkable structural plasticity and versatile chemical/electronic features [Fe-S] clusters participate in electron transfer, substrate binding/activation, iron/sulfur storage, regulation of gene expression, and enzyme activity. Formation of intracellular [Fe-S] clusters does not occur spontaneously but requires a complex biosynthetic machinery. Three different types of [Fe-S] cluster biosynthetic systems have been discovered, and all of them are mechanistically unified by the requirement for a cysteine desulfurase and the participation of an [Fe-S] cluster scaffolding protein. Important mechanistic questions related to [Fe-S] cluster biosynthesis involve the molecular details of how [Fe-S] clusters are assembled on scaffold proteins, how [Fe-S] clusters are transferred from scaffolds to target proteins, how various accessory proteins participate in [Fe-S] protein maturation, and how the biosynthetic process is regulated.
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    ZONA PELLUCIDA DOMAIN PROTEINS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 83-114 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Many eukaryotic proteins share a sequence designated as the zona pellucida (ZP) domain. This structural element, present in extracellular proteins from a wide variety of organisms, from nematodes to mammals, consists of Đ♯260 amino acids with eight conserved cysteine (Cys) residues and is located close to the C terminus of the polypeptide. ZP domain proteins are often glycosylated, modular structures consisting of multiple types of domains. Predictions can be made about some of the structural features of the ZP domain and ZP domain proteins. The functions of ZP domain proteins vary tremendously, from serving as structural components of egg coats, appendicularian mucous houses, and nematode dauer larvae, to serving as mechanotransducers in flies and receptors in mammals and nonmammals. Generally, ZP domain proteins are present in filaments and/or matrices, which is consistent with the role of the domain in protein polymerization. A general mechanism for assembly of ZP domain proteins has been presented. It is likely that the ZP domain plays a common role despite its presence in proteins of widely diverse functions.
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    THE STRUCTURAL BIOLOGY OF TYPE II FATTY ACID BIOSYNTHESIS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 791-831 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The type II fatty acid synthetic pathway is the principal route for the production of membrane phospholipid acyl chains in bacteria and plants. The reaction sequence is carried out by a series of individual soluble proteins that are each encoded by a discrete gene, and the pathway intermediates are shuttled between the enzymes as thioesters of an acyl carrier protein. The Escherichia coli system is the paradigm for the study of this system, and high-resolution X-ray and/or NMR structures of representative members of every enzyme in the type II pathway are now available. The structural biology of these proteins reveals the specific three-dimensional features of the enzymes that explain substrate recognition, chain length specificity, and the catalytic mechanisms that define their roles in producing the multitude of products generated by the type II system. These structures are also a valuable resource to guide antibacterial drug discovery.
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    CELLULAR DNA REPLICASES: Components and Dynamics at the Replication Fork (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 283-315 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Chromosomal DNA replicases are multicomponent machines that have evolved clever strategies to perform their function. Although the structure of DNA is elegant in its simplicity, the job of duplicating it is far from simple. At the heart of the replicase machinery is a heteropentameric AAA+ clamp-loading machine that couples ATP hydrolysis to load circular clamp proteins onto DNA. The clamps encircle DNA and hold polymerases to the template for processive action. Clamp-loader and sliding clamp structures have been solved in both prokaryotic and eukaryotic systems. The heteropentameric clamp loaders are circular oligomers, reflecting the circular shape of their respective clamp substrates. Clamps and clamp loaders also function in other DNA metabolic processes, including repair, checkpoint mechanisms, and cell cycle progression. Twin polymerases and clamps coordinate their actions with a clamp loader and yet other proteins to form a replisome machine that advances the replication fork.
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    ANTIBIOTICS TARGETING RIBOSOMES: Resistance, Selectivity, Synergism, and Cellular Regulation (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 649-679 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Antibiotics target ribosomes at distinct locations within functionally relevant sites. They exert their inhibitory action by diverse modes, including competing with substrate binding, interfering with ribosomal dynamics, minimizing ribosomal mobility, facilitating miscoding, hampering the progression of the mRNA chain, and blocking the nascent protein exit tunnel. Although the ribosomes are highly conserved organelles, they possess subtle sequence and/or conformational variations. These enable drug selectivity, thus facilitating clinical usage. The structural implications of these differences were deciphered by comparisons of high-resolution structures of complexes of antibiotics with ribosomal particles from eubacteria resembling pathogens and from an archaeon that shares properties with eukaryotes. The various antibiotic-binding modes detected in these structures demonstrate that members of antibiotic families possessing common chemical elements with minute differences might bind to ribosomal pockets in significantly different modes, governed by their chemical properties. Similarly, the nature of seemingly identical mechanisms of drug resistance is dominated, directly or via cellular effects, by the antibiotics' chemical properties. The observed variability in antibiotic binding and inhibitory modes justifies expectations for structurally based improved properties of existing compounds as well as for the discovery of novel drug classes.
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    GENE THERAPY: Twenty-First Century Medicine (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 74 (2005), S. 711-738 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Broadly defined, the concept of gene therapy involves the transfer of genetic material into a cell, tissue, or whole organ, with the goal of curing a disease or at least improving the clinical status of a patient. A key factor in the success of gene therapy is the development of delivery systems that are capable of efficient gene transfer in a variety of tissues, without causing any associated pathogenic effects. Vectors based upon many different viral systems, including retroviruses, lentiviruses, adenoviruses, and adeno-associated viruses, currently offer the best choice for efficient gene delivery. Their performance and pathogenicity has been evaluated in animal models, and encouraging results form the basis for clinical trials to treat genetic disorders and acquired diseases. Despite some initial success in these trials, vector development remains a seminal concern for improved gene therapy technologies.
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    QUANTUM MECHANICS OF DISSIPATIVE SYSTEMS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 187-219 
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    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: Quantum dissipation involves both energy relaxation and decoherence, leading toward quantum thermal equilibrium. There are several theoretical prescriptions of quantum dissipation but none of them is simple enough to be treated exactly in real applications. As a result, formulations in different prescriptions are practically used with different approximation schemes. This review examines both theoretical and application aspects on various perturbative formulations, especially those that are exact up to second-order but nonequivalent in high-order system-bath coupling contributions. Discrimination is made in favor of an unconventional formulation that in a sense combines the merits of both the conventional time-local and memory-kernel prescriptions, where the latter is least favorite in terms of the applicability range of parameters for system-bath coupling, non-Markovian, and temperature. Also highlighted is the importance of correlated driving and disspation effects, not only on the dynamics under strong external field driving, but also in the calculation of field-free correlation and response functions.
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    QUANTUM CHAOS MEETS COHERENT CONTROL (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 1-23 
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    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: Coherent control of atomic and molecular processes has been a rapidly developing field. Applications of coherent control to large and complex molecular systems are expected to encounter the effects of chaos in the underlying classical dynamics, i.e., quantum chaos. Hence, recent work has focused on examining control in model chaotic systems. This work is reviewed, with an emphasis on a variety of new quantum phenomena that are of interest to both areas of quantum chaos and coherent control.
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    ULTRAFAST ELECTRON TRANSFER AT THE MOLECULE-SEMICONDUCTOR NANOPARTICLE INTERFACE (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 491-519 
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    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: Electron transfer across the molecule-semiconductor interface is a fundamental process that is relevant to many applications of nanoparticles, such as dye-sensitized solar cells and molecular electronics. This review summarizes recent progress in understanding electron transfer dynamics from molecular adsorbates to semiconductor nanoparticles. Photoexcitation of molecular adsorbates to their excited states is followed by electron injection into semiconductor nanoparticles. The products of electron injection (oxidized adsorbate and electrons in semiconductor) are monitored by their electronic and vibrational spectra, allowing direct measurement of injection rate. The dependence of injection rate on the properties of semiconductor nanoparticle, molecular adsorbate, intervening bridging and anchoring group, and interfacial environment are discussed and compared with Marcus theory of interfacial electron transfer.
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    TIME-RESOLVED SPECTROSCOPY OF ORGANIC DENDRIMERS AND BRANCHED CHROMOPHORES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 581-603 
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    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: Organic dendrimers have been considered for a number of optical applications and are now of great interest for the purpose of enhanced nonlinear optical effects. In order to understand the mechanism of the enhanced effects in branched structures it is important to probe the fundamental excitations and the degree of intramolecular interactions utilizing various spectroscopic techniques. In this review, the nonlinear optical and excited state dynamics of different dendritic and other branching chromophore structures are discussed. The methods of two-photon absorption, time-resolved fluorescence, transient absorption, and three-pulse photon echo peak shift are discussed in regards to the degree of intramolecular coupling in the macromolecular systems. These techniques are also used for a comparison of the dynamics in the linear molecular analog systems as well. Thus, this review focuses on the aspect of intramolecular interactions in a branched system and its importance to enhanced nonlinear optical effects useful for modern optical devices.
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    FORMATION AND TOXICITY OF ANESTHETIC DEGRADATION PRODUCTS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 147-176 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Toxic degradation products are formed from a range of old and modern anesthetic agents. The common element in the formation of degradation products is the reaction of the anesthetic agent with the bases in the carbon dioxide absorbents in the anesthesia circuit. This reaction results in the conversion of trichloroethylene to dichloroacetylene, halothane to 2-bromo-2-chloro-1,1-difluoroethylene, sevoflurane to 2-(fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (Compound A), and desflurane, isoflurane, and enflurane to carbon monoxide. Dichloroacetylene, 2-bromo-2-chloro-1,1-difluoroethylene, and Compound A form glutathione S-conjugates that undergo hydrolysis to cysteine S-conjugates and bioactivation of the cysteine S-conjugates by renal cysteine conjugate ?‚-lyase to give nephrotoxic metabolites. The elucidation of the mechanisms of formation and bioactivation of degradation products has allowed for the safe use of anesthetics that may undergo degradation in the anesthesia circuit.
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    NEONICOTINOID INSECTICIDE TOXICOLOGY: Mechanisms of Selective Action (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 247-268 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The neonicotinoids, the newest major class of insecticides, have outstanding potency and systemic action for crop protection against piercing-sucking pests, and they are highly effective for flea control on cats and dogs. Their common names are acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. They generally have low toxicity to mammals (acute and chronic), birds, and fish. Biotransformations involve some activation reactions but largely detoxification mechanisms. In contrast to nicotine, epibatidine, and other ammonium or iminium nicotinoids, which are mostly protonated at physiological pH, the neonicotinoids are not protonated and have an electronegative nitro or cyano pharmacophore. Agonist recognition by the nicotinic receptor involves cation-?? interaction for nicotinoids in mammals and possibly a cationic subsite for interaction with the nitro or cyano substituent of neonicotinoids in insects. The low affinity of neonicotinoids for vertebrate relative to insect nicotinic receptors is a major factor in their favorable toxicological profile.
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    REGULATION AND INHIBITION OF ARACHIDONIC ACID ?-HYDROXYLASES AND 20-HETE FORMATION (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 413-438 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Cytochrome P450Đ??catalyzed metabolism of arachidonic acid is an important pathway for the formation of paracrine and autocrine mediators of numerous biological effects. The ?-hydroxylation of arachidonic acid generates significant levels of 20-hydroxyeicosatetraenoic acid (20-HETE) in numerous tissues, particularly the vasculature and kidney tubules. Members of the cytochrome P450 4A and 4F families are the major ?-hydroxylases, and the substrate selectivity and regulation of these enzymes has been the subject of numerous studies. Altered expression and function of arachidonic acid ?-hydroxylases in models of hypertension, diabetes, inflammation, and pregnancy suggest that 20-HETE may be involved in the pathogenesis of these diseases. Our understanding of the biological significance of 20-HETE has been greatly aided by the development and characterization of selective and potent inhibitors of the arachidonic acid ?-hydroxylases. This review discusses the substrate selectivity and expression of arachidonic acid ?-hydroxylases, regulation of these enzymes during disease, and the application of enzyme inhibitors to study 20-HETE function.
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    THE MAGIC BULLETS AND TUBERCULOSIS DRUG TARGETS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 529-564 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Modern chemotherapy has played a major role in our control of tuberculosis. Yet tuberculosis still remains a leading infectious disease worldwide, largely owing to persistence of tubercle bacillus and inadequacy of the current chemotherapy. The increasing emergence of drug-resistant tuberculosis along with the HIV pandemic threatens disease control and highlights both the need to understand how our current drugs work and the need to develop new and more effective drugs. This review provides a brief historical account of tuberculosis drugs, examines the problem of current chemotherapy, discusses the targets of current tuberculosis drugs, focuses on some promising new drug candidates, and proposes a range of novel drug targets for intervention. Finally, this review addresses the problem of conventional drug screens based on inhibition of replicating bacilli and the challenge to develop drugs that target nonreplicating persistent bacilli. A new generation of drugs that target persistent bacilli is needed for more effective treatment of tuberculosis.
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    SIGNALING NETWORKS IN LIVING CELLS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 587-603 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Recent advances in cell signaling research suggest that multiple sets of signal transducing molecules are preorganized and sequestered in distinct compartments within the cell. These compartments are assembled and maintained by specific cellular machinery. The molecular ecology within a compartment creates an environment that favors the efficient and accurate integration of signaling information arriving from humoral, mechanical, and nutritional sources. The functional organization of these compartments suggests they are the location of signaling networks that naturally organize into hierarchical interconnected sets of molecules through their participation in different classes of interacting units. An important goal is to determine the contribution of the compartment to the function of these networks in living cells.
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    DUAL SPECIFICITY PROTEIN PHOSPHATASES: Therapeutic Targets for Cancer and Alzheimer's Disease (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 725-750 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The complete sequencing of the human genome is generating many novel targets for drug discovery. Understanding the pathophysiological roles of these putative targets and assessing their suitability for therapeutic intervention has become the major hurdle for drug discovery efforts. The dual-specificity phosphatases (DSPases), which dephosphorylate serine, threonine, and tyrosine residues in the same protein substrate, have important roles in multiple signaling pathways and appear to be deregulated in cancer and Alzheimer's disease. We examine the potential of DSPases as new molecular therapeutic targets for the treatment of human disease.
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    EVALUATION OF DRUG-DRUG INTERACTION IN THE HEPATOBILIARY AND RENAL TRANSPORT OF DRUGS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 689-723 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Recent studies have revealed the import role played by transporters in the renal and hepatobiliary excretion of many drugs. These transporters exhibit a broad substrate specificity with a degree of overlap, suggesting the possibility of transporter-mediated drug-drug interactions with other substrates. This review is an overview of the roles of transporters and the possibility of transporter-mediated drug-drug interactions. Among the large number of transporters, we compare the Ki values of inhibitors for organic anion transporting polypeptides (OATPs) and organic anion transporters (OATs) and their therapeutic unbound concentrations. Among them, cephalosporins and probenecid have the potential to produce clinically relevant OAT-mediated drug-drug interactions, whereas cyclosporin A and rifampicin may trigger OATP-mediated ones. These drugs have been reported to cause drug-drug interactions in vivo with OATs or OATP substrates, suggesting the possibility of transporter-mediated drug-drug interactions. To avoid adverse consequences of such transporter-mediated drug-drug interactions, we need to be more aware of the role played by drug transporters as well as those caused by drug metabolizing enzymes.
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    CO AS A CELLULAR SIGNALING MOLECULE (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 411-449 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Many biological functions of heme oxygenase (HO), such as cytoprotection against oxidative stress, vasodilation, neurotransmission in the central or peripheral nervous systems, and anti-inflammatory, anti-apoptotic, or anti-proliferative potential, have been attributed to its enzymatic byproduct carbon monoxide (CO), although roles for biliverdin/bilirubin and iron have also been proposed. In addition to these well-characterized effects, recent findings reveal that HO-derived CO may act as an oxygen sensor and circadian modulator of heme biosynthesis. In lymphocytes, CO may participate in regulatory T cell function. A number of the known signaling effects of CO depend on stimulation of soluble guanylate cyclase and/or activation of mitogen-activated protein kinases (MAPK). Furthermore, modulation of caveolin-1 status may serve as an essential component of certain aspects of CO action, such as growth control. In this review, we summarize recent findings of the beneficial or detrimental effects of endogenous CO with an emphasis on the signaling pathways and downstream targets that trigger the action of this gas.
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    REGULATION OF PHOSPHOLIPASE C ISOZYMES BY RAS SUPERFAMILY GTPASES (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 355-379 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The physiological effects of many extracellular stimuli are mediated by receptor-promoted activation of phospholipase C (PLC) and consequential activation of inositol lipid-signaling pathways. These signaling responses include the classically described conversion of PtdIns(4,5)P2 to the Ca2+-mobilizing second messenger Ins(1,4,5)P3 and the protein kinase CĐ??activating second messenger diacylglycerol as well as alterations in membrane association or activity of many proteins that harbor phosphoinositide binding domains. Here we discuss how the family of PLCs elaborates a minimal catalytic core typified by PLC-?? to confer multiple modes of regulation on their phospholipase activities. Although PLC-dependent signaling is prominently regulated by direct interactions with heterotrimeric G proteins or tyrosine kinases, the existence of at least 13 divergent PLC isozymes promises a diverse repertoire of regulatory mechanisms for this class of important signaling proteins. We focus here on the recently realized and extensive regulation of inositol lipid signaling by Ras superfamily GTPases directly acting on PLC isozymes and conclude by considering the biological and pharmacological ramifications of this regulation.
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    REGULATION OF DRUG-METABOLIZING ENZYMES AND TRANSPORTERS IN INFLAMMATION (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 123-149 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Inflammation and infection have long been known to downregulate the activity and expression of cytochrome P450 (CYP) enzymes involved in hepatic drug clearance. This can result in elevated plasma drug levels and increased adverse effects. Recent information on regulation of human CYP enzymes is presented, as are new developments in our understanding of the mechanisms of regulation. Experiments to study the effects of modulating CYP activities on the inflammatory response have yielded possible insights into the physiological consequences, if not the purpose, of the downregulation. Regulation of hepatic flavin monooxygenases, UDP-glucuronosyltransferases, sulfotransferases, glutathione S-transferases, as well as of hepatic transporters during the inflammatory response, exhibits similarities and differences with regulation of CYPs.
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    PHARMACOGENOMICS OF ACUTE LEUKEMIA (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 317-353 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Over the past four decades, treatment of acute leukemia in children has made remarkable progress, from this disease being lethal to now achieving cure rates of 80% for acute lymphoblastic leukemia and 45% for acute myeloid leukemia. This progress is largely owed to the optimization of existing treatment modalities rather than the discovery of new agents. However, the annual number of patients with leukemia who experience relapse after initial therapy remains greater than that of new cases of most childhood cancers. The aim of pharmacogenetics is to develop strategies to personalize medications and tailor treatment regimens to individual patients, with the goal of enhancing efficacy and safety through better understanding of the person's genetic makeup. In this review, we summarize recent pharmacogenomic studies related to the treatment of pediatric acute leukemia. These include work using candidate-gene approaches, as well as genome-wide studies using haplotype mapping and gene expression profiling. These strategies illustrate the promise of pharmacogenomics to further advance the treatment of human cancers, with childhood leukemia serving as a paradigm.
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    THE PROTEASOME AND PROTEASOME INHIBITORS IN CANCER THERAPY (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 189-213 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The proteasome, a multicatalytic proteinase complex, is responsible for the majority of intracellular protein degradation. Pharmacologic inhibitors of the proteasome possess in vitro and in vivo antitumor activity, and bortezomib, the first such agent to undergo clinical testing, has significant efficacy against multiple myeloma and non-Hodgkin lymphoma (NHL). Preclinical studies demonstrate that proteasome inhibition potentiates the activity of other cancer therapeutics, in part by downregulating chemoresistance pathways. Early clinical studies of bortezomib-based combinations, showing encouraging activity, support this observation. Molecular characterization of resistance to proteasome inhibitors has revealed novel therapeutic targets for sensitizing malignancies to these agents, such as the heat shock pathway. Below, we review the pharmacologic, preclinical, and clinical data that have paved the way for the use of proteasome inhibitors for cancer therapy; outline strategies aimed at enhancing the efficacy of proteasome inhibitors; and review other potential targets in the ubiquitin proteasome pathway for the treatment of cancer.
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    CYTOCHROME P450 ACTIVATION OF ARYLAMINES AND HETEROCYCLIC AMINES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 27-49 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Arylamines and heterocyclic arylamines (HAAs) are of particular interest because of demonstrated carcinogenicity in animals and humans and the broad exposure to many of these compounds. The activation of these, and also some arylamine drugs, involves N-hydroxylation, usually by cytochrome P450 (P450). P450 1A2 plays a prominent role in these reactions. However, P450 1A1 and 1B1 and other P450s are also important in humans as well as experimental animals. Some arylamines (including drugs) are N-hydroxylated predominantly by P450s other than those in Family 1. Other oxygenases can also have roles. An important issue is extrapolation between species in predicting cancer risks, as shown by the low rates of HAA activation by rat P450 1A2 and low levels of P450 1A2 expression in some nonhuman primates.
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    CYTOCHROME P450 UBIQUITINATION: Branding for the Proteolytic Slaughter? (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 439-464 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The hepatic cytochromes P450 (P450s) are monotopic endoplasmic reticulum (ER)-anchored hemoproteins engaged in the enzymatic oxidation of a wide variety of endo- and xenobiotics. In the course of these reactions, the enzymes generate reactive O2 species and/or reactive metabolic products that can attack the P450 heme and/or protein moiety and structurally and functionally damage the enzyme. The in vivo conformational unraveling of such a structurally damaged P450 signals its rapid removal via the cellular sanitation system responsible for the proteolytic disposal of structurally aberrant, abnormal, and/or otherwise malformed proteins. A key player in this process is the ubiquitin (Ub)-dependent 26S proteasome system. Accordingly, the structurally deformed P450 protein is first branded for recognition and proteolytic removal by the 26S proteasome with an enzymatically incorporated polyUb tag. P450s of the 3A subfamily such as the major human liver enzyme CYP3A4 are notorious targets for this process, and they represent excellent prototypes for the understanding of integral ER protein ubiquitination. Not all the participants in hepatic CYP3A ubiquitination and subsequent proteolytic degradation have been identified. The following discussion thus addresses the various known and plausible events and/or cellular participants involved in this multienzymatic P450 ubiquitination cascade, on the basis of our current knowledge of other eukaryotic models. In addition, because the detection of ubiquitinated P450s is technically challenging, the critical importance of appropriate methodology is also discussed.
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    CLINICAL AND TOXICOLOGICAL RELEVANCE OF CYP2C9: Drug-Drug Interactions and Pharmacogenetics (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 477-494 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: CYP2C9 is a major cytochrome P450 enzyme that is involved in the metabolic clearance of a wide variety of therapeutic agents, including nonsteroidal antiinflammatories, oral anticoagulants, and oral hypoglycemics. Disruption of CYP2C9 activity by metabolic inhibition or pharmacogenetic variability underlies many of the adverse drug reactions that are associated with the enzyme. CYP2C9 is also the first human P450 to be crystallized, and the structural basis for its substrate and inhibitor selectivity is becoming increasingly clear. New, ultrapotent inhibitors of CYP2C9 have been synthesised that aid in the development of quantitative structure-activity relationship (QSAR) models to facilitate drug redesign, and extensive resequencing of the gene and studies of its regulation will undoubtedly help us understand interindividual variability in drug response and toxicity controlled by this enzyme.
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    GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE, APOPTOSIS, AND NEURODEGENERATIVE DISEASES * (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 269-290 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Increasing evidence supports the notion that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a protein with multiple functions, including its surprising role in apoptosis. GAPDH is overexpressed and accumulates in the nucleus during apoptosis induced by a variety of insults in diverse cell types. Knockdown of GAPDH using an antisense strategy demonstrates its involvement in the apoptotic cascade in which GAPDH nuclear translocation appears essential. Knowledge concerning the mechanisms underlying GAPDH nuclear translocation and subsequent cell death is growing. Additional evidence suggests that GAPDH may be an intracellular sensor of oxidative stress during early apoptosis. Abnormal expression, nuclear accumulation, changes in physical properties, and loss of glycolytic activity of GAPDH have been found in cellular and transgenic models as well as postmortem tissues of several neurodegenerative diseases. The interaction of GAPDH with disease-related proteins as well as drugs used to treat these diseases suggests that it is a potential molecular target for drug development.
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    TYROSINE KINASE INHIBITORS AND THE DAWN OF MOLECULAR CANCER THERAPEUTICS * (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 357-384 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The clinical application of tyrosine kinase inhibitors for cancer treatment represents a therapeutic breakthrough. The rationale for developing these compounds rests on the observation that tyrosine kinase enzymes are critical components of the cellular signaling apparatus and are regularly mutated or otherwise deregulated in human malignancies. Novel tyrosine kinase inhibitors are designed to exploit the molecular differences between tumor cells and normal tissues. Herein, we will review the current state-of-the-art using agents that target as prototypes Bcr-Abl, platelet-derived growth factor receptor (PDGFR), KIT (stem cell factor receptor), and epidermal growth factor receptor (EGFR). These compounds are remarkably effective in treating diverse cancers that are highly resistant to conventional treatment, including various forms of leukemia, hypereosinophilic syndrome, mast cell disease, sarcomas, and lung cancer. It is now clear that the molecular defects underlying cancer can be targeted with designer drugs that yield striking salutary effects with minimal toxicity.
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    CLINICAL DEVELOPMENT OF HISTONE DEACETYLASE INHIBITORS AS ANTICANCER AGENTS * (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 495-528 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Acetylation is a key posttranslational modification of many proteins responsible for regulating critical intracellular pathways. Although histones are the most thoroughly studied of acetylated protein substrates, histone acetyltransferases (HATs) and deacetylases (HDACs) are also responsible for modifying the activity of diverse types of nonhistone proteins, including transcription factors and signal transduction mediators. HDACs have emerged as uncredentialed molecular targets for the development of enzymatic inhibitors to treat human cancer, and six structurally distinct drug classes have been identified with in vivo bioavailability and intracellular capability to inhibit many of the known mammalian members representing the two general types of NAD+-independent yeast HDACs, Rpd3 (HDACs 1, 2, 3, 8) and Hda1 (HDACs 4, 5, 6, 7, 9a, 9b, 10). Initial clinical trials indicate that HDAC inhibitors from several different structural classes are very well tolerated and exhibit clinical activity against a variety of human malignancies; however, the molecular basis for their anticancer selectivity remains largely unknown. HDAC inhibitors have also shown preclinical promise when combined with other therapeutic agents, and innovative drug delivery strategies, including liposome encapsulation, may further enhance their clinical development and anticancer potential. An improved understanding of the mechanistic role of specific HDACs in human tumorigenesis, as well as the identification of more specific HDAC inhibitors, will likely accelerate the clinical development and broaden the future scope and utility of HDAC inhibitors for cancer treatment.
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    HEPATIC FIBROSIS: Molecular Mechanisms and Drug Targets (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 605-628 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Liver fibrosis is the common response to chronic liver injury, ultimately leading to cirrhosis and its complications, portal hypertension, liver failure, and hepatocellular carcinoma. Efficient and well-tolerated antifibrotic drugs are currently lacking, and current treatment of hepatic fibrosis is limited to withdrawal of the noxious agent. Efforts over the past decade have mainly focused on fibrogenic cells generating the scarring response, although promising data on inhibition of parenchymal injury and/or reduction of liver inflammation have also been obtained. A large number of approaches have been validated in culture studies and in animal models, and several clinical trials are underway or anticipated for a growing number of molecules. This review highlights recent advances in the molecular mechanisms of liver fibrosis and discusses mechanistically based strategies that have recently emerged.
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    MOLECULAR MECHANISM OF 7TM RECEPTOR ACTIVATIONĐ??A GLOBAL TOGGLE SWITCH MODEL (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 481-519 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The multitude of chemically highly different agonists for 7TM receptors apparently do not share a common binding mode or active site but nevertheless act through induction of a common molecular activation mechanism. A global toggle switch model is proposed for this activation mechanism to reconcile the accumulated biophysical data supporting an outward rigid-body movement of the intracellular segments, as well as the recent data derived from activating metal ion sites and tethered ligands, which suggests an opposite, inward movement of the extracellular segments of the transmembrane helices. According to this model, a vertical see-saw movement of TM-VIĐ??and to some degree TM-VIIĐ??around a pivot corresponding to the highly conserved prolines will occur during receptor activation, which may involve the outer segment of TM-V in an as yet unclear fashion. Small-molecule agonists can stabilize such a proposed active conformation, where the extracellular segments of TM-VI and -VII are bent inward toward TM-III, by acting as molecular glue deep in the main ligand-binding pocket between the helices, whereas larger agonists, peptides, and proteins can stabilize a similar active conformation by acting as Velcro at the extracellular ends of the helices and the connecting loops.
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    SEMICLASSICAL INITIAL VALUE TREATMENTS OF ATOMS AND MOLECULES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 255-280 
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    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: This review describes some developments in the theory and application of the semiclassical initial representation for the treatment of the dynamical and static properties of atoms and molecules. The theoretical basis of initial value treatments for the propagator is discussed. A variety of useful alternative initial value expressions for the propagator and other quantities are presented as generalizations of the well-known Herman-Kluk approximation. Special emphasis is given to treatments that involve integration over only half the phase space variables. The recent development of semiclassical initial value expressions that are exact for specific, desired systems is reviewed and some of the implications are described.
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    ELECTRON INJECTION AT DYE-SENSITIZED SEMICONDUCTOR ELECTRODES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 119-156 
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    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: Electron injection at dye-sensitized semiconductors is reviewed. Particular emphasis is placed on theoretical and photoelectrochemical studies of dye-sensitized planar and single-crystal electrodes. The accepted mechanism of electron injection, which was derived from these classical studies, is introduced. Selected photoelectrochemical studies of dye-sensitized nanocrystalline semiconductors are reviewed; emphasis is given to factors that influence the efficiencies of electron injection and charge recombination. The development of quasi-solid-state nanocrystalline dye-sensitized solar cells is also discussed. Recent time-resolved spectroscopic studies of electron injection and charge recombination are reviewed. These studies have led to a better understanding of electron injection mechanisms, and have revealed the limitations of the classical models.
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    FOURIER TRANSFORM INFRARED VIBRATIONAL SPECTROSCOPIC IMAGING: Integrating Microscopy and Molecular Recognition * (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 429-474 
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    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: The recent development of Fourier transform infrared (FTIR) spectroscopic imaging has enhanced our capability to examine, on a microscopic scale, the spatial distribution of vibrational spectroscopic signatures of materials spanning the physical and biomedical disciplines. Recent activity in this emerging area has concentrated on instrumentation development, theoretical analyses to provide guidelines for imaging practice, novel data processing algorithms, and the introduction of the technique to new fields. To illustrate the impact and promise of this spectroscopic imaging methodology, we present fundamental principles of the technique in the context of FTIR spectroscopy and review new applications in various venues ranging from the physical chemistry of macromolecular systems to the detection of human disease.
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    AB INITIO QUANTUM CHEMICAL AND MIXED QUANTUM MECHANICS/MOLECULAR MECHANICS (QM/MM) METHODS FOR STUDYING ENZYMATIC CATALYSIS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 389-427 
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    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: We describe large scale ab initio quantum chemical and mixed quantum mechanics/molecular mechanics (QM/MM) methods for studying enzymatic reactions. First, technical aspects of the methodology are reviewed, including the hybrid density functional theory (DFT) methods that are typically employed for the QM aspect of the calculations, and various approaches to defining the interface between the QM and MM regions in QM/MM approaches. The modeling of the enzymatic catalytic cycle for three examplesĐ??methane monooxygenase, cytochrome P450, and triose phosphate isomeraseĐ??are discussed in some depth, followed by a brief summary of other systems that have been investigated by ab initio methods over the past several years. Finally, a discussion of the qualitative and quantitative conclusions concerning enzymatic catalysis that are available from modern ab initio approaches is presented, followed by a conclusion briefly summarizing future prospects.
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    NONSTATISTICAL DYNAMICS IN THERMAL REACTIONS OF POLYATOMIC MOLECULES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 57-89 
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    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: A brief review is presented of post-RRKM models for unimolecular reaction kinetics. The dynamics of the gas-phase SN2 reaction are discussed, and the important role of phase-space bottlenecks is highlighted. The remainder of the review is devoted to experimental and trajectory simulation results on thermal reactions of organic molecules that exhibit nonstatistical dynamics quite unlike that seen in the SN2 reaction. Specifically, the intermediates generated in these reactions decay much faster than RRKM theory would predict, and often with bimodal or multimodal lifetime distributions. A qualitative model for this behavior based on overlaps of transitional regions in the molecular phase space is discussed.
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    QUANTUM MODE-COUPLING THEORY: Formulation and Applications to Normal and Supercooled Quantum Liquids (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 157-185 
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    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: We review our recent efforts to formulate and study a mode-coupling approach to real-time dynamic fluctuations in quantum liquids. Comparison is made between the theory and recent neutron scattering experiments performed on liquid ortho-deuterium and para-hydrogen. We discuss extensions of the theory to supercooled and glassy states where quantum fluctuations compete with thermal fluctuations. Experimental scenarios for quantum glassy liquids are briefly discussed.
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    HEAT CAPACITY IN PROTEINS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 521-548 
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    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: Heat capacity (Cp) is one of several major thermodynamic quantities commonly measured in proteins. With more than half a dozen definitions, it is the hardest of these quantities to understand in physical terms, but the richest in insight. There are many ramifications of observed Cp changes: The sign distinguishes apolar from polar solvation. It imparts a temperature (T) dependence to entropy and enthalpy that may change their signs and which of them dominate. Protein unfolding usually has a positive ??Cp, producing a maximum in stability and sometimes cold denaturation. There are two heat capacity contributions, from hydration and protein-protein interactions; which dominates in folding and binding is an open question. Theoretical work to date has dealt mostly with the hydration term and can account, at least semiquantitatively, for the major Cp-related features: the positive and negative Cp of hydration for apolar and polar groups, respectively; the convergence of apolar group hydration entropy at T Đ 112ʻ́C; the decrease in apolar hydration Cp with increasing T; and the T-maximum in protein stability and cold denaturation.
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    METAL TO INSULATOR TRANSITIONS IN CLUSTERS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 549-580 
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    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: The strict criterion for metallicity, a finite density of states (DOS) at the Fermi energy (EF), cannot be applied to clusters because energy levels are always discrete in a system of finite size. We propose an alternative definition whereby clusters can be considered metallic when the gap between occupied and unoccupied states at EF is consistently smaller than or equal to the Kubo band gap ??. We use the experimental findings of photoelectron spectroscopy of anionic clusters to analyze band gaps of various cluster families. Monovalent clusters (alkali and noble metals) grossly follow the shell structure pattern, producing band gaps smaller than ?? for most cluster sizes, with some exceptional sizes exhibiting electronic shell closure or symmetry-induced band gaps. Among the bivalent metals, only mercury shows consistent band gap closure with increasing cluster size, that is a simple insulator-metal transition. Other bivalent elements such as Zn and Mg exhibit a much more complicated behavior. We also briefly discuss complex cluster families such as aluminum and transition metals.
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    MICROFLUIDIC TOOLS FOR STUDYING THE SPECIFIC BINDING, ADSORPTION, AND DISPLACEMENT OF PROTEINS AT INTERFACES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 369-387 
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    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: A combination of temperature and concentration gradient microfluidic devices were employed to study the mechanistic details of biomacromolecule interactions at oxide interfaces. These lab-on-a-chip techniques allowed high-throughput, multiplexed data collection using only nanoliters of analyte. The three examples presented demonstrate rapid data acquisition relative to standard methods. First, we show ligand-receptor binding data for multivalent binding between membrane-bound ligands and incoming aqueous proteins with several binding pockets. A model is described for obtaining both the first and second dissociation constant for the reaction. The second example employs temperature gradient microfluidics to study the thermoresponsive properties of polymers and proteins. Both the folding mechanism and subsequent formation of an aqueous two-phase system were followed. Finally, these microfluidic techniques were combined with fluorescence microscopy and nonlinear optical spectroscopy to elucidate the mechanism of fibrinogen displacement from silica surfaces. This combination of methods enabled both direct and indirect observation of protein conformational changes.
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    VIBRATIONAL AUTOIONIZATION IN POLYATOMIC MOLECULES 1 (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 281-308 
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    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: The vibrationally autoionizing Rydberg states of small polyatomic molecules provide a fascinating laboratory in which to study fundamental nonadiabatic processes. In this review, recent results on the vibrational mode dependence of vibrational autoionization are discussed. In general, autoionization rates depend strongly on the character of the normal mode driving the process and on the electronic character of the Rydberg electron. Although quantitative calculations based on multichannel quantum defect theory are available for some polyatomic molecules, including H3, only qualitative information exists for most molecules. This review shows how qualitative information, such as Walsh diagrams along different normal coordinates of the molecule, can provide insight into the vibrational autoionization rates.
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    DETECTING MICRODOMAINS IN INTACT CELL MEMBRANES (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 56 (2005), S. 309-336 
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    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: Current models for cellular plasma membranes focus on spatial heterogeneity and how this heterogeneity relates to cell function. In particular, putative lipid raft membrane domains have been postulated to exist based in large part on the results that a significant fraction of the membrane is detergent insoluble and that molecules facilitating key membrane processes like signal transduction are often found in the detergent-resistant membrane fraction. Yet, the in vivo existence of lipid rafts remains extremely controversial because, despite being sought for more than a decade, evidence for their presence in intact cell membranes is inconclusive. In this review, a variety of experimental techniques that have been or might be used to look for lipid microdomains in intact cell membranes are described. Experimental results are highlighted and the strengths and limitations of different techniques for microdomain identification and characterization are assessed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.physchem.56.092503.141211
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    ABERRANT DNA METHYLATION AS A CANCER-INDUCING MECHANISM (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 629-656 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Aberrant DNA methylation is the most common molecular lesion of the cancer cell. Neither gene mutations (nucleotide changes, deletions, recombinations) nor cytogenetic abnormalities are as common in human tumors as DNA methylation alterations. The most studied change of DNA methylation in neoplasms is the silencing of tumor suppressor genes by CpG island promoter hypermethylation, which targets genes such as p16INK4a, BRCA1, and hMLH1. There is a profile of CpG island hypermethylation according to the tumor type, and genes silent by methylation represent all cellular pathways. The introduction of bisulfite-PCR methodologies combined with new genomic approaches provides a comprehensive spectrum of the genes undergoing this epigenetic change across all malignancies. However, we still know very little about how this aberrant DNA methylation "invades" the previously unmethylated CpG island and how it is maintained through cell divisions. Furthermore, we should remember that this methylation occurs in the context of a global genomic loss of 5-methylcytosine (5mC). Initial clues to understand this paradox should be revealed from the current studies of DNA methyltransferases and methyl CpG binding proteins. From the translational standpoint, we should make an effort to validate the use of some hypermethylated genes as biomarkers of the disease; for example, it may occur with MGMT and GSTP1 in brain and prostate tumors, respectively. Finally, we must expect the development of new and more specific DNA demethylating agents that awake these methyl-dormant tumor suppressor genes and prove their therapeutic values. The expectations are high.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095832
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    FUNCTION OF RETINOID NUCLEAR RECEPTORS: Lessons from Genetic and Pharmacological Dissections of the Retinoic Acid Signaling Pathway During Mouse Embryogenesis (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 451-480 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Retinoic acid (RA) is involved in vertebrate morphogenesis, growth, cellular differentiation, and tissue homeostasis. The use of in vitro systems initially led to the identification of nuclear receptor RXR/RAR heterodimers as possible transducers of the RA signal. To unveil the physiological functions of RARs and RXRs, genetic and pharmacological studies have been performed in the mouse. Together, their results demonstrate that (a) RXR/RAR heterodimers in which RXR is either transcriptionally active or silent are involved in the transduction of the RA signal during prenatal development, (b) specific RXRʼ̛/RAR heterodimers are required at many distinct stages during early embryogenesis and organogenesis, (c) the physiological role of RA and its receptors cannot be extrapolated from teratogenesis studies using retinoids in excess. Additional cell typeĐ??restricted and temporally controlled somatic mutagenesis is required to determine the functions of RARs and RXRs during postnatal life.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.46.120604.141156
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    CANNABINOID RECEPTORS AS THERAPEUTIC TARGETS (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 101-122 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: CB1 and CB2 cannabinoid receptors are the primary targets of endogenous cannabinoids (endocannabinoids). These G proteinĐ??coupled receptors play an important role in many processes, including metabolic regulation, craving, pain, anxiety, bone growth, and immune function. Cannabinoid receptors can be engaged directly by agonists or antagonists, or indirectly by manipulating endocannabinoid metabolism. In the past several years, it has become apparent from preclinical studies that therapies either directly or indirectly influencing cannabinoid receptors might be clinically useful. This review considers the components of the endocannabinoid system and discusses some of the most promising endocannabinoid-based therapies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.46.120604.141254
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    REGULATION OF PLATELET FUNCTIONS BY P2 RECEPTORS (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 277-300 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The main role of blood platelets is to ensure primary hemostasis, which is the maintenance of vessel integrity and cessation of bleeding upon injury. While playing a major part in acute arterial thrombosis, platelets are also involved in inflammation, atherosclerosis, and angiogenesis. ADP and ATP play a crucial role in platelet activation, and their receptors are potential targets for antithrombotic drugs. The ATP-gated cation channel P2X1 and the two G proteinĐ??coupled ADP receptors, P2Y1 and P2Y12, selectively contribute to platelet aggregation and formation of a thrombus. Owing to its central role in the growth and stabilization of a thrombus, the P2Y12 receptor is an established target of antithrombotic drugs such as clopidogrel. Studies in P2Y1 and P2X1 knockout mice and selective P2Y1 and P2X1 antagonists have shown that these receptors are also attractive targets for new antithrombotic compounds. The potential role of platelet P2 receptors in the involvement of platelets in inflammatory processes is also discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.46.120604.141207
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    FUNCTIONAL IMAGING OF TUMOR PROTEOLYSIS (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 301-315 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The roles of proteases in cancer are now known to be much broader than simply degradation of extracellular matrix during tumor invasion and metastasis. Furthermore, proteases from tumor-associated cells (e.g., fibroblasts, inflammatory cells, endothelial cells) as well as tumor cells are recognized to contribute to pathways critical to neoplastic progression. Although elevated expression (transcripts and proteins) of proteases, and in some cases protease inhibitors, has been documented in many tumors, techniques to assess functional roles for proteases require that we measure protease activity and inhibition of that activity rather than levels of proteases, activators, and inhibitors. Novel techniques for functional imaging of protease activity, both in vitro and in vivo, are being developed as are imaging probes that will allow us to determine protease activity and in some cases to discriminate among protease activities. These should be useful clinically as surrogate endpoints for therapies that alter protease activities.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095853
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    PLEIOTROPIC EFFECTS OF STATINS (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 89-118 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Statins are potent inhibitors of cholesterol biosynthesis. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. However, the overall benefits observed with statins appear to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. Indeed, recent studies indicate that some of the cholesterol-independent or "pleiotropic" effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Furthermore, statins have beneficial extrahepatic effects on the immune system, CNS, and bone. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the pleiotropic effects of statins.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095748
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    BIOMARKERS IN PSYCHOTROPIC DRUG DEVELOPMENT: Integration of Data across Multiple Domains (2005)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 45 (2005), S. 227-246 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: This review focuses on the current status of biomarkers and/or approaches critical to assessing novel neuroscience targets with an emphasis on new paradigms and challenges in this field of research. The importance of biomarker data integration for psychotropic drug development is illustrated with examples for clinically used medications and investigational drugs. The question remains how to verify access to the brain. Early imaging studies including micro-PET can help to overcome this. However, in case of delayed tracer development or because of no feasible application of brain imaging effects of the molecule, using CSF as a matrix could fill this gap. Proteomic research using CSF will hopefully have a major impact on the development of treatments for psychiatric disorders.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.095758
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    ROLE OF ABCG2/BCRP IN BIOLOGY AND MEDICINE (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 381-410 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The protein variously named ABCG2/BCRP/MXR/ABCP is a recently described ATP-binding cassette (ABC) transporter originally identified by its ability to confer drug resistance that is independent of Mrp1 (multidrug-resistance protein 1) and Pgp (P-glycoprotein). Unlike Mrp1 and Pgp, ABCG2 is a half-transporter that must homodimerize to acquire transport activity. ABCG2 is found in a variety of stem cells and may protect them from exogenous and endogenous toxins. ABCG2 expression is upregulated under low-oxygen conditions, consistent with its high expression in tissues exposed to low-oxygen environments. ABCG2 interacts with heme and other porphyrins and protects cells and/or tissues from protoporphyrin accumulation under hypoxic conditions. Individuals who carry ABCG2 alleles that have impaired function may be more susceptible to porphyrin-induced toxicity. Abcg2 knock-out models have allowed in vivo studies of Abcg2 function in host and cellular defense. In combination with immunohistochemical analyses, these studies have revealed how ABCG2 influences the absorption, distribution, and excretion of drugs and cytotoxins.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.46.120604.141238
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    ACCESSORY PROTEINS FOR G PROTEINS: Partners in Signaling (2006)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 151-187 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Accessory proteins involved in signal processing through heterotrimeric G proteins are generally defined as proteins distinct from G proteinĐ??coupled receptor (GPCR), G protein, or classical effectors that regulate the strength/efficiency/specificity of signal transfer upon receptor activation or position these entities in the right microenvironment, contributing to the formation of a functional signal transduction complex. A flurry of recent studies have implicated an additional class of accessory proteins for this system that provide signal input to heterotrimeric G proteins in the absence of a cell surface receptor, serve as alternative binding partners for G protein subunits, provide unexpected modes of G protein regulation, and have introduced additional functional roles for G proteins. This group of accessory proteins includes the recently discovered Activators of G protein Signaling (AGS) proteins identified in a functional screen for receptor-independent activators of G protein signaling as well as several proteins identified in protein interaction screens and genetic screens in model organisms. These accessory proteins may influence GDP dissociation and nucleotide exchange at the G subunit, alter subunit interactions within heterotrimeric G independent of nucleotide exchange, or form complexes with G or G independent of the typical G heterotrimer. AGS and related accessory proteins reveal unexpected diversity in G protein subunits as signal transducers within the cell.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.46.120604.141115
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    Real-time Imaging and Quantification of Brain Delivery of Liposomes (2006)
    Springer
    Details
    Publication Date: 2006-09-14
    Print ISSN: 0724-8741
    Electronic ISSN: 1573-904X
    Topics: Chemistry and Pharmacology
    Published by Springer
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    Papain: An Effective Permeation Enhancer for Orally Administered Low Molecular Weight Heparin (2007)
    Springer
    Details
    Publication Date: 2007-03-20
    Print ISSN: 0724-8741
    Electronic ISSN: 1573-904X
    Topics: Chemistry and Pharmacology
    Published by Springer
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    Encapsulation of Nucleic Acids and Opportunities for Cancer Treatment (2007)
    Springer
    Details
    Publication Date: 2007-02-15
    Print ISSN: 0724-8741
    Electronic ISSN: 1573-904X
    Topics: Chemistry and Pharmacology
    Published by Springer
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    Cell Type-Specific Targeting with Surface-Engineered Lentiviral Vectors Co-displaying OKT3 Antibody and Fusogenic Molecule (2009)
    Springer
    Details
    Publication Date: 2009-03-04
    Print ISSN: 0724-8741
    Electronic ISSN: 1573-904X
    Topics: Chemistry and Pharmacology
    Published by Springer
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    Semiparametric Distributions With Estimated Shape Parameters (2009)
    Springer
    Details
    Publication Date: 2009-07-01
    Print ISSN: 0724-8741
    Electronic ISSN: 1573-904X
    Topics: Chemistry and Pharmacology
    Published by Springer
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    Receptor-Specific Targeting with Liposomes In Vitro Based on Sterol-PEG1300 Anchors (2008)
    Springer
    Details
    Publication Date: 2008-11-18
    Print ISSN: 0724-8741
    Electronic ISSN: 1573-904X
    Topics: Chemistry and Pharmacology
    Published by Springer
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