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  • Articles  (377)
  • Annual Reviews  (228)
  • De Gruyter
  • 2000-2004  (377)
  • 1985-1989
  • 2004  (377)
  • Chemistry and Pharmacology  (336)
  • Technology  (41)
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  • Articles  (377)
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Years
  • 2000-2004  (377)
  • 1985-1989
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Journal
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  • 1
    Electronic Resource
    Electronic Resource
    ADVANCES IN QUANTITATIVE ELECTROENCEPHALOGRAM ANALYSIS METHODS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 453-495 
    Details
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Quantitative electroencephalogram (qEEG) plays a significant role in EEG-based clinical diagnosis and studies of brain function. In past decades, various qEEG methods have been extensively studied. This article provides a detailed review of the advances in this field. qEEG methods are generally classified into linear and nonlinear approaches. The traditional qEEG approach is based on spectrum analysis, which hypothesizes that the EEG is a stationary process. EEG signals are nonstationary and nonlinear, especially in some pathological conditions. Various time-frequency representations and time-dependent measures have been proposed to address those transient and irregular events in EEG. With regard to the nonlinearity of EEG, higher order statistics and chaotic measures have been put forward. In characterizing the interactions across the cerebral cortex, an information theory-based measure such as mutual information is applied. To improve the spatial resolution, qEEG analysis has also been combined with medical imaging technology (e.g., CT, MR, and PET). With these advances, qEEG plays a very important role in basic research and clinical studies of brain injury, neurological disorders, epilepsy, sleep studies and consciousness, and brain function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bioeng.5.040202.121601
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  • 2
    Electronic Resource
    Electronic Resource
    FLUID MECHANICS OF HEART VALVES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 331-362 
    Details
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Valvular heart disease is a life-threatening disease that afflicts millions of people worldwide and leads to approximately 250,000 valve repairs and/or replacements each year. Malfunction of a native valve impairs its efficient fluid mechanic/hemodynamic performance. Artificial heart valves have been used since 1960 to replace diseased native valves and have saved millions of lives. Unfortunately, despite four decades of use, these devices are less than ideal and lead to many complications. Many of these complications/problems are directly related to the fluid mechanics associated with the various mechanical and bioprosthetic valve designs. This review focuses on the state-of-the-art experimental and computational fluid mechanics of native and prosthetic heart valves in current clinical use. The fluid dynamic performance characteristics of caged-ball, tilting-disc, bileaflet mechanical valves and porcine and pericardial stented and nonstented bioprostheic valves are reviewed. Other issues related to heart valve performance, such as biomaterials, solid mechanics, tissue mechanics, and durability, are not addressed in this review.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bioeng.6.040803.140111
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  • 3
    Electronic Resource
    Electronic Resource
    BIOMATERIALS: Where We Have Been and Where We are Going (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 41-75 
    Details
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Since its inception just over a half century ago, the field of biomaterials has seen a consistent growth with a steady introduction of new ideas and productive branches. This review describes where we have been, the state of the art today, and where we might be in 10 or 20 years. Herein, we highlight some of the latest advancements in biomaterials that aim to control biological responses and ultimately heal. This new generation of biomaterials includes surface modification of materials to overcome nonspecific protein adsorption in vivo, precision immobilization of signaling groups on surfaces, development of synthetic materials with controlled properties for drug and cell carriers, biologically inspired materials that mimic natural processes, and design of sophisticated three-dimensional (3-D) architectures to produce well-defined patterns for diagnostics, e.g., biological microelectromechanical systems (bioMEMs), and tissue engineering.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bioeng.6.040803.140027
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  • 4
    Electronic Resource
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    THE NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 1-26 
    Details
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bioeng.6.062403.131947
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  • 5
    Electronic Resource
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    FRACTAL ANALYSIS OF THE VASCULAR TREE IN THE HUMAN RETINA (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 427-452 
    Details
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: The retinal circulation of the normal human retinal vasculature is statistically self-similar and fractal. Studies from several groups present strong evidence that the fractal dimension of the blood vessels in the normal human retina is approximately 1.7. This is the same fractal dimension that is found for a diffusion-limited growth process, and it may have implications for the embryological development of the retinal vascular system. The methods of determining the fractal dimension for branching trees are reviewed together with proposed models for the optimal formation (Murray Principle) of the branching vascular tree in the human retina and the branching pattern of the human bronchial tree. The limitations of fractal analysis of branching biological structures are evaluated. Understanding the design principles of branching vascular systems and the human bronchial tree may find applications in tissue and organ engineering, i.e., bioartificial organs for both liver and kidney.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bioeng.6.040803.140100
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  • 6
    Electronic Resource
    Electronic Resource
    BIOMATERIALS: Where We Have Been and Where We are Going (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 41-75 
    Details
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Since its inception just over a half century ago, the field of biomaterials has seen a consistent growth with a steady introduction of new ideas and productive branches. This review describes where we have been, the state of the art today, and where we might be in 10 or 20 years. Herein, we highlight some of the latest advancements in biomaterials that aim to control biological responses and ultimately heal. This new generation of biomaterials includes surface modification of materials to overcome nonspecific protein adsorption in vivo, precision immobilization of signaling groups on surfaces, development of synthetic materials with controlled properties for drug and cell carriers, biologically inspired materials that mimic natural processes, and design of sophisticated three-dimensional (3-D) architectures to produce well-defined patterns for diagnostics, e.g., biological microelectromechanical systems (bioMEMs), and tissue engineering.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bioeng.6.040803.140027
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  • 7
    Electronic Resource
    Electronic Resource
    TISSUE GROWTH AND REMODELING (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 77-107 
    Details
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: The growth and remodeling of a tissue depends on certain features in the history of its mechanical environment as well as its genetic makeup. The mechanical environment influences the tissue's developing morphology, the process of simply increasing the size of existing morphological structures, and the formation of the proteins of which the tissue is constructed. The relationships between genetic information, various epigenetic mechanisms and tissue development are discussed. The developmental growth and remodeling of most structural tissues are enhanced by the use of those tissues and retarded by their disuse. The mechanical or mathematical modeling of tissue growth and development using cellular automata models and continuum mechanical models is reviewed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bioeng.6.040803.140250
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  • 8
    Electronic Resource
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    OPTICAL PROJECTION TOMOGRAPHY (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 209-228 
    Details
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Optical projection tomography is a new approach for three-dimensional (3-D) imaging of small biological specimens. It fills an imaging gap between MRI and confocal microscopy, being most suited to specimens that are from 1 to 10 mm across. The tomographic principles of optical projection tomography (OPT) are explained, its most important applications in biomedical research explored, and comparisons drawn of its pros and cons compared to a number of alternative imaging technologies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bioeng.6.040803.140210
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  • 9
    Electronic Resource
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    STRUCTURAL BASIS OF ION PUMPING BY CA2+-ATPASE OF THE SARCOPLASMIC RETICULUM (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 269-292 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The structures of the Ca2+-ATPase (SERCA1a) have been determined for five different states by X-ray crystallography. Detailed comparison of the structures in the Ca2+ bound form and unbound (but thapsigargin bound) form reveals that very large rearrangements of the transmembrane helices take place accompanying Ca2+ dissociation and binding and that they are mechanically linked with equally large movements of the cytoplasmic domains. The meanings of the rearrangements of the transmembrane helices and those of the cytoplasmic domains as well as the mechanistic roles of phosphorylation are now becoming clear. Furthermore, the roles of critical amino acid residues identified by extensive mutagenesis studies are becoming evident in terms of atomic structure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073700
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  • 10
    Electronic Resource
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    STRUCTURE AND FUNCTION OF TOLC: The Bacterial Exit Duct for Proteins and Drugs (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 467-489 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The bacterial TolC protein plays a common role in the expulsion of diverse molecules, which include protein toxins and antibacterial drugs, from the cell. TolC is a trimeric 12-stranded alpha/beta barrel, comprising an alpha-helical trans-periplasmic tunnel embedded in the outer membrane by a contiguous beta-barrel channel. This structure establishes a 140 A long single pore fundamentally different to other membrane proteins and presents an exit duct to substrates, large and small, engaged at specific inner membrane translocases. TolC is open to the outside medium but is closed at its periplasmic entrance. When TolC is recruited by a substrate-laden translocase, the entrance is opened to allow substrate passage through a contiguous machinery spanning the entire cell envelope, from the cytosol to the external environment. Transition to the transient open state is achieved by an iris-like mechanism in which entrance alpha-helices undergo an untwisting realignment, thought to be stabilized by interaction with periplasmic helices of the translocase. TolC family proteins are ubiquitous among gram-negative bacteria, and the conserved entrance aperture presents a possible cheomotherapeutic target in multidrug-resistant pathogens.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.074104
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  • 11
    Electronic Resource
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    REGULATION OF TELOMERASE BY TELOMERIC PROTEINS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 177-208 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Telomeres are essential for genome stability in all eukaryotes. Changes in telomere functions and the associated chromosomal abnormalities have been implicated in human aging and cancer. Telomeres are composed of repetitive sequences that can be maintained by telomerase, a complex containing a reverse transcriptase (hTERT in humans and Est2 in budding yeast), a template RNA (hTERC in humans and Tlc1 in yeast), and accessory factors (the Est1 proteins and dyskerin in humans and Est1, Est3, and Sm proteins in budding yeast). Telomerase is regulated in cis by proteins that bind to telomeric DNA. This regulation can take place at the telomere terminus, involving single-stranded DNA-binding proteins (POT1 in humans and Cdc13 in budding yeast), which have been proposed to contribute to the recruitment of telomerase and may also regulate the extent or frequency of elongation. In addition, proteins that bind along the length of the telomere (TRF1/TIN2/tankyrase in humans and Rap1/Rif1/Rif2 in budding yeast) are part of a negative feedback loop that regulates telomere length. Here we discuss the details of telomerase and its regulation by the telomere.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.071403.160049
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  • 12
    Electronic Resource
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    PALMITOYLATION OF INTRACELLULAR SIGNALING PROTEINS: Regulation and Function (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 559-587 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Protein S-palmitoylation is the thioester linkage of long-chain fatty acids to cysteine residues in proteins. Addition of palmitate to proteins facilitates their membrane interactions and trafficking, and it modulates protein-protein interactions and enzyme activity. The reversibility of palmitoylation makes it an attractive mechanism for regulating protein activity, and this feature has generated intensive investigation of this modification. The regulation of palmitoylation occurs through the actions of protein acyltransferases and protein acylthioesterases. Identification of the protein acyltransferases Erf2/Erf4 and Akr1 in yeast has provided new insight into the palmitoylation reaction. These molecules work in concert with thioesterases, such as acyl-protein thioesterase 1, to regulate the palmitoylation status of numerous signaling molecules, ultimately influencing their function. This review discusses the function and regulation of protein palmitoylation, focusing on intracellular proteins that participate in cell signaling or protein trafficking.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073954
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  • 13
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    STRUCTURAL ASPECTS OF LIGAND BINDING TO AND ELECTRON TRANSFER IN BACTERIAL AND FUNGAL P450S (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 991-1018 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Cytochrome P450 enzymes are heme-containing monooxygenases that are named after an absorption band at 450 nm when complexed with carbon monoxide. They catalyze a wide variety of reactions and are unique in their ability to hydroxylate nonactivated hydrocarbons. P450 enzymes are involved in numerous biological processes, which include the biosynthesis of lipids, steroids, antibiotics, and the degradation of xenobiotics. In line with the variety of reactions catalyzed, the size of their substrates varies significantly. Some P450s have open active sites (e.g., BM3), and some have shielded active sites that open only transiently (e.g., P450cam), whereas others bind the substrate only when attached to carrier proteins (e.g., Oxy proteins). Structural aspects of both organic and gaseous ligand binding and electron transfer are described.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073711
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  • 14
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    ATP-BINDING CASSETTE TRANSPORTERS IN BACTERIA (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 241-268 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: ATP-binding cassette (ABC) transporters couple ATP hydrolysis to the uptake and efflux of solutes across the cell membrane in bacteria and eukaryotic cells. In bacteria, these transporters are important virulence factors because they play roles in nutrient uptake and in secretion of toxins and antimicrobial agents. In humans, many diseases, such as cystic fibrosis, hyperinsulinemia, and macular dystrophy, are traced to defects in ABC transporters. Recent advances in structural determination and functional analysis of bacterial ABC transporters, reviewed herein, have greatly increased our understanding of the molecular mechanism of transport in this transport superfamily.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073626
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  • 15
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    DIRECTED EVOLUTION OF NUCLEIC ACID ENZYMES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 791-836 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Just as Darwinian evolution in nature has led to the development of many sophisticated enzymes, Darwinian evolution in vitro has proven to be a powerful approach for obtaining similar results in the laboratory. This review focuses on the development of nucleic acid enzymes starting from a population of random-sequence RNA or DNA molecules. In order to illustrate the principles and practice of in vitro evolution, two especially well-studied categories of catalytic nucleic acid are considered: RNA enzymes that catalyze the template-directed ligation of RNA and DNA enzymes that catalyze the cleavage of RNA. The former reaction, which involves attack of a 2'- or 3'-hydroxyl on the alpha-phosphate of a 5'-triphosphate, is more difficult. It requires a comparatively larger catalytic motif, containing more nucleotides than can be sampled exhaustively within a starting population of random-sequence RNAs. The latter reaction involves deprotonation of the 2'-hydroxyl adjacent to the cleavage site, resulting in cleaved products that bear a 2',3'-cyclic phosphate and 5'-hydroxyl. The difficulty of this reaction, and therefore the complexity of the corresponding DNA enzyme, depends on whether a catalytic cofactor, such as a divalent metal cation or small molecule, is present in the reaction mixture.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073717
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  • 16
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    INCORPORATION OF NONNATURAL AMINO ACIDS INTO PROTEINS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 147-176 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The genetic code is established by the aminoacylation of transfer RNA, reactions in which each amino acid is linked to its cognate tRNA that, in turn, harbors the nucleotide triplet (anticodon) specific to the amino acid. The accuracy of aminoacylation is essential for building and maintaining the universal tree of life. The ability to manipulate and expand the code holds promise for the development of new methods to create novel proteins and to understand the origins of life. Recent efforts to manipulate the genetic code have fulfilled much of this potential. These efforts have led to incorporation of nonnatural amino acids into proteins for a variety of applications and have demonstrated the plausibility of specific proposals for early evolution of the code.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.012803.092429
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  • 17
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    MOLECULAR MECHANISMS OF MAMMALIAN DNA REPAIR AND THE DNA DAMAGE CHECKPOINTS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 39-85 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: DNA damage is a relatively common event in the life of a cell and may lead to mutation, cancer, and cellular or organismic death. Damage to DNA induces several cellular responses that enable the cell either to eliminate or cope with the damage or to activate a programmed cell death process, presumably to eliminate cells with potentially catastrophic mutations. These DNA damage response reactions include: (a) removal of DNA damage and restoration of the continuity of the DNA duplex; (b) activation of a DNA damage checkpoint, which arrests cell cycle progression so as to allow for repair and prevention of the transmission of damaged or incompletely replicated chromosomes; (c) transcriptional response, which causes changes in the transcription profile that may be beneficial to the cell; and (d) apoptosis, which eliminates heavily damaged or seriously deregulated cells. DNA repair mechanisms include direct repair, base excision repair, nucleotide excision repair, double-strand break repair, and cross-link repair. The DNA damage checkpoints employ damage sensor proteins, such as ATM, ATR, the Rad17-RFC complex, and the 9-1-1 complex, to detect DNA damage and to initiate signal transduction cascades that employ Chk1 and Chk2 Ser/Thr kinases and Cdc25 phosphatases. The signal transducers activate p53 and inactivate cyclin-dependent kinases to inhibit cell cycle progression from G1 to S (the G1/S checkpoint), DNA replication (the intra-S checkpoint), or G2 to mitosis (the G2/M checkpoint). In this review the molecular mechanisms of DNA repair and the DNA damage checkpoints in mammalian cells are analyzed.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073723
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  • 18
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    OPIOID RECEPTORS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 953-990 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Opioid receptors belong to the large superfamily of seven transmembrane-spanning (7TM) G protein-coupled receptors (GPCRs). As a class, GPCRs are of fundamental physiological importance mediating the actions of the majority of known neurotransmitters and hormones. Opioid receptors are particularly intriguing members of this receptor family. They are activated both by endogenously produced opioid peptides and by exogenously administered opiate compounds, some of which are not only among the most effective analgesics known but also highly addictive drugs of abuse. A fundamental question in addiction biology is why exogenous opioid drugs, such as morphine and heroin, have a high liability for inducing tolerance, dependence, and addiction. This review focuses on many aspects of opioid receptors with the aim of gaining a greater insight into mechanisms of opioid tolerance and dependence.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073940
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  • 19
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    MECHANICAL PROCESSES IN BIOCHEMISTRY (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 705-748 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Mechanical processes are involved in nearly every facet of the cell cycle. Mechanical forces are generated in the cell during processes as diverse as chromosomal segregation, replication, transcription, translation, translocation of proteins across membranes, cell locomotion, and catalyzed protein and nucleic acid folding and unfolding, among others. Because force is a product of all these reactions, biochemists are beginning to directly apply external forces to these processes to alter the extent or even the fate of these reactions hoping to reveal their underlying molecular mechanisms. This review provides the conceptual framework to understand the role of mechanical force in biochemistry.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.72.121801.161542
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  • 20
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    USING PROTEIN FOLDING RATES TO TEST PROTEIN FOLDING THEORIES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 837-859 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The fastest simple, kinetically two-state protein folds a million times more rapidly than the slowest. Here we review many recent theories of protein folding kinetics in terms of their ability to qualitatively rationalize, if not quantitatively predict, this fundamental experimental observation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073904
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  • 21
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    THE EXCITEMENT OF DISCOVERY (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 1-37 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: I had the good luck to start research at the dawn of molecular biology when it was possible to ask fundamental questions about the nature of the nucleic acids and how information is transferred in living systems. The search for answers led me into many different areas, often with the question of how molecular structure leads to biological function. Early work in this period provided some of the roots supporting the current explosive developments in life sciences. Here I give a brief account of my development, describe some contributions, and provide a hint of the exhilaration in discovering new things. Most of all, I had the good fortune to have inspiring teachers, stimulating colleagues, and excellent students.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073945
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  • 22
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    EUKARYOTIC mRNA DECAPPING (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 861-890 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Eukaryotic mRNAs are primarily degraded by removal of the 3' poly(A) tail, followed either by cleavage of the 5' cap structure (decapping) and 5'-〉3' exonucleolytic digestion, or by 3' to 5' degradation. mRNA decapping represents a critical step in turnover because this permits the degradation of the mRNA and is a site of numerous control inputs. Recent analyses suggest decapping of an mRNA consists of four central and related events. These include removal, or inactivation, of the poly(A) tail as an inhibitor of decapping, exit from active translation, assembly of a decapping complex on the mRNA, and sequestration of the mRNA into discrete cytoplasmic foci where decapping can occur. Each of these steps is a demonstrated, or potential, site for the regulation of mRNA decay. We discuss the decapping process in the light of these central properties, which also suggest fundamental aspects of cytoplasmic mRNA physiology that connect decapping, translation, and storage of mRNA.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.074032
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  • 23
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    EMERGING PRINCIPLES OF CONFORMATION-BASED PRION INHERITANCE (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 617-656 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The prion hypothesis proposes that proteins can act as infectious agents. Originally formulated to explain transmissible spongiform encephalopathies (TSEs), the prion hypothesis has been extended with the finding that several non-Mendelian traits in fungi are due to heritable changes in protein conformation, which may in some cases be beneficial. Although much remains to be learned about the specific role of cellular cofactors, mechanistic parallels between the mammalian and yeast prion phenomena point to universal features of conformation-based infection and inheritance involving propagation of ordered beta-sheet-rich protein aggregates commonly referred to as amyloid. Here we focus on two such features and discuss recent efforts to explain them in terms of the physical properties of amyloid-like aggregates. The first is prion strains, wherein chemically identical infectious particles cause distinct phenotypes. The second is barriers that often prohibit prion transmission between different species. There is increasing evidence suggesting that both of these can be manifestations of the same phenomenon: the ability of a protein to misfold into multiple self-propagating conformations. Even single mutations can change the spectrum of favored misfolded conformations. In turn, changes in amyloid conformation can shift the specificity of propagation and alter strain phenotypes. This model helps explain many common and otherwise puzzling features of prion inheritance as well as aspects of noninfectious diseases involving toxic misfolded proteins.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.72.121801.161837
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    PYRIDOXAL PHOSPHATE ENZYMES: Mechanistic, Structural, and Evolutionary Considerations (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 383-415 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Pyridoxal phosphate (PLP)-dependent enzymes are unrivaled in the diversity of reactions that they catalyze. New structural data have paved the way for targeted mutagenesis and mechanistic studies and have provided a framework for interpretation of those results. Together, these complementary approaches yield new insight into function, particularly in understanding the origins of substrate and reaction type specificity. The combination of new sequences and structures enables better reconstruction of their evolutionary heritage and illuminates unrecognized similarities within this diverse group of enzymes. The important metabolic roles of many PLP-dependent enzymes drive efforts to design specific inhibitors, which are now guided by the availability of comprehensive structural and functional databases. Better understanding of the function of this important group of enzymes is crucial not only for inhibitor design, but also for the design of improved protein-based catalysts.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.074021
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    INTERMEDIATE FILAMENTS: Molecular Structure, Assembly Mechanism, and Integration Into Functionally Distinct Intracellular Scaffolds (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 749-789 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The superfamily of intermediate filament (IF) proteins contains at least 65 distinct proteins in man, which all assemble into ~10 nm wide filaments and are principal structural elements both in the nucleus and the cytoplasm with essential scaffolding functions in metazoan cells. At present, we have only circumstantial evidence of how the highly divergent primary sequences of IF proteins lead to the formation of seemingly similar polymers and how this correlates with their function in individual cells and tissues. Point mutations in IF proteins, particularly in lamins, have been demonstrated to lead to severe, inheritable multi-systemic diseases, thus underlining their importance at several functional levels. Recent structural work has now begun to shed some light onto the complex fine tuning of structure and function in these fibrous, coiled coil forming multidomain proteins and their contribution to cellular physiology and gene regulation.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073823
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    PALMITOYLATION OF INTRACELLULAR SIGNALING PROTEINS: Regulation and Function (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 559-587 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Protein S-palmitoylation is the thioester linkage of long-chain fatty acids to cysteine residues in proteins. Addition of palmitate to proteins facilitates their membrane interactions and trafficking, and it modulates protein-protein interactions and enzyme activity. The reversibility of palmitoylation makes it an attractive mechanism for regulating protein activity, and this feature has generated intensive investigation of this modification. The regulation of palmitoylation occurs through the actions of protein acyltransferases and protein acylthioesterases. Identification of the protein acyltransferases Erf2/Erf4 and Akr1 in yeast has provided new insight into the palmitoylation reaction. These molecules work in concert with thioesterases, such as acyl-protein thioesterase 1, to regulate the palmitoylation status of numerous signaling molecules, ultimately influencing their function. This review discusses the function and regulation of protein palmitoylation, focusing on intracellular proteins that participate in cell signaling or protein trafficking.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073954
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    THE MOLECULAR MECHANICS OF EUKARYOTIC TRANSLATION (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 657-704 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Great advances have been made in the past three decades in understanding the molecular mechanics underlying protein synthesis in bacteria, but our understanding of the corresponding events in eukaryotic organisms is only beginning to catch up. In this review we describe the current state of our knowledge and ignorance of the molecular mechanics underlying eukaryotic translation. We discuss the mechanisms conserved across the three kingdoms of life as well as the important divergences that have taken place in the pathway.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.73.030403.080419
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    STRUCTURAL INSIGHTS INTO THE SIGNAL RECOGNITION PARTICLE (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 539-557 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The signal recognition particle (SRP) directs integral membrane and secretory proteins to the cellular protein translocation machinery during translation. The SRP is an evolutionarily conserved RNA-protein complex whose activities are regulated by GTP hydrolysis. Recent structural investigations of SRP functional domains and interactions provide new insights into the mechanisms of SRP activity in all cells, leading toward a comprehensive understanding of protein trafficking by this elegant pathway.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.074048
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    ROLES OF N-LINKED GLYCANS IN THE ENDOPLASMIC RETICULUM (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 1019-1049 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: From a process involved in cell wall synthesis in archaea and some bacteria, N-linked glycosylation has evolved into the most common covalent protein modification in eukaryotic cells. The sugars are added to nascent proteins as a core oligosaccharide unit, which is then extensively modified by removal and addition of sugar residues in the endoplasmic reticulum (ER) and the Golgi complex. It has become evident that the modifications that take place in the ER reflect a spectrum of functions related to glycoprotein folding, quality control, sorting, degradation, and secretion. The glycans not only promote folding directly by stabilizing polypeptide structures but also indirectly by serving as recognition "tags" that allow glycoproteins to interact with a variety of lectins, glycosidases, and glycosyltranferases. Some of these (such as glucosidases I and II, calnexin, and calreticulin) have a central role in folding and retention, while others (such as alpha-mannosidases and EDEM) target unsalvageable glycoproteins for ER-associated degradation. Each residue in the core oligosaccharide and each step in the modification program have significance for the fate of newly synthesized glycoproteins.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073752
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    THE MOLECULAR MECHANICS OF EUKARYOTIC TRANSLATION (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 657-704 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Great advances have been made in the past three decades in understanding the molecular mechanics underlying protein synthesis in bacteria, but our understanding of the corresponding events in eukaryotic organisms is only beginning to catch up. In this review we describe the current state of our knowledge and ignorance of the molecular mechanics underlying eukaryotic translation. We discuss the mechanisms conserved across the three kingdoms of life as well as the important divergences that have taken place in the pathway.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.73.030403.080419
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    DIRECTED EVOLUTION OF NUCLEIC ACID ENZYMES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 791-836 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Just as Darwinian evolution in nature has led to the development of many sophisticated enzymes, Darwinian evolution in vitro has proven to be a powerful approach for obtaining similar results in the laboratory. This review focuses on the development of nucleic acid enzymes starting from a population of random-sequence RNA or DNA molecules. In order to illustrate the principles and practice of in vitro evolution, two especially well-studied categories of catalytic nucleic acid are considered: RNA enzymes that catalyze the template-directed ligation of RNA and DNA enzymes that catalyze the cleavage of RNA. The former reaction, which involves attack of a 2'- or 3'-hydroxyl on the alpha-phosphate of a 5'-triphosphate, is more difficult. It requires a comparatively larger catalytic motif, containing more nucleotides than can be sampled exhaustively within a starting population of random-sequence RNAs. The latter reaction involves deprotonation of the 2'-hydroxyl adjacent to the cleavage site, resulting in cleaved products that bear a 2',3'-cyclic phosphate and 5'-hydroxyl. The difficulty of this reaction, and therefore the complexity of the corresponding DNA enzyme, depends on whether a catalytic cofactor, such as a divalent metal cation or small molecule, is present in the reaction mixture.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073717
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    NOVEL LIPID MODIFICATIONS OF SECRETED PROTEIN SIGNALS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 891-923 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Secreted signaling proteins function in a diverse array of essential patterning events during metazoan development, ranging from embryonic segmentation in insects to neural tube differentiation in vertebrates. These proteins generally are expressed in a localized manner, and they may elicit distinct concentration-dependent responses in the cells of surrounding tissues and structures, thus functioning as morphogens that specify the pattern of cellular responses by their tissue distribution. Given the importance of signal distribution, it is notable that the Hedgehog (Hh) and Wnt proteins, two of the most important families of such signals, are known to be covalently modified by lipid moieties, the membrane-anchoring properties of which are not consistent with passive models of protein mobilization within tissues. This review focuses on the mechanisms underlying biogenesis of the mature Hh proteins, which are dually modified by cholesteryl and palmitoyl adducts, as well as on the relationship between Hh proteins and the self-splicing proteins (i.e., proteins containing inteins) and the Hh-like proteins of nematodes. We further discuss the cellular mechanisms that have evolved to handle lipidated Hh proteins in the spatial deployment of the signal in developing tissues and the more recent findings that implicate palmitate modification as an important feature of Wnt signaling proteins.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073933
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    ROLE OF GLYCOSYLATION IN DEVELOPMENT (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 491-537 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Researchers have long predicted that complex carbohydrates on cell surfaces would play important roles in developmental processes because of the observation that specific carbohydrate structures appear in specific spatial and temporal patterns throughout development. The astounding number and complexity of carbohydrate structures on cell surfaces added support to the concept that glycoconjugates would function in cellular communication during development. Although the structural complexity inherent in glycoconjugates has slowed advances in our understanding of their functions, the complete sequencing of the genomes of organisms classically used in developmental studies (e.g., mice, Drosophila melanogaster, and Caenorhabditis elegans) has led to demonstration of essential functions for a number of glycoconjugates in developmental processes. Here we present a review of recent studies analyzing function of a variety of glycoconjugates (O-fucose, O-mannose, N-glycans, mucin-type O-glycans, proteoglycans, glycosphingolipids), focusing on lessons learned from human disease and genetic studies in mice, D. melanogaster, and C. elegans.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.074043
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    EMERGING PRINCIPLES OF CONFORMATION-BASED PRION INHERITANCE (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 617-656 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The prion hypothesis proposes that proteins can act as infectious agents. Originally formulated to explain transmissible spongiform encephalopathies (TSEs), the prion hypothesis has been extended with the finding that several non-Mendelian traits in fungi are due to heritable changes in protein conformation, which may in some cases be beneficial. Although much remains to be learned about the specific role of cellular cofactors, mechanistic parallels between the mammalian and yeast prion phenomena point to universal features of conformation-based infection and inheritance involving propagation of ordered beta-sheet-rich protein aggregates commonly referred to as amyloid. Here we focus on two such features and discuss recent efforts to explain them in terms of the physical properties of amyloid-like aggregates. The first is prion strains, wherein chemically identical infectious particles cause distinct phenotypes. The second is barriers that often prohibit prion transmission between different species. There is increasing evidence suggesting that both of these can be manifestations of the same phenomenon: the ability of a protein to misfold into multiple self-propagating conformations. Even single mutations can change the spectrum of favored misfolded conformations. In turn, changes in amyloid conformation can shift the specificity of propagation and alter strain phenotypes. This model helps explain many common and otherwise puzzling features of prion inheritance as well as aspects of noninfectious diseases involving toxic misfolded proteins.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.72.121801.161837
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    EUKARYOTIC mRNA DECAPPING (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 861-890 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Eukaryotic mRNAs are primarily degraded by removal of the 3' poly(A) tail, followed either by cleavage of the 5' cap structure (decapping) and 5'-〉3' exonucleolytic digestion, or by 3' to 5' degradation. mRNA decapping represents a critical step in turnover because this permits the degradation of the mRNA and is a site of numerous control inputs. Recent analyses suggest decapping of an mRNA consists of four central and related events. These include removal, or inactivation, of the poly(A) tail as an inhibitor of decapping, exit from active translation, assembly of a decapping complex on the mRNA, and sequestration of the mRNA into discrete cytoplasmic foci where decapping can occur. Each of these steps is a demonstrated, or potential, site for the regulation of mRNA decay. We discuss the decapping process in the light of these central properties, which also suggest fundamental aspects of cytoplasmic mRNA physiology that connect decapping, translation, and storage of mRNA.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.074032
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    STRUCTURAL ASPECTS OF LIGAND BINDING TO AND ELECTRON TRANSFER IN BACTERIAL AND FUNGAL P450S (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 991-1018 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Cytochrome P450 enzymes are heme-containing monooxygenases that are named after an absorption band at 450 nm when complexed with carbon monoxide. They catalyze a wide variety of reactions and are unique in their ability to hydroxylate nonactivated hydrocarbons. P450 enzymes are involved in numerous biological processes, which include the biosynthesis of lipids, steroids, antibiotics, and the degradation of xenobiotics. In line with the variety of reactions catalyzed, the size of their substrates varies significantly. Some P450s have open active sites (e.g., BM3), and some have shielded active sites that open only transiently (e.g., P450cam), whereas others bind the substrate only when attached to carrier proteins (e.g., Oxy proteins). Structural aspects of both organic and gaseous ligand binding and electron transfer are described.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073711
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    NEUTRON REFLECTION FROM LIQUID INTERFACES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 55 (2004), S. 391-426 
    Details
    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: Recent applications of neutron reflectometry to the study of wet interfaces are described. An outline is given of the basic principles that allow the techniques to determine composition and structure in a variety of situations. These are the adsorption of surfactant molecules at air/liquid and solid/liquid interfaces, the shape of the segment-density profiles of different types of polymer, including block copolymers and polyelectrolytes, adsorption in mixed surfactant and polymer/surfactant systems, and interfacial systems of biophysical interest.
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    URL: http://dx.doi.org/10.1146/annurev.physchem.54.011002.103830
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    CHARGE TRANSPORT AT CONJUGATED POLYMER-INORGANIC SEMICONDUCTOR AND CONJUGATED POLYMER-METAL INTERFACES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 55 (2004), S. 257-298 
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    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: Charge transport at conjugated polymer interfaces with metals and inorganic semiconductors is reviewed. Experiments on the equilibrium properties and DC current-voltage behavior of four specific classes of interfaces-metal-doped conjugated polymer, inorganic semiconductor-doped conjugated polymer, metal-intrinsic conjugated polymer, and metal-intrinsic conjugated polymer/electrolyte-are discussed. To facilitate this discussion, classic models of equilibration at ideal interfaces between electronic conductors and free-electron transport are introduced and their limitations discussed. Particular emphasis is placed on the charge distributions and interfacial potential profiles expected at various types of electroactive interfaces.
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    URL: http://dx.doi.org/10.1146/annurev.physchem.55.091602.094421
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    SEMICLASSICAL DESCRIPTION OF MOLECULAR DYNAMICS BASED ON INITIAL-VALUE REPRESENTATION METHODS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 55 (2004), S. 299-332 
    Details
    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: Recent progress in the development of semiclassical methods to describe quantum effects in molecular dynamics is reviewed. Focusing on rigorous semiclassical methods that are based on the initial-value representation of the semiclassical propagator, we discuss several promising schemes that have been developed in the past few years to extend the applicability of semiclassical approaches to complex molecular systems. In particular, integral-filtering techniques and forward-backward methods are surveyed. Furthermore, recently proposed approaches that allow the semiclassical description of nonadiabatic molecular dynamics are discussed. The potential and efficiency of these methods is illustrated by selected applications.
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    TIME-DEPENDENT DENSITY FUNCTIONAL THEORY (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 55 (2004), S. 427-455 
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    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: Time-dependent density functional theory (TDDFT) can be viewed as an exact reformulation of time-dependent quantum mechanics, where the fundamental variable is no longer the many-body wave function but the density. This time-dependent density is determined by solving an auxiliary set of noninteracting Schrodinger equations, the Kohn-Sham equations. The nontrivial part of the many-body interaction is contained in the so-called exchange-correlation potential, for which reasonably good approximations exist. Within TDDFT two regimes can be distinguished: (a) If the external time-dependent potential is "small," the complete numerical solution of the time-dependent Kohn-Sham equations can be avoided by the use of linear response theory. This is the case, e.g., for the calculation of photoabsorption spectra. (b) For a "strong" external potential, a full solution of the time-dependent Kohn-Sham equations is in order. This situation is encountered, for instance, when matter interacts with intense laser fields. In this review we give an overview of TDDFT from its theoretical foundations to several applications both in the linear and in the nonlinear regime.
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    OPTICALLY DETECTED MAGNETIC RESONANCE STUDIES OF COLLOIDAL SEMICONDUCTOR NANOCRYSTALS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physical Chemistry 55 (2004), S. 509-557 
    Details
    ISSN: 0066-426X
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Physics
    Notes: The review describes the studies of the magneto-optical properties of II-VI and III-V semiconductor nanocrystals (NCs) capped with organic or inorganic epitaxial shells. The investigations focused on the chemical identification of localization sites (core, shell, or interface) of photogenerated carriers in spherical NCs and elucidated the influence of the surface/interface quality on the optical properties of the materials. Optically detected magnetic resonance (ODMR) spectroscopy was used for the study of the proposed physical properties. The ODMR method provides the means to identify the surface/interface sites and correlate them with specific optical transition. In addition, this method reveals information about the spin multiplicity of band edge and trapped states and the electron-hole exchange interaction, determines the spectroscopic g-factors, distinguishes between the radiative and nonradiative characteristic of a trapping site, and evaluates the spin-lattice relaxation times.
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    OXIDATIVE STRESS, TOXICOLOGY, AND PHARMACOLOGY OF CYP2E1 * (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 27-42 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: This review describes some of the biochemical and toxicological properties of CYP2E1, especially as it relates to alcohol metabolism and toxicity and the establishment of human hepatoma HepG2 cell lines that overexpress human CYP2E1. Ethanol, polyunsaturated fatty acids, and iron were found to be cytotoxic in HepG2 cells that overexpress CYP2E1. GSH appears to be essential in protecting HepG2 cells against the CYP2E1-dependent cytotoxicity, and GSH levels were elevated owing to a twofold increase in activity and expression of glutamate cysteine ligase. We suggest that this up-regulation of GSH synthesis was an adaptive response to attenuate CYP2E1-dependent oxidative stress and toxicity. Induction of a state of oxidative stress appears to play a central role in the CYP2E1-dependent cytotoxicity. Mitochondrial membrane potential decreased in the CYP2E1-expressing HepG2 cells, and this decrease shared similar characteristics with the developing toxicity. Alcohol-dependent liver injury is likely to be a multifactorial process involving several mechanisms. We believe that the linkage between CYP2E1-dependent oxidative stress, mitochondrial injury, and GSH homeostasis contribute to the toxic actions of ethanol on the liver.
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    URL: http://dx.doi.org/10.1146/annurev.pharmtox.44.101802.121704
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    THE INTEGRATION OF PHARMACOKINETICS AND PHARMACODYNAMICS: Understanding Dose-Response (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 111-136 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Pharmacokinetic (PK) and pharmacodynamic (PD) studies have proven to be powerful and instructive tools, particularly in elucidating important aspects of human pharmacology. Nevertheless, they remain imperfect tools in that they only allow researchers to indirectly extrapolate, through computational modeling, the dynamic processes of drug action. Furthermore, neither tool alone provides a complete nor necessarily relevant picture of drug action. This review explores the utility and applications of PK and PD in the study of drugs, provides examples of lessons learned from their application to studies of human pharmacology, points out some of their limitations, and advances the thesis that these tools ideally should be employed together in an integrated approach. As we continue to apply these tools across the continuum of age and disease, they provide a powerful means to enhance our understanding of drug action, drug interactions, and intrinsic host factors that influence pharmacologic response.
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    URL: http://dx.doi.org/10.1146/annurev.pharmtox.44.101802.121347
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    THE ROLE OF OXIDATIVE STRESS IN CARCINOGENESIS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 239-267 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Chemical carcinogenesis follows a multistep process involving both mutation and increased cell proliferation. Oxidative stress can occur through overproduction of reactive oxygen and nitrogen species through either endogenous or exogenous insults. Important to carcinogenesis, the unregulated or prolonged production of cellular oxidants has been linked to mutation (induced by oxidant-induced DNA damage), as well as modification of gene expression. In particular, signal transduction pathways, including AP-1 and NFkappaB, are known to be activated by reactive oxygen species, and they lead to the transcription of genes involved in cell growth regulatory pathways. This review examines the evidence of cellular oxidants' involvement in the carcinogenesis process, and focuses on the mechanisms for production, cellular damage produced, and the role of signaling cascades by reactive oxygen species.
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    THE ROLE OF CALPAIN IN ONCOTIC CELL DEATH (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 349-370 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Numerous lines of evidence demonstrate that calpains, a family of 14 Ca2+-activated neutral cysteine proteases, are involved in oncotic cell death in a variety of models. At this time, the biochemistry of most calpains and the specific roles of different calpains in physiology and pathology remain to be determined. A number of calpain substrates have been identified in cellular systems, including cytoskeletal proteins, and recent studies suggest that calpains mediate the increase in plasma membrane permeability to ions and the progressive breakdown of the plasma membrane observed in oncosis through the proteolysis of cystokeletal and plasma membrane proteins. Further, a number of reports provide evidence that the mitochondrial dysfunction observed in oncosis may be mediated by a mitochondrial calpain of unknown identity. Finally, a number of diverse calpain inhibitors have been developed that show cytoprotective properties in cellular systems and in vivo following diverse insults. It is suggested that future research be directed toward elucidation of the role(s) of specific calpain isozymes in physiological and pathological conditions; identifying and linking specific calpain substrates with altered cellular functions; and developing cell-permeable, potent, isozyme-selective calpain inhibitors.
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    ANALYSIS OF GABAA RECEPTOR FUNCTION AND DISSECTION OF THE PHARMACOLOGY OF BENZODIAZEPINES AND GENERAL ANESTHETICS THROUGH MOUSE GENETICS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 475-498 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: GABAA receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity, and memory functions, and the enhancement of GABAA receptor-mediated fast synaptic inhibition is the basis for the pharmacotherapy of various neurological and psychiatric disorders. Two kinds of GABAA receptor-targeted mutant mice have been generated: (a) knockout mice that lack individual GABAA receptor subunits (alpha1, alpha5, alpha6, beta2, beta3, gamma2, delta, and rho1) and (b) knockin mice that carry point mutations affecting the action of modulatory drugs [alpha1(H101R), alpha2(H101R), alpha3(H126R), alpha5(H105R), and beta3(N265M)]. Whereas the knockout mice have provided information primarily with respect to the regulation of subunit gene transcription, receptor assembly, and some physiological functions of individual receptor subtypes, the point-mutated knockin mice in which specific GABAA receptor subtypes are insensitive to diazepam or some general anesthetics have revealed the specific contribution of individual receptor subtypes to the pharmacological spectrum of diazepam and general anesthetics.
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    MEMBRANE TRAFFICKING OF G PROTEIN-COUPLED RECEPTORS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 559-609 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: G protein-coupled receptors (GPCRs) modulate diverse physiological and behavioral signaling pathways by virtue of changes in receptor activation and inactivation states. Functional changes in receptor properties include dynamic interactions with regulatory molecules and trafficking to various cellular compartments at various stages of the life cycle of a GPCR. This review focuses on trafficking of GPCRs to the cell surface, stabilization there, and agonist-regulated turnover. GPCR interactions with a variety of newly revealed partners also are reviewed with the intention of provoking further analysis of the relevance of these interactions in GPCR trafficking, signaling, or both. The disease consequences of mislocalization of GPCRs also are described.
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    PREDICTING HUMAN DRUG GLUCURONIDATION PARAMETERS: Application of In Vitro and In Silico Modeling Approaches (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), 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: Cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), which both exist as enzyme "superfamilies," are together responsible for the metabolism of most hepatically cleared drugs. There is currently intense interest in the development of techniques that permit identification of the CYP and UGT isoform(s) involved in the metabolism of a newly discovered drug, and hence prediction of factors likely to alter elimination in vivo. In addition, the quantitative scaling of kinetic parameters for a metabolic pathway assumes importance for identifying newly discovered drugs with undesirable in vivo pharmacokinetic properties. Although qualitative and quantitative in vitro-in vivo correlation based on data generated using human liver tissue or recombinant enzymes have been applied successfully to many drugs eliminated by CYP, these strategies have proved less definitive for glucuronidated compounds. Computational (in silico) modeling techniques that potentially provide a facile and economic alternative to the in vitro methods are now emerging. This review assesses the utility of in vitro and in silico approaches for the qualitative and quantitative prediction of drug glucuronidation parameters and the challenges facing the development of generalizable models.
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    DEVELOPMENTAL NEUROPATHOLOGY OF ENVIRONMENTAL AGENTS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 87-110 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The developing central nervous system (CNS) is more vulnerable to injury than the adult one. Although a great deal of research has been devoted to subtle effects of developmental exposure, such as neurobehavioral changes, this review instead focuses on a number of chemicals that have been shown, in several experimental models as well as humans, to cause morphological changes in the developing nervous system. Chemicals that are discussed include methylmercury (MeHg), lead (Pb), antiepileptic drugs, and ethanol. Additionally, the issue of silent neurotoxicity, i.e., persistent morphological and/or biochemical injury that remains clinically unapparent until later in life, is discussed.
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    ERBB RECEPTORS: Directing Key Signaling Networks Throughout Life (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 195-217 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The epidermal growth factor (EGF)-related peptides bind the ErbB receptors, inducing the formation of different homo- and heterodimers. Receptor dimerization promotes activation of the intrinsic kinase, leading to phosphorylation of specific tyrosines located in the ErbB's cytoplasmic region. These phosphorylated residues serve as docking sites for a variety of signaling molecules whose recruitment stimulates intracellular signaling cascades, which ultimately control diverse genetic programs. Particular ligand-receptor complexes have essential roles in embryonic development as well as in the adult. Finally, ErbB receptors are being pursued as therapeutic targets because aberrant ErbB activity has been observed in many human cancers. In this review, we discuss these data in more detail, illustrating the importance of tightly regulated ErbB signaling throughout life.
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    PROTEIN SULFENIC ACIDS IN REDOX SIGNALING (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 325-347 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Reactive (low pKa) cysteine residues in proteins are critical components in redox signaling. A particularly reactive and versatile reversibly oxidized form of cysteine, the sulfenic acid (Cys-SOH), has important roles as a catalytic center in enzymes and as a sensor of oxidative and nitrosative stress in enzymes and transcriptional regulators. Depending on environment, sometimes the sulfenic acid provides a metastable oxidized form, and other times it is a fleeting intermediate giving rise to more stable disulfide, sulfinic acid, or sulfenyl-amide forms.
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    NEUROGENESIS IN THE ADULT BRAIN: New Strategies for Central Nervous System Diseases (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 399-421 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: New cells are continuously generated from immature proliferating cells throughout adulthood in many organs, thereby contributing to the integrity of the tissue under physiological conditions and to repair following injury. In contrast, repair mechanisms in the adult central nervous system (CNS) have long been thought to be very limited. However, recent findings have clearly demonstrated that in restricted areas of the mammalian brain, new functional neurons are constantly generated from neural stem cells throughout life. Moreover, stem cells with the potential to give rise to new neurons reside in many different regions of the adult CNS. These findings raise the possibility that endogenous neural stem cells can be mobilized to replace dying neurons in neurodegenerative diseases. Indeed, recent reports have provided evidence that, in some injury models, limited neuronal replacement occurs in the CNS. Here, we summarize our current understanding of the mechanisms controlling adult neurogenesis and discuss their implications for the development of new strategies for the treatment of neurodegenerative diseases.
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    SEX DIFFERENCES IN PHARMACOKINETICS AND PHARMACODYNAMICS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 499-523 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The importance of reviewing and studying sex-based differences in pharmacologic parameters is demonstrated by the increasing data on gender variation in drug efficacy and toxicity profiles. Sex-based differences in the four major factors that contribute to interindividual pharmacokinetic variability-bioavailability, distribution, metabolism, and elimination-are theorized to stem from variations between men and women in factors such as body weight, plasma volume, gastric emptying time, plasma protein levels, cytochrome P450 activity, drug transporter function, and excretion activity. Sex-determined variations in pharmacodynamics have traditionally been more difficult to study, but a number of recent studies have explored these differences. This review examines the biologic basis of differences in pharmacokinetics and pharmacodynamics between the sexes and summarizes studies that have addressed these differences. As an example, sex-based variation in the efficacy and toxicity of antiretroviral therapy in human immunodeficiency virus (HIV)-infected patients is explored more thoroughly to illustrate some of the factors underlying sex-based differences in drug therapy.
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    CRF AND CRF RECEPTORS: Role in Stress Responsivity and Other Behaviors (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 525-557 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Since corticotropin-releasing factor (CRF) was first characterized, a growing family of ligands and receptors has evolved. The mammalian family members include CRF, urocortinI (UcnI), UcnII, and UcnIII, along with two receptors, CRFR1 and CRFR2, and a CRF binding protein. These family members differ in their tissue distribution and pharmacology. Studies have provided evidence supporting an important role of this family in regulation of the endocrine and behavioral responses to stress. Although CRF appears to play a stimulatory role in stress responsivity through activation of CRFR1, specific actions of UcnII and UcnIII on CRFR2 may be important for dampening stress sensitivity. As the only ligand with high affinity for both receptors, UcnI's role may be promiscuous. Regulation of the relative contribution of the two CRF receptors to brain CRF pathways may be essential in coordinating physiological responses to stress. The development of disorders related to heightened stress sensitivity and dysregulation of stress-coping mechanisms appears to involve regulatory mechanisms of CRF family members.
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    BIOCHEMICAL MECHANISM OF NITROGLYCERIN ACTION AND TOLERANCE: Is This Old Mystery Solved? (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 67-85 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Organic nitrates such as nitroglycerin (NTG) have been used as potent vasodilators in medicine for more than a century, but their biochemical mechanisms of action, particularly in relation to tolerance development, are still incompletely defined. Numerous candidate enzymes for NTG metabolism, as well as a multiplicity of tolerance mechanisms, have been proposed in the literature, but a consolidating hypothesis that links these phenomena together has not appeared. Here, we outline a "thionitrate oxidation hypothesis," which attempts to link nitrate bioactivation and tolerance development in an overall mechanism. We also attempt to compare and contrast the proposed mechanism against existing theories of nitrate action and tolerance. Interactions between organic nitrates, which have been thought of as endothelium-independent agents, and the vascular endothelium and endothelial nitric oxide synthase (eNOS) are also discussed.
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    IDENTIFICATION OF THE MAJOR STEPS IN BOTULINUM TOXIN ACTION (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 167-193 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Botulinum toxin is a uniquely potent substance synthesized by the organisms Clostridium botulinum, Clostridium baratii, and Clostridium butyricum. This toxin, which acts preferentially on peripheral cholinergic nerve endings to block acetylcholine release, is both an agent that causes disease (i.e., botulism) as well as an agent that can be used to treat disease (e.g., dystonia). The ability of botulinum toxin to produce its effects is largely dependent on its ability to penetrate cellular and intracellular membranes. Thus, toxin that is ingested or inhaled can bind to epithelial cells and be transported to the general circulation. Toxin that reaches peripheral nerve endings binds to the cell surface then penetrates the plasma membrane by receptor-mediated endocytosis and the endosome membrane by pH-induced translocation. Internalized toxin acts in the cytosol as a metalloendoprotease to cleave polypeptides that are essential for exocytosis. This review seeks to identify and characterize all major steps in toxin action, from initial absorption to eventual paralysis of cholinergic transmission.
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    DARPP-32: An Integrator of Neurotransmission (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 269-296 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32), was identified initially as a major target for dopamine and protein kinase A (PKA) in striatum. However, recent advances now indicate that regulation of the state of DARPP-32 phosphorylation provides a mechanism for integrating information arriving at dopaminoceptive neurons, in multiple brain regions, via a variety of neurotransmitters, neuromodulators, neuropeptides, and steroid hormones. Activation of PKA or PKG stimulates DARPP-32 phosphorylation at Thr34 and thereby converts DARPP-32 into a potent inhibitor of protein phosphatase-1 (PP-1). DARPP-32 is also phosphorylated at Thr75 by Cdk5 and this converts DARPP-32 into an inhibitor of PKA. Thus, DARPP-32 has the unique property of being a dual-function protein, acting either as an inhibitor of PP-1 or of PKA. The state of phosphorylation of DARPP-32 at Thr34 depends on the phosphorylation state of two serine residues, Ser102 and Ser137, which are phosphorylated by CK2 and CK1, respectively. By virtue of its ability to modulate the activity of PP-1 and PKA, DARPP-32 is critically involved in regulating electrophysiological, transcriptional, and behavioral responses to physiological and pharmacological stimuli, including antidepressants, neuroleptics, and drugs of abuse.
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    VOLTAGE-GATED SODIUM CHANNELS AND HYPERALGESIA (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 371-397 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Physiological and pharmacological evidence both have demonstrated a critical role for voltage-gated sodium channels (VGSCs) in many types of chronic pain syndromes because these channels play a fundamental role in the excitability of neurons in the central and peripheral nervous systems. Alterations in function of these channels appear to be intimately linked to hyperexcitability of neurons. Many types of pain appear to reflect neuronal hyperexcitability, and importantly, use-dependent sodium channel blockers are effective in the treatment of many types of chronic pain. This review focuses on the role of VGSCs in the hyperexcitability of sensory primary afferent neurons and their contribution to the inflammatory or neuropathic pain states. The discrete localization of the tetrodotoxin (TTX)-resistant channels, in particular NaV1.8, in the peripheral nerves may provide a novel opportunity for the development of a drug targeted at these channels to achieve efficacious pain relief with an acceptable safety profile.
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    MIXED-LINEAGE KINASES: A Target for the Prevention of Neurodegeneration (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 44 (2004), S. 451-474 
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    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The activation of the c-Jun N-terminal kinase (JNK) pathway is critical for naturally occurring neuronal cell death during development and may be important for the pathological neuronal cell death of neurodegenerative diseases. The small molecule inhibitor of the mixed-lineage kinase (MLK) family of kinases, CEP-1347, inhibits the activation of the JNK pathway and, consequently, the cell death in many cell culture and animal models of neuronal death. CEP-1347 has the ability not only to inhibit cell death but also to maintain the trophic status of neurons in culture. The possible importance of the JNK pathway in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases provides a rationale for the use of CEP-1347 for the treatment of these diseases. CEP-1347 has the potential of not only retarding disease progression but also reversing the severity of symptoms by improving the function of surviving neurons.
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    THE NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 1-26 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
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    URL: http://dx.doi.org/10.1146/annurev.bioeng.6.062403.131947
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    ENGINEERING SYNTHETIC VECTORS FOR IMPROVED DNA DELIVERY: Insights from Intracellular Pathways (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 397-426 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Significant progress has been made in the area of nonviral gene delivery to date. Yet, synthetic vectors remain less efficient by orders of magnitude than their viral counterparts. Research continues toward unraveling and overcoming various barriers to the efficient delivery of DNA, whether in plasmid form encoding a gene or as an oligonucleotide for the selective inhibition of target gene expression. Novel components for overcoming these hurdles are continually being incorporated into the design of synthetic vectors, leading to increasingly more virus-like particles. Despite these advances, general principles defining the design of synthetic vectors are yet to be developed fully. A more quantitative analysis of the cellular uptake and intracellular processing of these vectors is required for the rational manipulation of vector design. Mathematical frameworks with a more conceptual basis will help obtain an integrated perspective on these complex systems. In this review, we critically examine the progress made toward the improved design of synthetic vectors by the strategic exploitation of intracellular mechanisms and explore newer possibilities to overcome obstacles in the practical realization of this field.
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    TISSUE ENGINEERING APPLICATIONS OF THERAPEUTIC CLONING (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 27-40 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Few treatment options are available for patients suffering from diseased and injured organs because of a severe shortage of donor organs available for transplantation. Therapeutic cloning, where the nucleus from a donor cell is transferred into an enucleated oocyte in order to extract pluripotent embryonic stem cells, offers a potentially limitless source of cells for replacement therapy. Scientists in the field of tissue engineering apply the principles of cell transplantation, material science, and engineering to construct biological substitutes that will restore and maintain normal function in diseased and injured tissues. The present chapter reviews recent advances that have occurred in therapeutic cloning and tissue engineering and describes applications of these new technologies that may offer novel therapies for patients with end-stage organ failure.
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    BREAST TISSUE ENGINEERING (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 109-130 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Tissue engineering has the potential to redefine rehabilitation for the breast cancer patient by providing a translatable strategy that restores the postmastectomy breast mound while concomitantly obviating limitations realized with contemporary reconstructive surgery procedures. The engineering design goal is to provide a sufficient volume of viable fat tissue based on a patient's own cells such that deficits in breast volume can be abrogated. To be sure, adipose tissue engineering is in its infancy, but tremendous strides have been made. Numerous studies attest to the feasibility of adipose tissue engineering. The field is now poised to challenge barriers to clinical translation that are germane to most tissue engineering applications, namely scale-up, large animal model development, and vascularization. The innovative and rapid progress of adipose engineering to date, as well as opportunities for its future growth, is presented.
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    FUNCTIONAL EFFICACY OF TENDON REPAIR PROCESSES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 303-329 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Despite various attempts to repair and replace injured tendon, an understanding of the repair processes and a systematic approach to achieving functional efficacy remain elusive. In this review the epidemiology of tendon injury and repair is first examined. Using a traditional paradigm for repair assessment, the biology and biomechanics of normal tendon, natural healing, and repair are then explored. New treatment strategies such as functional tissue engineering are discussed, including a functional approach to treatment that involves the development of in vivo functional design parameters to judge the acceptability of a repair outcome. The paper concludes with future directions.
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    TISSUE ENGINEERING OF LIGAMENTS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 131-156 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Tissue engineering is emerging as a significant clinical option to address tissue and organ failure by implanting biological substitutes for the compromised tissues. As compared to the transplantation of cells alone, engineered tissues offer the potential advantage of immediate functionality. Engineered tissues can also serve as physiologically relevant models for controlled studies of cells and tissues designed to distinguish the effects of specific signals from the complex milieu of factors present in vivo. A high number of ligament failures and the lack of adequate options to fully restore joint functions have prompted the need to develop new tissue engineering strategies. We discuss the requirements for ligament reconstruction, the available treatment options and their limitations, and then focus on the tissue engineering of ligaments. One representative tissue engineering system involving the integrated use of adult human stem cells, custom-designed scaffolds, and advanced bioreactors with dynamic loading is described.
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    MICRO-COMPUTED TOMOGRAPHY-CURRENT STATUS AND DEVELOPMENTS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 185-208 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: The recent rapid increase in interest in tomographic imaging of small animals and of human (and large animal) organ biopsies is driven largely by drug discovery, cancer detection/monitoring, phenotype identification and/or characterization, and development of disease detection methods and monitoring efficacies of drugs in disease treatment. In biomedical applications, micro-computed tomography (CT) scanners can function as scaled-down (i.e., mini) clinical CT scanners that provide a three-dimensional (3-D) image of most, if not the entire, torso of a mouse at image resolution (50-100 mum) scaled proportional to that of a human CT image. Micro-CT scanners, on the other hand, image specimens the size of intact rodent organs at spatial resolutions from cellular (20 mum) down to subcellular dimensions (e.g., 1 mum) and fill the resolution-hiatus between microscope imaging, which resolves individual cells in thin sections of tissue, and mini-CT imaging of intact volumes.
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    MOLECULAR MACHINES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 363-395 
    Details
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Molecular machines are tiny energy conversion devices on the molecular-size scale. Whether naturally occurring or synthetic, these machines are generally more efficient than their macroscale counterparts. They have their own mechanochemistry, dynamics, workspace, and usability and are composed of nature's building blocks: namely proteins, DNA, and other compounds, built atom by atom. With modern scientific capabilities it has become possible to create synthetic molecular devices and interface them with each other. Countless such machines exist in nature, and it is possible to build artificial ones by mimicking nature. Here we review some of the known molecular machines, their structures, features, and characteristics. We also look at certain devices in their early development stages, as well as their future applications and challenges.
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    ROBOTICS, MOTOR LEARNING, AND NEUROLOGIC RECOVERY (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 497-525 
    Details
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Robotic devices are helping shed light on human motor control in health and injury. By using robots to apply novel force fields to the arm, investigators are gaining insight into how the nervous system models its external dynamic environment. The nervous system builds internal models gradually by experience and uses them in combination with impedance and feedback control strategies. Internal models are robust to environmental and neural noise, generalized across space, implemented in multiple brain regions, and developed in childhood. Robots are also being used to assist in repetitive movement practice following neurologic injury, providing insight into movement recovery. Robots can haptically assess sensorimotor performance, administer training, quantify amount of training, and improve motor recovery. In addition to providing insight into motor control, robotic paradigms may eventually enhance motor learning and rehabilitation beyond the levels possible with conventional training techniques.
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    URL: http://dx.doi.org/10.1146/annurev.bioeng.6.040803.140223
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    ADVANCES IN HIGH-FIELD MAGNETIC RESONANCE IMAGING (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 157-184 
    Details
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Among advances in magnetic resonance imaging (MRI), the increase of the magnetic field strength is perhaps one of the most significant. The use of high magnetic fields for in vivo magnetic resonance is motivated by a number of considerations. Advantages are increases in signal-to-noise ratio, blood-oxygenation level-dependent contrast, and spectral resolution, while disadvantages include potential reduction of contrast in anatomic imaging owing to lengthening of T1 and effects of susceptibility of high fields. To address these challenges, technical advances have been made in various aspects of MRI, allowing high-field MRI to provide exquisite morphological and functional details in clinical and research settings. This review provides an overview of technical issues and applications of high-field MRI.
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    MECHANICAL BIOEFFECTS OF ULTRASOUND (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 229-248 
    Details
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Ultrasound is used widely in medicine as both a diagnostic and therapeutic tool. Through both thermal and nonthermal mechanisms, ultrasound can produce a variety of biological effects in tissues in vitro and in vivo. This chapter provides an overview of the fundamentals of key nonthermal mechanisms for the interaction of ultrasound with biological tissues. Several categories of mechanical bioeffects of ultrasound are then reviewed to provide insight on the range of ultrasound bioeffects in vivo, the relevance of these effects to diagnostic imaging, and the potential application of mechanical bioeffects to the design of new therapeutic applications of ultrasound in medicine.
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    URL: http://dx.doi.org/10.1146/annurev.bioeng.6.040803.140126
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    OCULAR BIOMECHANICS AND BIOTRANSPORT (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 249-273 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: The eye transduces light, and we usually do not think of it as a biomechanical structure. Yet it is actually a pressurized, thick-walled shell that has an internal and external musculature, a remarkably complex internal vascular system, dedicated fluid production and drainage tissues, and a variety of specialized fluid and solute transport systems. Biomechanics is particularly involved in accommodation (focusing near and far), as well as in common disorders such as glaucoma, macular degeneration, myopia, and presbyopia. In this review, we give a (necessarily brief) overview of many of the interesting biomechanical aspects of the eye, concluding with a list of open problems.
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    MECHANICAL PROCESSES IN BIOCHEMISTRY (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 705-748 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Mechanical processes are involved in nearly every facet of the cell cycle. Mechanical forces are generated in the cell during processes as diverse as chromosomal segregation, replication, transcription, translation, translocation of proteins across membranes, cell locomotion, and catalyzed protein and nucleic acid folding and unfolding, among others. Because force is a product of all these reactions, biochemists are beginning to directly apply external forces to these processes to alter the extent or even the fate of these reactions hoping to reveal their underlying molecular mechanisms. This review provides the conceptual framework to understand the role of mechanical force in biochemistry.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.72.121801.161542
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    ANALYZING CELLULAR BIOCHEMISTRY IN TERMS OF MOLECULAR NETWORKS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 1051-1087 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: One way to understand cells and circumscribe the function of proteins is through molecular networks. These networks take a variety of forms including webs of protein-protein interactions, regulatory circuits linking transcription factors and targets, and complex pathways of metabolic reactions. We first survey experimental techniques for mapping networks (e.g., the yeast two-hybrid screens). We then turn our attention to computational approaches for predicting networks from individual protein features, such as correlating gene expression levels or analyzing sequence coevolution. All the experimental techniques and individual predictions suffer from noise and systematic biases. These problems can be overcome to some degree through statistical integration of different experimental datasets and predictive features (e.g., within a Bayesian formalism). Next, we discuss approaches for characterizing the topology of networks, such as finding hubs and analyzing subnetworks in terms of common motifs. Finally, we close with perspectives on how network analysis represents a preliminary step toward a systems approach for modeling cells.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073950
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    CYTOCHROME C-MEDIATED APOPTOSIS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 87-106 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Apoptosis, or programmed cell death, is involved in development, elimination of damaged cells, and maintenance of cell homeostasis. Deregulation of apoptosis may cause diseases, such as cancers, immune diseases, and neurodegenerative disorders. Apoptosis is executed by a subfamily of cysteine proteases known as caspases. In mammalian cells, a major caspase activation pathway is the cytochrome c-initiated pathway. In this pathway, a variety of apoptotic stimuli cause cytochrome c release from mitochondria, which in turn induces a series of biochemical reactions that result in caspase activation and subsequent cell death. In this review, we focus on the recent progress in understanding the biochemical mechanisms and regulation of the pathway, the roles of the pathway in physiology and disease, and their potential therapeutic values.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073706
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    REGULATION OF TELOMERASE BY TELOMERIC PROTEINS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 177-208 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Telomeres are essential for genome stability in all eukaryotes. Changes in telomere functions and the associated chromosomal abnormalities have been implicated in human aging and cancer. Telomeres are composed of repetitive sequences that can be maintained by telomerase, a complex containing a reverse transcriptase (hTERT in humans and Est2 in budding yeast), a template RNA (hTERC in humans and Tlc1 in yeast), and accessory factors (the Est1 proteins and dyskerin in humans and Est1, Est3, and Sm proteins in budding yeast). Telomerase is regulated in cis by proteins that bind to telomeric DNA. This regulation can take place at the telomere terminus, involving single-stranded DNA-binding proteins (POT1 in humans and Cdc13 in budding yeast), which have been proposed to contribute to the recruitment of telomerase and may also regulate the extent or frequency of elongation. In addition, proteins that bind along the length of the telomere (TRF1/TIN2/tankyrase in humans and Rap1/Rif1/Rif2 in budding yeast) are part of a negative feedback loop that regulates telomere length. Here we discuss the details of telomerase and its regulation by the telomere.
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    DNA POLYMERASE gamma, THE MITOCHONDRIAL REPLICASE 1 (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 293-320 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: DNA polymerase (pol) gamma is the sole DNA polymerase in animal mitochondria. Biochemical and genetic evidence document a key role for pol gamma in mitochondrial DNA replication, and whereas DNA repair and recombination were thought to be limited or absent in animal mitochondria, both have been demonstrated in recent years. Thus, the mitochondrial replicase is also apparently responsible for the relevant DNA synthetic reactions in these processes. Pol gamma comprises a catalytic core in a heterodimeric complex with an accessory subunit. The two-subunit holoenzyme is an efficient and processive polymerase, which exhibits high fidelity in nucleotide selection and incorporation while proofreading errors with its intrinsic 3' 5' exonuclease. Incorporation of nucleotide analogs followed by proofreading failure leads to mitochondrial toxicity in antiviral therapy, and misincorporation during DNA replication leads to mitochondrial mutagenesis and dysfunction. This review describes our current understanding of pol gamma biochemistry and biology, and it introduces other key proteins that function at the mitochondrial DNA replication fork.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.72.121801.161455
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    THE SIR2 FAMILY OF PROTEIN DEACETYLASES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 417-435 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The yeast SIR protein complex has been implicated in transcription silencing and suppression of recombination. The Sir complex represses transcription at telomeres, mating-type loci, and ribosomal DNA. Unlike SIR3 and SIR4, the SIR2 gene is highly conserved in organisms ranging from archaea to humans. Interestingly, Sir2 is active as an NAD+-dependent deacetylase, which is broadly conserved from bacteria to higher eukaryotes. In this review, we discuss the role of NAD+, the unusual products of the deacetylation reaction, the Sir2 structure, and the Sir2 chemical inhibitors and activators that were recently identified. We summarize the current knowledge of the Sir2 homologs from different organisms, and finally we discuss the role of Sir2 in caloric restriction and aging.
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    STRUCTURAL BASIS OF ION PUMPING BY CA2+-ATPASE OF THE SARCOPLASMIC RETICULUM (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 269-292 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The structures of the Ca2+-ATPase (SERCA1a) have been determined for five different states by X-ray crystallography. Detailed comparison of the structures in the Ca2+ bound form and unbound (but thapsigargin bound) form reveals that very large rearrangements of the transmembrane helices take place accompanying Ca2+ dissociation and binding and that they are mechanically linked with equally large movements of the cytoplasmic domains. The meanings of the rearrangements of the transmembrane helices and those of the cytoplasmic domains as well as the mechanistic roles of phosphorylation are now becoming clear. Furthermore, the roles of critical amino acid residues identified by extensive mutagenesis studies are becoming evident in terms of atomic structure.
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    STRUCTURAL INSIGHTS INTO THE SIGNAL RECOGNITION PARTICLE (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 539-557 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The signal recognition particle (SRP) directs integral membrane and secretory proteins to the cellular protein translocation machinery during translation. The SRP is an evolutionarily conserved RNA-protein complex whose activities are regulated by GTP hydrolysis. Recent structural investigations of SRP functional domains and interactions provide new insights into the mechanisms of SRP activity in all cells, leading toward a comprehensive understanding of protein trafficking by this elegant pathway.
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    INOSITOL 1,4,5-TRISPHOSPHATE RECEPTORS AS SIGNAL INTEGRATORS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 437-465 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The inositol 1,4,5 trisphosphate (IP3) receptor (IP3R) is a Ca2+ release channel that responds to the second messenger IP3. Exquisite modulation of intracellular Ca2+ release via IP3Rs is achieved by the ability of IP3R to integrate signals from numerous small molecules and proteins including nucleotides, kinases, and phosphatases, as well as nonenzyme proteins. Because the ion conduction pore composes only ~5% of the IP3R, the great bulk of this large protein contains recognition sites for these substances. Through these regulatory mechanisms, IP3R modulates diverse cellular functions, which include, but are not limited to, contraction/excitation, secretion, gene expression, and cellular growth. We review the unique properties of the IP3R that facilitate cell-type and stimulus-dependent control of function, with special emphasis on protein-binding partners.
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    FLAP ENDONUCLEASE 1: A Central Component of DNA Metabolism (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 589-615 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: One strand of cellular DNA is generated as RNA-initiated discontinuous segments called Okazaki fragments that later are joined. The RNA terminated region is displaced into a 5' single-stranded flap, which is removed by the structure-specific flap endonuclease 1 (FEN1), leaving a nick for ligation. Similarly, in long-patch base excision repair, a damaged nucleotide is displaced into a flap and removed by FEN1. FEN1 is a genome stabilization factor that prevents flaps from equilibrating into structures that lead to duplications and deletions. As an endonuclease, FEN1 enters the flap from the 5' end and then tracks to cleave the flap base. Cleavage is oriented by the formation of a double flap. Analyses of FEN1 crystal structures suggest mechanisms for tracking and cleavage. Some flaps can form self-annealed and template bubble structures that interfere with FEN1. FEN1 interacts with other nucleases and helicases that allow it to act efficiently on structured flaps. Genetic and biochemical analyses continue to reveal many roles of FEN1.
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    ROLE OF GLYCOSYLATION IN DEVELOPMENT (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 491-537 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Researchers have long predicted that complex carbohydrates on cell surfaces would play important roles in developmental processes because of the observation that specific carbohydrate structures appear in specific spatial and temporal patterns throughout development. The astounding number and complexity of carbohydrate structures on cell surfaces added support to the concept that glycoconjugates would function in cellular communication during development. Although the structural complexity inherent in glycoconjugates has slowed advances in our understanding of their functions, the complete sequencing of the genomes of organisms classically used in developmental studies (e.g., mice, Drosophila melanogaster, and Caenorhabditis elegans) has led to demonstration of essential functions for a number of glycoconjugates in developmental processes. Here we present a review of recent studies analyzing function of a variety of glycoconjugates (O-fucose, O-mannose, N-glycans, mucin-type O-glycans, proteoglycans, glycosphingolipids), focusing on lessons learned from human disease and genetic studies in mice, D. melanogaster, and C. elegans.
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    PROTEIN MODIFICATION BY SUMO (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 355-382 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Small ubiquitin-related modifier (SUMO) family proteins function by becoming covalently attached to other proteins as post-translational modifications. SUMO modifies many proteins that participate in diverse cellular processes, including transcriptional regulation, nuclear transport, maintenance of genome integrity, and signal transduction. Reversible attachment of SUMO is controlled by an enzyme pathway that is analogous to the ubiquitin pathway. The functional consequences of SUMO attachment vary greatly from substrate to substrate, and in many cases are not understood at the molecular level. Frequently SUMO alters interactions of substrates with other proteins or with DNA, but SUMO can also act by blocking ubiquitin attachment sites. An unusual feature of SUMO modification is that, for most substrates, only a small fraction of the substrate is sumoylated at any given time. This review discusses our current understanding of how SUMO conjugation is controlled, as well as the roles of SUMO in a number of biological processes.
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    ROLES OF N-LINKED GLYCANS IN THE ENDOPLASMIC RETICULUM (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 1019-1049 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: From a process involved in cell wall synthesis in archaea and some bacteria, N-linked glycosylation has evolved into the most common covalent protein modification in eukaryotic cells. The sugars are added to nascent proteins as a core oligosaccharide unit, which is then extensively modified by removal and addition of sugar residues in the endoplasmic reticulum (ER) and the Golgi complex. It has become evident that the modifications that take place in the ER reflect a spectrum of functions related to glycoprotein folding, quality control, sorting, degradation, and secretion. The glycans not only promote folding directly by stabilizing polypeptide structures but also indirectly by serving as recognition "tags" that allow glycoproteins to interact with a variety of lectins, glycosidases, and glycosyltranferases. Some of these (such as glucosidases I and II, calnexin, and calreticulin) have a central role in folding and retention, while others (such as alpha-mannosidases and EDEM) target unsalvageable glycoproteins for ER-associated degradation. Each residue in the core oligosaccharide and each step in the modification program have significance for the fate of newly synthesized glycoproteins.
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    INOSITOL 1,4,5-TRISPHOSPHATE RECEPTORS AS SIGNAL INTEGRATORS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 437-465 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The inositol 1,4,5 trisphosphate (IP3) receptor (IP3R) is a Ca2+ release channel that responds to the second messenger IP3. Exquisite modulation of intracellular Ca2+ release via IP3Rs is achieved by the ability of IP3R to integrate signals from numerous small molecules and proteins including nucleotides, kinases, and phosphatases, as well as nonenzyme proteins. Because the ion conduction pore composes only ~5% of the IP3R, the great bulk of this large protein contains recognition sites for these substances. Through these regulatory mechanisms, IP3R modulates diverse cellular functions, which include, but are not limited to, contraction/excitation, secretion, gene expression, and cellular growth. We review the unique properties of the IP3R that facilitate cell-type and stimulus-dependent control of function, with special emphasis on protein-binding partners.
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    THE SIR2 FAMILY OF PROTEIN DEACETYLASES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 417-435 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The yeast SIR protein complex has been implicated in transcription silencing and suppression of recombination. The Sir complex represses transcription at telomeres, mating-type loci, and ribosomal DNA. Unlike SIR3 and SIR4, the SIR2 gene is highly conserved in organisms ranging from archaea to humans. Interestingly, Sir2 is active as an NAD+-dependent deacetylase, which is broadly conserved from bacteria to higher eukaryotes. In this review, we discuss the role of NAD+, the unusual products of the deacetylation reaction, the Sir2 structure, and the Sir2 chemical inhibitors and activators that were recently identified. We summarize the current knowledge of the Sir2 homologs from different organisms, and finally we discuss the role of Sir2 in caloric restriction and aging.
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    RETURN OF THE GDI: The GoLoco Motif in Cell Division (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 925-951 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The GoLoco motif is a 19-amino-acid sequence with guanine nucleotide dissociation inhibitor activity against G-alpha subunits of the adenylyl-cyclase-inhibitory subclass. The GoLoco motif is present as an independent element within multidomain signaling regulators, such as Loco, RGS12, RGS14, and Rap1GAP, as well as in tandem arrays in proteins, such as AGS3, G18, LGN, Pcp-2/L7, and Partner of Inscuteable (Pins/Rapsynoid). Here we discuss the biochemical mechanisms of GoLoco motif action on G-alpha subunits in light of the recent crystal structure of G-alpha-i1 bound to the RGS14 GoLoco motif. Currently, there is sparse evidence for GoLoco motif regulation of canonical G-protein-coupled receptor signaling. Rather, studies of asymmetric cell division in Drosophila and Caenorhabditis elegans, as well as mammalian mitosis, implicate GoLoco proteins, such as Pins, GPR-1/GPR-2, LGN, and RGS14, in mitotic spindle organization and force generation. We discuss potential mechanisms by which GoLoco/Galpha complexes might modulate spindle dynamics.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073756
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    THE EXCITEMENT OF DISCOVERY (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 1-37 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: I had the good luck to start research at the dawn of molecular biology when it was possible to ask fundamental questions about the nature of the nucleic acids and how information is transferred in living systems. The search for answers led me into many different areas, often with the question of how molecular structure leads to biological function. Early work in this period provided some of the roots supporting the current explosive developments in life sciences. Here I give a brief account of my development, describe some contributions, and provide a hint of the exhilaration in discovering new things. Most of all, I had the good fortune to have inspiring teachers, stimulating colleagues, and excellent students.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073945
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    NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY OF HIGH-MOLECULAR-WEIGHT PROTEINS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 107-146 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Recent developments in NMR spectroscopy, which include new experiments that increase the lifetimes of NMR signals or that precisely define the orientation of internuclear bond vectors with respect to a common molecular frame, have significantly increased the size of proteins for which quantitative structural and dynamic information can be obtained. These experiments have, in turn, benefited from new labeling strategies that continue to drive the field. The utility of the new methodology is illustrated by considering applications to malate synthase G, a 723 residue enzyme, which is the largest single polypeptide chain for which chemical shift assignments have been obtained to date. New experiments developed specifically to address the complexity and low sensitivity of spectra recorded on this protein are presented. A discussion of the chemical information that is readily available from studies of systems in the 100 kDa mol wt range is included. Prospects for membrane protein structure determination are discussed briefly in the context of an application to an Escherichia coli enzyme, PagP, localized to the outer membrane of gram-negative bacteria.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.074004
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    ATP-BINDING CASSETTE TRANSPORTERS IN BACTERIA (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 241-268 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: ATP-binding cassette (ABC) transporters couple ATP hydrolysis to the uptake and efflux of solutes across the cell membrane in bacteria and eukaryotic cells. In bacteria, these transporters are important virulence factors because they play roles in nutrient uptake and in secretion of toxins and antimicrobial agents. In humans, many diseases, such as cystic fibrosis, hyperinsulinemia, and macular dystrophy, are traced to defects in ABC transporters. Recent advances in structural determination and functional analysis of bacterial ABC transporters, reviewed herein, have greatly increased our understanding of the molecular mechanism of transport in this transport superfamily.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073626
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    PROTEIN MODIFICATION BY SUMO (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 355-382 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Small ubiquitin-related modifier (SUMO) family proteins function by becoming covalently attached to other proteins as post-translational modifications. SUMO modifies many proteins that participate in diverse cellular processes, including transcriptional regulation, nuclear transport, maintenance of genome integrity, and signal transduction. Reversible attachment of SUMO is controlled by an enzyme pathway that is analogous to the ubiquitin pathway. The functional consequences of SUMO attachment vary greatly from substrate to substrate, and in many cases are not understood at the molecular level. Frequently SUMO alters interactions of substrates with other proteins or with DNA, but SUMO can also act by blocking ubiquitin attachment sites. An unusual feature of SUMO modification is that, for most substrates, only a small fraction of the substrate is sumoylated at any given time. This review discusses our current understanding of how SUMO conjugation is controlled, as well as the roles of SUMO in a number of biological processes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.074118
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    STRUCTURE AND FUNCTION OF TOLC: The Bacterial Exit Duct for Proteins and Drugs (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 467-489 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The bacterial TolC protein plays a common role in the expulsion of diverse molecules, which include protein toxins and antibacterial drugs, from the cell. TolC is a trimeric 12-stranded alpha/beta barrel, comprising an alpha-helical trans-periplasmic tunnel embedded in the outer membrane by a contiguous beta-barrel channel. This structure establishes a 140 A long single pore fundamentally different to other membrane proteins and presents an exit duct to substrates, large and small, engaged at specific inner membrane translocases. TolC is open to the outside medium but is closed at its periplasmic entrance. When TolC is recruited by a substrate-laden translocase, the entrance is opened to allow substrate passage through a contiguous machinery spanning the entire cell envelope, from the cytosol to the external environment. Transition to the transient open state is achieved by an iris-like mechanism in which entrance alpha-helices undergo an untwisting realignment, thought to be stabilized by interaction with periplasmic helices of the translocase. TolC family proteins are ubiquitous among gram-negative bacteria, and the conserved entrance aperture presents a possible cheomotherapeutic target in multidrug-resistant pathogens.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.074104
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    FLAP ENDONUCLEASE 1: A Central Component of DNA Metabolism (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 589-615 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: One strand of cellular DNA is generated as RNA-initiated discontinuous segments called Okazaki fragments that later are joined. The RNA terminated region is displaced into a 5' single-stranded flap, which is removed by the structure-specific flap endonuclease 1 (FEN1), leaving a nick for ligation. Similarly, in long-patch base excision repair, a damaged nucleotide is displaced into a flap and removed by FEN1. FEN1 is a genome stabilization factor that prevents flaps from equilibrating into structures that lead to duplications and deletions. As an endonuclease, FEN1 enters the flap from the 5' end and then tracks to cleave the flap base. Cleavage is oriented by the formation of a double flap. Analyses of FEN1 crystal structures suggest mechanisms for tracking and cleavage. Some flaps can form self-annealed and template bubble structures that interfere with FEN1. FEN1 interacts with other nucleases and helicases that allow it to act efficiently on structured flaps. Genetic and biochemical analyses continue to reveal many roles of FEN1.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.012803.092453
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    INTERMEDIATE FILAMENTS: Molecular Structure, Assembly Mechanism, and Integration Into Functionally Distinct Intracellular Scaffolds (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 749-789 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The superfamily of intermediate filament (IF) proteins contains at least 65 distinct proteins in man, which all assemble into ~10 nm wide filaments and are principal structural elements both in the nucleus and the cytoplasm with essential scaffolding functions in metazoan cells. At present, we have only circumstantial evidence of how the highly divergent primary sequences of IF proteins lead to the formation of seemingly similar polymers and how this correlates with their function in individual cells and tissues. Point mutations in IF proteins, particularly in lamins, have been demonstrated to lead to severe, inheritable multi-systemic diseases, thus underlining their importance at several functional levels. Recent structural work has now begun to shed some light onto the complex fine tuning of structure and function in these fibrous, coiled coil forming multidomain proteins and their contribution to cellular physiology and gene regulation.
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    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073823
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    RETURN OF THE GDI: The GoLoco Motif in Cell Division (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 925-951 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The GoLoco motif is a 19-amino-acid sequence with guanine nucleotide dissociation inhibitor activity against G-alpha subunits of the adenylyl-cyclase-inhibitory subclass. The GoLoco motif is present as an independent element within multidomain signaling regulators, such as Loco, RGS12, RGS14, and Rap1GAP, as well as in tandem arrays in proteins, such as AGS3, G18, LGN, Pcp-2/L7, and Partner of Inscuteable (Pins/Rapsynoid). Here we discuss the biochemical mechanisms of GoLoco motif action on G-alpha subunits in light of the recent crystal structure of G-alpha-i1 bound to the RGS14 GoLoco motif. Currently, there is sparse evidence for GoLoco motif regulation of canonical G-protein-coupled receptor signaling. Rather, studies of asymmetric cell division in Drosophila and Caenorhabditis elegans, as well as mammalian mitosis, implicate GoLoco proteins, such as Pins, GPR-1/GPR-2, LGN, and RGS14, in mitotic spindle organization and force generation. We discuss potential mechanisms by which GoLoco/Galpha complexes might modulate spindle dynamics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073756
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    OPIOID RECEPTORS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 953-990 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: Opioid receptors belong to the large superfamily of seven transmembrane-spanning (7TM) G protein-coupled receptors (GPCRs). As a class, GPCRs are of fundamental physiological importance mediating the actions of the majority of known neurotransmitters and hormones. Opioid receptors are particularly intriguing members of this receptor family. They are activated both by endogenously produced opioid peptides and by exogenously administered opiate compounds, some of which are not only among the most effective analgesics known but also highly addictive drugs of abuse. A fundamental question in addiction biology is why exogenous opioid drugs, such as morphine and heroin, have a high liability for inducing tolerance, dependence, and addiction. This review focuses on many aspects of opioid receptors with the aim of gaining a greater insight into mechanisms of opioid tolerance and dependence.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073940
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    ANALYZING CELLULAR BIOCHEMISTRY IN TERMS OF MOLECULAR NETWORKS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 1051-1087 
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    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: One way to understand cells and circumscribe the function of proteins is through molecular networks. These networks take a variety of forms including webs of protein-protein interactions, regulatory circuits linking transcription factors and targets, and complex pathways of metabolic reactions. We first survey experimental techniques for mapping networks (e.g., the yeast two-hybrid screens). We then turn our attention to computational approaches for predicting networks from individual protein features, such as correlating gene expression levels or analyzing sequence coevolution. All the experimental techniques and individual predictions suffer from noise and systematic biases. These problems can be overcome to some degree through statistical integration of different experimental datasets and predictive features (e.g., within a Bayesian formalism). Next, we discuss approaches for characterizing the topology of networks, such as finding hubs and analyzing subnetworks in terms of common motifs. Finally, we close with perspectives on how network analysis represents a preliminary step toward a systems approach for modeling cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073950
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    TISSUE GROWTH AND REMODELING (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 77-107 
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    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: The growth and remodeling of a tissue depends on certain features in the history of its mechanical environment as well as its genetic makeup. The mechanical environment influences the tissue's developing morphology, the process of simply increasing the size of existing morphological structures, and the formation of the proteins of which the tissue is constructed. The relationships between genetic information, various epigenetic mechanisms and tissue development are discussed. The developmental growth and remodeling of most structural tissues are enhanced by the use of those tissues and retarded by their disuse. The mechanical or mathematical modeling of tissue growth and development using cellular automata models and continuum mechanical models is reviewed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bioeng.6.040803.140250
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    MECHANOTRANSDUCTION AT CELL-MATRIX AND CELL-CELL CONTACTS (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biomedical Engineering 6 (2004), S. 275-302 
    Details
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: Mechanical forces play an important role in the organization, growth, maturation, and function of living tissues. At the cellular level, many of the biological responses to external forces originate at two types of specialized microscale structures: focal adhesions that link cells to their surrounding extracellular matrix and adherens junctions that link adjacent cells. Transmission of forces from outside the cell through cell-matrix and cell-cell contacts appears to control the maturation or disassembly of these adhesions and initiates intracellular signaling cascades that ultimately alter many cellular behaviors. In response to externally applied forces, cells actively rearrange the organization and contractile activity of the cytoskeleton and redistribute their intracellular forces. Recent studies suggest that the localized concentration of these cytoskeletal tensions at adhesions is also a major mediator of mechanical signaling. This review summarizes the role of mechanical forces in the formation, stabilization, and dissociation of focal adhesions and adherens junctions and outlines how integration of signals from these adhesions over the entire cell body affects how a cell responds to its mechanical environment. This review also describes advanced optical, lithographic, and computational techniques for the study of mechanotransduction.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.bioeng.6.040803.140040
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    USING PROTEIN FOLDING RATES TO TEST PROTEIN FOLDING THEORIES (2004)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Biochemistry 73 (2004), S. 837-859 
    Details
    ISSN: 0066-4154
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Chemistry and Pharmacology , Biology
    Notes: The fastest simple, kinetically two-state protein folds a million times more rapidly than the slowest. Here we review many recent theories of protein folding kinetics in terms of their ability to qualitatively rationalize, if not quantitatively predict, this fundamental experimental observation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.biochem.73.011303.073904
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