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  • Annual Reviews  (23,896)
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  • 101
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 437-454 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Stent-assisted carotid angioplasty (CAS) is increasingly utilized for hemodynamically significant stenoses of the extracranial carotid artery. Carotid endarterectomy (CEA) is still considered the gold standard in the management of symptomatic hemodynamically significant carotid stenoses. However, endovascular device technology is rapidly evolving and the recent introduction of embolic filtration devices (EFD) proved to reduce periprocedural stroke rates in CAS considerably. Several randomized multicenter trials are currently recruiting patients to compare CAS with EFD to carotid endarterectomy in different cohorts, such as patients at high surgical risk for CEA and those with asymptomatic stenosis. The review presents current developments in CAS.
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  • 102
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 223-241 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Amyloidosis is a clinical disorder caused by extracellular deposition of insoluble abnormal fibrils, derived from aggregation of misfolded, normally soluble, protein. About 23 different unrelated proteins are known to form amyloid fibrils in vivo, which share a pathognomonic structure although they are associated with clinically distinct conditions. Systemic amyloidosis, with amyloid deposits in the viscera, blood vessel walls, and connective tissue, is usually fatal and is the cause of about one per thousand deaths in developed countries. This rarity and the variable involvement of different organs and tissues are often responsible for missed or delayed diagnosis, and amyloidosis remains a considerable clinical challenge. However, recent elucidation of important aspects of pathogenesis, as well as developments in diagnosis, monitoring, and treatment, have greatly improved outcomes, especially when patients are managed in specialist centers.
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  • 103
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 33-47 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: VELCADE?℗ (bortezomib, Millennium Pharmaceuticals, Inc., Cambridge, MA, and Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ) is a first-in-class proteasome inhibitor developed specifically for use as an antineoplastic agent. Inhibition of the proteasome results in disruption of homeostatic mechanisms within the cell that can lead to cell death. Bortezomib's first indication, for the treatment of relapsed myeloma in patients who have received at least two prior treatments and progressed on their previous treatment, was based in part on the magnitude of activity demonstrated in phase II trials. Bortezomib is currently indicated for patients who have received at least one prior therapy in the United States and European Union, although patients in the European Union must have already undergone bone marrow transplantation or be unsuitable for the procedure. A phase III trial demonstrated the superiority of bortezomib over high-dose dexamethasone in response rate, time to progression, and survival in patients with myeloma who had relapsed after 1Đ??3 prior therapies. Clinical development is ongoing to investigate its activity as monotherapy and in combination regimens for the treatment of non-Hodgkin's lymphoma, solid tumors, and earlier presentations of myeloma.
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  • 104
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 195-206 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: We review the diagnosis, categorization, and treatment of prostatitis/chronic pelvic pain syndrome based on the National Institutes of Health (NIH) classification. Prostatitis is an extremely common syndrome that afflicts 2%Đ??10% of men. Formerly a purely clinical diagnosis, prostatitis is now classified within a complex series of syndromes (NIH category IĐ??IV prostatitis) that vary widely in clinical presentation and response to treatment. Acute bacterial prostatitis (category I) and chronic bacterial prostatitis (category II) are characterized by uropathogenic infections of the prostate gland that respond well to antimicrobial treatment. In contrast, chronic prostatitis/chronic pelvic pain syndrome (category III), which accounts for 90%Đ??95% of prostatitis cases, is of unknown etiology and is marked by a mixture of pain, urinary, and ejaculatory symptoms with no uniformly effective therapy. Asymptomatic inflammatory prostatitis (category IV) is an incidental finding of unknown clinical significance. This review describes the current status of prostatitis syndromes and explores the future prospects of new diagnostic tools and therapies.
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  • 105
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 455-471 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: More than three decades of clinical experience in cardiac transplantation resulted in the spread of the procedure worldwide with a wealth of knowledge and advancements. Developments included liberalization of recipient and donor selection criteria, improved surgical techniques, novel immunosuppressive drugs and protocols, new rejection surveillance techniques, and better understanding of the pathophysiology of cardiac allograft vasculopathy to direct interventions for prevention and treatment.
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  • 106
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Medicine 57 (2006), S. 99-118 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Researchers have made great progress in defining genetic and molecular alterations that contribute to cancer. New therapeutic targets have been identified and targeted therapeutic agents have been developed, but our ability to evaluate potential drugs has not kept pace. Molecular imaging technologies that monitor biological processes and/or measure levels of targeted macromolecules can contribute significantly to preclinical and clinical drug evaluation. This article describes the drug discovery process, economic problems facing drug discovery and development, and successes and failures in this realm. We briefly describe the available molecular imaging tools, with emphasis on positron emission tomography. We discuss biological processes that are altered in tumors and can be measured by molecular imaging; examples include gene expression, signal transduction, tumor cell metabolism, proliferation, apoptosis, hypoxia, and angiogenesis. We conclude with a proposal to integrate molecular imaging into the drug development process.
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  • 107
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 431-459 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The FXYD proteins are a family of seven homologous single transmembrane segment proteins (FXYD1Đ??7), expressed in a tissue-specific fashion. The FXYD proteins modulate the function of Na,K-ATPase, thus adapting kinetic properties of active Na+ and K+ transport to the specific needs of different cells. Six FXYD proteins ( 1Đ??5, 7 ) are known to interact with Na,K-ATPase and affect its kinetic properties in specific ways. Although effects of FXYD proteins on parameters such as K1/2Na+, K1/2K+, KmATP, and Vmax are modest, usually twofold, these effects may have important long-term consequences for homeostasis of cation balance. In this review we summarize basic features of FXYD proteins and present recent evidence for functional effects, structure-function relations and structural interactions with Na,K-ATPase. We then discuss possible physiological roles, based on in vitro observations and newly available knockout mice models. Finally, we also consider evidence that FXYD proteins affect functioning of other ion transport systems.
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  • 108
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 67-95 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Because of the anatomy, function, and nonregenerative nature of the myocardium, inflammation in this tissue is not well tolerated. Nevertheless, various diseases of the heart are characterized by inflammatory responses involving the effector mechanisms of innate and adaptive (lymphocyte-dependent) immunity. The innate immune response to ischemia-reperfusion injury is, by far, the most common cause of myocardial inflammation. Innate responses may have beneficial influences that preserve myocardial function in the short term but may be maladaptive in chronic states. Adaptive responses in the myocardium occur with infection or loss of tolerance, and lead to myocarditis. Given the narrow margin for benefit of cardiac inflammation, special regulatory mechanisms likely raise the threshold, compared to other tissues, for the induction and persistence of adaptive immune responses. These mechanisms include strong central and peripheral T cell tolerance to heart antigens and induction of anti-inflammatory feedback mechanisms involving cytokines such as interferon-??.
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  • 109
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 649-684 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Transient receptor potential (TRP) channels mediate responses in a large variety of signaling mechanisms. Most studies on mammalian TRP channels rely on heterologous expression, but their relevance to in vivo tissues is not entirely clear. In contrast, Drosophila TRP and TRP-like (TRPL) channels allow direct analyses of in vivo function. In Drosophila photoreceptors, activation of TRP and TRPL is mediated via the phosphoinositide cascade, with both Ca2+ and diacylglycerol (DAG) essential for generating the light response. In tissue culture cells, TRPL channels are constitutively active, and lipid second messengers greatly facilitate this activity. Inhibition of phospholipase C (PLC) completely blocks lipid activation of TRPL, suggesting that lipid activation is mediated via PLC. In vivo studies in mutant Drosophila also reveal an acute requirement for lipid-producing enzyme, which may regulate PLC activity. Thus, PLC and its downstream second messengers, Ca2+ and DAG, constitute critical mediators of TRP/TRPL gating in vivo.
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  • 110
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Psychology 57 (2006), S. 557-583 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: Family violence occurs in many forms; the most prominent are domestic violence, child abuse, and elder abuse. Family violence affects many persons at some point in their life and constitutes the majority of violent acts in our society. Although there has been considerable study of the patterns, risk factors, and interventions for each form of family violence, great controversy still exists within each area. There is growing recognition of an overlap in the patterns, causes, and effective interventions across types of family violence. There is also an increasing awareness of the value of greater integration of theory and research across areas into a family violence approach through an ecological perspective. This review focuses on current knowledge related to these problems and suggests integrative steps to advance knowledge.
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  • 111
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Psychology 57 (2006), S. 585-611 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: Affirmative action is a controversial and often poorly understood policy. It is also a policy that has been widely studied by social scientists. In this review, we outline how affirmative action operates in employment and education settings and consider the major points of controversy. In addition, we detail the contributions of psychologists and other social scientists in helping to demonstrate why affirmative action is needed; how it can have unintended negative consequences; and how affirmative action programs can be most successful. We also review how psychologists have examined variations in people's attitudes toward affirmative action, in part as a means for testing different theories of social behavior.
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  • 112
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 1-39 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Peroxisome proliferator-activated receptors (PPARs) alpha (ʼ̛), beta/delta (?‚/??), and gamma (??) are members of the nuclear receptor superfamily, which also includes the estrogen, androgen, and glucocorticoid receptors. Recent evidence suggests that PPARs regulate genes involved in lipid metabolism, glucose homeostasis, and inflammation in various tissues; however, the mechanisms involved are not completely understood. Anti-diabetic drugs, called glitazones, can selectively activate PPAR??, and hypolipidemic drugs, called fibrates, can weakly activate PPARʼ̛. Both classes of drugs can decrease insulin resistance and dyslipidemias, which also makes them attractive for treating the metabolic syndrome. The metabolic syndrome exhibits a constellation of risk factors for atherosclerosis that include obesity, insulin resistance, dyslipidemias, and hypertension. Interestingly, all three PPARs are present in macrophages and can therefore have a profound effect on several disease processes, including atherosclerosis. Macrophages are key players in atherosclerotic lesion development. Currently, the first line of defense in reducing the risk of atherosclerosis is aimed at lowering low-density lipoproteins (LDL) and raising high-density lipoproteins (HDL), but a large percentage of patients on statins still succumb to coronary artery disease. However, with the development of drugs selectively activating PPARs, a new arsenal of drugs specifically targeting to the macrophage/foam cell may potentially have a profound impact on how we treat cardiovascular disease.
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  • 113
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 481-519 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The multitude of chemically highly different agonists for 7TM receptors apparently do not share a common binding mode or active site but nevertheless act through induction of a common molecular activation mechanism. A global toggle switch model is proposed for this activation mechanism to reconcile the accumulated biophysical data supporting an outward rigid-body movement of the intracellular segments, as well as the recent data derived from activating metal ion sites and tethered ligands, which suggests an opposite, inward movement of the extracellular segments of the transmembrane helices. According to this model, a vertical see-saw movement of TM-VIĐ??and to some degree TM-VIIĐ??around a pivot corresponding to the highly conserved prolines will occur during receptor activation, which may involve the outer segment of TM-V in an as yet unclear fashion. Small-molecule agonists can stabilize such a proposed active conformation, where the extracellular segments of TM-VI and -VII are bent inward toward TM-III, by acting as molecular glue deep in the main ligand-binding pocket between the helices, whereas larger agonists, peptides, and proteins can stabilize a similar active conformation by acting as Velcro at the extracellular ends of the helices and the connecting loops.
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  • 114
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    Annual Review of Pharmacology 46 (2006), S. 301-315 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The roles of proteases in cancer are now known to be much broader than simply degradation of extracellular matrix during tumor invasion and metastasis. Furthermore, proteases from tumor-associated cells (e.g., fibroblasts, inflammatory cells, endothelial cells) as well as tumor cells are recognized to contribute to pathways critical to neoplastic progression. Although elevated expression (transcripts and proteins) of proteases, and in some cases protease inhibitors, has been documented in many tumors, techniques to assess functional roles for proteases require that we measure protease activity and inhibition of that activity rather than levels of proteases, activators, and inhibitors. Novel techniques for functional imaging of protease activity, both in vitro and in vivo, are being developed as are imaging probes that will allow us to determine protease activity and in some cases to discriminate among protease activities. These should be useful clinically as surrogate endpoints for therapies that alter protease activities.
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  • 115
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 215-234 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: New methods to measure thiol oxidation show that redox compartmentation functions as a mechanism for specificity in redox signaling and oxidative stress. Redox Western analysis and redox-sensitive green fluorescent proteins provide means to quantify thiol/disulfide redox changes in specific subcellular compartments. Analyses using these techniques show that the relative redox states from most reducing to most oxidizing are mitochondria 〉 nuclei 〉 cytoplasm 〉 endoplasmic reticulum 〉 extracellular space. Mitochondrial thiols are an important target of oxidant-induced apoptosis and necrosis and are especially vulnerable to oxidation because of the relatively alkaline pH. Maintenance of a relatively reduced nuclear redox state is critical for transcription factor binding in transcriptional activation in response to oxidative stress. The new methods are applicable to a broad range of experimental systems and their use will provide improved understanding of the pharmacologic and toxicologic actions of drugs and toxicants.
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  • 116
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    Annual Review of Pharmacology 46 (2006), S. 317-353 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Over the past four decades, treatment of acute leukemia in children has made remarkable progress, from this disease being lethal to now achieving cure rates of 80% for acute lymphoblastic leukemia and 45% for acute myeloid leukemia. This progress is largely owed to the optimization of existing treatment modalities rather than the discovery of new agents. However, the annual number of patients with leukemia who experience relapse after initial therapy remains greater than that of new cases of most childhood cancers. The aim of pharmacogenetics is to develop strategies to personalize medications and tailor treatment regimens to individual patients, with the goal of enhancing efficacy and safety through better understanding of the person's genetic makeup. In this review, we summarize recent pharmacogenomic studies related to the treatment of pediatric acute leukemia. These include work using candidate-gene approaches, as well as genome-wide studies using haplotype mapping and gene expression profiling. These strategies illustrate the promise of pharmacogenomics to further advance the treatment of human cancers, with childhood leukemia serving as a paradigm.
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  • 117
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 381-410 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The protein variously named ABCG2/BCRP/MXR/ABCP is a recently described ATP-binding cassette (ABC) transporter originally identified by its ability to confer drug resistance that is independent of Mrp1 (multidrug-resistance protein 1) and Pgp (P-glycoprotein). Unlike Mrp1 and Pgp, ABCG2 is a half-transporter that must homodimerize to acquire transport activity. ABCG2 is found in a variety of stem cells and may protect them from exogenous and endogenous toxins. ABCG2 expression is upregulated under low-oxygen conditions, consistent with its high expression in tissues exposed to low-oxygen environments. ABCG2 interacts with heme and other porphyrins and protects cells and/or tissues from protoporphyrin accumulation under hypoxic conditions. Individuals who carry ABCG2 alleles that have impaired function may be more susceptible to porphyrin-induced toxicity. Abcg2 knock-out models have allowed in vivo studies of Abcg2 function in host and cellular defense. In combination with immunohistochemical analyses, these studies have revealed how ABCG2 influences the absorption, distribution, and excretion of drugs and cytotoxins.
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  • 118
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    Annual Review of Fluid Mechanics 38 (2006), S. 193-224 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: What mechanisms of flow control do animals use to enhance hydrodynamic performance? Animals are capable of manipulating flow around the body and appendages both passively and actively. Passive mechanisms rely on structural and morphological components of the body (i.e., humpback whale tubercles, riblets). Active flow control mechanisms use appendage or body musculature to directly generate wake flow structures or stiffen fins against external hydrodynamic loads. Fish can actively control fin curvature, displacement, and area. The vortex wake shed by the tail differs between eel-like fishes and fishes with a discrete narrowing of the body in front of the tail, and three-dimensional effects may play a major role in determining wake structure in most fishes.
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  • 119
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Fluid Mechanics 38 (2006), S. 111-128 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: Wind tunnels have wide-ranging functionality, including many applications beyond aeronautics, and historically have been the major source of information for technological aerodynamics/aeronautical applications. There are a myriad of scaling issues/differences from flight to wind tunnel, and their study and impacts are uneven and a function of the particular type of extant flow phenomena. Typically, the most serious discrepancies are associated with flow separation. The tremendous ongoing increases in numerical simulation capability are changing and in many aspects have changed the function of the wind tunnel from a (scaled) "predictor" to a source of computational calibration/validation information with the computation then utilized as the flight prediction/scaling tool. Numerical simulations can increasingly include the influences of the various scaling issues. This wind tunnel role change has been occurring for decades as computational capability improves in all aspects. Additional issues driving this trend are the increasing cost (and time) disparity between physical experiments and computations, and increasingly stringent accuracy requirements.
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  • 120
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    Annual Review of Fluid Mechanics 38 (2006), S. 427-452 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: When the free surfaces of most solids approach their bulk melting temperatures from below, the molecular structure of the material gives way to a disordered structure with some attributes of both the solid and liquid phases. When the temperature is sufficiently close to that of bulk transition, the surface melts and literally flows as a viscous fluid. This phenomenon, called interfacial premelting, lies at the heart of the microscopic theory of melting of solid matter, and captures the interest of condensed matter physicists and physical chemists alike. The process is ubiquitous and responsible for a wide range of consequences in materials with biological, geophysical, and technological significance. Because such systems are often exposed to spatial or temporal variations in thermodynamic forcing, there are a host of fluid mechanical phenomena that result from this underlying melting behavior. The fluid dynamics of unfrozen surfaces holds clues for understanding the bulk behavior of polycrystalline materials, from Earth's mantle to the stratosphere and beyond. In this review we focus on the fluid dynamical consequences of the premelting of solids.
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  • 121
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    Annual Review of Fluid Mechanics 38 (2006), S. 483-512 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: This article provides a critical review of computational techniques for flow-noise prediction and the underlying theories. Hybrid approaches, in which the turbulent noise source field is computed and/or modeled separately from the far-field calculation, are afforded particular attention. Numerical methods and modern flow simulation techniques are discussed in terms of their suitability and accuracy for flow-noise calculations. Other topics highlighted include some important formulation and computational issues in the application of aeroacoustic theories, generalized acoustic analogies with better accounts of flow-sound interaction, and recent computational investigations of noise-control strategies. The review ends with an analysis of major challenges and key areas for improvement in order to advance the state of the art of computational aeroacoustics.
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  • 122
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    Annual Review of Fluid Mechanics 38 (2006), S. 277-307 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: We review mathematical models of confined bubbles, emphasizing physical mechanisms as expressed in simple geometries. Molecular interactions between liquid, gas, and the confining solid are all important and are described through the disjoining pressure concept. Methods for finding static shapes are considered. The static solution is a springboard for discussing pressure-driven and surface-tension-driven flows, both of which involve viscous effects and macroscopic films entrained near apparent contact lines. We next discuss vapor bubbles produced by thermal effects. Vaporization localized near contact lines and condensation distributed in colder parts of the interface lead to steady vapor bubbles. Their size is determined through global constraints. Unsteady vapor bubbles are discussed and we end with thoughts on open problems.
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  • 123
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    Annual Review of Fluid Mechanics 38 (2006), S. 309-338 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: Electrophoretic separation of a mixture of chemical species is a fundamental technique of great usefulness in biology, health care, and forensics. In capillary electrophoresis (which has evolved from its predecessor, slab-gel electrophoresis), the sample migrates through a single microcapillary instead of through the network of pores in a gel. A fundamental design problem is to minimize dispersion in the separation direction. Molecular diffusion is inevitable and sets a theoretical limit on the best separation that can be achieved. But in practice, there are a number of effects arising out of the interplay between fluid flow, chemistry, thermal effects, and electric fields that result in enhanced dispersion. This paper reviews the subject of fluid flow in such capillary microchannels and examines the various causes of enhanced dispersion that limit the efficiency of separation.
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  • 124
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Fluid Mechanics 38 (2006), S. 453-482 
    ISSN: 0066-4189
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: Large-eddy simulation (LES) of turbulent combustion is a relatively new research field. Much research has been carried out over the past years, but to realize the full predictive potential of combustion LES, many fundamental questions still have to be addressed, and common practices of LES of nonreacting flows revisited. The focus of the present review is to highlight the fundamental differences between Reynolds-averaged Navier-Stokes (RANS) and LES combustion models for nonpremixed and premixed turbulent combustion, to identify some of the open questions and modeling issues for LES, and to provide future perspectives.
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  • 125
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    Annual Review of Physiology 68 (2006), S. 123-158 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The insulin resistance syndrome refers to a constellation of findings, including glucose intolerance, obesity, dyslipidemia, and hypertension, that promote the development of type 2 diabetes, cardiovascular disease, cancer, and other disorders. Defining the pathophysiological links between insulin resistance, the insulin resistance syndrome, and its sequelae is critical to understanding and treating these disorders. Over the past decade, two approaches have provided important insights into how changes in insulin signaling produce the spectrum of phenotypes associated with insulin resistance. First, studies using tissue-specific knockouts or tissue-specific reconstitution of the insulin receptor in vivo in mice have enabled us to deconstruct the insulin resistance syndromes by dissecting the contributions of different tissues to the insulin-resistant state. Second, in vivo and in vitro studies of the complex network of insulin signaling have provided insight into how insulin resistance can develop in some pathways whereas insulin sensitivity is maintained in others. These data, taken together, give us a framework for understanding the relationship between insulin resistance and the insulin resistance syndromes.
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  • 126
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    Annual Review of Physiology 68 (2006), S. 223-251 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The ability of animals to survive food deprivation is clearly of considerable survival value. Unsurprisingly, therefore, all animals exhibit adaptive biochemical and physiological responses to the lack of food. Many animals inhabit environments in which food availability fluctuates or encounters with appropriate food items are rare and unpredictable; these species offer interesting opportunities to study physiological adaptations to fasting and starvation. When deprived of food, animals employ various behavioral, physiological, and structural responses to reduce metabolism, which prolongs the period in which energy reserves can cover metabolism. Such behavioral responses can include a reduction in spontaneous activity and a lowering in body temperature, although in later stages of food deprivation in which starvation commences, activity may increase as food-searching is activated. In most animals, the gastrointestinal tract undergoes marked atrophy when digestive processes are curtailed; this structural response and others seem particularly pronounced in species that normally feed at intermittent intervals. Such animals, however, must be able to restore digestive functions soon after feeding, and these transitions appear to occur at low metabolic costs.
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  • 127
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 685-717 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Ion channels are pore-forming transmembrane proteins that allow ions to permeate biological membranes. Pore structure plays a crucial role in determining the ion permeation and selectivity properties of particular channels. In the past few decades, efforts have been undertaken to identify key elements of the pore regions of different classes of ion channels. In this review, we summarize current knowledge about permeation and selectivity of channel proteins from the transient receptor potential (TRP) superfamily. Whereas all TRP channels are permeable for cations, only two TRP channels are impermeable for Ca2+ (TRPM4, TRPM5), and two others are highly Ca2+ permeable (TRPV5, TRPV6). Despite the great advances in the TRP channel field during the past decade, only a limited number of reports have dealt with functional characterization of pore properties, biophysical aspects of cation permeation, or description of pore structures of TRP channels. This review gives an overview of available experimental and theoretical data and discusses the functional impact of pore-structure modifications on TRP channel properties.
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 719-736 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The TRP (transient receptor potential) superfamily of cation channels is present in all eukaryotes, from yeast to mammals. Many TRP channels have been studied in the nematode Caenorhabditis elegans, revealing novel biological functions, regulatory modes, and mechanisms of localization. C. elegans TRPV channels function in olfaction, mechanosensation, osmosensation, and activity-dependent gene regulation. Their activity is regulated by G protein signaling and polyunsaturated fatty acids. C. elegans TRPPs related to human polycystic kidney disease genes are expressed in male-specific neurons. The KLP-6 kinesin directs TRPP channels to cilia, where they may interact with F0/F1 ATPases. A sperm-specific TRPC channel, TRP-3, is required for fertilization. Upon sperm activation, TRP-3 translocates from an intracellular compartment to the plasma membrane to allow store-operated Ca2+ entry. The TRPM channels GON-2 and GTL-2 regulate Mg2+ homeostasis and Mg2+ uptake by intestinal cells; GON-2 is also required for gonad development. The TRPML CUP-5 promotes normal lysosome biogenesis and prevents apoptosis. Dynamic, precise expression of TRP proteins generates a remarkable range of cellular functions.
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    Annual Review of Physiology 68 (2006), S. 29-49 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Many forms of pediatric and adult heart disease result from a deficiency in cardiomyocyte number. Through repopulation of the heart with new cardiomyocytes (that is, induction of regenerative cardiac growth), cardiac disease potentially can be reversed, provided that the newly formed myocytes structurally and functionally integrate in the preexisting myocardium. A number of approaches have been utilized to effect regenerative growth of the myocardium in experimental animals. These include interventions aimed at enhancing the ability of cardiomyocytes to proliferate in response to cardiac injury, as well as transplantation of cardiomyocytes or myogenic stem cells into diseased hearts. Here we review efforts to induce myocardial regeneration. We also provide a critical review of techniques currently used to assess cardiac regeneration and functional integration of de novo cardiomyocytes.
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    Annual Review of Physiology 68 (2006), S. 253-278 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Oxidative stressĐ??the production and accumulation of reduced oxygen intermediates such as superoxide radicals, singlet oxygen, hydrogen peroxide, and hydroxyl radicalsĐ??can damage lipids, proteins, and DNA. Many disease processes of clinical interest and the aging process involve oxidative stress in their underlying etiology. The production of reactive oxygen species is also prevalent in the world's oceans, and oxidative stress is an important component of the stress response in marine organisms exposed to a variety of insults as a result of changes in environmental conditions such as thermal stress, exposure to ultraviolet radiation, or exposure to pollution. As in the clinical setting, reactive oxygen species are also important signal transduction molecules and mediators of damage in cellular processes, such as apoptosis and cell necrosis, for marine organisms. This review brings together the voluminous literature on the biochemistry and physiology of oxidative stress from the clinical and plant physiology disciplines with the fast-increasing interest in oxidative stress in marine environments.
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    Annual Review of Physiology 68 (2006), S. 491-505 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The sodium-hydrogen exchanger regulatory factors (NHERF-1 and NHERF-2) are a family of adaptor proteins characterized by the presence of two tandem PDZ protein interaction domains and a C-terminal domain that binds the cytoskeleton proteins ezrin, radixin, moesin, and merlin. The NHERF proteins are highly expressed in the kidney, small intestine, and other organs, where they associate with a number of transporters and ion channels, signaling proteins, and transcription factors. Recent evidence has revealed important associations between the NHERF proteins and several G proteinĐ??coupled receptors such as the ?‚2-adrenergic receptor, the ?”-opioid receptor, and the parathyroid hormone receptor, as well as growth factor tyrosine kinase receptors such as the platelet-derived growth factor receptor and the epidermal growth factor receptor. This review summarizes the emerging data on the biochemical mechanisms, physiologic outcomes, and potential clinical implications of the assembly and disassembly of receptor/NHERF complexes.
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    Annual Review of Physiology 68 (2006), S. 307-343 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: In the gastrointestinal tract, phasic contractions are caused by electrical activity termed slow waves. Slow waves are generated and actively propagated by interstitial cells of Cajal (ICC). The initiation of pacemaker activity in the ICC is caused by release of Ca2+ from inositol 1,4,5-trisphosphate (IP3) receptorĐ??operated stores, uptake of Ca2+ into mitochondria, and the development of unitary currents. Summation of unitary currents causes depolarization and activation of a dihydropyridine-resistant Ca2+ conductance that entrains pacemaker activity in a network of ICC, resulting in the active propagation of slow waves. Slow wave frequency is regulated by a variety of physiological agonists and conditions, and shifts in pacemaker dominance can occur in response to both neural and nonneural inputs. Loss of ICC in many human motility disorders suggests exciting new hypotheses for the etiology of these disorders.
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    Annual Review of Physiology 68 (2006), S. 345-374 
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    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Phosphorylation of Ser19 on the 20-kDa regulatory light chain of myosin II (MLC20) by Ca2+/calmodulin-dependent myosin light-chain kinase (MLCK) is essential for initiation of smooth muscle contraction. The initial [Ca2+]i transient is rapidly dissipated and MLCK inactivated, whereas MLC20 and muscle contraction are well maintained. Sustained contraction does not reflect Ca2+ sensitization because complete inhibition of MLC phosphatase activity in the absence of Ca2+ induces smooth muscle contraction. This contraction is suppressed by staurosporine, implying participation of a Ca2+-independent MLCK. Thus, sustained contraction, as with agonist-induced contraction at experimentally fixed Ca2+ concentrations, involves (a) G protein activation, (b) regulated inhibition of MLC phosphatase, and (c) MLC20 phosphorylation via a Ca2+-independent MLCK. The pathways that lead to inhibition of MLC phosphatase by Gq/13-coupled receptors are initiated by sequential activation of Gʼ̛q/ʼ̛13, RhoGEF, and RhoA, and involve Rho kinaseĐ??mediated phosphorylation of the regulatory subunit of MLC phosphatase (MYPT1) and/or PKC-mediated phosphorylation of CPI-17, an endogenous inhibitor of MLC phosphatase. Sustained MLC20 phosphorylation is probably induced by the Ca2+-independent MLCK, ZIP kinase. The pathways initiated by Gi-coupled receptors involve sequential activation of G?‚??i, PI 3-kinase, and the Ca2+-independent MLCK, integrin-linked kinase. The last phosphorylates MLC20 directly and inhibits MLC phosphatase by phosphorylating CPI-17. PKA and PKG, which mediate relaxation, act upstream to desensitize the receptors (VPAC2 and NPR-C), inhibit adenylyl and guanylyl cyclase activities, and stimulate cAMP-specific PDE3 and PDE4 and cGMP-specific PDE5 activities. These kinases also act downstream to inhibit (a) initial contraction by inhibiting Ca2+ mobilization and (b) sustained contraction by inhibiting RhoA and targets downstream of RhoA. This increases MLC phosphatase activity and induces MLC20 dephosphorylation and muscle relaxation.
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    Annual Review of Physiology 68 (2006), S. 51-66 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Communication between endothelial cells and cardiomyocytes regulates not only early cardiac development but also adult cardiomyocyte function, including the contractile state. In the normal mammalian myocardium, each cardiomyocyte is surrounded by an intricate network of capillaries and is next to endothelial cells. Cardiomyocytes depend on endothelial cells not only for oxygenated blood supply but also for local protective signals that promote cardiomyocyte organization and survival. While endothelial cells direct cardiomyocytes, cardiomyocytes reciprocally secrete factors that impact endothelial cell function. Understanding how endothelial cells communicate with cardiomyocytes will be critical for cardiac regeneration, in which the ultimate goal is not simply to improve systolic function transiently but to establish new myocardium that is both structurally and functionally normal in the long term.
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    Annual Review of Physiology 68 (2006), S. 619-647 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: The aim of this review is to provide a basic framework for understanding the function of mammalian transient receptor potential (TRP) channels, particularly as they have been elucidated in heterologous expression systems. Mammalian TRP channel proteins form six-transmembrane (6-TM) cation-permeable channels that may be grouped into six subfamilies on the basis of amino acid sequence homology (TRPC, TRPV, TRPM, TRPA, TRPP, and TRPML). Selected functional properties of TRP channels from each subfamily are summarized in this review. Although a single defining characteristic of TRP channel function has not yet emerged, TRP channels may be generally described as calcium-permeable cation channels with polymodal activation properties. By integrating multiple concomitant stimuli and coupling their activity to downstream cellular signal amplification via calcium permeation and membrane depolarization, TRP channels appear well adapted to function in cellular sensation. Our review of recent literature implicating TRP channels in neuronal growth cone steering suggests that TRPs may function more widely in cellular guidance and chemotaxis. The TRP channel gene family and its nomenclature, the encoded proteins and alternatively spliced variants, and the rapidly expanding pharmacology of TRP channels are summarized in online supplemental material.
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    Annual Review of Psychology 57 (2006), S. 87-115 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: The functions of rewards are based primarily on their effects on behavior and are less directly governed by the physics and chemistry of input events as in sensory systems. Therefore, the investigation of neural mechanisms underlying reward functions requires behavioral theories that can conceptualize the different effects of rewards on behavior. The scientific investigation of behavioral processes by animal learning theory and economic utility theory has produced a theoretical framework that can help to elucidate the neural correlates for reward functions in learning, goal-directed approach behavior, and decision making under uncertainty. Individual neurons can be studied in the reward systems of the brain, including dopamine neurons, orbitofrontal cortex, and striatum. The neural activity can be related to basic theoretical terms of reward and uncertainty, such as contiguity, contingency, prediction error, magnitude, probability, expected value, and variance.
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    Annual Review of Psychology 57 (2006), S. 199-226 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: What makes a face attractive and why do we have the preferences we do? Emergence of preferences early in development and cross-cultural agreement on attractiveness challenge a long-held view that our preferences reflect arbitrary standards of beauty set by cultures. Averageness, symmetry, and sexual dimorphism are good candidates for biologically based standards of beauty. A critical review and meta-analyses indicate that all three are attractive in both male and female faces and across cultures. Theorists have proposed that face preferences may be adaptations for mate choice because attractive traits signal important aspects of mate quality, such as health. Others have argued that they may simply be by-products of the way brains process information. Although often presented as alternatives, I argue that both kinds of selection pressures may have shaped our perceptions of facial beauty.
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    Annual Review of Psychology 57 (2006), S. 285-315 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: Recent studies suggest that cognitive and behavioral interventions have enduring effects that reduce risk for subsequent symptom return following treatment termination. These enduring effects have been most clearly demonstrated with respect to depression and the anxiety disorders. It remains unclear whether these effects are a consequence of the amelioration of the causal processes that generate risk or the introduction of compensatory strategies that offset them and whether these effects reflect the mobilization of cognitive or other mechanisms. No such enduring effects have been observed for the psychoactive medications, which appear to be largely palliative in nature. Other psychosocial interventions remain largely untested, although claims that they produce lasting change have long been made. Whether such enduring effects extend to other disorders remains to be seen, but the capacity to reduce risk following treatment termination is one of the major benefits provided by the cognitive and behavioral interventions with respect to the treatment of depression and the anxiety disorders.
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    Annual Review of Psychology 57 (2006), S. 505-528 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: This article argues that ideal longitudinal research is characterized by the seamless integration of three elements: (a) a well-articulated theoretical model of change observed using (b) a temporal design that affords a clear and detailed view of the process, with the resulting data analyzed by means of (c) a statistical model that is an operationalization of the theoretical model. Two general varieties of theoretical models are considered: models in which the time-related change of primary interest is continuous, and those in which it is characterized by movement between discrete states. In addition, two general types of temporal designs are considered: the longitudinal panel design and the intensive longitudinal design. For each general category of theoretical models, some of the analytic possibilities available for longitudinal panel designs and for intensive longitudinal designs are discussed. The article concludes with brief discussions of two issues particularly relevant to longitudinal researchĐ??missing data and measurementĐ??and a few words about exploratory research.
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    Annual Review of Psychology 57 (2006), S. 27-53 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: Traditional approaches to the study of cognition emphasize an information-processing view that has generally excluded emotion. In contrast, the recent emergence of cognitive neuroscience as an inspiration for understanding human cognition has highlighted its interaction with emotion. This review explores insights into the relations between emotion and cognition that have resulted from studies of the human amygdala. Five topics are explored: emotional learning, emotion and memory, emotion's influence on attention and perception, processing emotion in social stimuli, and changing emotional responses. Investigations into the neural systems underlying human behavior demonstrate that the mechanisms of emotion and cognition are intertwined from early perception to reasoning. These findings suggest that the classic division between the study of emotion and cognition may be unrealistic and that an understanding of human cognition requires the consideration of emotion.
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    Annual Review of Psychology 57 (2006), S. 139-166 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: Although the functions of sleep remain largely unknown, one of the most exciting hypotheses is that sleep contributes importantly to processes of memory and brain plasticity. Over the past decade, a large body of work, spanning most of the neurosciences, has provided a substantive body of evidence supporting this role of sleep in what is becoming known as sleep-dependent memory processing. We review these findings, focusing specifically on the role of sleep in (a) memory encoding, (b) memory consolidation, (c) brain plasticity, and (d) memory reconsolidation; we finish with a summary of the field and its potential future directions.
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    Annual Review of Psychology 57 (2006), S. 487-503 
    ISSN: 0066-4308
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Psychology
    Notes: Over the past 25 years, achievement goal theory has emerged as one of the most prominent theories of achievement motivation. This chapter uses an achievement goal framework to examine the influence of classroom and school environments on students' academic motivation and achievement. Considerable evidence suggests that elementary and secondary students show the most positive motivation and learning patterns when their school settings emphasize mastery, understanding, and improving skills and knowledge. Whereas school environments that are focused on demonstrating high ability and competing for grades can increase the academic performance of some students, research suggests that many young people experience diminished motivation under these conditions. The implications of achievement goal theory for examining the impact of school reform are discussed.
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    Annual Review of Medicine 57 (2006), S. 297-311 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Selective loss of body fat is the hallmark of patients with lipodystrophies. Among genetic lipodystrophies, fat loss is observed either from birth, as in congenital generalized lipodystrophy, or later in life, as in familial partial lipodystrophy. The extent of fat loss also varies among subtypes of lipodystrophies. Patients develop hyperinsulinemia, acanthosis nigricans, hypertriglyceridemia, diabetes mellitus, and hepatic steatosis. Defects in several genes, such as those encoding an enzyme (AGPAT2), a nuclear receptor (PPAR??), a nuclear lamina protein (LMNA) and its processing endoprotease (ZMPSTE24), a kinase (AKT2), and a protein of unknown function (BSCL2), have been found in patients with genetic lipodystrophies. Additional loci remain to be discovered. We discuss features of autosomal recessive and dominant types of lipodystrophies and therapeutic interventions available for these patients.
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    Annual Review of Medicine 57 (2006), S. 553-574 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Although used for more than 4000 years for recreational and medicinal purposes, Cannabis and its best-known pharmacologically active constituents, the cannabinoids, became a protagonist in medical research only recently. This revival of interest is explained by the finding in the 1990s of the mechanism of action of the main psychotropic cannabinoid, ??9-tetrahydrocannabinol (THC), which acts through specific membrane receptors, the cannabinoid receptors. The molecular characterization of these receptors allowed the development of synthetic molecules with cannabinoid and noncannabinoid structure and with higher selectivity, metabolic stability, and efficacy than THC, as well as the development of antagonists that have already found pharmaceutical application. The finding of endogenous agonists at these receptors, the endocannabinoids, opened new therapeutic possibilities through the modulation of the activity of cannabinoid receptors by targeting the biochemical mechanisms controlling endocannabinoid tissue levels.
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    Annual Review of Medicine 57 (2006), S. 155-166 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Hepatitis B is a global health problem. Patients with chronic hepatitis B (CHB) carry a significant risk to eventually develop cirrhotic liver disease. Recent therapeutic advances against CHB offer excellent potential for long-term suppression of hepatitis B virus (HBV) replication during antiviral therapy, and occasionally a durable remission off medication. Selection of appropriate patients for antiviral therapy depends on identification of HBV replication and an elevated alanine aminotransferase level or histologic liver injury. Pegylated interferon alpha offers potent immunomodulatory and antiviral activity with the potential for durability, but also with adverse effects and significant cost. The nucleoside or nucleotide analogs, lamivudine, adefovir, and entecavir, suppress HBV replication and are extremely well-tolerated, but long-term or even lifelong therapy is required. Most experience has been gained with lamivudine, but viral resistance occurs frequently. Newer analogs appear to be relatively free of this problem. Approaches using a combination of agents have promise, but have yet to be proven superior to individual drugs alone.
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    Annual Review of Medicine 57 (2006), S. 83-97 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: The use of molecular approaches has become part of the standard of care in the management of pediatric cancer patients. Molecular approaches are now included in the initial diagnosis, definition of prognostically distinct patient subgroups, selection of patients for specific therapies, prediction of risk for toxicities to therapy, and monitoring of patients receiving both conventional and novel targeted therapies. This clinical application of molecular medicine has been based on a growing molecular understanding of cancer biology. Studies of pediatric cancers have contributed to this understanding in many ways. We present a model for understanding cancer biology, using specific examples taken from pediatric oncology, and then discuss the application of molecular techniques to the clinical management of pediatric cancer patients.
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    Annual Review of Medicine 57 (2006), S. 181-194 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: West Nile virus (WNV) was first detected in North America in 1999 during an outbreak of encephalitis in New York City. Since then the virus has spread across North America and into Canada, Latin America, and the Caribbean. The largest epidemics of neuroinvasive WNV disease ever reported occurred in the United States in 2002 and 2003. This paper reviews new information on the epidemiology and clinical aspects of WNV disease derived from greatly expanded surveillance and research on WNV during the past six years.
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    Annual Review of Medicine 57 (2006), S. 243-264 
    ISSN: 0066-4219
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Obesity is a major epidemic in developed countries. It induces or exacerbates hypertension, diabetes mellitus, obstructive sleep apnea, dyslipidemia, and many other disease processes, which cumulatively contribute to premature mortality on a scale rivaling that of smoking. At present, bariatric surgery is the only therapeutic modality that can produce sustained weight loss and halt or resolve comorbidities. This success results from the ability to perform the operation reliably, usually laparoscopically, with low mortality. The most commonly performed operation is Roux-en-Y gastric bypass. Other bypasses discussed in this review include biliopancreatic diversion with and without duodenal switch. Purely restrictive operations, especially adjustable gastric banding, have a lower risk but are somewhat less effective. We focus on the more controversial aspects of commonly accepted operations, including patient selection, the spectrum and frequency of complications, and the long-term outcome.
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    Annual Review of Physiology 68 (2006), S. 563-583 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Airways are embedded in the mechanically dynamic environment of the lung. In utero, this mechanical environment is defined largely by fluid secretion into the developing airway lumen. Clinical, whole lung, and cellular studies demonstrate pivotal roles for mechanical distention in airway morphogenesis and cellular behavior during lung development. In the adult lung, the mechanical environment is defined by a dynamic balance of surface, tissue, and muscle forces. Diseases of the airways modulate both the mechanical stresses to which the airways are exposed as well as the structure and mechanical behavior of the airways. For instance, in asthma, activation of airway smooth muscle abruptly changes the airway size and stress state within the airway wall; asthma also results in profound remodeling of the airway wall. Data now demonstrate that airway epithelial cells, smooth muscle cells, and fibroblasts respond to their mechanical environment. A prominent role has been identified for the epithelium in transducing mechanical stresses, and in both the fetal and mature airways, epithelial cells interact with mesenchymal cells to coordinate remodeling of tissue architecture in response to the mechanical environment.
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    Annual Review of Physiology 68 (2006), S. 585-618 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Patients with severe acute respiratory distress syndrome who die usually succumb to multiorgan failure as opposed to hypoxia. Despite appropriate resuscitation, some patients' symptoms persist on a downward spiral, apparently propagated by an uncontained systemic inflammatory response. This phenomenon is not well understood. However, a novel hypothesis to explain this observation proposes that it is related to the life-saving ventilatory support used to treat the respiratory failure. According to this hypothesis, mechanical ventilation per se, by alterating both the magnitude and the pattern of lung stretch, can cause changes in gene expression and/or cellular metabolism that ultimately can lead to the development of an overwhelming inflammatory responseĐ??even in the absence of overt structural damage. This mechanism of injury has been termed biotrauma. In this review we explore the biotrauma hypothesis, the causal relationship between biophysical injury and organ failure, and its implications for the future therapy and management of critically ill patients.
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    Annual Review of Physiology 68 (2006), S. 1-28 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: This commentary presents a series of examples of "impossible experimental problems" that we have encountered over the years in addressing various challenging questions in physiology. We aim to show how stimulating the challenges of physiology can be and demonstrate how our naive invocation of methods from disparate fields of science and engineering has led to delightful resolutions of physiological challenges that were utterly new to this intrepid interdisciplinary researcher.
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    Annual Review of Physiology 68 (2006), S. 97-121 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Although there have been important advances in diagnostic modalities and therapeutic strategies for congenital heart defects (CHD), these malformations still lead to significant morbidity and mortality in the human population. Over the past 10 years, characterization of the genetic causes of CHD has begun to elucidate some of the molecular causes of these defects. Linkage analysis and candidate-gene approaches have been used to identify gene mutations that are associated with both familial and sporadic cases of CHD. Complementation of the human studies with developmental studies in mouse models provides information for the roles of these genes in normal development as well as indications for disease pathogenesis. Biochemical analysis of these gene mutations has provided further insight into the molecular effects of these genetic mutations. Here we review genetic, developmental, and biochemical studies of six cardiac transcription factors that have been identified as genetic causes for CHD in humans.
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    Annual Review of Physiology 68 (2006), S. 159-191 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Liver X receptors (LXRs) and farnesoid X receptor (FXR) are nuclear receptors that function as intracellular sensors for sterols and bile acids, respectively. In response to their ligands, these receptors induce transcriptional responses that maintain a balanced, finely tuned regulation of cholesterol and bile acid metabolism. LXRs also permit the efficient storage of carbohydrate- and fat-derived energy, whereas FXR activation results in an overall decrease in triglyceride levels and modulation of glucose metabolism. The elegant, dual interplay between these two receptor systems suggests that they coevolved to constitute a highly sensitive and efficient system for the maintenance of total body fat and cholesterol homeostasis. Emerging evidence suggests that the tissue-specific action of these receptors is also crucial for the proper function of the cardiovascular, immune, reproductive, endocrine pancreas, renal, and central nervous systems. Together, LXRs and FXR represent potential therapeutic targets for the treatment and prevention of numerous metabolic and lipid-related diseases.
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    Annual Review of Physiology 68 (2006), S. 507-541 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Gas exchange, the primary function of the lung, can come about only with the application of physical forces on the macroscale and their transmission to the scale of small airway, small blood vessel, and alveolus, where they serve to distend and stabilize structures that would otherwise collapse. The pathway for force transmission then continues down to the level of cell, nucleus, and molecule; moreover, to lesser or greater degrees most cell types that are resident in the lung have the ability to generate contractile forces. At these smallest scales, physical forces serve to distend the cytoskeleton, drive cytoskeletal remodeling, expose cryptic binding domains, and ultimately modulate reaction rates and gene expression. Importantly, evidence has now accumulated suggesting that multiscale phenomena span these scales and govern integrative lung behavior.
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  • 155
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    Annual Review of Physiology 68 (2006), S. 279-305 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Brainstem parasympathetic circuits that modulate digestive functions of the stomach are comprised of afferent vagal fibers, neurons of the nucleus tractus solitarius (NTS), and the efferent fibers originating in the dorsal motor nucleus of the vagus (DMV). A large body of evidence has shown that neuronal communications between the NTS and the DMV are plastic and are regulated by the presence of a variety of neurotransmitters and circulating hormones as well as the presence, or absence, of afferent input to the NTS. These data suggest that descending central nervous system inputs as well as hormonal and afferent feedback resulting from the digestive process can powerfully regulate vago-vagal reflex sensitivity. This paper first reviews the essential "static" organization and function of vago-vagal gastric control neurocircuitry. We then present data on the opioidergic modulation of NTS connections with the DMV as an example of the "gating" of these reflexes, i.e., how neurotransmitters, hormones, and vagal afferent traffic can make an otherwise static autonomic reflex highly plastic.
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  • 156
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 68 (2006), S. 193-221 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Superfast muscles of vertebrates power sound production. The fastest, the swimbladder muscle of toadfish, generates mechanical power at frequencies in excess of 200 Hz. To operate at these frequencies, the speed of relaxation has had to increase approximately 50-fold. This increase is accomplished by modifications of three kinetic traits: (a) a fast calcium transient due to extremely high concentration of sarcoplasmic reticulum (SR)-Ca2+ pumps and parvalbumin, (b) fast off-rate of Ca2+ from troponin C due to an alteration in troponin, and (c) fast cross-bridge detachment rate constant (g, 50 times faster than that in rabbit fast-twitch muscle) due to an alteration in myosin. Although these three modifications permit swimbladder muscle to generate mechanical work at high frequencies (where locomotor muscles cannot), it comes with a cost: The high g causes a large reduction in attached force-generating cross-bridges, making the swimbladder incapable of powering low-frequency locomotory movements. Hence the locomotory and sound-producing muscles have mutually exclusive designs.
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  • 157
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    Annual Review of Physiology 68 (2006), S. 403-429 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Tight junctions form continuous intercellular contacts controlling solute movement through the paracellular pathway across epithelia. Paracellular barriers vary among epithelia in electrical resistance and behave as if they are lined with pores that have charge and size selectivity. Recent evidence shows that claudins, a large family (at least 24 members) of intercellular adhesion molecules, form the seal and its variable pore-like properties. This evidence comes from the study of claudins expressed in cultured epithelial cell models, genetically altered mice, and human mutants. We review information on the structure, function, and transcriptional and posttranslational regulation of the claudin family as well as of their evolutionarily distant relatives called the PMP22/EMP/MP20/claudin, or pfam00822, superfamily.
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  • 158
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    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 46 (2006), S. 277-300 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The main role of blood platelets is to ensure primary hemostasis, which is the maintenance of vessel integrity and cessation of bleeding upon injury. While playing a major part in acute arterial thrombosis, platelets are also involved in inflammation, atherosclerosis, and angiogenesis. ADP and ATP play a crucial role in platelet activation, and their receptors are potential targets for antithrombotic drugs. The ATP-gated cation channel P2X1 and the two G proteinĐ??coupled ADP receptors, P2Y1 and P2Y12, selectively contribute to platelet aggregation and formation of a thrombus. Owing to its central role in the growth and stabilization of a thrombus, the P2Y12 receptor is an established target of antithrombotic drugs such as clopidogrel. Studies in P2Y1 and P2X1 knockout mice and selective P2Y1 and P2X1 antagonists have shown that these receptors are also attractive targets for new antithrombotic compounds. The potential role of platelet P2 receptors in the involvement of platelets in inflammatory processes is also discussed.
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  • 159
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    Annual Review of Pharmacology 46 (2006), S. 235-276 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Nitric oxide (NO) is a small, diffusible, lipophilic free radical gas that mediates significant and diverse signaling functions in nearly every organ system in the body. The endothelial isoform of nitric oxide synthase (eNOS) is a key source of NO found in the cardiovascular system. This review summarizes the pharmacology of NO and the cellular regulation of endothelial NOS (eNOS). The molecular intricacies of the chemistry of NO and the enzymology of NOSs are discussed, followed by a review of the biological activities of NO. This information is then used to develop a more global picture of the pharmacological control of NO synthesis by NOSs in both physiologic conditions and pathophysiologic states.
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  • 160
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    Annual Review of Pharmacology 46 (2006), S. 123-149 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Inflammation and infection have long been known to downregulate the activity and expression of cytochrome P450 (CYP) enzymes involved in hepatic drug clearance. This can result in elevated plasma drug levels and increased adverse effects. Recent information on regulation of human CYP enzymes is presented, as are new developments in our understanding of the mechanisms of regulation. Experiments to study the effects of modulating CYP activities on the inflammatory response have yielded possible insights into the physiological consequences, if not the purpose, of the downregulation. Regulation of hepatic flavin monooxygenases, UDP-glucuronosyltransferases, sulfotransferases, glutathione S-transferases, as well as of hepatic transporters during the inflammatory response, exhibits similarities and differences with regulation of CYPs.
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  • 161
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    Annual Review of Pharmacology 46 (2006), S. 101-122 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: CB1 and CB2 cannabinoid receptors are the primary targets of endogenous cannabinoids (endocannabinoids). These G proteinĐ??coupled receptors play an important role in many processes, including metabolic regulation, craving, pain, anxiety, bone growth, and immune function. Cannabinoid receptors can be engaged directly by agonists or antagonists, or indirectly by manipulating endocannabinoid metabolism. In the past several years, it has become apparent from preclinical studies that therapies either directly or indirectly influencing cannabinoid receptors might be clinically useful. This review considers the components of the endocannabinoid system and discusses some of the most promising endocannabinoid-based therapies.
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  • 162
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    Annual Review of Pharmacology 46 (2006), S. 355-379 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: The physiological effects of many extracellular stimuli are mediated by receptor-promoted activation of phospholipase C (PLC) and consequential activation of inositol lipid-signaling pathways. These signaling responses include the classically described conversion of PtdIns(4,5)P2 to the Ca2+-mobilizing second messenger Ins(1,4,5)P3 and the protein kinase CĐ??activating second messenger diacylglycerol as well as alterations in membrane association or activity of many proteins that harbor phosphoinositide binding domains. Here we discuss how the family of PLCs elaborates a minimal catalytic core typified by PLC-?? to confer multiple modes of regulation on their phospholipase activities. Although PLC-dependent signaling is prominently regulated by direct interactions with heterotrimeric G proteins or tyrosine kinases, the existence of at least 13 divergent PLC isozymes promises a diverse repertoire of regulatory mechanisms for this class of important signaling proteins. We focus here on the recently realized and extensive regulation of inositol lipid signaling by Ras superfamily GTPases directly acting on PLC isozymes and conclude by considering the biological and pharmacological ramifications of this regulation.
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  • 163
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    Annual Review of Pharmacology 46 (2006), S. 41-64 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Most xenobiotics that enter the body are subjected to metabolism that functions primarily to facilitate their elimination. Metabolism of certain xenobiotics can also result in the production of electrophilic derivatives that can cause cell toxicity and transformation. Many xenobiotics can also activate receptors that in turn induce the expression of genes encoding xenobiotic-metabolizing enzymes and xenobiotic transporters. However, there are marked species differences in the way mammals respond to xenobiotics, which are due in large part to molecular differences in receptors and xenobiotic-metabolizing enzymes. This presents a problem in extrapolating data obtained with rodent model systems to humans. There are also polymorphisms in xenobiotic-metabolizing enzymes that can impact drug therapy and cancer susceptibility. In an effort to generate more reliable in vivo systems to study and predict human response to xenobiotics, humanized mice are under development.
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  • 164
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    Annual Review of Pharmacology 46 (2006), S. 151-187 
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Accessory proteins involved in signal processing through heterotrimeric G proteins are generally defined as proteins distinct from G proteinĐ??coupled receptor (GPCR), G protein, or classical effectors that regulate the strength/efficiency/specificity of signal transfer upon receptor activation or position these entities in the right microenvironment, contributing to the formation of a functional signal transduction complex. A flurry of recent studies have implicated an additional class of accessory proteins for this system that provide signal input to heterotrimeric G proteins in the absence of a cell surface receptor, serve as alternative binding partners for G protein subunits, provide unexpected modes of G protein regulation, and have introduced additional functional roles for G proteins. This group of accessory proteins includes the recently discovered Activators of G protein Signaling (AGS) proteins identified in a functional screen for receptor-independent activators of G protein signaling as well as several proteins identified in protein interaction screens and genetic screens in model organisms. These accessory proteins may influence GDP dissociation and nucleotide exchange at the G subunit, alter subunit interactions within heterotrimeric G independent of nucleotide exchange, or form complexes with G or G independent of the typical G heterotrimer. AGS and related accessory proteins reveal unexpected diversity in G protein subunits as signal transducers within the cell.
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  • 165
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    Palo Alto, Calif. : Annual Reviews
    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Notes: Structural data on protein-DNA complexes provide clues for understanding the mechanism of protein-DNA recognition. Although the structures of a large number of protein-DNA complexes are known, the mechanisms underlying their specific binding are still only poorly understood. Analysis of these structures has shown that there is no simple one-to-one correspondence between bases and amino acids within protein-DNA complexes; nevertheless, the observed patterns of interaction carry important information on the mechanisms of protein-DNA recognition. In this review, we show how the patterns of interaction, either observed in known structures or derived from computer simulations, confer recognition specificity, and how they can be used to examine the relationship between structure and specificity and to predict target DNA sequences used by regulatory proteins.
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  • 166
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    ISSN: 1056-8700
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Physics
    Notes: The recent development of new techniques to manipulate single DNA molecules has opened new opportunities for the study of the enzymes that control DNA topology: the type I and II topoisomerases. These single-molecule assays provide a unique way to study the uncoiling of single supercoiled DNA molecules and the unlinking of two intertwined DNAs. They allow for a detailed characterization of the activity of topoisomerases, including the processivity, the chiral discrimination, and the dependence of their enzymatic rate on ATP concentration, degree of supercoiling, and the tension in the molecule. These results shed new light on the mechanism of these enzymes and their function in vivo.
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  • 167
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    Palo Alto, Calif. : Annual Reviews
    ISSN: 1523-9829
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Technology , Medicine
    Notes: We review the history of DNA mechanics and its analysis. We evaluate several methods to analyze the structures of superhelical DNA molecules, each predicated on the assumption that DNA can be modeled with reasonable accuracy as an extended, linearly elastic polymer. Three main approaches are considered: mechanical equilibrium methods, which seek to compute minimum energy conformations of topologically constrained molecules; statistical mechanical methods, which seek to compute the Boltzmann distribution of equilibrium conformations that arise in a finite temperature environment; and dynamic methods, which seek to compute deterministic trajectories of the helix axis by solving equations of motion. When these methods include forces of self-contact, which prevent strand passage and preserve the topological constraint, each predicts plectonemically interwound structures. On the other hand, the extent to which these mechanical methods reliably predict energetic and thermodynamic properties of superhelical molecules is limited, in part because of their inability to account explicitly for interactions involving solvent. Monte Carlo methods predict the entropy associated with supercoiling to be negative, in conflict with a body of experimental evidence that finds it is large and positive, as would be the case if superhelical deformations significantly disrupt the ordering of ambient solvent molecules. This suggests that the large-scale conformational properties predicted by elastomechanical models are not the only ones determining the energetics and thermodynamics of supercoiling. Moreover, because all such models that preserve the topological constraint correctly predict plectonemic interwinding, despite these and other limitations, this constraint evidently dominates energetic and thermodynamic factors in determining supercoil geometry. Therefore, agreement between predicted structures and structures obtained experimentally, for example, by electron microscopy, does not in itself provide evidence for the correctness or completeness of any given model of DNA mechanics.
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  • 168
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    Palo Alto, Calif. : Annual Reviews
    ISSN: 1527-8204
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: The ATP-binding cassette (ABC) superfamily of genes encode membrane proteins that transport a diverse set of substrates across membranes. Mutations in ABC transporters cause or contribute to many different Mendelian and complex disorders including adrenoleukodystrophy, cystic fibrosis, retinal degeneration, hypercholesterolemia, and cholestasis. The genes play important roles in protecting organisms from xenobiotics and transport compounds across the intestine, blood-brain barrier, and the placenta. There are 48 ABC genes in the human genome divided into seven subfamilies based on amino acid sequence similarities and phylogeny. These seven subfamilies are represented in all eukaryotic genomes and are therefore of ancient origin. Sequencing the genomes of numerous vertebrate organisms has allowed the complement of ABC transporters to be characterized and the evolution of the genes to be assessed. Most ABC transporters are conserved in all vertebrates, but there are also several examples of recent duplication and gene loss. For genes with a conserved ortholog, animal models have been identified or developed that can be used to probe the function and regulation of selected genes. Genes that are restricted to a specific group of animals may represent specialized functions that could provide insight into unique biological properties of that organism. Further characterization of all ABC transporters from the human genome and from model organisms will lead to additional insights into normal physiology and human disease.
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  • 169
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    ISSN: 1527-8204
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
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  • 170
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    ISSN: 1527-8204
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: Glaucoma describes a group of diseases that kill retinal ganglion cells. There are different types of glaucoma, and each appears to be genetically heterogeneous. Different glaucoma genes have been identified, but these genes account for only a small proportion of glaucoma. Most glaucoma cases appear to be multifactorial, and are likely affected by multiple interacting loci. A number of genetic susceptibility factors have been suggested to contribute to glaucoma. These factors fit into two broad groups, those affecting intraocular pressure and those important in modulating retinal ganglion cell viability. Defining the complex genetics of glaucoma will require significant further study of the human disease and animal models. Genetic approaches are essential and will be enhanced by recently developed genomic and proteomic technologies. These technologies will provide valuable clues about pathogenesis for subsequent testing. In this review, we focus on endogenous genetic susceptibility factors and on how experimental studies will be valuable for dissecting the multifactorial complexity of their interactions.
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  • 171
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    ISSN: 1527-8204
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: The availability of complete genome sequences and the wealth of large-scale biological data sets now provide an unprecedented opportunity to elucidate the genetic basis of rare and common human diseases. Here we review some of the emerging genomics technologies and data resources that can be used to infer gene function to prioritize candidate genes. We then describe some computational strategies for integrating these large-scale data sets to provide more faithful descriptions of gene function, and how such approaches have recently been applied to discover genes underlying Mendelian disorders. Finally, we discuss future prospects and challenges for using integrative genomics to systematically discover not only single genes but also entire gene networks that underlie and modify human disease.
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  • 172
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    ISSN: 1527-8204
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: Several unique properties of human mitochondrial DNA (mtDNA), including its high copy number, maternal inheritance, lack of recombination, and high mutation rate, have made it the molecule of choice for studies of human population history and evolution. Here we review the current state of knowledge concerning these properties, how mtDNA variation is studied, what we have learned, and what the future likely holds. We conclude that increasingly, mtDNA studies are (and should be) supplemented with analyses of the Y-chromosome and other nuclear DNA variation. Some serious issues need to be addressed concerning nuclear inserts, database quality, and the possible influence of selection on mtDNA variation. Nonetheless, mtDNA studies will continue to play an important role in such areas as examining socio-cultural influences on human genetic variation, ancient DNA, certain forensic DNA applications, and in tracing personal genetic history.
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  • 173
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    ISSN: 1527-8204
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: Mammalian X chromosome inactivation is one of the most striking examples of epigenetic gene regulation. Early in development one of the pair of Đ♯160-Mb X chromosomes is chosen to be silenced, and this silencing is then stably inherited through subsequent somatic cell divisions. Recent advances have revealed many of the chromatin changes that underlie this stable silencing of an entire chromosome. The key initiator of these changes is a functional RNA, XIST, which is transcribed from, and associates with, the inactive X chromosome, although the mechanism of association with the inactive X and recruitment of facultative heterochromatin remain to be elucidated. This review describes the unique evolutionary history and resulting genomic structure of the X chromosome as well as the current understanding of the factors and events involved in silencing an X chromosome in mammals.
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  • 174
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    ISSN: 1527-8204
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology
    Notes: Cystic fibrosis (CF) is the most common lethal autosomal recessive disorder in the Caucasian population, affecting about 30,000 individuals in the United States. The gene responsible for CF, the CF transmembrane conductance regulator (CFTR), was identified 15 years ago. Substantial variation in the many aspects of the CF phenotype among individuals with the same CFTR genotype demonstrates that factors independent of CFTR exert considerable influence on outcome in CF. To date, the majority of published studies investigating the cause of disease variability in CF report associations between candidate genes and some aspect of the CF phenotype. However, a definitive modifier gene for CF remains to be identified. Despite the challenges posed by searches for modifier effects, studies of affected twins and siblings indicate that genetic factors play a substantial role in intestinal manifestations. Identifying the factors contributing to variation in pulmonary disease, the primary cause of mortality, remains a challenge for CF research.
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    Palo Alto, Calif. : Annual Reviews
    ISSN: 1548-5943
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine
    Notes: Pathological alcohol use is a complex and costly problem. This chapter focuses on recent developments in the etiology of alcohol use disorders. Literature is reviewed from the fields of epidemiology, genetics, personality, neuropsychology, parenting, and social influences. In addition, theoretical models that describe pathways to the development of alcohol use disorders are presented. Particular emphasis is given to ways in which genetic, environmental, psychopharmacological, and personological literatures can inform one another.
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