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Selected AbstractsBioenergetics and the epigenome: Interface between the environment and genes in common diseasesDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2010Douglas C. Wallace Abstract Extensive efforts have been directed at using genome-wide association studies (GWAS) to identify the genes responsible for common metabolic and degenerative diseases, cancer, and aging, but with limited success. While environmental factors have been evoked to explain this conundrum, the nature of these environmental factors remains unexplained. The availability of and demands for energy constitute one of the most important aspects of the environment. The flow of energy through the cell is primarily mediated by the mitochondrion, which oxidizes reducing equivalents from hydrocarbons via acetyl-CoA, NADH + H+, and FADH2 to generate ATP through oxidative phosphorylation (OXPHOS). The mitochondrial genome encompasses hundreds of nuclear DNA (nDNA)-encoded genes plus 37 mitochondrial DNA (mtDNA)-encoded genes. Although the mtDNA has a high mutation rate, only milder, potentially adaptive mutations are introduced into the population through female oocytes. In contrast, nDNA-encoded bioenergetic genes have a low mutation rate. However, their expression is modulated by histone phosphorylation and acetylation using mitochondrially-generated ATP and acetyl-CoA, which permits increased gene expression, growth, and reproduction when calories are abundant. Phosphorylation, acetylaton, and cellular redox state also regulate most signal transduction pathways and activities of multiple transcription factors. Thus, mtDNA mutations provide heritable and stable adaptation to regional differences while mitochondrially-mediated changes in the epigenome permit reversible modulation of gene expression in response to fluctuations in the energy environment. The most common genomic changes that interface with the environment and cause complex disease must, therefore, be mitochondrial and epigenomic in origin. © 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:114,119. [source] Mutations towards enantioselectivity adversely affect secretion of Pseudomonas aeruginosa lipaseFEMS MICROBIOLOGY LETTERS, Issue 1 2008Sascha Hausmann Abstract Lipases are important biocatalysts used as detergent additives to manufacture biodiesel, and in particular, for the production of enantiopure compounds such as alcohols, amines and carboxylic acids. Extensive efforts were conducted trying to optimize lipase properties and lipase LipA of Pseudomonas aeruginosa comprises the best-studied example in terms of optimizing enantioselectivity by application of numerous directed evolution methods. Its enantioselectivity in the asymmetric hydrolysis of the model substrate 2-methyldecanoic acid p -nitrophenyl ester was increased from E=1.1 for the wild-type enzyme to E=51 for the best (S)-enantioselective variant which carried six amino acid exchanges. We have observed that overexpression of this variant in the homologous host resulted in only marginal yields of enzyme in the bacterial culture supernatant, suggesting that the enantioselective LipA variant was secreted with only low efficiency. Hence, we have analysed the secretion of this lipase variant and compared it to variants carrying either the respective single mutations or some combinations. We report here the identification of two amino acid substitutions located on the protein surface, which significantly impair lipase secretion. [source] Functional IrIII Complexes and Their ApplicationsADVANCED MATERIALS, Issue 13 2010Zhu-qi Chen Abstract Iridium complexes are drawing great interest because they exhibit high phosphorescence quantum efficiency. Extensive efforts have been devoted to the molecular design of ligands to achieve phosphorescent emission over a wide range of wavelengths that is compatible with many applications. In this research news article, we focus on materials design to improve the performance of phosphorescent IrIII complexes for organic light-emitting diodes (OLEDs), luminescence sensitizers, and biological imaging. [source] Synthesis and characterization of copolymers of alkyl- and azo-thiophenes: Chromic properties and photoinduced birefringenceJOURNAL OF APPLIED POLYMER SCIENCE, Issue 2 2009Vanessa C. Gonçalves Abstract Polyazothiophene is a type of polythiophene derivative that combines the electrical and luminescent properties of polythiophenes with the photoisomerization property of azopolymers. Extensive efforts have been made to improve the properties of polyazothiophenes, such as solubility, optical, and chromic properties. We report the preparation of copolymers of an alkylthiophene (3-octylthiophene, 3-OT) and an azothiophene (2-[N -ethyl- N -[4-[(4-(4-nitrophenyl)azo]phenyl]amino]ethyl 3-thienylacetate, 3-AzoT) in different ratios as an alternative route to improve these properties. The azosubstituted monomer contents in these copolymers were 6, 9, 12, and 51% (in mol), as evaluated by elemental analysis. Their chemical structures were confirmed by FTIR and 1H-NMR. HPSEC and thermal analysis were used to characterize the polymers. The presence of thermochromic and solvatochromic properties was demonstrated by UV-Vis spectroscopy. Optically induced birefringence was detected only in polymers with 12 and 51 mol % of azo-units. The introduction of different ratios of the azothiophene in the copolymer alters the polymer solubility and emissive properties. The results indicate that the polyazothiophene copolymers presented are promising active layers for optical devices and sensors. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009 [source] Deficiency of oncoretrovirally transduced hematopoietic stem cells and correction through ex vivo expansionTHE JOURNAL OF GENE MEDICINE, Issue 2 2005David Bryder Abstract Background Extensive efforts to develop hematopoietic stem cell (HSC) based gene therapy have been hampered by low gene marking. Major emphasis has so far been directed at improving gene transfer efficiency, but low gene marking in transplanted recipients might equally well reflect compromised repopulating activity of transduced cells, competing for reconstitution with endogenous and unmanipulated stem cells. Methods The autologous settings of clinical gene therapy protocols preclude evaluation of changes in repopulating ability following transduction; however, using a congenic mouse model, allowing for direct evaluation of gene marking of lympho-myeloid progeny, we show here that these issues can be accurately addressed. Results We demonstrate that conditions supporting in vitro stem cell self-renewal efficiently promote oncoretroviral-mediated gene transfer to multipotent adult bone marrow stem cells, without prior in vivo conditioning. Despite using optimized culture conditions, transduction resulted in striking losses of repopulating activity, translating into low numbers of gene marked cells in competitively repopulated mice. Subjecting transduced HSCs to an ex vivo expansion protocol following the transduction procedure could partially reverse this loss. Conclusions These studies suggest that loss of repopulating ability of transduced HSCs rather than low gene transfer efficiency might be the main problem in clinical gene therapy protocols, and that a clinically feasible ex vivo expansion approach post-transduction can markedly improve reconstitution with gene marked stem cells. Copyright © 2004 John Wiley & Sons, Ltd. [source] Introducing dimensionless parameters into the correlation of NMR relaxation time to transport properties of porous mediaCONCEPTS IN MAGNETIC RESONANCE, Issue 3 2007Manolis M. Tomadakis Abstract Dimensionless parameters representing the viscous permeability (k) and NMR relaxation time (T1) of particle beds, while accounting also for the particle size, are shown to improve drastically the accuracy of k-T1 correlations in the slow diffusion regime, in the absence of bulk relaxation effects. The finding is based on a regression analysis of numerical results for k and T1 in both random and ordered isotropic and anisotropic beds of fibers. Use of the formation factor (F) improves further the accuracy of the correlations only for the strongly anisotropic unidirectional arrays of fibers. A survey of related literature reveals an extensive effort in recent years in upgrading k-T1 correlations, driven primarily by applications in petroleum and gas field exploration and recovery. © 2007 Wiley Periodicals, Inc. Concepts Magn Reson Part A 30A: 154,164, 2007. [source] Immunohistochemical characteristics of melanomaJOURNAL OF CUTANEOUS PATHOLOGY, Issue 5 2008Steven J. Ohsie Melanoma has a wide spectrum of histologic features which mimic epithelial, hematologic, mesenchymal, and neural tumors. Immunohistochemistry has been the primary tool to distinguish melanomas from these other tumors; it has also been studied for use as an adjunct to distinguish benign and malignant melanocytic tumors and to elucidate prognosis. Furthermore, there has been extensive effort to find a suitable marker to differentiate spindle cell and desmoplastic melanoma from other tumors. We have reviewed the literature investigating melanocytic differentiation markers, proliferation markers, immunomodulatory markers, signaling molecules, and nerve growth factors and receptors. Despite the proliferation of immunohistochemical markers, S-100 remains the most sensitive marker for melanocytic lesions, while markers such as HMB-45, MART-1/Melan-A, tyrosinase, and MITF demonstrate relatively good specificity but not as good sensitivity as S-100. No marker has proven useful in distinguishing spindle cell and desmoplastic melanomas from other tumors. Ki67 remains the most useful adjunct in distinguishing benign from malignant melanocytic tumors. None of the markers reviewed has been shown conclusively to have prognostic value for melanocytic neoplasms. [source] Ribosome's mode of function: myths, facts and recent results,JOURNAL OF PEPTIDE SCIENCE, Issue 3 2009Itai Wekselman Abstract Ribosomes translate the genetic code into proteins in all living cells with extremely high efficiency, owing to their inherent flexibility and to their spectacular architecture. During the last 6 decades, extensive effort has been made to elucidate the molecular mechanisms associated with their function, and a quantum jump has been made in recent years, once the three dimensional structures of ribosomes and their functional complexes have been determined. These illuminated key issues in ribosome function, confirmed various biochemical, genetic, and medical findings, and revealed mechanistic details beyond previous expectation, thus leading to conceptual revolutions, and turning old myths into actual facts. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd. [source] Understanding the Search for Meaning in Life: Personality, Cognitive Style, and the Dynamic Between Seeking and Experiencing MeaningJOURNAL OF PERSONALITY, Issue 2 2008Michael F. Steger ABSTRACT Although several theories assert that understanding the search for meaning in life is important, empirical research on this construct is sparse. Three studies provide the first extensive effort to understand the correlates of the search for meaning in a multistudy research program. Assessed were relations between search for meaning and well-being, cognitive style, and the Big Five, Big Three, Approach/Avoidance, and Interest models of personality, with a particular emphasis on understanding the correlates of search for meaning that are independent of presence of meaning. Conceptual models of the relation between search and presence were tested. Findings suggest that people lacking meaning search for it; the search for meaning did not appear to lead to its presence. Study 3 found that basic motive dispositions moderated relations between search for meaning and its presence. Results highlight the importance of basic personality dispositions in understanding the search for meaning and its correlates. [source] Microstructure,Property Correlations in Industrial Thermal Barrier CoatingsJOURNAL OF THE AMERICAN CERAMIC SOCIETY, Issue 7 2004Anand A. Kulkarni This paper describes the results from multidisciplinary characterization/scattering techniques used for the quantitative characterization of industrial thermal barrier coating (TBC) systems used in advanced gas turbines. While past requirements for TBCs primarily addressed the function of insulation/life extension of the metallic components, new demands necessitate a requirement for spallation resistance/strain tolerance, i.e., prime reliance, on the part of the TBC. In an extensive effort to incorporate these TBCs, a design-of-experiment approach was undertaken to develop tailored coating properties by processing under varied conditions. Efforts focusing on achieving durable/high-performance coatings led to dense vertically cracked (DVC) TBCs, exhibiting quasi-columnar microstructures approximating electron-beam physical-vapor-deposited (EB-PVD) coatings. Quantitative representation of the microstructural features in these vastly different coatings is obtained, in terms of porosity, opening dimensions, orientation, morphologies, and pore size distribution, by means of small-angle neutron scattering (SANS) and ultra-small-angle X-ray scattering (USAXS) studies. Such comprehensive characterization, coupled with elastic modulus and thermal conductivity measurements of the coatings, help establish relationships between microstructure and properties in a systematic manner. [source] SOFTWARE ENGINEERING CONSIDERATIONS FOR INDIVIDUAL-BASED MODELSNATURAL RESOURCE MODELING, Issue 1 2002GLEN E. ROPELLA ABSTRACT. Software design is much more important for individual-based models (IBMs) than it is for conventional models, for three reasons. First, the results of an IBM are the emergent properties of a system of interacting agents that exist only in the software; unlike analytical model results, an IBMs outcomes can be reproduced only by exactly reproducing its software implementation. Second, outcomes of an IBM are expected to be complex and novel, making software errors difficult to identify. Third, an IBM needs ,systems software' that manages populations of multiple kinds of agents, often has nonlinear and multi-threaded process control and simulates a wide range of physical and biological processes. General software guidelines for complex models are especially important for IBMs. (1) Have code critically reviewed by several people. (2) Follow prudent release management prac-tices, keeping careful control over the software as changes are implemented. (3) Develop multiple representations of the model and its software; diagrams and written descriptions of code aid design and understanding. (4) Use appropriate and widespread software tools which provide numerous major benefits; coding ,from scratch' is rarely appropriate. (5) Test the software continually, following a planned, multi-level, exper-imental strategy. (6) Provide tools for thorough, pervasive validation and verification. (7) Pay attention to how pseudorandom numbers are generated and used. Additional guidelines for IBMs include: (a) design the model's organization before starting to write code,(b) provide the ability to observe all parts of the model from the beginning,(c) make an extensive effort to understand how the model executes how often different pieces of code are called by which objects, and (d) design the software to resemble the system being mod-eled, which helps maintain an understanding of the software. Strategies for meeting these guidelines include planning adequate resources for software development, using software professionals to implement models and using tools like Swarm that are designed specifically for IBMs. [source] The high-resolution structure of dihydrodipicolinate synthase from Escherichia coli bound to its first substrate, pyruvateACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 12 2008Sean R. A. Devenish Dihydrodipicolinate synthase (DHDPS) mediates the key first reaction common to the biosynthesis of (S)-lysine and meso -diaminopimelate, molecules which play a crucial cross-linking role in bacterial cell walls. An effective inhibitor of DHDPS would represent a useful antibacterial agent; despite extensive effort, a suitable inhibitor has yet to be found. In an attempt to examine the specificity of the active site of DHDPS, the enzyme was cocrystallized with the substrate analogue oxaloacetate. The resulting crystals diffracted to 2.0,Å resolution, but solution of the protein structure revealed that pyruvate was bound in the active site rather than oxaloacetic acid. Kinetic analysis confirmed that the decarboxylation of oxaloacetate was not catalysed by DHDPS and was instead a slow spontaneous chemical process. [source] An "Omics" view of drug developmentDRUG DEVELOPMENT RESEARCH, Issue 2 2004Russ B. Altman Abstract The pharmaceutical industry cannot be blamed for having a love/hate relationship with the fields of pharmacogenetics and pharmacogenomics. At the same time that pharmacogenetics and pharmacogenomics promise to save pipeline drugs by identifying subsets of the population for which they work best, they also threaten to increase the complexity of new drug applications, fragment markets, and create uncertainty for prescribers who simply do not understand or have time to master "personalized medicine." Most importantly, the logical case for genetics-specific drug selection and dosing is much more mature than the practical list of drugs for which outcomes are demonstrably improved. Understandably, pharmaceutical developers and regulators have been careful in creating strategies for using genetics in drug development, and only recently has the FDA begun to establish preliminary rules for pharmacogenetic testing. A growing public academic effort in pharmacogenetics and pharmacogenomics is helping flesh out the basic science underpinnings of the field, and this should combine with extensive efforts of industry to create a solid foundation for future use of genetics in drug development. Two grand challenges to accelerate our capabilities include the characterization of all human genes involved in the basic pharmacokinetics of drugs, and the detailed study of the genes and pathways associated with G-protein-coupled receptors and how they are affected by genetic variation. Drug Dev. Res. 62:81,85, 2004. © 2004 Wiley-Liss, Inc. [source] Cognitive control processes during an anticipated switch of taskEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2003G. R. Wylie Abstract For successful negotiation of our environment, humans must be readily able to switch from one task to another. This ability relies on ,executive control' processes and despite extensive efforts to detail the nature of these processes, there is little consensus as to how the brain achieves this critical function. Behavioural studies show that as subjects are given more time to prepare to switch task, performance improves; yet even with the longest preparation intervals, there remains an ineradicable performance cost on switch trials. As such, some elements of the switching process must wait until the stimulus to be acted upon has actually been presented. Here, using the methods of high-density mapping of brain potentials, we show that early visual processes are substantially different on switch trials than on later trials. Our data show that while there is clearly a degree of preparatory processing that occurs prior to a predictable switch of task, some elements of switching are only achieved after the switch stimulus has been presented. Our findings are discussed in the context of a new model of executive control processes that suggests that preparing to switch task may not be a separate (control) process per se, but rather, the beginning of a competition between the potentially relevant tasks, a competition that is ultimately resolved during the switch trial. [source] Novel alternatively spliced endoplasmic reticulum retention signal in the cytoplasmic loop of Proteolipid Protein-1JOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2007Cherie Southwood Abstract Increased awareness about the importance of protein folding and trafficking to the etiology of gain-of-function diseases has driven extensive efforts to understand the cell and molecular biology underlying the life cycle of normal secretory pathway proteins and the detrimental effects of abnormal proteins. In this regard, the quality-control machinery in the endoplasmic reticulum (ER) has emerged as a major mechanism by which cells ensure that secreted and transmembrane proteins either adopt stable secondary, tertiary, and quaternary structures or are retained in the ER and degraded. Here we examine cellular and molecular aspects of ER retention in transfected fibroblasts expressing missense mutations in the Proteolipid Protein-1 (PLP1) gene that cause mild or severe forms of neurodegenerative disease in humans. Mild mutations cause protein retention in the ER that is partially dependent on the presence of a cytoplasmically exposed heptapeptide, KGRGSRG. In contrast, retention associated with severe mutations occurs independently of this peptide. Accordingly, the function of this novel heptapeptide has a significant impact on pathogenesis and provides new insight into the functions of the two splice isoforms encoded by the PLP1 gene, PLP1 and DM-20. © 2006 Wiley-Liss, Inc. [source] Comparison of mechanical properties of epoxy composites reinforced with stitched glass and carbon fabrics: Characterization of mechanical anisotropy in composites and investigation on the interaction between fiber and epoxy matrixPOLYMER COMPOSITES, Issue 8 2008Volkan Çeçen The primary purpose of the study is to evaluate and compare the mechanical properties of epoxy-based composites having different fiber reinforcements. Glass and carbon fiber composite laminates were manufactured by vacuum infusion of epoxy resin into two commonly used noncrimp stitched fabric (NCF) types: unidirectional and biaxial fabrics. The effects of geometric variables on composite structural integrity and strength were illustrated. Hence, tensile and three-point bending flexural tests were conducted up to failure on specimens strengthened with different layouts of fibrous plies in NCF. In this article, an important practical problem in fibrous composites, interlaminar shear strength as measured in short beam shear test, is discussed. The fabric composites were tested in three directions: at 0°, 45°, and 90°. In addition to the extensive efforts in elucidating the variation in the mechanical properties of noncrimp glass and carbon fabric reinforced laminates, the work presented here focuses, also, on the type of interactions that are established between fiber and epoxy matrix. The experiments, in conjunction with scanning electron photomicrographs of fractured surfaces of composites, were interpreted in an attempt to explain the failure mechanisms in the composite laminates broken in tension. POLYM. COMPOS., 2008. © 2008 Society of Plastics Engineers [source] Developing strategies for detection of gene dopingTHE JOURNAL OF GENE MEDICINE, Issue 1 2008Anna Baoutina Abstract It is feared that the use of gene transfer technology to enhance athletic performance, the practice that has received the term ,gene doping', may soon become a real threat to the world of sport. As recognised by the anti-doping community, gene doping, like doping in any form, undermines principles of fair play in sport and most importantly, involves major health risks to athletes who partake in gene doping. One attraction of gene doping for such athletes and their entourage lies in the apparent difficulty of detecting its use. Since the realisation of the threat of gene doping to sport in 2001, the anti-doping community and scientists from different disciplines concerned with potential misuse of gene therapy technologies for performance enhancement have focused extensive efforts on developing robust methods for gene doping detection which could be used by the World Anti-Doping Agency to monitor athletes and would meet the requirements of a legally defensible test. Here we review the approaches and technologies which are being evaluated for the detection of gene doping, as well as for monitoring the efficacy of legitimate gene therapy, in relation to the detection target, the type of sample required for analysis and detection methods. We examine the accumulated knowledge on responses of the body, at both cellular and systemic levels, to gene transfer and evaluate strategies for gene doping detection based on current knowledge of gene technology, immunology, transcriptomics, proteomics, biochemistry and physiology. Copyright © 2008 John Wiley & Sons, Ltd. [source] Regulation of hematopoietic niches by sympathetic innervationBIOESSAYS, Issue 7 2006Hector Leonardo Aguila Once hematopoiesis is established in the bone marrow, a continuous egress of hematopoietic stem cells (HSCs) to the periphery occurs at a low frequency. It has been proposed that this phenomenon is part of a regenerative homeostatic mechanism that ensures the maintenance of hematopoiesis through the life of the individual. The administration of certain cytotoxic drugs or cytokines can enhance the mobilization of hematopoietic progenitors to the periphery. During the past 15 years, granulocyte-colony stimulating factor (G-CSF) has been used as a standard cytokine for mobilization protocols in experimental models and in humans. Despite extensive efforts by multiple groups, a definitive mechanism explaining its role in mobilization has not been provided. In a recent paper, Katayama et al.,1 through a series of clever associations supported by well-defined experimental systems, proposed that signals through the sympathetic nervous system modify the activity of the hematopoietic niche, acting as regulators of the mobilization of hematopoietic progenitors. This surprising finding adds a new level of complexity to the cellular milieu responsible for generation and maintenance of the hematopoietic niche. BioEssays 28: 687,691, 2006. © 2006 Wiley Periodicals, Inc. [source] Tracking Inner City Substance Users from the Emergency Department: How Many Contacts Does It Take?ACADEMIC EMERGENCY MEDICINE, Issue 2 2008Rebecca Cunningham MD Abstract Background:, Longitudinal studies of substance users report difficulty in locating and completing 12-month interviews, which may compromise study validity. Objectives:, This study examined rates and predictors of contact difficulty and in-person follow-up completion among patients presenting with cocaine-related chest pain to an inner-city emergency department (ED). The authors hypothesize that less staff effort in contacting patients and lower follow-up rates would bias subsequent substance use analysis by missing those with heavier substance misuse. Methods:, A total of 219 patients aged 19 to 60 years (65% males; 78% African American) with cocaine-related chest pain were interviewed in the ED and then in person at 3, 6, and 12 months. Demographics, substance use measures, and amount/type of research staff contacts (telephone, letters, home visits, and locating patient during return ED visits) were recorded. Poisson and negative binomial regression analyses were conducted to predict quantity of patient contacts for the 12-month follow-up. Results:, Interview completion rates at 3, 6, and 12 months were 78, 82, and 80%, respectively. Average contact attempts to obtain each interview were 10 at 3 months (range 3,44), 8 at 6 months (1,31), and 8 at 12 months (1,49); 13% of patients required a home visit to complete the 12-month interview. Participants requiring more contact attempts by staff were younger and reported more frequent binge drinking at baseline (p < 0.05), but were less likely to meet criteria for substance abuse or dependence (p < 0.5), or to report prior mental health treatment (p < 0.05). Comparisons of parallel regressions predicting contact difficulty based on the entire sample, the low-effort group, and the difficult-to-reach group showed variation in findings. Conclusions:, This study demonstrates that substantial staff effort is required to achieve adequate retention over 12 months of patients with substance misuse. Without these extensive efforts at follow-up, longitudinal analyses may be biased. [source] Are MAP Kinases Drug Targets?CHEMMEDCHEM, Issue 8 2007but Difficult Ones Abstract Pharmaceutical companies are facing an increasing interest in new target identification and validation. In particular, extensive efforts are being made in the field of protein kinase inhibitors research and development, and the past ten years of effort in this field have altered our perception of the potential of kinases as drug targets. Therefore, in the drug discovery process, the selection of relevant, susceptible protein kinase targets combined with searches for leads and candidates have become a crucial approach. The success of recent launches of protein kinase inhibitors (Gleevec, Imatinib, Sutent, Iressa, Nexavar, Sprycel) gave another push to this field. Numerous other kinase inhibitors are currently undergoing clinical trials or clinical development. Some questions are nevertheless unanswered, mostly related to the great number of known kinases in the human genome, to their similarity with each other, to the existence of functionally redundant kinases for specific pathways, and also because the connection between particular pathways and diseases is not always clear. The review is leading the reader through a panoramic view of protein kinase inhibition with a major focus on MAPK, successful examples and clinical candidates. [source] | ||||||||||||||||||||||