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Computer Modeling (computer + modeling)
Selected AbstractsAnalysis of Cardiac Development in the Turtle Emys orbicularis (Testudines: Emidydae) using 3-D Computer Modeling from Histological SectionsTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 7 2010Laura M.F. Bertens Abstract In this article we present a 3-D modeling study of cardiac development in the European pond turtle, Emys orbicularis (of the reptilian order Testudines). The study is aimed at elucidating the embryonic development of the horizontal septum in the ventricle and underscoring the importance of 3-D reconstructions in studying morphogenesis. Turtles possess one common ventricle, partly divided into three cava by a vertical and a horizontal septum, of which the embryonic origins have so far not been described. We used serial sectioning and computerized high-resolution 3-D reconstructions of different developmental stages to create a chronological overview of cardiogenesis, in order to study this process. This has yielded a new understanding of the development of the horizontal septum and (directly related) the looping of the heart tube. This looping is found to be markedly different from that in the human heart, with the turtle having two clear bends in the part of the heart tube leaving the primitive ventricle, as opposed to one in humans. It is this particular looping that is reponsible for the formation of the horizontal septum. In addition to our findings on the ventricular septation this study has also yielded new insights into the developmental origins of the pulmonary vein. The 3-D reconstructions were built using our platform TDR-3-D base and enabled us to study the developmental processes in specific parts of the turtle heart separately and in three dimensions, over time. The complete 3-D reconstructions have been made available to the reader via internet using our 3-D model browser application, which allows interactive viewing of the models. The browser application can be found on bio-imaging.liacs.nl/galleries/emysorbicularis/TurtleGallery.html, along with additional images of both models and histological sections and animation sequences of the models. By allowing the reader to view the material in such an interactive way, we hope to make optimal use of the new 3-D reconstruction techniques and to engage the reader in a more direct manner. Anat Rec 239:1101,1114, 2010. © 2010 Wiley-Liss, Inc. [source] p.Gln200Glu, a putative constitutively active mutant of rod ,-transducin (GNAT1) in autosomal dominant congenital stationary night blindness,,HUMAN MUTATION, Issue 7 2007Viktoria Szabo Abstract Congenital stationary night blindness (CSNB) is a non-progressive Mendelian condition resulting from a functional defect in rod photoreceptors. A small number of unique missense mutations in the genes encoding various members of the rod phototransduction cascade, e.g. rhodopsin (RHO), cGMP phosphodiesterase ,-subunit (PDE6B), and transducin ,-subunit (GNAT1) have been reported to cause autosomal dominant (ad) CSNB. While the RHO and PDE6B mutations result in constitutively active proteins, the only known adCSNB-associa-ted GNAT1 change (p.Gly38Asp) produces an ,-transducin that is unable to activate its downstream effector molecule in vitro. In a multigeneration Danish family with adCSNB, we identified a novel heterozygous C to G transversion (c.598C>G) in exon 6 of GNAT1 that should result in a p.Gln200Glu substitution in the evolutionarily highly conserved Switch 2 region of ,-transducin, a domain that has an important role in binding and hydrolyzing GTP. Computer modeling based on the known crystal structure of transducin suggests that the p.Gln200Glu mutant exhibits impaired GTPase activity, and thereby leads to constitutive activation of phototransduction. This assumption is in line with our results of trypsin protection assays as well as previously published biochemical data on mutants of this glutamine in the GTPase active site of ,-transducin following in vitro expression, and observations that inappropriately activating mutants of various members of the rod phototransduction cascade represent one of the major molecular causes of adCSNB. © 2007 Wiley-Liss, Inc. [source] Computer modeling of frequency-modulation spectra of coherent dark resonancesLASER PHYSICS LETTERS, Issue 9 2006J. Vladimirova Abstract Dynamics of a three-level quantum system in , -configuration driven by a resonant laser field with and without frequency modulation (FM) is studied for the first time in detail using two simulation techniques , the density matrix and quantum trajectories analysis. This analysis was applied to the Fmspectroscopy of coherent dark resonances in Cs atoms and computer simulation results for the absorption spectra are in qualitative agreement with those taken in an experiment. (© 2006 by Astro, Ltd. Published exclusively by WILEY-VCH Verlag GmbH & Co. KGaA) [source] Computer modeling of optical properties of gold ellipsoidal nanoparticles at laser radiation wavelengthsLASER PHYSICS LETTERS, Issue 2 2005V. K. Pustovalov Abstract Processes of laser interaction with metal (gold) nanoparticles are of great interest for laser applications in nanotechnology, engineering, and medicine. Optical properties of nanoparticles determine photophysical and photochemical processes during laser treatment. Computer calculation of efficiency factors of absorption, scattering and extinction of radiation by ellipsoidal gold nanoparticles (two-dimensional ellipsoids of revolution) with small semiaxes in the range 5,100 nm, for some values of aspect ratio and angle of orientation of ellipsoid with respect to direction of laser radiation propagation and for some laser wavelengths is performed. The estimation of absorbed and scattered laser radiation energy by gold ellipsoidal nanoparticles, their maximal temperatures and comparison with experimental data is made. (© 2005 by Astro, Ltd. Published exclusively by WILEY-VCH Verlag GmbH & Co. KGaA) [source] A recurrent ITGA9 missense mutation in human fetuses with severe chylothorax: possible correlation with poor response to fetal therapyPRENATAL DIAGNOSIS, Issue 11 2008Gwo-Chin Ma Abstract Objectives To assess the possible correlations between the reported candidate genes (VEGFR3, FOXC2, ITGA9 and ITGB1) and the clinical response in fetuses with severe congenital chylothorax (CC) treated by prenatal OK-432 pleurodesis. Methods We studied 12 unrelated fetuses with severe CC, receiving fetal therapy by OK-432 pleurodesis. Genotyping of the candidate genes and the clinical parameters of these 12 fetuses were investigated. Additional 96 control individuals were enrolled to evaluate the possible polymorphisms at these candidate genes in population. Results A recurrent heterozygous missense mutation (c.1210G > A, p.G404S) was identified in the beta-propeller domain of integrin ,9 (ITGA9), a cell adhesion receptor, in four of the five fetuses who failed to respond to the OK-432 treatment. Computer modeling of the p.G404S substitution supported the deleterious nature of this mutation. Family analyses in three affected fetuses demonstrated that the heterozygous mutant allele is of parental origin, suggesting an autosomal recessive inheritance of this genetic defect. Conclusions To the best of our knowledge, this is the first insight into the possible link between ITGA9 and CC in human fetuses. The identification of pathogenetic mutations and their possible link to the clinical responses of particular treatments may contribute to better pregnancy counseling and management. Copyright © 2008 John Wiley & Sons, Ltd. [source] An Inverse Substrate Orientation for the Regioselective Acylation of 3,,5,-Diaminonucleosides Catalyzed by Candida antarctica lipase B?CHEMBIOCHEM, Issue 8 2005Iván Lavandera Dr. Abstract Candida antarctica lipase B (CAL-B) catalyzes the regioselective acylation of natural thymidine with oxime esters and also the regioselective acylation of an analogue, 3,,5,-diamino-3,,5,-dideoxythymidine with nonactivated esters. In both cases, acylation favors the less hindered 5,-position over the 3,-position by upto 80-fold. Computer modeling of phosphonate transition-state analogues for the acylation of thymidine suggests that CAL-B favors acylation of the 5,-position because this orientation allows the thymine ring to bind in a hydrophobic pocket and forms stronger key hydrogen bonds than acylation of the 3,-position. On the other hand, computer modeling of phosphonamidate analogues of the transition states for acylation of either the 3,- or 5,-amino groups in 3,,5,-diamino-3,,5,-dideoxythymidine shows similar orientations and hydrogen bonds and, thus, does not explain the high regioselectivity. However, computer modeling of inverse structures, in which the acyl chain binds in the nucleophile pocket and vice versa, does rationalize the observed regioselectivity. The inverse structures fit the 5,-, but not the 3,-intermediate thymine ring, into the hydrophobic pocket, and form a weak new hydrogen bond between the O-2 carbonyl atom of the thymine and the nucleophile amine only for the 5,-intermediate. A water molecule might transfer a proton from the ammonium group to the active-site histidine. As a test of this inverse orientation, we compared the acylation of thymidine and 3,,5,-diamino-3,,5,-dideoxythymidine with butyryl acyl donors and with isosteric methoxyacetyl acyl donors. Both acyl donors reacted at equal rates with thymidine, but the methoxyacetyl acyl donor reacted four times faster than the butyryl acyl donor with 3,,5,-diamino-3,,5,-dideoxythymidine. This faster rate is consistent with an inverse orientation for 3,,5,-diamino-3,,5,-dideoxythymidine, in which the ether oxygen atom of the methoxyacetyl group can form a similar hydrogen bond to the nucleophilic amine. This combination of modeling and experiments suggests that such lipase-catalyzed reactions of apparently close substrate analogues like alcohols and amines might follow different pathways. [source] Long-term corrosion-induced copper runoff from natural and artificial patina and its environmental impact,ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2006Sofia Bertling Abstract The overall objective of this paper is to present an extensive set of data for corrosion-induced copper dispersion and its environmental interaction with solid surfaces in the near vicinity of buildings. Copper dispersion is discussed in terms of total copper flows, copper speciation and bioavailability at the immediate release situation, and its changes during transport from source to recipient. Presented results are based on extensive field exposures (eight years) at an urban site, laboratory investigations of the runoff process, published field data, generated predictive site-specific runoff rate models, and reactivity investigations toward various natural and manmade surfaces, such as those in soil, limestone, and concrete. Emphasis is placed on the interaction of copper-containing runoff water with different soil systems through long-term laboratory column investigations. The fate of copper is discussed in terms of copper retention, copper chemical speciation, breakthrough capacities, and future mobilization based on changes in copper concentrations in the percolate water, computer modeling using the Windermere Humic Aqueous Model, and sequential extractions. The results illustrate that, for scenarios where copper comes in extensive contact with solid surfaces, such as soil and limestone, a large fraction of released copper is retained already in the immediate vicinity of the building. In all, both the total copper concentration in runoff water and its bioavailable part undergo a significant and rapid reduction. [source] The Precipitation Behavior of Superalloy ATI Allvac 718PlusADVANCED ENGINEERING MATERIALS, Issue 3 2010Gerald A. Zickler Abstract ATI Allvac 718Plus is a novel nickel-based superalloy, which was designed for heavy-duty applications in aerospace gas turbines. The precipitation kinetics of the intermetallic , (Ni3Nb) and ,, (Ni3(Al,Ti)) phases in this alloy are of scientific as well as technological interest because of their significant influence on the mechanical properties. Important parameters like grain size are controlled by coarse , precipitates located at grain boundaries, whereas small ,, precipitates are responsible for strengthening by precipitation hardening. In the present study, the microstructure is investigated by three-dimensional atom probe tomography and simulated by computer modeling using the thermo-kinetic software MatCalc. The results of numerical simulations and experimental data are compared and critically discussed. It is shown that the chemical compositions of the phases change during isothermal aging, and the precipitation kinetics of , and ,, phases interact with each other as shown in a time temperature precipitation (TTP) plot. The TTP plot shows C-shaped curves with characteristic discontinuities in the temperature range, where simultaneous and concurrent precipitation of the , and ,, phases occurs. This leads to a competition in the diffusion of Nb and Al, which are partly present in both phases. Thus, the present study gives important information on heat treatments for ATI Allvac 718Plus in order to achieve the desired microstructure and mechanical properties. [source] Synthesis, NMR, and Conformational Studies of Cyclic Oligo-(1,6)-,- D -Glucosamines,EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 13 2010Marina L. Gening Abstract The first synthesis of a series of homologous cyclic oligo-(1,6)-,- D -glucosamines consisting of two to seven residues and representing a new type of functionalized cyclic oligosaccharides is reported. Remarkably high yields of the studied macrocyclization reaction irrespective of the length of the acyclic precursors were observed. In the case of compounds constituted of four to seven glucosamine units ,-stereoisomers formed as side products despite the presence of a strongly participating 2- N -phthaloyl group to control ,-glycosylation. Both phenomena may be accounted for by conformational features of the linear bifunctional precursors. According to computer modeling and NMR conformational studies, the described linear (1,6)-,-linked oligoglucosamines exist in a right-handed helix-like conformation, in which the glycosyl donor and acceptor moieties are prearranged in a way that facilitates intramolecular glycosylation from the ,-side. Prepared cyclo-oligoglucosamines differ in their conformational flexibilities, as illustrated by their spectral characteristics and calculated asphericity distributions. Moreover, the obtained compounds do not possess a distinct hydrophobic cavity, which is in contrast to the well-known cyclodextrins. All these characteristics provide an excellent basis for the use of these novel cyclic oligosaccharides as scaffolds for the construction of biomolecular conjugates. [source] Structure-Based Design and Synthesis of the First Weak Non-Phosphate Inhibitors for IspF, an Enzyme in the Non-Mevalonate Pathway of Isoprenoid BiosynthesisHELVETICA CHIMICA ACTA, Issue 6 2007Corinne Baumgartner Abstract In this paper, we describe the structure-based design, synthesis, and biological evaluation of cytosine derivatives and analogues that inhibit IspF, an enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. This pathway is responsible for the biosynthesis of the C5 precursors to isoprenoids, isopentenyl diphosphate (IPP, 1) and dimethylallyl diphosphate (DMAPP, 2; Scheme,1). The non-mevalonate pathway is the sole source for 1 and 2 in the protozoan Plasmodium parasites. Since mammals exclusively utilize the alternative mevalonate pathway, the enzymes of the non-mevalonate pathway have been identified as attractive new drug targets in the fight against malaria. Based on computer modeling (cf. Figs.,2 and 3), new cytosine derivatives and analogues (Fig.,1) were selected as potential drug-like inhibitors of IspF protein, and synthesized (Schemes,2,5). Determination of the enzyme activity by 13C-NMR spectroscopy in the presence of the new ligands showed inhibitory activities for some of the prepared cytosine and pyridine-2,5-diamine derivatives in the upper micromolar range (IC50 values; Table). The data suggest that it is possible to inhibit IspF protein without binding to the polar diphosphate binding site and the side chain of Asp56,, which interacts with the ribose moiety of the substrate and substrate analogues. Furthermore, a new spacious sub-pocket was discovered which accommodates aromatic spacers between cytosine derivatives or analogues (binding to ,Pocket III') and rings that occupy the flexible hydrophobic region of ,Pocket II'. The proposed binding mode remains to be further validated by X-ray crystallography. [source] A Novel Synthesis of Highly Substituted Perhydropyrrolizines, Perhydroindolizines, and Pyrrolidines: Inhibition of the Peptidyl-Prolyl cis/trans Isomerase (PPIase) Pin1HELVETICA CHIMICA ACTA, Issue 2 2007Romain Siegrist Abstract In this paper, we describe the synthesis and biological evaluation of highly substituted perhydropyrrolizines that inhibit the peptidyl-prolyl cis/trans isomerase (PPIase) Pin1, an oncogenic target. The enzyme selectively catalyzes the cis/trans isomerization of peptide bonds between a phosphorylated serine or threonine, and proline, thereby inducing a conformational change. Such structural modifications play an important role in many cellular events, such as cell-cycle progression, transcriptional regulation, RNA processing, as well as cell proliferation and differentiation. Based on computer modeling (Fig.,2), the new perhydropyrrolizinone derivatives (,)- 1a,b, decorated with two substituents, were selected and synthesized (Schemes,1,3). While enzymatic assays showed no biological activity, 15N,1H-HSQC-NMR spectroscopy revealed that (,)- 1a,b bind to the WW recognition domain of Pin1, apparently in a mode that does not inhibit PPIase activity. To enforce complexation into the larger active site rather than into the tighter WW domain of Pin1 and to enhance the overall binding affinity, we designed a perhydropyrrolizine scaffold substituted with additional aromatic residues (Fig.,5). A novel, straightforward synthesis towards this class of compounds was developed (Schemes,4 and 5), and the racemic compounds (±)- 22a,22d were found to inhibit Pin1 with Ki values (Ki,=,inhibition constant) in the micromolar range (Table,2). To further enhance the potency of these inhibitors, the optically pure ligands (+)- 22a and (+)- 33b,c were prepared (Schemes,6 and 7) and shown to inhibit Pin1 with Ki values down to the single-digit micromolar range. According to 15N,1H-HSQC-NMR spectroscopy and enzymatic activity assays, binding occurs at both the WW domain and the active site of Pin1. Furthermore, the new synthetic protocol towards perhydropyrrolizines was extended to the preparation of highly substituted perhydroindolizine ((±)- 43; Scheme,8) and pyrrolidine ((±)- 48a,b; Scheme,9) derivatives, illustrating a new, potentially general access to these highly substituted heterocycles. [source] Importance of O(3P) atoms and OH radicals in hydrocarbon oxidation during the nonthermal plasma treatment of diesel exhaust inferred using relative-rate methods,INTERNATIONAL JOURNAL OF CHEMICAL KINETICS, Issue 6 2003John Hoard The consumption of acetylene and propene during passage of simulated diesel exhaust through a nonthermal plasma at 453 K and atmospheric pressure was studied using experimental and computational techniques. Experimental observations of the relative decay rates of acetylene and propene and computer modeling of the chemical and physical processes in the plasma suggest that O(3P) atoms and, to a lesser extent, OH radicals are the dominant species responsible for initiating hydrocarbon oxidation in this system. Results are discussed in terms of the gas-phase chemistry occurring during the nonthermal plasma treatment of diesel exhaust. © 2003 Wiley Periodicals, Inc. Int J Chem Kinet 35: 231,238, 2003 [source] A Strategic Story of Using Computer Technology: The EPA Project by HOKJOURNAL OF INTERIOR DESIGN, Issue 1 2000Joan McLain-Kark Ph.D. ABSTRACT Interior design researchers study computer technology in order to understand its impact on design processes and education. Yet, whether the use of the computer has made interior designers better at improving the life of users remains to be seen. The purpose of this research is to examine the use of technology in design through a narrative case, the EPA project by Hellmuth, Obata, and Kassabaum (HOK), to offer insights into how computers can be used to make a design compatible with user needs. Three indivdiuals involved with the EPA project were interviewed and audiotaped regarding the design and computer modeling of the labs. The transcripts were subsequently analyzed for dominant themes. The researcher developed a narrative using a structure established by the FIDER Research Council. The results indicate that repeated involvement of the scientists in the design process through evaluation via the walk-through animation and other means resulted in a positive evaluation. The case provides insights on how computer technology can be optimized to improve the design for end-users. Using the EPA story and present trends in computer technology as a foundation, the article presents a scenario to help designers consider ways for integrating the latest computer modeling technology into their practice. [source] Three-dimensional reconstruction and neural map of the serotonergic brain of Asplanchna brightwellii (Rotifera, Monogononta)JOURNAL OF MORPHOLOGY, Issue 4 2009Rick Hochberg Abstract The basic organization of the rotifer brain has been known for nearly a century; yet, fine details on its structure and organization remain limited despite the importance of rotifers in studies of evolution and population biology. To gain insight into the structure of the rotifer brain, and provide a foundation for future neurophysiologic and neurophylogenetic research, the brain of Asplanchna brightwellii was studied with immunohistochemistry, confocal laser scanning microscopy, and computer modeling. A three-dimensional map of serotonergic connections reveals a complex network of approximately 28 mostly unipolar, cerebral perikarya and associated neurites. Cells and their projections display symmetry in quantity, size, connections, and pathways between cerebral hemispheres within and among individuals. Most immunopositive cells are distributed close to the brain midline. Three pairs of neurites form decussations at the brain midline and may innervate sensory receptors in the corona. A single neuronal pathway appears to connect both the lateral horns and dorsolateral apical receptors, suggesting that convergence of synaptic connections may be common in the afferent sensory systems of rotifers. Results show that the neural map of A. brightwellii is much more intricate than that of other monogonont rotifers; nevertheless, the consistency in neural circuits provides opportunities to identify homologous neurons, distinguish functional regions based on neurotransmitter phenotype, and explore new avenues of neurophylogeny in Rotifera. J. Morphol. 2009. © 2008 Wiley-Liss, Inc. [source] Technical Performance of Percutaneous and Laminectomy Leads Analyzed by ModelingNEUROMODULATION, Issue 4 2004Ljubomir Manola Dipl. Abstract The objective of this study was to compare the technical performance of laminectomy and percutaneous spinal cord stimulation leads with similar contact spacing by computer modeling. Monopolar and tripolar (guarded cathode) stimulation with both lead types in a low-thoracic spine model was simulated using UT-SCS software. Dorsal column and dorsal root fiber thresholds were calculated as well as the area of recruited fibers in the dorsal columns, the rostrocaudal span of recruited dorsal root fibers and the energy consumption at discomfort threshold. Tripolar stimulation is superior to monopolar stimulation in the recruitment of the dorsal columns, a percutaneous lead recruits a ,12% larger dorsal column area than a laminectomy lead does. This difference is reduced when the contact spacing of the lead models is the same. A percutaneous lead with significant wire impedance (140 Ohms) consumes ,115,240% more energy, whereas the same lead with negligible wire impedance consumes ,40,85% more energy. A deterioration of all performance parameters is predicted when a percutaneous lead is placed more dorsally in the epidural tissue. When positioned next to the dura mater, a percutaneous lead has a similar performance (fiber recruitment in the dorsal columns and the dorsal roots) as a laminectomy lead with similar contact spacing, but substantially higher energy consumption. The superior clinical performance of the laminectomy lead is most probably due to the difference in volume and insertion technique of the two lead types. [source] Profiling human gut bacterial metabolism and its kinetics using [U- 13C]glucose and NMRNMR IN BIOMEDICINE, Issue 1 2010Albert A. de Graaf Abstract This study introduces a stable-isotope metabolic approach employing [U- 13C]glucose that, as a novelty, allows selective profiling of the human intestinal microbial metabolic products of carbohydrate food components, as well as the measurement of the kinetics of their formation pathways, in a single experiment. A well-established, validated in vitro model of human intestinal fermentation was inoculated with standardized gastrointestinal microbiota from volunteers. After culture stabilization, [U- 13C]glucose was added as an isotopically labeled metabolic precursor. System lumen and dialysate samples were taken at regular intervals. Metabolite concentrations and isotopic labeling were determined by NMR, GC, and enzymatic methods. The main microbial metabolites were lactate, acetate, butyrate, formate, ethanol, and glycerol. They together accounted for a 13C recovery rate as high as 91.2%. Using an NMR chemical shift prediction approach, several minor products that showed 13C incorporation were identified as organic acids, amino acids, and various alcohols. Using computer modeling of the 12C contents and 13C labeling kinetics, the metabolic fluxes in the gut microbial pathways for synthesis of lactate, formate, acetate, and butyrate were determined separately for glucose and unlabeled background substrates. This novel approach enables the study of the modulation of human intestinal function by single nutrients, providing a new rational basis for achieving control of the short-chain fatty acids profile by manipulating substrate and microbiota composition in a purposeful manner. Copyright © 2009 John Wiley & Sons, Ltd. [source] Hydrostatic pressure effects on the structural and electronic properties of carbon nanotubesPHYSICA STATUS SOLIDI (B) BASIC SOLID STATE PHYSICS, Issue 14 2004Rodrigo B. Capaz This issue's Editor's Choice [1] is a theoretical study of the properties of single-wall carbon nanotubes (SWNTs) under hydro-static pressure. The cover picture is a snapshot of room-temperature molecular dynamics simulations of a chiral (8,7) SWNT at a pressure of 4 GPa, where a symmetry-breaking collapse of the tube into a flat shape is observed. This paper is an invited presentation from the 11th Interna-tional Conference on High Pressure Semiconductor Physics (HPSP-11), held in Berkeley, California, USA, 2,5 August 2004. The Proceedings of this conference series have been published for the fifth time in physica status solidi (b). The first author, Rodrigo Barbosa Capaz, is Associate Professor of Physics at Universidade Federal do Rio de Janeiro and works on electronic properties and computer modeling of materials. [source] Wetting of a fiber bundle in fibrous structuresPOLYMER COMPOSITES, Issue 3 2003David Lukas In this paper we dealt with the problem of wetting and ascending of a liquid along a fiber bundle. Two issues are first addressed including the criterion for complete wetting of the fiber bundle and the ascension liquid profile on a partially dipped vertical fiber bundle. Both topics are studied theoretically by deriving a mathematical theory by which predictions are generated and important parametric analyses are carried out. Further, a 3D Ising model is used for computer modeling to simulate the fiber wetting and liquid ascending processes on a partially dipped single fiber. The significance and potential applications of the study are also summarized. [source] Upregulation of K2P5.1 potassium channels in multiple sclerosisANNALS OF NEUROLOGY, Issue 1 2010Stefan Bittner BSc Objective Activation of T cells critically depends on potassium channels. We here characterize the impact of K2P5.1 (KCNK5; TASK2), a member of the 2-pore domain family of potassium channels, on T-cell function and demonstrate its putative relevance in a T-cell,mediated autoimmune disorder, multiple sclerosis (MS). Methods Expression of K2P5.1 was investigated on RNA and protein level in different immune cells and in MS patients' biospecimens (peripheral blood mononuclear cells, cerebrospinal fluid cells, brain tissue specimen). Functional consequences of K2P5.1 expression were analyzed using pharmacological modulation, small interfering RNA (siRNA), overexpression, electrophysiological recordings, and computer modeling. Results Human T cells constitutively express K2P5.1. After T-cell activation, a significant and time-dependent upregulation of K2P5.1 channel expression was observed. Pharmacological blockade of K2P5.1 or knockdown with siRNA resulted in reduced T-cell functions, whereas overexpression of K2P5.1 had the opposite effect. Electrophysiological recordings of T cells clearly dissected K2P5.1-mediated effects from other potassium channels. The pathophysiological relevance of these findings was demonstrated by a significant K2P5.1 upregulation in CD4+ and CD8+ T cells in relapsing/remitting MS (RRMS) patients during acute relapses as well as higher levels on CD8+ T cells of clinically isolated syndrome, RRMS, and secondary progressive multiple sclerosis patients during clinically stable disease. T cells in the cerebrospinal fluid from MS patients exhibit significantly elevated K2P5.1 levels. Furthermore, K2P5.1-positive T cells can be found in inflammatory lesions in MS tissue specimens. Interpretation Selective targeting of K2P5.1 may hold therapeutic promise for MS and putatively other T-cell,mediated disorders. ANN NEUROL 2010;68:58,69 [source] Importance of addressing National Electrical Code® violations that result in unusual exposure to 60 Hz magnetic fieldsBIOELECTROMAGNETICS, Issue 2 2004Jack Adams Abstract We evaluated wiring in multifamily developments containing National Electrical Code® (NEC®) violations as a source of unusual exposure to 60 Hz magnetic fields. Two methods were used in this evaluation: measurement and modeling. We measured the building wiring as a source of magnetic fields in six multifamily developments in Michigan. In this small sample, building wiring proved to be an important source of exposure in four of the six cases. In all four cases with exposure from building wiring, one or more NEC violations were involved. To supplement our measurement efforts, we used computer modeling to compare magnetic field exposure due to building wiring with magnetic field exposure from external power lines. Our calculations showed that where the building wiring has a NEC violation leading to net current loops, the exposure due to wiring is likely to be more important than that from external power lines. Our results support the results obtained in a recent study of the exposure of Californian K-12 students to magnetic fields, where building wiring with one or more NEC violation was found to be the single most important exposure source. If 60 Hz magnetic fields are important to avoid, then improved enforcement of the NEC, as required by law, is perhaps the single most important mitigation policy to adopt. Bioelectromagnetics 25:102,106, 2004. © 2004 Wiley-Liss, Inc. [source] An Inverse Substrate Orientation for the Regioselective Acylation of 3,,5,-Diaminonucleosides Catalyzed by Candida antarctica lipase B?CHEMBIOCHEM, Issue 8 2005Iván Lavandera Dr. Abstract Candida antarctica lipase B (CAL-B) catalyzes the regioselective acylation of natural thymidine with oxime esters and also the regioselective acylation of an analogue, 3,,5,-diamino-3,,5,-dideoxythymidine with nonactivated esters. In both cases, acylation favors the less hindered 5,-position over the 3,-position by upto 80-fold. Computer modeling of phosphonate transition-state analogues for the acylation of thymidine suggests that CAL-B favors acylation of the 5,-position because this orientation allows the thymine ring to bind in a hydrophobic pocket and forms stronger key hydrogen bonds than acylation of the 3,-position. On the other hand, computer modeling of phosphonamidate analogues of the transition states for acylation of either the 3,- or 5,-amino groups in 3,,5,-diamino-3,,5,-dideoxythymidine shows similar orientations and hydrogen bonds and, thus, does not explain the high regioselectivity. However, computer modeling of inverse structures, in which the acyl chain binds in the nucleophile pocket and vice versa, does rationalize the observed regioselectivity. The inverse structures fit the 5,-, but not the 3,-intermediate thymine ring, into the hydrophobic pocket, and form a weak new hydrogen bond between the O-2 carbonyl atom of the thymine and the nucleophile amine only for the 5,-intermediate. A water molecule might transfer a proton from the ammonium group to the active-site histidine. As a test of this inverse orientation, we compared the acylation of thymidine and 3,,5,-diamino-3,,5,-dideoxythymidine with butyryl acyl donors and with isosteric methoxyacetyl acyl donors. Both acyl donors reacted at equal rates with thymidine, but the methoxyacetyl acyl donor reacted four times faster than the butyryl acyl donor with 3,,5,-diamino-3,,5,-dideoxythymidine. This faster rate is consistent with an inverse orientation for 3,,5,-diamino-3,,5,-dideoxythymidine, in which the ether oxygen atom of the methoxyacetyl group can form a similar hydrogen bond to the nucleophilic amine. This combination of modeling and experiments suggests that such lipase-catalyzed reactions of apparently close substrate analogues like alcohols and amines might follow different pathways. [source] Anion,, Slides for Transmembrane TransportCHEMISTRY - A EUROPEAN JOURNAL, Issue 1 2009Jiri Mareda Dr. Abstract The recognition and transport of anions is usually accomplished by hydrogen bonding, ion pairing, metal coordination, and anion,dipole interactions. Here, we elaborate on the concept to use anion,, interactions for this purpose. Different to the popular cation,, interactions, applications of the complementary ,-acidic surfaces do not exist. This is understandable because the inversion of the aromatic quadrupole moment to produce ,-acidity is a rare phenomenon. Here, we suggest that ,-acidic aromatics can be linked together to produce an unbendable scaffold with multiple binding sites for anions to move along across a lipid bilayer membrane. The alignment of multiple anion,, sites is needed to introduce a cooperative multi-ion hopping mechanism. Experimental support for the validity of the concept comes from preliminary results with oligonaphthalenediimide (O-NDI) rods. Predicted by strongly positive facial quadrupole moments, the cooperativity and chloride selectivity found for anion transport by O-NDI rods were consistent with the existence of anion,, slides. The proposed mechanism for anion transport is supported by DFT results for model systems, as well as MD simulations of rigid O-NDI rods. Applicability of anion,, slides to achieve electroneutral photosynthesis is elaborated with the readily colorizable oligoperylenediimide (O-PDI) rods. To clarify validity, scope and limitations of these concepts, a collaborative research effort will be needed to address by computer modeling and experimental observations the basic questions in simple model systems and to design advanced multifunctional anion,, architectures. [source] Enantiomeric separation of dansyl amino acids using macrocyclic antibiotics as chiral mobile phase additives by narrow-bore high-performance liquid chromatographyCHIRALITY, Issue 3 2004V. Scott Sharp Abstract Seven macrocyclic antibiotics were evaluated as chiral selectors for the enantiomeric separation of 11 dansyl amino acids using narrow-bore high-performance liquid chromatography (HPLC). The macrocyclic antibiotics were incorporated as mobile phase additives to determine the enantioselective effects on the chiral analytes. The resolution and capacity factor (k,) of each analyte were assessed while varying the structure of macrocyclic antibiotic and the mobile phase buffer pH. The selectivity of the chiral selectors was measured as a function of changes in these parameters. All 11 dansyl amino acids were separated by at least one of the chiral selectors. Three-dimensional computer modeling of the more effective chiral selectors illustrated the importance of macrocyclic antibiotic structure concerning stereospecific analyte interaction. Chirality 16:153,161, 2004. © 2004 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||