Abstract

We present a methodology for implementing discrete-time signal processing operations, such as filtering, with molecular reactions. The reactions produce time-varying output quantities of molecules as a function of time-varying input quantities according to a functional specification. This computation is robust and independent of the reaction rates, provided that the rate constants fall within coarse categories. We describe two approaches: one entails synchronization with a clock signal, implemented through sustained chemical oscillations; the other is ?self-timed? or asynchronous. We illustrate the methodology ...

Abstract

The dissociative electron-attachment (DEA) phenomena at the N1?H and N3?H bonds observed experimentally at low energies (<3 eV) in uracil are studied with the CASSCF/CASPT2 methodology. Two valence-bound π? and two dissociative σ? states of the uracil anionic species, together with the ground state of the neutral molecule, are proven to contribute to the shapes appearing in the experimental DEA cross sections. Conical intersections (CI) between the π? and σ? are established as the structures which activate the DEA processes. The ...

Abstract

Both protein and solid-state nanopores are under intense investigation for the analysis of nucleic acids. A crucial advantage of protein nanopores is that site-directed mutagenesis permits precise tuning of their properties. Here, by augmenting the internal positive charge within the alpha-hemolysin pore and varying its distribution, we increase the frequency of translocation of a 92-nt single-stranded DNA through the pore at +120 mV by approximately ...

Abstract

The scanning tunnelling microscope is capable of the real-space imaging and spectroscopy of molecules on an atomic scale. Numerous attempts have been made to use the scanning tunnelling microscope to sequence single DNA molecules, but difficulties in preparing samples of long-chain DNA molecules on surfaces, and problems in reproducing results have limited these experiments1, 2, 3, 4, 5, 6. Here, we report single-molecule DNA sequencing with a scanning tunnelling microscope by using an oblique pulse-injection method to deposit the molecules onto ...

Abstract

Solid-state nanopores have emerged as possible candidates for next-generation DNA sequencing devices. In such a device, the DNA sequence would be determined by measuring how the forces on the DNA molecules, and also the ion currents through the nanopore, change as the molecules pass through the nanopore. Unlike their biological counterparts, solid-state nanopores have the advantage that they can withstand a wide range of analyte solutions and environments. Here we report solid-state nanopore channels that are selective towards single-stranded DNA (ssDNA). Nanopores functionalized with a `probe' of hair-pin loop DNA ...

Abstract

DNA nanotechnology1, 2 and particularly DNA origami3, in which long, single-stranded DNA molecules are folded into predetermined shapes, can be used to form complex self-assembled nanostructures4, 5, 6, 7, 8, 9, 10. Although DNA itself has limited chemical, optical or electronic functionality, DNA nanostructures can serve as templates for building materials with new functional properties. Relatively large nanocomponents such as nanoparticles and biomolecules can also be integrated into DNA nanostructures and imaged11, 12, 13. Here, we show that chemical reactions with ...

Abstract

Under dilute in vitro conditions transcription factors rapidly locate their target sequence on DNA by using the facilitated diffusion mechanism. However, whether this strategy of alternating between three-dimensional bulk diffusion and one-dimensional sliding along the DNA contour is still beneficial in the crowded interior of cells is highly disputed. Here we use a simple model for the bacterial genome inside the cell and present a semi-analytical model for the in vivo target search of transcription factors within the facilitated diffusion framework. ...

Abstract

The ability to control the interaction of polyelectrolytes, such as DNA or proteins, with charged surfaces is of pivotal importance for a multitude of biotechnological applications. Previously, we measured the desorption forces of single polymers on charged surfaces using an atomic force microscope. Here, we show that the adhesion of DNA on gold electrodes modified with self-assembled monolayers can be biased by the composition of the monolayer and externally controlled by means of the electrode potential. Positive potentials induced DNA adsorption ...

Abstract

The anionic nickel(II) porphyrin NiTPPS is able to selectively sense the spermine induced left-handed Z-form of DNA while it is completely silent in the presence of right-handed B-DNA. Interactions between the DNA and the porphyrin can be easily modulated by pH and temperature. The resulting Z-DNA?porphyrin?spermine complex behaves as a supramolecular reversible information storage system and as a reversible AND logic gate. ...

Abstract

We have explored the utility, strength, and limitation of through-space exciton-coupled circular dichroism in determination of the secondary structure of optically active chromophoric nanoarrays using the example of end-capped porphyrin– and metalloporphyrin–oligodeoxynucleotide conjugates. We put special emphasis on the explanation of the origin and significance of the distinctive multiple bands in the CD spectra (trisignate and tetrasignate CD bands). Such CD profiles are often observed in chiral aggregates or multichromophoric arrays but have never before been studied in detail. We found ...

Abstract

The interesting structural, electronic, and optical properties of DNA provide fascinating opportunities for developing nanoscale smart materials by integrating DNA with opto-electronic components. In this article we demonstrate the electrostatic binding of an amine-terminated dithienylethene (DET) molecular switch to double-stranded synthetic polynucleotides. The DET switch can undergo photochemical ring-closure and opening reactions. Circular dichroism (CD) and UV?vis spectroscopy show that both the open, 1o, and the closed, 1c, forms of the switch bind to DNA. Upon addition of DNA to a ...

Abstract

Archimedean tilings are periodic polygonal tessellations that are created by placing regular polygons edge-to-edge around a vertex to fill the plane. Here we show that three- and four-arm DNA junction tiles with specifically designed arm lengths and intertile sticky-end interactions can be used to form sophisticated two-dimensional (2D) and three-dimensional (3D) tessellation patterns. We demonstrate two different complex Archimedean patterns, (33.42) and (32.4.3.4), and the formation of 2D lattices, 3D tubes, and sealed polygon-shaped pockets from the tessellations. The successful growth ...

Abstract

Summary: The mesoscopic statistical physics models, known generically as Peyrard–Bishop (PB) models, have found many applications for the study of oligonucleotide properties. Unfortunately, PB models have not reached a wider non-specialized audience for the lack of freely available software implementations. Here we present an extensible C++ implementation of four variants of the PB model, which allows the user to calculate melting temperatures from tested model parameters. Even for a non-specialist, it should be straightforward to change these parameters to reflect different ...

Abstract

DNA methylation is an important epigenetic mark in many eukaryotic organisms. De novo DNA methylation in plants can be achieved by the RNA-directed DNA methylation (RdDM) pathway, where the plant-specific DNA-dependent RNA polymerase IV (Pol IV) transcribes target sequences to initiate 24-nt siRNA production and action. The putative DNA binding protein DTF1/SHH1 of Arabidopsis has been shown to associate with Pol IV and is required for 24-nt siRNA accumulation and transcriptional silencing at several RdDM target loci. However, the extent and ...

Abstract

The capacity for sustained self-renewal膒the generation of daughter cells having the same regenerative properties as the parent cell膒is the defining feature of hematopoietic stem cells (HSCs). Strong evidence exists that self-renewal of HSC is under extrinsic biological control in vivo. A variety of cytokines, morphogenic ligands and associated signaling components influence self-renewal in culture and in vivo. Specific homeobox transcription factors act as powerful intrinsic agonists of HSC self-renewal in vitro and in vivo when supplied either as transduced cDNAs or ...

Abstract

In Saccharomyces cerevisiae and higher eukaryotes, the loading of the replicative helicase MCM2-7 onto DNA requires the combined activities of ORC, Cdc6, and Cdt1. These proteins load MCM2-7 in an unknown way into a double hexamer around DNA. Here we show that MCM2-7 recruitment by ORC/Cdc6 is blocked by an autoinhibitory domain in the C terminus of Mcm6. Interestingly, Cdt1 can overcome this inhibitory activity, ...

Abstract

Plant improvement depends on generating phenotypic variation and selecting for characteristics that are heritable. Classical genetics and early molecular genetics studies on single genes showed that differences in chromatin structure, especially cytosine methylation, can contribute to heritable phenotypic variation. Recent molecular genetic and genomic studies have revealed a new importance of cytosine methylation for gene regulation and have identified RNA interference (RNAi)-related proteins that are necessary for methylation. Methylation differences among plants can be caused by cis- or trans-acting DNA polymorphisms ...

Abstract

The reference sequence for each human chromosome provides the framework for understanding genome function, variation and evolution. Here we report the finished sequence and biological annotation of human chromosome 1. Chromosome 1 is gene-dense, with 3,141 genes and 991 pseudogenes, and many coding sequences overlap. Rearrangements and mutations of chromosome 1 are prevalent in cancer and many other diseases. Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, and also in regions ...

Abstract

RNA is sensed by Toll-like receptor 7 (TLR7) and TLR8 or by the RNA helicases LGP2, Mda5 and RIG-I to trigger antiviral responses. Much less is known about sensors for DNA. Here we identify a novel DNA-sensing pathway involving RNA polymerase III and RIG-I. In this pathway, AT-rich double-stranded DNA (dsDNA) served as a template for RNA polymerase III and was transcribed into double-stranded RNA (dsRNA) containing a 5'-triphosphate moiety. Activation of RIG-I by this dsRNA induced production of type I ...

Note (first note only)

Ablasser, Andrea Bauernfeind, Franz Hartmann, Gunther Latz, Eicke Fitzgerald, Katherine A Hornung, Veit AI-065483/AI/NIAID NIH HHS/ AI-067497/AI/NIAID NIH HHS/ AI-083713/AI/NIAID NIH HHS/ Nat Immunol. 2009 Oct;10(10):1065-72. Epub 2009 Jul 16.

Abstract

Generation of high titer lentiviral stocks and efficient virus concentration are central to maximize the utility of lentiviral technology. Here we evaluate published protocols for lentivirus production on a range of transfer vectors differing in size (7.5-13.2 kb). We present a modified virus production protocol robustly yielding useful titers (up to 10(7)/ml) for a range of different transfer vectors containing packaging inserts up to 7.5 kb. Moreover, we find that virus recovery after concentration by ultracentrifugation depends on the size of ...

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al Yacoub, Nadya Romanowska, Malgorzata Haritonova, Natalie Foerster, John eng England 2007/05/30 09:00 J Gene Med. 2007 Jul;9(7):579-84.

Abstract

Interferon-gamma receptor ligand-binding chain (IFN-gammaR1) or signaling chain (IFN-gammaR2) deficiency, like interleukin 12 receptor beta1 chain (IL-12Rbeta1) deficiency, predispose to severe infections due to poorly virulent mycobacteria and salmonella. A child with bacille Calmette-Guerin and Salmonella enteritidis infection was investigated. Mutations in the genes for IFN-gammaR1, IFN-gammaR2, IL-12Rbeta1, and other molecules implicated in IL-12- or IFN-gamma-mediated immunity were sought. A large homozygous deletion within the IL-12 p40 subunit gene was found, precluding expression of functional IL-12 p70 cytokine by activated dendritic ...

Note (first note only)

Altare, F Lammas, D Revy, P Jouanguy, E Doffinger, R Lamhamedi, S Drysdale, P Scheel-Toellner, D Girdlestone, J Darbyshire, P Wadhwa, M Dockrell, H Salmon, M Fischer, A Durandy, A Casanova, J L Kumararatne, D S J Clin Invest. 1998 Dec 15;102(12):2035-40.

Abstract

Infectious diseases have been paramount among the threats to health and survival throughout human evolutionary history. Natural selection is therefore expected to act strongly on host defense genes, particularly on innate immunity genes whose products mediate the direct interaction between the host and the microbial environment. In insects and mammals, the Toll-like receptors (TLRs) appear to play a major role in initiating innate immune responses against microbes. In humans, however, it has been speculated that the set of TLRs could be ...

Note (first note only)

Barreiro, Luis B Ben-Ali, Meriem Quach, Helene Laval, Guillaume Patin, Etienne Pickrell, Joseph K Bouchier, Christiane Tichit, Magali Neyrolles, Olivier Gicquel, Brigitte Kidd, Judith R Kidd, Kenneth K Alcais, Alexandre Ragimbeau, Josiane Pellegrini, Sandra Abel, Laurent Casanova, Jean-Laurent Quintana-Murci, Lluis eng Howard Hughes Medical Institute/ Research Support, Non-U.S. Gov't 2009/07/18 09:00 PLoS Genet. 2009 Jul;5(7):e1000562. doi: 10.1371/journal.pgen.1000562. Epub 2009 Jul 17.

Abstract

Herpes simplex virus (HSV) hepatitis is a rare and potential life-threatening disease. The diagnosis of HSV hepatitis is hampered by its indifferent clinical presentation, which necessitates confirmatory laboratory data to identify HSV in the affected liver. However, liver biopsies are often contraindicated in the context of coagulopathy, are prone to sampling errors and have low sensitivity in mild HSV hepatitis cases. There is an unmet need for less invasive diagnostic tools. The diagnostic and therapeutic value of HSV DNA load and ...

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Beersma, M F C Verjans, G M G M Metselaar, H J Osterhaus, A D M E Berrington, W R van Doornum, G J K08 AI080952 01A1/AI/NIAID NIH HHS/ England J Viral Hepat. 2011 Apr;18(4):e160-6. doi: 10.1111/j.1365-2893.2010.01352.x. Epub 2010 Aug 12.

Abstract

BACKGROUND: Quantification of herpes simplex virus (HSV) DNA in the peripheral blood is often used to evaluate patients suspected of having disseminated HSV infection. Few studies have examined the clinical correlates of HSV viremia among adults. METHODS: We conducted a retrospective analysis of blood samples sent to a molecular virology reference laboratory at a university hospital for quantification of HSV DNA from October 2001 through June 2006. Medical records of patients with detectable HSV DNA were reviewed to abstract relevant clinical ...

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Berrington, William R Jerome, Keith R Cook, Linda Wald, Anna Corey, Lawrence Casper, Corey AI-030731/AI/NIAID NIH HHS/ AI-07044/AI/NIAID NIH HHS/ AI-54162/AI/NIAID NIH HHS/ K08 AI080952-01A1/AI/NIAID NIH HHS/ K23 AI054162-01/AI/NIAID NIH HHS/ K23 AI054162-02/AI/NIAID NIH HHS/ K23 AI054162-03/AI/NIAID NIH HHS/ K23 AI054162-04/AI/NIAID NIH HHS/ K23 AI054162-05/AI/NIAID NIH HHS/ K24 AI-071113/AI/NIAID NIH HHS/ K24 AI071113-01/AI/NIAID NIH HHS/ K24 AI071113-02/AI/NIAID NIH HHS/ K24 AI071113-03/AI/NIAID NIH HHS/ K24 AI071113-04/AI/NIAID NIH HHS/ L30 AI075827-02/AI/NIAID NIH HHS/ P01 AI030731-18/AI/NIAID NIH HHS/ T32 AI007044-34/AI/NIAID NIH HHS/ Clin Infect Dis. 2009 Nov 1;49(9):1295-301.

Abstract

Legionella pneumophila, the causative agent of Legionnaires' disease and related pneumonias, infects, replicates within and eventually kills human macrophages. A key feature of the intracellular life-style is the ability of the organism to replicate within a specialized phagosome which does not fuse with lysosomes or acidify. Avirulent mutants that are defective in intracellular multiplication and host-cell killing are unable to prevent phagosome-lysosome fusion. In a previous study, a 12 kb fragment of the L. pneumophila genome containing the icm locus (intracellular ...

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Brand, B C Sadosky, A B Shuman, H A AI-08304/AI/NIAID NIH HHS/ AI-23549/AI/NIAID NIH HHS/ ENGLAND Mol Microbiol. 1994 Nov;14(4):797-808.

Abstract

Adaptation to the host environment and exploitation of host cell functions are critical to the success of intracellular pathogens. Here, insight to these virulence mechanisms was obtained for the first time from the transcriptional program of the human pathogen Legionella pneumophila during infection of its natural host, Acanthamoeba castellanii. The biphasic life cycle of L. pneumophila was reflected by a major shift in gene expression from replicative to transmissive phase, concerning nearly half of the genes predicted in the genome. However, ...

Note (first note only)

Bruggemann, Holger Hagman, Arne Jules, Matthieu Sismeiro, Odile Dillies, Marie-Agnes Gouyette, Catherine Kunst, Frank Steinert, Michael Heuner, Klaus Coppee, Jean-Yves Buchrieser, Carmen England Cell Microbiol. 2006 Aug;8(8):1228-40.

Abstract

We have identified and analyzed the mRNA sequence of 20 new defensin-like peptides from 11 Australian termite species of Nasutitermes and from an outgroup, Drepanotermes rubriceps. The sequence was amplified by reverse transcriptase PCR with a degenerate primer designed from termicin, an antifungal peptide previously characterized from the termite Pseudocanthotermes spiniger. All 20 genes show high sequence identity with P. spiniger termicin and have duplicated repeatedly during the radiation of Nasutitermes. Comparison of the relative fixation rates of synonymous (silent) and ...

Note (first note only)

Bulmer, Mark S Crozier, Ross H eng Comparative Study Research Support, Non-U.S. Gov't 2004/08/20 05:00 Mol Biol Evol. 2004 Dec;21(12):2256-64. Epub 2004 Aug 18.

Abstract

Alteration of correct splicing patterns by disruption of an exonic splicing enhancer may be a frequent mechanism by which point mutations cause genetic diseases. Spinal muscular atrophy results from the lack of functional survival of motor neuron 1 gene (SMN1), even though all affected individuals carry a nearly identical, normal SMN2 gene. SMN2 is only partially active because a translationally silent, single-nucleotide difference in exon 7 causes exon skipping. Using ESE motif-prediction tools, mutational analysis and in vivo and in vitro ...

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Cartegni, Luca Krainer, Adrian R Nat Genet. 2002 Apr;30(4):377-84. Epub 2002 Mar 4.

Abstract

Bacteria use conjugation systems, a subfamily of the type IV secretion systems, to transfer DNA to recipient cells. Despite 50 years of research, the architecture and mechanism of action of the channel mediating DNA transfer across the bacterial cell envelope remains obscure. By use of a sensitive, quantifiable assay termed transfer DNA immunoprecipitation (TrIP), we identify contacts between a DNA substrate (T-DNA) and 6 of 12 components of the VirB/D4 conjugation system of the phytopathogen Agrobacterium tumefaciens. Our results define the ...

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Cascales, Eric Christie, Peter J GM48746/GM/NIGMS NIH HHS/ New York, N.Y. Science. 2004 May 21;304(5674):1170-3.

Abstract

Helicobacter spp. represent a proportionately small but significant component of the normal intestinal microflora of animal hosts. Several of these intestinal Helicobacter spp. are known to induce colitis in mouse models, yet the mechanisms by which these bacteria induce intestinal inflammation are poorly understood. To address this question, we performed in vitro co-culture experiments with mouse and human epithelial cell lines stimulated with a selection of Helicobacter spp., including known pathogenic species as well as ones for which the pathogenic potential ...

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Chaouche-Drider, Nadia Kaparakis, Maria Karrar, Abdulgader Fernandez, Maria-Isabel Carneiro, Letitia A M Viala, Jerome Boneca, Ivo Gomperts Moran, Anthony P Philpott, Dana J Ferrero, Richard L Howard Hughes Medical Institute/ PLoS One. 2009;4(4):e5396. Epub 2009 Apr 29.

Abstract

We have shown by a variety of microscopical and biochemical techniques that Salmonella spp. are cytotoxic for cultured J774A.1 and bone marrow-derived murine macrophages. The cytotoxicity is initially manifested by inhibition of membrane ruffling and macropinocytosis in infected macrophages, and is followed by cell death. Macrophages killed by Salmonella spp. exhibited features of apoptosis such as condensation and fragmentation of chromatin, membrane blebbing, and the presence of cytoplasmic nucleosomes and apoptotic bodies. Cytotoxicity does not require bacterial internalization as cytochalasin D, ...

Note (first note only)

Chen, L M Kaniga, K Galan, J E eng AI30492/AI/NIAID NIH HHS/ GM52543/GM/NIGMS NIH HHS/ Comparative Study Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. ENGLAND 1996/09/01 Mol Microbiol. 1996 Sep;21(5):1101-15.

Abstract

Type I interferons (IFNs) are important for antiviral and autoimmune responses. Retinoic acid-induced gene I (RIG-I) and mitochondrial antiviral signaling (MAVS) proteins mediate IFN production in response to cytosolic double-stranded RNA or single-stranded RNA containing 5'-triphosphate (5'-ppp). Cytosolic B form double-stranded DNA, such as poly(dA-dT)*poly(dA-dT) [poly(dA-dT)], can also induce IFN-beta, but the underlying mechanism is unknown. Here, we show that the cytosolic poly(dA-dT) DNA is converted into 5'-ppp RNA to induce IFN-beta through the RIG-I pathway. Biochemical purification led to the ...

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Chiu, Yu-Hsin Macmillan, John B Chen, Zhijian J R01 AI060919-05/AI/NIAID NIH HHS/ R01 GM063692-08/GM/NIGMS NIH HHS/ Cell. 2009 Aug 7;138(3):576-91. Epub 2009 Jul 23.

Abstract

Chronic active EBV disease (CAEBV) is a lymphoproliferative disorder characterized by markedly elevated levels of antibody to EBV or EBV DNA in the blood and EBV RNA or protein in lymphocytes in tissues. We present our experience with CAEBV during the last 28 years, including the first 8 cases treated with hematopoietic stem cell transplantation in the United States. Most cases of CAEBV have been reported from Japan. Unlike CAEBV in Japan, where EBV is nearly always found in T or ...

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Cohen, Jeffrey I Jaffe, Elaine S Dale, Janet K Pittaluga, Stefania Heslop, Helen E Rooney, Cliona M Gottschalk, Stephen Bollard, Catherine M Rao, V Koneti Marques, Adriana Burbelo, Peter D Turk, Siu-Ping Fulton, Rachael Wayne, Alan S Little, Richard F Cairo, Mitchell S El-Mallawany, Nader K Fowler, Daniel Sportes, Claude Bishop, Michael R Wilson, Wyndham Straus, Stephen E eng CA094237/CA/NCI NIH HHS/ P01 CA094237-09/CA/NCI NIH HHS/ P50 CA126752-04/CA/NCI NIH HHS/ P50CA126752/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural 2011/04/02 06:00 Blood. 2011 Jun 2;117(22):5835-49. doi: 10.1182/blood-2010-11-316745. Epub 2011 Mar 31.

Abstract

Mycobacterium tuberculosis is an obligate human pathogen capable of persisting in individual hosts for decades. We sequenced the genomes of 21 strains representative of the global diversity and six major lineages of the M. tuberculosis complex (MTBC) at 40- to 90-fold coverage using Illumina next-generation DNA sequencing. We constructed a genome-wide phylogeny based on these genome sequences. Comparative analyses of the sequences showed, as expected, that essential genes in MTBC were more evolutionarily conserved than nonessential genes. Notably, however, most of ...

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Comas, Inaki Chakravartti, Jaidip Small, Peter M Galagan, James Niemann, Stefan Kremer, Kristin Ernst, Joel D Gagneux, Sebastien eng AI034238/AI/NIAID NIH HHS/ AI046097/AI/NIAID NIH HHS/ AI051242/AI/NIAID NIH HHS/ HHSN266200400001C/PHS HHS/ HHSN266200700022C/PHS HHS/ R01 AI046097/AI/NIAID NIH HHS/ R01 AI046097-10/AI/NIAID NIH HHS/ R01 AI051242/AI/NIAID NIH HHS/ R01 AI051242-08/AI/NIAID NIH HHS/ R01 AI051242-10/AI/NIAID NIH HHS/ R01 AI090928/AI/NIAID NIH HHS/ U117588500(88500)/Medical Research Council/United Kingdom Howard Hughes Medical Institute/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2010/05/25 06:00 Nat Genet. 2010 Jun;42(6):498-503. doi: 10.1038/ng.590. Epub 2010 May 23.