A novel two-step recombinogenic engineering method for bacterial artificial chromosome manipulation

published_or_final_versio

Diesel exhaust and house dust mite allergen lead to common changes in the airway methylome and hydroxymethylome.

Exposures to diesel exhaust particles (DEP) from traffic and house dust mite (HDM) allergens significantly increase risks of airway diseases, including asthma. This negative impact of DEP and HDM may in part be mediated by epigenetic mechanisms. Beyond functioning as a mechanical barrier, airway epithelial cells provide the first line of immune defense towards DEP and HDM exposures. To understand the epigenetic responses of airway epithelial cells to these exposures, we exposed human bronchial epithelial cells to DEP and HDM and studied genome-wide 5-methyl-cytosine (5mC) and 5-hydroxy-methylcytosine (5hmC) at base resolution. We found that exposures to DEP and HDM result in elevated TET1 and DNMT1 expression, associated with 5mC and 5hmC changes. Interestingly, over 20% of CpG sites are responsive to both exposures and changes in 5mC at these sites negatively correlated with gene expression differences. These 5mC and 5hmC changes are located in genes and pathways related to oxidative stress responses, epithelial function and immune cell responses and are enriched for binding sites of transcription factors (TFs) involved in these pathways. Histone marks associated with promoters, enhancers and actively transcribed gene bodies were associated with exposure-induced DNA methylation changes. Collectively, our data suggest that exposures to DEP and HDM alter 5mC and 5hmC levels at regulatory regions bound by TFs, which coordinate with histone marks to regulate gene networks of oxidative stress responses, epithelial function and immune cell responses. These observations provide novel insights into the epigenetic mechanisms that mediate the epithelial responses to DEP and HDM in airways

Effective temperature for black holes

The physical interpretation of black hole's quasinormal modes is fundamental for realizing unitary quantum gravity theory as black holes are considered theoretical laboratories for testing models of such an ultimate theory and their quasinormal modes are natural candidates for an interpretation in terms of quantum levels. The spectrum of black hole's quasinormal modes can be re-analysed by introducing a black hole's effective temperature which takes into account the fact that, as shown by Parikh and Wilczek, the radiation spectrum cannot be strictly thermal. This issue changes in a fundamental way the physical understanding of such a spectrum and enables a re-examination of various results in the literature which realizes important modifies on quantum physics of black holes. In particular, the formula of the horizon's area quantization and the number of quanta of area result modified becoming functions of the quantum "overtone" number n. Consequently, the famous formula of Bekenstein-Hawking entropy, its sub-leading corrections and the number of microstates are also modified. Black hole's entropy results a function of the quantum overtone number too. We emphasize that this is the first time that black hole's entropy is directly connected with a quantum number. Previous results in the literature are re-obtained in the limit n \to \infty.Comment: 10 pages,accepted for publication in Journal of High Energy Physics. Comments are welcom

Spatial and temporal variations of aerosols around Beijing in summer 2006: Model evaluation and source apportionment

Regional aerosol model calculations were made using the Weather Research and Forecasting (WRF)-Community Multiscale Air Quality (CMAQ) and WRF-chem models to study spatial and temporal variations of aerosols around Beijing, China, in the summer of 2006, when the Campaigns of Air Quality Research in Beijing and Surrounding Region 2006 (CAREBeijing) intensive campaign was conducted. Model calculations captured temporal variations of primary (such as elemental carbon. (EC)) and secondary (such as sulfate) aerosols observed in and around Beijing. The spatial distributions of aerosol optical depth observed by the MODTS satellite sensors were also reproduced over northeast China. Model calculations showed distinct differences in spatial distributions between primary and secondary aerosols in association with synoptic-scale meteorology. Secondary aerosols increased in air around Beijing on a scale of about 1000 × 1000 km2 under an anticyclonic pressure system. This air mass was transported northward from the high anthropogenic emission area extending south of Beijing with continuous photochemical production. Subsequent cold front passage brought clean air from the north, and polluted air around Beijing was swept to the south of Beijing. This cycle was repeated about once a week and was found to be responsible for observed enhancements/reductions of aerosols at the intensive measurement sites. In contrast to secondary aerosols, the spatial distributions of primary aerosols (EC) reflected those of emissions, resulting in only slight variability despite the changes in synopticscale meteorology. In accordance with these results, source apportionment simulations revealed that primary aerosols around Beijing were controlled by emissions within 100 km around Beijing within the preceding 24 h, while emissions as far as 500 km and within the preceding 3 days were found to affect secondary aerosols. Copyright 2009 by the American Geophysical Union

A simple and robust method for connecting small-molecule drugs using gene-expression signatures

Interaction of a drug or chemical with a biological system can result in a gene-expression profile or signature characteristic of the event. Using a suitably robust algorithm these signatures can potentially be used to connect molecules with similar pharmacological or toxicological properties. The Connectivity Map was a novel concept and innovative tool first introduced by Lamb et al to connect small molecules, genes, and diseases using genomic signatures [Lamb et al (2006), Science 313, 1929-1935]. However, the Connectivity Map had some limitations, particularly there was no effective safeguard against false connections if the observed connections were considered on an individual-by-individual basis. Further when several connections to the same small-molecule compound were viewed as a set, the implicit null hypothesis tested was not the most relevant one for the discovery of real connections. Here we propose a simple and robust method for constructing the reference gene-expression profiles and a new connection scoring scheme, which importantly allows the valuation of statistical significance of all the connections observed. We tested the new method with the two example gene-signatures (HDAC inhibitors and Estrogens) used by Lamb et al and also a new gene signature of immunosuppressive drugs. Our testing with this new method shows that it achieves a higher level of specificity and sensitivity than the original method. For example, our method successfully identified raloxifene and tamoxifen as having significant anti-estrogen effects, while Lamb et al's Connectivity Map failed to identify these. With these properties our new method has potential use in drug development for the recognition of pharmacological and toxicological properties in new drug candidates.Comment: 8 pages, 2 figures, and 2 tables; supplementary data supplied as a ZIP fil

An improved multiquadric collocation method for 3-D electromagnetic problems

The multiquadric radial basis function method (MQ RBF or, simply, MQ) developed recently is a truly meshless collocation method with global basis functions. It was introduced for solving many 1- and 2-D partial differential equations (PDEs), including linear and nonlinear problems. However, few works are found for electromagnetic PDEs, especially for 3-D problems. This paper presents an improved MQ collocation method for 3-D electromagnetic problems. Numerical results show a considerable improvement in accuracy over the traditional MQ collocation method, although both methods are direct collocation method with exponential convergence. © 2007 IEEE

The HATNet and HATSouth Exoplanet Surveys

The Hungarian-made Automated Telescope Network (HATNet) has been in operation since 2003, with the key science goal being the discovery and accurate characterization of transiting extrasolar planets (TEPs) around bright stars. Using six small, 11\,cm\ aperture, fully automated telescopes in Arizona and Hawaii, as of 2017 March, it has discovered and accurately characterized 67 such objects. The HATSouth network of telescopes has been in operation since 2009, using slightly larger, 18\,cm diameter optical tubes. It was the first global network of telescopes using identical instrumentation. With three premier sites spread out in longitude (Chile, Namibia, Australia), the HATSouth network permits round-the-clock observations of a 128 square arcdegree swath of the sky at any given time, weather permitting. As of this writing, HATSouth has discovered 36 transiting exoplanets. Many of the altogether ~100 HAT and HATSouth exoplanets were the first of their kind. They have been important contributors to the rapidly developing field of exoplanets, motivating and influencing observational techniques, theoretical studies, and also actively shaping future instrumentation for the detection and characterization of such objects.Comment: Invited review chapter, accepted for publication in "Handbook of Exoplanets", edited by H.J. Deeg and J.A. Belmonte, Springer Reference Work

State Transfer Between a Mechanical Oscillator and Microwave Fields in the Quantum Regime

Recently, macroscopic mechanical oscillators have been coaxed into a regime of quantum behavior, by direct refrigeration [1] or a combination of refrigeration and laser-like cooling [2, 3]. This exciting result has encouraged notions that mechanical oscillators may perform useful functions in the processing of quantum information with superconducting circuits [1, 4-7], either by serving as a quantum memory for the ephemeral state of a microwave field or by providing a quantum interface between otherwise incompatible systems [8, 9]. As yet, the transfer of an itinerant state or propagating mode of a microwave field to and from a mechanical oscillator has not been demonstrated owing to the inability to agilely turn on and off the interaction between microwave electricity and mechanical motion. Here we demonstrate that the state of an itinerant microwave field can be coherently transferred into, stored in, and retrieved from a mechanical oscillator with amplitudes at the single quanta level. Crucially, the time to capture and to retrieve the microwave state is shorter than the quantum state lifetime of the mechanical oscillator. In this quantum regime, the mechanical oscillator can both store and transduce quantum information

Signal peptide peptidases and gamma-secretase: Cousins of the same protease family?

Signal peptide peptidase (SPIP) is an unusual aspartyl protease, which mediates clearance of signal peptides by proteolysis within the endoplasmic reticulum (ER). Like presenilins, which provide the proteolytically active subunit of the,gamma-secretase complex, SPP contains a conserved GxGD motif in its C-terminal domain which is critical for its activity. While SPIP is known to be an aspartyl protease of the GxGD type, several presenilin homologues/SPP-like proteins (PSHs/ SPPL) of unknown function have been identified by database searches. In contrast to SPP and SPPL3, which are both restricted to the endoplasmic reticulum, SPPL2b is targeted through the secretory pathway to endosomes/lysosomes. As suggested by the differential subcellular localization of SPPL2b and SPPL3 distinct phenotypes were found upon antisense gripNA-mediated knockdown in zebrafish. spp and sppl3 knockdowns in zebrafish result in cell death within the central nervous system, whereas reduction of sppl2b expression causes erythrocyte accumulation in an enlarged caudal vein. Moreover, expression of D/A mutants of the putative C-terminal active sites of spp, sppl2, and spp13 produced phenocopies of the respective knockdown phenotypes. These data suggest that all investigated PSHs/SPPLs are members of the novel family of GxGD aspartyl proteases. More recently, it was shown that SPPL2b utilizes multiple intramembrane cleavages to liberate the TNF(x intracellular domain into the cytosol and to release the C-terminal counterpart into the lumen. These findings suggest common principles of intramembrane proteolysis by GxGD type aspartyl proteases. In this article,we will review the similarities of SPPs and gamma-secretase based on recent findings by us and others