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

Trace chemical measurements from the northern midlatitude lowermost stratosphere in early spring: Distributions, correlations, and fate

In situ measurements of a large number of trace chemicals from the midlatitude (37-57°N) lower stratosphere were performed with the NASA DC-8 aircraft during March 1994. Deepest penetrations into the stratosphere (550 ppb O3, 279 ppb N2O, and 350 K potential temperature) corresponded to a region that has been defined as the "lowermost stratosphere" (LS) by Holton et al [1995]. Analysis of data shows that the mixing ratios of long-lived tracer species (e. g. CH4, HNO3, NOy, CFCs) are linearly correlated with those of O3 and N2O. A ΔNOy/ΔO3 of 0.0054 ppb/ppb and ΔNOy/ΔN2O of -0.081 ppb/ppb is in good agreement with other reported measurements from the DC-8. These slopes are however, somewhat steeper than those reported from the ER-2 airborne studies. We find that the reactive nitrogen budget in the LS is largely balanced with HNO3 accounting for 80% of NOy, and PAN and NOx together accounting for 5%. A number of oxygenated species (e. g. acetone, H2O2) were present and may provide an important in situ source of HOx in the LS. SO2 mixing ratios were found to increase in the stratosphere at a rate that was comparable to the decline in OCS levels. No evidence of particle formation could be observed. Ethane, propane, and acetylene mixing ratios declined rapidly in the LS with Cl atoms likely playing a key role in this process. A number of reactive hydrocarbons/halocarbons (e. g. C6H6, CH3I) were present at low but measurable concentrations

Latitudinal distribution of reactive nitrogen in the free troposphere over the Pacific Ocean in late winter/early spring

The late winter/early spring (February/March, 1994) measurements of Pacific Exploratory Mission-West (PEM-W) B have been analyzed to show latitudinal distributions (45°N to 10°S) of the mixing ratios of reactive nitrogen species (NO, peroxyacetylnitrate (PAN), HNO3, and NOy), ozone, and chemical tracers (CO, NMHCs, acetone, and C2Cl4) with a focus on the upper troposphere. Mixing ratios of all species are relatively low in the warm tropical and subtropical air south of the polar jetstream (≈28°N) but increase sharply with latitude in the cold polar air north of the jetstream. Noteworthy is the continuous increase in reservoir species (PAN and HNO3) and the simultaneous decrease in NOx toward the northern midlatitudes. The Harvard global three-dimensional model of tropospheric chemistry has been used to compare these observations with predictions. In the upper troposphere the magnitude and distribution of measured NOy and PAN as a function of latitude is well represented by this model, while NOx (measured NO + model calculated NO2) is underpredicted, especially in the tropics. Unlike several previous studies, where model-predicted HNO3 exceeded observations by as much as a factor of 10, the present data/model comparison is improved to within a factor of 2. The predicted upper tropospheric HNO3 is generally below or near measured values, and there is little need to invoke particle reactions as a means of removing or recycling HNO3. Comparison between measured NOy and the sum of its three main constituents (PAN + NOx + HNO3) on average show a small mean shortfall (<15%). This shortfall could be attributed to the presence of known but unmeasured species (e.g., peroxynitric acid and alkyl nitrates) as well as to instrument errors. Copyright 1998 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

Hidden Conformal Symmetry of Extremal Kerr-Bolt Spacetimes

We show that extremal Kerr-Bolt spacetimes have a hidden conformal symmetry. In this regard, we consider the wave equation of a massless scalar field propagating in extremal Kerr-Bolt spacetimes and find in the "near region", the wave equation in extremal limit can be written in terms of the $SL(2,R)$ quadratic Casimir. Moreover, we obtain the microscopic entropy of the extremal Kerr-Bolt spacetimes also we calculate the correlation function of a near-region scalar field and find perfect agreement with the dual 2D CFT.Comment: 13 page

Analytical and numerical analyses of the micromechanics of soft fibrous connective tissues

State of the art research and treatment of biological tissues require accurate and efficient methods for describing their mechanical properties. Indeed, micromechanics motivated approaches provide a systematic method for elevating relevant data from the microscopic level to the macroscopic one. In this work the mechanical responses of hyperelastic tissues with one and two families of collagen fibers are analyzed by application of a new variational estimate accounting for their histology and the behaviors of their constituents. The resulting, close form expressions, are used to determine the overall response of the wall of a healthy human coronary artery. To demonstrate the accuracy of the proposed method these predictions are compared with corresponding 3-D finite element simulations of a periodic unit cell of the tissue with two families of fibers. Throughout, the analytical predictions for the highly nonlinear and anisotropic tissue are in agreement with the numerical simulations

New Near Horizon Limit in Kerr/CFT

The extremal Kerr black hole with the angular momentum J is conjectured to be dual to CFT with central charges c_L=c_R=12J. However, the central charge in the right sector remains to be explicitly derived so far. In order to investigate this issue, we introduce new near horizon limits of (near) extremal Kerr and five-dimensional Myers-Perry black holes. We obtain Virasoro algebras as asymptotic symmetries and calculate the central charges associated with them. One of them is equivalent to that of the previous studies, and the other is non-zero, but still the order of near extremal parameter. Redefining the algebras to take the standard form, we obtain a finite value as expected by the Kerr/CFT correspondence.Comment: 25 pages, minor changes, references adde

Ligand-based virtual screening using binary kernel discrimination

This paper discusses the use of a machine-learning technique called binary kernel discrimination (BKD) for virtual screening in drug- and pesticide-discovery programmes. BKD is compared with several other ligand-based tools for virtual screening in databases of 2D structures represented by fragment bit-strings, and is shown to provide an effective, and reasonably efficient, way of prioritising compounds for biological screening