Kinetic analysis of an efficient DNA-dependent TNA polymerase.

alpha-l-Threofuranosyl nucleoside triphosphates (tNTPs) are tetrafuranose nucleoside derivatives and potential progenitors of present-day beta-d-2'-deoxyribofuranosyl nucleoside triphosphates (dNTPs). Therminator DNA polymerase, a variant of the 9 degrees N DNA polymerase, is an efficient DNA-directed threosyl nucleic acid (TNA) polymerase. Here we report a detailed kinetic comparison of Therminator-catalyzed TNA and DNA syntheses. We examined the rate of single-nucleotide incorporation for all four tNTPs and dNTPs from a DNA primer-template complex and carried out parallel experiments with a chimeric DNA-TNA primer-DNA template containing five TNA residues at the primer 3'-terminus. Remarkably, no drop in the rate of TNA incorporation was observed in comparing the DNA-TNA primer to the all-DNA primer, suggesting that few primer-enzyme contacts are lost with a TNA primer. Moreover, comparison of the catalytic efficiency of TNA synthesis relative to DNA synthesis at the downstream positions reveals a difference of no greater than 5-fold in favor of the natural DNA substrate. This disparity becomes negligible when the TNA synthesis reaction mixture is supplemented with 1.25 mM MnCl(2). These results indicate that Therminator DNA polymerase can recognize both a TNA primer and tNTP substrates and is an effective catalyst of TNA polymerization despite changes in the geometry of the reactants

Ehrenfest-time dependence of counting statistics for chaotic ballistic systems

Transport properties of open chaotic ballistic systems and their statistics can be expressed in terms of the scattering matrix connecting incoming and outgoing wavefunctions. Here we calculate the dependence of correlation functions of arbitrarily many pairs of scattering matrices at different energies on the Ehrenfest time using trajectory based semiclassical methods. This enables us to verify the prediction from effective random matrix theory that one part of the correlation function obtains an exponential damping depending on the Ehrenfest time, while also allowing us to obtain the additional contribution which arises from bands of always correlated trajectories. The resulting Ehrenfest-time dependence, responsible e.g. for secondary gaps in the density of states of Andreev billiards, can also be seen to have strong effects on other transport quantities like the distribution of delay times.Comment: Refereed version. 15 pages, 14 figure

Factors Associated with N-specific IgG Response in Piglets Experimentally Infected with Porcine Reproductive and Respiratory Syndrome Virus

This study examined serum porcine reproductive and respiratory syndrome virus (PRRSV) N protein-specific IgG levels from sera collected from 464 Large White-Landrace commercial crossbred piglets from three separate experimental infection trials with PRRSV isolate NVSL-97- 7895. IgG levels at 42 days post infection (dpi) were measured by fluorescent microsphere immunoassay, herein referred to as total antibody (tAb) response. tAb levels were assessed for an association with different disease-related traits, the presence of a heritable genetic component, and for genomic regions associated with tAb response. tAb response was negatively associated with viral load (VL) and weight gain from 28-42 dpi (WG) and positively associated with virus rebound (REB) and neutralizing antibody (nAb) levels. Furthermore, tAb response had a heritable genetic component, with a major QTL located on chromosome 7 in the major histocompatibility complex (MHC), whereby heterozygous individuals had a lower tAb response and increased weight gain from 28-42 dpi. These results suggest that genetic selection for tAb response may be useful for selecting for pigs that have increased resistance or reduced susceptibility to PRRSV

Prevalence and determinants of dietary supplement and non-prescription medicine use by men and women over 53 years old in Taiwan. Results from a population-based cross-sectional survey

This study investigated the prevalence and determinants of the use of dietary supplements and non-prescription medicines by older adults in Taiwan. Methods:  Data are from the 1999 Survey of Health and Living Status of the Elderly in Taiwan. The survey involved a national random sample of 2360 men and 2080 women, 53 years or older. Results:  Overall, 32.4% of elderly men and 42.7% of elderly women used at least one kind of dietary supplement during the past 12 months. Approximately 16% of elderly men and 19% of elderly women used multivitamin and mineral supplements, 10.5 and 22% used calcium, and 10 and 14% used vitamin E, respectively. Conclusions:  The rates of supplement use are generally lower than those observed in the USA but comparable to that in other industrialised countries. Elderly who are females or who are more highly educated or physically more active are more frequent supplement users.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72609/1/j.1741-6612.2006.00183.x.pd

Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment.

The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Activation of JAK/STAT signaling is thought to be a central component of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor Food and Drug Administration (FDA) approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Herein, we validated in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated xenograft models of myeloma, that tofacitinib showed efficacy in myeloma models. Furthermore, tofacitinib strongly synergized with venetoclax in coculture with bone marrow stromal cells but not in monoculture. Surprisingly, we found that ruxolitinib, an FDA approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not enhance ruxolitinib effects. Transcriptome analysis and unbiased phosphoproteomics revealed that bone marrow stromal cells stimulate a JAK/STAT-mediated proliferative program in myeloma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib reverses the growth-promoting effects of the tumor microenvironment. As tofacitinib is already FDA approved, these results can be rapidly translated into potential clinical benefits for myeloma patients

Sensitivity to grid resolution in the ability of a chemical transport model to simulate observed oxidant chemistry under high-isoprene conditions

Formation of ozone and organic aerosol in continental atmospheres depends on whether isoprene emitted by vegetation is oxidized by the high-NOx pathway (where peroxy radicals react with NO) or by low-NOx pathways (where peroxy radicals react by alternate channels, mostly with HO2). We used mixed layer observations from the SEAC4RS aircraft campaign over the Southeast US to test the ability of the GEOS-Chem chemical transport model at different grid resolutions (0.25°  ×  0.3125°, 2°  ×  2.5°, 4°  ×  5°) to simulate this chemistry under high-isoprene, variable-NOx conditions. Observations of isoprene and NOx over the Southeast US show a negative correlation, reflecting the spatial segregation of emissions; this negative correlation is captured in the model at 0.25°  ×  0.3125° resolution but not at coarser resolutions. As a result, less isoprene oxidation takes place by the high-NOx pathway in the model at 0.25°  ×  0.3125° resolution (54 %) than at coarser resolution (59 %). The cumulative probability distribution functions (CDFs) of NOx, isoprene, and ozone concentrations show little difference across model resolutions and good agreement with observations, while formaldehyde is overestimated at coarse resolution because excessive isoprene oxidation takes place by the high-NOx pathway with high formaldehyde yield. The good agreement of simulated and observed concentration variances implies that smaller-scale non-linearities (urban and power plant plumes) are not important on the regional scale. Correlations of simulated vs. observed concentrations do not improve with grid resolution because finer modes of variability are intrinsically more difficult to capture. Higher model resolution leads to decreased conversion of NOx to organic nitrates and increased conversion to nitric acid, with total reactive nitrogen oxides (NOy) changing little across model resolutions. Model concentrations in the lower free troposphere are also insensitive to grid resolution. The overall low sensitivity of modeled concentrations to grid resolution implies that coarse resolution is adequate when modeling continental boundary layer chemistry for global applications

Non-Markovian stochastic Schr\"odinger equations: Generalization to real-valued noise using quantum measurement theory

Do stochastic Schr\"odinger equations, also known as unravelings, have a physical interpretation? In the Markovian limit, where the system {\em on average} obeys a master equation, the answer is yes. Markovian stochastic Schr\"odinger equations generate quantum trajectories for the system state conditioned on continuously monitoring the bath. For a given master equation, there are many different unravelings, corresponding to different sorts of measurement on the bath. In this paper we address the non-Markovian case, and in particular the sort of stochastic \sch equation introduced by Strunz, Di\' osi, and Gisin [Phys. Rev. Lett. 82, 1801 (1999)]. Using a quantum measurement theory approach, we rederive their unraveling which involves complex-valued Gaussian noise. We also derive an unraveling involving real-valued Gaussian noise. We show that in the Markovian limit, these two unravelings correspond to heterodyne and homodyne detection respectively. Although we use quantum measurement theory to define these unravelings, we conclude that the stochastic evolution of the system state is not a true quantum trajectory, as the identity of the state through time is a fiction.Comment: 17 pages, 3 figure

Why do models overestimate surface ozone in the Southeast United States

Ozone pollution in the Southeast US involves complex chemistry driven by emissions of anthropogenic nitrogen oxide radicals (NOx  ≡  NO + NO2) and biogenic isoprene. Model estimates of surface ozone concentrations tend to be biased high in the region and this is of concern for designing effective emission control strategies to meet air quality standards. We use detailed chemical observations from the SEAC4RS aircraft campaign in August and September 2013, interpreted with the GEOS-Chem chemical transport model at 0.25°  ×  0.3125° horizontal resolution, to better understand the factors controlling surface ozone in the Southeast US. We find that the National Emission Inventory (NEI) for NOx from the US Environmental Protection Agency (EPA) is too high. This finding is based on SEAC4RS observations of NOx and its oxidation products, surface network observations of nitrate wet deposition fluxes, and OMI satellite observations of tropospheric NO2 columns. Our results indicate that NEI NOx emissions from mobile and industrial sources must be reduced by 30–60 %, dependent on the assumption of the contribution by soil NOx emissions. Upper-tropospheric NO2 from lightning makes a large contribution to satellite observations of tropospheric NO2 that must be accounted for when using these data to estimate surface NOx emissions. We find that only half of isoprene oxidation proceeds by the high-NOx pathway to produce ozone; this fraction is only moderately sensitive to changes in NOx emissions because isoprene and NOx emissions are spatially segregated. GEOS-Chem with reduced NOx emissions provides an unbiased simulation of ozone observations from the aircraft and reproduces the observed ozone production efficiency in the boundary layer as derived from a regression of ozone and NOx oxidation products. However, the model is still biased high by 6 ± 14 ppb relative to observed surface ozone in the Southeast US. Ozonesondes launched during midday hours show a 7 ppb ozone decrease from 1.5 km to the surface that GEOS-Chem does not capture. This bias may reflect a combination of excessive vertical mixing and net ozone production in the model boundary layer

Nanoscale Nucleation and Growth of Non-Stoichiometric V-Shaped InP Defect in Heterogeneous InGaAsP/InP Array

Nanotechnology is a broad field that involves the manipulation of atoms and molecules. For nanophotonics, defect formation in nanostructured compound semiconductor system is of great technological interest. In this paper, we study the nanoscale nucleation and growth of V-shaped defect in the heterogeneous InGaAsP/InP array. We have observed that the nucleation originated from the phosphorus-deficient disordering that was likely induced by reactive ion etching. During the nucleation, the phosphorus-deficient In1+xP1-x compound was developed at the trench. The triangular nano-precipitates of In1+xP1-x with sizes of 20-30nm were formed. The ratio of In to P in the non-stoichiometric compound was higher in the upper portion of the V-defect, likely due to antisite defect mechanism. During the defect growth process, the phosphorus-deficient nucleation site expanded to form open, inverted pyramid with sidewalls following the crystallographic planes

Antioxidants, Minerals, and Vitamins in Relation to Crohn’s disease and Ulcerative Colitis:A Mendelian Randomization Study

Background Evidence for antioxidants, minerals and vitamins in relation to the risk of Crohn's disease (CD) and ulcerative colitis (UC) is limited and inconsistent. This mendelian randomization (MR) study aimed to examine the causal associations of circulating levels of antioxidants, minerals and vitamins with CD and UC. Methods Single-nucleotide polymorphisms associated with antioxidants (beta-carotene, lycopene and uric acid), minerals (copper, calcium, iron, magnesium, phosphorus, zinc and selenium), and vitamins (folate, vitamins A, B6, B12, C, D, E and K1) were employed as instrumental variables. Genetic associations with CD and UC were extracted from the UK Biobank, the FinnGen study and the International Inflammatory Bowel Disease Genetics Consortium. The inverse variance weighted method and sensitivity analyses were performed. Results Genetically predicted higher lycopene (OR = 0.94, 95% CI: 0.91–0.97), vitamins D (OR = 0.65, 95% CI: 0.54–0.79) and K1 (OR = 0.93, 95% CI: 0.90–0.97) levels were inversely associated with CD risk, whereas genetically predicted higher magnesium (OR = 1.53, 95% CI: 1.23–1.90) levels were positively associated with CD risk. Higher levels of genetically predicted lycopene (OR = 0.91, 95% CI: 0.88–0.95), phosphorus (OR = 0.69, 95% CI: 0.58–0.82), selenium (OR = 0.91, 95% CI: 0.85–0.97), zinc (OR = 0.91, 95% CI: 0.89–0.94), folate (OR = 0.71, 95% CI: 0.56–0.92) and vitamin E (OR = 0.78, 95% CI: 0.69–0.88) were associated with reduced UC risk, whereas genetically predicted high levels of calcium (OR = 1.46, 95% CI: 1.22–1.76) and magnesium (OR = 1.24, 95% CI: 1.03–1.49) were associated with increased risk of UC. Conclusions Our study provided evidence that circulating levels of antioxidants, minerals and vitamins might be causally linked to the development of IBD