BKB_K using HYP-smeared staggered fermions in Nf=2+1N_f=2+1 unquenched QCD

We present results for kaon mixing parameter $B_K$ calculated using HYP-smeared improved staggered fermions on the MILC asqtad lattices. We use three lattice spacings ($a\approx 0.12$, $0.09$ and $0.06\;$fm), ten different valence quark masses ($m\approx m_s/10-m_s$), and several light sea-quark masses in order to control the continuum and chiral extrapolations. We derive the next-to-leading order staggered chiral perturbation theory (SChPT) results necessary to fit our data, and use these results to do extrapolations based both on SU(2) and SU(3) SChPT. The SU(2) fitting is particularly straightforward because parameters related to taste-breaking and matching errors appear only at next-to-next-to-leading order. We match to the continuum renormalization scheme (NDR) using one-loop perturbation theory. Our final result is from the SU(2) analysis, with the SU(3) result providing a (less accurate) cross check. We find $B_K(\text{NDR}, \mu = 2 \text{GeV}) = 0.529 \pm 0.009 \pm 0.032$ and $\hat{B}_K =B_K(\text{RGI})= 0.724 \pm 0.012 \pm 0.043$, where the first error is statistical and the second systematic. The error is dominated by the truncation error in the matching factor. Our results are consistent with those obtained using valence domain-wall fermions on lattices generated with asqtad or domain-wall sea quarks.Comment: 37 pages, 31 figures, most updated versio

Source region and growth analysis of narrowband Z-mode emission at Saturn

Intense Z-mode emission is observed in the lower density region near the inner edge of the Enceladus torus at Saturn, where these waves may resonate with MeV electrons. The source mechanism of this emission, which is narrow-banded and most intense near 5 kHz, is not well understood. We survey the Cassini Radio and Plasma Wave Science data to isolate several probable source regions near the inner edge of the Enceladus density torus. Electron phase space distributions are obtained from the Cassini Electron Spectrometer, part of the Cassini Plasma Spectrometer investigation. We perform a plasma wave growth analysis to conclude that an electron temperature anisotropy and possibly a weak loss cone can drive the Z mode as observed. Electrostatic electron acoustic waves and perhaps weak beam modes are also found to be unstable coincident with the Z mode. Quasi-steady conditions near the Enceladus density torus may result in the observations of narrowband Z-mode emission at Saturn

Mixture modeling of microarray gene expression data

About 28% of genes appear to have an expression pattern that follows a mixture distribution. We use first- and second-order partial correlation coefficients to identify trios and quartets of non-sex-linked genes that are highly associated and that are also mixtures. We identified 18 trio and 35 quartet mixtures and evaluated their mixture distribution concordance. Concordance was defined as the proportion of observations that simultaneously fall in the component with the higher mean or simultaneously in the component with the lower mean based on their Bayesian posterior probabilities. These trios and quartets have a concordance rate greater than 80%. There are 33 genes involved in these trios and quartets. A factor analysis with varimax rotation identifies three gene groups based on their factor loadings. One group of 18 genes has a concordance rate of 56.7%, another group of 8 genes has a concordance rate of 60.8%, and a third group of 7 genes has a concordance rate of 69.6%. Each of these rates is highly significant, suggesting that there may be strong biological underpinnings for the mixture mechanisms of these genes. Bayesian factor screening confirms this hypothesis by identifying six single-nucleotide polymorphisms that are significantly associated with the expression phenotypes of the five most concordant genes in the first group

Safety and Efficacy of Dacomitinib in Korean Patients with KRAS Wild-Type Advanced Non–Small-Cell Lung Cancer Refractory to Chemotherapy and Erlotinib or Gefitinib: A Phase I/II Trial

IntroductionDacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor ([HER]-1/EGFR, HER-2, and HER-4) tyrosine kinase inhibitor, demonstrated antitumor activity in Western patients with non–small-cell lung cancer (NSCLC) at a dose of 45 mg once daily. We report data from a phase I/II, multicenter, open-label study of Korean patients with refractory KRAS wild-type adenocarcinoma NSCLC (defined as patients with evidence of disease progression during or within 6 months of treatment with chemotherapy and gefitinib or erlotinib).MethodsThe phase I dose-finding portion identified the recommended phase II dose (RP2D) in Korean patients, evaluated safety, and characterized the pharmacokinetics of dacomitinib. In the phase II portion, patients received dacomitinib at the RP2D. The primary end point was progression-free survival at 4 months (PFS4m).ResultsTwelve patients enrolled in phase I, and 43 patients enrolled in phase II at the RP2D of 45 mg once daily. In phase II, PFS4m was 47.2% (95% confidence interval [CI], 31.6–61.3; one-sided p-value = 0.0007). Median PFS was 15.4 weeks (95% CI, 9.7–17.6); median overall survival was 46.3 weeks (95% CI, 32.7–not reached); and the objective response rate was 17.1% (95% CI, 7.2–32.1). Common treatment-related adverse events were dermatitis acneiform, diarrhea, and paronychia; there were no treatment-related grade 4 or 5 adverse events. Pharmacokinetic parameters of dacomitinib in Korean patients were similar to those reported in Western patients. By patient report, NSCLC symptoms “cough” and “pain” showed improvement within 3 weeks of initiating treatment.ConclusionsDacomitinib was well tolerated and had antitumor activity in Korean patients with NSCLC who had previously progressed on chemotherapy and an epidermal growth factor receptor tyrosine kinase inhibitor

Photoactivation of the BLUF protein PixD Probed by the Site-Specific Incorporation of Fluorotyrosine Residues

The flavin chromophore in blue light using FAD (BLUF) photoreceptors is surrounded by a hydrogen bond network that senses and responds to changes in the electronic structure of the flavin on the ultrafast time scale. The hydrogen bond network includes a strictly conserved Tyr residue, and previously we explored the role of this residue, Y21, in the photoactivation mechanism of the BLUF protein AppA by the introduction of fluorotyrosine (F-Tyr) analogs that modulated the pKa and reduction potential of Y21 by 3.5 pH units and 200 mV, respectively. Although little impact on the forward (dark to light adapted form) photoreaction was observed, the change in Y21 pKa led to a 4,000-fold increase in the rate of dark state recovery. In the present work we have extended these studies to the BLUF protein PixD, where, in contrast to AppA, modulation in the Tyr (Y8) pKa has a profound impact on the forward photoreaction. In particular, a decrease in Y8 pKa by 2 or more pH units prevents formation of a stable light state, consistent with a photoactivation mechanism that involves proton transfer or proton coupled electron transfer from Y8 to the electronically excited FAD. Conversely, the effect of pKa on the rate of dark recovery is markedly reduced in PixD. These observations highlight very significant differences between the photocycles of PixD and AppA, despite their sharing highly conserved FAD binding architectures

Global distribution and diversity of marine Verrucomicrobia

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in The ISME Journal 6 (2012): 1499-1505, doi:10.1038/ismej.2012.3.Verrucomicrobia is a bacterial phylum that is commonly detected in soil but little is known about the distribution and diversity of this phylum in the marine environment. To address this, we analyzed the marine microbial community composition in 506 samples from the International Census of Marine Microbes as well as eleven coastal samples taken from the California Current. These samples from both the water column and sediments covered a wide range of environmental conditions. Verrucomicrobia were present in 98% of the analyzed samples and thus appeared nearly ubiquitous in the ocean. Based on the occurrence of amplified 16S rRNA sequences, Verrucomicrobia constituted on average 2% of the water column and 1.4% of the sediment bacterial communities. The diversity of Verrucomicrobia displayed a biogeography at multiple taxonomic levels and thus, specific lineages appeared to have clear habitat preference. We found that Subdivision 1 and 4 generally dominated marine bacterial communities, whereas Subdivision 2 was confined to low salinity waters. Within the subdivisions, Verrucomicrobia community composition were significantly different in the water column compared to sediment as well as within the water column along gradients of salinity, temperature, nitrate, depth, and overall water column depth. Although we still know little about the ecophysiology of Verrucomicrobia lineages, the ubiquity of this phylum suggests that it may be important for the biogeochemical cycle of carbon in the ocean.We would like to thank the UCI Undergraduate Research Opportunity Program (S.F.), the National Science Foundation (OCE-0928544 and OCE-1046297, A.C.M.) and the Alfred P. Sloan Foundation (S.H., D.M.W., M.S.) for supporting the work

X-ray absorption spectroscopy systematics at the tungsten L-edge

A series of mononuclear six-coordinate tungsten compounds spanning formal oxidation states from 0 to +VI, largely in a ligand environment of inert chloride and/or phosphine, has been interrogated by tungsten L-edge X-ray absorption spectroscopy. The L-edge spectra of this compound set, comprised of [W<sup>0</sup>(PMe<sub>3</sub>)<sub>6</sub>], [W<sup>II</sup>Cl<sub>2</sub>(PMePh<sub>2</sub>)<sub>4</sub>], [W<sup>III</sup>Cl<sub>2</sub>(dppe)<sub>2</sub>][PF<sub>6</sub>] (dppe = 1,2-bis(diphenylphosphino)ethane), [W<sup>IV</sup>Cl<sub>4</sub>(PMePh<sub>2</sub>)<sub>2</sub>], [W<sup>V</sup>(NPh)Cl<sub>3</sub>(PMe<sub>3</sub>)<sub>2</sub>], and [W<sup>VI</sup>Cl<sub>6</sub>] correlate with formal oxidation state and have usefulness as references for the interpretation of the L-edge spectra of tungsten compounds with redox-active ligands and ambiguous electronic structure descriptions. The utility of these spectra arises from the combined correlation of the estimated branching ratio (EBR) of the L<sub>3,2</sub>-edges and the L<sub>1</sub> rising-edge energy with metal Z<sub>eff</sub>, thereby permitting an assessment of effective metal oxidation state. An application of these reference spectra is illustrated by their use as backdrop for the L-edge X-ray absorption spectra of [W<sup>IV</sup>(mdt)<sub>2</sub>(CO)<sub>2</sub>] and [W<sup>IV</sup>(mdt)<sub>2</sub>(CN)<sub>2</sub>]<sup>2–</sup> (mdt<sup>2–</sup> = 1,2-dimethylethene-1,2-dithiolate), which shows that both compounds are effectively W<sup>IV</sup> species. Use of metal L-edge XAS to assess a compound of uncertain formulation requires: 1) Placement of that data within the context of spectra offered by unambiguous calibrant compounds, preferably with the same coordination number and similar metal ligand distances. Such spectra assist in defining upper and/or lower limits for metal Z<sub>eff</sub> in the species of interest; 2) Evaluation of that data in conjunction with information from other physical methods, especially ligand K-edge XAS; 3) Increased care in interpretation if strong π-acceptor ligands, particularly CO, or π-donor ligands are present. The electron-withdrawing/donating nature of these ligand types, combined with relatively short metal-ligand distances, exaggerate the difference between formal oxidation state and metal Z<sub>eff</sub> or, as in the case of [W<sup>IV</sup>(mdt)<sub>2</sub>(CO)<sub>2</sub>], add other subtlety by modulating the redox level of other ligands in the coordination sphere

An Innovative, Prospective, Hybrid Cohort-Cluster Study Design to Characterize Dengue Virus Transmission in Multigenerational Households in Kamphaeng Phet, Thailand

Difficulties inherent in the identification of immune correlates of protection or severe disease have challenged the development and evaluation of dengue vaccines. There persist substantial gaps in knowledge about the complex effects of age and sequential dengue virus (DENV) exposures on these correlations. To address these gaps, we were conducting a novel family-based cohort-cluster study for DENV transmission in Kamphaeng Phet, Thailand. The study began in 2015 and is funded until at least 2023. As of May 2019, 2,870 individuals in 485 families were actively enrolled. The families comprise at least 1 child born into the study as a newborn, 1 other child, a parent, and a grandparent. The median age of enrolled participants is 21 years (range 0–93 years). Active surveillance is performed to detect acute dengue illnesses, and annual blood testing identifies subclinical seroconversions. Extended follow-up of this cohort will detect sequential infections and correlate antibody kinetics and sequence of infections with disease outcomes. The central goal of this prospective study is to characterize how different DENV exposure histories within multigenerational family units, from DENV-naive infants to grandparents with multiple prior DENV exposures, affect transmission, disease, and protection at the level of the individual, household, and community