High concentrations of morphine sensitize and activate mouse dorsal root ganglia via TRPV1 and TRPA1 receptors.

BACKGROUND: Morphine and its derivatives are key drugs in pain control. Despite its well-known analgesic properties morphine at high concentrations may be proalgesic. Particularly, short-lasting painful sensations have been reported upon dermal application of morphine. To study a possible involvement of TRP receptors in the pro-nociceptive effects of morphine (0.3 - 10 mM), two models of nociception were employed using C57BL/6 mice and genetically related TRPV1 and TRPA1 knockout animals, which were crossed and generated double knockouts. Hindpaw skin flaps were used to investigate the release of calcitonin gene-related peptide indicative of nociceptive activation. RESULTS: Morphine induced release of calcitonin gene-related peptide and sensitized the release evoked by heat or the TRPA1 agonist acrolein. Morphine activated HEK293t cells transfected with TRPV1 or TRPA1. Activation of C57BL/6 mouse dorsal root ganglion neurons in culture was investigated with calcium imaging. Morphine induced a dose-dependent rise in intracellular calcium in neurons from wild-type animals. In neurons from TRPV1 and TRPA1 knockout animals activation by morphine was markedly reduced, in the TRPV1/A1 double knockout animals this morphine effect was abrogated. Naloxone induced an increase in calcium levels similar to morphine. The responses to both morphine and naloxone were sensitized by bradykinin. CONCLUSION: Nociceptor activation and sensitization by morphine is conveyed by TRPV1 and TRPA1

Stage IV Colorectal Cancer Patients with High Risk Mutation Profiles Survived 16 Months Longer with Individualized Therapies.

Personalized treatment vs. standard of care is much debated, especially in clinical practice. Here we investigated whether overall survival differences in metastatic colorectal cancer patients are explained by tumor mutation profiles or by treatment differences in real clinical practice. Our retrospective study of metastatic colorectal cancer patients of confirmed European ancestry comprised 54 Americans and 54 gender-matched Germans. The Americans received standard of care, and on treatment failure, 35 patients received individualized treatments. The German patients received standard of care only. Tumor mutations, tumor mutation burden and microsatellite status were identified by using the FoundationOne assay or the IDT Pan-Cancer assay. High-risk patients were identified according to the mutational classification by Schell and colleagues. Results: Kaplan-Meier estimates show the high-risk patients to survive 16 months longer under individualized treatments than those under only standard of care, in the median (p < 0.001). Tumor mutation profiles stratify patients by risk groups but not by country. Conclusions: High-risk patients appear to survive significantly longer (p < 0.001) if they receive individualized treatments after the exhaustion of standard of care treatments. Secondly, the tumor mutation landscape in Americans and Germans is congruent and thus warrants the transatlantic exchange of successful treatment protocols and the harmonization of guidelines

Dispersion Coefficients by a Field-Theoretic Renormalization of Fluid Mechanics

We consider subtle correlations in the scattering of fluid by randomly placed obstacles, which have been suggested to lead to a diverging dispersion coefficient at long times for high Peclet numbers, in contrast to finite mean-field predictions. We develop a new master equation description of the fluid mechanics that incorporates the physically relevant fluctuations, and we treat those fluctuations by a renormalization group procedure. We find a finite dispersion coefficient at low volume fraction of disorder and high Peclet numbers.Comment: 4 pages, 1 figure; to appear in Phys. Rev. Let

From Next-Generation Sequencing Alignments to Accurate Comparison and Validation of Single-Nucleotide Variants: The Pibase Software

Scientists working with single-nucleotide variants (SNVs), inferred by next-generation sequencing software, often need further information regarding true variants, artifacts and sequence coverage gaps. In clinical diagnostics, e.g. SNVs must usually be validated by visual inspection or several independent SNV-callers. We here demonstrate that 0.5–60% of relevant SNVs might not be detected due to coverage gaps, or might be misidentified. Even low error rates can overwhelm the true biological signal, especially in clinical diagnostics, in research comparing healthy with affected cells, in archaeogenetic dating or in forensics. For these reasons, we have developed a package called pibase, which is applicable to diploid and haploid genome, exome or targeted enrichment data. pibase extracts details on nucleotides from alignment files at user-specified coordinates and identifies reproducible genotypes, if present. In test cases pibase identifies genotypes at 99.98% specificity, 10-fold better than other tools. pibase also provides pair-wise comparisons between healthy and affected cells using nucleotide signals (10-fold more accurately than a genotype-based approach, as we show in our case study of monozygotic twins). This comparison tool also solves the problem of detecting allelic imbalance within heterozygous SNVs in copy number variation loci, or in heterogeneous tumor sequences

Reactive Turbulent Flow in Low-Dimensional, Disordered Media

We analyze the reactions $A+A \to \emptyset$ and $A + B \to \emptyset$ occurring in a model of turbulent flow in two dimensions. We find the reactant concentrations at long times, using a field-theoretic renormalization group analysis. We find a variety of interesting behavior, including, in the presence of potential disorder, decay rates faster than that for well-mixed reactions.Comment: 6 pages, 4 figures. To appear in Phys. Rev.

The first IEEE workshop on the Future of Research Curation and Research Reproducibility

This report describes perspectives from the Workshop on the Future of Research Curation and Research Reproducibility that was collaboratively sponsored by the U.S. National Science Foundation (NSF) and IEEE (Institute of Electrical and Electronics Engineers) in November 2016. The workshop brought together stakeholders including researchers, funders, and notably, leading science, technology, engineering, and mathematics (STEM) publishers. The overarching objective was a deep dive into new kinds of research products and how the costs of creation and curation of these products can be sustainably borne by the agencies, publishers, and researcher communities that were represented by workshop participants.National Science Foundation Award #164101

The WiggleZ Dark Energy Survey: Star-formation in UV-luminous galaxies from their luminosity functions

We present the ultraviolet (UV) luminosity function of galaxies from the GALEX Medium Imaging Survey with measured spectroscopic redshifts from the first data release of the WiggleZ Dark Energy Survey. This sample selects galaxies with high star formation rates: at 0.6 < z < 0.9 the median star formation rate is at the upper 95th percentile of optically-selected (r<22.5) galaxies and the sample contains about 50 per cent of all NUV < 22.8, 0.6 < z < 0.9 starburst galaxies within the volume sampled. The most luminous galaxies in our sample (-21.0>M_NUV>-22.5) evolve very rapidly with a number density declining as (1+z)^{5\pm 1} from redshift z = 0.9 to z = 0.6. These starburst galaxies (M_NUV<-21 is approximately a star formation rate of 30 \msuny) contribute about 1 per cent of cosmic star formation over the redshift range z=0.6 to z=0.9. The star formation rate density of these very luminous galaxies evolves rapidly, as (1+z)^{4\pm 1}. Such a rapid evolution implies the majority of star formation in these large galaxies must have occurred before z = 0.9. We measure the UV luminosity function in 0.05 redshift intervals spanning 0.1<z<0.9, and provide analytic fits to the results. At all redshifts greater than z=0.55 we find that the bright end of the luminosity function is not well described by a pure Schechter function due to an excess of very luminous (M_NUV<-22) galaxies. These luminosity functions can be used to create a radial selection function for the WiggleZ survey or test models of galaxy formation and evolution. Here we test the AGN feedback model in Scannapieco et al. (2005), and find that this AGN feedback model requires AGN feedback efficiency to vary with one or more of the following: stellar mass, star formation rate and redshift.Comment: 27 pages; 13 pages without appendices. 22 figures; 11 figures in the main tex

Directed polymers in high dimensions

We study directed polymers subject to a quenched random potential in d transversal dimensions. This system is closely related to the Kardar-Parisi-Zhang equation of nonlinear stochastic growth. By a careful analysis of the perturbation theory we show that physical quantities develop singular behavior for d to 4. For example, the universal finite size amplitude of the free energy at the roughening transition is proportional to (4-d)^(1/2). This shows that the dimension d=4 plays a special role for this system and points towards d=4 as the upper critical dimension of the Kardar-Parisi-Zhang problem.Comment: 37 pages REVTEX including 4 PostScript figure

The WiggleZ Dark Energy Survey: improved distance measurements to z = 1 with reconstruction of the baryonic acoustic feature

We present significant improvements in cosmic distance measurements from the WiggleZ Dark Energy Survey, achieved by applying the reconstruction of the baryonic acoustic feature technique. We show using both data and simulations that the reconstruction technique can often be effective despite patchiness of the survey, significant edge effects and shot-noise. We investigate three redshift bins in the redshift range 0.2 < z < 1, and in all three find improvement after reconstruction in the detection of the baryonic acoustic feature and its usage as a standard ruler. We measure model-independent distance measures DV(rsfid/rs) of 1716 ± 83, 2221 ± 101, 2516 ± 86 Mpc (68 per cent CL) at effective redshifts z = 0.44, 0.6, 0.73, respectively, where DV is the volume-averaged distance, and rs is the sound horizon at the end of the baryon drag epoch. These significantly improved 4.8, 4.5 and 3.4 per cent accuracy measurements are equivalent to those expected from surveys with up to 2.5 times the volume of WiggleZ without reconstruction applied. These measurements are fully consistent with cosmologies allowed by the analyses of the Planck Collaboration and the Sloan Digital Sky Survey. We provide the DV(rsfid/rs) posterior probability distributions and their covariances. When combining these measurements with temperature fluctuations measurements of Planck, the polarization of Wilkinson Microwave Anisotropy Probe 9, and the 6dF Galaxy Survey baryonic acoustic feature, we do not detect deviations from a flat Λ cold dark matter (ΛCDM) model. Assuming this model, we constrain the current expansion rate to H₀ = 67.15 ± 0.98 km s⁻¹Mpc⁻¹. Allowing the equation of state of dark energy to vary, we obtain wDE = −1.080 ± 0.135. When assuming a curved ΛCDM model we obtain a curvature value of ΩK = −0.0043 ± 0.0047

The Star Formation and Extinction Co-Evolution of UV-Selected Galaxies over 0.05<z<1.2

We use a new stacking technique to obtain mean mid IR and far IR to far UV flux ratios over the rest near-UV/near-IR color-magnitude diagram. We employ COMBO-17 redshifts and COMBO-17 optical, GALEX far and near UV, Spitzer IRAC and MIPS Mid IR photometry. This technique permits us to probe infrared excess (IRX), the ratio of far IR to far UV luminosity, and specific star formation rate (SSFR) and their co-evolution over two orders of magnitude of stellar mass and redshift 0.1<z<1.2. We find that the SSFR and the characteristic mass (M_0) above which the SSFR drops increase with redshift (downsizing). At any given epoch, IRX is an increasing function of mass up to M_0. Above this mass IRX falls, suggesting gas exhaustion. In a given mass bin below M_0 IRX increases with time in a fashion consistent with enrichment. We interpret these trends using a simple model with a Schmidt-Kennicutt law and extinction that tracks gas density and enrichment. We find that the average IRX and SSFR follows a galaxy age parameter which is determined mainly by the galaxy mass and time since formation. We conclude that blue sequence galaxies have properties which show simple, systematic trends with mass and time such as the steady build-up of heavy elements in the interstellar media of evolving galaxies and the exhaustion of gas in galaxies that are evolving off the blue sequence. The IRX represents a tool for selecting galaxies at various stages of evolution.Comment: Accepted for publication in GALEX Special Ap.J.Suppl., December, 200