Changes in epithelial proportions and transcriptional state underlie major premenopausal breast cancer risks

The human breast undergoes lifelong remodeling in response to estrogen and progesterone, but hormone exposure also increases breast cancer risk. Here, we use single-cell analysis to identify distinct mechanisms through which breast composition and cell state affect hormone signaling. We show that prior pregnancy reduces the transcriptional response of hormone-responsive (HR+) epithelial cells, whereas high body mass index (BMI) reduces overall HR+ cell proportions. These distinct changes both impact neighboring cells by effectively reducing the magnitude of paracrine signals originating from HR+ cells. Because pregnancy and high BMI are known to protect against hormone-dependent breast cancer in premenopausal women, our findings directly link breast cancer risk with person-to-person heterogeneity in hormone responsiveness. More broadly, our findings illustrate how cell proportions and cell state can collectively impact cell communities through the action of cell-to-cell signaling networks

Quantitative changes in intracellular calcium and extracellular-regulated kinase activation measured in parallel in CHO cells stably expressing serotonin (5-HT) 5-HT2A or 5-HT2C receptors

<p>Abstract</p> <p>Background</p> <p>The serotonin (5-HT) 2A and 2C receptors (5-HT_2AR and 5-HT_2CR) are involved in a wide range of physiological and behavioral processes in the mammalian central and peripheral nervous systems. These receptors share a high degree of homology, have overlapping pharmacological profiles, and utilize many of the same and richly diverse second messenger signaling systems. We have developed quantitative assays for cells stably expressing these two receptors involving minimal cell sample manipulations that dramatically improve parallel assessments of two signaling responses: intracellular calcium (<it>Ca_i</it>⁺⁺) changes and activation (phosphorylation) of downstream kinases. Such profiles are needed to begin to understand the simultaneous contributions from the multiplicity of signaling cascades likely to be initiated by serotonergic ligands.</p> <p>Results</p> <p>We optimized the <it>Ca_i</it>⁺⁺assay for stable cell lines expressing either 5-HT_2AR or 5-HT_2CR (including dye use and measurement parameters; cell density and serum requirements). We adapted a quantitative 96-well plate immunoassay for pERK in the same cell lines. Similar cell density optima and time courses were observed for 5-HT_2AR- and 5-HT_2CR-expressing cells in generating both types of signaling. Both cell lines also require serum-free preincubation for maximal agonist responses in the pERK assay. However, 5-HT_2AR-expressing cells showed significant release of <it>Ca_i</it>⁺⁺in response to 5-HT stimulation even when preincubated in serum-replete medium, while the response was completely eliminated by serum in 5-HT_2CR-expressing cells. Response to another serotonergic ligand (DOI) was eliminated by serum-replete preincubation in both cells lines.</p> <p>Conclusions</p> <p>These data expand our knowledge of differences in ligand-stimulated signaling cascades between 5-HT_2AR and 5-HT_2CR. Our parallel assays can be applied to other cell and receptor systems for monitoring and dissecting concurrent signaling responses.</p

Sequence alignment, mutual information, and dissimilarity measures for constructing phylogenies

Existing sequence alignment algorithms use heuristic scoring schemes which cannot be used as objective distance metrics. Therefore one relies on measures like the p- or log-det distances, or makes explicit, and often simplistic, assumptions about sequence evolution. Information theory provides an alternative, in the form of mutual information (MI) which is, in principle, an objective and model independent similarity measure. MI can be estimated by concatenating and zipping sequences, yielding thereby the "normalized compression distance". So far this has produced promising results, but with uncontrolled errors. We describe a simple approach to get robust estimates of MI from global pairwise alignments. Using standard alignment algorithms, this gives for animal mitochondrial DNA estimates that are strikingly close to estimates obtained from the alignment free methods mentioned above. Our main result uses algorithmic (Kolmogorov) information theory, but we show that similar results can also be obtained from Shannon theory. Due to the fact that it is not additive, normalized compression distance is not an optimal metric for phylogenetics, but we propose a simple modification that overcomes the issue of additivity. We test several versions of our MI based distance measures on a large number of randomly chosen quartets and demonstrate that they all perform better than traditional measures like the Kimura or log-det (resp. paralinear) distances. Even a simplified version based on single letter Shannon entropies, which can be easily incorporated in existing software packages, gave superior results throughout the entire animal kingdom. But we see the main virtue of our approach in a more general way. For example, it can also help to judge the relative merits of different alignment algorithms, by estimating the significance of specific alignments.Comment: 19 pages + 16 pages of supplementary materia

Beam instrumentation for the Tevatron Collider

The Tevatron in Collider Run II (2001-present) is operating with six times more bunches and many times higher beam intensities and luminosities than in Run I (1992-1995). Beam diagnostics were crucial for the machine start-up and the never-ending luminosity upgrade campaign. We present the overall picture of the Tevatron diagnostics development for Run II, outline machine needs for new instrumentation, present several notable examples that led to Tevatron performance improvements, and discuss the lessons for future colliders

Precision measurements of the total and partial widths of the psi(2S) charmonium meson with a new complementary-scan technique in antiproton-proton annihilations

We present new precision measurements of the psi(2S) total and partial widths from excitation curves obtained in antiproton-proton annihilations by Fermilab experiment E835 at the Antiproton Accumulator in the year 2000. A new technique of complementary scans was developed to study narrow resonances with stochastically cooled antiproton beams. The technique relies on precise revolution-frequency and orbit-length measurements, while making the analysis of the excitation curve almost independent of machine lattice parameters. We study the psi(2S) meson through the processes pbar p -> e+ e- and pbar p -> J/psi + X -> e+ e- + X. We measure the width to be Gamma = 290 +- 25(sta) +- 4(sys) keV and the combination of partial widths Gamma_e+e- * Gamma_pbarp / Gamma = 579 +- 38(sta) +- 36(sys) meV, which represent the most precise measurements to date.Comment: 17 pages, 3 figures, 3 tables. Final manuscript accepted for publication in Phys. Lett. B. Parts of the text slightly expanded or rearranged; results are unchange

The Panarea natural CO2 seeps: fate and impact of the leaking gas (PaCO2) ; R/V URANIA, Cruise No. U10/2011, 27 July – 01 August 2011, Naples (Italy) – Naples (Italy)

Carbon capture and storage (CCS), both on- and offshore, is expected to be an important technique to mitigate anthropogenic effects on global climate by isolating man-made carbon dioxide (CO2) in deep geological formations. In marine environments, however, the potential impacts of CO2 leakage, appropriate detection methods, and risk and pathways of atmospheric emissions are poorly defined. The natural CO2 gas seeps that occur in the relatively shallow waters off the coast of Panarea Island (Aeolian Islands, Italy) can be studied as a large-scale, real-world analogue of what might occur at a leaking offshore CCS site and what tools can be used to study it. The oceanographic survey PaCO2 was performed aboard R/V Urania from 27 July – 01 August 2011 (Naples – Naples). The project’s ship-time was funded by Eurofleets, with work being performed as a sub-project of the Seventh Framework Programme projects “ECO2” and “RISCS”, which provided subsidiary funding. Large amounts of data and samples were collected during the cruise which will be interpreted in the coming months, with preliminary results detailed here. Of particular importance was the discovery of much larger areas showing gas seepage than previously reported. Interdisciplinary measurements were performed at the Panarea seepage site. The international team of scientists onboard R/V Urania performed complementary sampling and measurements for biological, chemical, and physical parameters throughout the area. Together with the dedication of R/V Urania’s Captain and crew, and the eagerness and cooperation of the scientific crew, we were able to obtain excellent scientific results during this six-day cruise

CSI 2264: Accretion process in classical T Tauri stars in the young cluster NGC 2264

Context. NGC 2264 is a young stellar cluster (~3 Myr) with hundreds of low-mass accreting stars that allow a detailed analysis of the accretion process taking place in the pre-main sequence. Aims. Our goal is to relate the photometric and spectroscopic variability of classical T Tauri stars to the physical processes acting in the stellar and circumstellar environment, within a few stellar radii from the star. Methods. NGC 2264 was the target of a multiwavelength observational campaign with CoRoT, MOST, Spitzer, and Chandra satellites and photometric and spectroscopic observations from the ground. We classified the CoRoT light curves of accreting systems according to their morphology and compared our classification to several accretion diagnostics and disk parameters. Results. The morphology of the CoRoT light curve reflects the evolution of the accretion process and of the inner disk region. Accretion burst stars present high mass-accretion rates and optically thick inner disks. AA Tau-like systems, whose light curves are dominated by circumstellar dust obscuration, show intermediate mass-accretion rates and are located in the transition of thick to anemic disks. Classical T Tauri stars with spot-like light curves correspond mostly to systems with a low mass-accretion rate and low mid-IR excess. About 30% of the classical T Tauri stars observed in the 2008 and 2011 CoRoT runs changed their light-curve morphology. Transitions from AA Tau-like and spot-like to aperiodic light curves and vice versa were common. The analysis of the Hα emission line variability of 58 accreting stars showed that 8 presented a periodicity that in a few cases was coincident with the photometric period. The blue and red wings of the Hα line profiles often do not correlate with each other, indicating that they are strongly influenced by different physical processes. Classical T Tauri stars have a dynamic stellar and circumstellar environment that can be explained by magnetospheric accretion and outflow models, including variations from stable to unstable accretion regimes on timescales of a few years

CSI 2264 : accretion process in classical T Tauri stars in the young cluster NGC 2264

APS and SHPA acknowledge support from CNPq, CAPES and Fapemig. JFG acknowledges support from FCT ref project UID/FIS/04434/2013.Context. NGC 2264 is a young stellar cluster (~3 Myr) with hundreds of low-mass accreting stars that allow a detailed analysis of the accretion process taking place in the pre-main sequence. Aims. Our goal is to relate the photometric and spectroscopic variability of classical T Tauri stars to the physical processes acting in the stellar and circumstellar environment, within a few stellar radii from the star. Methods. NGC 2264 was the target of a multiwavelength observational campaign with CoRoT, MOST, Spitzer, and Chandra satellites and photometric and spectroscopic observations from the ground. We classified the CoRoT light curves of accreting systems according to their morphology and compared our classification to several accretion diagnostics and disk parameters. Results. The morphology of the CoRoT light curve reflects the evolution of the accretion process and of the inner disk region. Accretion burst stars present high mass-accretion rates and optically thick inner disks. AA Tau-like systems, whose light curves are dominated by circumstellar dust obscuration, show intermediate mass-accretion rates and are located in the transition of thick to anemic disks. Classical T Tauri stars with spot-like light curves correspond mostly to systems with a low mass-accretion rate and low mid-IR excess. About 30% of the classical T Tauri stars observed inthe 2008 and 2011 CoRoT runs changed their light-curve morphology.Transitions from AA Tau-like and spot-like to a periodic light curves and vice versa were common. The analysis of the Hα emission line variability of 58 accreting stars showed that 8 presented a periodicity that in a few cases was coincident with the photometric period. The blue and red wings of the Hα line profiles often do not correlate with each other, indicating that they are strongly influenced by different physical processes. Classical T Tauri stars have a dynamic stellar and circumstellar environment that can be explained by magnetospheric accretion and outflow models, including variations from stable to unstable accretion regimes on timescales of a few years.PostprintPeer reviewe

A focused telephonic nursing intervention delivers improved adherence to A1c testing

Compliance with hemoglobin A1c (A1c) testing is suboptimal despite the clear national recommendations and guidelines established for care of patients with diabetes. Recent studies have demonstrated a relationship between participation in a diabetes disease management (DM) program and improved adherence to A1c testing. A focused intervention study was initiated to investigate the ability of a DM program to drive improvement in A1c testing. A cohort of 36,327 members experienced a statistically significant increase (29%) in A1c testing while participating in the 6-month focused intervention. This finding demonstrated that a focused DM intervention is able to deliver improvement in a clinical process metric critical for managing patients with diabetes, thereby reducing their risk of disease exacerbation