Simultaneous Water Vapor and Dry Air Optical Path Length Measurements and Compensation with the Large Binocular Telescope Interferometer

The Large Binocular Telescope Interferometer uses a near-infrared camera to measure the optical path length variations between the two AO-corrected apertures and provide high-angular resolution observations for all its science channels (1.5-13 $\mu$m). There is however a wavelength dependent component to the atmospheric turbulence, which can introduce optical path length errors when observing at a wavelength different from that of the fringe sensing camera. Water vapor in particular is highly dispersive and its effect must be taken into account for high-precision infrared interferometric observations as described previously for VLTI/MIDI or the Keck Interferometer Nuller. In this paper, we describe the new sensing approach that has been developed at the LBT to measure and monitor the optical path length fluctuations due to dry air and water vapor separately. After reviewing the current performance of the system for dry air seeing compensation, we present simultaneous H-, K-, and N-band observations that illustrate the feasibility of our feedforward approach to stabilize the path length fluctuations seen by the LBTI nuller.Comment: SPIE conference proceeding

Therapeutic Challenge with a CDK 4/6 Inhibitor Induces an RB-Dependent SMAC-Mediated Apoptotic Response in Non-Small Cell Lung Cancer.

Purpose: The retinoblastoma tumor suppressor (RB), a key regulator of cell-cycle progression and proliferation, is functionally suppressed in up to 50% of non-small cell lung cancer (NSCLC). RB function is exquisitely controlled by a series of proteins, including the CyclinD-CDK4/6 complex. In this study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function. Experimental Design and Results: We employed multiple isogenic RB-proficient and -deficient NSCLC lines to interrogate the cytostatic and cytotoxic capacity of CDK 4/6 inhibition in vitro and in vivo We demonstrate that while short-term exposure to palbociclib induces cellular senescence, prolonged exposure results in inhibition of tumor growth. Mechanistically, CDK 4/6 inhibition induces a proapoptotic transcriptional program through suppression of IAPs FOXM1 and Survivin, while simultaneously augmenting expression of SMAC and caspase-3 in an RB-dependent manner. Conclusions: This study uncovers a novel function of RB activation to induce cellular apoptosis through therapeutic administration of a palbociclib and provides a rationale for the clinical evaluation of CDK 4/6 inhibitors in the treatment of patients with NSCLC

Lagrangian particle paths and ortho-normal quaternion frames

Experimentalists now measure intense rotations of Lagrangian particles in turbulent flows by tracking their trajectories and Lagrangian-average velocity gradients at high Reynolds numbers. This paper formulates the dynamics of an orthonormal frame attached to each Lagrangian fluid particle undergoing three-axis rotations, by using quaternions in combination with Ertel's theorem for frozen-in vorticity. The method is applicable to a wide range of Lagrangian flows including the three-dimensional Euler equations and its variants such as ideal MHD. The applicability of the quaterionic frame description to Lagrangian averaged velocity gradient dynamics is also demonstrated.Comment: 9 pages, one figure, revise

Direct Use of Carboxylic Acids in the Photocatalytic Hydroacylation of Styrenes To Generate Dialkyl Ketones

A general protocol for the hydroacylation of styrenes from aliphatic carboxylic acids is reported. These reactions proceed via β-scission of a phosphoranyl radical that is accessed by photoredox catalysis, followed by addition of the resulting acyl radical to the styrenyl olefin. We show that phosphine tunability is critical for efficient intermolecular coupling due to competitive quenching of the photocatalyst by the olefin. Primary, secondary, and structurally rigid tertiary carboxylic acids all generate valuable unsymmetrical dialkyl ketones

In vivo E2F reporting reveals efficacious schedules of MEK1/2–CDK4/6 targeting and mTOR–s6 resistance mechanisms

Targeting cyclin-dependent kinases 4/6 (CDK4/6) represents a therapeutic option in combination with BRAF inhibitor and/or MEK inhibitor (MEKi) in melanoma; however, continuous dosing elicits toxicities in patients. Using quantitative and temporal in vivo reporting, we show that continuous MEKi with intermittent CDK4/6 inhibitor (CDK4/6i) led to more complete tumor responses versus other combination schedules. Nevertheless, some tumors acquired resistance that was associated with enhanced phosphorylation of ribosomal S6 protein. These data were supported by phospho-S6 staining of melanoma biopsies from patients treated with CDK4/6i plus targeted inhibitors. Enhanced phospho-S6 in resistant tumors provided a therapeutic window for the mTORC1/2 inhibitor AZD2014. Mechanistically, upregulation or mutation of NRAS was associated with resistance in in vivo models and patient samples, respectively, and mutant NRAS was sufficient to enhance resistance. This study utilizes an in vivo reporter model to optimize schedules and supports targeting mTORC1/2 to overcome MEKi plus CDK4/6i resistance. SIGnIFICAnCE: Mutant BRAF and NRAS melanomas acquire resistance to combined MEK and CDK4/6 inhibition via upregulation of mTOR pathway signaling. This resistance mechanism provides the preclinical basis to utilize mTORC1/2 inhibitors to improve MEKi plus CDK4/6i drug regimens

The potential role of T-cells and their interaction with antigen-presenting cells in mediating immunosuppression following trauma-hemorrhage

Objective: Trauma-hemorrhage results in depressed immune responses of antigen-presenting cells (APCs) and T-cells. Recent studies suggest a key role of depressed T-cell derived interferon (IFN)-g in this complex immune cell interaction. The aim of this study was to elucidate further the underlying mechanisms responsible for dysfunctional T-cells and their interaction with APCs following trauma-hemorrhage. Design: Adult C3H/HeN male mice were subjected to trauma-hemorrhage (3-cm midline laparotomy) followed by hemorrhage (blood pressure of 35�5mmHg for 90 min and resuscitation) or sham operation. At 24 h thereafter, spleens were harvested and T-cells (by Microbeads) and APCs (via adherence) were Isolated. Co-cultures of T-cells and APCs were established for 48 h and stimulated with concanavalin A and lipopolysaccharide. T-Cell specific cytokines known to affect APC function (i.e. interleukin(IL)-2, IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF)) were measured in culture supernatants by Multiplex assay. The expression of MHC class II as well as co-stimulatory surface molecules on T-cells and APCs was determined by flow cytometry. Results: The release of IL-4 and GM-CSF by T-cells was suppressed following trauma-hemorrhage, irrespective of whether sham or trauma-hemorrhage APCs were present. Antigen-presenting cells from animals subjected to trauma-hemorrhage did not affect T-cell derived cytokine release by sham T-cells. In contrast, T-cells from traumahemorrhage animals depressed MHC class II expression of CD11c(þ) cells, irrespective of whether APCs underwent sham or trauma-hemorrhage procedure. Surprisingly, co-stimulatory molecules on APCs (CD80, CD86) were not affected by trauma-hemorrhage. Conclusions: These results suggest that beside IFN-g other T-cell derived cytokines contribute to immunosuppression following trauma-hemorrhage causing diminished MHC II expression on APCs. Thus, T-cells appear to play an important role in this interaction at the time-point examined. Therapeutic approaches should aim at maintenance of T-cell function and their interaction with APCs to prevent extended immunosuppression following trauma-hemorrhage

Lagrangian analysis of alignment dynamics for isentropic compressible magnetohydrodynamics

After a review of the isentropic compressible magnetohydrodynamics (ICMHD) equations, a quaternionic framework for studying the alignment dynamics of a general fluid flow is explained and applied to the ICMHD equations.Comment: 12 pages, 2 figures, submitted to a Focus Issue of New Journal of Physics on "Magnetohydrodynamics and the Dynamo Problem" J-F Pinton, A Pouquet, E Dormy and S Cowley, editor

Incidence of debris discs around FGK stars in the solar neighbourhood

Debris discs are a consequence of the planet formation process and constitute the fingerprints of planetesimal systems. Their solar system's counterparts are the asteroid and Edgeworth-Kuiper belts. The aim of this paper is to provide robust numbers for the incidence of debris discs around FGK stars in the solar neighbourhood. The full sample of 177 FGK stars with d<20 pc proposed for the DUNES survey is presented. Herschel/PACS observations at 100 and 160 micron complemented with data at 70 micron, and at 250, 350 and 500 micron SPIRE photometry, were obtained. The 123 objects observed by the DUNES collaboration were presented in a previous paper. The remaining 54 stars, shared with the DEBRIS consortium and observed by them, and the combined full sample are studied in this paper. The incidence of debris discs per spectral type is analysed and put into context together with other parameters of the sample, like metallicity, rotation and activity, and age. The subsample of 105 stars with d<15 pc containing 23 F, 33 G and 49 K stars, is complete for F stars, almost complete for G stars and contains a substantial number of K stars to draw solid conclusions on objects of this spectral type. The incidence rates of debris discs per spectral type 0.26 (6 objects with excesses out of 23 F stars), 0.21 (7 out of 33 G stars) and 0.20 (10 out of 49 K stars), the fraction for all three spectral types together being 0.22 (23 out of 105 stars). Uncertainties corresponding to a 95% confidence level are given in the text for all these numbers. The medians of the upper limits of L_dust/L_* for each spectral type are 7.8E-7 (F), 1.4E-6 (G) and 2.2E-6 (K); the lowest values being around 4.0E-7. The incidence of debris discs is similar for active (young) and inactive (old) stars. The fractional luminosity tends to drop with increasing age, as expected from collisional erosion of the debris belts.Comment: 31 pages, 15 figures, 10 tables, 2 appendice

Exocomet signatures around the A-shell star Φ\Phi Leo?

We present an intensive monitoring of high-resolution spectra of the Ca {\sc ii} K line in the A7IV shell star $\Phi$ Leo at very short (minutes, hours), short (night to night), and medium (weeks, months) timescales. The spectra show remarkable variable absorptions on timescales of hours, days, and months. The characteristics of these sporadic events are very similar to most that are observed toward the debris disk host star $\beta$ Pic, which are commonly interpreted as signs of the evaporation of solid, comet-like bodies grazing or falling onto the star. Therefore, our results suggest the presence of solid bodies around $\Phi$ Leo. To our knowledge, with the exception of $\beta$ Pic, our monitoring has the best time resolution at the mentioned timescales for a star with events attributed to exocomets. Assuming the cometary scenario and considering the timescales of our monitoring, our results indicate that $\Phi$ Leo presents the richest environment with comet-like events known to date, second only to $\beta$ Pic.Comment: A&A letters, proof-correcte