1,944 research outputs found
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 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
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
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
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
Monitor zur Ueberwachung der Gadolinium-Konzentration in Make up-Loesungen des Purex-Prozesses
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