Modulation of docetaxel-induced apoptosis and cell cycle arrest by all- trans retinoic acid in prostate cancer cells

We report that all- trans retinoic acid (ATRA) enhanced the toxicity of docetaxel against DU145 and LNCaP prostate cancer cells, and that the nature of the interaction between ATRA and docetaxel was highly synergistic. Docetaxel-induced apoptotic cell death was associated with phosphorylation and hence inactivation of Bcl-2. ATRA enhanced docetaxel-induced apoptosis and combined treatment with ATRA and docetaxel resulted in down-regulation of Bcl-2. Docetaxel caused phosphorylation and hence inactivation of cdc2 kinase result ing in G2/M arrest. ATRA inhibited docetaxel-induced phosphorylation of cdc2 resulting in activation of cdc2 kinase and partial reversal of the G2/M arrest. ATRA also inhibited docetaxel-induced activation of MAPK indicating that the effects of docetaxel and ATRA on cdc2 phosphorylation are dependent on MAPK. We conclude that ATRA synergistically enhances docetaxel toxicity by down-regulating Bcl-2 expression and partially reverses the docetaxel-induced G2/M arrest by inhibiting docetaxel-induced cdc2 phosphorylation in a pathway that is dependent on MAPK. © 2001 Cancer Research Campaign http://www.bjcancer.co

Optical performance of the JWST MIRI flight model: characterization of the point spread function at high-resolution

The Mid Infra Red Instrument (MIRI) is one of the four instruments onboard the James Webb Space Telescope (JWST), providing imaging, coronagraphy and spectroscopy over the 5-28 microns band. To verify the optical performance of the instrument, extensive tests were performed at CEA on the flight model (FM) of the Mid-InfraRed IMager (MIRIM) at cryogenic temperatures and in the infrared. This paper reports on the point spread function (PSF) measurements at 5.6 microns, the shortest operating wavelength for imaging. At 5.6 microns the PSF is not Nyquist-sampled, so we use am original technique that combines a microscanning measurement strategy with a deconvolution algorithm to obtain an over-resolved MIRIM PSF. The microscanning consists in a sub-pixel scan of a point source on the focal plane. A data inversion method is used to reconstruct PSF images that are over-resolved by a factor of 7 compared to the native resolution of MIRI. We show that the FWHM of the high-resolution PSFs were 5-10% wider than that obtained with Zemax simulations. The main cause was identified as an out-of-specification tilt of the M4 mirror. After correction, two additional test campaigns were carried out, and we show that the shape of the PSF is conform to expectations. The FWHM of the PSFs are 0.18-0.20 arcsec, in agreement with simulations. 56.1-59.2% of the total encircled energy (normalized to a 5 arcsec radius) is contained within the first dark Airy ring, over the whole field of view. At longer wavelengths (7.7-25.5 microns), this percentage is 57-68%. MIRIM is thus compliant with the optical quality requirements. This characterization of the MIRIM PSF, as well as the deconvolution method presented here, are of particular importance, not only for the verification of the optical quality and the MIRI calibration, but also for scientific applications.Comment: 13 pages, submitted to SPIE Proceedings vol. 7731, Space Telescopes and Instrumentation 2010: Optical, Infrared, and Millimeter Wav

Molecular Basis of ß-­arrestin Coupling to Formoterol-­Bound ß1-­adrenoceptor

The β1-adrenoceptor (β1AR) is a G-protein-coupled receptor (GPCR) that couples1 to the heterotrimeric G protein Gs. G-protein-mediated signalling is terminated by phosphorylation of the C terminus of the receptor by GPCR kinases (GRKs) and by coupling of β-arrestin 1 (βarr1, also known as arrestin 2), which displaces Gs and induces signalling through the MAP kinase pathway2. The ability of synthetic agonists to induce signalling preferentially through either G proteins or arrestins-known as biased agonism3-is important in drug development, because the therapeutic effect may arise from only one signalling cascade, whereas the other pathway may mediate undesirable side effects4. To understand the molecular basis for arrestin coupling, here we determined the cryo-electron microscopy structure of the β1AR-βarr1 complex in lipid nanodiscs bound to the biased agonist formoterol5, and the crystal structure of formoterol-bound β1AR coupled to the G-protein-mimetic nanobody6 Nb80. βarr1 couples to β1AR in a manner distinct to that7 of Gs coupling to β2AR-the finger loop of βarr1 occupies a narrower cleft on the intracellular surface, and is closer to transmembrane helix H7 of the receptor when compared with the C-terminal α5 helix of Gs. The conformation of the finger loop in βarr1 is different from that adopted by the finger loop of visual arrestin when it couples to rhodopsin8. β1AR coupled to βarr1 shows considerable differences in structure compared with β1AR coupled to Nb80, including an inward movement of extracellular loop 3 and the cytoplasmic ends of H5 and H6. We observe weakened interactions between formoterol and two serine residues in H5 at the orthosteric binding site of β1AR, and find that formoterol has a lower affinity for the β1AR-βarr1 complex than for the β1AR-Gs complex. The structural differences between these complexes of β1AR provide a foundation for the design of small molecules that could bias signalling in the β-adrenoceptors

Water in the terrestrial planet-forming zone of the PDS 70 disk

Terrestrial and sub-Neptune planets are expected to form in the inner ($<10~$AU) regions of protoplanetary disks. Water plays a key role in their formation, although it is yet unclear whether water molecules are formed in-situ or transported from the outer disk. So far Spitzer Space Telescope observations have only provided water luminosity upper limits for dust-depleted inner disks, similar to PDS 70, the first system with direct confirmation of protoplanet presence. Here we report JWST observations of PDS 70, a benchmark target to search for water in a disk hosting a large ($\sim54~$AU) planet-carved gap separating an inner and outer disk. Our findings show water in the inner disk of PDS 70. This implies that potential terrestrial planets forming therein have access to a water reservoir. The column densities of water vapour suggest in-situ formation via a reaction sequence involving O, H$_2$, and/or OH, and survival through water self-shielding. This is also supported by the presence of CO$_2$ emission, another molecule sensitive to UV photodissociation. Dust shielding, and replenishment of both gas and small dust from the outer disk, may also play a role in sustaining the water reservoir. Our observations also reveal a strong variability of the mid-infrared spectral energy distribution, pointing to a change of inner disk geometry.Comment: To appear in Nature on 24 July 2023. 21 pages, 10 figures; includes extended data. Part of the JWST MINDS Guaranteed Time Observations program's science enabling products. Spectra downloadable on Zenodo at https://zenodo.org/record/799102

On Computing the Minimal Generator Family for Concept Lattices and Icebergs

Abstract. Minimal generators (or mingen) constitute a remarkable part of the closure space landscape since they are the antipodes of the closures, i.e., minimal sets in the underlying equivalence relation over the powerset of the ground set. As such, they appear in both theoretical and practical problem settings related to closures that stem from fields as diverging as graph theory, database design and data mining. In FCA, though, they have been almost ignored, a fact that has motivated our long-term study of the underlying structures under different perspectives. This paper is a two-fold contribution to the study of mingen families associated to a context or, equivalently, a closure space. On the one hand, it sheds light on the evolution of the family upon increases in the context attribute set (e.g., for purposes of interactive data exploration). On the other hand, it proposes a novel method for computing the mingen family that, although based on incremental lattice construction, is intended to be run in a batch mode. Theoretical and empirical evidence witnessing the potential of our approach is provided.

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