94 research outputs found
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
Mini G protein probes for active G proteinâ coupled receptors (GPCRs) in live cells
G proteinâcoupled receptors (GPCRs) are key signaling proteins that regulate nearly every aspect of cell function. Studies of GPCRs have benefited greatly from the development of molecular tools to monitor receptor activation and downstream signaling. Here, we show that mini G proteins are robust probes that can be used in a variety of assay formats to report GPCR activity in living cells. Mini G (mG) proteins are engineered GTPase domains of G subunits that were developed for struc- tural studies of active-state GPCRs. Confocal imaging revealed that mG proteins fused to fluorescent proteins were located diffusely in the cytoplasm and translocated to sites of receptor activation at the cell surface and at intracellular organ- elles. Bioluminescence resonance energy transfer (BRET) assays with mG proteins fused to either a fluorescent protein or luciferase reported agonist, superagonist, and inverse agonist activities. Variants of mG proteins (mGs, mGsi, mGsq, and mG12) corresponding to the four families of G subunits displayed appropriate coupling to their cognate GPCRs, allowing quantitative profiling of subtype-specific coupling to individual receptors. BRET between luciferaseâmG fusion proteins and fluorescent markers indicated the presence of active GPCRs at the plasma membrane, Golgi apparatus, and endosomes. Complementation assays with fragments of NanoLuc luciferase fused to GPCRs and mG proteins reported constitutive receptor activity and agonist-induced activation with up to 20-fold increases in luminescence. We conclude that mG proteins are versatile tools for studying GPCR activation and coupling specificity in cells and should be useful for discovering and characterizing G protein sub- typeâbiased ligands
Effect of c-Abl tyrosine kinase on the cellular response to paclitaxel-induced microtubule damage
DNA damage has been shown to activate c-Abl tyrosine kinase. We now report that, in addition to DNA damage, microtubule damage induced by paclitaxel results in activation of c-Abl kinase. In 3T3 cells, the presence of c-Abl kinase increased paclitaxel-induced cell death. In Abl-proficient cells, paclitaxel produced a marked and prolonged G2/M arrest which peaked at 24âh and a rapid and marked induction of p21WAF1which also peaked at 24âh. In Abl-deficient cells, the G2/M arrest induced by paclitaxel was less prominent and shorter in duration and the effect of paclitaxel on p21WAF1expression was reduced and delayed. Paclitaxel had no effect on p53 expression and MAPK phosphorylation. These findings indicate that, in 3T3 cells, c-Abl kinase facilitates cell death and regulates G2/M arrest in response to paclitaxel-induced microtubule damage in a pathway that is dependent on p21WAF1and independent of MAPK activity. © 2000 Cancer Research Campaig
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
The kinetic temperature in a damped Lyman-alpha absorption system in Q2206-199 - an example of the warm neutral medium
By comparing the widths of absorption lines from OI, SiII and FeII in the
redshift z=2.076 single-component damped Lyman alpha absorption system in the
spectrum of Q2206-199 we establish that these absorption lines arise in Warm
Neutral Medium gas at ~12000 +/- 3000K. This is consistent with thermal
equilibrium model estimates of ~ 8000K for the Warm Neutral Medium in galaxies,
but not with the presence of a significant cold component. It is also
consistent with, but not required by, the absence of CII* fine structure
absorption in this system. Some possible implications concerning abundance
estimates in narrow-line WNM absorbers are discussed.Comment: 9 pages, 3 figures. MNRAS accepte
Increased sensitivity of p53-deficient cells to anticancer agents due to loss of Pms2
A large fraction of human tumours carries mutations in the p53 gene. p53 plays a central role in controlling cell cycle checkpoint regulation, DNA repair, transcription, and apoptosis upon genotoxic stress. Lack of p53 function impairs these cellular processes, and this may be the basis of resistance to chemotherapeutic regimens. By virtue of the involvement of DNA mismatch repair in modulating cytotoxic pathways in response to DNA damaging agents, we investigated the effects of loss of Pms2 on the sensitivity to a panel of widely used anticancer agents in E1A/Ha-Ras-transformed p53-null mouse fibroblasts either proficient or deficient in Pms2. We report that lack of the Pms2 gene is associated with an increased sensitivity, ranging from 2â6-fold, to some types of anticancer agents including the topoisomerase II poisons doxorubicin, etoposide and mitoxantrone, the platinum compounds cisplatin and oxaliplatin, the taxanes docetaxel and paclitaxel, and the antimetabolite gemcitabine. In contrast, no change in sensitivity was found after treatment with 5-fluorouracil. Cell cycle analysis revealed that both, Pms2-deficient and -proficient cells, retain the ability to arrest at the G2/M upon cisplatin treatment. The data indicate that the concomitant loss of Pms2 function chemosensitises p53-deficient cells to some types of anticancer agents, that Pms2 positively modulates cell survival by mechanisms independent of p53, and that increased cytotoxicity is paralleled by increased apoptosis. Tumour-targeted functional inhibition of Pms2 may be a valuable strategy for increasing the efficacy of anticancer agents in the treatment of p53-mutant cancers
Water in the terrestrial planet-forming zone of the PDS 70 disk
Terrestrial and sub-Neptune planets are expected to form in the inner
(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 (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,
and/or OH, and survival through water self-shielding. This is also supported by
the presence of CO 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
Excitation of H in photodissociation regions as seen by Spitzer
We present spectroscopic observations obtained with the infrared Spitzer
Space Telescope, which provide insight into the H physics and gas
energetics in photodissociation Regions (PDRs) of low to moderate
far-ultraviolet (FUV) fields and densities. We analyze data on six well known
Galactic PDRs (L1721, California, N7023E, Horsehead, rho Oph, N2023N), sampling
a poorly explored range of excitation conditions (), relevant
to the bulk of molecular clouds in galaxies. Spitzer observations of H
rotational lines are complemented with H data, including ro-vibrational
line measurements, obtained with ground-based telescopes and ISO, to constrain
the relative contributions of ultraviolet pumping and collisions to the H
excitation. The data analysis is supported by model calculations with the
Meudon PDR code. The observed column densities of rotationally excited H
are observed to be much higher than PDR model predictions. In the lowest
excitation PDRs, the discrepancy between the model and the data is about one
order of magnitude for rotational levels 3. We discuss whether an
enhancement in the H formation rate or a local increase in photoelectric
heating, as proposed for brighter PDRs in former ISO studies, may improve the
data-model comparison. We find that an enhancement in the H formation rates
reduces the discrepancy, but the models still fall short of the data. This
large disagreement suggests that our understanding of the formation and
excitation of H and/or of PDRs energetics is still incomplete. We discuss
several explanations, which could be further tested using the Herschel Space
TelescopeComment: A&A in pres
Gi/o-protein coupled receptors in the aging brain
Cells translate extracellular signals to regulate processes such as differentiation, metabolism and proliferation, via transmembranar receptors. G protein-coupled receptors (GPCRs) belong to the largest family of transmembrane receptors, with over 800 members in the human species. Given the variety of key physiological functions regulated by GPCRs, these are main targets of existing drugs. During normal aging, alterations in the expression and activity of GPCRs have been observed. The central nervous system (CNS) is particularly affected by these alterations, which results in decreased brain functions, impaired neuroregeneration, and increased vulnerability to neuropathologies, such as Alzheimer's and Parkinson diseases. GPCRs signal via heterotrimeric G proteins, such as Go, the most abundant heterotrimeric G protein in CNS. We here review age-induced effects of GPCR signaling via the Gi/o subfamily at the CNS. During the aging process, a reduction in protein density is observed for almost half of the Gi/o-coupled GPCRs, particularly in age-vulnerable regions such as the frontal cortex, hippocampus, substantia nigra and striatum. Gi/o levels also tend to decrease with aging, particularly in regions such as the frontal cortex. Alterations in the expression and activity of GPCRs and coupled G proteins result from altered proteostasis, peroxidation of membranar lipids and age-associated neuronal degeneration and death, and have impact on aging hallmarks and age-related neuropathologies. Further, due to oligomerization of GPCRs at the membrane and their cooperative signaling, down-regulation of a specific Gi/o-coupled GPCR may affect signaling and drug targeting of other types/subtypes of GPCRs with which it dimerizes. Gi/o-coupled GPCRs receptorsomes are thus the focus of more effective therapeutic drugs aiming to prevent or revert the decline in brain functions and increased risk of neuropathologies at advanced ages.This work was supported by Fundação para a CiĂȘncia e
Tecnologia, Centro 2020 and Portugal 2020, the COMPETE
program, QREN, and the European Union (FEDER program)
via the GoBack project (PTDC/CVT-CVT/32261/2017),
the pAGE program (Centro-01-0145-FEDER-000003), and
Institute for Biomedicine iBiMED (UID/BIM/04501/2013;
UID/BIM/04501/2019).publishe
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