Effect of P-glycoprotein on flavopiridol sensitivity

Flavopiridol is the first potent inhibitor of cyclin-dependent kinases (CDKs) to enter clinical trials. Little is known about mechanisms of resistance to this agent. In order to determine whether P-glycoprotein (Pgp) might play a role in flavopiridol resistance, we examined flavopiridol sensitivity in a pair of Chinese hamster ovary cell lines differing with respect to level of Pgp expression. The IC 50 s of flavopiridol in parental AuxB1 (lower Pgp) and colchicine-selected CHRC5 (higher Pgp) cells were 90.2 ± 6.6 nM and 117 ± 2.3 nM, respectively (P< 0.01), suggesting that Pgp might have a modest effect on flavopiridol action. Consistent with this hypothesis, pretreatment with either quinidine or verapamil (inhibitors of Pgp-mediated transport) sensitized CHRC5 cells to the antiproliferative effects of flavopiridol. Because of concern that colony forming assays might not accurately reflect cytotoxicity, we also examined flavopiridol-treated cells by trypan blue staining and flow cytometry. These assays confirmed that flavopiridol was less toxic to cells expressing higher levels of Pgp. Further experiments revealed that flavopiridol inhibited the binding of [3H]-azidopine to Pgp in isolated membrane vesicles, but only at high concentrations. Collectively, these results identify flavopiridol as a weak substrate for Pgp. © 2001 Cancer Research Campaign www.bjcancer.co

Prevention of neonatal oxygen-induced brain damage by reduction of intrinsic apoptosis

International audienceWithin the last decade, it became clear that oxygen contributes to the pathogenesis of neonatal brain damage, leading to neurocognitive impairment of prematurely born infants in later life. Recently, we have identified a critical role for receptor-mediated neuronal apoptosis in the immature rodent brain. However, the contribution of the intrinsic apoptotic pathway accompanied by activation of caspase-2 under hyperoxic conditions in the neonatal brain still remains elusive. Inhibition of caspases appears a promising strategy for neuroprotection. In order to assess the influence of specific caspases on the developing brain, we applied a recently developed pentapeptide-based group II caspase inhibitor (5-(2,6-difluorophenoxy)-3(R,S)-(2(S)-(2(S)-(3-methoxycarbonyl-2(S)-(3-m ethyl-2(S)-((quinoline-2-carbonyl)-amino)-butyrylamino)propionylamino) 3-methylbutyrylamino) propionylamino)-4-oxo-pentanoic acid methyl ester; TRP601). Here, we report that elevated oxygen (hyperoxia) triggers a marked increase in active caspase-2 expression, resulting in an initiation of the intrinsic apoptotic pathway with upregulation of key proteins, namely, cytochrome c, apoptosis protease-activating factor-1, and the caspase-independent protein apoptosis-inducing factor, whereas BH3-interacting domain death agonist and the anti-apoptotic protein B-cell lymphoma-2 are downregulated. These results coincide with an upregulation of caspase-3 activity and marked neurodegeneration. However, single treatment with TRP601 at the beginning of hyperoxia reversed the detrimental effects in this model. Hyperoxia-mediated neurodegeneration is supported by intrinsic apoptosis, suggesting that the development of highly selective caspase inhibitors will represent a potential useful therapeutic strategy in prematurely born infants. Cell Death and Disease (2012) 3, e250; doi:10.1038/cddis.2011.133; published online 12 January 201

Homologous Helical Jets: Observations by IRIS, SDO and Hinode and Magnetic Modeling with Data-Driven Simulations

We report on observations of recurrent jets by instruments onboard the Interface Region Imaging Spectrograph (IRIS), Solar Dynamics Observatory (SDO) and Hinode spacecrafts. Over a 4-hour period on July 21st 2013, recurrent coronal jets were observed to emanate from NOAA Active Region 11793. FUV spectra probing plasma at transition region temperatures show evidence of oppositely directed flows with components reaching Doppler velocities of +/- 100 km/s. Raster Doppler maps using a Si IV transition region line show all four jets to have helical motion of the same sense. Simultaneous observations of the region by SDO and Hinode show that the jets emanate from a source region comprising a pore embedded in the interior of a supergranule. The parasitic pore has opposite polarity flux compared to the surrounding network field. This leads to a spine-fan magnetic topology in the coronal field that is amenable to jet formation. Time-dependent data-driven simulations are used to investigate the underlying drivers for the jets. These numerical experiments show that the emergence of current-carrying magnetic field in the vicinity of the pore supplies the magnetic twist needed for recurrent helical jet formation.Comment: 15 pages, 10 figures, accepted by Ap

An Interface Region Imaging Spectrograph first view on Solar Spicules

Solar spicules have eluded modelers and observers for decades. Since the discovery of the more energetic type II, spicules have become a heated topic but their contribution to the energy balance of the low solar atmosphere remains unknown. Here we give a first glimpse of what quiet Sun spicules look like when observed with NASA's recently launched Interface Region Imaging Spectrograph (IRIS). Using IRIS spectra and filtergrams that sample the chromosphere and transition region we compare the properties and evolution of spicules as observed in a coordinated campaign with Hinode and the Atmospheric Imaging Assembly. Our IRIS observations allow us to follow the thermal evolution of type II spicules and finally confirm that the fading of Ca II H spicules appears to be caused by rapid heating to higher temperatures. The IRIS spicules do not fade but continue evolving, reaching higher and falling back down after 500-800 s. Ca II H type II spicules are thus the initial stages of violent and hotter events that mostly remain invisible in Ca II H filtergrams. These events have very different properties from type I spicules, which show lower velocities and no fading from chromospheric passbands. The IRIS spectra of spicules show the same signature as their proposed disk counterparts, reinforcing earlier work. Spectroheliograms from spectral rasters also confirm that quiet Sun spicules originate in bushes from the magnetic network. Our results suggest that type II spicules are indeed the site of vigorous heating (to at least transition region temperatures) along extensive parts of the upward moving spicular plasma.Comment: 6 pages, 4 figures, accepted for publication in ApJ Letters. For associated movies, see http://folk.uio.no/tiago/iris_spic

Technical Note: Asteroid Detection Demonstration from SkySat-3 - B612 Data Using Synthetic Tracking

We report results from analyzing the data taken by the sCMOS cameras on board of SkySat3 using the synthetic tracking technique. The analysis demonstrates the expected sensitivity improvement in the signal-to-noise ratio of the faint asteroids from properly stacking up the short exposure images in post-processing

Detection of supersonic downflows and associated heating events in the transition region above sunspots

IRIS data allow us to study the solar transition region (TR) with an unprecedented spatial resolution of 0.33 arcsec. On 2013 August 30, we observed bursts of high Doppler shifts suggesting strong supersonic downflows of up to 200 km/s and weaker, slightly slower upflows in the spectral lines Mg II h and k, C II 1336 \AA, Si IV 1394 \AA, and 1403 \AA, that are correlated with brightenings in the slitjaw images (SJIs). The bursty behavior lasts throughout the 2 hr observation, with average burst durations of about 20 s. The locations of these short-lived events appear to be the umbral and penumbral footpoints of EUV loops. Fast apparent downflows are observed along these loops in the SJIs and in AIA, suggesting that the loops are thermally unstable. We interpret the observations as cool material falling from coronal heights, and especially coronal rain produced along the thermally unstable loops, which leads to an increase of intensity at the loop footpoints, probably indicating an increase of density and temperature in the TR. The rain speeds are on the higher end of previously reported speeds for this phenomenon, and possibly higher than the free-fall velocity along the loops. On other observing days, similar bright dots are sometimes aligned into ribbons, resembling small flare ribbons. These observations provide a first insight into small-scale heating events in sunspots in the TR.Comment: accepted by ApJ

High-resolution Observations of the Shock Wave Behavior for Sunspot Oscillations with the Interface Region Imaging Spectrograph

We present the first results of sunspot oscillations from observations by the Interface Region Imaging Spectrograph. The strongly nonlinear oscillation is identified in both the slit-jaw images and the spectra of several emission lines formed in the transition region and chromosphere. We first apply a single Gaussian fit to the profiles of the Mgii 2796.35 {\AA}, Cii 1335.71 {\AA}, and Si iv 1393.76 {\AA} lines in the sunspot. The intensity change is about 30%. The Doppler shift oscillation reveals a sawtooth pattern with an amplitude of about 10 km/s in Si iv. In the umbra the Si iv oscillation lags those of Cii and Mgii by about 3 and 12 s, respectively. The line width suddenly increases as the Doppler shift changes from redshift to blueshift. However, we demonstrate that this increase is caused by the superposition of two emission components. We then perform detailed analysis of the line profiles at a few selected locations on the slit. The temporal evolution of the line core is dominated by the following behavior: a rapid excursion to the blue side, accompanied by an intensity increase, followed by a linear decrease of the velocity to the red side. The maximum intensity slightly lags the maximum blueshift in Si iv, whereas the intensity enhancement slightly precedes the maximum blueshift in Mgii. We find a positive correlation between the maximum velocity and deceleration, a result that is consistent with numerical simulations of upward propagating magnetoacoustic shock waves.Comment: 5 figures, in ApJ. Correction of time lags (correct values are 3 and 12s) made on June 17 201

Scaling algebras and pointlike fields: A nonperturbative approach to renormalization

We present a method of short-distance analysis in quantum field theory that does not require choosing a renormalization prescription a priori. We set out from a local net of algebras with associated pointlike quantum fields. The net has a naturally defined scaling limit in the sense of Buchholz and Verch; we investigate the effect of this limit on the pointlike fields. Both for the fields and their operator product expansions, a well-defined limit procedure can be established. This can always be interpreted in the usual sense of multiplicative renormalization, where the renormalization factors are determined by our analysis. We also consider the limits of symmetry actions. In particular, for suitable limit states, the group of scaling transformations induces a dilation symmetry in the limit theory.Comment: minor changes and clarifications; as to appear in Commun. Math. Phys.; 37 page

Prevalence of Small-scale Jets from the Networks of the Solar Transition Region and Chromosphere

As the interface between the Sun's photosphere and corona, the chromosphere and transition region play a key role in the formation and acceleration of the solar wind. Observations from the Interface Region Imaging Spectrograph reveal the prevalence of intermittent small-scale jets with speeds of 80-250 km/s from the narrow bright network lanes of this interface region. These jets have lifetimes of 20-80 seconds and widths of 300 km or less. They originate from small-scale bright regions, often preceded by footpoint brightenings and accompanied by transverse waves with ~20 km/s amplitudes. Many jets reach temperatures of at least ~100000 K and constitute an important element of the transition region structures. They are likely an intermittent but persistent source of mass and energy for the solar wind.Comment: Figs 1-4 & S1-S5; Movies S1-S8; published in Science, including the main text and supplementary materials. Reference: H. Tian, E. E. DeLuca, S. R. Cranmer, et al., Science 346, 1255711 (2014