Persistent inhibition of pore-based cell migration by sub-toxic doses of miuraenamide, an actin filament stabilizer

Opposed to tubulin-binding agents, actin-binding small molecules have not yet become part of clinical tumor treatment, most likely due to the fear of general cytotoxicity. Addressing this problem, we investigated the long-term efficacy of sub-toxic doses of miuraenamide, an actin filament stabilizing natural compound, on tumor cell (SKOV3) migration. No cytotoxic effects or persistent morphological changes occurred at a concentration of miuraenamide of 20 nM. After 72 h treatment with this concentration, nuclear stiffness was increased, causing reduced migration through pores in a Boyden chamber, while cell migration and chemotaxis per se were unaltered. A concomitant time-resolved proteomic approach showed down regulation of a protein cluster after 56 h treatment. This cluster correlated best with the Wnt signaling pathway. A further analysis of the actin associated MRTF/SRF signaling showed a surprising reduction of SRF-regulated proteins. In contrast to acute effects of actin-binding compounds on actin at high concentrations, long-term low-dose treatment elicits much more subtle but still functionally relevant changes beyond simple destruction of the cytoskeleton. These range from biophysical parameters to regulation of protein expression, and may help to better understand the complex biology of actin, as well as to initiate alternative regimes for the testing of actin-targeting drugs

Localized inhibition of protein phosphatase 1 by NUAK1 promotes spliceosome activity and reveals a MYC-sensitive feedback control of transcription.

Deregulated expression of MYC induces a dependence on the NUAK1 kinase, but the molecular mechanisms underlying this dependence have not been fully clarified. Here, we show that NUAK1 is a predominantly nuclear protein that associates with a network of nuclear protein phosphatase 1 (PP1) interactors and that PNUTS, a nuclear regulatory subunit of PP1, is phosphorylated by NUAK1. Both NUAK1 and PNUTS associate with the splicing machinery. Inhibition of NUAK1 abolishes chromatin association of PNUTS, reduces spliceosome activity, and suppresses nascent RNA synthesis. Activation of MYC does not bypass the requirement for NUAK1 for spliceosome activity but significantly attenuates transcription inhibition. Consequently, NUAK1 inhibition in MYC-transformed cells induces global accumulation of RNAPII both at the pause site and at the first exon-intron boundary but does not increase mRNA synthesis. We suggest that NUAK1 inhibition in the presence of deregulated MYC traps non-productive RNAPII because of the absence of correctly assembled spliceosomes

Integrated Detector Control and Calibration Processing at the European XFEL

The European X-ray Free Electron Laser is a high-intensity X-ray light source currently being constructed in the area of Hamburg, that will provide spatially coherent X-rays in the energy range between $0.25\,\mathrm{keV}$ and $25\,\mathrm{keV}$. The machine will deliver $10\,\mathrm{trains/s}$, consisting of up to $2700\,\mathrm{pulses}$, with a $4.5\,\mathrm{MHz}$ repetition rate. The LPD, DSSC and AGIPD detectors are being developed to provide high dynamic-range Mpixel imaging capabilities at the mentioned repetition rates. A consequence of these detector characteristics is that they generate raw data volumes of up to $15\,\mathrm{Gbyte/s}$. In addition the detector's on-sensor memory-cell and multi-/non-linear gain architectures pose unique challenges in data correction and calibration, requiring online access to operating conditions and control settings. We present how these challenges are addressed within XFEL's control and analysis framework Karabo, which integrates access to hardware conditions, acquisition settings (also using macros) and distributed computing. Implementation of control and calibration software is mainly in Python, using self-optimizing (py) CUDA code, numpy and iPython parallels to achieve near-real time performance for calibration application.Comment: Proceeding ICALEPS 201

The X-ray Telescope of CAST

The Cern Axion Solar Telescope (CAST) is in operation and taking data since 2003. The main objective of the CAST experiment is to search for a hypothetical pseudoscalar boson, the axion, which might be produced in the core of the sun. The basic physics process CAST is based on is the time inverted Primakoff effect, by which an axion can be converted into a detectable photon in an external electromagnetic field. The resulting X-ray photons are expected to be thermally distributed between 1 and 7 keV. The most sensitive detector system of CAST is a pn-CCD detector combined with a Wolter I type X-ray mirror system. With the X-ray telescope of CAST a background reduction of more than 2 orders off magnitude is achieved, such that for the first time the axion photon coupling constant g_agg can be probed beyond the best astrophysical constraints g_agg < 1 x 10^-10 GeV^-1.Comment: 19 pages, 25 figures and images, replaced by the revised version accepted for publication in New Journal of Physic

The CAST Time Projection Chamber

One of the three X-ray detectors of the CAST experiment searching for solar axions is a Time Projection Chamber (TPC) with a multi-wire proportional counter (MWPC) as a readout structure. Its design has been optimized to provide high sensitivity to the detection of the low intensity X-ray signal expected in the CAST experiment. A low hardware threshold of 0.8 keV is safely set during normal data taking periods, and the overall efficiency for the detection of photons coming from conversion of solar axions is 62 %. Shielding has been installed around the detector, lowering the background level to 4.10 x 10^-5 counts/cm^2/s/keV between 1 and 10 keV. During phase I of the CAST experiment the TPC has provided robust and stable operation, thus contributing with a competitive result to the overall CAST limit on axion-photon coupling and mass.Comment: 19 pages, 11 figures and images, submitted to New Journal of Physic

Cluster analysis of the organic peaks in bulk mass spectra obtained during the 2002 New England Air Quality Study with an Aerodyne aerosol mass spectrometer

International audienceWe applied hierarchical cluster analysis to an Aerodyne aerosol mass spectrometer (AMS) bulk mass spectral dataset collected aboard the NOAA research vessel Ronald H. Brown during the 2002 New England Air Quality Study off the east coast of the United States. Emphasizing the organic peaks, the cluster analysis yielded a series of categories that are distinguishable with respect to their mass spectra and their occurrence as a function of time. The differences between the categories mainly arise from relative intensity changes rather than from the presence or absence of specific peaks. The most frequent category exhibits a strong signal at m/z 44 and represents oxidized organic matter most probably originating from both, anthropogenic as well as biogenic sources. On the basis of spectral and trace gas correlations, the second most common category with strong signals at m/z 29, 43, and 44 contains contributions from isoprene oxidation products. The third through the fifth most common categories have peak patterns characteristic of monoterpene oxidation products and were most frequently observed when air masses from monoterpene rich regions were sampled. Taken together, the second through the fifth most common categories represent as much as 5 µg/m3 organic aerosol mass ? 17% of the total organic mass ? that can be attributed to biogenic sources. These numbers have to be viewed as lower limits since the most common category was attributed to anthropogenic sources for this calculation. The cluster analysis was also very effective in identifying a few contaminated mass spectra that were not removed during pre-processing. This study demonstrates that hierarchical clustering is a useful tool to analyze the complex patterns of the organic peaks in bulk aerosol mass spectra from a field study

Ozone variability and halogen oxidation within the Arctic and sub-Arctic springtime boundary layer

The influence of halogen oxidation on the variabilities of ozone (O&lt;sub&gt;3&lt;/sub&gt;) and volatile organic compounds (VOCs) within the Arctic and sub-Arctic atmospheric boundary layer was investigated using field measurements from multiple campaigns conducted in March and April 2008 as part of the POLARCAT project. For the ship-based measurements, a high degree of correlation (&lt;i&gt;r&lt;/i&gt; = 0.98 for 544 data points collected north of 68° N) was observed between the acetylene to benzene ratio, used as a marker for chlorine and bromine oxidation, and O&lt;sub&gt;3&lt;/sub&gt; signifying the vast influence of halogen oxidation throughout the ice-free regions of the North Atlantic. Concurrent airborne and ground-based measurements in the Alaskan Arctic substantiated this correlation and were used to demonstrate that halogen oxidation influenced O&lt;sub&gt;3&lt;/sub&gt; variability throughout the Arctic boundary layer during these springtime studies. Measurements aboard the R/V &lt;i&gt;Knorr&lt;/i&gt; in the North Atlantic and Arctic Oceans provided a unique view of the transport of O&lt;sub&gt;3&lt;/sub&gt;-poor air masses from the Arctic Basin to latitudes as far south as 52° N. FLEXPART, a Lagrangian transport model, was used to quantitatively determine the exposure of air masses encountered by the ship to first-year ice (FYI), multi-year ice (MYI), and total ICE (FYI+MYI). O&lt;sub&gt;3&lt;/sub&gt; anti-correlated with the modeled total ICE tracer (&lt;i&gt;r&lt;/i&gt; = &amp;minus;0.86) indicating that up to 73% of the O&lt;sub&gt;3&lt;/sub&gt; variability measured in the Arctic marine boundary layer could be related to sea ice exposure

Climate and Weather Impact Timing of Emergence of Bats

We thank two anonymous reviewers for helpful comments on the manuscript and Barry Nickel for advice on statistical analysis. We thank the National Severe Storms Laboratory for radar data processing and access, in particular Brian Kaney and Katherine Willingham. We thank Danny Scipión and Sarah Stough for help with data preparation.Conceived and designed the experiments: WFF THK JFK KWH PBC. Performed the experiments: WFF PMS PBC. Analyzed the data: WFF. Contributed reagents/materials/analysis tools: KWH CMK. Wrote the paper: WFF PMS JFK PBC.Interest in forecasting impacts of climate change have heightened attention in recent decades to how animals respond to variation in climate and weather patterns. One difficulty in determining animal response to climate variation is lack of long-term datasets that record animal behaviors over decadal scales. We used radar observations from the national NEXRAD network of Doppler weather radars to measure how group behavior in a colonially-roosting bat species responded to annual variation in climate and daily variation in weather over the past 11 years. Brazilian free-tailed bats (Tadarida brasiliensis) form dense aggregations in cave roosts in Texas. These bats emerge from caves daily to forage at high altitudes, which makes them detectable with Doppler weather radars. Timing of emergence in bats is often viewed as an adaptive trade-off between emerging early and risking predation or increased competition and emerging late which restricts foraging opportunities. We used timing of emergence from five maternity colonies of Brazilian free-tailed bats in south-central Texas during the peak lactation period (15 June–15 July) to determine whether emergence behavior was associated with summer drought conditions and daily temperatures. Bats emerged significantly earlier during years with extreme drought conditions than during moist years. Bats emerged later on days with high surface temperatures in both dry and moist years, but there was no relationship between surface temperatures and timing of emergence in summers with normal moisture levels. We conclude that emergence behavior is a flexible animal response to climate and weather conditions and may be a useful indicator for monitoring animal response to long-term shifts in climate.Yeshttp://www.plosone.org/static/editorial#pee

Total Observed Organic Carbon (TOOC): A synthesis of North American observations

Measurements of organic carbon compounds in both the gas and particle phases measured upwind, over and downwind of North America are synthesized to examine the total observed organic carbon (TOOC) over this region. These include measurements made aboard the NOAA WP-3 and BAe-146 aircraft, the NOAA research vessel Ronald H. Brown, and at the Thompson Farm and Chebogue Point surface sites during the summer 2004 ICARTT campaign. Both winter and summer 2002 measurements during the Pittsburgh Air Quality Study are also included. Lastly, the spring 2002 observations at Trinidad Head, CA, surface measurements made in March 2006 in Mexico City and coincidentally aboard the C-130 aircraft during the MILAGRO campaign and later during the IMPEX campaign off the northwestern United States are incorporated. Concentrations of TOOC in these datasets span more than two orders of magnitude. The daytime mean TOOC ranges from 4.0 to 456 μgC m^−3 from the cleanest site (Trinidad Head) to the most polluted (Mexico City). Organic aerosol makes up 3–17% of this mean TOOC, with highest fractions reported over the northeastern United States, where organic aerosol can comprise up to 50% of TOOC. Carbon monoxide concentrations explain 46 to 86% of the variability in TOOC, with highest TOOC/CO slopes in regions with fresh anthropogenic influence, where we also expect the highest degree of mass closure for TOOC. Correlation with isoprene, formaldehyde, methyl vinyl ketene and methacrolein also indicates that biogenic activity contributes substantially to the variability of TOOC, yet these tracers of biogenic oxidation sources do not explain the variability in organic aerosol observed over North America. We highlight the critical need to develop measurement techniques to routinely detect total gas phase VOCs, and to deploy comprehensive suites of TOOC instruments in diverse environments to quantify the ambient evolution of organic carbon from source to sink