Context.
The origin of the
γ
-ray emission of the blazar
Mrk 421
is still a matter of debate.
Aims.
We used 5.5 years of unbiased observing campaign data, obtained using the FACT telescope and the
...Fermi
-LAT detector at TeV and GeV energies, the longest and densest so far, together with contemporaneous multi-wavelength observations, to characterise the variability of
Mrk 421
and to constrain the underlying physical mechanisms.
Methods.
We studied and correlated light curves obtained by ten different instruments and found two significant results.
Results.
The TeV and X-ray light curves are very well correlated with a lag of < 0.6 days. The GeV and radio (15 Ghz band) light curves are widely and strongly correlated. Variations of the GeV light curve lead those in the radio.
Conclusions.
Lepto-hadronic and purely hadronic models in the frame of shock acceleration predict proton acceleration or cooling timescales that are ruled out by the short variability timescales and delays observed in Mrk 421. Instead the observations match the predictions of leptonic models.
Pifithrin-alpha (PFT-alpha) was shown to specifically block transcriptional activity of the tumor suppressor p53 and was therefore proposed to be useful in preventing the severe side effects often ...associated with chemo- and radiotherapy. We report here that although PFT-alpha efficiently protected different cell types from DNA damage-induced apoptosis, it mediated this effect regardless of the presence or absence of p53. Interestingly, PFT-alpha blocked the apoptosome-mediated processing and activation of caspase-9 and -3 without interfering with the activation of mitochondria. Neither the DNA damage-induced activation of Bax or Bak nor the loss of the mitochondrial membrane potential or the final release of cytochrome c were inhibited by this compound. Instead, the ability of PFT-alpha to protect p53-deficient cells from DNA damage-induced caspase activation and apoptosis was greatly diminished after siRNA-mediated downregulation of cyclin-D1 expression. In contrast, downregulation of other proteins involved in cell-cycle progression, such as the retinoblastoma protein, cyclin D3, as well as the cyclin-dependent kinases, 2, 4 and 6, could not abolish this protection. Thus, our data show that PFT-alpha protects cells from DNA damage-induced apoptosis also by a p53-independent mechanism that takes place downstream of mitochondria and that might involve cyclin D1.
The p90 ribosomal S6 kinase (RSK) family is a group of highly conserved Ser/Thr kinases that promote cell proliferation, growth, motility and survival. As they are almost exclusively activated ...downstream of extracellular signal-regulated kinases 1 and 2 (ERK1/2), therapeutic intervention by RSK inhibition is less likely to produce such severe side effects as those observed following inhibition of the upstream master regulators Raf, MEK and ERK1/2. Here, we report that BI-D1870, a potent small molecule inhibitor of RSKs, induces apoptosis, although preferentially, in a p21-deficient background. On the other hand, BI-D1870 also induces a strong transcription- and p53-independent accumulation of p21 protein and protects cells from gamma irradiation (γIR)-induced apoptosis, driving them into senescence even in the absence of γIR. Although we identified p21 in in vitro kinase assays as a novel RSK substrate that specifically becomes phosphorylated by RSK1-3 at Ser116 and Ser146, RNA-interference, overexpression and co-immunoprecipitation studies as well as the use of SL0101, another specific RSK inhibitor, revealed that BI-D1870 mediates p21 accumulation via a yet unknown pathway that, besides its off-site targets polo-like kinase-1 and AuroraB, also does also not involve RSKs. Thus, this novel off-target effect of BI-D1870 should be taken into serious consideration in future studies investigating the role of RSKs in cellular signaling and tumorigenesis.
The First G-APD Cherenkov Telescope (FACT) demonstrates the usability of novel Geiger-mode operated Avalanche Photo Diodes (G-APD, often called SiPM) for Imaging Atmospheric Cherenkov Telescopes ...(IACT). The camera consists of 1440pixels with dedicated electronics operating at 2 Giga samples per second. It is installed on the refurbished HEGRA telescope with a mirror area of ≈9.5m2 on the Canary Island La Palma. FACT is taking data almost every night since the camera was installed in October 2011. It was possible to improve the data taking efficiency to very high values due to the very stable and reliable operation. This also allows to operate FACT remotely without any need for operators on site. Even remote human intervention became less and less frequent over the years, allowing operation to become mostly automatic. FACT is monitoring the long-term behavior of some very-high energy variable extra-galactic sources with unparalleled sampling density as well as testing the behavior of the sensors under severe weather conditions. Due to the long exposure of FACT's G-APDs under strong moonlight conditions it was possible to evaluate the aging effects of G-APDs due to collected charge. No indication of aging was found. No external calibration device is needed to operate FACT since the properties of the sensors themselves allow for a high precision self-calibration of the camera.
•SiPMs show no sign of ageing in 5years of operation.•High precision self calibration is possible without external calibration device.•Very high data taking efficiency has been reach due to excessive automation.
Geiger-mode Avalanche Photodiodes (G-APD) bear the potential to significantly improve the sensitivity of Imaging Air Cherenkov Telescopes (IACT). We are currently building the First G-APD Cherenkov ...Telescope (FACT) by refurbishing an old IACT with a mirror area of 9.5 square meters and are constructing a new, fine-pixelized camera using novel G-APDs. The main goal is to evaluate the performance of a complete system by observing very high energy gamma-rays from the Crab Nebula. This is an important field test to check the feasibility of G-APD-based cameras to replace at some time the PMT-based cameras of planned future IACTs like AGIS and CTA. In this article, we present the basic design of such a camera as well as some important details.
Among the members of the Bcl-2 family, the multidomain proteins Bax and Bak are crucial for the activation of mitochondria. However, it is still unclear whether they act in a unique and distinct ...manner or whether they exhibit redundant functions. To systematically investigate their activation on a single-cell level, we established MCF-7 cell lines stably expressing GFP-fusion variants of these proteins. We found that MCF-7/GFP-Bak cells showed an increased sensitivity to apoptosis induction by staurosporine, actinomycin D, TRAIL and overexpression of Puma compared to GFP-Bax-expressing cells. Independently of the death stimulus used, oligomerization of endogenous and exogenous Bak was mostly detected prior to an activation of Bax, whereas cells displaying oligomerized Bax in the absence of Bak clusters were not observed. In addition, activation of Bax but not Bak was attenuated by a caspase inhibitor. Consistent with this, caspase-3-deficient MCF-7 cells displayed a significantly reduced activation of endogenous Bax than caspase-3-proficient MCF-7 cells. Thus, our data strongly suggest that diverse apoptotic stimuli preferentially engage the Bak pathway, whereas the triggering of Bax occurs, at least partially, downstream of mitochondrial caspase activation, most likely constituting a positive feedback loop for the amplification of the death signal.
Results of the prototype camera for FACT Anderhub, H.; Backes, M.; Biland, A. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
05/2011, Volume:
639, Issue:
1
Journal Article
Peer reviewed
The maximization of the photon detection efficiency (PDE) is a key issue in the development of cameras for Imaging Atmospheric Cherenkov Telescopes. Geiger-mode Avalanche Photodiodes (G-APD) are a ...promising candidate to replace the commonly used photomultiplier tubes by offering a larger PDE and in addition a facilitated handling. The FACT (First G-APD Cherenkov Telescope) project evaluates the feasibility of this change by building a camera based on 1440 G-APDs for an existing small telescope. As a first step towards a full camera, a prototype module using 144 G-APDs was successfully built and tested. The strong temperature dependence of G-APDs is compensated using a feedback system, which allows to keep the gain of the G-APDs constant to 0.5%.
A G-APD based Camera for Imaging Atmospheric Cherenkov Telescopes Anderhub, H.; Backes, M.; Biland, A. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
02/2011, Volume:
628, Issue:
1
Journal Article
Peer reviewed
Imaging Atmospheric Cherenkov Telescopes (IACT) for Gamma-ray astronomy are presently using photomultiplier tubes as photo sensors. Geiger-mode avalanche photodiodes (G-APD) promise an improvement in ...sensitivity and, important for this application, ease of construction, operation and ruggedness. G-APDs have proven many of their features in the laboratory, but a qualified assessment of their performance in an IACT camera is best undertaken with a prototype. This paper describes the design and construction of a full-scale camera based on G-APDs realized within the FACT project (First G-APD Cherenkov Telescope).
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