164 research outputs found
NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer
Alternative splicing is dysregulated in cancer and the reactivation of telomerase involves the splicing of TERT transcripts to produce full-length (FL) TERT. Knowledge about the splicing factors that enhance or silence FL hTERT is lacking. We identified splicing factors that reduced telomerase activity and shortened telomeres using a siRNA minigene reporter screen and a lung cancer cell bioinformatics approach. A lead candidate, NOVA1, when knocked down resulted in a shift in hTERT splicing to non-catalytic isoforms, reduced telomerase activity, and progressive telomere shortening. NOVA1 knockdown also significantly altered cancer cell growth in vitro and in xenografts. Genome engineering experiments reveal that NOVA1 promotes the inclusion of exons in the reverse transcriptase domain of hTERT resulting in the production of FL hTERT transcripts. Utilizing hTERT splicing as a model splicing event in cancer may provide new insights into potentially targetable dysregulated splicing factors in cancer
Telomerase inhibition improves tumor response to radiotherapy in a murine orthotopic model of human glioblastoma
Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells
Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 +/- A 11 vs 64 +/- A 18 %; p = 0.03) and overall survival (58 +/- A 12 vs 83 +/- A 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.Canadian Institutes of Health Research [MOP 82727]info:eu-repo/semantics/publishedVersio
A lower bound on intergalactic magnetic fields from time variability of 1ES 0229+200 from MAGIC and Fermi/LAT observations
Extended and delayed emission around distant TeV sources induced by the
effects of propagation of gamma rays through the intergalactic medium can be
used for the measurement of the intergalactic magnetic field (IGMF). We search
for delayed GeV emission from the hard-spectrum TeV blazar 1ES 0229+200 with
the goal to detect or constrain the IGMF-dependent secondary flux generated
during the propagation of TeV gamma rays through the intergalactic medium. We
analyze the most recent MAGIC observations over a 5 year time span and
complement them with historic data of the H.E.S.S. and VERITAS telescopes along
with a 12-year long exposure of the Fermi/LAT telescope. We use them to trace
source evolution in the GeV-TeV band over one-and-a-half decade in time. We use
Monte Carlo simulations to predict the delayed secondary gamma-ray flux,
modulated by the source variability, as revealed by TeV-band observations. We
then compare these predictions for various assumed IGMF strengths to all
available measurements of the gamma-ray flux evolution. We find that the source
flux in the energy range above 200 GeV experiences variations around its
average on the 14 years time span of observations. No evidence for the flux
variability is found in 1-100 GeV energy range accessible to Fermi/LAT.
Non-detection of variability due to delayed emission from electromagnetic
cascade developing in the intergalactic medium imposes a lower bound of
B>1.8e-17 G for long correlation length IGMF and B>1e-14 G for an IGMF of the
cosmological origin. Though weaker than the one previously derived from the
analysis of Fermi/LAT data, this bound is more robust, being based on a
conservative intrinsic source spectrum estimate and accounting for the details
of source variability in the TeV energy band. We discuss implications of this
bound for cosmological magnetic fields which might explain the baryon asymmetry
of the Universe.Comment: 10 pages, 5 figures, accepted to A&A. Corresponding authors: Ievgen
Vovk, Paolo Da Vela (mailto:[email protected]) and Andrii Neronov
(mailto:[email protected]
Long-term multi-wavelength study of 1ES 0647+250
The BL Lac object 1ES 0647+250 is one of the few distant -ray
emitting blazars detected at very high energies (VHE, 100 GeV) during
a non-flaring state. It was detected with the MAGIC telescopes during its low
activity in the years 2009-2011, as well as during three flaring activities in
the years 2014, 2019 and 2020, with the highest VHE flux in the latter epoch.
An extensive multi-instrument data set was collected within several coordinated
observing campaigns throughout these years. We aim to characterise the
long-term multi-band flux variability of 1ES 0647+250, as well as its broadband
spectral energy distribution (SED) during four distinct activity states
selected in four different epochs, in order to constrain the physical
parameters of the blazar emission region under certain assumptions. We evaluate
the variability and correlation of the emission in the different energy bands
with the fractional variability and the Z-transformed Discrete Correlation
Function, as well as its spectral evolution in X-rays and rays. Owing
to the controversy in the redshift measurements of 1ES 0647+250 reported in the
literature, we also estimate its distance in an indirect manner through the
comparison of the GeV and TeV spectra from simultaneous observations with
Fermi-LAT and MAGIC during the strongest flaring activity detected to date.
Moreover, we interpret the SEDs from the four distinct activity states within
the framework of one-component and two-component leptonic models, proposing
specific scenarios that are able to reproduce the available multi-instrument
data.Comment: 20 pages, 7 figures. Accepted in A&A. Corresponding authors: Jorge
Otero-Santos; Daniel Morcuende; Vandad Fallah Ramazani; Daniela Dorner; David
Paneque (mailto: [email protected]
Investigating the blazar TXS 0506+056 through sharp multi-wavelength eyes during 2017-2019
The blazar TXS 0506+056 got into the spotlight of the astrophysical community
in September 2017, when a high-energy neutrino detected by IceCube
(IceCube-170922A) was associated at the 3 level to a -ray
flare from this source. This multi-messenger photon-neutrino association
remains, as per today, the most significant one ever observed. TXS 0506+056 was
a poorly studied object before the IceCube-170922A event. To better
characterize its broad-band emission, we organized a multi-wavelength campaign
lasting 16 months (November 2017 to February 2019), covering the radio-band
(Mets\"ahovi, OVRO), the optical/UV (ASAS-SN, KVA, REM, Swift/UVOT), the X-rays
(Swift/XRT, NuSTAR), the high-energy rays (Fermi/LAT) and the
very-high-energy (VHE) rays (MAGIC). In rays, the behaviour
of the source was significantly different from the 2017 one: MAGIC observations
show the presence of flaring activity during December 2018, while the source
only shows an excess at the 4 level during the rest of the campaign (74
hours of accumulated exposure); Fermi/LAT observations show several short
(days-to-week timescale) flares, different from the long-term brightening of
2017. No significant flares are detected at lower energies. The radio light
curve shows an increasing flux trend, not seen in other wavelengths. We model
the multi-wavelength spectral energy distributions in a lepto-hadronic
scenario, in which the hadronic emission emerges as Bethe-Heitler and
pion-decay cascade in the X-rays and VHE rays. According to the model
presented here, the December 2018 -ray flare was connected to a
neutrino emission that was too brief and not bright enough to be detected by
current neutrino instruments.Comment: 18 pages, 6 figures; in press in Ap
First detection of VHE gamma-ray emission from TXS 1515-273, study of its X-ray variability and spectral energy distribution
We report here on the first multi-wavelength (MWL) campaign on the blazar TXS
1515-273, undertaken in 2019 and extending from radio to very-high-energy gamma
rays (VHE). Up until now, this blazar had not been the subject of any detailed
MWL observations. It has a rather hard photon index at GeV energies and was
considered a candidate extreme high-synchrotronpeaked source. MAGIC
observations resulted in the first-time detection of the source in VHE with a
statistical significance of 7.6. The average integral VHE flux of the
source is 6 1% of the Crab nebula flux above 400 GeV. X-ray coverage was
provided by Swift-XRT, XMMNewton, and NuSTAR. The long continuous X-ray
observations were separated by 9 h, both showing clear hour scale
flares. In the XMM-Newton data, both the rise and decay timescales are longer
in the soft X-ray than in the hard X-ray band, indicating the presence of a
particle cooling regime. The X-ray variability timescales were used to
constrain the size of the emission region and the strength of the magnetic
field. The data allowed us to determine the synchrotron peak frequency and
classify the source as a flaring high, but not extreme, synchrotron peaked
object. Considering the constraints and variability patterns from the X-ray
data, we model the broad-band spectral energy distribution. We applied a simple
one-zone model, which could not reproduce the radio emission and the shape of
the optical emission, and a two-component leptonic model with two interacting
components, enabling us to reproduce the emission from radio to VHE band
Multi-year characterisation of the broad-band emission from the intermittent extreme BL Lac 1ES~2344+514
The BL Lac 1ES 2344+514 is known for temporary extreme properties (e.g., a
shift of the synchrotron SED peak energy above 1keV). While
those extreme states were so far observed only during high flux levels,
additional multi-year observing campaigns are required to achieve a coherent
picture. Here, we report the longest investigation of the source from radio to
VHE performed so far, focusing on a systematic characterisation of the
intermittent extreme states. While our results confirm that 1ES 2344+514
typically exhibits 1keV during elevated flux periods, we also
find periods where the extreme state coincides with low flux activity. A strong
spectral variability thus happens in the quiescent state, and is likely caused
by an increase of the electron acceleration efficiency without a change in the
electron injection luminosity. We also report a strong X-ray flare (among the
brightest for 1ES 2344+514) without a significant shift of .
During this particular flare, the X-ray spectrum is among the softest of the
campaign. It unveils complexity in the spectral evolution, where the common
harder-when-brighter trend observed in BL Lacs is violated. During a low and
hard X-ray state, we find an excess of the UV flux with respect to an
extrapolation of the X-ray spectrum to lower energies. This UV excess implies
that at least two regions contribute significantly to the
infrared/optical/ultraviolet/X-ray emission. Using the simultaneous MAGIC,
XMM-Newton, NuSTAR, and AstroSat observations, we argue that a region possibly
associated with the 10 GHz radio core may explain such an excess. Finally, we
investigate a VHE flare, showing an absence of simultaneous variability in the
0.3-2keV band. Using a time-dependent leptonic modelling, we show that this
behaviour, in contradiction to single-zone scenarios, can instead be explained
by a two-component model.Comment: Accepted for publication in Astronomy & Astrophysic
MAGIC observations provide compelling evidence of hadronic multi-TeV emission from the putative PeVatron SNR G106.3+2.7
Context. Certain types of supernova remnants (SNRs) in our Galaxy are assumed to be PeVatrons, capable of accelerating cosmic rays (CRs) to ∼ PeV energies. However, conclusive observational evidence for this has not yet been found. The SNR G106.3+2.7, detected at 1- 100 TeV energies by different γ-ray facilities, is one of the most promising PeVatron candidates. This SNR has a cometary shape, which can be divided into a head and a tail region with different physical conditions. However, in which region the 100 TeV emission is produced has not yet been identified because of the limited position accuracy and/or angular resolution of existing observational data. Additionally, it remains unclear as to whether the origin of the γ-ray emission is leptonic or hadronic. Aims. With the better angular resolution provided by new MAGIC data compared to earlier γ-ray datasets, we aim to reveal the acceleration site of PeV particles and the emission mechanism by resolving the SNR G106.3+2.7 with 0.1 resolution at TeV energies. Methods. We observed the SNR G106.3+2.7 using the MAGIC telescopes for 121.7 h in total - after quality cuts - between May 2017 and August 2019. The analysis energy threshold is ∼0.2 TeV, and the angular resolution is 0.07-0.1. We examined the γ-ray spectra of different parts of the emission, whilst benefitting from the unprecedented statistics and angular resolution at these energies provided by our new data. We also used measurements at other wavelengths such as radio, X-rays, GeV γ-rays, and 10 TeV γ-rays to model the emission mechanism precisely. Results. We detect extended γ-ray emission spatially coincident with the radio continuum emission at the head and tail of SNR G106.3+2.7. The fact that we detect a significant γ-ray emission with energies above 6.0 TeV from only the tail region suggests that the emissions above 10 TeV detected with air shower experiments (Milagro, HAWC, Tibet ASγ and LHAASO) are emitted only from the SNR tail. Under this assumption, the multi-wavelength spectrum of the head region can be explained with either hadronic or leptonic models, while the leptonic model for the tail region is in contradiction with the emission above 10 TeV and X-rays. In contrast, the hadronic model could reproduce the observed spectrum at the tail by assuming a proton spectrum with a cutoff energy of ∼1 PeV for that region. Such high-energy emission in this middle-aged SNR (4-10 kyr) can be explained by considering a scenario where protons escaping from the SNR in the past interact with surrounding dense gases at present. Conclusions. The γ-ray emission region detected with the MAGIC telescopes in the SNR G106.3+2.7 is extended and spatially coincident with the radio continuum morphology. The multi-wavelength spectrum of the emission from the tail region suggests proton acceleration up to ∼PeV, while the emission mechanism of the head region could either be hadronic or leptonic
MAGIC observations provide compelling evidence of the hadronic multi-TeV emission from the putative PeVatron SNR G106.3+2.7
The SNR G106.3+2.7, detected at 1--100 TeV energies by different -ray
facilities, is one of the most promising PeVatron candidates. This SNR has a
cometary shape which can be divided into a head and a tail region with
different physical conditions. However, it is not identified in which region
the 100 TeV emission is produced due to the limited position accuracy and/or
angular resolution of existing observational data. Additionally, it remains
unclear whether the origin of the -ray emission is leptonic or
hadronic. With the better angular resolution provided by these new MAGIC data
compared to earlier -ray datasets, we aim to reveal the acceleration
site of PeV particles and the emission mechanism by resolving the SNR
G106.3+2.7 with 0.1 resolution at TeV energies. We detected extended
-ray emission spatially coincident with the radio continuum emission at
the head and tail of SNR G106.3+2.7. The fact that we detected a significant
-ray emission with energies above 6.0 TeV from the tail region only
suggests that the emissions above 10 TeV, detected with air shower experiments
(Milagro, HAWC, Tibet AS and LHAASO), are emitted only from the SNR
tail. Under this assumption, the multi-wavelength spectrum of the head region
can be explained with either hadronic or leptonic models, while the leptonic
model for the tail region is in contradiction with the emission above 10 TeV
and X-rays. In contrast, the hadronic model could reproduce the observed
spectrum at the tail by assuming a proton spectrum with a cutoff energy of
PeV for the tail region. Such a high energy emission in this
middle-aged SNR (4--10 kyr) can be explained by considering the scenario that
protons escaping from the SNR in the past interact with surrounding dense gases
at present.Comment: 13 pages, 7 figures, Accepted for publication in A&
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