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 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]

MAGIC detection of GRB 201216C at z = 1.1

Gamma-ray bursts (GRBs) are explosive transient events occurring at cosmological distances, releasing a large amount of energy as electromagnetic radiation over several energy bands. We report the detection of the long GRB 201216C by the MAGIC telescopes. The source is located at z = 1.1 and thus it is the farthest one detected at very high energies. The emission above 70 GeV of GRB 201216C is modelled together with multiwavelength data within a synchrotron and synchrotron self-Compton (SSC) scenario. We find that SSC can explain the broad-band data well from the optical to the very-high-energy band. For the late-time radio data, a different component is needed to account for the observed emission. Differently from previous GRBs detected in the very-high-energy range, the model for GRB 201216C strongly favours a wind-like medium. The model parameters have values similar to those found in past studies of the afterglows of GRBs detected up to GeV energies

Long-term multi-wavelength study of 1ES 0647+250

The BL Lac object 1ES 0647+250 is one of the few distant $\gamma$-ray emitting blazars detected at very high energies (VHE, $\gtrsim$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 $\gamma$ 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 $\sigma$ level to a $\gamma$-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 $\gamma$ rays (Fermi/LAT) and the very-high-energy (VHE) $\gamma$ rays (MAGIC). In $\gamma$ 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$\sigma$ 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 $\gamma$ rays. According to the model presented here, the December 2018 $\gamma$-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$\sigma$. The average integral VHE flux of the source is 6 $\pm$ 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 $\sim$ 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

Follow-up observations of GW170817 with the MAGIC telescopes

The discovery of the electromagnetic counterpart AT2017gfo and the GRB 170817A, associated to the binary neutron star merger GW170817, was one of the major advances in the study of gamma-ray bursts (GRBs) and the hallmark of the multi-messenger astronomy with gravitational waves. Another breakthrough in GRB physics is represented by the discovery of the highly energetic, teraelectronvolt (TeV) component in the GRB 190114C, possibly an universal component in all GRBs. This conclusion is also suggested by the hint of TeV emission in the short GRB 160821B and a few more events reported in the literature. The missing observational piece is the joint detection of TeV emission and gravitational waves from a short GRB and its progenitor. MAGIC observed the counterpart AT2017gfo as soon as the visibility conditions allowed it, namely from January to June 2018. These observations correspond to the maximum flux level observed in the radio and X-ray bands. The upper limits derived from TeV observations are compared with the modelling of the late non-thermal emission using the multi-frequency SED

Multi-year characterisation of the broad-band emission from the intermittent extreme BL Lac 1ES 2344+514

Aims. The BL Lac 1ES 2344+514 is known for temporary extreme properties characterised by a shift of the synchrotron spectral energy distribution (SED) peak energy νsynch;p above 1 keV. While those extreme states have only been observed during high flux levels thus far, additional multi-year observing campaigns are required to achieve a coherent picture. Here, we report the longest investigation of the source from radio to very high energy (VHE) performed so far, focussing on a systematic characterisation of the intermittent extreme states. Methods.We organised a monitoring campaign covering a 3-year period from 2019 to 2021.Morethan ten instruments participated in the observations in order to cover the emission from radio to VHE. In particular, sensitive X-ray measurements by XMM-Newton, NuSTAR, and AstroSat took place simultaneously with multi-hour MAGIC observations, providing an unprecedented constraint of the two SED components for this blazar. Results. While our results confirm that 1ES 2344+514 typically exhibits νsynch;p > 1 keV 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 in the electron acceleration efficiency without a change in the electron injection luminosity. On the other hand, we also report a strong X-ray flare (among the brightest for 1ES 2344+514) without a significant shift of νsynch;p. 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. By combining Swift-XRT and Swift-UVOT measurements 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 significantly contribute 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 0.3-2 keV band. Using time-dependent leptonic modelling, we show that this behaviour, in contradiction to single-zone scenarios, can instead be explained by a two-component model