Melanomas are characterised by accelerated cell proliferation and metabolic reprogramming resulting from the contemporary dysregulation of the MAPK pathway, glycolysis and the tricarboxylic acid ...(TCA) cycle. Here, we suggest that the oncogenic transcription factor EB (TFEB), a key regulator of lysosomal biogenesis and function, controls melanoma tumour growth through a transcriptional programme targeting ERK1/2 activity and glucose, glutamine and cholesterol metabolism. Mechanistically, TFEB binds and negatively regulates the promoter of DUSP-1, which dephosphorylates ERK1/2. In melanoma cells, TFEB silencing correlates with ERK1/2 dephosphorylation at the activation-related p-Thr185 and p-Tyr187 residues. The decreased ERK1/2 activity synergises with TFEB control of CDK4 expression, resulting in cell proliferation blockade. Simultaneously, TFEB rewires metabolism, influencing glycolysis, glucose and glutamine uptake, and cholesterol synthesis. In TFEB-silenced melanoma cells, cholesterol synthesis is impaired, and the uptake of glucose and glutamine is inhibited, leading to a reduction in glycolysis, glutaminolysis and oxidative phosphorylation. Moreover, the reduction in TFEB level induces reverses TCA cycle, leading to fatty acid production. A syngeneic BRAFV600E melanoma model recapitulated the in vitro study results, showing that TFEB silencing sustains the reduction in tumour growth, increase in DUSP-1 level and inhibition of ERK1/2 action, suggesting a pivotal role for TFEB in maintaining proliferative melanoma cell behaviour and the operational metabolic pathways necessary for meeting the high energy demands of melanoma cells.
The Large Area Telescope onboard the Fermi Gamma-ray Space Telescope has collected the largest ever sample of high-energy cosmic-ray electron and positron events. Possible features in their energy ...spectrum could be a signature of the presence of nearby astrophysical sources or of more exotic sources, such as annihilation or decay of dark matter (DM) particles in the Galaxy. In this paper, for the first time we search for a deltalike line feature in the cosmic-ray electron and positron spectrum. We also search for a possible feature originating from DM particles annihilating into electron-positron pairs. Both searches yield negative results, but we are able to set constraints on the line intensity and on the velocity-averaged DM annihilation cross section. Our limits extend up to DM masses of 1.7 TeV/c2 and exclude the thermal value of the annihilation cross section for DM lighter than 150 GeV/c2.
Abstract In 2021 JET exploited its unique capabilities to operate with T and D-T fuel with an ITER-like Be/W wall (JET-ILW). This second major JET D-T campaign (DTE2), after DTE1 in 1997, represented ...the culmination of a series of JET enhancements – new fusion diagnostics, new T injection capabilities, refurbishment of the T plant, increased auxiliary heating, in-vessel calibration of 14MeV neutron yield monitors – as well as significant advances in plasma theory and modelling in the fusion community. DTE2 was complemented by a sequence of isotope physics campaigns encompassing operation in pure tritium at high T-NBI power. Carefully conducted for safe operation with tritium, the new T and D-T experiments used 1 kg of T (vs 100 g in DTE1), yielding the most fusion reactor relevant D-T plasmas to date and expanding our understanding of isotopes and D-T mixture physics. Furthermore, since the JET T and DTE2 campaigns occurred almost 25 years after the last major D-T tokamak experiment, it was also a strategic goal of the European fusion programme to refresh operational experience of a nuclear tokamak to prepare staff for ITER operation. The key physics results of the JET T and DTE2 experiments, carried out within the EUROfusion JET1 work package, are reported in this paper. Progress in the technological exploitation of JET D-T operations, development and validation of nuclear codes, neutronic tools and techniques for ITER operations carried out by EUROfusion (started within the Horizon 2020 Framework Programme and continuing under the Horizon Europe FP) are reported in 1, while JET experience on T and D-T operations is presented in 2.
A rare cause of dyspnea on exertion Maccari, Uberto; Rosini, Costanza F; Scala, Raffaele ...
Giornale italiano di cardiologia (2006)
17, Številka:
1
Journal Article
Recenzirano
Vascular rings are rare anomalies accounting for 1% to 3% of all congenital heart diseases with a similar frequency in both sexes, which can result in a variable degree of extrinsic compression of ...the trachea and esophagus. We report the case of a 46-year-old woman with symptomatic dyspnea and double aortic arch that caused esophageal tracheal compression. Considering the little impact of the functional vascular anomaly in our case, a conservative approach was adopted with clinical and functional annual follow-up.
We report on the search for spectral irregularities induced by oscillations between photons and axion-like particles (ALPs) in the gamma-ray spectrum of NGC 1275, the central galaxy of the Perseus ...cluster. Using 6 years of Fermi Large Area Telescope data, we find no evidence for ALPs and exclude couplings above 5 times 10 (sup -12) per gigaelectronvolt for ALP masses less than or approximately equal to 0.5 apparent magnitude (m (sub a)) less than or approximately equal to 5 nanoelectronvolts at 95 percent confidence. The limits are competitive withthe sensitivity of planned laboratory experiments, and, together with other bounds, strongly constrain thepossibility that ALPs can reduce the gamma-ray opacity of the Universe.
ABSTRACT On 2015 June 16, Fermi-LAT observed a giant outburst from the flat spectrum radio quasar 3C 279 with a peak >100 MeV flux of ∼3.6 × 10−5 photons cm−2 s−1, averaged over orbital period ...intervals. It is historically the highest γ-ray flux observed from the source, including past EGRET observations, with the γ-ray isotropic luminosity reaching ∼1049 erg s−1. During the outburst, the Fermi spacecraft, which has an orbital period of 95.4 minutes, was operated in a special pointing mode to optimize the exposure for 3C 279. For the first time, significant flux variability at sub-orbital timescales was found in blazar observations by Fermi-LAT. The source flux variability was resolved down to 2-minute binned timescales, with flux doubling times of less than 5 minutes. The observed minute-scale variability suggests a very compact emission region at hundreds of Schwarzschild radii from the central engine in conical jet models. A minimum bulk jet Lorentz factor (Γ) of 35 is necessary to avoid both internal γ-ray absorption and super-Eddington jet power. In the standard external radiation Comptonization scenario, Γ should be at least 50 to avoid overproducing the synchrotron self-Compton component. However, this predicts extremely low magnetization (∼5 × 10−4). Equipartition requires Γ as high as 120, unless the emitting region is a small fraction of the dissipation region. Alternatively, we consider γ rays originating as synchrotron radiation of γe ∼ 1.6 × 106 electrons, in a magnetic field B ∼ 1.3 kG, accelerated by strong electric fields E ∼ B in the process of magnetoluminescence. At such short distance scales, one cannot immediately exclude the production of γ-rays in hadronic processes.
The Fermi Large Area Telescope (LAT) has opened the way for comparative studies of cosmic rays (CRs) and high-energy objects in the Milky Way (MW) and in other, external, star-forming galaxies. Using ...2 yr of observations with the Fermi LAT, Local Group galaxy M31 was detected as a marginally extended gamma-ray source, while only an upper limit has been derived for the other nearby galaxy M33. We revisited the gamma-ray emission in the direction of M31 and M33 using more than 7 yr of LAT Pass 8 data in the energy range 0.1 - 100 GeV , presenting detailed morphological and spectral analyses. M33 remains undetected, and we computed an upper limit of 2.0 × 10 − 12 erg cm − 2 s − 1 on the 0.1 - 100 GeV energy flux (95% confidence level). This revised upper limit remains consistent with the observed correlation between gamma-ray luminosity and star formation rate tracers and implies an average CR density in M33 that is at most half of that of the MW. M31 is detected with a significance of nearly 10 . Its spectrum is consistent with a power law with photon index Γ = 2.4 0.1 stat + syst and a 0.1 - 100 GeV energy flux of ( 5.6 0.6 stat + syst ) × 10 − 12 erg cm − 2 s − 1 . M31 is detected to be extended with a 4 significance. The spatial distribution of the emission is consistent with a uniform-brightness disk with a radius of 0 4 and no offset from the center of the galaxy, but nonuniform intensity distributions cannot be excluded. The flux from M31 appears confined to the inner regions of the galaxy and does not fill the disk of the galaxy or extend far from it. The gamma-ray signal is not correlated with regions rich in gas or star formation activity, which suggests that the emission is not interstellar in origin, unless the energetic particles radiating in gamma rays do not originate in recent star formation. Alternative and nonexclusive interpretations are that the emission results from a population of millisecond pulsars dispersed in the bulge and disk of M31 by disrupted globular clusters or from the decay or annihilation of dark matter particles, similar to what has been proposed to account for the so-called Galactic center excess found in Fermi-LAT observations of the MW.
The Fermi Large Area Telescope (LAT) Collaboration has recently released a catalog of 360 sources detected above 50 GeV (2FHL). This catalog was obtained using 80 months of data re-processed with ...Pass 8, the newest event-level analysis, which significantly improves the acceptance and angular resolution of the instrument. Most of the 2FHL sources at high Galactic latitude are blazars. Using detailed Monte Carlo simulations, we measure, for the first time, the source count distribution, dN/dS, of extragalactic γ-ray sources at E>50 GeV and find that it is compatible with a Euclidean distribution down to the lowest measured source flux in the 2FHL (∼8×10^{-12} ph cm^{-2} s^{-1}). We employ a one-point photon fluctuation analysis to constrain the behavior of dN/dS below the source detection threshold. Overall, the source count distribution is constrained over three decades in flux and found compatible with a broken power law with a break flux, S_{b}, in the range 8×10^{-12},1.5×10^{-11} ph cm^{-2} s^{-1} and power-law indices below and above the break of α_{2}∈1.60,1.75 and α_{1}=2.49±0.12, respectively. Integration of dN/dS shows that point sources account for at least 86_{-14}^{+16}% of the total extragalactic γ-ray background. The simple form of the derived source count distribution is consistent with a single population (i.e., blazars) dominating the source counts to the minimum flux explored by this analysis. We estimate the density of sources detectable in blind surveys that will be performed in the coming years by the Cherenkov Telescope Array.
Abstract We investigated the influence of computer's use on metabolic control in 115 patients with type 1 diabetes (DM1). Multiple linear regression showed that HbA1c% was not related to age, DM1 ...duration, TV watching or computer use but was independently and negatively related to the weekly hours spent on physical exercise.
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