GPER agonist G-1 decreases adrenocortical carcinoma (ACC) cell growth in vitro and in vivo

We have previously demonstrated that estrogen receptor (ER) alpha (ESR1) increases proliferation of adrenocortical carcinoma (ACC) through both an estrogen-dependent and -independent (induced by IGF-II/IGF1R pathways) manner. Then, the use of tamoxifen, a selective estrogen receptor modulator (SERM), appears effective in reducing ACC growth in vitro and in vivo. However, tamoxifen not only exerts antiestrogenic activity, but also acts as full agonist on the G protein-coupled estrogen receptor (GPER). Aim of this study was to investigate the effect of a non-steroidal GPER agonist G-1 in modulating ACC cell growth. We found that G-1 is able to exert a growth inhibitory effect on H295R cells both in vitro and, as xenograft model, in vivo. Treatment of H295R cells with G-1 induced cell cycle arrest, DNA damage and cell death by the activation of the intrinsic apoptotic mechanism. These events required sustained extracellular regulated kinase (ERK) 1/2 activation. Silencing of GPER by a specific shRNA partially reversed G-1-mediated cell growth inhibition without affecting ERK activation. These data suggest the existence of G-1 activated but GPER-independent effects that remain to be clarified. In conclusion, this study provides a rational to further study G-1 mechanism of action in order to include this drug as a treatment option to the limited therapy of ACC

A wide field X-ray telescope for astronomical survey purposes: from theory to practice

X-ray mirrors are usually built in the Wolter I (paraboloid-hyperboloid) configuration. This design exhibits no spherical aberration on-axis but suffers from field curvature, coma and astigmatism, therefore the angular resolution degrades rapidly with increasing off-axis angles. Different mirror designs exist in which the primary and secondary mirror profiles are expanded as a power series in order to increase the angular resolution at large off-axis positions, at the expanses of the on-axis performances. Here we present the design and global trade off study of an X-ray mirror systems based on polynomial optics in view of the Wide Field X-ray Telescope (WFXT) mission. WFXT aims at performing an extended cosmological survey in the soft X-ray band with unprecedented flux sensitivity. To achieve these goals the angular resolution required for the mission is very demanding ~5 arcsec mean resolution across a 1-deg field of view. In addition an effective area of 5-9000 cm^2 at 1 keV is needed.Comment: Accepted for publication in the MNRAS (11pages, 3 table, 13 figures

KLOE results in kaon physics and prospects for KLOE-2

The phi-factory DAPHNE offers a possibility to select pure kaon beams, charged and neutral ones. In particular, neutral kaons from phi->KS KL are produced in pairs and the detection of a KS (KL) tags the presence of a KL (KS). This allows to perform precise measurements of kaon properties by means of KLOE detector. Another advantage of a phi-factory consists in fact that the neutral kaon pairs are produced in a pure quantum state (J^(PC) = 1^(--)), which allowsto investigate CP and CPT symmetries via quantum interference effects, as well as the basic principles of quantum mechanics.A review of the most recent results of the KLOE experiment at DAPHNE using pure kaon beams or via quantum interferometry is presented together with prospects for kaon physics at KLOE-2.Comment: 5 pages, 4 figures, From Phi To Psi 2011 conference, to be published in Nuclear Physics B (Proceedings Supplements

The SPTLC1 p.S331 mutation bridges sensory neuropathy and motor neuron disease and has implications for treatment

Aims SPTLC1-related disorder is a late onset sensory-autonomic neuropathy associated with perturbed sphingolipid homeostasis which can be improved by supplementation with the serine palmitoyl-CoA transferase (SPT) substrate, l-serine. Recently, a juvenile form of motor neuron disease has been linked to SPTLC1 variants. Variants affecting the p.S331 residue of SPTLC1 cause a distinct phenotype, whose pathogenic basis has not been established. This study aims to define the neuropathological and biochemical consequences of the SPTLC1 p.S331 variant, and test response to l-serine in this specific genotype. Methods We report clinical and neurophysiological characterisation of two unrelated children carrying distinct p.S331 SPTLC1 variants. The neuropathology was investigated by analysis of sural nerve and skin innervation. To clarify the biochemical consequences of the p.S331 variant, we performed sphingolipidomic profiling of serum and skin fibroblasts. We also tested the effect of l-serine supplementation in skin fibroblasts of patients with p.S331 mutations. Results In both patients, we recognised an early onset phenotype with prevalent progressive motor neuron disease. Neuropathology showed severe damage to the sensory and autonomic systems. Sphingolipidomic analysis showed the coexistence of neurotoxic deoxy-sphingolipids with an excess of canonical products of the SPT enzyme. l-serine supplementation in patient fibroblasts reduced production of toxic 1-deoxysphingolipids but further increased the overproduction of sphingolipids. Conclusions Our findings suggest that p.S331 SPTLC1 variants lead to an overlap phenotype combining features of sensory and motor neuropathies, thus proposing a continuum in the spectrum of SPTLC1-related disorders. l-serine supplementation in these patients may be detrimental

Quantum numbers of the X(3872)X(3872) state and orbital angular momentum in its ρ0Jψ\rho^0 J\psi decay

Angular correlations in $B^+\to X(3872) K^+$ decays, with $X(3872)\to \rho^0 J/\psi$, $\rho^0\to\pi^+\pi^-$ and $J/\psi \to\mu^+\mu^-$, are used to measure orbital angular momentum contributions and to determine the $J^{PC}$ value of the $X(3872)$ meson. The data correspond to an integrated luminosity of 3.0 fb$^{-1}$ of proton-proton collisions collected with the LHCb detector. This determination, for the first time performed without assuming a value for the orbital angular momentum, confirms the quantum numbers to be $J^{PC}=1^{++}$. The $X(3872)$ is found to decay predominantly through S wave and an upper limit of $4\%$ at $95\%$ C.L. is set on the fraction of D wave.Comment: 16 pages, 4 figure

XIAO X-ray Imager for Afterglows Observations Proposta tecnico gestionale

SVOM e’ una missione franco-cinese dedicata alla rivelazione, localizzazione rapida, e studio dei GRB e di altre sorgenti transienti ad energie X/gamma. Si propone di partecipare alla missione SVOM contribuendo: a) al carico utile del satellite, fornendo un piccolo telescopio (XIAO), ottimizzato per la localizzazione precisa dei GRB e lo studio degli afterglow nella banda X soft b) al segmento di terra, fornendo l’utilizzo della stazione di Malindi e collaborando alla componente scientific

Gamma-Ray Burst observations by the high-energy charged particle detector on board the CSES-01 satellite between 2019 and 2021

In this paper we report the detection of five strong Gamma-Ray Bursts (GRBs) by the High-Energy Particle Detector (HEPD-01) mounted on board the China Seismo-Electromagnetic Satellite (CSES-01), operational since 2018 on a Sun-synchronous polar orbit at a $\sim$ 507 km altitude and 97$^\circ$ inclination. HEPD-01 was designed to detect high-energy electrons in the energy range 3 - 100 MeV, protons in the range 30 - 300 MeV, and light nuclei in the range 30 - 300 MeV/n. Nonetheless, Monte Carlo simulations have shown HEPD-01 is sensitive to gamma-ray photons in the energy range 300 keV - 50 MeV, even if with a moderate effective area above $\sim$ 5 MeV. A dedicated time correlation analysis between GRBs reported in literature and signals from a set of HEPD-01 trigger configuration masks has confirmed the anticipated detector sensitivity to high-energy photons. A comparison between the simultaneous time profiles of HEPD-01 electron fluxes and photons from GRB190114C, GRB190305A, GRB190928A, GRB200826B and GRB211211A has shown a remarkable similarity, in spite of the different energy ranges. The high-energy response, with peak sensitivity at about 2 MeV, and moderate effective area of the detector in the actual flight configuration explain why these five GRBs, characterised by a fluence above $\sim$ 3 $\times$ 10$^{-5}$ erg cm$^{-2}$ in the energy interval 300 keV - 50 MeV, have been detected.Comment: Accepted for publication in The Astrophysical Journal (ApJ

Long-lasting improvements in episodic memory among subjects with mild cognitive impairment who received transcranial direct current stimulation combined with cognitive treatment and telerehabilitation: a multicentre, randomized, active-controlled study

BackgroundIn recent years, an increasing number of studies have examined the potential efficacy of cognitive training procedures in individuals with normal ageing and mild cognitive impairment (MCI).ObjectiveThe aims of this study were to (i) evaluate the efficacy of the cognitive Virtual Reality Rehabilitation System (VRRS) combined with anodal transcranial direct current stimulation (tDCS) applied to the left dorsolateral prefrontal cortex compared to placebo tDCS stimulation combined with VRRS and (ii) to determine how to prolong the beneficial effects of the treatment. A total of 109 subjects with MCI were assigned to 1 of 5 study groups in a randomized controlled trial design: (a) face-to-face (FTF) VRRS during anodal tDCS followed by cognitive telerehabilitation (TR) (clinic-atDCS-VRRS+Tele@H-VRRS); (b) FTF VRRS during placebo tDCS followed by TR (clinic-ptDCS-VRRS+Tele@H-VRRS); (c) FTF VRRS followed by cognitive TR (clinic-VRRS+Tele@H-VRRS); (d) FTF VRRS followed by at-home unstructured cognitive stimulation (clinic-VRRS+@H-UCS); and (e) FTF cognitive treatment as usual (clinic-TAU).ResultsAn improvement in episodic memory was observed after the end of clinic-atDCS-VRRS (p < 0.001). We found no enhancement in episodic memory after clinic-ptDCS-VRRS or after clinic-TAU.Moreover, the combined treatment led to prolonged beneficial effects (clinic-atDCS-VRRS+Tele@H-VRRS vs. clinic-ptDCS-VRRS+Tele@H-VRRS: p = 0.047; clinic-atDCS-VRRS+Tele@H-VRRS vs. clinic-VRRS+Tele@H-VRRS: p = 0.06).DiscussionThe present study provides preliminary evidence supporting the use of individualized VRRS combined with anodal tDCS and cognitive telerehabilitation for cognitive rehabilitation.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT03486704?term=NCT03486704&rank=1, NCT03486704

Multicentre Italian study of SARS-CoV-2 infection in children and adolescents, preliminary data as at 10 April 2020

Data on features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children and adolescents are scarce. We report preliminary results of an Italian multicentre study comprising 168 laboratory-confirmed paediatric cases (median: 2.3 years, range: 1 day-17.7 years, 55.9% males), of which 67.9% were hospitalised and 19.6% had comorbidities. Fever was the most common symptom, gastrointestinal manifestations were frequent; two children required intensive care, five had seizures, 49 received experimental treatments and all recovered