Spinal cord hypermetabolism extends to skeletal muscle in amyotrophic lateral sclerosis: a computational approach to [18F]-fluorodeoxyglucose PET/CT images

Purpose: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to neuromuscular palsy and death. We propose a computational approach to [18F]-fluorodeoxyglucose (FDG) PET/CT images to analyze the structure and metabolic pattern of skeletal muscle in ALS and its relationship with disease aggressiveness. Materials and methods: A computational 3D method was used to extract whole psoas muscle\u2019s volumes and average attenuation coefficient (AAC) from CT images obtained by FDG PET/CT performed in 62 ALS patients and healthy controls. Psoas average standardized uptake value (normalized on the liver, N-SUV) and its distribution heterogeneity (defined as N-SUV variation coefficient, VC-SUV) were also extracted. Spinal cord and brain motor cortex FDG uptake were also estimated. Results: As previously described, FDG uptake was significantly higher in the spinal cord and lower in the brain motor cortex, in ALS compared to controls. While psoas AAC was similar in patients and controls, in ALS a significant reduction in psoas volume (3.6 \ub1 1.02 vs 4.12 \ub1 1.33 mL/kg; p < 0.01) and increase in psoas N-SUV (0.45 \ub1 0.19 vs 0.29 \ub1 0.09; p < 0.001) were observed. Higher heterogeneity of psoas FDG uptake was also documented in ALS (VC-SUV 8 \ub1 4%, vs 5 \ub1 2%, respectively, p < 0.001) and significantly predicted overall survival at Kaplan\u2013Meier analysis. VC-SUV prognostic power was confirmed by univariate analysis, while the multivariate Cox regression model identified the spinal cord metabolic activation as the only independent prognostic biomarker. Conclusion: The present data suggest the existence of a common mechanism contributing to disease progression through the metabolic impairment of both second motor neuron and its effector

X-ray and ultraviolet emission of the young planet-hosting star V1298 Tau from coordinated observations with XMM-Newton and Hubble Space Telescope

Atmospheric mass loss plays a major role in the evolution of exoplanets. This process is driven by the stellar high-energy irradiation, especially in the first hundreds of millions of years after dissipation of the proto-planetary disk. A major source of uncertainty in modeling atmospheric photoevaporation and photochemistry is due to the lack of direct measurements of the stellar flux at extreme-UV (EUV) wavelengths. Several empirical relationships have been proposed in the past to link EUV fluxes to emission levels in X-rays, but the stellar samples employed for this aim are heterogeneous, and the available scaling laws provide significantly different predictions, especially for very active stars. We present new far-UV and X-ray observations of V1298 Tau with Hubble Space Telescope/Cosmic Origins Spectrograph and XMM-Newton, aimed to determine more accurately the high-energy emission of this solar-mass pre-main-sequence star, which hosts four exoplanets. Spectroscopic data were employed to derive the plasma emission measure distribution versus temperature, from the chromosphere to the corona, and the possible variability of this irradiation on short and year-long timescales, due to magnetic activity. As a side result, we have also measured the chemical abundances of several elements in the outer atmosphere of V1298 Tau. We employ our results as a new benchmark point for the calibration of the X-ray to EUV scaling laws, and hence to predict the time evolution of the irradiation in the EUV band, and its effect on the evaporation of exo-atmospheres

Rapamycin treatment for amyotrophic lateral sclerosis protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial)

Introduction: Misfolded aggregated proteins and neuroinflammation significantly contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, hence representing therapeutic targets to modify disease expression. Rapamycin inhibits mechanistic target of Rapamycin (mTOR) pathway and enhances autophagy with demonstrated beneficial effects in neurodegeneration in cell line and animal models, improving phenotype in SQSTM1 zebrafish, in Drosophila model of ALS-TDP, and in the TDP43 mouse model, in which it reduced neuronal loss and TDP43 inclusions. Rapamycin also expands regulatory T lymphocytes (Treg) and increased Treg levels are associated with slow progression in ALS patients. Therefore, we planned a randomized clinical trial testing Rapamycin treatment in ALS patients. Methods: RAP-ALS is a phase II randomized, double-blind, placebo-controlled, multicenter (8 ALS centers in Italy), clinical trial. The primary aim is to assess whether Rapamycin administration increases Tregs number in treated patients compared with control arm. Secondary aims include the assessment of safety and tolerability of Rapamycin in patients with ALS; the minimum dosage to have Rapamycin in cerebrospinal fluid; changes in immunological (activation and homing of T, B, NK cell subpopulations) and inflammatory markers, and on mTOR downstream pathway (S6RP phosphorylation); clinical activity (ALS Functional Rating Scale-Revised, survival, forced vital capacity); and quality of life (ALSAQ40 scale). Discussion: Rapamycin potentially targets mechanisms at play in ALS (i.e., autophagy and neuroinflammation), with promising preclinical studies. It is an already approved drug, with known pharmacokinetics, already available and therefore with significant possibility of rapid translation to daily clinics. Findings will provide reliable data for further potential trials. Ethics and dissemination: The study protocol was approved by the Ethics Committee of Azienda Ospedaliero Universitaria of Modena and by the Ethics Committees of participating centers (Eudract n. 2016-002399-28) based on the Helsinki declaration

The GAPS programme at TNG. XLVI. Deep search for low-mass planets in late-dwarf systems hosting cold Jupiters

Context. With the growth of comparative exoplanetology, it is increasingly clear that the relationship between inner and outer planets plays a key role in unveiling the mechanisms governing formation and evolution models. For this reason, it is important to probe the inner region of systems hosting long-period giants in search of undetected lower mass planetary companions. Aims: We aim to present the results of a high-cadence and high-precision radial velocity (RV) monitoring of three late-type dwarf stars hosting long-period giants with well-measured orbits in order to search for short-period sub-Neptunes (SN, M sin i &lt; 30 M⊕). Methods: Building on the results and expertise of our previous studies, we carried out combined fits of our HARPS-N data with literature RVs. We used Markov chain Monte Carlo (MCMC) analyses to refine the literature orbital solutions and search for additional inner planets, applying Gaussian process regression techniques to deal with the stellar activity signals where required. We then used the results of our survey to estimate the frequency of sub-Neptunes in systems hosting cold Jupiters, f(SN|CJ), and compared it with the frequency around field M dwarfs, f(SN). Results: We identify a new short-period, low-mass planet orbiting GJ 328, GJ 328 c, with Pc = 241.8-1.7+1.3 days and Mc sin i = 21.4-3.2+3.4M⊕. We moreover identify and model the chromospheric activity signals and rotation periods of GJ 649 and GJ 849, around which no additional planet is found. Then, taking into account also planetary system around the previously analysed low-mass star BD-11 4672, we derive an estimate of the frequencies of inner planets in such systems. In particular, f(SN|CJ) = 0.25-0.07+0.58 for mini-Neptunes (10 M⊕ &lt; M sin i &lt; 30 M⊕, P &lt; 150 d), marginally larger than f(SN). For lower mass planets (M sin i &lt; 10 M⊕) instead f(SN|CJ) &lt; 0.69, which is compatible with f(SN). Conclusions: In light of the newly detected mini-Neptune, we find tentative evidence of a positive correlation between the presence of long-period giant planets and that of inner low-mass planets, f(SN|CJ) &gt; f(SN). This might indicate that cold Jupiters have an opposite influence in the formation of inner sub-Neptunes around late-type dwarfs as opposed to their solar-type counterparts, boosting the formation of mini-Neptunes instead of impeding it

The GAPS Programme at TNG : XLVII. A conundrum resolved: HIP 66074b/Gaia-3b characterised as a massive giant planet on a quasi-face-on and extremely elongated orbit

The nearby mid-K dwarf HIP 66074 was recently identified as host to a candidate super-Jupiter companion on a similar to 300 day, almost edge-on, orbit, based on Gaia Data Release 3 (DR3) astrometry. Initial attempts at confirming the planetary nature of the signal based on publicly available radial-velocity (RV) observations uncovered an intriguing conundrum: the inferred RV semi-amplitude appears to be a factor of 15 smaller than the one predicted based on the Gaia solution (corresponding to a 7-M-Jup companion on a close to edge-on orbit). We present the results of intensive RV monitoring of HIP 66074 with the HARPS-N spectrograph. We detected the companion at the Gaia period, but with an extremely eccentric orbit (e = 0:948 +/- 0:004), a semi-amplitude K = 93.9(-7.0)(+9.4) m s(-1), and a minimum mass mb sin i(b) = 0.79 +/- 0.05 M-Jup. We used detailed simulations of Gaia astrometry with the DR3 time-span to show that the conundrum can be fully resolved by taking into account the combination of the initially sub-optimal RV sampling and systematic biases in the Gaia astrometric solution, which include an underestimation of the eccentricity and incorrect identification of orbital inclination, which has turned out to correspond to a close to face-on configuration (i less than or similar to 13 degrees). With an estimated mass in the approximate range of 3-7 M-Jup, we find that HIP 66074b (equivalent to Gaia-3b) is the first exoplanet candidate astrometrically detected by Gaia to be successfully confirmed based on RV follow-up observations

The GAPS programme at TNG XLIX. TOI-5398, the youngest compact multi-planet system composed of an inner sub-Neptune and an outer warm Saturn

Short-period giant planets are frequently found to be solitary compared to other classes of exoplanets. Small inner companions to giant planets with $P \lesssim$ 15 days are known only in five compact systems: WASP-47, Kepler-730, WASP-132, TOI-1130, and TOI-2000. Here, we report the confirmation of TOI-5398, the youngest compact multi-planet system composed of a hot sub-Neptune (TOI-5398 c, $P_{\rm c}$ = 4.77271 days) orbiting interior to a short-period Saturn (TOI-5398 b, $P_{\rm b}$ = 10.590547 days) planet, both transiting around a 650 $\pm$ 150 Myr G-type star. As part of the GAPS Young Object project, we confirmed and characterised this compact system, measuring the radius and mass of both planets, thus constraining their bulk composition. Using multidimensional Gaussian processes, we simultaneously modelled stellar activity and planetary signals from TESS Sector 48 light curve and our HARPS-N radial velocity time series. We have confirmed the planetary nature of both planets, TOI-5398 b and TOI-5398 c, alongside a precise estimation of stellar parameters. Through the use of astrometric, photometric, and spectroscopic observations, our findings indicate that TOI-5398 is a young, active G dwarf star (650 $\pm$ 150 Myr), with a rotational period of $P_{\rm rot}$ = 7.34 days. The transit photometry and radial velocity measurements enabled us to measure both the radius and mass of planets b, $R_b = 10.30\pm0.40 R_{\oplus}$, $M_b = 58.7\pm5.7 M_{\oplus}$, and c, $R_c = 3.52 \pm 0.19 R_{\oplus}$, $M_c = 11.8\pm4.8 M_{\oplus}$. TESS observed TOI-5398 during sector 48 and no further observations are planned in the current Extended Mission, making our ground-based light curves crucial for ephemeris improvement. With a Transmission Spectroscopy Metric value of around 300, TOI-5398 b is the most amenable warm giant (10 < $P$ < 100 days) for JWST atmospheric characterisation.Comment: 29 pages, Paper accepted for publication in Astronomy & Astrophysic

VizieR Online Data Catalog: HAT-P-3b and TrES-3b light curves and Mid-times (Ricci+, 2017)

Tables contain the light curves and the calculated Mid-times. (15 data files)

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

The GAPS programme at TNG : XLIX. TOI-5398, the youngest compact multi-planet system composed of an inner sub-Neptune and an outer warm Saturn

Context. Short-period giant planets (P ≲ 10 days, Mp >0.1 MJ) are frequently found to be solitary compared to other classes of exo-planets. Small inner companions to giant planets with P ≲ 15 days are known only in five compact systems: WASP-47, Kepler-730, WASP-132, TOI-1130, and TOI-2000. Here, we report the confirmation of TOI-5398, the youngest known compact multi-planet system composed of a hot sub-Neptune (TOI-5398 c, Pc = 4.77271 days) orbiting interior to a short-period Saturn (TOI-5398 b, Pb = 10.590547 days) planet, both transiting around a 650 ± 150 Myr G-type star. Aims. As part of the Global Architecture of Planetary Systems (GAPS) Young Object project, we confirmed and characterised this compact system, measuring the radius and mass of both planets, thus constraining their bulk composition. Methods. Using multi-dimensional Gaussian processes, we simultaneously modelled stellar activity and planetary signals from the Transiting Exoplanet Survey Satellite (TESS) Sector 48 light curve and our High Accuracy Radial velocity Planet Searcher (HARPS-N) radial velocity (RV) time series. We confirmed the planetary nature of both planets, TOI-5398 b and TOI-5398 c, and obtained a precise estimation of their stellar parameters. Results. Through the use of astrometric, photometric, and spectroscopic observations, our findings indicate that TOI-5398 is a young, active G dwarf star (650 ± 150 Myr) with a rotational period of Prot = 7.34 days. The transit photometry and RV measurements enabled us to measure both the radius and mass of planets b, Rb = 10.30 ± 0.40 R⊕, Mb = 58.7 ± 5.7 M⊕, and c, Rc = 3.52 ± 0.19 R⊕, Mc = 11.8 ± 4.8 M⊕. TESS observed TOI-5398 during sector 48 and no further observations are planned in the current Extended Mission, making our ground-based light curves crucial for improvement of the ephemeris. With a transmission spectroscopy metric (TSM) value of around 300, TOI-5398 b is the most amenable warm giant (10 < P < 100 days) for JWST atmospheric characterisation