ACYLATED AND UNACYLATED GHRELIN IMPAIR SKELETAL MUSCLE ATROPHY IN MICE.

Cachexia is a wasting syndrome associated with cancer, AIDS, and multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghrelin is a peptide hormone that stimulates growth hormone (GH) release and positive energy balance through binding to the receptor GHSR-1a. Only acylated ghrelin (AG), but not the unacylated form (UnAG), can bind GHSR-1a; however, UnAG and AG share several GHSR-1aindependent biological activities. Here we investigated whether UnAG and AG could protect against skeletal muscle atrophy in a GHSR-1a-independent manner. We found that both AG and UnAG inhibited dexamethasone-induced skeletal muscle atrophy and atrogene expression through PI3K\u3b2-, mTORC2-, and p38-mediated pathways in myotubes. Up-regulation of circulating UnAG in mice impaired skeletal muscle atrophy induced by either fasting or denervation without stimulating muscle hypertrophy and GHSR-1a-mediated activation of the GH/IGF-1 axis. In Ghsrdeficient mice, both AG and UnAG induced phosphorylation of Akt in skeletal muscle and impaired fasting-induced atrophy. These results demonstrate that AG and UnAG act on a common, unidentified receptor to block skeletal muscle atrophy in a GH-independent manner

Indagini Geofisiche

Nell'ambito del progetto per la Microzonazione sismica dell'area aquilana, coordinata dal DPC, il Gruppo di Lavoro ha condotto le indagini di MS nella Conca di Roio.Published336-3854T. Sismologia, geofisica e geologia per l'ingegneria sismic

Design and performance of the field cage for the XENONnT experiment

The precision in reconstructing events detected in a dual-phase time projection chamber depends on an homogeneous and well understood electric field within the liquid target. In the XENONnT TPC the field homogeneity is achieved through a double-array field cage, consisting of two nested arrays of field shaping rings connected by an easily accessible resistor chain. Rather than being connected to the gate electrode, the topmost field shaping ring is independently biased, adding a degree of freedom to tune the electric field during operation. Two-dimensional finite element simulations were used to optimize the field cage, as well as its operation. Simulation results were compared to 83mKr calibration data. This comparison indicates an accumulation of charge on the panels of the TPC which is constant over time, as no evolution of the reconstructed position distribution of events is observed. The simulated electric field was then used to correct the charge signal for the field dependence of the charge yield. This correction resolves the inconsistent measurement of the drift electron lifetime when using different calibrations sources and different field cage tuning voltages

Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum

The Plasmodium falciparum parasite's ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (~1 SNP/kb), and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS), searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome.Bill & Melinda Gates FoundationEllison Medical FoundationExxon Mobil FoundationFogarty International CenterNational Institute of Allergy and Infectious Diseases (U.S.)Burroughs Wellcome FundDavid & Lucile Packard FoundationNational Science Foundation (U.S.). Graduate Research Fellowship Progra

Double-weak decays of 124Xe and 136Xe in the XENON1T and XENONnT experiments

We present results on the search for two-neutrino double-electron capture (2νECEC) of 124Xe and neutrinoless double-β decay (0νββ) of 136Xe in XENON1T. We consider captures from the K shell up to the N shell in the 2νECEC signal model and measure a total half-life of T2νECEC1/2=(1.1±0.2stat±0.1sys)×1022yr with a 0.87kgyr isotope exposure. The statistical significance of the signal is 7.0σ. We use XENON1T data with 36.16kgyr of 136Xe exposure to search for 0νββ. We find no evidence of a signal and set a lower limit on the half-life of T0νββ1/2>1.2×1024yrat90%CL. This is the best result from a dark matter detector without an enriched target to date. We also report projections on the sensitivity of XENONnT to 0νββ. Assuming a 275kgyr 136Xe exposure, the expected sensitivity is T0νββ1/2>2.1×1025yrat90%CL, corresponding to an effective Majorana mass range of ⟨mββ⟩<(0.19–0.59)eV/c2

Search for New Physics in Electronic Recoil Data from XENONnT

We report on a blinded analysis of low-energy electronic-recoil data from the first science run of the XENONnT dark matter experiment. Novel subsystems and the increased 5.9 tonne liquid xenon target reduced the background in the (1, 30) keV search region to (15.8±1.3) events/(tonne×year×keV), the lowest ever achieved in a dark matter detector and ∼5 times lower than in XENON1T. With an exposure of 1.16 tonne-years, we observe no excess above background and set stringent new limits on solar axions, an enhanced neutrino magnetic moment, and bosonic dark matter

Emission of single and few electrons in XENON1T and limits on light dark matter

Delayed single- and few-electron emissions plague dual-phase time projection chambers, limiting their potential to search for light-mass dark matter. This paper examines the origins of these events in the XENON1T experiment. Characterization of the intensity of delayed electron backgrounds shows that the resulting emissions are correlated, in time and position, with high-energy events and can effectively be vetoed. In this work we extend previous S2-only analyses down to a single electron. From this analysis, after removing the correlated backgrounds, we observe rates <30 events/(electron×kg×day) in the region of interest spanning 1 to 5 electrons. We derive 90% confidence upper limits for dark matter-electron scattering, first direct limits on the electric dipole, magnetic dipole, and anapole interactions, and bosonic dark matter models, where we exclude new parameter space for dark photons and solar dark photons