Observation of a Nuclear Recoil Peak at the 100 eV Scale Induced by Neutron Capture.

Coherent elastic neutrino-nucleus scattering and low-mass dark matter detectors rely crucially on the understanding of their response to nuclear recoils. We report the first observation of a nuclear recoil peak at around 112 eV induced by neutron capture. The measurement was performed with a CaWO_{4} cryogenic detector from the NUCLEUS experiment exposed to a ^{252}Cf source placed in a compact moderator. We identify the expected peak structure from the single-γ de-excitation of ^{183}W with 3σ and its origin by neutron capture with 6σ significance. This result demonstrates a new method for precise, in situ, and nonintrusive calibration of low-threshold experiments.

Measurement of the 2νßß Decay Rate and Spectral Shape of

Neutrinoless double beta decay (0νßß) is a yet unobserved nuclear process that would demonstrate Lepton number violation, a clear evidence of beyond standard model physics. The process two neutrino double beta decay (2νßß) is allowed by the standard model and has been measured in numerous experiments. In this Letter, we report a measurement of 2νßß decay half-life of ^{100}Mo to the ground state of ^{100}Ru of [7.07±0.02(stat)±0.11(syst)]×10^{18} yr by the CUPID-Mo experiment. With a relative precision of ±1.6% this is the most precise measurement to date of a 2νßß decay rate in ^{100}Mo. In addition, we constrain higher-order corrections to the spectral shape, which provides complementary nuclear structure information. We report a novel measurement of the shape factor ξ_{3,1}=0.45±0.03(stat)±0.05(syst) based on a constraint on the ratio of higher-order terms from theory, which can be reliably calculated. This is compared to theoretical predictions for different nuclear models. We also extract the first value for the effective axial vector coupling constant obtained from a spectral shape study of 2νßß decay.

Measurement of the 2νßß Decay Half-Life of

We report on the results obtained with the global CUPID-0 background model, which combines the data collected in the two measurement campaigns for a total exposure of 8.82 kg×yr of ^{82}Se. We identify with improved precision the background sources within the 3 MeV energy region, where neutrinoless double ß decay of ^{82}Se and ^{100}Mo is expected, making more solid the foundations for the background budget of the next-generation CUPID experiment. Relying on the excellent data reconstruction, we measure the two-neutrino double ß-decay half-life of ^{82}Se with unprecedented accuracy: T_{1/2}^{2ν}=[8.69±0.05(stat)_{-0.06}^{+0.09}(syst)]×10^{19} yr.

Erratum: Measurement of the 2νßß Decay Half-Life of

This corrects the article DOI: 10.1103/PhysRevLett.126.171801.

Determining g_{A}/g_{V} with High-Resolution Spectral Measurements Using a LiInSe_{2} Bolometer.

Neutrinoless double beta decay (0νßß) processes sample a wide range of intermediate forbidden nuclear transitions, which may be impacted by quenching of the axial vector coupling constant (g_{A}/g_{V}), the uncertainty of which plays a pivotal role in determining the sensitivity reach of 0νßß experiments. In this Letter, we present measurements performed on a high-resolution LiInSe_{2} bolometer in a "source=detector" configuration to measure the spectral shape of the fourfold forbidden ß decay of ^{115}In. The value of g_{A}/g_{V} is determined by comparing the spectral shape of theoretical predictions to the experimental ß spectrum taking into account various simulated background components as well as a variety of detector effects. We find evidence of quenching of g_{A}/g_{V} at >5σ with a model-dependent quenching factor of 0.655±0.002 as compared to the free-nucleon value for the interacting shell model. We also measured the ^{115}In half-life to be [5.18±0.06(stat)_{-0.015}^{+0.005}(sys)]×10^{14} yr within the interacting shell model framework. This Letter demonstrates the power of the bolometeric technique to perform precision nuclear physics single-ß decay measurements, which along with improved nuclear modeling can help reduce the uncertainties in the calculation of several decay nuclear matrix elements including those used in 0νßß sensitivity calculations.

Final Result on the Neutrinoless Double Beta Decay of

CUPID-0, an array of Zn^{82}Se cryogenic calorimeters, was the first medium-scale demonstrator of the scintillating bolometers' technology. The first project phase (March 2017-December 2018) allowed the most stringent limit on the neutrinoless double beta decay half-life of the isotope of interest, ^{82}Se, to be set. After a six month long detector upgrade, CUPID-0 began its second and last phase (June 2019-February 2020). In this Letter, we describe the search for neutrinoless double beta decay of ^{82}Se with a total exposure (phase I+II) of 8.82 kg yr^{-1} of isotope. We set a limit on the half-life of ^{82}Se to the ground state of ^{82}Kr of T_{1/2}^{0ν}(^{82}Se)>4.6×10^{24} yr (90% credible interval), corresponding to an effective Majorana neutrino mass m_{ßß}<(263-545) meV. We also set the most stringent lower limits on the neutrinoless decays of ^{82}Se to the 0_{1}^{+}, 2_{1}^{+}, and 2_{2}^{+} excited states of ^{82}Kr, finding 1.8×10^{23} yr, 3.0×10^{23} yr, and 3.2×10^{23} yr (90% credible interval) respectively.

Biomarkers of cell damage, neutrophil and macrophage activation associated with in-hospital mortality in geriatric COVID-19 patients.

BACKGROUND: The risk for symptomatic COVID-19 requiring hospitalization is higher in the older population. The course of the disease in hospitalised older patients may show significant variation, from mild to severe illness, ultimately leading to death in the most critical cases. The analysis of circulating biomolecules involved in mechanisms of inflammation, cell damage and innate immunity could lead to identify new biomarkers of COVID-19 severity, aimed to improve the clinical management of subjects at higher risk of severe outcomes. In a cohort of COVID-19 geriatric patients (n= 156) who required hospitalization we analysed, on-admission, a series of circulating biomarkers related to neutrophil activation (neutrophil elastase, LL-37), macrophage activation (sCD163) and cell damage (nuclear cfDNA, mithocondrial cfDNA and nuclear cfDNA integrity). The above reported biomarkers were tested for their association with in-hospital mortality and with clinical, inflammatory and routine hematological parameters. Aim of the study was to unravel prognostic parameters for risk stratification of COVID-19 patients. RESULTS: Lower n-cfDNA integrity, higher neutrophil elastase and higher sCD163 levels were significantly associated with an increased risk of in-hospital decease. Median (IQR) values observed in discharged vs. deceased patients were: 0.50 (0.30-0.72) vs. 0.33 (0.22-0.62) for n-cfDNA integrity; 94.0 (47.7-154.0) ng/ml vs. 115.7 (84.2-212.7) ng/ml for neutrophil elastase; 614.0 (370.0-821.0) ng/ml vs. 787.0 (560.0-1304.0) ng/ml for sCD163. The analysis of survival curves in patients stratified for tertiles of each biomarker showed that patients with n-cfDNA integrity < 0.32 or sCD163 in the range 492-811 ng/ml had higher risk of in-hospital decease than, respectively, patients with higher n-cfDNA integrity or lower sCD163. These associations were further confirmed in multivariate models adjusted for age, sex and outcome-related clinical variables. In these models also high levels of neutrophil elastase (>150 ng/ml) appeared to be independent predictor of in-hospital death. An additional analysis of neutrophil elastase in patients stratified for n-cfDNA integrity levels was conducted to better describe the association of the studied parameters with the outcome. CONCLUSIONS: On the whole, biomarkers of cell-free DNA integrity, neutrophil and macrophage activation might provide a valuable contribution to identify geriatric patients with high risk of COVID-19 in-hospital mortality.

A multicentre, open-label, single-arm phase II trial of the efficacy and safety of sclerotherapy using 3% polidocanol foam to treat second-degree haemorrhoids (SCLEROFOAM).

BACKGROUND: The aim of the present study was to evaluate the efficacy and safety of 3% polidocanol foam for treating 2nd-degree haemorrhoids. METHODS: A multicentre, open-label, single-arm, phase 2 trial involving 10 tertiary referral centres for haemorrhodal disease (HD) was performed. Between January and June 2019, patients with 2nd-degree haemorrhoids were prospectively included in this study. The primary outcome was to establish the success rate after one sclerotherapy session in terms of complete resolution of bleeding episodes one week after the injection. The Hemorrhoidal Disease Symptom Score (HDSS), the Short Health Scale for HD (SHS-HD) score and the Vaizey incontinence score were used to assess symptoms and their impact on quality of life and continence. Pain after the procedure, subjective symptoms and the amount and type of painkillers used were recorded. Patients were followed up for 1 year. RESULTS: There were 183 patients [111 males; 60.7%, mean age 51.3 ± 13.5 (18-75) years]. Complete resolution of bleeding was reached in 125/183 patients (68.3%) at 1 week and the recurrence rate was 12% (15/125). Thirteen patients (7.4%) underwent a second sclerotherapy session, while only 1 patient (1.8%) had to undergo a third session. The overall 1-year success rate was 95.6% (175/183). The HDSS and the SHS score significantly improved from a median preoperative value of 11 and 18 to 0 and 0, respectively (p < 0.001). There were 3 episodes of external thrombosis. No serious adverse events occurred. CONCLUSIONS: Sclerotherapy with 3% polidocanol foam is a safe, effective, painless, repeatable and low-cost procedure in patients with bleeding haemorrhoids.

New Limit for Neutrinoless Double-Beta Decay of

The CUPID-Mo experiment at the Laboratoire Souterrain de Modane (France) is a demonstrator for CUPID, the next-generation ton-scale bolometric 0νßß experiment. It consists of a 4.2 kg array of 20 enriched Li_{2}^{100}MoO_{4} scintillating bolometers to search for the lepton-number-violating process of 0νßß decay in ^{100}Mo. With more than one year of operation (^{100}Mo exposure of 1.17 kg×yr for physics data), no event in the region of interest and, hence, no evidence for 0νßß is observed. We report a new limit on the half-life of 0νßß decay in ^{100}Mo of T_{1/2}>1.5×10^{24} yr at 90% C.I. The limit corresponds to an effective Majorana neutrino mass ⟨m_{ßß}⟩<(0.31-0.54) eV, dependent on the nuclear matrix element in the light Majorana neutrino exchange interpretation.

Measurement of the 2νßß Decay Half-Life of

We measured two-neutrino double beta decay of ^{130}Te using an exposure of 300.7 kg yr accumulated with the CUORE detector. Using a Bayesian analysis to fit simulated spectra to experimental data, it was possible to disentangle all the major background sources and precisely measure the two-neutrino contribution. The half-life is in agreement with past measurements with a strongly reduced uncertainty: T_{1/2}^{2ν}=7.71_{-0.06}^{+0.08}(stat)_{-0.15}^{+0.12}(syst)×10^{20} yr. This measurement is the most precise determination of the ^{130}Te 2νßß decay half-life to date.

Effects of Topical Application of CHF6467, a Mutated Form of Human Nerve Growth Factor, on Skin Wound Healing in Diabetic Mice.

Nerve growth factor (NGF) is the protein responsible for the development and maintenance of sensory skin innervation. Given the role of appropriate innervation in skin healing, NGF has been indicated as a possible prohealing treatment in pathologic conditions characterized by nerve-ending loss, such as chronic ulcers in diabetes; however, its use as a therapeutic agent is limited by its hyperalgesic effect. We tested the effect of topical application of the nonalgogenic NGF derivative hNGFP61S/R100E in two models of skin ulcer induced in dbdb diabetic mice, investigating healing time, skin histology, reinnervation, and angiogenesis using morphologic and molecular approaches. We showed that the topical administration of CHF6467, a recombinant human NGF in which an amino acid substitution (R100E) abolished the hyperalgesic effect usually associated with NGF, accelerated skin repair in experimental wounds (full-excision and pressure-ulcer) induced in diabetic mice (dbdb). CHF6467-induced acceleration of wound healing was accompanied by increased re-epithelization, reinnervation, and revascularization as assessed by histology, immunohistochemistry, and image analysis. Bioinformatic analysis of differentially expressed genes and signaling pathways in the wound tissues showed that protein kinase B-mammalian target of rapamycin was the most regulated pathway. In spite of the transdermal absorption leading to measurable, dose-dependent increases in CHF6467 plasma levels, no systemic thermal or local mechanical hyperalgesia was observed in treated mice. When tested in vitro in human cell lines, CHF6467 stimulated keratinocyte and fibroblast proliferation and tube formation by endothelial cells. Collectively, these results support a possible use of CHF6467 as a prohealing agent in skin lesions in diabetes. SIGNIFICANCE STATEMENT: Topical application of CHF6467 accelerates reinnervation, neoangiogenesis, and wound healing in diabetic mice in both full-thickness skin-excision and pressure-ulcer models through the protein kinase B/mammalian target of rapamycin pathway and does not induce hyperalgesia.

First Germanium-Based Constraints on Sub-MeV Dark Matter with the EDELWEISS Experiment.

We present the first Ge-based constraints on sub-MeV/c^{2} dark matter (DM) particles interacting with electrons using a 33.4 g Ge cryogenic detector with a 0.53 electron-hole pair (rms) resolution, operated underground at the Laboratoire Souterrain de Modane. Competitive constraints are set on the DM-electron scattering cross section, as well as on the kinetic mixing parameter of dark photons down to 1 eV/c^{2}. In particular, the most stringent limits are set for dark photon DM in the 6 to 9 eV/c^{2} range. These results demonstrate the high relevance of Ge cryogenic detectors for the search of DM-induced eV-scale electron signals.

Improved Limit on Neutrinoless Double-Beta Decay in

We report new results from the search for neutrinoless double-beta decay in ^{130} Te with the CUORE detector. This search benefits from a fourfold increase in exposure, lower trigger thresholds, and analysis improvements relative to our previous results. We observe a background of (1.38±0.07)×10^{-2} counts/(keV kg yr)) in the 0νßß decay region of interest and, with a total exposure of 372.5 kg yr, we attain a median exclusion sensitivity of 1.7×10^{25} yr. We find no evidence for 0νßß decay and set a 90% credibility interval Bayesian lower limit of 3.2×10^{25} yr on the ^{130} Te half-life for this process. In the hypothesis that 0νßß decay is mediated by light Majorana neutrinos, this results in an upper limit on the effective Majorana mass of 75-350 meV, depending on the nuclear matrix elements used.

Final Result of CUPID-0 Phase-I in the Search for the

CUPID-0 is the first pilot experiment of CUPID, a next-generation project for the measurement of neutrinoless double beta decay (0νDBD) with scintillating bolometers. The detector, consisting of 24 enriched and 2 natural ZnSe crystals, has been taking data at Laboratori Nazionali del Gran Sasso from June 2017 to December 2018, collecting a ^{82}Se exposure of 5.29 kg×yr. In this Letter we present the phase-I results in the search for 0νDBD. We demonstrate that the technology implemented by CUPID-0 allows us to reach the lowest background for calorimetric experiments: (3.5_{-0.9}^{+1.0})×10^{-3} counts/(keV kg yr). Monitoring 3.88×10^{25} ^{82}Se nuclei×yr we reach a 90% credible interval median sensitivity of T_{1/2}^{0ν}>5.0×10^{24} yr and set the most stringent limit on the half-life of ^{82}Se 0νDBD: T_{1/2}^{0ν}>3.5×10^{24} yr (90% credible interval), corresponding to m_{ßß}<(311-638) meV depending on the nuclear matrix element calculations.

Evidence of Single State Dominance in the Two-Neutrino Double-ß Decay of

We report on the measurement of the two-neutrino double-ß decay of ^{82}Se performed for the first time with cryogenic calorimeters, in the framework of the CUPID-0 experiment. With an exposure of 9.95 kg yr of Zn^{82}Se, we determine the two-neutrino double-ß decay half-life of ^{82}Se with an unprecedented precision level, T_{1/2}^{2ν}=[8.60±0.03(stat) _{-0.13}^{+0.19}(syst)]×10^{19} yr. The very high signal-to-background ratio, along with the detailed reconstruction of the background sources allowed us to identify the single state dominance as the underlying mechanism of such a process, demonstrating that the higher state dominance hypothesis is disfavored at the level of 5.5σ.

Transcriptomic analysis and mutational status of IDH1 in paired primary-recurrent intrahepatic cholangiocarcinoma.

BACKGROUND: Effective target therapies for intrahepatic cholangiocarcinoma (ICC) have not been identified so far. One of the reasons may be the genetic evolution from primary (PR) to recurrent (REC) tumors. We aim to identify peculiar characteristics and to select potential targets specific for recurrent tumors. Eighteen ICC paired PR and REC tumors were collected from 5 Italian Centers. Eleven pairs were analyzed for gene expression profiling and 16 for mutational status of IDH1. For one pair, deep mutational analysis by Next Generation Sequencing was also carried out. An independent cohort of patients was used for validation. RESULTS: Two class-paired comparison yielded 315 differentially expressed genes between REC and PR tumors. Up-regulated genes in RECs are involved in RNA/DNA processing, cell cycle, epithelial to mesenchymal transition (EMT), resistance to apoptosis, and cytoskeleton remodeling. Down-regulated genes participate to epithelial cell differentiation, proteolysis, apoptotic, immune response, and inflammatory processes. A 24 gene signature is able to discriminate RECs from PRs in an independent cohort; FANCG is statistically associated with survival in the chol-TCGA dataset. IDH1 was mutated in the RECs of five patients; 4 of them displayed the mutation only in RECs. Deep sequencing performed in one patient confirmed the IDH1 mutation in REC. CONCLUSIONS: RECs are enriched for genes involved in EMT, resistance to apoptosis, and cytoskeleton remodeling. Key players of these pathways might be considered druggable targets in RECs. IDH1 is mutated in 30% of RECs, becoming both a marker of progression and a target for therapy.

First Result on the Neutrinoless Double-ß Decay of

We report the result of the search for neutrinoless double beta decay of ^{82}Se obtained with CUPID-0, the first large array of scintillating Zn^{82}Se cryogenic calorimeters implementing particle identification. We observe no signal in a 1.83 kg yr ^{82}Se exposure, and we set the most stringent lower limit on the 0νßß ^{82}Se half-life T_{1/2}^{0ν}>2.4×10^{24} yr (90% credible interval), which corresponds to an effective Majorana neutrino mass m_{ßß}<(376-770) meV depending on the nuclear matrix element calculations. The heat-light readout provides a powerful tool for the rejection of α particles and allows us to suppress the background in the region of interest down to (3.6_{-1.4}^{+1.9})×10^{-3} counts/(keV kg yr), an unprecedented level for this technique.

SOLEIL shining on the solution-state structure of biomacromolecules by synchrotron X-ray footprinting at the Metrology beamline.

Synchrotron X-ray footprinting complements the techniques commonly used to define the structure of molecules such as crystallography, small-angle X-ray scattering and nuclear magnetic resonance. It is remarkably useful in probing the structure and interactions of proteins with lipids, nucleic acids or with other proteins in solution, often better reflecting the in vivo state dynamics. To date, most X-ray footprinting studies have been carried out at the National Synchrotron Light Source, USA, and at the European Synchrotron Radiation Facility in Grenoble, France. This work presents X-ray footprinting of biomolecules performed for the first time at the X-ray Metrology beamline at the SOLEIL synchrotron radiation source. The installation at this beamline of a stopped-flow apparatus for sample delivery, an irradiation capillary and an automatic sample collector enabled the X-ray footprinting study of the structure of the soluble protein factor H (FH) from the human complement system as well as of the lipid-associated hydrophobic protein S3 oleosin from plant seed. Mass spectrometry analysis showed that the structural integrity of both proteins was not affected by the short exposition to the oxygen radicals produced during the irradiation. Irradiated molecules were subsequently analysed using high-resolution mass spectrometry to identify and locate oxidized amino acids. Moreover, the analyses of FH in its free state and in complex with complement C3b protein have allowed us to create a map of reactive solvent-exposed residues on the surface of FH and to observe the changes in oxidation of FH residues upon C3b binding. Studies of the solvent accessibility of the S3 oleosin show that X-ray footprinting offers also a unique approach to studying the structure of proteins embedded within membranes or lipid bodies. All the biomolecular applications reported herein demonstrate that the Metrology beamline at SOLEIL can be successfully used for synchrotron X-ray footprinting of biomolecules.

Multiple electron capture from isolated protein poly-anions in collision with slow highly charged ions.

Collisions of 375 keV Xe25+ ions with trapped mass/charge selected poly-anions of the cytochrome C protein (∼12.5 kDa) were studied by coupling a linear quadrupole ion trap with low-energy ion beam facility. Tandem mass spectra were recorded for the protein precursor charge states ranging from -9 to -17. The present work reports the first study of slow highly charged ion collisions with poly-anions. A high signal to noise ratio allowed the study of the intensity of single and multiple electron removal by a projectile, as well as associated neutral losses, as a function of the target charge state. Relative single and double electron detachment cross sections were found to increase with increasing charge state of the precursor anion. The experimental findings are supported by the calculations of the total electron capture cross sections, based on the classical over-the-barrier model, restricted to a simple uniformly charged linear protein structure and a near-end electron capture.

Extracellular microRNAs and endothelial hyperglycaemic memory: a therapeutic opportunity?

Type 2 diabetes mellitus (T2DM) is a major cause of cardiovascular (CV) disease. Several large clinical trials have shown that the risk for patients with diabetes of developing CV complications is only partially reduced by early, intensive glycaemic control and lifestyle interventions, and that such complications result from changes in complex, not fully explored networks that contribute to the maintenance of endothelial function. The accumulation of senescent cells and the low-grade, systemic, inflammatory status that accompanies aging (inflammaging) are involved in the development of endothelial dysfunction. Such phenomena are modulated by epigenetic mechanisms, including microRNAs (miRNAs). MiRNAs can modulate virtually all gene transcripts. They can be secreted by living cells and taken up in active form by recipient cells, providing a new communication tool between tissues and organs. MiRNA deregulation has been associated with the development and progression of a number of age-related diseases, including the enduring gene expression changes seen in patients with diabetes. We review recent evidence on miRNA changes in T2DM, focusing on the ability of diabetes-associated miRNAs to modulate endothelial function, inflammaging and cellular senescence. We also discuss the hypothesis that miRNA-containing extracellular vesicles (i.e. exosomes and microvesicles) could be harnessed to restore a 'physiological' signature capable of preventing or delaying the harmful systemic effects of T2DM.