Sex-specific behavioral and neurogenic responses to cocaine in mice lacking and blocking dopamine D1 or dopamine D2 receptors

Adult neurogenesis in rodents is modulated by dopaminergic signaling and inhibited by cocaine. However, the sex-specific role of dopamine D1 and D2 receptors (D1R, D2R) in the deleterious effect of cocaine on adult neurogenesis has not been described yet. Here, we explored sex differences in (a) cell proliferation (5′-bromo-2′-deoxyuridine [BrdU]), (b) neural precursor (nestin), (c) neuronal phenotype (BrdU/β3-tubulin), and (d) neuronal maturity (NeuN) in the subventricular zone (SVZ) of the lateral ventricles and striatum of mice with genetic deletion (D1, D2) or pharmacological blockage (SCH23390: 0.1 mg/kg/day/5 days; Raclopride: 0.3 mg/kg/day/5 days) of D1R and D2R, and treated (10 mg/kg/day/5 days) and then challenged (5 mg/kg, 48 hr later) with cocaine. Results indicated that hyperactivity responses to cocaine were absent in D1 mice and reduced in SCH23390-treated mice. Activity responses to cocaine were reduced in D2 males, but absent in D2 females and increased in Raclopride-treated females. D1R deletion blocked the deleterious effect of cocaine on SVZ cell proliferation in males. Cocaine-exposed D1 males also had reduced neuronal phenotype of SVZ newborn cells and increased striatal neuronal maturity. D2 mice had lower proliferative and neural precursor responses. Cocaine in D2 females or coadministered with Raclopride in wild-type females improved SVZ cell proliferation, an effect that positively correlated with plasma brain-derived neurotrophic factor (BDNF) concentrations. In conclusion, the sex-specific D1R and D2R signaling on SVZ cell proliferation, neural progenitor and neuronal maturity is differentially perturbed by cocaine, and BDNF may be required to link D2R to neuroplasticity in cocaine addiction in females.Consejería de Salud, Junta de Andalucía, Grant/Award Number: C1-0049-2019; Instituto de Salud Carlos III, Grant/Award Numbers: CP19/00068, CPII17/00024, CPII19/00022, CPII19/00031, PI19/01577, PI19/00886, PI17/02026, RD16/0017/0001; Ministerio de Sanidad, Servicios Sociales e Igualdad, Grant/Award Numbers: PND2017/043, PND2018/033, PND2018/044, PND2019/04

LOFT - a Large Observatory For x-ray Timing

The high time resolution observations of the X-ray sky hold the key to a number of diagnostics of fundamental physics, some of which are unaccessible to other types of investigations, such as those based on imaging and spectroscopy. Revealing strong gravitational field effects, measuring the mass and spin of black holes and the equation of state of ultradense matter are among the goals of such observations. At present prospects for future, non-focused X-ray timing experiments following the exciting age of RXTE/PCA are uncertain. Technological limitations are unavoidably faced in the conception and development of experiments with effective area of several square meters, as needed in order to meet the scientific requirements. We are developing large-area monolithic Silicon Drift Detectors offering high time and energy resolution at room temperature, which require modest resources and operation complexity (e.g., read-out) per unit area. Based on the properties of the detector and read-out electronics that we measured in the lab, we developed a realistic concept for a very large effective area mission devoted to X-ray timing in the 2-30 keV energy range. We show that effective areas in the range of 10-15 square meters are within reach, by using a conventional spacecraft platform and launcher of the small-medium class.Comment: 13 pages, 8 figures, 1 table, Proceedings of SPIE Vol. 7732, Paper No. 7732-66, 201

Validation of techniques to mitigate copper surface contamination in CUORE

In this article we describe the background challenges for the CUORE experiment posed by surface contamination of inert detector materials such as copper, and present three techniques explored to mitigate these backgrounds. Using data from a dedicated test apparatus constructed to validate and compare these techniques we demonstrate that copper surface contamination levels better than 10E-07 - 10E-08 Bq/cm2 are achieved for 238U and 232Th. If these levels are reproduced in the final CUORE apparatus the projected 90% C.L. upper limit on the number of background counts in the region of interest is 0.02-0.03 counts/keV/kg/y depending on the adopted mitigation technique.Comment: 10 pages, 6 figures, 6 table

CUORE and beyond: bolometric techniques to explore inverted neutrino mass hierarchy

The CUORE (Cryogenic Underground Observatory for Rare Events) experiment will search for neutrinoless double beta decay of $^{130}$Te. With 741 kg of TeO$_2$ crystals and an excellent energy resolution of 5 keV (0.2%) at the region of interest, CUORE will be one of the most competitive neutrinoless double beta decay experiments on the horizon. With five years of live time, CUORE projected neutrinoless double beta decay half-life sensitivity is $1.6\times 10^{26}$ y at $1\sigma$ ($9.5\times10^{25}$ y at the 90% confidence level), which corresponds to an upper limit on the effective Majorana mass in the range 40--100 meV (50--130 meV). Further background rejection with auxiliary light detector can significantly improve the search sensitivity and competitiveness of bolometric detectors to fully explore the inverted neutrino mass hierarchy with $^{130}$Te and possibly other double beta decay candidate nuclei.Comment: Submitted to the Proceedings of TAUP 2013 Conferenc

The low energy spectrum of TeO2 bolometers: results and dark matter perspectives for the CUORE-0 and CUORE experiments

We collected 19.4 days of data from four 750 g TeO2 bolometers, and in three of them we were able to set the energy threshold around 3 keV using a new analysis technique. We found a background rate ranging from 25 cpd/keV/kg at 3 keV to 2 cpd/keV/kg at 25 keV, and a peak at 4.7 keV. The origin of this peak is presently unknown, but its presence is confirmed by a reanalysis of 62.7 kg.days of data from the finished CUORICINO experiment. Finally, we report the expected sensitivities of the CUORE0 (52 bolometers) and CUORE (988 bolometers) experiments to a WIMP annual modulation signal.Comment: 9 pages, 10 figure

Exploring the Neutrinoless Double Beta Decay in the Inverted Neutrino Hierarchy with Bolometric Detectors

Neutrinoless double beta decay (0nubb) is one of the most sensitive probes for physics beyond the Standard Model, providing unique information on the nature of neutrinos. In this paper we review the status and outlook for bolometric 0nubb decay searches. We summarize recent advances in background suppression demonstrated using bolometers with simultaneous readout of heat and light signals. We simulate several configurations of a future CUORE-like bolometer array which would utilize these improvements and present the sensitivity reach of a hypothetical next-generation bolometric 0nubb experiment. We demonstrate that a bolometric experiment with the isotope mass of about 1 ton is capable of reaching the sensitivity to the effective Majorana neutrino mass (|mee|) of order 10-20 meV, thus completely exploring the so-called inverted neutrino mass hierarchy region. We highlight the main challenges and identify priorities for an R&D program addressing them.Comment: 22 pages, 15 figures, submitted to EPJ

Search for 14.4 keV solar axions from M1 transition of Fe-57 with CUORE crystals

We report the results of a search for axions from the 14.4 keV M1 transition from Fe-57 in the core of the sun using the axio-electric effect in TeO2 bolometers. The detectors are 5x5x5 cm3 crystals operated at about 10 mK in a facility used to test bolometers for the CUORE experiment at the Laboratori Nazionali del Gran Sasso in Italy. An analysis of 43.65 kg d of data was made using a newly developed low energy trigger which was optimized to reduce the detectors energy threshold. An upper limit of 0.63 c kg-1 d-1 was established at 95% C.L.. From this value, a lower bound at 95% C.L. was placed on the Peccei-Quinn energy scale of fa >= 0.76 10**6 GeV for a value of S=0.55 for the flavor-singlet axial vector matrix element. Bounds are given for the interval 0.15 < S < 0.55.Comment: 14 pages, 6 figures, submitted to JCA

Compensatory Evolution of pbp Mutations Restores the Fitness Cost Imposed by β-Lactam Resistance in Streptococcus pneumoniae

The prevalence of antibiotic resistance genes in pathogenic bacteria is a major challenge to treating many infectious diseases. The spread of these genes is driven by the strong selection imposed by the use of antibacterial drugs. However, in the absence of drug selection, antibiotic resistance genes impose a fitness cost, which can be ameliorated by compensatory mutations. In Streptococcus pneumoniae, β-lactam resistance is caused by mutations in three penicillin-binding proteins, PBP1a, PBP2x, and PBP2b, all of which are implicated in cell wall synthesis and the cell division cycle. We found that the fitness cost and cell division defects conferred by pbp2b mutations (as determined by fitness competitive assays in vitro and in vivo and fluorescence microscopy) were fully compensated by the acquisition of pbp2x and pbp1a mutations, apparently by means of an increased stability and a consequent mislocalization of these protein mutants. Thus, these compensatory combinations of pbp mutant alleles resulted in an increase in the level and spectrum of β-lactam resistance. This report describes a direct correlation between antibiotic resistance increase and fitness cost compensation, both caused by the same gene mutations acquired by horizontal transfer. The clinical origin of the pbp mutations suggests that this intergenic compensatory process is involved in the persistence of β-lactam resistance among circulating strains. We propose that this compensatory mechanism is relevant for β-lactam resistance evolution in Streptococcus pneumoniae

Direct evidence for shock-powered optical emission in a nova

Classical novae are thermonuclear explosions that occur on the surfaces of white dwarf stars in interacting binary systems1. It has long been thought that the luminosity of classical novae is powered by continued nuclear burning on the surface of the white dwarf after the initial runaway2. However, recent observations of gigaelectronvolt γ-rays from classical novae have hinted that shocks internal to the nova ejecta may dominate the nova emission. Shocks have also been suggested to power the luminosity of events as diverse as stellar mergers3, supernovae4 and tidal disruption events5, but observational confirmation has been lacking. Here we report simultaneous space-based optical and γ-ray observations of the 2018 nova V906 Carinae (ASASSN-18fv), revealing a remarkable series of distinct correlated flares in both bands. The optical and γ-ray flares occur simultaneously, implying a common origin in shocks. During the flares, the nova luminosity doubles, implying that the bulk of the luminosity is shock powered. Furthermore, we detect concurrent but weak X-ray emission from deeply embedded shocks, confirming that the shock power does not appear in the X-ray band and supporting its emergence at longer wavelengths. Our data, spanning the spectrum from radio to γ-ray, provide direct evidence that shocks can power substantial luminosity in classical novae and other optical transients