Effects of PDE4 inhibitors on lipopolysaccharide-induced priming of superoxide anion production from human mononuclear cells.

AIMS: Phosphodiesterase 4 (PDE4) inhibitors have been described as potent anti-inflammatory compounds, involving an increase in intracellular levels of cyclic 3',5'-adenosine monophosphate (AMP). The aim of this study was to compare the effects of selective PDE4 inhibitors, rolipram and RP 73-401 with the cell permeable analogue of cyclic AMP, dibutyryl-cyclic AMP (db-cAMP) and the anti-inflammatory cytokine interleukin-10 (IL-10) on superoxide anion production from peripheral blood mononuclear cells preincubated with lipopolysaccharide (LPS). MAJOR FINDINGS: We report that, after incubation of the cells with LPS, a large increase in superoxide anion production was observed. Rolipram or RP 73-401 (10(-8) to 10(-5) M) induced significant reductions of fMLP-induced superoxide anion production in cells incubated with or without LPS. The db-cAMP (10(-5) to 10(-3) M) also elicited dose-dependent inhibitions of the fMLP-induced superoxide anion production. In contrast, IL-10 (1 or 10 ng/ml) did not elicit a reduction in fMLP-induced superoxide anion production in both conditions. PRINCIPAL CONCLUSION: These results suggest that the inhibitory activity of PDE4 inhibitors on fMLP-induced production of superoxide anion production is mediated by db-cAMP rather than IL-10

Quadrupole resonances in unstable oxygen isotopes in time-dependent density-matrix formalism

The strength functions of quadrupole modes in the unstable oxygen isotopes 22O and 24O are calculated using an extended version of the time-dependent Hartree-Fock theory known as the time-dependent density-matrix theory (TDDM). It is found that TDDM gives the lowest quadrupole states which are energetically shifted upward and become significantly collective due to the coupling to two-body configurations. It is pointed out that these features of the lowest quadrupole states are similar to those obtained in the quasi-particle random phase approximation.Comment: 6 pages, 6 figure

Isostatic equilibrium in spherical coordinates and implications for crustal thickness on the Moon, Mars, Enceladus, and elsewhere

Isostatic equilibrium is commonly defined as the state achieved when there are no lateral gradients in hydrostatic pressure, and thus no lateral flow, at depth within the lower viscosity mantle that underlies a planetary body's outer crust. In a constant-gravity Cartesian framework, this definition is equivalent to the requirement that columns of equal width contain equal masses. Here we show, however, that this equivalence breaks down when the spherical geometry of the problem is taken into account. Imposing the "equal masses" requirement in a spherical geometry, as is commonly done in the literature, leads to significant lateral pressure gradients along internal equipotential surfaces, and thus corresponds to a state of disequilibrium. Compared with the "equal pressures" model we present here, the "equal masses" model always overestimates the compensation depth--by ~27% in the case of the lunar highlands and by nearly a factor of two in the case of Enceladus.Comment: 23 pages of text; 3 figures; accepted for publication in GR

Continuum Linear Response in Coordinate Space Hartree-Fock-Bogoliubov Formalism for Collective Excitations in Drip-line Nuclei

We formulate a continuum linear response theory on the basis of the Hartree-Fock-Bogoliubov formalism in the coordinate space representation in order to describe low-lying and high-lying collective excitations which couple to one-particle and two-particle continuum states. Numerical analysis is done for the neutron drip-line nucleus $^{24}$O. A low-lying collective mode that emerges above the continuum threshold with large neutron strength is analyzed. The collective state is sensitive to the density-dependence of the pairing. The present theory satisfies accurately the energy weighted sum rule. This is guaranteed by treating the pairing selfconsistently both in the static HFB and in the dynamical linear response equation.Comment: 19 pages, 6 figure

Continuum quasiparticle random phase approximation and the time dependent Hartree-Fock-Bogoliubov approach

Quadrupole excitations of neutron-rich nuclei are analyzed by using the linear response method in the Quasiparticle Random Phase Approximation (QRPA). The QRPA response is derived starting from the time-dependent Hartree-Fock-Bogoliubov (HFB) equations. The residual interaction between the quasiparticles is determined consistently from the two-body force used in the HFB equations, and the continuum coupling is treated exactly. Calculations are done for the neutron-rich oxygen isotopes. It is found that pairing correlations affect the low-lying states, and that a full treatment of the continuum can change the structure of the states in the giant resonance region.Comment: 17 pages, 7 figures. Revised version with comments and references adde

Harnessing Artificial Intelligence for Early and Evolution of Alzheimer’s Disease Detections and Enhancing Senior Mental Health through Innovative Art-Singing Therapies: A Multidisciplinary Approach

The well-documented therapeutic potential of group singing for patients living with Alzheimer’s disease (PLAD) has been hindered by COVID-19 restrictions, exacerbating loneliness and cognitive decline among seniors in residential and long-term care centers (CHSLDs). Addressing this challenge, the multidisciplinary study aims to develop a patient-oriented virtual reality (XR) interaction system facilitating group singing for mental health support during confinement and enhancing the understanding of the links between Alzheimer’s disease, social interaction, and singing. The researchers also propose to establish an early AD detection system using voice, facial, and non-invasive biometric measurements and validate the efficacy of selected intervention practices. The methodology involves co-designing an intelligent environment with caregivers to support PLAD mental health through online group singing, addressing existing constraints in CHSLDs. The researchers will engage volunteers in remote singing interactions and validate the impact of voice stimulation for PLADs using a control group. The primary expected outcome is the development of an “Intelligent Learning Health Environment,” fostering interactions while adapting to individual PLAD situations and incrementally accumulating knowledge on AD signs. This environment will facilitate the transfer of knowledge and technologies to promote non-verbal interactions via singing, enabling intervention at the first symptoms. Additionally, the research will contribute to transforming CHSLDs’ living environments, informed by neuroscience insights, and potentially extend the “collaborative self-care” approach to support seniors in aging safely and healthily at home

The differential effects of azithromycin on the airway epithelium in vitro and in vivo

Macrolides including azithromycin (AZM) can improve clinical symptoms in asthma regardless of infection status. The mechanisms underlying these benefi- cial effects are yet to be elucidated. The aim of this study was to determine the effect of AZM on the airway epithelial barrier both in an in vitro model and in patients with asthma. Primary human bronchial epithelial cells (HBEC) were grown at air liquid interface (ALI) and challenged using lipopolysaccharides from Pseudomonas aeruginosa. AZM was added at various stages and barrier integrity assessed using transepithelial electrical resistance (TEER) and permeability to FITC-dextran. MMP-9 levels were measured using ELISA. AZM enhanced barrier integrity (TEER/FITC-dextran), increased thickness, suppressed mucin production, and MMP-9 release during the formation of a normal epithelial barrier in vitro. MMP-9 levels inversely correlated with TEER. AZM also enhanced maintenance of the barrier and facilitated repair post-LPS challenge. To provide translation of our findings, 10 patients with moderatesevere asthma were recruited and received 250 mg AZM o.d for 6 weeks. Bronchial biopsies taken pre- and post-AZM treatment did not show evidence of increased epithelial barrier thickness or decreased mucin production. Similarly, bronchial wash samples did not show reduced MMP-9 levels. Overall, our data show that AZM can significantly improve the development of a normal bronchial epithelial barrier in vitro, mimicking reepithelization postinjury. AZM also suppressed MMP-9 release which correlated with barrier integrity, suggesting a putative mechanism. However, these effects were not observed in biopsy samples from asthma patients treated with AZM, possibly due to small sample size

On the relative importance of thermal and chemical buoyancy in regular and impact-induced melting in a Mars-like planet

We ran several series of two-dimensional numerical mantle convection simulations representing in idealized form the thermochemical evolution of a Mars-like planet. In order to study the importance of compositional buoyancy of melting mantle, the models were set up in pairs of one including all thermal and compositional contributions to buoyancy and one accounting only for the thermal contributions. In several of the model pairs, single large impacts were introduced as causes of additional strong local anomalies, and their evolution in the framework of the convecting mantle was tracked. The models confirm that the additional buoyancy provided by the depletion of the mantle by regular melting can establish a global stable stratification of the convecting mantle and throttle crust production. Furthermore, the compositional buoyancy is essential in the stabilization and preservation of local compositional anomalies directly beneath the lithosphere and offers a possible explanation for the existence of distinct, long-lived reservoirs in the martian mantle. The detection of such anomalies by geophysical means is probably difficult, however; they are expected to be detected by gravimetry rather than by seismic or heat flow measurements. The results further suggest that the crustal thickness can be locally overestimated by up to ~20 km if impact-induced density anomalies in the mantle are neglected.Comment: 29 pages, 10 figure

Maximum-likelihood estimation of lithospheric flexural rigidity, initial-loading fraction, and load correlation, under isotropy

Topography and gravity are geophysical fields whose joint statistical structure derives from interface-loading processes modulated by the underlying mechanics of isostatic and flexural compensation in the shallow lithosphere. Under this dual statistical-mechanistic viewpoint an estimation problem can be formulated where the knowns are topography and gravity and the principal unknown the elastic flexural rigidity of the lithosphere. In the guise of an equivalent "effective elastic thickness", this important, geographically varying, structural parameter has been the subject of many interpretative studies, but precisely how well it is known or how best it can be found from the data, abundant nonetheless, has remained contentious and unresolved throughout the last few decades of dedicated study. The popular methods whereby admittance or coherence, both spectral measures of the relation between gravity and topography, are inverted for the flexural rigidity, have revealed themselves to have insufficient power to independently constrain both it and the additional unknown initial-loading fraction and load-correlation fac- tors, respectively. Solving this extremely ill-posed inversion problem leads to non-uniqueness and is further complicated by practical considerations such as the choice of regularizing data tapers to render the analysis sufficiently selective both in the spatial and spectral domains. Here, we rewrite the problem in a form amenable to maximum-likelihood estimation theory, which we show yields unbiased, minimum-variance estimates of flexural rigidity, initial-loading frac- tion and load correlation, each of those separably resolved with little a posteriori correlation between their estimates. We are also able to separately characterize the isotropic spectral shape of the initial loading processes.Comment: 41 pages, 13 figures, accepted for publication by Geophysical Journal Internationa