Developmental regulation of GABAergic signalling in the hippocampus of neuroligin 3 R451C knock-in mice: an animal model of Autism

Autism Spectrum Disorders (ASDs) comprise an heterogeneous group of neuro-developmental abnormalities, mainly of genetic origin, characterized by impaired social interactions, communications deficits and stereotyped behaviors. In a small percentage of cases, ASDs have been found to be associated with single mutations in genes involved in synaptic function. One of these involves the postsynaptic cell adhesion molecule neuroligin (NL) 3. NLs interact with presynaptic neurexins (Nrxs) to ensure a correct cross talk between post and presynaptic specializations. Here, transgenic mice carrying the human R451C mutation of Nlgn3, were used to study GABAergic signaling in the hippocampus early in postnatal life. Whole cell recordings from CA3 pyramidal neurons in slices from NL3 R451C knock-in mice revealed an enhanced frequency of Giant Depolarizing Potentials, as compared to controls. This effect was probably dependent on an increased GABAergic drive to principal cells as demonstrated by the enhanced frequency of miniature GABAA-mediated (GPSCs), but not AMPA-mediated postsynaptic currents (EPSCs). Changes in frequency of mGPSCs were associated with an acceleration of their decay kinetics, in the absence of any change in unitary synaptic conductance or in the number of GABAA receptor channels, as assessed by peak scaled non-stationary fluctuation analysis. The enhanced GABAergic but not glutamatergic transmission early in postnatal life may change the excitatory/inhibitory balance known to play a key role in the construction and refinement of neuronal circuits during postnatal development. This may lead to behavioral deficits reminiscent of those observed in ASDs patients. \ua9 2013 Pizzarelli and Cherubini

Competing mechanisms of stress-assisted diffusivity and stretch-activated currents in cardiac electromechanics

We numerically investigate the role of mechanical stress in modifying the conductivity properties of the cardiac tissue and its impact in computational models for cardiac electromechanics. We follow a theoretical framework recently proposed in [Cherubini, Filippi, Gizzi, Ruiz-Baier, JTB 2017], in the context of general reaction-diffusion-mechanics systems using multiphysics continuum mechanics and finite elasticity. In the present study, the adapted models are compared against preliminary experimental data of pig right ventricle fluorescence optical mapping. These data contribute to the characterization of the observed inhomogeneity and anisotropy properties that result from mechanical deformation. Our novel approach simultaneously incorporates two mechanisms for mechano-electric feedback (MEF): stretch-activated currents (SAC) and stress-assisted diffusion (SAD); and we also identify their influence into the nonlinear spatiotemporal dynamics. It is found that i) only specific combinations of the two MEF effects allow proper conduction velocity measurement; ii) expected heterogeneities and anisotropies are obtained via the novel stress-assisted diffusion mechanisms; iii) spiral wave meandering and drifting is highly mediated by the applied mechanical loading. We provide an analysis of the intrinsic structure of the nonlinear coupling using computational tests, conducted using a finite element method. In particular, we compare static and dynamic deformation regimes in the onset of cardiac arrhythmias and address other potential biomedical applications

Excised acoustic black holes: the scattering problem in the time domain

The scattering process of a dynamic perturbation impinging on a draining-tub model of an acoustic black hole is numerically solved in the time domain. Analogies with real black holes of General Relativity are explored by using recently developed mathematical tools involving finite elements methods, excision techniques, and constrained evolution schemes for strongly hyperbolic systems. In particular it is shown that superradiant scattering of a quasi-monochromatic wavepacket can produce strong amplification of the signal, offering the possibility of a significant extraction of rotational energy at suitable values of the angular frequency of the vortex and of the central frequency of the wavepacket. The results show that theoretical tools recently developed for gravitational waves can be brought to fruition in the study of other problems in which strong anisotropies are present.Comment: 8 pages, 9 figure

Prion expression is activated by Adenovirus 5 infection and affects the adenoviral cycle in human cells

The prion protein is a cell surface glycoprotein whose physiological role remains elusive, while its implication in transmissible spongiform encephalopathies (TSEs) has been demonstrated. Multiple interactions between the prion protein and viruses have been described: viruses can act as co-factors in TSEs and life cycles of different viruses have been found to be controlled by prion modulation. We present data showing that human Adenovirus 5 induces prion expression. Inactivated Adenovirus did not alter prion transcription, while variants encoding for early products did, suggesting that the prion is stimulated by an early adenoviral function. Down-regulation of the prion through RNA interference showed that the prion controls adenovirus replication and expression. These data suggest that the prion protein could play a role in the defense strategy mounted by the host during viral infection, in a cell autonomous manner. These results have implications for the study of the prion protein and of associated TSEs

Electrocardiogram of the Mixmaster Universe

The Mixmaster dynamics is revisited in a new light as revealing a series of transitions in the complex scale invariant scalar invariant of the Weyl curvature tensor best represented by the speciality index $\mathcal{S}$, which gives a 4-dimensional measure of the evolution of the spacetime independent of all the 3-dimensional gauge-dependent variables except for the time used to parametrize it. Its graph versus time characterized by correlated isolated pulses in its real and imaginary parts corresponding to curvature wall collisions serves as a sort of electrocardiogram of the Mixmaster universe, with each such pulse pair arising from a single circuit or ``complex pulse'' around the origin in the complex plane. These pulses in the speciality index and their limiting points on the real axis seem to invariantly characterize some of the so called spike solutions in inhomogeneous cosmology and should play an important role as a gauge invariant lens through which to view current investigations of inhomogeneous Mixmaster dynamics.Comment: version 3: 20 pages iopart style, 19 eps figure files for 8 latex figures; added example of a transient true spike to contrast with the permanent true spike example from the Lim family of true spike solutions; remarks in introduction and conclusion adjusted and toned down; minor adjustments to the remaining tex

Neutrons from Piezonuclear Reactions

We report the results obtained by cavitating water solutions of iron salts (iron chloride and iron nitrate) with different concentrations at different ultrasound powers. In all cases we detected a neutron radiation well higher than the background level. The neutron production is perfectly reproducible and can at some extent be controlled. These evidences for neutron emission generated by cavitation support some preliminary clues for the possibility of piezonuclear reactions (namely nuclear reactions induced by pressure and shock waves) obtained in the last ten years. We have been able for the first time to state some basic features of such a neutron emission induced by cavitation, namely: 1) a marked threshold behavior in power, energy and time; 2) its occurring without a concomitant production of gamma radiation.Comment: 8 figures; we added some more important references; we replaced some figures with more detailed ones; we added more comprehensive details which could not be desclosed before as part of private patents which have been published no

Adenovirus-Mediated Sensitization to the Cytotoxic Drugs Docetaxel and Mitoxantrone Is Dependent on Regulatory Domains in the E1ACR1 Gene-Region

Oncolytic adenoviruses have shown promising efficacy in clinical trials targeting prostate cancers that frequently develop resistance to all current therapies. The replication-selective mutants AdΔΔ and dl922–947, defective in pRb-binding, have been demonstrated to synergise with the current standard of care, mitoxantrone and docetaxel, in prostate cancer models. While expression of the early viral E1A gene is essential for the enhanced cell killing, the specific E1A-regions required for the effects are unknown. Here, we demonstrate that replicating mutants deleted in small E1A-domains, binding pRb (dl1108), p300/CBP (dl1104) and p400/TRRAP or p21 (dl1102) sensitize human prostate cancer cells (PC-3, DU145, 22Rv1) to mitoxantrone and docetaxel. Through generation of non-replicating mutants, we demonstrate that the small E1A12S protein is sufficient to potently sensitize all prostate cancer cells to the drugs even in the absence of viral replication and the E1A transactivating domain, conserved region (CR) 3. Furthermore, the p300/CBP-binding domain in E1ACR1 is essential for drug-sensitisation in the absence (AdE1A1104) but not in the presence of the E1ACR3 (dl1104) domain. AdE1A1104 also failed to increase apoptosis and accumulation of cells in G2/M. All E1AΔCR2 mutants (AdE1A1108, dl922–947) and AdE1A1102 or dl1102 enhance cell killing to the same degree as wild type virus. In PC-3 xenografts in vivo the dl1102 mutant significantly prolongs time to tumor progression that is further enhanced in combination with docetaxel. Neither dl1102 nor dl1104 replicates in normal human epithelial cells (NHBE). These findings suggest that additional E1A-deletions might be included when developing more potent replication-selective oncolytic viruses, such as the AdΔCR2-mutants, to further enhance potency through synergistic cell killing in combination with current chemotherapeutics

e−e+e^-e^+ pair creation by vacuum polarization around electromagnetic black holes

The concept of "dyadotorus" was recently introduced to identify in the Kerr-Newman geometry the region where vacuum polarization processes may occur, leading to the creation of $e^--e^+$ pairs. This concept generalizes the original concept of "dyadosphere" initially introduced for Reissner-Nordstr\"{o}m geometries. The topology of the axially symmetric dyadotorus is studied for selected values of the electric field and its electromagnetic energy is estimated by using three different methods all giving the same result. It is shown by a specific example the difference between a dyadotorus and a dyadosphere. The comparison is made for a Kerr-Newman black hole with the same total mass energy and the same charge to mass ratio of a Reissner-Nordstr\"{o}m black hole. It turns out that the Kerr-Newman black hole leads to larger values of the electromagnetic field and energy when compared to the electric field and energy of the Reissner-Nordstr\"{o}m one. The significance of these theoretical results for the realistic description of the process of gravitational collapse leading to black hole formation as well as the energy source of gamma ray bursts are also discussed.Comment: Revised version with minor corrections; to appear on Phys. Rev.

Second Order Scalar Invariants of the Riemann Tensor: Applications to Black Hole Spacetimes

We discuss the Kretschmann, Chern-Pontryagin and Euler invariants among the second order scalar invariants of the Riemann tensor in any spacetime in the Newman-Penrose formalism and in the framework of gravitoelectromagnetism, using the Kerr-Newman geometry as an example. An analogy with electromagnetic invariants leads to the definition of regions of gravitoelectric or gravitomagnetic dominance