Clozapine Induces an Acute Proinflammatory Response That Is Attenuated by Inhibition of Inflammasome Signaling: Implications for Idiosyncratic Drug-Induced Agranulocytosis.

Although clozapine is a highly efficacious schizophrenia treatment, it is under-prescribed due to the risk of idiosyncratic drug-induced agranulocytosis (IDIAG). Clinical data indicate that most patients starting clozapine experience a transient immune response early in treatment and a similar response has been observed in clozapine-treated rats, but the mechanism by which clozapine triggers this transient inflammation remains unclear. Therefore, the aim of this study was to characterize the role of inflammasome activation during the early immune response to clozapine using in vitro and in vivo models. In both differentiated and nondifferentiated human monocytic THP-1 cells, clozapine, but not its structural analogues fluperlapine and olanzapine, caused inflammasome-dependent caspase-1 activation and IL-1ß release that was inhibited using the caspase-1 inhibitor yVAD-cmk. In Sprague Dawley rats, a single dose of clozapine caused an increase in circulating neutrophils and a decrease in lymphocytes within hours of drug administration along with transient spikes in the proinflammatory mediators IL-1ß, CXCL1, and TNF-α in the blood, spleen, and bone marrow. Blockade of inflammasome signaling using the caspase-1 inhibitor VX-765 or the IL-1 receptor antagonist anakinra attenuated this inflammatory response. These data indicate that caspase-1-dependent IL-1ß production is fundamental for the induction of the early immune response to clozapine and, furthermore, support the general hypothesis that inflammasome activation is a common mechanism by which drugs associated with the risk of idiosyncratic reactions trigger early immune system activation. Ultimately, inhibition of inflammasome signaling may reduce the risk of IDIAG, enabling safer, more frequent use of clozapine in patients.

The HANDE-QMC Project: Open-Source Stochastic Quantum Chemistry from the Ground State Up.

Building on the success of Quantum Monte Carlo techniques such as diffusion Monte Carlo, alternative stochastic approaches to solve electronic structure problems have emerged over the past decade. The full configuration interaction quantum Monte Carlo (FCIQMC) method allows one to systematically approach the exact solution of such problems, for cases where very high accuracy is desired. The introduction of FCIQMC has subsequently led to the development of coupled cluster Monte Carlo (CCMC) and density matrix quantum Monte Carlo (DMQMC), allowing stochastic sampling of the coupled cluster wave function and the exact thermal density matrix, respectively. In this Article, we describe the HANDE-QMC code, an open-source implementation of FCIQMC, CCMC and DMQMC, including initiator and semistochastic adaptations. We describe our code and demonstrate its use on three example systems; a molecule (nitric oxide), a model solid (the uniform electron gas), and a real solid (diamond). An illustrative tutorial is also included.

Cooperative Charge Pumping and Enhanced Skyrmion Mobility.

It is well known that moving magnetic textures may pump spin and charge currents along the direction of motion, a phenomenon called electronic pumping. Here, the electronic pumping arising from the steady motion of ferromagnetic skyrmions is investigated by solving the time evolution of the Schrödinger equation implemented on a tight-binding model with the statistical physics of the many-body problem. In contrast with rigid one-dimensional magnetic textures, we show that steadily moving magnetic skyrmions are able to pump large dc currents. This ability arises from their nontrivial magnetic topology, i.e., the coexistence of the spin-motive force and the topological Hall effect. Based on an adiabatic scattering theory, we compute the pumped current and demonstrate that it scales with the reflection coefficient of the conduction electrons against the skyrmion. In other words, in the semiclassical limit, reducing the size of the skyrmion and the width of the nanowire enhances this effect, making it scalable. We propose that such a phenomenon can be exploited in the context of racetrack devices, where the electronic pumping enhances the collective motion of the train of skyrmions.

The a.c. Josephson effect without superconductivity.

Superconductivity derives its most salient features from the coherence of the associated macroscopic wave function. The related physical phenomena have now moved from exotic subjects to fundamental building blocks for quantum circuits such as qubits or single photonic modes. Here we predict that the a.c. Josephson effect-which transforms a d.c. voltage Vb into an oscillating signal cos (2eVbt/h)-has a mesoscopic counterpart in normal conductors. We show that when a d.c. voltage Vb is applied to an electronic interferometer, there exists a universal transient regime where the current oscillates at frequency eVb/h. This effect is not limited by a superconducting gap and could, in principle, be used to produce tunable a.c. signals in the elusive 0.1-10-THz 'terahertz gap'.