Nitro-fatty acids decrease type I interferons and monocyte chemoattractant protein 1 in ex vivo models of inflammatory arthritis.

BACKGROUND: Inflammatory arthritis including rheumatoid arthritis (RA) and spondyloarthritis (SpA) is characterized by inflammation and destruction of the joints. Approximately one third of patients do not respond to first-line treatments. Nitro-fatty acids are bioactive lipids with anti-inflammatory properties and tissue-protective functions. The nitro-fatty acid 10-NO2-oleic acid (10-NO2-OA) is being tested in clinical trials for patients with fibrotic and inflammatory conditions. Here, we tested whether 10-NO2-OA could inhibit immune reactions involved in the inflammatory and joint destructive processes in inflammatory arthritis. METHODS: Synovial fluid and blood samples were obtained from 14 patients with active RA or SpA. The in vitro models consisted of synovial fluid mononuclear cells (SFMCs) cultured for 48 h, SFMCs cultured for 21 days, and fibroblast-like synovial cells (FLSs) co-cultured with peripheral blood mononuclear cells (PBMCs) for 48 h. Cells were treated with or without 10-NO2-OA or the tumor necrosis factor alpha (TNFα) inhibitor etanercept. Supernatants were analyzed for type I interferon, monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase 3 (MMP3) and tartrate resistant acid phosphatase (TRAP). RESULTS: In SFMCs cultured for 48 h, 10-NO2-OA dose-dependently decreased the secretion of bioactive type I interferons and MCP-1 but not MMP3 (P = 0.032, P = 0.0001, and P = 0.58, respectively). Both MCP-1 and MMP3 were decreased by etanercept (P = 0.0031 and P = 0.026, respectively). In SFMCs cultured for 21 days, 10-NO2-OA significantly decreased the production of MCP-1 but not TRAP (P = 0.027 and P = 0.1523, respectively). Etanercept decreased the production of TRAP but not MCP-1 (P < 0.001 and P = 0.84, respectively). In co-cultures of FLSs and PBMCs, 10-NO2-OA decreased the production of MCP-1 (P < 0.0001). This decrease in MCP-1 production was not seen with etanercept treatment (P = 0.47). CONCLUSION: 10-NO2-OA decreased the release of MCP-1 in three models of inflammatory arthritis. Of particular interest, 10-NO2-OA inhibited type I interferon, and 10-NO2-OA was more effective in reducing MCP-1 production in cultures dominated by FLSs compared with etanercept. Our results encourage clinical investigations of 10-NO2-OA in patients with inflammatory arthritis.

Distinct expression patterns of TLR transcripts in human oocytes and granulosa cells from primordial and primary follicles.

Ovulation has long been regarded as a process resembling an inflammatory response. Previously, luteinizing hormone (LH) was shown to induce Toll-like receptor 2 (TLR2) and TLR4 in granulosa cells from preovulatory hormone-dependent follicles. However, whether this could already initiate before the hormone-dependent phase is currently unknown. The aim of this study was to investigate TLR genes in human oocytes and granulosa cells from primordial and primary ovarian follicles during the hormone-independent phase. A class-comparison study of existing oocyte and granulosa cell RNA sequencing transcriptomes from primordial (n = 539 follicles) and primary (n = 261) follicles collected from three patients was examined. This revealed a distinct expression pattern of TLR3, TLR4 and TLR5 transcripts. Interestingly, the TLR3 protein was differentially detected in both the oocyte and the granulosa cells in primordial and primary follicles, suggesting that TLR3 is maternally contributed both as mRNA and protein. Intracellularly, the compartmentalized TLR3 dot-like staining in the intersection between the oocyte and the surrounding primordial granulosa cells. The TLR4 protein was detected in both primordial and primary follicles, with a notable staining in the granulosa cells. We functionally challenged ovaries in vitro, by polyinosinic:polycytidylic acid (poly I:C) and LPS, known to activate TLR3 and TLR4, respectively, and found a tendency for increased IL-6 production, which was particular evident in the LPS-treated group. Based on the expression of TLRs, it is notably that human primordial and primary follicles express genes that would allow them to respond to innate immune proteins and cytokines during follicle activation.

Phonon Decoherence of Quantum Dots in Photonic Structures: Broadening of the Zero-Phonon Line and the Role of Dimensionality.

We develop a general microscopic theory describing the phonon decoherence of quantum dots and indistinguishability of the emitted photons in photonic structures. The coherence is found to depend fundamentally on the dimensionality of the structure resulting in vastly different performance for quantum dots embedded in a nanocavity (0D), waveguide (1D), slab (2D), or bulk medium (3D). In bulk, we find a striking temperature dependence of the dephasing rate scaling as T^{11} implying that phonons are effectively "frozen out" for T≲4 K. The phonon density of states is strongly modified in 1D and 2D structures leading to a linear temperature scaling for the dephasing strength. The resulting impact on the photon indistinguishability can be important even at sub-Kelvin temperatures. Our findings provide a comprehensive understanding of the fundamental limits to photon indistinguishability in photonic structures.

Dissipative quantum error correction and application to quantum sensing with trapped ions.

Quantum-enhanced measurements hold the promise to improve high-precision sensing ranging from the definition of time standards to the determination of fundamental constants of nature. However, quantum sensors lose their sensitivity in the presence of noise. To protect them, the use of quantum error-correcting codes has been proposed. Trapped ions are an excellent technological platform for both quantum sensing and quantum error correction. Here we present a quantum error correction scheme that harnesses dissipation to stabilize a trapped-ion qubit. In our approach, always-on couplings to an engineered environment protect the qubit against spin-flips or phase-flips. Our dissipative error correction scheme operates in a continuous manner without the need to perform measurements or feedback operations. We show that the resulting enhanced coherence time translates into a significantly enhanced precision for quantum measurements. Our work constitutes a stepping stone towards the paradigm of self-correcting quantum information processing.

Coherent Backscattering of Light Off One-Dimensional Atomic Strings.

We present the first experimental realization of coherent Bragg scattering off a one-dimensional system-two strings of atoms strongly coupled to a single photonic mode-realized by trapping atoms in the evanescent field of a tapered optical fiber, which also guides the probe light. We report nearly 12% power reflection from strings containing only about 1000 cesium atoms, an enhancement of 2 orders of magnitude compared to reflection from randomly positioned atoms. This result paves the road towards collective strong coupling in 1D atom-photon systems. Our approach also allows for a straightforward fiber connection between several distant 1D atomic crystals.

Preparation of Entangled States through Hilbert Space Engineering.

We apply laser fields to trapped atomic ions to constrain the quantum dynamics from a simultaneously applied global microwave field to an initial product state and a target entangled state. This approach comes under what has become known in the literature as "quantum Zeno dynamics" and we use it to prepare entangled states of two and three ions. With two trapped ^{9}Be^{+} ions, we obtain Bell state fidelities up to 0.990_{-5}^{+2}; with three ions, a W-state fidelity of 0.910_{-7}^{+4} is obtained. Compared to other methods of producing entanglement in trapped ions, this procedure can be relatively insensitive to certain imperfections such as fluctuations in laser intensity.

Scalable photonic network architecture based on motional averaging in room temperature gas.

Quantum interfaces between photons and atomic ensembles have emerged as powerful tools for quantum technologies. Efficient storage and retrieval of single photons requires long-lived collective atomic states, which is typically achieved with immobilized atoms. Thermal atomic vapours, which present a simple and scalable resource, have only been used for continuous variable processing or for discrete variable processing on short timescales where atomic motion is negligible. Here we develop a theory based on motional averaging to enable room temperature discrete variable quantum memories and coherent single-photon sources. We demonstrate the feasibility of this approach to scalable quantum memories with a proof-of-principle experiment with room temperature atoms contained in microcells with spin-protecting coating, placed inside an optical cavity. The experimental conditions correspond to a few photons per pulse and a long coherence time of the forward scattered photons is demonstrated, which is the essential feature of the motional averaging.

Unraveling the Mesoscopic Character of Quantum Dots in Nanophotonics.

We provide a microscopic theory for semiconductor quantum dots that explains the pronounced deviations from the prevalent point-dipole description that were recently observed in spectroscopic experiments on quantum dots in photonic nanostructures. The deviations originate from structural inhomogeneities generating a large circular quantum current density that flows inside the quantum dot over mesoscopic length scales. The model is supported by the experimental data, where a strong variation of the multipolar moments across the emission spectrum of quantum dots is observed. Our work enriches the physical understanding of quantum dots and is of significance for the fields of nanophotonics, quantum photonics, and quantum-information science, where quantum dots are actively employed.

Heralded quantum gates with integrated error detection in optical cavities.

We propose and analyze heralded quantum gates between qubits in optical cavities. They employ an auxiliary qubit to report if a successful gate occurred. In this manner, the errors, which would have corrupted a deterministic gate, are converted into a nonunity probability of success: once successful, the gate has a much higher fidelity than a similar deterministic gate. Specifically, we describe that a heralded, near-deterministic controlled phase gate (CZ gate) with the conditional error arbitrarily close to zero and the success probability that approaches unity as the cooperativity of the system, C, becomes large. Furthermore, we describe an extension to near-deterministic N-qubit Toffoli gate with a favorable error scaling. These gates can be directly employed in quantum repeater networks to facilitate near-ideal entanglement swapping, thus greatly speeding up the entanglement distribution.

Probing electric and magnetic vacuum fluctuations with quantum dots.

The electromagnetic-vacuum-field fluctuations are intimately linked to the process of spontaneous emission of light. Atomic emitters cannot probe electric- and magnetic-field fluctuations simultaneously because electric and magnetic transitions correspond to different selection rules. In this Letter we show that semiconductor quantum dots are fundamentally different and are capable of mediating electric-dipole, magnetic-dipole, and electric-quadrupole transitions on a single electronic resonance. As a consequence, quantum dots can probe electric and magnetic fields simultaneously and can thus be applied for sensing the electromagnetic environment of complex photonic nanostructures. Our study opens the prospect of interfacing quantum dots with optical metamaterials for tailoring the electric and magnetic light-matter interaction at the single-emitter level.

Heisenberg-limited atom clocks based on entangled qubits.

We present a quantum-enhanced atomic clock protocol based on groups of sequentially larger Greenberger-Horne-Zeilinger (GHZ) states that achieves the best clock stability allowed by quantum theory up to a logarithmic correction. Importantly the protocol is designed to work under realistic conditions where the drift of the phase of the laser interrogating the atoms is the main source of decoherence. The simultaneous interrogation of the laser phase with a cascade of GHZ states realizes an incoherent version of the phase estimation algorithm that enables Heisenberg-limited operation while extending the coherent interrogation time beyond the laser noise limit. We compare and merge the new protocol with existing state of the art interrogation schemes, and identify the precise conditions under which entanglement provides an advantage for clock stabilization: it allows a significant gain in the stability for short averaging time.

Dissipative production of a maximally entangled steady state of two quantum bits.

Entangled states are a key resource in fundamental quantum physics, quantum cryptography and quantum computation. Introduction of controlled unitary processes--quantum gates--to a quantum system has so far been the most widely used method to create entanglement deterministically. These processes require high-fidelity state preparation and minimization of the decoherence that inevitably arises from coupling between the system and the environment, and imperfect control of the system parameters. Here we combine unitary processes with engineered dissipation to deterministically produce and stabilize an approximate Bell state of two trapped-ion quantum bits (qubits), independent of their initial states. Compared with previous studies that involved dissipative entanglement of atomic ensembles or the application of sequences of multiple time-dependent gates to trapped ions, we implement our combined process using trapped-ion qubits in a continuous time-independent fashion (analogous to optical pumping of atomic states). By continuously driving the system towards the steady state, entanglement is stabilized even in the presence of experimental noise and decoherence. Our demonstration of an entangled steady state of two qubits represents a step towards dissipative state engineering, dissipative quantum computation and dissipative phase transitions. Following this approach, engineered coupling to the environment may be applied to a broad range of experimental systems to achieve desired quantum dynamics or steady states. Indeed, concurrently with this work, an entangled steady state of two superconducting qubits was demonstrated using dissipation.

Near-Heisenberg-limited atomic clocks in the presence of decoherence.

The ultimate stability of atomic clocks is limited by the quantum noise of the atoms. To reduce this noise it has been suggested to use entangled atomic ensembles with reduced atomic noise. Potentially this can push the stability all the way to the limit allowed by the Heisenberg uncertainty relation, which is denoted the Heisenberg limit. In practice, however, entangled states are often more prone to decoherence, which may prevent reaching this performance. Here we present an adaptive measurement protocol that in the presence of a realistic source of decoherence enables us to get near-Heisenberg-limited stability of atomic clocks using entangled atoms. The protocol may thus realize the full potential of entanglement for quantum metrology despite the detrimental influence of decoherence.

Efficient atomic clocks operated with several atomic ensembles.

Atomic clocks are typically operated by locking a local oscillator (LO) to a single atomic ensemble. In this Letter, we propose a scheme where the LO is locked to several atomic ensembles instead of one. This results in an exponential improvement compared to the conventional method and provides a stability of the clock scaling as (αN)(-m/2) with N being the number of atoms in each of the m ensembles and α a constant depending on the protocol being used to lock the LO.

Single ascending oral dose pharmacokinetics and pharmacodynamics study of EV-077: the specific inhibitor of prostanoid- and isoprostane-induced cellular activation.

PURPOSE: This study was performed to determine the oral pharmacokinetics (PK) of EV-077 and its effects on pharmacodynamic (PD) markers. EV-077 blocks prostanoid-induced and isoprostane-induced cellular activation, and is in development for the treatment of vascular inflammation and associated complications of type-2 diabetes.. METHODS: This single-ascending-dose mono-centre study was randomised, placebo-controlled, and double-blinded within each dose group. Seven EV-077 doses were administered sequentially as an oral solution: 0.0125, 0.125, 0.375, 0.75, 1.25, 1.875 and 2.5 mg/kg body weight. PK, platelet aggregation, bleeding time and safety parameters were measured. Seven to eight healthy male subjects were dosed per group: five to six subjects received EV-077 and two subjects received placebo. RESULTS: Tmax was reached rapidly between 0.5 h and 1.0 h. Both Cmax and AUC increased linearly with the dose. The apparent terminal half-life (t½z) increased with the dose, most likely reflecting the increasing last quantifiable concentration with increasing dose; at 2.5 mg/kg, it was 2.7-6.9 h. Measurement of platelet aggregation showed no effect at 0.0125 mg/kg, and a full and reversible inhibition at doses of 0.125-2.5 mg/kg. The average bleeding time was dose-dependently prolonged, but was always below 9 min. The PK/PD profile showed that at plasma concentrations above 20 ng/ml, EV-077 platelet aggregation was completely inhibited (>90 %). All tested doses were well tolerated. CONCLUSIONS: Orally administered EV-077 was well tolerated, readily absorbed, reached Cmax within 1 h, with a linear PK based on Cmax and AUC. The inhibition of platelet aggregation was complete and reversible at doses of 0.125 mg/kg and higher, and average bleeding time was below 9 min.

Environment-assisted precision measurement.

We describe a method to enhance the sensitivity of precision measurements that takes advantage of the environment of a quantum sensor to amplify the response of the sensor to weak external perturbations. An individual qubit is used to sense the dynamics of surrounding ancillary qubits, which are in turn affected by the external field to be measured. The resulting sensitivity enhancement is determined by the number of ancillas that are coupled strongly to the sensor qubit; it does not depend on the exact values of the coupling strengths and is resilient to many forms of decoherence. The method achieves nearly Heisenberg-limited precision measurement, using a novel class of entangled states. We discuss specific applications to improve clock sensitivity using trapped ions and magnetic sensing based on electronic spins in diamond.

Dissipative preparation of entanglement in optical cavities.

We propose a novel scheme for the preparation of a maximally entangled state of two atoms in an optical cavity. Starting from an arbitrary initial state, a singlet state is prepared as the unique fixed point of a dissipative quantum dynamical process. In our scheme, cavity decay is no longer undesirable, but plays an integral part in the dynamics. As a result, we get a qualitative improvement in the scaling of the fidelity with the cavity parameters. Our analysis indicates that dissipative state preparation is more than just a new conceptual approach, but can allow for significant improvement as compared to preparation protocols based on coherent unitary dynamics.

Laser cooling and optical detection of excitations in a LC electrical circuit.

We explore a method for laser cooling and optical detection of excitations in a room temperature LC electrical circuit. Our approach uses a nanomechanical oscillator as a transducer between optical and electronic excitations. An experimentally feasible system with the oscillator capacitively coupled to the LC and at the same time interacting with light via an optomechanical force is shown to provide strong electromechanical coupling. Conditions for improved sensitivity and quantum limited readout of electrical signals with such an "optical loud speaker" are outlined.

Quantum entanglement between an optical photon and a solid-state spin qubit.

Quantum entanglement is among the most fascinating aspects of quantum theory. Entangled optical photons are now widely used for fundamental tests of quantum mechanics and applications such as quantum cryptography. Several recent experiments demonstrated entanglement of optical photons with trapped ions, atoms and atomic ensembles, which are then used to connect remote long-term memory nodes in distributed quantum networks. Here we realize quantum entanglement between the polarization of a single optical photon and a solid-state qubit associated with the single electronic spin of a nitrogen vacancy centre in diamond. Our experimental entanglement verification uses the quantum eraser technique, and demonstrates that a high degree of control over interactions between a solid-state qubit and the quantum light field can be achieved. The reported entanglement source can be used in studies of fundamental quantum phenomena and provides a key building block for the solid-state realization of quantum optical networks.

Hybrid long-distance entanglement distribution protocol.

We propose a hybrid (continuous-discrete variable) quantum repeater protocol for long-distance entanglement distribution. Starting from states created by single-photon detection, we show how entangled coherent state superpositions can be generated by means of homodyne detection. We show that near-deterministic entanglement swapping with such states is possible using only linear optics and homodyne detectors, and we evaluate the performance of our protocol combining these elements.