Stabilized entanglement of massive mechanical oscillators.

Quantum entanglement is a phenomenon whereby systems cannot be described independently of each other, even though they may be separated by an arbitrarily large distance 1 . Entanglement has a solid theoretical and experimental foundation and is the key resource behind many emerging quantum technologies, including quantum computation, cryptography and metrology. Entanglement has been demonstrated for microscopic-scale systems, such as those involving photons2-5, ions 6 and electron spins 7 , and more recently in microwave and electromechanical devices8-10. For macroscopic-scale objects8-14, however, it is very vulnerable to environmental disturbances, and the creation and verification of entanglement of the centre-of-mass motion of macroscopic-scale objects remains an outstanding goal. Here we report such an experimental demonstration, with the moving bodies being two massive micromechanical oscillators, each composed of about 10 12 atoms, coupled to a microwave-frequency electromagnetic cavity that is used to create and stabilize the entanglement of their centre-of-mass motion15-17. We infer the existence of entanglement in the steady state by combining measurements of correlated mechanical fluctuations with an analysis of the microwaves emitted from the cavity. Our work qualitatively extends the range of entangled physical systems and has implications for quantum information processing, precision measurements and tests of the limits of quantum mechanics.

Quantum Backaction Evading Measurement of Collective Mechanical Modes.

The standard quantum limit constrains the precision of an oscillator position measurement. It arises from a balance between the imprecision and the quantum backaction of the measurement. However, a measurement of only a single quadrature of the oscillator can evade the backaction and be made with arbitrary precision. Here we demonstrate quantum backaction evading measurements of a collective quadrature of two mechanical oscillators, both coupled to a common microwave cavity. The work allows for quantum state tomography of two mechanical oscillators, and provides a foundation for macroscopic mechanical entanglement and force sensing beyond conventional quantum limits.

Photon-assisted tunnelling with nonclassical light.

Among the most exciting recent advances in the field of superconducting quantum circuits is the ability to coherently couple microwave photons in low-loss cavities to quantum electronic conductors. These hybrid quantum systems hold great promise for quantum information-processing applications; even more strikingly, they enable exploration of new physical regimes. Here we study theoretically the new physics emerging when a quantum electronic conductor is exposed to nonclassical microwaves (for example, squeezed states, Fock states). We study this interplay in the experimentally relevant situation where a superconducting microwave cavity is coupled to a conductor in the tunnelling regime. We find that the conductor acts as a nontrivial probe of the microwave state: the emission and absorption of photons by the conductor is characterized by a nonpositive definite quasi-probability distribution, which is related to the Glauber-Sudarshan P-function of quantum optics. These negative quasi-probabilities have a direct influence on the conductance of the conductor.

Quantum interface between an electrical circuit and a single atom.

We show how to bridge the divide between atomic systems and electronic devices by engineering a coupling between the motion of a single ion and the quantized electric field of a resonant circuit. Our method can be used to couple the internal state of an ion to the quantized circuit with the same speed as the internal-state coupling between two ions. All the well-known quantum information protocols linking ion internal and motional states can be converted to protocols between circuit photons and ion internal states. Our results enable quantum interfaces between solid state qubits, atomic qubits, and light, and lay the groundwork for a direct quantum connection between electrical and atomic metrology standards.

Eosinophil apoptosis and the resolution of airway inflammation in asthma.

Asthma is accompanied by the accumulation of potentially damaging eosinophils within inflamed airways. How eosinophils may be removed from the airways is not clear. The phagocytic removal of eosinophils in vitro requires that they undergo apoptosis, a form of cell death. We postulated that eosinophil apoptosis may occur in vivo, promoting the removal of airway eosinophils and the resolution of inflammation in asthma. We examined eosinophil apoptosis in sputum samples obtained from 11 subjects during an asthma exacerbation and 2 wk after corticosteroid treatment of the exacerbation. Airway function improved following corticosteroid treatment, and eosinophilic inflammation subsided, with significant decreases occurring in the number of airway eosinophils and the percentage of activated eosinophils. The proportion of apoptotic airway eosinophils increased significantly following corticosteroid treatment, and eosinophil products were apparent within macrophages. Our findings indicate that eosinophil apoptosis is clinically relevant in asthma. Apoptosis may represent a mechanism that promotes the resolution of eosinophilic inflammation in asthma.

Interleukin-3 in bronchial biopsies from nonasthmatics and patients with mild and allergen-induced asthma.

Cytokines, such as interleukin-3 (IL-3), have been suggested to play an important role in mediating the increased number of airway eosinophils and metachromatic cells in patients with even mild asthma. We used immunohistochemistry to determine the presence of IL-3 protein in bronchial biopsies from nonasthmatics (n = 10) and subjects with mild (n = 8) and allergen-induced (n = 7) asthma. We also examined whether IL-3 was related to airway eosinophil number and activation, the number of airway metachromatic cells, or airway function. We found that the number and activation of eosinophils and the number of metachromatic cells were increased in the airways of asthmatics, compared with nonasthmatics, with further increases evident after allergen challenge. IL-3 protein was localized primarily to the epithelium in nonasthmatic and asthmatic subjects, with no difference apparent between groups or after allergen inhalation challenge. The extent of staining for IL-3 in the tissue was not correlated with eosinophil number or activity, metachromatic cell number, airway responsiveness, or the severity of the late asthmatic response. This study provides the first demonstration of IL-3 protein localization in bronchial tissue from human airways. The results suggest that the increases in eosinophils and metachromatic cells associated with mild and allergen-induced asthma occur independent of IL-3.

Role of airway eosinophils in the development of allergen-induced airway hyperresponsiveness in dogs.

The role of the eosinophil in the development of allergen-induced airway hyperresponsiveness is uncertain. We examined whether the development of airway hyperresponsiveness in 17 dogs after inhalation of Ascaris suum allergen (10(-6) to 10(-2) weight/volume [w/v]) was associated with increases in the number and level of activation of eosinophils before and after allergen inhalation. Airway responsiveness to inhaled acetylcholine was measured before and 24 h after Ascaris inhalation. Eosinophil number was assessed by bronchoalveolar lavage performed 1 wk before allergen inhalation and 15 min after the 24 h acetylcholine challenge. Dogs that developed Ascaris-induced airway hyperresponsiveness (n = 8) had a significantly greater number of bronchoalveolar lavage eosinophils before allergen inhalation (mean +/- SEM: 4.6 +/- 1.94 x 10(4) cells/ml) than dogs that did not become hyperresponsive (n = 9) (1.2 +/- 0.81 x 10(4) cells/ml) (p = 0.03). Ascaris-induced airway hyperresponsiveness, measured 24 h after allergen inhalation, was not associated with increases in eosinophil number after allergen challenge. These results suggest that the presence of airway eosinophils before allergen inhalation is necessary for the development of allergen-induced airway hyperresponsiveness.

The effects of an inhaled corticosteroid on oxygen radical production by bronchoalveolar cells after allergen or ozone in dogs.

Both ozone and allergen inhalation increase the capacity to produce oxygen radicals by bronchoalveolar lavage cells in dogs. The purpose of these studies was to determine whether inhaled corticosteroids inhibits these increases in oxygen radical production from bronchoalveolar lavage cells. Six random source dogs were studied after dry air or ozone inhalation (3 ppm, 30 min). Seven random source dogs were studied after diluent or allergen inhalation. The dogs inhaled budesonide (2.74 mg/day) or lactose powder, twice daily for 7 days before ozone and allergen. 90 min after ozone or dry air, and 24 h after Ascaris suum or diluent a bronchoalveolar lavage was carried out. Spontaneous luminol-enhanced chemiluminescence was measured from bronchoalveolar lavage cells (4 x 10(6) cells) for 10 min, followed by a measurement of phorbol myristate acetate (PMA 2.4 micromol/l) stimulated chemiluminescence for 10 min. Both ozone and allergen inhalation caused an increase in PMA stimulated chemiluminescence (P<0.05). Budesonide pretreatment inhibited ozone-induced (P<0.008), but not allergen-induced PMA stimulated chemiluminescence (P>0.90). Both ozone and allergen inhalation caused an increase in the bronchoalveolar lavage neutrophils. Budesonide pretreatment significantly inhibited the ozone-induced (P=0.007), but not the ascaris-induced neutrophil influx (P=0.93). These results demonstrate that ozone, but not allergen, stimulated oxygen radical release and neutrophil influx are attenuated by inhaled corticosteroids. This suggests that luminol-enhanced chemiluminescence from bronchoalveolar lavage cells measures oxygen radicals derived from neutrophils, and that ozone-and allergen-induced bronchoalveolar lavage neutrophilia are caused by different mechanisms.

Effects of allergen challenge on eosinophils, eosinophil cationic protein, and granulocyte-macrophage colony-stimulating factor in mild asthma.

Allergen inhalation challenge is associated with increases in eosinophil number and activation, and provides a useful model for investigating airway inflammation in asthma. Limited information, however, is available on the effect of allergen challenge on cytokines regulating eosinophil function. We investigated allergen-induced changes in eosinophil number and activation and in granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine known to regulate eosinophil function in vitro. Seven subjects with mild atopic asthma and late asthmatic responses completed diluent- and allergen-inhalation challenges. Blood, bronchoalveolar lavage fluid (BALF), and biopsy samples were collected 24 h after challenge. Allergen inhalation caused a significant increase in eosinophils in BALF and biopsy samples. Eosinophil activation, as assessed by secretion of eosinophil cationic protein, and GM-CSF levels were significantly increased in BALF and bronchoalveolar lavage (BAL) cells. Allergen inhalation did not cause a significant change in eosinophil activation in biopsy tissue but did result in a significant decrease in GM-CSF in the tissue. Significant correlations were shown between the concentration of GM-CSF in BALF and the percentage of BAL eosinophils (Rs = 0.75, p = 0.05), severity of the late asthmatic response, and number of BAL eosinophils (Rs = 0.82, p = 0.02). A trend was seen between the late response and the concentration of GM-CSF in BALF. These results are consistent with the hypothesis that eosinophils, regulated by GM-CSF, contribute to allergen-induced decreases in airway function.

Allergen-induced changes in bone marrow progenitors and airway responsiveness in dogs.

An increased production of inflammatory cell progenitors (colony-forming cells, CFUs) may contribute to airway inflammation, since CFUs increase after allergen inhalation in asthmatics. We examined the effect of allergen inhalation, with or without budesonide pretreatment, on bone marrow CFU production in dogs with allergen-induced airway hyperresponsiveness. Allergen inhalation increased airway responsiveness (p < 0.001) as well as the number of CFUs induced in vitro by recombinant canine stem cell factor (p < 0.001) and granulocyte-colony-stimulating factor (p = 0.035). Budesonide reduced the allergen-induced increases in airway responsiveness (p = 0.005) and abolished the allergen-induced increases in the numbers of CFUs (p < 0.005). These findings provide the first direct evidence that allergen inhalation increases bone marrow granulocyte progenitor production and suggest that such increases may contribute to the development of airway hyperresponsiveness in asthma. The effectiveness of inhaled corticosteroids in asthma may result, in part, from effect on bone marrow production of inflammatory cells.

Effect of inhaled budesonide on ozone-induced airway hyperresponsiveness and bronchoalveolar lavage cells in dogs.

Inhaled corticosteroids are known to reduce components of the airway inflammation characteristic of asthma and improve airway hyperresponsiveness. However, the effect of inhaled corticosteroids on ozone-induced airway responses is unknown. Eight dogs inhaled budesonide [2.74 +/- 0.25 (SE) mg/day] or lactose powder twice daily for 7 days before inhaling ozone (3 ppm for 30 min) or dry air. Acetylcholine airway responsiveness was measured before and 1 h after ozone, followed by a bronchoalveolar lavage (BAL). The response to acetylcholine was expressed as the concentration causing an increase in lung resistance of 5 cmH2O.l-1.s above baseline (acetylcholine provocation concentration). Budesonide pretreatment significantly attenuated the ozone-induced increase in pulmonary resistance (P = 0.003) and neutrophil influx into BAL (P = 0.001) and significantly reduced BAL eosinophils (P = 0.026). However, budesonide pretreatment had no significant effect on ozone-induced airway hyperresponsiveness. After budesonide, the acetylcholine provocative concentration fell from 5.96 mg/ml (%SE 1.46) before to 1.11 mg/ml (%SE 1.63) after ozone (P = 0.006). After lactose, the acetylcholine provocative concentration fell from 5.34 mg/ml (%SE 1.40) before to 0.50 mg/ml (%SE 1.85) after ozone (P = 0.001). Dry air inhalation did not cause airway hyperresponsiveness (P = 0.68). These results suggest that ozone-induced airway hyperresponsiveness is steroid resistant and that airway neutrophils or eosinophils are not important in its pathogenesis.

Allergen-induced changes in bone marrow progenitors and airway responsiveness in dogs and the effect of inhaled budesonide on these parameters.

Airway inflammation is implicated in the pathogenesis of the airway hyperresponsiveness in asthma. An increased production of inflammatory cell progenitors may contribute to asthmatic airway inflammation. Although the number of circulating inflammatory cell progenitors in asthmatic subjects increases after allergen inhalation, no direct evidence exists for increased bone marrow progenitor production. We examined the effect of allergen inhalation on bone marrow progenitor production in seven dogs that develop allergen-induced airway hyperresponsiveness. The effect of inhaled budesonide, a corticosteroid known to be effective in the treatment of asthma, on allergen-induced bone marrow progenitor production and airway hyperresponsiveness was also examined. Allergen inhalation increased airway responsiveness (P < 0.001) and the number of granulocyte-macrophage colony-forming units (CFU) when cultured with dog serum and either recombinant canine stem cell factor (rcSCF) (P < 0.001) or granulocyte colony-stimulating factor (rcG-CSF) (P = 0.035). Budesonide treatment reduced the allergen-induced increases in airway responsiveness (P = 0.005) and abolished the allergen-induced increases in the numbers of CFU cultured with dog serum and either rcSCF (P < 0.001) or rcG-CSF (P = 0.009). These findings provide the first direct evidence that allergen inhalation increases bone marrow progenitor production and suggest that such increases may contribute to the development of airway hyperresponsiveness in asthma. In addition, the effectiveness of inhaled corticosteroids in asthma may result, in part, from their ability to suppress bone marrow production of inflammatory cells.

Effect of an inhaled corticosteroid on airway eosinophils and allergen-induced airway hyperresponsiveness in dogs.

The presence of airway eosinophils before allergen inhalation may contribute to the development of allergen-induced airway responses. We examined whether a reduction in airway eosinophil numbers before allergen inhalation as a result of inhalation of the corticosteroid budesonide would prevent allergen-induced airway hyperresponsiveness in seven dogs. Acetylcholine airway responsiveness was measured before and 24 h after inhalation of Ascaris suum allergen (10(-6)-10(-2) wt/vol) or its diluent on 4 test days separated by > or = 4 wk. Dogs were pretreated for 7 days before and on the morning of each test day with inhaled budesonide (2.69 mg/day) or a placebo (lactose). Airway eosinophil numbers were assessed by bronchoalveolar lavage. Inhaled budesonide significantly reduced the number of airway eosinophils before allergen inhalation from 3.6 +/- 2.38 x 10(4) (SE) cells/ml after inhaled lactose to 0.3 +/- 0.21 x 10(4) cells/ml after inhaled budesonide (P = 0.028). The decrease in eosinophil number was associated with a significant reduction in allergen-induced airway hyperresponsiveness (P = 0.005). These results support the hypothesis that the number of eosinophils in the airways before allergen inhalation is an important determinant in the development of allergen-induced airway hyperresponsiveness in dogs.

Granulocyte-macrophage colony-stimulating factor, eosinophils and eosinophil cationic protein in subjects with and without mild, stable, atopic asthma.

Increasing evidence implicates the eosinophil as an important effector cell in asthma, but little is known regarding its regulation in vivo. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to regulate eosinophil function in vitro. We investigated the in vivo role of eosinophils and GM-CSF in mild asthma. We compared the number and function of eosinophils and the presence of GM-CSF in blood, bronchoalveolar lavage (BAL) and biopsy tissue obtained from eight mild, stable, atopic asthmatics and 10 nonasthmatics, five of whom were atopic and five nonatopic. Eosinophils were significantly increased in the blood, BAL and biopsy tissue from asthmatics. Activated eosinophils, assessed by immunostaining for the secreted form of eosinophil cationic protein (EG2), were also increased in asthmatic BAL cells and biopsy tissue. Significant increases in GM-CSF in BAL cells and biopsy tissue from asthmatics were also evident. Significant positive correlations existed between GM-CSF in BAL and EG2, and GM-CSF in biopsy tissue and BAL and biopsy eosinophils. Airway responsiveness was also significantly positively correlated with eosinophil number and activation, and with GM-CSF. These results demonstrate that there are increased numbers of activated eosinophils and GM-CSF is increased in patients with mild asthma. Furthermore, GM-CSF is correlated with eosinophil number and function in vivo and these indices are significantly correlated with airway function. These findings emphasize the importance of eosinophils, potentially regulated in vivo by GM-CSF, in contributing to the disordered airway function evident even in mild asthma.

Effect of FLAP antagonist MK-0591 on leukotriene production and ozone-induced airway responses in dogs.

We used the 5-lipoxygenase-activating protein (FLAP) antagonist MK-0591 to investigate the importance of leukotrienes (LT) in causing ozone-induced bronchoconstriction, airway inflammation, and airway hyperresponsiveness in dogs. Six random source dogs were studied. On one day, dogs were treated with MK-0591 (2 mg/kg iv) followed by a continuous intravenous infusion of 8 micrograms.kg-1.min-1. On the other day, the diluent was infused. Acetylcholine airway responsiveness was measured before and 1 h after ozone inhalation (3 ppm for 30 min). On each day, whole blood and bronchoalveolar lavage (BAL) cells were challenged with calcium ionophore to stimulate LTB4 production. Urinary LTE4 levels were measured before and after ozone. MK-0591 inhibited LTB4 production in whole blood by 96% (P = 0.001) and that from BAL cells by 91% (P = 0.001). By contrast, MK-0591 had no effect on ozone-induced bronchoconstriction, airway hyperresponsiveness, or influx of neutrophils into BAL. The mean log difference of the pre- to post-acetylcholine provocative concentration was 0.64 +/- 0.40 during MK-0591 treatment and 0.68 +/- 0.40 during diluent treatment (P = 0.71). These results indicate that peptidoleukotrienes are produced during ozone inhalation and that MK-0591 inhibits LT production in dogs. However, LTs do not play a role in ozone-induced bronchoconstriction, airway inflammation, or airway hyperresponsiveness in dogs.

The effect of antioxidants on ozone-induced airway hyperresponsiveness in dogs.

The role of oxygen radicals in causing ozone-induced airway hyperresponsiveness in dogs was examined by pretreating dogs with allopurinol and/or deferoxamine mesylate (desferal), which are inhibitors of oxygen radical generation, before ozone inhalation. Acetylcholine airway responsiveness was measured before and after either air or ozone inhalation (3 ppm for 20 min) on 5 experimental days separated by at least 2 wk. On each day, the dogs were pretreated intravenously with allopurinol (50 mg/kg) followed by inhaled desferal (1,000 mg inhalation) or with allopurinol followed by the diluent for desferal or with the diluent for allopurinol and desferal or with both diluents. The effect of ozone on acetylcholine airway responsiveness was expressed as the differences in the log-transformed preozone-postozone acetylcholine provocative concentrations. When dogs received both diluents or either treatment alone, ozone inhalation caused airway hyperresponsiveness. The mean log differences for the preozone-postozone acetylcholine provocative concentration were 0.804 (SEM, 0.17) for both diluents, 0.524 (SEM, 0.16) for allopurinol alone, and 0.407 (SEM, 0.22) for desferal alone. However, the combination of allopurinol and desferal significantly inhibited the development of ozone-induced airway hyperresponsiveness, the log difference being 0.195 (SEM, 0.11) (p less than 0.05), without inhibiting ozone-induced neutrophil influx into the airways. The results suggest that the production of oxygen radicals is important in the pathogenesis of ozone-induced airway hyperresponsiveness.