Absolute frequency measurement of the 40Ca+ 4s(2)S_(1/2)-3d(2)D_(5/2) clock transition.

We report on the first absolute transition frequency measurement at the 10;{-15} level with a single, laser-cooled 40Ca+ ion in a linear Paul trap. For this measurement, a frequency comb is referenced to the transportable Cs atomic fountain clock of LNE-SYRTE and is used to measure the 40Ca+ 4s ;{2}S_{1/2}-3d ;{2}D_{5/2} electric-quadrupole transition frequency. After the correction of systematic shifts, the clock transition frequency nu_{Ca;{+}}=411 042 129 776 393.2(1.0) Hz is obtained, which corresponds to a fractional uncertainty within a factor of 3 of the Cs standard. In addition, we determine the Landé g factor of the 3d;{2}D_{5/2} level to be g_{5/2}=1.200 334 0(3).

Realization of the quantum Toffoli gate with trapped ions.

Gates acting on more than two qubits are appealing as they can substitute complex sequences of two-qubit gates, thus promising faster execution and higher fidelity. One important multiqubit operation is the quantum Toffoli gate that performs a controlled NOT operation on a target qubit depending on the state of two control qubits. Here we present the first experimental realization of the quantum Toffoli gate in an ion trap quantum computer, achieving a mean gate fidelity of 71(3)%. Our implementation is particularly efficient as the relevant logic information is directly encoded in the motion of the ion string.

Realization of universal ion-trap quantum computation with decoherence-free qubits.

Any residual coupling of a quantum computer to the environment results in computational errors. Encoding quantum information in a so-called decoherence-free subspace provides means to avoid these errors. Despite tremendous progress in employing this technique to extend memory storage times by orders of magnitude, computation within such subspaces has been scarce. Here, we demonstrate the realization of a universal set of quantum gates acting on decoherence-free ion qubits. We combine these gates to realize the first controlled-NOT gate towards a decoherence-free, scalable quantum computer.

Process tomography of ion trap quantum gates.

A crucial building block for quantum information processing with trapped ions is a controlled-NOT quantum gate. In this Letter, two different sequences of laser pulses implementing such a gate operation are analyzed using quantum process tomography. Fidelities of up to 92.6(6)% are achieved for single-gate operations and up to 83.4(8)% for two concatenated gate operations. By process tomography we assess the performance of the gates for different experimental realizations and demonstrate the advantage of amplitude-shaped laser pulses over simple square pulses. We also investigate whether the performance of concatenated gates can be inferred from the analysis of the single gates.

'Designer atoms' for quantum metrology.

Entanglement is recognized as a key resource for quantum computation and quantum cryptography. For quantum metrology, the use of entangled states has been discussed and demonstrated as a means of improving the signal-to-noise ratio. In addition, entangled states have been used in experiments for efficient quantum state detection and for the measurement of scattering lengths. In quantum information processing, manipulation of individual quantum bits allows for the tailored design of specific states that are insensitive to the detrimental influences of an environment. Such 'decoherence-free subspaces' (ref. 10) protect quantum information and yield significantly enhanced coherence times. Here we use a decoherence-free subspace with specifically designed entangled states to demonstrate precision spectroscopy of a pair of trapped Ca+ ions; we obtain the electric quadrupole moment, which is of use for frequency standard applications. We find that entangled states are not only useful for enhancing the signal-to-noise ratio in frequency measurements--a suitably designed pair of atoms also allows clock measurements in the presence of strong technical noise. Our technique makes explicit use of non-locality as an entanglement property and provides an approach for 'designed' quantum metrology.

Scalable multiparticle entanglement of trapped ions.

The generation, manipulation and fundamental understanding of entanglement lies at the very heart of quantum mechanics. Entangled particles are non-interacting but are described by a common wavefunction; consequently, individual particles are not independent of each other and their quantum properties are inextricably interwoven. The intriguing features of entanglement become particularly evident if the particles can be individually controlled and physically separated. However, both the experimental realization and characterization of entanglement become exceedingly difficult for systems with many particles. The main difficulty is to manipulate and detect the quantum state of individual particles as well as to control the interaction between them. So far, entanglement of four ions or five photons has been demonstrated experimentally. The creation of scalable multiparticle entanglement demands a non-exponential scaling of resources with particle number. Among the various kinds of entangled states, the 'W state' plays an important role as its entanglement is maximally persistent and robust even under particle loss. Such states are central as a resource in quantum information processing and multiparty quantum communication. Here we report the scalable and deterministic generation of four-, five-, six-, seven- and eight-particle entangled states of the W type with trapped ions. We obtain the maximum possible information on these states by performing full characterization via state tomography, using individual control and detection of the ions. A detailed analysis proves that the entanglement is genuine. The availability of such multiparticle entangled states, together with full information in the form of their density matrices, creates a test-bed for theoretical studies of multiparticle entanglement. Independently, 'Greenberger-Horne-Zeilinger' entangled states with up to six ions have been created and analysed in Boulder.

Bell states of atoms with ultralong lifetimes and their tomographic state analysis.

Arbitrary atomic Bell states with two trapped ions are generated in a deterministic and preprogrammed way. The resulting entanglement is quantitatively analyzed using various measures of entanglement. For this, we reconstruct the density matrix using single qubit rotations and subsequent measurements with near-unity detection efficiency. This procedure represents the basic building block for future process tomography of quantum computations. As a first application, the temporal decay of entanglement is investigated in detail. We observe ultralong lifetimes for the Bell states Psi(+/-), close to the fundamental limit set by the spontaneous emission from the metastable upper qubit level and longer than all reported values by 3 orders of magnitude.

Deterministic quantum teleportation with atoms.

Teleportation of a quantum state encompasses the complete transfer of information from one particle to another. The complete specification of the quantum state of a system generally requires an infinite amount of information, even for simple two-level systems (qubits). Moreover, the principles of quantum mechanics dictate that any measurement on a system immediately alters its state, while yielding at most one bit of information. The transfer of a state from one system to another (by performing measurements on the first and operations on the second) might therefore appear impossible. However, it has been shown that the entangling properties of quantum mechanics, in combination with classical communication, allow quantum-state teleportation to be performed. Teleportation using pairs of entangled photons has been demonstrated, but such techniques are probabilistic, requiring post-selection of measured photons. Here, we report deterministic quantum-state teleportation between a pair of trapped calcium ions. Following closely the original proposal, we create a highly entangled pair of ions and perform a complete Bell-state measurement involving one ion from this pair and a third source ion. State reconstruction conditioned on this measurement is then performed on the other half of the entangled pair. The measured fidelity is 75%, demonstrating unequivocally the quantum nature of the process.

Quantum information processing with trapped Ca(+) ions.

Quantum information processing is performed with single trapped Ca(+) ions, stored in a linear Paul trap and laser-cooled to the ground state of their harmonic quantum motion. Composite laser-pulse sequences were used to implement SWAP gate, phase gate and controlled-NOT gate operations. Stark shifts on the quantum-bit transitions were precisely measured and compensated. For a demonstration of quantum information processing, a Deutsch-Jozsa algorithm has been implemented using two quantum bits encoded on a single ion.

Precision measurement and compensation of optical stark shifts for an ion-trap quantum processor.

Using optical Ramsey interferometry, we precisely measure the laser-induced ac-Stark shift on the S(1/2)-D(5/2) "quantum bit" transition near 729 nm in a single trapped 40Ca+ ion. We cancel this shift using an additional laser field. This technique is of particular importance for the implementation of quantum information processing with cold trapped ions. As a simple application we measure the atomic phase evolution during a n x 2 pi rotation of the quantum bit.

Pharmaceutical transition to non-CFC pressurized metered dose inhalers.

The production of ozone-depleting chlorofluorocarbons (CFCs) was discontinued on 1 January 1996 for all uses deemed non-essential under the Montreal Protocol. However, the use of CFCs as propellants in pressurized metered dose inhalers (pMDIs) was classed as essential, providing an exemption from the agreement. Following extensive research, the hydrofluoroalkanes (HFA) 134a and 227 were identified as the only suitable replacements for CFC propellants in pMDIs. The drug delivery of pMDIs formulated with HFA 134a as a propellant and containing either salbutamol (100 microg per actuation) or fluticasone propionate (125 and 250 microg per actuation) have been assessed for dose uniformity and particle size distribution. All of the HFA 134a pMDIs delivered doses throughout the life of the canisters that were reproducible and within specified regulatory requirements. Each of the products provided an emitted dose which was within +/- 25% of the mean value indicating accurate and consistent dosing (93, 112 and 221 microg per metered dose for the salbutamol 100 microg and fluticasone propionate 125 and 250 microg HFA 134a pMDIs, respectively). These findings were unaffected by changing the storage orientation of the pMDI or by using the device in a manner designed to simulate typical patient use. The particle size distributions of HFA 134a pMDI doses did not differ significantly from those of the corresponding CFC pMDIs. As a result of the similar pharmaceutical performance, it is unnecessary to change the label claim dose of active drug when making the transition from a CFC to an HFA 134a pMDI for salbutamol (Ventolin) and fluticasone propionate (Flixotide). A seamless transition to non-CFC pMDIs will help to maintain the confidence of patients and healthcare professionals in asthma therapy.

A matrixed approach to long-term stability testing of pharmaceutical products.

A matrixed approach to long-term stability testing of pharmaceutical products is presented. The basic matrix design, suitable for testing three lots at one storage condition, may be extended to multiple product presentations or storage conditions. The design has full testing at the endpoints (0 and 36 months) and partial testing at the interim time points (3, 6, 9, 12, 18, and 24 months). The test points were selected with the assistance of a statistical search algorithm. The proposed matrix design provides a 37.5% reduction in analytical testing, while still permitting a reliable interim expiry estimate based on 12-month stability data. The expiration dating periods estimated using the matrixed approach are typically more conservative than estimates derived from a full-testing approach. A comparison of expiration dating period estimates for a metered-dose inhaler and capsule drug product using the matrixed and full-testing approaches is presented.

Unscheduled DNA synthesis and HPRT mutation in fetal Syrian hamster and human respiratory epithelial cells exposed to ethylnitrosourea.

We previously reported that the chromosomes of fetal Syrian hamster respiratory epithelial cells were less stable toward ethylnitrosourea (ENU) than those of comparable human cells. Following this, we compared the sensitivity of genetic materials of the same cell systems to the same mutagen in terms of unscheduled DNA synthesis (UDS) and mutation at HPRT locus (HPRT-). UDS occurred 5 (with 0.1 mg ENU/ml) to 7 (with 0.4 mg ENU/ml) times more frequently in the hamster cells than in the human cells. This much lower UDS frequency in human cells cannot be solely explained by the fact that the human cells possess only a moderately larger (1.6 to 2.9 times) size of intracellular deoxythymidine triphosphate (dTTP) pool than the hamster cells. This finding would thus indicate that the hamster cells actually carry out DNA repair, whether correct or aberrant, more often than the human cells. Moreover, HPRT- was also 5 (at 0.4 mg/ml) to 26 (at 0.8 mg/ml) times more frequent in the hamster cells than in the human cells. Therefore, the current results suggest that the DNA repair mechanisms of the hamster cells are less accurate and more unstable than those of the human cells. Our previous findings with regard to the chromosomal stability give support to this hypothesis.

New functional cell-culture approach to pulmonary carcinogenesis and toxicology.

Modern pulmonary toxicology (including lung carcinogenesis) has, to assist its rapid development, constantly incorporated the knowledge obtained through cell and tissue-culture studies. While this has been carried out in rather a passive manner until quite recently, the currently necessary multi-disciplinary approach increasingly requires more active involvement of cell/tissue-culture techniques in this area. Our understanding in this regard is that one of such requirements is to establish a cell-culture system consisting of a single population of possible target cells for certain classes of hazardous inhalants. In addition, such target cells in culture should be able to function in a manner as closely resembling the situation in vivo as possible. In view of the culture techniques presently available, this requirement is probably too ideal to be met immediately. Nevertheless, efforts have been made in the last decade to achieve functioning cultures of Clara cells, type II pneumocytes or small mucus granule cells (SMGC), using undifferentiated cells obtained from animal and human fetuses. This attempt forms a sharp contrast to the usual approach, in that while the latter tries to keep the functions of adult cells in an already differentiated state, the former aims at inducing functional differentiation in undifferentiated cells by manipulating culture conditions. In carrying out these efforts, we have shown clear evidence that the type II pneumocytes and Clara cells induced in vitro are closely cognate and share a common precursor cell in culture, and that SMGC are at a pre-stage of differentiation to Clara cells. We have also shown an induced capacity for xenobiotic activation and conjugation in SMGC in culture. Our next plan is to prove similar activity (of mixed-function oxidase) in Clara cells and type II pneumocytes induced to differentiate in culture.

Secretory differentiation of human fetal bronchial epithelial cells in culture. A study by histochemistry and electron microscopy.

Human fetal bronchial epithelial (HFBE) cells at 6-8 passages were cultivated on a collagen gel for 10 days. A basal differentiative medium (BDM), consisting of RPMI 1640 supplemented with hormones and growth factors, was employed. Histochemistry, scanning electron microscopy and transmission electron microscopy revealed that HFBE cells developed secretory granules when cultivated on collagen gel in BDM. They were electron-dense and stained positive for PAS but negative for alcian blue. On additional treatment with 8 micrograms/ml vitamin A (VA), the number of secretory granules was increased. Moreover, the HFBE cells lost their surface microvilli, and dilation of rough endoplasmic reticulum was more marked than in culture without VA.

Possible role of genetic predisposition in multigeneration carcinogenesis.

A peculiar phenomenon in experimental transplacental carcinogenesis is that in certain animal species or strains, and with certain types of carcinogens, a tumorigenic risk is observed not only in the F1 generation but also in subsequent F2 and even F3 generations when only the P generation has been exposed to a carcinogen. Additionally, in many cases, specific types of organs tend to be involved. For example, lung tumours are most common in P, F1 and F2 generations of Swiss, ICR, MA and CD-1 mice after exposure of the pregnant P generation to 7,12-dimethylbenz[a]anthracene (DMBA), urethane, DMBA and diethylstilboestrol, respectively. In such mice, the mammary glands, lymphatic tissues and ovaries are also frequently involved. Recently, two-stage tumorigenesis in skin with a phorbol acetate as promoter was transmitted to F2 descendants born of F1 SHR mice exposed transplacentally to DMBA. In WKA, BD IV and BD VI rats, nervous tissues seem to be prone to tumour development in F2 and/or F3 descendants born of F1 exposed transplacentally to N-methyl-N-nitrosourethane, N-methyl-N-nitrosourea, N-ethyl-N-nitrosourea (ENU), respectively. In F344 strain rats, however, two-stage genesis of preneoplastic foci in the liver with 2-acetylaminofluorene (2-AAF) as the promoter failed to be transmitted to F2 and F3 generations from the F1 generation, which developed the preneoplastic hepatocellular foci after prenatal exposure to ENU followed by postnatal promotion by 2-AAF. Our own recent experiments with Syrian hamsters, in which multigeneration transmission of organ-specific (tracheal epithelium) tumorigenicity of N-nitrosodiethylamine was investigated, have also failed to show this phenomenon in F2 and F3 descendants. However, various field studies on pedigrees with frequently affected siblings indicate the existence of a heritable predisposition to tumour development over more than two generations. The organs involved include ovaries, mammary glands, stomach, lympho- and myelogenic systems, skin and nervous system. Interestingly, little or no such evidence has been found in the liver, respiratory tract (except for the nasopharyngeal region) or urinary tract. In the light of these experimental and human observations, the authors are currently inclined to hypothesize a heritable predisposition to tumour development in organs specific to animal species and strains, or certain families in human cases, for explaining the mechanisms underlying multigeneration transmission of chemical carcinogenicity.

Quantification of proliferative lesions in hamster lungs after chronic exposure to cadmium aerosols.

The development of proliferative areas in the lungs of Syrian golden hamsters was studied after chronic inhalation of cadmium oxide, cadmium sulfide, cadmium chloride or cadmium sulfate. Lung tissue from randomly selected animals in each group was evaluated by morphometric histopathologic techniques. Estimation of the volumetric ratio of proliferative areas within the lungs of exposed animals showed significantly different extents of these lesions in dependence on the respective cadmium compound administered. The most severe changes were observed after inhalation of cadmium oxide and cadmium sulfide. Lesions were mainly found in the peribronchial region of the lung. Electron microscopic analysis of these proliferative areas revealed that they were composed of ciliated and Clara cells. From its histophatologic appearance this of lesion was qualitatively comparable in all hamsters which had been treated with the different cadmium compounds.

Toxicity and chromosomal damage in fetal Syrian hamster and human pulmonary epithelial cells.

In order to test the hypothesis that human chromosomes are more stable than those of rodents, we compared the fetal human and Syrian hamster pulmonary epithelial cell lines for their sensitivity to the induction of cytotoxicity (CT), chromosomal aberrations (CAs) and sister-chromatid exchanges (SCEs). One day after plating, the cells were exposed for 2 h to various doses of ENU dissolved in an exposure medium consisting of McIlvaine buffer, RPMI 1640, and bovine serum albumin. CAs and SCEs were examined in 24-64 post-exposure hours by the standard methods, while CT was determined by cell counts. The frequency of CAs (particularly chromatid exchanges) and that of SCEs showed clear dose dependency and was remarkably higher in the hamster than in the human cells. CT determined in 1 week of post-exposure incubation showed a similar dose response for both cell lines with sharply declining regressions. These results suggest that human chromosomes are indeed more resistant to ENU-inducible aberrations than hamster chromosomes and that CT may not always be directly associated with chromosomal damage.

Regulation of growth and differentiation by vitamin A in a cloned fetal lung epithelial cell line cultured on collagen gel in hormone-supplemented medium.

Proliferative and differentiative responses to various doses of vitamin A (VA) were studied in the predifferentiated cells of a fetal Syrian hamster pulmonary epithelial line (M3E3/C3), which were cultured on a collagen gel in a hormone-supplemented medium. These predifferentiated cells possessed well-developed endoplasmic reticulum (ER) and Golgi apparatus. At VA doses higher than 8 micrograms/ml, periodic acid Schiff and slightly alcian blue positive mucuslike granules were produced, which were also detectable electron microscopically. These mucuslike products were rich in sialic acid and resembled quite well those from primary cultures of tracheal epithelial cells of Syrian hamster sucklings when analyzed by column chromatography on various types of gel. At all VA doses studied (2.4, 8, 24 micrograms/ml), cells grew exponentially with an average population doubling time of around 74 h, whereas in the absence of VA they had a linear growth rate and a population doubling time of 158 h between Days 4 and 11. The uptake of [3H]glucosamine into the whole cell homogenates showed a peak at Day 8, irrespective of VA doses (0 to 24 micrograms/ml), and at the highest VA dose (24 micrograms/ml) it exceeded by twofold the control (0 microgram/ml) level. At the same time, [14C]thymidine demonstrated a high peak of uptake on Day 8 at 8 and 24 micrograms/ml VA. There was virtually no difference between 0 and 2.4 micrograms/ml VA, with both doses yielding much lower peaks. Based on the results currently presented and previously reported, three successive stages were hypothesized for the mucous differentiation processes in M3E3/C3. The process from the first undifferentiated stage to the second predifferentiated stage with well-developed ER and Golgi apparatus requires both collagen gels and hormones. Differentiation from the second stage to the third secretory stage with mucous granules is stimulated by VA. These observations indicate that the cell line M3E3/C3 could provide a new system for investigating the mechanisms of mucus differentiation by VA.