Continuous Variable Entanglement in an Optical Parametric Oscillator Based on a Nondegenerate Four Wave Mixing Process in Hot Alkali Atoms.

We present the measurement of entanglement between twin beams generated with a doubly resonant optical parameter oscillator (OPO) based on four-wave mixing in hot ^{85}Rb vapor above threshold. This is the first measurement of entanglement in an OPO with a χ^{(3)} media above threshold. We reconstruct the covariance matrix for several configurations and based on a full picture of the four side band mode state, we study entanglement between all possible bipartitions. We show a robust generation of entanglement with stronger generation for a specific pair of modes. For this system, we show that atomic density is a determinant factor for the generation and loss of quantum correlations. The generation of entangled fields with an atomic OPO operating close to atomic resonance of alkali atoms enables a natural integration into quantum networks.

Quantum Noise Correlations of an Optical Parametric Oscillator Based on a Nondegenerate Four Wave Mixing Process in Hot Alkali Atoms.

We present the first measurement of two-mode squeezing between the twin beams produced by a doubly resonant optical parameter oscillator (OPO) in an above threshold operation based on parametric amplification by nondegenerate four wave mixing with rubidium (^{85}Rb). We demonstrate a maximum intensity difference squeezing of -2.7 dB (-3.5 dB corrected for losses) with a pump power of 285 mW and an output power of 12 mW for each beam, operating close to the D1 line of Rb atoms. The use of open cavities combined with the high gain media can provide a strong level of noise compression and the access to new operation regimes that could not be explored by crystal based OPOs. The spectral bandwidth of the squeezed light is broadened by the cavity dynamics, and the squeezing level is robust for strong pump powers. Stable operation was obtained up to 4 times above the threshold. Moreover, operation of the OPO close to the atomic resonances of alkali atoms allows a natural integration into quantum networks, including structures such as quantum memories.

Experimental generation of multiple quantum correlated beams from hot rubidium vapor.

Quantum correlations and entanglement shared among multiple quantum modes are important for both fundamental science and the future development of quantum technologies. This development will also require an efficient quantum interface between multimode quantum light sources and atomic ensembles, which makes it necessary to implement multimode quantum light sources that match the atomic transitions. Here, we report on such a source that provides a method for generating quantum correlated beams that can be extended to a large number of modes by using multiple four-wave mixing (FWM) processes in hot rubidium vapor. Experimentally, we show that two cascaded FWM processes produce strong quantum correlations between three bright beams but not between any two of them. In addition, the intensity-difference squeezing is enhanced with the cascaded system to -7.0±0.1 dB from the -5.5±0.1/-4.5±0.1 dB squeezing obtained with only one FWM process. One of the main advantages of our system is that as the number of quantum modes increases, so does the total degree of quantum correlations. The proposed method is also immune to phase instabilities due to its phase insensitive nature, can easily be extended to multiple modes, and has potential applications in the production of multiple quantum correlated images.

Noiseless optical amplifier operating on hundreds of spatial modes.

We implement a noiseless optical amplifier using a phase-sensitive four-wave mixing process in rubidium vapor. We observe performance near the quantum limit for this type of amplifier over a range of experimental parameters and show that the noise figure is always better than would be obtained with a phase-insensitive amplifier with the same gain. Additionally, we observe that the amplifier supports hundreds of spatial modes, making it possible to amplify complex two-dimensional spatial patterns with less than a 10% degradation of the input signal-to-noise ratio for gains up to 4.6. To confirm the multimode character of the amplifier, we study the noise figure as a function of spatially-varying losses. Additionally, we investigate the spatial resolution of the amplifier and show that it supports a range of spatial frequencies from 1.3 to more than 35 line pairs per millimeter.

Quantum correlated light beams from non-degenerate four-wave mixing in an atomic vapor: the D1 and D2 lines of 85Rb and 87Rb.

We present experimental results showing that quantum correlated light can be produced using non-degenerate, off-resonant, four-wave mixing (4WM) on both the D1 (795 nm) and D2 (780 nm) lines of (85)Rb and (87)Rb, extending earlier work on the D1 line of (85)Rb. Using this 4WM process in a hot vapor cell to produce bright twin beams, we characterize the degree of intensity-difference noise reduction below the standard quantum limit for each of the four systems. Although each system approximates a double-lambda configuration, differences in details of the actual level structure lead to varying degrees of noise reduction. The observation of quantum correlations on light produced using all four of these systems, regardless of their substructure, suggests that it should be possible to use other systems with similar level structures in order to produce narrow frequency, non-classical beams at a particular wavelength.

Low-noise amplification of a continuous-variable quantum state.

We present an experimental realization of a low-noise, phase-insensitive optical amplifier using a four-wave mixing interaction in hot Rb vapor. Performance near the quantum limit for a range of amplifier gains, including near unity, can be achieved. Such low-noise amplifiers are essential for so-called quantum cloning machines and are useful in quantum information protocols. We demonstrate that amplification and "cloning" of one half of a two-mode squeezed state is possible while preserving entanglement.

Tunable delay of Einstein-Podolsky-Rosen entanglement.

Entangled systems display correlations that are stronger than can be obtained classically. This makes entanglement an essential resource for a number of applications, such as quantum information processing, quantum computing and quantum communications. The ability to control the transfer of entanglement between different locations will play a key role in these quantum protocols and enable quantum networks. Such a transfer requires a system that can delay quantum correlations without significant degradation, effectively acting as a short-term quantum memory. An important benchmark for such systems is the ability to delay Einstein-Podolsky-Rosen (EPR) levels of entanglement and to be able to tune the delay. EPR entanglement is the basis for a number of quantum protocols, allowing the remote inference of the properties of one system (to better than its standard quantum limit) through measurements on the other correlated system. Here we show that a four-wave mixing process based on a double-lambda scheme in hot (85)Rb vapour allows us to obtain an optically tunable delay for EPR entangled beams of light. A significant maximum delay, of the order of the width of the cross-correlation function, is achieved. The four-wave mixing also preserves the quantum spatial correlations of the entangled beams. We take advantage of this property to delay entangled images, making this the first step towards a quantum memory for images.

Delocalized correlations in twin light beams with orbital angular momentum.

We generate intensity-difference-squeezed Laguerre-Gauss twin beams of light carrying orbital angular momentum by using four-wave mixing in a hot atomic vapor. The conservation of orbital angular momentum in the four-wave mixing process is studied as well as the spatial distribution of the quantum correlations obtained with different configurations of orbital angular momentum. Intensity-difference squeezing of up to -6.7 dB is demonstrated with beams carrying orbital angular momentum. Delocalized spatial correlations between the twin beams are observed.

Violation of the Cauchy-Schwarz inequality in the macroscopic regime.

We have observed a violation of the Cauchy-Schwarz inequality in the macroscopic regime by more than 8 standard deviations. The violation has been obtained while filtering out only the low-frequency noise of the quantum-correlated beams that results from the technical noise of the laser used to generate them. We use bright intensity-difference squeezed beams produced by four-wave mixing as the source of the correlated fields. We also demonstrate that squeezing does not necessarily imply a violation of the Cauchy-Schwarz inequality.

Generation of spatially broadband twin beams for quantum imaging.

We generate spatially multimode twin beams using 4-wave mixing in a hot atomic vapor in a phase-insensitive traveling-wave amplifier configuration. The far-field coherence area measured at 3.5 MHz is shown to be much smaller than the angular bandwidth of the process and bright twin images with independently quantum-correlated subareas can be generated with little distortion. The available transverse degrees of freedom form a high-dimensional Hilbert space that we use to produce quantum-correlated twin beams with finite orbital angular momentum.

Study of gastrointestinal nematodes in Sicilian sheep and goats.

Parasitic gastroenteritis is one of the major causes of productivity loss in sheep and goats. This report records two studies of the helminth fauna from post-mortem examination. The first study, performed on the digestive tract of 72 sheep from a central part of Sicily in a high hill village (1,360 meters above sea level), between April 1996 and March 1997, showed an infection rate of 78%. The second study targeted goats from the western part of Sicily and showed an infection rate of 90%. For sheep, a total of 23 species of helminths were identified belonging to the family of Trichostrongyloidea, with the genera Haemonchus, Ostertagia (Teladorsagia), Trichostrongylus, Cooperia, and Nematodirus; Strongilolidea with the genera Oesophagostomum and Chabertia: Ancylostomidea with Bunostomum; and Tricuridea with Tricuris. Teladorsagia circumcincta was the most common in the sheep abomasum, Bunostomum trigonocephalum and Trichostrongylus spp. in the small intestine, and Chabertia ovina and Trichuris ovis in the large intestine. For goats, a total of 12 species were isolated in the abomasum with Teladorsagia circumcincta and Trichostrongylus axei the most common species. In the small intestine, five species were isolated and Trichostrongylus capricola was the dominant species. T. ovis and O. venulosum were dominant in large intestine and in the cecum. We also found species belonging to other ruminants such as O. ostertagi (in cattle) and S. kolchida and O. leptospicularis (in wild ruminants).

Benign fibrous histiocytoma of the small intestine in a cow.

A well circumscribed, firm nodule was found protruding from the duodenal wall of an adult cow at routine meat inspection. On the basis of morphological and immunophenotypic features, a diagnosis of benign fibrous histiocytoma (BFH) was established. Malignant fibrous histiocytoma has been reported previously in the cow, albeit rarely, but to the best of our knowledge this is the first recorded case of bovine intestinal BFH.

Modelling the distribution of outbreaks and Culicoides vectors in Sicily: towards predictive risk maps for Italy.

Vector (911 light-trap catches from 269 sites) and serological surveillance data were obtained during recent bluetongue (BT) outbreaks in Sicily. The distributions of Culicoides vectors are compared with that of bluetongue virus (BTV) to determine the relative role of different vectors in BTV transmission in Sicily. The 'best' climatic predictors of distribution for each vector species were selected from 40 remotely-sensed variables and altitude at a 1 km spatial resolution using discriminant analysis. These models were used to predict species presence in unsampled pixels across Italy. Although Culicoides imicola, the main European vector, was found in only 12% of sites, there was close correspondence between its spatial distribution and that of the 2000 and 2001 outbreaks. All three candidate vectors C. pulicaris, C. newsteadi and C. obsoletus group were widespread across 2002 outbreak sites but C. newsteadi was significantly less prevalent in outbreak versus non-outbreak sites in Messina and BTV has been isolated from wild-caught adults of both C. pulicaris and C. obsoletus in Italy. The yearly distribution and intensity of outbreaks is attributable to the distribution and abundance of the vectors operating in each year. Outbreaks were few and coastal in 2000 and 2001 due to the low abundance and prevalence of the vector, C. imicola. They were numerous and widespread in 2002, following hand-over of the virus to more prevalent and abundant novel vector species, C. pulicaris and C. obsoletus. Climatic determinants of distribution were species-specific, with those of C. obsoletus group and C. newsteadi predicted by temperature variables, and those of C. pulicaris and C. imicola determined mainly by normalised difference vegetation index (NDVI), a variable correlated with soil moisture, vegetation biomass and productivity. The predicted continuous presence of C. pulicaris along the Appenine mountains, from north to south Italy, suggests BTV transmission may be possible in a large proportion of this region and that seasonal transhumance between C. imicola-free areas should not generally be considered safe. Future distribution models for C. imicola in Sicily should include non-climatic environmental variables that may influence breeding site suitability such as soil type.

Application of structure-metabolism relationships in the identification of a selective endothelin A antagonist, BMS-193884, with favourable pharmacokinetic properties.

1. Based on binding affinity, 2'-amino-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-methylpropyl)[1,1'-biphenyl]-2-sulfonamide (2) was identified as an initial lead in a programme to identify selective endothelin (ET) receptor antagonists. However, the compound was extensively metabolized in preclinical animal species and human in vitro systems due to oxidative biotransformation. 2. To optimize this structural class, the site of metabolism of 2 was determined. This allowed for focussed structure-activity and structure-metabolism studies aimed at finding more metabolically stable analogues that maintained potency. New analogues were screened for their ET binding characteristics and their stability in rat and human liver microsomes. 3. The use of the microsomal stability screen was tested by the determination of the pharmacokinetic parameters of select analogues. A good correlation was found between reduced rates of rat microsomal metabolism and reduced clearance in the rat. 4. N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (3) was identified as an analogue with improved in vitro properties and further studies revealed that the compound had improved pharmacokinetic properties. 5. N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]acetamide (4) was subsequently identified as a compound with superior in vitro properties compared with compound 3, but when tested in vivo it had a substantially increased rate of clearance. Further studies demonstrated that the clearance of this closely related structural analogue was not dictated by metabolic processes, but was mediated by transport-mediated direct biliary excretion. 6. The utility of screening for in vitro liver microsomal stability as part of the lead optimization process for compounds with metabolic liabilities was shown. It was also shown that relatively small molecular changes can dramatically change the disposition of closely related analogues and care must be used when screening for a single property.

Intestinal absorption of captopril and two thioester analogs in rats and dogs.

The objectives of this study were (i) to determine whether the reduced absorption of captopril from the colon of humans also occurs in rats and (ii), after confirmation of the relevance of a new rat model, to evaluate the intestinal absorption of captopril and several of its analogs. A model was developed and validated in which specific sites within the GI tract of rats were surgically implanted with a cannula such that animals could be dosed while conscious and unrestrained. The absorption of captopril after administration into the lower GI tract of rats was significantly reduced relative to the upper GI tract, which was consistent with results reported previously in humans. In rats, the absorption of the S-benzoyl thioester prodrug of captopril (SQ-25868) from the lower GI tract was substantially greater than that of captopril. However, the absorption of the S-benzoyl thioester prodrug of 4-phenyl thio-captopril (SQ-26991) from the lower GI tract was only marginally better than that of captopril. In additional studies in dogs, a 12h controlled-release formulation of SQ-25868 provided sustained blood levels of captopril while maintaining acceptable bioavailability (> 80%). Two approaches were tried, without success, to stabilize captopril in vivo: (i) complexation with zinc (SQ-26284) and (ii) use of ascorbic-acid-buffered (pH 3.5) vehicle. The zinc complex might have failed because it has very low solubility, whereas the pH-3.5-buffered vehicle was quickly neutralized within the colonic lumen in rats, and did not stabilize captopril against oxidation. Rapid neutralization might explain why the colonic bioavailability of captopril was not substantially increased when this pH-3.5-buffered vehicle was tried in humans.

Prodrugs of BMS-183920: metabolism and permeability considerations.

The oral bioavailability of BMS-183920, a diacidic, potent angiotensin II receptor antagonist, is low in rats (approximately 11%). In vivo studies in bile duct-cannulated rats indicated that BMS-183920 was metabolically stable and that the low bioavailability was due to incomplete intestinal absorption. Five acyl-ester prodrugs were synthesized which were 5-15 times more permeable than BMS-183920 through Caco-2 cells. However, limited studies in rats indicated that the oral bioavailability of BMS-183920 was improved only 2-fold, in the best case. The lack of a substantial increase in bioavailability was apparently due to presystemic prodrug hydrolysis or metabolism via N-glucuronidation. Bioavailability of BMS-183920 after oral dosing of a tetrazole-ester prodrug averaged 37%, the most significant improvement within this prodrug series. Interestingly, in vitro studies indicated that the tetrazole-ester prodrug was a substrate for glucuronosyl transferase; however, its rate of bioactivation (hydrolysis) was sufficiently high to provide a substantial increase in bioavailability of BMS-183920. Therefore, while prodrug modification of BMS-183920 improved Caco-2 cell permeability and oral absorption in vivo, the relative extents of hydrolysis (bioactivation) vs metabolism of the prodrug determined whether a substantial improvement in bioavailability was achieved.

Suitability of enalapril as a probe of the dipeptide transporter system: in vitro and in vivo studies.

PURPOSE: Previous in situ and in vitro studies indicated that the intestinal absorption of enalapril is a saturable carrier-mediated process via the dipeptide transporter system (DTS); however, the oral absorption of enalapril has not been reported to be a saturable process in vivo. Our objectives were to: 1) evaluate the suitability of enalapril as a probe of the DTS, and 2) compare various experimental models as they pertain to studying the DTS. METHODS: The in vitro uptake of enalapril by rat intestinal rings and permeability across Caco-2 cells were studied as a function of concentration and in the presence of compounds that are known substrates of the DTS. The effect of enalapril on the uptake of [3H]-glycyl-L-proline (gly-L-pro) by Caco-2 cells was also examined. In vivo studies were conducted in rats (1 to 50 mg/kg) and dogs (0.06 to 6 mg/kg) to evaluate the oral absorption of enalapril over a wide dose range. RESULTS: In vitro intestinal uptake/permeability of enalapril was not saturable nor inhibited by beta-lactam antibiotics, gly-L-pro, or SQ-29852. Moreover, a 20,000-fold molar excess of enalapril did not inhibit the uptake of [3H]-gly-L-pro by Caco-2 cells. The in vivo studies in rats and dogs did not demonstrate saturable absorption. CONCLUSIONS: The present in vitro and in vivo results indicated that enalapril is primarily absorbed by a non-saturable, passive diffusion process and it is not a suitable model compound for studying the DTS.