Superconducting quantum node for entanglement and storage of microwave radiation.

Superconducting circuits and microwave signals are good candidates to realize quantum networks, which are the backbone of quantum computers. We have realized a quantum node based on a 3D microwave superconducting cavity parametrically coupled to a transmission line by a Josephson ring modulator. We first demonstrate the time-controlled capture, storage, and retrieval of an optimally shaped propagating microwave field, with an efficiency as high as 80%. We then demonstrate a second essential ability, which is the time-controlled generation of an entangled state distributed between the node and a microwave channel.

Observation of measurement-induced entanglement and quantum trajectories of remote superconducting qubits.

The creation of a quantum network requires the distribution of coherent information across macroscopic distances. We demonstrate the entanglement of two superconducting qubits, separated by more than a meter of coaxial cable, by designing a joint measurement that probabilistically projects onto an entangled state. By using a continuous measurement scheme, we are further able to observe single quantum trajectories of the joint two-qubit state, confirming the validity of the quantum Bayesian formalism for a cascaded system. Our results allow us to resolve the dynamics of continuous projection onto the entangled manifold, in quantitative agreement with theory.

Generating entangled microwave radiation over two transmission lines.

Using a superconducting circuit, the Josephson mixer, we demonstrate the first experimental realization of spatially separated two-mode squeezed states of microwave light. Driven by a pump tone, a first Josephson mixer generates, out of quantum vacuum, a pair of entangled fields at different frequencies on separate transmission lines. A second mixer, driven by a π-phase shifted copy of the first pump tone, recombines and disentangles the two fields. The resulting output noise level is measured to be lower than for the vacuum state at the input of the second mixer, an unambiguous proof of entanglement. Moreover, the output noise level provides a direct, quantitative measure of entanglement, leading here to the demonstration of 6 Mebit · s(-1) (mega entangled bits per second) generated by the first mixer.

Widely tunable, nondegenerate three-wave mixing microwave device operating near the quantum limit.

We present the first experimental realization of a widely frequency tunable, nondegenerate three-wave mixing device for quantum signals at gigahertz frequency. It is based on a new superconducting building block consisting of a ring of four Josephson junctions shunted by a cross of four linear inductances. The phase configuration of the ring remains unique over a wide range of magnetic fluxes threading the loop. It is thus possible to vary the inductance of the ring with flux while retaining a strong, dissipation-free, and noiseless nonlinearity. The device has been operated in amplifier mode, and its noise performance has been evaluated by using the noise spectrum emitted by a voltage-biased tunnel junction at finite frequency as a test signal. The unprecedented accuracy with which the crossover between zero-point fluctuations and shot noise has been measured provides an upper bound for the noise and dissipation intrinsic to the device.

Coupling a quantum dot, fermionic leads, and a microwave cavity on a chip.

We demonstrate a hybrid architecture consisting of a quantum dot circuit coupled to a single mode of the electromagnetic field. We use single wall carbon nanotube based circuits inserted in superconducting microwave cavities. By probing the nanotube dot using a dispersive readout in the Coulomb blockade and the Kondo regime, we determine an electron-photon coupling strength which should enable circuit QED experiments with more complex quantum dot circuits.

Bis(7-amino-4-azaheptyl)dimethlysilane and bis(7-ethylamino-4-azaheptyl)dimethylsilane: inhibition of tumor cell growth in vitro and in vivo.

Bis(7-amino-4-azaheptyl)dimethylsilane (AzhepSi) and its bis(ethyl) derivative [bis(7-ethylamino-4-azaheptyl)dimethylsilane] (EtAzhepSi) are the first examples of a new type of aliphatic tetramine with a dimethylsilane group incorporated into the central carbon chain. AzhepSi shares certain properties with the natural polyamines, but in contrast with spermidine and spermine it inhibits the growth of L1210 leukemia cells in culture at micromolar concentrations. The bis(ethyl) derivative of AzhepSi was made, in analogy to bis(ethyl) spermine, a polyamine derivative, which gained much attention during the last decade as a potential anticancer drug. Chinese hamster ovary (CHO) cells accumulate the dimethylsilyl tetramines considerably more and are more sensitive to these drugs than are CHO-MG cells, a polyamine uptake-deficient mutant. This and related observations demonstrate that AzhepSi and EtAzhepSi are preferentially taken up by a polyamine transport system. Both tetramines inhibit the growth of a variety of tumor cells at micromolar concentrations. AzhepSi turned out to be either equipotent or more potent, but in no case less potent than EtAzhepSi. When given alone at daily doses of 25 micromol/kg, the compounds did not prolong the survival time of L1210 leukemia mice. However, in combination with 2-(difluoromethyl)ornithine and neomycin, AzhepSi had a significant effect on the life span of the animals. The growth rate of 3LL Lewis lung carcinoma was reduced by both compounds at daily doses of 25 micromol/kg. The observations presented in this work suggest that the dimethylsilyl tetramines are antiproliferative agents in vitro and in vivo. Due to enhanced general toxicity, the introduction of N-ethyl substituents was of no advantage in the case of these polyamine analogues.

G-protein signaling abnormalities mediated by CD95 in salivary epithelial cells.

Salivary epithelial cells from patients with primary Sjögren's syndrome (SS) undergo Fas-mediated apoptosis. Bcl-2 and Bcl-xL are apoptosis suppressing oncogenes. Very little is known about the role of these oncogene molecules in salivary epithelial cells. To investigate the possible prevention of salivary glandular destruction in SS by Bcl-2 and Bcl-xL, stable transfectants expressing these molecules were made from HSY cells, a human salivary epithelial cell line. HSY cells were transfected with an expression vector for human Bcl-2 or Bcl-xL. Stable transfectants were selected and apoptosis was induced by anti-Fas antibody. Apoptosis was quantified by propidium iodide staining followed by flow cytometry. Caspase activity was detected by immunohistochemical analysis and enzyme cleavage of DEVD-AMC, a fluorescent substrate. Response to carbachol, a muscarinic receptor agonist, and EGF was measured by Ca2+ mobilization and influx. Fas-mediated apoptosis was significantly inhibited in Bcl-2 and Bcl-xL transfectants compared to wild-type and control transfectants (empty vector). Surprisingly, caspase activity was not inhibited in Bcl-2 and Bcl-xL transfectants. Activation of the Fas pathway in the Bcl-2 and Bcl-xL transfectants by antibody also inhibited carbachol and EGF responsiveness (i.e., Ca2+ mobilization and/or influx) by 50-60%. This Fas-mediated inhibition of cell activation was partially or completely restored by specific peptide interference of caspase enzyme activity. The prevention of Fas-mediated apoptosis by the overexpression of Bcl-2 and Bcl-xL in salivary gland epithelial cells results in injured cells expressing caspase activity and unable to respond normally to receptor agonists. Such damaged cells may exist in SS patients and could explain the severe dryness out of proportion to the actual number of apoptotic cells seen on salivary gland biopsy.

Fas-mediated apoptosis in a rat acinar cell line is dependent on caspase-1 activity.

Apoptosis plays an important role in the dysfunction of exocrine glands. Fas is a death-inducing receptor found on many types of cells including epithelial acinar cells. To elucidate the intracellular mechanism of Fas-mediated cell death in exocrine glands, an epithelial acinar cell line, SMG-C6, was studied. Caspase-1, -3, -8, and -9 activities were elevated in SMG-C6 cells after the induction of apoptosis by soluble Fas ligand (FasL). The activation of caspase-1 and -8 occurred prior to caspase-3 and -9 activation. The caspase-1 inhibitor, zYVAD-fmk, was effective in preventing cell death, whereas the caspase-3 and -8 inhibitors (ac-DEVD-CHO and ac-IETD-CHO, respectively) were not. zYVAD-fmk was able to inhibit caspase-3 activation indicating that caspase-1 is upstream to caspase-3. Furthermore, kinetic studies show that caspase-1 is an early event in the Fas apoptotic pathway. This study shows that caspase-1 participates in Fas-mediated apoptosis of epithelial cells by initiating the caspase cascade.

Amifostine reduces mucosal damage after high-dose melphalan conditioning and autologous peripheral blood progenitor cell transplantation for patients with multiple myeloma.

High-dose melphalan (HDM) has been adopted as standard therapy in the treatment of multiple myeloma. This treatment is associated with non-selective cytotoxicity, causing oral mucositis as the major non-hematological side-effect. Amifostine is a cytoprotector which prevents toxicity induced by anticancer therapy. We prospectively compared two groups of patients who either received (group A, n = 21) or did not receive (group B, n = 20) amifostine (740 mg/m(2)) before HDM (200 mg/m(2)) followed by autologous peripheral blood progenitor cell transplantation. The occurrence of severe oral mucositis was significantly decreased in group A in comparison to group B (33% vs 65%, P < 0.05). Six patients in group A required opioid analgesic therapy during a mean period of 4.8 days as compared to eight patients for 6.5 days in group B (P = NS). Delayed vomiting was less frequent in group A (43% vs 70%, P = 0.07) and significantly less severe in group A (grade 2-4) vomiting: two patients vs nine patients, P < 0.02). No difference was observed between the two groups in either hematological toxicity after HDM or in response rate. Grade I emesis was the only immediate side-effect observed after amifostine administration. We conclude that amifostine can reduce mucositis induced by HDM.

Inappropriate apoptosis of salivary and lacrimal gland epithelium of immunodeficient NOD-scid mice.

OBJECTIVE: The lesion is Sjögren's syndrome consists of lymphocytic infiltration and has a pathology characteristic of the potential apoptotic death of salivary gland secretory epithelial cells. To examine the role of the glandular epithelial cells in the pathogenesis of autoimmune exocrinopathy, we studied Fas and Fas ligand (FasL) expression and quantitated the levels of apoptosis in salivary and lacrimal glands from NOD and NOD-scid mice, an animal model that develops a Sjögren's syndrome-like pathology. METHODS: The parotid, submandibular and lacrimal tissues of NOD, NOD-scid, and BALB/c mice were evaluated by immunohistochemical analysis for the expression of Fas and FasL. Nuclear fragmentation of DNA from the epithelial cells of exocrine tissues was evaluated by the terminal UTP nucleotide end labeling method (TUNEL). Messenger RNA was isolated from 8 and 18 week old mice and was analyzed by the reverse transcription-polymerase chain reaction (RT-PCR) for the expression of Fas and FasL. RESULTS: We found suggestive evidence that apoptosis of the secretory epithelial cells occurs in both NOD and NOD-scid mice despite the lack of T- and B-lymphocytes in the latter. FasL mRNA and cell surface protein were expressed in salivary and lacrimal gland epithelial cells from 8 and 18 week old NOD, NOD-scid, and BALB/c mice. Fas protein and mRNA were expressed only in the exocrine glands from 18 week old NOD and NOD-scid mice. Glandular secretory epithelial cell apoptosis was elevated in both NOD and NOD-scid mice, however; there was little evidence of apoptosis in the control strain of BALB/c mice. CONCLUSION: These results suggest a potential apoptotic process dependent on Fas:FasL interactions occurring in NOD-scid glandular secretory epithelial cells in the absence of lymphocytic infiltration.

Dimethylsilane polyamines: cytostatic compounds with potentials as anticancer drugs. II. Uptake and potential cytotoxic mechanisms.

Dimethylsilane tetramines are structural analogues of spermine with a (CH3)2 Si-group incorporated into the central carbon chain. They have potential as anticancer drugs. Their cytotoxic effect was considered to rely mainly on their polyamine antagonist property. In order to obtain new ideas about cellular mechanisms, which are potential targets of the dimethylsilane polyamines, the effects of these compounds on some basic cell functions, such as protein and DNA synthesis, and calmodulin antagonism were studied. In addition, their mode of accumulation in cells was investigated. It became evident that the intracellular accumulation of dimethylsilane polyamines is almost exclusively achieved via the polyamine transport system. However, the exchange of a part of the intracellular natural polyamines against dimethylsilane polyamines has only a small effect on polyamine uptake. Binding to the endoplasmic reticulum and inhibition of protein synthesis are presumably important for the cytotoxic action of bis(11-amino-4,8-diazaundecyl)dimethylsilane, a hexamine, but seem of no importance for the tetramines. Calmodulin antagonism, however, is likely to contribute to their cytotoxic effect.

TGF-beta1 null mutation leads to CD154 upregulated expression in affected tissues.

The TGF-beta1(-/-) mouse is a murine model for systemic autoimmune disease. The aim of this study is to elucidate the immunological mechanism that leads to multifocal tissue inflammation and autoantibody production in TGF-beta1(-/-) mice. Heart, lung, liver, and salivary gland from TGF-beta1(-/-) were assessed for CD154 expression by RT-PCR and immunohistochemistry. Compared to wild-type littermates, CD154 expression was elevated in all tissues studied. Furthermore, IL-12 mRNA was expressed in the salivary gland and heart of TGF-beta1(-/-) mice and not in wild-type littermates. This suggests that the CD154 pathway is activated in these tissues. This shows that TGF-beta1 regulates CD154 expression leading to spontaneous IL-12 production and autoimmunity.

Emergence of tularemia in France: paradigm of the Burgundy region.

We report three consecutive cases of tularemia occurring in Burgundy, France, a region previously considered not endemic for tularemia. The patients presented with varied and unspecific clinical manifestations. The epidemiological circumstances, especially the mode of contamination, were not particularly suggestive of tularemia. Serological diagnosis was delayed in two cases because of the lack of significant antibody titers at the time of admission. In contrast, a diagnosis could readily be obtained in all three cases by detection of Francisella tularensis DNA from clinical samples using PCR-based methods. These cases highlight the increased incidence and geographical spread of tularemia in France, and the usefulness of real-time PCR technology for the early diagnostic confirmation of tularemia.

Multiple aggressive squamous cell carcinomas associated with prolonged voriconazole therapy in four immunocompromised patients.

Rare squamous cell carcinoma (SCC) cases associated with voriconazole therapy have been reported, but this risk may not receive enough consideration from clinicians. We describe four patients presenting with multiple SCC while receiving prolonged (two to three years) voriconazole therapy. Three patients had underwent lung transplantation. SCC were preceded by photosensitization lesions, and predominated in photoexposed area, particularly the face. Therapy associated surgery, chemotherapy in one case, and voriconazole discontinuation; replacement by posaconazole or itraconazole did not trigger other photosensitive lesions. Once voriconazole withdrawn, preneoplastic lesions regressed. In conclusion, prolonged voriconazole therapy may enhance the risk of photoinduced SCC in immunocompromised patients, and skin monitoring is mandatory.

[Severe infection following arteriotomy with Angio-Seal]. / Infection grave compliquant une angioplastie avec utilisation d'Angio-Seal((R)).

Diagnostic or interventional femoral artery catheterizations are more and more commonly practiced, so are haemostatic puncture closure devices, used to prevent bleeding complications and decrease hospital length of stay. Complications, such as infections, have been reported after using haemostatic puncture closure devices. We report the case of a female patient presenting with severe infection after Angio-Seal use: femoral artery infection with sepsis and multiple organ failure, septic embolism with embolic skin abscesses, bacterial arthritis and inferior limb necrosis. Studies comparing the infectious risk of manual compression versus haemostatic puncture closure devices are contradictory. Nevertheless, aseptic rules must be strictly observed. Indications for these devices concern only patients with high risk of hemorrhage and should be discussed for immunodepressed, diabetic, or obese patients.

Antibiotic susceptibilities of Legionella pneumophila strain Paris in THP-1 cells as determined by real-time PCR assay.

OBJECTIVES: Legionella species are facultative intracellular bacteria. Evaluation of the activity of antibiotics against intracellular L. pneumophila is more predictive of their in vivo efficacy than MICs as determined in axenic medium. However, current methodologies are based on cfu count determination, and are tedious because of the slow growth of Legionella spp. We investigated antibiotic susceptibilities of L. pneumophila strain Paris in THP-1-derived macrophages, using a real-time PCR assay for evaluation of bacterial growth. METHODS: Intracellular activities of seven antibiotic compounds against two human isolates of L. pneumophila strain Paris were determined in THP-1-derived macrophages in vitro. Bacterial growth was evaluated using either cfu methodology or a real-time PCR protocol targeting the mip gene. RESULTS: Bacterial titres as determined using real-time PCR were well correlated with cfu counts. Antibiotic susceptibilities for the two L. pneumophila isolates tested were comparable when using either of the two techniques. MICs were also similar to those previously reported for other L. pneumophila serogroup 1 strains. In particular, rifampicin and the fluoroquinolones were the most active compounds, both in extracellular medium and in THP-1 cells. Real-time PCR, however, was much less laborious than the traditional cfu method. CONCLUSIONS: Real-time PCR is better adapted than cfu-based methods to evaluating the antibiotic susceptibilities of large series of Legionella strains to newer antibiotic compounds.

Binding of nuclear proteins to the negative regulatory element of the IL-2 gene in lymphocytes from rheumatic patients.

T lymphocytes from several autoimmune diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) exhibit deficient mitogenic response in terms of proliferation and IL-2 production. The expression of the IL-2 gene is regulated by various transcription factors. One of these factors suppresses IL-2 expression and binds to the negative responsive element in the IL-2 gene 5' flanking region (NRE-A). The authors hypothesized that the decreased production of IL-2 by T cells from RA and SLE patients is at least partially caused by high expression of the NRE-A binding protein. To test this hypothesis T cells from healthy donors and patients with RA and SLE were stimulated. Using the electrophoretic mobility shift assay we detected NRE-A DNA-binding proteins in the nuclei of the stimulated cells. No difference was found between NRE-A DNA binding in nuclear extracts of T cells taken from healthy donors and those taken from patients. The specificity of the DNA-protein interactions was ascertained through the use of unlabeled DNA competitors. No correlation was found between DNA-binding and the patients' disease duration or medication. In conclusion, decreased IL-2 biosynthesis by T lymphocytes from RA and SLE patients can not be explained by abnormal expression of the NRE-A DNA-binding protein.

Bis(7-amino-4-azaheptyl)dimethylsilane: a new tetramine with polyamine-like features. Effects on cell growth.

Bis(7-amino-4-azaheptyl)dimethylsilane is a new type of aliphatic polycation with structural features resembling those of spermine. The elongation to a seven-membered carbon chain in which the central CH2-group was substituted by (CH3)2Si renders the molecule more lipophilic than spermine. Cells accumulate the compound via the polyamine transport system. Due to suppression of ornithine decarboxylase, de novo putrescine biosynthesis is impaired, and intracellular putrescine and spermidine concentrations are depleted. Depletion of intracellular spermidine together with binding to functionally important polyamine binding sites are considered the main features of the compound which cause cytostatic, and at high concentrations, cytotoxic effects.

Dimethylsilane polyamines: cytostatic compounds with potentials as anticancer drugs.

Several dimethylsilane tetramines [homologs of spermine with an Si(CH3)2 group in the central carbon chain], a carbon analog of the dimethylsilane tetramines [containing C(CH3)2 instead of Si(CH3)2] and a dimethylsilane hexamine were studied with regard to their cytotoxic activity and their ability to interact with double-stranded DNA. All polyamine analogs exerted cytostatic effects to several cell lines at micromolar concentrations. Their ability to condense DNA was comparable to and their ability to displace ethidium bromide from binding to DNA was superior to that of spermine. Their cytostatic effect was not correlated with the depletion of cellular spermidine concentrations. It is suggested that the new polyamine analogs act mainly by displacing spermidine from binding sites which are essential for the promotion of cell growth.

Monocyte rescue of human T cells from apoptosis is CD40/CD154 dependent.

The induction of T-cell apoptosis is regulated in part by monocytes (CD14+ cells). Human peripheral blood monocytes inhibited the spontaneous cell death of activated T cells in vitro. The inhibition of T-cell apoptosis did not require autologous monocytes. Inhibition required direct contact with monocytes and was not due to a soluble factor. Furthermore, treatment of monocytes with actinomycin D, cycloheximide and paraformaldehyde abrogated the anti-apoptotic activity of these cells. Blocking antibody to CD40 and CD154 (CD40 ligand) decreased the ability of monocytes to aid in T-cell survival, whereas, blocking LFA-1/I-CAM-1, Fas ligand and the CD4/major histocompatibility complex class II interaction did not affect the influence of monocytes on T-cell survival. This shows that monocytes rescue of activated T cells from apoptosis is dependent upon CD40/CD154 interaction.