Synthetic spin-orbit interaction for Majorana devices.

The interplay of superconductivity with non-trivial spin textures is promising for the engineering of non-Abelian Majorana quasiparticles. Spin-orbit coupling is crucial for the topological protection of Majorana modes as it forbids other trivial excitations at low energy but is typically intrinsic to the material1-7. Here, we show that coupling to a magnetic texture can induce both a strong spin-orbit coupling of 1.1 meV and a Zeeman effect in a carbon nanotube. Both of these features are revealed through oscillations of superconductivity-induced subgap states under a change in the magnetic texture. Furthermore, we find a robust zero-energy state-the hallmark of devices hosting localized Majorana modes-at zero magnetic field. Our findings are generalizable to any low-dimensional conductor, and future work could include microwave spectroscopy and braiding operations, which are at the heart of modern schemes for topological quantum computation.

Using Spontaneous Emission of a Qubit as a Resource for Feedback Control.

Persistent control of a transmon qubit is performed by a feedback protocol based on continuous heterodyne measurement of its fluorescence. By driving the qubit and cavity with microwave signals whose amplitudes depend linearly on the instantaneous values of the quadratures of the measured fluorescence field, we show that it is possible to stabilize permanently the qubit in any targeted state. Using a Josephson mixer as a phase-preserving amplifier, it was possible to reach a total measurement efficiency η=35%, leading to a maximum of 59% of excitation and 44% of coherence for the stabilized states. The experiment demonstrates multiple-input multiple-output analog Markovian feedback in the quantum regime.

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.

Observing interferences between past and future quantum states in resonance fluorescence.

The fluorescence of a resonantly driven superconducting qubit is measured in the time domain, providing a weak probe of the qubit dynamics. Prior preparation and final, single-shot measurement of the qubit allows us to average fluorescence records conditionally on past and future knowledge. The resulting interferences reveal purely quantum features characteristic of weak values. We demonstrate conditional averages that go beyond classical boundaries and probe directly the jump operator associated with relaxation. The experimental results are remarkably captured by a recent theory, which generalizes quantum mechanics to open quantum systems whose past and future are known.

Quantum heating of a nonlinear resonator probed by a superconducting qubit.

We measure the quantum fluctuations of a pumped nonlinear resonator using a superconducting artificial atom as an in situ probe. The qubit excitation spectrum gives access to the frequency and amount of excitation of the intracavity field fluctuations, from which we infer its effective temperature. These quantities are found to be in agreement with theoretical predictions; in particular, we experimentally observe the phenomenon of quantum heating.

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.

Quantum state tomography of an itinerant squeezed microwave field.

We perform state tomography of an itinerant squeezed state of the microwave field prepared by a Josephson parametric amplifier (JPA). We use a second JPA as a preamplifier to improve the quantum efficiency of the field quadrature measurement from 2% to 36%±4%. Without correcting for the detection inefficiency we observe a minimum quadrature variance which is 68(-7)(+9)% of the variance of the vacuum. We reconstruct the state's density matrix by a maximum likelihood method and infer that the squeezed state has a minimum variance less than 40% of the vacuum, with uncertainty mostly caused by calibration systematics.

Circuit QED with a nonlinear resonator: ac-Stark shift and dephasing.

We have performed spectroscopic measurements of a superconducting qubit dispersively coupled to a nonlinear resonator driven by a pump microwave field. Measurements of the qubit frequency shift provide a sensitive probe of the intracavity field, yielding a precise characterization of the resonator nonlinearity. The qubit linewidth has a complex dependence on the pump frequency and amplitude, which is correlated with the gain of the nonlinear resonator operated as a small-signal amplifier. The corresponding dephasing rate is found to be close to the quantum limit in the low-gain limit of the amplifier.

Influence of ageing, grinding and preheating on the thermal behaviour of alpha-lactose monohydrate.

It is shown that the onset temperature and the magnitude of thermal events observed during DSC analyses of alpha-lactose monohydrate can be strongly affected by various treatments such as ageing, manual grinding and preheating (cycle of preliminary dehydration and rehydration). In the case of grinding and preheating, the change of dehydration pathways was further investigated by using a suitable combination of characterization techniques, including X-ray powder diffraction (XRPD) performed with a synchrotron source (allowing an accurate Rietveld analysis), scanning electron microscopy (SEM), laser particle size measurements, FTIR spectroscopy and (1)H NMR for the determination of beta-lactose contents in samples. It appeared that the dehydration mechanism is affected not only by a smaller particle size distribution, but also by residual anisotropic lattice distortions and by the formation of surface defects or high energy surfaces. The fusion-recrystallization process occurring between anhydrous forms of alpha-lactose at ca. 170 degrees C is not significantly affected by grinding, whereas a preheating treatment induces an unexpected large increase of the enthalpy associated with this transition. Our observations and interpretations confirm the important role of water molecules in the crystal cohesion of the title compound and illustrate the necessity to consider the history of each sample for a satisfactory understanding of the physical properties and the behaviour of this important pharmaceutical excipient.

Contribution of Syncytins and Other Endogenous Retroviral Envelopes to Human Placenta Pathologies.

Fusion, proliferation, angiogenesis, immune tolerance, and tissue survival are some of the critical functions involved in the physiological and pathological processes of placenta development. Strikingly, some of these properties are shared by envelope glycoproteins of retroviruses. Part of the overall retroviral world, the human retroviral heritage consists of hundred thousands of elements representing a huge amount of genetic material as compared to our 25,000 genes, whereas only a few tenths of retroviral loci still contain envelope genes exhibiting large open reading frames. Some of these envelopes, namely Syncytin-1, Syncytin-2, and ERV-3 Env, were shown to support essential functions in placenta development. First, in order to understand where these envelope genes originate and what are the critical mechanisms involved in transcription regulation and protein basic functions such as recognition of cellular receptor by viral envelopes, we will describe the retroviral life cycle and how repeated infections during species evolution led to the formation of retroviral families. We will emphasize how many envelope genes remain in our genome and in which organs they were found to be expressed. Second, Syncytin-1 will be used as a model to decipher essentially in placental context (i) the detailed modalities of transcriptional control including repressive histone marks and CpG methylation epigenetic mechanisms, involvement of tissue-specific transcription factors, and control of mRNA splicing, as well as (ii) the multiple steps required for protein maturation finally leading to a functional trimeric glycosylated protein. The extraordinary versatility of Syncytin-1 will permit to demonstrate that such proteins are likely involved in physiological processes not only in placenta but also in other organs, based on evidence of fusion/differentiation, immunomodulation, apoptosis, and proliferation properties. Third, we will describe extensively the altered behavior of the various levels of transcriptional control or of protein functions/localization/maturation displayed by Syncytins and other endogenous retroviral envelopes. We will exemplify how such altered states may contribute to human placenta pathologies, including Down syndrome, preeclampsia/hemolysis, elevated liver enzymes, and low platelets syndrome/intrauterine growth restriction, and gestational trophoblastic diseases including mole and choriocarcinoma. Similar deregulations will be respectively mentioned on this target of fetal invasion that is the endometrium, the reproductive organs that are the testis and the ovary, and in the breast nourisher of the newborn child. All these observations draw outlines of the symbiotic and conflicting mechanisms at work where the retrovirus world and the human world have converged.

Mutual conformational adaptations in antigen and antibody upon complex formation between an Fab and HIV-1 capsid protein p24.

BACKGROUND: Elucidating the structural basis of antigen-antibody recognition ideally requires a structural comparison of free and complexed components. To this end we have studied a mouse monoclonal antibody, denoted 13B5, raised against p24, the capsid protein of HIV-1. We have previously described the first crystal structure of intact p24 as visualized in the Fab13B5-p24 complex. Here we report the structure of the uncomplexed Fab13B5 at 1.8 A resolution and analyze the Fab-p24 interface and the conformational changes occurring upon complex formation. RESULTS: Fab13B5 recognizes a nearly continuous epitope comprising a helix-turn-helix motif in the C-terminal domain of p24. Only 4 complementarity-determining regions (CDRs) are in contact with p24 with most interactions being by the heavy chain. Comparison of the free and complexed Fab reveals that structural changes upon binding are localized to a few side chains of CDR-H1 and -H2 but involve a larger, concerted displacement of CDR-H3. Antigen binding is also associated with an 8 degrees relative rotation of the heavy and light chain variable regions. In p24, small conformational changes localized to the turn between the two helices comprising the epitope result from Fab binding. CONCLUSIONS: The relatively small area of contact between Fab13B5 and p24 may be related to the fact that the epitope is a continuous peptide rather than a more complex protein surface and correlates with a relatively low affinity of antigen and antibody. Despite this, a significant quaternary structural change occurs in the Fab upon complex formation, with additional smaller adaptations of both antigen and antibody.

Human acute myeloid leukemia CD34+/CD38- progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities.

The destruction of cells capable of initiating and maintaining leukemia challenges the treatment of human acute myeloid leukemia. Recently, CD34+/CD38- leukemia progenitors have been defined as new leukemia-initiating cells less mature than colony-forming cells. Here we show that CD34+/CD38- leukemia precursors have reduced in vitro sensitivity to daunorubicin, a major drug used in leukemia treatment, in comparison with the CD34+/CD38+ counterpart, and increased expression of multidrug resistance genes (mrp/lrp). These precursors show lower expression of Fas/Fas-L and Fas-induced apoptosis than CD34+/CD38+ blasts. Moreover, the CD34+/CD38- leukemic subpopulation induces a weaker mixed leukocyte reaction of responding T-lymphocytes than the CD34+/CD38+ leukemic counterpart, either in a MHC-unmatched or MHC-matched settings. This weaker immunogenicity could be linked to lower expression on CD34+/CD38- leukemia precursors of major immune response molecules (MHC-DR, LFA-3, B7-1, or B7-2) than CD34+/CD38+ leukemic cells. Nonetheless, the susceptibility of the immature CD38- precursors to cytotoxicity was not different from the sensitivity of the CD38+ counterpart. Finally, CD34+/CD38- leukemia precursors, in contrast with CD38+ precursors, failed, under appropriate conditions, to differentiate into dendritic cells, a central step for antigen recognition. This is to our knowledge the first demonstration that the very immature phenotype of CD34+/CD38- leukemic progenitors confers both chemotherapy resistance and decreased capacities to induce an immune response. Because the susceptibility of the immature leukemia cells as cytotoxic targets is maintained, our data underline the importance of improving the initial steps of leukemia recognition, more particularly by defining optimal conditions of dendritic cell transformation of the very immature hematopoietic precursors.

Endogenous retroviruses and animal reproduction.

Endogenous retroviruses (ERV), as part of the host genetic heritage, are transmissible to the next generation in a Mendelian way. Their abundance in animal genomes and their expression primarily detected in germ cells, embryonic tissues and cancer cell lines, raised the question of their biological significance. This article reviews the possible role of ERVs in the physiology and diseases of animal reproduction, from Drosophila to human. In males, there is no trivial involvement of ERVs in a physiological process. Conversely, a spermatogenesis defect was associated in the human male with HERV-K expression and HERV15-induced chromosomal alteration, leading to cancer and infertility, respectively. In females, the study of insect ERVs (IERV) pointed out the overlap between genetics and virology with the genetic-dependent regulation of ZAM and the non-infectious and infectious life cycles of gypsy. The pattern of ERVs expression in rodent, ovine and human females suggest a hormone-dependent mechanism consistent with the mammalian oestrus cycle regulation. The differentiation of the mammary epithelium and breast tumorigenesis involving the mouse mammary tumour viruses (MMTV) illustrate the intimate connection between endogenous and exogenous retroviruses. Last, as a major site of ERVs transcription, placenta contributed to our understanding of ERVs modulation of neighbouring gene expression. As an interface, i.e. a site of conflicts and exchanges, placenta should resist infection and protect the foetus against the maternal immune system. Retroviral envelopes could theoretically provide such features due to receptor interference, immunosuppression and fusion properties, as shown by the HERV-W envelope involved in the syncytiotrophoblast formation. We conclude with an insight on the evolutionary and epigenetic consequences of the relationships of ERV guests with their animal hosts.

Expression of HERV-W Env glycoprotein (syncytin) in the extravillous trophoblast of first trimester human placenta.

Although the extravillous trophoblastic invasion has a critical role in human placental development, nothing is known about HERV-W expression in the extravillous phenotype. The aim of the present study was to localize in first trimester placenta the expression of HERV-W Env glycoprotein and its receptor all along the differentiation pathway of the extravillous phenotype. In addition using an in vitro model of extravillous cytotrophoblastic cell isolation and invasion we investigated the presence of HERV-W transcripts and envelope glycoprotein in cultured extravillous trophoblastic cells. Using monoclonal and polyclonal antibodies, the glycoprotein was immunolocalized in all the cell types of the extravillous phenotype lineage: cytotrophoblastic cells of the column, interstitial extravillous trophoblastic cells, multinucleated giant cells and endovascular trophoblast. Furthermore, using a polyclonal antibody, the D mammalian virus receptor was also localized in the various extravillous trophoblastic phenotypes. In addition, the presence of HERV-W transcripts and protein was demonstrated in cultured extravillous trophoblastic cells. HERV-W Env glycoprotein expressed in villous and extravillous trophoblast can be considered as a specific marker of the human trophoblast.

Acute myeloid leukaemia triggering via CD40 induces leukocyte chemoattraction and cytotoxicity against allogenic or autologous leukemic targets.

The CD40 antigen is a member of the tumor necrosis factor receptor superfamily which interacts with its ligand and regulates the immune response via a dialogue between T-lymphocytes and antigen-presenting or tumor cells. Tumor triggering via CD40 exerts direct effects on cancer cells, which have mainly been investigated in terminally differentiated hematological malignancies such as low-grade lymphoma. We focused our attention on minimally differentiated acute myeloid leukemia (AML-M0), an aggressive hematological malignancy in which severe prognosis suggests the requirement for innovative therapeutic strategies. Here we demonstrate, for the first time to our knowledge, a CD40-triggered IL-8, RANTES and IL-12 secretion by leukemic cells. Supernatants from CD40-stimulated leukemia cells had chemoattractant effects on T-lymphocytes, natural killer cells and monocytes. Moreover, these supernatants, when complemented with low-dose IL-2, induced significant lymphokine-activated and natural killer cytotoxicity, leading to leukemia lysis both in allogenic HLA-matched and autologous settings. Stimulation of leukemia cells via CD40 could participate significantly to the anti-leukemia immune response by contributing to the development of an inflammatory response and to in situ cytotoxicity. Leukemia(2000) 14, 123-128.

The immunophenotype of minimally differentiated acute myeloid leukemia (AML-M0): reduced immunogenicity and high frequency of CD34+/CD38- leukemic progenitors.

Minimally differentiated acute myeloid leukemia (AML-M0) is a rare FAB subtype (2-3% of AMLs) of poor prognosis. The aim of our study was to characterize AML-M0 expression and regulation of adhesion/costimulatory molecule involved in immune recognition, to test blast in vitro immunogenicity, and to determine the percentage of leukemia progenitor cells. Here, we demonstrate that alloimmune recognition of AML-M0 in primary mixed lymphocyte reaction, as evaluated by IL-2 secretion of responding T cells, is reduced in comparison with more differentiated subtypes (128 +/- 95 pg/ml vs304 +/- 159 pg/ml, P < 0.05). These data are in line with low blast cell expression of major histocompatibility complex (MHC) class II DR molecules, and of the CD28 ligand B7-2, which plays an important role in AML immune recognition. Adhesion/costimulatory molecules were up-regulated by leukemic cell stimulation via CD40, and, although less efficiently, by gamma-IFN; both stimuli improved blast cell immunogenicity. We also demonstrate that AML-M0 have a very high percentage (40% +/- 30) of CD34+/CD38- leukemic clonogenic precursors in comparison with more differentiated AMLs (2.5% +/- 2) or non-leukemic CD34+hematopoietic precursors (1.8% +/- 0.8). Since the presence of a leukemic cell population at an early differentiation stage has been identified as a poor prognostic factor, we conclude that the high frequency of CD34+/CD38- blasts in AML-M0 may converge with already identified poor prognosis factors such as chemotherapy resistance and cytogenetic abnormalities. The clinical implications of AML-M0 impaired in vitroimmunogenicity and a high percentage of CD34+/CD38- blasts will require comparative analysis of additional patients. The increased immunogenicity of blast cells after CD40 triggering provide interesting clues for AML-M0 immunotherapy, that have to be confirmed with an in vivo leukemia model in mice.

A novel mechanism of antitumor response involving the expansion of CD3+/CD56+ large granular lymphocytes triggered by a tumor-expressed activating ligand.

We describe a patient with acute myeloid leukemia (AML) who developed polyclonal large granular lymphocyte (LGL) proliferation. The reciprocal evolution of AML and LGLs suggested that these LGLs had an anti-tumor activity. The patient's LGLs killed autologous leukemia cells in a different way to classical T lymphocyte-mediated cytotoxicity since it did not rely on the recognition of target antigens presented by major histocompatibility complex (MHC) class I molecules by the CD3/TcRalphabeta complex. This killing was also different from natural killer (NK)-mediated cytotoxicity, which depends on the absence of MHC class I molecule recognition by NK inhibitory receptors. The LGLs were polyclonal, had a CD3+/CD8+/CD56+ phenotype, and did not express the natural killer cell receptors (NKRs) for MHC class I molecules. The LGLs did not express the NK-specific activating natural cytotoxicity receptors but expressed the 2B4 non-MHC restricted triggering receptor, whose ligand CD48 was expressed by leukemic cells and normal bone marrow cells. The 2B4 receptor participated in the ability of LGLs to lyse patient's leukemia. This represents a novel function for 2B4 in man, since this molecule, at variance with the murine system, was considered not to have direct effects on CD8+ T cell-mediated cytotoxicity. This case report allowed us to describe a novel T lymphocyte-mediated anti-tumor mechanism which relied on (1) the abnormal expansion of the rare 2B4-positive CD3+/CD8+/CD56+ T lymphocyte subset, (2) an as yet undescribed cytotoxicity mechanism in man which depended on 2B4 molecule. The relevance of this observation in human cancer immunotherapy has to be further investigated.

Stimulation of non-Hodgkin's lymphoma via HVEM: an alternate and safe way to increase Fas-induced apoptosis and improve tumor immunogenicity.

Stimulation by CD40 ligand (L) improves B-cell malignancy immunogenicity, and also induces proliferative signals. To avoid these tumorigenic effects, we studied an alternate way of tumor-cell stimulation by homologous to lymphotoxin, inducible expression, competing for GpD of herpesvirus, which binds to the herpesvirus entry mediator (HVEM), and is expressed on T-lymphocytes (LIGHT), the ligand for HVEM, a new member of the tumor necrosis factor (TNF)/TNF-receptor (-R) family. HVEM is constitutively expressed on the surface of tumor B cells. We focused our attention on mantle cell lymphoma, a subtype of B-cell malignancy of poor prognosis. Triggering by LIGHT, in contrast to CD40L stimulation, did not increase lymphoma proliferation nor decrease chemotherapy entrance. We observed an upregulation of the TNFR apoptosis-inducing ligand Fas, and in contrast to CD40L-induced protection, an enhancement of lymphoma sensitivity to Fas-induced apoptosis. LIGHT triggering increased lymphoma cell recognition in a mixed lymphocyte response. In conclusion, LIGHT-mediated triggering renders B-cell lymphomas more immunogenic and sensitive to apoptosis, without inducing proliferation. Since LIGHT triggering also enhances the functions of T-lymphocytes and dendritic cells, it could be a unique way to restore an efficient cancer control by its pleiotropic effects on immune effectors and tumor cells.

Quantum optics. Quantum dynamics of an electromagnetic mode that cannot contain N photons.

Electromagnetic modes are instrumental in building quantum machines. In this experiment, we introduce a method to manipulate these modes by effectively controlling their phase space. Preventing access to a single energy level, corresponding to a number of photons N, confined the dynamics of the field to levels 0 to N - 1. Under a resonant drive, the level occupation was found to oscillate in time, similarly to an N-level system. Performing a direct Wigner tomography of the field revealed its nonclassical features, including a Schrödinger cat-like state at half period in the evolution. This fine control of the field in its phase space may enable applications in quantum information and metrology.

Frequency of early in utero HIV-1 infection: a blind DNA polymerase chain reaction study on 100 fetal thymuses.

OBJECTIVE: To estimate the prevalence of in utero transmission of HIV-1 through the second trimester. MATERIAL AND METHODS: One hundred consecutive, unselected, intact fetuses, beyond 15 weeks gestational age (mean, 22.4 weeks) were studied. These were obtained following spontaneous intrauterine deaths (n = 4), miscarriages (n = 4), and elective mid-trimester terminations (n = 92), eight of which were fetuses with malformations from HIV-1-positive pregnancies. Coded DNA extracts from the fetal thymuses were tested blindly by polymerase chain reaction in three laboratories using a total of six different primer pairs. RESULTS: Two thymuses tested positive [95% confidence interval (Cl), 0.2-7]. Results from the three laboratories were consistent in all 100 cases. The two fetuses with HIV in the thymus both tested positive in other organs, demonstrating systemic HIV infection. The first fetus, whose mother had advanced AIDS, had died in utero and had diffuse toxoplasmosis. The second died following extremely premature delivery in a pregnancy complicated by repeated bleeding. HIV infection was observed in none of the 92 fetuses that resulted from elective mid-trimester terminations (95% Cl, 0-4). CONCLUSION: The frequency of early in utero HIV infection appears to be low, compared with transmission rates in infants born to HIV-1-infected mothers, suggesting that transmission occurs mostly later in pregnancy and/or at delivery. Specific risk factors may have implications in the occurrence of early as opposed to late transmission.