Presence of ectopic germinal center structures in autoimmune hepatitis.

Autoimmune tissues may contain ectopic germinal centers (EGCs). However, these structures have never been described in the liver of patients suffering from autoimmune hepatitis (AIH). We retrospectively reviewed histological features of 120 definite AIH cases, and found 10 cases harboring markers of EGCs. In these cases, CD21+ follicular dendritic cells were intermixed with CD3+ T and CD20+ B lymphocytes. The latter expressed the GC-specific marker bcl6, and some were proliferative as assessed by Ki67 expression. Antibody-secreting cells (ASCs) defined by expression of the mum-1 transcription factor and presence of cytoplasmic IgMs were usually present in the periphery of these structures, but some were also present within the EGCs. Notably, some ASCs were IgG-switched. Common treatment applied to AIH patients achieved biochemical normalization as efficiently as in patients without EGCs. In the present study, we provide the proof for the occurrence of functional EGCs enabling differentiation of B cells into ASCs and occurrence of immunoglobulin switch in AIH livers.

3-O sulfation of syndecan-1 mediated by the sulfotransferase HS3ST3a1 enhances myeloma aggressiveness.

Multiple myeloma is a hematological neoplasm derived from plasma cells invariably developing in the bone marrow (BM). The persisting clinical challenge in MM resides in its high ability to resist drugs as shown by the frequent relapses observed in patients regardless of the treatment applied. In a mouse model of MM, we identified a subpopulation of cells harboring increased resistance to current MM drugs. These cells bound a proliferation inducing ligand (APRIL), a key MM promoting/survival factor. APRIL binding involved the heparan sulfate (HS) chain present on syndecan-1 (SDC-1), and correlated with reactivity to the anti-HS antibody 10e4. 10e4+cells had a high proliferation activity, and were able to form colonies in 3-D cultures. 10e4+ cells were the only cells able to develop in BM after intravenous injection. They also resisted drugs in vivo, since their number increased after treatment in BM. Notably, 10e4+ cells differentiated into 10e4- cells upon in vitro and in vivo expansion. Expression of one sulfotransferase, HS3ST3a1, allowed modification of syndecan-1 to confer reactivity to 10e4 and binding to APRIL. HS3ST3a1 deletion inhibited tumorigenesis in BM. Notably, the two populations coexisted at a variable frequency in the BM of MM patients at diagnosis. In total, our results indicate that 3-O-sulfation on SDC-1 carried out by HS3ST3a1 defines aggressive MM cells, and that targeting of this enzyme could possibly be used to better control drug resistance.

Energetics of a Single Qubit Gate.

Qubits are physical, a quantum gate thus not only acts on the information carried by the qubit but also on its energy. What is then the corresponding flow of energy between the qubit and the controller that implements the gate? Here we exploit a superconducting platform to answer this question in the case of a quantum gate realized by a resonant drive field. During the gate, the superconducting qubit becomes entangled with the microwave drive pulse so that there is a quantum superposition between energy flows. We measure the energy change in the drive field conditioned on the outcome of a projective qubit measurement. We demonstrate that the drive's energy change associated with the measurement backaction can exceed by far the energy that can be extracted by the qubit. This can be understood by considering the qubit as a weak measurement apparatus of the driving field.

Sequential Dispersive Measurement of a Superconducting Qubit.

We present a superconducting device that realizes the sequential measurement of a transmon qubit. The device disables common limitations of dispersive readout such as Purcell effect or transients in the cavity mode by turning on and off the coupling to the measurement channel on demand. The qubit measurement begins by loading a readout resonator that is coupled to the qubit. After an optimal interaction time with negligible loss, a microwave pump releases the content of the readout mode by upconversion into a measurement line in a characteristic time as low as 10 ns, which is 400 times shorter than the lifetime of the readout resonator. A direct measurement of the released field quadratures demonstrates a readout fidelity of 97.5% in a total measurement time of 220 ns. The Wigner tomography of the readout mode allows us to characterize the non-Gaussian nature of the readout mode and its dynamics.

Deterministic and Stochastic Models of Arabidopsis thaliana Flowering.

Experimental studies of the flowering of Arabidopsis thaliana have shown that a large complex gene regulatory network (GRN) is responsible for its regulation. This process has been mathematically modelled with deterministic differential equations by considering the interactions between gene activators and inhibitors (Valentim et al. in PLoS ONE 10(2):e0116973, 2015; van Mourik et al. in BMC Syst Biol 4(1):1, 2010). However, due to complexity of the model, the properties of the network and the roles of the individual genes cannot be deducted from the numerical solution the published work offers. Here, we propose simplifications of the model, based on decoupling of the original GRN to motifs, described with three and two differential equations. A stable solution of the original model is sought by linearisation of the original model which contributes to further investigation of the role of the individual genes to the flowering. Furthermore, we study the role of noise by introducing and investigating two types of stochastic elements into the model. The deterministic and stochastic nonlinear dynamic models of Arabidopsis flowering time are considered by following the deterministic delayed model introduced in Valentim et al. (2015). Steady-state regimes and stability of the deterministic original model are investigated analytically and numerically. By decoupling some concentrations, the system was reduced to emphasise the role played by the transcription factor Suppressor of Overexpression of Constants1 ([Formula: see text]) and the important floral meristem identity genes, Leafy ([Formula: see text]) and Apetala1 ([Formula: see text]). Two-dimensional motifs, based on the dynamics of [Formula: see text] and [Formula: see text], are obtained from the reduced network and parameter ranges ensuring flowering are determined. Their stability analysis shows that [Formula: see text] and [Formula: see text] are regulating each other for flowering, matching experimental findings. New sufficient conditions of mean square stability in the stochastic model are obtained using a stochastic Lyapunov approach. Our numerical simulations demonstrate that the reduced models of Arabidopsis flowering time, describing specific motifs of the GRN, can capture the essential behaviour of the full system and also introduce the conditions of flowering initiation. Additionally, they show that stochastic effects can change the behaviour of the stability region through a stability switch. This study thus contributes to a better understanding of the role of [Formula: see text] and [Formula: see text] in Arabidopsis flowering.

Demonstration of an Effective Ultrastrong Coupling between Two Oscillators.

When the coupling rate between two quantum systems becomes as large as their characteristic frequencies, it induces dramatic effects on their dynamics and even on the nature of their ground state. The case of a qubit coupled to a harmonic oscillator in this ultrastrong coupling regime has been investigated theoretically and experimentally. Here, we explore the case of two harmonic oscillators in the ultrastrong coupling regime. Probing the properties of their ground state remains out of reach in natural implementations. Therefore, we have realized an analog quantum simulation of this coupled system by dual frequency pumping a nonlinear superconducting circuit. The pump amplitudes directly tune the effective coupling rate. We observe spectroscopic signature of a mode hybridization that is characteristic of the ultrastrong coupling. We experimentally demonstrate a key property of the ground state of this simulated ultrastrong coupling between modes by observing simultaneous single- and two-mode squeezing of the radiated field below vacuum fluctuations.

Author Correction: Dynamics of a qubit while simultaneously monitoring its relaxation and dephasing.

The original version of this Article omitted the following from the Acknowledgements: Z. Leghtas' primary affiliation is Centre Automatique et Systèmes, Mines ParisTech. This has been corrected in both the PDF and HTML versions of the Article.

Dynamics of a qubit while simultaneously monitoring its relaxation and dephasing.

Decoherence originates from the leakage of quantum information into external degrees of freedom. For a qubit, the two main decoherence channels are relaxation and dephasing. Here, we report an experiment on a superconducting qubit where we retrieve part of the lost information in both of these channels. We demonstrate that raw averaging the corresponding measurement records provides a full quantum tomography of the qubit state where all three components of the effective spin-1/2 are simultaneously measured. From single realizations of the experiment, it is possible to infer the quantum trajectories followed by the qubit state conditioned on relaxation and/or dephasing channels. The incompatibility between these quantum measurements of the qubit leads to observable consequences in the statistics of quantum states. The high level of controllability of superconducting circuits enables us to explore many regimes from the Zeno effect to underdamped Rabi oscillations depending on the relative strengths of driving, dephasing, and relaxation.

Mathematical investigation of diabetically impaired ultradian oscillations in the glucose-insulin regulation.

We study the effect of diabetic deficiencies on the production of an oscillatory ultradian regime using a deterministic nonlinear model which incorporates two physiological delays. It is shown that insulin resistance impairs the production of oscillations by dampening the ultradian cycles. Four strategies for restoring healthy regulation are explored. Through the introduction of an instantaneous glucose-dependent insulin response, explicit conditions for the existence of periodic solutions in the linearised model are formulated, significantly reducing the complexity of identifying an oscillatory regime. The model is thus shown to be suitable for representing the effect of diabetes on the oscillatory regulation and for investigating pathways to reinstating a physiological healthy regime.

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.

Autocrine amplification of immature myeloid cells by IL-6 in multiple myeloma-infiltrated bone marrow.

Multiple myeloma (MM) invariably develops in the bone marrow (BM), indicating the strong requirement of this tumor for the peculiar BM microenvironment, rich in cytokine and hematopoietic precursor cells. Interleukin-6 (IL-6) and a proliferation inducing ligand (APRIL) are key cytokines implicated in MM development. Here, we show that MM cells changed the hematopoietic microenvironment early upon BM infiltration by strongly downregulating hematopoietic precursor cells from all lineages except myeloid precursor cells. Myeloid precursor cells constituted a major source of APRIL in MM-infiltrated BM, and their proliferative response to IL-6 upregulation explained their relative resistance to MM infiltration. The osteolytic molecule receptor activator of NF-kB ligand (RANK-L) expressed by MM cells started this myeloid proliferation by inducing in a contact-dependent manner IL-6 production by myeloid precursor cells themselves. Taken together, our data demonstrate that MM cells do not simply displace hematopoietic cells upon BM infiltration, but rather selectively modulate the BM microenvironment to preserve a pool of high APRIL-producing myeloid precursor cells. Our data also identify a positive regulation of APRIL by IL-6 in myeloid precursor 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.

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.

Myelopoiesis dysregulation associated to sustained APRIL production in multiple myeloma-infiltrated bone marrow.

Multiple myeloma (MM) is a non-curable tumor developing in the bone marrow (BM). The BM microenvironment rich in hematopoietic precursors is suspected to have a role in MM development. Here we show that a proliferation-inducing ligand (APRIL) mediated in vivo MM promotion. In MM-infiltrated BM, APRIL originated from differentiating myeloid cells with an expression peak in precursor cells. Notably, APRIL expression stayed stable in BM despite MM infiltration. The pool of APRIL-producing cells changed upon MM infiltration. Although CD16(+) mature myeloid cells constituted about half of the APRIL-producing cells in healthy BM, CD16(-) Elastase(+) myeloid precursor cells were predominant in MM-infiltrated BM. Myeloid precursor cells secreted all the APRIL they produced, and binding of secreted APRIL to MM cells, strictly dependent of heparan sulfate carried by CD138, resulted in an in situ internalization by tumor cells. This indicated APRIL consumption by MM in BM. Taken together, our data show that myelopoiesis dysregulation characterized by an increased proportion of precursor cells occurs in MM patients. Such dysregulation correlates with a stable expression of the MM-promoting factor APRIL in infiltrated BM.

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.

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.

Evidence for a repertoire of functional untolerized CD4+ T cells specific for melanoma-associated antigens.

Active vaccination against melanoma requires tolerance break as melanoma-associated antigens (MAA) used in vaccine formula are mostly self-antigens. While tolerance to MAA in the CD8(+) T cell compartment is well characterized, it is still not the case for the CD4(+) T cell compartment. Here, we analysed CD4(+) T cell tolerance to such antigens in mice genetically engineered to express ovalbumin (OVA) in melanocytes (Tyr-OVA mice). When we crossed Tyr-OVA mice with DO11.10 and OT-II mice transgenic for an OVA-specific TCR restricted by MHC class II, we observed different tolerization levels. Central tolerance was complete for high avidity DO11.10 CD4(+) T cells, but absent for low avidity OT-II CD4(+) T cells. OT-II CD4(+) T cells also ignored OVA in the periphery of Tyr-OVA mice, albeit being potently reactive to vaccination. OVA challenge in single transgenic Tyr-OVA mice confirmed the existence of OVA-reactive CD4(+) T cells with the induction of efficient T helper cells for antibody production and anti-tumour T cell response. In total, our study demonstrates the existence of low avidity MAA-specific CD4(+) T cells escaping by ignorance central and peripheral tolerance, but valuable in the context of vaccination against melanoma.

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.