Violation of Bell's Inequality Using Continuous Variable Measurements.

A Bell inequality is a fundamental test to rule out local hidden variable model descriptions of correlations between two physically separated systems. There have been a number of experiments in which a Bell inequality has been violated using discrete-variable systems. We demonstrate a violation of Bell's inequality using continuous variable quadrature measurements. By creating a four-mode entangled state with homodyne detection, we recorded a clear violation with a Bell value of B=2.31±0.02. This opens new possibilities for using continuous variable states for device independent quantum protocols.

BTK drives neutrophil activation for sterilizing antifungal immunity.

We describe a previously-unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B-cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, BTKi-treated patients, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcγR-dependent manner, triggering the oxidative burst. BTK inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit p40phox and GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function, not recruitment or lifespan. Conversely, GM-CSF partially mitigated these deficits by enhancing p47phox activation. Our findings underline the crucial role of BTK signaling in neutrophils for antifungal immunity and provide a rationale for GM-CSF use to offset these deficits in susceptible patients.

Aspergillus fumigatus cytochrome c impacts conidial survival during sterilizing immunity.

Invasive pulmonary aspergillosis (IPA) is a life-threatening infection caused by species in the ubiquitous fungal genus Aspergillus . While leukocyte-generated reactive oxygen species (ROS) are critical for the clearance of fungal conidia from the lung and resistance to IPA, the processes that govern ROS-dependent fungal cell death remain poorly defined. Using a flow cytometric approach that monitors two independent cell death markers, an endogenous histone H2A:mRFP nuclear integrity reporter and Sytox Blue cell impermeable (live/dead) stain, we observed that loss of A. fumigatus cytochrome c ( cycA ) results in reduced susceptibility to cell death from hydrogen peroxide (H 2 O 2 ) treatment. Consistent with these observations in vitro , loss of cycA confers resistance to both NADPH-oxidase -dependent and -independent killing by host leukocytes. Fungal ROS resistance is partly mediated in part by Bir1, a homolog to survivin in humans, as Bir1 overexpression results in decreased ROS-induced conidial cell death and reduced killing by innate immune cells in vivo . We further report that overexpression of the Bir1 N-terminal BIR domain in A. fumigatus conidia results in altered expression of metabolic genes that functionally converge on mitochondrial function and cytochrome c ( cycA ) activity. Together, these studies demonstrate that cycA in A. fumigatus contributes to cell death responses that are induced by exogenous H 2 O 2 and by host leukocytes. Importance: Aspergillus fumigatus can cause a life-threatening infection known as invasive pulmonary aspergillosis (IPA), which is marked by fungus-attributable mortality rates of 20%-30%. Individuals at risk of IPA harbor genetic mutations or incur pharmacologic defects that impair myeloid cell numbers and/or function, exemplified by bone marrow transplant recipients, patients that receive corticosteroid therapy, or patients with Chronic Granulomatous Disease (CGD). However, treatments for Aspergillus infections remains limited, and resistance to the few existing drug classes is emerging. Recently, the World Health Organization (WHO) classified A. fumigatus as a critical priority fungal pathogen. Our research identifies an important aspect of fungal biology that impacts susceptibility to leukocyte killing. Furthering our understanding of mechanisms that mediate the outcome of fungal-leukocyte interactions will increase our understanding of both the underlying fungal biology governing cell death and innate immune evasion strategies utilized during mammalian infection pathogenesis. Consequently, our studies are a critical step toward leveraging these mechanisms for novel therapeutic advances.

Aspergillus fumigatus cytochrome c impacts conidial survival during sterilizing immunity.

IMPORTANCE: Aspergillus fumigatus can cause a life-threatening infection known as invasive pulmonary aspergillosis (IPA), which is marked by fungus-attributable mortality rates of 20%-30%. Individuals at risk for IPA harbor genetic mutations or incur pharmacologic defects that impair myeloid cell numbers and/or function, exemplified by bone marrow transplant recipients, patients that receive corticosteroid therapy, or patients with chronic granulomatous disease (CGD). However, treatments for Aspergillus infections remain limited, and resistance to the few existing drug classes is emerging. Recently, the World Health Organization classified A. fumigatus as a critical priority fungal pathogen. Our cell death research identifies an important aspect of fungal biology that impacts susceptibility to leukocyte killing. Furthering our understanding of mechanisms that mediate the outcome of fungal-leukocyte interactions will increase our understanding of both the underlying fungal biology governing cell death and innate immune evasion strategies utilized during mammalian infection pathogenesis. Consequently, our studies are a critical step toward leveraging these mechanisms for novel therapeutic advances.

Postinfluenza Environment Reduces Aspergillus fumigatus Conidium Clearance and Facilitates Invasive Aspergillosis In Vivo.

Aspergillus fumigatus is a human fungal pathogen that is most often avirulent in immunecompetent individuals because the innate immune system is efficient at eliminating fungal conidia. However, recent clinical observations have shown that severe influenza A virus (IAV) infection can lead to secondary A. fumigatus infections with high mortality. Little is currently known about how IAV infection alters the innate antifungal immune response. Here, we established a murine model of IAV-induced A. fumigatus (IAV-Af) superinfection by inoculating mice with IAV followed 6 days later by A. fumigatus conidia challenge. We observed increased mortality in the IAV-Af-superinfected mice compared to mice challenged with either IAV or A. fumigatus alone. A. fumigatus conidia were able to germinate and establish a biofilm in the lungs of the IAV-Af superinfection group, which was not seen following fungal challenge alone. While we did not observe any differences in inflammatory cell recruitment in the IAV-Af superinfection group compared to single-infection controls, we observed defects in Aspergillus conidial uptake and killing by both neutrophils and monocytes after IAV infection. pHrodo Green zymosan bioparticle (pHrodo-zymosan) and CM-H2DCFDA [5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate] staining, indicators of phagolysosome maturation and reactive oxygen species (ROS) production, respectively, revealed that the fungal killing defect was due in part to reduced phagolysosome maturation. Collectively, our data demonstrate that the ability of neutrophils and monocytes to kill and clear Aspergillus conidia is strongly reduced in the pulmonary environment of an IAV-infected lung, which leads to invasive pulmonary aspergillosis and increased overall mortality in our mouse model, recapitulating what is observed clinically in humans. IMPORTANCE Influenza A virus (IAV) is a common respiratory virus that causes seasonal illness in humans, but can cause pandemics and severe infection in certain patients. Since the emergence of the 2009 H1N1 pandemic strains, there has been an increase in clinical reports of IAV-infected patients in the intensive care unit (ICU) developing secondary pulmonary aspergillosis. These cases of flu-Aspergillus superinfections are associated with worse clinical outcomes than secondary bacterial infections in the setting of IAV. To date, we have a limited understanding of the cause(s) of secondary fungal infections in immunocompetent hosts. IAV-induced modulation of cytokine production and innate immune cellular function generates a unique immune environment in the lung, which could make the host vulnerable to a secondary fungal infection. Our work shows that defects in phagolysosome maturation in neutrophils and monocytes after IAV infection impair the ability of these cells to kill A. fumigatus, thus leading to increased fungal germination and growth and subsequent invasive aspergillosis. Our work lays a foundation for future mechanistic studies examining the exact immune modulatory events occurring in the respiratory tract after viral infection leading to secondary fungal infections.

A de novo duplication of Xp11.22-p11.4 in a girl with intellectual disability, structural brain anomalies, and preferential inactivation of the normal X chromosome.

Only a small number of individuals with duplications within the proximal short arm of the X chromosome have been reported. The majority of patients have duplications encompassing Xp11-p21, or extend more distally into Xp22. We report on a female patient who presented within the first year of life with plagiocephaly, speech delay, and epilepsy. Brain MRI showed a relatively thin cerebral cortex, abnormal periventricular white matter, and abnormal vessels in the left inferior parietal region. Cytogenetic and microsatellite analysis of the patient and her parents showed that she has a de novo duplication of Xp11.22-Xp11.4 on her paternal X chromosome. FISH analysis using fluorescently labeled BACs followed by array analysis including an X tilepath BAC array showed that a 12.3 Mb interval between 40.4 Mb and 52.7 Mb from the Xp telomere (NCBI build 36) was duplicated and excluded the presence of additional rearrangements along the X chromosome. Interestingly, X-inactivation studies in peripheral blood leukocytes showed that the duplicated (paternal) X chromosome was active in the majority of cells, in contrast to other patients with Xp duplications in whom X inactivation is random or skewed toward the normal X. These findings suggest that overexpression of genes from proximal Xp is likely to have contributed to her clinical phenotype.

Fan-out Estimation in Spin-based Quantum Computer Scale-up.

Solid-state spin-based qubits offer good prospects for scaling based on their long coherence times and nexus to large-scale electronic scale-up technologies. However, high-threshold quantum error correction requires a two-dimensional qubit array operating in parallel, posing significant challenges in fabrication and control. While architectures incorporating distributed quantum control meet this challenge head-on, most designs rely on individual control and readout of all qubits with high gate densities. We analysed the fan-out routing overhead of a dedicated control line architecture, basing the analysis on a generalised solid-state spin qubit platform parameterised to encompass Coulomb confined (e.g. donor based spin qubits) or electrostatically confined (e.g. quantum dot based spin qubits) implementations. The spatial scalability under this model is estimated using standard electronic routing methods and present-day fabrication constraints. Based on reasonable assumptions for qubit control and readout we estimate 102-105 physical qubits, depending on the quantum interconnect implementation, can be integrated and fanned-out independently. Assuming relatively long control-free interconnects the scalability can be extended. Ultimately, the universal quantum computation may necessitate a much higher number of integrated qubits, indicating that higher dimensional electronics fabrication and/or multiplexed distributed control and readout schemes may be the preferredstrategy for large-scale implementation.

Entropy Evolution in Consensus Networks.

We investigate the evolution of the network entropy for consensus dynamics in classical and quantum networks. We show that in the classical case, the network differential entropy is monotonically non-increasing if the node initial values are continuous random variables. While for quantum consensus dynamics, the network's von Neumann entropy is in contrast non-decreasing. In light of this inconsistency, we compare several distributed algorithms with random or deterministic coefficients for classical or quantum networks, and show that quantum algorithms with deterministic coefficients are physically related to classical algorithms with random coefficients.

Reaching Agreement in Quantum Hybrid Networks.

We consider a basic quantum hybrid network model consisting of a number of nodes each holding a qubit, for which the aim is to drive the network to a consensus in the sense that all qubits reach a common state. Projective measurements are applied serving as control means, and the measurement results are exchanged among the nodes via classical communication channels. In this way the quantum-opeartion/classical-communication nature of hybrid quantum networks is captured, although coherent states and joint operations are not taken into consideration in order to facilitate a clear and explicit analysis. We show how to carry out centralized optimal path planning for this network with all-to-all classical communications, in which case the problem becomes a stochastic optimal control problem with a continuous action space. To overcome the computation and communication obstacles facing the centralized solutions, we also develop a distributed Pairwise Qubit Projection (PQP) algorithm, where pairs of nodes meet at a given time and respectively perform measurements at their geometric average. We show that the qubit states are driven to a consensus almost surely along the proposed PQP algorithm, and that the expected qubit density operators converge to the average of the network's initial values.

Robust stability of uncertain linear quantum systems.

This paper considers the problem of robust stability for a class of uncertain linear quantum systems subject to unknown perturbations in the system Hamiltonian. The case of a nominal linear quantum system is considered with quadratic perturbations to the system Hamiltonian. A robust stability condition is given in terms of a strict bounded real condition.

Single photon quantum filtering using non-Markovian embeddings.

We determine quantum master and filter equations for continuous measurement of systems coupled to input fields in certain non-classical continuous-mode states, specifically single photon states. The quantum filters are shown to be derivable from an embedding into a larger non-Markovian system, and are given by a system of coupled stochastic differential equations.

Non-abelian Weyl commutation relations and the series product of quantum stochastic evolutions.

We show that the series product, which serves as an algebraic rule for connecting state-based input-output systems, is intimately related to the Heisenberg group and the canonical commutation relations. The series product for quantum stochastic models then corresponds to a non-abelian generalization of the Weyl commutation relation. We show that the series product gives the general rule for combining the generators of quantum stochastic evolutions using a Lie-Trotter product formula.