Loophole-free Bell inequality violation with superconducting circuits.

Superposition, entanglement and non-locality constitute fundamental features of quantum physics. The fact that quantum physics does not follow the principle of local causality1-3 can be experimentally demonstrated in Bell tests4 performed on pairs of spatially separated, entangled quantum systems. Although Bell tests, which are widely regarded as a litmus test of quantum physics, have been explored using a broad range of quantum systems over the past 50 years, only relatively recently have experiments free of so-called loopholes5 succeeded. Such experiments have been performed with spins in nitrogen-vacancy centres6, optical photons7-9 and neutral atoms10. Here we demonstrate a loophole-free violation of Bell's inequality with superconducting circuits, which are a prime contender for realizing quantum computing technology11. To evaluate a Clauser-Horne-Shimony-Holt-type Bell inequality4, we deterministically entangle a pair of qubits12 and perform fast and high-fidelity measurements13 along randomly chosen bases on the qubits connected through a cryogenic link14 spanning a distance of 30 metres. Evaluating more than 1 million experimental trials, we find an average S value of 2.0747 ± 0.0033, violating Bell's inequality with a P value smaller than 10-108. Our work demonstrates that non-locality is a viable new resource in quantum information technology realized with superconducting circuits with potential applications in quantum communication, quantum computing and fundamental physics15.

Realizing repeated quantum error correction in a distance-three surface code.

Quantum computers hold the promise of solving computational problems that are intractable using conventional methods1. For fault-tolerant operation, quantum computers must correct errors occurring owing to unavoidable decoherence and limited control accuracy2. Here we demonstrate quantum error correction using the surface code, which is known for its exceptionally high tolerance to errors3-6. Using 17 physical qubits in a superconducting circuit, we encode quantum information in a distance-three logical qubit, building on recent distance-two error-detection experiments7-9. In an error-correction cycle taking only 1.1 µs, we demonstrate the preservation of four cardinal states of the logical qubit. Repeatedly executing the cycle, we measure and decode both bit-flip and phase-flip error syndromes using a minimum-weight perfect-matching algorithm in an error-model-free approach and apply corrections in post-processing. We find a low logical error probability of 3% per cycle when rejecting experimental runs in which leakage is detected. The measured characteristics of our device agree well with a numerical model. Our demonstration of repeated, fast and high-performance quantum error-correction cycles, together with recent advances in ion traps10, support our understanding that fault-tolerant quantum computation will be practically realizable.

Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection.

Type 2 cytokines like IL-4 are hallmarks of helminth infection and activate macrophages to limit immunopathology and mediate helminth clearance. In addition to cytokines, nutrients and metabolites critically influence macrophage polarization. Choline is an essential nutrient known to support normal macrophage responses to lipopolysaccharide; however, its function in macrophages polarized by type 2 cytokines is unknown. Using murine IL-4-polarized macrophages, targeted lipidomics revealed significantly elevated levels of phosphatidylcholine, with select changes to other choline-containing lipid species. These changes were supported by the coordinated up-regulation of choline transport compared to naïve macrophages. Pharmacological inhibition of choline metabolism significantly suppressed several mitochondrial transcripts and dramatically inhibited select IL-4-responsive transcripts, most notably, Retnla. We further confirmed that blocking choline metabolism diminished IL-4-induced RELMα (encoded by Retnla) protein content and secretion and caused a dramatic reprogramming toward glycolytic metabolism. To better understand the physiological implications of these observations, naïve or mice infected with the intestinal helminth Heligmosomoides polygyrus were treated with the choline kinase α inhibitor, RSM-932A, to limit choline metabolism in vivo. Pharmacological inhibition of choline metabolism lowered RELMα expression across cell-types and tissues and led to the disappearance of peritoneal macrophages and B-1 lymphocytes and an influx of infiltrating monocytes. The impaired macrophage activation was associated with some loss in optimal immunity to H. polygyrus, with increased egg burden. Together, these data demonstrate that choline metabolism is required for macrophage RELMα induction, metabolic programming, and peritoneal immune homeostasis, which could have important implications in the context of other models of infection or cancer immunity.

Single-dose Effectiveness of Mpox Vaccine in Quebec, Canada: Test-negative Design With and Without Adjustment for Self-reported Exposure Risk.

INTRODUCTION: During the 2022 mpox outbreak, the province of Quebec, Canada, prioritized first doses for pre-exposure vaccination of people at high mpox risk, delaying second doses due to limited supply. We estimated single-dose mpox vaccine effectiveness (VE) adjusting for virus exposure risk based only on surrogate indicators available within administrative databases (eg, clinical record of sexually transmitted infections) or supplemented by self-reported risk factor information (eg, sexual contacts). METHODS: We conducted a test-negative case-control study between 19 June and 24 September 2022. Information from administrative databases was supplemented by questionnaire collection of self-reported risk factors specific to the 3-week period before testing. Two study populations were assessed: all within the administrative databases (All-Admin) and the subset completing the questionnaire (Sub-Quest). Logistic regression models adjusted for age, calendar-time and exposure-risk, the latter based on administrative indicators only (All-Admin and Sub-Quest) or with questionnaire supplementation (Sub-Quest). RESULTS: There were 532 All-Admin participants, of which 199 (37%) belonged to Sub-Quest. With exposure-risk adjustment based only on administrative indicators, single-dose VE estimates were similar among All-Admin and Sub-Quest populations at 35% (95% confidence interval [CI]:-2 to 59) and 30% (95% CI:-38 to 64), respectively. With adjustment supplemented by questionnaire information, the Sub-Quest VE estimate increased to 65% (95% CI:1-87), with overlapping confidence intervals. CONCLUSIONS: Using only administrative data, we estimate one vaccine dose reduced the mpox risk by about one-third; whereas, additionally adjusting for self-reported risk factor information revealed greater vaccine benefit, with one dose instead estimated to reduce the mpox risk by about two-thirds. Inadequate exposure-risk adjustment may substantially under-estimate mpox VE.

In Vitro Modeling of Congenital Heart Defects Associated with an NKX2-5 Mutation Revealed a Dysregulation in BMP/Notch-Mediated Signaling.

The Nkx2-5 gene codes for a transcription factor that plays a critical role in heart development. Heterozygous mutations in NKX2-5 in both human and mice result in congenital heart defects (CHDs). However, the molecular mechanisms by which these mutations cause the disease are still unknown. Recently, we have generated the heterozygous mouse model of the human CHDs associated mutation NKX2-5 R142C (Nkx2-5R141C/+ mouse ortholog of human NKX2-5 R142C variant) that developed septal and conduction defects. This study generated a heterozygous Nkx2-5 R141C mouse embryonic stem cell line (Nkx2-5R141C/+ mESCs) to model CHDs in vitro. We observed that Nkx2-5R141C/+ mESCs display an alteration in the expression of genes that are essential for normal heart development. Furthermore, the reduced cardiomyogenesis is paralleled by a reduction in nuclear import of Nkx2-5 protein. Examination of the Nkx2-5R141C/+ embryos at E8.5 revealed a transient loss of cardiomyogenesis, which is consistent with the phenotype observed in vitro. Moreover, gene expression profiling of Nkx2-5R141C/+ cells at an early stage of cardiac differentiation revealed pronounced deregulation of several cardiac differentiation and function genes. Collectively, our data showed that heterozygosity for the R141C mutation results in disruption of the cellular distribution of Nkx2-5 protein, a transient reduction in cardiomyogenesis that may disrupt the early patterning of the heart, and this, in turn, affects the intricate orchestration of signaling pathways leading to downregulation of Bone morphogenetic protein (BMP) and Notch signaling. Therefore, we have developed mESCs model of a human CHD, providing an in vitro system to examine early stages of heart development, which are otherwise difficult to study in vivo. Stem Cells 2018;36:514-526.

Insights into interplay between rexinoid signaling and myogenic regulatory factor-associated chromatin state in myogenic differentiation.

While skeletal myogenesis is tightly coordinated by myogenic regulatory factors including MyoD and myogenin, chromatin modifications have emerged as vital mechanisms of myogenic regulation. We have previously established that bexarotene, a clinically approved agonist of retinoid X receptor (RXR), promotes the specification and differentiation of skeletal muscle lineage. Here, we examine the genome-wide impact of rexinoids on myogenic differentiation through integral RNA-seq and ChIP-seq analyses. We found that bexarotene promotes myoblast differentiation through the coordination of exit from the cell cycle and the activation of muscle-related genes. We uncovered a new mechanism of rexinoid action which is mediated by the nuclear receptor and largely reconciled through a direct regulation of MyoD gene expression. In addition, we determined a rexinoid-responsive residue-specific histone acetylation at a distinct chromatin state associated to MyoD and myogenin. Thus, we provide novel molecular insights into the interplay between RXR signaling and chromatin states pertinent to myogenic programs in early myoblast differentiation.

Molecular basis for the methylation specificity of ATXR5 for histone H3.

In plants, the histone H3.1 lysine 27 (H3K27) mono-methyltransferases ARABIDOPSIS TRITHORAX RELATED PROTEIN 5 and 6 (ATXR5/6) regulate heterochromatic DNA replication and genome stability. Our initial studies showed that ATXR5/6 discriminate between histone H3 variants and preferentially methylate K27 on H3.1. In this study, we report three regulatory mechanisms contributing to the specificity of ATXR5/6. First, we show that ATXR5 preferentially methylates the R/F-K*-S/C-G/A-P/C motif with striking preference for hydrophobic and aromatic residues in positions flanking this core of five amino acids. Second, we demonstrate that post-transcriptional modifications of residues neighboring K27 that are typically associated with actively transcribed chromatin are detrimental to ATXR5 activity. Third, we show that ATXR5 PHD domain employs a narrow binding pocket to selectively recognize unmethylated K4 of histone H3. Finally, we demonstrate that deletion or mutation of the PHD domain reduces the catalytic efficiency (kcat/Km of AdoMet) of ATXR5 up to 58-fold, highlighting the multifunctional nature of ATXR5 PHD domain. Overall, our results suggest that several molecular determinants regulate ATXR5/6 methyltransferase activity and epigenetic inheritance of H3.1 K27me1 mark in plants.

Regulation of Hspb7 by MEF2 and AP-1: implications for Hspb7 in muscle atrophy.

Mycocyte enhancer factor 2 (MEF2) and activator protein 1 (AP-1) transcription complexes have been individually implicated in myogenesis, but their genetic interaction has not previously been addressed. Using MEF2A, c-Jun and Fra-1 chromatin immunoprecipitation sequencing (ChIP-seq) data and predicted AP-1 consensus motifs, we identified putative common MEF2 and AP-1 target genes, several of which are implicated in regulating the actin cytoskeleton. Because muscle atrophy results in remodelling or degradation of the actin cytoskeleton, we characterized the expression of putative MEF2 and AP-1 target genes (Dstn, Flnc, Hspb7, Lmod3 and Plekhh2) under atrophic conditions using dexamethasone (Dex) treatment in skeletal myoblasts. Heat shock protein b7 (Hspb7) was induced by Dex treatment and further analyses revealed that loss of MEF2A using siRNA prevented Dex-regulated induction of Hspb7. Conversely, ectopic Fra-2 or c-Jun expression reduced Dex-mediated upregulation of Hspb7 whereas AP-1 depletion enhanced Hspb7 expression. In vivo, expression of Hspb7 and other autophagy-related genes was upregulated in response to atrophic conditions in mice. Manipulation of Hspb7 levels in mice also impacted gross muscle mass. Collectively, these data indicate that MEF2 and AP-1 confer antagonistic regulation of Hspb7 gene expression in skeletal muscle, with implications for autophagy and muscle atrophy.

Itinerant Microwave Photon Detector.

The realization of a high-efficiency microwave single photon detector is a long-standing problem in the field of microwave quantum optics. Here, we propose a quantum nondemolition, high-efficiency photon detector that can readily be implemented in present state-of-the-art circuit quantum electrodynamics. This scheme works in a continuous fashion, gaining information about the photon arrival time as well as about its presence. The key insight that allows us to circumvent the usual limitations imposed by measurement backaction is the use of long-lived dark states in a small ensemble of inhomogeneous artificial atoms to increase the interaction time between the photon and the measurement device. Using realistic system parameters, we show that large detection fidelities are possible.

BRG1 interacts with GLI2 and binds Mef2c gene in a hedgehog signalling dependent manner during in vitro cardiomyogenesis.

BACKGROUND: The Hedgehog (HH) signalling pathway regulates cardiomyogenesis in vivo and in differentiating P19 embryonal carcinoma (EC) cells, a mouse embryonic stem (mES) cell model. To further assess the transcriptional role of HH signalling during cardiomyogenesis in stem cells, we studied the effects of overexpressing GLI2, a primary transducer of the HH signalling pathway, in mES cells. RESULTS: Stable GLI2 overexpression resulted in an enhancement of cardiac progenitor-enriched genes, Mef2c, Nkx2-5, and Tbx5 during mES cell differentiation. In contrast, pharmacological blockade of the HH pathway in mES cells resulted in lower expression of these genes. Mass spectrometric analysis identified the chromatin remodelling factor BRG1 as a protein which co-immunoprecipitates with GLI2 in differentiating mES cells. We then determined that BRG1 is recruited to a GLI2-specific Mef2c gene element in a HH signalling-dependent manner during cardiomyogenesis in P19 EC cells, a mES cell model. CONCLUSIONS: Thus, we propose a mechanism where HH/GLI2 regulates the expression of Mef2c by recruiting BRG1 to the Mef2c gene, most probably via chromatin remodelling, to ultimately regulate in vitro cardiomyogenesis.

High-Fidelity Resonator-Induced Phase Gate with Single-Mode Squeezing.

We propose to increase the fidelity of two-qubit resonator-induced phase gates in circuit QED by the use of narrow-band single-mode squeezing. We show that there exists an optimal squeezing angle and strength that erases qubit "which-path" information leaking out of the cavity and thereby minimizes qubit dephasing during these gates. Our analytical results for the gate fidelity are in excellent agreement with numerical simulations of a cascaded master equation that takes into account the dynamics of the source of squeezed radiation. With realistic parameters, we find that it is possible to realize a controlled-phase gate with a gate time of 200 ns and average infidelity of 10^{-5}.

Quantum Optics Theory of Electronic Noise in Coherent Conductors.

We consider the electromagnetic field generated by a coherent conductor in which electron transport is described quantum mechanically. We obtain an input-output relation linking the quantum current in the conductor to the measured electromagnetic field. This allows us to compute the outcome of measurements on the field in terms of the statistical properties of the current. We moreover show how under ac bias the conductor acts as a tunable medium for the field, allowing for the generation of single- and two-mode squeezing through fermionic reservoir engineering. These results explain the recently observed squeezing using normal tunnel junctions [G. Gasse et al., Phys. Rev. Lett. 111, 136601 (2013); J.-C. Forgues et al., Phys. Rev. Lett. 114, 130403 (2015)].

Genome-wide association between Six4, MyoD, and the histone demethylase Utx during myogenesis.

Adult skeletal muscles can regenerate after injury, due to the presence of satellite cells, a quiescent population of myogenic progenitor cells. Once activated, satellite cells repair the muscle damage by undergoing myogenic differentiation. The myogenic regulatory factors (MRFs) coordinate the process of progenitor differentiation in cooperation with other families of transcription factors (TFs). The Six1 and Six4 homeodomain TFs are expressed in developing and adult muscle and Six1 is critical for embryonic and adult myogenesis. However, the lack of a muscle developmental phenotype in Six4-null mice, which has been attributed to compensation by other Six family members, has discouraged further assessment of the role of Six4 during adult muscle regeneration. By employing genome-wide approaches to address the function of Six4 during adult skeletal myogenesis, we have identified a core set of muscle genes coordinately regulated in adult muscle precursors by Six4 and the MRF MyoD. Throughout the genome of differentiating adult myoblasts, the cooperation between Six4 and MyoD is associated with chromatin repressive mark removal by Utx, a demethylase of histone H3 trimethylated at lysine 27. Among the genes coordinately regulated by Six4 and MyoD are several genes critical for proper in vivo muscle regeneration, implicating a role of Six4 in this process. Using in vivo RNA interference of Six4, we expose an uncompensated function of this TF during muscle regeneration. Together, our results reveal a role for Six4 during adult muscle regeneration and suggest a widespread mechanism of cooperation between Six4 and MyoD.

Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms.

Polycomb group proteins are critical to maintaining gene repression established during Drosophila development. Part of this group forms the PRC2 complex containing Ez that catalyzes di- and trimethylation of histone H3 lysine 27 (H3K37me2/3), marks repressive to transcription. We report that the mammalian homologs Ezh1 and Ezh2 form similar PRC2 complexes but exhibit contrasting repressive roles. While PRC2-Ezh2 catalyzes H3K27me2/3 and its knockdown affects global H3K27me2/3 levels, PRC2-Ezh1 performs this function weakly. In accordance, Ezh1 knockdown was ineffectual on global H3K27me2/3 levels. Instead, PRC2-Ezh1 directly and robustly represses transcription from chromatinized templates and compacts chromatin in the absence of the methyltransferase cofactor SAM, as evidenced by electron microscopy. Ezh1 targets a subset of Ezh2 genes, yet Ezh1 is more abundant in nonproliferative adult organs while Ezh2 expression is tightly associated with proliferation, as evidenced when analyzing aging mouse kidney. These results might reflect subfunctionalization of a PcG protein during evolution.

Global MEF2 target gene analysis in cardiac and skeletal muscle reveals novel regulation of DUSP6 by p38MAPK-MEF2 signaling.

MEF2 plays a profound role in the regulation of transcription in cardiac and skeletal muscle lineages. To define the overlapping and unique MEF2A genomic targets, we utilized ChIP-exo analysis of cardiomyocytes and skeletal myoblasts. Of the 2783 and 1648 MEF2A binding peaks in skeletal myoblasts and cardiomyocytes, respectively, 294 common binding sites were identified. Genomic targets were compared to differentially expressed genes in RNA-seq analysis of MEF2A depleted myogenic cells, revealing two prominent genetic networks. Genes largely associated with muscle development were down-regulated by loss of MEF2A while up-regulated genes reveal a previously unrecognized function of MEF2A in suppressing growth/proliferative genes. Several up-regulated (Tprg, Mctp2, Kitl, Prrx1, Dusp6) and down-regulated (Atp1a2, Hspb7, Tmem182, Sorbs2, Lmod3) MEF2A target genes were chosen for further investigation. Interestingly, siRNA targeting of the MEF2A/D heterodimer revealed a somewhat divergent role in the regulation of Dusp6, a MAPK phosphatase, in cardiac and skeletal myogenic lineages. Furthermore, MEF2D functions as a p38MAPK-dependent repressor of Dusp6 in myoblasts. These data illustrate that MEF2 orchestrates both common and non-overlapping programs of signal-dependent gene expression in skeletal and cardiac muscle lineages.

Fast Quantum Nondemolition Readout by Parametric Modulation of Longitudinal Qubit-Oscillator Interaction.

We show how to realize fast and high-fidelity quantum nondemolition qubit readout using longitudinal qubit-oscillator interaction. This is accomplished by modulating the longitudinal coupling at the cavity frequency. The qubit-oscillator interaction then acts as a qubit-state dependent drive on the cavity, a situation that is fundamentally different from the standard dispersive case. Single-mode squeezing can be exploited to exponentially increase the signal-to-noise ratio of this readout protocol. We present an implementation of this longitudinal parametric readout in circuit quantum electrodynamics and a possible multiqubit architecture.

Heisenberg-Limited Qubit Read-Out with Two-Mode Squeezed Light.

We show how to use two-mode squeezed light to exponentially enhance cavity-based dispersive qubit measurement. Our scheme enables true Heisenberg-limited scaling of the measurement, and crucially, it is not restricted to small dispersive couplings or unrealistically long measurement times. It involves coupling a qubit dispersively to two cavities and making use of a symmetry in the dynamics of joint cavity quadratures (a so-called quantum-mechanics-free subsystem). We discuss the basic scaling of the scheme and its robustness against imperfections, as well as a realistic implementation in circuit quantum electrodynamics.

Identification of cis-regulatory modules in promoters of human genes exploiting mutual positioning of transcription factors.

In higher organisms, gene regulation is controlled by the interplay of non-random combinations of multiple transcription factors (TFs). Although numerous attempts have been made to identify these combinations, important details, such as mutual positioning of the factors that have an important role in the TF interplay, are still missing. The goal of the present work is in silico mapping of some of such associating factors based on their mutual positioning, using computational screening. We have selected the process of myogenesis as a study case, and we focused on TF combinations involving master myogenic TF Myogenic differentiation (MyoD) with other factors situated at specific distances from it. The results of our work show that some muscle-specific factors occur together with MyoD within the range of ±100 bp in a large number of promoters. We confirm co-occurrence of the MyoD with muscle-specific factors as described in earlier studies. However, we have also found novel relationships of MyoD with other factors not specific for muscle. Additionally, we have observed that MyoD tends to associate with different factors in proximal and distal promoter areas. The major outcome of our study is establishing the genome-wide connection between biological interactions of TFs and close co-occurrence of their binding sites.

UTX mediates demethylation of H3K27me3 at muscle-specific genes during myogenesis.

Polycomb (PcG) and Trithorax (TrxG) group proteins act antagonistically to establish tissue-specific patterns of gene expression. The PcG protein Ezh2 facilitates repression by catalysing histone H3-Lys27 trimethylation (H3K27me3). For expression, H3K27me3 marks are removed and replaced by TrxG protein catalysed histone H3-Lys4 trimethylation (H3K4me3). Although H3K27 demethylases have been identified, the mechanism by which these enzymes are targeted to specific genomic regions to remove H3K27me3 marks has not been established. Here, we demonstrate a two-step mechanism for UTX-mediated demethylation at muscle-specific genes during myogenesis. Although the transactivator Six4 initially recruits UTX to the regulatory region of muscle genes, the resulting loss of H3K27me3 marks is limited to the region upstream of the transcriptional start site. Removal of the repressive H3K27me3 mark within the coding region then requires RNA Polymerase II (Pol II) elongation. Interestingly, blocking Pol II elongation on transcribed genes leads to increased H3K27me3 within the coding region, and formation of bivalent (H3K27me3/H3K4me3) chromatin domains. Thus, removal of repressive H3K27me3 marks by UTX occurs through targeted recruitment followed by spreading across the gene.

E2F-associated chromatin modifiers and cell cycle control.

The E2F family of proteins was identified on the basis of its role in promoting the G0 to S phase transition. Research over the past several years has unveiled considerable complexity within the family, with numerous studies pointing to delegation of function for distinct family members. More recent studies highlighted in this review have expanded this picture, suggesting ways in which E2F target gene expression is refined during cell cycle progression by facilitating the acquisition of promoter-specific histone modifications. E2F associated co-activators promote activating histone marks while recruitment of co-repressors associated with E2Fs and the pRB family leads to accretion of inhibitory histone modifications that provoke chromatin compaction.