Publications by authors named "Alexandre Blais"

59 Publications

Bias-preserving gates with stabilized cat qubits.

Sci Adv 2020 Aug 21;6(34). Epub 2020 Aug 21.

Department of Physics, Yale University, New Haven, CT 06520, USA.

The code capacity threshold for error correction using biased-noise qubits is known to be higher than with qubits without such structured noise. However, realistic circuit-level noise severely restricts these improvements. This is because gate operations, such as a controlled-NOT (CX) gate, which do not commute with the dominant error, unbias the noise channel. Here, we overcome the challenge of implementing a bias-preserving CX gate using biased-noise stabilized cat qubits in driven nonlinear oscillators. This continuous-variable gate relies on nontrivial phase space topology of the cat states. Furthermore, by following a scheme for concatenated error correction, we show that the availability of bias-preserving CX gates with moderately sized cats improves a rigorous lower bound on the fault-tolerant threshold by a factor of two and decreases the overhead in logical Clifford operations by a factor of five. Our results open a path toward high-threshold, low-overhead, fault-tolerant codes tailored to biased-noise cat qubits.
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http://dx.doi.org/10.1126/sciadv.aay5901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442480PMC
August 2020

Gene expression profiling of skeletal myogenesis in human embryonic stem cells reveals a potential cascade of transcription factors regulating stages of myogenesis, including quiescent/activated satellite cell-like gene expression.

PLoS One 2019 27;14(9):e0222946. Epub 2019 Sep 27.

Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Human embryonic stem cell (hESC)-derived skeletal muscle progenitors (SMP)-defined as PAX7-expressing cells with myogenic potential-can provide an abundant source of donor material for muscle stem cell therapy. As in vitro myogenesis is decoupled from in vivo timing and 3D-embryo structure, it is important to characterize what stage or type of muscle is modeled in culture. Here, gene expression profiling is analyzed in hESCs over a 50 day skeletal myogenesis protocol and compared to datasets of other hESC-derived skeletal muscle and adult murine satellite cells. Furthermore, day 2 cultures differentiated with high or lower concentrations of CHIR99021, a GSK3A/GSK3B inhibitor, were contrasted. Expression profiling of the 50 day time course identified successively expressed gene subsets involved in mesoderm/paraxial mesoderm induction, somitogenesis, and skeletal muscle commitment/formation which could be regulated by a putative cascade of transcription factors. Initiating differentiation with higher CHIR99021 concentrations significantly increased expression of MSGN1 and TGFB-superfamily genes, notably NODAL, resulting in enhanced paraxial mesoderm and reduced ectoderm/neuronal gene expression. Comparison to adult satellite cells revealed that genes expressed in 50-day cultures correlated better with those expressed by quiescent or early activated satellite cells, which have the greatest therapeutic potential. Day 50 cultures were similar to other hESC-derived skeletal muscle and both expressed known and novel SMP surface proteins. Overall, a putative cascade of transcription factors has been identified which regulates four stages of myogenesis. Subsets of these factors were upregulated by high CHIR99021 or their binding sites were significantly over-represented during SMP activation, ranging from quiescent to late-activated stages. This analysis serves as a resource to further study the progression of in vitro skeletal myogenesis and could be mined to identify novel markers of pluripotent-derived SMPs or regulatory transcription/growth factors. Finally, 50-day hESC-derived SMPs appear similar to quiescent/early activated satellite cells, suggesting they possess therapeutic potential.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222946PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764674PMC
April 2020

Combinatorial Utilization of Murine Embryonic Stem Cells and In Vivo Models to Study Human Congenital Heart Disease.

Curr Protoc Stem Cell Biol 2019 02 12;48(1):e75. Epub 2018 Dec 12.

Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.

We have established an in vitro model of the human congenital heart defect (CHD)-associated mutation NKX2.5 R141C. We describe the use of the hanging drop method to differentiate Nkx2.5 murine embryonic stem cells (mESCs) along with Nkx2.5 control cells. This method allows us to recapitulate the early stages of embryonic heart development in tissue culture. We also use qRT-PCR and immunofluorescence to examine samples at different time points during differentiation to validate our data. The in vivo model is a mouse line with a knock-in of the same mutation. We describe the isolation of RNA from embryonic day 8.5 (E8.5) embryos and E9.5 hearts of wild-type and mutant mice. We found that the in vitro model shows reduced cardiomyogenesis, similar to Nkx2.5 embryos at E8.5, indicating a transient loss of cardiomyogenesis at this time point. These results suggest that our in vitro model can be used to study very early changes in heart development that cause CHD. © 2018 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cpsc.75DOI Listing
February 2019

Qubit parity measurement by parametric driving in circuit QED.

Sci Adv 2018 11 30;4(11):eaau1695. Epub 2018 Nov 30.

Institut quantique and Départment de Physique, Université de Sherbrooke, 2500 boulevard de l'Université, Sherbrooke, Québec J1K 2R1, Canada.

Multiqubit parity measurements are essential to quantum error correction. Current realizations of these measurements often rely on ancilla qubits, a method that is sensitive to faulty two-qubit gates and that requires notable experimental overhead. We propose a hardware-efficient multiqubit parity measurement exploiting the bifurcation dynamics of a parametrically driven nonlinear oscillator. This approach takes advantage of the resonator's parametric oscillation threshold, which depends on the joint parity of dispersively coupled qubits, leading to high-amplitude oscillations for one parity subspace and no oscillation for the other. We present analytical and numerical results for two- and four-qubit parity measurements, with high-fidelity readout preserving the parity eigenpaces. Moreover, we discuss a possible realization that can be readily implemented with the current circuit quantum electrodynamics (QED) experimental toolbox. These results could lead to substantial simplifications in the experimental implementation of quantum error correction and notably of the surface code.
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http://dx.doi.org/10.1126/sciadv.aau1695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269160PMC
November 2018

Itinerant Microwave Photon Detector.

Phys Rev Lett 2018 May;120(20):203602

Institut quantique and Départment de Physique, Université de Sherbrooke, 2500 boulevard de l'Université, Sherbrooke, Québec J1K 2R1, Canada.

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.
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http://dx.doi.org/10.1103/PhysRevLett.120.203602DOI Listing
May 2018

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

Stem Cells 2018 04 9;36(4):514-526. Epub 2018 Jan 9.

Center for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada.

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 (Nkx2-5 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 (Nkx2-5 mESCs) to model CHDs in vitro. We observed that Nkx2-5 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 Nkx2-5 embryos at E8.5 revealed a transient loss of cardiomyogenesis, which is consistent with the phenotype observed in vitro. Moreover, gene expression profiling of Nkx2-5 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.
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http://dx.doi.org/10.1002/stem.2766DOI Listing
April 2018

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

Nucleic Acids Res 2017 Nov;45(19):11236-11248

Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.

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.
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http://dx.doi.org/10.1093/nar/gkx800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737385PMC
November 2017

SOX7 Is Required for Muscle Satellite Cell Development and Maintenance.

Stem Cell Reports 2017 10 21;9(4):1139-1151. Epub 2017 Sep 21.

Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada. Electronic address:

Satellite cells are skeletal-muscle-specific stem cells that are activated by injury to proliferate, differentiate, and fuse to enable repair. SOX7, a member of the SRY-related HMG-box family of transcription factors is expressed in quiescent satellite cells. To elucidate SOX7 function in skeletal muscle, we knocked down Sox7 expression in embryonic stem cells and primary myoblasts and generated a conditional knockout mouse in which Sox7 is excised in PAX3 cells. Loss of Sox7 in embryonic stem cells reduced Pax3 and Pax7 expression. In vivo, conditional knockdown of Sox7 reduced the satellite cell population from birth, reduced myofiber caliber, and impaired regeneration after acute injury. Although Sox7-deficient primary myoblasts differentiated normally, impaired myoblast fusion and increased sensitivity to apoptosis in culture and in vivo were observed. Taken together, these results indicate that SOX7 is dispensable for myogenesis but is necessary to promote satellite cell development and survival.
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http://dx.doi.org/10.1016/j.stemcr.2017.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639291PMC
October 2017

A Single TCF Transcription Factor, Regardless of Its Activation Capacity, Is Sufficient for Effective Trilineage Differentiation of ESCs.

Cell Rep 2017 Sep;20(10):2424-2438

Department of Biochemistry and Biomedical Sciences, Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada. Electronic address:

Co-expression and cross-regulation of the four TCF/LEFs render their redundant and unique functions ambiguous. Here, we describe quadruple-knockout (QKO) mouse ESCs lacking all full-length TCF/LEFs and cell lines rescued with TCF7 or TCF7L1. QKO cells self-renew, despite gene expression patterns that differ significantly from WT, and display delayed, neurectoderm-biased, embryoid body (EB) differentiation. QKO EBs have no contracting cardiomyocytes and differentiate poorly into mesendoderm but readily generate neuronal cells. QKO cells and TCF7L1-rescued cells cannot efficiently activate TCF reporters, whereas TCF7-rescued cells exhibit significant reporter responsiveness. Surprisingly, despite dramatically different transactivation capacities, re-expression of TCF7L1 or TCF7 in QKO cells restores their tri-lineage differentiation ability, with similar lineage marker expression patterns and beating cardiomyocyte frequencies observed in EBs. Both factors also similarly affect the transcriptome of QKO cells. Our data reveal that a single TCF, regardless of its activation capacity, is sufficient for effective trilineage differentiation of ESCs.
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http://dx.doi.org/10.1016/j.celrep.2017.08.043DOI Listing
September 2017

Quantum annealing with all-to-all connected nonlinear oscillators.

Nat Commun 2017 06 8;8:15785. Epub 2017 Jun 8.

Institut quantique and Départment de Physique, Université de Sherbrooke, Sherbrooke, Québec, Canada J1K 2R1.

Quantum annealing aims at solving combinatorial optimization problems mapped to Ising interactions between quantum spins. Here, with the objective of developing a noise-resilient annealer, we propose a paradigm for quantum annealing with a scalable network of two-photon-driven Kerr-nonlinear resonators. Each resonator encodes an Ising spin in a robust degenerate subspace formed by two coherent states of opposite phases. A fully connected optimization problem is mapped to local fields driving the resonators, which are connected with only local four-body interactions. We describe an adiabatic annealing protocol in this system and analyse its performance in the presence of photon loss. Numerical simulations indicate substantial resilience to this noise channel, leading to a high success probability for quantum annealing. Finally, we propose a realistic circuit QED implementation of this promising platform for implementing a large-scale quantum Ising machine.
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http://dx.doi.org/10.1038/ncomms15785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472748PMC
June 2017

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

Nucleic Acids Res 2017 Jun;45(11):6375-6387

Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada.

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.
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http://dx.doi.org/10.1093/nar/gkx224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499861PMC
June 2017

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

J Cell Sci 2016 11 15;129(21):4076-4090. Epub 2016 Sep 15.

Department of Biology, York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3

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.
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http://dx.doi.org/10.1242/jcs.190009DOI Listing
November 2016

Inhibition of ROS and upregulation of inflammatory cytokines by FoxO3a promotes survival against Salmonella typhimurium.

Nat Commun 2016 09 7;7:12748. Epub 2016 Sep 7.

Faculty of Medicine, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H8M5.

Virulent intracellular pathogens, such as the Salmonella species, engage numerous virulence factors to subvert host defence mechanisms to induce a chronic infection that leads to typhoid or exacerbation of other chronic inflammatory conditions. Here we show the role of the forkhead transcription factor FoxO3a during infection of mice with Salmonella typhimurium (ST). Although FoxO3a signalling does not affect the development of CD8(+) T cell responses to ST, FoxO3a has an important protective role, particularly during the chronic stage of infection, by limiting the persistence of oxidative stress. Furthermore, FoxO3a signalling regulates ERK signalling in macrophages, which results in the maintenance of a proinflammatory state. FoxO3a signalling does not affect cell proliferation or cell death. Thus, these results reveal mechanisms by which FoxO3a promotes host survival during infection with chronic, virulent intracellular bacteria.
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http://dx.doi.org/10.1038/ncomms12748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023958PMC
September 2016

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

BMC Dev Biol 2016 08 2;16(1):27. Epub 2016 Aug 2.

Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Rd, K1H 8M5, Ottawa, Canada.

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.
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http://dx.doi.org/10.1186/s12861-016-0127-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970297PMC
August 2016

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

Phys Rev Lett 2016 May 2;116(18):180501. Epub 2016 May 2.

Départment de Physique, Université de Sherbrooke, Sherbrooke, Québec, Canada J1K 2R1.

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}.
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http://dx.doi.org/10.1103/PhysRevLett.116.180501DOI Listing
May 2016

Quantum Optics Theory of Electronic Noise in Coherent Conductors.

Phys Rev Lett 2016 Jan 27;116(4):043602. Epub 2016 Jan 27.

Départment de Physique, Université de Sherbrooke, 2500 boulevard de l'Université, Sherbrooke, Québec J1K 2R1, Canada.

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)].
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http://dx.doi.org/10.1103/PhysRevLett.116.043602DOI Listing
January 2016

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

Phys Rev Lett 2015 Nov 9;115(20):203601. Epub 2015 Nov 9.

Départment de Physique, Université de Sherbrooke, 2500 boulevard de l'Université, Sherbrooke, Québec J1K 2R1, Canada.

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.
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http://dx.doi.org/10.1103/PhysRevLett.115.203601DOI Listing
November 2015

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

Phys Rev Lett 2015 Aug 27;115(9):093604. Epub 2015 Aug 27.

Department of Physics, McGill University, 3600 rue University, Montreal, Quebec H3A 2T8, Canada.

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.
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http://dx.doi.org/10.1103/PhysRevLett.115.093604DOI Listing
August 2015

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

FASEB J 2015 Nov 30;29(11):4738-55. Epub 2015 Jul 30.

*Ottawa Institute of Systems Biology, Ottawa, Ontario, Canada; and Department of Biochemistry, Microbiology, and Immunology and Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

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.
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http://dx.doi.org/10.1096/fj.15-277053DOI Listing
November 2015

Transcriptional control of stem cell fate by E2Fs and pocket proteins.

Front Genet 2015 28;6:161. Epub 2015 Apr 28.

Ottawa Institute of Systems Biology, Ottawa, ON Canada ; Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON Canada.

E2F transcription factors and their regulatory partners, the pocket proteins (PPs), have emerged as essential regulators of stem cell fate control in a number of lineages. In mammals, this role extends from both pluripotent stem cells to those encompassing all embryonic germ layers, as well as extra-embryonic lineages. E2F/PP-mediated regulation of stem cell decisions is highly evolutionarily conserved, and is likely a pivotal biological mechanism underlying stem cell homeostasis. This has immense implications for organismal development, tissue maintenance, and regeneration. In this article, we discuss the roles of E2F factors and PPs in stem cell populations, focusing on mammalian systems. We discuss emerging findings that position the E2F and PP families as widespread and dynamic epigenetic regulators of cell fate decisions. Additionally, we focus on the ever expanding landscape of E2F/PP target genes, and explore the possibility that E2Fs are not simply regulators of general 'multi-purpose' cell fate genes but can execute tissue- and cell type-specific gene regulatory programs.
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http://dx.doi.org/10.3389/fgene.2015.00161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412126PMC
May 2015

Myogenesis in the genomics era.

Authors:
Alexandre Blais

J Mol Biol 2015 Jun 14;427(11):2023-38. Epub 2015 Feb 14.

Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada. Electronic address:

Skeletal myogenesis is the process of formation of the muscles that enable movement and breathing. Muscles form after the fate determination and differentiation of precursor cells. Being an extraordinarily complex process, myogenesis is regulated at multiple levels, and transcriptional regulation naturally plays a big part in the making of muscle. A significant part of what we know today of the transcriptional regulatory networks overseeing myogenesis comes from large-scale functional genomics studies. The objective of this review is to provide an overview of the various genomics techniques that have been employed over the years to understand myogenic regulation, to give a sense of the degree of understanding they have provided us up to now, and to highlight the next challenges to be overcome.
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http://dx.doi.org/10.1016/j.jmb.2015.02.009DOI Listing
June 2015

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

Nucleic Acids Res 2014 Oct 12;42(18):11349-62. Epub 2014 Sep 12.

Department of Biology, York University, 4700 Keele Street Toronto, Ontario, M3J 1P3 Canada Muscle Health Research Centre (MHRC), York University, 4700 Keele Street, Toronto, Ontario, M3J 1P3 Canada Centre for Research on Biomolecular Interactions (CRBI), 4700 Keele Street, Toronto, Ontario, M3J 1P3 Canada Centre for Research in Mass Spectrometry (CRMS), York University, 4700 Keele Street, Toronto, Ontario, M3J 1P3 Canada

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.
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http://dx.doi.org/10.1093/nar/gku813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191398PMC
October 2014

Keeping them all together: β-propeller domains in histone methyltransferase complexes.

J Mol Biol 2014 Oct 20;426(20):3363-75. Epub 2014 May 20.

Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, K1H 8M5, Canada. Electronic address:

Histone methyltransferases (HKMTs) residing in multi-subunit protein complexes frequently require the presence of β-propeller proteins to achieve their biological functions. Recent biochemical studies have highlighted the functional diversity of these scaffolding proteins in maintaining the integrity of the complexes, allosterically regulating HKMT enzymatic activity and acting as "histone tethering devices" to facilitate the interaction between HKMTs and their substrates. Structural studies have revealed that, while β-propeller domain proteins share structural similarity, they employ divergent mechanisms to achieve their functions. This review focuses on the progress made in the last decade to identify the biochemical determinants underlying the functions of these important proteins.
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http://dx.doi.org/10.1016/j.jmb.2014.05.010DOI Listing
October 2014

Photon-mediated interactions between distant artificial atoms.

Science 2013 Dec 14;342(6165):1494-6. Epub 2013 Nov 14.

Department of Physics, ETH Zurich, CH-8093 Zurich, Switzerland.

Photon-mediated interactions between atoms are of fundamental importance in quantum optics, quantum simulations, and quantum information processing. The exchange of real and virtual photons between atoms gives rise to nontrivial interactions, the strength of which decreases rapidly with distance in three dimensions. Here, we use two superconducting qubits in an open one-dimensional transmission line to study much stronger photon-mediated interactions. Making use of the possibility to tune these qubits by more than a quarter of their transition frequency, we observe both coherent exchange interactions at an effective separation of 3λ/4 and the creation of super- and subradiant states at a separation of one photon wavelength λ. In this system, collective atom-photon interactions and applications in quantum communication may be explored.
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http://dx.doi.org/10.1126/science.1244324DOI Listing
December 2013

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

Nucleic Acids Res 2013 Oct 2;41(19):8822-41. Epub 2013 Aug 2.

Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada and Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.

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.
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http://dx.doi.org/10.1093/nar/gkt578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799424PMC
October 2013

Six1 regulates MyoD expression in adult muscle progenitor cells.

PLoS One 2013 28;8(6):e67762. Epub 2013 Jun 28.

Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada.

Quiescent satellite cells are myogenic progenitors that enable regeneration of skeletal muscle. One of the early events of satellite cell activation following myotrauma is the induction of the myogenic regulatory factor MyoD, which eventually induces terminal differentiation and muscle function gene expression. The purpose of this study was to elucidate the mechanism by which MyoD is induced during activation of satellite cells in mouse muscle undergoing regeneration. We show that Six1, a transcription factor essential for embryonic myogenesis, also regulates MyoD expression in muscle progenitor cells. Six1 knock-down by RNA interference leads to decreased expression of MyoD in myoblasts. Chromatin immunoprecipitation assays reveal that Six1 binds the Core Enhancer Region of MyoD. Further, transcriptional reporter assays demonstrate that Core Enhancer Region reporter gene activity in myoblasts and in regenerating muscle depends on the expression of Six1 and on Six1 binding sites. Finally, we provide evidence indicating that Six1 is required for the proper chromatin structure at the Core Enhancer Region, as well as for MyoD binding at its own enhancer. Together, our results reveal that MyoD expression in satellite cells depends on Six1, supporting the idea that Six1 plays an important role in adult myogenesis, in addition to its role in embryonic muscle formation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067762PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695946PMC
April 2014

Rb and chromatin remodeling in the maintenance of the post-mitotic state of neurons.

Authors:
Alexandre Blais

Cell Cycle 2013 Jun 17;12(11):1661-2. Epub 2013 May 17.

Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON Canada.

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http://dx.doi.org/10.4161/cc.25071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713122PMC
June 2013

Opposing regulation of Sox2 by cell-cycle effectors E2f3a and E2f3b in neural stem cells.

Cell Stem Cell 2013 Apr 14;12(4):440-52. Epub 2013 Mar 14.

Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.

The mechanisms through which cell-cycle control and cell-fate decisions are coordinated in proliferating stem cell populations are largely unknown. Here, we show that E2f3 isoforms, which control cell-cycle progression in cooperation with the retinoblastoma protein (pRb), have critical effects during developmental and adult neurogenesis. Loss of either E2f3 isoform disrupts Sox2 gene regulation and the balance between precursor maintenance and differentiation in the developing cortex. Both isoforms target the Sox2 locus to maintain baseline levels of Sox2 expression but antagonistically regulate Sox2 levels to instruct fate choices. E2f3-mediated regulation of Sox2 and precursor cell fate extends to the adult brain, where E2f3a loss results in defects in hippocampal neurogenesis and memory formation. Our results demonstrate a mechanism by which E2f3a and E2f3b differentially regulate Sox2 dosage in neural precursors, a finding that may have broad implications for the regulation of diverse stem cell populations.
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http://dx.doi.org/10.1016/j.stem.2013.02.001DOI Listing
April 2013

A new mode of cell cycle stimulation: cyclin E and CDK2-mediated cytoplasmic retention of repressive E2F complexes.

Authors:
Alexandre Blais

Cell Cycle 2012 Aug 9;11(16):2978. Epub 2012 Aug 9.

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http://dx.doi.org/10.4161/cc.21531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442905PMC
August 2012

Discovery, optimization and validation of an optimal DNA-binding sequence for the Six1 homeodomain transcription factor.

Nucleic Acids Res 2012 Sep 22;40(17):8227-39. Epub 2012 Jun 22.

Ottawa Institute of Systems Biology and Biochemistry, Microbiology and Immunology Department, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

The Six1 transcription factor is a homeodomain protein involved in controlling gene expression during embryonic development. Six1 establishes gene expression profiles that enable skeletal myogenesis and nephrogenesis, among others. While several homeodomain factors have been extensively characterized with regards to their DNA-binding properties, relatively little is known of the properties of Six1. We have used the genomic binding profile of Six1 during the myogenic differentiation of myoblasts to obtain a better understanding of its preferences for recognizing certain DNA sequences. DNA sequence analyses on our genomic binding dataset, combined with biochemical characterization using binding assays, reveal that Six1 has a much broader DNA-binding sequence spectrum than had been previously determined. Moreover, using a position weight matrix optimization algorithm, we generated a highly sensitive and specific matrix that can be used to predict novel Six1-binding sites with highest accuracy. Furthermore, our results support the idea of a mode of DNA recognition by this factor where Six1 itself is sufficient for sequence discrimination, and where Six1 domains outside of its homeodomain contribute to binding site selection. Together, our results provide new light on the properties of this important transcription factor, and will enable more accurate modeling of Six1 function in bioinformatic studies.
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http://dx.doi.org/10.1093/nar/gks587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458543PMC
September 2012