Stress-triggered hematopoietic stem cell proliferation relies on PrimPol-mediated repriming.

Stem cell division is linked to tumorigenesis by yet-elusive mechanisms. The hematopoietic system reacts to stress by triggering hematopoietic stem and progenitor cell (HSPC) proliferation, which can be accompanied by chromosomal breakage in activated hematopoietic stem cells (HSCs). However, whether these lesions persist in their downstream progeny and induce a canonical DNA damage response (DDR) remains unclear. Inducing HSPC proliferation by simulated viral infection, we report that the associated DNA damage is restricted to HSCs and that proliferating HSCs rewire their DDR upon endogenous and clastogen-induced damage. Combining transcriptomics, single-cell and single-molecule assays on murine bone marrow cells, we found accelerated fork progression in stimulated HSPCs, reflecting engagement of PrimPol-dependent repriming, at the expense of replication fork reversal. Ultimately, competitive bone marrow transplantation revealed the requirement of PrimPol for efficient HSC amplification and bone marrow reconstitution. Hence, fine-tuning replication fork plasticity is essential to support stem cell functionality upon proliferation stimuli.

Optically Heralded Entanglement of Superconducting Systems in Quantum Networks.

Networking superconducting quantum computers is a longstanding challenge in quantum science. The typical approach has been to cascade transducers: converting to optical frequencies at the transmitter and to microwave frequencies at the receiver. However, the small microwave-optical coupling and added noise have proven formidable obstacles. Instead, we propose optical networking via heralding end-to-end entanglement with one detected photon and teleportation. This new protocol can be implemented on standard transduction hardware while providing significant performance improvements over transduction. In contrast to cascaded direct transduction, our scheme absorbs the low optical-microwave coupling efficiency into the heralding step, thus breaking the rate-fidelity trade-off. Moreover, this technique unifies and simplifies entanglement generation between superconducting devices and other physical modalities in quantum networks.

Room-temperature photonic logical qubits via second-order nonlinearities.

Recent progress in nonlinear optical materials and microresonators has brought quantum computing with bulk optical nonlinearities into the realm of possibility. This platform is of great interest, not only because photonics is an obvious choice for quantum networks, but also as a promising route to quantum information processing at room temperature. We propose an approach for reprogrammable room-temperature photonic quantum logic that significantly simplifies the realization of various quantum circuits, and in particular, of error correction. The key element is the programmable photonic multi-mode resonator that implements reprogrammable bosonic quantum logic gates, while using only the bulk χ(2) nonlinear susceptibility. We theoretically demonstrate that just two of these elements suffice for a complete, compact error-correction circuit on a bosonic code, without the need for measurement or feed-forward control. Encoding and logical operations on the code are also easily achieved with these reprogrammable quantum photonic processors. An extrapolation of current progress in nonlinear optical materials and photonic circuits indicates that such circuitry should be achievable within the next decade.

Controlled-Phase Gate Using Dynamically Coupled Cavities and Optical Nonlinearities.

We show that relatively simple integrated photonic circuits have the potential to realize a high fidelity deterministic controlled-phase gate between photonic qubits using bulk optical nonlinearities. The gate is enabled by converting travelling continuous-mode photons into stationary cavity modes using strong classical control fields that dynamically change the effective cavity-waveguide coupling rate. This architecture succeeds because it reduces the wave packet distortions that otherwise accompany the action of optical nonlinearities [J. Shapiro, Phys. Rev. A 73, 062305 (2006)PLRAAN1050-294710.1103/PhysRevA.73.062305; J. Gea-Banacloche, Phys. Rev. A 81, 043823 (2010)PLRAAN1050-294710.1103/PhysRevA.81.043823]. We show that high-fidelity gates can be achieved with self-phase modulation in χ^{(3)} materials as well as second-harmonic generation in χ^{(2)} materials. The gate fidelity asymptotically approaches unity with increasing storage time for an incident photon wave packet with fixed duration. We also show that dynamically coupled cavities enable a trade-off between errors due to loss and wave packet distortion. Our proposed architecture represents a new approach to practical implementation of quantum gates that is room-temperature compatible and only relies on components that have been individually demonstrated.

Driven Imposters: Controlling Expectations in Many-Body Systems.

We present a framework for controlling the observables of a general correlated electron system driven by an incident laser field. The approach provides a prescription for the driving required to generate an arbitrary predetermined evolution for the expectation value of a chosen observable, together with a constraint on the maximum size of this expectation. To demonstrate this, we determine the laser fields required to exactly control the current in a Fermi-Hubbard system under a range of model parameters, fully controlling the nonlinear high-harmonic generation and optically observed electron dynamics in the system. This is achieved for both the uncorrelated metalliclike state and deep in the strongly correlated Mott insulating regime, flipping the optical responses of the two systems so as to mimic the other, creating "driven imposters." We also present a general framework for the control of other dynamical variables, opening a new route for the design of driven materials with customized properties.

MCL1 Is Required for Maintenance of Intestinal Homeostasis and Prevention of Carcinogenesis in Mice.

BACKGROUND & AIMS: Intestinal epithelial homeostasis depends on a tightly regulated balance between intestinal epithelial cell (IEC) death and proliferation. While the disruption of several IEC death regulating factors result in intestinal inflammation, the loss of the anti-apoptotic BCL2 family members BCL2 and BCL2L1 has no effect on intestinal homeostasis in mice. We investigated the functions of the antiapoptotic protein MCL1, another member of the BCL2 family, in intestinal homeostasis in mice. METHODS: We generated mice with IEC-specific disruption of Mcl1 (Mcl1ΔIEC mice) or tamoxifen-inducible IEC-specific disruption of Mcl1 (i-Mcl1ΔIEC mice); these mice and mice with full-length Mcl1 (controls) were raised under normal or germ-free conditions. Mice were analyzed by endoscopy and for intestinal epithelial barrier permeability. Intestinal tissues were analyzed by histology, in situ hybridization, proliferation assays, and immunoblots. Levels of calprotectin, a marker of intestinal inflammation, were measured in intestinal tissues and feces. RESULTS: Mcl1ΔIEC mice spontaneously developed apoptotic enterocolopathy, characterized by increased IEC apoptosis, hyperproliferative crypts, epithelial barrier dysfunction, and chronic inflammation. Loss of MCL1 retained intestinal crypts in a hyperproliferated state and prevented the differentiation of intestinal stem cells. Proliferation of intestinal stem cells in MCL1-deficient mice required WNT signaling and was associated with DNA damage accumulation. By 1 year of age, Mcl1ΔIEC mice developed intestinal tumors with morphologic and genetic features of human adenomas and carcinomas. Germ-free housing of Mcl1ΔIEC mice reduced markers of microbiota-induced intestinal inflammation but not tumor development. CONCLUSION: The antiapoptotic protein MCL1, a member of the BCL2 family, is required for maintenance of intestinal homeostasis and prevention of carcinogenesis in mice. Loss of MCL1 results in development of intestinal carcinomas, even under germ-free conditions, and therefore does not involve microbe-induced chronic inflammation. Mcl1ΔIEC mice might be used to study apoptotic enterocolopathy and inflammatory bowel diseases.

Trapped Ion Quantum Information Processing with Squeezed Phonons.

Trapped ions offer a pristine platform for quantum computation and simulation, but improving their coherence remains a crucial challenge. Here, we propose and analyze a new strategy to enhance the coherent interactions in trapped ion systems via parametric amplification of the ions' motion-by squeezing the collective motional modes (phonons), the spin-spin interactions they mediate can be significantly enhanced. We illustrate the power of this approach by showing how it can enhance collective spin states useful for quantum metrology, and how it can improve the speed and fidelity of two-qubit gates in multi-ion systems, important ingredients for scalable trapped ion quantum computation. Our results are also directly relevant to numerous other physical platforms in which spin interactions are mediated by bosons.

Stroboscopic approach to trapped-ion quantum information processing with squeezed phonons.

In trapped-ion quantum information processing, interactions between spins (qubits) are mediated by collective modes of motion of an ion crystal. While there are many different experimental strategies to design such interactions, they all face both technical and fundamental limitations to the achievable coherent interaction strength. In general, obtaining strong interactions and fast gates is an ongoing challenge. Here, we extend previous work [W. Ge, B. C. Sawyer, J. W. Britton, K. Jacobs, J. J. Bollinger, and M. Foss-Feig, Phys. Rev. Lett. 122, 030501 (2019)] and present a general strategy for enhancing the interaction strengths in trapped-ion systems via parametric amplification of the ions' motion. Specifically, we propose a stroboscopic protocol using alternating applications of parametric amplification and spin-motion coupling. In comparison with the previous work, we show that the current protocol can lead to larger enhancements in the coherent interaction that increase exponentially with the gate time.

Human pluripotent stem cells in regenerative medicine: where do we stand?

Human pluripotent stem cells have the capacity to self-renew indefinitely and the ability to differentiate into all cell types of a human body. These characteristics instill them with an enormous promise in regenerative medicine, where they could be used in cell, tissue and even organ-based replacement therapy. In this review, we discuss their potential clinical applications and the advantages and pitfalls for the different types of human pluripotent stem cells to transition from the bench to the bedside. We provide an overview of the current clinical trials, and the specific challenges we are still facing, including immune compatibility, suboptimal differentiation, risk of tumor formation and genome instability.

Distributed Quantum Metrology with Linear Networks and Separable Inputs.

We derive a bound on the ability of a linear-optical network to estimate a linear combination of independent phase shifts by using an arbitrary nonclassical but unentangled input state, thereby elucidating the quantum resources required to obtain the Heisenberg limit with a multiport interferometer. Our bound reveals that while linear networks can generate highly entangled states, they cannot effectively combine quantum resources that are well distributed across multiple modes for the purposes of metrology: In this sense, linear networks endowed with well-distributed quantum resources behave classically. Conversely, our bound shows that linear networks can achieve the Heisenberg limit for distributed metrology when the input photons are concentrated in a small number of input modes, and we present an explicit scheme for doing so.

Replication fork reversal triggers fork degradation in BRCA2-defective cells.

Besides its role in homologous recombination, the tumor suppressor BRCA2 protects stalled replication forks from nucleolytic degradation. Defective fork stability contributes to chemotherapeutic sensitivity of BRCA2-defective tumors by yet-elusive mechanisms. Using DNA fiber spreading and direct visualization of replication intermediates, we report that reversed replication forks are entry points for fork degradation in BRCA2-defective cells. Besides MRE11 and PTIP, we show that RAD52 promotes stalled fork degradation and chromosomal breakage in BRCA2-defective cells. Inactivation of these factors restores reversed fork frequency and chromosome integrity in BRCA2-defective cells. Conversely, impairing fork reversal prevents fork degradation, but increases chromosomal breakage, uncoupling fork protection, and chromosome stability. We propose that BRCA2 is dispensable for RAD51-mediated fork reversal, but assembles stable RAD51 nucleofilaments on regressed arms, to protect them from degradation. Our data uncover the physiopathological relevance of fork reversal and illuminate a complex interplay of homologous recombination factors in fork remodeling and stability.BRCA2 is involved in both homologous recombination (HR) and the protection of stalled replication forks from degradation. Here the authors reveal how HR factors cooperate in fork remodeling, showing that BRCA2 supports RAD51 loading on the regressed arms of reversed replication forks to protect them from degradation.

High-Threshold Low-Overhead Fault-Tolerant Classical Computation and the Replacement of Measurements with Unitary Quantum Gates.

von Neumann's classic "multiplexing" method is unique in achieving high-threshold fault-tolerant classical computation (FTCC), but has several significant barriers to implementation: (i) the extremely complex circuits required by randomized connections, (ii) the difficulty of calculating its performance in practical regimes of both code size and logical error rate, and (iii) the (perceived) need for large code sizes. Here we present numerical results indicating that the third assertion is false, and introduce a novel scheme that eliminates the two remaining problems while retaining a threshold very close to von Neumann's ideal of 1/6. We present a simple, highly ordered wiring structure that vastly reduces the circuit complexity, demonstrates that randomization is unnecessary, and provides a feasible method to calculate the performance. This in turn allows us to show that the scheme requires only moderate code sizes, vastly outperforms concatenation schemes, and under a standard error model a unitary implementation realizes universal FTCC with an accuracy threshold of p<5.5%, in which p is the error probability for 3-qubit gates. FTCC is a key component in realizing measurement-free protocols for quantum information processing. In view of this, we use our scheme to show that all-unitary quantum circuits can reproduce any measurement-based feedback process in which the asymptotic error probabilities for the measurement and feedback are (32/63)p≈0.51p and 1.51p, respectively.

Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness.

Bacterial infection leads to consumption of short-lived innate immune effector cells, which then need to be replenished from hematopoietic stem and progenitor cells (HSPCs). HSPCs express pattern recognition receptors, such as Toll-like receptors (TLRs), and ligation of these receptors induces HSPC mobilization, cytokine production, and myeloid differentiation. The underlying mechanisms involved in pathogen signal transduction in HSCs and the resulting biological consequences remain poorly defined. Here, we show that in vivo lipopolysaccharide (LPS) application induces proliferation of dormant HSCs directly via TLR4 and that sustained LPS exposure impairs HSC self-renewal and competitive repopulation activity. This process is mediated via TLR4-TRIF-ROS-p38, but not MyD88 signaling, and can be inhibited pharmacologically without preventing emergency granulopoiesis. Live Salmonella Typhimurium infection similarly induces proliferative stress in HSCs, in part via TLR4-TRIF signals. Thus, while direct TLR4 activation in HSCs might be beneficial for controlling systemic infection, prolonged TLR4 signaling has detrimental effects and may contribute to inflammation-associated HSPC dysfunction.

Minimal noise subsystems.

A system subjected to noise contains a decoherence-free subspace or subsystem (DFS) only if the noise possesses an exact symmetry. Here we consider noise models in which a perturbation breaks a symmetry of the noise, so that if S is a DFS under a given noise process it is no longer so under the new perturbed noise process. We ask whether there is a subspace or subsystem that is more robust to the perturbed noise than S. To answer this question we develop a numerical method that allows us to search for subspaces or subsystems that are maximally robust to arbitrary noise processes. We apply this method to a number of examples, and find that a subsystem that is a DFS is often not the subsystem that experiences minimal noise when the symmetry of the noise is broken by a perturbation. We discuss which classes of noise have this property.

Higher-Density Culture in Human Embryonic Stem Cells Results in DNA Damage and Genome Instability.

Human embryonic stem cells (hESC) show great promise for clinical and research applications, but their well-known proneness to genomic instability hampers the development to their full potential. Here, we demonstrate that medium acidification linked to culture density is the main cause of DNA damage and genomic alterations in hESC grown on feeder layers, and this even in the short time span of a single passage. In line with this, we show that increasing the frequency of the medium refreshments minimizes the levels of DNA damage and genetic instability. Also, we show that cells cultured on laminin-521 do not present this increase in DNA damage when grown at high density, although the (long-term) impact on their genomic stability remains to be elucidated. Our results explain the high levels of genome instability observed over the years by many laboratories worldwide, and show that the development of optimal culture conditions is key to solving this problem.

Energy Cost of Controlling Mesoscopic Quantum Systems.

We determine the minimum energy required to control the evolution of any mesoscopic quantum system in the presence of arbitrary Markovian noise processes. This result provides the mesoscopic equivalent of the fundamental cost of refrigeration, sets the minimum power consumption of mesoscopic devices that operate out of equilibrium, and allows one to calculate the efficiency of any control protocol, whether it be open-loop or feedback control. As examples, we calculate the energy cost of maintaining a qubit in the ground state and the efficiency of resolved-sideband cooling of nano-mechanical resonators, and discuss the energy cost of quantum information processing.

Quantum brachistochrone curves as geodesics: obtaining accurate minimum-time protocols for the control of quantum systems.

Most methods of optimal control cannot obtain accurate time-optimal protocols. The quantum brachistochrone equation is an exception, and has the potential to provide accurate time-optimal protocols for a wide range of quantum control problems. So far, this potential has not been realized, however, due to the inadequacy of conventional numerical methods to solve it. Here we show that the quantum brachistochrone problem can be recast as that of finding geodesic paths in the space of unitary operators. We expect this brachistochrone-geodesic connection to have broad applications, as it opens up minimal-time control to the tools of geometry. As one such application, we use it to obtain a fast numerical method to solve the brachistochrone problem, and apply this method to two examples demonstrating its power.

Low-grade chromosomal mosaicism in human somatic and embryonic stem cell populations.

Current knowledge on chromosomal mosaicism in human cell cultures is mostly based on cytogenetic banding methods. The recent development of high-resolution full-genome analysis methods applicable to single cells is providing new insights into genetic and cellular diversity. Here we study the genetic content of 92 individual human cells, including fibroblasts, amniocytes and embryonic stem cells (hESCs), using single-cell array-based comparative genomic hybridization (aCGH). We find that human somatic and embryonic stem cell cultures show significant fractions of cells carrying unique megabase-scale chromosomal abnormalities, forming genetic mosaics that could not have been detected by conventional cytogenetic methods. These findings are confirmed by studying seven clonal hESC sub-lines by aCGH. Furthermore, fluorescent in situ hybridisation reveals an increased instability of the subtelomeric regions in hESC as compared to somatic cells. This genetic heterogeneity may have an impact on experimental results and, in the case of hESC, on their potential clinical use.

Typical, finite baths as a means of exact simulation of open quantum systems.

There is presently considerable interest in accurately simulating the evolution of open systems for which Markovian master equations fail. Examples are systems that are time dependent and/or strongly damped. A number of elegant methods have now been devised to do this, but all use a bath consisting of a continuum of harmonic oscillators. While this bath is clearly appropriate for, e.g., systems coupled to the electromagnetic field, it is not so clear that it is a good model for generic many-body systems. Here we explore a different approach to exactly simulating open systems: using a finite bath chosen to have certain key properties of thermalizing many-body systems. To explore the numerical resources required by this method to approximate an open system coupled to an infinite bath, we simulate a weakly damped system and compare to the evolution given by the relevant Markovian master equation. We obtain the Markovian evolution with reasonable accuracy by using an additional averaging procedure, and elucidate how the typicality of the bath generates the correct thermal steady state via the process of "eigenstate thermalization."