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Cytolysin LktA is one of the major pathogenicity factors of Mannheimia haemolytica (formerly Pasteurella haemolytica) that is the cause of pasteurellosis, also known as shipping fever pneumonia, causing substantial loss of sheep and cattle during transport. LktA belongs to the family of RTX-toxins (Repeats in ToXins) that are produced as pathogenicity factors by a variety of Gram-negative bacteria. Sublytic concentrations of LktA cause inflammatory responses of ovine leukocytes. Higher concentrations result in formation of transmembrane channels in target cells that may cause cell lysis and apoptosis. In this study we investigated channel formation by LktA in artificial lipid bilayer membranes made of different lipids. LktA purified from culture supernatants by polyethylene glycol 4000 precipitation and lyophilization had to be activated to frequently form channels by solution in 6 M urea. The LktA channels had a single-channel conductance of about 60 pS in 0.1 M KCl, which is about one tenth of the conductance of most RTX-toxins with the exception of adenylate cyclase toxin of Bordetella pertussis. The LktA channels are highly cation-selective caused by negative net charges. The theoretical treatment of the conductance of LktA as a function of the bulk aqueous concentration allowed a rough estimate of the channel diameter, which is around 1.5 nm. The size of the LktA channel is discussed with respect to channels formed by other RTX-toxins. We present here the first investigation of LktA in a reconstituted system.

Abstract Background Widefield radiation therapy (RT) has emerged as a treatment option for extensive skin field cancerization (ESFC), with or without keratinocyte cancer (KC). Objectives To assess the long‐term efficacy, safety, cosmesis and quality of life outcomes for patients with ESFC ± KC receiving widefield RT. Methods NDROR (National Dermatology Radiation Oncology Registry) is an open‐label, prospective, nonrandomized, multicentre registry of patients receiving widefield RT at 11 Australian radiation oncology clinics from a single organization. Field/lesion clearance efficacy and cosmesis were assessed in a cohort of patients with at least 24 months follow‐up. Patient‐reported quality of life using EQ‐5D‐5L questionnaires was performed at each visit. Toxicity analysis was performed on data from patients who completed treatment and had at least 3 months follow‐up. Results Combined investigator‐assessed field treatment success and lesion clearance at 24 months were ≥96% and 93.5%, respectively. The incidence of new KC within the treated field was 10%. Common Terminology Criteria for Adverse Event grade 1–2 radiation‐induced skin toxicities were reported in >92% of fields at the end of treatment, with 5.8% of fields exhibiting grade 3 toxicities. Toxicity resolved rapidly at the cessation of treatment, with grade 1–2 alopecia and xerosis the most prevalent toxicities after 24 months (51.8% and 43.4%, respectively). Cosmesis in treated fields was assessed as excellent or good in 98% of fields at 24 months. Quality of life significantly improved compared to baseline (baseline: mean visual analogue scale (VAS) 80.65, n = 183) at 24 months follow‐up (mean VAS 84.32, N = 83; improvement of 3.67; p = 0.026). Conclusions This analysis indicates that widefield RT is an effective and generally well‐tolerated treatment for ESFC ± KC. Treatment has a favourable safety and cosmesis profile within the period of follow‐up and is associated with significant improvements in quality of life for patients. Widefield RT may be considered for certain patients with extensive disease who have exhausted or are unsuitable for other therapies.

During a quantum measurement, superpositions of states with different observable properties probabilistically collapse into one with a sharp value of the measured observable. In macroscopic quantum systems, this collapse arises via a continuous measurement-induced phase transition (MIPT) at a critical value of the strength of interaction with the measurement apparatus. MIPTs lie outside established paradigms for equilibrium or nonequilibrium critical phenomena and delineate distinct, stable dynamical and computational phases of matter. Quantum computers enable programmable simulation of the interaction of a measurement apparatus with a dynamical quantum system, to explore MIPT phenomena over a range of system sizes while retaining quantum coherence. Yet, existing experimental protocols rely on fundamentally nonscalable postselection techniques or direct classical simulation of quantum circuits. Here, we report the scalable observation of finite-size scaling evidence for an observable-sharpening MIPT in monitored quantum circuits in a chain of ^{171}Yb^{+} ions in Quantinuum’s H1-1 trapped-ion quantum processor. By leveraging an equivalent description as a statistical physics problem, we implement scalable classical algorithms to infer the value of the measured observable from a single experimental shot. This technique enables a truly scalable protocol to observe observable-sharpening MIPTs in generic classes of circuits that cannot be directly classically simulated and also provides enhanced means to detect and suppress errors in the quantum simulation.

Abstract Background Individuals dually-enrolled in Medicare and Medicaid (dual eligibles) are disproportionately sicker, have higher health care costs, and are hospitalized more often for ambulatory care sensitive conditions (ACSCs) than other Medicare beneficiaries. Primary care may reduce ACSC hospitalizations, but this has not been well studied among dual eligibles. We examined the relationship between primary care and ACSC hospitalization among dual eligibles age 65 and older. Methods In this observational study, we used 100% Medicare claims data for dual eligibles ages 65 and over from 2012 to 2018 to estimate the likelihood of ACSC hospitalization as a function of primary care visits and other factors. We used linear probability models stratified by rurality, with subgroup analyses for dual eligibles with diabetes or congestive heart failure. Results Each additional primary care visit was associated with an 0.05 and 0.09 percentage point decrease in the probability of ACSC hospitalization among urban (95% CI: − 0.059, − 0.044) and rural (95% CI: − 0.10, − 0.08) dual eligibles, respectively. Among dual eligibles with CHF, the relationship was even stronger with decreases of 0.09 percentage points (95% CI: − 0.10, − 0.08) and 0.15 percentage points (95% CI: − 0.17, − 0.13) among urban and rural residents, respectively. Conclusions Increased primary care use is associated with lower rates of preventable hospitalizations for dual eligibles age 65 and older, especially for dual eligibles with diabetes and congestive heart failure. In turn, efforts to reduce preventable hospitalizations for this dual-eligible population should consider how to increase access to and use of primary care.

While standard approaches to quantum simulation require a number of qubits proportional to the number of simulated particles, current noisy quantum computers are limited to tens of qubits. With the technique of holographic quantum simulation, a D-dimensional system can be simulated with a (D−1)-dimensional subset of qubits, enabling the study of systems significantly larger than current quantum computers. Using circuits derived from the multiscale entanglement renormalization ansatz (MERA), we accurately prepare the ground state of an L=32 critical, nonintegrable perturbed Ising model and measure long-range correlations on the ten-qubit Quantinuum trapped-ion computer. We introduce generalized MERA networks that interpolate between MERA and matrix product state networks and demonstrate that generalized MERA can capture far longer correlations than a MERA with the same number of qubits, at the expense of greater circuit depth. Finally, we perform noisy simulations of these two network ansatzes and find that the optimal choice of network depends on the noise level, available qubits, and the state to be represented.

Monitored quantum circuits can exhibit an entanglement transition as a function of the rate of measurements, stemming from the competition between scrambling unitary dynamics and disentangling projective measurements. We study how entanglement dynamics in nonunitary quantum circuits can be enriched in the presence of charge conservation, using a combination of exact numerics and a mapping onto a statistical mechanics model of constrained hard-core random walkers. We uncover a charge-sharpening transition that separates different scrambling phases with volume-law scaling of entanglement, distinguished by whether measurements can efficiently reveal the total charge of the system. We find that while Rényi entropies grow sub-ballistically as sqrt[t] in the absence of measurement, for even an infinitesimal rate of measurements, all average Rényi entropies grow ballistically with time ∼t. We study numerically the critical behavior of the charge-sharpening and entanglement transitions in U(1) circuits, and show that they exhibit emergent Lorentz invariance and can also be diagnosed using scalable local ancilla probes. Our statistical mechanical mapping technique readily generalizes to arbitrary Abelian groups, and offers a general framework for studying dissipatively stabilized symmetry-breaking and topological orders.

We develop holographic quantum simulation techniques to prepare correlated electronic ground states in quantum matrix-product-state (QMPS) form, using far fewer qubits than the number of orbitals represented. Our approach starts with a holographic technique to prepare a compressed approximation to electronic mean-field ground states, known as fermionic Gaussian matrix-product states (GMPSs), with a polynomial reduction in qubit and (in select cases gate) resources compared to existing techniques. Correlations are then introduced by augmenting the GMPS circuits in a variational technique, which we denote GMPS+X. We demonstrate this approach on Quantinuum’s System Model H1 trapped-ion quantum processor for one-dimensional (1D) models of correlated metal and Mott-insulating states. Focusing on the 1D Fermi-Hubbard chain as a benchmark, we show that GMPS+X methods faithfully capture the physics of correlated electron states, including Mott insulators and correlated Luttinger liquid metals, using considerably fewer parameters than problem-agnostic variational circuits.

Summary: Microglia are ubiquitous central nervous system (CNS)-resident macrophages that maintain homeostasis of neural tissues and protect them from pathogen attacks. Yet, their differentiation in different compartments remains elusive. We performed single-cell RNA-seq to compare microglial subtypes in the cortex and the spinal cord. A multi-way comparative analysis was carried out on samples from C57/BL and HIV gp120 transgenic mice at two, four, and eight months of age. The results revealed overlapping but distinct microglial populations in the cortex and the spinal cord. The differential heterogeneity of microglia in these CNS regions was further suggested by their disparity of plasticity in response to life span progression and HIV-1 pathogenic protein gp120. Our findings indicate that microglia in different CNS compartments are adapted to their local environments to fulfill region-specific biological functions.

The cell envelope of pathogenic mycobacteria interfaces with the host. As such, the interaction of bacterial products localized at or released from the cell surface with the host’s immune system can determine the fate of the bacterium in its host. In this study, the effects of three different types of Mycobacterium bovis cell envelope fractions—purified protein derivative, total cell wall lipids and culture supernatant and surface extract—on bovine dendritic cells were assessed. We found that the culture supernatant and surface extract fraction induced little to no production of the pro-inflammatory cytokines TNF-α and IL-12 in bovine dendritic cells. Moreover, this muted response was associated with poor activation of ERK and NF-κB, both of which are critical for the pro-inflammatory response. Furthermore, culture supernatant and surface extract treatment increased the expression of suppressor of cytokine signaling 1 and 3, both of which are negative regulators of pro-inflammatory signaling, in bovine dendritic cells. These observations taken together suggest the M. bovis culture supernatant and surface extract fraction contain immunomodulatory molecules that may aid in M. bovis pathogenesis.

We characterize the variational power of quantum circuit tensor networks in the representation of physical many-body ground states. Such tensor networks are formed by replacing the dense block unitaries and isometries in standard tensor networks by local quantum circuits. We explore both quantum circuit matrix product states and the quantum circuit multiscale entanglement renormalization Ansatz, and introduce an adaptive method to optimize the resulting circuits to high fidelity with more than 10^{4} parameters. We benchmark their expressiveness against standard tensor networks, as well as other common circuit architectures, for the 1D and 2D Heisenberg and 1D Fermi-Hubbard models. We find quantum circuit tensor networks to be substantially more expressive than other quantum circuits for these problems, and that they can even be more compact than standard tensor networks. Extrapolating to circuit depths which can no longer be emulated classically, this suggests a region of advantage in quantum expressiveness in the representation of physical ground states.

We present a suite of “holographic” quantum algorithms for efficient ground-state preparation and dynamical evolution of correlated spin systems, which require far fewer qubits than the number of spins being simulated. The algorithms exploit the equivalence between matrix-product states (MPS) and quantum channels, along with partial measurement and qubit reuse, in order to simulate a D-dimensional spin system using only a (D−1)-dimensional subset of qubits along with an ancillary qubit register whose size scales logarithmically in the amount of entanglement present in the simulated state. Ground states can either be directly prepared from a known MPS representation or obtained via a holographic variational quantum eigensolver (holoVQE). Dynamics of MPS under local Hamiltonians for time t can also be simulated with an additional (multiplicative) poly(t) overhead in qubit resources. These techniques open the door to efficient quantum simulation of MPS with exponentially large bond dimension, including ground states of two- and three-dimensional systems, or thermalizing dynamics with rapid entanglement growth. As a demonstration of the potential resource savings, we implement a holoVQE simulation of the antiferromagnetic Heisenberg chain on a trapped-ion quantum computer, achieving within 10(3)% of the exact ground-state energy of an infinite chain using only a pair of qubits.

We present a general framework for modifying quantum approximate optimization algorithms (QAOA) to solve constrained network flow problems. By exploiting an analogy between flow-constraints and Gauss' law for electromagnetism, we design lattice quantum electrodynamics (QED)- inspired mixing Hamiltonians that preserve flow constraints throughout the QAOA process. This results in an exponential reduction in the size of the configuration space that needs to be explored, which we show through numerical simulations, yields higher quality approximate solutions compared to the original QAOA routine. We outline a specific implementation for edge-disjoint path (EDP) problems related to traffic congestion minimization, numerically analyze the effect of initial state choice, and explore trade-offs between circuit complexity and qubit resources via a particle-vortex duality mapping. Comparing the effect of initial states reveals that starting with an ergodic (unbiased) superposition of solutions yields better performance than beginning with the mixer ground-state, suggesting a departure from the ``short-cut to adiabaticity" mechanism often used to motivate QAOA.

Focal segmental glomerulosclerosis is a major cause of end stage renal disease. Many patients prove unresponsive to available therapies. An improved understanding of the molecular basis of the disease process could provide insights leading to novel therapeutic approaches. In this study we carried out an RNA-seq analysis of the altered gene expression patterns of podocytes, mesangial cells and glomerular endothelial cells of the bigenic Cd2ap+/-, Fyn-/- mutant mouse model of FSGS. In the podocytes we observed upregulation of many genes related to the Tgfβ family/pathway, including Gdnf, Tgfβ1, Tgfβ2, Snai2, Vegfb, Bmp4, and Tnc. The mutant podocytes also showed upregulation of Acta2, a marker of smooth muscle and associated with myofibroblasts, which are implicated in driving fibrosis. GO analysis of the podocyte upregulated genes identified elevated protein kinase activity, increased expression of growth factors, and negative regulation of cell adhesion, perhaps related to the observed podocyte loss. Both podocytes and mesangial cells showed strong upregulation of aldehyde dehydrogenase genes involved in the synthesis of retinoic acid. Similarly, the Cd2ap+/-, Fyn-/- mesangial cells, as well as podocytes in other genetic models, and the glomeruli of human FSGS patients, all show upregulation of the serine protease Prss23, with the common thread suggesting important functionality. Another gene with strong upregulation in the Cd2ap+/-, Fyn-/- mutant mesangial cells as well as multiple other mutant mouse models of FSGS was thrombospondin, which activates the secreted inactive form of Tgfβ. The Cd2ap+/-, Fyn-/- mutant endothelial cells showed elevated expression of genes involved in cell proliferation, angioblast migration, angiogenesis, and neovasculature, all consistent with the formation of new blood vessels in the diseased glomerulus. The resulting global definition of the perturbed molecular pathways in the three major cell types of the mutant glomerulus provide deeper understanding of the molecular pathogenic pathways.

Quantum simulators are a promising technology on the spectrum of quantum devices from specialized quantum experiments to universal quantum computers. These quantum devices utilize entanglement and many-particle behavior to explore and solve hard scientific, engineering, and computational problems. Rapid development over the last two decades has produced more than 300 quantum simulators in operation worldwide using a wide variety of experimental platforms. Recent advances in several physical architectures promise a golden age of quantum simulators ranging from highly optimized special purpose simulators to flexible programmable devices. These developments have enabled a convergence of ideas drawn from fundamental physics, computer science, and device engineering. They have strong potential to address problems of societal importance, ranging from understanding vital chemical processes, to enabling the design of new materials with enhanced performance, to solving complex computational problems. It is the position of the community, as represented by participants of the National Science Foundation workshop on “Programmable Quantum Simulators,” that investment in a national quantum simulator program is a high priority in order to accelerate the progress in this field and to result in the first practical applications of quantum machines. Such a program should address two areas of emphasis: (1) support for creating quantum simulator prototypes usable by the broader scientific community, complementary to the present universal quantum computer effort in industry; and (2) support for fundamental research carried out by a blend of multi-investigator, multidisciplinary collaborations with resources for quantum simulator software, hardware, and education.This document is a summary from a U.S. National Science Foundation supported workshop held on 16–17 September 2019 in Alexandria, VA. Attendees were charged to identify the scientific and community needs, opportunities, and significant challenges for quantum simulators over the next 2–5 years.

The topological character of electrons in semimetals subtly influences their bulk properties, leading typically to weak experimental signatures. Here, Moll et al. report a distinctive anomaly in the magnetic torque upon entering quantum limit state in the Weyl semimetal NbAs, which only appears due to the presence of Weyl fermions.

Objective: To determine whether younger dual-eligibles receiving care at federally qualified health centers (FQHCs) have lower rates of ambulatory care sensitive (ACS) hospitalization and emergency department (ED) visits. Data Sources: We used the 100% Medicare Part A and Part B institutional claims from 2007 to 2010 for dual-eligibles younger than 65 years, enrolled in traditional fee-for-service Medicare, who received care at an FQHC or lived in a primary care service area with an FQHC. Methods: Our cross-sectional analysis used negative binomial regressions to model ACS hospitalizations and ED visits as a function of prior year FQHC use. The model adjusted for beneficiary age, gender, race, and chronic diseases, as well as county fixed effects, time trends, and race-FQHC use interactions. Results: FQHC use is associated with a decrease in ACS hospitalization rates for whites (2.8 per 1000 persons), but an increase among blacks (2.5 per 1000 persons). FQHC use is also associated with an increase in ACS ED visits, from 27 to 33 more visits per 1000 persons per year, depending on patient race. Conclusions: ACS hospital use is higher for FQHC users than nonusers, but white FQHC users have fewer ACS hospitalizations. More research is needed to understand how this relationship varies within and between centers.

Palok Aich, Andrew A Potter, Philip J GriebelVaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, CanadaAbstract: Studies in animals and humans link both physical and psychological stress with an increased incidence and severity of respiratory infections. For this manuscript we define stress as the physiological responses an individual undergoes while adjusting to a continually changing environment. It is known that stressors of various types (psychological/physical) can alter the physiological levels of certain hormones, chemokines and cytokines. These alterations send information to the central nervous system to take necessary action which then sends messages to appropriate organs/tissues/cells to respond. These messages can either activate or suppress the immune system as needed and failure to compensate for this by the body can lead to serious health-related problems. Little is known how stress affects disease susceptibility, yet understanding this mechanism is important for developing effective treatments, and for improving health and food quality. The current review focuses on (a) the effects of psychological stressors in humans and animals, (b) various methodologies employed to understand stress responses and their outcomes, and (c) the current status of the attempts to correlate stress and disease with respiratory disease as model system. The methodologies included in this review span traditional epidemiological, behavioral and immunological studies to current high throughput genomic, proteomic, metabolomic/metabonomic approaches. With the advent of various newer omics and bioinformatics methodologies we postulate that it will become feasible to understand the mechanisms through which stress can influence disease onset. Although the literature in this area is limited because of the infancy of this research area, the objective of this review is to illustrate the power of new approaches to address complex biological questions. These new approaches will also aid in our understanding how these processes are related to the dynamics and kinetics of changes in expression of multiple genes at various levels.Keywords: stress, disease, biomarker discovery, systems biology, omics, respiratory disease