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Monitored quantum circuits (MRCs) exhibit a measurement-induced phase transition between area-law and volume-law entanglement scaling. MRCs with a conserved charge additionally exhibit two distinct volume-law entangled phases that cannot be characterized by equilibrium notions of symmetry-breaking or topological order, but rather by the non-equilibrium dynamics and steady-state distribution of charge fluctuations. These include a charge-fuzzy phase in which charge information is rapidly scrambled leading to slowly decaying spatial fluctuations of charge in the steady state, and a charge-sharp phase in which measurements collapse quantum fluctuations of charge without destroying the volume-law entanglement of neutral degrees of freedom. By taking a continuous-time, weak-measurement limit, we construct a controlled replica field theory description of these phases and their intervening charge-sharpening transition in one spatial dimension. We find that the charge fuzzy phase is a critical phase with continuously evolving critical exponents that terminates in a modified Kosterlitz-Thouless transition to the short-range correlated charge-sharp phase. We numerically corroborate these scaling predictions also hold for discrete-time projective-measurement circuit models using large-scale matrix-product state simulations, and discuss generalizations to higher dimensions., Comment: 5+8 pages, 3 figures

Recently, industrial and academic communities in the operations and supply chain management (OSCM) field are paying increasing attention to social media. However, the value of social media in OSCM is quite unclear, and more investigations are still needed. To pave the way for a directed future research, this paper systematically reviewed and synthesised 152 peer-review journal papers to identify research focus and gaps in this area, supported by an appropriate conceptual framework. The result reveals that the research interests in this area have increased dramatically within the last decade across various industries and regions. Different companies’ OSCM activities, such as sourcing and delivery, can benefit from employment of social media. This paper also indicates that future research can explore the value of social media in sourcing, delivery, product return and reverse logistics activities, forecasting and inventory management, and product development and production.

In order to observe the lunar sodium exosphere out to one-half degree around the Moon, we designed, built and installed a small robotically controlled coronagraph at the Winer Observatory in Sonoita, Arizona. Observations are obtained remotely every available clear night from our home base at Goddard Space Flight Center or from Prescott, Arizona. We employ an Andover temperature-controlled 1.5 A wide narrow-band filter centered on the sodium D2 line, and a similar 1.5 A filter centered blueward of the D2 line by 3 A for continuum observations. Our data encompass lunations in 2015, 2016, and 2017, thus we have a long baseline of sodium exospheric calibrated images. During the course of three years we have refined the observational sequence in many respects. Therefore this paper only presents the results of the spring, 2017, observing season. We present limb profiles from the south pole to the north pole for many lunar phases. Our data do not fit any power of cosine model as a function of lunar phase or with latitude. The extended Na exosphere has a characteristic temperature of about 2250–6750 K, indicative of a partially escaping exosphere. The hot escaping component may be indicative of a mixture of impact vaporization and a sputtered component.

Despite Little’s Law being considered as one of the ‘laws’ of operations management, evidence of its application in an empirical context is diverse and diffuse. Hence, this paper aims to identify, classify and consolidate published empirical applications of Little’s Law in a systematic manner to better understand its versatility. This paper undertakes a systematic literature review of the databases of the five main publishers of operations management journals and snowball sampling for additional papers. A final sample of 128 empirical journal articles is identified and categorized. Tactical, medium-term decisions relating to capacity dynamics and operations re-engineering are the most popular categories. To give further insights into versatility, vignettes for each category are developed. The review and vignettes confirm Little’s Law as a highly relevant paradigm to operations management decisions due to its empirical versatility across levels, sectors and time domains. The paper suggests four factors to underline the empirical versatility of Little’s Law in operations management: applicability, utility, simplicity and visibility.

Human parainfluenza virus 3 (PIV3) and respiratory syncytial virus (RSV) are major causative agents of serious respiratory tract illness in newborns and infants. Maternal vaccination could be a promising approach to provide immediate protection against severe PIV3 and RSV infection in young infants. Previously, we demonstrated that maternal immunization with a subunit vaccine consisting of the RSV fusion (F) protein formulated with TriAdj, an adjuvant consisting of poly(I:C), immune defense regulatory peptide and polyphosphazene, protects newborn lambs from RSV. In the present study we evaluated the protective efficacy of a novel bivalent RSV-PIV3 vaccine candidate, FRipScHN/TriAdj, as a maternal vaccine against PIV3 infection in a neonatal lamb model. This vaccine consists of the pre-fusion form of the RSV F protein linked to the haemagglutinin-neuraminidase (HN) of PIV3, formulated with TriAdj. First, we successfully established PIV3 infection in neonatal lambs. Lambs infected with human PIV3 showed gross pathology, bronchointerstitial pneumonia and viral replication in the lungs. Subsequently, ewes were immunized with FRipScHN/TriAdj. RSV FRipSc- and PIV3 HN-specific antibodies with virus-neutralizing activity were detected in both the serum and the colostrum of the vaccinated ewes. The newborn lambs had RSV- and PIV3- neutralizing antibodies in their serum, which demonstrates that maternal antibodies were transferred to the neonates. At three days of age, the newborn lambs received an intrapulmonary challenge with PIV3. The lung pathology and virus production were significantly reduced in lambs that had received PIV3-specific maternal antibodies compared to lambs born to non-vaccinated ewes. These results suggest that maternal vaccination with a bivalent FRipScHN/TriAdj vaccine might be an effective method to provide protection against both PIV3 and RSV in neonates.

Purpose With the diverse, heterogeneous nature of relationships being a key characteristic of service supply chains, their management is an important area for consideration. This is particularly true in the maritime logistics industry, yet the factors that lead to this heterogeneity are less well understood. This paper aims to explore the structure of relationships within the maritime logistics network and determine why they vary. Design/methodology/approach Interviews were carried out with 41 practitioners involved in the Taiwanese maritime logistics network. The data from these interviews were analyzed using thematic analysis and quasi-quantification. Findings The interviews identify that structural holes exist within this maritime logistics network, and that these particularly influence the relationships within this sector with ports being significantly affected. However, five factors are particularly identified that can further impact the strength of these relationships. Often, weak links between ports and both cargo owners and freight forwarders emerge as value-added services are provided by the network. Research limitations/implications The findings are framed in a Taiwanese context, where cultural and political norms may give different results to other geographical regions. The research also limits consideration to containerized flows. Practical implications By providing detailed insights into relationship structures within the maritime logistics network, managers can take steps to develop appropriate links with other members of the network, reflecting upon the factors that lead to heterogeneity. Originality/value This paper expands knowledge on logistics service supply chains, identifying the importance of relationships in a derived demand environment. For maritime researchers, specific factors leading to relationship heterogeneity in the network are detailed, to inform future research.

Obstructive sleep apnea (OSA) results from episodes of airway collapse and intermittent hypoxia and is associated with a host of health complications including dementia, diabetes, heart failure, and stroke. Although the lung is the first organ to sense changes in inspired oxygen levels, little is known about the consequences of IH to the lung hypoxia-inducible factor (HIF)-responsive pathways. Furthermore, cellular mechanisms causing disease progression across multiple systems in OSA are unknown. We hypothesized that exposure to IH would lead to up- and down-regulation of diverse expression pathways and that individual cell populations would show distinctive responses to IH. We identify changes in circadian and immune pathways in lungs from mice exposed to IH. Among all cell types, endothelial cells show the most prominent transcriptional changes. Interestingly, up-regulated genes in endothelial, fibroblast, and myofibroblast cells were enriched for genes associated with pulmonary fibrosis and pulmonary hypertension. These genes include targets of several drugs currently used to treat chronic pulmonary diseases. Our results reveal potential candidates for cell-targeted therapy seeking to minimize pulmonary effects of OSA. A better understanding of the pathophysiologic mechanisms underlying diseases associated with OSA could improve our therapeutic approaches, directing therapies to the most relevant cells and molecular pathways.

This paper extends existing research on the dynamic behaviour of supply chains by including the influence of online reviews. We model an online supply chain which contains customers and one e-commerce retailer. By using simulation, we compare the dynamic performance in a supply chain for two scenarios, namely adopting online review systems and without adopting the systems. The supply chain dynamic performance is measured by bullwhip effect and inventory variance amplification. The results demonstrate that online review systems increase both the bullwhip effect and inventory variance amplification, and this impact can be moderated by product quality, unit mismatch cost, lead time, and customer volatility. We further explore how our model could be extended to include market competition, dual sourcing, online review manipulation, and product returns. As the increase in the bullwhip effect and inventory variance amplification can be associated with supply chain inefficiency, managers who are aware of such consequence induced by online review adoption can make better decisions in supply chain management.

Subcutaneous vaccination of cattle for enterohemorrhagic Escherichia coli O157:H7 reduces the magnitude and duration of fecal shedding, but the often-required, repeated cattle restraint can increase costs, deterring adoption by producers. In contrast, live oral vaccines may be repeatedly administered in feed, without animal restraint. We investigated whether oral immunization with live stx-negative LEE(+) E. coli O157:H7 reduced rectoanal junction (RAJ) colonization by wild-type (WT) E. coli O157:H7 strains after challenge. Two groups of cattle were orally dosed twice weekly for 6 weeks with 3 × 10(9) CFU of a pool of three stx-negative LEE(+) E. coli O157:H7 strains (vaccine group) or three stx-negative LEE(−) non-O157:H7 E. coli strains (control group). Three weeks following the final oral dose, animals in both groups were orally challenged with a cocktail of four stx(+) LEE(+) E. coli O157:H7 WT strains. Subsequently, WT strains at the RAJ were enumerated weekly for 4 weeks. Serum antibodies against type III secretion protein (TTSP), the translocated intimin receptor (Tir), and EspA were determined by enzyme-linked immunosorbent assay (ELISA) at day 0 (preimmunization), day 61 (postimmunization, prechallenge), and day 89 (postchallenge). Vaccine group cattle had lower numbers of WT strains at the RAJ than control group cattle on postchallenge days 3 and 7 (P ≤ 0.05). Also, vaccine group cattle shed WT strains for a shorter duration than control group cattle. All cattle seroconverted to TTSP, Tir, and EspA, either following immunization (vaccine group) or following challenge (control group). Increased antibody titers against Tir and TTSP postimmunization were associated with decreased numbers of WT E. coli O157:H7 organisms at the RAJ. IMPORTANCE The bacterium E. coli O157:H7 causes foodborne disease in humans that can lead to bloody diarrhea, kidney failure, vascular damage, and death. Healthy cattle are the main source of this human pathogen. Reducing E. coli O157:H7 in cattle will reduce human disease. Using a randomized comparison, a bovine vaccine to reduce carriage of the human pathogen was tested. A detoxified E. coli O157:H7 strain, missing genes that cause disease, was fed to cattle as an oral vaccine to reduce carriage of pathogenic E. coli O157:H7. After vaccination, the cattle were challenged with disease-causing E. coli O157:H7. The vaccinated cattle had decreased E. coli O157:H7 during the first 7 days postchallenge and shed the bacteria for a shorter duration than the nonvaccinated control cattle. The results support optimization of the approach to cattle vaccination that would reduce human disease.

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 non-unitary 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 R\'enyi entropies grow sub-ballistically as $\sqrt{t}$ in the absence of measurement, for even an infinitesimal rate of measurements, all average R\'enyi entropies grow ballistically with time $\sim t$. 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., Comment: Updated some statements and a figure. 29 pages, 17 figures

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 (GMPS), 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 1$d$ 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., Comment: 16 pages, 10 figures

We theoretically explore 2d moir\'e heterostructures in lattice-commensurate magnetic fields as platforms for quantum simulation of a paradigmatic model of non-Fermi liquid physics: a Fermi-surface coupled to a fluctuating gauge field. In these moir\'e-Hofstadter (MH) systems, long-wavelength acoustic phonons exhibit singular interactions with electrons analogous to those of electrons with 2d gauge fields. This leads to a breakdown of Fermi-liquid theory at low temperatures. We show that a combination of large moir\'e-unit cell size, tunable Fermi-surface topology, and enhanced coupling to interlayer sliding modes, enhance these effects by over many orders-of-magnitude compared to bulk crystals, placing them within experimental reach. Though we find that the asymptotic low-temperature non-Fermi liquid regime remains at prohibitively low temperatures, striking precursor non-Fermi liquid signatures can be observed, and we propose surface acoustic wave attenuation and quantum oscillation transport experiments. We also study the motion of MH acoustic-polarons, which we predict exhibit logarithmically diverging effective mass and unconventional magnetic field scaling for scaling of cyclotron resonance frequency and quantum oscillation amplitude., Comment: 8+9 pages, 5 figures. v3 expands on non-Fermi liquid properties, adds Figure 3

BACKGROUND: Single-cell transcriptomes from dissociated tissues provide insights into cell types and their gene expression and may harbor additional information on spatial position and the local microenvironment. The kidney’s cells are embedded into a gradient of increasing tissue osmolality from the cortex to the medulla, which may alter their transcriptomes and provide cues for spatial reconstruction. METHODS: Single-cell or single-nuclei mRNA sequencing of dissociated mouse kidneys and of dissected cortex, outer, and inner medulla, to represent the corticomedullary axis, was performed. Computational approaches predicted the spatial ordering of cells along the corticomedullary axis and quantitated expression levels of osmo-responsive genes. In situ hybridization validated computational predictions of spatial gene-expression patterns. The strategy was used to compare single-cell transcriptomes from wild-type mice to those of mice with a collecting duct–specific knockout of the transcription factor grainyhead-like 2 (Grhl2(CD−/−)), which display reduced renal medullary osmolality. RESULTS: Single-cell transcriptomics from dissociated kidneys provided sufficient information to approximately reconstruct the spatial position of kidney tubule cells and to predict corticomedullary gene expression. Spatial gene expression in the kidney changes gradually and osmo-responsive genes follow the physiologic corticomedullary gradient of tissue osmolality. Single-nuclei transcriptomes from Grhl2(CD−/−) mice indicated a flattened expression gradient of osmo-responsive genes compared with control mice, consistent with their physiologic phenotype. CONCLUSIONS: Single-cell transcriptomics from dissociated kidneys facilitated the prediction of spatial gene expression along the corticomedullary axis and quantitation of osmotically regulated genes, allowing the prediction of a physiologic phenotype.

Mycobacterial diseases of cattle are responsible for considerable production losses worldwide. In addition to their importance in animals, these infections offer a nuanced approach to understanding persistent mycobacterial infection in native host species. Mycobacteriumavium ssp. paratuberculosis (MAP) is an enteric pathogen that establishes a persistent, asymptomatic infection in the small intestine. Difficulty in reproducing infection in surrogate animal models and limited understanding of mucosal immune responses that control enteric infection in the natural host have been major barriers to MAP vaccine development. We previously developed a reproducible challenge model to establish a consistent MAP infection using surgically isolated intestinal segments prepared in neonatal calves. In the current study, we evaluated whether intestinal segments could be used to screen parenteral vaccines that alter mucosal immune responses to MAP infection. Using Silirum® – a commercial MAP bacterin – we demonstrate that intestinal segments provide a platform for assessing vaccine efficacy within a relatively rapid period of 28 days post-infection. Significant differences between vaccinates and non-vaccinates could be detected using quantitative metrics including bacterial burden in intestinal tissue, MAP shedding into the intestinal lumen, and vaccine-induced mucosal immune responses. Comparing vaccine-induced responses in mucosal leukocytes isolated from the site of enteric infection versus blood leukocytes revealed substantial inconsistences between these immune compartments. Moreover, parenteral vaccination with Silirum did not induce equal levels of protection throughout the small intestine. Significant control of MAP infection was observed in the continuous but not the discrete Peyer’s patches. Analysis of these regional mucosal immune responses revealed novel correlates of immune protection associated with reduced infection that included an increased frequency of CD335+ innate lymphoid cells, and increased expression of IL21 and IL27. Thus, intestinal segments provide a novel model to accelerate vaccine screening and discovery by testing vaccines directly in the natural host and provides a unique opportunity to interrogate mucosal immune responses to mycobacterial infections.

We investigate the effects of quenched randomness on topological quantum phase transitions in strongly interacting two-dimensional systems. We focus first on transitions driven by the condensation of a subset of fractionalized quasiparticles (`anyons') identified with `electric charge' excitations of a phase with intrinsic topological order. All other anyons have nontrivial mutual statistics with the condensed subset and hence become confined at the anyon condensation transition. Using a combination of microscopically exact duality transformations and asymptotically exact real-space renormalization group techniques applied to these two-dimensional disordered gauge theories, we argue that the resulting critical scaling behavior is `superuniversal' across a wide range of such condensation transitions, and is controlled by the same infinite-randomness fixed point as that of the 2D random transverse-field Ising model. We validate this claim using large-scale quantum Monte Carlo simulations that allow us to extract zero-temperature critical exponents and correlation functions in (2+1)D disordered interacting systems. We discuss generalizations of these results to a large class of ground-state and excited-state topological transitions in systems with intrinsic topological order as well as those where topological order is either protected or enriched by global symmetries. When the underlying topological order and the symmetry group are Abelian, our results provide prototypes for topological phase transitions between distinct many-body localized phases., 33 pages, 35 figures; published version

Chronic enteric Mycobacterium avium ssp. paratuberculosis (MAP) infections are endemic in ruminants globally resulting in significant production losses. The mucosal immune responses occurring at the site of infection, specifically in Peyer's patches (PP), are not well-understood. The ruminant small intestine possesses two functionally distinct PPs. Discrete PPs function as mucosal immune induction sites and a single continuous PP, in the terminal small intestine, functions as a primary lymphoid tissue for B cell repertoire diversification. We investigated whether MAP infection of discrete vs. continuous PPs resulted in the induction of significantly different pathogen-specific immune responses and persistence of MAP infection. Surgically isolated intestinal segments in neonatal calves were used to target MAP infection to individual PPs. At 12 months post-infection, MAP persisted in continuous PP (n = 4), but was significantly reduced (p = 0.046) in discrete PP (n = 5). RNA-seq analysis revealed control of MAP infection in discrete PP was associated with extensive transcriptomic changes (1,707 differentially expressed genes) but MAP persistent in continuous PP elicited few host responses (4 differentially expressed genes). Cytokine gene expression in tissue and MAP-specific recall responses by mucosal immune cells isolated from PP, lamina propria and mesenteric lymph node revealed interleukin (IL)22 and IL27 as unique correlates of protection associated with decreased MAP infection in discrete PP. This study provides the first description of mucosal immune responses occurring in bovine discrete jejunal PPs and reveals that a significant reduction in MAP infection is associated with specific cytokine responses. Conversely, MAP infection persists in the continuous ileal PP with minimal perturbation of host immune responses. These data reveal a marked dichotomy in host-MAP interactions within the two functionally distinct PPs of the small intestine and identifies mucosal immune responses associated with the control of a mycobacterial infection in the natural host.

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 re-use, 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) ${\rm poly}(t)$ overhead in qubit resources. These techniques open the door to efficient quantum simulation of MPS with exponentially large bond-dimension, including ground-states of 2D and 3D 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., 13 pages, 9 figures

Background Mycoplasma mycoides subsp. mycoides (Mmm) is the causative agent of contagious bovine pleuropneumonia in cattle. A prototype subunit vaccine is being developed, however, there is currently no diagnostic test that can differentiate between infected cattle and those vaccinated with the prototype subunit vaccine. This study characterized Mmm proteins to identify potential antigens for use in differentiating infected from vaccinated animals. Results Ten Mmm antigens expressed as recombinant proteins were tested in an indirect ELISA using experimental sera from control groups, infected, and vaccinated animals. Data were imported into R software for analysis and drawing of the box and scatter plots while Cohen’s Kappa assessed the level of agreement between the Mmm antigens. Two vaccine antigens (MSC_0499 and MSC_0776) were superior in detecting antibodies in sera of animals vaccinated with the subunit vaccines while two non-vaccine antigens (MSC_0636 and LppB) detected antibodies in sera of infected animals showing all clinical stages of the disease. Sensitivity and specificity of above 87.5% were achieved when the MSC_0499 and MSC_0636 antigens were tested on sera from vaccinated and infected animals. Conclusions The MSC_0499 and MSC_0776 antigens were the most promising for detecting vaccinated animals, while MSC_0636 and LppB were the best targets to identify infected animals. Further testing of sera from vaccinated and infected animals collected at different time intervals in the field should help establish how useful a diagnostic test based on a cocktail of these proteins would be.

Network models for equilibrium integer quantum Hall (IQH) transitions are described by unitary scattering matrices, that can also be viewed as representing non-equilibrium Floquet systems. The resulting Floquet bands have zero Chern number, and are instead characterized by a chiral Floquet (CF) winding number. This begs the question: How can a model without Chern number describe IQH systems? We resolve this apparent paradox by showing that non-zero Chern number is recovered from the network model via the energy dependence of network model scattering parameters. This relationship shows that, despite their topologically distinct origins, IQH and CF topology-changing transitions share identical universal scaling properties., 5 pages, 3 figures, v2: references added, additional discussion of related prior work

The growth of containerisation and the increase in ship size have resulted in a greater need for transhipment hubs. Hence, some peripheral ports are upgrading to become secondary hub ports. However, it remains unclear why these ports would move towards this strategic direction. The aim of this study is to investigate stakeholders’ perceptions on the importance of peripherality, so as to understand their willingness to invest in secondary hub ports. Stakeholders from the Indonesian port and maritime industry were chosen as the focus of the present study, representing a connected network of peripheral and hub ports at a country level. The study used a mixed-methods approach. Qualitative interviews were conducted with 46 respondents, while quantitative data were collected through an online survey, involving 171 respondents. The data were subsequently analysed through exploratory factor analysis and correlation tests. Results show a pattern in stakeholder behaviour, explaining their reasoning, locational decisions, their perceptions on the importance of peripheral locations and their willingness to invest. It is believed that these findings will prove of value both for governments and the private sectors of international shipping and port operations.

For many products craft-specialisation and craftworkers were once the principal means of production, but these approaches were largely eclipsed as a result of the Industrial Revolution and subsequent rise of mass-manufacturing. Recently there has been increased interest in the market for craft and artisan produced items, and in this chapter we examine how 3D printing can successfully contribute to new craft-based business ventures.

We construct an example of a 1$d$ quasiperiodically driven spin chain whose edge states can coherently store quantum information, protected by a combination of localization, dynamics, and topology. Unlike analogous behavior in static and periodically driven (Floquet) spin chains, this model does not rely upon microscopic symmetry protection: Instead, the edge states are protected purely by emergent dynamical symmetries. We explore the dynamical signatures of this Emergent Dynamical Symmetry-Protected Topological (EDSPT) order through exact numerics, time evolving block decimation, and analytic high-frequency expansion, finding evidence that the EDSPT is a stable dynamical phase protected by bulk many-body localization up to (at least) stretched-exponentially long time scales, and possibly beyond. We argue that EDSPTs are special to the quasiperiodically driven setting, and cannot arise in Floquet systems. Moreover, we find evidence of a new type of boundary criticality, in which the edge spin dynamics transition from quasiperiodic to chaotic, leading to bulk thermalization., Comment: 7+8 pages, 5 figures

Microglia are heterogeneous and ubiquitous 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 (scRNA-seq) analysis to compare the transcriptomes of microglia in adult mouse (C57/Bl) brains and spinal cords to identify microglial subtypes in these CNS compartments. Cortical microglia from 2-month mice consisted of a predominant population of the homeostatic subtype (HOM-M) and a small population (4%) of the inflammatory subtype (IFLAM-M), while spinal microglia consisted of 55% HOM-M and 45% IFLAM-M subtype. Comparison of cortical and spinal microglia at 2, 4 and 8 months revealed consistently a higher composition of the IFLAM-M subtype in the spinal cord. At 8-month, cortical microglia differentiated a small new subtype with interferon response phenotypes (INF-M), while spinal microglia polarized toward a proinflammatory phenotype, as indicated by the increase of microglia expressing IL-1β. To further characterize the differential plasticity of cortical and spinal microglial heterogeneity, we determined the microglial transcriptomes from HIV-1 gp 120 transgenic (Tg) mice, a model of HIV-associated neurological disorders. Compared with wild-type (Wt) cortical microglia, the gp120Tg cortical microglia had three new subtypes, with signatures of interferon I response (INF-M), cell proliferation (PLF-M), and myelination or demyelination (MYE-M) respectively; while INF-M and PLF-M subtypes presented at all ages, the MYE-M only at 4-month. In contrast, only the INF-M subtype was observed in the spinal microglia from 2- and 4-month gp120tg mice. Bioinformatic analysis of regulated molecular pathways of individual microglial subtypes indicated that gp120 more severely impaired the biological function of microglia in cortices than in the spinal cord. The results collectively reveal differential heterogeneity and plasticity of cortical and spinal microglia, and suggest functional differentiation of microglia in different CNS compartments.

Discovered decades ago, the quantum Hall effect remains one of the most studied phenomena in condensed matter physics and is relevant for research areas such as topological phases, strong electron correlations and quantum computing1-5. The quantized electron transport that is characteristic of the quantum Hall effect typically originates from chiral edge states-ballistic conducting channels that emerge when two-dimensional electron systems are subjected to large magnetic fields2. However, whether the quantum Hall effect can be extended to higher dimensions without simply stacking two-dimensional systems is unknown. Here we report evidence of a new type of quantum Hall effect, based on Weyl orbits in nanostructures of the three-dimensional topological semimetal Cd3As2. The Weyl orbits consist of Fermi arcs (open arc-like surface states) on opposite surfaces of the sample connected by one-dimensional chiral Landau levels along the magnetic field through the bulk6,7. This transport through the bulk results in an additional contribution (compared to stacked two-dimensional systems and which depends on the sample thickness) to the quantum phase of the Weyl orbit. Consequently, chiral states can emerge even in the bulk. To measure these quantum phase shifts and search for the associated chiral modes in the bulk, we conduct transport experiments using wedge-shaped Cd3As2 nanostructures with variable thickness. We find that the quantum Hall transport is strongly modulated by the sample thickness. The dependence of the Landau levels on the magnitude and direction of the magnetic field and on the sample thickness agrees with theoretical predictions based on the modified Lifshitz-Onsager relation for the Weyl orbits. Nanostructures of topological semimetals thus provide a way of exploring quantum Hall physics in three-dimensional materials with enhanced tunability.

Chronic wasting disease (CWD) is a fatal prion disease affecting multiple cervid species. Effective management tools for this disease, particularly in free-ranging populations, are currently limited. We evaluated a novel CWD vaccine in elk (Cervus canadensis) naturally exposed to CWD through a prion-contaminated environment. The vaccine targets a YYR disease-specific epitope to induce antibody responses specific to the misfolded (PrPSc) conformation. Female elk calves (n = 41) were captured from western Wyoming and transported to the Thorne-Williams Wildlife Research Center where CWD has been documented since 1979. Elk were held in contaminated pens for 14 to 20 days before being alternately assigned to either a vaccine (n = 21) or control group (n = 20). Vaccinated animals initially received two vaccinations approximately 42 days apart and annual vaccinations thereafter. Vaccination induced elevated YYR-specific antibody titers in all animals. Elk were genotyped for the prion protein gene at codon 132, monitored for clinical signs of CWD through daily observation, for disease status through periodic biopsy of rrectoanal mucosa-associated lympoid tissue (RAMALT), and monitored for YYR-specific serum antibody titres. Mean survival of vaccinated elk with the 132MM genotype (n = 15) was significantly shorter (800 days) than unvaccinated elk (n = 13) of the same genotype (1062 days; p = 0.003). Mean days until positive RAMALT biopsy for 132MM vaccinated elk (6 7 8) were significantly shorter than unvaccinated 132MM elk (990; p = 0.012). There was, however, no significant difference in survival between vaccinated (n = 4) and control (n = 5) elk with the 132ML genotype (p = 0.35) or in timing of positive RAMALT biopsies of 132ML elk (p = 0.66). There was no strong (p = 0.17) correlation between YYR-specific antibody titers and survival time. Determining the mechanism by which this vaccine accelerates onset of CWD will be important to direct further CWD vaccine research.

Introduction. Lung cancer is a disease which, despite the advancements in treatment, still has a very poor 5-year survival rate. Stereotactic ablative radiation therapy (SABR) is a highly advanced, sophisticated, and safe treatment which allows patients with early stage lung cancer to be treated effectively without invasive procedures and with excellent clinical outcomes. Avoiding surgery minimises morbidity and recovery time, bettering patients’ quality of life. Furthermore, SABR allows patients unsuitable for surgery to still undergo curative treatment. Methods. We aimed to review SABR-related normal tissue toxicities reported in the literature. While many studies assess safety, clinical efficacy, and disease control of SABR for lung cancer, the number of comprehensive reviews that analyse SABR-related side-effects is scarce. This integrative review summarises the toxicities reported in literature based on published clinical trials and tumour location (central or peripheral tumours) for available SABR techniques. Given that the majority of the clinical studies did not report on the statistical significance (e.g., p-values and confidence intervals) of the toxicities experienced by patients, statistical analyses cannot be performed. As a result, adverse events are compiled from clinical reports; however, due to various techniques and nonstandard toxicity reports, no meta-analysis is possible at the current stage of reported data. Results. When comparing lobectomy and SABR in phase III trials, surgery resulted in increased procedure-related morbidity. In phase II trials, very few studies showed high grade toxicities/fatalities as a result of SABR for lung cancer. Gross target volume size was a significant predictor of toxicity. An ipsilateral mean lung dose larger than 9 Gy was significantly associated with radiation pneumonitis. Conclusions. Based on the studies reviewed SABR is a safe treatment technique for lung cancer; however, further well-designed phase III randomised clinical trials are required to produce timely conclusive results and to enable their comparison and statistical analysis.

The developing kidney provides a useful model for study of the principles of organogenesis. In this report we use three independent platforms, Drop-Seq, Chromium 10x Genomics and Fluidigm C1, to carry out single cell RNA-Seq (scRNA-Seq) analysis of the E14.5 mouse kidney. Using the software AltAnalyze, in conjunction with the unsupervised approach ICGS, we were unable to identify and confirm the presence of 16 distinct cell populations during this stage of active nephrogenesis. Using a novel integrative supervised computational strategy, we were able to successfully harmonize and compare the cell profiles across all three technological platforms. Analysis of possible cross compartment receptor/ligand interactions identified the nephrogenic zone stroma as a source of GDNF. This was unexpected because the cap mesenchyme nephron progenitors had been thought to be the sole source of GDNF, which is a key driver of branching morphogenesis of the collecting duct system. The expression of Gdnf by stromal cells was validated in several ways, including Gdnf in situ hybridization combined with immunohistochemistry for SIX2, and marker of nephron progenitors, and MEIS1, a marker of stromal cells. Finally, the single cell gene expression profiles generated in this study confirmed and extended previous work showing the presence of multilineage priming during kidney development. Nephron progenitors showed stochastic expression of genes associated with multiple potential differentiation lineages.

Human parainfluenza virus type 3 (PIV3) is a major cause of lower respiratory disease i.e. bronchitis, bronchiolitis or pneumonia, in infants and young children. Presently there is no licensed vaccine against PIV3. To produce an effective subunit vaccine, a chimeric FHN glycoprotein consisting of the N-terminal ectodomain of the fusion (F) protein linked to the haemagglutinin-neuraminidase (HN) protein without transmembrane domain, and secreted forms of the individual F and HN glycoproteins, were expressed in mammalian cells and purified. Mice and cotton rats were immunized intramuscularly (IM) with FHN or both F and HN proteins (F + HN), formulated with poly(I:C) and an innate defense regulator peptide in polyphosphazene (TriAdj). Significantly higher levels of systemic virus-neutralizing antibodies were observed in mice and cotton rats immunized with FHN/TriAdj when compared to animals immunized with the combination of F and HN proteins (F + HN/TriAdj). As PIV3 is a pneumotropic virus, another goal is to produce an effective mucosal subunit vaccine. Intranasal (IN) administration with FHN/TriAdj resulted in mucosal IgA production in the lung and virus neutralizing antibodies in the sera. After PIV3 challenge no virus was detected in cotton rats immunized with FHN/TriAdj regardless of the route of delivery. Protective immunity against PIV3 was also induced by FHN/TriAdj in hamsters. In conclusion, the FHN protein formulated with TriAdj has potential for development of a safe and effective vaccine against PIV3.

Older adults frequently experience adverse consequences as the result of unmet care needs, including not getting dressed and going without food when hungry. Previous studies have noted that characteristics of the caregiver network may be associated with unmet needs. Using National Health and Aging Trends Study data, I modeled the association between care configurations and unmet needs for men and women. In generalized linear models, formal care was not associated with unmet need among women or men. Compared with recipients of spousal care, men receiving care from one nonspousal caregiver, and men and women receiving care from any other configuration, had higher odds of unmet needs. The level of difficulty with daily tasks was strongly associated with unmet needs. These findings support monitoring older adults not receiving spousal care, increasing access to formal care, and regularly assessing level of difficulty with daily tasks in clinical and research settings.

The ongoing epidemic of chronic wasting disease (CWD) within cervid populations indicates the need for novel approaches for disease management. A vaccine that either reduces susceptibility to infection or reduces shedding of prions by infected animals, or a combination of both, could be of benefit for disease control. The development of such a vaccine is challenged by the unique nature of prion diseases and the requirement for formulation and delivery in an oral format for application in wildlife settings. To address the unique nature of prions, our group targets epitopes, termed disease specific epitopes (DSEs), whose exposure for antibody binding depends on disease-associated misfolding of PrPC into PrPSc. Here, a DSE corresponding to the rigid loop (RL) region, which was immunogenic following parenteral vaccination, was translated into an oral vaccine. This vaccine consists of a replication-incompetent human adenovirus expressing a truncated rabies glycoprotein G recombinant fusion with the RL ...

Respiratory syncytial virus (RSV) is the most common cause of respiratory tract infections in both children and elderly people. In this study we evaluated the short- and long-term protective efficacy of a single intranasal (IN) immunization with a RSV vaccine formulation consisting of a codon-optimized fusion (F) protein formulated with poly(I:C), an innate defense regulator peptide and a polyphosphazene (ΔF/TriAdj). This vaccine induced strong systemic and local immune responses, including RSV F-specific IgG1 and IgG2a, SIgA and virus neutralizing antibodies in mice. Furthermore, ΔF/TriAdj promoted production of IFN-γ-secreting T cells and RSV F85–93-specific CD8+ effector T cells. After RSV challenge, no virus was recovered from the lungs of the vaccinated mice. To evaluate the duration of immunity induced by a single IN vaccination, mice were again immunized once with ΔF/TriAdj and challenged with RSV five months later. High levels of IgG1, IgG2a and virus neutralizing antibodies were detected in the ΔF/TriAdj-vaccinated animals. Moreover, this vaccine formulation induced robust local SIgA production and IgA-secreting memory B cell development, and conferred complete protection against subsequent RSV challenge. In conclusion, a single IN vaccination with RSV ΔF protein formulated with TriAdj induced robust, long-term protective immune responses against RSV infection.

Purpose High rates of potentially preventable hospitalizations and emergency department (ED) visits indicate limited primary care access. Rural Health Clinics (RHCs) are intended to increase access to primary care. The goal of this study was to evaluate the role of RHCs and their impact on potentially preventable hospitalizations and ED visits among Medicare beneficiaries based on actual individual-level utilization patterns. Methods With Medicare Part A and Part B claims data from 2007 to 2010, we constructed a series of individual-level negative binomial regression models to examine the relationship between RHC use and the number of potentially preventable hospitalizations and ED visits. Findings RHC use was associated with a 27% increase in potentially preventable hospitalizations and a 24% increase in potentially preventable ED visits among older Medicare enrollees. Among younger, disabled Medicare beneficiaries, RHC use was associated with a 14% increase in potentially preventable hospitalizations and an 18% increase in potentially preventable ED visits. Potentially preventable hospitalizations and ED visits were more common among beneficiaries who were black or who had more chronic conditions. Conclusions The results of our study highlight that the Medicare population using RHCs is at especially high risk for potentially preventable hospitalizations and ED visits. The mechanisms behind this are not well understood and should receive continued attention from policy makers and researchers.

© 2017 Elsevier Ltd Arthritis and kerato-conjunctivitis caused by Chlamydia pecorum in lambs are difficult to diagnose and treat. We tested the ability of a prototype C. pecorum vaccine (SC-vaccine), comprised of C. pecorum major outer membrane protein (MOMP-G) and polymorphic membrane protein G (PmpG), to trigger a Chlamydia-specific humoral and cell-mediated immune response in lambs and pregnant ewes. Vaccinations with the SC-vaccine (one and two injections) were very well tolerated by all ewes and lambs. Although the overall immune responses of ewes to SC-vaccination was poor, their lambs showed stronger antigen-specific immune response than lambs from control vaccine ewes. SC-vaccination in lambs triggered production of systemic anti-MOMP-G and anti-PmpG IgG antibodies and secretory IgA in the ocular mucosa. Double vaccination caused statistically significant increases in the height and duration of the humoral response. Antigen-specific IFN-γ was produced in the peripheral blood mononuclear cells of vaccinated lambs.

SummaryAcute kidney injury (AKI) is a rapid decline of renal function, with an incidence of up to 67% of intensive care unit patients. Current treatments are merely supportive, emphasizing the need for deeper understanding that could lead to improved therapies. We used single cell RNA sequencing,in situhybridization and protein expression analyses to create comprehensive renal cell specific transcriptional profiles of multiple AKI stages. We revealed that AKI induces marked dedifferentiation, renal developmental gene activation and mixed identities in injured renal tubules. Moreover, we identified potential pathologic crosstalk between epithelial and stromal cells, and several novel genes involved in AKI. We also demonstrated the definitive effects of age on AKI outcome, and showed that renal developmental genes hold a potential as novel AKI markers. Moreover, our study provides the resource power which will aid in unraveling the molecular genetics of AKI.

Population leakage outside the qubit subspace presents a particularly harmful source of error that cannot be handled by standard error correction methods. Using a trapped $^{171}$Yb$+$ ion, we demonstrate an optical pumping scheme to suppress leakage errors in atomic hyperfine qubits. The selection rules and narrow linewidth of a quadrupole transition are used to selectively pump population out of leakage states and back into the qubit subspace. Each pumping cycle reduces the leakage population by a factor of $\sim3$, allowing for an exponential suppression in the number of cycles. We use interleaved randomized benchmarking on the qubit subspace to show that this pumping procedure has negligible side-effects on un-leaked qubits, bounding the induced qubit memory error by $\leq2.0(8)\times10^{-5}$ per cycle, and qubit population decay to $\leq1.4(3)\times10^{-7}$ per cycle. These results clear a major obstacle for implementations of quantum error correction and error mitigation protocols., 4 pages, 4 figures

Histophilus somni is a Gram-negative opportunistic pathogen associated with respiratory disease in cattle. Here, we report the draft genome sequences of 12 Histophilus somni strains isolated from feedlot cattle in Alberta, Canada, which were diagnosed with respiratory disease.

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.

Progenitor heterogeneity and identities underlying tumor initiation and relapse in medulloblastomas remain elusive. Utilizing single-cell transcriptomic analysis, we demonstrated a developmental hierarchy of progenitor pools in Sonic Hedgehog (SHH) medulloblastomas, and identified OLIG2-expressing glial progenitors as transit-amplifying cells at the tumorigenic onset. Although OLIG2+ progenitors become quiescent stem-like cells in full-blown tumors, they are highly enriched in therapy-resistant and recurrent medulloblastomas. Depletion of mitotic Olig2+ progenitors or Olig2 ablation impeded tumor initiation. Genomic profiling revealed that OLIG2 modulates chromatin landscapes and activates oncogenic networks including HIPPO-YAP/TAZ and AURORA-A/MYCN pathways. Co-targeting these oncogenic pathways induced tumor growth arrest. Together, our results indicate that glial lineage-associated OLIG2+ progenitors are tumor-initiating cells during medulloblastoma tumorigenesis and relapse, suggesting OLIG2-driven oncogenic networks as potential therapeutic targets.

Utilizing a dual description of two-dimensional elasticity theory as a rank-2 tensor gauge theory, the authors show that zero-temperature quantum melting of a two-dimensional crystal differs crucially from the Halperin-Nelson thermal melting scenario. This is due to the particle number conservation symmetry enforced dislocation glide constraint, or fractonicity. The authors show that quantum crystal fluctuations favor a supersolid phase before melting can occur and, furthermore, discuss applications to the quantum melting of a vortex-lattice and charge-stripe order in a metal.

The identity and degree of heterogeneity of glial progenitors and their contributions to brain tumor malignancy remain elusive. By applying lineage-targeted single-cell transcriptomics, we uncover an unanticipated diversity of glial progenitor pools with unique molecular identities in developing brain. Our analysis identifies distinct transitional intermediate states and their divergent developmental trajectories in astroglial and oligodendroglial lineages. Moreover, intersectional analysis uncovers analogous intermediate progenitors during brain tumorigenesis, wherein oligodendrocyte-progenitor intermediates are abundant, hyper-proliferative, and progressively reprogrammed toward a stem-like state susceptible to further malignant transformation. Similar actively cycling intermediate progenitors are prominent components in human gliomas with distinct driver mutations. We further unveil lineage-driving networks underlying glial fate specification and identify Zfp36l1 as necessary for oligodendrocyte-astrocyte lineage transition and glioma growth. Together, our results resolve the dynamic repertoire of common and divergent glial progenitors during development and tumorigenesis and highlight Zfp36l1 as a molecular nexus for balancing glial cell-fate decision and controlling gliomagenesis.

It is now a routine to carry out single-cell RNA-Seq to define the gene expression patterns of thousands of cells, thereby revolutionizing many areas of research. Projects are underway to use these techniques to create an atlas of the expressed genes in all cell types of the human body. Here we describe cold-active protease methods for single-cell dissociation of organs and tissues that better preserve the in vivo gene expression patterns.