High-fidelity initialization and control of electron and nuclear spins in a four-qubit register.

Single electron spins bound to multi-phosphorus nuclear spin registers in silicon have demonstrated fast (0.8 ns) two-qubit SWAP gates and long spin relaxation times (~30 s). In these spin registers, when the donors are ionized, the nuclear spins remain weakly coupled to their environment, allowing exceptionally long coherence times. When the electron is present, the hyperfine interaction allows coupling of the spin and charge degrees of freedom for fast qubit operation and control. Here we demonstrate the use of the hyperfine interaction to enact electric dipole spin resonance to realize high-fidelity ( F = 10 0 - 6 + 0 %) initialization of all the nuclear spins within a four-qubit nuclear spin register. By controllably initializing the nuclear spins to ⇓ ⇓ ⇓ , we achieve single-electron qubit gate fidelities of F = 99.78 ± 0.07% (Clifford gate fidelities of 99.58 ± 0.14%), above the fault-tolerant threshold for the surface code with a coherence time of T 2 * = 12 µ s .

Antimicrobial use for selected diseases in cats in Switzerland.

BACKGROUND: Antibiotic use in human and veterinary medicine is considered a main driver of antimicrobial resistance. Although guidelines to promote appropriate use of antimicrobials in veterinary patients have been developed, antibiotic overprescription is assumed to be a common problem. The goal of this study was to investigate antimicrobial use in cats in Switzerland with acute upper respiratory tract disease (aURTD), feline lower urinary tract disease (FLUTD) and abscesses, and to assess compliance of prescription with consensus guidelines. A total of 776 cases (aURTD, n = 227; FLUTD, n = 333; abscesses, n = 216) presented to two university hospitals and 14 private veterinary practices in Switzerland during 2016 were retrospectively evaluated. Clinical history, diagnostic work-up and antimicrobial prescription (class, dosage, duration) were assessed. RESULTS: A total of 77% (aURTD), 60% (FLUTD) and 96% (abscesses) of the cases received antibiotic therapy; 13-24% received combination or serial therapy. The cats were treated for a median of 7 (abscesses) and 10 days (aURTD, FLUTD). Treatments with potentiated aminopenicillins (40-64%), third generation cephalosporins (25-28%), aminopenicillins (12-24%) and fluoroquinolones (3-13%) were most common. Prescriptions were judged in complete accordance with consensus guidelines in 22% (aURTD), 24% (FLUTD) and 17% (abscesses) of the cases. Antibiotics were prescribed although not indicated in 34% (aURTD), 14% (FLUTD) and 29% (abscesses) of the cases. The presence of lethargy, anorexia or fever in cats with aURTD, and the detection of bacteriuria in cats with FLUTD were significantly associated with antibiotic therapy. Although diagnostic work-up was significantly more common (aURTD: university hospitals, 58%; private practices, 1%; FLUTD: university hospitals, 92%; private practices, 27%) and the use of critically important antibiotics significantly less common at the university hospitals (aURTD, 10%; FLUTD, 14%) compared to private practices (aURTD, 38%; FLUTD, 54%), the frequency of antibiotic treatment was not different between the university hospitals and private practices. CONCLUSIONS: Our results indicate that overprescription of antibiotics in cats in Switzerland is common and accordance with guidelines is poor. The study highlights the need to promote antimicrobial stewardship in small animal medicine.

Calculation of the Hadronic Vacuum Polarization Contribution to the Muon Anomalous Magnetic Moment.

We present a first-principles lattice QCD+QED calculation at physical pion mass of the leading-order hadronic vacuum polarization contribution to the muon anomalous magnetic moment. The total contribution of up, down, strange, and charm quarks including QED and strong isospin breaking effects is a_{µ}^{HVP LO}=715.4(18.7)×10^{-10}. By supplementing lattice data for very short and long distances with R-ratio data, we significantly improve the precision to a_{µ}^{HVP LO}=692.5(2.7)×10^{-10}. This is the currently most precise determination of a_{µ}^{HVP LO}.

Calculation of the Hadronic Vacuum Polarization Disconnected Contribution to the Muon Anomalous Magnetic Moment.

We report the first lattice QCD calculation of the hadronic vacuum polarization (HVP) disconnected contribution to the muon anomalous magnetic moment at physical pion mass. The calculation uses a refined noise-reduction technique that enables the control of statistical uncertainties at the desired level with modest computational effort. Measurements were performed on the 48^{3}×96 physical-pion-mass lattice generated by the RBC and UKQCD Collaborations. We find the leading-order hadronic vacuum polarization a_{µ}^{HVP(LO)disc}=-9.6(3.3)(2.3)×10^{-10}, where the first error is statistical and the second systematic.

The blood-tendon barrier: identification and characterisation of a novel tissue barrier in tendon blood vessels.

Tissue barriers function as "gate keepers" between different compartments (usually blood and tissue) and are formed by specialised membrane-associated proteins, localising to the apicolateral plasma membrane domain of epithelial and endothelial cells. By sealing the paracellular space, the free diffusion of solutes and molecules across epithelia and endothelia is impeded. Thereby, tissue barriers contribute to the establishment and maintenance of a distinct internal and external environment, which is crucial during organ development and allows maintenance of an organ-specific homeostatic milieu. So far, various epithelial and endothelial tissue barriers have been described, including the blood-brain barrier, the blood-retina barrier, the blood-testis barrier, the blood-placenta barrier, and the cerebrospinal fluid (CSF)-brain barrier, which are vital for physiological function and any disturbance of these barriers can result in severe organ damage or even death. Here, we describe the identification of a novel barrier, located in the vascular bed of tendons, which we term the blood-tendon barrier (BTB). By using immunohistochemistry, transmission electron microscopy, and tracer studies we demonstrate the presence of a functional endothelial barrier within tendons restricting the passage of large blood-borne molecules into the surrounding tendon tissue. We further provide in vitro evidence that the BTB potentially contributes to the creation of a distinct internal tissue environment impacting upon the proliferation and differentiation of tendon-resident cells, effects which might be fundamental for the onset of tendon pathologies.

Standard Model Prediction for Direct CP Violation in K→ππ Decay.

We report the first lattice QCD calculation of the complex kaon decay amplitude A_{0} with physical kinematics, using a 32³×64 lattice volume and a single lattice spacing a, with 1/a=1.3784(68) GeV. We find Re(A_{0})=4.66(1.00)(1.26)×10(-7) GeV and Im(A_{0})=-1.90(1.23)(1.08)×10(-11) GeV, where the first error is statistical and the second systematic. The first value is in approximate agreement with the experimental result: Re(A_{0})=3.3201(18)×10(-7) GeV, while the second can be used to compute the direct CP-violating ratio Re(ϵ^{'}/ϵ)=1.38(5.15)(4.59)×10^{-4}, which is 2.1σ below the experimental value 16.6(2.3)×10(-4). The real part of A_{0} is CP conserving and serves as a test of our method while the result for Re(ϵ^{'}/ϵ) provides a new test of the standard model theory of CP violation, one which can be made more accurate with increasing computer capability.

Asthma and allergies: is the farming environment (still) protective in Poland? The GABRIEL Advanced Studies.

BACKGROUND: Evidence exists that a farming environment in childhood may provide protection against atopic respiratory disease. In the GABRIEL project based in Poland and Alpine regions of Germany, Austria and Switzerland, we aimed to assess whether a farming environment in childhood is protective against allergic diseases in Poland and whether specific exposures explain any protective effect. METHODS: In rural Poland, 23 331 families of schoolchildren completed a questionnaire enquiring into farming practices and allergic diseases (Phase I). A subsample (n = 2586) participated in Phase II involving a more detailed questionnaire on specific farm exposures with objective measures of atopy. RESULTS: Farming differed between Poland and the Alpine centres; in the latter, cattle farming was prevalent, whereas in Poland 18% of village farms kept ≥1 cow and 34% kept ≥1 pig. Polish children in villages had lower prevalences of asthma and hay fever than children from towns, and in the Phase II population, farm children had a reduced risk of atopy measured by IgE (aOR = 0.72, 95% CI 0.57, 0.91) and skin prick test (aOR = 0.65, 95% CI 0.50, 0.86). Early-life contact with grain was inversely related to the risk of atopy measured by IgE (aOR = 0.66, 95% CI 0.47, 0.92) and appeared to explain part of the farming effect. CONCLUSION: While farming in Poland differed from that in the Alpine areas as did the exposure-response associations, we found in communities engaged in small-scale, mixed farming, there was a protective farming effect against objective measures of atopy potentially related to contact with grain or associated farm activities.

Emerging understanding of the ΔI=1/2 rule from lattice QCD.

There has been much speculation as to the origin of the ΔI=1/2 rule (ReA0/ReA2≃22.5). We find that the two dominant contributions to the ΔI=3/2, K→ππ correlation functions have opposite signs, leading to a significant cancelation. This partial cancelation occurs in our computation of ReA2 with physical quark masses and kinematics (where we reproduce the experimental value of A2) and also for heavier pions at threshold. For ReA0, although we do not have results at physical kinematics, we do have results for pions at zero momentum with mπ≃420 MeV [ReA0/ReA2=9.1(2.1)] and mπ≃330 MeV [ReA0/ReA2=12.0(1.7)]. The contributions which partially cancel in ReA2 are also the largest ones in ReA0, but now they have the same sign and so enhance this amplitude. The emerging explanation of the ΔI=1/2 rule is a combination of the perturbative running to scales of O(2 GeV), a relative suppression of ReA2 through the cancelation of the two dominant contributions, and the corresponding enhancement of ReA0. QCD and electroweak penguin operators make only very small contributions at such scales.

Tendons from non-diabetic humans and rats harbor a population of insulin-producing, pancreatic beta cell-like cells.

Diabetes mellitus is a risk factor for various types of tendon disorders. The mechanisms underlying diabetes associated tendinopathies remain unclear, but typically, systemic factors related to high blood glucose levels are thought to be causally involved. We hypothesize that tendon immanent cells might be directly involved in diabetic tendinopathy. We therefore analyzed human and rat tendons by immunohistochemistry, laser capture microdissection, and single cell PCR for pancreatic ß-cell associated markers. Moreover, we examined the short term effects of a single injection of streptozotocin, a toxin for GLUT2 expressing cells, in rats on insulin expression of tendon cells, and on the biomechanical properties of Achilles tendons. Tendon cells, both in the perivascular area and in the dense collagenous tissue express insulin and Glut2 on both protein and mRNA levels. In addition, glucagon and PDX-1 are present in tendon cells. Intraperitoneal injection of streptozotocin caused a loss of insulin and insulin mRNA in rat Achilles tendons after only 5 days, accompanied by a 40% reduction of mechanical strength. In summary, a so far unrecognized, extrapancreatic, insulin-producing cell type, possibly playing a major role in the pathophysiology of diabetic tendinopathy is described. In view of these data, novel strategies in tendon repair may be considered. The potential of the described cells as a tool for treating diabetes needs to be addressed by further studies.

K→(ππ)(I=2) decay amplitude from lattice QCD.

We report on the first realistic ab initio calculation of a hadronic weak decay, that of the amplitude A(2) for a kaon to decay into two π mesons with isospin 2. We find ReA(2)=(1.436±0.063(stat)±0.258(syst))10(-8) GeV in good agreement with the experimental result and for the hitherto unknown imaginary part we find ImA(2)=-(6.83±0.51(stat)±1.30(syst))10(-13) GeV. Moreover combining our result for ImA(2) with experimental values of ReA(2), ReA(0), and ε'/ε, we obtain the following value for the unknown ratio ImA(0)/ReA(0) within the standard model: ImA(0)/ReA(0)=-1.63(19)(stat)(20(syst)×10(-4). One consequence of these results is that the contribution from ImA(2) to the direct CP violation parameter ε' (the so-called Electroweak Penguin contribution) is Re(ε'/ε)(EWP)=-(6.52±0.49(stat)±1.24(syst))×10(-4). We explain why this calculation of A(2) represents a major milestone for lattice QCD and discuss the exciting prospects for a full quantitative understanding of CP violation in kaon decays.

New aspects of the molecular constituents of tissue barriers.

Epithelial and endothelial tissue barriers are based on tight intercellular contacts (Tight Junctions, TJs) between neighbouring cells. TJs are multimeric complexes, located at the most apical border of the lateral membrane. So far, a plethora of proteins locating at tight intercellular contacts have been discovered, the role of which has just partly been unraveled. Yet, there is convincing evidence that many TJ proteins exert a dual role: They act as structural components at the junctional site and they are involved in signalling pathways leading to alterations of gene expression and cell behaviour (migration, proliferation). This review will shortly summarize the classical functions of TJs and TJ-related proteins and will introduce a new category, termed the "non-classical" functions of junctional proteins. A particular focus will be directed towards the nuclear targeting of junctional proteins and the downstream effects elicited by their intranuclear activities.

Perivascular cells of the supraspinatus tendon express both tendon- and stem cell-related markers.

Tendons and ligaments are often affected by mechanical injuries or chronic impairment but other than muscle or bone they possess a low healing capacity. So far, little is known about regeneration of tendons and the role of tendon precursor cells in that process. We hypothesize that perivascular cells of tendon capillaries are progenitors for functional tendon cells and are characterized by expression of marker genes and proteins typical for mesenchymal stem cells and functional tendon cells. Immunohistochemical characterization of biopsies derived from intact human supraspinatus tendons was performed. From these biopsies perivascular cells were isolated, cultured, and characterized using RT-PCR and Western blotting. We have shown for the first time that perivascular cells within tendon tissue express both tendon- and stem/precursor cell-like characteristics. These findings were confirmed by results from in vitro studies focusing on cultured perivascular cells isolated from human supraspinatus tendon biopsies. The results suggest that the perivascular niche may be considered a source for tendon precursor cells. This study provides further information about the molecular nature and localization of tendon precursor cells, which is the basis for developing novel strategies towards tendon healing and facilitated regeneration.

Oxygen pre-breathing decreases dysbaric diseases in UW sheep undergoing hyperbaric exposure.

Prolonged exposure of humans and animals to increased pressure as in a disabled submarine (DISSUB) can saturate the body's tissues with dissolved N2 as compressed air is breathed. Decompression-induced bubble formation in the long bone marrow cavity may lead to a bone compartment syndrome resulting in bone ischemia and necrosis. We tested oxygen pre-breathing prior to decompression in sheep to assess the effect upon dysbaric osteonecrosis (DON) induction in a DISSUB simulation experiment. A total of sixteen adult female sheep were used throughout the experiment. Four sheep were used as controls without oxygen pre-breathing. All sheep (99 +/- 14 kg SD) underwent dry chamber air exposure at 60 fsw (2.79 atm abs) (.2827 MPa) for 24 h followed by oxygen (88-92%) pre-breathing (15-min, 1-h, and 2-h and air for control) before "dropout" decompression at 30 fsw/min (0.91 atm/min). 99mTc-methylene diphosphonate (MDP) bone scans of the distal (radii and tibiae) long bones were used to detect "hot spots" of remodeling suggestive of DON lesions. Alizarin complexone fluorochrome was injected to visualize sites of metabolic activity indicating DON repair of both the proximal and distal long bones (radii, tibiae, femora, and humeri). Our findings showed that the amount of alizarin complexone deposition and bone scan uptake was greater in sheep with shorter oxygen pre-breathing times than those undergoing longer pre-breathing dives (p = 0.0056 and p = 0.001, for one and two hour pre-breathes respectively). Proximal limb bones (femur, humerus) displayed less alizarin complexone deposition than the distal radius and tibia (p < 0.0001).

Platelets contribute to enhanced MCP-1 levels in patients with chronic heart failure.

BACKGROUND: Increasing scientific data suggest a role for inflammation in chronic heart failure (CHF), but up to now the exact mechanisms are still not clear. Recently, platelets were identified as inducing inflammation partly by releasing cytokines. This new aspect necessitates further studies about the contribution of platelets for the inflammatory setting of CHF. METHODS: 50 CHF patients (mean 66.9 (SD 12.6) years, mean EF 22.1% (SD 9.1)) and 25 healthy controls (mean 63.6 (SD 10.2) years) were examined. MCP-1 serum levels were measured via EIA, expression of platelet CD154 by flow cytometry. In in-vitro experiments activated platelets were cocultured with human umbilical vein endothelial cells (HUVEC) in the presence and absence of anti-CD154 antibodies. MCP-1 in the supernatants was measured by EIA. RESULTS: CHF patients showed significantly enhanced MCP-1 levels (median: 191.8; 25th centile: 153.7; 75th centile: 227.1 pg/ml vs median: 101.0; 25th centile: 86.7; 75th centile: 117.5 pg/ml, p<0.001). MCP-1 levels positively correlated with severity of CHF. In the cell coculture model activated platelets were able to significantly induce MCP-1 release from HUVEC in a CD154-dependent manner. Furthermore, CHF patients showed enhanced platelet CD154 expression with a positive correlation with MCP-1 levels. Aspirin therapy had no influence on either CD154 expression or MCP-1 levels. CONCLUSIONS: Platelets can contribute to enhanced MCP-1 levels in CHF. MCP-1 is markedly elevated in serum of CHF patients showing a direct correlation with the severity of symptoms and the degree of left ventricular dysfunction. Further studies are required to test whether MCP-1 blocking or sophisticated anti-platelet strategies may represent new therapeutic options in CHF.

Overexpression of the human neonatal Fc-receptor alpha-chain in trophoblast-derived BeWo cells increases cellular retention of beta2-microglobulin.

Major histocompatibility complex (MHC) class I and MHC class I-type molecules such as the neonatal Fcgamma-receptor, FcRn, are heterodimers consisting of a transmembrane alpha-chain non-covalently associated with beta2-microglobulin (beta2m). Human placental villous syncytiotrophoblast (STB) lacks MHC class I molecules, but express hFcRn that mediates materno-fetal transmission of immunoglobulin G (IgG). Trophoblast-derived BeWo cells that are used to study placental IgG transport likewise express beta2m and low levels of hFcRn alpha-chain. The contribution of FcRn alpha-chain in retention and subcellular distribution of beta2m in STB and BeWo cells is unclear. To investigate this issue, we increased expression of hFcRn alpha-chain in BeWo cells (BeWo/hFcRn) by cDNA transfection. Overexpressed hFcRn protein exhibited the characteristic pH-dependent IgG binding and association with beta2m. In comparison to parental BeWo cells, beta2m mRNA levels in BeWo/hFcRn cells were not significantly altered, but total cell-associated beta2m protein was increased by 120%. Treatment of BeWo and BeWo/hFcRn cells with brefeldin A, an inhibitor of the secretory pathway, abrogated this effect, demonstrating that hFcRn alpha-chain expression retained otherwise secreted beta2m. Flow cytometry revealed that beta2m plasma membrane expression was unaffected by alpha-chain overexpression whereas by fluorescence microscopy a preferential staining of beta2m in peripheral endosomes was observed.

Drosophila separase is required for sister chromatid separation and binds to PIM and THR.

Drosophila PIM and THR are required for sister chromatid separation in mitosis and associate in vivo. Neither of these two proteins shares significant sequence similarity with known proteins. However, PIM has functional similarities with securin proteins. Like securin, PIM is degraded at the metaphase-to-anaphase transition and this degradation is required for sister chromatid separation. Securin binds and inhibits separase, a conserved cysteine endoprotease. Proteolysis of securin at the metaphase-to-anaphase transition activates separase, which degrades a conserved cohesin subunit, thereby allowing sister chromatid separation. To address whether PIM regulates separase activity or functions with THR in a distinct pathway, we have characterized a Drosophila separase homolog (SSE). SSE is an unusual member of the separase family. SSE is only about one-third the size of other separases and has a diverged endoprotease domain. However, our genetic analyses show that SSE is essential and required for sister chromatid separation during mitosis. Moreover, we show that SSE associates with both PIM and THR. Although our work shows that separase is required for sister chromatid separation in higher eukaryotes, in addition, it also indicates that the regulatory proteins have diverged to a surprising degree, particularly in Drosophila.

Age-related decrease in paired-pulse intracortical inhibition in the human primary motor cortex.

Using biphasic magnetic stimuli, paired-pulse transcranial magnetic stimulation (TMS) at short interstimulus intervals (ISIs) was employed to investigate age-related changes in the balance between intracortical inhibition and facilitation. In 26 right-handed healthy individuals, motor evoked potentials were recorded from the relaxed right first dorsal interosseus muscle after paired-pulse TMS of the left primary motor hand area. The magnitude of intracortical paired-pulse inhibition at ISIs of 1-5 ms was markedly reduced in elderly individuals, whereas no age effect was observed for intracortical paired-pulse facilitation at ISIs of 11-15 ms. This finding demonstrates that normal aging is associated with a relative decrease in the excitability of intracortical inhibitory circuits. In conclusion, paired-pulse TMS provides a non-invasive means of studying age-related functional changes in the motor cortex.

Reduction of Cre recombinase toxicity in proliferating Drosophila cells by estrogen-dependent activity regulation.

The Cre/loxP site-specific recombination system has been used successfully for genome manipulation in a wide range of species. However, in Drosophila melanogaster, a major model organism for genetic analyses, the alternative FLP/FRT system, which is less efficient at least in mammalian cells, has been established, primarily for the generation of genetic mosaics for clonal analyses. To extend genetic methodology in D. melanogaster, we have created transgenic lines allowing tissue-specific expression of Cre recombinase with the UAS/GAL4 system. Surprisingly, chronic expression of Cre recombinase from these transgenes (UAST-cre) was found to be toxic for proliferating cells. Therefore, we also generated transgenic lines allowing the expression of Cre recombinase fused to the ligand-binding domain of the human estrogen receptor (UASP-cre-EBD). We demonstrate that recombination can be efficiently dissociated from toxicity by estrogen-dependent regulation of recombinase activity of the UASP-cre-EBD transgene products.