Compositional Synthesis via a Convex Parameterization of Assume-Guarantee Contracts

We develop an assume-guarantee framework for control of large scale linear (time-varying) systems from finite-time reach and avoid or infinite-time invariance specifications. The contracts describe the admissible set of states and controls for individual subsystems. A set of contracts compose correctly if mutual assumptions and guarantees match in a way that we formalize. We propose a rich parameterization of contracts such that the set of parameters that compose correctly is convex. Moreover, we design a potential function of parameters that describes the distance of contracts from a correct composition. Thus, the verification and synthesis for the aggregate system are broken to solving small convex programs for individual subsystems, where correctness is ultimately achieved in a compositional way. Illustrative examples demonstrate the scalability of our method

Clonal expansion within pneumococcal serotype 6C after use of seven-valent vaccine

Streptococcus pneumoniae causes invasive infections, primarily at the extremes of life. A seven-valent conjugate vaccine (PCV7) is used to protect against invasive pneumococcal disease in children. Within three years of PCV7 introduction, we observed a fourfold increase in serotype 6C carriage, predominantly due to a single clone. We determined the whole-genome sequences of nineteen S. pneumoniae serotype 6C isolates, from both carriage (n = 15) and disease (n = 4) states, to investigate the emergence of serotype 6C in our population, focusing on a single multi-locus sequence type (MLST) clonal complex 395 (CC395). A phylogenetic network was constructed to identify different lineages, followed by analysis of variability in gene sets and sequences. Serotype 6C isolates from this single geographical site fell into four broad phylogenetically distinct lineages. Variation was seen in the 6C capsular locus and in sequences of genes encoding surface proteins. The largest clonal complex was characterised by the presence of lantibiotic synthesis locus. In our population, the 6C capsular locus has been introduced into multiple lineages by independent capsular switching events. However, rapid clonal expansion has occurred within a single MLST clonal complex. Worryingly, plasticity exists within current and potential vaccine-associated loci, a consideration for future vaccine use, target selection and design

Signatures from a merging galaxy cluster and its AGN population : LOFAR observations of Abell 1682

Reproduced with permission from Astronomy & Astrophysics. © 2019 ESOWe present LOFAR data from 110-180 MHz of the merging galaxy cluster Abell 1682, alongside archival optical, radio, and X-ray data. Our images of 6 arcsec in resolution at low frequencies reveal new structures associated with numerous radio galaxies in the cluster. At a resolution of 20 arcsec we see diffuse emission throughout the cluster over hundreds of kiloparsecs, indicating particle acceleration mechanisms are in play as a result of the cluster merger event and powerful active galactic nuclei. We show that a significant part of the cluster emission is from an old radio galaxy with very steep spectrum emission (having a spectral index of α < -2.5). Furthermore, we identify a new region of diffuse steep-spectrum emission (α < -1.1) as a candidate for a radio halo which is co-spatial with the centre of the cluster merger. We suggest its origin as a population of old and mildly relativistic electrons left over from radio galaxies throughout the cluster which have been re-accelerated to higher energies by shocks and turbulence induced by the cluster merger event. We also note the discovery of six new giant radio galaxies in the vicinity of Abell 1682.Peer reviewedFinal Accepted Versio

Glucagon-like peptide-1 protects against ischemic left ventricular dysfunction during hyperglycemia in patients with coronary artery disease and type 2 diabetes mellitus.

BACKGROUND: Enhancement of myocardial glucose uptake may reduce fatty acid oxidation and improve tolerance to ischemia. Hyperglycemia, in association with hyperinsulinemia, stimulates this metabolic change but may have deleterious effects on left ventricular (LV) function. The incretin hormone, glucagon-like peptide-1 (GLP-1), also has favorable cardiovascular effects, and has emerged as an alternative method of altering myocardial substrate utilization. In patients with coronary artery disease (CAD), we investigated: (1) the effect of a hyperinsulinemic hyperglycemic clamp (HHC) on myocardial performance during dobutamine stress echocardiography (DSE), and (2) whether an infusion of GLP-1(7-36) at the time of HHC protects against ischemic LV dysfunction during DSE in patients with type 2 diabetes mellitus (T2DM). METHODS: In study 1, twelve patients underwent two DSEs with tissue Doppler imaging (TDI)-one during the steady-state phase of a HHC. In study 2, ten patients with T2DM underwent two DSEs with TDI during the steady-state phase of a HHC. GLP-1(7-36) was infused intravenously at 1.2 pmol/kg/min during one of the scans. In both studies, global LV function was assessed by ejection fraction and mitral annular systolic velocity, and regional wall LV function was assessed using peak systolic velocity, strain and strain rate from 12 paired non-apical segments. RESULTS: In study 1, the HHC (compared with control) increased glucose (13.0 ± 1.9 versus 4.8 ± 0.5 mmol/l, p < 0.0001) and insulin (1,212 ± 514 versus 114 ± 47 pmol/l, p = 0.01) concentrations, and reduced FFA levels (249 ± 175 versus 1,001 ± 333 μmol/l, p < 0.0001), but had no net effect on either global or regional LV function. In study 2, GLP-1 enhanced both global (ejection fraction, 77.5 ± 5.0 versus 71.3 ± 4.3%, p = 0.004) and regional (peak systolic strain -18.1 ± 6.6 versus -15.5 ± 5.4%, p < 0.0001) myocardial performance at peak stress and at 30 min recovery. These effects were predominantly driven by a reduction in contractile dysfunction in regions subject to demand ischemia. CONCLUSIONS: In patients with CAD, hyperinsulinemic hyperglycemia has a neutral effect on LV function during DSE. However, GLP-1 at the time of hyperglycemia improves myocardial tolerance to demand ischemia in patients with T2DM. TRIAL REGISTRATION: http://www.isrctn.org . Unique identifier ISRCTN69686930

Cognitive tests used in chronic adult human randomised controlled trial micronutrient and phytochemical intervention studies

In recent years there has been a rapid growth of interest in exploring the relationship between nutritional therapies and the maintenance of cognitive function in adulthood. Emerging evidence reveals an increasingly complex picture with respect to the benefits of various food constituents on learning, memory and psychomotor function in adults. However, to date, there has been little consensus in human studies on the range of cognitive domains to be tested or the particular tests to be employed. To illustrate the potential difficulties that this poses, we conducted a systematic review of existing human adult randomised controlled trial (RCT) studies that have investigated the effects of 24 d to 36 months of supplementation with flavonoids and micronutrients on cognitive performance. There were thirty-nine studies employing a total of 121 different cognitive tasks that met the criteria for inclusion. Results showed that less than half of these studies reported positive effects of treatment, with some important cognitive domains either under-represented or not explored at all. Although there was some evidence of sensitivity to nutritional supplementation in a number of domains (for example, executive function, spatial working memory), interpretation is currently difficult given the prevailing 'scattergun approach' for selecting cognitive tests. Specifically, the practice means that it is often difficult to distinguish between a boundary condition for a particular nutrient and a lack of task sensitivity. We argue that for significant future progress to be made, researchers need to pay much closer attention to existing human RCT and animal data, as well as to more basic issues surrounding task sensitivity, statistical power and type I error

EGFR-HIF1α signaling positively regulates the differentiation of IL-9 producing T helper cells

Interleukin 9 (IL-9)-producing helper T (Th9) cells are essential for inducing anti-tumor immunity and inflammation in allergic and autoimmune diseases. Although transcription factors that are essential for Th9 cell differentiation have been identified, other signaling pathways that are required for their generation and functions are yet to be explored. Here, we identify that Epidermal Growth Factor Receptor (EGFR) is essential for IL-9 induction in helper T (Th) cells. Moreover, amphiregulin (Areg), an EGFR ligand, is critical for the amplification of Th9 cells induced by TGF-β1 and IL-4. Furthermore, our data show that Areg-EGFR signaling induces HIF1α, which binds and transactivates IL-9 and NOS2 promoters in Th9 cells. Loss of EGFR or HIF1α abrogates Th9 cell differentiation and suppresses their anti-tumor functions. Moreover, in line with its reliance on HIF1α expression, metabolomics profiling of Th9 cells revealed that Succinate, a TCA cycle metabolite, promotes Th9 cell differentiation and Th9 cell-mediated tumor regression

Numerical Simulation of a Scanning Illumination System for Deep Tissue Fluorescence Imaging

he spatial resolution and light detected in fluorescence imaging for small animals are limited by light scattering, absorption and autofluorescence. To address this, novel near-infrared fluorescent contrast agents and imaging configurations have been investigated. In this paper, the influence of the light wavelength and imaging configurations (full-field illumination system and scanning system) on fluorescence imaging are compared quantitatively. The surface radiance for both systems is calculated by modifying the simulation tool Near-Infrared Fluorescence and Spectral Tomography. Fluorescent targets are embedded within a scattering medium at different positions. The surface radiance and spatial resolution are obtained for emission wavelengths between 620 nm and 1000 nm. It was found that the spatial resolution of the scanning system is independent of the tissue optical properties, whereas for full-field illumination, the spatial resolution degrades at longer wavelength. The full width at half maximum obtained by the scanning system is 25% lower than that obtained by the full-field illumination system when the targets are located in the middle of the phantom. The results indicate that although imaging at near-infrared wavelength can achieve a higher surface radiance, it may produce worse spatial resolution

The eventization of leisure and the strange death of alternative Leeds

The communicative potential of city spaces as leisure spaces is a central assumption of political activism and the creation of alternative, counter-cultural and subcultural scenes. However, such potential for city spaces is limited by the gentrification, privatization and eventization of city centres in the wake of wider societal and cultural struggles over leisure, work and identity formation. In this paper, we present research on alternative scenes in the city of Leeds to argue that the eventization of the city centre has led to a marginalization and of alternative scenes on the fringes of the city. Such marginalization has not caused the death of alternative Leeds or political activism associated with those scenes—but it has changed the leisure spaces (physical, political and social) in which alternative scenes contest the mainstream

Synthesis of Passerini-3CR Polymers and Assembly into Cytocompatible Polymersomes

© 2020 The Authors. Published by Wiley-VCH GmbH The versatility of the Passerini three component reaction (Passerini-3CR) is herein exploited for the synthesis of an amphiphilic diblock copolymer, which self-assembles into polymersomes. Carboxy-functionalized poly(ethylene glycol) methyl ether is reacted with AB-type bifunctional monomers and tert-butyl isocyanide in a single process via Passerini-3CR. The resultant diblock copolymer (P1) is obtained in good yield and molar mass dispersity and is well tolerated in model cell lines. The Passerini-3CR versatility and reproducibility are shown by the synthesis of P2, P3, and P4 copolymers. The ability of the Passerini P1 polymersomes to incorporate hydrophilic molecules is verified by loading doxorubicin hydrochloride in P1DOX polymersomes. The flexibility of the synthesis is further demonstrated by simple post-functionalization with a dye, Cyanine-5 (Cy5). The obtained P1-Cy5 polymersomes rapidly internalize in 2D cell monolayers and penetrate deep into 3D spheroids of MDA-MB-231 triple-negative breast cancer cells. P1-Cy5 polymersomes injected systemically in healthy mice are well tolerated and no visible adverse effects are seen under the conditions tested. These data demonstrate that new, biodegradable, biocompatible polymersomes having properties suitable for future use in drug delivery can be easily synthesized by the Passerini-3CR