An investigation of the antiplatelet effects of succinobucol (AGI-1067)

Succinobucol is a phenolic antioxidant with anti-inflammatory and antiplatelet effects. Given the importance of oxidant stress in modulating platelet–platelet and platelet–vessel wall interactions, the aim of this study was to establish if antioxidant activity was responsible for the antiplatelet activity of succinobucol. Platelet aggregation in response to collagen and adenosine diphosphate (ADP) was studied in rabbit whole blood and platelet-rich plasma using impedance aggregometry. The effect of oxidant stress on aggregation, platelet lipid peroxides, and vascular tone was studied by incubating platelets, washed platelets or preconstricted rabbit iliac artery rings respectively with a combination of xanthine and xanthine oxidase (X/XO). To study the effect of succinobucol in vivo, anaesthetized rats were injected with up to 150 mg/kg succinobucol and aggregation measured in blood removed 15 mins later. Succinobucol (10−5–10−4 M) significantly attenuated platelet aggregation to collagen and ADP in whole blood and platelet-rich plasma. X/XO significantly increased aggregation to collagen and platelet lipid peroxides and this was reversed by succinobucol. Addition of X/XO to denuded rabbit iliac arteries caused a dose-dependent relaxation which was significantly inhibited by succinobucol. In vivo administration up to 150 mg/kg had no effect on heart rate or mean arterial blood pressure but significantly inhibited platelet aggregation to collagen ex vivo. In conclusion, succinobucol displays anti-platelet activity in rabbit and rat blood and reverses the increase in platelet aggregation in response to oxidant stress

Effects of static and dynamic higher-order optical modes in balanced homodyne readout for future gravitational waves detectors

With the recent detection of Gravitational waves (GW), marking the start of the new field of GW astronomy, the push for building more sensitive laser-interferometric gravitational wave detectors (GWD) has never been stronger. Balanced homodyne detection (BHD) allows for a quantum noise (QN) limited readout of arbitrary light field quadratures, and has therefore been suggested as a vital building block for upgrades to Advanced LIGO and third generation observatories. In terms of the practical implementation of BHD, we develop a full framework for analyzing the static optical high order modes (HOMs) occurring in the BHD paths related to the misalignment or mode matching at the input and output ports of the laser interferometer. We find the effects of HOMs on the quantum noise limited sensitivity is independent of the actual interferometer configuration, e.g. Michelson and Sagnac interferometers are effected in the same way. We show that misalignment of the output ports of the interferometer (output misalignment) only effects the high frequency part of the quantum noise limited sensitivity (detection noise). However, at low frequencies, HOMs reduce the interferometer response and the radiation pressure noise (back action noise) by the same amount and hence the quantum noise limited sensitivity is not negatively effected in that frequency range. We show that the misalignment of laser into the interferometer (input misalignment) produces the same effect as output misalignment and additionally decreases the power inside the interferometer. We also analyze dynamic HOM effects, such as beam jitter created by the suspended mirrors of the BHD. Our analyses can be directly applied to any BHD implementation in a future GWD. Moreover, we apply our analytical techniques to the example of the speed meter proof of concept experiment under construction in Glasgow. We find that for our experimental parameters, the performance of our seismic isolation system in the BHD paths is compatible with the design sensitivity of the experiment

Local-Oscillator Noise Coupling in Balanced Homodyne Readout for Advanced Gravitational Wave Detectors

The second generation of interferometric gravitational wave detectors are quickly approaching their design sensitivity. For the first time these detectors will become limited by quantum back-action noise. Several back-action evasion techniques have been proposed to further increase the detector sensitivity. Since most proposals rely on a flexible readout of the full amplitude- and phase-quadrature space of the output light field, balanced homodyne detection is generally expected to replace the currently used DC readout. Up to now, little investigation has been undertaken into how balanced homodyne detection can be successfully transferred from its ubiquitous application in table-top quantum optics experiments to large-scale interferometers with suspended optics. Here we derive implementation requirements with respect to local oscillator noise couplings and highlight potential issues with the example of the Glasgow Sagnac Speed Meter experiment, as well as for a future upgrade to the Advanced LIGO detectors.Comment: 7 pages, 5 figure

Improving response rates using a monetary incentive for patient completion of questionnaires: an observational study

Background: Poor response rates to postal questionnaires can introduce bias and reduce the statistical power of a study. To improve response rates in our trial in primary care we tested the effect of introducing an unconditional direct payment of 5 pound for the completion of postal questionnaires. Methods: We recruited patients in general practice with knee problems from sites across the United Kingdom. An evidence-based strategy was used to follow-up patients at twelve months with postal questionnaires. This included an unconditional direct payment of 5 pound to patients for the completion and return of questionnaires. The first 105 patients did not receive the 5 pound incentive, but the subsequent 442 patients did. We used logistic regression to analyse the effect of introducing a monetary incentive to increase the response to postal questionnaires. Results: The response rate following reminders for the historical controls was 78.1% ( 82 of 105) compared with 88.0% ( 389 of 442) for those patients who received the 5 pound payment (diff = 9.9%, 95% CI 2.3% to 19.1%). Direct payments significantly increased the odds of response ( adjusted odds ratio = 2.2, 95% CI 1.2 to 4.0, P = 0.009) with only 12 of 442 patients declining the payment. The incentive did not save costs to the trial - the extra cost per additional respondent was almost 50 pound. Conclusion: The direct payment of 5 pound significantly increased the completion of postal questionnaires at negligible increase in cost for an adequately powered study

Neurobehavioral evidence of interoceptive sensitivity in early infancy

Interoception, the sensitivity to visceral sensations, plays an important role in homeostasis and guiding motivated behaviour. It is also considered to be fundamental to self-awareness. Despite its importance, the developmental origins of interoceptive sensitivity remain unexplored. We here provide the first evidence for implicit, flexible interoceptive sensitivity in 5 month old infants using a novel behavioural measure, coupled with an established cortical index of interoceptive processing. These findings have important implications for the understanding of the early developmental stages of self-awareness, self-regulation and socio-emotional abilities

The systematic development of a novel integrated spiral undergraduate course in general practice

In 2007 Keele University School of Medicine rolled out its novel curriculum to which general practice makes a major contribution. In this paper we describe the systematic approach we took to developing the GP curriculum; from the underlying educational principles which guided its development, the subsequent decisions we made to the curriculum itself. This consists of 23 weeks of clinical placements in general practice; four weeks in year 3, four weeks in year 4 and 15 weeks in year 5. We describe the steps which were necessary to prepare for the implementation of the GP curriculum. We consider that the successful implementation of our general practice contribution is a result of our systematic identification of these principles, the clearly articulated design decisions and the systematic preparation for implementation involving the academic GP team and all our potential teaching practices

Upstream Process Development approach to selectively reduce one or more unpaired cysteines of a monoclonal antibody

Please click Additional Files below to see the full abstract

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment