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

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

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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

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

Structure- and ligand-based virtual screening identifies new scaffolds for inhibitors of the oncoprotein MDM2

A major challenge in the field of ligand discovery is to identify chemically useful fragments that can be developed into inhibitors of specific protein-protein interactions. Low molecular weight fragments (with molecular weight less than 250 Da) are likely to bind weakly to a protein's surface. Here we use a new virtual screening procedure which uses a combination of similarity searching and docking to identify chemically tractable scaffolds that bind to the p53-interaction site of MDM2. The binding has been verified using capillary electrophoresis which has proven to be an excellent screening method for such small, weakly binding ligands

Utilizing Creativity for Adolescents’ Recovery in Inpatient Psychiatric Hospital (IPH)

The study aims to examine the impact of creative activities on adolescents, aged 12-18, hospitalized in an acute-care inpatient psychiatric hospital (IPH) setting. While research on the health impact of creative writing has been discussed with adults, research on adolescents hospitalized in acute inpatient psychiatric units (IPU) is limited. This study highlights how creative activities generate self-discovery and insights that are necessary for coping among adolescents in IPH. Seventy creative writing and origami sessions were embedded as a part of group education from March, 2018 until Feb. 2020. A curriculum that considered the interests of current teenagers and the IPH short length of stay (4-5 days) was designed and delivered by a professional writer and their team that consisted of health sciences students, medical students, and IPU nursing staff. After each session, a post-session survey was administered. The findings from 568 post-surveys suggest that the adolescents at the IPH expressed interest and engagement through creative activities. In addition, the findings suggest creative activities promote mood shifts, relaxation, and self-awareness, all critical for adolescents during a mental health crisis. Further studies are needed to assess if these activities lead to long-term coping strategies for participants following their hospitalization

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

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

Twenty-eight divergent polysaccharide loci specifying within- and amongst-strain capsule diversity in three strains of Bacteroides fragilis

Comparison of the complete genome sequence of Bacteroides fragilis 638R, originally isolated in the USA, was made with two previously sequenced strains isolated in the UK (NCTC 9343) and Japan (YCH46). The presence of 10 loci containing genes associated with polysaccharide (PS) biosynthesis, each including a putative Wzx flippase and Wzy polymerase, was confirmed in all three strains, despite a lack of cross-reactivity between NCTC 9343 and 638R surface PS-specific antibodies by immunolabelling and microscopy. Genomic comparisons revealed an exceptional level of PS biosynthesis locus diversity. Of the 10 divergent PS-associated loci apparent in each strain, none is similar between NCTC 9343 and 638R. YCH46 shares one locus with NCTC 9343, confirmed by mAb labelling, and a second different locus with 638R, making a total of 28 divergent PS biosynthesis loci amongst the three strains. The lack of expression of the phase-variable large capsule (LC) in strain 638R, observed in NCTC 9343, is likely to be due to a point mutation that generates a stop codon within a putative initiating glycosyltransferase, necessary for the expression of the LC in NCTC 9343. Other major sequence differences were observed to arise from different numbers and variety of inserted extra-chromosomal elements, in particular prophages. Extensive horizontal gene transfer has occurred within these strains, despite the presence of a significant number of divergent DNA restriction and modification systems that act to prevent acquisition of foreign DNA. The level of amongst-strain diversity in PS biosynthesis loci is unprecedented

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