922017 research outputs found
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Analysing single cell secretions by ‘shadow imaging’
No full textHere, we describe a method, which we term ‘shadow imaging’, to analyse the secretions of individual cells at immune synapses, or other cell contacts. Following immune synapse formation and cellular activation on ligand-rich slides the position of each cell is recorded using a pulsed immunofluorescence stain against the proteins on the ligand-rich slide surface. The pulsed stain does not penetrate the synaptic cleft, resulting in an unlabelled region or ‘shadow’ beneath cells that is retained following cellular detachment. The secreted components, such as perforin, exosomes or other types of extracellular vesicles are retained on the slide and can be analysed on a single-cell basis using immunofluorescence. The ability to identify single cells secreting different combinations of particles, proteins and vesicles, enables us to better understand the heterogeneity in immune cell secretions, and can be used as a novel approach for phenotyping cell populations
Flexible sensors, circuits, and systems for bioelectronic interfacing
No full textBioelectronics is an emerging research area where human-made electronic systems interface, bidirectionally, with the electrical systems present in biology. Flexible electronics are a critical development for bioelectronic systems which can flex and stretch with the body. Printing based manufacturing approaches have been heavily investigated in recent years for creating bioelectronic systems, as screen printing can potentially provide scaled-up roll-to-roll based manufacturing while 3D and inkjet printing can potentially provide opportunities for personalisation. This paper presents a brief narrative review bioelectronics, the materials challenges in flexible sensors, circuits, and systems for bioelectronic interfacing, and examples of our approaches to tackling these challenges
Theoretical study of the stability of the tetradymite-like phases of Sb2S3, Bi2S3, and Sb2Se3
No full textWe report a comparative theoretical study of the Pnma and R-3m phases of Sb2S3, Bi2S3, and Sb2Se3 close to ambient pressure. Our enthalpy calculations at 0 K show that at ambient pressure the R-3m (tetradymite-like) phase of Sb2Se3 is energetically more stable than the Pnma phase, contrary to what is observed for Sb2S3 and Bi2S3, and irrespective of the exchange-correlation functional employed in the calculations. The result for Sb2Se3 is in contradiction to experiments where all three compounds are usually grown in the Pnma phase. This result is further confirmed by free-energy calculations taking into account the temperature dependence of the unit-cell volumes and phonon frequencies. Lattice dynamics and elastic tensor calculations further show that both Pnma and R-3m phases of Sb2Se3 are dynamically and mechanically stable at zero applied pressure. Since these results suggest that the formation of the R-3m phase for Sb2Se3 should be feasible at close to ambient conditions, we provide a theoretical crystal structure and simulated Raman and infrared spectra to help in its identification. We also discuss the results of the two published works that have claimed to have synthesized tetradymite-like Sb2Se3. Finally, the stability of the R-3m phase across the three group-15 A2X3 sesquichalcogenides is analysed based on their van der Waals gap and X-X in-plane geometry
Structural insights into UbiD reversible decarboxylation
No full textThe ubiquitous UbiX-UbiD system is associated with a wide range of microbial (de)carboxylation reactions. Recent X-ray crystallographic studies have contributed to elucidating the enigmatic mechanism underpinning the conversion of α,β-unsaturated acids by this system. The UbiD component utilises a unique cofactor, prenylated flavin (prFMN), generated by the bespoke action of the associated UbiX flavin prenyltransferase. Structure determination of a range of UbiX/UbiD representatives has revealed a generic mode of action for both the flavin-to-prFMN metamorphosis and the (de)carboxylation. In contrast to the conserved UbiX, the UbiD superfamily is associated with a versatile substrate range. The latter is reflected in the considerable variety of UbiD quaternary structure, dynamic behaviour and active site architecture. Directed evolution of UbiD enzymes has taken advantage of this apparent malleability to generate new variants supporting in vivo hydrocarbon production. Other applications include coupling UbiD to carboxylic acid reductase to convert alkenes into α,β-unsaturated aldehydes via enzymatic CO2 fixation.<br/
The Effect of Compositional Heterogeneity on the Martensite Start Temperature of a High Strength Steel During Rapid Austenitisation and Cooling
No full textMany low alloy steels are compositionally heterogeneous due to the preferential segregation of alloying elements to the dendritic or interdendritic regions when the steel is first solidified (microsegregation). This segregation is often ignored when using CCT diagrams to predict the phase transformation behaviour of steels, but may be of importance in some industrially-relevant cases. This work focuses on the martensite start temperature (Ms) of Super CMV, a high strength aerospace steel, after rapid austenitisation treatment to various peak temperatures from 900 °C to 1300 °C. It was found that the average Ms temperature increased with increasing peak temperature (and prior austenite grain size) at peak temperatures of 1100°C and above, which is to be expected conventionally. However, at peak temperatures of below 1100°C, the Ms temperature increased with decreasing prior-austenite grain size. It is proposed that this was due to the presence of non-dissolved carbides in these conditions, particularly in enriched bands of material, which deplete the matrix and hence raise Ms
Sodium-glucose cotransporter 1 inhibition and gout: Mendelian randomization study
No full textObjective. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce serum urate, but their efficacy depends on renal function which is often impaired in patients with gout. SGLT1 is primarily expressed in the small intestine and its inhibition may be a more suitable target for gout. We aimed to investigate the association of genetically proxied SGLT1i with gout risk, serum urate levels and cardiovascular safety using Mendelian randomization (MR).Methods. Leveraging data from a genome-wide association study of 344,182 individuals in the UK Biobank, we identified a missense variant in the SLC5A1 gene that associated with glycated haemoglobin (HbA1c) to proxy SGLT1i. Outcome genetic data comprised 13,179 gout cases and 750,634 controls, 457,690 individuals for serum urate levels, and up to 977,323 individuals for cardiovascular safety outcomes. We applied the Wald ratio method and investigated potential genetic confounding using colocalization.Results. The rs17683430 missense variant was selected to instrument SGLT1i. Genetically proxied SGLT1i was associated with 75% reduction in gout risk (OR 0.25; 95%CI 0.06, 0.99; p=0.048) and 32.0μmol/L reduction in serum urate (95%CI -56.7, -7.3; p=0.01), per 6.7mmol/mol reduction in HbA1c. SGLT1i was associated with increased levels of low-density lipoprotein cholesterol (0.37mmol/L; 95%CI 0.17, 0.56; p=0.0002) but not coronary heart disease, stroke, or chronic kidney disease. Colocalization did not suggest that the results are attributable to genetic confounding.Conclusion. SGLT1 inhibition may represent a novel therapeutic option for preventing gout in patients with or without comorbid diabetes. Randomised trials are needed to formally investigate efficacy and safety.Keywords: Sodium-glucose cotransporter, gout, urate, cholesterol, SGLT1, glycated haemoglobin, diabetes.<br/
Denosumab and risk of community-acquired pneumonia: A population-based cohort study
No full textContext: Recent meta-analyses of randomized controlled trials raised concerns that denosumab might increase the risk of infection. However, data of denosumab on the risk of community-acquired pneumonia is sparse. Objective: To examine the risk of community-acquired pneumonia in subjects receiving denosumab compared to those receiving alendronate.Design: We conducted a propensity score-matched cohort study with a UK primary care database (IQVIA Medical Research Database). We examined the relation of denosumab to community-acquired pneumonia using a Cox proportional hazard model.Participants: The study subjects were osteoporotic patients >45 years who were initiators of denosumab or alendronate from August 1, 2010, to September 17, 2020.Outcome Measures: Community-acquired pneumonia.Results: Patients treated with denosumab (n=933) were compared with those treated with alendronate (n=4,652). In the matched population, the mean (SD) age was 77 (11) years, 89% were women, and about half of the study population had a history of major osteoporotic fracture. Over five years follow-up, the incidence of community-acquired pneumonia per 1000 person-years was 72.0 (95% confidence interval [CI] 60.1, 85.7) in the denosumab group and 75.1 (95%CI 69.4, 81.2) in the alendronate group. The hazard of community-acquired pneumonia was similar between denosumab and alendronate users (hazard ratio [HR] 0.96; 95% 0.79, 1.16). The results remain consistent in a series of sensitivity analyses, with HR ranging from 0.82 (95% CI 0.65, 1.04) to 0.99 (95% CI 0.81, 1.21).Conclusion: Denosumab does not significantly increase the susceptibility of community-acquired pneumonia and could possibly be safely used for the management of osteoporosis. <br/
Construction of a destabilizing nonlinearity for discrete-time uncertain Lurye systems
No full textThis paper considers the instability of a Lurye system consisting of an uncertain, discrete-time, linear time-invariant plant in feedback with a slope-restricted nonlinearity. There is a large literature on analyzing the stability of such systems. This includes various conditions for proving stability of the Lurye system, including the Circle criterion and the use of O’Shea-Zames-Falb multipliers. In many cases, these conditions are sufficient but not necessary to prove stability. In contrast, there is also some work to construct specific nonlinearities that demonstrate the instability of the Lurye system (with the nominal plant dynamics). This paper considers a more general case where the plant has dynamic uncertainty. The goal is to construct both an instance of the uncertain model and a corresponding nonlinearity that combined make the Lurye system unstable. A limit cycle oscillation is also computed to verify the instability. A simple example is provided to demonstrate the results
Holes, Piers and Canyons: Absence as Emancipatory Space in Ulysses
No full textIn this article, I suggest that James Joyce creates newly active reading practices through his use of textual gaps in Ulysses. Instead of presenting readers with difficulties or frustrations, these gaps can be seen as emancipatory, asking readers to choose their own path, create their own meanings, and sit with uncertainty. I focus on how textual gaps are created within the ostensibly traditional forms of ‘Circe’ and ‘Ithaca’, represented as a play-script and a catechism respectively. I metaphorically characterise these empty spaces in the text as a hole in rock, a pier, and a canyon to think through the different readerly responses they facilitate and inspire. Whether readers choose to move through the hole in rock, remain contemplative at the end of the pier, or shout across Joyce’s authorial canyon represents a democratic choice, giving us the important space to engage with Ulysses on our own terms