Products of Linear Forms and Tutte Polynomials

Let \Delta be a finite sequence of n vectors from a vector space over any field. We consider the subspace of \operatorname{Sym}(V) spanned by \prod_{v \in S} v, where S is a subsequence of \Delta. A result of Orlik and Terao provides a doubly indexed direct sum of this space. The main theorem is that the resulting Hilbert series is the Tutte polynomial evaluation T(\Delta;1+x,y). Results of Ardila and Postnikov, Orlik and Terao, Terao, and Wagner are obtained as corollaries.Comment: Minor changes. Accepted for publication in European Journal of Combinatoric

Structural studies of NADPH : protochlorophyllide oxidoreductase.

The light driven enzyme Protochlorophyllide Oxidoreductase (POR) is responsible for catalysing the reduction of the Cl7 – C18 double bond of the D ring of protochlorophyllide (Pchlide), in the presence of NADPH, forming chlorophyllide (Chlide). The reduction of Pchlide involves a light-induced hydride transfer reaction from the pro-S face of nicotinamide adenine dinucleotide phosphate (NADPH) to the C'7 position, coupled to the addition of a proton to the C'8 position forming Chlide. The reaction catalysed by POR is a key step in chlorophyll biosynthesis and is essential in the development of chloroplasts. To achieve the maximum yield of Thermosynechococcus POR, E. coli were grown at 37 degC to an optical density of 1. 7 before being induced with 0.1 mM IPTG and grown for a further two hours at 25 degC. Purification of the over-expressed protein was done using a nickel affinity chromatography column followed by a cation exchange chromatography column. Purified protein could then be concentrated in an Amicon stirred cell concentrator to a maximum concentration of 0.3 mM. The NMR conditions were optimised, and experiments conducted at 45 degC with a sample in sodium phosphate buffer pH 5.5, containing 100 mM NaCl, 1 mM DTT and Roche complete protease provided the best quality HSQC spectrum, along with stabilising the protein for an indefinite period of time. Full deuteration of the protein did not yield the spectral improvements expected, and as a result the assignment spectra were acquired at 600 MHz using a l3C 15N labelled sample. A partial assignment of POR identified that, compared to the rest of the protein, the 33-residue loop insertion unique to POR is significantly more mobile and moves on a timescale similar to that associated with substrate binding and product release. Mutagenesis of the loop, whilst not affecting substrate binding, has profound effects on the enzyme activity, implicating the loop to be involved in some way with enzyme activity. Incubation of the enzyme with Pchlide and NADP+ results in the aggregation of the enzyme and the formation of a complex, which has been shown by EM and AUC to consist of approximately 10 units. This is analogous to the light harvesting Pchlide POR complex identified to exist in plants and proves that in vitro such complexes exist in other organisms other than monocotyledonous plants

"Should I inhale?” : perceptions, barriers, and drivers for medicinal cannabis use amongst Australian women with primary dysmenorrhoea : a qualitative study

Objective: This study sought to investigate the perceptions, barriers, and drivers associated with medicinal cannabis use among Australian women with primary dysmenorrhea. A qualitative study via virtual focus groups involving 26 women experiencing regular, moderate, or greater menstrual pain explored categories including cost, associated stigma, current drug driving laws, community and workplace ethics, and geographical isolation within the context of patient access under current Australian laws and regulations. Results: A qualitative descriptive analysis identified that dissatisfaction with current management strategies such as over-the-counter analgesic usage was the key driver for wanting to use medicinal cannabis. A number of significant barriers to use were identified including patient access to medical prescribers, medical practitioner bias, current drug driving laws, geographic location, and cost. Community and cultural factors such as the history of cannabis as an illicit drug and the resulting stigma, even when prescribed by a medical doctor, still existed and was of concern to our participants. Conclusion: Whilst medicinal cannabis is legal in all states and territories within Australia, several barriers to access exist that require government regulatory attention to assist in increasing patient adoption, including possible subsidisation of cost. The high cost of legal, medicinal cannabis was a key factor in women’s choice to use illicit cannabis. Overall, the concerns raised by our participants are consistent with the broader findings of a recent Australian Senate inquiry report into barriers to patient access to medicinal cannabis in Australia, suggesting many of the issues are systematic rather than disease-specific. Given the interest in use of medicinal cannabis amongst women with primary dysmenorrhea, clinical trials in this area are urgently needed

Listening for landslides: method, measurements and the Peace River Case Study

Landslides cause many thousands of fatalities each year all over the globe and damage built environment infrastructure costing billions of pounds to repair, resulting in thousands of people being made homeless and the breakdown of basic services such as water supply and transport. There is a clear need for cost effective instrumentation that can provide an early warning of slope instability to enable evacuation of vulnerable people and timely repair and maintenance of critical infrastructure. An approach that uses detection and quantification of acoustic emission (AE) generated as a slope deforms has been developed through research and performance demonstrated in multiple field trials. This paper will describe the measurement system and the approach developed to quantify slope displacement rates. Measurements from long-running field trials in the UK will be shown to demonstrate performance of the method. Finally, the paper will introduce a case study at Peace River, Alberta, where the AE monitoring system is being used to monitor stability of a slope that threatens continued operation of a major highway. Initial AE readings will be presented and compared to surveys of an adjacent inclinometer casing. The influence of precipitation on generated AE and performance of the system during sustained low temperatures will be discussed

Correlation of acoustic emissions with patterns of movement in an extremely slow moving landslide at Peace River, Alberta, Canada

The Peace River region, Alberta, Canada, has experienced extensive landslide activity since deglaciation. Shear zones within weak lacustrine silt and clay layers typically experience continuous creep, damaging highway and utilities infrastructure. However, occasionally, movement accelerates and potentially catastrophic failures occur. Conventional deformation monitoring approaches provide incremental measurements with low temporal resolution and do not necessarily allow rapid changes in stability to be detected and communicated sufficiently in advance to provide early warning. The study objectives were to: (i) acquire a long-term dataset of continuous deformation measurements with high temporal resolution of a case study slope in Peace River; (ii) enhance understanding of a typical creeping Peace River slope’s behavior in response to climatic drivers; and (iii) investigate the potential of an Acoustic Emission (AE) monitoring system to provide early warning of accelerating deformation behavior. ShapeAccelArray (SAA) and AE instruments were installed, in addition to conventional inclinometers and piezometers. Measurements show that the landslide is ‘extremely slow’, moving on average 5-mm annually, and reveal seasonal activity with periods of acceleration and deceleration driven by pore-water pressures. Measured AE correlated strongly with the rate and magnitude of SAA-measured displacement, demonstrating the potential of the AE technique to warn of accelerating behavior

Adaptive Manufacturing for Healthcare During the COVID-19 Emergency and Beyond

During the COVID-19 pandemic, global health services have faced unprecedented demands. Many key workers in health and social care have experienced crippling shortages of personal protective equipment, and clinical engineers in hospitals have been severely stretched due to insufficient supplies of medical devices and equipment. Many engineers who normally work in other sectors have been redeployed to address the crisis, and they have rapidly improvised solutions to some of the challenges that emerged, using a combination of low-tech and cutting-edge methods. Much publicity has been given to efforts to design new ventilator systems and the production of 3D-printed face shields, but many other devices and systems have been developed or explored. This paper presents a description of efforts to reverse engineer or redesign critical parts, specifically a manifold for an anaesthesia station, a leak port, plasticware for COVID-19 testing, and a syringe pump lock box. The insights obtained from these projects were used to develop a product lifecycle management system based on Aras Innovator, which could with further work be deployed to facilitate future rapid response manufacturing of bespoke hardware for healthcare. The lessons learned could inform plans to exploit distributed manufacturing to secure back-up supply chains for future emergency situations. If applied generally, the concept of distributed manufacturing could give rise to “21st century cottage industries” or “nanofactories,” where high-tech goods are produced locally in small batches

Validation of the CREST score for predicting circulatory-aetiology death in out-of-hospital cardiac arrest without STEMI

Aims: The CREST tool was recently developed to stratify the risk of circulatory-aetiology death (CED) in out-of-hospital cardiac arrest (OHCA) patients without ST-elevation myocardial infarction (STEMI). We aimed to validate the CREST score using an external cohort and determine whether it could be improved by the addition of serum lactate on admission. Methods: The study involved the retrospective analysis of consecutive patients admitted to a single tertiary centre with OHCA of presumed cardiac origin over a 51-month period. The CREST score was calculated by attributing points to the following variables: Coronary artery disease (CAD), non-shockable Rhythm, Ejection fraction <30%, cardiogenic Shock at presentation and ischaemic Time ≥25 minutes. The primary endpoint was CED vs neurological aetiology death (NED) or survival. Results: Of 500 patients admitted with OHCA, 211 did not meet criteria for STEMI and were included. 115 patients died in hospital (71 NED, 44 CED). When analysed individually, CED was associated with all CREST variables other than a previous diagnosis of CAD. The CREST score accurately predicted CED with excellent discrimination (C-statistic 0.880, 95% CI 0.813-0.946) and calibration (Hosmer and Lemeshow P=0.948). Although an admission lactate ≥7 mmol/L also predicted CED, its addition to the CREST score (the C-AREST score) did not significantly improve the predictive ability (CS 0.885, 0.815-0.954, HS P=0.942, X2 difference in -2 log likelihood =0.326, P=0.850). Conclusion: Our study is the first to independently validate the CREST score for predicting CED in patients presenting with OHCA without STEMI. Addition of lactate on admission did not improve its predictive ability.Publisher PDFPeer reviewe

Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury.

BACKGROUND: Tumour necrosis factor alpha (TNF-α) is a pleiotropic cytokine with both injurious and protective functions, which are thought to diverge at the level of its two cell surface receptors, TNFR1 and TNFR2. In the setting of acute injury, selective inhibition of TNFR1 is predicted to attenuate the cell death and inflammation associated with TNF-α, while sparing or potentiating the protective effects of TNFR2 signalling. We developed a potent and selective antagonist of TNFR1 (GSK1995057) using a novel domain antibody (dAb) therapeutic and assessed its efficacy in vitro, in vivo and in a clinical trial involving healthy human subjects. METHODS: We investigated the in vitro effects of GSK1995057 on human pulmonary microvascular endothelial cells (HMVEC-L) and then assessed the effects of pretreatment with nebulised GSK1995057 in a non-human primate model of acute lung injury. We then tested translation to humans by investigating the effects of a single nebulised dose of GSK1995057 in healthy humans (n=37) in a randomised controlled clinical trial in which subjects were subsequently exposed to inhaled endotoxin. RESULTS: Selective inhibition of TNFR1 signalling potently inhibited cytokine and neutrophil adhesion molecule expression in activated HMVEC-L monolayers in vitro (P<0.01 and P<0.001, respectively), and also significantly attenuated inflammation and signs of lung injury in non-human primates (P<0.01 in all cases). In a randomised, placebo-controlled trial of nebulised GSK1995057 in 37 healthy humans challenged with a low dose of inhaled endotoxin, treatment with GSK1995057 attenuated pulmonary neutrophilia, inflammatory cytokine release (P<0.01 in all cases) and signs of endothelial injury (P<0.05) in bronchoalveolar lavage and serum samples. CONCLUSION: These data support the potential for pulmonary delivery of a selective TNFR1 dAb as a novel therapeutic approach for the prevention of acute respiratory distress syndrome. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01587807

Inflammation reduces mechanical thresholds in a population of transient receptor potential channel A1-expressing nociceptors in the rat

Inflammatory hypersensitivity is characterized by behavioural reductions in withdrawal thresholds to noxious stimuli. Although cutaneous primary afferent neurones are known to have lowered thermal thresholds in inflammation, whether their mechanical thresholds are altered remains controversial. The transient receptor potential channel A1 (TRPA1) is a receptor localized to putative nociceptive neurones and is implicated in mechanical and thermal nociception. Herein, we examined changes in the properties of single primary afferents in normal and acutely inflamed rats and determined whether specific nociceptive properties, particularly mechanical thresholds, are altered in the subpopulation of afferents that responded to the TRPA1 agonist cinnamaldehyde (TRPA1-positive afferents). TRPA1-positive afferents in normal animals belonged to the mechanonociceptive populations, many of which also responded to heat or capsaicin but only a few of which responded to cold. In acute inflammation, a greater proportion of afferents responded to cinnamaldehyde and an increased proportion of dorsal root ganglion neurones expressed TRPA1 protein. Functionally, in inflammation, TRPA1-positive afferents showed significantly reduced mechanical thresholds and enhanced activity to agonist stimulation. Inflammation altered thermal thresholds in both TRPA1-positive and TRPA1-negative afferents. Our data show that a subset of afferents is sensitized to mechanical stimulation by inflammation and that these afferents are defined by expression of TRPA1