Computationally Modelling Cholesterol Metabolism and Atherosclerosis

Cardiovascular disease (CVD) is the leading cause of death globally. The underlying pathological driver of CVD is atherosclerosis. The primary risk factor for atherosclerosis is elevated low-density lipoprotein cholesterol (LDL-C). Dysregulation of cholesterol metabolism is synonymous with a rise in LDL-C. Due to the complexity of cholesterol metabolism and atherosclerosis mathematical models are routinely used to explore their non-trivial dynamics. Mathematical modelling has generated a wealth of useful biological insights, which have deepened our understanding of these processes. To date however, no model has been developed which fully captures how whole-body cholesterol metabolism intersects with atherosclerosis. The main reason for this is one of scale. Whole body cholesterol metabolism is defined by macroscale physiological processes, while atherosclerosis operates mainly at a microscale. This work describes how a model of cholesterol metabolism was combined with a model of atherosclerotic plaque formation. This new model is capable of reproducing the output from its parent models. Using the new model, we demonstrate how this system can be utilized to identify interventions that lower LDL-C and abrogate plaque formation

Inhaling alcohol vapour or mist: An international study of use, effects and harms

Objectives. To determine the prevalence, patterns of use and consequences of inhaling alcohol vapour or mist. Design. Cross-sectional survey recruiting an international non-probability sample of people who use alcohol and other drugs as part of the annual Global Drug Survey (GDS). Setting. Online questionnaire translated into 19 languages. Participants. 110,557 people took part in GDS2020 and 88,124 completed a question about inhaling alcohol in the last 12 months. The focus of this study is GDS2020 respondents who reported inhaling alcohol mist/vapour from a balloon in the last 12 months. Main outcomes. Last 12-month use of alcohol vapour, onset duration, intensity of effects, value for money compared with alcohol, and incidence of falls/injuries. Results. A total of 803 people reported the use of alcohol vapour in the last 12 months, with 51% of the sample coming from 3 countries: Australia, Denmark and England. Two-thirds were male, and they were more likely to be under 25. 45.7% reported that they were a bit/very drunk before they inhaled alcohol. 51.3% reported that the effects lasted for less than 5 minutes. Both the intensity of effect and perceived value for money showed a normal distribution on a 10-point scale. 12.7% of respondents reported falling/injuring themselves. Conclusion. Inhaling alcohol vapour appears to be more common among younger, higher-risk drinkers. The rapid onset of action and inability to titrate consumption to effect is a risk for acute injury. We consider that alcohol is harmful enough through oral consumption without adding to the risk of injury by offering such a potentially risky additional administration method

Donor-acceptor dyads and triads employing core-substituted naphthalene diimides:a synthetic and spectro (electrochemical) study

Donor-acceptor dyads and triads comprising core-substituted naphthalene diimide (NDI) chromophores and either phenothiazine or phenoxazine donors are described. Synthesis combined with electrochemical and spectroelectrochemical investigations facilitates characterisation of the various redox states of these molecules, confirming the ability to combine arrays of electron donating and accepting moieties into single species that retain the redox properties of these individual moieties

An intelligent real-time cyber-physical toolset for energy and process prediction and optimisation in the future industrial Internet of Things

Energy waste significantly contributes to increased costs in the automotive manufacturing industry, which is subject to energy usage restrictions and taxation from national and international policy makers and restrictions and charges from national energy providers. For example, the UK Climate Change Levy, charged to businesses at 0.554p/kWh equates to 7.28% of a manufacturing business’s energy bill based on an average total usage rate of 7.61p/kWh. Internet of Things (IoT) energy monitoring systems are being developed, however, there has been limited consideration of services for efficient energy-use and minimisation of production costs in industry. This paper presents the design, development and validation of a novel, adaptive Cyber-Physical Toolset to optimise cumulative plant energy consumption through characterisation and prediction of the active and reactive power of three-phase industrial machine processes. Extensive validation has been conducted in automotive manufacture production lines with industrial three-phase Hurco VM1 computer numerical control (CNC) machines

Metagenomic next-generation sequencing aids the diagnosis of viral infections in febrile returning travellers

Objectives Travel-associated infections are challenging to diagnose because of the broad spectrum of potential aetiologies. As a proof-of-principle study, we used MNGS to identify viral pathogens in clinical samples from returning travellers in a single center to explore its suitability as a diagnostic tool. Methods Plasma samples from 40 returning travellers presenting with a fever of ≥38°C were sequenced using MNGS on the Illumina MiSeq platform and compared with standard-of-care diagnostic assays. Results In total, 11/40 patients were diagnosed with a viral infection. Standard of care diagnostics revealed 5 viral infections using plasma samples; dengue virus 1 (n = 2), hepatitis E (n = 1), Ebola virus (n = 1) and hepatitis A (n = 1), all of which were detected by MNGS. Three additional patients with Chikungunya virus (n = 2) and mumps virus were diagnosed by MNGS only. Respiratory infections detected by nasal/throat swabs only were not detected by MNGS of plasma. One patient had infection with malaria and mumps virus during the same admission. Conclusions MNGS analysis of plasma samples improves the sensitivity of diagnosis of viral infections and has potential as an all-in-one diagnostic test. It can be used to identify infections that have not been considered by the treating physician, co-infections and new or emerging pathogens. Summary Next generation sequencing (NGS) has potential as an all-in-one diagnostic test. In this study we used NGS to diagnose returning travellers with acute febrile illness in the UK, highlighting cases where the diagnosis was missed using standard methods

Quantitative Expression and Co-Localization of Wnt Signalling Related Proteins in Feline Squamous Cell Carcinoma.

Feline oral squamous cell carcinoma (FOSCC) is an aggressive neoplasm in cats. Little is known about the possible molecular mechanisms that may be involved in the initiation, maintenance and progression of FOSCC. Wnt signalling is critical in development and disease, including many mammalian cancers. In this study, we have investigated the expression of Wnt signalling related proteins using quantitative immunohistochemical techniques on tissue arrays. We constructed tissue arrays with 58 individual replicate tissue samples. We tested for the expression of four key Wnt/ß-catenin transcription targets, namely Cyclin D1 (CCND1 or CD1), FRA1, c-Myc and MMP7. All antibodies showed cross reactivity in feline tissue except MMP7. Quantitative immunohistochemical analysis of single proteins (expressed as area fraction / amount of tissue for normal vs tumor, mean ± SE) showed that the expression of CD1 (3.9 ± 0.5 vs 12.2 ± 0.9), FRA1 (5.5 ± 0.6 vs 16.8 ± 1.1) and c-Myc (5.4 ± 0.5 vs 12.5 ± 0.9) was increased in FOSCC tissue by 2.3 to 3 fold compared to normal controls (p<0.0001). By using a multilabel, quantitative fluorophore technique we further investigated if the co-localization of these proteins (all transcription factors) with each other and in the nucleus (stained with 4',6-diamidino-2-phenylindole, DAPI) was altered in FOSCC compared to normal tissue. The global intersection coefficients, a measure of the proximity of two fluorophore labeled entities, showed that there was a significant change (p < 0.01) in the co-localization for all permutations (e.g. CD1/FRA1 etc), except for the nuclear localization of CD1. Our results show that putative targets of Wnt signalling transcription are up-regulated in FOSCC with alterations in the co-localization of these proteins and could serve as a useful marker for the disease.This research was funded by the Prostate Cancer Research Centre charity (registered UK charity no. 1156027), Grant Number AA1. A small financial contribution was also made through intra-mural funds from the Royal Veterinary College.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pone.016110

Formation of a copper(II)-tyrosyl complex at the active site of lytic polysaccharide monooxygenases following oxidation by H2O2

Hydrogen peroxide is a cosubstrate for the oxidative cleavage of saccharidic substrates by copper-containing lytic polysaccharide monooxygenases (LPMOs). The rate of reaction of LPMOs with hydrogen peroxide is high, but it is accompanied by rapid inactivation of the enzymes, presumably through protein oxidation. Herein, we use UV− vis, CD, XAS, EPR, VT/VH-MCD, and resonance Raman spectroscopies, augmented with mass spectrometry and DFT calculations, to show that the product of reaction of an AA9 LPMO with H2O2 at higher pHs is a singlet Cu(II)−tyrosyl radical species, which is inactive for the oxidation of saccharidic substrates. The Cu(II)−tyrosyl radical center entails the formation of significant Cu(II)−(●OTyr) overlap, which in turn requires that the plane of the d(x2−y2) SOMO of the Cu(II) is orientated toward the tyrosyl radical. We propose from the Marcus cross-relation that the active site tyrosine is part of a “hole-hopping” charge-transfer mechanism formed of a pathway of conserved tyrosine and tryptophan residues, which can protect the protein active site from inactivation during uncoupled turnover

Clinical effectiveness of pharmacological interventions for managing chronic migraine in adults : a systematic review and network meta-analysis

Background: Chronic migraine can be a profoundly disabling disorder that may be treated with preventive medications. However, uncertainty remains as to which preventive medication is the most effective. We present a network meta-analysis to determine the effectiveness and rank of preventive drugs for chronic migraine in adults. Methods: We identified, reviewed, and extracted data from randomised controlled trials (RCTs) of preventive drugs for chronic migraine with at least 200 participants. Data were analysed using network meta-analysis. Findings: We included 12 RCTs of six medications (Eptinezumab, Erenumab, Fremanezumab, Galcanezumab, Onabotulinumtoxin A, and Topiramate) compared to placebo or each other. All drugs effectively reduced monthly headache and migraine days compared with placebo. The most effective drug for monthly headache days was Eptinezumab 300mg, with a mean difference of -2.46 days, 95% Credible Interval (CrI): -3.23 to -1.69. On the Surface Under the Cumulative Ranking Area (SUCRA) analysis, the probability that Eptinezumab 300mg was ranked highest was 0.82. For monthly migraine days, the most effective medication was Fremanezumab-monthly, with a mean difference: -2.77 days, 95% CrI: -3.36 to -2.17, and 0.98 probability of being ranked the highest. All included drugs, except Topiramate, improved headache-related quality of life. No eligible studies were identified for the other common preventive oral medications such as Amitriptyline, Candesartan, and Propranolol. The main reasons were that the studies did not define chronic migraine, were undertaken before the definition of chronic migraine, or were too small. Interpretation: All six medications were more effective than the placebo on monthly headache and migraine days. The absolute differences in the number of headache/migraine days are, at best, modest. No evidence was found to determine the relative effectiveness of the six included drugs with other oral preventive medications. Registration: PROSPERO (number CRD42021265990)

Blood sampling: two sides to the story

This study aimed to investigate why there is variability in taking blood. A multi method Pilot study was completed in four National Health Service Scotland hospitals. Human Factors/Ergonomics principles were applied to analyse data from 50 observations, 15 interviews and 12-months of incident data from all Scottish hospitals. The Functional Resonance Analysis Method (FRAM) was used to understand why variability may influence blood sampling functions. The analysis of the 61 pre blood transfusion sampling incidents highlighted limitations in the data collected to understand factors influencing performance. FRAM highlighted how variability in the sequence of blood sampling functions and the number of practitioners involved in a single blood sampling activity was influenced by the working environment, equipment, clinical context, work demands and staff resources. This pilot study proposes a realistic view of why blood sampling activities vary and proposes the need to consider the system’s resilience in future safety management strategies