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"Roberts, Timothy J."
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The biology of ergothioneine, an antioxidant nutraceutical
Ergothioneine (ERG) is an unusual thio-histidine betaine amino acid that has potent antioxidant activities. It is synthesised by a variety of microbes, especially fungi (including in mushroom fruiting bodies) and actinobacteria, but is not synthesised by plants and animals who acquire it via the soil and their diet, respectively. Animals have evolved a highly selective transporter for it, known as solute carrier family 22, member 4 (SLC22A4) in humans, signifying its importance, and ERG may even have the status of a vitamin. ERG accumulates differentially in various tissues, according to their expression of SLC22A4, favouring those such as erythrocytes that may be subject to oxidative stress. Mushroom or ERG consumption seems to provide significant prevention against oxidative stress in a large variety of systems. ERG seems to have strong cytoprotective status, and its concentration is lowered in a number of chronic inflammatory diseases. It has been passed as safe by regulatory agencies, and may have value as a nutraceutical and antioxidant more generally.
Journal Article
VAE-Sim: A Novel Molecular Similarity Measure Based on a Variational Autoencoder
Molecular similarity is an elusive but core “unsupervised” cheminformatics concept, yet different “fingerprint” encodings of molecular structures return very different similarity values, even when using the same similarity metric. Each encoding may be of value when applied to other problems with objective or target functions, implying that a priori none are “better” than the others, nor than encoding-free metrics such as maximum common substructure (MCSS). We here introduce a novel approach to molecular similarity, in the form of a variational autoencoder (VAE). This learns the joint distribution p(z|x) where z is a latent vector and x are the (same) input/output data. It takes the form of a “bowtie”-shaped artificial neural network. In the middle is a “bottleneck layer” or latent vector in which inputs are transformed into, and represented as, a vector of numbers (encoding), with a reverse process (decoding) seeking to return the SMILES string that was the input. We train a VAE on over six million druglike molecules and natural products (including over one million in the final holdout set). The VAE vector distances provide a rapid and novel metric for molecular similarity that is both easily and rapidly calculated. We describe the method and its application to a typical similarity problem in cheminformatics.
Journal Article
DeepGraphMolGen, a multi-objective, computational strategy for generating molecules with desirable properties: a graph convolution and reinforcement learning approach
We address the problem of generating novel molecules with desired interaction properties as a multi-objective optimization problem. Interaction binding models are learned from binding data using graph convolution networks (GCNs). Since the experimentally obtained property scores are recognised as having potentially gross errors, we adopted a robust loss for the model. Combinations of these terms, including drug likeness and synthetic accessibility, are then optimized using reinforcement learning based on a graph convolution policy approach. Some of the molecules generated, while legitimate chemically, can have excellent drug-likeness scores but appear unusual. We provide an example based on the binding potency of small molecules to dopamine transporters. We extend our method successfully to use a multi-objective reward function, in this case for generating novel molecules that bind with dopamine transporters but not with those for norepinephrine. Our method should be generally applicable to the generation in silico of molecules with desirable properties.
Journal Article
Relationship between Inflammatory Cytokines and Indices of Cardiac Dysfunction following Intense Endurance Exercise
Pro-inflammatory cytokines have been noted to increase following exercise but their relationship to exercise-induced cardiac dysfunction has not previously been investigated. We sought to evaluate whether exercise-induced cardiac dysfunction was associated with increases in cytokines, particularly the pro-inflammatory cytokines IL-1β, IL-12p70 and TNFα, which have been most implicated in cardiac pathology.
40 well-trained endurance athletes underwent evaluation prior to and immediately following one of four endurance sporting events ranging from 3 to 11 hours duration. Cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12p70 and TNFα) were analyzed by flow cytometry from serum samples collected within 50 minutes of race completion. Cardiac troponin (cTnI) and B-type natriuretic peptide were combined with an echocardiographic assessment of cardiac function, and a composite of cTnI > 0.04 μg/L, BNP increase > 10 ng/L and a decrease in right ventricular ejection (RVEF) > 10% were prospectively defined as evidence of myocardial dysfunction.
Relative to baseline, IL-6 IL-8 and IL-10 increased 8.5-, 2.9-, and 7.1-fold, respectively, P<0.0001. Thirty-one (78%), 19 (48%) and 18 (45%) of the athletes met the pre-specified criteria for significant cTnI, BNP and RVEF changes, respectively. TNFα, IL-12p70 were univariate predictors of ΔRVEF and ΔBNP whilst none of the anti-inflammatory cytokines were significantly associated with these measures. Ten athletes (25%, all athletes competing in the endurance event of longest duration) met criteria for exercise-induced myocardial dysfunction. In these 10 athletes with myocardial dysfunction, as compared to those without, there was significantly greater post-race expression of the pro-inflammatory cytokines IL-12p70 (8.1±3.8 pg/ml vs. 2.5±2.6 pg/ml, P<0.0001) and TNFα (6.5±3.1 pg/ml vs. 2.0±2.5 pg/ml, P<0.0001).
Cardiac dysfunction following intense endurance exercise was associated with increased expression of pro-inflammatory cytokines. This does not prove a causal relationship but provides rationale for further investigations into whether inflammation mediates exercise-induced myocardial dysfunction.
Journal Article
Psoriatic disease is associated with systemic inflammation, endothelial activation, and altered haemostatic function
Psoriasis is a chronic, immune-mediated inflammatory skin disease, affecting approximately 2% of the general population, which can be accompanied by psoriatic arthritis (PsA). The condition has been associated with an increased cardiovascular burden. Hypercoagulability is a potential underlying mechanism that may contribute to the increased risk of major cardiovascular events in psoriatic individuals. Whole blood samples were collected from 20 PsA patients and 20 healthy individuals. The concentrations of inflammatory molecules (C-reactive protein, serum amyloid A, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and soluble P-selectin) were determined by enzyme-linked immunosorbent assays. In addition, clotting efficiency was evaluated by thromboelastography. The fibrin network architecture was also assessed by scanning electron microscopy. Elevated levels of circulating inflammatory molecules were significantly associated with the presence of psoriatic disease. Furthermore, an increased tendency towards thrombus formation was significantly predictive of disease presence. Scanning electron microscopy revealed that fibrin clots were denser in psoriatic individuals, compared to healthy controls, with an increased fibrin fibre diameter associated with psoriatic disease. Our results add to the accumulating evidence of the systemic nature of psoriasis and the subsequent risk of cardiovascular comorbidities, potentially due to an acquired hypercoagulability. We suggest that haemostatic function should be monitored carefully in psoriatic patients that present with severe disease, due to the pre-eminent risk of developing thrombotic complications.
Journal Article
Exercise capacity in diabetes mellitus is predicted by activity status and cardiac size rather than cardiac function: a case control study
Background
The reasons for reduced exercise capacity in diabetes mellitus (DM) remains incompletely understood, although diastolic dysfunction and diabetic cardiomyopathy are often favored explanations. However, there is a paucity of literature detailing cardiac function and reserve during incremental exercise to evaluate its significance and contribution. We sought to determine associations between comprehensive measures of cardiac function during exercise and maximal oxygen consumption (
V
˙
O
2
peak), with the hypothesis that the reduction in exercise capacity and cardiac function would be associated with co-morbidities and sedentary behavior rather than diabetes itself.
Methods
This case–control study involved 60 subjects [20 with type 1 DM (T1DM), 20 T2DM, and 10 healthy controls age/sex-matched to each diabetes subtype] performing cardiopulmonary exercise testing and bicycle ergometer echocardiography studies. Measures of biventricular function were assessed during incremental exercise to maximal intensity.
Results
T2DM subjects were middle-aged (52 ± 11 years) with a mean T2DM diagnosis of 12 ± 7 years and modest glycemic control (HbA
1c
57 ± 12 mmol/mol). T1DM participants were younger (35 ± 8 years), with a 19 ± 10 year history of T1DM and suboptimal glycemic control (HbA
1c
65 ± 16 mmol/mol). Participants with T2DM were heavier than their controls (body mass index 29.3 ± 3.4 kg/m
2
vs. 24.7 ± 2.9, P = 0.001), performed less exercise (10 ± 12 vs. 28 ± 30 MET hours/week, P = 0.031) and had lower exercise capacity (
V
˙
O
2
peak = 26 ± 6 vs. 38 ± 8 ml/min/kg, P < 0.0001). These differences were not associated with biventricular systolic or left ventricular (LV) diastolic dysfunction at rest or during exercise. There was no difference in weight, exercise participation or
V
˙
O
2
peak in T1DM subjects as compared to their controls. After accounting for age, sex and body surface area in a multivariate analysis, significant positive predictors of
V
˙
O
2
peak were cardiac size (LV end-diastolic volume, LVEDV) and estimated MET-hours, while T2DM was a negative predictor. These combined factors accounted for 80% of the variance in
V
˙
O
2
peak (P < 0.0001).
Conclusions
Exercise capacity is reduced in T2DM subjects relative to matched controls, whereas exercise capacity is preserved in T1DM. There was no evidence of sub-clinical cardiac dysfunction but, rather, there was an association between impaired exercise capacity, small LV volumes and sedentary behavior.
Journal Article
Abnormal right ventricular relaxation in pulmonary hypertension
Left ventricular diastolic dysfunction is a well-described complication of systemic hypertension. However, less is known regarding the effect of chronic pressure overload on right ventricular (RV) diastolic function. We hypothesized that pulmonary hypertension (PHT) is associated with abnormal RV early relaxation and that this would be best shown by invasive pressure measurement. Twenty-five patients undergoing right heart catheterization for investigation of breathlessness and/or suspected PHT were studied. In addition to standard measurements, RV pressure was sampled with a high-fidelity micromanometer, and RV pressure/time curves were analyzed. Patients were divided into a PHT group and a non-PHT group on the basis of a derived mean pulmonary artery systolic pressure of 25 mmHg. Eleven patients were classified to the PHT group. This group had significantly higher RV minimum diastolic pressure (
vs.
mmHg,
) and RV end-diastolic pressure (RVEDP;
vs.
mmHg,
), and RV τ was significantly prolonged (
vs.
ms,
). There were strong correlations between RV τ and RV minimum diastolic pressure (
,
) and between RV τ and RVEDP (
,
). There was a trend toward increased RV contractility (end-systolic elastance) in the PHT group (
vs.
mmHg/mL,
) and a correlation between RV systolic pressure and first derivative of maximum pressure change (
,
). Stroke volumes were similar. Invasive measures of RV early relaxation are abnormal in patients with PHT, whereas measured contractility is static or increasing, which suggests that diastolic dysfunction may precede systolic dysfunction. Furthermore, there is a strong association between measures of RV relaxation and RV filling pressures.
Journal Article
Automated motion estimation of root responses to sucrose in two Arabidopsis thaliana genotypes using confocal microscopy
Root growth is a highly dynamic process influenced by genetic background and environment. This paper reports the development of R scripts that enable root growth kinematic analysis that complements a new motion analysis tool: PlantVis. Root growth of Arabidopsis thaliana expressing a plasma membrane targeted GFP (C24 and Columbia 35S:LTI6b-EGFP) was imaged using time-lapse confocal laser scanning microscopy. Displacement of individual pixels in the time-lapse sequences was estimated automatically by PlantVis, producing dense motion vector fields. R scripts were developed to extract kinematic growth parameters and report displacement to ±0.1 pixel. In contrast to other currently available tools, Plantvis-R delivered root velocity profiles without interpolation or averaging across the root surface and also estimated the uncertainty associated with tracking each pixel. The PlantVis-R analysis tool has a range of potential applications in root physiology and gene expression studies, including linking motion to specific cell boundaries and analysis of curvature. The potential for quantifying genotype × environment interactions was examined by applying PlantVis-R in a kinematic analysis of root growth of C24 and Columbia, under contrasting carbon supply. Large genotype-dependent effects of sucrose were recorded. C24 exhibited negligible differences in elongation zone length and elongation rate but doubled the density of lateral roots in the presence of sucrose. Columbia, in contrast, increased its elongation zone length and doubled its elongation rate and the density of lateral roots.
Journal Article
Human Pose Estimation Using Partial Configurations and Probabilistic Regions
A method for recovering a part-based description of human pose from single images of people is described. It is able to perform estimation efficiently in the presence significant background clutter, large foreground variation, self-occlusion and occlusion by other objects. This is achieved through two key developments. Firstly, a new formulation is proposed that allows partial configurations, hypotheses with differing numbers of parts, to be made and compared. This permits efficient global sampling in the presence of self and other object occlusions without prior knowledge of body part visibility. Secondly, a highly discriminatory likelihood model is proposed comprising two complementary components. A boundary component improves upon previous appearance distribution divergence methods by incorporating high-level shape and appearance information and hence better discriminates textured, overlapping body parts. An inter-part component uses appearance similarity of body parts to reduce the number of false-positive, multi-part hypotheses, hence increasing estimation efficiency. Results are presented for challenging images with unknown subject and large variations in subject appearance, scale and pose.[PUBLICATION ABSTRACT]
Journal Article