MicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease

MicroRNA (miRNA) has the potential for cross-regulation and functional integration of discrete biological processes during complex physiological events. Utilizing the common human condition tendinopathy as a model system to explore the cross-regulation of immediate inflammation and matrix synthesis by miRNA we observed that elevated IL-33 expression is a characteristic of early tendinopathy. Using in vitro tenocyte cultures and in vivo models of tendon damage, we demonstrate that such IL-33 expression plays a pivotal role in the transition from type 1 to type 3 collagen (Col3) synthesis and thus early tendon remodelling. Both IL-33 effector function, via its decoy receptor sST2, and Col3 synthesis are regulated by miRNA29a. Downregulation of miRNA29a in human tenocytes is sufficient to induce an increase in Col3 expression. These data provide a molecular mechanism of miRNA-mediated integration of the early pathophysiologic events that facilitate tissue remodelling in human tendon after injury

Targeting danger molecules in tendinopathy: the HMGB1/TLR4 axis

Objectives: To seek evidence of the danger molecule, high-mobility group protein B1 (HMGB1) expression in human tendinopathy and thereafter, to explore mechanisms where HMGB1 may regulate inflammatory mediators and matrix regulation in human tendinopathy. Methods: Torn supraspinatus tendon (established pathology) and matched intact subscapularis tendon (representing ‘early pathology’) biopsies were collected from patients undergoing arthroscopic shoulder surgery. Control samples of subscapularis tendon were collected from patients undergoing arthroscopic stabilisation surgery. Markers of inflammation and HMGB1 were quantified by reverse transcriptase PCR (RT-PCR) and immunohistochemistry. Human tendon-derived primary cells were derived from hamstring tendon tissue obtained during hamstring tendon anterior cruciate ligament reconstruction and used through passage 3. In vitro effects of recombinant HMGB1 on tenocyte matrix and inflammatory potential were measured using quantitative RT-PCR, ELISA and immunohistochemistry staining. Results: Tendinopathic tissues demonstrated significantly increased levels of the danger molecule HMGB1 compared with control tissues with early tendinopathy tissue showing the greatest expression. The addition of recombinant human HMGB1 to tenocytes led to significant increase in expression of a number of inflammatory mediators, including interleukin 1 beta (IL-1β), IL-6, IL-33, CCL2 and CXCL12, in vitro. Further analysis demonstrated rhHMGB1 treatment resulted in increased expression of genes involved in matrix remodelling. Significant increases were observed in Col3, Tenascin-C and Decorin. Moreover, blocking HMGB1 signalling via toll-like receptor 4 (TLR4) silencing reversed these key inflammatory and matrix changes. Conclusion: HMGB1 is present in human tendinopathy and can regulate inflammatory cytokines and matrix changes. We propose HMGB1 as a mediator driving the inflammatory/matrix crosstalk and manipulation of the HMGB1/TLR4 axis may offer novel therapeutic approaches targeting inflammatory mechanisms in the management of human tendon disorders

Blue emitting gold nanoclusters templated by poly-cytosine DNA at low pH and poly-adenine DNA at neutral pH

Blue fluorescent gold nanoclusters were prepared in the presence of poly-cytosine DNAs at low pH and poly-adenine at neutral pH using citrate as the reducing agent; various buffer conditions affecting the synthesis have been explored.University of Waterloo || Canadian Foundation for Innovation || Natural Sciences and Engineering Research Council || Ontario Ministry of Research and Innovation |

Seasonal effects to metallothionein responses to metal exposure in a naturalised population of Ruditapes philippinarum in a semi-enclosed estuarine environment

The Manila clam (Ruditapes philippinarum), an invasive species in Northern Europe, can be used as a bioindicator of metal pollution. Seasonal effects on metallothionein (MT) production have not been considered in this species at the northernmost extent of its European distribution. This study assesses the annual seasonal effects on MT and metal concentrations in R. philippinarum from Poole Harbour, UK. R. philippinarum were collected in winter, spring, summer, and autumn throughout 2015, and MT and metal concentrations, as well as biotic and abiotic variables, were quantified. During winter, linear regression analysis showed significant positive relationships between tissue metal and MT concentrations. However, during spring and summer, these relationships were mostly insignificant. MT concentrations during spring had significant positive relationships with tissue and whole weight. Significant positive relationships were also observed between MT and condition index, during summer. During spring and summer, biotic factors seem to override the role of MT as a detoxification mechanism for metal exposure in this species. This is probably due to an increase in MT concentration in spring caused by gametogenesis, associated with increased tissue weight as the gonads expand. A depletion of energy resources, or physical stressors such as heat, may be attributed to the reduced MT production in clams of poor body condition in summer. The evidence from this study suggests that MT may only be a useful biomarker of metal pollution during winter in R. philippinarum in the UK. This verifies the natural variability of MT in this species at high latitudes, and highlights the potential and limits to a widely available bioindicator of metal pollution

IL-21 receptor expression in human tendinopathy

The pathogenetic mechanisms underlying tendinopathy remain unclear, with much debate as to whether inflammation or degradation has the prominent role. Increasing evidence points toward and early inflammatory infiltrate and associated inflammatory cytokine production in human and animal models of tendon disease. The IL-21/IL-21R axis is a proinflammatory cytokine complex that has been associated with chronic inflammatory diseases including rheumatoid arthritis and inflammatory bowel disease. This project aimed to investigate the role and expression of the cytokine/receptor pair IL-21/IL-21R in human tendinopathy. We found significantly elevated expression of IL-21 receptor message and protein in human tendon samples but found no convincing evidence of the presence of IL-21 at message or protein level. The level of expression of IL-21R message/protein in human tenocytes was significantly up regulated by proinflammatory cytokines (TNFα/IL-1β) in vitro. These findings demonstrate that IL-21R is present in early human tendinopathy mainly expressed by tenocytes and macrophages. Despite a lack of IL-21 expression these data again suggest that early tendinopathy has an inflammatory/cytokine phenotype, which may provide novel translational targets in the treatment of tendinopathy

Engineering simulations for cancer systems biology

Computer simulation can be used to inform in vivo and in vitro experimentation, enabling rapid, low-cost hypothesis generation and directing experimental design in order to test those hypotheses. In this way, in silico models become a scientific instrument for investigation, and so should be developed to high standards, be carefully calibrated and their findings presented in such that they may be reproduced. Here, we outline a framework that supports developing simulations as scientific instruments, and we select cancer systems biology as an exemplar domain, with a particular focus on cellular signalling models. We consider the challenges of lack of data, incomplete knowledge and modelling in the context of a rapidly changing knowledge base. Our framework comprises a process to clearly separate scientific and engineering concerns in model and simulation development, and an argumentation approach to documenting models for rigorous way of recording assumptions and knowledge gaps. We propose interactive, dynamic visualisation tools to enable the biological community to interact with cellular signalling models directly for experimental design. There is a mismatch in scale between these cellular models and tissue structures that are affected by tumours, and bridging this gap requires substantial computational resource. We present concurrent programming as a technology to link scales without losing important details through model simplification. We discuss the value of combining this technology, interactive visualisation, argumentation and model separation to support development of multi-scale models that represent biologically plausible cells arranged in biologically plausible structures that model cell behaviour, interactions and response to therapeutic interventions

Pulmonary artery stiffness in chronic obstructive pulmonary disease (copd) and emphysema: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study

Purpose: Chronic obstructive pulmonary disease (COPD) and particularly emphysema are characterized by stiffness of the aorta, due in part to accelerated elastin degradation in the lungs and aorta. Stiffness of the pulmonary arteries (PAs) may also be increased in COPD and emphysema, but data are lacking. We assessed PA stiffness using MRI in patients with COPD and related these measurements to COPD severity and percent emphysema. Materials and Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited 290 participants, age 50–79 years with 10 or more packyears and free of clinical cardiovascular disease. COPD severity were defined on postbronchodilator spirometry by ATS/ERS criteria. Percent emphysema was defined as the percentage of regions of the lung < -950 Hounsfield units on full-lung computed tomography (CT). PA stain was defined by the percent change in cross-sectional PA area between systole and diastole on MRI. Blood flow across the tricuspid and mitral valves was assessed by phase-contrast MRI for determination of the ventricular diastolic dysfunction (E/A ratio). Results: PA strain was reduced in COPD compared with controls (P = 0.002) and was inversely correlated with COPD severity (P = 0.004). PA strain was inversely associated to percent emphysema (P = 0.01). PA strain was also markedly correlated with right ventricular diastolic dysfunction measured by E/A ratios in the fully adjusted mix models (P = 0.02). Conclusion: PA strain is reduced in COPD, related in part to percent emphysema on CT scan, which may have implications for pulmonary small vessel flow and right ventricular function. Level of Evidence: 2 Technical Efficacy: Stage

Evaluation of frameworks of analysis employed in studies of exclusion zones

The purpose of this Work Package is to examine the various approaches to analysing fishery exclusion zones (FEZs) and to identify the circumstances in which one approach might be preferred to another. Our concern here is not so much with answering questions about exclusion zones - these being dealt with in later Work Packages - as with articulating the questions themselves and in understanding how in principle they could be addressed. An important theme is the precision with which questions need to be answered, since this will determine the type of information collected and how such information is analysed. The question ' is an exclusion zone likely to improve the condition of this fishery ?' is less precise and less demanding of data than the question ' by how much will an exclusion zone improve this fishery ?' since it could in principle be answered by expert judgement rather than quantitative analysis. In practice fisheries managers may be confronted with situations where decisions have to be made quickly, and qualitative answers may be the only thing possible in circumstances where data cannot be obtained in the available time. The Work Package will look at FEZs from a number of different perspectives, but its dominant concern is with the information – principally in the form of socio-economic and biological indicators - needed by fisheries managers in order to evaluate the effectiveness of FEZs. To contextualise the discussion we start by outlining a paradigm for understanding the linkages between human activities and the environment, showing how it can be applied to fisheries and marine resources. The Work Package then considers the substantive information requirements of fisheries managers, commencing with socio-economic assessment and moving on to a review of biological assessment and the progress which has been made in the development of mathematical models of FEZs. Bio-economic modelling, which is essentially a specialised type of socio-economic assessment in which explicit account is taken of the interaction between the biological and economic components of the fishing system, is dealt with in the final section

The excitation spectrum of mesoscopic proximity structures

We investigate one aspect of the proximity effect, viz., the local density of states of a superconductor-normal metal sandwich. In contrast to earlier work, we allow for the presence of an arbitrary concentration of impurities in the structure. The superconductor induces a gap in the normal metal spectrum that is proportional to the inverse of the elastic mean free path l_N for rather clean systems. For a mean free path much shorter than the thickness of the normal metal, we find a gap size proportional to l_N that approaches the behavior predicted by the Usadel equation (diffusive limit). We also discuss the influence of interface and surface roughness, the consequences of a non-ideal transmittivity of the interface, and the dependence of our results on the choice of the model of impurity scattering.Comment: 7 pages, 8 figures (included), submitted to PR

Prevention of anxiety among at-risk children: a systematic review and meta-analysis

Background Anxiety disorders are common, often start in childhood and run a chronic course. As such there is a need for effective prevention. Methods We conducted a systematic review and meta-analyses of randomized, controlled trials to prevent the onset of anxiety disorders in ‘at risk’ young people. Diagnostic and symptom outcomes were examined. Putative moderators were tested as was publication bias. Results We included 16 trials (2545 young people). Two trials reported diagnostic outcomes, and significant effects were found for these at end-of-programme (RR = .09, 95%CI = .02 to .16), 6- (RR = .17, 95%CI = .06 to .27) and 12-month (RR = .31, 95%CI .17 to .45) follow-ups. Based on 16 trials, improved anxiety symptoms were significant compared to nonattention controls only, with small effect sizes reported by young people at the end-of-programmes, 6- and 12-month follow-ups; and by parents at the end of the programmes and 12-, but not 6-, month follow-ups. There was no evidence of significant moderation or publication bias. Conclusions Fourteen studies included children and young people who presented with elevated anxiety symptoms, but anxiety disorder was not ruled out in the participants in these studies. Hence, these studies might be reporting results of mixed prevention/early intervention programmes. Prevention programmes that target developmental risk factors, not only disorder maintaining factors, appear most promising. The clinically meaningful impact of anxiety disorder prevention programmes remains unknown