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Does dysregulation of redox state underpin the decline of innate immunity with ageing?
No full textSignificance
Anti-bacterial defence invokes the innate immune system as a first responder, with neutrophils phagocytosing and forming NETs around pathogens in a ROS-dependent manner. Increased NOX2 activity and mitochondrial ROS production in phagocytic, antigen-presenting cells affects local cytokine secretion and proteolysis of antigens for presentation to T cells at the immune synapse. Uncontrolled oxidative post-translational modifications to surface and cytoplasmic proteins in antigen presenting cells during ageing can impair innate immunity.
Recent Advances
NOX2 plays a role in the maturation of dendritic cells, but paradoxically, NOX2 activity has also been shown to promote viral pathogenicity. Accumulating evidence suggests that a reducing environment is essential to inhibit pathogen proliferation, facilitate antigenic processing in the endosomal lumen and enable an effective immune synapse between antigen presenting cells and T cells. This suggests that the kinetics and location of ROS production and reducing potential are important for effective innate immunity.
Critical Issues
During ageing, innate immune cells are less well able to phagocytose, kill bacteria/viruses and process proteins into antigenic peptides – three key steps that are necessary for developing a specific targeted response to protect against future exposure. Aberrant control of ROS production and impaired Nrf2-dependent reducing potential may contribute to age-associated immune decline.
Future Directions
Local changes in redox potential may be achieved through adjuvant formulations to improve innate immunity. Further work is needed to understand the timing of delivery for redox modulators to facilitate innate immune cell recruitment, survival, antigen processing and presentation activity without disrupting essential ROS-dependent bacterial killing.
Innovation
Immune memory of a pathogen depends on recognition of a unique antigenic “mark” or epitope on the pathogen. It requires carefully orchestrated interactions between the memory-holding lymphocytes in the adaptive arm of immune system, and the antigen presenting innate immune cells. The uptake and processing of pathogens to produce unique antigenic “marks” by macrophages and dendritic cells is modulated by redox state. With ageing-associated dysregulation of redox state, impaired immune memory may ensue. Approaches to manipulate redox state in specific subcellular endosomal compartments after antigen uptake should be explored to understand whether vaccination responses may be improved during ageing
Platelet-derived Transforming Growth Factor-β1 promotes keratinocyte proliferation in cutaneous wound healing
No full textPlatelets are a recognised potent source of Transforming Growth Factor-1 (TGF1), a cytokine known to promote wound healingand regenerationby stimulating dermal fibroblast proliferation and extracellular matrix deposition. Platelet lysate has been advocated as a novel personalised therapeutic to treat persistent wounds, although the precise platelet-derived growth factors responsible for these beneficial effects have not been fully elucidated. The aim of thisstudy was to investigate the specific role of platelet-derived TGF1in cutaneous wound healing.Using a transgenic mouse with a targeted deletion of TGF1in megakaryocytes and platelets (TGFβ1fl/fl.PF4-Cre), we show for the first-time platelet-derived TGF1 contributes to epidermal and dermal thickening and cellular turnover after excisional skin wounding. In vitrostudies demonstrate human dermal fibroblasts stimulated with platelet lysate containing high levels of platelet-derived TGF1 did not exhibit enhanced collagen deposition or proliferation, suggestingthat platelet-derived TGF1 is not a key promoter of these wound healing processes.Interestingly, human keratinocytes displayed enhanced TGF1-driven proliferation in response to platelet lysate, reminiscent of our in vivofindings. In summary, our novel findings define andemphasiseanimportant roleof platelet-derived TGF1in epidermal remodellingand regenerationprocessesduring cutaneous wound healing
On URLLC Downlink Transmission Modes for MEC Task Offloading
No full textMulti-access edge computing for mobile computingtask
offloading is driving the extreme utilization of available degrees of freedom (DoF) for ultra-reliable low-latency downlink communications. The fundamental aim of this work is to find latency-constrained transmission protocols that can achieve a very-low outage probability (e.g. 0:001%). Our investigation is mainly based upon the Polyanskiy-Poor-Verd´u formula on the finite-length coded channel capacity, which is extended from the
quasi-static fading channel to the frequency selective channel. Moreover, the use of a suitable duplexing mode is also critical to the downlink reliability. Specifically, time-division duplexing
(TDD) outperforms frequency-division duplexing (FDD) in terms of the frequency diversity-gain. On the other hand, FDD takes the advantage of having more temporal DoF in the downlink, which can be exchanged into the spatial diversity-gain through the use of space-time coding. Numerical study is carried out to compare the reliability between FDD and TDD under various latency constraints
Forum: Rethinking Neoclassical Realism at Theory's End
No full textThis forum presents a snapshot of the current state of neoclassical realist theorizing. Its contributors are self-identified neoclassical realists who delineate their version of neoclassical realism (NCR), its scope, object of analysis, and theoretical contribution. From the standpoint of NCR, they contribute to and reflect on the “end of IR theory” debate. NCR has come under criticism for its supposed lack of theoretical structure and alleged disregard for paradigmatic boundaries. This raises questions as to the nature of this (theoretical) beast. Is NCR a midrange, progressive research program? Can it formulate a grand theory informed by metatheoretical assumptions? Is it a reformulation of neorealism or classical realism or an eclectic mix of different paradigms? The forum contributors argue that NCR, in different variants, holds considerable promise to investigate foreign policy, grand strategy and international politics. They interrogate the interaction of international and domestic politics and consider normative implications as well as the sources and cases of NCR beyond the West. In so doing, they speak to theorizing and the utility of the theoretical enterprise in IR more generally
Is the content of patient’s written emotional disclosure associated with improved health outcomes for asthma patients?
No full textWritten Emotional Disclosure (WED) is a self-directed, writing intervention. Treatment effects post-WED vary between studies, prompting research into which variables promote the largest improvements. Thus far, research has focussed on the frequency of certain linguistic properties of the writing, and subjective stress-related ratings. This study tests the feasibility of using an objective coding framework for stress typology to categorise WED extracts and explores whether any characteristics of the stress described were associated with intervention outcomes. WED extracts from a randomised controlled trial of patients with asthma were coded using an objective stress typology framework. The contents of the WED extracts were reviewed to ascertain whether the experience met the DSM 5 definition for trauma, involved abuse, and was experienced directly or vicariously. Also analysed were the degree of upheaval and upset associated with the event described, together with the time of the event, and number of events written about. Correlational analyses indicated that improvements in asthma-related outcomes were associated with writing about experiences that occurred in childhood, constituted abuse, or caused greater upheaval (all ps<.05). We found some evidence that the treatment effects of WED may be dependent on what types of stressful experiences participants write about. The use of our objective stress coding scheme was only partially successful as it could not be applied consistently to all WED extracts. Findings require replication using a prospective experimental design
A novel scaffold based hybrid multicellular model for pancreatic ductal adenocarcinoma – towards a better mimicry of the in vivo tumour microenvironment
No full textWith a very low survival rate, pancreatic ductal adenocarcinoma (PDAC) is a deadly disease. This has been primarily attributed to – (i) its late diagnosis and (ii) its high resistance to current treatment methods. The later, specifically requires the development of robust, realistic in vitro models of PDAC, capable of accurately mimicking the in vivo tumour niche. Advancements in the field of Tissue Engineering (TE) have helped the development of such models for PDAC. Herein, we report for the first time a novel hybrid, poly- urethane (PU) scaffold based, long term, multicellular (tri-culture) model of pancreatic cancer involving cancer cells, endothelial cells and stellate cells. Recognising the importance of ECM proteins for optimal growth of different cell types, the model consists of two different zones/compartments: an inner tumour compartment consisting of cancer cells (fibronectin coated) and a surrounding stromal compartment consisting of stellate and endothelial cells (collagen I coated). Our developed novel hybrid, tri-culture model supports the proliferation of all different cell types for 35 days (5 weeks), which is the longest reported time frame in vitro. Furthermore, the hybrid model showed extensive collagen I production by the cells, mimicking desmoplasia, one of PDAC’s hallmark features. Fibril alignment of the stellate cells was observed, which attested for their activated state. All three cell types expressed various cell specific markers within the scaffolds, throughout the culture period and showed cellular migration between the two zones of the hybrid scaffold. Our novel model has great potential as a low cost tool for in vitro studies of PDAC as well as for treatment screening
Challenges to analysis of major, minor and trace elemental concentrations in two media of toxicological interest.
No full textSince the industrial revolution pollution has typically been classified according to whether it concerns air, water or noise, the issue of light-pollution now joining these. Pollution, direct or otherwise, causes damage to the living environment. In the present study of moderate to high atomic number media, analysis of major, minor and trace elemental concentrations is shown to be effective via x-ray fluorescence and mass spectroscopy (MS) based methods. Particular choice has been made of two media of highly differing constitution, both of toxicological consequence and each with its own challenges. Metals are prevalent in the widespread environmental emissions that result from the use of motorised vehicles, not least in road dust. Conversely, the metals manifest in Kohl have been analysed as an example of how an absence of regulatory control can allow the unimpeded marketing of personal products of clear human health impact. In conducting such a study, comparison has been made of several sensitive yet convenient sample analysis techniques (XRF, SEM/EDX, ICP-MS and ICP-OES), their relative efficacy being examined. The ICP-based methods provide for quantitative sample analysis while XRF/EDX can provide quantitative and qualitative analysis.
The XRF study of Kohl has involved analysis of Pb, Fe and Zn concentrations in 135 samples, obtained from nine randomly selected market outlets (15 aliquots of each brand being represented). Among the published physiological effects of exposure to Pb is replacement of Ca in bones and teeth, making them weak and fragile, other impacts including nephrotoxicity, linked with increased Pb blood levels. While in this study the work on Kohl formed an introduction to elemental analysis, one particular challenge, also one that quickly became apparent but yet notable in terms of its absence from discussion in the literature, was investigation of high concentrations of highly attenuating media. Sample dilution and account of it has been required in arriving at reliable quantification. One desire has been to draw regulator attention to the potentiality of convenient, compact instrumentation and associated methodology, allowing for product screening.
For road dust, obtained from a total of 60 locations, analysis has been conducted on particle sizes ranging from < 45 m up to 125 m. Arid climate samples were collected from the campuses of King Saud University, the Kuwait Research Institute and Qatar University, while maritime climate samples were collected from the Surrey University campus. Ttropical climate samples were collected from the campus of the University of Malaya as well as surrounding roads to the Malaysian radiation consultancy company, Asia Lab (now Alypz Sdn. Bhd.).
Roadside dirt has been sampled along busy campus roads of universities/research centres in Guildford, Riyadh, Kuwait City, Doha and Kuala Lumpur, satisfying interest in climatic influences as well as vehicle engine size (in the Gulf countries non-commercial vehicle engine capacities tend to be greater than those in the UK or Malaysia, a product of relatively cheap fuel prices). A total of 200 street dust samples have been analyzed, elemental concentrations being reported for Mg, Al, Ti, Mn, Fe, Co, Zr, Mo, Ba, Tl, V, Rd, Pb, Cu, Zn, Ni, Cr, Cd, As, Hg and Au. For all five urban centres, Al, Fe, Mg, and Si values were found to be well above background although concentrations of Ti, Cr and Ba were lower than values reported by others. The concentrations of Pb were relatively low, likely attributable to restrictions on lead in fuel. Au and Ag were detected in low quantities in both Arid and Maritime climates, use being made of the SEM/EDX, appearing at levels unlikely to make economic sense in terms of recovery. Note that elemental loadings are provided in terms of concentrations per unit mass of sample. In general, the elements found in elevated concentrations can all be linked to the wear and tear of motor parts as debris.
For the Guildford samples, obtained at three different times of the year, the main SEM/EDX findings were for Mg, Al, Cr, Ti, Mn, Fe, Co, Cu, Zr, Mo, Ba, Tl, V, Rh, Au and Ag, values ranging from non-detectable (below detection limits), through to from as low as 34.7 E-6 mg/m2 up to as high as 6 E-2 mg/m2. Note that the output provides estimates of elemental loadings per unit area at the sampling site. Using ICP-MS, Guildford concentrations in mg/kg (ppm) have been found for Al, V, Cr, Mn, Fe, Co, Cu, Zn, As, Se, Mo, Cd, Sb, Pb, and U, for samples of mean size < 45 micron. Respective values were 3081, 12.3, 40.2, 333, 14133, 3.5, 70.4, 288, 5.96, 0.400, 2.35, 0.567, 2.77, 78.0, 0.657, results showing particular elevations of Al, Fe, Cu, Zn and Pb. Other toxic metals found in the Guildford and Kuwait samples in different concentrations were V, Ti, Cr, and Ba. For Riyadh and Doha samples four elements have been observed to be particularly prominent: Al, Fe, Mg, and Si, notwithstanding that they all have natural abundance in desert sands.
Elemental presence has been seen to be influenced by climatic conditions as well as vehicle engine size. In conclusion, the various techniques offer complementary information on vehicular emission elemental concentrations in urban environments
Proof is still needed that an anti-inflammatory diet can benefit rheumatoid arthritis patients.
No full textA web-based geographic interface system to support decision making for municipal solid waste management in England
No full textTo evaluate the feasibility and sustainability of the waste
management solutions, it is necessary to assess the quantity and the flows of the waste generated. This research developed a web application which serves as a decision support system for those involved in the
planning and management of municipal solid waste . In contrast to present web-based solutions, this tool provides the necessary information regarding the supply chain that is required to assess the suitability of
waste valorisation in a particular location such as waste types, waste quantities and related waste contractors. Using publicly available data, a web geographic information system was designed where factors that affect the supply chain of municipal solid waste can be investigated.
These include spatial and temporal variation of waste generated. The concept was demonstrated in the developed web application using publicly available data about England. Waste market opportunities were identified, for example Kent County Council and Essex County Council were identified
to have the highest quantity of incinerated waste with and without energy recovery (344 and 65 kiloton) respectively. Then Staffordshire and Lancashire County Councils were identified to have the highest quantity
of hazardous and non-hazardous waste being landfilled (5 and 296 kiloton) respectively. Seasonal variation was inconsistent across counties, with East Northamptonshire having little seasonal variation in household waste
(<500 tonne variation) as opposed to East Riding of Yorkshire which had higher waste volumes in summer with up to 15,000 tonne variation). Circular economy partners were also identified through the web application and these results are presented in context of waste-derived
supply chain decisions. The web application is therefore able to provide a comprehensive tool for improving both strategic and logistical
decision-making process for municipal solid waste management
Employing a value-belief-norm framework togauge Carthage residents’ intentions to supportsustainable cultural heritage tourism
No full textIn light of the recent conflicts in Carthage over land use, culturalheritage preservation, and sustainable tourism, this work utilized avalue-belief-norm (VBN) theoretical framework to consider psychologicalantecedents of residents’behavioral intentions to support cultural heri-tage tourism. As such, personal values, cultural worldview, awareness ofconsequences, ascription of responsibility, and subjective norms wereconsidered antecedents of intentions to support cultural heritagetourism. Data were collected from 475 Carthage residents in nine neigh-borhoods adjacent to UNESCO World Heritage Sites using an on-siteself-administered questionnaire. The proposed model was assessedthrough confirmatory factor analysis (to demonstrate sound psychomet-ric properties across all 11 factors within the model), followed by struc-tural equation modelling. Overall, 15 of the 19 proposed hypotheseswere supported, ultimately contributing to 28% of the varianceexplained in residents’behavioral intentions to support cultural heritagetourism. This work not only provides support for the utilization of theVBN model within the context of cultural heritage tourism, it also deep-ens our understanding of the theoretical framework through the inclu-sion of the multi-dimensional construct cultural worldvie
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