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Agency: GTR | Branch: EPSRC | Program: | Phase: Research Grant | Award Amount: 4.56M | Year: 2016

Today we use many objects not normally associated with computers or the internet. These include gas meters and lights in our homes, healthcare devices, water distribution systems and cars. Increasingly, such objects are digitally connected and some are transitioning from cellular network connections (M2M) to using the internet: e.g. smart meters and cars - ultimately self-driving cars may revolutionise transport. This trend is driven by numerous forces. The connection of objects and use of their data can cut costs (e.g. allowing remote control of processes) creates new business opportunities (e.g. tailored consumer offerings), and can lead to new services (e.g. keeping older people safe in their homes). This vision of interconnected physical objects is commonly referred to as the Internet of Things. The examples above not only illustrate the vast potential of such technology for economic and societal benefit, they also hint that such a vision comes with serious challenges and threats. For example, information from a smart meter can be used to infer when people are at home, and an autonomous car must make quick decisions of moral dimensions when faced with a child running across on a busy road. This means the Internet of Things needs to evolve in a trustworthy manner that individuals can understand and be comfortable with. It also suggests that the Internet of Things needs to be resilient against active attacks from organised crime, terror organisations or state-sponsored aggressors. Therefore, this project creates a Hub for research, development, and translation for the Internet of Things, focussing on privacy, ethics, trust, reliability, acceptability, and security/safety: PETRAS, (also suggesting rock-solid foundations) for the Internet of Things. The Hub will be designed and run as a social and technological platform. It will bring together UK academic institutions that are recognised international research leaders in this area, with users and partners from various industrial sectors, government agencies, and NGOs such as charities, to get a thorough understanding of these issues in terms of the potentially conflicting interests of private individuals, companies, and political institutions; and to become a world-leading centre for research, development, and innovation in this problem space. Central to the Hub approach is the flexibility during the research programme to create projects that explore issues through impactful co-design with technical and social science experts and stakeholders, and to engage more widely with centres of excellence in the UK and overseas. Research themes will cut across all projects: Privacy and Trust; Safety and Security; Adoption and Acceptability; Standards, Governance, and Policy; and Harnessing Economic Value. Properly understanding the interaction of these themes is vital, and a great social, moral, and economic responsibility of the Hub in influencing tomorrows Internet of Things. For example, a secure system that does not adequately respect privacy, or where there is the mere hint of such inadequacy, is unlikely to prove acceptable. Demonstrators, like wearable sensors in health care, will be used to explore and evaluate these research themes and their tension. New solutions are expected to come out of the majority of projects and demonstrators, many solutions will be generalisable to problems in other sectors, and all projects will produce valuable insights. A robust governance and management structure will ensure good management of the research portfolio, excellent user engagement and focussed coordination of impact from deliverables. The Hub will further draw on the expertise, networks, and on-going projects of its members to create a cross-disciplinary language for sharing problems and solutions across research domains, industrial sectors, and government departments. This common language will enhance the outreach, development, and training activities of the Hub.

Kasper D.C.,Medical University of Vienna | Herman J.,Thermo Fisher Scientific | De Jesus V.R.,Centers for Disease Control and Prevention | Mechtler T.P.,Medical University of Vienna | And 2 more authors.
Rapid Communications in Mass Spectrometry | Year: 2010

Lysozomal storage disorders are just beginning to be routinely screened using enzyme activity assays involving dried blood spots and tandem mass spectrometry (MS/MS). This paper discusses some of the analytical challenges associated with published assays including complex sample preparation and potential interference from excess residual substrate. Solutions to these challenges are presented in the form of on-line two-dimensional chromatography to eliminate off-line liquid-liquid extraction (LLE) and solid-phase extraction (SPE), the use of ultra-high-performance liquid chromatography (UHPLC) to separate excess substrate from all other analytes and multiplexed sample introduction for higher throughput required of a population screening assay. High sensitivity, specificity and throughput were demonstrated using this novel method. © 2010 John Wiley & Sons, Ltd.

Mechtler T.P.,Medical University of Vienna | Metz T.F.,Medical University of Vienna | Muller H.G.,Medical University of Vienna | Ostermann K.,Medical University of Vienna | And 7 more authors.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2012

The interest in early detection strategies for lysosomal storage disorders (LSDs) in newborns and high-risk population has increased in the last years due to the availability of novel treatment strategies coupled with the development of diagnostic techniques. We report the development of a short-incubation mass spectrometry-based protocol that allows the detection of Gaucher, Niemann-Pick A/B, Pompe, Fabry and mucopolysaccharidosis type I disease within 4. h including sample preparation from dried blood spots. Optimized sample handling without the need of time-consuming offline preparations, such as liquid-liquid and solid-phase extraction, allows the simultaneous quantification of five lysosomal enzyme activities using a cassette of substrates and deuterated internal standards. Applying incubation times of 3. h revealed in intra-day CV% values ranging from 4% to 11% for all five enzyme activities, respectively. In a first clinical evaluation, we tested 825 unaffected newborns and 16 patients with LSDs using a multiplexed, turbulent flow chromatography-ultra high performance liquid chromatography-tandem mass spectrometer assay. All affected patients were identified accurately and could be differentiated from non-affected newborns. In comparison to previously published two-day assays, which included an overnight incubation, this protocol enabled the detection of lysosomal enzyme activities from sample to first result within half a day. © 2012 Elsevier B.V.

Martin P.,Max Planck Institute of Immunobiology | Martin P.,University of Geneva | Pardo J.,Max Planck Institute of Immunobiology | Pardo J.,University of Zaragoza | And 7 more authors.
Journal of Biological Chemistry | Year: 2010

Granule-associated perforin and granzymes (gzms) are key effector molecules of cytotoxic T lymphocytes (Tc cells) and natural killer cells and play a critical role in the control of intracellular pathogens and cancer. Based on the notion that many gzms, including A, B, C, K, H, and M exhibit cytotoxic activity in vitro, all gzms are believed to serve a similar function in vivo. However, more recent evidence supports the concept that gzms are not unidimensional but, rather, possess non-cytotoxic potential, including stimulation of pro-inflammatory cytokines and anti-viral activities. The present study shows that isolated mouse gzmB cleaves the actin-severing mouse protein, cytoplasmic gelsolin (c-gelsolin) in vitro. However, when delivered to intact target cells by ex vivo immune Tc cells, gzmB mediates c-gelsolin proteolysis via activation of caspases 3/7. The NH2-terminal c-gelsolin fragment generated by either gzmB or caspase 3 in vitro constitutively severs actin filaments without destroying the target cells. The observation that gzmB secreted by Tc cells initiates a caspase cascade that disintegrates the actin cytoskeleton in target cells suggests that this intracellular process may contribute to anti-viral host defense. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Metz T.F.,Medical University of Vienna | Mechtler T.P.,Medical University of Vienna | Orsini J.J.,New York State Department of Health | Martin M.,New York State Department of Health | And 7 more authors.
Clinical Chemistry | Year: 2011

BACKGROUND: Interest in lysosomal storage disorders, a collection of more than 40 inherited metabolic disorders, has increased because of new therapy options such as enzyme replacement, stem cell transplantation, and substrate reduction therapy. We developed a high-throughput protocol that simplifies analytical challenges such as complex sample preparation and potential interference from excess residual substrate associated with previously reported assays. METHODS: After overnight incubation (16-20 h) of dried blood spots with a cassette of substrates and deuterated internal standards, we used a TLX-2 system to quantify 6 lysosomal enzyme activities for Fabry, Gaucher, Niemann-Pick A/B, Pompe, Krabbe, and mucopolysaccharidosis I disease. This multiplexed, multidimensional ultra-HPLC - tandem mass spectrometry assay included Cyclone P Turbo Flow and Hypersil Gold C8 columns. The method did not require offline sample preparation such as liquid-liquid and solid-phase extraction, or hazardous reagents such as ethyl acetate. RESULTS: Obviating the offline sample preparation steps led to substantial savings in analytical time (approximately 70%) and reagent costs (approximately 50%). In a pilot study, lysosomal enzyme activities of 8586 newborns were measured, including 51 positive controls, and the results demonstrated 100% diagnostic sensitivity and high specificity. The results for Krabbe disease were validated with parallel measurements by the New York State Screening Laboratory. CONCLUSIONS: Turboflow online sample cleanup and the use of an additional analytical column enabled the implementation of lysosomal storage disorder testing in a nationwide screening program while keeping the total analysis time to <2 min per sample. © 2011 American Association for Clinical Chemistry.

Eva N.,50 North 1950 West | Eva N.,Utah State University | Durrant G.C.,Metropolitan Water District of Salt Lake and Sandy | Hoyt M.B.,Central Utah Water Conservancy District | And 6 more authors.
Journal / American Water Works Association | Year: 2010

This study evaluated the validity of monitoring for Escherichia coli in lieu of Cryptosporidium to assess the vulnerability of source waters to the presence of Cryptosporidium oocysts. Over a period of seven years, four large water systems in Utah collected Cryptosporidium, E. coli, and turbidity data from seven water treatment plants that treat both reservoir and stream sources. The data represented analyses completed by two US Environmental Protection Agency-approved protozoan laboratories and local state-certified laboratories for E coli. Results of the statistical analyses indicated poor correlation between Cryptosporidium and E. coli and between Cryptosporidium and turbidity in all monitored water sources throughout the entire monitoring period. The analyses indicate that elevated concentrations of E. coli are not indicative of the presence of Cryptosporidium in surface water. Both E. coli and turbidity are poor surrogates for occurrence of Cryptosporidium at treatment plant intakes. Further investigation is needed to establish appropriate surrogates for Cryptosporidium occurrence.

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