Metabolomics on integrated circuit

We have demonstrated a chip-based diagnostics tool for the quantification of metabolites, using specific enzymes, to study enzyme kinetics and calculate the Michaelis-Menten constant. An array of 256×256 ion-sensitive field effect transistors (ISFETs) fabricated in a complementary metal oxide semiconductor (CMOS) process is used for this prototype. We have used hexokinase enzyme reaction on the ISFET CMOS chip with glucose concentration in the physiological range of 0.05 mM – 231 mM and successfully studied the enzyme kinetics of hexokinase in detail. This will promote future research towards multiplexing enzyme-based metabolite quantification on a single chip, ultimately opening a pathway towards a personal metabolome machine

A 16 x 16 CMOS amperometric microelectrode array for simultaneous electrochemical measurements

There is a requirement for an electrochemical sensor technology capable of making multivariate measurements in environmental, healthcare, and manufacturing applications. Here, we present a new device that is highly parallelized with an excellent bandwidth. For the first time, electrochemical cross-talk for a chip-based sensor is defined and characterized. The new CMOS electrochemical sensor chip is capable of simultaneously taking multiple, independent electroanalytical measurements. The chip is structured as an electrochemical cell microarray, comprised of a microelectrode array connected to embedded self-contained potentiostats. Speed and sensitivity are essential in dynamic variable electrochemical systems. Owing to the parallel function of the system, rapid data collection is possible while maintaining an appropriately low-scan rate. By performing multiple, simultaneous cyclic voltammetry scans in each of the electrochemical cells on the chip surface, we are able to show (with a cell-to-cell pitch of 456 μm) that the signal cross-talk is only 12% between nearest neighbors in a ferrocene rich solution. The system opens up the possibility to use multiple independently controlled electrochemical sensors on a single chip for applications in DNA sensing, medical diagnostics, environmental sensing, the food industry, neuronal sensing, and drug discovery

A high-order finite volume method for Maxwell's equations in heterogeneous and time-varying media

We develop a finite volume method for Maxwell's equations in materials whose electromagnetic properties vary in space and time. We investigate both conservative and non-conservative numerical formulations. High-order methods accurately resolve fine structures that develop due to the varying material properties. Numerical examples demonstrate the effectiveness of the proposed method in handling temporal variation and its efficiency relative to traditional 2nd-order FDTD.Comment: 15 pages, 8 figure

An integrated circuit for chip-based analysis of enzyme kinetics and metabolite quantification

We have created a novel chip-based diagnostic tools based upon quantification of metabolites using enzymes specific for their chemical conversion. Using this device we show for the first time that a solid-state circuit can be used to measure enzyme kinetics and calculate the Michaelis-Menten constant. Substrate concentration dependency of enzyme reaction rates is central to this aim. Ion-sensitive field effect transistors (ISFET) are excellent transducers for biosensing applications that are reliant upon enzyme assays, especially since they can be fabricated using mainstream microelectronics technology to ensure low unit cost, mass-manufacture, scaling to make many sensors and straightforward miniaturisation for use in point-of-care devices. Here, we describe an integrated ISFET array comprising 216 sensors. The device was fabricated with a complementary metal oxide semiconductor (CMOS) process. Unlike traditional CMOS ISFET sensors that use the Si3N4 passivation of the foundry for ion detection, the device reported here was processed with a layer of Ta2O5 that increased the detection sensitivity to 45 mV/pH unit at the sensor readout. The drift was reduced to 0.8 mV/hour with a linear pH response between pH 2 – 12. A high-speed instrumentation system capable of acquiring nearly 500 fps was developed to stream out the data. The device was then used to measure glucose concentration through the activity of hexokinase in the range of 0.05 mM – 231 mM, encompassing glucose’s physiological range in blood. Localised and temporal enzyme kinetics of hexokinase was studied in detail. These results present a roadmap towards a viable personal metabolome machine

Monitoring groundwater temperatures in a shallow urban aquifer before, during and after installation of a Ground Source Heat System in Cardiff, U.K.

Exploitation of shallow urban aquifers, warmed by the Urban Heat Island Effect, is a relatively new concept in the U.K. An extensive groundwater temperature baseline monitoring network has been established for a shallow superficial aquifer in the city of Cardiff, U.K., to characterise groundwater temperatures and monitor the impacts of the first open-loop ground source heat pump (GSHP) installed in the city. In Spring 2014, temperature profiling was carried out at 1m depth intervals at 168 groundwater monitoring boreholes across Cardiff, establishing baseline groundwater temperatures within the shallow (<20m) superficial aquifer during the groundwater’s forecast coldest time of year. Data was contoured to form the first U.K. 2D city heat map. During the warmest time of year, Autumn 2014, a subset of boreholes were re-profiled to ascertain seasonal temperature variation, defining the Zone of Seasonal Fluctuation. Re-profiling was again carried out at these boreholes in Autumn 2015 to confirm these temperatures as normal for that time of year. By comparing Spring and Autumn profiles, the average depth to the base of the Zone of Seasonal Fluctuation was found to be 9.5mbgl. Two >100m boreholes showed the urban warming effect may extend to 80mbgl, before temperatures follow the predicted geothermal gradient. We term this the Zone of Anthropogenic Influence. After initial baseline temperatures were established, a site was selected for the installation of a shallow GSHP. Before installation work began, a monitoring network was set up to establish a temperature baseline for future GSHPs and identify any impacts on the thermal resource caused by removing ~2°C from the abstracted groundwater prior to reinjection into the aquifer. This comprised of 97 temperature loggers in 60 boreholes, including the abstraction and recharge boreholes and boreholes up and down gradient of the site. Some of these boreholes have multiple loggers at different depths, including the near-surface, but the majority of loggers were placed within the boreholes’ slotted sections, below the base of the Zone of Seasonal Fluctuation. In addition, six boreholes, including those used for the GSHP, have been telemetered, providing real-time temperature data. The aim of the monitoring network was to establish a baseline for groundwater temperatures in the shallow aquifer and to monitor local changes in temperatures close to the GSHP system. This study aimed to provide understanding of how GSHPs interact with the groundwater in order to confirm the sustainability of groundwater temperatures as a long-term thermal resource and provide planners with knowledge needed to develop sustainable wide-scale GSHP systems/networks. We present temperature data taken before and after installation

A colorimetric CMOS-based platform for rapid total serum cholesterol quantification

Elevated cholesterol levels are associated with a greater risk of developing cardiovascular disease and other illnesses, making it a prime candidate for detection on a disposable biosensor for rapid point of care diagnostics. One of the methods to quantify cholesterol levels in human blood serum uses an optically mediated enzyme assay and a bench top spectrophotometer. The bulkiness and power hungry nature of the equipment limits its usage to laboratories. Here, we present a new disposable sensing platform that is based on a complementary metal oxide semiconductor process for total cholesterol quantification in pure blood serum. The platform that we implemented comprises readily mass-manufacturable components that exploit colorimetric changes of cholesterol oxidase and cholesterol esterase reactions. We have shown that our quantification results are comparable to that obtained by a bench top spectrophotometer. Using the implemented device, we have measured cholesterol concentration in human blood serum as low as 29 μM with a limit of detection at 13 μM, which is approximately 400 times lower than average physiological range, implying that our device also has the potential to be used for applications that require greater sensitivity

Coupling of thermal and mass diffusion in regular binary thermal lattice-gases

We have constructed a regular binary thermal lattice-gas in which the thermal diffusion and mass diffusion are coupled and form two nonpropagating diffusive modes. The power spectrum is shown to be similar in structure as for the one in real fluids, in which the central peak becomes a combination of coupled entropy and concentration contributions. Our theoretical findings for the power spectra are confirmed by computer simulations performed on this model.Comment: 5 pages including 3 figures in RevTex

Therapeutic efficacy of favipiravir against Bourbon virus in mice

Bourbon virus (BRBV) is an emerging tick-borne RNA virus in the orthomyxoviridae family that was discovered in 2014. Although fatal human cases of BRBV have been described, little is known about its pathogenesis, and no antiviral therapies or vaccines exist. We obtained serum from a fatal case in 2017 and successfully recovered the second human infectious isolate of BRBV. Next-generation sequencing of the St. Louis isolate of BRBV (BRBV-STL) showed >99% nucleotide identity to the original reference isolate. Using BRBV-STL, we developed a small animal model to study BRBV-STL tropism in vivo and evaluated the prophylactic and therapeutic efficacy of the experimental antiviral drug favipiravir against BRBV-induced disease. Infection of Ifnar1-/- mice lacking the type I interferon receptor, but not congenic wild-type animals, resulted in uniformly fatal disease 6 to 10 days after infection. RNA in situ hybridization and viral yield assays demonstrated a broad tropism of BRBV-STL with highest levels detected in liver and spleen. In vitro replication and polymerase activity of BRBV-STL were inhibited by favipiravir. Moreover, administration of favipiravir as a prophylaxis or as post-exposure therapy three days after infection prevented BRBV-STL-induced mortality in immunocompromised Ifnar1-/- mice. These results suggest that favipiravir may be a candidate treatment for humans who become infected with BRBV

Bayesian parameter inference for shallow subsurface modeling using field data and impacts on geothermal planning

Understanding the subsurface is crucial in building a sustainable future, particularly for urban centers. Importantly, the thermal effects that anthropogenic infrastructure, such as buildings, tunnels, and ground heat exchangers, can have on this shared resource need to be well understood to avoid issues, such as overheating the ground, and to identify opportunities, such as extracting and utilizing excess heat. However, obtaining data for the subsurface can be costly, typically requiring the drilling of boreholes. Bayesian statistical methodologies can be used towards overcoming this, by inferring information about the ground by combining field data and numerical modeling, while quantifying associated uncertainties. This work utilizes data obtained in the city of Cardiff, UK, to evaluate the applicability of a Bayesian calibration (using GP surrogates) approach to measured data and associated challenges (previously not tested) and to obtain insights on the subsurface of the area. The importance of the data set size is analyzed, showing that more data are required in realistic (field data), compared to controlled conditions (numerically-generated data), highlighting the importance of identifying data points that contain the most information. Heterogeneity of the ground (i.e., input parameters), which can be particularly prominent in large-scale subsurface domains, is also investigated, showing that the calibration methodology can still yield reasonably accurate results under heterogeneous conditions. Finally, the impact of considering uncertainty in subsurface properties is demonstrated in an existing shallow geothermal system in the area, showing a higher than utilized ground capacity, and the potential for a larger scale system given sufficient demand

A combined geomorphological and geophysical approach to characterising relict landslide hazard on the Jurassic Escarpments of Great Britain

The Jurassic Escarpment in the North York Moors in Northern Britain has a high density of deep-seated relict landslides but their regional hazard is poorly understood due to a lack of detailed case studies. Investigation of a typical relict landslide at Great Fryup Dale suggests that the crop of the Whitby Mudstone Formation is highly susceptible to landslide hazards. The mudstone lithologies along the Escarpment form large multiple rotational failures which break down at an accelerated rate during wetter climates and degrade into extensive frontal mudflows. Geomorphological mapping, high resolution LiDAR imagery, boreholes, and geophysical ERT surveys are deployed in a combined approach to delimit internal architecture of the landslide. Cross-sections developed from these data indicate that the main movement displaced a bedrock volume of c. 1 × 107 m3 with a maximum depth of rupture of c. 50 m. The mode of failure is strongly controlled by lithology, bedding, joint pattern, and rate of lateral unloading. Dating of buried peats using the AMS method suggests that the 10 m thick frontal mudflow complex was last active in the Late Holocene, after c. 2270 ± 30 calendar years BP. Geomorphic mapping and dating work indicates that the landslide is dormant, but slope stability modelling suggests that the slope is less stable than previously assumed; implying that this and other similar landslides in Britain may become more susceptible to reactivation or extension during future wetter climatic phases. This study shows the value of a multi-technique approach for landslide hazard assessment and to enhance national landslide inventories