Systematic computation of non-linear cellular and molecular dynamics with low-power cytomimetic circuits: A simulation study

This paper presents a novel method for the systematic implementation of low-power microelectronic circuits aimed at computing nonlinear cellular and molecular dynamics. The method proposed is based on the Nonlinear Bernoulli Cell Formalism (NBCF), an advanced mathematical framework stemming from the Bernoulli Cell Formalism (BCF) originally exploited for the modular synthesis and analysis of linear, time-invariant, high dynamic range, logarithmic filters. Our approach identifies and exploits the striking similarities existing between the NBCF and coupled nonlinear ordinary differential equations (ODEs) typically appearing in models of naturally encountered biochemical systems. The resulting continuous-time, continuous-value, low-power CytoMimetic electronic circuits succeed in simulating fast and with good accuracy cellular and molecular dynamics. The application of the method is illustrated by synthesising for the first time microelectronic CytoMimetic topologies which simulate successfully: 1) a nonlinear intracellular calcium oscillations model for several Hill coefficient values and 2) a gene-protein regulatory system model. The dynamic behaviours generated by the proposed CytoMimetic circuits are compared and found to be in very good agreement with their biological counterparts. The circuits exploit the exponential law codifying the low-power subthreshold operation regime and have been simulated with realistic parameters from a commercially available CMOS process. They occupy an area of a fraction of a square-millimetre, while consuming between 1 and 12 microwatts of power. Simulations of fabrication-related variability results are also presented

Time domain optical imaging device based on a commercial time-to-digital converter

Time-domain diffuse optical imaging is a noninvasive technique that uses pulsed near-infrared light as the interrogation source to produce quantitative images displaying the variation in blood volume and oxygenation in the human brain. Measuring the times of flights of photons provides information on the photon pathlengths in tissue, which enables absolute concentrations of the oxygenated and deoxygenated forms of hemoglobin to be estimated. Recent advances in silicon electronics have enabled the development of time-domain systems, which are lightweight and low cost, potentially enabling the imaging technique to be applied to a far greater cohort of subjects in a variety of environments. While such technology usually depends on customized circuits, in this article, we present a system assembled from commercially available components, including a low-cost time-to-digital converter and a silicon photomultiplier detector. The system is able to generate histograms of photon flight times at a rate of 81–90 kS/s and with a sampled bin width of 54 ps. The linearity and performance of the system are presented, and its potential as the basis for a modular multi-detector imaging system is explored

A dual switched-capacitor integrator architecture for versatile, real-time amperometric biosensing

In this paper, a versatile, re-programmable, current-input bioinstrumentation board is presented for electrochemical amperometric measurements. The proposed instrument has been fabricated on a six layer printed circuit board (PCB) and exploits dual switched-capacitor (SC) integration and sample-and-hold (SH) techniques. It comprises off-the-shelf switch and amplifier ICs and a commercially available FPGA-based DSP unit for digital signal control and synchronisation. It features eight amperometric channels, has a dynamic current range of 100dB, can be powered-up by a USB port or a 5V battery and is portable, with dimensions of 110×110 mm2. An onboard digital-to-analog converter (DAC) combined with standard three-electrode potentiostats can provide precise, programmable biasing voltages to eight amperometric biosensors simultaneously. Validation of the robustness and accuracy of the proposed system is demonstrated by proof-of-concept amperometric measurements using a high-precision Keithley 6221 current source and NaCI solution on a PCB-based sensor

Equations over free inverse monoids with idempotent variables

We introduce the notion of idempotent variables for studying equations in inverse monoids. It is proved that it is decidable in singly exponential time (DEXPTIME) whether a system of equations in idempotent variables over a free inverse monoid has a solution. The result is proved by a direct reduction to solve language equations with one-sided concatenation and a known complexity result by Baader and Narendran: Unification of concept terms in description logics, 2001. We also show that the problem becomes DEXPTIME hard , as soon as the quotient group of the free inverse monoid has rank at least two. Decidability for systems of typed equations over a free inverse monoid with one irreducible variable and at least one unbalanced equation is proved with the same complexity for the upper bound. Our results improve known complexity bounds by Deis, Meakin, and Senizergues: Equations in free inverse monoids, 2007. Our results also apply to larger families of equations where no decidability has been previously known.Comment: 28 pages. The conference version of this paper appeared in the proceedings of 10th International Computer Science Symposium in Russia, CSR 2015, Listvyanka, Russia, July 13-17, 2015. Springer LNCS 9139, pp. 173-188 (2015

Towards a smartphone-aided electronic ELISA for real-time electrochemical monitoring

This paper details the design and fabrication of a portable, smartphone-integrated electronic platform, tailored to read-out electronic ELISA (eELISA) data from printed circuit board (PCB)-based sensors. The instrument features eight independent, re-configurable current input channels, each consisting of a low-noise transimpedance amplifier (TIA) and filtering stage coupled to low-noise switch ICs for automatic current range detection. A bipolar, 16-bit resolution voltage-input analog-to-digital converter (ADC) has been employed for digitisation of converted current values received from the analogue front-end. In addition, a bipolar, 12-bit resolution digital-to-analog converter (DAC) combined with standard three-electrode potentiostats provides wide range biasing voltages to the amperometric sensors. The resulting digital data is transmitted via serial interface to an Android-based smartphone, where an ergonomic user interface guides the operator through the detection process. The customised Android application (App) provides real-time monitoring of the electrochemical cell and stores returned biochemical data on the device once measurement is complete

Janus and Multifaced Supersymmetric Theories

We investigate the various properties Janus supersymmetric Yang-Mills theories. A novel vacuum structure is found and BPS monopoles and dyons are studied. Less supersymmetric Janus theories found before are derived by a simpler method. In addition, we find the supersymmetric theories when the coupling constant depends on two and three spatial coordinates.Comment: 20 pages, no figures, typos, equations corrected. Additional comment

A novel microfluidic point-of-care biosensor system on printed circuit board for cytokine detection

Point of Care (PoC) diagnostics have been the subject of considerable research over the last few decades driven by the pressure to detect diseases quickly and effectively and reduce healthcare costs. Herein, we demonstrate a novel, fully integrated, microfluidic amperometric enzyme-linked immunosorbent assay (ELISA) prototype using a commercial interferon gamma release assay (IGRA) as a model antibody binding system. Microfluidic assay chemistry was engineered to take place on Au-plated electrodes within an assay cell on a printed circuit board (PCB)-based biosensor system. The assay cell is linked to an electrochemical reporter cell comprising microfluidic architecture, Au working and counter electrodes and a Ag/AgCl reference electrode, all manufactured exclusively via standard commercial PCB fabrication processes. Assay chemistry has been optimised for microfluidic diffusion kinetics to function under continual flow. We characterised the electrode integrity of the developed platforms with reference to biological sampling and buffer composition and subsequently we demonstrated concentration-dependent measurements of H2O2 depletion as resolved by existing FDA-validated ELISA kits. Finally, we validated the assay technology in both buffer and serum and demonstrate limits of detection comparable to high-end commercial systems with the addition of full microfluidic assay architecture capable of returning diagnostic analyses in approximately eight minutes

A Novel Microfluidic Point-of-Care Biosensor System on Printed Circuit Board for Cytokine Detection

Point of Care (PoC) diagnostics have been the subject of considerable research over the last few decades driven by the pressure to detect diseases quickly and effectively and reduce healthcare costs. Herein, we demonstrate a novel, fully integrated, microfluidic amperometric enzyme-linked immunosorbent assay (ELISA) prototype using a commercial interferon gamma release assay (IGRA) as a model antibody binding system. Microfluidic assay chemistry was engineered to take place on Au-plated electrodes within an assay cell on a printed circuit board (PCB)-based biosensor system. The assay cell is linked to an electrochemical reporter cell comprising microfluidic architecture, Au working and counter electrodes and a Ag/AgCl reference electrode, all manufactured exclusively via standard commercial PCB fabrication processes. Assay chemistry has been optimised for microfluidic diffusion kinetics to function under continual flow. We characterised the electrode integrity of the developed platforms with reference to biological sampling and buffer composition and subsequently we demonstrated concentration-dependent measurements of H₂O₂ depletion as resolved by existing FDA-validated ELISA kits. Finally, we validated the assay technology in both buffer and serum and demonstrate limits of detection comparable to high-end commercial systems with the addition of full microfluidic assay architecture capable of returning diagnostic analyses in approximately eight minutes

An Assay System for Point-of-Care Diagnosis of Tuberculosis using Commercially Manufactured PCB Technology

Rapid advances in clinical technologies, detection sensitivity and analytical throughput have delivered a significant expansion in our knowledge of prognostic and diagnostic biomarkers in many common infectious diseases, such as Tuberculosis (TB). During the last decade, a significant number of approaches to TB diagnosis have been attempted at Point-of-Care (PoC), exploiting a large variation of techniques and materials. In this work, we describe an electronics-based Enzyme-Linked ImmunoSorbent Assay (eELISA), using a Lab-on-a-Printed Circuit Board (LoPCB) approach, for TB diagnosis based on cytokine detection. The test relies upon an electrochemical (amperometric) assay, comprising a high-precision bioinstrumentation board and amperometric sensors, produced exclusively using standard PCB manufacturing processes. Electrochemical detection uses standard Au and Ag electrodes together with a bespoke, low-power, multichannel, portable data-acquisition system. We demonstrate high-performance assay chemistry performed at microfluidic volumes on Au pads directly at the PCB surface with improved limit of detection (~10 pg/mL) over standard colorimetric ELISA methods. The assay has also been implemented in plasma, showing the utility of the system for medical applications. This work is a significant step towards the development of a low-cost, portable, high-precision diagnostic and monitoring technology, which once combined with appropriate PCB-based microfluidic networks will provide complete LoPCB platforms

Disturbed Cyclical Stretch of Endothelial Cells Promotes Nuclear Expression of the Pro-Atherogenic Transcription Factor NF-kappa B

Exposure of endothelial cells to low and multidirectional blood flow is known to promote a pro-atherogenic phenotype. The mechanics of the vessel wall is another important mechano-stimulus within the endothelial cell environment, but no study has examined whether changes in the magnitude and direction of cell stretch can be pro-atherogenic. Herein, we developed a custom cell stretching device to replicate the in vivo stretch environment of the endothelial cell and examined whether low and multidirectional stretch promote nuclear translocation of NF-κB. A fluid–structure interaction model of the device demonstrated a nearly uniform strain within the region of cell attachment and a negligible magnitude of shear stress due to cyclical stretching of the cells in media. Compared to normal cyclical stretch, a low magnitude of cyclical stretch or no stretch caused increased expression of nuclear NF-κB (p = 0.09 and p < 0.001, respectively). Multidirectional stretch also promoted significant nuclear NF-κB expression, comparable to the no stretch condition, which was statistically higher than the low (p < 0.001) and normal (p < 0.001) stretch conditions. This is the first study to show that stretch conditions analogous to atherogenic blood flow profiles can similarly promote a pro-atherogenic endothelial cell phenotype, which supports a role for disturbed vessel wall mechanics as a pathological cell stimulus in the development of advanced atherosclerotic plaques