Cellular heterogeneity mediates inherent sensitivity–specificity tradeoff in cancer targeting by synthetic circuits

Synthetic gene circuits are emerging as a versatile means to target cancer with enhanced specificity by combinatorial integration of multiple expression markers. Such circuits must also be tuned to be highly sensitive because escape of even a few cells might be detrimental. However, the error rates of decision-making circuits in light of cellular variability in gene expression have so far remained unexplored. Here, we measure the single-cell response function of a tunable logic AND gate acting on two promoters in heterogeneous cell populations. Our analysis reveals an inherent tradeoff between specificity and sensitivity that is controlled by the AND gate amplification gain and activation threshold. We implement a tumor-mimicking cellculture model of cancer cells emerging in a background of normal ones, and show that molecular parameters of the synthetic circuits control specificity and sensitivity in a killing assay. This suggests that, beyond the inherent tradeoff, synthetic circuits operating in a heterogeneous environment could be optimized to efficiently target malignant state with minimal loss of specificity. Keywords: synthetic gene circuits; cellular heterogeneity; cancer gene therapy; cell-state targeting; mammalian synthetic biolog

Variable domain transformation for linear PAC analysis of mixed-signal systems

This paper describes a method to perform linear AC analysis on mixed-signal systems which appear strongly nonlinear in the voltage domain but are linear in other variable domains. Common circuits like phase/delay-locked loops and duty-cycle correctors fall into this category, since they are designed to be linear with respect to phases, delays, and duty-cycles of the input and output clocks, respectively. The method uses variable domain translators to change the variables to which the AC perturbation is applied and from which the AC response is measured. By utilizing the efficient periodic AC (PAC) analysis available in commercial RF simulators, the circuit’s linear transfer function in the desired variable domain can be characterized without relying on extensive transient simulations. Furthermore, the variable domain translators enable the circuits to be macromodeled as weakly-nonlinear systems in the chosen domain and then converted to voltage-domain models, instead of being modeled as strongly-nonlinear systems directly

An Offset Cancelation Technique for Latch Type Sense Amplifiers

An offset compensation technique for a latch type sense amplifier is proposed in this paper. The proposed scheme is based on the recalibration of the charging/discharging current of the critical nodes which are affected by the device mismatches. The circuit has been designed in a 65 nm CMOS technology with 1.2 V core transistors. The auto-calibration procedure is fully digital. Simulation results are given verifying the operation for sampling a 5 Gb/s signal dissipating only 360 uW

Fast, non-monte-carlo estimation of transient performance variation due to device mismatch

This paper describes an efficient way of simulating the effects of device random mismatch on circuit transient characteristics, such as variations in delay or in frequency. The proposed method models DC random offsets as equivalent AC pseudo-noises and leverages the fast, linear periodically time-varying (LPTV) noise analysis available from RF circuit simulators. Therefore, the method can be considered as an extension to DC match analysis and offers a large speed-up compared to the traditional Monte-Carlo analysis. Although the assumed linear perturbation model is valid only for small variations, it enables easy ways to estimate correlations among variations and identify the most sensitive design parameters to mismatch, all at no additional simulation cost. Three benchmarks measuring the variations in the input offset voltage of a clocked comparator, the delay of a logic path, and the frequency of an oscillator demonstrate the speed improvement of about 100-1000x compared to a 1000-point Monte-Carlo method

Three Puzzles on Mathematics, Computation, and Games

In this lecture I will talk about three mathematical puzzles involving mathematics and computation that have preoccupied me over the years. The first puzzle is to understand the amazing success of the simplex algorithm for linear programming. The second puzzle is about errors made when votes are counted during elections. The third puzzle is: are quantum computers possible?Comment: ICM 2018 plenary lecture, Rio de Janeiro, 36 pages, 7 Figure