Dichotomous Feedback: A Signal Sequestration-based Feedback Mechanism for Biocontroller Design

We introduce a new design framework for implementing negative feedback regulation in Synthetic Biology, which we term "dichotomous feedback". Our approach is different from current methods, in that it sequesters existing fluxes in the process to be controlled, and in this way takes advantage of the process's architecture to design the control law. This signal sequestration mechanism appears in many natural biological systems and can potentially be easier to realise than 'molecular sequestration' and other comparison motifs that are nowadays common in biomolecular feedback control design. The loop is closed by linking the strength of signal sequestration to the process output. Our feedback regulation mechanism is motivated by two-component signalling systems, where we introduce a second response regulator competing with the natural response regulator thus sequestering kinase activity. Here, dichotomous feedback is established by increasing the concentration of the second response regulator as the level of the output of the natural process increases. Extensive analysis demonstrates how this type of feedback shapes the signal response, attenuates intrinsic noise while increasing robustness and reducing crosstalk.

Network design principle for robust oscillatory behaviors with respect to biological noise

Oscillatory behaviors, which are ubiquitous in transcriptional regulatory networks, are often subject to inevitable biological noise. Thus a natural question is how transcriptional regulatory networks can robustly achieve accurate oscillation in the presence of biological noise. Here, we search all two- and three-node transcriptional regulatory network topologies for those robustly capable of accurate oscillation against the parameter variability (extrinsic noise) or stochasticity of chemical reactions (intrinsic noise). We find that, no matter what source of the noise is applied, the topologies containing the repressilator with positive auto-regulation show higher robustness of accurate oscillation than those containing the activator-inhibitor oscillator, and additional positive auto-regulation enhances the robustness against noise. Nevertheless, the attenuation of different sources of noise is governed by distinct mechanisms: the parameter variability is buffered by the long period, while the stochasticity of chemical reactions is filtered by the high amplitude. Furthermore, we analyze the noise of a synthetic human nuclear factor κB (NF-κB) signaling network by varying three different topologies, and verify that the addition of a repressilator to the activator-inhibitor oscillator, which leads to the emergence of high-robustness motif—the repressilator with positive auto-regulation, improves the oscillation accuracy in comparison to the topology with only an activator-inhibitor oscillator. These design principles may be applicable to other oscillatory circuits.

LPIN: A Lightweight Progressive Inpainting Network for Improving the Robustness of Remote Sensing Images Scene Classification

At present, the classification accuracy of high-resolution Remote Sensing Image Scene Classification (RSISC) has reached a quite high level on standard datasets. However, when coming to practical application, the intrinsic noise of satellite sensors and the disturbance of atmospheric environment often degrade real Remote Sensing (RS) images. It introduces defects to them, which affects the performance and reduces the robustness of RSISC methods. Moreover, due to the restriction of memory and power consumption, the methods also need a small number of parameters and fast computing speed to be implemented on small portable systems such as unmanned aerial vehicles. In this paper, a Lightweight Progressive Inpainting Network (LPIN) and a novel combined approach of LPIN and the existing RSISC methods are proposed to improve the robustness of RSISC tasks and satisfy the requirement of methods on portable systems. The defects in real RS images are inpainted by LPIN to provide a purified input for classification. With the combined approach, the classification accuracy on RS images with defects can be improved to the original level of those without defects. The LPIN is designed on the consideration of lightweight model. Measures are adopted to ensure a high gradient transmission efficiency while reducing the number of network parameters. Multiple loss functions are used to get reasonable and realistic inpainting results. Extensive tests of image inpainting of LPIN and classification tests with the combined approach on NWPU-RESISC45, UC Merced Land-Use and AID datasets are carried out which indicate that the LPIN achieves a state-of-the-art inpainting quality with less parameters and a faster inpainting speed. Furthermore, the combined approach keeps the comparable classification accuracy level on RS images with defects as that without defects, which will improve the robustness of high-resolution RSISC tasks.

The chemical Langevin equation for biochemical systems in dynamic environments

Modelling and simulation of complex biochemical reaction networks form cornerstones of modern biophysics. Many of the approaches developed so far capture temporal fluctuations due to the inherent stochasticity of the biophysical processes, referred to as intrinsic noise. Stochastic fluctuations, however, predominantly stem from the interplay of the network with many other - and mostly unknown - fluctuating processes, as well as with various random signals arising from the extracellular world; these sources contribute extrinsic noise. Here we provide a computational simulation method to probe the stochastic dynamics of biochemical systems subject to both intrinsic and extrinsic noise. We develop an extrinsic chemical Langevin equation - a physically motivated extension of the chemical Langevin equation - to model intrinsically noisy reaction networks embedded in a stochastically fluctuating environment. The extrinsic CLE is a continuous approximation to the Chemical Master Equation (CME) with time-varying propensities. In our approach, noise is incorporated at the level of the CME, and can account for the full dynamics of the exogenous noise process, irrespective of timescales and their mismatches. We show that our method accurately captures the first two moments of the stationary probability density when compared with exact stochastic simulation methods, while reducing the computational runtime by several orders of magnitude. Our approach provides a method that is practical, computationally efficient and physically accurate to study systems that are simultaneously subject to a variety of noise sources.

Fabrication of Superconducting Nb–AlN–NbN Tunnel Junctions Using Electron-Beam Lithography

Mixers based on superconductor–insulator–superconductor (SIS) tunnel junctions are the best input devices at frequencies from 0.1 to 1.2 THz. This is explained by both the extremely high nonlinearity of such elements and their extremely low intrinsic noise. Submicron tunnel junctions are necessary to realize the ultimate parameters of SIS receivers, which are used as standard devices on both ground and space radio telescopes around the world. The technology for manufacturing submicron Nb–AlN–NbN tunnel junctions using electron-beam lithography was developed and optimized. This article presents the results on the selection of the exposure dose, development time, and plasma chemical etching parameters to obtain high-quality junctions (the ratio of the resistances below and above the gap Rj/Rn). The use of a negative-resist ma-N 2400 with lower sensitivity and better contrast in comparison with a negative-resist UVN 2300-0.5 improved the reproducibility of the structure fabrication process. Submicron (area from 2.0 to 0.2 µm2) Nb–AlN–NbN tunnel junctions with high current densities and quality parameters Rj/Rn > 15 were fabricated. The spread of parameters of submicron tunnel structures across the substrate and the reproducibility of the cycle-to-cycle process of tunnel structure fabrication were measured.

Modeling and Parallel Operation of Exchange-Biased Delta-E Effect Magnetometers for Sensor Arrays

Recently, Delta-E effect magnetic field sensors based on exchange-biased magnetic multilayers have shown the potential of detecting low-frequency and small-amplitude magnetic fields. Their design is compatible with microelectromechanical system technology, potentially small, and therefore, suitable for arrays with a large number N of sensor elements. In this study, we explore the prospects and limitations for improving the detection limit by averaging the output of N sensor elements operated in parallel with a single oscillator and a single amplifier to avoid additional electronics and keep the setup compact. Measurements are performed on a two-element array of exchange-biased sensor elements to validate a signal and noise model. With the model, we estimate requirements and tolerances for sensor elements using larger N. It is found that the intrinsic noise of the sensor elements can be considered uncorrelated, and the signal amplitude is improved if the resonance frequencies differ by less than approximately half the bandwidth of the resonators. Under these conditions, the averaging results in a maximum improvement in the detection limit by a factor of N. A maximum N≈200 exists, which depends on the read-out electronics and the sensor intrinsic noise. Overall, the results indicate that significant improvement in the limit of detection is possible, and a model is presented for optimizing the design of delta-E effect sensor arrays in the future.

Pathway dynamics can delineate the sources of transcriptional noise in gene expression

Single-cell expression profiling opens up new vistas on cellular processes. Extensive cell-to-cell variability at the transcriptomic and proteomic level has been one of the stand-out observations. Because most experimental analyses are destructive we only have access to snapshot data of cellular states. This loss of temporal information presents significant challenges for inferring dynamics, as well as causes of cell-to-cell variability. In particular, we typically cannot separate dynamic variability from within cells ('intrinsic noise') from variability across the population ('extrinsic noise'). Here we make this non-identifiability mathematically precise, allowing us to identify new experimental set-ups that can assist in resolving this non-identifiability. We show that multiple generic reporters from the same biochemical pathways (e.g. mRNA and protein) can infer magnitudes of intrinsic and extrinsic transcriptional noise, identifying sources of heterogeneity. Stochastic simulations support our theory, and demonstrate that 'pathway-reporters' compare favourably to the well-known, but often difficult to implement, dual-reporter method.

Spatiotemporal development of coexisting wave domains of Rho activity in the cell cortex

The Rho family GTPases are molecular switches that regulate cytoskeletal dynamics and cell movement through a complex spatiotemporal organization of their activity. In Patiria miniata (starfish) oocytes under in vitro experimental conditions (with overexpressed Ect2, induced expression of Δ90 cyclin B, and roscovitine treatment), such activity generates multiple co-existing regions of coherent propagation of actin waves. Here we use computational modeling to investigate the development and properties of such wave domains. The model reveals that the formation of wave domains requires a balance between the activation and inhibition in the Rho signaling motif. Intriguingly, the development of the wave domains is preceded by a stage of low-activity quasi-static patterns, which may not be readily observed in experiments. Spatiotemporal patterns of this stage and the different paths of their destabilization define the behavior of the system in the later high-activity (observable) stage. Accounting for a strong intrinsic noise allowed us to achieve good quantitative agreement between simulated dynamics in different parameter regimes of the model and different wave dynamics in Patiria miniata and wild type Xenopus laevis (frog) data. For quantitative comparison of simulated and experimental results, we developed an automated method of wave domain detection, which revealed a sharp reversal in the process of pattern formation in starfish oocytes. Overall, our findings provide an insight into spatiotemporal regulation of complex and diverse but still computationally reproducible cell-level actin dynamics.

Image De-Speckling Based on the Coefficient of Variation, Improved Guided Filter, and Fast Bilateral Filter

Images are widely used in engineering. Unfortunately, medical ultrasound images and synthetic aperture radar (SAR) images are mainly degraded by an intrinsic noise called speckle. Therefore, de-speckling is a main pre-processing stage for degraded images. In this paper, first, an optimized adaptive Wiener filter (OAWF) is proposed. OAWF can be applied to the input image without the need for logarithmic transform. In addition its performance is improved. Next, the coefficient of variation (CV) is computed from the input image. With the help of CV, the guided filter converts to an improved guided filter (IGF). Next, the improved guided filter is applied on the image. Subsequently, the fast bilateral filter is applied on the image. The proposed filter has a better image detail preservation compared to some other standard methods. The experimental outcomes show that the proposed denoising algorithm is able to preserve image details and edges compared with other de-speckling methods.