Ultrasensitive Switch Research Articles

A robust ultrasensitive transcriptional switch in noisy cellular environments

Ultrasensitive transcriptional switches enable sharp transitions between transcriptional on and off states and are essential for cells to respond to environmental cues with high fidelity. However, conventional switches, which rely on direct repressor-DNA binding, are extremely noise-sensitive, leading to unintended changes in gene expression. Here, through model simulations and analysis, we discovered that an alternative design combining three indirect transcriptional repression mechanisms, sequestration, blocking, and displacement, can generate a noise-resilient ultrasensitive switch. Although sequestration alone can generate an ultrasensitive switch, it remains sensitive to noise because the unintended transcriptional state induced by noise persists for long periods. However, by jointly utilizing blocking and displacement, these noise-induced transitions can be rapidly restored to the original transcriptional state. Because this transcriptional switch is effective in noisy cellular contexts, it goes beyond previous synthetic transcriptional switches, making it particularly valuable for robust synthetic system design. Our findings also provide insights into the evolution of robust ultrasensitive switches in cells. Specifically, the concurrent use of seemingly redundant indirect repression mechanisms in diverse biological systems appears to be a strategy to achieve noise-resilience of ultrasensitive switches.

Singular optical propagation properties of two types of one-dimensional anti- PT -symmetric periodic ring optical waveguide networks

Two types of one-dimensional (1D) anti- PT -symmetric periodic ring optical waveguide networks, consisting of gain and loss materials, are constructed. The singular optical propagation properties of these networks are investigated. The results show that the system composed of gain materials exhibits characteristics of ultra-strong transmission and bidirectional reflection. Conversely, the system composed of loss materials demonstrates equal transmittance and reflectance at some frequencies. In both the systems, a new type of total reflection phenomenon is observed. When the imaginary part of the refractive indices of waveguide segments is smaller than 10−5, the system shows bidirectional transparency with the transmittance tending to be 1 and reflectivity to be smaller than 10−8 at some bands. When the refractive indices of the waveguide segments are real, the system will be bidirectional transparent at the full band. These findings may deepen the understanding of anti- PT -symmetric optical systems and optical waveguide networks, and possess potential applications in efficient optical energy storage, ultra-sensitive optical filters, ultra-sensitive all-optical switches, integrated optical chips, stealth physics, and so on.

Plasmon mediated coherent population oscillations in molecular aggregates

The strong coherent coupling of quantum emitters to vacuum fluctuations of the light field offers opportunities for manipulating the optical and transport properties of nanomaterials, with potential applications ranging from ultrasensitive all-optical switching to creating polariton condensates. Often, ubiquitous decoherence processes at ambient conditions limit these couplings to such short time scales that the quantum dynamics of the interacting system remains elusive. Prominent examples are strongly coupled exciton-plasmon systems, which, so far, have mostly been investigated by linear optical spectroscopy. Here, we use ultrafast two-dimensional electronic spectroscopy to probe the quantum dynamics of J-aggregate excitons collectively coupled to the spatially structured plasmonic fields of a gold nanoslit array. We observe rich coherent Rabi oscillation dynamics reflecting a plasmon-driven coherent exciton population transfer over mesoscopic distances at room temperature. This opens up new opportunities to manipulate the coherent transport of matter excitations by coupling to vacuum fields.

Ultrasensitive Photothermal Switching with Resonant Silicon Metasurfaces at Visible Bands.

Dynamic access to quasi-bound states in the continuum (q-BICs) offers a highly desired platform for silicon-based active nanophotonic applications, while the prevailing tuning approaches by free carrier injections via an all-optical stimulus are yet limited to THz and infrared ranges and are less effective in visible bands. In this work, we present the realization of active manipulations on q-BICs for nanoscale optical switching in the visible by introducing a local index perturbation through a photothermal mechanism. The sharp q-BIC resonance exhibits an ultrasensitive susceptibility to the complex index perturbation, which can be flexibly fulfilled by optical heating of silicon. Consequently, a mild pump intensity of 1 MW/cm2 can yield a modification of the imaginary part of the refractive index of less than 0.05, which effectively suppresses the sharp q-BIC resonances and renders an active modulation depth of reflectance exceeding 80%. Our research might open up an enabling platform for ultrasensitive dynamic nanophotonic devices.

The Influence of Dimensionality on the Charge‐Density‐Wave Transition and its Application on Mid‐Infrared Photodetection

Abstract2D charge density wave (CDW) materials receive much attention for high responsivity and broadband photodetection in recent years due to their collective electron transport and narrow bandgap. However, the high dark current density problem hinders their real application. Here, a sharp CDW transition in quasi‐1D (TaSe4)2I is reported and applied for broadband photodetection. Especially at mid‐infrared region, the device shows both high photo responsivity of 1.18 ×103 A W−1 and large light on/off ratio of 80, which is superior to 2D CDW TaS2 and most reported low‐dimensional materials. Such high performance relies on two aspects. One is the much lower dark current density resulting from the pseudo gap associated with 1D Luttinger liquid state, which is supported by finite size scaling of nonlinear I–V at variable temperatures and occurrence of 1D structural phase transition consolidated by in situ Raman spectroscopy. The other is the high photocurrent associated with the “Fröhlich superconductivity” state, manifested by an ultrasensitive switching, which can be only accessible in 1D CDW materials, in agreement with the authors’ density functional theory calculation. This work thus reveals the pivotal role of dimensionality in CDW phase transition and paves a way for implementing highly sensitive broadband photodetector.

Thermodynamic bounds on ultrasensitivity in covalent switching

Switch-like motifs are among the basic building blocks of biochemical networks. A common motif that can serve as an ultrasensitive switch consists of two enzymes acting antagonistically on a substrate, one making and the other removing a covalent modification. To work as a switch, such covalent modification cycles must be held out of thermodynamic equilibrium by continuous expenditure of energy. Here, we exploit the linear framework for timescale separation to establish tight bounds on the performance of any covalent-modification switch in terms of the chemical potential difference driving the cycle. The bounds apply to arbitrary enzyme mechanisms, not just Michaelis-Menten, with arbitrary rate constants and thereby reflect fundamental physical constraints on covalent switching.

Ultrasensitive dose-response for asbestos cancer risk implied by new inflammation-mutation model

Alterations in complex cellular phenotype each typically involve multistep activation of an ultrasensitive molecular switch (e.g., to adaptively initiate an apoptosis, inflammasome, Nrf2-ARE anti-oxidant, or heat-shock activation pathway) that triggers expression of a suite of target genes while efficiently limiting false-positive switching from a baseline state. Such switches exhibit nonlinear signal-activation relationships. In contrast, a linear no-threshold (LNT) dose-response relationship is expected for damage that accumulates in proportion to dose, as hypothesized for increased risk of cancer in relation to genotoxic dose according to the multistage somatic mutation/clonal-expansion theory of cancer, e.g., as represented in the Moolgavkar-Venzon-Knudsen (MVK) cancer model by a doubly stochastic nonhomogeneous Poisson process. Mesothelioma and lung cancer induced by exposure to carcinogenic (e.g., certain asbestos) fibers in humans and experimental animals are thought to involve modes of action driven by mutations, cytotoxicity-associated inflammation, or both, rendering ambiguous expectations concerning the nature of model-implied shape of the low-dose response for above-background increase in risk of incurring these endpoints. A recent Inflammation Somatic Mutation (ISM) theory of cancer posits instead that tissue-damage-associated inflammation that epigenetically recruits, activates and orchestrates stem cells to engage in tissue repair does not merely promote cancer, but rather is a requisite co-initiator (acting together with as few as two somatic mutations) of the most efficient pathway to any type of cancer in any reparable tissue (Dose-Response 2019; 17(2):1–12). This theory is reviewed, implications of this theory are discussed in relation to mesothelioma and lung cancer associated with chronic asbestos inhalation, one of the two types of ISM-required mutations is here hypothesized to block or impede inflammation resolution (e.g., by doing so for GPCR-mediated signal transduction by one or more endogenous autacoid specialized pro-resolving mediators or SPMs), and supporting evidence for this hypothesis is discussed.

Rate and oscillatory switching dynamics of a multilayer visual microcircuit model.

The neocortex is organized around layered microcircuits consisting of a variety of excitatory and inhibitory neuronal types which perform rate- and oscillation-based computations. Using modeling, we show that both superficial and deep layers of the primary mouse visual cortex implement two ultrasensitive and bistable switches built on mutual inhibitory connectivity motives between somatostatin, parvalbumin, and vasoactive intestinal polypeptide cells. The switches toggle pyramidal neurons between high and low firing rate states that are synchronized across layers through translaminar connectivity. Moreover, inhibited and disinhibited states are characterized by low- and high-frequency oscillations, respectively, with layer-specific differences in frequency and power which show asymmetric changes during state transitions. These findings are consistent with a number of experimental observations and embed firing rate together with oscillatory changes within a switch interpretation of the microcircuit.

Intercellular model predicts mechanisms of inflammation-fibrosis coupling after myocardial infarction.

After myocardial infarction (MI), cardiac cells work together to regulate wound healing of the infarct. The pathological response to MI yields cardiac remodelling comprising inflammatory and fibrosis phases, and the interplay of cellular dynamics that underlies these phases has not been elucidated. This study developed a computational model to identify cytokine and cellular dynamics post-MI to predict mechanisms driving post-MI inflammation, resolution of inflammation, andscar formation. Additionally, this study evaluated the interdependence between inflammation and fibrosis. Our model bypassed limitations of in vivo approaches in achieving cellular specificity and performing specific perturbations such as global knockouts of chemical factors. The model predicted that inflammation is a graded response to initial infarct size that is amplified by a positive feedback loop between neutrophils and interleukin 1β (IL-1β). Resolution of inflammation was driven by degradation of IL-1β, matrix metalloproteinase 9, and transforming growth factor β (TGF-β), as well as apoptosis of neutrophils. Inflammation regulated TGFβ secretion directly through immune cell recruitment and indirectly through upregulation of macrophage phagocytosis. Lastly, we found that mature collagen deposition was an ultrasensitive switch in response to inflammation, which was amplified primarily by cardiac fibroblast proliferation. These findings describe the relationship between inflammation and fibrosis and highlight how the two responses work together post-MI. This model revealed that post-MI inflammation and fibrosis are dynamically coupled, which provides rationale for designing novel anti-inflammatory, pro-resolving or anti-fibrotic therapies that may improve the response to MI. KEY POINTS: Inflammation and matrix remodelling are two processes involved in wound healing after a heart attack. Cardiac cells work together to facilitate these processes; this is done by secreting cytokines that then regulate the cells themselves or other cells surrounding them. This study developed a computational model of the dynamics of cardiac cells and cytokines to predict mechanisms through which inflammation and matrix remodelling is regulated. We show the roles of various cytokines and signalling motifs in driving inflammation, resolution of inflammation and fibrosis. The novel concept of inflammation-fibrosis coupling, based on the model prediction that inflammation and fibrosis are dynamically coupled, provides rationale for future studies and for designing therapeutics to improve the response after a heart attack.

Ultrasensitive Sub-monolayer Palladium Induced Chirality Switching and Topological Evolution of Skyrmions.

Chiral spin textures are fundamentally interesting, with promise for device applications. Stabilizing chirality is conventionally achieved by introducing Dzyaloshinskii-Moriya interaction (DMI) in asymmetric multilayers, where the thickness of each layer is at least a few monolayers. Here we report an ultrasensitive chirality switching in (Ni/Co)n multilayer induced by capping with only 0.22 monolayer of Pd. Using spin-polarized low-energy electron microscopy, we monitor the gradual evolution of domain walls from left-handed to right-handed Néel walls and quantify the DMI induced by the Pd capping layer. We also observe the chiral evolution of a skyrmion during the DMI switching, where no significant topological protection is found as the skyrmion winding number varies. This corresponds to a minimum energy cost of <1 attojoule during the skyrmion chirality switching. Our results demonstrate the detailed chirality evolution within skyrmions during the DMI sign switching, which is relevant to practical applications of skyrmionic devices.

An engineered protein-phosphorylation toggle network with implications for endogenous network discovery.

Synthetic biological networks comprising fast, reversible reactions could enable engineering of new cellular behaviors that are not possible with slower regulation. Here, we created a bistable toggle switch in Saccharomyces cerevisiae using a cross-repression topology comprising 11 protein-protein phosphorylation elements. The toggle is ultrasensitive, can be induced to switch states in seconds, and exhibits long-term bistability. Motivated by our toggle's architecture and size, we developed a computational framework to search endogenous protein pathways for other large and similar bistable networks. Our framework helped us to identify and experimentally verify five formerly unreported endogenous networks that exhibit bistability. Building synthetic protein-protein networks will enable bioengineers to design fast sensing and processing systems, allow sophisticated regulation of cellular processes, and aid discovery of endogenous networks with particular functions.

Building synthetic protein–based switches

Synthetic Biology Synthetic circuits can potentially help to control complex biological processes, but systems based on regulating gene expression respond to stimuli at the minute to the hour time scale. Working in yeast cells, Mishra et al. report synthetic regulatory circuits based on protein phosphorylation reactions that respond to inputs within seconds (see the Perspective by Kholodenko and Okada). Multicomponent logic gates allowed ultrasensitive and stable switching between states. After validating their effective synthetic circuit, the authors searched known yeast protein interaction networks for similar regulatory motifs and found previously unrecognized circuits that function as native toggle switches in yeast. Science , aav0780, this issue p. [eaav0780][1]; see also abj5028, p. [25][2] [1]: /lookup/doi/10.1126/science.aav0780 [2]: /lookup/doi/10.1126/science.abj5028

Ultra-sensitive charge detection and latch memory using MoS2-nanoresonator-based bifurcation amplifiers

Bifurcation amplifiers are known for their extremely high sensitivity to weak input signals. We implement a bifurcation amplifier by harnessing the Duffing nonlinearity in a parametrically excited MoS2 nano-electromechanical system. We utilize the ultra-sensitive switching response between the two states of the bifurcation amplifier to detect as well as register charge-fluctuation events. We demonstrate open-loop real-time detection of ultra-low electrical charge perturbations of magnitude &amp;lt;10 e at room temperature. Furthermore, we show latching of the resonator onto one of the two states in response to short-lived charge fluctuations. These charge detectors offer advantages of room-temperature operation and tunable operation in the radio frequency regime, which could open several possibilities in quantum sensing.

Filtering input fluctuations in intensity and in time underlies stochastic transcriptional pulses without feedback

Stochastic pulsatile dynamics have been observed in an increasing number of biological circuits with known mechanism involving feedback control and bistability. Surprisingly, recent single-cell experiments in Escherichia coli flagellar synthesis showed that flagellar genes are activated in stochastic pulses without the means of feedback. However, the mechanism for pulse generation in these feedbackless circuits has remained unclear. Here, by developing a system-level stochastic model constrained by a large set of single-cell E. coli flagellar synthesis data from different strains and mutants, we identify the general underlying design principles for generating stochastic transcriptional pulses without feedback. Our study shows that an inhibitor (YdiV) of the transcription factor (FlhDC) creates a monotonic ultrasensitive switch that serves as a digital filter to eliminate small-amplitude FlhDC fluctuations. Furthermore, we find that the high-frequency (fast) fluctuations of FlhDC are filtered out by integration over a timescale longer than the timescale of the input fluctuations. Together, our results reveal a filter-and-integrate design for generating stochastic pulses without feedback. This filter-and-integrate mechanism enables a general strategy for cells to avoid premature activation of the expensive downstream gene expression by filtering input fluctuations in both intensity and time so that the system only responds to input signals that are both strong and persistent.

Extraordinary characteristics of one-dimensional PT-symmetric ring optical waveguide networks with near-isometric and isometric arms

We construct one-dimensional -symmetric ring optical waveguide networks with near-isometric and isometric arms and investigate their extraordinary optical properties. It is found that the features for the former and the latter are quite different, although extraordinary ultrastrong transmission and reflection exist in both of them. When the former changes to be the latter, the extraordinary optical properties will all change remarkably, and the fitting formulae are obtained. The bidirectional invisibility only exists in the former and the principle is analyzed. This work may be helpful for designing ultra-narrow optical filters, ultra-sensitive optical switches, and resonant component for high-monochromatic lasing.

Implications of nonlinearity, confounding, and interactions for estimating exposure concentration-response functions in quantitative risk analysis

Recent advances in understanding of biological mechanisms and adverse outcome pathways for many exposure-related diseases show that certain common mechanisms involve thresholds and nonlinearities in biological exposure concentration-response (C-R) functions. These range from ultrasensitive molecular switches in signaling pathways, to assembly and activation of inflammasomes, to rupture of lysosomes and pyroptosis of cells. Realistic dose-response modeling and risk analysis must confront the reality of nonlinear C-R functions. This paper reviews several challenges for traditional statistical regression modeling of C-R functions with thresholds and nonlinearities, together with methods for overcoming them. Statistically significantly positive exposure-response regression coefficients can arise from many non-causal sources such as model specification errors, incompletely controlled confounding, exposure estimation errors, attribution of interactions to factors, associations among explanatory variables, or coincident historical trends. If so, the unadjusted regression coefficients do not necessarily predict how or whether reducing exposure would reduce risk. We discuss statistical options for controlling for such threats, and advocate causal Bayesian networks and dynamic simulation models as potentially valuable complements to nonparametric regression modeling for assessing causally interpretable nonlinear C-R functions and understanding how time patterns of exposures affect risk. We conclude that these approaches are promising for extending the great advances made in statistical C-R modeling methods in recent decades to clarify how to design regulations that are more causally effective in protecting human health.

Qualitative and quantitative nature of mutual interactions dictate chemical noise in a democratic reaction network.

The functions of a living cell rely on a complex network of biochemical reactions that allow it to respond against various internal and external cues. The outcomes of these chemical reactions are often stochastic due to intrinsic and extrinsic noise leading to population heterogeneity. The majority of calculations of stochasticity in reaction networks have focused on small regulatory networks addressing the role of timescales, feedback regulations, and network topology in propagation of noise. Here we computationally investigated chemical noise in a network with democratic architecture where each node is regulated by all other nodes in the network. We studied the effects of the qualitative and quantitative nature of mutual interactions on the propagation of both intrinsic and extrinsic noise in the network. We show that an increased number of inhibitory signals lead to ultrasensitive switching of average and that leads to sharp transition of intrinsic noise. The intrinsic noise exhibits a biphasic power-law scaling with the average, and the scaling coefficients strongly correlate with the strength of inhibitory signal. The noise strength critically depends on the strength of the interactions, where negative interactions attenuate both intrinsic and extrinsic noise.

Synthesizing multi-dimensional excitation dynamics and localization transition in one-dimensional lattices

The geometric dimensionality of a physical system significantly impacts its fundamental characteristics. While experiments are fundamentally limited to the maximum of three spatial dimensions, there is a growing interest in harnessing additional synthetic dimensions. In our work, we introduce a new paradigm for the experimental realization of excitation dynamics associated with many-dimensional systems. Crucially, it relies solely on static one-dimensional equivalent structures with judiciously tailored parameters to faithfully reproduce the same optical spectrum and density of states of the high-dimensional system to be represented. In order to showcase the capabilities of our approach, we fabricate 1D photonic lattices that exhibit the characteristic non-monotonic excitation decays associated with quantum walks in up to 7D square lattices. Furthermore, we find that a new type of bound state at the edge of the continuum emerges in higher-than-three dimensions and gives rise to a sharp localisation transition at defect sites. In a series of experiments, we implement the mapped equivalent lattices of up to 5D systems and observe an extreme increase of sensitivity with respect to the detuning of the respective anchor sites. Our findings demonstrate the feasibility and applicative potential of harnessing high-dimensional effects in planar photonics for ultra-sensitive switching or sensing. Notably, our general approach is by no means limited to optics, and can readily be adapted to a variety of other physical contexts, including cold atoms and superconducting qubits with exclusively nearest-neighbour interactions, promising to drive significant advances in different fields including quantum simulations and information processing.

Application-Specific Oxide-Based and Metal-Dielectric Thin-Film Materials Prepared by Radio Frequency Magnetron Sputtering.

We report on the development of several different thin-film functional material systems prepared by radio frequency (RF) magnetron sputtering at Edith Cowan University nanofabrication labs. While focusing on the RF sputtering process optimizations for new or the previously underexplored material compositions and multilayer structures, we disclose several unforeseen material properties and behaviours. Among these are an unconventional magnetic hysteresis loop with an intermediate saturation state observed in garnet trilayers, and an ultrasensitive magnetic switching behaviour in garnet-oxide composites (GOC). We also report on the unusually high thermal exposure stability observed in some nanoengineered metal–dielectric multilayers. We communicate research results related to the design, prototyping, and practical fabrication of high-performance magneto-optic (MO) materials, oxide-based sensor components, and heat regulation coatings for advanced construction and solar windows.

Nonlinear Regulation of Enzyme-Free DNA Circuitry with Ultrasensitive Switches.

DNA is used to construct synthetic chemical reaction networks (CRNs), such as inorganic oscillators and gene regulatory networks. Nonlinear regulation with a simpler molecular mechanism is particularly important in large-scale CRNs with complex dynamics, such as bistability, adaptation, and oscillation of cellular functions. Here we introduce a new approach based on ultrasensitive switches as modular regulatory elements to nonlinearly regulate DNA-based CRNs. The nonlinear behavior of the systems can be finely tuned by programmable regulation of the linker length and the ligand binding sites, of which the Hill coefficients (nH) are in the range of 1.00-2.32. By integrating two different strand displacement reactions with low-order nonlinearities (nH ≈ 1.44 and 1.54), we could construct CRNs exhibiting high-order nonlinearities with Hill coefficients of up to ∼2.70. In addition, this could provide an efficient approach for designing CRNs at will with complex chemical dynamics by incorporating our design with previously developed enzyme-free DNA circuits.