Ultrasensitive Switch Research Articles

Positive Feedback Defines the Timing, Magnitude, and Robustness of Angiogenesis

SummaryAngiogenesis is driven by the coordinated collective branching of specialized leading “tip” and trailing “stalk” endothelial cells (ECs). While Notch-regulated negative feedback suppresses excessive tip selection, roles for positive feedback in EC identity decisions remain unexplored. Here, by integrating computational modeling with in vivo experimentation, we reveal that positive feedback critically modulates the magnitude, timing, and robustness of angiogenic responses. In silico modeling predicts that positive-feedback-mediated amplification of VEGF signaling generates an ultrasensitive bistable switch that underpins quick and robust tip-stalk decisions. In agreement, we define a positive-feedback loop exhibiting these properties in vivo, whereby Vegf-induced expression of the atypical tetraspanin, tm4sf18, amplifies Vegf signaling to dictate the speed and robustness of EC selection for angiogenesis. Consequently, tm4sf18 mutant zebrafish select fewer motile ECs and exhibit stunted hypocellular vessels with unstable tip identity that is severely perturbed by even subtle Vegfr attenuation. Hence, positive feedback spatiotemporally shapes the angiogenic switch to ultimately modulate vascular network topology.

Enhanced extraordinary optical transmission and refractive-index sensing sensitivity in tapered plasmonic nanohole arrays

The phenomenon of extraordinary optical transmission (EOT) caused by light through metallic nanohole arrays has attracted significant attention due to its potential applications for monolithic color filters and ultrasensitive label-free biosensing. However, the EOT spectra of these nanohole arrays have multiple resonance peaks that are spectrally close to each other due to the multiple resonance modes generated by different media on the upper and lower surfaces of metal. In addition, owing to the absorption loss of metal and the scattering of holes, the EOT resonance peaks have low transmission coefficient for practical applications. In this work, utilizing a tapered nanohole arrays structure which is stacked by multiple cylindrical holes with the same depth but different radii, we show that tapered nanohole arrays can effectively suppress the excitation of multiple resonance peaks, and a single EOT peak emerges in the transmission spectrum and simultaneously exhibits significantly enhanced transmission (∼7 times) and narrow linewidth (∼15 nm). The enhanced EOT of tapered nanohole arrays can be also found in other wavelength regions and plasmonic materials. Benefiting from isolated transmission peak, high transmission efficiency and extremely narrow linewidth, a highly sensitive plasmonic nanosensor with sensitivity of 1580 nm/RIU and figure of merit of 105 can be attained. We believe that the tapered nanohole structure would enable applications for ultrasensitive sensors, switches and efficient filters.

Optogenetic Downregulation of Protein Levels with an Ultrasensitive Switch.

Optogenetic control of protein activity is a versatile technique to gain control over cellular processes, for example, for biomedical and biotechnological applications. Among other techniques, the regulation of protein abundance by controlling either transcription or protein stability found common use as this controls the activity of any type of target protein. Here, we report modules of an improved variant of the photosensitive degron module and a light-sensitive transcription factor, which we compared to doxycycline-dependent transcriptional control. Given their modularity the combined control of synthesis and stability of a given target protein resulted in the synergistic down regulation of its abundance by light. This combined module exhibits very high switching ratios, profound downregulation of protein abundance at low light-fluxes, and fast protein depletion kinetics. Overall, this synergistic optogenetic multistep control (SOMCo) module is easy to implement and results in a regulation of protein abundance superior to each individual component.

The threshold of an excitable system serves as a control mechanism for noise filtering during chemotaxis.

Chemotaxis, the migration of cells in the direction of a chemical gradient, is of utmost importance in various biological processes. In recent years, research has demonstrated that the underlying mechanism that controls cell migration is an excitable network. One of the properties that characterizes excitability is the presence of a threshold for activation. Here, we show that excitable systems possess noise filtering capabilities that enable faster and more efficient directed migration compared to other systems that also include a threshold, such as ultrasensitive switches. We demonstrate that this filtering ability is a consequence of the varying responses of excitable systems to step and pulse stimuli. Whereas the response to step inputs is determined solely by the magnitude of the stimulus, for pulse stimuli, the response depends on both the magnitude and duration of the stimulus. We then show that these two forms of threshold behavior can be decoupled from one another, allowing finer control in chemotaxis. Finally, we use a simple model of chemotaxis to demonstrate that cells that rely on an excitable system display faster and more effective directed migration that a hypothetical cell guided by an ultra-sensitive switch.

A Superconducting Dual-Channel Photonic Switch.

The mechanism of Cooper pair formation and its underlying physics has long occupied the investigation into high temperature (high-Tc ) cuprate superconductors. One of the ways to unravel this is to observe the ultrafast response present in the charge carrier dynamics of a photoexcited specimen. This results in an interesting approach to exploit the dissipation-less dynamic features of superconductors to be utilized for designing high-performance active subwavelength photonic devices with extremely low-loss operation. Here, dual-channel, ultrafast, all-optical switching and modulation between the resistive and the superconducting quantum mechanical phase is experimentally demonstrated. The ultrafast phase switching is demonstrated via modulation of sharp Fano resonance of a high-Tc yttrium barium copper oxide (YBCO) superconducting metamaterial device. Upon photoexcitation by femtosecond light pulses, the ultrasensitive cuprate superconductor undergoes dual dissociation-relaxation dynamics, with restoration of superconductivity within a cycle, and thereby establishes the existence of dual switching windows within a timescale of 80 ps. Pathways are explored to engineer the secondary dissociation channel which provides unprecedented control over the switching speed. Most importantly, the results envision new ways to accomplish low-loss, ultrafast, and ultrasensitive dual-channel switching applications that are inaccessible through conventional metallic and dielectric based metamaterials.

Electrically Tunable Slow Light Using Graphene Metamaterials

Metamaterials with classical analogues of electromagnetically induced transparency open new avenues in photonics for realizing smaller, more efficient slow light devices without quantum approaches. However, most of the metamaterial-based slow light devices are passive, which limits their practical applications. Here, by combining diatomic metamaterials with a gated single-layer graphene, we demonstrate that the group delay of terahertz light can be dynamically controlled under a small gate voltage. Using a two coupled harmonic oscillators model, we show that this active control of group delay is made possible by an effective control of the dissipative loss of the radiative dark resonator by varying the graphene’s optical conductivity. Our work may provide opportunities in the design of various applications such as compact slow light devices and ultrasensitive sensors and switches.

Biphasic hCAR Inhibition-Activation by Two Aminoazo Liver Carcinogens

Detailed dose-response data recently archived by the National Center for Biotechnology Information (NCBI) identified 853 human CAR (hCAR) agonists by quantitative high-throughput screening (qHTS) assays applied to >9,000 chemicals tested at ≥14 concentrations using n = 3–48 replicates. By re-examining NCBI data on 746 agonists with replicate data sets each satisfying additional quality criteria, ∼95% had average values of agonist-specific Hill-model slopes estimated by NCBI that exceed 1 (i.e., exhibited an overall sublinear low-dose dose-response), and two unambiguously biphasic hCAR inhibitor-agonists were identified, 4-aminoazobenzene (n = 37) and ortho-aminoazotoluene (n = 3), both of which also cause rodent liver tumors. Although evidently rare among hCAR agonists, such biphasic responses add to evidence that nuclear receptors can exhibit complex patterns of low-dose response, consistent with previous observations and theoretical predictions for endpoints governed by ultrasensitive molecular switches. The pronounced biphasic hCAR response pattern observed for 4-aminoazobenzene is particularly noteworthy insofar as it was identified with statistical power that exceeds that of most if not all other receptor-mediated biphasic cellular responses to any single-chemical exposure reported to date.

Ultrastrong extraordinary transmission and reflection in PT-symmetric Thue-Morse optical waveguide networks.

In this paper, we construct a 1D PT-symmetric Thue-Morse aperiodic optical waveguide network (PTSTMAOWN) and mainly investigate the ultrastrong extraordinary transmission and reflection. We propose an approach to study the photonic modes and solve the problem of calculating photonic modes distributions in aperiodic networks due to the lack of dispersion functions and find that in a PTSTMAOWN there exist more photonic modes and more spontaneous PT-symmetric breaking points, which are quite different from other reported PT-symmetric optical systems. Additionally, we develop a method to sort spontaneous PT-symmetric breaking point zones to seek the strongest extraordinary point and obtain that at this point the strongest extraordinary transmission and reflection arrive at 2.96316 × 105 and 1.32761 × 105, respectively, due to the PT-symmetric coupling resonance and the special symmetry pattern of TM networks. These enormous gains are several orders of magnitude larger than the previous results. This optical system may possess potential in designing optical amplifier, optical logic elements in photon computers and ultrasensitive optical switches with ultrahigh monochromatity.

MoS2 for Ultrafast All‐Optical Switching and Modulation of THz Fano Metaphotonic Devices

AbstractIn recent years, the stunning performance of transition metal dichalcogenides (TMDCs) has been utilized in the area of field effect transistors, integrated circuits, photodetectors, light generation and harvesting, valleytronics, and van der Waals (vdW) heterostructures. However, the optoelectronic application of TMDCs in realizing efficient, ultrafast metaphotonic devices in the terahertz part of the electromagnetic spectrum has remained unexplored. The most studied member of the TMDC family, i.e., MoS2, shows an ultrafast carrier relaxation after photoexcitation with near‐infrared femtosecond pulse of energy above the bandgap. Here, this study investigates the photoactive properties of MoS2 to demonstrate an ultrasensitive active switching and modulation of the sharp Fano resonances in MoS2‐coated metamaterials consisting of asymmetric split ring resonator arrays. The results show that all‐optical switching and modulation of micrometer scale subwavelength Fano resonators can be achieved on a timescale of hundred picoseconds at moderate excitation pump fluences. The precise and active control of the MoS2‐based hybrid metaphotonic devices open up opportunities for the real‐world technologies and realization of ultrafast switchable sensors, modulators, filters, and nonlinear devices.

Low-Dose Dose-Response for In Vitro Nrf2-ARE Activation in Human HepG2 Cells.

Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-like factor 2-related factor 2 (Nrf2), and the antioxidant response element (ARE) are interacting components of a master regulatory signaling pathway that coordinates redox homeostasis, cytoprotective responses, and shifts in stem cell state. This study reexamined detailed dose–response (DR) data reported for in vitro Nrf2-ARE activation in human hepatoblastoma HepG2 cell lines containing either a ARE-bla or ARE-luc reporter at 12 different concentrations of each of 15 chemicals. The normalized study data were combined among chemicals exhibiting a positive response, yielding n = 531 (179) DR data for 9 (7) chemicals using the ARE-bla (ARE-luc) assay. Three-parameter linear/kth-power regression fits obtained to each combined set of ARE-bla- or ARE-luc-assay response data provided good fits (R 2 = .99 or .91, respectively, P fit > .99) that each incorporate a highly significant negative initial linear slope (P = 4 × 10−5 or .00025) and an overall J-shaped DR pattern. Results from this reanalysis of high-resolution ARE response data support the hypothesis that nonlinear ARE-mediated adaptive cellular responses to oxidative stress are governed by an ultrasensitive molecular switch.

Rational Design of an Ultrasensitive Quorum-Sensing Switch

One of the purposes of synthetic biology is to develop rational methods that accelerate the design of genetic circuits, saving time and effort spent on experiments and providing reliably predictable circuit performance. We applied a reverse engineering approach to design an ultrasensitive transcriptional quorum-sensing switch. We want to explore how systems biology can guide synthetic biology in the choice of specific DNA sequences and their regulatory relations to achieve a targeted function. The workflow comprises network enumeration that achieves the target function robustly, experimental restriction of the obtained candidate networks, global parameter optimization via mathematical analysis, selection and engineering of parts based on these calculations, and finally, circuit construction based on the principles of standardization and modularization. The performance of realized quorum-sensing switches was in good qualitative agreement with the computational predictions. This study provides practical principles for the rational design of genetic circuits with targeted functions.

Linear-No-Threshold Default Assumptions are Unwarranted for Cytotoxic Endpoints Independently Triggered by Ultrasensitive Molecular Switches.

Crump's response in this issue to my critique of linear-no-threshold (LNT) default assumptions for noncancer and nongenotoxic cancer risks (Risk Analysis 2016; 36(3):589-604) is rebutted herein. Crump maintains that distinguishing between a low-dose linear dose response and a threshold dose response on the basis of dose-response data is impossible even for endpoints involving increased cytotoxicity. My rebuttal relies on descriptions and specific illustrations of two well-characterized ultrasensitive molecular switches that govern two key cytoprotective responses to cellular stress-heat shock response and antioxidant response element activation, respectively-each of which serve to suppress stress-induced apoptotic cell death unless overwhelmed. Because detailed dose-response data for each endpoint is shown to be J- or inverted-J-shaped with high confidence, and because independent pathways can explain background rates of apoptosis, LNT assumptions for this cytotoxic endpoint are unwarranted, at least in some cases and perhaps generally.

Smart Superstructures with Ultrahigh pH-Sensitivity for Targeting Acidic Tumor Microenvironment: Instantaneous Size Switching and Improved Tumor Penetration.

The currently low delivery efficiency and limited tumor penetration of nanoparticles remain two major challenges of cancer nanomedicine. Here, we report a class of pH-responsive nanoparticle superstructures with ultrasensitive size switching in the acidic tumor microenvironment for improved tumor penetration and effective in vivo drug delivery. The superstructures were constructed from amphiphilic polymer directed assembly of platinum-prodrug conjugated polyamidoamine (PAMAM) dendrimers, in which the amphiphilic polymer contains ionizable tertiary amine groups for rapid pH-responsiveness. These superstructures had an initial size of ∼80 nm at neutral pH (e.g., in blood circulation), but once deposited in the slightly acidic tumor microenvironment (pH ∼6.5-7.0), they underwent a dramatic and sharp size transition within a very narrow range of acidity (less than 0.1-0.2 pH units) and dissociated instantaneously into the dendrimer building blocks (less than 10 nm in diameter). This rapid size-switching feature not only can facilitate nanoparticle extravasation and accumulation via the enhanced permeability and retention effect but also allows faster nanoparticle diffusion and more efficient tumor penetration. We have further carried out comparative studies of pH-sensitive and insensitive nanostructures with similar size, surface charge, and chemical composition in both multicellular spheroids and poorly permeable BxPC-3 pancreatic tumor models, whose results demonstrate that the pH-triggered size switching is a viable strategy for improving drug penetration and therapeutic efficacy.

Tunable high quality factor in two multimode plasmonic stubs waveguide.

We numerically investigate the optical characteristics of a metal-dielectric-metal (MDM) waveguide side-coupled with two identical multimode stub resonators. Double plasmon-induced transparency (PIT) peaks with narrow full width at half maximum (FWHM) and high quality factor (Q-factor) can be observed in this structure. The Q-factors of PIT peaks in two stub resonators system are larger than those in single stub resonator system. A multimode coupled-radiation oscillator theory (MC-ROT), which is derived from ROT, is proposed to analyze the spectral response in the multimode system for the first time. The analytical results are confirmed by the finite-difference time-domain (FDTD) simulation results. We can also find that the Q-factors of the two PIT peaks have an opposite evolution tendency with the change of the stubs parameters and the maximum can reach to 427. These results may provide some applications for ultrasensitive sensors, switches and efficient filters.

DYNAMICS OF GLI REGULATION AND A STRATEGY TO CONTROL CANCEROUS SITUATION: HEDGEHOG SIGNALING PATHWAY REVISITED

The hedgehog signaling cascade generates highly diverse, fine-tuned responses in response to the external stimulus by the sonic hedgehog (SHH) protein. This is required for the flawless functioning of the cell, its development, survival and proliferation; maintained through production of Glioma protein (GLI) and transcriptional activation of its target genes. Any change in the behavior of GLI response by ectopic expression of SHH or mutations in the core pathway components may cause serious consequences in the cell fate through rapid, uncontrolled and elevated production of GLI. Here, we present a simple but extensive computational model that considers the detailed reaction mechanisms involved in the hedgehog signal transduction and provides a detailed insight into regulation of GLI. For the first time, by explicit involvement of suppressor of fused (SUFU) and Hedgehog interacting protein (HHIP) reaction kinetics in the model, we try to demonstrate the vital importance of HHIP and SUFU in maintaining the graded response of GLI in response to SHH. By performing parameter variations, we capture the conversion of a graded response of GLI to an ultrasensitive switch under SUFU-deficient conditions that might predispose abnormal embryonic development and the irreversible switching response of GLI that corresponds to signal-independent pathway activation observed in cancers.

MAGNETIZED PLASMA AS A VERSATILE PLATFORM FOR SWITCHING

We study the magneto-permittivity effect in a magnetized plasma with appropriately designed parameters. We show that at frequencies near the plasma frequency, magneto-optical activity plays an important role to manipulate and control the wave propagations in the magnetized plasma. Such a unique feature can be utilized to establish sensitive magnetic field switching mechanism, which is confirmed by detailed numerical investigations. Switching by magnetic field based on magnetized plasma is flexible and compatible with other optical system; moreover it is applicable to any frequency by tuning the plasma density. For these reasons, our work shows the possibility for developing a new family of high frequency and ultrasensitive switching applications.

Three level signal transduction cascades lead to reliably timed switches

Signaling cascades proliferate signals received on the cell membrane to the nucleus. While noise filtering, ultra-sensitive switches, and signal amplification have all been shown to be features of such signaling cascades, it is not understood why cascades typically show three or four layers. Using singular perturbation theory, Michaelis–Menten type equations are derived for open enzymatic systems. Cascading these equations we demonstrate that the output signal as a function of time becomes sigmoidal with the addition of more layers. Furthermore, it is shown that the activation time will speed up to a point, after which more layers become superfluous. It is shown that three layers create a reliable sigmoidal response progress curve from a wide variety of time-dependent signaling inputs arriving at the cell membrane, suggesting the evolutionary benefit of the observed cascades.

Hiding objects and obtaining Fano resonances in index-near-zero and epsilon-near-zero metamaterials with Bragg-fiber-like defects

We achieve one-dimensional cloaking effects in index-near-zero and epsilon-near-zero metamaterials embedded with just dielectric Bragg-fiber-structured defects. The dielectric Bragg-fiber structure (BFS) within the bandgap region can act as a perfect electric or magnetic conductor which prevents electromagnetic waves from penetrating into the core. As a result, one can hide objects inside the dielectric core without leading large distortion to the transmission. Moreover, both narrow and broad Fano profiles with variations between the total reflections and total transmissions are obtained, corresponding to the core resonances and the BFS resonances, respectively. The conditions of the total reflections and total transmissions are derived. Our work may have potential applications including applications in ultrasensitive sensors and switches.

The Cdk1–APC/C cell cycle oscillator circuit functions as a time-delayed, ultrasensitive switch

Despite the complexity and variety of biological oscillators, their core design invariably includes an essential negative feedback loop. In the Xenopus laevis embryonic cell cycle oscillator, this loop consists of the kinase cyclin B-Cdk1 and the ubiquitin ligase APC/C(Cdc20); active Cdk1 activates APC/C(Cdc20), which then brings about cyclin B degradation and inactivates Cdk1. Here we ask how this negative feedback loop functions quantitatively, with the aim of understanding what mechanisms keep the Cdk1-APC/C(Cdc20) system from settling into a stable steady state with intermediate levels of Cdk1 and APC/C(Cdc20) activity. We found that the system operates as a time-delayed, digital switch, with a time lag of ∼ 15 min between Cdk1 and APC/C(Cdc20) activation and a tremendously high degree of ultrasensitivity (n(H)≈17). Computational modelling shows how these attributes contribute to the generation of robust, clock-like oscillations. Principles uncovered here may also apply to other activator-repressor oscillators and help in designing robust synthetic clocks.

The Delicate Bistability of CaMKII Activation

Calcium/calmodulin-dependent protein kinase II (CaMKII) is one of the most abundant proteins in the brain and is essential for learning and memory. The activity of CaMKII is regulated both by calmodulin binding and by phosphorylation on Thr286, which maintains the kinase in a partially active state even in the absence of a calcium/calmodulin signal, thus prolonging the effects of transient calcium signaling. CaMKII exists as a 12 subunit holoenzyme, and phosphorylation at Thr286 occurs by an intra-holoenzyme, inter-subunit reaction. An autophosphorylating kinase, in conjunction with a phosphatase, can potentially form a bistable switch, and it has been proposed that bistability in the CaMKII system may constitute the biochemical change underlying long-term memory. Previous modeling efforts have suggested that bistability is likely under physiological conditions, but experimental studies have proved inconclusive. Previous modeling efforts involved several significant approximations in order to overcome the combinatorial complexity inherent in a multi-subunit, multi-state system. Here we develop a stochastic, particle-based model of CaMKII dynamics and activation which naturally avoids the issues of combinatorial complexity, and thus allows us to study an exact model without resorting to severe approximations. We find that bistability is possible, but for any reasonable choice of parameters bistability only occurs at calcium concentrations much higher than basal calcium levels, and then only over a very narrow range of calcium concentration. We conclude that bistability is not a physiologically relevant feature of the CaMKII system, which should appear to behave as an ultra-sensitive switch. On the other hand, the system dynamics are generally very slow. Transiently activated kinase can maintain its activity over the time scales of many of the published experimental protocols, which may account for the conflicting reports of kinase bistability. This work was supported by NIH grants 1F32-NS077751-01 and P41GM103313.