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The burgeoning advancement of information technology has engendered a discernible surge in the examination of neuromorphic devices, notably drawing broader attention to artificial vision systems endowed with sensory recognition capabilities. Current photoelectric synapse devices employed in artificial vision systems are generally well‐suited for well‐illuminated conditions, yet exhibit diminished sensitivity in weak‐light scenarios, resulting in a pronounced deterioration of recognition accuracy. Here, an ultrasensitive photoelectric synaptic transistor based on negative quantum capacitance effect resulted from the 2D semi‐metallic graphene layer that partially enclosed within the gate dielectric layer, which manifests a noteworthy reduction in device control voltage and exhibits perception and storage capabilities for weak light of 39.4 nW cm−2 with detectivity above 1016 cm Hz1/2 W−1 is demonstrated. The voltage amplification effect and the concomitant formation of an equivalent local electrostatic field induced by the negative quantum capacitance effect engenders a robust programmable synaptic plasticity for extremely weak light by modifying the control gate. These results represent the inaugural integration of the negative quantum capacitance effect into optoelectronic devices and furnish a robust hardware foundation for developing vision systems in weak‐light environments. [ABSTRACT FROM AUTHOR]

The ultrasensitivity of a dose response function can be quantifiably defined using the generalized Hill coefficient of the function. We examined an upper bound for the Hill coefficient of the composition of two functions, namely the product of their individual Hill coefficients. We proved that this upper bound holds for compositions of Hill functions, and that there are instances of counterexamples that exist for more general sigmoidal functions. Additionally, we tested computationally other types of sigmoidal functions, such as the logistic and inverse trigonometric functions, and we provided computational evidence that in these cases the inequality also holds. We show that in large generality there is a limit to how ultrasensitive the composition of two functions can be, which has applications to understanding signaling cascades in biochemical reactions. [ABSTRACT FROM AUTHOR]

Living systems have developed control mechanisms for achieving homeostasis. Here, we propose a plausible biological feedback architecture that exploits ultrasensitivity and shows adaptive responses without requiring error detection mechanism (i.e., by measuring an external reference signal and deviation from this). While standard engineering control systems are usually based on error measurements, this is not the case for biological systems. We find that a two-state negative feedback control system, without explicit error measurements, is able to track a reference signal that is implicitly determined by the tunable threshold and slope characterizing the sigmoidal ultrasensitive relationship implemented by the control system. We design different ultrasensitive control functions (ultrasensitive up- or down-regulation, or both) and, by performing sensitivity analysis, show that increasing the sensitivity level of the control allows achieving robust adaptive responses to the effects of parameter variations and step disturbances. Finally, we show that the devised control system architecture without error detection is implemented within the yeast osmoregulatory response network and allows achieving adaptive responses to osmotic stress, by exploiting the ubiquitous ultrasensitive features of the involved biomolecular circuitry. [ABSTRACT FROM AUTHOR]

IR spectroelectrochemistry (EC‐IR) is a cutting‐edge operando method for exploring electrochemical reaction mechanisms. However, detection of interfacial molecules is challenged by the limited sensitivity of existing EC‐IR platforms due to the lack of high‐enhancement substrates. Here, we propose an innovative plasmon‐enhanced infrared spectroelectrochemistry (EC‐PEIRS) platform to overcome this sensitivity limitation. Plasmonic antennae with ultrahigh IR signal enhancement are electrically connected via monolayer graphene while preserving optical path integrity, serving as both the electrode and IR substrate. The [Fe(CN)6]3−/[Fe(CN)6]4− redox reaction and electrochemical CO2 reduction reaction (CO2RR) are investigated on the EC‐PEIRS platform with a remarkable signal enhancement. Notably, the enhanced IR signals enable a reconstruction of the electrochemical curve of the redox reactions and unveil the CO2RR mechanism. This study presents a promising technique for boosting the in‐depth understanding of interfacial events across diverse applications. [ABSTRACT FROM AUTHOR]

Nanomechanical resonators are expected to be exceptional sensors for high‐performance mass detection, mechanical sensing, and signal processing. In this paper, zinc oxide nanobeam resonators are produced based on single‐crystal ZnO nanowire, which has a typical diameter down to a few nanometers and the length of hundreds of micrometers. This resonator has the characteristics of high aspect ratio nanobeam structure and reliable material. It is observed that the resonance frequency of ZnO nanobeam resonator is up to 1.47 MHz with a high quality factor of 2300 at room temperature, which will play a key role in high‐sensitivity mass detection. The mass detection of ZnO nanobeam resonator is demonstrated by depositing platinum atoms on the middle of the beam, which shows a sensitivity of 11.13 Hz fg−1 indicating its ultrasensitive mass detection capability. In addition, according to the experiment, the molecular dynamics simulations for the resonator is established, which shows that the detection resolution down to 0.2 yg at room temperature can be realized based on this resonator. The results show that the ZnO nanobeam resonator has enormous potential in ultrasensitive detection for biosensing and gas sensing. [ABSTRACT FROM AUTHOR]

The transformation of molecular binding events into cellular decisions is the basis of most biological signal transduction. A fundamental challenge faced by these systems is that reliance on protein-ligand chemical affinities alone generally results in poor sensitivity to ligand concentration, endangering the system to error. Here, we examine the lipid-binding pleckstrin homology and Tec homology (PH-TH) module of Bruton's tyrosine kinase (Btk). Using fluorescence correlation spectroscopy (FCS) and membrane-binding kinetic measurements, we identify a phosphatidylinositol (3-5)-trisphosphate (PIP3) sensing mechanism that achieves switch-like sensitivity to PIP3 levels, surpassing the intrinsic affinity discrimination of PIP3:PH binding. This mechanism employs multiple PIP3 binding as well as dimerization of Btk on the membrane surface. Studies in live cells confirm that mutations at the dimer interface and peripheral site produce effects comparable to that of the kinase-dead Btk in vivo. These results demonstrate how a single protein module can institute an allosteric counting mechanism to achieve high-precision discrimination of ligand concentration. Furthermore, this activation mechanism distinguishes Btk from other Tec family member kinases, Tec and Itk, which we show are not capable of dimerization through their PH-TH modules. This suggests that Btk plays a critical role in the stringency of the B cell response, whereas T cells rely on other mechanisms to achieve stringency.

Abstract Nanomechanical resonators are expected to be exceptional sensors for high‐performance mass detection, mechanical sensing, and signal processing. In this paper, zinc oxide nanobeam resonators are produced based on single‐crystal ZnO nanowire, which has a typical diameter down to a few nanometers and the length of hundreds of micrometers. This resonator has the characteristics of high aspect ratio nanobeam structure and reliable material. It is observed that the resonance frequency of ZnO nanobeam resonator is up to 1.47 MHz with a high quality factor of 2300 at room temperature, which will play a key role in high‐sensitivity mass detection. The mass detection of ZnO nanobeam resonator is demonstrated by depositing platinum atoms on the middle of the beam, which shows a sensitivity of 11.13 Hz fg−1 indicating its ultrasensitive mass detection capability. In addition, according to the experiment, the molecular dynamics simulations for the resonator is established, which shows that the detection resolution down to 0.2 yg at room temperature can be realized based on this resonator. The results show that the ZnO nanobeam resonator has enormous potential in ultrasensitive detection for biosensing and gas sensing.

Ultrasensitive molecular detection and quantization are crucial for many applications including clinical diagnostics, functional proteomics, and drug discovery; however, conventional biochemical sensors cannot satisfy the stringent requirements, and this has resulted in a long-standing dilemma regarding sensitivity improvement. To this end, we have developed an ultrasensitive relay-type nanomechanical sensor based on a magneto lever. By establishing the link between very weak molecular interaction and five orders of magnitude larger magnetic force, analytes at ultratrace level can produce a clearly observable mechanical response. Initially, proof-of-concept studies showed an improved detection limit up to five orders of magnitude when employing the magneto lever, as compared with direct detection using probe alone. In this study, we subsequently demonstrated that the relay-type sensing mode was universal in application ranging from micromolecule to macromolecule detection, which can be easily extended to detect enzymes, DNA, proteins, cells, viruses, bacteria, chemicals, etc. Importantly, we found that, sensitivity was no longer subject to probe affinity when the magneto lever was sufficiently high, theoretically, even reaching single-molecule resolution. [ABSTRACT FROM AUTHOR]

Noncoding RNAs (ncRNAs) play critical roles in essential cell fate decisions. However, the exact molecular mechanisms underlying ncRNA-mediated bistable switches remain elusive and controversial. In recent years, systematic mathematical and quantitative experimental analyses have made significant contributions to elucidating the molecular mechanisms of controlling ncRNA-mediated cell fate decision processes. In this chapter, we review and summarize the general framework of mathematical modeling of ncRNA in a pedagogical way and the application of this general framework to real biological processes. We discuss the emerging properties resulting from the reciprocal regulation between mRNA, miRNA, and competing endogenous mRNA (ceRNA). We also explore the efforts within the synthetic biology approach to understand the fundamental design principles underlying cell fate decisions. Both the positive feedback loops between ncRNAs and transcription factors and the emerging properties from the miRNA-mRNA reciprocal regulation enable bistable switches to direct cell fate decisions., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Abstract Background RhoA is a master regulator of cytoskeletal contractility, while nitric oxide (NO) is a master regulator of relaxation, e.g., vasodilation. There are multiple forms of cross-talk between the RhoA/ROCK pathway and the eNOS/NO/cGMP pathway, but previous work has not studied their interplay at a systems level. Literature review suggests that the majority of their cross-talk interactions are antagonistic, which motivates us to ask whether the RhoA and NO pathways exhibit mutual antagonism in vitro, and if so, to seek the theoretical implications of their mutual antagonism. Results Experiments found mutual antagonism between RhoA and NO in epithelial cells. Since mutual antagonism is a common motif for bistability, we sought to explore through theoretical simulations whether the RhoA-NO network is capable of bistability. Qualitative modeling showed that there are parameters that can cause bistable switching in the RhoA-NO network, and that the robustness of the bistability would be increased by positive feedback between RhoA and mechanical tension. Conclusions We conclude that the RhoA-NO bistability is robust enough in silico to warrant the investment of further experimental testing. Tension-dependent bistability has the potential to create sharp concentration gradients, which could contribute to the localization and self-organization of signaling domains during cytoskeletal remodeling and cell migration.

The KEAP1-NRF2-ARE signaling pathway plays a central role in mediating the adaptive cellular stress response to oxidative and electrophilic chemicals. This canonical pathway has been extensively studied and reviewed in the past two decades, but rarely was it looked at from a quantitative signaling perspective. Signal amplification, i.e., ultrasensitivity, is crucially important for robust induction of antioxidant genes to appropriate levels that can adequately counteract the stresses. In this review article, we examined a number of well-known molecular events in the KEAP1-NRF2-ARE pathway from a quantitative perspective with a focus on how signal amplification can be achieved. We illustrated, by using a series of mathematical models, that redox-regulated protein sequestration, stabilization, translation, nuclear trafficking, DNA promoter binding, and transcriptional induction – which are embedded in the molecular network comprising KEAP1, NRF2, sMaf, p62, and BACH1 – may generate highly ultrasensitive NRF2 activation and antioxidant gene induction. The emergence and degree of ultrasensitivity depend on the strengths of protein-protein and protein-DNA interaction and protein abundances. A unique, quantitative understanding of signal amplification in the KEAP1-NRF2-ARE pathway will help to identify sensitive targets for the prevention and therapeutics of oxidative stress-related diseases and develop quantitative adverse outcome pathway models to facilitate the health risk assessment of oxidative chemicals.

Microorganisms are shown to actively partition their intracellular resources, such as proteins, for growth optimization. Recent experiments have begun to reveal molecular components unpinning the partition; however, quantitatively, it remains unclear how individual parts orchestrate to yield precise resource allocation that is both robust and dynamic. Here, we developed a coarse-grained mathematical framework that centers on guanosine pentaphosphate (ppGpp)-mediated regulation and used it to systematically uncover the design principles of proteome allocation in Escherichia coli . Our results showed that the cellular ability of resource partition lies in an ultrasensitive, negative feedback-controlling topology with the ultrasensitivity arising from zero-order amino acid kinetics and the negative feedback from ppGpp-controlled ribosome synthesis. In addition, together with the time-scale separation between slow ribosome kinetics and fast turnovers of ppGpp and amino acids, the network topology confers the organism an optimization mechanism that mimics sliding mode control, a nonlinear optimization strategy that is widely used in man-made systems. We further showed that such a controlling mechanism is robust against parameter variations and molecular fluctuations and is also efficient for biomass production over time. This work elucidates the fundamental controlling mechanism of E. coli proteome allocation, thereby providing insights into quantitative microbial physiology as well as the design of synthetic gene networks.

This paper reports the synthesis of a S, N co-doped carbon dot (C-dot)-functionalized WO3 (C-(S, N)-WO3) nanostructure via a hydrothermal method, which exhibits ultrasensitivity for NO2 at the ppb level and H2S at the ppm level along with remarkable selectivity. The WO3 morphology is optimized by varying the pH (1.5–3.5) of the solution. Characterization results reveal that the surface morphology at pH 3 is superior for producing uniform nanoneedle nanostructures with high sensitivity toward NO2 and H2S. To further enhance the sensitivity and selectivity of WO3 nanoneedles, the effect of mixing of C-dots into WO3 is investigated systematically. The optimized weight of C-dots in the C-(S, N)-WO3 composite is 10 mg, which exhibits sensitivity values of 2.2 to 250 ppb for NO2 and 29.5 to 100 ppm for H2S. The C-(S, N)-WO3 composite material shows the highest sensitivity at an optimum substrate temperature of 150 °C, without an obvious influence of humidity up to 50% relative humidity. The limit of detection of the composite sensor is 250 ppb NO2 along with excellent repeatability and good long-term stability. [ABSTRACT FROM AUTHOR]

Under oxidative and electrophilic stresses, cells launch an NRF2-mediated transcriptional antioxidant program. The activation of NRF2 depends on a redox sensor, KEAP1, which promotes the ubiquitination and degradation of NRF2. While a great deal has been learned about this duo, its quantitative signaling properties are largely unexplored. Here we examined these properties, including half-life, maximal activation, and response steepness (ultrasensitivity) of NRF2, through mathematical modeling. The models describe the binding of KEAP1 and NRF2 via ETGE and DLG motifs, NRF2 production, KEAP1-dependent and independent NRF2 degradation, and perturbations by different classes of NRF2 activators. Simulations revealed at the basal condition, NRF2 is sequestered by KEAP1 and the KEAP1-NRF2 complex is distributed comparably in an ETGE-bound (open) state and an ETGE and DLG dual-bound (closed) state. When two-step ETGE binding is considered, class I–V, electrophilic NRF2 activators shift the balance to a closed state incompetent to degrade NRF2, while the open and closed KEAP1-NRF2 complexes transition from operating in cycle mode to equilibrium mode. Ultrasensitive NRF2 activation (a steep rise of free NRF2) can occur when NRF2 nearly saturates KEAP1. The ultrasensitivity results from zero-order degradation through DLG binding and protein sequestration through ETGE binding. Optimal abundances of cytosolic and nuclear KEAP1 exist to maximize ultrasensitivity. These response characteristics do not require disruption of DLG binding as suggested by the hinge-latch hypothesis. In comparison, class VI NRF2 activators cause a shift to the open KEAP1-NRF2 complex and ultimately its complete dissociation, resulting in a fast release of NRF2 followed by stabilization. However, ultrasensitivity is lost due to decreasing free KEAP1 abundance. In summary, by simulating the dual role of KEAP1, i.e., sequestering and promoting degradation of NRF2, our modeling provides novel quantitative insights into NRF2 activation, which may help design novel NRF2 modulators and understand the oxidative actions of environmental stressors.

Background: RhoA is a master regulator of cytoskeletal contractility, while nitric oxide (NO) is a master regulator of relaxation, e.g., vasodilation. There are multiple forms of cross-talk between the RhoA/ROCK pathway and the eNOS/NO/cGMP pathway, but previous work has not studied their interplay at a systems level. Literature review suggests that the majority of their cross-talk interactions are antagonistic, which motivates us to ask whether the RhoA and NO pathways exhibit mutual antagonism in vitro, and if so, to seek the theoretical implications of their mutual antagonism. Results: Experiments found mutual antagonism between RhoA and NO in epithelial cells. Since mutual antagonism is a common motif for bistability, we sought to explore through theoretical simulations whether the RhoA-NO network is capable of bistability. Qualitative modeling showed that there are parameters that can cause bistable switching in the RhoA-NO network, and that the robustness of the bistability would be increased by positive feedback between RhoA and mechanical tension. Conclusions: We conclude that the RhoA-NO bistability is robust enough in silico to warrant the investment of further experimental testing. Tension-dependent bistability has the potential to create sharp concentration gradients, which could contribute to the localization and self-organization of signaling domains during cytoskeletal remodeling and cell migration. [ABSTRACT FROM AUTHOR]

Proteins expressed in human cells contain about 50% intrinsically disordered regions (IDRs). An unexpectedly large content of IDRs in human proteins prompted exploring how IDRs exert elaborate functions that are not associated with the folded parts of proteins. This review reports the ultrasensitive change in the nucleosome binding of FACT, a nucleosome remodeler, according to the degree of phosphorylation: in which FACT binding ability to nucleosomal DNA changes in a sigmoidal manner along with the number of phosphorylation to the IDR in its DNA binding domain. This finding adds a new function exclusively achieved by IDRs. [ABSTRACT FROM AUTHOR]

Lateral flow assays (LFA), as the most commonly used commercialized point-of-care testing (POCT), has been limited by the detection accuracy for decades. To address this challenge, the improvement of detection sensitivity and quantitative ability become necessary. Therefore, increasing new fluorescent LFA have been developed and attracted lots of attentions. Wherein, the upconversion nanoparticles (UCNPs)-based LFA stand out, due to its advantages of high photostability, great robustness and long shelf life. In this review, we summarized the recent advances in UCNPs-based LFA. First, we summarized the luminescent properties of UCNPs and described its relationship with LFA properties. Next, the common signal enhancement, signal readout manner and multiplex detection strategies in UCNPs-based LFA were reviewed to meet diverse detection requirements. Following, the wide applications in food safety, disease diagnosis, and environmental monitoring were discussed. Finally, the current challenges and perspectives on the future development of UCNPs-based LFA were also provided. [ABSTRACT FROM AUTHOR]

Control over the sensitivity with which biomolecular receptors respond to small changes in the concentration of their target ligand is critical for the proper function of many cellular processes. Such control could likewise be of utility in artificial biotechnologies, such as biosensors, genetic logic gates, and "smart" materials, in which highly responsive behavior is of value. In nature, the control of molecular responsiveness is often achieved using "Hill-type" cooperativity, a mechanism in which sequential binding events on a multivalent receptor are coupled such that the first enhances the affinity of the next, producing a steep, higher-order dependence on target concentration. Here, we use an intrinsic-disorder-based mechanism that can be implemented without requiring detailed structural knowledge to rationally introduce this potentially useful property into several normally noncooperative biomolecules. To do so, we fabricate a tandem repeat of the receptor that is destabilized (unfolded) via the introduction of a long, unstructured loop. The first binding event requires the energetically unfavorable closing of this loop, reducing its affinity relative to that of the second binding event, which, in contrast occurs at a preformed site. Using this approach, we have rationally introduced cooperativity into three unrelated DNA aptamers, achieving in the best of these a Hill coefficient experimentally indistinguishable from the theoretically expected maximum. The extent of cooperativity and thus the steepness of the binding transition are, moreover, well modeled as simple functions of the energetic cost of binding-induced folding, speaking to the quantitative nature of this design strategy.

BACKGROUND: The ultrasensitive monitoring strategy of zearalenone (ZEN) is essential and desirable for food safety and human health. In the present study, a coupling of gold nanoparticles-DNA barcode and direct competitive immunoassay-based real-time polymerase chain reaction signal amplification (RT-IPCR) for ZEN close to the sensitivity of PCR-like levels is described and evaluated. RESULTS: The RT-IPCR benefited from the use of a DNA barcode and RT-PCR detection strategy, thus resulting in ultrasensitive and simple detection for ZEN. Under the optimal RT-IPCR, the linear range of detection was from 0.5 to 1000 pg mL-1 and the limit of detection was 0.5 pg mL-1, which was 400-fold lower than the enzyme-linked immunosorbent assay. The detection procedure was simplified and the detection time was shortened. The specificity, accuracy and precision of the RT-IPCR confirmed a high performance. ZEN-positive contamination levels were from 0.056 to 152.12 ng g-1 by the RT-IPCR, which was demonstrated to be highly reliable by liquid chromatography-tandem mass spectrometry. CONCLUSION: The proposed RT-IPCR could be used as an alternative for detecting ZEN with satisfactory ultrasensitivity, simplicity, low cost and high-throughput. The present study could provide a strategy for the ultrasensitive detection of the small molecule with a simple and practical approach, which has significant appeal and application prospects. [ABSTRACT FROM AUTHOR]

Hedgehog signaling is fundamental in animal embryogenesis, and its dysregulation causes cancer and birth defects. The pathway is triggered when the Hedgehog ligand inhibits the Patched1 membrane receptor, relieving repression that Patched1 exerts on the GPCR-like protein Smoothened. While it is clear how loss-of-function Patched1 mutations cause hyperactive Hedgehog signaling and cancer, how other Patched1 mutations inhibit signaling remains unknown. Here, we develop quantitative single-cell functional assays for Patched1, which, together with mathematical modeling, indicate that Patched1 inhibits Smoothened enzymatically, operating in an ultrasensitive regime. Based on this analysis, we propose that Patched1 functions in cilia, catalyzing Smoothened deactivation by removing cholesterol bound to its extracellular, cysteine-rich domain. Patched1 mutants associated with holoprosencephaly dampen signaling by three mechanisms: reduced affinity for Hedgehog ligand, elevated catalytic activity, or elevated affinity for the Smoothened substrate. Our results clarify the enigmatic mechanism of Patched1 and explain how Patched1 mutations lead to birth defects. [ABSTRACT FROM AUTHOR]

Biomolecular detection at a low concentration is usually the most important criterion for biological measurement and early stage disease diagnosis. In this paper, a highly sensitive nanoplasmonic biosensing approach is demonstrated by achieving near‐infrared plasmonic excitation on a continuous gold‐coated nanotriangular array. Near‐infrared incident light at a small incident angle excites surface plasmon resonance with much higher spectral sensitivity compared with traditional configuration, due to its greater interactive volume and the stronger electric field intensity. By introducing sharp nanotriangular metallic tips, intense localization of plasmonic near‐fields is realized to enhance the molecular perception ability on sensing surface. This approach with an enhanced sensitivity (42103.8 nm per RIU) and a high figure of merit (367.812) achieves a direct assay of ssDNA at nanomolar level, which is a further step in label‐free ultrasensitive sensing technique. Considerable improvement is recorded in the detection limit of ssDNA as 1.2 × 10−18m based on the coupling effect between nanotriangles and gold nanoparticles. This work combines high bulk‐ and surface‐sensitivities, providing a simple way toward label‐free ultralow‐concentration biomolecular detection. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

As a large number of strain sensors are put into practical use, their stability should be considered, especially in harsh environments containing water or microorganisms, which could affect strain sensing. Herein, a novel strategy to overcome liquid interference is proposed. The strain sensor is constructed with a sandwich architecture through layer‐by‐layer (LBL) spray‐coating of a 3‐(aminopropyl)triethoxysilane (APTES) bonding layer and multi‐walled carbon nanotubes/graphene (MWCNT/G) conductive layers on an elastomeric polydimethysiloxane (PDMS) substrate, and is further decorated with silver (Ag) nanoparticles and the (heptadecafluoro‐1,1,2,2‐tetradecyl) trimethoxysilane (FAS, F in short) to obtain a F/Ag/MWCNG/G‐PDMS (FAMG) strain sensor. The superhydrophobicity and underwater oleophobicity of the outer cover layer causes this FAMG strain sensor surface to exhibit stable strain sensing resistant to liquid interference upon stretching in the Cassie−Baxter wetting state, and resistance to bacterial adhesion (Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli)). The sensor attains ultrasensitivity (with a maximum gauge factor of 1989 in the condition of liquid interference), broad strain range (0.1–170%), fast response time (150 ms), and stable response after 1000 stretching–releasing cycles. The ultrasensitivity is provided by propagation of cracks in MWCNT/G conductive layers and terminal fracture of the intermediate separating layers (APTES/MWCNT/G). The microbridge effect of MWCNTs and slippage of APTES/MWCNT/G provide a large strain range. The FAMG strain sensor is successfully used to monitor a series of human activities and an electronic bird under artificial rain and bacterial droplets, indicating the potential use of this sensor in complex environments. [ABSTRACT FROM AUTHOR]

One of the most widely used approaches to characterize transmembrane ion transport through nanoscale synthetic or biological channels is a straightforward, liposome-based assay that monitors changes in ionic flux across the vesicle membrane using pH- or ion-sensitive dyes. However, failure to account for the precise experimental conditions, in particular the complete ionic composition on either side of the membrane and the inherent permeability of ions through the lipid bilayer itself, can prevent quantifications and lead to fundamentally incorrect conclusions. Here we present a quantitative model for this assay based on the Goldman–Hodgkin–Katz flux theory, which enables accurate measurements and identification of optimal conditions for the determination of ion channel permeability and selectivity. Based on our model, the detection sensitivity of channel permeability is improved by two orders of magnitude over the commonly used experimental conditions. Further, rather than obtaining qualitative preferences of ion selectivity as is typical, we determine quantitative values of these parameters under rigorously controlled conditions even when the experimental results would otherwise imply (without our model) incorrect behavior. We anticipate that this simply employed ultrasensitive assay will find wide application in the quantitative characterization of synthetic or biological ion channels. Image 1 • Popular liposome-based assay only provides qualitative properties of ion channels. • First theoretical description of this assay enables optimization and quantification. • The sensitivity to detect channel permeability improves ∼100-fold. • Misleading experimental results of ion selectivity can be distinguished and corrected. [ABSTRACT FROM AUTHOR]

Immunoassay, as the most commonly used method for protein detection, is simple to operate and highly specific. Sensitivity improvement is always the thrust of immunoassays, especially for the detection of trace quantities. The emergence of artificial enzyme, i.e., DNAzyme, provides a novel approach to improve the detection sensitivity of immunoassay. Simultaneously, its advantages of simple synthesis and high stability enable low cost, broad applicability and long shelf life for immunoassay. In this review, we summarized the recent advances in DNAzyme-based immunoassay. First, we summarized the existing different DNAzymes based on their catalytic activities. Next, the common signal amplification strategies used for DNAzyme-based immunoassays were reviewed to cater to diverse detection requirements. Following, the wide applications in disease diagnosis, environmental monitoring and food safety were discussed. Finally, the current challenges and perspectives on the future development of DNAzyme-based immunoassays were also provided. Immunoassay, as the most commonly used method for protein detection, is simple to operate and highly specific. Sensitivity improvement is always the thrust of immunoassays, especially for the detection of trace quantities. The emergence of artificial enzyme, i.e. , DNAzyme, has opened up a novel avenue for improving the detection sensitivity of immunoassays, due to their dual capability of serving as enzymes for signal amplification and their amenability to straightforward replication through nucleic acid amplification technologies. This review summarizes DNAzyme function, signal amplification strategy, applications, and proposes the future trend and potential development directions. We hope that this review can help junior researchers to quickly understand this field, and provide inspirations for relevant researchers to develop new DNAzyme-based immunoassays. [Display omitted] [ABSTRACT FROM AUTHOR]

Graphene has been widely used in photodetectors; however its photoresponsivity is limited due to the intrinsic low absorption of graphene. To enhance the graphene absorption, a waveguide structure with an extended interaction length and plasmonic resonance with light field enhancement are often employed. However, the operation bandwidth is narrowed when this happens. Here, a novel graphene-based all-fiber photodetector (AFPD) was demonstrated with ultrahigh responsivity over a full near-infrared band. The AFPD benefits from the gold-enhanced absorption when an interdigitated Au electrode is fabricated onto a Graphene-PMMA film covered over a side-polished fiber (SFP). Interestingly, the AFPD shows a photoresponsivity of >1 × 104 A/W and an external quantum efficiency of >4.6 × 106% over a broadband region of 980–1620 nm. The proposed device provides a simple, low-cost, efficient, and robust way to detect optical fiber signals with intriguing capabilities in terms of distributed photodetection and on-line power monitoring, which is highly desirable for a fiber-optic communication system.

Long-term depression (LTD) and long-term potentiation (LTP) in the cerebellum are important for motor learning. However, the signaling mechanisms controlling whether LTD or LTP is induced in response to synaptic stimulation remain obscure. Using a unified model of LTD and LTP at the cerebellar parallel fiber-Purkinje cell (PF-PC) synapse, we delineate the coordinated pre- and postsynaptic signaling that determines the direction of plasticity. We show that LTP is the default response to PF stimulation above a well-defined frequency threshold. However, if the calcium signal surpasses the threshold for CaMKII activation, then an ultrasensitive “on switch” activates an extracellular signal-regulated kinase (ERK)-based positive feedback loop that triggers LTD instead. This postsynaptic feedback loop is sustained by another, trans-synaptic, feedback loop that maintains nitric oxide production throughout LTD induction. When full depression is achieved, an automatic “off switch” inactivates the feedback loops, returning the network to its basal state and demarcating the end of the early phase of LTD.

Signal amplification in biomolecular networks converts a linear input to a steeply sigmoid output and is central to a number of cellular functions including proliferation, differentiation, homeostasis, adaptation, and biological rhythms. One canonical signal amplifying motif is zero-order ultrasensitivity that is mediated through the posttranslational modification (PTM) cycle of signaling proteins. The functionality of this signaling motif has been examined conventionally by supposing that the total amount of the protein substrates remains constant, as by the classical Koshland–Goldbeter model. However, covalent modification of signaling proteins often results in changes in their stability, which affects the abundance of the protein substrates. Here, we use mathematical models to explore the signal amplification properties in such scenarios and report some novel aspects. Our analyses indicate that PTM-induced protein stabilization brings the enzymes closer to saturation. As a result, ultrasensitivity may emerge or is greatly enhanced, with a steeper sigmoidal response, higher magnitude, and generally longer response time. In cases where PTM destabilizes the protein, ultrasensitivity can be regained through changes in the activities of the involved enzymes or from increased protein synthesis. Importantly, ultrasensitivity is not limited to modified or unmodified protein substrates—when protein turnover is considered, the total free protein substrate can also exhibit ultrasensitivity under several conditions. When full enzymatic reactions are used instead of Michaelis–Menten kinetics for the modeling, the total free protein substrate can even exhibit nonmonotonic dose–response patterns. It is conceivable that cells use inducible protein stabilization as a strategy in the signaling network to boost signal amplification while saving energy by keeping the protein substrate levels low at basal conditions.

Circadian rhythms are generated by complex interactions among genes and proteins. Self-sustained ∼24 h oscillations require negative feedback loops and sufficiently strong nonlinearities that are the product of molecular and network switches. Here, we review common mechanisms to obtain switch-like behavior, including cooperativity, antagonistic enzymes, multisite phosphorylation, positive feedback, and sequestration. We discuss how network switches play a crucial role as essential components in cellular circadian clocks, serving as integral parts of transcription-translation feedback loops that form the basis of circadian rhythm generation. The design principles of network switches and circadian clocks are illustrated by representative mathematical models that include bistable systems and negative feedback loops combined with Hill functions. This work underscores the importance of negative feedback loops and network switches as essential design principles for biological oscillations, emphasizing how an understanding of theoretical concepts can provide insights into the mechanisms generating biological rhythms., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Diagnostic tests for Clostridioides difficile infection (CDI) lack either specificity (nucleic acid amplification tests) or sensitivity (enzyme immunoassays; EIAs). The performance of the Singulex Clarity® C. diff toxins A/B assay was compared to cell cytotoxicity neutralization assay. Testing was also performed using an EIA for glutamate dehydrogenase (GDH) and C. difficile toxins A and B (C. Diff Quik Chek Complete®), polymerase chain reaction (PCR) (BD MAX™ Cdiff Assay), and 2 multistep algorithms: algorithm 1 (discordant GDH/toxin results arbitrated by PCR) and algorithm 2 (PCR-positive samples tested with toxin EIA). The Clarity assay and PCR both had 97% sensitivity, while specificity was 100% for Clarity and 79% for PCR. Algorithm 1 yielded 41% discordant results, and both toxin EIA and algorithm 2 had 58% sensitivity. Median toxin concentrations, as measured by the Clarity C. difficile toxin assay, were 3590, 11.5, 0.4, and 0 pg/mL for GDH+/toxin+, GDH+/toxin−/PCR+, GDH+/toxin−/PCR−, and GDH−/toxin− samples, respectively (P < 0.001). The Clarity assay may offer a single-test solution for CDI. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AhR) is a nuclear receptor that facilitates a wide transcriptional response and causes a variety of adaptive and maladaptive physiological functions. Such functions are entirely dependent on the type of ligand activating it, and therefore, the nuances in the activation of this receptor at the single-cell level have become a research interest for different pharmacological and toxicological applications. Here, we investigate the activation of the AhR by diverse classes of compounds in a Hepa1c1c7-based murine hepatoma cell line. The exogenous compounds analyzed produced different levels of ultrasensitivity in AhR activation as measured by XRE-coupled EGFP production and analyzed by both flow cytometric and computational simulation techniques. Interestingly, simulation experiments reported herein were able to reproduce and quantitate the natural single-cell stochasticity inherent to mammalian cell lines as well as the ligand-specific differences in ultrasensitivity. Classical AhR modulators 2,3,7,8-tetrachlorodibenzodioxin (10− 1–105 pM), PCB-126 (10− 1–107 pM), and benzo[a]pyrene (10− 1–107 pM) produced the greatest levels of single-cell ultrasensitivity and most maximal responses, while consumption-based ligands indole-3-carbinol (103–109 pM), 3,3′-diindolylmethane (103–108 pM), and cannabidiol (103–108 pM) caused low-level AhR activation in more purely graded single-cell fashions. All compounds were tested and analyzed over a 24 h period for consistency. The comparative quantitative results for each compound are presented within. This study aids in defining the disparity between different types of AhR modulators that produce distinctly different physiological outcomes. In addition, the simulation tool developed for this study can be used in future studies to predict the quantitative effects of diverse types of AhR ligands in the context of pharmacological therapies or toxicological concerns. [ABSTRACT FROM AUTHOR]

[Display omitted] • A sensitive fluorescence probe TZ-NBD for the recognition of biothiols with dual-channel was constructed. • Dual-channel response improves the probe's anti-interference ability. • TZ-NBD showed fast response, good sensitivity, and near-infrared fluorescence signal. • TZ-NBD was successfully used for high-quality imaging of biothiols in living cancer cells and zebrafish. Biothiols play a crucial role in maintaining redox balance in organisms, and anomalous levels of biothiols in human organs can lead to various sicknesses and biological disorders. This work developed a novel sensitive fluorescent probe TZ-NBD with double channels for highly efficient recognition of biothiols. TZ-NBD adopts 4-Chloro-7-nitrobenzofurazan (NBD-Cl) as the recognition moiety with simultaneous fluorescence output. By incorporating NBD-Cl with the other fluorophore, benzothiazole dihydrocyclopentachromene derivative (TZ-OH), the dual-channel sensitive fluorescence probe TZ-NBD was built. The existence of Cys/ Hcy could significantly trigger both the green and red fluorescent emissions, which were derived from fluorophores amine-substituted NBD and TZ-OH, respectively. While exposing to GSH, only the red-channel fluorescence signal could be detected, indicating the release of TZ-OH. The phenomena was mainly attributed to the fact that sulfur-substituted NBD has nearly no fluorescence, while amine-substituted NBD shows obvious green fluorescence. In our study, TZ-NBD exhibited dual-channel sensitivity, fast response, and excellent selectivity to biothiols in vitro. Moreover, TZ-NBD was favorably utilized for recognition of biothiols in vivo. We believe that the sensitive fluorescence probe with double channels can afford an alternate approach for monitoring biothiols in organisms and would be useful for studying diseases associated with biothiols. [ABSTRACT FROM AUTHOR]

Sensitive detection of cardiac biomarkers is critical for clinical diagnostics of myocardial infarction (MI) while such detection is quite challenging due to the ultra-low concentration of cardiac biomarkers. In this work, a label-free immunosensor based on optical microfiber coupler (OMC) has been developed for the ultrasensitive detection of cardiac troponin I (cTnI), a selective and highly sensitive biomarker of acute myocardial infarction (AMI). CTnI monoclonal antibodies were immobilized on the surface of the fiber through polyelectrolyte layer using layer-by-layer deposition technique. For refractive index sensing characterization, an ultra-high sensitivity of 91777.9 nm/RIU was achieved when the OMC works around the dispersion turning point, which is the highest experimental demonstration in the field of fiber-optic evanescent biosensors. For biosensing, the immunosensor with good specificity showed a linear wavelength shift in the range of 2–10 fg/mL and an ultra-low detection limit of 2 fg/mL. Such immunosensors have huge application potential for the detection of cardiac biomarkers of myocardial infarction due to simple detection scheme, quick response time, ease of handling and miniaturation. [ABSTRACT FROM AUTHOR]

Abstract: A novel Au dimer‐based colorimetric sensor is reported that consists of Au dimers to a chitosan hydrogel film. It utilizes the ultrasensitively gap‐dependent properties of plasmonic coupling (PC) peak shift, which is associated with the dynamical tuning of the interparticle gap of the Au dimer driven by the volume swelling of the chitosan hydrogel film. The interparticle gap and PC peak shift of the Au dimer can be precisely and extensively controlled through the pH‐driven volume change of chitosan hydrogel film. This colorimetric sensor exhibits a high optical sensitivity and stability, and it works in a completely reversible manner at high pH values. Importantly, the sensitivity of the composite film can be tuned by controlling the crosslinking time of the composite film, and thus leading to a wide dynamic tuning sensitive range for different applications. This presented strategy paves a way to achieve the construction of high‐quality colorimetric sensors with ultrahigh sensitivity, stability and wide dynamic tuning sensitive range. [ABSTRACT FROM AUTHOR]

[Display omitted] • Aligned silver nanowires/polymer composite films. • Ultrasensitive and highly stretchable strain sensors. • Large and subtle deformations can be detected. • Human health monitoring and body movement detection. • Early warning of earthquake. Strain sensor films are widely applied in electronic skins, soft robotics and human health monitoring etc. However, fabrication of ultrasensitive and highly stretchable strain sensor films remains a great challenge because of the trade-off between sensitivity and stretchability. Here, we report an aligned silver nanowires (Ag NWs)/polymer composite film prepared by a float assembly method. After perpendicularly stacking two layers of Ag NWs/polymer composite films into one sensor film, it exhibits an ultrahigh sensitivity with gauge factor (GF) up to 2.98 × 106 and a very large working range of 200% due to different resistance response mechanism of the cross film structure. The low limit of detection is as low as 0.001%. Accordingly, the strain sensor films can detect both large deformation and subtle vibration for human motion and monitoring, even early warning of earthquakes. This work provides a new idea to fabricate stain sensor films with both ultrahigh sensitivity and large stretchability. [ABSTRACT FROM AUTHOR]