Treatment of HNSC and pulmonary metastasis using the anti-helminthic drug niclosamide to modulate Stat3 signaling activity.

Background: Head and neck squamous cell carcinoma (HNSC) is a dangerous cancer that represents an important threat to human health. Niclosamide is an anti-helminthic drug that has received FDA approval. In drug repurposing screens, niclosamide was found to inhibit proliferative activity for a range of tumor types. Its functional effects in HNSC, however, have yet to be established. Methods: MTT and colony formation assays were used to explore the impact of niclosamide on the proliferation of HNSC cells, while wound healing and Transwell assays were employed to assess migration and invasivity. Flow cytometry and Western immunoblotting were respectively used to assess cellular apoptosis and protein expression patterns. An HNSC xenograft tumor model system was used to evaluate the in vivo antitumor activity of niclosamide, and immunofluorescent staining was employed to assess cleaved Caspase3 and Ki67 expression. The ability of niclosamide to prevent metastatic progression in vivo was assessed with a model of pulmonary metastasis. Results: These analyses revealed the ability of niclosamide to suppress HNSC cell migration, proliferation, and invasivity in vitro while promoting apoptotic death. From a mechanistic perspective, this drug suppressed Stat3 phosphorylation and ß-catenin expression, while increasing cleaved Caspase3 levels in HNSC cells and reducing Bcl-2 levels. Importantly, this drug was able to suppress in vivo tumor growth and pulmonary metastasis formation, with immunofluorescent staining confirming that it reduced Ki67 levels and increased cleaved Caspase3 content. Conclusion: In conclusion, these analyses highlight the ability of niclosamide to inhibit HNSC cell migration and proliferative activity while provoking apoptotic death mediated via p-Stat3 and ß-catenin pathway inactivation. Niclosamide thus holds promise for repurposing as a candidate drug for the more effective clinical management of HNSC.

Silk Fibroin-Regulated Nanochannels for Flexible Hydrovoltaic Ion Sensing.

The evaporation-induced hydrovoltaic effect based on ion-selective nanochannels can theoretically be employed for high-performance ion sensing; yet, the indeterminate ion-sensing properties and the acquisition of high sensing performance are rarely explored. Herein, a controllable nanochannel regulation strategy for flexible hydrovoltaic devices with highly sensitive ion-sensing abilities is presented across a wide concentration range. By multiple dip-coating of silk fibroin (SF) on an electrospinning nylon-66 nanofiber (NNF) film, the surface polarity enhancement, the fibers size regulation with a precision of ≈25 nm, and the nanostructure firm binding are achieved simultaneously. The resultant flexible freestanding hydrovoltaic device exhibits an open circuit voltage up to 4.82 V in deionized water, a wide ion sensing range of 10-7 to 100 m, and ultrahigh sensitivity as high as 1.37 V dec-1, which is significantly higher than the sensitivity of the traditional solid-contact ion-selective electrodes (SC-ISEs). The fabricated flexible ion-sensitive hydrovoltaic device is successfully applied for wearable human sweat electrolyte sensing and for environmental trace-ion monitoring, thereby confirming the potential application of the hydrovoltaic effect for ion sensing.

NLRP3/miR-223-3p axis attenuates neuroinflammation induced by chronic intermittent hypoxia.

Obstructive sleep apnea (OSA) is mainly characterized by chronic intermittent hypoxia (CIH) with multiple brain injuries. Nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome is considered the most important factor inducing and maintaining inflammation. However, the role of NLRP3 and its underlying mechanism in CIH-elicited neuroinflammation remains unclear. We constructed an OSA-related CIH in vivo model and assessed the rats' cognitive behavior in the Morris water maze. The combination of miR-223-3p and NLRP3 was confirmed by the TargetScan database, double luciferase reporter gene experiment, and RNA immunoprecipitation (RIP) experiment. Western blot and ELISA assay were used to analyze the effects of miR-223-3p targeting NLRP3 on the expression of pyroptotic or inflammatory factors in vivo in CIH rats. Severe cognitive impairment was observed in rats at week 6 post-treatment, with increased inflammatory factors in the blood and hippocampus, heightened NLRP3 expression, and low miR-223-3p levels. And the good binding activity of the two was confirmed by dual luciferase reporter and RIP experiments. Next, we found that silencing NLRP3 or overexpression of miR-223-3p in the CIH model could improve cognitive deficits and reduce the level of proinflammatory factors and pyroptosis factors in rats. Finally, based on silencing NLRP3 or overexpression miR-223-3p, we confirmed that there was a regulatory relationship between miR-223-3p and NLRP3. Our results suggested that the NLRP3/ miR-223-3p axis played a role in attenuating CIH-induced neuroinflammation.

A Flexible Tough Hydrovoltaic Coating for Wearable Sensing Electronics.

The lack of a strong binding mechanism between nanomaterials severely restricts the advantages of the evaporation-driven hydrovoltaic effect in wearable sensing electronics. It is a challenging task to observably improve the mechanical toughness and flexibility of hydrovoltaic devices to match the wearable demand without abandoning the nanostructures and surface function. Here, a flexible tough polyacrylonitrile/alumina (PAN/Al2 O3 ) hydrovoltaic coating with both good electricity generation (open-circuit voltage, Voc  ≈ 3.18 V) and sensitive ion sensing (2285 V M-1 for NaCl solutions in 10-4 to 10-3  m) capabilities is developed. The porous nanostructure composed of Al2 O3 nanoparticles is firmly locked by the strong binding effect of PAN, giving a critical binding force 4 times that of Al2 O3 film to easily deal with 9.92 m s-1 strong water-flow impact. Finally, skin-tight and non-contact device structures are proposed to achieve wearable multifunctional self-powered sensing directly using sweat. The flexible tough PAN/Al2 O3 hydrovoltaic coating breaks through the mechanical brittleness limitation and broadens the applications of the evaporation-induced hydrovoltaic effect in self-powered wearable sensing electronics.

Neuron-Inspired Sticky Artificial Spider Silk for Signal Transmission.

Neurons exhibit excellent signal transmission capacity, which inspire artificial neuron materials for applications in the field of wearable electronics and soft robotics. In addition, the neuron fibers exhibit good mechanical robustness by sticking to the organs, which currently has rarely been studied. Here, a sticky artificial spider silk is developed by employing a proton donor-acceptor (PrDA) hydrogel fiber for application as artificial neuron fibers. Tuning the molecular electrostatic interactions by modulating the sequences of proton donors and acceptors, enables combination of excellent mechanical properties, stickiness, and ion conductivity. In addition, the PrDA hydrogel exhibits high spinning capacity for a wide range of donor-acceptor combinations. The PrDA artificial spider silk would shed light on the design of new generation of artificial neuron materials, bio-electrodes, and artificial synapses.

Biological Tissue-Inspired Ultrasoft, Ultrathin, and Mechanically Enhanced Microfiber Composite Hydrogel for Flexible Bioelectronics.

Hydrogels offer tissue-like softness, stretchability, fracture toughness, ionic conductivity, and compatibility with biological tissues, which make them promising candidates for fabricating flexible bioelectronics. A soft hydrogel film offers an ideal interface to directly bridge thin-film electronics with the soft tissues. However, it remains difficult to fabricate a soft hydrogel film with an ultrathin configuration and excellent mechanical strength. Here we report a biological tissue-inspired ultrasoft microfiber composite ultrathin (< 5 µm) hydrogel film, which is currently the thinnest hydrogel film as far as we know. The embedded microfibers endow the composite hydrogel with prominent mechanical strength (tensile stress ~ 6 MPa) and anti-tearing property. Moreover, our microfiber composite hydrogel offers the capability of tunable mechanical properties in a broad range, allowing for matching the modulus of most biological tissues and organs. The incorporation of glycerol and salt ions imparts the microfiber composite hydrogel with high ionic conductivity and prominent anti-dehydration behavior. Such microfiber composite hydrogels are promising for constructing attaching-type flexible bioelectronics to monitor biosignals.

Fast and High-Performance Self-Powered Photodetector Based on the ZnO/Metal-Organic Framework Heterojunction.

Electrical conductive metal-organic frameworks (EC-MOFs) are emerging as an appealing class of highly tailorable electrically conducting materials with potential applications in optoelectronics. Here, we in situ grew nickel hexahydroxytriphenylene (Ni-CAT) on the surface of ZnO nanorods (NRs). The self-powered photodetectors (PDs) were fabricated with heterojunctions formed at the interface of ZnO NRs and Ni-CAT. With this, the built-in electric field (BEF) can effectively separate the photogenerated electron-hole pairs and enhance the photoresponse. We observe that the PDs based on hybrid ZnO/Ni-CAT with 3 h of growth time (ZnO/Ni-CAT-3) show good photoresponse (137 µA/W) with the fast rise (3 ms) and decay time (50 ms) under 450 nm light illumination without biased voltage. This work provides a facile and controllable method for the growth of the ZnO/Ni-CAT heterojunction with an effective BEF zone, which will benefit their optoelectronic applications.

Tough Engineering Hydrogels Based on Swelling-Freeze-Thaw Method for Artificial Cartilage.

Articular cartilage, which exhibits toughness and ultralow friction even under high squeezing pressures, plays an important role in the daily movement of joints. However, joint soft tissue lesions or injuries caused by diseases, trauma, or human functional decline are inevitable. Poly(vinyl alcohol) (PVA) hydrogels, which have a water content and compressive strength similar to those of many tissues and organs, have the potential to replace tough connective tissues, including cartilage. However, currently, PVA hydrogels are not suitable for complex dynamic environments and lack rebound resilience, especially under long-term or multicycle mechanical loads. Inspired by biological tissues that exhibit increased mechanical strength after swelling, we report a tough engineered hydrogel (TEHy) fabricated by swelling and freeze-thaw methods with a high compressive strength (31 MPa), high toughness (1.17 MJ m-3), a low friction coefficient (0.01), and a low energy loss factor (0.22). Notably, the TEHy remained remarkably resilient after 100 000 cycles of contact extrusion and remains intact after being compressed by an automobile with a weight of approximately 1600 kg. The TEHy also exhibited excellent water swelling resistance (volume and weight changes less than 5%). Moreover, skeletal muscle cells were able to readily attach and proliferate on the surface of TEHy-6, suggesting its outstanding biocompatibility. Overall, this swelling and freeze-thaw strategy solves the antifatigue and stability problems of PVA hydrogels under large static loads (>10 000 N) and provides an avenue to fabricate engineering hydrogels with strong antifatigue and antiswelling properties and ultralow friction for potential use as biomaterials in tissue engineering.

Enhancing hydrovoltaic power generation through heat conduction effects.

Restricted ambient temperature and slow heat replenishment in the phase transition of water molecules severely limit the performance of the evaporation-induced hydrovoltaic generators. Here we demonstrate a heat conduction effect enhanced hydrovoltaic power generator by integrating a flexible ionic thermoelectric gelatin material with a porous dual-size Al2O3 hydrovoltaic generator. In the hybrid heat conduction effect enhanced hydrovoltaic power generator, the ionic thermoelectric gelatin material can effectively improve the heat conduction between hydrovoltaic generator and near environment, thus increasing the water evaporation rate to improve the output voltage. Synergistically, hydrovoltaic generator part with continuous water evaporation can induce a constant temperature difference for the thermoelectric generator. Moreover, the system can efficiently achieve solar-to-thermal conversion to raise the temperature difference, accompanied by a stable open circuit voltage of 6.4 V for the hydrovoltaic generator module, the highest value yet.

Stretchable multifunctional hydrogels for sensing electronics with effective EMI shielding properties.

Hydrogel-based soft and stretchable materials with skin/tissue-like mechanical properties provide new avenues for the design and fabrication of wearable sensors. However, synthesizing multifunctional hydrogels that simultaneously possess excellent mechanical, electrical and electromagnetic interference (EMI) shielding effectiveness is still a great challenge. In this work, the freeze-casting method is employed to fabricate a multifunctional hydrogel by filling Fe3O4 clusters into poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonic acid) (PEDOT:PSS) and polyvinyl alcohol (PVA) composite aqueous solution. The hydrogel possesses superior electrical and mechanical properties as well as great electromagnetic wave shielding properties. Benefiting from the high stretchability (∼904.5%) and fast sensing performance (response time ∼9 ms and self-recovery time ∼12 ms within the strain range ∼100%), the monitoring of human activities and manipulation of a remote-controlled toy car using the hydrogel-based stretchable strain sensors are successfully demonstrated. In addition, a great EMI shielding effectiveness with more than 46 dB in the frequencies of 8-12.5 GHz can be obtained, which provides an alternative strategy for designing next-generation EMI shielding materials. These results indicate that the multifunctional hydrogels can be used as flexible and stretchable sensing electronics requiring effective EMI shielding.

Stable epidermal electronic device with strain isolation induced by in situ Joule heating.

Epidermal electronics play increasingly important roles in human-machine interfaces. However, their efficient fabrication while maintaining device stability and reliability remains an unresolved challenge. Here, a facile in situ Joule heating method is proposed for fabricating stable epidermal electronics on a polyvinyl alcohol (PVA) substrate. Benefitting from the precise control of heating locations, the crystallization and enhanced rigidity of PVA are restricted to desired areas, leading to strain isolation of the active regions. As a result, the electronic device can be conformably attached to skin while showing negligible degradation in device performance during deformation. Based on this method, a flexible surface electromyography (sEMG) sensor with outstanding stability and highly comfortable wearability is demonstrated, showing high accuracy (91.83%) for human hand gesture recognition. These results imply that the fabrication method proposed in this research is a facile and reliable approach for the fabrication of epidermal electronics.

Humidity-Insensitive NO2 Sensors Based on SnO2/rGO Composites.

This study reported a novel humidity-insensitive nitrogen dioxide (NO2) gas sensor based on tin dioxide (SnO2)/reduced graphene oxide (rGO) composites through the sol-gel method. The sensor demonstrated ppb-level NO2 detection in p-type sensing behaviors (13.6% response to 750 ppb). Because of the synergistic effect on SnO2/rGO p-n heterojunction, the sensing performance was greatly enhanced compared to that of bare rGO. The limit of detection of sensors was as low as 6.7 ppb under dry air. Moreover, benefited from the formed superhydrophobic structure of the SnO2/rGO composites (contact angle: 149.0°), the humidity showed a negligible influence on the dynamic response (Sg) of the sensor to different concentration of NO2 when increasing the relative humidity (RH) from 0 to 70% at 116°C. The relative conductivity of the sensor to 83% relative humidity was 0.11%. In addition, the response ratio (Sg/SRH) between 750 ppb NO2 and 83% RH was 649.0, indicating the negligible impaction of high-level ambient humidity on the sensor. The as-fabricated humidity-insensitive gas sensor can promise NO2 detection in real-world applications such as safety alarm, chemical engineering, and so on.

Flexible Artificial Sensory Systems Based on Neuromorphic Devices.

Emerging flexible artificial sensory systems using neuromorphic electronics have been considered as a promising solution for processing massive data with low power consumption. The construction of artificial sensory systems with synaptic devices and sensing elements to mimic complicated sensing and processing in biological systems is a prerequisite for the realization. To realize high-efficiency neuromorphic sensory systems, the development of artificial flexible synapses with low power consumption and high-density integration is essential. Furthermore, the realization of efficient coupling between the sensing element and the synaptic device is crucial. This Review presents recent progress in the area of neuromorphic electronics for flexible artificial sensory systems. We focus on both the recent advances of artificial synapses, including device structures, mechanisms, and functions, and the design of intelligent, flexible perception systems based on synaptic devices. Additionally, key challenges and opportunities related to flexible artificial perception systems are examined, and potential solutions and suggestions are provided.

Highly Selective Biomimetic Flexible Tactile Sensor for Neuroprosthetics.

Biomimetic flexible tactile sensors endow prosthetics with the ability to manipulate objects, similar to human hands. However, it is still a great challenge to selectively respond to static and sliding friction forces, which is crucial tactile information relevant to the perception of weight and slippage during grasps. Here, inspired by the structure of fingerprints and the selective response of Ruffini endings to friction forces, we developed a biomimetic flexible capacitive sensor to selectively detect static and sliding friction forces. The sensor is designed as a novel plane-parallel capacitor, in which silver nanowire-3D polydimethylsiloxane (PDMS) electrodes are placed in a spiral configuration and set perpendicular to the substrate. Silver nanowires are uniformly distributed on the surfaces of 3D polydimethylsiloxane microcolumns, and silicon rubber (Ecoflex®) acts as the dielectric material. The capacitance of the sensor remains nearly constant under different applied normal forces but increases with the static friction force and decreases when sliding occurs. Furthermore, aiming at the slippage perception of neuroprosthetics, a custom-designed signal encoding circuit was designed to transform the capacitance signal into a bionic pulsed signal modulated by the applied sliding friction force. Test results demonstrate the great potential of the novel biomimetic flexible sensors with directional and dynamic sensitivity of haptic force for smart neuroprosthetics.

"Top-down" and "bottom-up" strategies for wafer-scaled miniaturized gas sensors design and fabrication.

Manufacture of large-scale patterned nanomaterials via top-down techniques, such as printing and slurry coating, have been used for fabrication of miniaturized gas sensors. However, the reproducibility and uniformity of the sensors in wafer-scale fabrication are still a challenge. In this work, a "top-down" and "bottom-up" combined strategy was proposed to manufacture wafer-scaled miniaturized gas sensors with high-throughput by in-situ growth of Ni(OH)2 nanowalls at specific locations. First, the micro-hotplate based sensor chips were fabricated on a two-inch (2") silicon wafer by micro-electro-mechanical-system (MEMS) fabrication techniques ("top-down" strategy). Then a template-guided controllable de-wetting method was used to assemble a porous thermoplastic elastomer (TPE) thin film with uniform micro-sized holes (relative standard deviation (RSD) of the size of micro-holes <3.5 %, n > 300), which serves as the patterned mask for in-situ growing Ni(OH)2 nanowalls at the micro-hole areas ("bottom-up" strategy). The obtained gas microsensors based on this strategy showed great reproducibility of electric properties (RSD < 0.8%, n = 8) and sensing response toward real-time H2S detection (RSD < 3.5%, n = 8).

Biological receptor-inspired flexible artificial synapse based on ionic dynamics.

The memristor has been regarded as a promising candidate for constructing a neuromorphic computing platform that is capable of confronting the bottleneck of the traditional von Neumann architecture. Here, inspired by the working mechanism of the G-protein-linked receptor of biological cells, a novel double-layer memristive device with reduced graphene oxide (rGO) nanosheets covered by chitosan (an ionic conductive polymer) as the channel material is constructed. The protons in chitosan and the functional groups in rGO nanosheets imitate the functions of the ligands and receptors of biological cells, respectively. Smooth changes in the response current depending on the historical applied voltages are observed, offering a promising pathway toward biorealistic synaptic emulation. The memristive behavior is mainly a result of the interaction between protons provided by chitosan and the defects and functional groups in the rGO nanosheets. The channel current is due to the hopping of protons through functional groups and is limited by the traps in the rGO nanosheets. The transition from short-term to long-term potentiation is achieved, and learning-forgetting behaviors of the memristor mimicking those of the human brain are demonstrated. Overall, the bioinspired memristor-type artificial synaptic device shows great potential in neuromorphic networks.

Moisture-Driven Power Generation for Multifunctional Flexible Sensing Systems.

Flexible self-powered multifunctional sensing systems provide a promising direction for the development of wearable electronics. Although increased efforts have been devoted to developing self-powered integrated devices, the development of flexible and adaptable sensing systems with miniaturized stable power supplies is highly desirable yet greatly challenging. Herein, an ambient moisture-induced self-powered wearable sensing system was fabricated by integrating a porous polydopamine layer with a hydroxy group gradient (called g-PDA) based moisture-enabled power generator and a flexible pressure sensor. Due to the large amount of gradient-distributed free cations (H+) and locally confined anions produced in wide electrode spaces during hydration of the thin porous g-PDA film, the moisture-induced potential and effective output power density of the g-PDA-based power generator rapidly reaches up to 0.52 V and 0.246 mW cm-2, respectively. Importantly, the voltage output within 120 s only has 6% change, and a continuously open-circuit voltage can be maintained after 1900 s of attenuation, which is a breakthrough for the duration of humidity generation. Finally, a self-powered wearable multifunctional sensing system has been demonstrated to be able to provide real-time monitoring of human physiological signals, without an external power supply, which opens new opportunities for future self-powered multifunctional sensing systems.

Stretchable, self-healing, transient macromolecular elastomeric gel for wearable electronics.

Flexible and stretchable electronics are emerging in mainstream technologies and represent promising directions for future lifestyles. Multifunctional stretchable materials with a self-healing ability to resist mechanical damage are highly desirable but remain challenging to create. Here, we report a stretchable macromolecular elastomeric gel with the unique abilities of not only self-healing but also transient properties at room temperature. By inserting small molecule glycerol into hydroxyethylcellulose (HEC), forming a glycerol/hydroxyethylcellulose (GHEC) macromolecular elastomeric gel, dynamic hydrogen bonds occur between the HEC chain and the guest small glycerol molecules, which endows the GHEC with an excellent stretchability (304%) and a self-healing ability under ambient conditions. Additionally, the GHEC elastomeric gel is completely water-soluble, and its degradation rate can be tuned by adjusting the HEC molecular weight and the ratio of the HEC to glycerol. We demonstrate several flexible and stretchable electronics devices, such as self-healing conductors, transient transistors, and electronic skins for robots based on the GHEC elastomeric gel to illustrate its multiple functions.

Bioinspired Flexible Volatile Organic Compounds Sensor Based on Dynamic Surface Wrinkling with Dual-Signal Response.

Living systems can respond to external stimuli by dynamic interface changes. Moreover, natural wrinkle structures allow the surface to switch dynamically and reversibly from flat to rough in response to specific stimuli. Artificial wrinkle structures have been developed for applications such as optical devices, mechanical sensors, and microfluidic devices. However, chemical molecule-triggered flexible sensors based on dynamic surface wrinkling have not been demonstrated. Inspired by human skin wrinkling, herein, a volatile organic compound (VOC)-responsive flexible sensor with a switchable dual-signal response (transparency and resistance) is achieved based on a multilayered Ag nanowire (AgNW)/SiOx /polydimethylsiloxane (PDMS) film. Wrinkle structures can form dynamically in response to VOC vapors (such as ethanol, toluene, acetone, formaldehyde, and methanol) due to the instability of the multilayer induced by their different swelling capabilities. By controlling the modulus of PDMS and the thickness of the SiOx layer, tunable sensitivities in resistance and transparency of the device are achieved. Additionally, the proximity mechanism of the solubility parameter is proposed, which explains the high selectivity of the device toward ethanol vapor compared with that of other VOCs well. This stimuli-responsive sensor exhibits the dynamic visual feedback and the quantitative electrical signal, which provide a novel approach for developing smart flexible electronics.

The Key Transcription Factor Expression in the Developing Vestibular and Auditory Sensory Organs: A Comprehensive Comparison of Spatial and Temporal Patterns.

Inner ear formation requires that a series of cell fate decisions and morphogenetic events occur in a precise temporal and spatial pattern. Previous studies have shown that transcription factors, including Pax2, Sox2, and Prox1, play important roles during the inner ear development. However, the temporospatial expression patterns among these transcription factors are poorly understood. In the current study, we present a comprehensive description of the temporal and spatial expression profiles of Pax2, Sox2, and Prox1 during auditory and vestibular sensory organ development in mice. Using immunohistochemical analyses, we show that Sox2 and Pax2 are both expressed in the prosensory cells (the developing hair cells), but Sox2 is later restricted to only the supporting cells of the organ of Corti. In the vestibular sensory organ, however, the Pax2 expression is localized in hair cells at postnatal day 7, while Sox2 is still expressed in both the hair cells and supporting cells at that time. Prox1 was transiently expressed in the presumptive hair cells and developing supporting cells, and lower Prox1 expression was observed in the vestibular sensory organ compared to the organ of Corti. The different expression patterns of these transcription factors in the developing auditory and vestibular sensory organs suggest that they play different roles in the development of the sensory epithelia and might help to shape the respective sensory structures.