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Neural electrodes have been widely used to monitor neurological disorders and have a major impact on neuroscience, whereas traditional electrodes are limited to their inherent high impedance, which makes them insensitive to weak signals during recording neural signals. Herein, we developed a neural electrode based on the graphene/Ag van der Waals heterostructure for improving the detection sensitivity and signal-to-noise ratio (SNR). The impedance of the graphene/Ag electrode is reduced to 161.4 ± 13.4 MΩ μm

Background The RNA-binding protein (RBP) played an important role in tumors. FSCN1 functioned as an oncogene in bladder carcinoma (BLCA). FSCN1 has not been reported as an RBP in BLCA. The mechanism by which FSCN1 promoted BLCA invasion and metastasis has remained unclear. Methods The FSCN1-bound RNAs in BLCA cell lines were identified using RIP-sequencing. The regulatory relationship between FSCN1 and METTL3 or TLN1 was verified by RNA immunoprecipitation (RIP), RNA pulldown assay, co-immunoprecipitation (Co-IP), western blotting, quantitative real-time PCR (qRT-PCR) and immunofluorescence. The metastatic abilities of the BCLA cells were evaluated by in vitro wound healing and transwell assays, as well as in vivo models. Results TLN1 protein levels were higher in BLCA tissues compared to the paired para-tumor tissues, whereas its mRNA expression was lower in the tumors. Mechanistically, FSCN1 bound to and upregulated METTL3, which in turn repressed TLN1 mRNA expression through the latter’s 3'UTR. In addition, FSCN1 bound to the CDS region of TLN1 mRNA and promoted its translation. Knocking down FSCN1, METTL3 and TLN1 individually had an inhibitory effect on the proliferation, invasion, migration and metastasis of BLCA cells. Conclusions FSCN1 functions as an RBP to promote proliferation, invasion and migration of BLCA cells. The FSCN1/METTL3/TLN1 axis is a potential therapeutic target for BLCA.

Natural enzymes are efficient and versatile biocatalysts but suffer in their environmental tolerance and catalytic stability. As artificial enzymes, nanozymes can improve the catalytic stability, but it is still a challenge to achieve high catalytic activity. Here, we employed atomic engineering to build the artificial enzyme named Au24Ag1 clusterzyme that hosts an ultrahigh catalytic activity as well as strong physiological stability via atom manipulation. The designed Au24Ag1 clusterzyme activates the Ag-S active site via lattice expansion in the oligomer atom layer, showing an antioxidant property 72 times higher than that of natural antioxidant Trolox. Enzyme-mimicked studies find that Au24Ag1 clusterzyme exhibits high catalase-like (CAT-like) and glutathione peroxidase-like (GPx-like) activity with a maximum reaction rate of 68.9 and 17.8 μM/min, respectively. Meanwhile, the unique catalytic landscape exhibits distinctive reactions against inflammation by inhibiting the cytokines at an early stage in the brain. Atomic engineering of clusterzymes provides a powerful and attractive platform with satisfactory atomic dispersion for tailoring biocatalysts freely at the atomic level.

Traumatic brain injury (TBI) is a sudden injury to the brain, accompanied by the production of large amounts of reactive oxygen and nitrogen species (RONS) and acute neuroinflammation responses. Although traditional pharmacotherapy can effectively decrease the immune response of neuron cells via scavenging free radicals, it always involves in short reaction time as well as rigorous clinical trial. Therefore, a noninvasive topical treatment method that effectively eliminates free radicals still needs further investigation. Methods: In this study, a type of catalytic patch based on nanozymes with the excellent multienzyme-like activity is designed for noninvasive treatment of TBI. The enzyme-like activity, free radical scavenging ability and therapeutic efficacy of the designed catalytic patch were assessed in vitro and in vivo. The structural composition was characterized by the X-ray diffraction, X-ray photoelectron spectroscopy and high-resolution transmission electron microscopy technology. Results: Herein, the prepared Cr-doped CeO2 (Cr/CeO2) nanozyme increases the reduced Ce3+ states, resulting in its enzyme-like activity 3-5 times higher than undoped CeO2. Furthermore, Cr/CeO2 nanozyme can improve the survival rate of LPS induced neuron cells via decreasing excessive RONS. The in vivo experiments show the Cr/CeO2 nanozyme can promote wound healing and reduce neuroinflammation of mice following brain trauma. The catalytic patch based on nanozyme provides a noninvasive topical treatment route for TBI as well as other traumas diseases. Conclusions: The catalytic patch based on nanozyme provides a noninvasive topical treatment route for TBI as well as other traumas diseases.

Finding cancer-driver genes – the genes whose mutations may transform normal cells into cancerous ones – remains a central theme of cancer research. We took a different perspective; instead of considering normal cells, we focused on cancerous cells and genes that maintained abnormal cell growth which we namedcancer-keeping genes(CKGs). Intervention in CKGs may rectify aberrant cell growth so that they can be adopted as therapeutic targets for cancer treatment. We developed a novel approach to identifying CKGs by extending the well-established theory of network structural controllability, which aims at finding a control scheme (i.e., a minimal set of non-overlapping control paths covering all nodes) and control nodes (driver genes) that can steer the cell from any state to the designated state. Going beyond driver genes defined by one control scheme, we introducedcontrol-hubgenes located in the middle of a control path ofeverycontrol scheme. Control hubs are essential for maintaining cancerous states and thus can be taken as CKGs. We applied our CKG-based approach to bladder cancer (BLCA) as a case study. All the genes on the cell cycle and p53 pathways in BLCA were identified as CKGs, showing the importance of these genes in cancer and demonstrating the power of our new method. Furthermore, sensitive CKGs that could be easily changed by structural perturbation were better suited as therapeutic targets. Six sensitive CKGs (RPS6KA3, FGFR3, N-cadherin (CDH2), EP300, caspase-1, and FN1) were subjected to small-interferencing-RNA knockdown in two BLCA cell lines to validate their cancer-suppressing effects. Knocking down RPS6KA3 in a mouse model of BLCA significantly inhibited the growth of tumor xenografts in mice. Combined, our results demonstrated the value of CKGs as therapeutic targets for cancer therapy.Key pointsFocus on genes that maintain aberrant cell growth, namedcancer-keeping genes(CKGs).Develop a novel approach for finding CKGs by extending the well-estabilished theory of network structural controllability to total network controllability.Apply the new method to bladder cancer and experimentally validated the cancer-suppressing function of six CKGs in two bladder cancer cell lines and that of one CKG in bladder cancer mice.

Atomically precise Au25(SG)18 clusters have shown great promise in near-infrared II cerebrovascular imaging, X-ray imaging, and cancer radiotherapy due to their high atomic number, unique molecular-like electronic structure, and renal clearable properties. Therefore, it is important to study the in vivo toxicity of Au25 clusters. Unfortunately, previous toxicological investigations focused on low injected doses (

Bladder cancer is a common tumor with a high recurrence rate and high fatality rate, and its mechanism of occurrence and development remains unclear. Many proteins and metabolites reprogram at different stages of tumor development to support tumor cell growth. The moonlighting effect happens when a protein performs multiple functions simultaneously in a cell. In this study, we identified a metabolic protein, MTHFD2, which participates in the cell cycle by binding to CDK2 in bladder cancer. MTHFD2 has been shown to affect bladder cancer cell growth, which is independent of its metabolic function. We found that MTHFD2 was involved in cell cycle regulation and could encourage cell cycle progression by activating CDK2 and sequentially affecting E2F1 activation. In addition, moonlighting MTHFD2 might be regulated by the dynamics of the mitochondria. In conclusion, MTHFD2 localizes in the nucleus to perform a distinct function of catalyzing metabolic reactions. Moreover, the nuclear MTHFD2 activates CDK2 and promotes bladder cancer cell growth by modulating the cell cycle., This study showed that MTHFD2's expression is correlated with poor prognosis in bladder cancer. Moreover, it could precipitate with CDK2 in a metabolic manner and activate E2F1 through CDK2 to induce rapid cell growth. Furthermore, MTHFD2 could be transcriptionally regulated by the CDK2‐E2F1 axis and translocated into the nucleus at the G1‐S phase associated with mitochondrial fusion. These results suggest that MTHFD2 participates in the cell cycle using a non‐metabolic function, which should be considered in the development of related therapeutics.

This paper analyzed the effects of setback micro-springs on a MEMS safety and arming (S&A) device. To make up for defects related to current methods of obtaining the elastic coefficients of micro-springs, a computational formula for the elastic coefficients of S-shaped micro-springs was developed in accordance with Castigliano’s second theorem and Hooke’s law and verified for three types of setback micro-springs with different structures through finite element simulations and a self-designed testing system for the elastic coefficients of micro-springs. The testing values and the simulation values were in good agreement with the theoretical values. The results indicate that the precise measurement and calculation of the elastic coefficients of micro-springs in the transverse, longitudinal and vertical directions can be realized with the method presented in this paper. For the S-shaped setback micro-spring, the elastic coefficient in the transverse direction is the smallest and the most prone to fracture and plastic deformation. In the design of MEMS S&A devices, priority should be given to applying the deformation of the micro-spring in the longitudinal and vertical directions.

Conducting polymer actuators have shown wide application prospects in the field of biomedical sensors and micro-/nanorobotics. In order to explore more applications in biomedical sensing and robotics, it is essential to understand the actuator static behavior from an engineering perspective, before incorporating them into a design. In this article, we have established the mathematical model of a trilayer polypyrrole (PPy) cantilever actuator and validated it experimentally. The model helps in enhancing the efficiency and in improving the performance, predictability, and control of the actuator. The thermal expansion analogy, which is similar to volume change of the multilayer PPy actuator due to ion migration, has been considered to develop a mathematical model in COMSOL Multiphysics. To further validate the actuator deformation predicted by the mathematical modeling, a multilayer PPy actuator was fabricated by electrochemical synthesis and the experimentally determined deflection of the actuator was compared to simulation data. Both the theoretical and experimental results depict that the model is effective for predicting the bending behavior of multilayer PPy actuators at different input voltages.

To make up for the deficiencies in the present method of measuring microdetonator output energy, this paper uses PVDF (Polyvinylidene Fluoride) piezoelectric films as sensors and designs a system to test the output pressure of microdetonators with a 2.5 mm diameter. The average measured output pressure was 9.87GPa. In addition, detonation tests were carried out which showed that a microdetonator with a 10 mg charge could reliably detonate a JO-9C(III model) lead explosive with an 8 mg charge in a 0.7 mm air-gap. The detonation simulations for lead explosives using LS-DYNA software were consistent with the detonation test results. There was less than 5% error between the output pressure values and the test values of microdetonators. The results showed that PVDF piezoelectric films have rapid response times, high precision and low production cost in output pressure tests. The simulation model has practical significance for the quantitative evaluation of microdetonator output energy.

The manufacturing process of planar microsprings by the UV-LIGA process was introduced; the mechanism of fabrication error was analyzed from three process stages of exposure, SU-8 swelling, and corrosion; and the corresponding improvement measures were proposed. The line width of two groups of microsprings after the exposure, SU-8 swelling, and debonding was measured, and the elastic coefficients in three coordinate directions were accurately measured. The results show that the factors that affect the line width error are stable. The effects of the exposure diffraction, swelling of SU-8 glue, and debonding corrosion process on the line width size follow the order: corrosion error > swelling error > exposure error. When the line width is small, the aspect ratio of the microspring is large, and the direction of machining error is generally negative. The relative error of the elastic coefficient of microsprings in three coordinate directions is larger. The influence rule of the line width error on the elastic coefficient follows the order: kerrory > kerrorx > kerrorz.

As the transmembrane receptor of Netrin-1, the tumor suppressor gene Unc-5 Netrin Receptor C (UNC5C) can trigger apoptosis. Although its tumor suppressor effects have been demonstrated in solid tumors such as colon cancer, there is still a lack of systematic research on its expression regulation mechanism. To address this need, we analyzed datasets from The Cancer Genome Atlas (TCGA) database, including multi-omics data for 32 types of cancers and 10,967 cases. Analysis of these data revealed a trend of significantly decreased UNC5C expression in 16 types of solid tumors. Additionally, low UNC5C expression is related to poor prognosis of five types of tumors and restoring the expression of UNC5C can effectively inhibit the proliferation potential of renal cancer cells. Promoter DNA methylation, chromatin remodeling-mediated epigenetic regulation, transcriptional inhibition, RNA-binding protein and miRNA-mediated post-transcriptional inhibition, genetic changes caused by deep deletion and truncated mutations, and ubiquitinating enzyme-mediated protein degradation can synergistically cause the down-regulation of UNC5C expression in solid tumors. This study is the first to analyze the comprehensive molecular mechanism of down-regulation of the tumor suppressor gene UNC5C from multiple dimensions using pan-cancer data. Our results suggest that analyses of gene expression regulation relying on computational biological methods may help guide the targeted therapy of tumor suppressor gene reactivation.

Due to the complexity of industrial intelligent diagnosis, transfer learning-based fault diagnosis has become an evolving focus of the research field. Transfer learning uses knowledge of the source domain to identify faults in the target domain, which is a powerful tool to solve the problem of fault signal domain shift. However, existing methods have a limitation on multiple target domains. In other words, for different domains, respective transfer tasks are necessary. To seek a breakthrough, a adversarial multi-domain adaptation (AMDA) fault diagnosis method is proposed, realizing the fault diagnosis of multiple target domains by using the knowledge of a single source domain. AMDA is divided into three parts, namely, feature extractor, fault classifier and domain classifier. Through multi-domain adversarial learning, feature extractor and domain classifier mine the knowledge shared by multiple domains, and fault classifier can identify fault features distributed in different domains. The proposed AMDA method can surpass some traditional transfer learning fault diagnosis methods. Furthermore, as feature visualization result revealed, AMDA has significant advantages in multi-domain and broad research prospects.

Implantable neural electrodes can record and regulate neural activities with high spatial resolution of single-neuron and high time resolution of sub-millisecond, which are the most extensive window in neuroscience research. However, the mechanical mismatch between conventional stiff electrodes and soft neural tissue can lead to inflammatory responses and degradation of signals in chronic recordings. Although remarkable breakthroughs have been made in sensing and regulation of neural signals, the long-term stability and chronic inflammatory response of the neural electrode-tissue interfaces still needs further development. In this review, we focus on the latest developments for the optimization of neural electrode-tissue interfaces, including electrode materials (graphene fiber-based and CNT fiber-based), electrode structures (flexible electrodes), nano-coatings and hydrogel-based neural interfaces. The parameters of impedance, charge injection limit, signal-to-noise ratio and neuron lost zone are used to evaluate the electrochemical performance of the devices, the recording performance of biosignals and the stability of the neural interfaces, respectively. These optimization methods can effectively improve the long-term stability and the chronic inflammatory response of neural interfaces during the recording and modulation of biosignals.

Background Chemo-resistance of bladder cancer has been considered to be one of the serious issues to be solved. In this study, we revealed pivotal role of miR-424 in the regulation of CDDP sensitivity of bladder cancer cells. Methods The cytotoxicity of cisplatin and effect of miR-424 were assessed by flow cytometry and TUNEL. Transcriptional regulation of miR-424 by HIF-1α was assessed by Chromatin immunoprecipitation (ChIP). Effect of miR-424 on expression of UNC5B, SIRT4 (Sirtuin4) and apoptotic markers was measured by QRT-PCR and/or Western blot. The regulation of miR-424 for UNC5B and SIRT4 were tested by luciferase reporter assay. The 5637-inoculated nude mice xenograft model was used for the in vivo study. The clinical significance of miR-424 was demonstrated mainly through data mining and statistical analysis of TCGA. Results In this study, we have found for the first time that cisplatin (CDDP) induces the expression of miR-424 in a HIF-1α-dependent manner under normoxia, and miR-424 plays a vital role in the regulation of CDDP resistance of bladder cancer cells in vitro. Mechanistically, we have found that UNC5B and SIRT4 are the direct downstream target genes of miR-424. CDDP-mediated suppression of xenograft bladder tumor growth was prohibited by the addition of miR-424, whereas ectopic expression of UNC5B or SIRT4 partially restored miR-424-dependent decrease in CDDP sensitivity of bladder cancer 5637 and T24 cells. Moreover, knockdown of UNC5B or SIRT4 prohibited CDDP-mediated proteolytic cleavage of PARP and also decreased CDDP sensitivity of these cells. Consistently, the higher expression levels of miR-424 were closely associated with the poor clinical outcome of the bladder cancer patients. There existed a clear inverse relationship between the expression levels of miR-424 and pro-apoptotic UNC5B or SIRT4 in bladder cancer tissues. Conclusions Collectively, our current results strongly suggest that miR-424 tightly participates in the acquisition/maintenance of CDDP-resistant phenotype of bladder cancer cells through down-regulation of its targets UNC5B and SIRT4, and thus combination chemotherapy of CDDP plus HIF-1α/miR-424 inhibition might have a significant impact on hypoxic as well as normoxic bladder cancer cells.

Background Small compound oridonin acts as an effective anti-tumor agent used for a wide variety of human malignancies, while the antitumor efficacy and molecular mechanism of oridonin against bladder cancer remains unclear. Methods Four independent cohorts of bladder cancer were employed to assess the correlation between netrin-1 expression and progression and prognosis of bladder cancer. Clinical potential of netrin-1 as a biomarker and oridonin-mediated netrin-1-targeting anti-tumor mechanism were investigated by QRT-PCR, Western blot and ELISA. Regulatory mechanisms of Netrin-1 were investigated by luciferase reporter assay and Western blot. The EJ-inoculated nude mice xenograft model was used for the in vivo study. Results High expression of netrin-1 was significantly correlated with a poor overall survival in three independent bladder cancer cohorts. Urinary netrin-1 level was significantly elevated in bladder cancer patients correlating with tumor invasion and grade. Netrin-1 promoted cell proliferation, tumorsphere-forming, migration and invasion in bladder cancer cells. Oridonin treatment strikingly suppressed these malignant phenotypes and induced cell death in TCC cell lines and murine xenografts. Oridonin markedly decreased netrin-1 through inhibiting NF-κB transcriptional activity and shortening the half-life of NTN1 mRNA via inducing IRE1α, resulting in repression of its downstream signaling. Conclusions Together, these results strongly suggest that netrin-1 promotes the progression of bladder cancer, and acts as a potential urinary biomarker for the diagnosis as well as the prediction of the tumor progression. Oridonin exerts its strong anti-tumor activity against the invasive bladder cancer by suppressing netrin-1 mRNA production and stability.

Additional file 1: Supplementary Table 1. Sequences of oligonucleotide primers used for qPCR in the study. Supplementary Table 2. Clinicopathological characters of the patients with bladder cancer in our dataset.

Mechanical fault diagnosis is an indispensable part of the modern industrial production process. The application scenario of fault diagnosis according to a neural network from theory to practical application is worth exploring. Most existing work focuses on remaining life prediction and fault classification, treating these two steps independently. This study aims at coherent real-time monitoring of bearing status and proposes a gated recurrent unit -based fault monitoring structure to obtain timely response and preliminary classification of sudden faults. In the existing fault classification research, more attention is paid to the classification accuracy of the fault details. The time sequence law followed by the sudden fault and the short-term prediction of that fault are easily overlooked. The proposed method is trained by key-frames of bearing data. These data frames first pass through the feature extraction layer which consists of two layers of 1D convolution. Then, the reset gates and update gates of developed units keep the valid information at the last moment and update the unit state at that instant. A sudden fault will trigger the detection network, and the detected fault frame will be extracted for further classification by the independently trained fault classification network. During the test, a prediction of the moment of failure occurrence is directly obtained. When the status is judged to be faulty, the fault frame is directly extracted and used as the input of the classification network. Experimental results confirm that the network quickly responds to sudden failures under an operating environment, and the classification accuracy rate can stably reach more than 98%.

In this work, the organic light-emitting diodes (OLEDs) based on Alq3 are fabricated. In order to make clear the transport mechanism of carriers in organic light-emitting devices at low temperature, detailed electroluminescence transient response and the current-voltage–luminescence (I–V–L) characteristics under different temperatures in those OLEDs are investigated. It founds that the acceleration of brightness increases with increasing temperature is maximum when the temperature is 200 K and it is mainly affected by the electron transport layer (Alq3). The MoO3 injection layer and the electroluminescent layer have great influence on the delay time when the temperature is 200 K. Once the temperature is greater than 250 K, the delay time is mainly affected by the MoO3 injection layer. On the contrary, the fall time is mainly affected by the electroluminescent material. The Vf is the average growth rate of fall time when the temperature increases 1 K which represents the accumulation rate of carriers. The difference between Vf caused by the MoO3 injection layer is 0.52 us/K and caused by the electroluminescent material Ir(ppy)3 is 0.73 us/K.

This paper studies the aerodynamic characteristics of the composite motion of the wing during the flight of the bionic flapping wing. The dynamic hybrid mesh technique is used to solve the Nave Stokes (N-S) equation, and the changes of the lift resistance generated by the wing under different flapping amplitude, flapping frequency and chord torsion angle parameters are analyzed. By analyzing the aerodynamic efficiency of the wing, the optimal motion parameters of the flapping wing are obtained, which provides a theoretical basis for the design of the flapping bionic aircraft.

Mobile medical devices provide great promise for self-health monitoring and preventive medicine. Especially, photodetectors (PDs) based on two-dimensional (2D) materials have attracted the wide interest in biomedicine and healthcare. In this review, we summarized the research progress of PDs based on 2D materials, and described the important applications of these devices in the wearable and implantable devices. We also analyzed their various properties such as sensitivity, mechanical flexibility, robustness and biocompatibility of the wearable and implantable devices. The typical biomedical application, such as UV-radiation monitor, pulse oximeters and retinal prosthesis were reviewed. We also discussed some of the technical challenges in wearable and implantable device and possible solutions. The state of art, non-invasive devices show great promising for real-time pathological monitor, health management and tracking.