NRDE2 deficiency impairs homologous recombination repair and sensitizes hepatocellular carcinoma to PARP inhibitors.

To identify novel susceptibility genes for hepatocellular carcinoma (HCC), we performed a rare-variant association study in Chinese populations consisting of 2,750 cases and 4,153 controls. We identified four HCC-associated genes, including NRDE2, RANBP17, RTEL1, and STEAP3. Using NRDE2 (index rs199890497 [p.N377I], p = 1.19 × 10-9) as an exemplary candidate, we demonstrated that it promotes homologous recombination (HR) repair and suppresses HCC. Mechanistically, NRDE2 binds to the subunits of casein kinase 2 (CK2) and facilitates the assembly and activity of the CK2 holoenzyme. This NRDE2-mediated enhancement of CK2 activity increases the phosphorylation of MDC1 and then facilitates the HR repair. These functions are eliminated almost completely by the NRDE2-p.N377I variant, which sensitizes the HCC cells to poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with chemotherapy. Collectively, our findings highlight the relevance of the rare variants to genetic susceptibility to HCC, which would be helpful for the precise treatment of this malignancy.

Continuous roller nanoimprinting: next generation lithography.

Nanoimprint lithography (NIL) is a cost-effective and high-throughput technique for replicating nanoscale structures that does not require expensive light sources for advanced photolithography equipment. NIL overcomes the limitations of light diffraction or beam scattering in traditional photolithography and is suitable for replicating nanoscale structures with high resolution. Roller nanoimprint lithography (R-NIL) is the most common NIL technique benefiting large-scale, continuous, and efficient industrial production. In the past two decades, a range of R-NIL equipment has emerged to meet the industrial needs for applications including biomedical devices, semiconductors, flexible electronics, optical films, and interface functional materials. R-NIL equipment has a simple and compact design, which allows multiple units to be clustered together for increased productivity. These units include transmission control, resist coating, resist curing, and imprinting. This critical review summarizes the hitherto R-NIL processes, their typical technical problems, and corresponding solutions and gives guidelines for developing advanced R-NIL equipment.

The effect of the subthreshold oscillation induced by the neurons' resonance upon the electrical stimulation-dependent instability.

Repetitive electrical nerve stimulation can induce a long-lasting perturbation of the axon's membrane potential, resulting in unstable stimulus-response relationships. Despite being observed in electrophysiology, the precise mechanism underlying electrical stimulation-dependent (ES-dependent) instability is still an open question. This study proposes a model to reveal a facet of this problem: how threshold fluctuation affects electrical nerve stimulations. This study proposes a new method based on a Circuit-Probability theory (C-P theory) to reveal the interlinkages between the subthreshold oscillation induced by neurons' resonance and ES-dependent instability of neural response. Supported by in-vivo studies, this new model predicts several key characteristics of ES-dependent instability and proposes a stimulation method to minimize the instability. This model provides a powerful tool to improve our understanding of the interaction between the external electric field and the complexity of the biophysical characteristics of axons.

Ion-Assisted Preparation of Bimetallic Porous Nanodendrites for Active and Stable Water Electrolysis.

Delicate electrochemical active surface area (ECSA) engineering over the exposed catalytic interface and surface topology of platinum-based nanomaterial represents an effective pathway to boost its catalytic properties toward the clean energy conversion system. Here, for the first time, the facial and universal production of dendritic Pt-based nanoalloys (Pt-Ni, Co, Fe) with highly porous feature via a novel Zn2+ -mediated solution approach is demonstrated. In the presence of Zn2+ during synthesis, the competition of different galvanic replacement reactions and consequently generated "branch-to-branch" growth mode are believed to play key roles for the in situ fabrication of such unique nanostructure. Due to the fully exposed active sites and ligand effect-induced electronic optimization, electrochemical hydrogen evolution in alkaline media on these catalysts exhibit dramatic activity enhancement, delivering a current density of 30.6 mA cm-2 at a 70 mV overpotential for the Pt3 Ni nanodendrites and over 7.4 times higher than that of commercial Pt/C. This work highlights a general and powerful ion-assisted strategy for exploiting dendritic Pt-based nanostructures with efficient activities for water electrolysis.

Slippery Epidural ECoG Electrode for High-Performance Neural Recording and Interface.

Chronic implantation of an epidural Electrocorticography (ECoG) electrode produces thickening of the dura mater and proliferation of the fibrosis around the interface sites, which is a significant concern for chronic neural ECoG recording applications used to monitor various neurodegenerative diseases. This study describes a new approach to developing a slippery liquid-infused porous surface (SLIPS) on the flexible ECoG electrode for a chronic neural interface with the advantage of increased cell adhesion. In the demonstration, the electrode was fabricated on the polyimide (PI) substrate, and platinum (Pt)-gray was used for creating the porous nanocone structure for infusing the silicone oil. The combination of nanocone and the infused slippery oil layer created the SLIPS coating, which has a low impedance (4.68 kΩ) level favourable for neural recording applications. The electrochemical impedance spectroscopy and equivalent circuit modelling also showed the effect of the coating on the recording site. The cytotoxicity study demonstrated that the coating does not have any cytotoxic potentiality; hence, it is biocompatible for human implantation. The in vivo (acute recording) neural recording on the rat model also confirmed that the noise level could be reduced significantly (nearly 50%) and is helpful for chronic ECoG recording for more extended neural signal recording applications.

A physical perspective to understand myelin. I. A physical answer to Peter's quadrant mystery.

In the development of oligodendrocytes in the central nervous systems, the inner and outer tongue of the myelin sheath tend to be located within the same quadrant, which was named as Peters quadrant mystery. In this study, we conduct in silico investigations to explore the possible mechanisms underlying the Peters quadrant mystery. A biophysically detailed model of oligodendrocytes was used to simulate the effect of the actional potential-induced electric field across the myelin sheath. Our simulation suggests that the paranodal channel connecting the inner and outer tongue forms a low impedance route, inducing two high-current zones at the area around the inner and outer tongue. When the inner tongue and outer tongue are located within the same quadrant, the interaction of these two high-current-zones will induce a maximum amplitude and a polarity reverse of the voltage upon the inner tongue, resulting in the same quadrant phenomenon. This model indicates that the growth of myelin follows a simple principle: an external negative or positive E-field can promote or inhibit the growth of the inner tongue, respectively.

A physical perspective to understand myelin II: The physical origin of myelin development.

The physical principle of myelin development is obtained from our previous study by explaining Peter's quadrant mystery: an externally applied negative and positive E-field can promote and inhibit the growth of the inner tongue of the myelin sheath, respectively. In this study, this principle is considered as a fundamental hypothesis, named Hypothesis-E, to explain more phenomena about myelin development systematically. Specifically, the g-ratio and the fate of the Schwann cell's differentiation are explained in terms of the E-field. Moreover, an experiment is proposed to validate this theory.

Microglial debris is cleared by astrocytes via C4b-facilitated phagocytosis and degraded via RUBICON-dependent noncanonical autophagy in mice.

Microglia are important immune cells in the central nervous system (CNS) that undergo turnover throughout the lifespan. If microglial debris is not removed in a timely manner, accumulated debris may influence CNS function. Clearance of microglial debris is crucial for CNS homeostasis. However, underlying mechanisms remain obscure. We here investigate how dead microglia are removed. We find that although microglia can phagocytose microglial debris in vitro, the territory-dependent competition hinders the microglia-to-microglial debris engulfment in vivo. In contrast, microglial debris is mainly phagocytosed by astrocytes in the brain, facilitated by C4b opsonization. The engulfed microglial fragments are then degraded in astrocytes via RUBICON-dependent LC3-associated phagocytosis (LAP), a form of noncanonical autophagy. Interference with C4b-mediated engulfment and subsequent LAP disrupt the removal and degradation of microglial debris, respectively. Together, we elucidate the cellular and molecular mechanisms of microglial debris removal in mice, extending the knowledge on the maintenance of CNS homeostasis.

Research Progress of Long Non-Coding RNA GAS5 in Malignant Tumors.

With completing the whole genome sequencing project, awareness of lncRNA further deepened. The growth arrest-specific transcript 5 (GAS5) was initially identified in growth-inhibiting cells. GAS5 is a lncRNA (long non-coding RNA), and it plays a crucial role in various human cancers. There are small ORFs (open reading frames) in the exons of the GAS5 gene sequence, but they do not encode functional proteins. In addition, GAS5 is also the host gene of several small nucleolar RNAs (snoRNA). These snoRNAs are believed to play a suppressive role during tumor progression by methylating ribosomal RNA (rRNA). As a result, GAS5 expression levels in tumor tissues are significantly reduced, leading to increased malignancy, poor prognosis, and drug resistance. Recent studies have demonstrated that GAS5 can interact with miRNAs by base-pairing and other functional proteins to inhibit their biological functions, impacting signaling pathways and changing the level of intracellular autophagy, oxidative stress, and immune cell function in vivo. In addition, GAS5 participates in regulating proliferation, invasion, and apoptosis through the above molecular mechanisms. This article reviews the recent discoveries on GAS5, including its expression levels in different tumors, its biological behavior, and its molecular regulation mechanism in human cancers. The value of GAS5 as a molecular marker in the prevention and treatment of cancers is also discussed.

The Effect of Electrical Stimulation on the Response of Mouse Retinal Ganglion Cells.

Retinal prostheses can restore the basic visual function of patients with retinal degeneration, which relies on effective electrical stimulation to evoke the physiological activities of retinal ganglion cells (RGCs). Current electrical stimulation strategies suffer from unstable effects and insufficient stimulation positions. Therefore, it is crucial to determine the optimal parameters for precise and safe electrical stimulation. Biphasic voltages (cathode-first) with a pulse width of 25 ms and different amplitudes were used to ex vivo stimulate RGCs of three wild-type (WT) mice using a commercial microelectrode array (MEA) recording system. Based on a facile and efficient spike sorting method, comprehensive statistics of RGCs response types were performed, and the influence of electrical stimulation on RGCs response status was analyzed. There were three types of RGCs response measured from the retinas of three WT mice, and the proportions were calculated to be 91.5%, 3.11% and 5.39%, respectively. This work can provide an in-depth understanding of the internal effects of electrical stimulation and RGCs response, with the potential as a useful guidance for optimizing parameters of electrical stimulation strategies in retinal prostheses.

Monitoring Cortical Response and Electrode-Retina Impedance Under Epiretinal Stimulation in Rats.

Retinal prosthesis can restore partial vision in patients with retinal degenerative diseases such as retinitis pigmentosa and age-related macular degeneration. Epiretinal prosthesis is one of three therapeutic approaches, which received regulatory approval several years ago. The thresholds of an epiretinal stimulation is partly determined by the size of the physical gap between the electrode and the retina after implantation. Precise positioning of epiretinal stimulating electrode array is still a challenging task. In this study, we demonstrate an approach to positioning epiretinal prostheses for an optimal response at the cortical output by monitoring both the impedance at the electrode-retina interface and the evoked-potential at the cortical level. We implanted a single-channel electrode on the epiretinal surface in adult rats, acutely, guided by both the impedance at the electrode-retina interface and by electrically evoked potentials (EEPs) in the visual cortex during retinal stimulation. We observe that impedance monotonously increases with decreasing electrode-retina distance, but that the strongest cortical responses were achieved at intermediate impedance levels. When the electrode penetrates the retina, the impedance keeps increasing. The effect of stimulation on the retina changes from epiretinal paradigm to intra-retinal paradigm and a decrease in cortical activation is observed. It is found that high impedance is not always favorable to elicit best cortical responses. Histopathological results showed that the electrode was placed at the intra-retinal space at high impedance value. These results show that monitoring impedance at the electrode-retina interface is necessary but not sufficient in obtaining strong evoked-potentials at the cortical level. Monitoring the cortical EEPs together with the impedance can improve the safety of implantation as well as efficacy of stimulation in the next generation of retinal implants.

A compact fiber-integrated optofluidic platform for highly specific microRNA Förster resonance energy transfer detection.

MicroRNAs (miRNAs) have attracted extensive interest as promising biomarkers for the profiling of diseases. However, quantitative measurement of miRNAs presents a significant challenge in biochemical studies. In this work, we developed an innovative optofluidic platform to perform a rapid, simple, quantitative and high-specificity miRNA assay using the Förster resonance energy transfer (FRET) principle. A novel three-way junction FRET probe was proposed to enable rapid and enzyme-free miRNA detection. Using this platform, we performed one-step, amplification-free miRNA detection with simple device operation and achieved miRNA identification at a low concentration. The detection system could achieve high specificity for discrimination of three-base mismatches, and the sample volume was significantly reduced, favorable for low-level miRNA detection in material-limited samples. The establishment of a compact, low-cost, highly sensitive and selective miRNA analysis platform provides a valuable tool for point-of-care diagnosis.

A facile and comprehensive algorithm for electrical response identification in mouse retinal ganglion cells.

Retinal prostheses can restore the basic visual function of patients with retinal degeneration, which relies on effective electrical stimulation to evoke the physiological activities of retinal ganglion cells (RGCs). Current electrical stimulation strategies have defects such as unstable effects and insufficient stimulation positions, therefore, it is crucial to determine the optimal pulse parameters for precise and safe electrical stimulation. Biphasic voltages (cathode-first) with a pulse width of 25 ms and different amplitudes were used to ex vivo stimulate RGCs of three wild-type (WT) mice using a commercial microelectrode array (MEA) recording system. An algorithm is developed to automatically realize both spike-sorting and electrical response identification for the spike signals recorded. Measured from three WT mouse retinas, the total numbers of RGC units and responsive RGC units were 1193 and 151, respectively. In addition, the optimal pulse amplitude range for electrical stimulation was determined to be 0.43 V-1.3 V. The processing results of the automatic algorithm we proposed shows high consistency with those using traditional manual processing. We anticipate the new algorithm can not only speed up the elaborate electrophysiological data processing, but also optimize pulse parameters for the electrical stimulation strategy of neural prostheses.

Slippery liquid-infused porous surfaces with inclined microstructures to enhance durable anti-biofouling performances.

In the development of biocompatible materials for biomedical applications, infections and their resulting inflammation responses are important issues caused typically by the adhesion of micro-organisms on medical devices. Recently slippery liquid-infused porous surfaces (SLIPS) has provided a new strategy for anti-biofouling and low-adhesion surfaces, however, there are still some bottlenecks in practical uses, particularly the loss of lubricant significantly restricts the durability and stability of SLIPS. In this paper, we micro-fabricated well-controlled micro-cavities with different profiles (vertical or inclined walls) to investigate the long-term anti-biofouling effect of SLIPS. We explored microstructure geometries in two aspects: the aspect ratio and the slope angle relevant with the Laplace pressure and the oil contact area which lead to different oil-locking abilities. High aspect ratio and inclined slope were demonstrated with better oil-locking ability as well as significantly increased anti-fouling performances. Under the same experimental setup, the Escherichia coli and Staphylococcus aureus bacteria coverage on SLIPS with 80 µm-depth 20° inclined micro-cavities was only ∼30 % of that with vertical micro-cavities, while increasing aspect ratio by 4 times induced ∼3 times enhanced anti-fouling effect. On basis of these findings, we propose the enhanced SLIPS with inclined microstructures to achieve better oil-locking ability and long-term anti-biofouling performance, which may broaden many practical applications of SLIPS.

Microscale magnetic field modulation using rapidly patterned soft magnetic microstructures.

The ability to locally modulate the magnetic field distribution is a prerequisite for efficient manipulation in magnetic force-based microfluidic devices. Here, we report a simple, robust, and fast fabrication method of magnetic microstructures for locally modulating magnetic fields. In the proposed method, a photosensitive magnetic composite consisting of carbonyl-iron microparticles in a poly(ethylene glycol) diacrylate (PEGDA) matrix was utilized to photolithographically fabricate magnetic microstructures. The magnetic behavior of the composite was first evaluated, and then various complicated patterns were fabricated on a glass slide within a few minutes. To demonstrate the capability of magnetic microstructures as a magnetic field concentrator, magnetic microstructures with different orientations to the external magnetic field were designed and fabricated, such as square arrays and grid-like magnetic microstructures. The modulated magnetic fields from such magnetic microstructures were numerically analyzed and then experimentally validated by trapping magnetic hydrogel beads. Further, the magnetically labeled cells were applied to the magnetic microstructures to prove the possibility of cell confinement via magnetic guidance in regions that exhibit enhanced magnetic field gradients. Overall, the proposed approach facilitates simple and fast fabrication of soft magnetic microstructures for microscale modulation of magnetic fields, which exhibits an immense application potential in magnetic force-based microfluidic techniques.

Ultrafast Microdroplet Generation and High-Density Microparticle Arraying Based on Biomimetic Nepenthes Peristome Surfaces.

Manipulation of massive droplets, particles, as well as cells has enabled wide applications. However, most existing technologies require complicated processes, operations, or external setup. This article demonstrates the employment of biomimetic Nepenthes peristome surfaces (NPS) in achieving ultrafast microdroplet generation and high-density microparticle arraying, with the assistance of curvature-induced Laplace pressure in slipping mode and evaporation-driven Marangoni effect in climbing mode, respectively. Different wetting phenomena on the biomimetic NPS were observed under variable contact angles and tilting angles, strongly affecting the microdroplet generation and microparticle array. As the optimal results, 5 µm-size microparticles were arrayed with 85% coverage rate in 65 s and 20 µm-size microdroplets were arrayed with 100% coverage rate in 3 s. In this study, this well-designed bionic surface shows excellent performances as an ultrafast, universal, and straightforward approach to capture and array micro-objects in aqueous solutions for various biological and chemical analyses.

A Review and Perspective for the Development of Triboelectric Nanogenerator (TENG)-Based Self-Powered Neuroprosthetics.

Neuroprosthetics have become a powerful toolkit for clinical interventions of various diseases that affect the central nervous or peripheral nervous systems, such as deep brain stimulation (DBS), functional electrical stimulation (FES), and vagus nerve stimulation (VNS), by electrically stimulating different neuronal structures. To prolong the lifetime of implanted devices, researchers have developed power sources with different approaches. Among them, the triboelectric nanogenerator (TENG) is the only one to achieve direct nerve stimulations, showing great potential in the realization of a self-powered neuroprosthetic system in the future. In this review, the current development and progress of the TENG-based stimulation of various kinds of nervous systems are systematically summarized. Then, based on the requirements of the neuroprosthetic system in a real application and the development of current techniques, a perspective of a more sophisticated neuroprosthetic system is proposed, which includes components of a thin-film TENG device with a biocompatible package, an amplification circuit to enhance the output, and a self-powered high-frequency switch to generate high-frequency current pulses for nerve stimulations. Then, we review and evaluate the recent development and progress of each part.

Optimization of stimulation parameters for epi-retinal implant based on biosafety consideration.

BACKGROUND: Optimizing stimulation protocol is essential for clinical application of retinal prosthesis. Elongating stimulation pulse width (~25ms /phase) has been proposed as an effective method to improve spatial resolution of epi-retinal implants. However, it is unknown whether longer stimulus pulse width will increase the risk of damaging the retina. In addition, with the advent of next generation retinal prosthesis featuring high-density microelectrode array, it is tempting to optimizing a single set of parameters for all electrodes instead of optimizing parameters of each electrode, but this approach raised biosafety concern. We sought to study the effect of stimulus pulse width on the response of retinal ganglion cells to electrical stimulation, and evaluate if the single parameter set approach was valid based on biosafety measures. METHODS: We stimulated mouse retina using biphasic pulse waveform generated by chosen electrodes (single or a 3x3 assembly) from multiple microelectrode arrays, recorded their action potentials and performed spike sorting. We tested various stimulus intensity with two fixed pulse width: a short one for 1 millisecond per phase, and a long one for 25 milliseconds per phase. All these assays were performed on two mouse models: the wildtype C57BL/6J mice and the photoreceptor degenerated rd10 mice. The action-potential-frequency vs stimulus amplitude profiles were plotted, and three parameters were extracted: the threshold (the lowest stimulus amplitude activating RGC units), safety-limit (stimulus amplitude that attenuated the firing rate to half of the maximum response), and the stimulation amplitude range (the difference between threshold and safety limit parameters). RESULTS: In single-electrode stimulation experiment, we found that on average 85% of the recorded units showed attenuated response to extreme stimulation; among those units, an average of 51% stopped responding during stimulation ramping and failed to recover after one-hour post-stimulation, indicating extreme stimulation can damage RGC units. Twenty-five-millisecond pulse stimulation significantly reduced safety-limit and stimulation-amplitude-range parameters of recorded RGC units compared to 1ms pulse stimulation. During stimulus amplitude ramping, the maximum proportion of responsive healthy RGC units was 51% on average in 25ms pulse condition, and 76% on average in 1ms pulse condition, indicating long pulse may inflict more strain on RGCs, and a significant amount of inappropriately stimulated RGCs always exist. The contrast of these proportions could be explained by the tight correlation between the threshold and safety-limit parameter in 25ms pulse condition. These results were corroborated by those from 3x3 array stimulation experiments. CONCLUSION: Base on a biosafety measure (RGCs' evoked firing rate in response to electrical stimulation), we proposed that longer stimulation pulse width could lead to reduced retinal response and thus highlighted the importance of carefully setting the stimulation amplitude in this case. Our results also suggested that optimizing a single set of parameters for all electrodes without individual tweaking always generated a significant amount of inappropriately stimulated RGCs, especially in the long pulse stimulation condition.

Fast Polymerization of Polydopamine Based on Titanium Dioxide for High-Performance Flexible Electrodes.

Dopamine (DA) and its derivatives are promising for the fabrication of functional films and devices with excellent conductivity and long-term stability; nevertheless its polymerization process is typically prolonged. We have proposed the accelerated deposition process using ultraviolet (UV) irradiation with the existence of nanotitanium dioxide (nano-TiO2) in order to realize the rapid and stable synthesis of polydopamine (PDA) films. The in situ deposition process of nanostructured coatings such as platinum nanowire (PtNW) was also proposed by reducing the time of polymerization process to less than 1 h. It also increased the platinum (Pt) chelating rate with PDA, which was about 12 times faster than the traditional photo-oxidation method. Compared with the electrodes of the same size based on Ti/Pt sputtering, the impedance of the proposed PDA/TiO2/PtNW coated electrode was as low as 0.0968 ± 0.0054 kΩ at 1 kHz (reduction of 99.74%). An extremely high cathodic charge storage capacity (CSCc) up to 234.4 ± 3.16 mC cm-2 was also observed, which was about 106.5 and 1.6 times higher than that of Ti/Pt and PDA/PtNW electrodes, respectively. In addition to that, significant photocurrent polarization responses were presented for PDA/TiO2/PtNW electrodes with a stable current of -136.1 µA, exhibiting excellent charge transfer and UV absorption capacities. This co-deposition method has demonstrated great potential to speed up the polymerization process and enhance the electrical performance for flexible electrodes.