N6-Methyladenosine-Modified KREMEN2 Promotes Tumorigenesis and Malignant Progression of High-Grade Serous Ovarian Cancer.

High-grade serous ovarian cancer (HGSOC) remains the most lethal female cancer by far. Herein, clinical HGSOC samples had higher N6-methyladenosine (m6A) modification than normal ovarian tissue, and its dysregulation had been reported to drive aberrant transcription and translation programs. However, Kringle-containing transmembrane protein 2 (KREMEN2) and its m6A modification have not been fully elucidated in HGSOC. In this study, the data from the high-throughput messenger RNA (mRNA) sequencing of clinical samples were processed using the weighted correlation network analysis and functional enrichment analysis. Results revealed that KREMEN2 was a driver gene in the tumorigenesis of HGSOC and a potential target of m6A demethylase fat-mass and obesity-associated protein (FTO). KREMEN2 and FTO levels were upregulated and downregulated, respectively, and correlation analysis showed a significant negative correlation in HGSOC samples. Importantly, upregulated KREMEN2 was remarkably associated with lymph node metastasis, distant metastasis, peritoneal metastasis, and high International Federation of Gynecology and Obstetrics stage (Ⅲ/Ⅳ), independent of the age of patients. KREMEN2 promoted the growth of HGSOC in vitro and in vivo, which was dependent on FTO. The methylated RNA immunoprecipitation qPCR and RNA immunoprecipitation assays were performed to verify the m6A level and sites of KREMEN2. FTO overexpression significantly decreased m6A modification in the 3' and 5' untranslated regions of KREMEN2 mRNA and downregulated its expression. In addition, we found that FTO-mediated m6A modification of KREMEN2 mRNA was recognized and stabilized by the m6A reader IGF2BP1 rather than by IGF2BP2 or IGF2BP3. This study highlights the m6A modification of KREMEN2 and extends the importance of RNA epigenetics in HGSOC.

Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function.

BACKGROUND AND AIMS: Sex determining region Y related high-mobility group box protein 9 (Sox9) is expressed in a subset of hepatocytes, and it is important for chronic liver injury. However, the roles of Sox9+ hepatocytes in response to the acute liver injury and repair are poorly understood. METHODS: In this study, we developed the mature hepatocyte-specific Sox9 knockout mouse line and applied three acute liver injury models including PHx, CCl4 and hepatic ischemia reperfusion (IR). Huh-7 cells were subjected to treatment with hydrogen peroxide (H2O2) in order to induce cellular damage in an in vitro setting. RESULTS: We found the positive effect of Sox9 deletion on acute liver injury repair. Small heterodimer partner (SHP) expression was highly suppressed in hepatocyte-specific Sox9 deletion mouse liver, accompanied by less cell death and more cell proliferation. However, in mice with hepatocyte-specific Sox9 deletion and SHP overexpression, we observed an opposite phenotype. In addition, the overexpression of SOX9 in H2O2-treated Huh-7 cells resulted in an increase in cytoplasmic SHP accumulation, accompanied by a reduction of SHP in the nucleus. This led to impaired mitochondrial function and subsequent cell death. Notably, both the mitochondrial dysfunction and cell damage were reversed when SHP siRNA was employed, indicating the crucial role of SHP in mediating these effects. Furthermore, we found that Sox9, as a vital transcription factor, directly bound to SHP promoter to regulate SHP transcription. CONCLUSIONS: Overall, our findings unravel the mechanism by which hepatocyte-specific Sox9 knockout ameliorates acute liver injury via suppressing SHP signaling and improving mitochondrial function. This study may provide a new treatment strategy for acute liver injury in future.

Lgr5 + cell fate regulation by coordination of metabolic nuclear receptors during liver repair.

Background: Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) is a target gene of Wnt/ß-Catenin which plays a vital role in hepatic development and regeneration. However, the regulation of Lgr5 gene and the fate of Lgr5 + cells in hepatic physiology and pathology are little known. This study aims to clarify the effect of metabolic nuclear receptors on Lgr5 + cell fate in liver. Methods: We performed cell experiments with primary hepatocytes, Hep 1-6, Hep G2, and Huh 7 cells, and animal studies with wild-type (WT), farnesoid X receptor (FXR) knockout mice, peroxisome proliferator-activated receptor α (PPARα) knockout mice and Lgr5-CreERT2; Rosa26-mTmG mice. GW4064 and CDCA were used to activate FXR. And GW7647 or Wy14643 was used for PPARα activation. Regulation of Lgr5 by FXR and PPARα was determined by QRT-PCR, western blot (WB) and RNAscope® in situ hybridization (ISH) and immunofluorescence (IF), luciferase reporter assay, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). Diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) diet was used to induce liver injury. Results: Pharmacologic activation of FXR induced Lgr5 expression, whereas activation of PPARα suppressed Lgr5 expression. Furthermore, FXR and PPARα competed for binding to shared site on Lgr5 promoter with opposite transcriptional outputs. DDC diet triggered the transition of Lgr5 + cells from resting state to proliferation. FXR activation enhanced Lgr5 + cell expansion mainly by symmetric cell division, but PPARα activation prevented Lgr5 + cell proliferation along with asymmetric cell division. Conclusion: Our findings unravel the opposite regulatory effects of FXR and PPARα on Lgr5 + cell fate in liver under physiological and pathological conditions, which will greatly assist novel therapeutic development targeting nuclear receptors.

PPARα alleviates iron overload-induced ferroptosis in mouse liver.

Ferroptosis is an iron-dependent form of non-apoptotic cell death implicated in liver, brain, kidney, and heart pathology. How ferroptosis is regulated remains poorly understood. Here, we show that PPARα suppresses ferroptosis by promoting the expression of glutathione peroxidase 4 (Gpx4) and by inhibiting the expression of the plasma iron carrier TRF. PPARα directly induces Gpx4 expression by binding to a PPRE element within intron 3. PPARα knockout mice develop more severe iron accumulation and ferroptosis in the liver when fed a high-iron diet than wild-type mice. Ferrous iron (Fe2+ ) triggers ferroptosis via Fenton reactions and ROS accumulation. We further find that a rhodamine-based "turn-on" fluorescent probe(probe1) is suitable for the in vivo detection of Fe2+ . Probe1 displays high selectivity towards Fe2+ , and exhibits a stable response for Fe2+ with a concentration of 20 µM in tissue. Our data thus show that PPARα activation alleviates iron overload-induced ferroptosis in mouse livers through Gpx4 and TRF, suggesting that PPARα may be a promising therapeutic target for drug discovery in ferroptosis-related tissue injuries. Moreover, we identified a fluorescent probe that specifically labels ferrous ions and can be used to monitor Fe2+ in vivo.

[A preliminary study on the negative wave mismatch in patients with unilateral total sudden deafness].

Objective:To observe the characteristics of different negativity negativity （MMN） in patients with unilateral sudden deafness, and compare them with normal MMN, in order to provide theoretical reference for discussing the pathogenesis of unilateral sudden deafness and their relationship with the auditory centers, and to provide theoretical basis for the treatment of sudden deafness in the future. Methods:Twenty-six cases of unilateral total sudden deafness were recruited as experimental group, 25 cases of normal healthy people as control group, the MMN inspections was performed respectively, the two groups using classical mode of oddball, standard and deviation stimulate with 1000 Hz and 2000 Hz short pure tone test MMN respectively, to observe the MMN latency and amplitude characteristics, and compare the latent period and amplitude difference between the two groups. Results:Among the 51 subjects, only 1 patient with unilateral total sudden deafness did not elicit MMN waveform, while the rest were all induced. The average incubation period of MMN in the experimental group was （162.03±38.64） ms, the average amplitude was （2.83±1.14）µV, and the mean age was （48.64±10.27） y. While the average incubation period of MMN in the control group was （197.52±27.43） ms, the average amplitude was （2.58±1.07）µV, and the mean age was （45.00±8.20） y. The MMN latency was significantly different between the two groups （P<0.01）. There was no statistical difference in amplitude between the two groups （P>0.05）. There was no statistical difference in age between the two groups （P>0.05）. Conclusion:The latency period of MMN of unilateral total sudden deafness is shorter than that of the control group. It suggests that the auditory center function of patients with acute sudden deafness has changed, and we speculate that the auditory center of patients with acute sudden deafness may have corresponding emergency changes, so as to make its function have adaptive changes, which will provide further reference for the discussion of the pathophysiological mechanism and treatment of sudden deafness in the future.We speculated that acute unilateral auditory deprivation caused by unilateral total deafness sudden deafness has an impact on cerebral cortical auditory function, which provides further reference for the discussion of pathophysiological mechanism and treatment plan of sudden deafness in the future.

Metastable Intermediates in Amorphous Titanium Oxide: A Hidden Role Leading to Ultra-Stable Photoanode Protection.

Metastable intermediates represent a non-equilibrium state of matter that may impose profound impacts to materials properties beyond our understandings of monolithic and equilibrium systems. Here, we report a discovery of hidden metastable intermediates in amorphous TiO2 thin films and their critical role in electrochemical damage. These intermediates have a non-bulk crystal-like structure and exhibit significantly higher electrical conductivity than both the amorphous and the crystalline phases. When these TiO2 films are applied to protect Si photoelectrochemical (PEC) photoanodes, the intermediates can induce localized high electrical currents that largely accelerate the etching of the TiO2 film and the Si electrode underneath. The intermediates can be effectively suppressed by raising their nucleation barrier via reducing the film thickness from 24 to 2.5 nm. The homogeneous amorphous TiO2-film-coated Si photoanodes achieved more than 500 h of PEC water oxidation at a steady photocurrent density of over 30 mA·cm-2.

A three-dimensional reticulate CNT-aerogel for a high mechanical flexibility fiber supercapacitor.

In recent years, the rapid development of portable and wearable electronic products has promoted the prosperity of fiber supercapacitors (FSCs), which serve as flexible and lightweight energy supply devices. However, research on FSCs is still in its infancy and the energy density of FSCs is far below the level of lithium-ion batteries. Here, we report a facile method to prepare a novel fibrous CNT-aerogel by electrochemical activation and freeze-drying. The fibrous CNT-aerogel electrode possesses a large specific surface area, high mechanical strength, excellent electrical conductivity, as well as a high specific capacitance of 160.8 F g-1 at 0.5 mA and long cycling stability. Then we assembled a non-faradaic FSC based on a fibrous CNT-aerogel as the electrode and a P(VDF-HFP)/EMIMBF4 ionogel as the electrolyte. The introduction of the ionogel electrolyte increases the operating voltage of the FSC to 3 V, and makes the device combine the intrinsic high power density (27.3 kW kg-1) of non-faradaic SCs with an ultrahigh energy density of 29.6 W h kg-1. More importantly, the assembled FSCs show excellent flexibility and bending-stability, and can still operate normally within a wide working temperature window (0-80 °C). The outstanding electrochemical performance and the mechanical/thermal stability indicate that the assembled FSC device is a promising power source for flexible electronics.

Self-Powered Photoelectrochemical Biosensor Based on CdS/RGO/ZnO Nanowire Array Heterostructure.

A CdS/reduced graphene oxide (RGO)/ZnO nanowire array (NWAs) heterostructure is designed, which exhibits enhanced photoelectrochemical (PEC) activity compared to pure ZnO, RGO/ZnO, and CdS/ZnO. The enhancement can be attributed to the synergistic effect of the high electron mobility of ordered 1D ZnO NWAs, extended visible-light absorption of CdS nanocrystals, and the formed type II band alignment between them. Moreover, the incorporation of RGO further promotes the charge carrier separation and transfer process due to its excellent charge collection and shuttling characteristics. Subsequently, the CdS/RGO/ZnO heterostructure is successfully utilized for the PEC bioanalysis of glutathione at 0 V (vs Ag/AgCl). The self-powered device demonstrates satisfactory sensing performance with rapid response, a wide detection range from 0.05 mm to 1 mm, an acceptable detection limit of 10 µm, as well as certain selectivity, reproducibility, and stability. Therefore, the CdS/RGO/ZnO heterostructure has opened up a promising channel for the development of PEC biosensors.

Integrated active sensor system for real time vibration monitoring.

We report a self-powered, lightweight and cost-effective active sensor system for vibration monitoring with multiplexed operation based on contact electrification between sensor and detected objects. The as-fabricated sensor matrix is capable of monitoring and mapping the vibration state of large amounts of units. The monitoring contents include: on-off state, vibration frequency and vibration amplitude of each unit. The active sensor system delivers a detection range of 0-60 Hz, high accuracy (relative error below 0.42%), long-term stability (10000 cycles). On the time dimension, the sensor can provide the vibration process memory by recording the outputs of the sensor system in an extend period of time. Besides, the developed sensor system can realize detection under contact mode and non-contact mode. Its high performance is not sensitive to the shape or the conductivity of the detected object. With these features, the active sensor system has great potential in automatic control, remote operation, surveillance and security systems.