Circ_0008234 regulates the biological process of gallbladder carcinoma by targeting the miR-204-5p/FGFR2 axis

Background. Gallbladder carcinoma (GBC) is a common cancer disease with high mortality. Circular RNA_0008234 (circ_0008234) has been shown to play a key role in many tumors, including GBC. However, the function between circ_0008234 and microRNA-204-5p (miR-204-5p) in the progression of GBC has not been clarified. Methods. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expressions of circ_0008234, miR-204-5p and fibroblast growth factor receptor-2 (FGFR2) in GBC cells and tissues. Western blot was used to detect the expression of relative proteins. Cell proliferation, apoptosis, invasion and migration were detected by 3-(4, 5-dimethylthiazol2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, thymidine analog 5-ethynyl-2’-deoxyuridine (EdU) assay, flow cytometry, transwell assay and wound healing assay. Mechanically, the interaction of miR-2045p with circ_0008234/FGFR2 was notarized by dualluciferase reporter assay. A xenotransplantation model was established to study the role of circ_0008234 in vivo. Results. Circ_0008234 and FGFR2 were highly expressed in GBC tissues and cells. Silencing circ_0008234 down-regulated cell proliferation, migration and invasion of NOZ and SGC-996 cells, while miR-204-5p inhibitors reversed these effects. In addition, overexpression of FGFR2 restored the cell malignant behavior of GBC cells inhibited by miR-2045p mimic. Animal experiments confirmed the anti-tumor effect of silenced circ_0008234 in vivo. Conclusion: Circ_0008234 mediated GBC via the miR-204-5p/FGFR2 axis, providing a novel targeted therapy for gallbladder carcinom

Elucidation of the 1-phenethylisoquinoline pathway from an endemic conifer Cephalotaxus hainanensis

Cephalotaxines harbor great medical potential, but their natural source, the endemic conifer Cephalotaxus is highly endangered, creating a conflict between biotechnological valorization and preservation of biodiversity. Here, we construct the whole biosynthetic pathway to the 1-phenethylisoquinoline scaffold, as first committed compound for phenylethylisoquinoline alkaloids (PIAs), combining metabolic modeling, and transcriptome mining of Cephalotaxus hainanensis to infer the biosynthesis for PIA precursor. We identify a novel protein, ChPSS, driving the Pictet–Spengler condensation and show that this enzyme represents the branching point where PIA biosynthesis diverges from the concurrent benzylisoquinoline-alkaloids pathway. We also pinpoint ChDBR as crucial step to form 4-hydroxydihydrocinnamaldehyde diverging from lignin biosynthesis. The elucidation of the early PIA pathway represents an important step toward microbe-based production of these pharmaceutically important alkaloids resolving the conflict between biotechnology and preservation of biodiversity

YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression

Uveal melanoma (UM), the most common ocular malignancy, is characterized by GNAQ/11 mutations. Hippo/YAP and Ras/mitogen-activated protein kinase (MAPK) emerge as two important signaling pathways downstream of G protein alpha subunits of the Q class (GalphaQ/11)-mediated transformation, although whether and how they contribute to UM genesis in vivo remain unclear. Here, we adapt an adeno-associated virus (AAV)-based ocular injection method to directly deliver Cre recombinase into the mouse uveal tract and demonstrate that Lats1/2 kinases suppress UM formation specifically in uveal melanocytes. We find that genetic activation of YAP, but not Kras, is sufficient to initiate UM. We show that YAP/TAZ activation induced by Lats1/2 deletion cooperates with Kras to promote UM progression via downstream transcriptional reinforcement. Furthermore, dual inhibition of YAP/TAZ and Ras/MAPK synergizes to suppress oncogenic growth of human UM cells. Our data highlight the functional significance of Lats-YAP/TAZ in UM initiation and progression in vivo and suggest combination inhibition of YAP/TAZ and Ras/MAPK as a new therapeutic strategy for UM

Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease

Importance Metabolic dysfunction–associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis.Objective To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)–based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD.Design, Setting, and Participants This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE).Main Outcomes and Measures The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests.Results A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group.Conclusions and Relevance Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis

Study of bismuth based material for supercapacitor applications

The rapid development of industrial production has made the energy supply increasingly tight and accelerated the exploitation of fossil energy, which not only caused a sharp decline in the reserves of fossil energy, but also brought environmental pollution, which strongly promoted the development of new energy sources such as wind, water, and solar energy. However, the storage and transportation of new energy are affected by time and space, which limits its application. In order to ensure the effective storage and stable output of new energy, the development of high-performance energy storage devices has become a current research focus. As a new type of energy storage device, supercapacitors have great application prospects in the fields of renewable energy, transportation, and wearable portable devices because of their high power density, fast charge and discharge, and stable cycle performance. As one of the key factors affecting the performance of supercapacitors, electrode materials are the focus of research in the scientific community. The electrode materials currently studied include carbon materials, conductive polymer materials, and metal compound materials. Compared with carbon materials and conductive polymers, metal compounds have become an important research object for supercapacitor electrode materials because of their higher specific capacitance. Bi-based compounds are favored by researchers because of their relatively rich content in the crust, wide sources, and high theoretical specific capacitance. This thesis focuses on Bi-based materials and studies the application of Bi2S3, Bi2O3, BiSI and Bil13S18I2 as supercapacitor materials. The first chapter introduces the background of supercapacitors and the production process of supercapacitors, and the comparison with other main energy storage materials, ion batteries and fuel cells. The classification of supercapacitors, the current main supercapacitor structure, electrode, and electrolyte materials are explained. Chapter 2 introduces the characterization methods used in the experiments, including X-ray diffraction (XRD), elemental analysis (EDS), scanning electron microscope (SEM), transmission electron microscope (TEM) and other physical characterization methods were also introduced to study the phase structure and morphology of the material. Moreover, the electrode assembly process and various electrochemical tests are described in detail, including cyclic voltammetry, constant current charge and discharge, and electrochemical impedance spectroscopy. In chapter 3, there are three main parts. First, a novel synthetic route for two 3-D hexagonal bismuth chalcogenide materials Bi13S18I2 and BiSI is demonstrated, and their potential as the active electrode material for supercapacitors is investigated. Both pure BiSI and Bi13S18I2 powder were obtained for the first time at a relatively low temperature (120 °C) in a solution system. The effects of different reaction conditions on the surface morphology of the product were studied, showing that at a relatively low temperature of 120 °C under atmospheric pressure, the materials can yield smaller crystallite size and higher specific surface area, further increasing the capacitance compared to the synthesis under hydrothermal conditions. The galvanostatic charge-discharge measurement results show that Bi13S18I2 electrode has a maximum capacitance of 50 C g-1 at the current density of 1.0 A g-1 and excellent capacitance retention of 98.4% after 5000 cycles at the current density of 10.0 A g-1 in 3.0 M KOH electrolyte as a two-electrode electrical double-layer capacitor system (EDLC). This facile route to the synthesis of both Bi13S18I2 and BiSI with superior stability has promising potential for low-cost and effective electrochemical supercapacitor applications. In chapter 4, a novel method was used to employ the -OH group on the graphene oxide (GO) surface and ethylene glycol (EG) as a linker to anchor Bi ions on the GO surface, and further in situ generate BiSI crystals to obtain a BiSI composite structure with a uniform surface coating of reduced graphene oxide (rGO). Through the electrochemical testing of BiSI-rGO, it has both the pseudocapacitance of BiSI and the EDLC performance of rGO, which greatly improves the capacitance from 88 C g-1 to 195 C g-1, greater than the sum of the simple BiSI and rGO capacitances, which shows that BISI-rGO produces a synergistic energy storage effect. By assembling an asymmetric capacitor with Ni(OH)2 as a counter electrode, it exhibits a high energy density of 12.8 W h kg−1 at a power density of 8 KW kg−1. The synthesis mechanism is further discussed, showing that Bi ions are anchored on the GO surface first, then GO is bent to finally form BiSI-rGO uniformly coated with rGO, instead of first generating BiSI crystals and then coating with GO during the formation of BiSI crystals. This is the first time that chemical energy has been used to coat Bi-based substances with rGO instead of a simple physical attachment. This route uniformly coats the Bi-based active substances with GO, which improves new ideas and synthetic routes for Bismuth-based material surface modification. In chapter 5, there are three parts. In the first part, three 3-D structured Bismuth-MOFs on carbon paper BA, PA and MBA were prepared through a facile solvothermal method. The as-prepared MOF/CP electrodes were directly used as an electrode material with superior capacitive behavior in 2 M KOH. All of the three bismuth-MOF materials show high specific capacitance in three electrodes system as pseudo-capacitor, BA 153 C g-1, PA 246 C g-1 and MBA 267 C g-1 at 1 A g-1 discharge density; BA 56 F g-1, PA 58 F g-1 and MBA 62 F g-1 at 1 A g-1 discharge density in two-electrode symmetric devices. It is the first time that these bismuth MOF materials have been proven to have the potential for supercapacitor applications. In the second part, three unique Bi2S3 negative electrode materials for SCs derived from different Bi-MOF precursors are reported through a facile self-sacrificing template strategy and in-situ synthesized them on Bi-MOF coated carbon paper without any bonding material. The prepared Bi2S3 nanorods electrode exhibits a large specific surface area (54.3 m2 g−1) and an ultrahigh specific capacity (664 C g−1 at 1 A g−1) that is the highest among all Bi2S3 reported. Moreover, a hybrid supercapacitor (HSC) device using a layered double hydroxide Ni(OH)2 as a positive electrode delivers an excellent energy density of 41.5 Wh kg-1 at a power density of 8 KW kg−1. This is the first study to control the structure of synthetic Bi2S3 using the structure of Bi-MOF materials as the precursor and in-situ grow inorganics Bi2S3 on the surface of hydrophobic carbon cloth without adding adhesives. In the third part, Bismuth-MOF MBA was used as a precursor to synthesize Bi2O3-C composite material by a simple heating process. The prepared Bi2O3-C composite material has a capacity of 1233 C g-1 at 1 A g-1 discharge density. In addition, a hybrid supercapacitor (HSC) device using a layered double hydroxide Ni(OH)2 as a positive electrode delivers an excellent capacity of 263 C g-1 at 1 A g-1 discharge density. The above advantages suggest that the current strategy for the derivation of Bi-MOFs will provide a valuable route for the preparation of bismuth-based inorganic nanomaterials for use in high-performance energy storage technologies and other areas