MYC determines lineage commitment in KRAS-driven primary liver cancer development.

BACKGROUND & AIMS: Primary liver cancer (PLC) comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), two frequent and lethal tumour types that differ regarding their tumour biology and responses to cancer therapies. Liver cells harbour a high degree of cellular plasticity and can give rise to either HCC or iCCA. However, little is known about the cell-intrinsic mechanisms directing an oncogenically transformed liver cell to either HCC or iCCA. The scope of this study was to identify cell-intrinsic factors determining lineage commitment in PLC. METHODS: Cross-species transcriptomic and epigenetic profiling was applied to murine HCCs and iCCAs and to two human PLC cohorts. Integrative data analysis comprised epigenetic Landscape In Silico deletion Analysis (LISA) of transcriptomic data and Hypergeometric Optimization of Motif EnRichment (HOMER) analysis of chromatin accessibility data. Identified candidate genes were subjected to functional genetic testing in non-germline genetically engineered PLC mouse models (shRNAmir knockdown or overexpression of full-length cDNAs). RESULTS: Integrative bioinformatic analyses of transcriptomic and epigenetic data pinpointed the Forkhead-family transcription factors FOXA1 and FOXA2 as MYC-dependent determination factors of the HCC lineage. Conversely, the ETS family transcription factor ETS1 was identified as a determinant of the iCCA lineage, which was found to be suppressed by MYC during HCC development. Strikingly, shRNA-mediated suppression of FOXA1 and FOXA2 with concomitant ETS1 expression fully switched HCC to iCCA development in PLC mouse models. CONCLUSIONS: The herein reported data establish MYC as a key determinant of lineage commitment in PLC and provide a molecular explanation why common liver-damaging risk factors such as alcoholic or non-alcoholic steatohepatitis can lead to either HCC or iCCA. IMPACT AND IMPLICATIONS: Liver cancer is a major health problem and comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), two frequent and lethal tumour types that differ regarding their morphology, tumour biology, and responses to cancer therapies. We identified the transcription factor and oncogenic master regulator MYC as a switch between HCC and iCCA development. When MYC levels are high at the time point when a hepatocyte becomes a tumour cell, an HCC is growing out. Conversely, if MYC levels are low at this time point, the result is the outgrowth of an iCCA. Our study provides a molecular explanation why common liver-damaging risk factors such as alcoholic or non-alcoholic steatohepatitis can lead to either HCC or iCCA. Furthermore, our data harbour potential for the development of better PLC therapies.

Novel Nanoarchitectured Cu2Te as a Photocathodes for Photoelectrochemical Water Splitting Applications.

Designing photocathodes with nanostructures has been considered a promising way to improve the photoelectrochemical (PEC) water splitting activity. Cu2Te is one of the promising semiconducting materials for photoelectrochemical water splitting, the performance of Cu2Te photocathodes remains poor. In this work, we report the preparation of Cu2Te nanorods (NRs) and vertical nanosheets (NSs) assembled film on Cu foil through a vapor phase epitaxy (VPE) technique. The obtained nano architectures as photocathodes toward photoelectrochemical (PEC) performance was tested afterwards for the first time. Optimized Cu2Te NRs and NSs photocathodes showed significant photocurrent density up to 0.53 mA cm-2 and excellent stability under illumination. Electrochemical impedance spectroscopy and Mott-Schottky analysis were used to analyze in more detail the performance of Cu2Te NRs and NSs photocathodes. From these analyses, we propose that Cu2Te NRs and NSs photocathodes are potential candidate materials for use in solar water splitting.

High Power Generation with Reducing Agents Using Compost Soil as a Novel Electrocatalyst for Ammonium Fuel Cells.

Ammonium toxicity is a significant source of pollution from industrial civilization that is disrupting the balance of natural systems, adversely affecting soil and water quality, and causing several environmental problems that affect aquatic and human life, including the strong promotion of eutrophication and increased dissolved oxygen consumption. Thus, a cheap catalyst is required for power generation and detoxification. Herein, compost soil is employed as a novel electrocatalyst for ammonium degradation and high-power generation. Moreover, its effect on catalytic activity and material performances is systematically optimized and compared by treating it with various reducing agents, including potassium ferricyanide, ferrocyanide, and manganese dioxide. Ammonium fuel was supplied to the compost soil ammonium fuel cell (CS-AFC) at concentrations of 0.1, 0.2, and 0.3 g/mL. The overall results show that ferricyanide affords a maximum power density of 1785.20 mW/m2 at 0.2 g/mL fuel concentration. This study focuses on high-power generation for CS-AFC. CS-AFCs are sustainable for many hours without any catalyst deactivation; however, they need to be refueled at regular intervals (every 12 h). Moreover, CS-AFCs afford the best performance when ferricyanide is used as the electron acceptor at the cathode. This study proposes a cheap electrocatalyst and possible solutions to the more serious energy generation problems. This study will help in recycling ammonium-rich wastewaters as free fuel for running CS-AFC devices to yield high-power generation with reducing agents for ammonium fuel cell power applications.

CLUSTER guide RNAs enable precise and efficient RNA editing with endogenous ADAR enzymes in vivo.

RNA base editing represents a promising alternative to genome editing. Recent approaches harness the endogenous RNA-editing enzyme adenosine deaminase acting on RNA (ADAR) to circumvent problems caused by ectopic expression of engineered editing enzymes, but suffer from sequence restriction, lack of efficiency and bystander editing. Here we present in silico-optimized CLUSTER guide RNAs that bind their target messenger RNAs in a multivalent fashion, achieve editing with high precision and efficiency and enable targeting of sequences that were not accessible using previous gRNA designs. CLUSTER gRNAs can be genetically encoded and delivered using viruses, and are active in a wide range of cell lines. In cell culture, CLUSTER gRNAs achieve on-target editing of endogenous transcripts with yields of up to 45% without bystander editing. In vivo, CLUSTER gRNAs delivered to mouse liver by hydrodynamic tail vein injection edited reporter constructs at rates of up to 10%. The CLUSTER approach opens avenues for drug development in the field of RNA base editing.

Exploring the Intra Entrepreneurship-Employee Engagement-Creativity Linkage and the Diverse Effects of Gender and Marital Status.

This research examines which of the sub-dimensions of intra entrepreneurship (innovativeness, pro-activeness, risk-taking), and corporate social responsibility (CSR) support affects employee engagement (organizational and job engagement), which leads to employee creativity. The study uses survey data from SME employees in South Korea and applies the Structural Equation Modeling (SEM)-Artificial Neural Network (ANN) approach, to find that innovativeness and CSR support affect creativity through mediating roles of organizational engagement and job engagement, where job engagement plays a mediating role in the relationship between organizational engagement and creativity. The study also examines how employee gender and marital status effects the relative importance of intra entrepreneurship, organizational engagement, and job engagement on creativity. Findings of ANN analysis evaluates the effects per group (male-unmarried, male-married, female-unmarried, female-married) and shows how the importance of organizational engagement, job engagement, CSR support and innovativeness differ for each group. Contribution to theory and practice are discussed.

A Bidirectional Interpolation Method for Post-Processing in Sampling-Based Robot Path Planning.

This paper proposes a post-processing method called bidirectional interpolation method for sampling-based path planning algorithms, such as rapidly-exploring random tree (RRT). The proposed algorithm applies interpolation to the path generated by the sampling-based path planning algorithm. In this study, the proposed algorithm is applied to the path created by RRT-connect and six environmental maps were used for the verification. It was visually and quantitatively confirmed that, in all maps, not only path lengths but also the piecewise linear shape were decreased compared to the path generated by RRT-connect. To check the proposed algorithm's performance, visibility graph, RRT-connect algorithm, Triangular-RRT-connect algorithm and post triangular processing of midpoint interpolation (PTPMI) were compared in various environmental maps through simulation. Based on these experimental results, the proposed algorithm shows similar planning time but shorter path length than previous RRT-like algorithms as well as RRT-like algorithms with PTPMI having a similar number of samples.

LXRα activation and Raf inhibition trigger lethal lipotoxicity in liver cancer.

The success of molecular therapies targeting specific metabolic pathways in cancer is often limited by the plasticity and adaptability of metabolic networks. Here we show that pharmacologically induced lipotoxicity represents a promising therapeutic strategy for the treatment of hepatocellular carcinoma (HCC). LXRα-induced liponeogenesis and Raf-1 inhibition are synthetic lethal in HCC owing to a toxic accumulation of saturated fatty acids. Raf-1 was found to bind and activate SCD1, and conformation-changing DFG-out Raf inhibitors could disrupt this interaction, thereby blocking fatty acid desaturation and inducing lethal lipotoxicity. Studies in genetically engineered and nonalcoholic steatohepatitis-induced HCC mouse models and xenograft models of human HCC revealed that therapies comprising LXR agonists and Raf inhibitors were well tolerated and capable of overcoming therapy resistance in HCC. Conceptually, our study suggests pharmacologically induced lipotoxicity as a new mode for metabolic targeting of liver cancer.

Memristive Devices from CuO Nanoparticles.

Memristive systems can provide a novel strategy to conquer the von Neumann bottleneck by evaluating information where data are located in situ. To meet the rising of artificial neural network (ANN) demand, the implementation of memristor arrays capable of performing matrix multiplication requires highly reproducible devices with low variability and high reliability. Hence, we present an Ag/CuO/SiO2/p-Si heterostructure device that exhibits both resistive switching (RS) and negative differential resistance (NDR). The memristor device was fabricated on p-Si and Indium Tin Oxide (ITO) substrates via cost-effective ultra-spray pyrolysis (USP) method. The quality of CuO nanoparticles was recognized by studying Raman spectroscopy. The topology information was obtained by scanning electron microscopy. The resistive switching and negative differential resistance were measured from current-voltage characteristics. The results were then compared with the Ag/CuO/ITO device to understand the role of native oxide. The interface barrier and traps associated with the defects in the native silicon oxide limited the current in the negative cycle. The barrier confined the filament rupture and reduced the reset variability. Reset was primarily influenced by the filament rupture and detrapping in the native oxide that facilitated smooth reset and NDR in the device. The resistive switching originated from traps in the localized states of amorphous CuO. The set process was mainly dominated by the trap-controlled space-charge-limited; this led to a transition into a Poole-Frenkel conduction. This research opens up new possibilities to improve the switching parameters and promote the application of RS along with NDR.

Molybdenum Disulfide Nanosheet/Quantum Dot Dynamic Memristive Structure Driven by Photoinduced Phase Transition.

MoS2 2D nanosheets (NS) with intercalated 0D quantum dots (QDs) represent promising structures for creating low-dimensional (LD) resistive memory devices. Nonvolatile memristors based 2D materials demonstrate low power consumption and ultrahigh density. Here, the observation of a photoinduced phase transition in the 2D NS/0D QDs MoS2 structure providing dynamic resistive memory is reported. The resistive switching of the MoS2 NS/QD structure is observed in an electric field and can be controlled through local QD excitations. Photoexcitation of the LD structure at different laser power densities leads to a reversible MoS2 2H-1T phase transition and demonstrates the potential of the LD structure for implementing a new dynamic ultrafast photoresistive memory. The dynamic LD photomemristive structure is attractive for real-time pattern recognition and photoconfiguration of artificial neural networks in a wide spectral range of sensitivity provided by QDs.

Effective Modulation of Optical and Photoelectrical Properties of SnS2 Hexagonal Nanoflakes via Zn Incorporation.

Tin sulfides are promising materials in the fields of photoelectronics and photovoltaics because of their appropriate energy bands. However, doping in SnS2 can improve the stability and robustness of this material in potential applications. Herein, we report the synthesis of SnS2 nanoflakes with Zn doping via simple hydrothermal route. The effect of doping Zn was found to display a huge influence in the structural and crystalline order of as synthesized SnS2. Their optical properties attest Zn doping of SnS2 results in reduction of the band gap which benefits strong visible-light absorption. Significantly, enhanced photoresponse was observed with respect to pristine SnS2. Such enhancement could result in improved electronic conductivity and sensitivity due to Zn doping at appropriate concentration. These excellent performances show that Sn1-xZnxS2 nanoflakes could offer huge potential for nanoelectronics and optoelectronics device applications.

Arrayed CdTeMicrodots and Their Enhanced Photodetectivity via Piezo-Phototronic Effect.

In this paper, a photodetector based on arrayed CdTe microdots was fabricated on Bi coated transparent conducting indium tin oxide (ITO)/glass substrates. Current-voltage characteristics of these photodetectors revealed an ultrahigh sensitivity under stress (in the form of force through press) while compared to normal condition. The devices exhibited excellent photosensing properties with photoinduced current increasing from 20 to 76 µA cm-2 under stress. Furthermore, the photoresponsivity of the devices also increased under stress from 3.2 × 10-4 A/W to 5.5 × 10-3 A/W at a bias of 5 V. The observed characteristics are attributed to the piezopotential induced change in Schottky barrier height, which actually results from the piezo-phototronic effect. The obtained results also demonstrate the feasibility in realization of a facile and promising CdTe microdots-based photodetector via piezo-phototronic effect.

Author Correction: Necroptosis microenvironment directs lineage commitment in liver cancer.

In this Article, the pCaMIN construct consisted of 'mouse MYC and mouse NrasG12V' instead of 'mouse Myc and human NRASG12V; and the pCAMIA construct consisted of 'mouse Myc and human AKT1' instead of 'mouse Myc and Akt1' this has been corrected online.

Necroptosis microenvironment directs lineage commitment in liver cancer.

Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, metastatic potential and responses to therapy. However, the regulatory molecules and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here we show that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. Together, our results provide insight into lineage commitment in liver tumorigenesis, and explain molecularly why common liver-damaging risk factors can lead to either HCC or ICC.

TNFα sensitizes hepatocytes to FasL-induced apoptosis by NFκB-mediated Fas upregulation.

Although it is well established that TNFα contributes to hepatitis, liver failure and associated hepatocarcinogenesis via the regulation of inflammation, its pro-apoptotic role in the liver has remained enigmatic. On its own, TNFα is unable to trigger apoptosis. However, when combined with the transcriptional inhibitor GaLN, it can cause hepatocyte apoptosis and liver failure in mice. Moreover, along with others, we have shown that TNFα is capable of sensitizing cells to FasL- or drug-induced cell death via c-Jun N-terminal kinase (JNK) activation and phosphorylation/activation of the BH3-only protein Bim. In this context, TNFα could exacerbate hepatocyte cell death during simultaneous inflammatory and T-cell-mediated immune responses in the liver. Here we show that TNFα sensitizes primary hepatocytes, established hepatocyte cell lines and mouse embryo fibroblasts to FasL-induced apoptosis by the transcriptional induction and higher surface expression of Fas via the NFκB pathway. Genetic deletion, diminished expression or dominant-negative inhibition of the NFκB subunit p65 resulted in lower Fas expression and inhibited TNFα-induced Fas upregulation and sensitization to FasL-induced cell death. By hydrodynamic injection of p65 shRNA into the tail vein of mice, we confirm that Fas upregulation by TNFα is also NFκB-mediated in the liver. In conclusion, TNFα sensitization of FasL-induced apoptosis in the liver proceeds via two parallel signaling pathways, activation of JNK and Bim phosphorylation and NFκB-mediated Fas upregulation.

The effect of atmospheric doping on pressure-dependent Raman scattering in supported graphene.

Atmospheric doping of supported graphene was investigated by Raman scattering under different pressures. Various Raman spectra parameters were found to depend on the pressure and the substrate material. The results are interpreted in terms of atmospheric adsorption leading to a change in graphene charge carrier density and the effect of the substrate on the electronic and phonon properties of graphene. It was found that adsorption of molecules from the atmosphere onto graphene doped with nitrogen (electron doping) compensates for the electron charge. Furthermore, the atmosphere-induced doping drastically decreases the spatial heterogeneity of charge carriers in graphene doped with nitrogen, while the opposite effect was observed for undoped samples. The results of this study should be taken into account for the development of sensors and nanoelectronic devices based on graphene.

Self-assembled MoS2/rGO nanocomposites with tunable UV-IR absorption.

MoS2/reduced graphene oxide (rGO) nanocomposites were synthesized using an ultrasonic pretreatment with a single-stage hydrothermal and reduction process. Self-assembled MoS2 layers in the rGO matrix were obtained. The effect of quantum confinement in the structure, controlled by the degree of reduction of graphene oxide and the size of the 2D MoS2 nanocrystals, made it possible to obtain tunable optical absorption. MoS2/rGO layered nanocomposites exhibit a wide UV-IR absorption in the wavelength range from 280 nm to 973 nm, which is attractive for highly efficient multiband solar cells and advanced photonics.

A patterned single layer graphene resistance temperature sensor.

Micro-fabricated single-layer graphenes (SLGs) on a silicon dioxide (SiO2)/Si substrate, a silicon nitride (SiN) membrane, and a suspended architecture are presented for their use as temperature sensors. These graphene temperature sensors act as resistance temperature detectors, showing a quadratic dependence of resistance on the temperature in a range between 283 K and 303 K. The observed resistance change of the graphene temperature sensors are explained by the temperature dependent electron mobility relationship (~T-4) and electron-phonon scattering. By analyzing the transient response of the SLG temperature sensors on different substrates, it is found that the graphene sensor on the SiN membrane shows the highest sensitivity due to low thermal mass, while the sensor on SiO2/Si reveals the lowest one. Also, the graphene on the SiN membrane reveals not only the fastest response, but also better mechanical stability compared to the suspended graphene sensor. Therefore, the presented results show that the temperature sensors based on SLG with an extremely low thermal mass can be used in various applications requiring high sensitivity and fast operation.

Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence.

Cellular senescence is triggered by various distinct stresses and characterized by a permanent cell cycle arrest. Senescent cells secrete a variety of inflammatory factors, collectively referred to as the senescence-associated secretory phenotype (SASP). The mechanism(s) underlying the regulation of the SASP remains incompletely understood. Here we define a role for innate DNA sensing in the regulation of senescence and the SASP. We find that cyclic GMP-AMP synthase (cGAS) recognizes cytosolic chromatin fragments in senescent cells. The activation of cGAS, in turn, triggers the production of SASP factors via stimulator of interferon genes (STING), thereby promoting paracrine senescence. We demonstrate that diverse stimuli of cellular senescence engage the cGAS-STING pathway in vitro and we show cGAS-dependent regulation of senescence following irradiation and oncogene activation in vivo. Our findings provide insights into the mechanisms underlying cellular senescence by establishing the cGAS-STING pathway as a crucial regulator of senescence and the SASP.

Highly Sensitive Flexible Photodetectors Based on Self-Assembled Tin Monosulfide Nanoflakes with Graphene Electrodes.

Tin monosulfide (SnS) nanostructures have attracted huge attention recently because of their high absorption coefficient, high photoconversion efficiencies, low energy cost, ease of deposition, and so on. Here, in this paper, we report on the low-cost hydrothermal synthesis of the self-assembled SnS nanoflake-like structures in terms of performance for the photodetectors. High-performance photodetectors were fabricated using SnS nanoflakes as active layers and graphene as the lateral electrodes. The SnS photodetectors exhibited excellent photoresponse properties with a high responsivity of 1.7 × 104 A/W and have fast response and recovery times. In addition, the photodetectors exhibited long-term stability and strong dependence of photocurrent on light intensity. These excellent characteristics were attributed to the larger surface-to-volume ratio of the self-assembled SnS nanoflakes and the effective separation of the photogenerated carriers at graphene/SnS interfaces. Additionally, a flexible photodetector based on SnS nanoflakes was also fabricated on a flexible substrate that demonstrated similar photosensitive properties. Furthermore, this study also demonstrates the potential of hydrothermal-processed SnS nanoflakes for high-performance photodetectors and their application in flexible low-cost optoelectronic devices.

Formation of self-assembled nanoscale graphene/graphene oxide photomemristive heterojunctions using photocatalytic oxidation.

Photocatalytic oxidation of graphene with ZnO nanoparticles was found to create self-assembled graphene oxide/graphene (G/GO) photosensitive heterostructures, which can be used as memristors. Oxygen groups released during photodecomposition of water molecules on the nanoparticles under ultraviolet light, oxidized graphene, locally forming the G/GO heterojunctions with ultra-high density. The G/GO nanostructures have non-linear current-voltage characteristics and switch the resistance in the dark and under white light, providing four resistive states at room temperature. Photocatalytic oxidation of graphene with ZnO nanoparticles is proposed as an effective method for creating two-dimensional memristors with a photoresistive switching for ultra-high capacity non-volatile memory.