Tcf7l2 in hepatocytes regulates de novo lipogenesis in diet-induced non-alcoholic fatty liver disease in mice.

AIMS/HYPOTHESIS: Non-alcoholic fatty liver disease (NAFLD) associated with type 2 diabetes may more easily progress towards severe forms of non-alcoholic steatohepatitis (NASH) and cirrhosis. Although the Wnt effector transcription factor 7-like 2 (TCF7L2) is closely associated with type 2 diabetes risk, the role of TCF7L2 in NAFLD development remains unclear. Here, we investigated how changes in TCF7L2 expression in the liver affects hepatic lipid metabolism based on the major risk factors of NAFLD development. METHODS: Tcf7l2 was selectively ablated in the liver of C57BL/6N mice by inducing the albumin (Alb) promoter to recombine Tcf7l2 alleles floxed at exon 5 (liver-specific Tcf7l2-knockout [KO] mice: Alb-Cre;Tcf7l2f/f). Alb-Cre;Tcf7l2f/f and their wild-type (Tcf7l2f/f) littermates were fed a high-fat diet (HFD) or a high-carbohydrate diet (HCD) for 22 weeks to reproduce NAFLD/NASH. Mice were refed a standard chow diet or an HCD to stimulate de novo lipogenesis (DNL) or fed an HFD to provide exogenous fatty acids. We analysed glucose and insulin sensitivity, metabolic respiration, mRNA expression profiles, hepatic triglyceride (TG), hepatic DNL, selected hepatic metabolites, selected plasma metabolites and liver histology. RESULTS: Alb-Cre;Tcf7l2f/f essentially exhibited increased lipogenic genes, but there were no changes in hepatic lipid content in mice fed a normal chow diet. However, following 22 weeks of diet-induced NAFLD/NASH conditions, liver steatosis was exacerbated owing to preferential metabolism of carbohydrate over fat. Indeed, hepatic Tcf7l2 deficiency enhanced liver lipid content in a manner that was dependent on the duration and amount of exposure to carbohydrates, owing to cell-autonomous increases in hepatic DNL. Mechanistically, TCF7L2 regulated the transcriptional activity of Mlxipl (also known as ChREBP) by modulating O-GlcNAcylation and protein content of carbohydrate response element binding protein (ChREBP), and targeted Srebf1 (also called SREBP1) via miRNA (miR)-33-5p in hepatocytes. Eventually, restoring TCF7L2 expression at the physiological level in the liver of Alb-Cre;Tcf7l2f/f mice alleviated liver steatosis without altering body composition under both acute and chronic HCD conditions. CONCLUSIONS/INTERPRETATION: In mice, loss of hepatic Tcf7l2 contributes to liver steatosis by inducing preferential metabolism of carbohydrates via DNL activation. Therefore, TCF7L2 could be a promising regulator of the NAFLD associated with high-carbohydrate diets and diabetes since TCF7L2 deficiency may lead to development of NAFLD by promoting utilisation of excess glucose pools through activating DNL. DATA AVAILABILITY: RNA-sequencing data have been deposited into the NCBI GEO under the accession number GSE162449 ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162449 ).

Fresnel-type solid immersion lens for efficient light collection from quantum defects in diamond.

Quantum defects in diamonds have been studied as a promising resource for quantum science. The subtractive fabrication process for improving photon collection efficiency often require excessive milling time that can adversely affect the fabrication accuracy. We designed and fabricated a Fresnel-type solid immersion lens using the focused ion beam. For a 5.8 µm-deep Nitrogen-vacancy (NV-) center, the milling time was highly reduced (1/3 compared to a hemispherical structure), while retaining high photon collection efficiency (> 2.24 compared to a flat surface). In numerical simulation, this benefit of the proposed structure is expected for a wide range of milling depths.

Single-Shot Readout of a Driven Hybrid Qubit in a GaAs Double Quantum Dot.

We report a single-shot-based projective readout of a semiconductor hybrid qubit formed by three electrons in a GaAs double quantum dot. Voltage-controlled adiabatic transitions between the qubit operations and readout conditions allow high-fidelity mapping of quantum states. We show that a large ratio both in relaxation time vs tunneling time (≈50) and singlet-triplet splitting vs thermal energy (≈20) allows energy-selective tunneling-based spin-to-charge conversion with a readout visibility of ≈92.6%. Combined with ac driving, we demonstrate high visibility coherent Rabi and Ramsey oscillations of a hybrid qubit in GaAs. Further, we discuss the generality of the method for use in other materials, including silicon.

Wigner-molecularization-enabled dynamic nuclear polarization.

Multielectron semiconductor quantum dots (QDs) provide a novel platform to study the Coulomb interaction-driven, spatially localized electron states of Wigner molecules (WMs). Although Wigner-molecularization has been confirmed by real-space imaging and coherent spectroscopy, the open system dynamics of the strongly correlated states with the environment are not yet well understood. Here, we demonstrate efficient control of spin transfer between an artificial three-electron WM and the nuclear environment in a GaAs double QD. A Landau-Zener sweep-based polarization sequence and low-lying anticrossings of spin multiplet states enabled by Wigner-molecularization are utilized. Combined with coherent control of spin states, we achieve control of magnitude, polarity, and site dependence of the nuclear field. We demonstrate that the same level of control cannot be achieved in the non-interacting regime. Thus, we confirm the spin structure of a WM, paving the way for active control of correlated electron states for application in mesoscopic environment engineering.

Endotracheal intubation in rabbits using a video laryngoscope with a modified blade.

Rabbits are being increasingly used as companion animals, and in research; thus, the need for proper veterinary care for rabbits has increased. Surgical access is more challenging in rabbits under inhalation anesthesia compared to other animals, such as dogs and cats. Rabbits have a very narrow and deep oral cavity, large incisors, and a large tongue. Moreover, their temporomandibular joint has limited mobility, making it more difficult to approach the larynx. Various methods have been proposed to overcome this difficulty. The video laryngoscope was introduced in 1999 and is useful when airway intubation is unsuccessful using a conventional laryngoscope. We postulated that a video laryngoscope with a modified size 1 Macintosh blade (McGrath MAC Video Laryngoscope, Medtronic, USA) would facilitate the intubation of New Zealand White rabbits. Sixteen specific-pathogen-free male New Zealand White rabbits weighing 3.45-4.70 kg were studied. All rabbits were intubated using the video laryngoscope. Typically, a 3.0 mm endotracheal tube was used for rabbits weighing < 4 kg, while a 3.5 mm tube was used in those weighing > 4 kg. During surgery, anesthesia was well maintained, and there were no major abnormalities in the animals' conditions. No rabbit developed breathing difficulties or anorexia after recovering from anesthesia. We established an intubation method using a video laryngoscope with a modified blade and stylet in the supine (ventrodorsal) position and successfully applied it in 16 rabbits. It is useful for training novices and for treating rabbits in veterinary hospitals with few staff members and animal research facilities where there are insufficient human resources.

Cu2Se-based thermoelectric cellular architectures for efficient and durable power generation.

Thermoelectric power generation offers a promising way to recover waste heat. The geometrical design of thermoelectric legs in modules is important to ensure sustainable power generation but cannot be easily achieved by traditional fabrication processes. Herein, we propose the design of cellular thermoelectric architectures for efficient and durable power generation, realized by the extrusion-based 3D printing process of Cu2Se thermoelectric materials. We design the optimum aspect ratio of a cuboid thermoelectric leg to maximize the power output and extend this design to the mechanically stiff cellular architectures of hollow hexagonal column- and honeycomb-based thermoelectric legs. Moreover, we develop organic binder-free Cu2Se-based 3D-printing inks with desirable viscoelasticity, tailored with an additive of inorganic Se82- polyanion, fabricating the designed topologies. The computational simulation and experimental measurement demonstrate the superior power output and mechanical stiffness of the proposed cellular thermoelectric architectures to other designs, unveiling the importance of topological designs of thermoelectric legs toward higher power and longer durability.

Sasa quelpaertensis leaves ameliorate alcohol-induced liver injury by attenuating oxidative stress in HepG2 cells and mice.

Oxidative stress plays a crucial role in the progression of alcoholic liver diseases and substances of antioxidant property are of special interest for therapeutic purposes. We investigated the hepatoprotective effect of leaf extracts of Sasa quelpaertensis, an edible bamboo mainly cultivated in Jeju Island, South Korea. We examined the cytotoxicity of different extracts (distilled water, 20-80% EtOH) of S. quelpaertensis on HepG2 cells and their hepatoprotective effect on HepG2 cells stimulated by ethanol (800 mM, 24 h). Furthermore, we measured reactive oxygen species (ROS) production, ethanol toxicity induced cell death, and the activity of antioxidant enzymes. In in vivo experiments, liver damage was induced by oral administration of 5 g/kg ethanol with or without potent ethanol extract of S. quelpaertensis (10 or 100 mg/kg) 12 h interval for a total of 3 doses. Only 80% ethanol extract of S. quelpaertensis (SQEE80) exhibited cytoprotective effect on HepG2 cells against alcohol-induced toxicity. SQEE80 treatment (250, 500 µg/mL) in ethanol exposed HepG2 cells showed significant attenuation of ROS production and ethanol toxicity induced cell death. Furthermore, SQEE80 markedly increased the activity of antioxidant enzyme glutathione peroxidase 1 in ethanol exposed HepG2 cells compared to ethanol stimulated cells. In in vivo experiments, SQEE80 treatment evidently suppressed the alcohol-induced histopathological changes in liver, serum ethanol content, and expression of cytochrome P450 2E1. Furthermore, SQEE80 significantly reversed the reduction of glutathione level in the ethanol challenged liver. Taken together, we suggest the possibility of developing SQEE80 as a natural hepatoprotective substance in attenuating alcohol-induced oxidative stress.