Interaction Between Leucine and Phosphodiesterase 5 Inhibition in Modulating Insulin Sensitivity and Lipid Metabolism

Purpose: Leucine activates SIRT1/AMP-activated protein kinase (AMPK) signaling and markedly potentiates the effects of other sirtuin and AMPK activators on insulin signaling and lipid metabolism. Phosphodiesterase 5 inhibition increases nitric oxide–cGMP signaling, which in turn exhibits a positive feedback loop with both SIRT1 and AMPK, thus amplifying peroxisome proliferator-activated receptor γ co-activator α (PGC1α)-mediated effects. Methods: We evaluated potential synergy between leucine and PDE5i on insulin sensitivity and lipid metabolism in vitro and in diet-induced obese (DIO) mice. Results: Leucine (0.5 mM) exhibited significant synergy with subtherapeutic doses (0.1–10 nM) of PDE5-inhibitors (sildenafil and icariin) on fat oxidation, nitric oxide production, and mitochondrial biogenesis in hepatocytes, adipocytes, and myotubes. Effects on insulin sensitivity, glycemic control, and lipid metabolism were then assessed in DIO-mice. DIO-mice exhibited fasting and postprandial hyperglycemia, insulin resistance, and hepatic steatosis, which were not affected by the addition of leucine (24 g/kg diet). However, the combination of leucine and a subtherapeutic dose of icariin (25 mg/kg diet) for 6 weeks reduced fasting glucose (38%, P,0.002), insulin (37%, P,0.05), area under the glucose tolerance curve (20%, P,0.01), and fully restored glucose response to exogenous insulin challenge. The combination also inhibited hepatic lipogenesis, stimulated hepatic and muscle fatty acid oxidation, suppressed hepatic inflammation, and reversed high-fat diet-induced steatosis. Conclusion: These robust improvements in insulin sensitivity, glycemic control, and lipid metabolism indicate therapeutic potential for leucine–PDE5 inhibitor combinations

Study on the Size-Dependent Oxidation Reaction Kinetics of Nanosized Zinc Sulfide

Numerous oxidation problems of nanoparticles are often involved during the preparation and application of nanomaterials. The oxidation rate of nanomaterials is much faster than bulk materials due to nanoeffect. Nanosized zinc sulfide (nano-ZnS) and oxygen were chosen as a reaction system. The influence regularities were discussed and the influence essence was elucidated theoretically. The results indicate that the particle size can remarkably influence the oxidation reaction kinetics. The rate constant and the reaction order increase, while the apparent activation energy and the preexponential factor decrease with the decreasing particle size. Furthermore, the logarithm of rate constant, the apparent activation energy and the logarithm of preexponential factor are linearly related to the reciprocal of particle diameter, respectively. The essence is that the rate constant is influenced by the combined effect of molar surface energy and molar surface entropy, the reaction order by the molar surface area, the apparent activation energy, by the molar surface energy, and the preexponential factor by the molar surface entropy. The influence regularities and essence can provide theoretical guidance to solve the oxidation problems involved in the process of preparation and application of nanomaterials

Beating the fundamental rate-distance limit in a proof-of-principle quantum key distribution system

With the help of quantum key distribution (QKD), two distant peers are able to share information-theoretically secure key bits. Increasing key rate is ultimately significant for the applications of QKD in lossy channel. However, it has proved that there is a fundamental rate-distance limit, named linear bound, which limits the performance of all existing repeaterless protocols and realizations. Surprisingly, a recently proposed protocol, called twin-field (TF) QKD can beat linear bound with no need of quantum repeaters. Here, we present the first implementation of TF-QKD protocol and demonstrate its advantage of beating linear bound at the channel distance of 300 km. In our experiment, a modified TF-QKD protocol which does not assume phase post-selection is considered, and thus higher key rate than the original one is expected. After well controlling the phase evolution of the twin fields travelling hundreds of kilometers of optical fibres, the implemented system achieves high-visibility single-photon interference, and allows stable and high-rate measurement-device-independent QKD. Our experimental demonstration and results confirm the feasibility of the TF-QKD protocol and its prominent superiority in long distance key distribution services

Targeting USP1-dependent KDM4A protein stability as a potential prostate cancer therapy

The histone demethylase lysine-specific demethylase 4A (KDM4A) is reported to be overexpressed and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 or H3K36 methylation marks. However, the biological role and mechanism of KDM4A in prostate cancer (PC) remain unclear. Herein, we reported KDM4A expression was upregulation in phosphatase and tensin homolog knockout mouse prostate tissue. Depletion of KDM4A in PC cells inhibited their proliferation and survival in vivo and vitro. Further studies reveal that USP1 is a deubiquitinase that regulates KDM4A K48-linked deubiquitin and stability. Interestingly, we found c-Myc was a key downstream effector of the USP1-KDM4A/androgen receptor axis in driving PC cell proliferation. Notably, upregulation of KDM4A expression with high USP1 expression was observed in most prostate tumors and inhibition of USP1 promotes PC cells response to therapeutic agent enzalutamide. Our studies propose USP1 could be an anticancer therapeutic target in PC

Three-Dimensional Visualisation of Gas-water Two-phase Flow Based on Bubble Mapping Method and Size Projection Algorithm

Electrical impedance tomography (EIT) has been successfully applied on gas-water flow applications, but it is incapable to identify small bubbles or the sharp gas-water interface of a large bubble due to its relatively low spatial resolution. A new visualisation approach, bubble mapping method (BM3D), offers a good 3D visualisation of bubble size and distribution. However, the empirical thresholding value method used in BM3D might meet a challenging from various flow setups and conditions in practice. Recently, the size projection algorithm (SPA) was proposed to determine the closest thresholding value for each frame of tomogram by minimising projection error. In this paper, the performances of BM3D and SPA methods are individually analysed and evaluated. Then a new method based on the combination of BM3D and SPA methods is reported to achieve better visualisation of gas-water flow, where the SPA is employed to determine the optimised thresholding values for BM3D method. Experiments are conducted to evaluate the proposed combination method for typical gas-water pipeline flow regimes, including horizontal stratified, bubble, plug, slug, annular flow regimes and vertical bubble, slug, annular flow regimes. The results are compared with the BM3D method, colour mapping method, and high-speed camera video recorded from a transparent chamber. A brief discussion on the effects of reconstruction algorithms and thresholding value for horizontal and vertical flows visulaisation is also given

GeoGauss: Strongly Consistent and Light-Coordinated OLTP for Geo-Replicated SQL Database

Multinational enterprises conduct global business that has a demand for geo-distributed transactional databases. Existing state-of-the-art databases adopt a sharded master-follower replication architecture. However, the single-master serving mode incurs massive cross-region writes from clients, and the sharded architecture requires multiple round-trip acknowledgments (e.g., 2PC) to ensure atomicity for cross-shard transactions. These limitations drive us to seek yet another design choice. In this paper, we propose a strongly consistent OLTP database GeoGauss with full replica multi-master architecture. To efficiently merge the updates from different master nodes, we propose a multi-master OCC that unifies data replication and concurrent transaction processing. By leveraging an epoch-based delta state merge rule and the optimistic asynchronous execution, GeoGauss ensures strong consistency with light-coordinated protocol and allows more concurrency with weak isolation, which are sufficient to meet our needs. Our geo-distributed experimental results show that GeoGauss achieves 7.06X higher throughput and 17.41X lower latency than the state-of-the-art geo-distributed database CockroachDB on the TPC-C benchmark