Cardiac Fibroblasts Contribute to Myocardial Dysfunction in Mice with Sepsis: The Role of NLRP3 Inflammasome Activation

Myocardial contractile dysfunction in sepsis is associated with the increased morbidity and mortality. Although the underlying mechanisms of the cardiac depression have not been fully elucidated, an exaggerated inflammatory response is believed to be responsible. Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome is an intracellular platform that is involved in the maturation and release of interleukin (IL)-1β. The aim of the present study is to evaluate whether sepsis activates NLRP3 inflammasome/caspase-1/IL-1β pathway in cardiac fibroblasts (CFs) and whether this cytokine can subsequently impact the function of cardiomyocytes (cardiac fibroblast-myocyte cross-talk). We show that treatment of CFs with lipopolysaccharide (LPS) induces upregulation of NLRP3, activation of caspase-1, as well as the maturation (activation) and release of IL-1β. In addition, the genetic (small interfering ribonucleic acid [siRNA]) and pharmacological (glyburide) inhibition of the NLRP3 inflammasome in CFs can block this signaling pathway. Furthermore, the inhibition of the NLRP3 inflammasome in cardiac fibroblasts ameliorated the ability of LPS-chalenged CFs to impact cardiomyocyte function as assessed by intracellular cyclic adenosine monophosphate (cAMP) responses in cardiomyocytes. Salient features of this the NLP3 inflammasome/ caspase-1 pathway were confirmed in in vivo models of endotoxemia/sepsis. We found that inhibition of the NLRP3 inflammasome attenuated myocardial dysfunction in mice with LPS and increased the survival rate in mice with feces-induced peritonitis. Our results indicate that the activation of the NLRP3 inflammasome in cardiac fibroblasts is pivotal in the induction of myocardial dysfunction in sepsis.     

Long non‐coding RNA LINC01225 promotes proliferation,invasion and migration of gastric cancer via Wnt/β‐catenin signalling pathway

Emerging evidence has classified the aberrant expression of long non‐coding RNAs (lncRNAs) as a basic signature of various malignancies including gastric cancer (GC). LINC01225 has been shown to act as a hepatocellular carcinoma‐related gene, with its expression pattern and biological function not clarified in GC. Here, we verified that LINC01225 was up‐regulated in tumour tissues and plasma of GC. Analysis with clinicopathological information suggested that up‐regulation of LINC01225 was associated with advanced disease and poorer overall survival. Receiver operating characteristic (ROC) analysis showed that plasma LINC01225 had a moderate accuracy for diagnosis of GC. In addition, knockdown of LINC01225 led to retardation of cell proliferation, invasion and migration, and overexpression of LINC01225 showed the opposite effects. Mechanistic investigations showed that LINC01225 silencing inhibited epithelial‐mesenchymal transition (EMT) process and attenuated Wnt/β‐catenin signalling of GC. Furthermore, ectopic expression of Wnt1 or suppression of GSK‐3β abolished the si‐LINC01225‐mediated suppression against EMT, thereby promoting cell proliferation, invasion and migration of GC. In conclusion, LINC01225 promotes the progression of GC through Wnt/β‐catenin signalling pathway, and it may serve as a potential target or strategy for diagnosis or treatment of GC.     

Berberine attenuates XRCC1‐mediated base excision repair and sensitizes breast cancer cells to the chemotherapeutic drugs

Berberine (BBR) is a natural isoquinoline alkaloid, which is used in traditional medicine for its anti‐microbial, anti‐protozoal, anti‐diarrhoeal activities. Berberine interacts with DNA and displays anti‐cancer activities, yet its effects on cellular DNA repair and on synthetic treatments with chemotherapeutic drugs remain unclear. In this study, we investigated the effects of BBR on DNA repair and on sensitization of breast cancer cells to different types of DNA damage anti‐tumoural drugs. We found BBR arrested cells in the cell cycle S phase and induced DNA breaks. Cell growth analysis showed BBR sensitized MDA‐MB‐231 cells to cisplatin, camptothecin and methyl methanesulfonate; however, BBR had no synergistic effects with hydroxurea and olaparib. These results suggest BBR only affects specific DNA repair pathways. Western blot showed BBR down‐regulated XRCC1 expressions, and the rescued XRCC1 recovered the resistance of cancer cells to BBR. Therefore, we conclude that BBR interferes with XRCC1‐mediated base excision repair to sensitize cancer cells to chemotherapeutic drugs. These finding can contribute to understanding the effects of BBR on cellular DNA repair and the clinical employment of BBR in treatment of breast cancer.     

SH3‐class Ras guanine nucleotide exchange factors are essential for Aspergillus fumigatus invasive growth

Proper hyphal morphogenesis is essential for the establishment and progression of invasive disease caused by filamentous fungi. In the human pathogen Aspergillus fumigatus, signalling cascades driven by Ras and Ras‐like proteins orchestrate a wide variety of cellular processes required for hyphal growth. For activation, these proteins require interactions with Ras‐subfamily‐specific guanine nucleotide exchange factors (RasGEFs). Although Ras‐protein networks are essential for virulence in all pathogenic fungi, the importance of RasGEF proteins is largely unexplored. A. fumigatus encodes four putative RasGEFs that represent three separate classes of RasGEF proteins (SH3‐, Ras guanyl nucleotide‐releasing protein [RasGRP]–, and LTE‐class), each with fungus‐specific attributes. Here, we show that the SH3‐class and RasGRP‐class RasGEFs are required for properly timed polarity establishment during early growth and branch emergence as well as for cell wall stability. Further, we show that SH3‐class RasGEF activity is essential for polarity establishment and maintenance, a phenotype that is, at least, partially independent of the major A. fumigatus Ras proteins, RasA and RasB. Finally, loss of both SH3‐class RasGEFs resulted in avirulence in multiple models of invasive aspergillosis. Together, our findings suggest that RasGEF activity is essential for the integration of multiple signalling networks to drive invasive growth in A. fumigatus.     

Boosting Oxygen Evolution Kinetics by Mn–N–C Motifs with Tunable Spin State for Highly Efficient Solar‐Driven Water Splitting

Solar‐driven water splitting is in urgent need for sustainable energy research, for which accelerating oxygen evolution kinetics along with charge migration is the key issue. Herein, Mn³⁺ within π‐conjugated carbon nitride (C₃N₄) in form of Mn–N–C motifs is coordinated. The spin state (e_g orbital filling) of Mn centers is regulated by controlling the bond strength of Mn–N. It is demonstrated that Mn serves as intrinsic oxygen evolution reaction (OER) site and the kinetics is dependent on its spin state with an optimized e_g occupancy of ≈0.95. Specifically, the governing role of e_g occupancy originates from the varied binding strength between Mn and OER intermediates. Benefiting from the rapid spin state‐mediated OER kinetics, as well as extended optical absorption (to 600 nm) and accelerated charge separation by intercalated metal‐to‐ligand state, Mn–C₃N₄ stoichiometrically splits pure water with H₂ production rate up to 695.1 µmol g^?1 h^?1 under simulated sunlight irradiation (AM1.5), and achieves an apparent quantum efficiency of 4.0% at 420 nm, superior to most solid‐state based photocatalysts to date. This work for the first time correlates photocatalytic redox kinetics with the spin state of active sites, and suggests a nexus between photocatalysis and spin theory.     

Boost the Performance of Triboelectric Nanogenerators through Circuit Oscillation

Triboelectric nanogenerator (TENG) which harvests ubiquitous ambient mechanical energy is a promising power source that can meet the distributed energy demand in the internet of things, wearable electronics, etc. However, the available output of TENG is severely limited by the saturated polarized charge density, small intrinsic capacitance, and large matching impedance. Herein, an effective power management strategy is proposed that flips the free charges on the conductive layer through a controlled LC oscillating circuit composed of the diode, switch, inductor, and the intrinsic capacitor of TENG. In this way, the equivalent charge density reaches a level higher than the saturated polarized charge density. The simulation and experiments show that the limit of energy output can be exceeded under arbitrary load resistance, especially for the low‐impedance common electronics. It is believed that such a general, low‐cost, and highly effective strategy can further broaden the applications of TENG devices across the fields and probably be a new performance evaluation standard for TENG.     

秦岭南坡陕西洋县辖区哺乳动物物种多样性的空间分布格局

物种多样性的空间分布格局一直是生态学和生物地理学研究的一个热点问题。山地生态系统的生境异质性和物种多样性高, 适合研究物种多样性空间分布格局及其相关机制。2016年11月至2017年11月, 本研究选取秦岭南坡陕西洋县辖区作为研究区域, 采用样线法、红外相机法和笼捕/夹捕法, 系统分析了8目21科48种哺乳动物物种多样性的空间分布格局。研究结果发现秦岭南坡洋县辖区哺乳动物物种丰富度的空间分布格局大致是中南部低, 北部和东部高; 物种多样性指数大致是中南部和北部低, 东部高。啮齿类动物和非啮齿类动物的空间分布格局存在差异。哺乳动物物种丰富度和多样性指数的垂直分布格局都符合中峰模式, 但啮齿类动物和非啮齿类动物间存在差异。最优线性模型结果表明, 研究地区哺乳动物物种多样性的空间分布格局受到多种环境因素的共同影响。其中, 年均温与物种多样性的相关性最强, 在6个最优线性模型中贡献都是最大。综上, 秦岭南坡洋县辖区中高海拔区域的物种多样性较高, 应加强对中高海拔地区的保护, 以维系该区域较高的生物多样性。