No abstract

With sufficient high cooling rates, a variety of liquids, including metallic melts, will cross a glass transition temperature and solidify into glass accompanying a marked increase of the shear viscosity in approximately 17 orders of magnitude. Because of the intricate atomic structure and dynamic behaviours of liquid, it is yet difficult to capture the underlying structural mechanism responsible for the marked slowing down during glass transition, which impedes deep understanding of the formation and nature of glasses. Here, we report that a universal structural indicator, the average degree of five-fold local symmetry, can well describe the slowdown dynamics during glass transition. A straightforward relationship between structural parameter and viscosity (or α-relaxation time) is introduced to connect the dynamic arrest and the underlying structural evolution. This finding would be helpful in understanding the long-standing challenges of glass transition mechanism in the structural perspective.

properties could be achieved for their use in a variety of important applications, such as wastewater remediation, [4][5][6][7][8] catalysis, [9,10] energy storage, [11] and fuel cells. [12] Recently, a similar design principle was proposed by metallurgists to enhance the chemical complexity of alloys through the synthesis of multi-principal element alloys, also known as high entropy alloys (HEAs), [13,14] for enhanced mechanical properties. [13,15,16] In addition, some HEAs also show promising functional properties, such as super-paramagneticity and superconductivity. [17,18] Interestingly, it is noteworthy that most HEAs reported so far contain active transition metals, [19] such as Ni, Co, and Fe, which are commonly used for electrochemical catalysis; however, to our best knowledge, the research on HEAs for electrocatalysis is still rare.In the broad field of clean energy, it is critical to promote oxidation reaction and O 2 production in the state-of-the-art energy storage devices, such as fuel cells and metal oxygen batteries. However, the kinetics of such reactions, which is of a multistep process, [19] is usually sluggish; therefore, high performance electrochemically catalytic materials are in great need today to improve the efficiency of oxygen evolution Designing active, stable, yet low cost electrocatalysts for the oxygen evolution reaction (OER) is pivotal to the next generation energy storage technology. However, conventional OER catalysts are of low electrochemical efficiency while the state-of-the-art nanoparticle-based catalysts require mechanical supports, thereby limiting their wide deployment. Here, it is demonstrated that, due to the excellent corrosion resistance of the Fe-Co-Ni-Cr-Nb high entropy intermetallic Laves phase, fabricating a high entropy bulk porous nanostructure is possible by dealloying the corresponding eutectic alloy precursor. As a result, a core-shell nanostructure with amorphous high entropy oxide ultrathin films wrapped around the nanosized intermetallic ligaments is obtained, which together, exhibits an extraordinarily large active surface area, fast dynamics, and superb long-term durability, outperforming the existing alloy-and ceramic-based OER electrocatalysts. The outcome of the research suggests that the paradigm of "high entropy" design can be used to develop high performance catalytic materials.

Currently, trastuzumab resistance is a major clinical problem in the treatment of Her2-overexpressing breast cancer. The underlying molecular mechanisms are not fully understood. Our previous study demonstrates that β2-adrenergic receptor (β2-AR) and Her2 comprise a positive feedback loop in human breast cancer cells and that crosstalk between Her2 and β2-AR affects the bio-behaviors of breast cancer cells, suggesting that the β2-AR activation may be involved in trastuzumab resistance. In this study, we show that the expression of β2-AR, which mediates most catecholamine-induced effects, negatively correlates with trastuzumab response in the patients with Her2-overexpressing breast cancer. Catecholamines potently antagonize the anti-proliferative effects of trastuzumab both in vitro and in vivo. Catecholamine stimulation upregulates the expression of miR-21 and MUC-1 by activating Her2 and STAT3, leading to deficiency of phosphatase and tensin homolog and activation of phosphatidylinositol-3-kinase (PI3K) and Akt. Through inhibition of miR-199a/b-3p, catecholamines induce the mammalian target of rapamycin (mTOR) activation. Thus, trastuzumab resistance-dependent PI3K/Akt/mTOR pathway is controlled by catecholamine-induced β2-AR activation. The data indicate that β2-AR is a reliable molecular marker for prediction of response probability to trastuzumab-based therapy in breast cancer. We also demonstrate that β-blocker propranolol not only enhances the antitumor activities of trastuzumab but also re-sensitizes the resistant cells to trastuzumab. Our retrospective study shows that concurrent treatment of β-blocker and trastuzumab significantly improved progression-free survival and overall survival in the patients with Her2-overexpressing metastatic breast cancer, implicating the possibility for combination therapy with trastuzumab plus β-blocker in Her2-overexpressing breast cancer.

Trastuzumab is currently used for patients with Her2+ advanced gastric cancer. However, the response rate to trastuzumab among the patients is low. The molecular mechanisms underlying trastuzumab resistance in gastric cancer are unknown. Our in vitro data show that activation of β2-adrenergic receptor (β2-AR) triggered by catecholamine caused “targeting failure” of trastuzumab in gastric cancer cells. The antitumor activities of trastuzumab were significantly impeded by chronic catecholamine stimulation in gastric cancer cells and in the mice bearing human gastric cancer xenografts. Mechanistically, catecholamine induced upregulation of the MUC4 expression at both transcription and protein levels via activating STAT3 and ERK. The effects of catecholamine could be effectively blocked by β2-AR antagonist ICI-118,551, indicating that β2-AR–mediated signaling pathway plays a key role in upregulation of MUC4, which was previously demonstrated to interfere with the recognition and physical binding of trastuzumab to Her2 molecules. Moreover, a significant elevation of the MUC4 level was observed in the xenograft tissues in nude mice chronically treated with isoproterenol. Knockdown of MUC4 restored the binding activities of trastuzumab to Her2-overexpressing gastric cancer cells. In addition, coexpression of β2-AR and MUC4 were observed in gastric cancer tissues. Our data indicated a novel trastuzumab resistance mechanism, by which catecholamine-induced β2-AR activation mediates desensitization of gastric cancer cells to trastuzumab through upregulating the MUC4 expression.