Discovery of selective EGFR modulator to inhibit L858R/T790M double mutants bearing a N-9-Diphenyl-9H-purin-2-amine scaffold

Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of N-9-Diphenyl-9H-purin-2-amine derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 23a showed excellent enzyme inhibitory activities and selectivity with nanomolar IC₅₀ values for both the single T790M and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 23a displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R. And it was less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index.     

Hierarchically Porous,Ultrathick, “Breathable” Wood‐Derived Cathode for Lithium‐Oxygen Batteries

In this work, a hierarchically porous and ultrathick “breathable” wood‐based cathode for high‐performance Li‐O₂ batteries is developed. The 3D carbon matrix obtained from the carbonized and activated wood (denoted as CA‐wood) serves as a superconductive current collector and an ideal porous host for accommodating catalysts. The ruthenium (Ru) nanoparticles are uniformly anchored on the porous wall of the aligned microchannels (denoted as CA‐wood/Ru). The aligned open microchannels inside the carbon matrix contribute to unimpeded oxygen gas diffusion. Moreover, the hierarchical pores on the microchannel walls can be facilely impregnated by electrolyte, forming a continuous supply of electrolyte. As a result, numerous ideal triphase active sites are formed where electrolyte, oxygen, and catalyst accumulate on the porous walls of microchannels. Benefiting from the numerous well‐balanced triple‐phase active sites, the assembled Li‐O₂ battery with the CA‐wood/Ru cathode (thickness: ≈700 µm) shows a high specific area capacity of 8.58 mA h cm^?2 at 0.1 mA cm^?2. Moreover, the areal capacity can be further increased to 56.0 mA h cm^?2 by using an ultrathick CA‐wood/Ru cathode with a thickness of ≈3.4 mm. The facile ultrathick wood‐based cathodes can be applied to other cathodes to achieve a super high areal capacity without sacrificing the electrochemical performance.     

Influence of Donor Polymer on the Molecular Ordering of Small Molecular Acceptors in Nonfullerene Polymer Solar Cells

Nonfullerene polymer solar cells (PSCs) based on polymer donors and nonfullerene small molecular acceptors (SMAs) have recently attracted considerable attention. Although much of the progress is driven by the development of novel SMAs, the donor polymer also plays an important role in achieving efficient nonfullerene PSCs. However, it is far from clear how the polymer donor choice influences the morphology and performance of the SMAs and the nonfullerene blends. In addition, it is challenging to carry out quantitative analysis of the morphology of polymer:SMA blends, due to the low material contrast and overlapping scattering features of the π–π stacking between the two organic components. Here, a series of nonfullerene blends is studied based on ITIC‐Th blended with five different donor polymers. Through quantitative morphology analysis, the (010) coherence length of the SMA is characterized and a positive correlation between the coherence length of the SMA and the device fill factor (FF) is established. The study reveals that the donor polymer can significantly change the molecular ordering of the SMA and thus improve the electron mobility and domain purity of the blend, which has an overall positive effect that leads to the enhanced device FF for nonfullerene PSCs.     

Ultrafine Pt Nanoparticle‐Decorated Pyrite‐Type CoS2 Nanosheet Arrays Coated on Carbon Cloth as a Bifunctional Electrode for Overall Water Splitting

To improve the utilization efficiency of precious metals, metal‐supported materials provide a direction for fabricating highly active and stable heterogeneous catalysts. Herein, carbon cloth (CC)‐supported Earth‐abundant CoS₂ nanosheet arrays (CoS₂/CC) are presented as ideal substrates for ultrafine Pt deposition (Pt‐CoS₂/CC) to achieve remarkable performance toward the hydrogen and oxygen evolution reactions (HER/OER) in alkaline solutions. Notably, the Pt‐CoS₂/CC hybrid delivers an overpotential of 24 mV at 10 mA cm^?2 and a mass activity of 3.89 A Pt_mg^?1, which is 4.7 times higher than that of commercial Pt/C, at an overpotential of 130 mV for catalyzing the HER. An alkali‐electrolyzer using Pt‐CoS₂/CC as a bifunctional electrode enables a water‐splitting current density of 10 mA cm^?2 at a low voltage of 1.55 V and can sustain for more than 20 h, which is superior to that of the state‐of‐the‐art Pt/C+RuO₂ catalyst. Further experimental and theoretical simulation studies demonstrate that strong electronic interaction between Pt and CoS₂ synergistically optimize hydrogen adsorption/desorption behaviors and facilitate the in situ generation of OER active species, enhancing the overall water‐splitting performance. This work highlights the regulation of interfacial and electronic synergy in pursuit of highly efficient and durable supported catalysts for hydrogen and oxygen electrocatalytic applications.     

Epirubicin induces apoptosis in osteoblasts through death-receptor and mitochondrial pathways

Epirubicin is an anthracycline and is widely used in tumor treatment, but has toxic and undesirable side effects on wide range of cells and hematopoietic stem cells (HSC). Osteoblasts play important roles in bone development and in supporting HSC differentiation and maturation. It remains unknown whether epirubicin-induced bone loss and hematological toxicity are associated with its effect on osteoblasts. In primary osteoblast cell cultures, epirubicin inhibited cell growth and decreased mineralization. Moreover, epirubicin arrested osteoblasts in the G2/M phase, and this arrest was followed by apoptosis in which both the extrinsic (death receptor-mediated) and intrinsic (mitochondrial-mediated) apoptotic pathways were evoked. The factors involved in the extrinsic apoptotic pathway were increased FasL and FADD as well as activated caspase-8. Those involved in the intrinsic apoptotic pathway were decreased Bcl-2; increased reactive oxygen species, Bax, cytochrome c; and activated caspase-9 and caspase-3. These results demonstrate that epirubicin induced osteoblast apoptosis through the extrinsic and intrinsic apoptotic pathways, leading to the destruction of osteoblasts and consequent lessening of their functions in maintaining bone density and supporting hematopoietic stem cell differentiation and maturation.     

真菌降解木质素研究进展及在好氧堆肥中的研究展望

综述了近十年来真菌降解木质素的研究进展,包括木质素的存在与结构,真菌降解木质素生物学、酶系及作用机理、生理学以及在环境工程中应用方面的研究进展,并对好氧堆肥处理城市垃圾中木质素生物降解的研究作了展望 。     

Dissecting a complex chemical stress: chemogenomic profiling of plant hydrolysates

The efficient production of biofuels from cellulosic feedstocks will require the efficient fermentation of the sugars in hydrolyzed plant material. Unfortunately, plant hydrolysates also contain many compounds that inhibit microbial growth and fermentation. We used DNA‐barcoded mutant libraries to identify genes that are important for hydrolysate tolerance in both Zymomonas mobilis (44 genes) and Saccharomyces cerevisiae (99 genes). Overexpression of a Z. mobilis tolerance gene of unknown function (ZMO1875) improved its specific ethanol productivity 2.4‐fold in the presence of miscanthus hydrolysate. However, a mixture of 37 hydrolysate‐derived inhibitors was not sufficient to explain the fitness profile of plant hydrolysate. To deconstruct the fitness profile of hydrolysate, we profiled the 37 inhibitors against a library of Z. mobilis mutants and we modeled fitness in hydrolysate as a mixture of fitness in its components. By examining outliers in this model, we identified methylglyoxal as a previously unknown component of hydrolysate. Our work provides a general strategy to dissect how microbes respond to a complex chemical stress and should enable further engineering of hydrolysate tolerance.     

Design,modification and 3D QSAR studies of novel naphthalin-containing pyrazoline derivatives with/without thiourea skeleton as anticancer agents

Two series of novel naphthalin-containing pyrazoline derivatives C1–C14 and D1–D14 have been synthesized and evaluated for their EGFR/HER-2 inhibitory and anti-proliferation activities. Compound D14 displayed the most potent activity against EGFR and A549 cell line (IC₅₀ = 0.05 μM and GI₅₀ = 0.11 μM), being comparable with the positive control Erlotinib (IC₅₀ = 0.03 μM and GI₅₀ = 0.03 μM) and more potent than our previous compounds C0–A (IC₅₀ = 5.31 μM and GI₅₀ = 33.47 μM) and C0–B (IC₅₀ = 0.09 μM and GI₅₀ = 0.34 μM). Meanwhile, compound C14 displayed the most potent activity against HER-2 and MCF-7 cell line (IC₅₀ = 0.88 μM and GI₅₀ = 0.35 μM), being a little less potent than Erlotinib (IC₅₀ = 0.16 μM and GI₅₀ = 0.08 μM) but far more potent than C0–A (IC₅₀ = 6.58 μM and GI₅₀ = 27.62 μM) and C0–B (IC₅₀ = 2.77 μM and GI₅₀ = 3.79 μM). The docking simulation was performed to analyze the probable binding models and the QSAR models were built for reasonable design of EGFR/HER-2 inhibitors at present and in future. The structural modification of introducing naphthalin moiety reinforced the combination of our compounds and the receptor, resulting in progress of bioactivity. Moreover, the replacement of thiourea skeleton by using benzene ring resulted in the slight diversity of the two series towards specific targets.     

The effects of post-stroke upper-limb training with an electromyography (EMG)-driven hand robot

Loss of hand function and finger dexterity are main disabilities in the upper limb after stroke. An electromyography (EMG)-driven hand robot had been developed for post-stroke rehabilitation training. The effectiveness of the hand robot assisted whole upper limb training was investigated on persons with chronic stroke (n = 10) in this work. All subjects attended a 20-session training (3–5 times/week) by using the hand robot to practice object grasp/release and arm transportation tasks. Significant motor improvements were observed in the Fugl-Meyer hand/wrist and shoulder/elbow scores (p < 0.05), and also in the Action Research Arm Test and Wolf Motor Function Test (p < 0.05). Significant reduction in spasticity of the fingers as was measured by the Modified Ashworth Score (p < 0.05). The training improved the muscle co-ordination between the antagonist muscle pair (flexor digitorum (FD) and extensor digitorum (ED)), associated with a significant reduction in the ED EMG level (p < 0.05) and a significant decrease of ED and FD co-contraction during the training (p < 0.05); the excessive muscle activities in the biceps brachii were also reduced significantly after the training (p < 0.05).