Hydrogen/functionalized benzoquinone for a high-performance regenerative fuel cell as a potential large-scale energy storage platform

The redox flow battery (RFB) is a suitable option for electricity storage due to its high energy efficiency, scalability and relative safety. However, the limited metallic resources for redox materials and the high cost in systems such as the all-vanadium RFB are major challenges for wider application. Organics may be sourced more abundantly and have lower prices than metal based redox couples. In this work a regenerative fuel cell involving relatively inexpensive organic redox couples is demonstrated. The electrochemical properties of 1,2-dihydrobenzoquinone-3,5-disulfonic acid (BQDS) are characterised by cyclic voltammetry and linear-sweep voltammetry under hydrodynamic conditions. A regenerative fuel cell using 0.65 M BQDS in 1 M H2SO4 as positive electrolyte and gaseous hydrogen (1 bar) as negative redox-material results in an open circuit cell voltage of 0.86 V, a power density of 122 mW/cm2, and an energy density of 10.90 Wh L-1 without considering the volume occupied by the hydrogen. Very promising performance with an energy efficiency >60% at 100 mA cm-2 for 200 cycles is reported. New organic redox species resistant to side reactions could facilitate the use of this new system in practical applications. The use of hydrogen may also contribute to reduced side reactions of the organic redox associated with degradation in the presence of oxygen

Advanced glycation end products accelerate ischemia/reperfusion injury through receptor of advanced end product/nitrative thioredoxin inactivation in cardiac microvascular endothelial cells.

The advanced glycation end products (AGEs) are associated with increased cardiac endothelial injury. However, no causative link has been established between increased AGEs and enhanced endothelial injury after ischemia/reperfusion. More importantly, the molecular mechanisms by which AGEs may increase endothelial injury remain unknown. Adult rat cardiac microvascular endothelial cells (CMECs) were isolated and incubated with AGE-modified bovine serum albumin (BSA) or BSA. After AGE-BSA or BSA preculture, CMECs were subjected to simulated ischemia (SI)/reperfusion (R). AGE-BSA increased SI/R injury as evidenced by enhanced lactate dehydrogenase release and caspase-3 activity. Moreover, AGE-BSA significantly increased SI/R-induced oxidative/nitrative stress in CMECs (as measured by increased inducible nitric oxide synthase expression, total nitric oxide production, superoxide generation, and peroxynitrite formation) and increased SI/R-induced nitrative inactivation of thioredoxin-1 (Trx-1), an essential cytoprotective molecule. Supplementation of EUK134 (peroxynitrite decomposition catalyst), human Trx-1, or soluble receptor of advanced end product (sRAGE) (a RAGE decoy) in AGE-BSA precultured cells attenuated SI/R-induced oxidative/nitrative stress, reduced SI/R-induced Trx-1 nitration, preserved Trx-1 activity, and reduced SI/R injury. Our results demonstrated that AGEs may increase SI/R-induced endothelial injury by increasing oxidative/nitrative injury and subsequent nitrative inactivation of Trx-1. Interventions blocking RAGE signaling or restoring Trx activity may be novel therapies to mitigate endothelial ischemia/reperfusion injury in the diabetic population

Pharmacological targeting of STK19 inhibits oncogenic NRAS driven melanomagenesis

黑色素瘤是由黑色素细胞恶性转化产生的恶性程度极高的皮肤癌，含有NRAS激活突变的黑色素瘤约占20-30%，但至今还未有靶向NRAS的有效黑色素瘤治疗方案。针对这一难题，波士顿大学医学中心崔儒涛教授、厦门大学生命科学学院邓贤明教授、复旦大学附属肿瘤医院王鹏教授组成的联合研究团队利用激酶组siRNA文库筛选发现新颖的丝/苏氨酸激酶STK19是NRAS的上游激活子，进一步分子机制研究揭示STK19通过磷酸化NRAS的89位丝氨酸（S89）促进了NRAS介导的黑色素细胞恶性转化。该研究揭示了一种经由新颖激酶STK19调控NRAS突变黑色素瘤的分子机制，验证了STK19有望作为NRAS介导的黑色素瘤的有效靶标，为发展新的黑色素瘤靶向药物提供了先导化合物，同时也为发展其它素有“癌基因之王---RAS”驱动的相关肿瘤靶向药物发展提供了新思路。该论文由波士顿大学医学中心、厦门大学生命科学学院、复旦大学附属肿瘤医院等单位合作完成，共同第一作者厦门大学生命科学学院博士生张婷负责了该系列化合物的设计、合成与优化，崔儒涛教授、邓贤明教授和王鹏教授为共同通讯作者。【Abstract】Activating mutations in NRAS account for 20-30% of melanoma, but despite decades of research and in contrast to BRAF, no effective anti-NRAS therapies have been forthcoming. Here we identify a previously uncharacterized serine/threonine kinase STK19 as a novel NRAS activator. STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation. A recurrent D89N substitution in STK19 whose alterations were identified in 25% of human melanomas represents a gain-of-function mutation that interacts better with NRAS to enhance melanocyte transformation. STK19 D89N knockin leads to skin hyperpigmentation and promotes NRAS Q61R -driven melanomagenesis in vivo. Finally, we developed ZT-12-037-01 (1a) as a specific STK19-targeted inhibitor and showed that it effectively blocks oncogenic NRAS-driven melanocyte malignant transformation and melanoma growth in vitro and in vivo. Together, our findings provide a new and viable therapeutic strategy for melanomas harboring NRAS mutations.We thank Drs. Norman Sharpless and David Fisher for kindly providing the loxP/STOP/loxP NRAS Q61R knockin (LSL-NRAS Q61R ) mice. We thank Dr. Anurag Singh for kindly sharing cell lines. We also thank Drs. X. Shirley Liu, Tao Wang, Wantao Chen, Dali Liu, Chunxiao Xu, Jianming Zhang and Junrong Zou for discussion and assistance. This work was supported by grants from Boston University (to R.C.), the National Key R&D Program and the National Natural Science Foundation of China (No. 2017YFA0504504, 2016YFA0502001, 81422045, U1405223 and 81661138005 to X.D.), the Fundamental Research Funds for the Central Universities of China (No. 20720160064 to X.D.), and the Program of Introducing Talents of Discipline to Universities (111 Project, B12001).该研究得到了科技部重点研发计划、国家自然科学基金委和中央高校基本科研业务费等的资助

Binding of Tetracycline and Chlortetracycline to the Enzyme Trypsin: Spectroscopic and Molecular Modeling Investigations

Tetracycline (TC) and chlortetracycline (CTC) are common members of the widely used veterinary drug tetracyclines, the residue of which in the environment can enter human body, being potentially harmful. In this study, we establish a new strategy to probe the binding modes of TC and CTC with trypsin based on spectroscopic and computational modeling methods. Both TC and CTC can interact with trypsin with one binding site to form trypsin-TC (CTC) complex, mainly through van der Waals' interactions and hydrogen bonds with the affinity order: TC>CTC. The bound TC (CTC) can result in inhibition of trypsin activity with the inhibition order: CTC>TC. The secondary structure and the microenvironment of the tryptophan residues of trypsin were also changed. However, the effect of CTC on the secondary structure content of trypsin was contrary to that of TC. Both the molecular docking study and the trypsin activity experiment revealed that TC bound into S1 binding pocket, competitively inhibiting the enzyme activity, and CTC was a non-competitive inhibitor which bound to a non-active site of trypsin, different from TC due to the Cl atom on the benzene ring of CTC which hinders CTC entering into the S1 binding pocket. CTC does not hinder the binding of the enzyme substrate, but the CTC-trypsin-substrate ternary complex can not further decompose into the product. The work provides basic data for clarifying the binding mechanisms of TC (CTC) with trypsin and can help to comprehensively understanding of the enzyme toxicity of different members of tetracyclines in vivo

The protective role of DOT1L in UV-induced melanomagenesis

The DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLL-rearranged leukemogenesis. Here, we demonstrate that, in contrast to MLL-rearranged leukemia, DOT1L plays a protective role in ultraviolet radiation (UVR)-induced melanoma development. Specifically, the DOT1L gene is located in a frequently deleted region and undergoes somatic mutation in human melanoma. Specific mutations functionally compromise DOT1L methyltransferase enzyme activity leading to reduced H3K79 methylation. Importantly, in the absence of DOT1L, UVR-induced DNA damage is inefficiently repaired, so that DOT1L loss promotes melanoma development in mice after exposure to UVR. Mechanistically, DOT1L facilitates DNA damage repair, with DOT1L-methylated H3K79 involvement in binding and recruiting XPC to the DNA damage site for nucleotide excision repair (NER). This study indicates that DOT1L plays a protective role in UVR-induced melanomagenesis

Pilot-Scale Production, Properties and Application of Fe/Cu Catalytic-Ceramic-Filler for Nitrobenzene Compounds Wastewater Treatment

Iron powder, Kaolin powder and CuSO4∙5H2O were employed as the main materials for the pilot-scale production of Fe/Cu catalytic- ceramic-filler (CCF) by way of wet type replacement-thermo-solidification. The physical properties, half-life, microstructure, removal rate of nitrobenzene compounds and the biodegradability-improvement of military chemical factory comprehensive wastewater were tested in comparison with commercial Fe/C ceramic-filler (CF). Catalytic micro-electrolysis bed reactors (CBRs) designed as pretreatment process and BAFs (Biological Aerated Filters) were utilized in a 90 days field pilot-scale test at last. The results showed the characteristics of optimum CCF were: 1150 kg/m3 of bulk density, 1700 kg/m3 of grain density, lower than 3.5% of shrinking ratio, 3.5% of 24 h water absorption, 6.0 Mpa of numerical tube pressure, 0.99 acid-resistance softening co-efficiency and 893.55 days of half-life. 25% addition of Fe with 1% of copper plating rate was efficient for the removal of nitrobenzene compounds and significant in promoting the biodegradability of military chemical factory comprehensive wastewater. The two-stage design of CBRs and BAFs showed high dependability and stability for the practical engineering application

Comparison of the binding of the dyes Sudan II and Sudan IV to bovine hemoglobin

Sudan dyes are widely used in industry, and sometimes illegally used as food additives despite their potential toxicity. In this work, the interactions of Sudan II and Sudan IV with bovine hemoglobin (BHb) were investigated by fluorescence, synchronous fluorescence, resonance light scattering (RLS), UV-vis absorption, circular dichroism (CD), and molecular modeling techniques. Binding of Sudan dyes to BHb could cause static quenching of the fluorescence, indicating changes in the microenvironment of tryptophan and tyrosine residues. The binding constants estimated for Sudan II and IV were 1.84 x 10(4) L mol(-1) and 254 x 10(4) L mol(-1), respectively, at 293 K (20 degrees C). Each protein molecule bound one Sudan molecule approximately. Sudan II and IV were held at the hydrophobic cavity of BHb mainly by hydrophobic interaction. The decrease of alpha-helix and the increase of beta-sheet seen in the CD spectra revealed a conformational alteration of the protein. From all the results, we conclude that Sudan IV has a stronger impact on the structure and function of BHb than that of Sudan H. (C) 2013 Elsevier B.V. All rights reserve