Design and synthesis of gallocyanine inhibitors of DKK1/LRP6 interactions for treatment of Alzheimer’s disease

Based on NCI8642, a series of gallocyanine derivatives was synthesized with modifications of the substituent groups in position 1, 2 and 4 of the phenoxazinone scaffold. The effectiveness of gallocyanines to inhibit DKK1/LRP6 interactions and Tau phosphorylation induced by prostaglandin J2 and DKK1 was elucidated by both experimental data and molecular docking simulations. Bis-alkylated with flexible alkyl ester groups on C1 and bis-benzyl gallocyanines provided the most active inhibitors, while amino derivatives on C2 of NCI8642 that have alkoxy or benzyloxy substituents on C4, were less active. Furthermore, it is shown that treating of SHSY5Y cells with NCI8642 derivatives activates Wnt signaling and increases the levels of pGSK3β kinase and β-catenin.     

Glucocerebrosidase Activity Modulates Neuronal Susceptibility to Pathological α-Synuclein Insult

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PSDS 2.0: 一个基于GIS和多个模型的生物潜在分布地预测系统

根据对生物分布地预测模型和软件发展现状的分析和总结, 本研究在PSDS 1.0的基础上提出并实现一个基于GIS且具有多个代表性模型的生物分布地预测系统(PSDS 2.0)。PSDS 2.0系统继承了1.0的环境包络和聚类包络模型, 进一步引入了限制因子包络、马氏距离、支持向量机等新模型, 并针对本领域中模型比较与选择的难点增加了迭代交叉验证的多模型选择功能。系统还实现了灵活定制和评估伪负样本的功能, 通过用只需要正样本的I类模型预测的结果对随机产生的伪负样本进行评估, 减小其落入适宜地区的概率, 进一步提高需要正负样本的II类模型的准确率。GIS功能在PSDS 2.0中也得到加强, 被应用于数据准备及结果分析等重要环节。文章最后以白冠长尾雉(Syrmaticus reevesii)为例, 运用PSDS 2.0系统预测其在中国范围内的潜在分布地, 并对各种模型的预测结果进行评估和比较。     

红火蚁工蚁对跟踪信息素的触角电位和行为反应

【目的】测定红火蚁Solenopsis invicta Buren工蚁对其跟踪信息素的触角电位（EAG）及行为反应。【方法】解剖红火蚁工蚁的杜氏腺, 用正己烷溶剂提取其分泌的跟踪信息素进行气相色谱-质谱（GC-MS）分析, 并测定了红火蚁工蚁对杜氏腺提取物、 工蚁提取物和合成的法尼烯混合物的EAG和招募行为反应。【结果】通过与合成的法尼烯混合物的气相色谱（GC）保留时间和质谱图比对, 发现杜氏腺提取物的主要成分并不是Z, E-α-法尼烯。EAG测定结果表明, 红火蚁工蚁对杜氏腺提取物、 工蚁提取物及100 μg的法尼烯混合物均有较强的EAG反应, 其次为10 μg和1 μg的法尼烯混合物。在招募行为测定中, 杜氏腺提取物和工蚁提取物招募作用明显, 而10, 1, 0.1和0.01 μg法尼烯混合物的作用均不显著。【结论】Z, E-α-法尼烯不是红火蚁跟踪信息素的主要成分; 红火蚁工蚁对杜氏腺提取物、 工蚁提取物有较强的EAG反应和明显的招募行为反应。     

弄岗黑叶猴旱季食物营养组分及其对食物选择的影响

正蛋白质与纤维素的比值以及能量高低是影响灵长类动物食物选择的重要因素(Oftedal,1991;Waterman and Kool,1994;Chapman and Chapman,2002;Wasserman and Chapman,2003;Hanya et al.,2007;Huang et al.,2010),但它们是否影响疣猴的食物选择目前尚具有较大的争议。Waterman     

Synthesis and biological evaluation of quinazolinone-based hydrazones with potential use in Alzheimer’s disease

Discovering multifunctional agents for the treatment of Alzheimer’s disease (AD) is an attractive therapeutic approach. BACE1 (β-site amyloid precursor protein cleaving enzyme 1) inhibitors may play a pivotal role in treating AD. Therefore, the discovery of novel non-peptide BACE1 inhibitors with desirable blood brain barrier permeability is a favorable approach for treatment. Moreover, the antioxidant potential of a drug could serve as an added value for designing dual-acting therapeutic agents. Here, we report the design, synthesis and biological evaluation of quinazolinone-hydrazone derivatives as new multi-target candidates for the treatment of AD. The compounds were investigated for their in vitro BACE1 inhibitory potential using a FRET-based enzymatic assay and also screened for antioxidant activity using DPPH. Among them, compound 4h bearing a 2,3-dichlorophenyl moiety showed the highest activity with an IC₅₀ value of 3.7 μM against BACE1. In addition, compound 4i with a 2,4-dihydroxyphenyl scaffold demonstrated moderate BACE1 inhibitory activity (IC₅₀ = 27.6 μM) with a significant antioxidant effect (IC₅₀ = 8.4 μM). Furthermore, docking studies revealed strong interaction between compound 4h and the key residues of BACE1 active site. These results demonstrate that quinazolinone-hydrazone derivatives represent a valuable scaffold for the discovery of novel non-peptidic BACE1 inhibitors.     

Was Australopithecus afarensis able to make the Lomekwian stone tools? Towards a realistic biomechanical simulation of hand force capability in fossil hominins and new insights on the role of the fifth digit

While no consensus allows explaining how and when human-like traits arose in fossil hominin hands, the recent discoveries of the Lomekwian stone tools (3.3 Ma) support the view that early hominins were able to use forceful grips in order to manipulate large-sized blocks for pounding activities. Then, assessing gripping abilities of contemporaneous hominin, i.e. Australopithecus afarensis, is necessary, particularly with regards to its unusual 5th ray morphology that has been deemed crucial to ensure forceful grips. Here, we present a musculoskeletal simulation based on the A. afarensis hand morphology that includes an original 5th carpometacarpal joint. Our first results suggest a limited influence of muscle parameters (e.g., PCSA) and support the value of simulations for studying extinct taxa even in absence of soft-tissue data. Given the inability for the pulp of the 5th ray to face the surface of a large-sized object, the A. afarensis hand would have had limited possibility to exert sufficient force to make the Lomekwian stone tools.