Copper inducing Aβ42 rather than Aβ40 nanoscale oligomer formation is the key process for Aβ neurotoxicity

Copper is known to be a critical factor in Alzheimer's disease (AD) pathogenesis, as it is involved in amyloid-β (Aβ) peptide related toxicity. However, the relationship between neurotoxicity and Aβ peptide in the presence of copper remains unclear. The effect of copper has not been clearly differentiated between Aβ42 and Aβ40, and it is still debated whether copper-mediated neurotoxicity is due to reactive oxygen species (ROS) accumulation or other molecular mechanisms. Here, we describe that copper dramatically affects Aβ42 aggregation and enhances Aβ42 cytotoxicity while it shows no significant effects on Aβ40. These phenomena are mainly because that the strong interactions between copper and Aβ42 lead to great conformation changes, and stabilize Aβ42 aggregates at highly toxic nanoscale oligomer stage, whereas copper shows no similar impact on Aβ40. We also propose a possible molecular mechanism that copper enhances Aβ42 cytotoxicity via perturbing membrane structure. Moreover, we test the effect of an analogue of copper, nickel, on Aβ aggregation and cytotoxicity, finding that nickel also enhances cytotoxicity via Aβ42 nanoscale oligomer formation. These results clarify that the copper-induced Aβ42 nanoscale oligomer formation is the key process for Aβ neurotoxicity, and suggest that disrupting the interactions between copper and Aβ42 peptide to inhibit nanoscale oligomerization process, deserves more attention in AD drug development.     

LL-40A型腰轮气量计

一、概述我厂广大工人、技术人员和革命干部,遵照毛主席“独立自主、自力更生”的伟大教导,急国家之所急,在一无样机、二无外来图纸的情况下,于七五年短短的几个月里,克服种种困难,自行设计、试制成功LL-40A型腰轮气量计。它的试制成功,解决了为国防配套的急需,为我国仪表工业填补了一个空白。     

Aβ-40 Y10F Increases βfibrils Formation but Attenuates the Neurotoxicity of Amyloid-β Peptide

Alzheimer's disease (AD) is characterized by the abnormal aggregation of amyloid-β peptide (Aβ) in extracellular deposits known as senile plaques. The tyrosine residue (Tyr-10) is believed to be important in Aβ-induced neurotoxicity due to the formation of tyrosyl radicals. To reduce the likelihood of cross-linking, here we designed an Aβ-40 analogue (Aβ-40 Y10F) in which the tyrosine residue was substituted by a structurally similar residue, phenylalanine. The aggregation rate was determined by the Thioflavin T (ThT) assay, in which Aβ-40 Y10F populated an ensemble of folded conformations much quicker and stronger than the wild type Aβ. Biophysical tests subsequently confirmed the results of the ThT assay, suggesting the measured increase of β-aggregation may arise predominantly from enhancement of hydrophobicity upon substitution and thus the propensity of intrinsic β-sheet formation. Nevertheless, Aβ-40 Y10F exhibited remarkably decreased neurotoxicity compared to Aβ-40 which could be partly due to the reduced generation of hydrogen peroxide. These findings may lead to further understanding of the structural perturbation of Aβ to its fibrillation.     

β-环糊精促进双酚A光催化降解

研究了双酚A在β-环糊精存在的TiO2光催化体系中的光降解行为,结果表明：β-环糊精能促进双酚A的光催化降解,经过250W的金属卤化物灯（λ≥365nm）光照40min,β-环糊精能提高双酚A23％的光降解效率,同时研究了双酚A光降解的动力学规律及pH、β-环糊精浓度、双酚A初始浓度对双酚A的光降解的影响。光催化降解的促进作用源于β-环糊精促进双酚A在TiO2表面的吸附。     

β-环糊精聚合物可快速移除双酚A

正近日,康奈尔大学研究人员研制出一种新的过滤材料。这种材料有助于移除水源中的双酚A(BPA)等有机小分子,且比活性炭价格更便宜、过滤效率更高、更容易清洗。这种材料是一种β-环糊精聚合物,其基本的分子单元包含环糊精和四氟对苯二腈。研究人员将这两种成分放在碳酸钾和四氢呋喃的溶液中加热,使之聚合在一起,并且创     

Dissecting the role of single regions of an IAPP mimic and IAPP in inhibition of Aβ40 amyloid formation and cytotoxicity

Alzheimer's disease (AD) and type 2 diabetes (T2D) are linked to the self-association of β-amyloid peptide (Aβ) and islet amyloid polypeptide (IAPP), respectively. We have shown that IAPP-GI, a soluble IAPP analogue and mimic of nonamyloidogenic and nontoxic IAPP, binds Aβ with high affinity and blocks its cytotoxic self-assembly and fibrillogenesis. We have also shown that IAPP and Aβ interact with each other into nonfibrillar and nontoxic heterocomplexes that suppress cytotoxic self-association by both polypeptides. The Aβ-IAPP interaction might thus be a molecular link between AD and T2D. We studied the role of individual IAPP-GI and IAPP regions in their inhibitory function on Aβ40 self-association and cytotoxicity. We found that the presence of the two hot-spot regions of the Aβ-IAPP interaction interface in IAPP(8-28) is not sufficient for inhibitory function and that, in addition to IAPP(8-28), the presence of the N-terminal region IAPP(1-7) is absolutely required. By contrast, the C-terminal region, IAPP(30-37), is not required although its presence together with IAPP(1-7) in IAPP-GI results in a marked enhancement of the inhibitory effect as compared to IAPP(1-28)-GI. We suggest that the inhibitory effect of IAPP-GI and IAPP on Aβ40 fibrillogenesis and cell toxicity is mediated primarily by interactions involving the hot regions of the Aβ-IAPP interaction interface and the N terminus of IAPP while a concerted and likely structure-stabilizing action of the N- and C-terminal IAPP regions potentiates this effect. These results identify important molecular determinants of the amyloid suppressing function of the Aβ40-IAPP interaction and could contribute to the design of novel inhibitors of Aβ40 aggregation and cell degeneration.     

LHRH-PE40对黑色素瘤A375细胞的诱导凋亡作用

目的 研究促黄体激素释放激素-绿脓杆菌外毒素(Luteinizing hormone releasing hormone-Pseudomonas aeru-gionosa exotoxin 40,LHRH-PE40)对黑色素瘤A375细胞的诱导凋亡作用。方法用LHRH-PE40处理A375细胞,透射电镜观察细胞结构的改变;DNA ladder和流式细胞仪检测细胞的凋亡。结果经LHRH-PE40作用后,透射电镜观察可见A375细胞核聚集于一侧;DNA ladder检测发现,A375细胞的DNA电泳图像呈梯形条带;流式细胞术检测结果显示,A375细胞出现明显的二倍体峰,细胞周期也发生了相应的改变。结论 LHRH-PE40对A375细胞的细胞毒性作用可以有效诱导A375细胞凋亡。     

FH-40A催化剂对煤油加氢装置的适应性试验

为了考察抚顺石化公司石油三厂分子筛脱蜡装置煤油加氢单元换用国产加氢精制催化剂的可行性,采用抚顺石油化工研究院新近开发的FH-40A轻质馏分油加氢精制催化剂,以石油三厂煤油为原料油,在装置工况条件下分别考察了拔头后的煤油和全馏分煤油采用FH-40A催化剂的可能性.试验结果标明:FH-40A催化剂具有优异的加氢脱硫、加氢脱氮和芳烃饱和性能,可以使精制油的硫质量分数＜0.5 μg/g,氮的质量分数＜1 μg/g,溴指数＜150 mg/100 g,芳烃的体积分数＜5 %,满足分子筛脱蜡装置进料质量的要求.     

β-环糊精维生素A包结及其在化妆品中的应用

通过对β-环糊精的提纯和对防晒物VA包结及其在化妆品中的应用研究,得出了提纯和包结的适宜条件及维生素A包结后在化妆品中防晒性能的研究结果。维生素A在λm ax=209 nm的紫外光区有较强的紫外吸收,说明其具有抗紫外活性。维生素A包结后的紫外摩尔吸光系数ε由未包结时1.94×104L/mol.cm提高到4.25×105L/mol.cm,整整提高了近20多倍,可见,经包结后维生素A的紫外活性大大提高,起到了较好的防晒效果。     

β-环糊精包结维生素A醋酸酯的条件研究

研究了β-环糊精与维生素A醋酸酯的包结,探讨了客体添加速度、溶剂、温度等对包结物产率的影响。25℃下,往1 g的β-环糊精水溶液(60 mL)中滴加0.289 0 g的维生素A醋酸酯乙醇溶液(6 mL),滴加时间70 min,搅拌10 h,包结率可达78.0%。利用分子模拟软件模拟了β-环糊精与维生素A醋酸酯的包结。     

40．5＂、46＂A型硫化机的改造

４０．５＂、４６＂Ａ型硫化机的改造王富石（江阴市橡胶机械维修备件厂江苏２１４４１６）１４０．５″、４６″Ａ型硫化机夹具的改造４０．５″、４６″Ａ型双模轮胎定型硫化机脱胎、卸胎是靠推顶器操作夹具来完成的，比Ｂ型硫化机方便，但是，目前４０．５”、４６”Ａ...     

PCX—IV-40A型熟料破碎机锤头的二次改进

某厂PCX-Ⅳ-40A型熟料破碎机于2002年12月投入使用，破碎立窑熟料。使用的锤头除3副为原厂的，其余均为本地仿原结构的自制锤头。原厂锤头的使用寿命分别为3057h、2733h和2280h，从耐磨性能看，好于本地生产的。这两类锤头均表现为使用初期出料较细，粉料含量较多，但工作面磨损较快，当出料明显变粗后，需更换工作面或锤头。为提高锤头的使用寿命和降低生产费用，我们渐次对锤头结构进行改进，取得了不错的效果。     

FH-40A型催化剂在裂解汽油二段加氢中的应用

通过对FH-40A型加氢催化剂在辽阳石化裂解汽油加氢装置二段加氢开工过程中工艺参数及分析数据的讨论,介绍了该催化剂在此过程中的实际运行状况。     

双酚A环氧树脂为硬模板剂制备等级孔β分子筛

以四乙基氢氧化铵(TEAOH)为微孔模板剂,双酚A环氧树脂为介孔模板剂,通过水热合成法制备了等级孔β分子筛。采用X射线衍射(XRD)、透射电镜(TEM)和N2吸附/脱附手段对合成的等级孔β分子筛进行了表征。结果表明,合成的分子筛具备了良好的β分子筛晶相结构,同时还形成了丰富的最可几分布在20 nm左右的介孔结构。在此基础上,较为系统地讨论了制备条件如碱度、晶化时间及母液中水含量等因素对等级孔β分子筛相对结晶度和介孔结构的影响。     

PCX-Ⅳ-40A型熟料破碎机锤头的二次改进

某厂PCX-Ⅳ-40A型熟料破碎机于2002年12月投入使用,破碎立窑熟料。使用的锤头除3副为原厂的,其余均为本地仿原结构的自制锤头。原厂锤头的使用寿命分别为3057h、2733h和2280h,从耐磨性能看,好于本地生产的。这两类锤头均表现为使用初期出料较细,粉料含量较多,但工作面磨损较快,     

Modulation of Aβ42 Aggregation Kinetics and Pathway by Low-Molecular-Weight Inhibitors

The aggregation of amyloid-β 42 (Aβ42) is directly related to the pathogenesis of Alzheimer's disease. Here, we have investigated the early stages of the aggregation process, during which most of the cytotoxic species are formed. Aβ42 aggregation kinetics, characterized by the quantification of Aβ42 monomer consumption, were tracked by real-time solution NMR spectroscopy (RT-NMR) allowing the impact that low-molecular-weight (LMW) inhibitors and modulators exert on the aggregation process to be analysed. Distinct differences in the Aβ42 kinetic profiles were apparent and were further investigated kinetically and structurally by using thioflavin T (ThT) and transmission electron microscopy (TEM), respectively. LMW inhibitors were shown to have a differential impact on early-state aggregation. Insight provided here could direct future therapeutic design based on kinetic profiling of the process of fibril formation.     

H4SiW12O40催化合成乙酸-β-萘酯

以H4SiW12O40为催化剂,用乙酸酐和β-萘酚合成了乙酸-β-萘酯.结果表明,H4SiW12O40催化效果明显,产品后处理简单,催化剂可重复使用4次以上.乙酸-β-萘酯合成的最佳工艺条件为:乙酸酐0.06 mol、β-萘酚0.05 mol、H4SiW12O40 1.0 g、反应温度80℃、反应时间30 min,此时产率达93.5%.     

A two-step strategy for structure-activity relationship studies of N-methylated aβ42 C-terminal fragments as aβ42 toxicity inhibitors

Neurotoxic Aβ42 oligomers are believed to be the main cause of Alzheimer's disease. Previously, we found that the C-terminal fragments (CTFs), Aβ(30-42) and Aβ(31-42) were the most potent inhibitors of Aβ42 oligomerization and toxicity in a series of Aβ(x-42) peptides (x=28-39). Therefore, we chose these peptides as leads for further development. These CTFs are short (12-13 amino acids) hydrophobic peptides with limited aqueous solubility. Our first attempt to attach hydrophilic groups to the N?terminus resulted in toxic peptides. Therefore, we next incorporated N-methyl amino acids, which are known to increase the solubility of such peptides by disrupting the β-sheet formation. Focusing on Aβ(31-42), we used a two-step N-methyl amino acid substitution strategy to study the structural factors controlling inhibition of Aβ42-induced toxicity. First, each residue was substituted by N-Me-alanine (N-Me-A). In the next step, in positions where substitution produced a significant effect, we restored the original side chain. This strategy allowed exploring the role of both side chain structure and N-Me substitution in inhibitory activity. We found that the introduction of an N-Me amino acid was an effective way to increase both the aqueous solubility and the inhibitory activity of Aβ(31-42). In particular, N-Me amino acid substitution at position 9 or 11 increased the inhibitory activity relative to the parent peptide. The data suggest that inhibition of Aβ42 toxicity by short peptides is highly structure-specific, providing a basis for the design of new peptidomimetic inhibitors with improved activity, physicochemical properties, and metabolic stability.     

神马集团40万t PC及配套双酚A项目一期即将试车

正9月15日上午,在位于叶县产业集聚区的河南平煤神马聚碳材料有限公司40万t/年聚碳酸酯(PC)及配套双酚A项目(以下简称BPA)区,工程技术人员和施工人员正在加紧进收尾安装、罐体制作、中心控制室调试及相关辅助设施建设,为项目试车生产全力"冲刺"攻坚。河南平煤神马聚碳材料有限责任公司一期10万t/年PC及13万t/年BPA项目是集团转型发展的重点工程,同时也是河南省和平顶山市重点项目。