Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer’s disease

Amyloid-beta-induced neuronal cell death contributes to cognitive decline in Alzheimer’s disease.Citri Reticulatae Semen has diverse beneficial effects on neurodegenerative diseases,including Parkinson’s and Huntington’s diseases,however,the effect of Citri Reticulatae Semen on Alzheimer’s disease remains unelucidated.In the current study,the anti-apoptotic and autophagic roles of Citri Reticulatae Semen extract on amyloid-beta-induced apoptosis in PC12 cells were first investigated.Citri Reticulatae Semen extract protected PC12 cells from amyloid-beta-induced apoptosis by attenuating the Bax/Bcl-2 ratio via activation of autophagy.In addition,Citri Reticulatae Semen extract was confirmed to bind amyloid-beta as revealed by biolayer interferometry in vitro,and suppress amyloid-beta-induced pathology such as paralysis,in a transgenic Caenorhabditis elegans in vivo model.Moreover,genetically defective Caenorhabditis elegans further confirmed that the neuroprotective effect of Citri Reticulatae Semen extract was autophagy-dependent.Most importantly,Citri Reticulatae Semen extract was confirmed to improve cognitive impairment,neuronal injury and amyloid-beta burden in 3×Tg Alzheimer’s disease mice.As revealed by both in vitro and in vivo models,these results suggest that Citri Reticulatae Semen extract is a potential natural therapeutic agent for Alzheimer’s disease via its neuroprotective autophagic effects.

恩沙替尼、安罗替尼、培美曲塞、唑来膦酸联用致重度贫血1例

1例42岁男性Ⅳ期右肺腺癌患者,病史9年,既往曾予多种化疗和靶向药物,因疾病进展,靶向治疗调整为盐酸恩沙替尼胶囊,联合安罗替尼、培美曲塞二钠和唑来膦酸抗肿瘤治疗。患者连续服用恩沙替尼胶囊82 d后,无明显诱因突发乏力,血红蛋白从用药前的132 g·L^(-1)降至59 g·L^(-1),确诊为重度贫血,考虑与恩沙替尼、安罗替尼、培美曲塞以及唑来膦酸相关,不良反应关联性评价为“可能”。经停药、对症支持治疗后,入院第6天血红蛋白恢复至97 g·L^(-1)。恩沙替尼在我国上市时间较短,出现重度贫血的相关报道较少。该病例提示临床治疗中应重点关注使用经验较为有限的药物,及时发现其少见的不良反应。

基于主动学习方法的汽轮机排缸参数分析

It is well known that the efficiency of a steam turbine is affected by the pressure recovery performance of its low-pressure exhaust hood,and therefore,parametric analysis of the exhaust hood is of great importance in the steam turbine design process.In recent years,computationally inexpensive metamodels have been widely used in the parametric analysis of exhaust hood.However,the prediction accuracy of metamodels is highly dependent on the number and distribution of sample points in the design space.The purpose of active learning is selecting informative samples sequentially to obtain an accurate metamodel within a reasonable computational budget.However,the impact of active learning on the accuracy of metamodels such as exhaust hood parameter analysis has not been fully explored.Therefore,this paper investigates and compares four representative active learning methods on the parametric modeling of turbine exhaust hoods,and the comparison results highlight the advantages of active learning and the analysis of the exhaust hood based on the metamodel with the highest accuracy.

简化间隙泄漏结构对离心压缩机性能影响研究

针对流量系数为0.196的大流量系数离心压缩机模型级,采用CFD方法,研究其在简化动静间隙泄漏结构时替换壁面旋转区域大小对离心压缩机流场及性能的影响。计算结果表明:叶轮出口替换间隙壁面的旋转长度小于23.33%间隙高度时预报结果相差较小,与实验值较为吻合,超过该值计算得到的多变效率与旋转壁面长度呈线性增长趋势。这主要由于旋转壁面长度小于23.33%间隙高度时,静止壁面的粘性阻力作用强行将叶轮出口盖侧高速区减速,产生了较大损失,而超过该高度时,该高速区域的形态基本发展完整,从而使得额外旋转壁面对流体做功直接增加了轮盖侧流体的总压值,增加了轮盖侧流体气流角,提高了整级性能。设计工况下,当叶轮出口旋转壁面长度等于6.67%间隙高度时,计算得到的扩压器进口周向平均气流角与考虑间隙结构时结果基本一致,得到的多变效率比考虑间隙泄漏结构时高1.56%,总压比高1.82%。由此说明不考虑动静间隙泄漏时,合理选取叶轮出口替换间隙物面的旋转长度能够保证计算结果的可靠性。

错列导叶对反应堆冷却剂泵水力性能的影响

本文采用数值模拟对交错形式的导叶叶片对于三代核电站反应堆冷却剂泵性能的影响进行研究。通过数值模拟和试验结果的比较验证了数值模拟的有效性。数值研究获得了不同交错叶片导叶方案下核主泵性能的变化。得到了水力性能曲线,轴向力曲线和压力脉动频谱图。数值结果表明:在额定流量下交错叶片稍微减少了水力效率,但对扬程、轴向力和功率几乎没有影响。交错叶片导叶有利于压力脉动,降低了水力部件内部压力脉动的振幅幅值,交错角3/4的方案是一个比较好的选择。

基于谐响应分析的水环境下核主泵叶轮动应力研究

准确计算核主泵叶轮在流体介质中的动应力对核主泵安全可靠运行具有十分重要的意义。本文开展了基于谐响应分析的叶轮动应力的研究,完成了叶轮模态分析、阻尼比分析,压力脉动分析以及动应力分析。得到了叶轮各阶模态频率、叶轮阻尼比以及压力荷载,并对比了缩尺模型实验与数值模拟水力性能,计算了叶轮动应力。结果表明,叶轮湿模态频率比干模态频率低;叶轮流体介质阻尼比比材料阻尼比大一个数量级,并且基本不随着振幅变化;缩尺模型试验与数值模拟水力性能最大误差为2.8%;叶片表面压力脉动主要表现为转频及其谐频振动;叶轮共振模态为1节径1模态,最大动应力为2.02MPa。本文通过分析叶轮模态、阻尼比、压力荷载以及动应力,提供了水环境下叶轮动应力分析方法。

离心叶轮分流叶片位置与扩压器相互影响的模拟研究

叶轮分流叶片周向位置改变,将对叶轮与扩压器内部流场产生干扰。对带分流叶片离心压缩机叶轮及扩压器流场进行数值模拟,结果表明:当叶轮匹配叶片扩压器,分流叶片向主叶片吸力面偏置较居中时,叶轮进出口压比降低3.66%,平均出口气流角增加1.54°;分流叶片向主叶片压力面偏置相比于居中,叶轮进出口压比增加1.85%,平均出口气流角增加2.09°,分流叶片吸力面侧低能区减小,气流分离受到抑制,叶轮效率提高。因此分流叶片向主叶片压力面偏置有利于提高叶轮性能。但由于分流叶片偏置后叶轮平均出口气流角较居中时变大,对扩压器叶片形成正冲角,在叶片背弧处产生了分离涡,造成扩压器内流场混乱,使扩压器效率降低。因此,分流叶片偏置后与之相匹配的扩压器叶片的安装角也要相应改变,以抑制扩压器内的分离涡及二次流,提高整级效率。

Application of the Modified nverse Design Method in the Optimization of the Runner Blade of a Mixed-Flow Pump

To improve the design speed and reduce the design cost for the previous blade design method, a modified inverse design method is presented. In the new method, after a series of physical and mathematical simplifications, a sail?like constrained area is proposed, which can be used to configure di erent runner blade shapes. Then, the new method is applied to redesign and optimize the runner blade of the scale core component of the 1400?MW canned nuclear coolant pump in an established multi?optimization system compromising the Computational Fluid Dynamics(CFD) analysis, the Response Surface Methodology(RSM) and the Non?dominated Sorting Genetic Algorithm?II(NSGA?II). After the execution of the optimization procedure, three optimal samples were ultimately obtained. Then, through comparative analysis using the target runner blade, it was found that the maximum e ciency improvement reached 1.6%, while the head improvement was about 10%. Overall, a promising runner blade inverse design method which will benefit the hydraulic design of the mixed?flow pump has been proposed.

Characterization of Fam20C expression in odontogenesis and osteogenesis using transgenic mice

Our previous studies have demonstrated that Fam20 C promotes differentiation and mineralization of odontoblasts,ameloblasts,osteoblasts and osteocytes during tooth and bone development.Ablation of the Fam20 C gene inhibits bone and tooth growth by increasing fibroblast growth factor 23 in serum and causing hypophosphatemia in conditional knockout mice.However,control and regulation of the expression of Fam20 C are still unknown.In this study,we generated a transgenic reporter model which expresses green fluorescence protein(GFP) driven by the Fam20 C promoter.Recombineering was used to insert a 16 kb fragment of the mouse Fam20 C gene(containing the 15 kb promoter and 1.1 kb of exon 1) intoa pBluescript SK vector with the topaz variant of GFP and a bovine growth hormone polyadenylation sequence.GFP expression was subsequently evaluated by histomorphometry on cryosections from E14 to adult mice.Fluorescence was evident in the bone and teeth as early as E17.5.The GFP signal was maintained stably in odontoblasts and osteoblasts until 4 weeks after birth.The expression of GFP was significantly reduced in teeth,alveolar bone and muscle by 8 weeks of age.We also observed colocalization of the GFP signal with the Fam20 C antibody in postnatal 1- and 7-day-old animals.Successful generation of Fam20C-GFP transgenic mice will provide a unique model for studying Fam20 C gene expression and the biological function of this gene during odontogenesis and osteogenesis.

半开式离心叶轮气动阻尼的影响规律研究

离心压缩机半开式叶轮的阻尼是影响叶轮振动应力水平的重要因素,主要包括材料阻尼和气动阻尼。其中,气动阻尼的准确计算是叶轮动应力分析的前提。本文通过流固弱耦合方法研究了压缩机运行工况以及叶片振幅对气动阻尼的影响,并对影响规律进行了理论分析。研究结果表明,进口温度一定时,叶片气动阻尼比随进口流量的增大而增大;进口质量流量一定时,气动阻尼比随进口温度的减小而增大;对同一工况,气动阻尼比基本与振幅无关。研究结果对叶轮结构在实际运行工况条件下的强度校核具有重要的参考意义。

The importance of a potential phosphorylation site in enamelin on enamel formation

Enamelin(ENAM) has three putative phosphoserines(p Sers) phosphorylated by a Golgi-associated secretory pathway kinase(FAM20 C) based on their distinctive Ser-x-Glu(S-x-E) motifs. Fam20 C-knockout mice show severe enamel defects similar to those in the Enam-knockout mice, implying an important role of the p Sers in ENAM. To determine the role of pSer^(55) in ENAM, we characterized ENAM^(Rgsc514) mice, in which Ser^(55) cannot be phosphorylated by FAM20 C due to an E^(57)>G^(57) mutation in the S-x-E motif. The enamel microstructure of 4-week-old mice was examined by scanning electron microscopy.The teeth of 6-day-old mice were characterized by histology and immunohistochemistry. The protein lysates of the first lower molars of 4-day-old mice were analyzed by Western immunoblotting using antibodies against ENAM, ameloblastin and amelogenin. ENAM^(Rgsc514) heterozygotes showed a disorganized enamel microstructure, while the homozygotes had no enamel on the dentin surface. The N-terminal fragments of ENAM in the heterozygotes were detained in the ameloblasts and localized in the mineralization front of enamel matrix, while those in the WT mice were secreted out of ameloblasts and distributed evenly in the outer 1/2 of enamel matrix. Surprisingly, the ~ 15 k Da C-terminal fragments of ameloblastin were not detected in the molar lysates of the homozygotes. These results suggest that the phosphorylation of Ser^(55) may be an essential posttranslational modification of ENAM and is required for the interaction with other enamel matrix molecules such as ameloblastin in mediating the structural organization of enamel matrix and protein-mineral interactions during enamel formation.

Recombinant Human IgG antibodies against Human Cytomegalovirus

Objective To study the passive immunization with human monoclonal antibodies as for prophylaxis of human cytomegalovirus(HCMV) infection.Methods Fab monoclonal antibodies to HCMV were recovered by repertoire cloning of mRNA from a HCMV infected individual.Antigen binding specificity,CDR sequence of VH and VL and neutralizing activity on HCMV AD169 stain were analyzed in vitro.The light and heavy chain Fd fragment genes of Fab antibodies were further cloned into a recombinant baculovirus expression vector pAC-κ-Fc to express intact IgG.Secreted products were purified with affinity chromatography using protein G.Results SDS-PAGE and Western blot confirmed the expression of the intact IgG.Immuno-blotting and -precipitation were used to identify HCMV proteins.One Fab monoclonal antibody recognized a conformational HCMV protein.Conclusion IgG antibodies can neutralize the HCMV AD169 strain efficiently at a titer of 2.5 μg/mL and may prove valuable for passive immunoprophylaxis against HCMV infection in humans.

SARS Patients-derived Human Recombinant Antibodies to S and M Proteins Efficiently Neutralize SARS-Coronavirus Infectivity

Objective To develop a specific SARS virus-targeted antibody preparation for emergent prophylaxis and treatment of SARS virus infection. Methods By using phage display technology, we constructed a naive antibody library from convalescent SARS patient lymphocytes. To obtain the neutralizing antibody to SARS virus surface proteins, the library panning procedure was performed on purified SARS virions and the specific Fab antibody clones were enriched by four rounds of repeated panning procedure and screened by highthroughput selection. The selected Fab antibodies expressed in the periplasma of E. Coli were soluble and further purified and tested for their binding properties and antiviral function to SARS virus. The functional Fab antibodies were converted to full human IgG antibodies with recombinant baculovirus/insect cell systems and their neutralizing activities were further determined. Results After four rounds of the panning, a number of SARS-CoV virus-targeted human recombinant Fab antibodies were isolated from the SARS patient antibody library. Most of these were identified to recognize both natural and recombinant SARS spike (S) proteins, two Fab antibodies were specific for the virus membrane (M) protein, only one bound to SARS-CoV nucleocapsid protein. The SARS-CoV S and M protein-targeted Fab or IgG antibodies showed significant neutralizing activities in cytopathic effect (CPE) inhibition neutralization test, these antibodies were able to completely neutralize the SARS virus and protect the Vero cells from CPE after virus infection. However, the N protein-targeted Fab or IgG antibodies failed to neutralize the virus. In addition, the SARS N protein-targeted human Fab antibody reacted with the denatured N proteins, whereas none of the S and M protein specific neutralizing antibodies did. These results suggested that the S and M protein-specific neutralizing antibodies could recognize conformational epitopes which might be involved in the binding of virions to cellular receptors and the fusion activity of the virus.Conclusion The SARS-CoV spike protein and membrane proteins are able to elicite efficient neutralizing antibodies in SARS patients. The neutralizing antibodies we generated in this study may be more promising candidates for prophylaxis and treatment of SARS infection.

面向变精度仿真数据建模分析的多任务学习方法比较研究

多任务学习(Multi-task Learning,MTL)是利用多个目标任务之间的关联性,实现跨任务知识迁移和共享,从而提高预测精度的一种数据驱动的机器学习范式。基于数值仿真器工程设计问题中经常存在多精度建模分析场景,即采用不同精度的数值仿真器获取数据进行建模。在上述场景中,仿真器的高/低计算精度可以被视为两种目标任务,同时,由于高/低精度数据针对的是同一个研究对象,彼此具有很强的相关性。其中的关键是如何从便宜、丰富的低精度数据中迁移出共享知识以提高基于昂贵、稀少的高精度数据的学习模型的预测质量。本文重点研究基于高斯过程(Gaussian Process,GP)或Kriging模型的多任务统计学习方法及其在高/低精度仿真建模分析方面的应用。首先,本文在典型多精度数值算例上对比分析了单任务Kriging模型,以及三种多任务(精度)模型CoKriging、MTGP(Multi-task Gaussian Process)和SDK(Simple Discrepancy Framework by Kriging,SDK)的特点及预测能力。最后,本文基于多精度仿真数据使用Kriging模型、MTGP模型和CoKriging模型预测RAE2822翼型的空气动力系数。结果表明:将多任务学习应用于多精度工程建模分析可以提高预测的准确度,进而提高产品的设计效率。

Separating the contributions of electric and magnetic fields in deflecting the probes in proton radiography with multiple proton energies

In proton radiography,degeneracy of electric and magnetic fields in deflecting the probe protons can prevent full interpretation of proton flux perturbations in the detection plane.In this paper,theoretical analyses and numerical simulations suggest that the contributions of the electric and magnetic fields can be separately obtained by analyzing the difference between the flux distributions of two discriminated proton energies in a single shot of proton radiography.To eliminate the influence of field evolution on the separation,a strategy is proposed in which slow field evolution is assumed or an approximate estimate of field growth is made.This could help achieve a clearer understanding of the radiographic process and allow further quantitative analysis.

Clinical metabolic analysis combined with traceability of biosynthetic pathway:a new approach to quality marker of Chinese materia medica

中药质量标志物在中药质量控制中具有重要作用,然而中药质量标志物研究策略与技术尚不明确。立足于“中药质量标准应关联临床疗效”,以临床疗效确切(治疗2型糖尿病)的金芪降糖片为例,通过临床代谢逆向解析和植物生源合成途径追溯研究思路,发现并确认关联活性的金芪降糖片质量标志物,旨在构建“以临床活性成分发现为导向、代谢转化逆向解析为纽带、生源合成途径追溯为关键”的中药质量标志物研究新路径,推动中药质量标志物理论创新与技术突破。

Interleukin-18, matrix metalloproteinase-22 and -29 are independent risk factors of human coronary heart disease

Background： Coronary heart disease （CHD） is characterized by arterial wall inflammation and matrixdegradation. Matrix metalloproteinase （MMP）-22 and -29 and pro-inflammatory cytokine interleukin-18 （IL18） arepresent in human hearts. IL18 may regulate MMP-22 and -29 expression, which may correlate with CHD progression.Methods and results： Immunoblot analysis showed that ILl8 induced MMP-22 expression in human aortic smoothmuscle cells. The Mann Whitney test from a prospective study of 194 CHD patients and 68 non-CHD controlsdemonstrated higher plasma levels of IL18, MMP-22 and-29 in CHD patients than in the controls. A logistic regressiontest suggested that plasma IL18 （odds ratio （OR）=1.131, P=0.007）, MMP-22 （OR=1.213, P=0.040）, and MMP-29（OR=1.198, P=0.033） were independent risk factors of CHD. Pearson＇s correlation test showed that IL18 （coefficient（r）=0.214, P=0.045; r=0.246, P=0.031） and MMP-22 （t=0.273, P=0.006; r=0.286, P=0.012） were associated with theGensini score before and after adjusting for potential confounding factors. The multivariate Pearson＇s correlation testshowed that plasma MMP-22 levels correlated positively with high-sensitive-C-reactive protein （hs-CRP） （r=0.167,P=0.023）, and MMP-29 levels correlated negatively with triglyceride （t=-0.169, ,P=-0.018）. Spearman＇s correlation testindicated that plasma IL18 levels associated positively with plasma MMP-22 （t=0.845, P〈0.001） and MMP-29 （r=0.548P〈0.001）. Conclusions： Our observations suggest that IL18, MMP-22 and -29 serve as biomarkers and independentrisk factors of CHD. Increased systemic IL18 in CHD patients may contribute to elevated plasma MMP-22 and -29levels in these patients.

Arabidopsis Sucrose Transporter SUT4 Interacts with Cytochrome b5-2 to Regulate Seed Germination in Response to Sucrose and Glucose

蔗糖 transporter 是否调停，仍然保持未知糖发信号。这里，我们报导 Arabidopsis (Arabidopsis thaliana ) 蔗糖 transporter SUT4 与 Arabidopsis 细胞色素 b5 (Cyb5 ) 的五个成员一起交往家庭，和蔗糖镇压在 SUT4 和 Cyb5 成员 Cyb5-2/A 之间的相互作用。我们观察到 SUT4 和三个细胞色素 b5 成员(Cyb5-2， Cyb5-4，和 Cyb5-6 ) 的下面规定在种子萌芽的 sucrose/glucose-induced 抑制授与蔗糖感觉迟钝、葡萄糖感觉迟钝的显型。sut4 cyb5-2 两倍异种比 sut4 或 cyb5-2 单身者显示稍微更强壮的 sucrose/glucose-insensitive 显型变异。我们证明在种子萌芽的 sucrose/glucose-induced 抑制发信号的 SUT4/Cyb5-2-mediated 不要求骆驼毛的织物或表明小径的当前已知的 ABI2/ABI4/ABI5-mediated。这些数据提供蔗糖 transporter SUT4 与 Cyb5 交往断然调停的证据在种子萌芽的 sucrose/glucose-induced 抑制发信号的蔗糖和葡萄糖。

Thermo-reversible MWCNTs/Epoxy Polymer for Use in Self-healing and Recyclable Epoxy Adhesive

A self-healing and recyclable carbon tube/epoxy adhesive was prepared by epoxy monomer with Diels-Alder(DA) bonds, diethylenetriamine and polyethyleneimine modified multi-wall carbon nanotubes(MWCNTs). The self-healing and recyclable ability was attained by thermally reversible Diels-Alder reaction between furan and maleimide in the epoxy monomer. By controlling the molar ratio of furfuryl glycidyl ether and 4,4′-methylenebis(N-phenylmaleimide), the glass transition temperature and mechanical properties of MWCNTs/epoxy adhesives were varied. The self-healing properties of MWCNTs/epoxy polymers were evaluated by lap shear experiment and the results showed that the MWCNTs/epoxy adhesives exhibited enhanced mechanical properties and excellent self-healing ability under heat stimulus. The healing efficiency was related to the molecule mobility and the conversion of DA reaction between furan and maleimide. The MWCNTs/epoxy adhesives also displayed excellent recyclable ability by transforming into soluble polymer under heating. These materials offer a wide range of possibilities to produce materials with healing and recyclable ability and have the potential to bring great benefits to our daily lives by enhancing the safety, performance, and lifetime of products.

A new active piggyBac-like element in Aphis gossypii

九个象 piggyBac 一样元素(PLE ) 从棉花蚜虫蚜虫属 gossypii 格洛弗被识别。所有 PLE 与对方一起分享了高顺序类似。然而，九 PLE 中的八个是不大可能的在编码区域以内由于造成分裂的变化的存在编码功能的 transposase。另一个 PLE 在 piggyBac 家庭包含了成员的主要特征，包括 TTAA 目标地点复制，转换终端重复(国际互联网广播台) ，和与一个通常认为的 DDD 领域为 transposase 编码的一个开的读物框架(ORF ) 。有未经触动的 transposase ORF 的这被称为 AgoPLE1.1。预言的 transposase 与 Trichoplusia ni piggyBac IFP2 的分享了 47% 类似。种系发生的分析证明 AgoPLE1.1 是最与 Heliothis virescens PLE1.1 (HvPLE1.1 ) 元素有关与在核苷酸和氨基酸层次的 45% 和 60% 类似，分别地。功能的试金证明 AgoPLE1.1 编码了功能的 transposase 并且能在房间文化引起精确切除。在另一方面， AgoPLE1 的很少 genomic 插入多型性在棉花蚜虫的染色体被观察。这些观察建议 AgoPLE1.1 是在最近的时期入侵了棉花蚜虫染色体并且保留了它的活动的 PLE。