A Comprehensive Method for the Optimization of Cement Slurry and to Avoid Air Channeling in High Temperature and High-Pressure Conditions

Air channeling in the annulus between the casing and the cement sheath and/or between the cement sheath and formation is the main factor affecting the safe operation of natural gas wells at high temperatures and pressures.Prevention of this problem requires,in general,excellent anti-channeling performances of the cement sheath.Three methods to predict such anti-channeling performances are proposed here,which use the weightless pressure of cement slurry,the permeability of cement stone and the volume expansion rate of cement sheath as input parameters.Guided by this approach,the anti-channeling performances of the cement slurry are evaluated by means of indoor experiments,and the cement slurry is optimized accordingly.The results show that the dangerous transition time of the cement slurry with optimized dosage of admixture is only 76 min,the permeability of cement stone is 0.005 md,the volume shrinkage at final setting is only 0.72%,and the anti-channeling performances are therefore maximized.The effective utilization of the optimized cement slurry in some representative wells(LD10–1-A1 and LD10–1-A2 in LD10–1 gas field)is also discussed.

ApoE基因、CYP46A1基因和RXRA基因与阿尔茨海默病的关联

目的探索ApoE基因(rs429358,T)、CYP46A1基因(rs4900442,T)和RXRA基因(rs3132299,G)的常见变异类型与阿尔茨海默病患病风险的关联研究,分析这些常见变异位点的基因型和等位基因的分布频率。方法运用病例对照研究设计,包括北京和呼和浩特146例确诊的阿尔茨海默病患者和140例健康对照,通过聚合酶链反应(PCR)和限制性片段长度多态性(RFLP)以及测序的方法,比较病例组和对照组ApoE基因(rs429358,T)、CYP46A1(rs4900442,T)基因和RXRA基因(rs3132299,G)的等位基因和基因型频率的差异。结果 ApoE基因(rs429358,T)的基因型和等位基因在病例组和对照组中的频率分布差异均有统计学意义(P=4.7×10-9,P=2.7×10-10)。ApoE基因(rs429358,T)和CYP46A1基因rs4900442,T)的TT+CT和CC基因型在病例组和对照组中的频率分布差异均有统计学意义(P=0.007,P=0.034)。RXRA基因(rs3132299,G)的基因型和等位基因在病例组和对照组中的频率分布差异均无统计学意义(P>0.05)。结论 ApoE基因与中国人阿尔茨海默病患病风险有关,CYP46A1(rs4900442,T)基因和RXRA基因(rs3132299,G)基因可能与阿尔茨海默病的患病风险无关。

ZNF224基因与阿尔茨海默病风险关联的研究

目的阿尔茨海默病(AD)作为老年痴呆的一种主要类型,其特征为进行性认知功能障碍和记忆损害。本文旨在探索ZNF224基因(rs2061332,rs4508518)与中国北方人群阿尔茨海默病患病风险的关联。方法本研究采用病例-对照,在来自中国北方人群的48例散发性AD患者和48例对照者中,对ZNF224基因(rs2061332,rs4508518)进行两组间的等位基因及基因型遗传模型差异分析,ZNF224基因使用聚合酶连反应-高分辨率溶解曲线(PCR-HRM)方法分型并对其分型结果进行测序验证。结果①ZNF224基因(rs2061332,rs4508518)风险等位基因和基因型的频率在病例组和对照间组间的分布无显著性差异(P>0.05);②ZNF224基因(rs2061332,rs4508518)在临床变量痴呆程度上其病例组内等位基因与基因型也无统计学差异。结论研究显示ZNF224基因(rs2061332,rs4508518)可能与中国北方人群AD患病风险无关联。

APOE and APOC1 gene polymorphisms are associated with cognitive impairment progression in Chinese patients with late-onset Alzheimer's disease

Current evidence shows that apolipoprotein E （APOE）, apolipoprotein CI （APOC1） and low density lipoprotein receptor-related protein （LRP） variations are related to late-onset Alzheimer＇s disease. However, it remains unclear if genetic polymorphisms in these genes are associated with cognitive decline in late-onset Alzheimer＇s disease patients. We performed a 30-month longitudi- nal cohort study to investigate the relationship between Alzheimer＇s disease and APOE, APOC1, and LRP. In this study, 78 Chinese Han patients with late-onset Alzheimer＇s disease were recruit- ed form Guangxi Zhuang Autonomous Region in China. APOE, APOC1, and LRP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphisms. The Mini-Mental State Examination and Clinical Dementia Rating Scale were used to assess pa- tients＇ cognitive function. After a 30-month follow-up period, we found a significant reduction in Mini-Mental State Examination total score, a higher proportion of patients fulfilling cognitive impairment progression criteria, and a higher proportion of APOC1 H2 carriers in APOE 4 carriers compared with non-carriers. In addition, the APOE 4 allele frequency was significantly higher in the cognitive impairment progression group compared with the non-cognitive im- pairment progression group. In conclusion, APOE e4 plays an important role in augmenting cognitive decline, and APOC1 H2 may act synergistically with APOE ~4 in increasing the risk of cognitive decline in Chinese patients with late-onset Alzheimer＇s disease.

Prognostic significance of MDR-1 P-glycoprotein expression in breast cancer

Objective： To investigate the expression of MDR-1 P-glycoprotein（MDR-1 Pgp） in breast cancer and analyze its correlation to the biological behavior and prognosis of the disease. Methods：The expression of MDR-1 Pgp was examined in 75 cases of breast cancer patients by using three different monoclonal antibodies（JSB1, C219 and C494） with S-P immunohistochemisty. These patients were followed up for 5 years, and the correlation between MDR-1 Pgp expression, survival rate and lymph metastasis was analyzed. Results： Positive detection of MDR-1 Pgp by JSB1, C219 and C494 in 75 cases of breast cancer was 86.7%, 48% and 85.3%, respectively. MDR-1 Pgp expression was not related to ages of patients （P 〉 0.05）. JSBl-detected expression of MDR-1 Pgp was related to lymph node metastasis（P〈 0.05）; while C219 and C494 were not（P 〉 0.05）. The patients with MDR-1 Pgp expression positively detected by either two of the three antibodies, had five-year survival rate that was significantly higher than those positively detected by all the three antibodies（P 〈 0.05）. Conclusion：Three antibodies should be used simultaneously to detect MDR-1 Pgp expression in breast cancer. Positive MDR-1 Pgp expression in breast cancer detected by all the three antibodies may represent a poor prognosis; while positive MDR-1 Pgp detection by JSB1 and C494 is associated with lymph metastasis.

Oligodendrocyte transcription factor 1 mRNA and protein expression in organotypic rat brain slices

Numerous studies have confirmed that oligodendrocyte transcription factor 1 （Olig-1） is vital for myelin repair. However, the effects of hypoxia and ischemia on Olig-1 expression remain unknown. In this study, Olig-1 mRNA and protein expressions were analyzed by in situ hybridization and immunohistochemistry, to determine the expression profile of Olig-1 in rat brain slices exposed to hypoxia and ischemia. Brains were obtained from 2-day-old Sprague-Dawley rats, and sections were randomly assigned to control and hypoxia/ischemia groups. Hematoxylin-eosin staining revealed karyorrhexis and karyopyknosis in cells from the hypoxia/ischemia group. Under electron microscopy, mitochondria swelling and neuropil edema were observed in the hypoxiaJischemia group. Olig-1 mRNA and protein expressions were increased at 1 day after hypoxia and ischemia treatment. These results suggest that in situ hybridization and immunohistochemistry could be used simultaneously to detect mRNA and protein expression in brain slices.

Expression of human hepatic lipase negatively impacts apolipoprotein A-Ⅰ production in primary hepatocytes from Lipc-null mice

This study aimed to examine whether expression of human hepatic lipase（hHL） exerted an intracellular effect on hepatic production of apolipoprotein（apo） A-I.The levels of secreted and cell-associated apoA-I were contrasted between primary hepatocytes isolated from Lipc-nuW and C57BL/6 mice,and between Lipc-nuW hepatocytes transfected with either hHL-encoding or control adenovirus.An HSPG-binding deficient hHL protein（hHLmt） was used to determine the impact of cell surface binding on HL action.Accumulation of apoA-I in conditioned media of primary hepatocytes isolated from Lipc-nuW mice was increased as compared to that from C57BL/6 mice.Metabolic labeling experiments showed that secretion of ＇＇S-apoA-I from Lipc-nuW cells was significantly higher than that from C57BL/6 cells.Expression of hHL in Lipc-nuW hepatocytes,through adenovirus-mediated gene transfer,resulted in decreased synthesis and secretion of ＇S-apoA-I,but not S-apoE,as compared with cells transfected with control adenovirus.Expression of HSPG-binding deficient hHLmt in Lipc-nuW cells also exerted an inhibitory effect on apoA-I production,even though hHLmt displayed impaired exit from the endoplasmic reticulum as compared with hHL.Subcellular fractionation revealed that expression of hHL or hHLmt led to increased microsome-association of apoA-I relative to non-transfected control.Expression of hHL negatively impacts hepatic production of apoA-I.

Effects of Xinfeng capsule on pulmonary function based on treg-mediated notch pathway in a rat model of adjuvant arthritis

OBJECTIVE:To observe the impact of xinfeng xapsule(XFC) on pulmonary function in a rat model of adjuvant arthritis(AA) and to investigate the mechanism of action.METHODS:Forty rats were randomly divided into four groups of ten:normal control(NC);model control(MC);tripterygium glycosides tablet(TPT);and xinfeng capsule(XFC).Except for the NC group,AA was induced in all rats by intracutaneous injection of 0.1 mL Freund's complete adjuvant in the right paw on the 19th day.NC and MC groups were given(0.9%) physiological saline.The TPT and XFC groups were given TPT(10 mg/kg) and XFC(1.2 g/kg),respectively.Thirty days after administration,changes in paw edema(E),the arthritis index(AI),pulmonary function,levels of regulatory T-cells(Treg),ultrastructure of lung tissue,and expression of Notch receptors and ligands in lung tissue were observed.RESULTS:In the MC group,E and the AI were increased and pulmonary function significantly decreased;the structure of alveolar type-II cells was damaged;ratios of Treg in peripheral blood were reduced;and expression of Notch receptors such as Notch3 and Notch4 and ligands such as Delta1 in lung tissue were significantly increased whereas expression of Notch1,Jagged1 and Jagged2 were significantly decreased.After intervention with XFC,E and the AI were decreased;pulmonary function was enhanced;the structure of alveolar type-II cells was improved;and expression of Treg,Notch1,Jagged1,Jagged2 was elevated,whereas that of Notch3,Notch4 and Delta1 was reduced.CONCLUSION:XFC can not only inhibit E and the AI and improve joint symptoms,it can also improve pulmonary function and reduce inflammation in lung tissue.These actions could be carried out through increases in the expression of Treg,Notch receptors(Notch1) and ligands(Jagged1,Jagged2),and reductions in the expression of Notch3,Notch4 and Delta1.These phenomena would reduce the deposition of immune complexes and the inflammatory response in lung tissue,thereby improving joint symptoms and pulmonary function.

Use of Xinfeng capsule to treat abarticular pathologic changes in patients with rheumatoid arthritis

OBJECTIVE: To observe the influence of Xinfengcapsule(XFC) on abarticular pathologic changes(APCs) and other indices of patients with rheumatoid arthritis(RA) and explore the mechanism of action of XFC in improving such changes.METHODS: Three-hundred RA patients were divided randomly into a treatment group(n=150) and control group(n=150). A normal control(NC)group(n=90) was also created. Changes in cardiac function, pulmonary function, anemia indices and platelet parameters of RA patients were measured.Curative effects of the two groups were compared,and comparison carried out with the NC group.RESULTS: In 300 RA patients, late diastolic peak flow velocity(A peak) was much higher(P<0.01)and early diastolic peak flow velocity(E peak), E/A,and left ventricular fraction shortening much lower(P<0.01) than those in the NC group. Vital capacity(VC), forced vital capacity in one second, forced vital capacity(FVC), maximal voluntary ventilation(MVV), maximal expiratory flow in 50% of VC(FEF50) and FEF75 were lowered remarkably(P<0.05 or P<0.01). Platelet count(PLT), plateletcrit(PCT) and mean platelet volume(MPV) increased markedly(P<0.05 or P<0.01), and hemoglobin(Hb)level decreased significantly(P<0.05). After XFC treatment, the A peak and PLT and PCT were much lower(P<0.05), and E/A and the number of red blood cells as well as Hb level were much higher(P<0.05), as were FVC, MVV and FEF50(P<0.05 or P<0.01), in the treatment group than those in the NC group. Total score of pain and swelling in joints,uric-acid level and high-sensitivity C-reactive protein level were much lower, and superoxide dismutase level as well as the number of CD4 +CD25+ regulation T cells(Treg) and CD4+CD25+CD127- Treg were much higher(P<0.05 or P<0.01)in the treatment group than those in the NC group.CONCLUSION: RA patients with pathologic changes in joints also suffer from lower cardiac and pulmonary functions and from parameters of anemia and platelet factors. XFC can improve the symptoms of RA patients, ameliorate their cardiac and pulmonary functions and reduce the parameters of anemia and platelet factors. XFC lowers the immune inflammatory reaction to improve APCs in RA patients.

Apolipoprotein E, amyloid-beta, and neuroinflammation in Alzheimer's disease

Alzheimer＇s disease （AD） is characterized by the accumulation and deposition of amyloid-beta （Aβ） peptides in the brain. Neuroinflammation occurs in the AD brain and plays a critical role in the neurodegenerative pathology. Particularly, Aβ evokes an inflammatory response that leads to synaptic dysfunction, neuronal death, and neurodegeneration. Apolipoprotein E （ApoE） proteins are involved in cholesterol transport, Aβ binding and clearance, and synaptic functions in the brain. The ApoE4 isoform is a key risk factor for AD, while the ApoE2 isoform has a neuroprotective effect. However, studies have reached different conclusions about the roles of the isoforms; some show that both ApoE3 and ApoE4 have anti-inflammatory effects, while others show that ApoE4 causes a predisposition to inflammation or promotes an inflammatory response following lipopolysaccharide treatment. These discrepancies may result from the differences in models, cell types, experimental conditions, and inflammatory stimuli used. Further, little was known about the role of ApoE isoforms in the Aβ-induced inflammatory response and in the neuroinflammation of AD. Our recent work showed that ApoE isoforms differentially regulate and modify the Aβ-induced inflammatory response in neural cells, with ApoE2 suppressing and ApoE4 promoting the response. In this article, we review the roles, mechanisms, and interrelations among Aβ, ApoE, and neuroinflammation in AD.

Development of Human in vitro Brain-blood Barrier Model from Induced Pluripotent Stem Cell-derived Endothelial Cells to Predict the in vivo Permeability of Drugs

An in vitro blood-brain barrier(BBB) model is critical for enabling rapid screening of the BBB permeability of the drugs targeting on the central nervous system.Though many models have been developed, their reproducibility and renewability remain a challenge. Furthermore, drug transport data from many of the models do not correlate well with the data for in vivo BBB drug transport.Induced-pluripotent stem cell(i PSC) technology provides reproducible cell resources for in vitro BBB modeling.Here, we generated a human in vitro BBB model by differentiating the human i PSC(hi PSC) line GM25256 into brain endothelial-type cells. The model displayed BBB characteristics including tight junction proteins(ZO-1,claudin-5, and occludin) and endothelial markers(von Willebrand factor and Ulex), as well as high transendothelial electrical resistance(TEER)(1560 X.cm2±230 X.cm2) and c-GTPase activity. Co-culture with primary rat astrocytes significantly increased the TEER of the model(2970 X.cm2 to 4185 X.cm2). RNAseq analysis confirmed the expression of key BBB-related genes in the hi PSC-derived endothelial cells in comparison with primary human brain microvascular endothelial cells,including P-glycoprotein(Pgp) and breast cancer resistant protein(BCRP). Drug transport assays for nine CNS compounds showed that the permeability of non-Pgp/BCRP and Pgp/BCRP substrates across the model was strongly correlated with rodent in situ brain perfusion data for these compounds(R2= 0.982 and R2= 0.9973,respectively), demonstrating the functionality of the drug transporters in the model. Thus, this model may be used to rapidly screen CNS compounds, to predict the in vivo BBB permeability of these compounds and to study the biology of the BBB.

阿尔茨海默病APPswe/PS1dE9双转基因小鼠的病理生化和行为学研究(英文)

目的阿尔茨海默病(Alzheimer’sdisease,AD)APPswe/PS1dE9双转基因小鼠已被广泛运用于各种实验研究。AD小鼠脑内产生过量的β淀粉样蛋白(Aβ),后者会影响突触功能和中枢神经系统的发育。然而,该转基因小鼠模型的生化和行为学特征却未见报道。本研究旨在对该小鼠模型的病理从生化和行为学角度进行检测。方法对6月和12月龄转基因和野生型小鼠取血约100μL,1200g离心后,分离血清。在小鼠6月和12月龄时,进行为期15天的辐射状六臂水迷宫实验。ELISA法检测血清和大脑中Aβ1-40和Aβ1-42的含量,以及血清中8-羟基脱氧鸟苷的含量。比较转基因和野生型小鼠大脑不同部位中α-,β-和γ-分泌酶活性的差异。结果在6月龄之前,APP-swe/PS1dE9双转基因小鼠的死亡率约为35%,这些死亡的小鼠脑内Aβ1-40和Aβ1-42水平较高,两者比例约为1:10。在6月和12月龄时,转基因小鼠血清中Aβ1-40水平均显著高于Aβ1-42水平,Aβ1-40与Aβ1-42比例为2.37:1。在12月龄时,转基因小鼠大脑中Aβ1-42水平显著高于Aβ1-40水平,两者比例约为2.17:1,并且在不同脑区中,Aβ1-42和Aβ1-40含量变化较大。在小脑、前、后部皮质层以及海马中,Aβ1-42水平显著高于Aβ1-40。分泌酶活性在转基因和野生型小鼠之间以及在不同脑部位之间没有很大的差异,这提示PS1转基因并没有导致高γ-分泌酶活性,该基因可能使γ-分泌酶更有效的切割和产生Aβ1-42。此外,转基因小鼠血清中8-羟基脱氧鸟苷含量较野生型小鼠升高,但没有显著性差异。行为学结果显示,在6月龄时,转基因小鼠与野生型相比呈现出显著的记忆障碍,到12月龄时,这种障碍变得更为严重,表现为水迷宫实验中产生更多的错误。结论 APPswe/PS1dE9双转基因小鼠最早在6月龄时就能很好地模拟早发性AD,可用于实验研究。

Ab-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Ab Secretion in Neural Cells

Alzheimer＇s disease（AD） is characterized by amyloid-b（Ab） toxicity,tau pathology,insulin resistance,neuroinflammation,and dysregulation of cholesterol homeostasis,all of which play roles in neurodegeneration.Insulin has polytrophic effects on neurons and may be at the center of these pathophysiological changes.In this study,we investigated possible relationships among insulin signaling and cholesterol biosynthesis,along with the effects of Ab42 on these pathways in vitro.We found that neuroblastoma 2a（N2a） cells transfected with the human gene encoding amyloid-b protein precursor（Ab PP）（N2aAb PP） produced Ab and exhibited insulin resistance by reduced p-Akt and a suppressed cholesterol-synthesis pathway following insulin treatment,and by increased phosphorylation of insulin receptor subunit-1 at serine 612（p-IRS-S612） as compared to parental N2 a cells.Treatment of human neuroblastoma SH-SY5 Y cells with Ab42 also increased p-IRS-S612,suggesting that Ab42 is responsible for insulin resistance.The insulin resistance was alleviated when N2a-Ab PP cells were treated with higher insulin concentrations.Insulin increased Ab release from N2 aAb PP cells,by which it may promote Ab clearance.Insulin increased cholesterol-synthesis gene expression in SHSY5 Y and N2 a cells,including 24-dehydrocholesterol reductase（DHCR24） and 3-hydroxy-3-methyl-glutaryl-Co A reductase（HMGCR） through sterol-regulatory element-binding protein-2（SREBP2）.While Ab42-treated SH-SY5 Y cells exhibited increased HMGCR expression and c-Jun phosphorylation as pro-inflammatory responses,they also showed down-regulation of neuro-protective/antiinflammatory DHCR24.These results suggest that Ab42 may cause insulin resistance,activate JNK for c-Jun phosphorylation,and lead to dysregulation of cholesterol homeostasis,and that enhancing insulin signaling may relieve the insulin-resistant phenotype and the dysregulated cholesterol-synthesis pathway to promote Ab release for clearance from neural cells.

Novel n-channel organic semiconductor based on pyrene-phenazine fused monoimide and bisimides

Large π-conjugated pyrene-phenazine monoimide and bisimides were synthesized by imine condensation reaction. These imides form well ordered 1D nanotapes upon self-assembly in solution. Electrochemical and electric conductivity measurement reveal it can be served as an n-channel semiconductor with large charge carrier mobility up to 4.1 cm^2 V^-1 s^-1. Both alkylated imides are highly luminescent, and can be quenched via protonization using trifluoroacetic acid, which could be served as potential colorimetric acid sensors.