Non-target Screening and Quantitation of Organic Chlorides in Oilfield Chemicals with Comprehensive Two Dimensional Gas Chromatography Coupled with Time of Flight Mass Spectrometry

Advanced analytical methodology based on comprehensive two-dimensional gas chromatography-time of flight mass spectrometry(GC×GC-TOFMS) is proposed for investigation of organic chlorides in different oilfield chemicals.The target screening was initially carried out on 8 suspected organic chlorides by evaluating the capability of the enhanced separation and reliable identification at a trace concentration. GC×GC-TOFMS allowed for the fast and automated analysis of organic chlorides at a level of 200 μg/L. This method was subsequently applied for non-target screening of organic chlorides in different oilfield chemicals at various locations across China. 22 organic chlorides were identified and verified by comparison with pure standards in the mixed sample. Finally, this method was used to determine the content of the organic chlorides in individual samples. The result showed that the organic chloride levels in 19 of the 39 tested oilfield chemicals were above the threshold limit of 1.0 mg/L.

Methodology of drug screening and target identification for new necroptosis inhibitors

Apoptosis has been considered as the only form of regulated cell death for a long time. However, a novel form of programmed cell death called necroptosis was recently reported. The process of necroptosis is regulated and plays a critical role in the occurrence and development of multiple human diseases. Thus,the study on the molecular mechanism of necroptosis and its effective inhibitors has been an attractive field for researchers. Herein, we introduce the molecular mechanism of necroptosis and focus on the literature about necroptosis drug screening in recent years. In addition, the identification of the critical drug targets of the necroptosis is also discussed.

Single Source Self-Screen Jamming Elimination and Target Detection for Distributed Dual Antennas Radar System

Detecting target echo in the existence of self-screen jamming is a challenging work for radar system, especially when digital radio frequency memory(DRFM) technique is employed that mixes the jamming and target echo both in spatial and time-frequency domain. The conventional way to solve this problem would suffer from performance degradation when physical target(PT) and false target(FT) are superposed in time. In this paper, we propose a new spatial filter according to the different correlation characteristic between PT and FT. The filter takes the ratio of expected signal power to expected jamming and noise power as the objective function under the constant filter modulus constraint. The optimal filter coefficients are derived with a generalized rayleigh quotient approach. Moreover, we analytically compute the target detection probability and demonstrate the applicability of the proposed method to the correlation coefficient. Monte Carlo simulations are provided to corroborate the proposed studies. Furthermore, the proposed method has simple architecture and low computation complexity, making it easily applied in modern radar system.

Hypothyroidism during pregnancy: Controversy over screening and intervention

Thyroid hormones are critical for foetal neurological development and maternal health. Maternal hypothyroidism during pregnancy is associated with adverse impact on health of the mother as well as the progeny. Reduced thyroid hormone levels predispose the child to develop mental retardation and cognitive delay in early life. In the mother, hypothyroidism during pregnancy is associated with spontaneous abortion, placental abruption, preterm delivery and hypertensive disorders. Therefore, screening and therapeutic intervention is justified to prevent foetal as well as maternal co-morbidities. In view of impact of such a large-scale screening and intervention program on limited healthcare resources, it is debatable if a targeted rather than universal screening program will result in comparable outcomes. In addition, there is an ongoing debate regarding best evidence-based practice for the management of isolated hypothyroxinaemia, subclinical hypothyroidism and euthyroid women with autoimmune hypothyroidism. We have carried out a review of the literature; firstly, to determine whether universal screening for asymptomatic women in early pregnancy would be cost-effective. Secondly, we have retrospectively reviewed the literature to analyse the evidence regarding the impact of therapeutic intervention in women with subclinical hypothyroidism.

Development of a risk score to guide targeted hepatitis C testing among human immunodeficiency virus patients in Cambodia

BACKGROUND The World Health Organization recommends testing all human immunodeficiency virus(HIV)patients for hepatitis C virus(HCV).In resource-constrained contexts with low-to-intermediate HCV prevalence among HIV patients,as in Cambodia,targeted testing is,in the short-term,potentially more feasible and cost-effective.AIM To develop a clinical prediction score(CPS)to risk-stratify HIV patients for HCV coinfection(HCV RNA detected),and derive a decision rule to guide prioritization of HCV testing in settings where‘testing all’is not feasible or unaffordable in the short term.METHODS We used data of a cross-sectional HCV diagnostic study in the HIV cohort of Sihanouk Hospital Center of Hope in Phnom Penh.Key populations were very rare in this cohort.Score development relied on the Spiegelhalter and Knill-Jones method.Predictors with an adjusted likelihood ratio≥1.5 or≤0.67 were retained,transformed to natural logarithms,and rounded to integers as score items.CPS performance was evaluated by the area-under-the-ROC curve(AUROC)with 95% confidence intervals(CI),and diagnostic accuracy at the different cut-offs.For the decision rule,HCV coinfection probability≥1% was agreed as test-threshold.RESULTS Among the 3045 enrolled HIV patients,106 had an HCV coinfection.Of the 11 candidate predictors(from history-taking,laboratory testing),seven had an adjusted likelihood ratio≥1.5 or≤0.67:≥50 years(+1 point),diabetes mellitus(+1),partner/household member with liver disease(+1),generalized pruritus(+1),platelets<200×10^(9)/L(+1),aspartate transaminase(AST)<30 IU/L(-1),AST-to-platelet ratio index(APRI)≥0.45(+1),and APRI<0.45(-1).The AUROC was 0.84(95%CI:0.80-0.89),indicating good discrimination of HCV/HIV coinfection and HIV mono-infection.The CPS result≥0 best fits the test-threshold(negative predictive value:99.2%,95%CI:98.8-99.6).Applying this threshold,30%(n=926)would be tested.Sixteen coinfections(15%)would have been missed,none with advanced fibrosis.CONCLUSION The CPS performed well in the derivation cohort,and bears potential for other contexts of low-to-intermediate prevalence and little onward risk of transmission(i.e.cohorts without major risk factors as injecting drug use,men having sex with men),and where available resources do not allow to test all HIV patients as recommended by WHO.However,the score requires external validation in other patient cohorts before any wider use can be considered.

Antibody Phage Library Screening Efficiency Measured by KD Values

An antibody phage library was screened with two target molecules, IFNα-2a and FGFR-GST, and the KD value of each round of panning was measured. It was found that the apparent KD values decreased along with each additional panning round, which indicates the increase of the binding affinity between the phage and the target molecules. This result shows that the KD value is a reliable intrinsic parameter and a new method for screening efficiency detection is thus provided.

Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas

Cutaneous malignant melanoma is the most aggressive form of skin cancer with an extremely poor survival rate for the patients diagnosed with locally invasive and metastatic disease states. Intensive research has led in last few years to an improvement of the early detection and curative treatment of primary cutaneous melanomas that are confined to the skin by tumor surgical resection. However, locally advanced and disseminated melanomas are generally resistant to conventional treatments, including ionizing radiation, systemic chemotherapy, immunotherapy and/or adjuvant stem cellbased therapies, and result in the death of patients. The rapid progression of primary melanomas to locally invasive and/or metastatic disease states remains a major obstacle for an early effective diagnosis and a curative therapeutic intervention for melanoma patients. Importantly, recent advances in the melanoma research have led to the identification of different gene products that are often implicated in the malignant transforma-tion of melanocytic cells into melanoma cells, including melanoma stem/progenitor cells, during melanoma initiation and progression to locally advanced and metastatic disease states. The frequent deregulated genes products encompass the oncogenic B-Raf V600 E and N-RasQ 61 R mutants, different receptor tyrosine kinases and developmental pathways such as epidermal growth factor receptor(EGFR), stem cell-like factor(SCF) receptor KIT, hedgehog, Wnt/β-catenin, Notch, stromal cell-derived factor-1(SDF-1)/CXC chemokine receptor-4(CXCR4) and vascular endothelial growth factor(VEGF)/VEGFR receptor. These growth factors can cooperate to activate distinct tumorigenic downstream signaling elements and epithelial-mesenchymal transition(EMT)-associated molecules, including phosphatidylinositol 3'-kinase(PI3K)/Akt/ molecular target of rapamycin(mT OR), nuclear factor-kappaB(NF-κB), macrophage inhibitory cytokine-1(MIC-1), vimentin, snail and twist. Of therapeutic relevance, these deregulated signal transduction components constitute new potential biomarkers and therapeutic targets of great clinical interest for improving the efficacy of current diagnostic and prognostic methods and management of patients diagnosed with locally advanced, metastatic and/or relapsed melanomas.

基于全二维气相色谱−飞行时间质谱技术对上海农田土壤中有机污染物的高通量筛查

为探究路边农田土壤中未知有机物赋存情况,利用全二维气相色谱−飞行时间质谱技术对上海不同道路等级路边农田土壤(n=8)中的有机物进行了非靶向定性筛查.通过空白过滤和谱库匹配(相似度大于700),在所有样品中均检出了1000多个质谱峰,其中,与谱库保留指数偏差在±2%以内的物质数有275~341种.所有采样点共同检出的有机物有66种,信噪比较高的前10种物质主要是多环芳烃类、邻苯二甲酸酯类、苯酚类、噻吩类和四氯乙烷类.费雪比值(Fisher ratio,FR)法分析揭示出具有明显道路等级差异的化合物有29种(FR为22.6~60.3),而这些化合物主要来自化工产品、生物医药和个人护理品等产品,推断其差异主要受控于邻近区域工业活动、污水灌溉和居民生活源排放的影响.元素组成分析表明,在所有采样点中有机物组成主要以CHO和CH为主,峰面积占比分别为39.9%~59.1%和30.2%~45.8%.对人为源有机物进一步地分类分析,发现烷烃、多环芳烃和邻苯二甲酸酯类是上海路边农田土壤中含量较高的3类污染物,表明汽油柴油燃烧、轮胎磨损、润滑油挥发泄漏等交通源排放对路边农田土质的影响不容忽视.总的来说,全二维技术能够准确地定性筛查出农田土壤中大量未关注的有机污染物,为今后污染管控和治理提供了科学依据.

Screening of Protease Inhibitory Activity in Aqueous Extracts of Marine Invertebrates from Cuban Coast

Protease inhibitors have been isolated from many variable sources;however, the need to identify and characterize new molecules has increased with the discovery of new therapeutic targets and the lack of specificity of already identified compounds with inhibitory activity. The goal of this work was to search for inhibitory activity against four proteolytic enzymes already recognized as therapeutic targets: human neutrophil elastase, dipeptidyl peptidase IV, subtilisin from Bacillus licheniformis and cathepsin K in selected marine invertebrates from the Caribbean Sea. A systematic screening was carried out with selected aqueous extracts belonging to 20 species from seven different phyla: Annelida, Bryozoa, Chordata, Cnidaria, Equinodermata, Mollusca and Porifera, all collected at the coast of Havana (Cuba). All extracts showing initial inhibitory activity were characterized in terms of IC50 values and specific inhibitory activity (SIA). Model enzymes were used in the case of human neutrophil elastase (porcine pancreatic elastase) and cathepsin K (papain) for the screening and all positive results were confirmed by testing toward the therapeutic targets. Ten extracts were identified showing inhibitory activity against human neutrophil elastase, for which the most promising values were obtained for Nerita peloronta. Only one extract, Bunodosoma granulifera, showed inhibitory activity against dipeptidyl peptidase IV with rather poor values of IC50 and SIA. Seven extracts showed inhibitory activity against B. licheniformis subtilisin with very good IC50 and SIA values for Lissodendorix isodyctialis, Cenchritis muricatus, and N. peloronta. Finally, eight extracts were positive for cathepsin K with almost similar parameters values among them. All these results confirmed the richness and potential of the marine invertebrate’s fauna and indicated new promising sources for the identification of natural compounds with potential application in therapeutics.

子宫颈癌十年研究回顾

子宫颈癌是一种病因明确且可防可控的恶性肿瘤。尽管人乳头瘤病毒(human papillomavirus,HPV)疫苗研发和子宫颈癌筛查已广泛开展,但其发病率仍逐年上升,并呈现低龄化的趋势,提示子宫颈癌防控仍有待优化。因此世界卫生组织提出加速消除子宫颈癌全球战略。随着对HPV致癌机制的深入研究,子宫颈癌筛查技术不断革新,出现HPV拓展分型、p16INK4a(p16)/Ki-67双重染色(双染)、基因甲基化和HPV整合检测等具有临床前景的新技术。另外,为改善子宫颈癌患者的预后,基于新辅助化疗、同步放化疗、免疫治疗和靶向治疗等不同治疗方式的联合方案成为临床研究热点。本文就子宫颈癌10年研究现状进行述评。

基于双N型的六光幕天幕立靶测量方法研究

弹丸的着靶坐标一直是身管武器外弹道测试领域经常测量的参数,针对现有六光幕阵列天幕立靶存在的系统复杂,主探测器比较笨重的问题,提出一种集成化双N型六光幕立靶测量方案,在每台主探测器的一个光学镜头内集成三个探测光幕,两台主探测器在空中形成两个N型的三光幕探测阵列。当弹丸依次穿越六个探测光幕,对应的两台主探测器三光幕天幕靶的电路依次输出六个弹丸信号,采用数据采集仪对弹丸信号进行采集,并通过弹丸信号处理算法对采集到的弹丸信号进行处理,得到弹丸穿越六个探测光幕的时刻值,再进一步通过对应的探测光幕参数和靶距参数计算得到弹丸的着靶坐标值。对系统着靶坐标测量误差进行了分析,并通过两种不同口径的实弹测试验证了系统的弹丸着靶坐标测量精度。

微乳头型肺腺癌类器官的构建及其靶向药物的筛选

目的建立微乳头型肺腺癌类器官的培养方法,并开展靶向药物的筛选。方法自确诊为微乳头型肺腺癌患者手术组织样本中提取和培养原代肺癌类器官,动态观察和记录肺癌类器官生长情况;苏木精-伊红(HE)染色法及免疫组化染色法比较肺癌类器官与亲本组织间肿瘤细胞形态及蛋白表达特征;实时荧光定量聚核酶链反应检测肺癌亲本组织和类器官中基因突变情况;基于基因检测结果挑选靶向药物并验证其体外抑瘤效果。结果成功从微乳头型肺腺癌组织中培养出类球形肿瘤类器官,可传代至少3代。HE染色结果可见类器官中肿瘤细胞形态与亲本组织细胞基本一致;免疫组化染色结果显示肺癌类器官与亲本组织中各基因的蛋白表达水平大致相同;基因突变分析结果显示,肺癌亲本组织和类器官的突变基因结果一致,均体现为原癌基因酪氨酸蛋白激酶受体Ret(RET)融合突变。基于肺癌类器官的靶向药物筛选结果显示,凡德他尼的体外抑瘤效果最佳。结论基于微乳头型肺腺癌类器官的药筛实验可在短时间内筛选出高效靶向药物,可使微乳头型肺腺癌患者从中获益。

塑料添加剂的环境迁移、毒性测试与风险筛查:进展与挑战

塑料和微塑料污染日益严峻,因此引发了对塑料添加剂释放现象的广泛关注,塑料添加剂在固废处置和回收过程中会大量向环境中释放。塑料添加剂种类繁多,功能多样,数量庞大,其复杂性使得其评估工作面临巨大挑战,尤其是目前塑料添加剂的风险评估工作尚未建立起完善的体系。本研究对现有塑料添加剂的释放迁移研究、毒性测试及风险预测方法进行梳理,并基于塑料添加剂在种类、功能、添加量、监管、数据可用性等方面对公开信息的塑料添加剂逐级筛查,最终从1万多种现有塑料添加剂中筛选出106种值得关注的未监管添加剂物质。然后综合以下4项危害性指标,包括基于QSAR模型预测的物质毒性作用方式和危害等级、各化学品机构评估的PBT/PMT性质(持久性、生物累积性、迁移性、毒性)、生态毒性数据可用性、是否纳入化学品未来评估计划(CoRAP,ECHA),使用毒理学优先指数(ToxPi)方法按照等权重计算综合得分并排序,通过层次聚类分析对其进行优先级分类,提出相应风险评估优先序和研究关注的建议。结果表明,这其中很多尚未监管的塑料添加剂物质的潜在生态风险可能被低估。最后,我们提出对微塑料未来的研究挑战应主要聚焦在填补危害数据缺口和技术方法空白,包括其迁移释放机制、环境转化、混合效应及对生态系统的潜在影响等方面。

强肝胶囊治疗非酒精性脂肪性肝病网络药理学研究

基于多靶点虚拟筛选、网络药理学分析和体外实验,探讨强肝胶囊(QGC)治疗非酒精性脂肪性肝病(NAFLD)的潜在作用机制。利用基于PPARα/γ、FXR及sEH的多靶点虚拟筛选选出QGC中具有治疗NAFLD的活性成分,运用网络药理学预测活性成分靶点、疾病相关靶点,筛选调控疾病的关键靶点,通过Discovery Studio 2020软件和Gromacs软件对关键活性成分和关键靶点进行分子对接和分子动力学模拟分析。最后,通过实验验证QGC中的关键活性成分对肝细胞脂肪变性的改善作用。多靶点虚拟筛选得到235个QGC活性成分,网络药理学分析得到320个成分-疾病共同靶点。分子对接结果表明,芹菜素、异鼠李素、迷迭香酸、大黄素甲醚、木犀草素与关键靶点PTPN1、PPARα、PPARγ、AR具有良好的结合能力。分子动力学模拟进一步验证了迷迭香酸、大黄素甲醚等化合物与关键靶点具有良好的结合稳定性。体外实验结果显示,5个关键活性成分均能改善HepG2细胞的脂肪变性,其中异鼠李素、迷迭香酸、大黄素甲醚改善细胞脂肪变性模型的效果最佳。本研究通过多层面探讨,为QGC在NAFLD治疗中的开发和应用提供理论依据。

文库构建与基因簇靶向筛选驱动的微生物天然产物高效发现

微生物天然产物作为小分子药物的主要来源,已被广泛应用于医药与农业等领域。随着全球抗生素耐药性与其他公共健康问题的加剧,新结构、新靶点微生物天然产物发现迫在眉睫。大规模(宏)基因组测序揭示微生物蕴含了巨大的生物合成潜力,相继催生了多种不同类型的天然产物挖掘策略。然而,目前仍然缺乏将天然产物合成基因簇与编码产物快速关联的高效方案。近年来,(宏)基因组文库构建在获取批量天然产物合成基因簇方面展现出明显优势,结合高效的基因簇靶向筛选方法,显著加速了新结构天然产物系统发现。本文综述了三类基于(宏)基因组文库构建与靶向筛选驱动天然产物创新发现的策略,主要从克隆载体类型、文库构建方式、基因簇靶向筛选方法等角度进行了阐述,并对Cosmid/Fosmid文库、BAC/PAC文库、FAC/YAC文库等不同文库类型的优缺点及应用范围进行了对比,最后对这些策略的发展前景进行了展望。未来,基于文库构建与基因簇靶向筛选策略将极大驱动不同生境微生物来源的活性天然产物挖掘,预期大量新靶点、新结构天然产物将不断涌现。

固定化药靶蛋白中药活性成分定向筛选研究进展

中药活性成分筛选及作用评价一直是破解药物发现周期长和成功率低等瓶颈问题的核心突破口和重要技术支撑。作者团队创新亲和色谱原理,将药靶蛋白定向固定于色谱担体表面,制备了系列高活性功能化色谱固定相,并提出了固定化药靶蛋白定向筛选中药功效成分的新观点。主要综述了作者团队近五年在固定化药靶蛋白色谱固定相制备技术、中药活性成分定向筛选技术以及活性成分早期成药性评价色谱技术等方面的工作,并对固定化药靶蛋白在中药活性成分定向筛选方面的研究进行了展望。

分子对接在筛选抗宫颈癌药物中的研究进展

宫颈癌是最常见的妇科恶性肿瘤之一,在淋巴结转移和远处转移的情况下,五年生存率显著下降,因此研发新型抗宫颈癌药物对于治疗宫颈癌有重大的意义。分子对接技术是计算机辅助药物设计技术中最常用的研究方法之一,在筛选药物有效成分、发现药物作用于肿瘤的靶点以及探索抗肿瘤药物的作用机制中被广泛应用。本文将分子对接技术在抗宫颈癌药物筛选、抗肿瘤靶标确定方面以及抗宫颈癌作用机制等方面作一综述,为筛选抗宫颈癌药物及新药研发提供更充分的理论依据。

食品接触用多层复合包装中迁移物质的非靶向筛查和风险评价

目的以食品接触用纸/铝/塑复合包装为研究对象,结合应用非靶向高通量筛查技术和安全风险评价方法,全面研究这类多层复合包装在接触食品过程中的迁移风险。方法采用顶空气相色谱-串联质谱、气相色谱-四极杆飞行时间质谱和液相色谱-四级杆飞行时间质谱全面筛查食品接触用纸/铝/塑复合包装在不同迁移条件下的挥发性、半挥发性和非挥发性迁移物质,基于商业数据库、实验室自建库及行业信息解析物质化学结构及可能来源,利用内标半定量迁移水平,结合国内外食品接触材料法规和安全风险评估方法进行符合性评价及风险评价。结果20批纸/铝/塑复合食品包装在体积分数为4%的乙酸模拟物中未发现迁移风险,在体积分数为95%的乙醇模拟物中共计检出35种物质,可能源于溶剂、抗氧剂、爽滑剂、低聚物、抗氧剂氧化/降解产物等物质。其中,33种物质经法规评估及毒理学评估,显示风险较低;其余2类聚烯烃低聚物因结构难以确定、缺乏毒理学研究建议持续关注毒理学研究进展及国内外法律法规动态。结论通过结合应用非靶向高通量筛查技术和安全风险评估方法研究表明,在通常的使用条件下,纸/铝/塑多层复合包装用于盛装果汁等水性食品时不存在安全风险,但接触高乙醇含量或油脂类食品时建议关注聚烯烃类低聚物的迁移安全性。

全二维气相色谱—飞行时间质谱非靶向筛查页岩气场地不同样品中的微量有机污染物及溯源分析

以全二维气相色谱—飞行时间质谱为技术手段,通过对某页岩气开采场地样品中微量有机污染物进行非靶向筛查,构建了基于实际样品分析的有机污染物清单。通过对不同样品中有机污染物特征分析,解析了部分有机污染物的来源。烷烃是钻井泥浆中被识别出的主要有机污染物类型。与钻井泥浆相比,脱油岩屑中烷烃占比显著降低而羰基、醇类化合物占比升高,说明热脱附技术对石油烃类具有良好的去除效果,但对极性更强的羰基和醇类化合物的去除效果可能欠佳。烷烃和羰基化合物是压裂液和返排液中的主要污染物。在压裂液和返排液中还可识别出大量被用作抗菌剂、增塑剂、表面活性剂和引发剂的有机污染物。

豆薯抗氧化成分提取工艺优化及其活性成分分析

采用酶解辅助乙醇浸提豆薯抗氧化活性成分。以ABTS、DPPH自由基清除率为评价指标,通过单因素试验和正交试验对提取工艺进行优化。在最佳提取条件下,测定豆薯提取液中总酚、总黄酮和维生素C含量,并分析其抗氧化活性组分。结果表明:最佳提取工艺条件为酶添加量0.4%(以豆薯干粉质量计)、提取时间60 min、提取温度50℃、料液比1∶10(g/mL);在此条件下制备的豆薯提取液对ABTS、DPPH自由基清除率分别为90.45%、56.28%,总酚、总黄酮和维生素C含量分别为(111.31±2.35)、(92.41±3.07)、(20.77±2.31)mg/100 g。豆薯提取液的主要抗氧化成分为香兰素、大豆甙元、芒柄花素和大豆素。