Predictions of genotoxic potential,mode of action,molecular targets,and potency via a tiered multiflow® assay data analysis strategy

The in vitro MultiFlow® DNA Damage Assay multiplexes γH2AX, p53, phospho-histone H3, and polyploidization biomarkers into a single flow cytometric analysis. The current report describes a tiered sequential data analysis strategy based on data generated from exposure of human TK6 cells to a previously described 85 chemical training set and a new pharmaceutical-centric test set (n = 40). In each case, exposure was continuous over a range of closely spaced concentrations, and cell aliquots were removed for analysis following 4 and 24 hr of treatment. The first data analysis step focused on chemicals' genotoxic potential, and for this purpose, we evaluated the performance of a machine learning (ML) ensemble, a rubric that considered fold increases in biomarkers against global evaluation factors (GEFs), and a hybrid strategy that considered ML and GEFs. This first tier further used ML output and/or GEFs to classify genotoxic activity as clastogenic and/or aneugenic. Test set results demonstrated the generalizability of the first tier, with particularly good performance from the ML ensemble: 35/40 (88%) concordance with a priori genotoxicity expectations and 21/24 (88%) agreement with expected mode of action (MoA). A second tier applied unsupervised hierarchical clustering to the biomarker response data, and these analyses were found to group certain chemicals, especially aneugens, according to their molecular targets. Finally, a third tier utilized benchmark dose analyses and MultiFlow biomarker responses to rank genotoxic potency. The relevance of these rankings is supported by the strong agreement found between benchmark dose values derived from MultiFlow biomarkers compared to those generated from parallel in vitro micronucleus analyses. Collectively, the results suggest that a tiered MultiFlow data analysis pipeline is capable of rapidly and effectively identifying genotoxic hazards while providing additional information that is useful for modern risk assessments—MoA, molecular targets, and potency. Environ. Mol. Mutagen. 60:513–533, 2019. © 2019 Wiley Periodicals, Inc.     

基于FPGA的神经突触的硬件实现及放电性能比较

目前专门对化学突触硬件实现的研究较少,采用FPGA芯片技术硬件实现化学突触,对神经元网络的硬件实现具有重要价值。运用DSP Builder软件,对以Hodgkin-Huxley神经元为突触前神经元和突触后神经元的化学突触数学模型进行建模。在DSP Builder模型的基础上,将化学突触的DSP Builder模型进行合理的拆分,然后分别将各个模块在FPGA所对应的软件环境下进行编译运行,最后下载到FPGA核心芯片中,硬件实现5种基于不同机理的化学突触模型。采用相关系数法,对仿真结果和硬件结果在同一个周期内的突触前神经元动作电位、突触后神经元动作电位以及突触电流的幅值进行对比,验证硬件实现的准确性。5种硬件实现的化学突触均可以较好地传递动作电位,但是各个模型消耗资源不同,模型3所消耗的内部乘法器资源(69%),约为模型5资源(31%)的2倍,表明突触模型数学复杂度越高,其消耗的乘法器资源越多。相关系数法的对比结果显示,模型3相关度最高,为0.791 3,模型4相关度最低,为0.693 5。虽然模型3数学复杂度高、硬件资源消耗多,但是其表现的生物性最好。硬件实现的5种突触模型均能较好地呈现化学突触的单向传递性,其中模型5硬件资源消耗少、相关度高,建议以其作为化学突触硬件实现的首选。     

八珍汤对肺癌化疗致白细胞减少症临床疗效及部分机制研究

目的:探究八珍汤对肺癌化疗所致白细胞减少症的疗效及作用机制,有助于精准治疗并提高疗效。方法:选取2017年4月至2018年4月哈尔滨医科大学附属第一医院收治的肺癌化疗所致白细胞减少症患者66例作为研究对象,采用数字随机表法按就诊顺序号,分为对照组和观察组,每组33例。对照组予利血生20 mg口服,3次/d;鲨肝醇100 mg口服,3次/d,升白治疗,观察组在对照组基础上加用八珍汤化裁治疗,均治疗4周,观察不同方法治疗后在白细胞水平含量比较,比较治疗前、治疗末神疲乏力、心悸气短、头晕目眩、面色淡白、畏寒肢冷、纳呆食少中医症候积分和免疫功能指标CD4^+、CD8^+、CD4^+/CD8^+、NK细胞变化情况,治疗过程中收集不良反应情况,结束治疗后观察疗效情况。结果:1)2组治疗1周、2周、3周、4周后白细胞计数菌显著高于治疗前(P<0.05),观察组治疗1周、2周、3周、4周后显著优于对照组(P<0.05);2)2组患者治疗前神疲乏力、心悸气短、头晕目眩、面色淡白、畏寒肢冷、纳呆食少,比较差异无统计学意义(P>0.05),完成治疗方案后,2组患者以上指标较治疗前均显著下降(P<0.05)。治疗末观察组患者以上指标显著低于对照组(P<0.05)。3)2组患者治疗前CD4^+、CD8^+、CD4^+/CD8^+、NK细胞比较,差异无统计学意义(P>0.05),完成治疗方案后,2组患者CD8^+较治疗前均显著下降,CD4^+、CD4^+/CD8^+、NK细胞较治疗前显著升高(P<0.05),治疗末观察组患者以上指标显著优于对照组(P<0.05)。4)完成治疗后观察组患者显效率、总有效率明显高于对照组(P<0.05)。5)2组在不良反应发生率上比较,差异无统计学意义(P>0.05)。结论:八珍汤对肺癌化疗所致白细胞减少症能升高白细胞水平,提高疗效,改善症状。可能和该药能提高机体免疫力,促使骨髓造血功能有关。     

The link between language and action in aging

ObjectiveMany studies have demonstrated the existence of a link between action verb processing and action. However, little is known about the changes in this relationship with aging.MethodTo assess this point, we compare the performances of younger and older people during a priming task consisting of judging whether an image contains a human after listening to an action verb.ResultsIn accordance with previous literature, the results showed that younger people were faster to detect the presence of a human in the image in congruent conditions, namely, when the action verb and the image refer to the same action. However, this effect was not present in older adults’ participants.ConclusionThese findings suggest that the link between action and language decreases with age. We discuss these findings in the context of the embodied view of cognition.     

肉毒毒素注射引起的不良反应

肉毒毒素注射引起的不良反应,是药物本身的组成成分引起的与用药目的无关的有害反应,与医生注射方式和注射技术无关。尽管肉毒毒素生产厂家的药品说明书上也有提示,但其所提供的信息不够全面,也未必能引起医生的足够重视。目前文献上多为散发病例。为此作者对过去20年有关肉毒毒素注射引起的过敏反应、肉瘤样肉芽肿、眼睑水肿、流感样症状等相关不良反应的临床表现、发病机制与治疗方法进行综述。     

温阳解郁颗粒调节BDNF/TrkB/ERK信号通路保护皮质酮诱导损伤型海马神经细胞的作用机制研究＊

目的 观察温阳解郁颗粒（Wenyang Jieyu granule，WYJY）对皮质酮（Corticosterone，CORT）诱导损伤型小鼠海马神经细胞（TH22 cell）的保护作用，基于脑源性神经营养因子（Brain derived neurotrophic factor， BDNF）/酪氨酸激酶B（Tyrosine kinase B， TrkB）/细胞外信号调节蛋白激酶（Extra cellular regulated protein kinases， ERK）信号通路探讨WYJY保护海马神经细胞的作用机制。方法 体外构建小鼠海马神经细胞皮质酮诱导损伤模型，以不同浓度的WYJY和氟西汀（Fluoxetine，FXT）含药血清作用于模型细胞，细胞增殖-毒性检测（Cell Counting Kit-8， CCK-8）法分析细胞活性，倒置显微镜下观察给药前后细胞形态结构的改变，采用蛋白免疫印迹法（Western Blot）、实时荧光定量PCR（Quantitative real-time PCR， qPCR）法检测神经细胞内凋亡因子（BCL2-Associated X， Bax）、抗凋亡因子（B-cell lymphoma-2， Bcl-2）、BDNF、Trkb、ERK以及丝氨酸/苏氨酸激酶（Phospho-p90RSK， RSK）、环磷腺苷效应元件结合蛋白（cAMP-response element binding protein， CREB）蛋白表达水平以及相关基因的表达水平。结果 在浓度为459.5 μmol·L^-1的CORT作用24 h后，HT22细胞的活性抑制率达到50%，在此条件作用下细胞形态结构损伤明显，凋亡程度严重，细胞上清中BDNF的含量显著减少（P<0.05），细胞内凋亡相关因子Bax/Bcl-2的比值明显升高（P<0.01），BDNF、Trkb、ERK、RSK、CREB磷酸化蛋白表达水平和mRNA表达水平明显降低（P<0.01）；以5%的浓度为2.85 g·kg^-1的WYJY和10%的FXT含药血清作用于受损的HT22细胞后，HT22细胞存活率明显提升（P<0.01），细胞结构的损伤明显改善，细胞凋亡程度减轻，细胞外BDNF的含量显著升高（P<0.05），细胞内Bax/Bcl-2比值显著下调（P<0.01），BDNF、Trkb、ERK、RSK、CREB磷酸化蛋白表达水平和mRNA表达水平显著提升（P<0.05，P<0.01）。结论 温阳解郁颗粒可有效保护高浓度CORT造成的小鼠海马神经细胞损伤。调控BDNF/Trkb/ERK通路，放大CREB信号传导，影响Bcl-2、BDNF水平，可能是其保护海马神经元，发挥抗抑郁疗效的重要机制。     

Early axonal loss predicts long-term disability in chronic inflammatory demyelinating polyneuropathy

ObjectiveTo investigate early pre-treatment nerve fiber loss as a predictor of long-term clinical outcome in chronic inflammatory demyelinating polyneuropathy (CIDP).MethodsIn 14 patients, motor and sensory conduction studies of the median, fibular, and sural nerves were performed at pre-treatment and follow-up 11–28 years later. Z-scores of amplitudes were combined as biomarkers of axonal loss and Z-scores of conduction properties as demyelination scores. The axonal loss was further examined by electromyography (EMG) and motor unit number estimation. Axonal and demyelination scores were compared to clinical outcomes in the Inflammatory Rasch-built Overall Disability Scale, the Neuropathy Impairment Score, and dynamometry.ResultsAt follow-up 12 patients walked independently, one needed support and one could not walk. The initial and follow-up axonal and demyelination scores were markedly abnormal. The initial axonal loss but not demyelination was strongly associated with both the follow-up axonal loss and the clinical measures. Moreover, delay of treatment initiation negatively influenced the axonal scores and clinical outcomes.ConclusionIn this hypothesis generating limited study, we found that axonal loss at early CIDP was highly predictive for long-term nerve fiber loss and disability.SignificanceThe study indicates that prompt initiation of treatment to prevent nerve fiber loss is necessary for outcome in CIDP.     

基于数据挖掘和网络药理学的血脂异常用药规律和作用机制研究＊

目的 从文献研究的角度出发，运用数据挖掘和网络药理学研究方法，探讨中医药在血脂异常治疗中的组成规律和作用机制研究，为该病的防治提供参考。方法 以1979-2019年“中国知网（CNKI）”、“万方数据”、“维普中文期刊”等数据库中检索到的中药复方治疗血脂异常文献为数据来源，采用中医传承辅助平台对其进行频次分析、关联规则分析和熵聚类方法分析，研究防治血脂异常方药组成规律，并在此基础上采用网络药理学方法，通过KEGG通路和基因本体富集分析，研究高频核心药物的生物信号通路，阐明其作用机制。结果 共计786篇文献符合检索条件，包含314味中药，发现48味高频中药，按照药物使用频次从高到低排序为：活血化瘀药、补虚药（健脾补肾为主）、利水渗湿药、消食化积药；药物性味以温、苦为主，归肝经和脾经最多；进一步关联分析得到高频药对（药组）17个；经过熵聚类分析发现潜在药物组合22个和新方组合11个。应用网络药理学研究方法，对核心药组“山楂、泽泻和决明子”的作用机制进行探索，发现其主要通过作用于包括雌激素受体1（ESR1）、大麻素受体1型（CNR1）、糖皮质激素受体基因（NR3C1）、环氧合酶2（PTGS2/COX2）等潜在靶点，干预三羧酸（TCA）循环、脂质代谢、脂肪酸降解等调节血脂相关的关键信号通路而发挥调节血脂作用。结论 中药治疗血脂异常以健脾补肾治其本，活血化瘀、消痰化积治其标的方法为主，核心药组的作用机制可能是通过干预脂质代谢和基础代谢相关通路发挥治疗作用。