Objective: Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and monocyte-lymphocyte ratio (MLR) had emerged as useful inflammatory biomarkers in multiple diseases. The study aimed to explore the possible relationships between NLR, PLR, MLR and methylamphetamine dependence, and explore their potential wider use in clinical research.Methods: 632 methylamphetamine-dependent patients and 325 controls were enrolled. The demographics, complication of de-pendence, and hematologic parameters were compared. The NLR, PLR, and MLR were estimated and compared between the two groups.Result: The count of white blood cell (WBC), neutrophil, monocyte, NLR, MLR, and PLR were significantly higher and the lym-phocyte count was significantly lower in methylamphetamine-dependent patients than controls (p < 0.05). Multivariate analysis showed that the NLR, MLR, monocyte, and platelet were screened as useful biomarkers to evaluate the inflammatory states of methylamphetamine dependence, respectively (NLR: OR (odds ratio) = 71.72, 95% CI (confidence interval) [27.63-186.19], p < 0.001. MLR: OR = 6.34, 95% CI [3.27-12.27], p < 0.001. Monocyte: OR = 26.34, 95% CI [3.44-206.11], p = 0.002. Platelets: OR = 3.71, 95% CI [1.97-7.02], p < 0.001). However, there were no significant differences in WBC, neutrophil cell, lymphocyte, and PLR (p > 0.05). Similar results were obtained after adjusting for age and gender. The receiver operating characteristic curve (ROC) analysis indicated that the NLR and MLR were useful parameters to identify the inflammatory states of methy-lamphetamine dependence (AUC (area under the curve): NLR = 0.89, MLR = 0.82, platelet = 0.64, monocyte = 0.77,p < 0.001). Furthermore, the NLR was significantly and positively associated with severity of dependence scale (SDS) score and hallucination in methylamphetamine-dependent patients (p < 0.05). However, the MLR was uncorrelated with those variables (p > 0.05).Conclusions: The NLR might serve as a useful clinical biomarker in inflammatory states of methylamphetamine dependence, and positively correlated with hallucination and severity of methylamphetamine dependence. [GRAPHICS]
FAK mediated tumour cell migration, invasion, survival, proliferation and regulation of tumour stem cells through its kinase-dependent enzymatic functions and kinase-independent scaffolding functions. At present, the development of FAK PROTACs has become one of the hotspots in current pharmaceutical research to solve above problems. Herein, we designed and synthesised a series of FAK-targeting PROTACs consisted of PF-562271 derivative 1 and Pomalidomide. All compounds showed significant in vitro FAK kinase inhibitory activity, the IC50 value of the optimised PROTAC A13 was 26.4 nM. Further, A13 exhibited optimal protein degradation (85% degradation at 10 nM). Meantime, compared with PF-562271, PROTAC A13 exhibited better antiproliferative activity and anti-invasion ability in A549 cells. More, A13 had excellent plasma stability with T1/2 >194.8 min. There are various signs that PROTAC A13 could be useful as expand tool for studying functions of FAK in biological system and as potential therapeutic agents.
目的 对亚洲兰茂牛肝菌(Lanmaoa asiatica)内生真菌Penicillium cinereoatrum Chalab.JSQ-15的次级代谢产物进行分离与鉴定,并探究其细胞毒活性.方法 采用多种色谱技术分离纯化次级代谢产物,根据理化性质和波谱数据(质谱、核磁共振谱和Marfey分析)鉴定化合物结构,并采用噻唑蓝比色法(MTT法)评价其细胞毒活性.结果 与结论从内生真菌P.cinereoatrum Chalab.JSQ-15发酵产物中分离鉴定出18个化合物,分别为9(11)-去氢过氧化麦角甾醇(1)、过氧化麦角甾醇(2)、23-甲基过氧化麦角甾醇(3)、环(L-4-羟脯氨酸-L-亮氨酸)(4)、环(L-脯氨酸-L-亮氨酸)(5)、环(L-4-羟脯氨酸-L-苯丙氨酸)(6)、3-甲氧基-环(L-脯氨酸-L-亮氨酸)(7)、环(甘氨酸-L-脯氨酸)(8)、botryolide B(9)、decarestrictine I(10)、邻苯二酚(11)、5,6-二氢尿嘧啶(12)、2-哌啶酮(13)、trans-L-4-羟脯氨酸-L-亮氨酸(14)、1-亚油酰基溶血磷脂酰胆碱(15)、油酸-α-单甘油酯(16)、油酸(17)和丁二酸(18),18个化合物均为首次从P.cinereoatrum Chalab.中分离得到.化合物对肿瘤细胞的细胞毒活性测试结果表明:甾体类化合物1、2对小鼠小胶质细胞(BV2)、人肺癌细胞(A549)和人乳腺癌细胞(MCF-7)均呈现出较强的细胞毒活性(IC50≤30 μmol·L-1),化合物3、11对BV2细胞呈现出较强的细胞毒活性(IC50≤22μmol·L-1).本研究对亚洲兰茂牛肝菌内生真菌P.cinereoatrum Chalab.JSQ-15次级代谢产物进行了较为系统的分离鉴定,为该菌种次级代谢产物的首次报道.
目的 制备盐酸非索非那定杂质G,并对其安全性进行评价,为其质量标准研究提供依据.方法 以盐酸非索非那定为起始原料,经酸降解反应得到杂质G,并研究杂质G对小鼠细胞毒性、遗传毒性及生殖毒性的影响.结果 与结论盐酸非索非那定杂质G的结构经1H-NMR、13C-NMR、MS、IR、UV谱确证,其收率为57.35％,HPLC法检测纯度为98.23％.杂质G在0.25～2.00 mg·mL-1浓度范围内,随着浓度的增大,细胞毒性也逐渐增大;杂质G在40 mg·kg-1高剂量浓度下对小鼠骨髓细胞染色体无畸变作用,未显示对小鼠骨髓细胞染色体和微核有影响,且无致雄性小鼠生殖毒性作用.制备盐酸非索非那定杂质G的方法简便可行,评价杂质G对小鼠细胞毒性、遗传毒性及生殖毒性的方法真实有效.
应激颗粒(stress granule,SG)是细胞在遇到外界环境压力时形成的一种无膜细胞器.目前已经发现SG的组装和解体与多种疾病的发生发展过程密切相关,包括神经退行性疾病、癌症、病毒感染等,因此SG被认为是一个极具开发前景的潜在药物作用靶标.本文作者介绍了 SG的生物学特征及其与疾病发生发展的关系,并在此基础上对通过不同途径与机制干预SG组装或解体的化合物进行了归纳总结与评述,以期为SG作为药物靶点的可行性探讨以及靶向SG小分子化合物的研发提供参考.
To establish an affinity ultrafiltration mass spectrometry method for rapid screening of active components of Paeonia lactiflora,and to obtain it′s anticoagulant active components, the components of different polar parts of P.lactiflora were identified, and thrombin inhibitors in P.lactiflora were inverse-targeted screened by affinity ultrafiltration with thrombin（THR） as the target, and the obtained active components were analyzed and identified.Its activity was tested by chromogenic substrate method and in vitro anticoagulant method, and its binding ability was preliminarily analyzed by molecular docking.In this experiment, the active components in different polar parts of P.lactiflora were qualitatively analyzed, and 17 components were detected.An anticoagulant active component, ellagic acid, was screened by affinity ultrafiltration mass spectrometry.When the concentration of ellagic acid was 1 g·L -1 ,the inhibition rate of thrombin was 98.34%.In vitro coagulation experiments showed that the thrombin time（TT） of ellagic acid was significantly different from the blank group（P＜0.01）,indicating that it was a potential direct thrombin inhibitor.Molecular docking results showed that ellagic acid had many binding sites with thrombin activity, low binding energy, and good binding effect.The screening results showed that ellagic acid might be a potential thrombin inhibitor.At the same time, a rapid screening method for anticoagulant active ingredients in P.lactiflora was established, which provided valuable reference for targeted therapy, mechanism exploration and quality control of traditional Chinese medicine.
为了掌握《中国药物依赖性杂志》2010-2020年甲基苯丙胺研究文章载文特点和内容,基于文献计量学的研究方法,对2010-2020年《中国药物依赖性杂志》甲基苯丙胺研究文章的发文量、研究机构、发文作者、高被引论文、获基金资助分布情况和甲基苯丙胺研究热点共6个方面进行统计分析.结果表明:2010-2020年《中国药物依赖性杂志》共发表甲基苯丙胺研究论文192篇,约占主要毒品研究的39.34％;121篇论文获各类基金资助共211项次,获基金资助的文章占总发文量的63.02％;北京大学中国药物依赖性研究所总发文量最高,发文28篇.研究结果客观展示了 2010-2020年《中国药物依赖性杂志》甲基苯丙胺研究文章的质量在不断提高,且获国家类基金资助也较多,北京大学中国药物依赖性研究所在甲基苯丙胺研究领域处于领先地位.
本文讨论动词因果蕴含义的互转问题.有的动词可以用原因转指结果,有的动词可以用结果转指原因,从而造成动词词义的相互演变.动词因果蕴含义互转的语义特点是:有的动词字面义弱化,甚至消失,只表示原因或只表示结果;有的动词字面义保留,既表示原因也表示结果.因果推理是因果互转的大前提,词义因果潜质是因果互转的小前提.词义所蕴含的因果关系的强弱程度是能否发生因果互转的重要因素,强度越高可能性越大,强度越低可能性越小.可以把因果推理看作动词因果互转的总路径,而省略是某些动词因果互转的具体路径.因果互转具有具体、形象和委婉、含蓄的表达效果.
《新华字典》全版本的连续统集合记录了新中国语言文字事业的发展历程,贮存了文字学、词汇学、语音学等多方面的中华语言文化,是一份极为珍贵的史料财富.本文从学术层面综合考察《新华字典》七十年全版本第一手资料,分析研究这部字典同新中国语言文字规范化的关系.认为,《新华字典》以学术研究为支撑,创新字书形式,反映国家通用语言文字规范,在引导正确使用现代通用汉字、推广普通话、推行汉语拼音等我国语言文字重大方针政策及各项规范标准和相关规定上,发挥了规范型权威字典特有的示范引领作用,为新中国语言文字规范化作出了十分重要的贡献,对语言文字学研究、语言文字规范化研究、辞书学研究均有启发意义和参考价值.
《新华字典》第12版根据自身的规模、读者对象主要为中小学生等特点,本着通行性、规范性、查考性、积极性等原则,增补部分字词新义、增收部分新词语,并按照字典的体例、风格等采取了适当的释义方式.
程度特指问提问属性量,构造形式是"程度疑问代词+量项成分",量项成分为等级义成分;由于程度具有数值和等级描写的双重内涵,程度特指问也能用以上两者回答.基于跨方言比较,汉语程度特指问的类型特点有:1)构造类型有光杆型、后缀型、正反型、正反-后缀型和重叠型五种;2)部分方言存在句法变异,构造类型和程度疑问代词的选择,与量项成分是否可量度、是否区分中性问和偏向问相关;3)程度疑问代词来源于数量疑问代词、方式疑问代词或程度副词.文章最后提出汉语程度疑问代词的语义演变模型,讨论共性与个性问题.
《滕王阁序》为"初唐四杰"之首的王勃所作.此序措辞联句,语多俪辞,且颇多"工对",故辞采雅丽,抑扬顿挫;虽典故错陈,辞藻浩博,却言之有物,字无虚设,实千古传诵之名篇.因此,王力主编的《古代汉语》、郭锡良等编的《古代汉语》、朱东润主编的《中国历代文学作品选》等高校教材以及诸版高中语文教材均选录了此文.然而,读罢序文及注释,颇感诸家对"屈贾谊于长沙,非无圣主;窜梁鸿于海曲,岂乏明时?"句中"屈""窜"的释义似有未恰.
"可是(NP)说的"是明清时期汉语常用引语标记.本文基于对其类别、形式-结构、意义-功能的共时描写,追溯其历时演变.经考察发现,当NP为二身代词时,"可是(NP)说的"易向观点认同标记"可是说的"演变;当NP为一身代词时,"可是(NP)说的"易向合预期语用标记演变.从引语标记向认同标记的演变习见于汉、日、英诸语,是立场语义化的结果,与其主要语用功能从概念表达功能、语篇组织功能向人际互动功能的转变相伴随.
本文根据语言的实际产出论证元音的复杂性问题.来自汉语方言的材料显示,升峰与降峰双元音性质不同.升峰双元音是一个元音序列,拥有两个声学目标;而降峰双元音是一个动态元音,只拥有一个动态的声学目标.而且,单双元音之间甚至并非明确二分.来自徽语的材料显示,央化双元音化呈现一个渐变的过程,即单元音从语音层面的央化双元音化开始,渐渐获得音系地位,并在语音上也变得越来越接近常态双元音.此外,来自北京地区儿童普通话元音的早期产出数据也显示,元音的动态与静态区别是元音的高低、前后对立之外的另一项重要的早期发展.因此,证据导向的元音产出研究抛弃传统上关于单复元音的机械分类,提倡元音动态理论.
非奈利酮(finerenone,BAY 94-8862,1)是由拜耳公司开发的首个全新非甾体、高选择性盐皮质激素受体拮抗剂(MRA),可直接精准抑制盐皮质激素受体(MR)过度活化,发挥抗炎抗纤维化作用,进而带来肾心双重获益.该药于2021年7月9日经美国FDA批准上市[1],商品名为Ke-rendia.2022年6月28日,非奈利酮在中国上市,商品名为可申达,用于治疗由Ⅱ型糖尿病所致的成人慢性肾病.
古代契约文书常见的立契原因表达套语句式是"空口无凭,立此为照""恐人难信,立此为用".元朝时出现了"立此为照者""立此为用者",一直延续至明朝万历年间,之后趋于消失,而福建地区滞后至清朝,是为例外.从历史发展背景看,元朝"立此为照者"之类是汉语与蒙古语接触的结果,明朝使用"者"是受元朝行文习惯影响的结果.元明时期在契约文书范本中偶见用例,说明蒙古语在当时的影响力比较大;明朝中叶以后使用逐渐减少,是汉语回归自身用法的体现,也从侧面说明了"者"的接触性质.蒙汉语言接触是"者"产生的外在原因,两种语言共有的功能上的相似性和句法位置的一致性是祈使语气用法产生的内在原因,类推是"者"的陈述语气用法产生的机制.
本文主要讨论汉语史上如何用词汇构式表达整体部分关系的问题.历时考察表明,隋唐之前以简单构式为主,隋唐以来以复杂构式为主,主要包括[整体+部分象征]、[整体+部分像似]和[整体+部分指示]三类构式,各类构式的形义组配关系发生了历时变化.复杂构式的衍生经历了组合成型为主到聚合成型为主的转变,起初主要根据语法规则组合而成,再基于系列同类词汇构式抽象出"整体部分"构词图式,据此构造出形、义均可扩展的复杂构式.研究表明,构式理论可以对表征特定语义关系的多词表达式的演变作出较为合理的理论解释,汉语词汇史研究中应重视构词图式对词汇演变所起的作用.
以往在讨论删略与语言演变关系时主要聚焦于删略(或脱落)引发的词汇-语义演变、句法演变和语音演变.本文从语法化角度探讨删略引发的语言演变,将删略导致新的语法成分产生这一现象谓之"删略导致的语法化".这类语法化最主要的特点是不涉及任何语用-语义过程,是一种典型的形式语法化.因为这种形式语法化本质上是一种定名学演变,所以很难用现有的基于符义学演变的语法化理论框架来描述和解释.本文的考察显示,删略导致的语法化现象广泛见于汉语方言和历史文献,源于删略的语法成分涉及指代词(人称代词、指示代词和疑问代词)、助动词、副词、介词、连词、体助词、语气词等多种功能语类.
Threonine tyrosine kinase（TTK）,also known as monopolar spindle 1（Mps1） kinase, is a core component of the spindle assembly checkpoint, which functions to ensure proper distribution of chromosomes to daughter cells.TTK is overexpressed in a variety of malignant tumor cells and selectively induces aneuploid tumor cell apoptosis, which makes TTK a potent target for cancer therapy.So far, a variety of small molecular TTK inhibitors with novel structures have been developed and even promoted into clinical trial phases.In this paper, the research progress of small molecule TTK inhibitors was summarized, their modes of action with TTK according to the structural features of the compounds were analyzed, the problems faced in the current research were discussed, and a prospect to the research direction in the future was given.This review will provide a reference for the research and development of new TTK inhibitors.
目的 比较冲动和渴求在男性酒依赖患者与健康对照之间的差异,并探究冲动和渴求对酒依赖患者复饮的影响.方法 选取2018年1月至2020年12月在北京回龙观医院的男性酒依赖患者及社区健康男性为研究对象.所有患者均给予常规急性脱瘾治疗,并在治疗后的12周末随访患者的复饮情况.比较酒依赖患者与健康对照在基线人口学资料、冲动方面的差异,并比较复饮组和非复饮组在冲动、渴求方面的差异.结果 酒依赖组与健康对照组在年龄、共同居住者、在职情况及受教育年限的比较,差异无统计学意义(P＞0.05);但酒依赖患者的吸烟比例、酗酒家族史阳性者比例、酒精使用障碍筛查量表总分(Alcohol Use Disorder Identification Test,AUDIT)、Barratt冲动量表(Barratt Impulsiveness Scale-11,BIS-11)各个分量表分数均高于对照组(P均＜0.05).复饮组患者的Barratt冲动量表的各分量表分数、饮酒迫促性问卷(Alcohol Urgent Questionnaire,AUQ)总分及视觉模拟渴求量表(Visual Analog Scale,VAS)总分均高于非复饮组患者,且差异具有统计学意义(P＜0.001).Logistic回归分析显示,注意冲动性及非计划冲动性是酒依赖患者复饮的危险因素(P均＜0.05),较晚的起病年龄和在职状态是酒依赖患者复饮的保护因素(P均＜0.05).结论 与健康对照相比,酒依赖患者具有更高的冲动性;复饮者的冲动和渴求均高于未复饮者.注意冲动性及非计划冲动性是酒依赖患者复饮的危险因素,较晚的起病年龄和在职状态是酒依赖患者复饮的保护因素.
