Synthesis,structure, in vitro pharmacology,and in vivo activity of trans-3,4-dichloro-N-[[1-(dimethylamino)-4-phenylcyclohexyl]methyl]-benzamide (AP01; 4-phenyl-AH-7921), a novel mixed μ-/κ-opioid

Analogs of non-fentanyl novel synthetic opioids (NSO) with modifications that fall outside of established structure–activity relationships (SARs) for that class of drugs create the question whether or not it should be considered an analog, as defined by 21 U.S.C. §802(32)(A), which is important for its inclusion in the US system of drug scheduling. AH-7921 is a US Schedule I drug and an example of the 1-benzamidomethyl-1-cyclohexyldialkylamine class of NSO. The SARs regarding substitution of the central cyclohexyl ring have not been well characterized in the literature. Therefore, in order to expand the SAR surrounding AH-7921 analogs, trans-3,4-dichloro-N-[[1-(dimethylamino)-4-phenylcyclohexyl]methyl]-benzamide (AP01; 4-phenyl-AH-7921) has been synthesized, analytically characterized, and tested in vitro and in vivo pharmacologically. Using methods described in the original patents for this class of NSO, it was found that the single trans geometric isomer was obtained. The proton nuclear magnetic resonance, mass spectrum, infrared spectrum, and Raman spectrum are reported along with the melting point of the hydrochloride salt. In vitro binding to a battery of 43 central nervous system receptors showed it to be a high-affinity μ-opioid receptor (MOR) and κ-opioid receptor (KOR) ligand (60 nM and 34 nM, respectively). AP01 also had a 4 nM affinity for the serotonin transporter (SERT), which is a higher level of potency at this receptor than most other opioids. In rats, it exhibited antinociception in the acetic acid writhing test. Therefore, the 4-phenyl modification results in an active NSO, but carries with it potential toxicities beyond those expected for currently approved opioid drugs.     

CREATING “REAL LEARNING” FOR CHINA’S SURVIVAL: LIANG QICHAO AND THE MA BROTHERS, 1896–1898

Abstract

Liang Qichao used the Taoist term zhenzhi to express his admiration for the Ma brothers who he felt personified his ideal of seamlessly blending together Chinese and Western knowledge. This article considers Liang’s interaction with the Ma brothers as the vantage point from which to trace the formation and development of his concept of “real learning” and to show the Ma brothers’ influence on his understanding of the West and Western learning prior to the 1898 Reform. It further analyzes Liang’s thought by examining the rationale and logic behind his great appreciation for The Ma Grammar and his dialogue with Ma Jianzhong on how to train qualified translators. The final section employs the reflections of Liang Qichao and Ma Xiangbo in the aftermath of the 1898 Reform to examine the differences as well as their shared views on the synthesis of Chinese and Western learning, and the relationship between language and scholarship.     

Facial Age Synthesis Using Sparse Partial Least Squares (The Case of Ben Needham)

Automatic facial age progression (AFAP) has been an active area of research in recent years. This is due to its numerous applications which include searching for missing. This study presents a new method of AFAP. Here, we use an active appearance model (AAM) to extract facial features from available images. An aging function is then modelled using sparse partial least squares regression (sPLS). Thereafter, the aging function is used to render new faces at different ages. To test the accuracy of our algorithm, extensive evaluation is conducted using a database of 500 face images with known ages. Furthermore, the algorithm is used to progress Ben Needham's facial image that was taken when he was 21 months old to the ages of 6, 14, and 22 years. The algorithm presented in this study could potentially be used to enhance the search for missing people worldwide.     

论课程的综合化

高校课程综合化的哲学基础是系统整体论 ,其直接原因则是学科的分化。学科的分化 ,深化了人类对自然界具体领域的认识 ,但同时它反映到高等学校的课程里 ,导致了科目增多 ,课程与社会要求的分离和课程与学习者的分离。这种弊端呼唤新的课程理念的建立 ,而课程综合化则应运而生     

Games,Claims, and New Frames: Rethinking the Use of Simulation in Negotiation Education

Negotiation educators have long considered the use of role‐play simulations as an essential classroom teaching method, and have had high expectations regarding their suitability and efficacy for teaching. In this article, we review the literature to examine the degree to which simulations deliver on these perceived benefits, finding that simulations enjoy only limited advantages over other teaching methods. We note three trends that have developed as part of this reevaluation process: improving the way simulations are conducted, deemphasizing the use of simulations as a teaching tool while seeking new methods, and finding paradigm‐changing uses for simulations. With regard to this last trend, we describe our own experiments assigning students to design their own simulations, rather than participate in them as role players. Among other benefits of the design method, we found that designers showed greater improvements in concept learning and motivation than did role players.     

新时期合成警务机制研究

现代警务迫切要求整合社会信息资源,推动公安工作模式转变,合成警务由此应运而生。合成警务以信息共享、扁平化管理以及情报主导决策为基本要求,以公安机关内部警务合成、公安机关与社会间警务合成为表现形式。为了便于理解和应用,可以将合成警务中的相关主体整合为指挥机构要素、侦查机构要素、防控机构要素三类,构建合成警务模型,推动打防控一体化。     

刑事影像技术新体系

目的阐述刑事影像领域内影像技术及应用的现状和发展。方法从理论方面研究国内外刑事影像技术文献。结果提出了刑事影像影像技术新的框架体系。结论刑事影像技术三个主要组成部分是影像成像检验、影像分析检验和影像合成演示。     

模糊综合评判法在围岩稳定性分类中的应用

为了分析某水电站导流隧洞的围岩稳定性,选取影响围岩稳定性的一些主要因素,如岩石质量指标、湿抗压强度、完整性系数、结构面强度系数、地下水渗流量,引入评分机制来评价定性因素对围岩稳定的影响.利用模糊数学原理建立模糊综合评判模型进行分析,获得了与实际情况相一致的结果.     

公司社会责任若干问题研究

本文选取公司社会责任理论的三方面问题予以了讨论。首先公司社会责任理论和实践发端的两个里程碑 ,挖掘其历史背景 ,正本清源 ,探寻有益的启示 ;其次就当今中国推行公司社会责任的两个特殊问题加以讨论 ;最后研究的是公司承担社会责任的法律调整方式上的两方面问题     

自主合成标准物质鉴定缴获物中的新精神活性物质ADB-FUBINACA

目的新精神活性物质在世界范围内蔓延迅速,但相关标准物质的短缺制约着其分析方法的研究和案件检验。本文以我国首次出现的N-(1-氨甲酰基-2,2-二甲基丙基)-1-(4-氟苄基)吲唑-3-甲酰胺(ADB-FUBINACA)制毒案件为例,介绍在无法及时获得商业化标准物质的情况下,不得不通过自主合成制备标准物质解决案件检验难题,建立该新精神活性物质检验的方法。方法建立气相色谱-质谱检验方法,分析条件:色谱柱为Aglient DB-5MS石英毛细管柱(30.00m×0.25mm×0.25μm);初始柱温60℃,按15℃/min升至300℃,保持15min;载气为氦,流速1.0mL/min,分流进样,进样量1.0μL,分流比20∶1;进样口温度280℃;电子轰击(EI)离子源,电子能量70eV,离子源温度230℃,四级杆温度150℃,传输线温度280℃,质量扫描范围m/z 40~500amu,全扫描模式(SCAN)采集总离子流图,溶剂延迟3.0min。案件缴获的送检未知样品经甲醇提取,超声、离心后,取上清液以GC-MS分析;将所得主要质谱特征碎片峰(m/z)通过NIST质谱库、SWGDRUG质谱数据库以及相关文献进行检索,初步确定待测目标物。采用有机合成技术制备ADB-FUBINACA标准物质,合成路线为:吲唑-3-甲酸甲酯与4-氟苄溴发生取代反应,生成1-(4-氟苄基)-1H-吲唑-3-甲酸甲酯;取代产物在碱性条件下经水解反应得到有机酸1-(4-氟苄基)-1H-吲唑-3-甲酸;在催化剂作用下,有机酸与L-叔亮酰胺发生酰化反应,制得化合物ADB-FUBINACA。经气相色谱-质谱(GC-MS)、液相色谱-离子阱-飞行时间质谱(LCMS-IT-TOF)、核磁共振(NMR)等分析,合成化合物的结构得以确证;同时采用超高效液相色谱-二极管阵列检测器(HPLC-PDA)进行分析,对其归一化纯度进行测定。将案件未知样品和合成标准物质分别用甲醇提取,超声、离心后,再行上清液GC-MS分析。结果经GC-MS分析,案件未知样品(RT=19.818min)的质谱特征碎片峰(m/z)信息为109.0(基峰)、253.1、338.1、309.1和145.0,经与合成标准物质的保留时间及质谱图检测比对,证实为N-(1-氨甲酰基-2,2-二甲基丙基)-1-(4-氟苄基)吲唑-3-甲酰胺;通过查阅相关资料,对上述质谱特征碎片峰的产生机制进行了推断,并对1H-NMR、13C-NMR和DEPT-135等一维核磁谱图的信号进行了归属分析。结论本文报道的新精神活性物质ADB-FUBINACA其GC-MS分析方法,可用于实际案件检验鉴定;合成化合物的结构表征方法也可用于固体ADB-FUBINACA的定性分析。基于有机合成技术的新精神活性物质制备与案件检验方法,可缓解有关标准物质短缺制约该类案件检验鉴定的现状。