基于分子对接研究黄酮及异黄酮类化合物与G-四链体DNA的相互作用

摘要：目的:探讨端粒G-四链体DNA稳定剂黄酮及异黄酮类化合物的作用模式,进而确立比较可靠的化合物分子对接模型用于后续研究。方法:以两个具有与黄酮及异黄酮相似结构配体的G-四链体DNA晶体为受体,将文献中报道了活性的黄酮及异黄酮类化合物经过能量优化后作为配体,采用SYBYL-X 2.0的对接模块进行分子对接。通过对接总评分与活性数据对比来分析对接模型的合理性,同时研究化合物与G-四链体DNA的相互作用。结果:分子对接软件计算出的总评分与化合物活性数据比较匹配,预测的受体-配体间相互作用对化合物结构优化具有较好的参考意义。结论:通过分子模拟及结果分析建立了比较合理的对接模型,在下一步工作中可应用该模型进行虚拟筛选,指导化合物设计。     

CpG基序的免疫效果和作用机理

不同于脊椎动物的DNA,细菌DNA含有高得多的非甲基化CpG二核苷酸,具体说是称为"CpG基序"的碱基成分.脊椎动物的免疫系统看来可能有一种进化的将"CpG基序"视为外源物质的识别分子,能激发机体产生强烈偏向Th1型的保护性免疫应答.这些应答可以用合成的寡脱氧核糖核苷酸(ODN)来模拟,实验表明,ODN在疫苗佐剂和肿瘤及变态反应的免疫治疗方面有很大的应用潜力.     

DNA疫苗佐剂的研究进展

DNA疫苗是一种很有希望的免疫方法,经多途径接种质粒DNA能引起有效的免疫应答,重复给予不会产生抗载体免疫.然而,质粒DNA疫苗在小型实验动物中诱导的免疫应答远强于在人类和其他非人灵长类动物中.已设计多种佐剂通过直接刺激免疫系统或增强DNA表达来提高疫苗的免疫原性,这些佐剂包括免疫协同刺激分子、细胞因子、补体分子、脂质体、核酸、聚合物、纳米粒和微粒类佐剂.此文对DNA疫苗佐剂的研究进展作一综述.     

DNA疫苗佐剂的研究进展

DNA疫苗是一种很有希望的免疫方法,经多途径接种质粒DNA能引起有效的免疫应答,重复给予不会产生抗载体免疫.然而,质粒DNA疫苗在小型实验动物中诱导的免疫应答远强于在人类和其他非人灵长类动物中.已设计多种佐剂通过直接刺激免疫系统或增强DNA表达来提高疫苗的免疫原性,这些佐剂包括免疫协同刺激分子、细胞因子、补体分子、脂质体、核酸、聚合物、纳米粒和微粒类佐剂.此文对DNA疫苗佐剂的研究进展作一综述.     

基于布尔矩阵的模糊粗糙集代数运算与表示定理

主要研究模糊粗糙集理论基本概念与基本运算的矩阵表示,用布尔矩阵对模糊粗糙集理论中的基本概念进行描述,并通过布尔矩阵运算性质研究、揭示和刻画模糊粗糙集知识空间的基本代数性质.文中定义了布尔矩阵"与积"和"或积"两种逻辑运算,分别对模糊粗糙集理论中的模糊可能(fuzzy diamond)算子和模糊必然(fuzzy box)算子计算过程进行描述,对模糊粗糙集理论的基本概念和基本代数性质给出了基于布尔矩阵的表示定理,为基于模糊粗糙集理论的知识表示与知识获取提供了一种能行与可计算的思路与方法.     

POLH基因实时荧光定量PCR检测条件的建立

研究表明,环境化学污染物可以引起各种类型的DNA损伤,而POLH基因与DNA损伤所引起的细胞内反应即DNA的跨损伤合成(translesion synthesis,TLS)有关.因此,有必要寻找出一种敏感度极高的方法来检测POLH基因在mRNA水平上的表达变化,从而为探讨POLH基因在环境化学污染物所诱导的跨损伤DNA合成中的分子作用机制提供相应的线索.     

白细胞介素12在DNA疫苗中的分子佐剂效应

白细胞介素12(IL-12)作为分子佐剂,可促进或抑制DNA疫苗的免疫效果.本文就近年来IL-12作为分子佐剂应用于多种传染病和肿瘤DNA疫苗的研究进展作一综述.       

一种新的可用于预测分子活性的受体模拟方法

我们尝试利用遗传算法来构造虚拟受体模型，并利用虚拟受体模型与配 体分子的相互作用能对已知分子的生活活性数据进行回归来预测未知分子的生物活性，对ALS酶抑制剂体系的计算表明，此方法能给出ALS酶抑制剂的合理的预报值。     

DNA测序:由科幻走到现实

人类基因组计划、基因芯片、个性化分子诊断、生物云计算……这些在21世纪第一个十年里吸引无数眼球的热门词汇,都和一个产业颇有渊源——DNA测序。脱氧核糖核酸(DNA)是一种长链状分子,可组成遗传指令,以引导生物发育与生命机能运作。DNA测序技术,又叫基因测序技术。人类基因组这部生命天书如同一座宝库,保藏着几千年来人们迫切想知道的秘密,DNA测序技术就好似"芝麻开门"这样的咒语,是我们打开宝库的金钥匙。     

A New Method of Receptor Mapping to Predict Bioactivity

我们尝试利用遗传算法来构造虚拟受体模型，并利用虚拟受体模型与配体分子的相互作用能对已知分子的生物活性数据进行回归来预测未知分子的生物活性。对ＡＬＳ酶抑制剂体系的计算表明，此方法能给出ＡＬＳ酶抑制剂的合理的预报值。     

Advanced technologies and devices for inhalational anesthetic drug dosing

Technological advances in micromechanics, optical sensing, and computing have led to innovative and reliable concepts of precise dosing and sensing of modern volatile anesthetics. Mixing of saturated desflurane flow with fresh gas flow (FGF) requires differential pressure sensing between the two circuits for precise delivery. The medical gas xenon is administered most economically in a closed circuit breathing system. Sensing of xenon in the breathing system is achieved with miniaturized and unique gas detector systems. Innovative sensing principles such as thermal conductivity and sound velocity are applied. The combination of direct injection of volatile anesthetics and low-flow in a closed circuit system requires simultaneous sensing of the inhaled and exhaled gas concentrations. When anesthetic conserving devices are used for sedation with volatile anesthetics, regular gas concentration monitoring is advised. High minimal alveolar concentration (MAC) of some anesthetics and low-flow conditions bear the risk of hypoxic gas delivery. Oxygen sensing based on paramagnetic thermal transduction has become the choice when long lifetime and one-time calibration are required. Compact design of beam splitters, infrared filters, and detectors have led to multiple spectra detector systems that fit in thimble-sized housings. Response times of less than 500 ms allow systems to distinguish inhaled from exhaled gas concentrations. The compact gas detector systems are a prerequisite to provide "quantitative anesthesia" in closed circuit feedback-controlled breathing systems. Advanced anesthesia devices in closed circuit mode employ multiple feedback systems. Multiple feedbacks include controls of volume, concentrations of anesthetics, and concentration of oxygen with a corresponding safety system. In the ideal case, the feedback system delivers precisely what the patient is consuming. In this chapter, we introduce advanced technologies and device concepts for delivering inhalational anesthetic drugs. First, modern vaporizers are described with special attention to the particularities of delivering desflurane. Delivery of xenon is presented, followed by a discussion of direct injection of volatile anesthetics and of a device designed to conserve anesthetic drugs. Next, innovative sensing technologies are presented for reliable control and precise metering of the delivered volatile anesthetics. Finally, we discuss the technical challenges of automatic control in low-flow and closed circuit breathing systems in anesthesia.     

Extracorporeal cephalic blood autoperfusion method in the rat: Hemorrheological evaluation and proposed pharmacological uses

We propose a constant cephalic blood perfusion method especially suitable to the rat. Cerebrovascular blood pressure is artificially regulated by an extracorporeal circuit with a perfusion pump and a Starling valve. A hemorrheological evaluation allows one to demonstrate an extracorporeal circuit that shows a growing pathological evolution, which can be purposely accelerated by iterative ischemie episodes. This method can be used (as shown by some examples) as a model for cerebrovascular failure or to study deleterious effects of the extracorporeal circuit.     

Component architecture in drug discovery informatics

This paper reviews the characteristics of a new model of computing that has been spurred on by the Internet, known as Netcentric computing. Developments in this model led to distributed component architectures, which, although not new ideas, are now realizable with modern tools such as Enterprise Java. The application of this approach to scientific computing, particularly in pharmaceutical discovery research, is discussed and highlighted by a particular case involving the management of biological assay data.     

Making the most of spontaneous adverse drug reaction reporting

The primary purpose of spontaneous adverse drug reaction reporting is to provide early warnings or "signals" of previously unrecognized drug toxicity. The method was developed in the 1960s in response to the thalidomide tragedy and is now well-established throughout the developed world. Health professionals are the key original source of reports, the value of patient reporting is yet unclear. Electronic transmission of all reports is likely to become the norm within a few years. This is well-advanced between pharmaceutical companies and regulatory authorities but still in its infancy for health professionals in many parts of the world. Considered globally, the process may be inefficient and movement towards centralization of databases with appropriate access controls is logical. Alternative methods for capturing clinical suspicions of adverse drug reactions should be investigated and could provide more systematic data. However much it can be improved, spontaneous adverse drug reaction reporting is unlikely to identify all important unrecognized drug safety hazards. Complementary approaches therefore still need to be identified and developed.     

Dorsal striatal dopamine induces fronto-cortical hypoactivity and attenuates anxiety and compulsive behaviors in rats

Dorsal striatal dopamine transmission engages the cortico-striato-thalamo-cortical (CSTC) circuit, which is implicated in many neuropsychiatric diseases, including obsessive-compulsive disorder (OCD). Yet it is unknown if dorsal striatal dopamine hyperactivity is the cause or consequence of changes elsewhere in the CSTC circuit. Classical pharmacological and neurotoxic manipulations of the CSTC and other brain circuits suffer from various drawbacks related to off-target effects and adaptive changes. Chemogenetics, on the other hand, enables a highly selective targeting of specific neuronal populations within a given circuit. In this study, we developed a chemogenetic method for selective activation of dopamine neurons in the substantia nigra, which innervates the dorsal striatum in the rat. We used this model to investigate effects of targeted dopamine activation on CSTC circuit function, especially in fronto-cortical regions. We found that chemogenetic activation of these neurons increased movement (as expected with increased dopamine release), rearings and time spent in center, while also lower self-grooming. Furthermore, this activation increased prepulse inhibition of the startle response in females. Remarkably, we observed reduced [¹⁸F]FDG metabolism in the frontal cortex, following dopamine activation in the dorsal striatum, while total glutamate levels- in this region were increased. This result is in accord with clinical studies of increased [¹⁸F]FDG metabolism and lower glutamate levels in similar regions of the brain of people with OCD. Taken together, the present chemogenetic model adds a mechanistic basis with behavioral and translational relevance to prior clinical neuroimaging studies showing deficits in fronto-cortical glucose metabolism across a variety of clinical populations (e.g. addiction, risky decision-making, compulsivity or obesity).Subject terms: Neuroscience, Behavioural methods, Human behaviour     

对《药物吸收速率常数的一种简便计算法》一文的几点看法

本文对药物吸收速率常数(K_α)的简便计算法的可靠性进行了讨论并对应用中的具体措施提出了不同看法。无论是在特征值左右多取几个血样或是用“二次抛物线拟合”都不能肯定地提高计算精度。对于K_α精度要求较高的药代动力学实验研究,该法还有待进一步改进。     

国家医药储备存储决策模型的遴选

目的探讨适用于国家医药储备的存储决策模型。方法针对药品的特点,运用逻辑分析法、文献调研法比较各类存储模型的适用性。结果对于战略储备药品的需求是离散型随机变量,备运时间短的定量库存模型、备运时间是离散随机变量的库存模型、信息熵模型和不同有效期的药品混杂储备数量模型等可用于战略储备药品存储决策。结论影响药品战略储备的因素多而复杂,常用的贮存模型尚不足以反映药品战略储备行为,系统仿真技术的应用可弥补常用模型的不足。     

Special aspects of pharmacokinetics of inhalation anesthesia

Recent interest in the use of low-flow or closed circuit anesthesia has rekindled interest in the pharmacokinetics of inhaled anesthetics. The kinetic properties of inhaled anesthetics are most often modeled by physiologic models because of the abundant information that is available on tissue solubilities and organ perfusion. These models are intuitively attractive because they can be easily understood in terms of the underlying anatomy and physiology. The use of classical compartment modeling, on the other hand, allows modeling of data that are routinely available to the anesthesiologist, and eliminates the need to account for every possible confounding factor at each step of the partial pressure cascade of potent inhaled agents. Concepts used to describe IV kinetics can readily be applied to inhaled agents (e.g., context-sensitive half-time and effect site concentrations). The interpretation of the F(A)/F(I) vs time curve is expanded by reintroducing the concept of the general anesthetic equation-the focus is shifted from "how F(A) approaches F(I)" to "what combination of delivered concentration and fresh gas flow (FGF) can be used to attain the desired F(A)." When the desired F(A) is maintained with a FGF that is lower than minute ventilation, rebreathing causes a discrepancy between the concentration delivered by the anesthesia machine (=selected by the anesthesiologist on the vaporizer, F(D)) and that inspired by the patient. This F(D)-F(I) discrepancy may be perceived as "lack of control" and has been the rationale to use a high FGF to ensure the delivered matched the inspired concentration. Also, with low FGF there is larger variability in F(D) because of interpatient variability in uptake. The F(D)-F(I) discrepancy increases with lower FGF because of more rebreathing, and as a consequence the uptake pattern seems to be more reflected in the F(D) required to keep F(A) constant. The clinical implication for the anesthesiologist is that with high FGF few F(D) adjustments have to be made, while with a low FGF F(D) has to be adjusted according to a pattern that follows the decreasing uptake pattern in the body. The ability to model and predict the uptake pattern of the individual patient and the resulting kinetics in a circle system could therefore help guide the anesthesiologist in the use of low-flow anesthesia with conventional anesthesia machines. Several authors have developed model-based low FGF administration schedules, but biologic variability limits the performance of any model, and therefore end-expired gas analysis is obligatory. Because some fine-tuning based on end-expired gas analysis will always be needed, some clinicians may not be inclined to use very low FGF in a busy operating room, considering the perceived increase in complexity. This practice may be facilitated by the development of anesthesia machines that use closed circuit anesthesia (CCA) with end-expired feedback control--they "black box" these issues (see Chapter 21). In this chapter, we first explore how and why the kinetic properties of intravenous and inhaled anesthetics have been modeled differently. Next, we will review the method most commonly used to describe the kinetics of inhaled agents, the F(A)/F(I) vs time curve that describes how the alveolar (F(A)) approaches the inspired (F(I)) fraction (in the gas phase, either "fraction," "concentration," or "partial pressure" can be used). Finally, we will reintroduce the concept of the general anesthetic equation to explain why the use of low-flow or closed circuit anesthesia has rekindled interest in the modeling of pharmacokinetics of inhaled anesthetics. Clinical applications of some of these models are reviewed. A basic understanding of the circle system is required, and will be provided in the introduction.