美国生物类似药的使用与医疗保险支付策略分析——基于Pfizer vs. Johnson案的思考 *

近几年全球生物类似药发展如火如荼,各国出台积极政策响应与推动生物类似药的研发和应用,大型制药企业也通过一系列对生物医药公司的收购完成生物类似药研发先机的抢占。以Pfizer vs. Johnson案为研究对象,对美国生物类似药的保障政策、诉讼案件发展和系列焦点问题进行整体描述与深入分析。研究发现,来自原研企业的竞争压力及临床对生物类似药可替代性的质疑与保守态度,都在一定程度上对类似药的应用和推广构成威胁,而其价格优势和越来越明朗的政策环境使得生物类似药的未来可期。     

A double bootstrap approach to Superposed Epoch Analysis to evaluate response uncertainty

The association between climate variability and episodic events, such as the antecedent moisture conditions prior to wildfire or the cooling following volcanic eruptions, is commonly assessed using Superposed Epoch Analysis (SEA). In SEA the epochal response is typically calculated as the average climate conditions prior to and following all event years or their deviation from climatology. However, the magnitude and significance of the inferred climate association may be sensitive to the selection or omission of individual key years, potentially resulting in a biased assessment of the relationship between these events and climate. Here we describe and test a modified double-bootstrap SEA that generates multiple unique draws of the key years and evaluates the sign, magnitude, and significance of event-climate relationships within a probabilistic framework. This multiple resampling helps quantify multiple uncertainties inherent in conventional applications of SEA within dendrochronology and paleoclimatology. We demonstrate our modified SEA by evaluating the volcanic cooling signal in a Northern Hemisphere tree-ring temperature reconstruction and the link between drought and wildfire events in the western United States. Finally, we make our Matlab and R code available to be adapted for future SEA applications.     

A glycosylated type I membrane protein becomes cytosolic when peptide: N-glycanase is compromised

The human cytomegalovirus-encoded glycoprotein US2 catalyzes proteasomal degradation of Class I major histocompatibility complex (MHC) heavy chains (HCs) through dislocation of the latter from the endoplasmic reticulum (ER) to the cytosol. During this process, the Class I MHC HCs are deglycosylated by an N-glycanase-type activity. siRNA molecules designed to inhibit the expression of the light chain, beta(2)-microglobulin, block the dislocation of Class I MHC molecules, which implies that US2-dependent dislocation utilizes correctly folded Class I MHC molecules as a substrate. Here we demonstrate it is peptide: N-glycanase (PNGase or PNG1) that deglycosylates dislocated Class I MHC HCs. Reduction of PNGase activity by siRNA expression in US2-expressing cells inhibits deglycosylation of Class I MHC HC molecules. In PNGase siRNA-treated cells, glycosylated HCs appear in the cytosol, providing the first evidence for the presence of an intact N-linked type I membrane glycoprotein in the cytosol. N-glycanase activity is therefore not required for dislocation of glycosylated Class I MHC molecules from the ER.     

人类巨细胞病毒编码US28受体拮抗性多肽的筛选鉴定及体外活性研究

立足US28的广谱趋化因子结合活性,寻找拮抗剂多肽的先导物．通过预测US28的结合模拟位设计多肽序列,合成相关多肽,再利用自建的25种趋化因子随机构成的噬菌体12肽库筛选结合模拟位,竞争性ELISA方法验证,从而获得30个阳性克隆,测序并推导氨基酸序列,得到7种序列：GSESLNAHCALW、EIDGFNAHCALL、VIARLNAHCALR、ATECLNAHCALW、VIESLNAHCALW、DNGSINAHCALL及VKKTLNAHCALR．所有序列富含疏水氨基酸,其中8个克隆有LNAHCAL保守序列．采用趋化抑制实验检测多肽对生理性趋化因子引起的细胞迁移活性的影响,流式细胞仪检测细胞内钙离子浓度变化．结果表明,利用人源趋化因子序列构建肽库并筛选有效序列的方法取得成功,筛选出的阳性克隆保守序列LNAHCAL可以模拟Human MIP-1β与US28 N端的结合位,从而与合成多肽H22结合,多肽H22可以阻断受体结合生理性趋化因子形成的趋化作用,本身不引起趋化运动,不影响胞内信号转导和细胞自然活性,具有广谱趋化因子拮抗剂的可能性．     

Identification of novel allosteric modulators for the G-protein coupled US28 receptor of human cytomegalovirus

The highly constitutively active G-protein coupled receptor US28 of human cytomegalovirus (HCMV) is an interesting pharmacological target because of its implication on viral dissemination, cardiovascular diseases and tumorigenesis. We found that dihydroisoquinolinone and tetrahydroisoquinoline scaffolds may be promising lead structures for novel US28 allosteric inverse agonists. These scaffolds were rapidly synthesized by radical carboamination reactions followed by non-radical transformations. Our novel US28 allosteric modulators provide valuable scaffolds for further ligand optimization and may be helpful chemical tools to investigate molecular mechanisms of US28 constitutive signaling and its role in pathogenesis.     

Life Cycle Inventory Information of the United States Electricity System (11/17 pp)

Goal and Scope This study estimates the life cycle inventory (LCI) of the electricity system in the United States, including the 10 NERC (North American Electric Reliability Council) regions, Alaska, Hawaii, off-grid non-utility plants and the US average figures. The greenhouse gas emissions associated with the United States electricity system are also estimated. Methods The fuel mix of the electricity system based on year 2000 data is used. The environmental burdens associated with raw material extraction, petroleum oil production and transportation for petroleum oil and natural gas to power plants are adopted from the DEAMTM LCA database. Coal transportation from a mining site to a power plant is specified with the data from the Energy Information Administration (EIA), which includes the mode of transportation as well as the distance traveled. The gate-to-gate environmental burdens associated with generating electricity from a fossil-fired power plant are obtained from the DEAMTM LCA database and the eGRID model developed by the United States Environmental Protection Agency. For nuclear power plants and hydroelectric power plants, the data from the DEAMTM LCA database are used.Results and Discussion Selected environmental profiles of the US electricity system are presented in the paper version, while the on-line version presents the whole LCI data. The overall US electricity system in the year 2000 released about 2,654 Tg CO2 eq. of greenhouse gas emissions based on 100-year global warming potentials with 193 g CO2 eq. MJe–1 as an weighted average emission rate per one MJ electricity generated. Most greenhouse gases are released during combusting fossil fuels, accounting for 78–95% of the total. The greenhouse gas emissions released from coal-fired power plants account for 81% of the total greenhouse gas emissions associated with electricity generation, and natural gas-fired power plants contribute about 16% of the total. The most significant regions for the total greenhouse gas emissions are the SERC (Southeastern Electric Reliability Council) and ECAR (East Central Area Reliability Coordination Agreement) regions, which account for 22% and 21% of the total, respectively. A sensitivity analysis on the generation and consumption based calculations indicates that the environmental profiles of electricity based on consumption are more uncertain than those based on generation unless exchange data from the same year are available because the exchange rates (region to region import and export of electricity) vary significantly from year to year.Conclusions and Outlook Those who are interested in the LCI data of the US electricity system can refer to the on-line version. When the inventory data presented in the on-line version are used in a life cycle assessment study, the distribution and transmission losses should be taken into account, which is about 9.5% of the net generation [1]. The comprehensive technical information presented in this study can be used in estimating the environmental burdens when new information on the regional fuel mix or the upstream processes is available. The exchange rates presented in this study also offer useful information in consequential LCI studies.     

Herpes simplex virus US3 protein kinase regulates host responses and determines neurovirulence

The US3 of HSV encodes a serine/threonine protein kinase that is highly conserved among members of the alphaherpesviruses. It is an accessory gene that is not required for viral replication in cultured cells but appears essential for viral survival in humans. Although accumulating in vitro evidence suggested that the viral protein kinase is multifunctional, little information is available about its functions in vivo. Several reports point out that, upon invasion into the peripheral nervous system, HSV blocks virus-induced neuronal apoptosis, while presumably subverting host immune responses, largely through actions of the US3 protein kinase. In addition, the US3 protein kinase confers the viral neurovirulence. In the present article, functions of the HSV US3 protein kinase are briefly reviewed, with special attention given to its role in regulating host responses and neurovirulence.     

Renewal and reinstatement of the conditioned but not the unconditioned response following habituation of the unconditioned stimulus

Research on the inhibition of learned fear currently relies almost exclusively on one specific procedure, namely extinction of the conditioned stimulus (CS). Importantly, however, learned fear responses can be reduced by a number of other procedures, including habituation of the unconditioned stimulus (US). We recently demonstrated that reductions in learned fear following US habituation, like CS extinction, were subject to both renewal and reinstatement (Storsve et al., 2010). The present study further investigates the associative and non-associative processes shared between habituation and extinction. Given that habituation is typically context-independent (Mackintosh, 1987), in the present study we directly compared renewal and reinstatement of both a conditioned response (CR; freezing) and an unconditioned response (UR; startle) following habituation. It was found that the reduction in conditioned freezing resulting from habituation was context specific (i.e., a change in context led to a renewal of the conditioned fear response; Experiment 1) and was attenuated when a pre-test shock was given (i.e., reinstatement of conditioned fear was observed; Experiment 2). In contrast, habituation of an unconditioned response elicited by the US (i.e., a startle response) was unaffected by either a change in test context or administration of a pre-test shock. This dissociation in the effects of habituation on learned and unlearned responses is discussed in relation to theories of fear extinction.     

Fruit fly behavior in response to chemosensory signals

An important question in contemporary sensory neuroscience is how animals perceive their environment and make appropriate behavioral choices based on chemical perceptions. The fruit fly Drosophila melanogaster exhibits robust tastant and odor-evoked behaviors. Understanding how the gustatory and olfactory systems support the perception of these contact and volatile chemicals and translate them into appropriate attraction or avoidance behaviors has made an unprecedented contribution to our knowledge of the organization of chemosensory systems. In this review, I begin by describing the receptors and signaling mechanisms of the Drosophila gustatory and olfactory systems and then highlight their involvement in the control of simple and complex behaviors. The topics addressed include feeding behavior, learning and memory, navigation behavior, neuropeptide modulation of chemosensory behavior, and I conclude with a discussion of recent work that provides insight into pheromone signaling pathways.