抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Experimental introduction of RNA into cells can be used in certain biological systems to interfere with the function of an endogenous gene Such effects have been proposed to result from a simple antisense mechanism that depends on hybridization between the injected RNA and endogenous messenger RNA transcripts RNA interference has been used in the nematode Caenorhabditis elegans to manipulate gene expression Here we investigate the requirements for structure and delivery of the interfering RNA To our surprise, we found that double-stranded RNA was substantially more effective at producing interference than was either strand individually After injection into adult animals, purified single strands had at most a modest effect, whereas double-stranded mixtures caused potent and specific interference The effects of this interference were evident in both the injected animals and their progeny Only a few molecules of injected double-stranded RNA were required per affected cell, arguing against stochiometric interference with endogenous mRNA and suggesting that there could be a catalytic or amplification component in the interference process

Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans

Ligand: a versatile computerized approach for characterization of ligand-binding systems.

Cell signaling by receptor-tyrosine kinases

The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

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How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

The interaction of hormones and drugs with their respective targets has been widely studied with the hope that a better understanding of the molecular basis of their actions would provide insights not only into the nature of their specific mechanisms but those involved in certain pathophysiologic states. Receptors represent the central locus of interaction between ligands/drugs and cells. Adrenergic receptors because of their ubiquitous and well defined effector mechanisms have been excellent models for the study of these processes. Catecholamines and various synthetic analogs bind to adrenergic receptors that are integral membrane proteins and lead to the generation of intracellular second messengers culminating in a physiologic response. As with many other types of receptors this cascade of events is mediated by specific effector molecules which are coupled to adrenergic receptors in the plasma membrane. These intermediary signal transducing proteins are called guanine nucleotide regulatory proteins or G-proteins because they bind and hydrolyze guanine nucleotide triphosphate (1).

Structure and function of the adrenergic receptor family.

Erratum: Identification and sequence of a binding site peptide of the β2-adrenergic receptor (Biochemistry (1988) 27, 6, (1813-1817))

Structure and function of beta-adrenergic receptors: regulation at the molecular level.

Publisher Summary This chapter relates the study of adrenergic receptors to the regulation of adenylate cyclase activity. The ubiquitous nature of the adrenergic responses has made these systems prototypes or models for the study of receptor-effector coupling in general. Progress is being made in the elucidation of the molecular mechanisms of transmembrane signaling via adrenergic receptors. The focus is primarily on studies of the β-adrenergic receptor-adenylate cyclase complex. Smooth muscle relaxation, inotropic and chronotropic regulation in the heart, and metabolic effects such as lipolysis are mediated through β-adrenergic receptors. β- Adrenergic responses are inhibited by a different set of drugs, which has little affinity for the α-receptors, such as propranolol, alprenolol, and pindolol. The characteristics of high potency and biological specificity make antagonist compounds particularly useful in the classification of adrenergic responses and in the direct study of adrenergic receptors. β-Adrenergic responses are directly linked to the activation of adenylate cyclase in the plasma membranes of target cells, suggesting that cyclic AMP (CAMP) mediates the regulatory effects of β-adrenergic agonists. The chapter discusses how understanding of receptor-cyclase coupling distilled from the investigations of the stimulatory β-adrenergic receptor-adenylate cyclase system may be applicable in understanding inhibition of adenylate cyclase activity, as mediated, for example, by α2- adrenergic receptors.

The β-Adrenergic Receptor: Ligand Binding Studies Illuminate the Mechanism of Receptor-Adenylate Cyclase Coupling

Publisher Summary This chapter provides an overview of the regulation of β-adrenergic receptors by β-adrenergic agonistsrecent investigations in the laboratory that have concentrated on the endeavors to define the molecular mechanisms necessary for the phenomenon of catecholamine-induced tolerance or desensitization. It also discusses the molecular mechanisms necessary for the phenomenon of catecholamine-induced tolerance or desensitization. By desensitization, it is meant loss of responsiveness of a tissue to the physiological effects of some specific drug or hormone effector. The important feature of such a desensitization phenomenon is the specificity for a particular type of drug. Specific desensitization phenomena emerge to be quite general, though not universal phenomena. The chapter also describes the method applied for direct study of β-adrenergic receptors. For the studies of desensitization, a series of in vivo experiments were started and it frogs were used and they were injected with β-adrenergic catecholamines. After varying periods of time or injection schedules, animals were sacrificed, and the status of the s-adrenergic receptor-adenylyl cyclase system in the frog erythrocyte was studied.

Robert J. Lefkowitz

Papers

Structure and function of the adrenergic receptor family.

Erratum: Identification and sequence of a binding site peptide of the β2-adrenergic receptor (Biochemistry (1988) 27, 6, (1813-1817))

Structure and function of beta-adrenergic receptors: regulation at the molecular level.

The β-Adrenergic Receptor: Ligand Binding Studies Illuminate the Mechanism of Receptor-Adenylate Cyclase Coupling

Regulation of β-Adrenergic Receptors by β-Adrenergic Agonists