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)

/pdf/how-do-glucocorticoids-influence-stress-responses-4egr3fa2k0.pdf

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

Inhibitory effect of ristocetin and factor VIII/von Willebrand factor protein on human platelet adenylate cyclase activity

Publisher Summary Signaling by G-protein-coupled receptors (GPCR) can be achieved through receptor phosphorylation and desensitization by the G-protein-coupled receptor kinases (GRKs), a family of serine/threonine kinases, which rapidly phosphorylates agonist-bound receptors and uncouples them from their cognate G protein. There has been an increase in the awareness of the importance of the GRKs in the pathophysiology of disease, particularly ischemic and congestive heart diseases, where changes in the levels and functions of the GRKs have been shown to occur in patients and models of cardiac disease. GPCR mediates the action of a vast array of cellular activators, ranging from the senses of light, taste, and smell, to the circulating hormones and cytokines, and to the complexity of neurotransmitters within the synapse. The uncoupling of the receptor from its G protein has been explained in detail. Here the receptor undergoes phosphorylation either heterologously, in a nonagonist-dependent manner, by the second-messenger-dependent protein kinases, or homologously by the agonist dependent receptor specific G-protein-coupled receptor kinases. The possibility that the GRKs may be involved in the pathogenesis of disease states, or that they are potential targets for therapeutic intervention, offers many possibilities for new avenues of research.

The Function and Regulation of the G-Protein-Coupled Receptor Kinases

Many membrane bound hormone receptors are coupled to the adenylate cyclase system, and function as mediators of the hormonal stimulation at the cell surface (27). The activity of the effector enzyme, the adenylate cyclase is dually regulated via stimulatory and inhibitory receptors (27,15). After activation by a hormone stimulatory receptors like the β-adrenergic receptors and the prostaglandin E1 receptors couple to the stimulatory guanine nucleotide regulatory protein (Ns-protein) to stimulate the adenylate cyclase, while inhibitory receptors like the α2-adrenergic receptors couple to the inhibitory guanine nucleotide regulatory protein or N1-protein to inhibit the adenylate cyclase (15). Yet prolonged exposure to a hormone — stimulatory or inhibitory — leads to a decreased response to further activation of that receptor, a general phenomenon called tachyphylaxis or desensitization. One of the best studied models for desensitization is the β-adrenergic coupled adenylate cyclase (18, 24, 26).

Desensitization of the β-Adrenergic Coupled Adenylate Cyclase. The β-Adrenergic Receptor Kinase Phosphorylates Agonist-Occupied Cyclase-Coupled Receptors

Beta-arrestins regulate signaling by bone morphogenetic protein type ii receptor in pulmonary arterial hypertension

Recent developments in the characterization of the adrenergic receptors have led to the identification and purification of the binding subunits of the various catecholamine receptors. beta-Adrenergic receptors have been identified in a wide variety of tissues by photoaffinity labeling with the antagonist [125I]p-azidobenzylcrazolol and have been purified to apparent homogeneity from several of these tissues. Thus, beta 1- and beta 2-adrenergic receptor binding sites appear to reside on peptides with molecular weights of 60,000 to 65,000. The alpha 1-adrenergic receptor binding subunit has been identified in several peripheral tissues by photoaffinity labeling with a newly developed probe (4-amino-6,7-dimethoxy-2[4(5(3-[125I]-iodo-4-azidophenyl) pentanoyl)-1-piperazinyl]-quinazoline, or [125I]APDQ). This binding site resides on a peptide with a molecular weight of 80,000. These techniques have been applied to the elucidation of the binding subunit structure of these receptors in the rat central nervous system with the result that beta 1-, beta 2-, and alpha 1-adrenergic binding sites appear to reside on peptides of similar molecular weight to those identified in peripheral tissues (i.e., 60,000-65,000 and 80,000). Using immunocytochemical techniques with antibodies raised to the frog erythrocyte, beta 2-adrenergic receptor, beta-adrenergic receptors were identified at the light microscopic level in regions of the rat and frog brain previously found by ligand binding and autoradiography to be richest in beta-adrenergic receptors. At the electron microscopic level, beta-receptor immunoreactivity was found throughout dendritic processes with local accumulations at certain postsynaptic sites. This finding is consistent with the idea that the density of the receptors might be significantly increased at postsynaptic junctions of adrenergic neurons.

Robert J. Lefkowitz

Papers

Inhibitory effect of ristocetin and factor VIII/von Willebrand factor protein on human platelet adenylate cyclase activity

The Function and Regulation of the G-Protein-Coupled Receptor Kinases

Desensitization of the β-Adrenergic Coupled Adenylate Cyclase. The β-Adrenergic Receptor Kinase Phosphorylates Agonist-Occupied Cyclase-Coupled Receptors

Beta-arrestins regulate signaling by bone morphogenetic protein type ii receptor in pulmonary arterial hypertension

Molecular biology of adrenergic receptors in the rat and frog central nervous system.