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.

DIRECT radioligand binding methods have been used extensively to identify and characterise a wide range of hormone, drug and neurotransmitter receptors. Among the most intensively studied have been the β adrenergic receptors which mediate stimulation of the enzyme adenylate cyclase by catecholamines1. Until recently all of the successful binding studies of β adrenergic receptors have been performed with specific high affinity β adrenergic antagonists such as (−) 3H-dihydroalprenolol2, (±) 3H-propranolol3 or (±) 125I-hydroxybenzylpindolol4. Earlier attempts to use radioligand β adrenergic agonists were generally frustrated by a great deal of nonspecific (that is non-receptor) binding5. We have developed a high affinity radiolabelled β adrenergic agonist, 3H-hydroxybenzylisoprenaline, which, when used in conjunction with high concentrations of catechol and ascorbic acid which block non-receptor binding sites, seems to be a useful ligand for studying the β-adrenergic receptors6. We present here the results of parallel studies of agonist (3H-hydroxybenzylisoprenaline, HBI) and antagonist (3H-dihydroalprenolol, DHA) binding to β-adrenergic receptors in frog erythrocyte membranes. The ability of sixteen β-adrenergic agents (agonists and antagonists) to competitively inhibit binding of the two ligands in identical assay conditions (including catechol and ascorbate) has been compared. The results suggest an impressive coincidence of the binding data obtained with the two radioligands. These results are in contrast with those recently described for several central nervous system neurotransmitter receptors where it seems to be possible to identify discrete ‘agonist’ and ‘antagonist’ conformations of the receptors by performing binding studies with either a radiolabelled agonist or antagonist respectively7–11.

Comparison of specificity of agonist and antagonist radioligand binding to β adrenergic receptors

Allosteric activation of proto-oncogene kinase Src by GPCR-beta-arrestin complexes.

DiscussionNew directions in adrenergic receptor research: Part I

G protein-coupled receptors (GPCRs) are a large class of cell-surface receptor involved in cellular signaling that are currently the target of over one third of all clinically approved therapeutics. Classically, an agonist-bound, active GPCR couples to and activates G proteins through the receptor intracellular core. To attenuate G protein signaling, the GPCR is phosphorylated at its C-terminal tail and/or relevant intracellular loops, allowing for the recruitment of β-arrestins (βarrs). βarrs then couple to the receptor intracellular core in order to mediate receptor desensitization and internalization. However, our laboratory and others have observed that some GPCRs are capable of continuously signaling through G protein even after internalization. This mode of sustained signaling stands in contrast with our previous understanding of GPCR signaling, and its molecular mechanism is still not well understood. Recently, we have solved the structure of a GPCR-G protein-βarr megacomplex by cryo-electron microscopy. This 'megaplex' structure illustrates the independent and simultaneous coupling of a G protein to the receptor intracellular core, and binding of a βarr to a phosphorylated receptor C-terminal tail, with all three components maintaining their respective canonically active conformations. The structure provides evidence for the ability of a GPCR to activate G protein even while being bound to and internalized by βarr. It also reveals that the binding of G protein and βarr to the same GPCR is not mutually exclusive, and raises a number of future questions to be answered regarding the mechanism of sustained signaling.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/febs.15773

Robert J. Lefkowitz

Papers

Comparison of specificity of agonist and antagonist radioligand binding to β adrenergic receptors

Allosteric activation of proto-oncogene kinase Src by GPCR-beta-arrestin complexes.

DiscussionNew directions in adrenergic receptor research: Part I

Signaling at the endosome: cryo-EM structure of a GPCR-G protein-beta-arrestin megacomplex.

Overexpression of pp60c-src is associated with altered regulation of adenylyl cyclase.