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

▪ Abstract Synaptic transmission is a dynamic process. Postsynaptic responses wax and wane as presynaptic activity evolves. This prominent characteristic of chemical synaptic transmission is a crucial determinant of the response properties of synapses and, in turn, of the stimulus properties selected by neural networks and of the patterns of activity generated by those networks. This review focuses on synaptic changes that result from prior activity in the synapse under study, and is restricted to short-term effects that last for at most a few minutes. Forms of synaptic enhancement, such as facilitation, augmentation, and post-tetanic potentiation, are usually attributed to effects of a residual elevation in presynaptic [Ca2+]i, acting on one or more molecular targets that appear to be distinct from the secretory trigger responsible for fast exocytosis and phasic release of transmitter to single action potentials. We discuss the evidence for this hypothesis, and the origins of the different kinetic phases...

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Short-Term Synaptic Plasticity

The ionotropic glutamate receptors are ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the brain. The cloning of cDNAs encoding glutamate receptor subunits, which occurred mainly between 1989 and 1992 ([Hollmann and Heinemann, 1994][1]), stimulated this

/pdf/the-glutamate-receptor-ion-channels-560mntczdb.pdf

The glutamate receptor ion channels

We describe the derivation of pluripotent embryonic stem (ES) cells from human blastocysts. Two diploid ES cell lines have been cultivated in vitro for extended periods while maintaining expression of markers characteristic of pluripotent primate cells. Human ES cells express the transcription factor Oct-4, essential for development of pluripotential cells in the mouse. When grafted into SCID mice, both lines give rise to teratomas containing derivatives of all three embryonic germ layers. Both cell lines differentiate in vitro into extraembryonic and somatic cell lineages. Neural progenitor cells may be isolated from differentiating ES cell cultures and induced to form mature neurons. Embryonic stem cells provide a model to study early human embryology, an investigational tool for discovery of novel growth factors and medicines, and a potential source of cells for use in transplantation therapy.

Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro.

Ecotoxicology of human pharmaceuticals.

This chapter discusses the gamma-aminobutyric acid (GABA) receptor channels, which are the most abundant inhibitory neurotransmitter in the CNS. Following release from presynaptic vesicles, GABA exerts fast inhibitory effects by interacting with GABA receptors, whose primary function is to hyperpolarize neuronal membranes in mature CNS neurons. GABA receptors are found both presynaptically, where they decrease the likelihood of neurotransmitter release, and postsynaptically, where they decrease the likelihood of neuronal firing. There are two types of GABA receptor, termed GABA A and GABA B receptors. GABA A receptors are fast-activating Clˉ channels from the Cys-loop family of ligand-gated ion channels. Activation of GABA A receptors causes membrane hyperpolarization by allowing Clˉ influx, reflecting the relatively low concentration of Clˉ found intracellularly in most adult CNS neurons. GABA A receptors can also mediate depolarizing responses in most immature CNS neurons and in mature peripheral neurons.

GABAA Receptor Channels

Generalized, tonic-clonic status epilepticus is well recognized as a common neurologic emergency requir- ing prompt treatment. The diagnosis is usually not diffi- cult, other than for patients with prolonged seizures, who often develop increasingly subtle clinical features (1,2). There also appears to be a consensus among physicians regarding treatment (3). Nonetheless, there is a major, persistent dilemma regarding status epilepticus: its defi- nition. Discussions concerning the precise definition of status epilepticus all too often result in agreement that current “textbook” definitions are either imprecise, at odds with clinical practice, or both. Here we propose a revised system for defining status epilepticus that ad- dresses these problems. References to status epilepticus prior to the mid- 19th century focused on cases in which seizures lasted many hours to days (4). In 1904, Clark and Prout (5) defined status epilepticus as a state in which seizures occur so frequently that ‘‘the coma and exhaustion are continuous between the seizures.” In his general textbook of neu- rology published in 1940, Kinnier Wilson (6) referred to status epilepticus as the severest form of seizures in which “the post-convulsive sleep of one attack is cut short by development of the next.” Aspects of these definitions were mirrored in the first International Clas- sification of Epileptic Seizures that was developed in 1964 by the International League Against Epilepsy (ILAE). Status epilepticus was defined as the situation in which “a seizure persists for a sufficient length of time or is repeated frequently enough to produce a fixed and enduring epileptic condition” (7). The same definition was retained in the revised classification published in 1970 (8), and it was modified slightly in 1981 to refer to the situation in which “a seizure persists for a sufficient length of time or is repeated frequently enough that re- covery between attacks does not occur” (9).

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It's Time to Revise the Definition of Status Epilepticus

Clinically used antiepileptic drugs (AEDs) decrease membrane excitability by interacting with ion channels or neurotransmitter receptors. Currently available AEDs appear to act on sodium channels, GABAA receptors, or calcium channels. Phenytoin, carbamazepine, and possibly valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing sodium channel inactivation. Benzodiazepines and barbiturates enhance GABAA receptor-mediated inhibition. Ethosuximide and possibly VPA reduce a low-threshold calcium current. The mechanisms of action of AEDs currently under development are less clear. Lamotrigine may decrease sustained high-frequency repetitive firing. The mechanisms of action of felbamate are unknown. Gabapentin (GBP) appears to bind to a specific binding site in the central nervous system with a restricted regional distribution, but the identity of the binding site and the mechanism of action of GBP remain uncertain.

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Antiepileptic Drug Mechanisms of Action

GABA is the principal inhibitory neurotransmitter in the CNS and acts via GABA(A) and GABA(B) receptors. Recently, a novel form of GABA(A) receptor-mediated inhibition, termed "tonic" inhibition, has been described. Whereas synaptic GABA(A) receptors underlie classical "phasic" GABA(A) receptor-mediated inhibition (inhibitory postsynaptic currents), tonic GABA(A) receptor-mediated inhibition results from the activation of extrasynaptic receptors by low concentrations of ambient GABA. Extrasynaptic GABA(A) receptors are composed of receptor subunits that convey biophysical properties ideally suited to the generation of persistent inhibition and are pharmacologically and functionally distinct from their synaptic counterparts. This mini-symposium review highlights ongoing work examining the properties of recombinant and native extrasynaptic GABA(A) receptors and their preferential targeting by endogenous and clinically relevant agents. In addition, it emphasizes the important role of extrasynaptic GABA(A) receptors in GABAergic inhibition throughout the CNS and identifies them as a major player in both physiological and pathophysiological processes.

https://www.jneurosci.org/content/jneuro/29/41/12757.full.pdf

Extrasynaptic GABAA Receptors: Form, Pharmacology, and Function

Fast synaptic inhibition in the forebrain is mediated primarily by GABA acting on GABAA receptors (GABARs). GABARs are regulated by numerous positive (barbiturates, benzodiazepines, and neurosteroids) and negative (picrotoxin, bicuculline, and Zn2+) allosteric modulators. The sensitivity of GABARs to GABA and to allosteric modulators changes gradually during normal development, during development of chronic epilepsy, and after prolonged exposure to GABAR agonists. Here we report the development of rapid functional plasticity of GABARs occurring over 45 min of continuous seizures (status epilepticus) in rats. Seizures induced in rats by administration of lithium followed by pilocarpine were readily terminated by the benzodiazepine diazepam when administered early during the seizures (after 10 min of seizures). However, during status epilepticus, there was a substantial reduction of diazepam potency for termination of the seizures. To determine whether the loss of sensitivity of the animals to diazepam was caused by an alteration of GABAR functional properties, we obtained whole-cell GABAR currents from hippocampal dentate granule cells isolated acutely from control rats and from rats undergoing status epilepticus. GABAR properties were characterized by determining GABA sensitivity and the sensitivity of GABARs to regulation by benzodiazepines, barbiturates, and Zn2+. When compared with those from naive controls, GABAR currents from rats undergoing status epilepticus were less sensitive to diazepam and Zn2+ but retained their sensitivity to GABA and pentobarbital. We conclude that the prolonged seizures of status epilepticus rapidly altered the functional properties of hippocampal dentate granule cell GABARs.

https://www.jneurosci.org/content/jneuro/17/19/7532.full.pdf

Robert L. Macdonald

Papers

GABAA Receptor Channels

It's Time to Revise the Definition of Status Epilepticus

Antiepileptic Drug Mechanisms of Action

Extrasynaptic GABAA Receptors: Form, Pharmacology, and Function

Rapid Seizure-Induced Reduction of Benzodiazepine and Zn2+ Sensitivity of Hippocampal Dentate Granule Cell GABAA Receptors