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

This book explains the relationship of electrophysiology, nonlinear dynamics, and the computational properties of neurons, with each concept presented in terms of both neuroscience and mathematics and illustrated using geometrical intuition In order to model neuronal behavior or to interpret the results of modeling studies, neuroscientists must call upon methods of nonlinear dynamics This book offers an introduction to nonlinear dynamical systems theory for researchers and graduate students in neuroscience It also provides an overview of neuroscience for mathematicians who want to learn the basic facts of electrophysiology "Dynamical Systems in Neuroscience" presents a systematic study of the relationship of electrophysiology, nonlinear dynamics, and computational properties of neurons It emphasizes that information processing in the brain depends not only on the electrophysiological properties of neurons but also on their dynamical properties The book introduces dynamical systems starting with one- and two-dimensional Hodgkin-Huxley-type models and continuing to a description of bursting systems Each chapter proceeds from the simple to the complex, and provides sample problems at the end The book explains all necessary mathematical concepts using geometrical intuition; it includes many figures and few equations, making it especially suitable for non-mathematicians Each concept is presented in terms of both neuroscience and mathematics, providing a link between the two disciplines Nonlinear dynamical systems theory is at the core of computational neuroscience research, but it is not a standard part of the graduate neuroscience curriculum - or taught by math or physics department in a way that is suitable for students of biology This book offers neuroscience students and researchers a comprehensive account of concepts and methods increasingly used in computational neuroscience

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Dynamical Systems in Neuroscience

https://www.cell.com/cell/pdf/S0092-8674(09)01243-4.pdf

Cellular and Molecular Mechanisms of Pain

中枢神経系疾患の治療は正常細胞（ニューロン）の機能維持を目的とするが，脳血管障害のように機能障害の原因が細胞の死滅に基づくことは多い．一方，脳腫瘍の治療においては薬物療法や放射線療法といった腫瘍細胞の死滅を目標とするものが大きな位置を占める．いずれの場合にも，細胞死の機序を理解することは各種病態や治療法の理解のうえで重要である．現在のところ最も研究の進んでいる細胞死の型はアポトーシスである．そのなかで重要な位置を占めるミトコンドリアにおける反応および抗アポトーシス因子について概要を紹介する．

Neuroscience 細胞死：最近の知見

There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABAB1b mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABAAα2 mRNA expression in the prefrontal cortex and amygdala, but increased GABAAα2 in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut–brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.

https://www.pnas.org/content/pnas/108/38/16050.full.pdf

Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.

GABAA (γ-aminobutyric acidA) receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from the spectrum of actions elicited by clinically effective drugs acting at their modulatory benzodiazepine-binding site. Here we show, by introducing a histidine-to-arginine point mutation at position 101 of the murine α1-subunit gene, that α1-type GABAA receptors, which are mainly expressed in cortical areas and thalamus1, are rendered insensitive to allosteric modulation by benzodiazepine-site ligands, whilst regulation by the physiological neurotransmitter γ-aminobutyric acid is preserved. α1(H101R) mice failed to show the sedative, amnesic and partly the anticonvulsant action of diazepam. In contrast, the anxiolytic-like, myorelaxant, motor-impairing and ethanol-potentiating effects were fully retained, and are attributed to the nonmutated GABAA receptors found in the limbic system (α2, α5), in monoaminergic neurons (α3) and in motoneurons (α2, α5)1. Thus, benzodiazepine-induced behavioural responses are mediated by specific GABAA receptor subtypes in distinct neuronal circuits, which is of interest for drug design.

Benzodiazepine actions mediated by specific γ-aminobutyric acid A receptor subtypes

Benzodiazepine tranquilizers are used in the treatment of anxiety disorders. To identify the molecular and neuronal target mediating the anxiolytic action of benzodiazepines, we generated and analyzed two mouse lines in which the alpha2 or alpha3 GABAA (gamma-aminobutyric acid type A) receptors, respectively, were rendered insensitive to diazepam by a knock-in point mutation. The anxiolytic action of diazepam was absent in mice with the alpha2(H101R) point mutation but present in mice with the alpha3(H126R) point mutation. These findings indicate that the anxiolytic effect of benzodiazepine drugs is mediated by alpha2 GABAA receptors, which are largely expressed in the limbic system, but not by alpha3 GABAA receptors, which predominate in the reticular activating system.

https://science.sciencemag.org/content/sci/290/5489/131.full.pdf

Molecular and neuronal substrate for the selective attenuation of anxiety.

Although general anaesthesia has been of tremendous importance for the development of surgery, the underlying mechanisms by which this state is achieved are only just beginning to be understood in detail. In this review, we describe the neuronal systems that are thought to be involved in mediating clinically relevant actions of general anaesthetics, and we go on to discuss how the function of individual drug targets, in particular GABA(A)-receptor subtypes, can be revealed by genetic studies in vivo.

Molecular and neuronal substrates for general anaesthetics.

Classical benzodiazepine drugs are in wide clinical use as anxiolytics, hypnotics, anticonvulsants, and muscle relaxants. They act by enhancing the γ-aminobutyric acid A (GABA A ) receptor function in the central nervous system. The pharmacological relevance of the multitude of structurally diverse GABA A receptor subtypes has only recently been identified. Based on an in vivo point mutation strategy, α 1 -GABA A receptors were found to mediate sedation, anterograde amnesia, and part of the seizure protection, whereas α 2 -GABA A receptors, but not α 3 -receptors, mediate anxiolysis. Rational drug targeting to specific receptor subtypes has now become possible. Only restricted neuronal networks will be modulated by the new subtype-selective drugs. Promising new anxiolytics have already been developed. A new pharmacology of the benzodiazepine site is on the horizon.

A New Benzodiazepine Pharmacology

The identification of physiological and pharmacological functions of GABAA (γ-aminobutyric acid, type A) receptor subtypes has renewed the interest in the GABAA receptor system as a target for the development of non-sedating anxiolytics, as well as of drugs for indications that are distinct from those of classical benzodiazepines, such as analgesia, schizophrenia and depression.

/pdf/beyond-classical-benzodiazepines-novel-therapeutic-potential-45twhzo9gn.pdf

Uwe Rudolph

Papers

Benzodiazepine actions mediated by specific γ-aminobutyric acid A receptor subtypes

Molecular and neuronal substrate for the selective attenuation of anxiety.

Molecular and neuronal substrates for general anaesthetics.

A New Benzodiazepine Pharmacology

Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes.