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

Chromatin Modifications and Their Function

Chromatin, the physiological template of all eukaryotic genetic information, is subject to a diverse array of posttranslational modifications that largely impinge on histone amino termini, thereby regulating access to the underlying DNA. Distinct histone amino-terminal modifications can generate synergistic or antagonistic interaction affinities for chromatin-associated proteins, which in turn dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states. The combinatorial nature of histone amino-terminal modifications thus reveals a “histone code” that considerably extends the information potential of the genetic code. We propose that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.

/pdf/translating-the-histone-code-l291mddcr9.pdf

Translating the Histone Code

The GABAergic neurotransmission is a highly conserved system that has been attributed to various regulatory events. There has been a notable number of studies on the importance of GABAergic neurotrans

/pdf/epigenetic-regulations-of-gabaergic-neurotransmission-5aszwmn24m.pdf

Epigenetic Regulations of GABAergic Neurotransmission: Relevance for Neurological Disorders and Epigenetic Therapy

The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved small protein. Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation, and endocytosis. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Abnormalities in ubiquitin-mediated processes have been shown to cause pathological conditions, including malignant transformation. In this review we discuss recent information on functions and mechanisms of the ubiquitin system. Since the selectivity of protein degradation is determined mainly at the stage of ligation to ubiquitin, special attention is focused on what we know, and would like to know, about the mode of action of ubiquitin-protein ligation systems and about signals in proteins recognized by these systems.

The Ubiquitin System

Similar to direct RNA labeling, direct DNA labeling with Cy-dCTP is the simplest and fastest method for labeling DNA. This is a standard Klenow labeling protocol in which Cy-dCTP is incorporated during the labeling reaction. After stopping the reaction, labeled nucleotide is separated from unreacted Cy-dCTP, and Cy3- and Cy5-labeled materials are combined for hybridization. This protocol is suitable for many applications, including detection of copy-number variation, nucleosome mapping, and other location analysis (e.g., chromatin immunoprecipitation [ChIP]-chip).

Direct Cyanine-dCTP Labeling of DNA for Microarrays

As with RNA labeling protocols, the main difference between direct and indirect DNA labeling protocols is a trade-off of cost and time. Indirect labeling of DNA, described here, takes ∼2 h longer than direct labeling but is hundreds of dollars cheaper.

Indirect Labeling of DNA for Microarrays.

The development of tools to manipulate the mouse genome, including knockout and transgenic technology, revolutionized our ability to explore gene function in mammals. Moreover, for genes that are expressed in multiple tissues or at multiple stages of development, the use of tissue-specific expression of the Cre recombinase allows gene function to be perturbed in specific cell types and/or at specific times. However, it is well known that putative tissue-specific promoters often drive unanticipated “off target” expression. In our efforts to explore the biology of the male reproductive tract, we unexpectedly found that expression of Cre in the central nervous system resulted in recombination in the epididymis, a tissue where sperm mature for ~1-2 weeks following the completion of testicular development. Remarkably, we not only observed reporter expression in the epididymis when Cre expression was driven from neuron-specific transgenes, but also when Cre expression in the brain was induced from an AAV vector carrying a Cre expression construct. A surprisingly wide range of Cre drivers – including six different neuronal promoters as well as the adipose-specific AdipoQ Cre promoter – exhibited off target recombination in the epididymis, with a subset of drivers also exhibiting unexpected activity in other tissues such as the reproductive accessory glands. Finally, using a combination of parabiosis and serum transfer experiments, we find evidence supporting the hypothesis that Cre may be trafficked from its cell of origin to the epididymis through the circulatory system. Together, our findings should motivate extreme caution when interpreting conditional alleles, and suggest the exciting possibility of inter-tissue RNA or protein trafficking in modulation of reproductive biology.

Evidence for RNA or protein transport from somatic tissues to the male reproductive tract in mouse

Competitive hybridization of labeled nucleic acids to a microarray is conceptually similar to other hybridization methods, such as Southern blotting. For massively multiplexed microarrays, the adoption of two-color hybridization schemes has been a significant advance. The use of two colors-typically Cy3- and Cy5-labeled nucleic acids-makes it possible to control for factors that affect hybridization intensity, including the number of labeled nucleotides and the T m of each oligonucleotide. Thus, the difference in intensity among spots on a microarray can be quantified and analyzed to assess biological phenomena, like changes in gene expression or details of transcript structure. This protocol for hybridization is conceptually straightforward-"cold" (nonfluorescent) blocking nucleotide is added to the mixed nucleic acid material, Hybridization buffer is added, and the mixture is applied to the microarray surface. Hybridization occurs overnight, after which the microarray is washed and scanned.

Hybridization to Homemade Microarrays

Homemade microarrays are printed on polylysine-coated slides. The lysines form a positively charged surface that can bind nonspecifically to the acidic nucleic acids during hybridization, resulting in significant background fluorescence. Thus, a key step in microarray processing is blocking all of the surface lysines not associated with the oligonucleotides in the microarray spots. In this protocol, the e-amino group of lysine is succinylated by reacting with succinic anhydride. The procedure is straightforward. Microarrays are, if necessary, rehydrated; excess liquid is removed by drying at a moderate temperature; and the succinylation reaction is performed. After the reaction is complete, the slides are washed and dried with ethanol, at which point they are ready for hybridization or they can be stored in a desiccator.

Blocking Polylysines on Homemade Microarrays.

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