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

Despite the concern that has been expressed about potential method biases, and the pervasiveness of research settings with the potential to produce them, there is disagreement about whether they really are a problem for researchers in the behavioral sciences. Therefore, the purpose of this review is to explore the current state of knowledge about method biases. First, we explore the meaning of the terms “method” and “method bias” and then we examine whether method biases influence all measures equally. Next, we review the evidence of the effects that method biases have on individual measures and on the covariation between different constructs. Following this, we evaluate the procedural and statistical remedies that have been used to control method biases and provide recommendations for minimizing method bias.

Sources of Method Bias in Social Science Research and Recommendations on How to Control It

The lion's share of bacteria in various environments cannot be cloned in the laboratory and thus cannot be sequenced using existing technologies. A major goal of single-cell genomics is to complement gene-centric metagenomic data with whole-genome assemblies of uncultivated organisms. Assembly of single-cell data is challenging because of highly non-uniform read coverage as well as elevated levels of sequencing errors and chimeric reads. We describe SPAdes, a new assembler for both single-cell and standard (multicell) assembly, and demonstrate that it improves on the recently released E+V-SC assembler (specialized for single-cell data) and on popular assemblers Velvet and SoapDeNovo (for multicell data). SPAdes generates single-cell assemblies, providing information about genomes of uncultivatable bacteria that vastly exceeds what may be obtained via traditional metagenomics studies. SPAdes is available online ( http://bioinf.spbau.ru/spades ). It is distributed as open source software.

SPAdes, a new genome assembly algorithm and its applications to single-cell sequencing ( 7th Annual SFAF Meeting, 2012)

An MRI time course of 512 echo-planar images (EPI) in resting human brain obtained every 250 ms reveals fluctuations in signal intensity in each pixel that have a physiologic origin. Regions of the sensorimotor cortex that were activated secondary to hand movement were identified using functional MRI methodology (FMRI). Time courses of low frequency (< 0.1 Hz) fluctuations in resting brain were observed to have a high degree of temporal correlation (P < 10(-3)) within these regions and also with time courses in several other regions that can be associated with motor function. It is concluded that correlation of low frequency fluctuations, which may arise from fluctuations in blood oxygenation or flow, is a manifestation of functional connectivity of the brain.

Functional connectivity in the motor cortex of resting human brain using echo-planar MRI.

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within ...

The Microbiota-Gut-Brain Axis

Stimulation of target cells using light, e.g., in vivo or in vitro, is implemented using a variety of methods and devices. One example involves a vector for delivering a light-activated NpHR-based molecule comprising a nucleic acid sequence that codes for light-activated NpHR-based molecule and a promoter. Either a high expression of the molecule manifests a toxicity level that is less than about 75%, or the light-activated NpHR-based proteins are expressed using at least two NpHR-based molecular variants. Each of the variants characterized in being useful for expressing a light-activated NpHR-based molecule that responds to light by producing an inhibitory current to dissuade depolarization of the neuron. Other aspects and embodiments are directed to systems, methods, kits, compositions of matter and molecules for ion pumps or for controlling inhibitory currents in a cell (e.g., in in vivo and in vitro environments).

Method for optically controlling a neuron with a mammalian codon optimized nucleotide sequence that encodes a variant opsin polypeptide derived from natromonas pharaonis (NpHR)

The application of recombinant Adeno-Associated Virus (rAAV) vectors as gene delivery vehicles has been limited by the modest packaging capacity (5.2kb) of rAAV. Th is limitation is imposed by the capsid size of 25nm diameter, which is determined by the capsid’s T=1 icosahedral geometry. Current methods for rAAV delivery of oversized cargo, typically involving co-delivery of dual vectors, suffer from challenges such as low efficiency in co-infection and reassembly of full-length products, indefinite ratios of the two vectors in individual cells, and necessity of re-design and re-validation for every new cargo. 

Inspired by the size polymorphism observed in natural viruses, we hypothesized that the T=1 icosahedral geometry of AAV capsids could be changed so that each capsid is built from more than 60 subunits. 

Here we present two rational design strategies that lead to eXtra Large AAV capsids (XL-AAVs). Th ese strategies involve modifying the intersubunit interactions and the assembly pathway of AAV capsids. Capsids engineered through both strategies form heterogeneous, 35nm-70nm spherical particles (Figure 1). Th e XL-AAV capsids can still package rAAV genomes, and the same protein design principles can be applied across multiple serotypes we tested (including AAV9, AAV2, AAV5, and AAVDJ). Ongoing work seeks to determine whether the XL-AAV capsids can fully protect and deliver conventionally oversized rAAV genomes. These design principles and the emerging XL-AAV capsids represent the first steps towards creating rAAV vectors with larger clone capacities, opening a path towards the delivery of disease-related genes and genetically-encoded tools with long coding sequences in single rAAV vectors.

Structure-Guided Rational Design of Adeno-Associated Viral Capsids with Expanded Sizes

Copy number variations, and particularly duplications of genomic regions, have been strongly associated with various neurodegenerative conditions including autism spectrum disorder (ASD). These genetic variations have been found to have a significant impact on brain development and function, which can lead to the emergence of neurological and behavioral symptoms. Developing strategies to target these genomic duplications has been challenging, as the presence of endogenous copies of the duplicate genes often complicates the editing strategies. Using the ASD and anxiety mouse model Flailer, that contains a duplication working as a dominant negative for MyoVa, we demonstrate the use of DN-CRISPRs to remove a 700bp genomic duplication in vitro and in vivo. Importantly, DN-CRISPRs have not been used to remove more gene regions <100bp successfully and with high efficiency. We found that editing the flailer gene in primary cortical neurons reverts synaptic transport and transmission defects. Moreover, long-term depression (LTD), disrupted in Flailer animals, is recovered after gene edition. Delivery of DN-CRISPRs in vivo shows that local delivery to the ventral hippocampus can rescues some of the mutant behaviors, while intracerebroventricular delivery, completely recovers Flailer animal phenotype associated to anxiety and ASD. Our results demonstrate the potential of DN-CRISPR to efficiently (>60% editing in vivo) remove large genomic duplications, working as a new gene therapy approach for treating neurodegenerative diseases.

/pdf/removal-of-a-genomic-duplication-by-double-nicking-crispr-2ev9be06.pdf

Removal of a genomic duplication by double-nicking CRISPR restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer

Immediate Responses to Ambient Light in the Suprachiasmatic Nucleus Reveal Distinct Activity Profiles and Retinal Connectivity for SCN VIP Neurons

Adeno-Associated Viral Gene Therapy Using PHP.B:NPC1 Ameliorates Disease Phenotype in Mouse Model of Niemann-Pick C1 Disease

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Method for optically controlling a neuron with a mammalian codon optimized nucleotide sequence that encodes a variant opsin polypeptide derived from natromonas pharaonis (NpHR)

Structure-Guided Rational Design of Adeno-Associated Viral Capsids with Expanded Sizes

Removal of a genomic duplication by double-nicking CRISPR restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer

Immediate Responses to Ambient Light in the Suprachiasmatic Nucleus Reveal Distinct Activity Profiles and Retinal Connectivity for SCN VIP Neurons

Adeno-Associated Viral Gene Therapy Using PHP.B:NPC1 Ameliorates Disease Phenotype in Mouse Model of Niemann-Pick C1 Disease