Comparative analyses of multi-species sequences from targeted genomic regions

The systematic comparison of genomic sequences from different organisms represents a central focus of contemporary genome analysis. Comparative analyses of vertebrate sequences can identify coding and conserved non-coding regions, including regulatory elements, and provide insight into the forces that have rendered modern-day genomes. As a complement to whole-genome sequencing efforts, we are sequencing and comparing targeted genomic regions in multiple, evolutionarily diverse vertebrates. Here we report the generation and analysis of over 12 megabases (Mb) of sequence from 12 species, all derived from the genomic region orthologous to a segment of about 1.8 Mb on human chromosome 7 containing ten genes, including the gene mutated in cystic fibrosis. These sequences show conservation reflecting both functional constraints and the neutral mutational events that shaped this genomic region. In particular, we identify substantial numbers of conserved non-coding segments beyond those previously identified experimentally, most of which are not detectable by pair-wise sequence comparisons alone. Analysis of transposable element insertions highlights the variation in genome dynamics among these species and confirms the placement of rodents as a sister group to the primates.     

杨树泛基因组构建与基因组变异分析

【目的】杨树是重要的速生用材、生态防护和碳汇造林树种,也是林木遗传研究的模式树种。开展杨树泛基因组构建与基因组变异分析,可为杨树精准育种和林木泛基因组研究提供理论先导。【方法】 以公开发表的高质量杨树基因组序列为基础,分析不同类型的序列变异,总结变异特征,并构建基于基因和图形结构的杨树泛基因组。【结果】 本研究收集到8个杨属树种和3个二倍体或三倍体杨树杂交品种的基因组序列,3个杂交品种包含7个单倍型亚基因组序列,较好地代表了杨树4个组派的基因组特征。分析结果表明,杨树基因组间存在较多大的结构变异。在基于基因的泛基因组中,共线核心基因、非共线核心基因、次核心基因、非必需基因、特异基因占比分别为12.5%、34.9%、31.4%、16.5%、4.7%。其中,非必需基因在功能上具有较高的多样性。以基因组序列变异为基础构建杨树图形结构泛基因组,大幅提升2代测序数据的变异检测效果。通过泛基因组变异热点分析,鉴定出2个与物候关联的基因位点。【结论】 杨属基因组中存在大量染色体重排,进而增加了基因调控的多样性。杨树组/派间的基因组结构变异可能与物候适应存在关联。基于林木基因组序列的复杂性,在林木泛基因组研究中应注意基因组整合范围与研究目标相匹配,结合基因泛基因组和图形结构泛基因组结果,综合解析林木的遗传变异规律和物种演化特征。     

Epigenetics in human disease and prospects for epigenetic therapy

Epigenetic mechanisms, which involve DNA and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. The study of human disease has focused on genetic mechanisms, but disruption of the balance of epigenetic networks can cause several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. Great potential lies in the development of 'epigenetic therapies'--several inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and histone deacetylases, have shown promising anti-tumorigenic effects for some malignancies.     

纳米材料在基因治疗中的研究进展:从肿瘤治疗到新冠病毒疫苗

基因治疗作为一种精准有效的策略,可用于治疗包括癌症在内的多种疾病以及预防病毒性感染疾病．然而,基因治疗中使用的核酸药物自身不稳定性和大尺寸阻碍了它们的广泛应用．纳米材料因其免疫原性低、可控性好、易于进行表面修饰等特点,已被证明是基因治疗中最有前途的载体之一．特别是新型冠状病毒肺炎（COVID-19）疫情爆发以来,与传统疫苗不同的mRNA疫苗备受关注,而脂质纳米颗粒（LNP）作为该疫苗的递送系统发挥了至关重要的作用,展现了纳米材料巨大的应用前景．本文概述了基因治疗的主要类型;介绍了基于脂质的纳米颗粒、基于聚合物的纳米颗粒、无机纳米颗粒及新型纳米材料如碳点等核酸递送平台;强调了其在肿瘤治疗和COVID-19核酸疫苗中的最新研究进展;提出了纳米材料用于基因治疗的挑战与前景．      

黄瓜花叶病毒小青菜分离物RNA3全长序列分析

对侵染十字花科小青菜的黄瓜花叶病毒YN分离物（CMV-YN）RNA3进行全长克隆和序列分析．CMV-YNRNA3全长2220nt,分别编码279个氨基酸的3a蛋白和218个氨基酸的CP．序列同源性比较结果如下;CMV-YNRNA3核苷酸及其编码蛋白的氨基酸序列与亚组IA株系CMV-Fny、亚组IB株系CMV-Nt9、亚组Ⅱ株系CMV-Q的同源性,RNA3序列分别为92．7％、96．7％、74．2％,3a蛋白氨基酸序列分别为96．4％、98．6％、83．2％,CP氨基酸序列分别为97．7％、98．2％、83．1％．该结果表明CMV-YN与亚组IB株系CMV-Nt9的同源关系更密切．对CP核苷酸序列的系统进化树分析表明：CMV-YN归属于亚组IB,本研究为首次报道侵染我国十字花科植物的CMV基因组序列．     

A novel cancer therapy using a M?ssbauer-isotope compound

Cancer radiotherapy uses high doses of ionizing radiation (1-10(2) Gy; 10(2)-10(4) rad) because only a small fraction of the absorbed dose leads to lethal double-strand breaks in DNA. These breaks are more efficiently produced by Auger electrons (1-10 eV nm-1) generated in proximity to the DNA. The energy of these electrons (on average 21 electrons for the decay of 125I) is dissipated within 10-100 nm of the Auger event and produces multiple double-strand DNA breaks. A single Auger event can be lethal to a cell and is comparable to more than 10(5) photon absorption events in conventional radiotherapy. We now report that 57Fe(III).bleomycin, administered to malignant cells in vitro and in vivo and irradiated with resonant M?ssbauer gamma rays (14.4 keV), causes ablation of the malignant cells, presumably by Auger cascade, with extremely small radiation doses--about 10(-5) Gy. As a basis for comparison, about 5 Gy is necessary to achieve a similar effect with conventional radiotherapy.     

A Polycomb-based switch underlying quantitative epigenetic memory

The conserved Polycomb repressive complex 2 (PRC2) generates trimethylation of histone 3 lysine 27 (H3K27me3), a modification associated with stable epigenetic silencing. Much is known about PRC2-induced silencing but key questions remain concerning its nucleation and stability. Vernalization, the perception and memory of winter in plants, is a classic epigenetic process that, in Arabidopsis, involves PRC2-based silencing of the floral repressor FLC. The slow dynamics of vernalization, taking place over weeks in the cold, generate a level of stable silencing of FLC in the subsequent warm that depends quantitatively on the length of the prior cold. These features make vernalization an ideal experimental system to investigate both the maintenance of epigenetic states and the switching between them. Here, using mathematical modelling, chromatin immunoprecipitation and an FLC:GUS reporter assay, we show that the quantitative nature of vernalization is generated by H3K27me3-mediated FLC silencing in the warm in a subpopulation of cells whose number depends on the length of the prior cold. During the cold, H3K27me3 levels progressively increase at a tightly localized nucleation region within FLC. At the end of the cold, numerical simulations predict that such a nucleation region is capable of switching the bistable epigenetic state of an individual locus, with the probability of overall FLC coverage by silencing H3K27me3 marks depending on the length of cold exposure. Thus, the model predicts a bistable pattern of FLC gene expression in individual cells, a prediction we verify using the FLC:GUS reporter system. Our proposed switching mechanism, involving the local nucleation of an opposing histone modification, is likely to be widely relevant in epigenetic reprogramming.     

A nuclear Argonaute promotes multigenerational epigenetic inheritance and germline immortality

Epigenetic information is frequently erased near the start of each new generation. In some cases, however, epigenetic information can be transmitted from parent to progeny (multigenerational epigenetic inheritance). A particularly notable example of this type of epigenetic inheritance is double-stranded RNA-mediated gene silencing in Caenorhabditis elegans. This RNA-mediated interference (RNAi) can be inherited for more than five generations. To understand this process, here we conduct a genetic screen for nematodes defective in transmitting RNAi silencing signals to future generations. This screen identified the heritable RNAi defective 1 (hrde-1) gene. hrde-1 encodes an Argonaute protein that associates with small interfering RNAs in the germ cells of progeny of animals exposed to double-stranded RNA. In the nuclei of these germ cells, HRDE-1 engages the nuclear RNAi defective pathway to direct the trimethylation of histone H3 at Lys?9 (H3K9me3) at RNAi-targeted genomic loci and promote RNAi inheritance. Under normal growth conditions, HRDE-1 associates with endogenously expressed short interfering RNAs, which direct nuclear gene silencing in germ cells. In hrde-1- or nuclear RNAi-deficient animals, germline silencing is lost over generational time. Concurrently, these animals exhibit steadily worsening defects in gamete formation and function that ultimately lead to sterility. These results establish that the Argonaute protein HRDE-1 directs gene-silencing events in germ-cell nuclei that drive multigenerational RNAi inheritance and promote immortality of the germ-cell lineage. We propose that C. elegans use the RNAi inheritance machinery to transmit epigenetic information, accrued by past generations, into future generations to regulate important biological processes.     

新型均苯型芳香族聚酰亚胺的研究

以二步法制备了一种新型均苯型芳香族聚酰亚胺。测定了聚酰亚胺的预聚体－－聚酰胺酸特性粘度（Iυ）随反应时间的变化曲线，聚酰亚胺以N－甲基－2－吡咯烷酮（NMP）中的特性粘度在1.2dL/g左右，玻璃化温度高于250℃，在氧气中失重5％的温度在500℃以上。经红外光谱测定，样品在1780cm^-1和1380cm^-1附近观察到聚酰亚胺的特征峰。     

A genomic view of immunology

The outstanding problems facing immunology are whole system issues: curing allergic and autoimmune disease and developing vaccines to stimulate stronger immune responses against pathogenic organisms and cancer. We hope that the human genome sequence will reveal the molecular checks and balances that ensure both an effective immunogenic response against pathogenic microorganisms and a suitably tolerogenic response to self antigens and innocuous environmental antigens. Three synergistic approaches--sequence homology searches, messenger RNA expression profiling on microarrays, and mutagenesis in mice--provide the best opportunities to reveal, in the genome sequence, key proteins and pathways for targeting by new immunomodulatory treatments.     

L-精氨、5-氟脲嘧啶对艾氏腹水癌鼠的治疗分析

将１００只小白鼠制成ＥＡＣ模型鼠,随机分成四组,分别向腹腔注射Ｌ－精氨酸、５－氟脲嘧啶、Ｌ－精氨酸＋５氟脲嘧啶、生国水、同时记录各组小鼠自然存活时间、处死时平均腹水量、每毫升腹水中肿瘤细胞数、接种ＥＡＣ细胞两周后平均体重,以探讨Ｌ－精氨酸、５－氟脲嘧啶对艾氏腹水癌小鼠的治疗效果。实验结果显示：Ｌ精氨酸＋５氟脲嘧啶组小鼠自然存活时间最长,无腹水。说明两者联合使用具有一定抗癌作用,而且延长了ＥＡＣ小鼠     

Genetic and structural analyses suggest that a novel SPG3A mutation causes severe phenotypes of hereditary spastic paraplegia

Hereditary spastic paraplegia (HSP) (MIM# 182600, etc.) is a group of heterogeneous neurodegenerative disorders, characterized by lower limb spasticity, hy- perreflexia, progressive spastic gait abnormalities and an extensor-plantar response[1]. The genot…     

A novel method for tracking pedestrians from real-time video

This novel method of Pedestrian Tracking using Support Vector (PTSV) proposed for a video surveillance instrument combines the Support Vector Machine (SVM) classifier into an optic-flow based tracker. The traditional method using optical flow tracks objects by minimizing an intensity difference function between successive frames, while PTSV tracks objects by maximizing the SVM classification score. As the SVM classifier for object and non-object is pre-trained, there is need only to classify an image block as object or non-ob-ject without having to compare the pixel region of the tracked object in the previous frame. To account for large motions between successive frames we build pyramids from the support vectors and use a coarse-to-fine scan in the classification stage. To accelerate the training of SVM, a Sequential Minimal Optimization Method (SMO) is adopted. The results of using a kernel-PTSV for pedestrian tracking from real time video are shown at the end. Comparative experimental results showed that PTSV improves the reliability of tracking compared to that of traditional tracking method using optical flow.     

一种从已调信号产生系统时钟的新方法

介绍一种从调频信号中获取系统时钟的新方法,该方法是在分频器中应用调制补偿、及Σ△抖动技术。应用该技术,基于全数字锁相环的调频广播发射机可以产生更高频率的时钟信号,以用于基带信号处理。