寄生虫生物学冲压通过液泡膜
Some apicomplexan parasites, including Toxoplasma gondii and Plasmodium falciparum, replicate within parasitophorous vacuoles (PVs) after invading the host cell. Amino acids and other metabolites that are essential for parasite growth are delivered to the PV by transport through its membrane, which is made
在裂纹扩展的小于一微米斯石英断裂阻力大增
The development of strong, tough, and damage-tolerant ceramics requires nano/microstructure design to utilize toughening mechanisms operating at different length scales. The toughening mechanisms so far known are effective in micro-scale, then, they require the crack extension of more than a few micrometers to increase the fracture resistance. Here, we developed a micro-mechanical test method using micro-cantilever beam specimens to determine the very early part of resistance-curve of nanocrystalline SiO2 stishovite, which exhibited fracture-induced amorphization. We revealed that this novel toughening mechanism was effective even at length scale of nanometer due to narrow transformation zone width of a few tens of nanometers and large dilatational strain (from 60 to 95%) associated with the transition of crystal to amorphous state. This testing method will be a powerful tool to search for toughening mechanisms that may operate at nanoscale for attaining both reliability and strength of structural materials.
抗菌药物：调整抗真菌药物
Resistance to the antifungal drug Amphotericin B (AmB) has not evolved but it is extremely toxic to humans. AmB extracts the fungal sterol ergosterol from fungal membranes and its toxicity probably results from cross-reactivity with human cholesterol. Davis et al. designed a new class
微生物：用于恢复本能
Childhood diarrhoea is associated with infection of the gut by pathogens such as Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC), but how the gut microbiota recovers post infection is incompletely understood. David et al. analysed the microbiome of rectal samples from 13
探讨了表面活性剂对斑马鱼胚胎和幼虫不同类型的影响
Currently, surfactants are widely distributed in the environment. As organic pollutants, their toxicities have drawn extensive attention. In this study, the effects of anionic [sodium dodecyl sulphate (SDS) ], cationic [dodecyl dimethyl benzyl ammonium chloride (1227)] and non-ionic [fatty alcohol polyoxyethylene ether (AEO) ] surfactants on zebrafish larval behaviour were evaluated. Five behavioural parameters were recorded using a larval rest/wake assay, including rest total, number of rest bouts, rest bouts length, total activity and waking activity. The results revealed that 1227 and AEO at 1 μg/mL were toxic to larval locomotor activity and that SDS had no significant effects. Moreover, we tested the toxicities of the three surfactants in developing zebrafish embryos. AEO exposure resulted in smaller head size, smaller eye size and shorter body length relative to SDS and 1227. All three surfactants incurred concentration-dependent responses. Furthermore, in situ hybridisation indicated that smaller head size may be associated with a decreased expression of krox20. The altered expression of ntl demonstrated that the developmental retardation stemmed from inhibited cell migration and growth. These findings provide references for ecotoxicological assessments of different types of surfactants, and play a warning role in the application of surfactants.
在里德伯相位调制波多穿混合过程
We study the enhancement and suppression of different multi-waving mixing (MWM) processes in a Rydberg-EIT rubidium vapor system both theoretically and experimentally. The nonlinear dispersion property of hot rubidium atoms is modulated by the Rydberg-Rydberg interaction, which can result in a nonlinear phase shift of the relative phase between dark and bright states. Such Rydberg-induced nonlinear phase shift can be quantitatively estimated by the lineshape asymmetry in the enhancedand suppressed MWM processes, which can also demonstrate the cooperative atom-light interaction caused by Rydberg blockaded regime. Current study on phase shift is applicable to phase-sensitive detection and the study of strong Rydberg-Rydberg interaction.
通过表达蛋白质组学功能目标识别（fitexp）揭示了靶蛋白和小分子药物作用机制集锦
Phenomenological screening of small molecule libraries for anticancer activity yields potentially interesting candidate molecules, with a bottleneck in the determination of drug targets and the mechanism of anticancer action. We have found that, for the protein target of a small-molecule drug, the abundance change in late apoptosis is exceptional compared to the expectations based on the abundances of co-regulated proteins. Based on this finding, a novel method to drug target deconvolution is proposed. In a proof of principle experiment, the method yielded known targets of several common anticancer agents among a few (often, just one) likely candidates identified in an unbiased way from cellular proteome comprising more than 4,000 proteins. A validation experiment with a different set of cells and drugs confirmed the findings. As an additional benefit, mapping most specifically regulated proteins on known protein networks highlighted the mechanism of drug action. The new method, if proven to be general, can significantly shorten drug target identification, and thus facilitate the emergence of novel anticancer treatments.
在HIV-1传播的瓶颈：从创始人病毒研究的见解
HIV-1 infection typically results from the transmission of a single viral variant, the transmitted/founder (T/F) virus. Studies of these HIV-1 variants provide critical information about the transmission bottlenecks and the selective pressures acting on the virus in the transmission fluid and in the recipient tissues.
分散的误解和识别“土壤微生物生态组学”的机会
Technological advances are enabling the sequencing of environmental DNA and RNA at increasing depth and with decreasing costs. Metagenomic and transcriptomic analysis of soil microbial communities and the assembly of 'population genomes' from soil DNA are therefore now feasible. Although the value of such 'omic'
网站的f-recruitment ERK2驱动底物磷酸化的结构和动态特征
The F-recruitment site (FRS) of active ERK2 binds F-site (Phe-x-Phe-Pro) sequences found downstream of the Ser/Thr phospho-acceptor on cellular substrates. Here we apply NMR methods to analyze the interaction between active ERK2 (ppERK2), and a 13-residue F-site-bearing peptide substrate derived from its cellular target, the transcription factor Elk-1. Our results provide detailed insight into previously elusive structural and dynamic features of FRS/F-site interactions and FRS-driven substrate phosphorylation. We show that substrate F-site engagement significantly quenches slow dynamics involving the ppERK2 activation-loop and the FRS. We also demonstrate that the F-site phenylalanines make critical contacts with ppERK2, in contrast to the proline whose cis-trans isomerization has no significant effect on F-site recognition by the kinase FRS. Our results support a mechanism where phosphorylation of the disordered N-terminal phospho-acceptor is facilitated by its increased productive encounters with the ppERK2 active site due to docking of the proximal F-site at the kinase FRS.
通过高通量率测定量化域配体的亲和力和特异性
This paper reports an approach to measure equilibrium binding affinities for interacting proteins in high throughput, allowing the rapid and quantitative profiling of the specificity of interaction motifs.
同源性较大的蛋白质的化学位移引导建模
An NMR chemical shift–guided protein alignment method is combined with a comparative modeling pipeline to readily solve structures of large proteins.
文本挖掘有利于数据库管理-从生物医学文献中提取突变疾病的关联
Background: Advances in the next generation sequencing technology has accelerated the pace of individualized medicine (IM), which aims to incorporate genetic/genomic information into medicine. One immediate need in interpreting sequencing data is the assembly of information about genetic variants and their corresponding associations with other entities (e.g., diseases or medications). Even with dedicated effort to capture such information in biological databases, much of this information remains ‘locked’ in the unstructured text of biomedical publications. There is a substantial lag between the publication and the subsequent abstraction of such information into databases. Multiple text mining systems have been developed, but most of them focus on the sentence level association extraction with performance evaluation based on gold standard text annotations specifically prepared for text mining systems. Results: We developed and evaluated a text mining system, MutD, which extracts protein mutation-disease associations from MEDLINE abstracts by incorporating discourse level analysis, using a benchmark data set extracted from curated database records. MutD achieves an F-measure of 64.3 % for reconstructing protein mutation disease associations in curated database records. Discourse level analysis component of MutD contributed to a gain of more than 10 % in F-measure when compared against the sentence level association extraction. Our error analysis indicates that 23 of the 64 precision errors are true associations that were not captured by database curators and 68 of the 113 recall errors are caused by the absence of associated disease entities in the abstract. After adjusting for the defects in the curated database, the revised F-measure of MutD in association detection reaches 81.5 %. Conclusions: Our quantitative analysis reveals that MutD can effectively extract protein mutation disease associations when benchmarking based on curated database records. The analysis also demonstrates that incorporating discourse level analysis significantly improved the performance of extracting the protein-mutation-disease association. Future work includes the extension of MutD for full text articles.
从混合DNA样本矢量病原体全基因组捕获：<它>伯氏疏螺旋体< / >为例
Background: Rapid and accurate retrieval of whole genome sequences of human pathogens from disease vectors or animal reservoirs will enable fine-resolution studies of pathogen epidemiological and evolutionary dynamics. However, next generation sequencing technologies have not yet been fully harnessed for the study of vector-borne and zoonotic pathogens, due to the difficulty of obtaining high-quality pathogen sequence data directly from field specimens with a high ratio of host to pathogen DNA. Results: We addressed this challenge by using custom probes for multiplexed hybrid capture to enrich for and sequence 30 Borrelia burgdorferi genomes from field samples of its arthropod vector. Hybrid capture enabled sequencing of nearly the complete genome (~99.5 %) of the Borrelia burgdorferi pathogen with 132-fold coverage, and identification of up to 12,291 single nucleotide polymorphisms per genome. Conclusions: The proprosed culture-independent method enables efficient whole genome capture and sequencing of pathogens directly from arthropod vectors, thus making population genomic study of vector-borne and zoonotic infectious diseases economically feasible and scalable. Furthermore, given the similarities of invertebrate field specimens to other mixed DNA templates characterized by a high ratio of host to pathogen DNA, we discuss the potential applicabilty of hybrid capture for genomic study across diverse study systems.
温度相关的基因表达反应规范：监管结构和功能的影响
The environment has profound effects on the expression of many traits and reaction norms describe the expression dynamics of a trait across a broad range of environmental conditions. Here, we analyze gene expression in Drosophila melanogaster across four different developmental temperatures (13–29 °C). Gene expression is highly plastic with 83.3% of the genes being differentially expressed. We distinguished three components of plasticity: 1) Dynamics of gene expression intensity (sum of change), 2) direction of change, and 3) curvature of the reaction norm (linear vs. quadratic). Studying their regulatory architecture we found that all three plasticity components were most strongly affected by the number of different transcription factors (TFs) binding to the target gene. More TFs were found in genes with less expression changes across temperatures. Although the effect of microRNAs was weaker, we consistently noted a trend in the opposite direction. The most plastic genes were regulated by fewer TFs and more microRNAs than less plastic genes. Different patterns of plasticity were also reflected by their functional characterization based on gene ontology. Our results suggest that reaction norms provide an important key to understand the functional requirements of natural populations exposed to variable environmental conditions.
动态的和广泛的lncRNA的表达和海绵动物复杂性的起源
Long noncoding RNAs (lncRNAs) are important developmental regulators in bilaterian animals. A correlation has been claimed between the lncRNA repertoire expansion and morphological complexity in vertebrate evolution. However, this claim has not been tested by examining morphologically simple animals. Here, we undertake a systematic investigation of lncRNAs in the demosponge Amphimedon queenslandica, a morphologically simple, early-branching metazoan. We combine RNA-Seq data across multiple developmental stages of Amphimedon with a filtering pipeline to conservatively predict 2,935 lncRNAs. These include intronic overlapping lncRNAs, exonic antisense overlapping lncRNAs, long intergenic nonprotein coding RNAs, and precursors for small RNAs. Sponge lncRNAs are remarkably similar to their bilaterian counterparts in being relatively short with few exons and having low primary sequence conservation relative to protein-coding genes. As in bilaterians, a majority of sponge lncRNAs exhibit typical hallmarks of regulatory molecules, including high temporal specificity and dynamic developmental expression. Specific lncRNA expression profiles correlate tightly with conserved protein-coding genes likely involved in a range of developmental and physiological processes, such as the Wnt signaling pathway. Although the majority of Amphimedon lncRNAs appears to be taxonomically restricted with no identifiable orthologs, we find a few cases of conservation between demosponges in lncRNAs that are antisense to coding sequences. Based on the high similarity in the structure, organization, and dynamic expression of sponge lncRNAs to their bilaterian counterparts, we propose that these noncoding RNAs are an ancient feature of the metazoan genome. These results are consistent with lncRNAs regulating the development of animals, regardless of their level of morphological complexity.
卡布里:有效推理的癌症进展从横截面数据模型
Summary: We devise a novel inference algorithm to effectively solve the cancer progression model reconstruction problem. Our empirical analysis of the accuracy and convergence rate of our algorithm, CAncer PRogression Inference (CAPRI), shows that it outperforms the state-of-the-art algorithms addressing similar problems.
Motivation: Several cancer-related genomic data have become available (e.g. The Cancer Genome Atlas, TCGA) typically involving hundreds of patients. At present, most of these data are aggregated in a cross-sectional fashion providing all measurements at the time of diagnosis. Our goal is to infer cancer ‘progression’ models from such data. These models are represented as directed acyclic graphs (DAGs) of collections of ‘selectivity’ relations, where a mutation in a gene A ‘selects’ for a later mutation in a gene B. Gaining insight into the structure of such progressions has the potential to improve both the stratification of patients and personalized therapy choices.
Results: The CAPRI algorithm relies on a scoring method based on a probabilistic theory developed by Suppes, coupled with bootstrap and maximum likelihood inference. The resulting algorithm is efficient, achieves high accuracy and has good complexity, also, in terms of convergence properties. CAPRI performs especially well in the presence of noise in the data, and with limited sample sizes. Moreover CAPRI, in contrast to other approaches, robustly reconstructs different types of confluent trajectories despite irregularities in the data. We also report on an ongoing investigation using CAPRI to study atypical Chronic Myeloid Leukemia, in which we uncovered non trivial selectivity relations and exclusivity patterns among key genomic events.
Availability and implementation: CAPRI is part of the TRanslational ONCOlogy R package and is freely available on the web at: http://bimib.disco.unimib.it/index.php/Tronco
Contact: daniele.ramazzotti@disco.unimib.it
Supplementary information: Supplementary data are available at Bioinformatics online.
BinDNase:歧视性的方法预测转录因子结合使用DNase我敏感数据
Motivation: Transcription factors (TFs) are a class of DNA-binding proteins that have a central role in regulating gene expression. To reveal mechanisms of transcriptional regulation, a number of computational tools have been proposed for predicting TF-DNA interaction sites. Recent studies have shown that genome-wide sequencing data on open chromatin sites from a DNase I hypersensitivity experiments (DNase-seq) has a great potential to map putative binding sites of all transcription factors in a single experiment. Thus, computational methods for analysing DNase-seq to accurately map TF-DNA interaction sites are highly needed.
Results: Here, we introduce a novel discriminative algorithm, BinDNase, for predicting TF-DNA interaction sites using DNase-seq data. BinDNase implements an efficient method for selecting and extracting informative features from DNase I signal for each TF, either at single nucleotide resolution or for larger regions. The method is applied to 57 transcription factors in cell line K562 and 31 transcription factors in cell line HepG2 using data from the ENCODE project. First, we show that BinDNase compares favourably to other supervised and unsupervised methods developed for TF-DNA interaction prediction using DNase-seq data. We demonstrate the importance to model each TF with a separate prediction model, reflecting TF-specific DNA accessibility around the TF-DNA interaction site. We also show that a highly standardised DNase-seq data (pre)processing is a requisite for accurate TF binding predictions and that sequencing depth has on average only a moderate effect on prediction accuracy. Finally, BinDNase’s binding predictions generalise to other cell types, thus making BinDNase a versatile tool for accurate TF binding prediction.
Availability and implementation: R implementation of the algorithm is available in: http://research.ics.aalto.fi/csb/software/bindnase/.
Contact: juhani.kahara@aalto.fi
Supplementary information: Supplemental data are available at Bioinformatics online.
的普遍性和可塑性：昼夜振荡耦合的昼夜节律振荡器的框架
Motivation: Circadian oscillations have been observed in animals, plants, fungi, and cyanobacteria and play a fundamental role in coordinating the homeostasis and behavior of biological systems. Genetically encoded molecular clocks found in nearly every cell, based on negative transcription/translation feedback loops and involving only a dozen genes, play a central role in maintaining these oscillations. However, high-throughput gene expression experiments reveal that in a typical tissue, a much larger fraction (~ 10%) of all transcripts oscillate with the day-night cycle and the oscillating species vary with tissue type suggesting that perhaps a much larger fraction of all transcripts, and perhaps also other molecular species, may bear the potential for circadian oscillations.
Results: To better quantify the pervasiveness and plasticity of circadian oscillations, we conduct the first large-scale analysis aggregating the results of 18 circadian transcriptomic studies and 10 circadian metabolomic studies conducted in mice using different tissues and under different conditions. We find that over half of protein coding genes in the cell can produce transcripts that are circadian in at least one set of conditions, and similarly for measured metabolites. Genetic or environmental perturbations can disrupt existing oscillations by changing their amplitudes and phases, suppressing them, or giving rise to novel circadian oscillations. The oscillating species and their oscillations provide a characteristic signature of the physiological state of the corresponding cell/tissue. Molecular networks comprise many oscillator loops that have been sculpted by evolution over two trillion day-night cycles to have intrinsic circadian frequency. These oscillating loops are coupled by shared nodes in a large network of coupled circadian oscillators where the clock genes form a major hub. Cells can program and re-program their circadian repertoire through epigenetic and other mechanisms.
Availability: High-resolution and tissue/condition specific circadian data and networks available at http://circadiomics.igb.uci.edu (upon acceptance).
Contact: pfbaldi@ics.uci.edu
感性：一种测绘综合DNA元件的管道
Summary: There are several experimental contexts in which it is important to identify DNA integration sites, such as insertional mutagenesis screens, gene and enhancer trap applications, and gene therapy. We previously developed an assay to identify millions of integrations in multiplexed barcoded samples at base-pair resolution. The sheer amount of data produced by this approach makes the mapping of individual sites non-trivial without bioinformatics support. This article presents the Genomic Integration Site Tracker (GeIST), a command-line pipeline designed to map the integration sites produced by this assay and identify the samples from which they came. GeIST version 2.1.0, a more adaptable version of our original pipeline, can identify integrations of murine leukemia virus, adeno-associated virus, Tol2 transposons, or Ac/Ds transposons, and can be adapted for other inserted elements. It has been tested on experimental data for each of these delivery vectors and fine-tuned to account for sequencing and cloning artifacts.
Availability and Implementation: GeIST uses a combination of Bash shell scripting and Perl. GeIST is available at http://research.nhgri.nih.gov/software/GeIST/.
Contact: matthew.lafave@nih.gov; burgess@mail.nih.gov
利用基因本体描述的复杂的人的小腿neurexin蛋白作用，小鼠、大鼠和自闭症的相关性
Background: People with an autistic spectrum disorder (ASD) display a variety of characteristic behavioral traits, including impaired social interaction, communication difficulties and repetitive behavior. This complex neurodevelopment disorder is known to be associated with a combination of genetic and environmental factors. Neurexins and neuroligins play a key role in synaptogenesis and neurexin-neuroligin adhesion is one of several processes that have been implicated in autism spectrum disorders. Results: In this report we describe the manual annotation of a selection of gene products known to be associated with autism and/or the neurexin-neuroligin-SHANK complex and demonstrate how a focused annotation approach leads to the creation of more descriptive Gene Ontology (GO) terms, as well as an increase in both the number of gene product annotations and their granularity, thus improving the data available in the GO database. Conclusions: The manual annotations we describe will impact on the functional analysis of a variety of future autism-relevant datasets. Comprehensive gene annotation is an essential aspect of genomic and proteomic studies, as the quality of gene annotations incorporated into statistical analysis tools affects the effective interpretation of data obtained through genome wide association studies, next generation sequencing, proteomic and transcriptomic datasets.
蛋白质相互作用的低含量的研究发现过程动力学
Background: Thousands of biological and biomedical investigators study of the functional role of single genes and their protein products in normal physiology and in disease. The findings from these studies are reported in research articles that stimulate new research. It is now established that a complex regulatory networks's is controlling human cellular fate, and this community of researchers are continually unraveling this network topology. Attempts to integrate results from such accumulated knowledge resulted in literature-based protein-protein interaction networks (PPINs) and pathway databases. These databases are widely used by the community to analyze new data collected from emerging genome-wide studies with the assumption that the data within these literature-based databases is the ground truth and contain no biases. While suspicion for research focus biases is growing, a concrete proof for it is still missing. It is difficult to prove because the real PPINs are mostly unknown. Results: Here we analyzed the longitudinal discovery process of literature-based mammalian and yeast PPINs to observe that these networks are discovered non-uniformly. The pattern of discovery is related to a theoretical concept proposed by Kauffman called “expanding the adjacent possible”. We introduce a network discovery model which explicitly includes the space of possibilities in the form of a true underlying PPIN. Conclusions: Our model strongly suggests that research focus biases exist in the observed discovery dynamics of these networks. In summary, more care should be placed when using PPIN databases for analysis of newly acquired data, and when considering prior knowledge when designing new experiments.
使用一种新的报告系统随机显示一组，优先为塔塔和塔塔喜欢在酿酒酵母CYC1启动子序列
by Kiyoshi Watanabe, Makoto Yabe, Koji Kasahara, Tetsuro Kokubo
In Saccharomyces cerevisiae, the core promoters of class II genes contain either TATA or TATA-like elements to direct accurate transcriptional initiation. Genome-wide analyses show that the consensus sequence of the TATA element is TATAWAWR (8 bp), whereas TATA-like elements carry one or two mismatches to this consensus. The fact that several functionally distinct TATA sequences have been identified indicates that these elements may function, at least to some extent, in a gene-specific manner. The purpose of the present study was to identify functional TATA sequences enriched in one particular core promoter and compare them with the TATA or TATA-like elements that serve as the pre-initiation complex (PIC) assembly sites on the yeast genome. For this purpose, we conducted a randomized screen of the TATA element in the CYC1 promoter by using a novel reporter assay system and identified several hundreds of unique sequences that were tentatively classified into nine groups. The results indicated that the 7 bp TATA element (i.e., TATAWAD) and several sets of TATA-like sequences are preferred specifically by this promoter. Furthermore, we find that the most frequently isolated TATA-like sequence, i.e., TATTTAAA, is actually utilized as a functional core promoter element for the endogenous genes, e.g., ADE5,7 and ADE6. Collectively, these results indicate that the sequence requirements for the functional TATA or TATA-like elements in one particular core promoter are not as stringent. However, the variation of these sequences differs significantly from that of the PIC assembly sites on the genome, presumably depending on promoter structures and reflecting the gene-specific function of these sequences.
第一个完整的叶绿体基因组序列在猕猴桃科：基因组结构与比较分析
by Xiaohong Yao, Ping Tang, Zuozhou Li, Dawei Li, Yifei Liu, Hongwen Huang
Actinidia chinensis is an important economic plant belonging to the basal lineage of the asterids. Availability of a complete Actinidia chloroplast genome sequence is crucial to understanding phylogenetic relationships among major lineages of angiosperms and facilitates kiwifruit genetic improvement. We report here the complete nucleotide sequences of the chloroplast genomes for Actinidia chinensis and A. chinensis var deliciosa obtained through de novo assembly of Illumina paired-end reads produced by total DNA sequencing. The total genome size ranges from 155,446 to 157,557 bp, with an inverted repeat (IR) of 24,013 to 24,391 bp, a large single copy region (LSC) of 87,984 to 88,337 bp and a small single copy region (SSC) of 20,332 to 20,336 bp. The genome encodes 113 different genes, including 79 unique protein-coding genes, 30 tRNA genes and 4 ribosomal RNA genes, with 16 duplicated in the inverted repeats, and a tRNA gene (trnfM-CAU) duplicated once in the LSC region. Comparisons of IR boundaries among four asterid species showed that IR/LSC borders were extended into the 5’ portion of the psbA gene and IR contraction occurred in Actinidia. The clap gene has been lost from the chloroplast genome in Actinidia, and may have been transferred to the nucleus during chloroplast evolution. Twenty-seven polymorphic simple sequence repeat (SSR) loci were identified in the Actinidia chloroplast genome. Maximum parsimony analyses of a 72-gene, 16 taxa angiosperm dataset strongly support the placement of Actinidiaceae in Ericales within the basal asterids.
