ALBERT

Description: Most RNAs generated by the human genome have no protein-coding ability and are termed non-coding RNAs. Among these include circular RNAs, which include exonic circular RNAs (circRNA), mainly found in the cytoplasm, and intronic RNAs (ciRNA), predominantly detected in the nucleus. The biological functions of circular RNAs remain largely unknown, although ciRNAs have been reported to promote gene transcription, while circRNAs may function as microRNA sponges. We demonstrate that the circular RNA circ-Foxo3 was highly expressed in non-cancer cells and were associated with cell cycle progression. Silencing endogenous circ-Foxo3 promoted cell proliferation. Ectopic expression of circ-Foxo3 repressed cell cycle progression by binding to the cell cycle proteins cyclin-dependent kinase 2 (also known as cell division protein kinase 2 or CDK2) and cyclin-dependent kinase inhibitor 1 (or p21), resulting in the formation of a ternary complex. Normally, CDK2 interacts with cyclin A and cyclin E to facilitate cell cycle entry, while p21works to inhibit these interactions and arrest cell cycle progression. The formation of this circ-Foxo3-p21-CDK2 ternary complex arrested the function of CDK2 and blocked cell cycle progression.

Description: Reproductive infertility affects seventh of couples, which is most attributed to the obstacle of gametogenesis. Characterizing the epigenetic modification factors involved in gametogenesis is fundamental to understand the molecular mechanisms and to develop treatments for human infertility. Although the genetic factors have been implicated in gametogenesis, no dedicated bioinformatics resource for gametogenesis is available. To elucidate the relationship of epigenetic modification and mammalian gametogenesis, we developed a new database, gametogenesis epigenetic modification database (GED), a manually curated database, which aims at providing a comprehensive resource of epigenetic modification of gametogenesis. The database integrates three kinds information of epigenetic modifications during gametogenesis (DNA methylation, histone modification and RNA regulation), and the gametogenesis has been detailed as 16 stages in seven mammal species ( Homo sapiens , Mus musculus , Rattus norvegicus , Sus scrofa , Bos taurus , Capra hircus and Ovis aries ). Besides, we have predicted the linear pathways of epigenetic modification which were composed of 211 genes/proteins and microRNAs that were involved in gametogenesis. GED is a user-friendly Web site, through which users can obtain the comprehensive epigenetic factor information and molecular pathways by visiting our database freely. GED is free available at http://gametsepi.nwsuaflmz.com .

Description: The ciliate protozoan Tetrahymena thermophila contains two types of structurally and functionally differentiated nuclei: the transcriptionally active somatic macronucleus (MAC) and the transcriptionally silent germ-line micronucleus (MIC). Here, we demonstrate that MAC features well-positioned nucleosomes downstream of transcription start sites and flanking splice sites. Transcription-associated trans -determinants promote nucleosome positioning in MAC. By contrast, nucleosomes in MIC are dramatically delocalized. Nucleosome occupancy in MAC and MIC are nonetheless highly correlated with each other, as well as with in vitro reconstitution and predictions based upon DNA sequence features, revealing unexpectedly strong contributions from cis -determinants. In particular, well-positioned nucleosomes are often matched with GC content oscillations. As many nucleosomes are coordinately accommodated by both cis - and trans -determinants, we propose that their distribution is shaped by the impact of these nucleosomes on the mutational and transcriptional landscape, and driven by evolutionary selection.

Description: In this paper, the asymptotic stability of uncertain discrete switched systems with interval time-varying delay and linear fractional perturbations is achieved via switching signal design. Some linear matrix inequality (LMI) stability criteria are provided to design the switching signal by the proposed non-uniform delay-partitioning approach. Finally, some numerical examples are illustrated to show the main developed results.

Description: Motivation: The importance of testing associations allowing for interactions has been demonstrated by Marchini et al . (2005). A fast method detecting associations allowing for interactions has been proposed by Wan et al . (2010a). The method is based on likelihood ratio test with the assumption that the statistic follows the 2 distribution. Many single nucleotide polymorphism (SNP) pairs with significant associations allowing for interactions have been detected using their method. However, the assumption of 2 test requires the expected values in each cell of the contingency table to be at least five. This assumption is violated in some identified SNP pairs. In this case, likelihood ratio test may not be applicable any more. Permutation test is an ideal approach to checking the P -values calculated in likelihood ratio test because of its non-parametric nature. The P -values of SNP pairs having significant associations with disease are always extremely small. Thus, we need a huge number of permutations to achieve correspondingly high resolution for the P -values. In order to investigate whether the P -values from likelihood ratio tests are reliable, a fast permutation tool to accomplish large number of permutations is desirable. Results: We developed a permutation tool named PBOOST. It is based on GPU with highly reliable P -value estimation. By using simulation data, we found that the P -values from likelihood ratio tests will have relative error of 〉100% when 50% cells in the contingency table have expected count less than five or when there is zero expected count in any of the contingency table cells. In terms of speed, PBOOST completed 10 7 permutations for a single SNP pair from the Wellcome Trust Case Control Consortium (WTCCC) genome data (Wellcome Trust Case Control Consortium, 2007) within 1 min on a single Nvidia Tesla M2090 device, while it took 60 min in a single CPU Intel Xeon E5-2650 to finish the same task. More importantly, when simultaneously testing 256 SNP pairs for 10 7 permutations, our tool took only 5 min, while the CPU program took 10 h. By permuting on a GPU cluster consisting of 40 nodes, we completed 10 12 permutations for all 280 SNP pairs reported with P -values smaller than $$1.6\times {10}^{-12}$$ in the WTCCC datasets in 1 week. Availability and implementation: The source code and sample data are available at http://bioinformatics.ust.hk/PBOOST.zip . Contact: gyang@ust.hk ; eeyu@ust.hk Supplementary information: Supplementary data are available at Bioinformatics online.

Description: G-quadruplexes have attracted growing attention as a potential cancer-associated target for both treatment and detection in recent years. For detection purpose, high specificity is one of the most important factors to be considered in G-quadruplex probe design. It is well known that end stacking and groove binding are two dominated quadruplex-ligand binding modes, and currently most reported G-quadruplex probes are designed based on the former, which has been proven to show good selectivity between quadruplexes and non-quadruplexes. Because groove of G-quadruplex also has some unique chemical properties, it could be inferred that probes that can interact with both the groove and G-tetrad site of certain G-quadruplexes simultaneously might possess higher specificity in aspects of discriminating different quadruplexes. In this article, we report a cyanine dye as a potential novel probe scaffold that could occupy both the 5'-end external G-tetrad and the corresponding groove of the G-quadruplex simultaneously. By using various spectrum and nuclear magnetic resonance techniques, we give a detailed binding characterization for this dual-site simultaneous binding mode. A preliminary result suggests that this mode might provide highly specific recognition to a parallel-stranded G-quadruplex. These findings and the structural elucidation might give some clues in aspects of developing highly specific G-quadruplex probes.

Description: Motivation : The three dimensional tertiary structure of a protein at near atomic level resolution provides insight alluding to its function and evolution. As protein structure decides its functionality, similarity in structure usually implies similarity in function. As such, structure alignment techniques are often useful in the classifications of protein function. Given the rapidly growing rate of new, experimentally determined structures being made available from repositories such as the Protein Data Bank, fast and accurate computational structure comparison tools are required. This paper presents SPalignNS, a non-sequential protein structure alignment tool using a novel asymmetrical greedy search technique. Results : The performance of SPalignNS was evaluated against existing sequential and non-sequential structure alignment methods by performing trials with commonly used datasets. These benchmark datasets used to gauge alignment accuracy include (i) 9538 pairwise alignments implied by the HOMSTRAD database of homologous proteins; (ii) a subset of 64 difficult alignments from set (i) that have low structure similarity; (iii) 199 pairwise alignments of proteins with similar structure but different topology; and (iv) a subset of 20 pairwise alignments from the RIPC set. SPalignNS is shown to achieve greater alignment accuracy (lower or comparable root-mean squared distance with increased structure overlap coverage) for all datasets, and the highest agreement with reference alignments from the challenging dataset (iv) above, when compared with both sequentially constrained alignments and other non-sequential alignments. Availability and implementation : SPalignNS was implemented in C++. The source code, binary executable, and a web server version is freely available at: http://sparks-lab.org Contact : yaoqi.zhou@griffith.edu.au

Description: Analysis of RNA-seq data often detects numerous ‘non-co-linear’ (NCL) transcripts, which comprised sequence segments that are topologically inconsistent with their corresponding DNA sequences in the reference genome. However, detection of NCL transcripts involves two major challenges: removal of false positives arising from alignment artifacts and discrimination between different types of NCL transcripts ( trans -spliced, circular or fusion transcripts). Here, we developed a new NCL-transcript-detecting method (‘NCLscan’), which utilized a stepwise alignment strategy to almost completely eliminate false calls (〉98% precision) without sacrificing true positives, enabling NCLscan outperform 18 other publicly-available tools (including fusion- and circular-RNA-detecting tools) in terms of sensitivity and precision, regardless of the generation strategy of simulated dataset, type of intragenic or intergenic NCL event, read depth of coverage, read length or expression level of NCL transcript. With the high accuracy, NCLscan was applied to distinguishing between trans -spliced, circular and fusion transcripts on the basis of poly(A)- and nonpoly(A)-selected RNA-seq data. We showed that circular RNAs were expressed more ubiquitously, more abundantly and less cell type-specifically than trans -spliced and fusion transcripts. Our study thus describes a robust pipeline for the discovery of NCL transcripts, and sheds light on the fundamental biology of these non-canonical RNA events in human transcriptome.

Description: This study investigated the response of antibiotic resistance genes (ARGs) to nanosilver (Ag) in lab-scale nitrifying sequencing batch reactors (SBRs), compared to Ag + -dosed and undosed controls. Quantitative polymerase chain reaction (q-PCR) targeting sul 1, tet (O), erm B and the class I integron gene int I1 and corresponding RNA expression did not indicate measureable effects of nanoAg or Ag + on abundance or expression of these genes. However, high-throughput sequencing based metagenomic analysis provided a much broader profile of gene responses and revealed a greater abundance of aminoglycoside resistance genes (mainly str A) in reactors dosed with nanoAg. In contrast, bacitracin and macrolide-lincosamide-streptogramin (MLS) resistance genes were more abundant in the SBRs dosed with Ag + . The distinct ARG profiles associated with nanoAg and Ag + were correlated with the taxonomic composition of the microbial communities. This study indicates that nanoAg may interact with bacteria differently from Ag + during biological wastewater treatment. Therefore, it cannot necessarily be assumed that nanosilver behaves identically as Ag + when conducting a risk assessment for release into the environment.

Description: The higher order chromatin structure has recently been revealed as a critical new layer of gene transcriptional control. Changes in higher order chromatin structures were shown to correlate with the availability of transcriptional factors and/or MAR (matrix attachment region) binding proteins, which tether genomic DNA to the nuclear matrix. How posttranslational modification to these protein organizers may affect higher order chromatin structure still pending experimental investigation. The type III histone deacetylase silent mating type information regulator 2, S. cerevisiae, homolog 1 (SIRT1) participates in many physiological processes through targeting both histone and transcriptional factors. We show that MAR binding protein SATB1, which mediates chromatin looping in cytokine, MHC-I and β-globin gene loci, as a new type of SIRT1 substrate. SIRT1 expression increased accompanying erythroid differentiation and the strengthening of β-globin cluster higher order chromatin structure, while knockdown of SIRT1 in erythroid k562 cells weakened the long-range interaction between two SATB1 binding sites in the β-globin locus, MAR HS2 and MAR . We also show that SIRT1 activity significantly affects -globin gene expression in a SATB1-dependent manner and that knockdown of SIRT1 largely blocks -globin gene activation during erythroid differentiation. Our work proposes that SIRT1 orchestrates changes in higher order chromatin structure during erythropoiesis, and reveals the dynamic higher order chromatin structure regulation at posttranslational modification level.