ALBERT

Description: Increasing amounts of genes have been shown to utilize alternative polyadenylation (APA) 3'-processing sites depending on the cell and tissue type and/or physiological and pathological conditions at the time of processing, and the construction of genome-wide database regarding APA is urgently needed for better understanding poly(A) site selection and APA-directed gene expression regulation for a given biology. Here we present a web-accessible database, named APASdb ( http://mosas.sysu.edu.cn/utr ), which can visualize the precise map and usage quantification of different APA isoforms for all genes. The datasets are deeply profiled by the sequencing alternative polyadenylation sites (SAPAS) method capable of high-throughput sequencing 3'-ends of polyadenylated transcripts. Thus, APASdb details all the heterogeneous cleavage sites downstream of poly(A) signals, and maintains near complete coverage for APA sites, much better than the previous databases using conventional methods. Furthermore, APASdb provides the quantification of a given APA variant among transcripts with different APA sites by computing their corresponding normalized-reads, making our database more useful. In addition, APASdb supports URL-based retrieval, browsing and display of exon-intron structure, poly(A) signals, poly(A) sites location and usage reads, and 3'-untranslated regions (3'-UTRs). Currently, APASdb involves APA in various biological processes and diseases in human, mouse and zebrafish.

Description: The mechanical damage characteristics of sandstone subjected to cyclic loading is very significant to evaluate the stability and safety of deep excavation damage zones. However to date, there are very few triaxial experimental studies of sandstone under cyclic loading. Moreover, few X-ray micro-computed tomography (micro-CT) observations have been adopted to reveal the damage mechanism of sandstone under triaxial cyclic loading. Therefore, in this research, a series of triaxial cyclic loading tests and X-ray micro-CT observations were conducted to analyse the mechanical damage characteristics of sandstone with respect to different confining pressures. The results indicated that at lower confining pressures, the triaxial strength of sandstone specimens under cyclic loading is higher than that under monotonic loading; whereas at confining pressures above 20 MPa, the triaxial strength of sandstone under cyclic loading is approximately equal to that under monotonic loading. With the increase of cycle number, the crack damage threshold of sandstone first increases, and then significantly decreases and finally remains constant. Based on the damage evolution of irreversible deformation, it appears that the axial damage value of sandstone is all higher than the radial damage value before the peak strength; whereas the radial damage value is higher than the axial damage value after the peak strength. The evolution of Young's modulus and Poisson's ratio of sandstone can be characterized as having four stages: (i) Stage I: material strengthening; (ii) Stage II: material degradation; (iii) Stage III: material failure and (iv) Stage IV: structure slippage. X-ray micro-CT observations demonstrated that the CT scanning surface images of sandstone specimens are consistent with actual surface crack photographs. The analysis of the cross-sections of sandstone supports that the system of crack planes under triaxial cyclic loading is much more complicated than that under triaxial monotonic loading. More axial and lateral tensile cracks were observed in the specimens under cyclic loading than under monotonic loading.

Description: The modulation of chromatin structure is a key step in transcription regulation in mammalian cells and eventually determines lineage commitment and differentiation. USF1/2, Setd1a and NURF complexes interact to regulate chromatin architecture in erythropoiesis, but the mechanistic basis for this regulation is hitherto unknown. Here we showed that Setd1a and NURF complexes bind to promoters to control chromatin structural alterations and gene activation in a cell context dependent manner. In human primary erythroid cells USF1/2, H3K4me3 and the NURF complex were significantly co-enriched at transcription start sites of erythroid genes, and their binding was associated with promoter/enhancer accessibility that resulted from nucleosome repositioning. Mice deficient for Setd1a , an H3K4 trimethylase, in the erythroid compartment exhibited reduced Ter119/CD71 positive erythroblasts, peripheral blood RBCs and hemoglobin levels. Loss of Setd1a led to a reduction of promoter-associated H3K4 methylation, inhibition of gene transcription and blockade of erythroid differentiation. This was associated with alterations in NURF complex occupancy at erythroid gene promoters and reduced chromatin accessibility. Setd1a deficiency caused decreased associations between enhancer and promoter looped interactions as well as reduced expression of erythroid genes such as the adult β-globin gene. These data indicate that Setd1a and NURF complexes are specifically targeted to and coordinately regulate erythroid promoter chromatin dynamics during erythroid lineage differentiation.

Description: We present a systematic analysis of the rotation curves of 187 galaxies with stellar masses greater than 10 10 M , with atomic gas masses from the GALEX Arecibo Sloan Survey (GASS) and with follow-up long-slit spectroscopy from the MMT. Our analysis focuses on stellar rotation curves derived by fitting stellar template spectra to the galaxy spectra binned along the slit. In this way, we are able to obtain accurate rotation velocity measurements for a factor of 2 more galaxies than possible with the Hα line. Galaxies with high atomic gas mass fractions are the most dark-matter-dominated galaxies in our sample and have dark matter halo density profiles that are to first order well described by Navarro–Frenk–White profiles with an average concentration parameter of 10. The inner slopes of the rotation curves correlate more strongly with stellar population age than with galaxy mass or structural parameters. At fixed stellar mass, the rotation curves of more actively star-forming galaxies have steeper inner slopes than less actively star-forming galaxies. The ratio between the galaxy specific angular momentum and the total specific angular momentum of its dark matter halo, R j , correlates strongly with galaxy mass, structure and gas content. Low-mass, disc-dominated galaxies with atomic gas mass fractions greater than 20 per cent have median values of R j of around 1, but massive, bulge-dominated galaxies have R j  = 0.2–0.3. We argue that these trends can be understood in a picture where gas inflows triggered by disc instabilities lead to the formation of passive, bulge-dominated galaxies with low specific angular momentum.

Description: Given the increasing number of proteins reported to be regulated by S -nitrosylation (SNO), it is considered to act, in a manner analogous to phosphorylation, as a pleiotropic regulator that elicits dual effects to regulate diverse pathophysiological processes by altering protein function, stability, and conformation change in various cancers and human disorders. Due to its importance in regulating protein functions and cell signaling, dbSNO ( http://dbSNO.mbc.nctu.edu.tw ) is extended as a resource for exploring structural environment of SNO substrate sites and regulatory networks of S -nitrosylated proteins. An increasing interest in the structural environment of PTM substrate sites motivated us to map all manually curated SNO peptides (4165 SNO sites within 2277 proteins) to PDB protein entries by sequence identity, which provides the information of spatial amino acid composition, solvent-accessible surface area, spatially neighboring amino acids, and side chain orientation for 298 substrate cysteine residues. Additionally, the annotations of protein molecular functions, biological processes, functional domains and human diseases are integrated to explore the functional and disease associations for S -nitrosoproteome. In this update, users are allowed to search a group of interested proteins/genes and the system reconstructs the SNO regulatory network based on the information of metabolic pathways and protein-protein interactions. Most importantly, an endogenous yet pathophysiological S -nitrosoproteomic dataset from colorectal cancer patients was adopted to demonstrate that dbSNO could discover potential SNO proteins involving in the regulation of NO signaling for cancer pathways.

Description: The stable ribonucleoprotein (RNP) complex formed between the Lactococcus lactis group II intron and its self-encoded LtrA protein is essential for the intron’s genetic mobility. In this study, we report the biochemical, compositional, hydrodynamic and structural properties of active group II intron RNP particles (+A) isolated from its native host using a novel purification scheme. We employed small-angle X-ray scattering to determine the structural properties of these particles as they exist in solution. Using sucrose as a contrasting agent, we derived a two-phase quaternary model of the protein–RNA complex. This approach revealed that the spatial properties of the complex are largely defined by the RNA component, with the protein dimer located near the center of mass. A transfer RNA fusion engineered into domain II of the intron provided a distinct landmark consistent with this interpretation. Comparison of the derived +A RNP shape with that of the previously reported precursor intron (A) particle extends previous findings that the loosely packed precursor RNP undergoes a dramatic conformational change as it compacts into its active form. Our results provide insights into the quaternary arrangement of these RNP complexes in solution, an important step to understanding the transition of the group II intron from the precursor to a species fully active for DNA invasion.

Description: Motivation: PIWI-interacting RNAs (piRNAs) are a class of small non-coding RNAs that are highly abundant in the germline. One important role of piRNAs is to defend genome integrity by guiding PIWI proteins to silence transposable elements (TEs), which have a high potential to cause deleterious effects on their host. The mechanism of piRNA-mediated post-transcriptional silencing was also observed to affect mRNAs, suggesting that piRNAs might play a broad role in gene expression regulation. However, there has been no systematic report with regard to how many protein-coding genes might be targeted and regulated by piRNAs. Results: We trained a support vector machine classifier based on a combination of Miwi CLIP-Seq-derived features and position-derived features to predict the potential targets of piRNAs on mRNAs in the mouse. Reanalysis of a published microarray dataset suggested that the expression level of the 2587 protein-coding genes predicted as piRNA targets showed significant upregulation as a whole after abolishing the slicer activity of Miwi, supporting the conclusion that they are subject to piRNA-mediated regulation. Availability and implementation: A web version of the method called pirnaPre as well as our results for browse is available at http://www.regulatoryrna.org/software/piRNA/piRNA_target_mRNA/index.php . Contact: crs@sun5.ibp.ac.cn or heshunmin@gmail.com Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Graves' disease (GD), characterized by autoantibodies targeting antigens specifically expressed in thyroid tissues causing hyperthyroidism, is triggered by a combination of genetic and environmental factors. However, only a few loci for GD risk were confirmed in the various ethnic groups, and additional genetic determinants have to be detected. In this study, we carried out a three-stage study in 9529 patients with GD and 9984 controls to identify new risk loci for GD and found genome-wide significant associations in the overall populations for five novel susceptibility loci: the GPR174 - ITM2A at Xq21.1, C1QTNF6-RAC2 at 22q12.3–13.1, SLAMF6 at 1q23.2, ABO at 9q34.2 and an intergenic region harboring two non-coding RNAs at 14q32.2 and one previous indefinite locus, TG at 8q24.22 ( P combined 〈 5 x 10 –8 ). The genotypes of corresponding variants at 14q32.2 and 8q24.22 were correlated with the expression levels of C14orf64 and a TG transcript skipping exon 46, respectively. This study increased the number of GD loci with compelling evidence and indicated that non-coding RNAs might be potentially involved in the pathogenesis of GD.

Description: Motivation: TRAIL has been widely studied for the ability to kill cancer cells selectively, but its clinical usefulness has been hindered by the development of resistance. Multiple compounds have been identified that sensitize cancer cells to TRAIL-induced apoptosis. The drug LY303511 (LY30), combined with TRAIL, caused synergistic (greater than additive) killing of multiple cancer cell lines. We used mathematical modelling and ordinary differential equations to represent how LY30 and TRAIL individually affect HeLa cells, and to predict how the combined treatment achieves synergy. Results: Model-based predictions were compared with in vitro experiments. The combination treatment model was successful at mimicking the synergistic levels of cell death caused by LY30 and TRAIL combined. However, there were significant failures of the model to mimic upstream activation at early time points, particularly the slope of caspase-8 activation. This flaw in the model led us to perform additional measurements of early caspase-8 activation. Surprisingly, caspase-8 exhibited a transient decrease in activity after LY30 treatment, prior to strong activation. cFLIP, an inhibitor of caspase-8 activation, was up-regulated briefly after 30 min of LY30 treatment, followed by a significant down-regulation over prolonged exposure. A further model suggested that LY30-induced fluctuation of cFLIP might result from tilting the ratio of two key species of reactive oxygen species (ROS), superoxide and hydrogen peroxide. Computational modelling extracted novel biological implications from measured dynamics, identified time intervals with unexplained effects, and clarified the non-monotonic effects of the drug LY30 on cFLIP during cancer cell apoptosis. Supplementary information: Supplementary data are available at Bioinformatics online. Contact: LisaTK@nus.edu.sg or Shazib_Pervaiz@nuhs.edu.sg

Description: We have updated our radially resolved semi-analytic models (SAMs) of galaxy formation, which track both the atomic and molecular gas phases of the interstellar medium. The models are adapted from those of Guo et al. using similar methodology as by Fu et al. and are run on halo merger trees from the Millennium and Millennium-II simulations with the following main changes. (1) We adopt a simple star formation law SFR H 2 . (2) We inject the heavy elements produced by supernovae directly into the halo hot gas, instead of first mixing them with the cold gas in the disc. (3) We include radial gas inflows in discs using a model of the form v inflow  = α r . The models are used to study the radial profiles of star formation rate and gas-phase metallicity in present-day galaxies. The surface density profiles of molecular gas in L * galaxies place strong constraints on inflow velocities, favouring models where v inflow  ~ 7 km s –1 at a galactocentric radius of 10 kpc. Radial gas inflow has little influence on gas-phase and stellar metallicity gradients, which are affected much more strongly by the fraction of metals that are directly injected into the halo gas, rather than mixed with the cold gas. Metals ejected out of the galaxy in early epochs result in late infall of pre-enriched gas and flatter present-day gas-phase metallicity gradients. A prescription in which 80 per cent of the metals are injected into the halo gas results in good fits to the flat observed metallicity gradients in galaxies with stellar masses greater than 10 10 M , as well as the relations between gas-phase metallicity and specific star formation rate in the outer parts of galactic discs. We examine the correlation between the gas-phase metallicity gradient and global galaxy properties, finding that it is most strongly correlated with the bulge-to-total ratio of the galaxy. This is because gas is consumed when the bulge forms during galaxy mergers, and the gas-phase metallicity gradient is then set by newly accreted gas.