ALBERT

Description: Natural tetracyclic diterpenoid aphidicolin is a potent and specific inhibitor of B-family DNA polymerases, haltering replication and possessing a strong antimitotic activity in human cancer cell lines. Clinical trials revealed limitations of aphidicolin as an antitumor drug because of its low solubility and fast clearance from human plasma. The absence of structural information hampered the improvement of aphidicolin-like inhibitors: more than 50 modifications have been generated so far, but all have lost the inhibitory and antitumor properties. Here we report the crystal structure of the catalytic core of human DNA polymerase α (Pol α) in the ternary complex with an RNA-primed DNA template and aphidicolin. The inhibitor blocks binding of dCTP by docking at the Pol α active site and by rotating the template guanine. The structure provides a plausible mechanism for the selectivity of aphidicolin incorporation opposite template guanine and explains why previous modifications of aphidicolin failed to improve its affinity for Pol α. With new structural information, aphidicolin becomes an attractive lead compound for the design of novel derivatives with enhanced inhibitory properties for B-family DNA polymerases.

Description: We present Doppler images of RS CVn-type binary II Peg based on two data sets obtained in 2004 February and November. In order to improve signal-to-noise ratio and reliability, we apply least-squares deconvolution technique to calculate average profiles from 2032 photospheric absorption lines. Both of the resulting surface images show a wide latitude distribution of starspots. Most spots are concentrated at a high-latitude belt above 60° and a low-latitude belt near equator. The starspots evolved dramatically between two observing runs, which may indicate shorter time-scale evolution in this epoch, especially for low-latitude belt. There is no stable preferred active longitude that can be found in our images. We also find out a possible phenomenon that the intermediate-latitude spot migrated poleward and merged with the high-latitude spot to make it stronger, which may reveal a more complex behaviour of starspots on II Peg. A potential change of orbital ephemeris zero-point was detected. This may imply an orbital period change of II Peg like other active close binaries.

Description: We present Doppler images of both components of the eclipsing binary system ER Vul, based on the spectra obtained in 2004 November, 2006 September and 2008 November. The least-squares deconvolution technique is used for enhancing the signal-to-noise ratios of the observed profiles. The new surface images reveal that both stars of ER Vul show strong starspot activities and the starspots appear at various latitudes. The surface maps of 2006 and 2008 both show the presence of large high-latitude starspots on each component of ER Vul. We find no obvious phase shift of the active regions during our observations. The longitude distributions of starspots are non-uniform on both stars. At low-to-mid latitudes, the active regions are almost exclusively found in the hemisphere facing the other star. However, we find no pronounced concentration of spots at the sub-stellar points.

Description: We present Doppler images of both components of the eclipsing binary system ER Vul, based on the spectra obtained in 2004 November, 2006 September and 2008 November. The least-squares deconvolution technique is used for enhancing the signal-to-noise ratios of the observed profiles. The new surface images reveal that both stars of ER Vul show strong starspot activities and the starspots appear at various latitudes. The surface maps of 2006 and 2008 both show the presence of large high-latitude starspots on each component of ER Vul. We find no obvious phase shift of the active regions during our observations. The longitude distributions of starspots are non-uniform on both stars. At low-to-mid latitudes, the active regions are almost exclusively found in the hemisphere facing the other star. However, we find no pronounced concentration of spots at the sub-stellar points.

Description: Knowledge of the mantle reflectivity structure is highly dependent on our ability to efficiently extract, and properly interpret, small seismic arrivals. Among the various data types and techniques, long-period SS/PP precursors and high-frequency receiver functions are routinely utilized to increase the confidence of the recovered mantle stratifications at distinct spatial scales. However, low resolution and a complex Fresnel zone are glaring weaknesses of SS precursors, while over-reliance on receiver distribution is a formidable challenge for the analysis of converted waves from oceanic regions. A promising high frequency alternative to receiver functions is P ' P ' precursors, which are capable of resolving mantle structures at vertical and lateral resolution of ~5 and ~200 km, respectively, owing to their spectral content, shallow angle of incidence and near-symmetric Fresnel zones. This study presents a novel processing method for both SS (or PP) and P ' P ' precursors based on deconvolution, stacking, Radon transform and depth migration. A suite of synthetic tests is performed to quantify the fidelity and stability of this method under different data conditions. Our multiresolution survey of the mantle at targeted areas near Nazca-South America subduction zone reveal both olivine and garnet related transitions at depths below 400 km. We attribute a depressed 660 to thermal variations, whereas compositional variations atop the upper-mantle transition zone are needed to explain the diminished or highly complex reflected/scattered signals from the 410 km discontinuity. We also observe prominent P ' P ' reflections within the transition zone, and the anomalous amplitudes near the plate boundary zone indicate a sharp (~10 km thick) transition that likely resonates with the frequency content of P ' P ' precursors. The migration of SS precursors in this study shows no evidence of split 660 reflections, but potential majorite–ilmenite (590–640 km) and ilmenite–perovskite transitions (740–750 km) are identified based on similarly processed high-frequency P ' P ' precursors. Additional findings of severely scattered energy in the lithosphere and distinct lower mantle reflections at ~800 km could be potentially important but require further verifications. Overall, our improved imaging methods and the strong sensitivity of P ' P ' precursors to the existence, depth, sharpness and strength of reflective structures offer significant future promise for the understanding of mantle mineralogy and dynamics.

Description: The Arabidopsis DA1 genes appear to have multiple functions in regulating organ size and abiotic stress response, but the biological roles of its closely related genes remain unknown. Evolutionary analyses might provide some clues to aid in an understanding of their functional diversification. In this work, we characterized the molecular evolution and expressional diversification of DA1 -like genes. Surveying 354 sequenced genomes revealed 142 DA1 -like genes only in plants, indicating plant-specificity of these genes. The DA1-like protein modular structure was composed of two UIMs (ubiquitin interaction motifs), one LIM-domain (from lin-11 , isl-1 , and mec-3 ), and a conserved C-terminal, and was distinguishable from the already defined three groups of LIM-domain proteins. We further found that the DA1 -like genes diverged into Classes I and II at the ancestor of seed plants and acquired 13 clade-specific residues during their evolutionary history. Moreover, diverse intron size evolution was noted following the transition from size-expandable introns to minimal ones, accompanying the emergence and diversification of angiosperms. Functional diversification as it relates to gene expression was further investigated in soybean. Glycine max DA1 genes showed diverse tissues expression patterns during development and had substantially varied abiotic stress response expression. Thus, variations in the coding regions, intron size, and gene expression contributed to the functional diversification of this gene family. Our data suggest that the evolution of the DA1 -like genes facilitated the development of diverse molecular and functional diversification patterns to accompany the successful radiation of plants into diverse environments during evolution.

Description: In high-throughput studies of diseases, terms enriched with disease-related genes based on Gene Ontology (GO) are routinely found. However, most current algorithms used to find significant GO terms cannot handle the redundancy that results from the dependencies of GO terms. Simply based on some numerical considerations, current algorithms developed for reducing this redundancy may produce results that do not account for biologically interesting cases. In this article, we present several rules used to design a tool called GO-function for extracting biologically relevant terms from statistically significant GO terms for a disease. Using one gene expression profile for colorectal cancer, we compared GO-function with four algorithms designed to treat redundancy. Then, we validated results obtained in this data set by GO-function using another data set for colorectal cancer. Our analysis showed that GO-function can identify disease-related terms that are more statistically and biologically meaningful than those found by the other four algorithms.

Description: Gene families often show degrees of differences in terms of exon–intron structures depending on their distinct evolutionary histories. Comparative analysis of gene structures is important for understanding their evolutionary and functional relationships within plant species. Here, we present a comparative genomics database named PIECE ( http://wheat.pw.usda.gov/piece ) for Plant Intron and Exon Comparison and Evolution studies. The database contains all the annotated genes extracted from 25 sequenced plant genomes. These genes were classified based on Pfam motifs. Phylogenetic trees were pre-constructed for each gene category. PIECE provides a user-friendly interface for different types of searches and a graphical viewer for displaying a gene structure pattern diagram linked to the resulting bootstrapped dendrogram for each gene family. The gene structure evolution of orthologous gene groups was determined using the GLOOME, Exalign and GECA software programs that can be accessed within the database. PIECE also provides a web server version of the software, GSDraw, for drawing schematic diagrams of gene structures. PIECE is a powerful tool for comparing gene sequences and provides valuable insights into the evolution of gene structure in plant genomes.

Description: Arrhythmogenic right ventricular cardiomyopathy (ARVC) termed a ‘disease of the desmosome’ is an inherited cardiomyopathy that recently underwent reclassification owing to the identification of left-dominant and biventricular disease forms. Homozygous loss-of-function mutations in the desmosomal component, desmoplakin, are found in patients exhibiting a biventricular form of ARVC; however, no models recapitulate the postnatal hallmarks of the disease as seen in these patients. To gain insights into the homozygous loss-of-function effects of desmoplakin in the heart, we generated cardiomyocyte-specific desmoplakin-deficient mice (DSP-cKO) using ventricular myosin light chain-2-Cre mice. Homozygous DSP-cKO mice are viable but display early ultrastructural defects in desmosomal integrity leading to a cardiomyopathy reminiscent of a biventricular form of ARVC, which includes cell death and fibro-fatty replacement within the ventricle leading to biventricular dysfunction, failure and premature death. DSP-cKO mice also exhibited ventricular arrhythmias that are exacerbated with exercise and catecholamine stimulation. Furthermore, DSP-cKO hearts exhibited right ventricular conduction defects associated with loss of connexin 40 expression and electrical wavefront propagation defects associated with loss of connexin 43 expression. Dose-dependent assessment of the effects of loss of desmoplakin in neonatal ventricular cardiomyocytes revealed primary loss of connexin 43 levels, phosphorylation and function independent of the molecular dissociation of the mechanical junction complex and fibro-fatty manifestation associated with ARVC, suggesting a role for desmoplakin as a primary stabilizer of connexin integrity. In summary, we provide evidence for a novel mouse model, which is reminiscent of the postnatal onset of ARVC while highlighting mechanisms underlying a biventricular form of human ARVC.

Description: Motivation: The differential expression analysis focusing on inter-group comparison can capture only differentially expressed genes (DE genes) at the population level, which may mask the heterogeneity of differential expression in individuals. Thus, to provide patient-specific information for personalized medicine, it is necessary to conduct differential expression analysis at the individual level. Results: We proposed a method to detect DE genes in individual disease samples by using the disrupted ordering in individual disease samples. In both simulated data and real paired cancer-normal sample data, this method showed excellent performance. It was found to be insensitive to experimental batch effects and data normalization. The landscape of stable gene pairs in a particular type of normal tissue could be predetermined using previously accumulated data, based on which dysregulated genes and pathways for any disease sample can be readily detected. The usefulness of the RankComp method in clinical settings was exemplified by the identification and application of prognostic markers for lung cancer. Availability and Implementation: RankComp is implemented in R script that is freely available from Supplementary Materials. Contact: guoz@ems.hrbmu.edu.cn or slliu@ucalgary.ca Supplementary information: Supplementary data are available at Bioinformatics online.