ALBERT

Beschreibung: CDD, the Conserved Domain Database, is part of NCBI’s Entrez query and retrieval system and is also accessible via http://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml . CDD provides annotation of protein sequences with the location of conserved domain footprints and functional sites inferred from these footprints. Pre-computed annotation is available via Entrez, and interactive search services accept single protein or nucleotide queries, as well as batch submissions of protein query sequences, utilizing RPS-BLAST to rapidly identify putative matches. CDD incorporates several protein domain and full-length protein model collections, and maintains an active curation effort that aims at providing fine grained classifications for major and well-characterized protein domain families, as supported by available protein three-dimensional (3D) structure and the published literature. To this date, the majority of protein 3D structures are represented by models tracked by CDD, and CDD curators are characterizing novel families that emerge from protein structure determination efforts.

Beschreibung: The North Anatolian Fault Zone (NAFZ) starts to branch off in the western Bolu plain. The branches of the NAFZ in this location create the Almacık block which is surrounded by the latest surface ruptures of significant earthquakes that occurred between 1944 and 1999, but its northeastern part remains unruptured. The most recently formed rupture, that was a result of the 1999 November 12 Düzce earthquake, ended to the northwest of the Bakacak Fault. The connection between the Bakacak Fault and the main branch of the NAFZ via the Bolu plain has until now remained unknown. This paper establishes that the route of the missing link runs through the Dağkent, Kasaplar and Bürnük faults, a finding achieved with the help of seismic reflection studies. The paper also argues that the cross cutting nature of these newly determined faults and a stress analysis based on focal mechanism solutions of recent earthquakes demonstrate the termination of the suggested pull-apart nature of the Bolu plain.

Beschreibung: Many analytic applications require analyzing user interaction data. In particular, such data can be aggregated over a window to build user activity profiles . Clustering such aggregate profiles is useful for grouping together users with similar behaviors, so that common models could be built for them. In this paper, we present an approach for clustering profiles that are incrementally maintained over a stream of updates. Owing to the potentially large number of users and high rate of interactions, maintaining profile clusters can have high processing and memory resource requirements. To tackle this problem, we apply distributed stream processing. However, in the presence of distributed state, it is a major challenge to partition the profiles over nodes such that memory and computation balance is maintained, while keeping the clustering accuracy high. Furthermore, in order to adapt to potentially changing user interaction patterns, the partitioning of profiles to nodes should be continuously revised, yet one should minimize the migration of profiles so as not to disturb the online processing of updates. We develop a re-partitioning technique that achieves all these goals. To achieve this, we keep micro-cluster summaries at each node and periodically collect these summaries at a central node to perform re-partitioning. We use a greedy algorithm with novel affinity heuristics to revise the partitioning and update the routing tables without introducing a lengthy pause. We showcase the effectiveness of our approach using an application that clusters customers of a telecommunications company based on their aggregate calling profiles.

Beschreibung: Motivation: Network comparison is a computationally intractable problem with important applications in systems biology and other domains. A key challenge is to properly quantify similarity between wiring patterns of two networks in an alignment-free fashion. Also, alignment-based methods exist that aim to identify an actual node mapping between networks and as such serve a different purpose. Various alignment-free methods that use different global network properties (e.g. degree distribution) have been proposed. Methods based on small local subgraphs called graphlets perform the best in the alignment-free network comparison task, due to high level of topological detail that graphlets can capture. Among different graphlet-based methods, Graphlet Correlation Distance (GCD) was shown to be the most accurate for comparing networks. Recently, a new graphlet-based method called NetDis was proposed, which was claimed to be superior. We argue against this, as the performance of NetDis was not properly evaluated to position it correctly among the other alignment-free methods. Results : We evaluate the performance of available alignment-free network comparison methods, including GCD and NetDis. We do this by measuring accuracy of each method (in a systematic precision-recall framework) in terms of how well the method can group (cluster) topologically similar networks. By testing this on both synthetic and real-world networks from different domains, we show that GCD remains the most accurate, noise-tolerant and computationally efficient alignment-free method. That is, we show that NetDis does not outperform the other methods, as originally claimed, while it is also computationally more expensive. Furthermore, since NetDis is dependent on the choice of a network null model (unlike the other graphlet-based methods), we show that its performance is highly sensitive to the choice of this parameter. Finally, we find that its performance is not independent on network sizes and densities, as originally claimed. Contact : natasha@imperial.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.

Beschreibung: Genomic integrity is compromised by DNA polymerase replication errors, which occur in a sequence-dependent manner across the genome. Accurate and complete quantification of a DNA polymerase's error spectrum is challenging because errors are rare and difficult to detect. We report a high-throughput sequencing assay to map in vitro DNA replication errors at the single-molecule level. Unlike previous methods, our assay is able to rapidly detect a large number of polymerase errors at base resolution over any template substrate without quantification bias. To overcome the high error rate of high-throughput sequencing, our assay uses a barcoding strategy in which each replication product is tagged with a unique nucleotide sequence before amplification. This allows multiple sequencing reads of the same product to be compared so that sequencing errors can be found and removed. We demonstrate the ability of our assay to characterize the average error rate, error hotspots and lesion bypass fidelity of several DNA polymerases.

Beschreibung: Motivation: Proteins underlay the functioning of a cell and the wiring of proteins in protein–protein interaction network (PIN) relates to their biological functions. Proteins with similar wiring in the PIN ( topology around them) have been shown to have similar functions. This property has been successfully exploited for predicting protein functions. Topological similarity is also used to guide network alignment algorithms that find similarly wired proteins between PINs of different species; these similarities are used to transfer annotation across PINs, e.g. from model organisms to human. To refine these functional predictions and annotation transfers, we need to gain insight into the variability of the topology-function relationships. For example, a function may be significantly associated with specific topologies, while another function may be weakly associated with several different topologies. Also, the topology-function relationships may differ between different species. Results: To improve our understanding of topology-function relationships and of their conservation among species, we develop a statistical framework that is built upon canonical correlation analysis. Using the graphlet degrees to represent the wiring around proteins in PINs and gene ontology (GO) annotations to describe their functions, our framework: (i) characterizes statistically significant topology-function relationships in a given species, and (ii) uncovers the functions that have conserved topology in PINs of different species, which we term topologically orthologous functions. We apply our framework to PINs of yeast and human, identifying seven biological process and two cellular component GO terms to be topologically orthologous for the two organisms. Availability and implementation: http://bio-nets.doc.ic.ac.uk/goCCA.zip Contact: natasha@imperial.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.

Beschreibung: The recent detection of pulsations from the ultraluminous X-ray source (ULX) NuSTAR J095551+6940.8 in M82 by Bachetti et al. indicates that the object is an accreting neutron star in a high-mass X-ray binary (HMXB) system. The super-Eddington luminosity of the object implies that the magnetic field is sufficiently strong to suppress the scattering cross-section unless its beam is viewed at a favourable angle. We show that the torque equilibrium condition for the pulsar indicates that the dipole magnetic field of the neutron star is 6.7 10 13 G, two orders of magnitude higher than that estimated by Bachetti et al., and further point to the possibility that even stronger magnetic fields could well be in the higher multipoles. This supports the recent view that magnetars descent from HMXBs if the magnetic field decays an order of magnitude during the process of transition.

Beschreibung: Three members of p53 family, p53, p63 and p73, can transactivate their specific target genes through a p53 consensus sequence-binding motif which consists with direct repeats of PuPuPuC(T/A)(T/A)GPyPyPy as a whole-site of p53-binding site. p63, an epidermal stem cells marker, can regulate epidermal development and differentiation, but p53 has no similar biological activity. One isoform of p63, TAp63α, can active an epidermal basal cell marker, keratin 14. However, the p53-binding site does not exist as a whole-site in the K14 promoter region, although it contains three putative p53 half-binding sites at –269 to –1 of the K14 promoter. Two of three putative half-sites of the p53-binding site can be bound by p63α by electrophoresis mobility shift assay and DNA affinity purification assay. Only mutation of the p53 half-binding site at –140 to –131, the TAp63α induced K14 promoter activity can be abolished. This half-site was specifically activated by p63, but not by p53. Once we extend this p53 half-site to a whole p53-binding site in K14 promoter, both p53 and p63 expression vectors can activate its activity. Therefore, we propose that the different length of p53-binding site would determinate the gene regulated by different p53 family proteins.

Beschreibung: Glitches are sudden changes in rotation frequency and spin-down rate, observed from pulsars of all ages. Standard glitches are characterized by a positive step in angular velocity ( 〉 0) and a negative step in the spin-down rate ( $\Delta \dot{\Omega }$  〈 0) of the pulsar. There are no glitch-associated changes in the electromagnetic signature of rotation-powered pulsars in all cases so far. For the first time, in the last glitch of PSR J1119–6127, there is clear evidence for changing emission properties coincident with the glitch. This glitch is also unusual in its signature. Further, the absolute value of the spin-down rate actually decreases in the long term. This is in contrast to usual glitch behaviour. In this paper we extend the vortex creep model in order to take into account these peculiarities. We propose that a starquake with crustal plate movement towards the rotational poles of the star induces inward vortex motion which causes the unusual glitch signature. The component of the magnetic field perpendicular to the rotation axis will decrease, giving rise to a permanent change in the pulsar external torque.

Beschreibung: The surrounding capsule of Streptococcus pneumoniae has been identified as a major virulence factor and is targeted by pneumococcal conjugate vaccines (PCV). However, nonencapsulated S. pneumoniae (non-Ec- Sp ) have also been isolated globally, mainly in carriage studies. It is unknown if non-Ec- Sp evolve sporadically, if they have high antibiotic nonsusceptiblity rates and a unique, specific gene content. Here, whole-genome sequencing of 131 non-Ec- Sp isolates sourced from 17 different locations around the world was performed. Results revealed a deep-branching classic lineage that is distinct from multiple sporadic lineages. The sporadic lineages clustered with a previously sequenced, global collection of encapsulated S. pneumoniae (Ec- Sp ) isolates while the classic lineage is comprised mainly of the frequently identified multilocus sequences types (STs) ST344 ( n = 39) and ST448 ( n = 40). All ST344 and nine ST448 isolates had high nonsusceptiblity rates to β-lactams and other antimicrobials. Analysis of the accessory genome reveals that the classic non-Ec- Sp contained an increased number of mobile elements, than Ec- Sp and sporadic non-Ec- Sp . Performing adherence assays to human epithelial cells for selected classic and sporadic non-Ec- Sp revealed that the presence of a integrative conjugative element (ICE) results in increased adherence to human epithelial cells ( P = 0.005). In contrast, sporadic non-Ec- Sp lacking the ICE had greater growth in vitro possibly resulting in improved fitness. In conclusion, non-Ec- Sp isolates from the classic lineage have evolved separately. They have spread globally, are well adapted to nasopharyngeal carriage and are able to coexist with Ec- Sp. Due to continued use of PCV, non-Ec- Sp may become more prevalent.