Developing sensitive and reliable methods to distinguish normal and abnormal brain states is a key neuroscientific challenge. Topological Data Analysis, despite its relative novelty, already generated many promising applications, including in neuroscience. We conjecture its prominent tool of persistent homology may benefit from going beyond analysing structural and functional connectivity to effective connectivity graphs capturing the direct causal interactions or information flows. Therefore, we assess the potential of persistent homology to directed brain network analysis by testing its discriminatory power in two distinctive examples of disease-related brain connectivity alterations: epilepsy and schizophrenia. We estimate connectivity from functional magnetic resonance imaging and electrophysiology data, employ Persistent Homology and quantify its ability to distinguish healthy from diseased brain states by applying a support vector machine to features quantifying persistent homology structure. We show how this novel approach compares to classification using standard undirected approaches and original connectivity matrices. In the schizophrenia classification, topological data analysis generally performs close to random, while classifications from raw connectivity perform substantially better; potentially due to topographical, rather than topological, specificity of the differences. In the easier task of seizure discrimination from scalp electroencephalography data, classification based on persistent homology features generally reached comparable performance to using raw connectivity, albeit with typically smaller accuracies obtained for the directed (effective) connectivity compared to the undirected (functional) connectivity. Specific applications for topological data analysis may open when direct comparison of connectivity matrices is unsuitable - such as for intracranial electrophysiology with individual number and location of measurements. While standard homology performed overall better than directed homology, this could be due to notorious technical problems of accurate effective connectivity estimation.
- MeSH
- Electroencephalography MeSH
- Epilepsy diagnostic imaging physiopathology MeSH
- Connectome * MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Brain Mapping MeSH
- Models, Neurological * MeSH
- Brain diagnostic imaging physiopathology MeSH
- Nerve Net diagnostic imaging physiopathology MeSH
- Schizophrenia diagnostic imaging physiopathology MeSH
- Seizures diagnostic imaging physiopathology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Franckeite is a natural superlattice composed of two alternating layers of different composition which has shown potential for optoelectronic applications. In part, the interest in franckeite lies in its layered nature which makes it easy to exfoliate into very thin heterostructures. Not surprisingly, its chemical composition and lattice structure are so complex that franckeite has escaped screening protocols and high-throughput searches of materials with nontrivial topological properties. On the basis of density functional theory calculations, we predict a quantum phase transition originating from stoichiometric changes in one of franckeite composing layers (the quasihexagonal one). While for a large concentration of Sb, franckeite is a sequence of type-II semiconductor heterojunctions, for a large concentration of Sn, these turn into type-III, much alike InAs/GaSb artificial heterojunctions, and franckeite becomes a strong topological insulator. Transmission electron microscopy observations confirm that such a phase transition may actually occur in nature.
DNA double-strand breaks (DSBs), known as the most severe damage in chromatin, were induced in breast cancer cells and normal skin fibroblasts by 2 Gy ionizing photon radiation. In response to DSB induction, phosphorylation of the histone variant H2AX to γH2AX was observed in the form of foci visualized by specific antibodies. By means of super-resolution single-molecule localization microscopy (SMLM), it has been recently shown in a first article about these data that these foci can be separated into clusters of about the same size (diameter ~400 nm). The number of clusters increased with the dose applied and decreased with the repair time. It has also been shown that during the repair period, antibody-labeled MRE11 clusters of about half of the γH2AX cluster diameter were formed inside several γH2AX clusters. MRE11 is part of the MRE11-RAD50-NBS1 (MRN) complex, which is known as a DNA strand resection and broken-end bridging component in homologous recombination repair (HRR) and alternative non-homologous end joining (a-NHEJ). This article is a follow-up of the former ones applying novel procedures of mathematics (topology) and similarity measurements on the data set: to obtain a measure for cluster shape and shape similarities, topological quantifications employing persistent homology were calculated and compared. In addition, based on our findings that γH2AX clusters associated with heterochromatin show a high degree of similarity independently of dose and repair time, these earlier published topological analyses and similarity calculations comparing repair foci within individual cells were extended by topological data averaging (2nd-generation heatmaps) over all cells analyzed at a given repair time point; thereby, the two dimensions (0 and 1) expressed by components and holes were studied separately. Finally, these mean value heatmaps were averaged, in addition. For γH2AX clusters, in both normal fibroblast and MCF-7 cancer cell lines, an increased similarity was found at early time points (up to 60 min) after irradiation for both components and holes of clusters. In contrast, for MRE11, the peak in similarity was found at later time points (2 h up to 48 h) after irradiation. In general, the normal fibroblasts showed quicker phosphorylation of H2AX and recruitment of MRE11 to γH2AX clusters compared to breast cancer cells and a shorter time interval of increased similarity for γH2AX clusters. γH2AX foci and randomly distributed MRE11 molecules naturally occurring in non-irradiated control cells did not show any significant topological similarity.
- Publication type
- Journal Article MeSH
The Complex Portal (www.ebi.ac.uk/complexportal) is a manually curated, encyclopaedic database that collates and summarizes information on stable, macromolecular complexes of known function. It captures complex composition, topology and function and links out to a large range of domain-specific resources that hold more detailed data, such as PDB or Reactome. We have made several significant improvements since our last update, including improving compliance to the FAIR data principles by providing complex-specific, stable identifiers that include versioning. Protein complexes are now available from 20 species for download in standards-compliant formats such as PSI-XML, MI-JSON and ComplexTAB or can be accessed via an improved REST API. A component-based JS front-end framework has been implemented to drive a new website and this has allowed the use of APIs from linked services to import and visualize information such as the 3D structure of protein complexes, its role in reactions and pathways and the co-expression of complex components in the tissues of multi-cellular organisms. A first draft of the complete complexome of Saccharomyces cerevisiae is now available to browse and download.
- MeSH
- Databases, Protein * MeSH
- Protein Conformation MeSH
- Humans MeSH
- Macromolecular Substances chemistry MeSH
- Multiprotein Complexes chemistry metabolism MeSH
- Mice MeSH
- Nucleic Acids chemistry MeSH
- Computer Graphics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Complex decision making tasks of different natures, e.g. economics, safety engineering, ecology and biology, are based on vague, sparse, partially inconsistent and subjective knowledge. Moreover, decision making economists / engineers are usually not willing to invest too much time into study of complex formal theories. They require such decisions which can be (re)checked by human like common sense reasoning. One important problem related to realistic decision making tasks are incomplete data sets required by the chosen decision making algorithm. This paper presents a relatively simple algorithm how some missing III (input information items) can be generated using mainly decision tree topologies and integrated into incomplete data sets. The algorithm is based on an easy to understand heuristics, e.g. a longer decision tree sub-path is less probable. This heuristic can solve decision problems under total ignorance, i.e. the decision tree topology is the only information available. But in a practice, isolated information items e.g. some vaguely known probabilities (e.g. fuzzy probabilities) are usually available. It means that a realistic problem is analysed under partial ignorance. The proposed algorithm reconciles topology related heuristics and additional fuzzy sets using fuzzy linear programming. The case study, represented by a tree with six lotteries and one fuzzy probability, is presented in details.
- MeSH
- Algorithms MeSH
- Fuzzy Logic * MeSH
- Heuristics physiology MeSH
- Humans MeSH
- Decision Support Techniques MeSH
- Probability MeSH
- Decision Trees * MeSH
- Decision Making physiology MeSH
- Models, Theoretical MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
G-quadruplexes (G4s), a type of non-B DNA, play important roles in a wide range of molecular processes, including replication, transcription, and translation. Genome integrity relies on efficient and accurate DNA synthesis, and is compromised by various stressors, to which non-B DNA structures such as G4s can be particularly vulnerable. However, the impact of G4 structures on DNA polymerase fidelity is largely unknown. Using an in vitro forward mutation assay, we investigated the fidelity of human DNA polymerases delta (δ4, four-subunit), eta (η), and kappa (κ) during synthesis of G4 motifs representing those in the human genome. The motifs differ in sequence, topology, and stability, features that may affect DNA polymerase errors. Polymerase error rate hierarchy (δ4 < κ < η) is largely maintained during G4 synthesis. Importantly, we observed unique polymerase error signatures during synthesis of VEGF G4 motifs, stable G4s which form parallel topologies. These statistically significant errors occurred within, immediately flanking, and encompassing the G4 motif. For pol δ4, the errors were deletions, insertions and complex errors within the G4 or encompassing the G4 motif and surrounding sequence. For pol η, the errors occurred in 3' sequences flanking the G4 motif. For pol κ, the errors were frameshift mutations within G-tracts of the G4. Because these error signatures were not observed during synthesis of an antiparallel G4 and, to a lesser extent, a hybrid G4, we suggest that G4 topology and/or stability could influence polymerase fidelity. Using in silico analyses, we show that most polymerase errors are predicted to have minimal effects on predicted G4 stability. Our results provide a unique view of G4s not previously elucidated, showing that G4 motif heterogeneity differentially influences polymerase fidelity within the motif and flanking sequences. Thus, our study advances the understanding of how DNA polymerase errors contribute to G4 mutagenesis.
- MeSH
- DNA-Directed DNA Polymerase genetics metabolism MeSH
- DNA genetics MeSH
- G-Quadruplexes * MeSH
- Humans MeSH
- DNA Replication MeSH
- Vascular Endothelial Growth Factor A genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
Rose chafers (Cetoniinae) are a large group of flower visitors within the pleurostict Scarabaeidae that are characterized by their distinctive flight mode with nearly closed forewings. Despite their popularity, this is the first study to use molecular data to infer their phylogenetic relationships. We used partial gene sequences for 28S rRNA, cytochrome oxidase I (cox1) and 16S rRNA (rrnL) for 299 species, representing most recognized subfamilies of Scarabaeidae, including 125 species of Cetoniinae. Combined analyses using maximum parsimony, maximum likelihood and Bayesian inferences recovered Cetoniinae as monophyletic in all analyses, with the sister clade composed of Rutelinae and Dynastinae. Rutelinae was always recovered as paraphyletic with respect to Dynastinae. Trichiini sensu lato (s.l.) was recovered as a polyphyletic clade, while Cetoniini s.l. was recovered as paraphyletic. The inferred topologies were also supported by site bootstrapping of the ML trees. With the exception of Cremastochelini, most tribes of Cetoniinae were poly- or paraphyletic, indicating the critical need for a careful revision of rose chafer classification. Analysis of elytral base structure (including 11 scored characters) in the context of phylogeny, revealed a complex, concerted and rapid transformation of the single trait elements linked to a modified flight mode with closed elytra. This appears to be unlinked to the lateral sinuation of the elytra, which originated independently several times at later stages in the evolution of the group.
- MeSH
- Bayes Theorem MeSH
- Biological Evolution * MeSH
- Coleoptera classification genetics MeSH
- DNA chemistry isolation & purification metabolism MeSH
- Phylogeny MeSH
- Wings, Animal anatomy & histology MeSH
- Electron Transport Complex IV genetics MeSH
- RNA, Ribosomal, 16S genetics MeSH
- RNA, Ribosomal, 28S genetics MeSH
- Sequence Analysis, DNA MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
Structure validation has become a major issue in the structural biology community, and an essential step is checking the ligand structure. This paper introduces MotiveValidator, a web-based application for the validation of ligands and residues in PDB or PDBx/mmCIF format files provided by the user. Specifically, MotiveValidator is able to evaluate in a straightforward manner whether the ligand or residue being studied has a correct annotation (3-letter code), i.e. if it has the same topology and stereochemistry as the model ligand or residue with this annotation. If not, MotiveValidator explicitly describes the differences. MotiveValidator offers a user-friendly, interactive and platform-independent environment for validating structures obtained by any type of experiment. The results of the validation are presented in both tabular and graphical form, facilitating their interpretation. MotiveValidator can process thousands of ligands or residues in a single validation run that takes no more than a few minutes. MotiveValidator can be used for testing single structures, or the analysis of large sets of ligands or fragments prepared for binding site analysis, docking or virtual screening. MotiveValidator is freely available via the Internet at http://ncbr.muni.cz/MotiveValidator.
- MeSH
- Acetylglucosamine chemistry MeSH
- Ephrin-B3 chemistry MeSH
- Glycoproteins chemistry MeSH
- Internet MeSH
- Cholic Acid chemistry MeSH
- Ligands MeSH
- Macromolecular Substances chemistry MeSH
- Proteins chemistry MeSH
- Software * MeSH
- Binding Sites MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Naive use of molecular data may lead to ambiguous conclusions, especially within the context of "cryptic" species. Here, we integrated molecular and morphometric data to evaluate phylogenetic relationships in the widespread terrestrial micro-snail genus, Euconulus. We analyzed mitochondrial (16S + COII) and nuclear (ITS1 + ITS2) sequence across 94 populations from Europe, Asia and North America within the nominate species E. alderi, E. fulvus and E. polygyratus, and used the southeastern USA E. chersinus, E. dentatus, and E. trochulus as comparative outgroups. Phylogeny was reconstructed using four different reconstruction methods to identify robust, well-supported topological features. We then performed discriminant analysis on shell measurements between these genetically-identified species-level clades. These analyses provided evidence for a biologically valid North American "cryptic" species within E. alderi. However, while highly supported polyphyletic structure was also observed within E. fulvus, disagreement in placement of individuals between mtDNA and nDNA clades, lack of morphological differences, and presence of potential hybrids imply that these lineages do not rise to the threshold as biologically valid cryptic species, and rather appear to simply represent a complex of geographically structured populations within a single species. These results caution that entering into a cryptic species hypothesis should not be undertaken lightly, and should be optimally supported along multiple lines of evidence. Generally, post-hoc analyses of macro-scale features should be conducted to attempt identification of previously ignored diagnostic traits. If such traits cannot be found, i.e. in the case of potentially "fully cryptic" species, additional criteria should be met to propound a cryptic species hypothesis, including the agreement in tree topology among both mtDNA and nDNA, and little (or no) evidence of hybridization based on a critical analysis of sequence chromatograms. Even when the above conditions are satisfied, it only implies that the cryptic species hypothesis is plausible, but should optimally be subjected to further careful examination.
- MeSH
- Principal Component Analysis MeSH
- Cell Nucleus genetics MeSH
- Phylogeny MeSH
- Snails classification genetics MeSH
- Likelihood Functions MeSH
- Electron Transport Complex IV classification genetics MeSH
- RNA, Ribosomal, 16S classification genetics MeSH
- Base Sequence MeSH
- Sequence Analysis, DNA MeSH
- Sequence Alignment MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
RNA polymerase II contains a long C-terminal domain (CTD) that regulates interactions at the site of transcription. The CTD architecture remains poorly understood due to its low sequence complexity, dynamic phosphorylation patterns, and structural variability. We used integrative structural biology to visualize the architecture of the CTD in complex with Rtt103, a 3'-end RNA-processing and transcription termination factor. Rtt103 forms homodimers via its long coiled-coil domain and associates densely on the repetitive sequence of the phosphorylated CTD via its N-terminal CTD-interacting domain. The CTD-Rtt103 association opens the compact random coil structure of the CTD, leading to a beads-on-a-string topology in which the long rod-shaped Rtt103 dimers define the topological and mobility restraints of the entire assembly. These findings underpin the importance of the structural plasticity of the CTD, which is templated by a particular set of CTD-binding proteins.
- MeSH
- Protein Interaction Domains and Motifs MeSH
- Crystallography, X-Ray MeSH
- Magnetic Resonance Spectroscopy MeSH
- Protein Multimerization MeSH
- RNA Polymerase II metabolism MeSH
- Saccharomyces cerevisiae Proteins chemistry metabolism MeSH
- Amino Acid Sequence MeSH
- Transcription Factors chemistry metabolism MeSH
- Publication type
- Video-Audio Media MeSH
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
