ALBERT

Description: Histone modifications are associated with meiotic recombination hotspots, discrete sites with augmented recombination frequency. For example, trimethylation of histone H3 lysine4 (H3K4me3) marks most hotspots in budding yeast and mouse. Modified histones are known to regulate meiotic recombination partly by promoting DNA double-strand break (DSB) formation at hotspots, but the role and precise landscape of involved modifications remain unclear. Here, we studied hotspot-associated modifications in fission yeast and found general features: acetylation of H3 lysine9 (H3K9ac) is elevated, and H3K4me3 is not significantly enriched. Mutating H3K9 to non-acetylatable alanine mildly reduced levels of the DSB-inducing protein Rec12 (the fission yeast homologue of Spo11) and DSB at hotspots, indicating that H3K9ac may be involved in DSB formation by enhancing the interaction between Rec12 and hotspots. In addition, we found that the lack of the H3K4 methyltransferase Set1 generally increased Rec12 binding to chromatin but partially reduced DSB formation at some loci, suggesting that Set1 is also involved in DSB formation. These results suggest that meiotic DSB formation is redundantly regulated by multiple chromatin-related factors including H3K9ac and Set1 in fission yeast.

Description: Motivation: Event extraction using expressive structured representations has been a significant focus of recent efforts in biomedical information extraction. However, event extraction resources and methods have so far focused almost exclusively on molecular-level entities and processes, limiting their applicability. Results: We extend the event extraction approach to biomedical information extraction to encompass all levels of biological organization from the molecular to the whole organism. We present the ontological foundations, target types and guidelines for entity and event annotation and introduce the new multi-level event extraction (MLEE) corpus, manually annotated using a structured representation for event extraction. We further adapt and evaluate named entity and event extraction methods for the new task, demonstrating that both can be achieved with performance broadly comparable with that for established molecular entity and event extraction tasks. Availability: The resources and methods introduced in this study are available from http://nactem.ac.uk/MLEE/ . Contact: pyysalos@cs.man.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.

Description: In this short note, we give two simple examples of metric measure spaces containing branching geodesics and satisfying Lott, Sturm and Villani's curvature-dimension condition. In the first example, only geodesics in a subspace of co-dimension 1 can branch. The second one is positively curved in the sense of the curvature-dimension condition. We also discuss related open problems.

Description: Glioblastomas frequently harbour genetic lesions that stimulate the activity of mammalian target of rapamycin complex 1 (mTORC1). Loss of heterozygosity of tuberous sclerosis complex 1 ( TSC1 ) or TSC2 , which together form a critical negative regulator of mTORC1, is also seen in glioblastoma; however, it is not known how loss of the TSC complex affects the development of malignant gliomas. Here we investigated the role of Tsc1 in gliomagenesis in mice. Tsc1 deficiency up-regulated mTORC1 activity and suppressed the proliferation of neural stem/progenitor cells (NSPCs) in a serial neurosphere-forming assay, suggesting that Tsc1 -deficient NSPCs have defective self-renewal activity. The neurosphere-forming capacity of Tsc1 -deficient NSPCs was restored by p16 Ink4a p19 Arf deficiency. Combined Tsc1 and p16 Ink4a p19 Arf deficiency in NSPCs did not cause gliomagenesis in vivo . However, in a glioma model driven by an active mutant of epidermal growth factor receptor (EGFR), EGFRvIII, loss of Tsc1 resulted in an earlier onset of glioma development. The mTORC1 hyperactivation by Tsc1 deletion accelerated malignant phenotypes, including increased tumour mass and enhanced microvascular formation, leading to intracranial haemorrhage. These data demonstrate that, although mTORC1 hyperactivation itself may not be sufficient for gliomagenesis, it is a potent modifier of glioma development when combined with oncogenic signals.

Description: To obtain the correct tomographic reconstruction of micron-sized materials, the nonlinear intensity attenuation of bright-field transmission electron microscopy (BF-TEM) images was analyzed as a function of the sample thickness using a high-voltage electron microscope. The intensity attenuation was precisely measured relative to the projection thickness of carbon microcoils (CMCs) at acceleration voltages of 400–1000 kV using objective apertures (OAs) with radii of 2.1–28 nm –1 . The results show that the nonlinearity is strongly dependent on the OA size and the acceleration voltage. The influence of nonlinearity on tomographic reconstructions was also examined using a specially developed 360°-tilt sample holder. Sliced images of the reconstructed volumes indicated that an increase in the nonlinearity caused artificial fluctuations in the internal density of materials and inaccurate shapes of the objects in more significant cases. Conditions sufficient for reconstruction with the correct density have been estimated to be 0.67 of the minimum electron transmittance, and for reconstructions with correct shapes, 0.4. This information enables foreseeing the quality of the reconstruction from a single BF-TEM image prior to the tilt-series acquisition. As a result to demonstrate the appropriateness of these conditions, a CMC with a diameter of 3.7 µm was reconstructed successfully; i.e. not only the shape but also the internal density were correctly reproduced using electron tomography.

Description: Scanning electron microscopy (SEM) has made remarkable progress and has become an essential tool for observing biological materials at microscopic level. However, various complex procedures have precluded observation of living organisms to date. Here, a new method is presented by which living organisms can be observed by field emission (FE)-SEM. Using this method, active movements of living animals were observed in vacuo (10 –5 –10 –7 Pa) by protecting them with a coating of thin polymer membrane, a NanoSuit, and it was found that the surface fine structure of living organisms is very different from that of traditionally fixed samples. After observation of mosquito larvae in the high vacuum of the FE-SEM, it was possible to rear them subsequently in normal culture conditions. This method will be useful for numerous applications, particularly for electron microscopic observations in the life sciences.

Description: Meiotic homologous recombination is markedly activated during meiotic prophase to play central roles in faithful chromosome segregation and conferring genetic diversity to gametes. It is initiated by programmed DNA double-strand breaks (DSBs) by the conserved protein Spo11, and preferentially occurs at discrete sites called hotspots. Since the functions of Spo11 are influenced by both of local chromatin at hotspots and higher-order chromosome structures, formation of meiotic DSBs is under regulation of chromatin structure. Therefore, investigating features and roles of meiotic chromatin is crucial to elucidate the in vivo mechanism of meiotic recombination initiation. Recent progress in genome-wide chromatin analyses tremendously improved our understanding on this point, but many critical questions are left unaddressed. In this review, we summarize current knowledge in the field, and also discuss the future problems that must be solved to understand the role of chromatin structure in meiotic recombination.

Description: We present an investigation into how well the properties of the accretion flow on to a supermassive black hole may be coupled to those of the overlying hot corona. To do so, we specifically measure the characteristic spectral index, , of a power-law energy distribution, over an energy range of 2–10 keV, for X-ray selected, broad-lined radio-quiet active galactic nuclei (AGN) up to z  ~ 2 in Cosmic Evolution Survey (COSMOS) and Extended Chandra Deep Field South (E-CDF-S). We test the previously reported dependence between and black hole mass, full width at half-maximum (FWHM) and Eddington ratio using a sample of AGN covering a broad range in these parameters based on both the Mg  ii and Hα emission lines with the later afforded by recent near-infrared spectroscopic observations using Subaru/Fibre Multi Object Spectrograph. We calculate the Eddington ratios, Edd , for sources where a bolometric luminosity ( L Bol ) has been presented in the literature, based on spectral energy distribution fitting, or, for sources where these data do not exist, we calculate L Bol using a bolometric correction to the X-ray luminosity, derived from a relationship between the bolometric correction and L X / L 3000 . From a sample of 69 X-ray bright sources (〉250 counts), where can be measured with greatest precision, with an estimate of L Bol , we find a statistically significant correlation between and Edd , which is highly significant with a chance probability of 6.59 x 10 –8 . A statistically significant correlation between and the FWHM of the optical lines is confirmed, but at lower significance than with Edd indicating that Edd is the key parameter driving conditions in the corona. Linear regression analysis reveals that  = (0.32 ± 0.05) log 10 Edd  + (2.27 ± 0.06) and  = (–0.69 ± 0.11) log 10 (FWHM/km s –1 ) + (4.44 ± 0.42). Our results on – Edd are in very good agreement with previous results. While the – Edd relationship means that X-ray spectroscopy may be used to estimate black hole accretion rate, considerable dispersion in the correlation does not make this viable for single sources, however could be valuable for large X-ray spectral samples, such as those to be produced by eROSITA .

Description: Many chronic inflammatory conditions are associated with an increased risk of cancer development. At the site of inflammation, cellular DNA is damaged by hypochlorous acid (HOCl), a potent oxidant generated by myeloperoxidase. 8-Chloro-2'-deoxyguanosine (8-Cl-dG) is a major DNA adduct formed by HOCl and has been detected from the liver DNA and urine of rats administered lipopolysaccharide in an inflammation model. Thus, the 8-Cl-dG lesion may be associated with the carcinogenesis of inflamed tissues. In this study, we explored the miscoding properties of the 8-Cl-dG adduct generated by human DNA polymerases (pols). Site-specifically modified oligodeoxynucleotide containing a single 8-Cl-dG was prepared and used as a template in primer extension reactions catalysed by human pol α, or . Primer extension reactions catalysed by pol α and in the presence of all four dNTPs were slightly retarded at the 8-Cl-dG site, while pol readily bypassed the lesion. The fully extended products were analysed to quantify the miscoding frequency and specificity of 8-Cl-dG using two-phased polyacrylamide gel electrophoresis (PAGE). During the primer extension reaction in the presence of four dNTPs, pol promoted one-base deletion (6.4%), accompanied by the misincorporation of 2'-deoxyguanosine monophosphate (5.5%), dAMP (3.7%), and dTMP (3.5%) opposite the lesion. Pol α and , on the other hand, exclusively incorporated dCMP opposite the lesion. The steady-state kinetic studies supported the results obtained from the two-phased PAGE assay. These results indicate that 8-Cl-dG is a mutagenic lesion; the miscoding frequency and specificity varies depending on the DNA polymerase used. Thus, HOCl-induced 8-Cl-dG adduct may be involved in inflammation-driven carcinogenesis.

Description: Motivation: To create, verify and maintain pathway models, curators must discover and assess knowledge distributed over the vast body of biological literature. Methods supporting these tasks must understand both the pathway model representations and the natural language in the literature. These methods should identify and order documents by relevance to any given pathway reaction. No existing system has addressed all aspects of this challenge. Method: We present novel methods for associating pathway model reactions with relevant publications. Our approach extracts the reactions directly from the models and then turns them into queries for three text mining-based MEDLINE literature search systems. These queries are executed, and the resulting documents are combined and ranked according to their relevance to the reactions of interest. We manually annotate document-reaction pairs with the relevance of the document to the reaction and use this annotation to study several ranking methods, using various heuristic and machine-learning approaches. Results: Our evaluation shows that the annotated document-reaction pairs can be used to create a rule-based document ranking system, and that machine learning can be used to rank documents by their relevance to pathway reactions. We find that a Support Vector Machine-based system outperforms several baselines and matches the performance of the rule-based system. The success of the query extraction and ranking methods are used to update our existing pathway search system, PathText. Availability: An online demonstration of PathText 2 and the annotated corpus are available for research purposes at http://www.nactem.ac.uk/pathtext2/ . Contact: makoto.miwa@manchester.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.