ALBERT

Description: Golgi fragmentation is an early hallmark of many neurodegenerative diseases but its pathophysiological relevance and molecular mechanisms are unclear. We here demonstrate severe and progressive Golgi fragmentation in motor neurons of progressive motor neuronopathy (pmn) mice due to loss of the Golgi-localized tubulin-binding cofactor E (TBCE). Loss of TBCE in mutant pmn and TBCE-depleted motor neuron cultures causes defects in Golgi-derived microtubules, as expected, but surprisingly also reduced levels of COPI subunits, decreased recruitment of tethering factors p115/GM130 and impaired Golgi SNARE-mediated vesicle fusion. Conversely, ARF1, which stimulates COPI vesicle formation, enhances the recruitment of TBCE to the Golgi, increases polymerization of Golgi-derived microtubules and rescues TBCE-linked Golgi fragmentation. These data indicate an ARF1/TBCE-mediated cross-talk that coordinates COPI formation and tubulin polymerization at the Golgi. We conclude that interruption of this cross-talk causes Golgi fragmentation in pmn mice and hypothesize that similar mechanisms operate in human amyotrophic lateral sclerosis and spinal muscular atrophy.

Description: Motivated by possible observations of the black hole candidate in the centre of our Galaxy and the galaxy M87, ray-tracing methods are applied to both standard General Relativity (GR) and a recently proposed extension, the pseudo-complex GR (pc-GR). The correction terms due to the investigated pc-GR model lead to slower orbital motions close to massive objects. Also the concept of an innermost stable circular orbit is modified for the pc-GR model, allowing particles to get closer to the central object for most values of the spin parameter a than in GR. Thus, the accretion disc, surrounding a massive object, is brighter in pc-GR than in GR. Iron Kα emission-line profiles are also calculated as those are good observables for regions of strong gravity. Differences between the two theories are pointed out.

Description: Motivation: Histone modifications are a key epigenetic mechanism to activate or repress the transcription of genes. Datasets of matched transcription data and histone modification data obtained by ChIP-seq exist, but methods for integrative analysis of both data types are still rare. Here, we present a novel bioinformatics approach to detect genes that show different transcript abundances between two conditions putatively caused by alterations in histone modification. Results: We introduce a correlation measure for integrative analysis of ChIP-seq and gene transcription data measured by RNA sequencing or microarrays and demonstrate that a proper normalization of ChIP-seq data is crucial. We suggest applying Bayesian mixture models of different types of distributions to further study the distribution of the correlation measure. The implicit classification of the mixture models is used to detect genes with differences between two conditions in both gene transcription and histone modification. The method is applied to different datasets, and its superiority to a naive separate analysis of both data types is demonstrated. Availability and implementation: R/Bioconductor package epigenomix. Contact: h.klein@uni-muenster.de Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Dnmt2 enzymes are conserved in eukaryotes, where they methylate C38 of tRNA-Asp with high activity. Here, the activity of one of the very few prokaryotic Dnmt2 homologs from Geobacter species (GsDnmt2) was investigated. GsDnmt2 was observed to methylate tRNA-Asp from flies and mice. Unexpectedly, it had only a weak activity toward its matching Geobacter tRNA-Asp, but methylated Geobacter tRNA-Glu with good activity. In agreement with this result, we show that tRNA-Glu is methylated in Geobacter while the methylation is absent in tRNA-Asp. The activities of Dnmt2 enzymes from Homo sapiens , Drosophila melanogaster , Schizosaccharomyces pombe and Dictyostelium discoideum for methylation of the Geobacter tRNA-Asp and tRNA-Glu were determined showing that all these Dnmt2s preferentially methylate tRNA-Asp. Hence, the GsDnmt2 enzyme has a swapped transfer ribonucleic acid (tRNA) specificity. By comparing the different tRNAs, a characteristic sequence pattern was identified in the variable loop of all preferred tRNA substrates. An exchange of two nucleotides in the variable loop of murine tRNA-Asp converted it to the corresponding variable loop of tRNA-Glu and led to a strong reduction of GsDnmt2 activity. Interestingly, the same loss of activity was observed with human DNMT2, indicating that the variable loop functions as a specificity determinant in tRNA recognition of Dnmt2 enzymes.

Description: Full-waveform inversion (FWI) of shallow-seismic surface waves is able to reconstruct lateral variations of subsurface elastic properties. Line-source simulation for point-source data is required when applying algorithms of 2-D adjoint FWI to recorded shallow-seismic field data. The equivalent line-source response for point-source data can be obtained by convolving the waveforms with $\sqrt{t^{-1}}$ ( t : traveltime), which produces a phase shift of /4. Subsequently an amplitude correction must be applied. In this work we recommend to scale the seismograms with $\sqrt{2 r v_{\rm ph}}$ at small receiver offsets r , where v ph is the phase velocity, and gradually shift to applying a $\sqrt{t^{-1}}$ time-domain taper and scaling the waveforms with $r\sqrt{2}$ for larger receiver offsets r . We call this the hybrid transformation which is adapted for direct body and Rayleigh waves and demonstrate its outstanding performance on a 2-D heterogeneous structure. The fit of the phases as well as the amplitudes for all shot locations and components (vertical and radial) is excellent with respect to the reference line-source data. An approach for 1-D media based on Fourier–Bessel integral transformation generates strong artefacts for waves produced by 2-D structures. The theoretical background for both approaches is presented in a companion contribution. In the current contribution we study their performance when applied to waves propagating in a significantly 2-D-heterogeneous structure. We calculate synthetic seismograms for 2-D structure for line sources as well as point sources. Line-source simulations obtained from the point-source seismograms through different approaches are then compared to the corresponding line-source reference waveforms. Although being derived by approximation the hybrid transformation performs excellently except for explicitly back-scattered waves. In reconstruction tests we further invert point-source synthetic seismograms by a 2-D FWI to subsurface structure and evaluate its ability to reproduce the original structural model in comparison to the inversion of line-source synthetic data. Even when applying no explicit correction to the point-source waveforms prior to inversion only moderate artefacts appear in the results. However, the overall performance is best in terms of model reproduction and ability to reproduce the original data in a 3-D simulation if inverted waveforms are obtained by the hybrid transformation.

Description: Equivalent line-source seismograms can be obtained from shallow seismic field recordings by (1) convolving the waveforms with $\sqrt{t^{-1}}$ , (2) applying a $\sqrt{t^{-1}}$ time-domain taper, where t is traveltime and (3) scaling the waveform with $r_{{\rm offset}}\sqrt{2}$ , where r offset is source-to-receiver offset. We require such a procedure when applying algorithms of 2-D adjoint full-waveform inversion (FWI) to shallow-seismic data. Although derived from solutions for acoustic waves in homogeneous full space this simple procedure performs surprisingly well when applied to vertical and radial components of shallow-seismic recordings from hammer blows or explosions. This is the case even in the near field of the force, although the procedure is derived from a far-field approximation. Similar approximative procedures recommended in literature are optimized for reflected waves and do not convert the amplitudes of all shallow seismic wavefield constituents equally well. We demonstrate the suitability of the proposed method for the viscoelastic case by numerical examples as well as analytical considerations. In contrast to the proposed single-trace procedure, integral-transform approaches are exact for all viscoelastic wavefield constituents of the near- and far-field in unknown 1-D-heterogeneous structure. Unfortunately, integral-transform approaches suffer from artefacts in applications to data sampled on 2-D structures. Here, we use the Fourier–Bessel integral transformation as a reference in 1-D heterogeneous structures. We unroll the wave-theoretical background of both approaches in order to demonstrate, why the simplistic single-trace simulation approach derived from the asymptotic acoustic case can perform so well when applied to the shallow elastic wavefield. Further we give recommendations for practical implementation and application to field data of the proposed simulation method and compare to the results of alternative conversion rules. The performance of the conversion procedure to data recorded on 2-D heterogeneous structures is presented in a companion study by FWI reconstruction tests.

Description: A variety of genome-wide profiling techniques are available to investigate complementary aspects of genome structure and function. Integrative analysis of heterogeneous data sources can reveal higher level interactions that cannot be detected based on individual observations. A standard integration task in cancer studies is to identify altered genomic regions that induce changes in the expression of the associated genes based on joint analysis of genome-wide gene expression and copy number profiling measurements. In this review, we highlight common approaches to genomic data integration and provide a transparent benchmarking procedure to quantitatively compare method performances in cancer gene prioritization. Algorithms, data sets and benchmarking results are available at http://intcomp.r-forge.r-project.org .

Description: Based on previous publications exploring pseudo-complex General Relativity (pc-GR) we present a selection of observable consequences of pc-GR and possible ways to experimentally access them. Whenever possible we compare the results to Einstein's GR and differences are worked out in detail. We propose experimental tests to check the predictions of pc-GR for the orbital frequency of test particles, the gravitational redshift effect and the last stable orbit. We will show that the orbital frequency of test particles at a given radius in pc-GR is in general lower compared to standard GR. Also the effect of frame dragging is modified (weakened) in pc-GR. Concerning the gravitational redshift of a radiation emitting object we find that it is also lower in pc-GR than in standard GR. Eventually, the classical concept of a last stable orbit has to be modified in pc-GR.