ALBERT

Description: In this paper, we will present a generalized convolution quadrature for solving linear parabolic and hyperbolic evolution equations. The original convolution quadrature method by Lubich works very nicely for equidistant time steps while the generalization of the method and its analysis to nonuniform time stepping is by no means obvious. We will introduce the generalized convolution quadrature allowing for variable time steps and develop a theory for its error analysis. This method opens the door for further development towards adaptive time stepping for evolution equations. As the main application of our new theory, we will consider the wave equation in exterior domains which is formulated as a retarded boundary integral equation.

Description: We previously showed that disease-linked metabolic genes are often under combinatorial regulation. Using the genome-wide ChIP-Seq binding profiles for 93 transcription factors in nine different cell lines, we show that genes under high regulatory load are significantly enriched for disease-association across cell types. We find that transcription factor load correlates with the enhancer load of the genes and thereby allows the identification of genes under high regulatory load by epigenomic mapping of active enhancers. Identification of the high enhancer load genes across 139 samples from 96 different cell and tissue types reveals a consistent enrichment for disease-associated genes in a cell type-selective manner. The underlying genes are not limited to super-enhancer genes and show several types of disease-association evidence beyond genetic variation (such as biomarkers). Interestingly, the high regulatory load genes are involved in more KEGG pathways than expected by chance, exhibit increased betweenness centrality in the interaction network of liver disease genes, and carry longer 3' UTRs with more microRNA (miRNA) binding sites than genes on average, suggesting a role as hubs integrating signals within regulatory networks. In summary, epigenetic mapping of active enhancers presents a promising and unbiased approach for identification of novel disease genes in a cell type-selective manner.

Description: We present the first estimates of Southwest Indian Ridge (SWIR) plate motions at high temporal resolution during the Quaternary and Neogene based on nearly 5000 crossings of 21 magnetic reversals out to C6no (19.72 Ma) and the digitized traces of 17 fracture zones and transform faults. Our reconstructions of this slow-spreading mid-ocean ridge reveal several unexpected results with notable implications for regional and global plate reconstructions since 20 Ma. Extrapolations of seafloor opening distances to zero-age seafloor based on reconstructions of reversals C1n (0.78 Ma) through C3n.4 (5.2 Ma) reveal evidence for surprisingly large outward displacement of 5 ± 1 km west of 32°E, where motion between the Nubia and Antarctic plates occurs, but 2 ± 1 km east of 32°E, more typical of most mid-ocean ridges. Newly estimated SWIR seafloor spreading rates are up to 15 per cent slower everywhere along the ridge than previous estimates. Reconstructions of the numerous observations for times back to 11 Ma confirm the existence of the hypothesized Lwandle plate at high confidence level and indicate that the Lwandle plate's western and eastern boundaries respectively intersect the ridge near the Andrew Bain transform fault complex at 32°E and between ~45°E and 52°E, in accord with previous results. The Nubia–Antarctic, Lwandle–Antarctic and Somalia–Antarctic rotation sequences that best fit many magnetic reversal, fracture zone and transform fault crossings define previously unknown changes in the Neogene motions of all three plate pairs, consisting of ~20 per cent slowdowns in their spreading rates at 7.2 $^{+0.9 }_{ -1.4}$ Ma if we enforce a simultaneous change in motion everywhere along the SWIR and gradual 3°–7° anticlockwise rotations of the relative slip directions. We apply trans-dimensional Bayesian analysis to our noisy, best-fitting rotation sequences in order to estimate less-noisy rotation sequences suitable for use in future global plate reconstructions and geodynamic studies. Notably, our new Nubia–Antarctic reconstruction of C5n.2 (11.0 Ma) predicts 20 per cent less opening than do two previous estimates, with important implications for motion that is estimated between the Nubia and Somalia plates. A Nubia–Somalia rotation determined from our Nubia–Antarctic and Somalia–Antarctic plate rotations for C5n.2 (11.0 Ma) predicts cumulative opening of 45 ± 4 km (95 per cent uncertainty) across the northernmost East Africa rift since 11.0 Ma, 70 per cent less than a recent 129 ± 62 km opening estimate based on a now-superseded interpretation of Anomaly 5 along the western portion of the SWIR.

Description: Metabolic diseases and comorbidities represent an ever-growing epidemic where multiple cell types impact tissue homeostasis. Here, the link between the metabolic and gene regulatory networks was studied through experimental and computational analysis. Integrating gene regulation data with a human metabolic network prompted the establishment of an open-sourced web portal, IDARE (Integrated Data Nodes of Regulation), for visualizing various gene-related data in context of metabolic pathways. Motivated by increasing availability of deep sequencing studies, we obtained ChIP-seq data from widely studied human umbilical vein endothelial cells. Interestingly, we found that association of metabolic genes with multiple transcription factors (TFs) enriched disease-associated genes. To demonstrate further extensions enabled by examining these networks together, constraint-based modeling was applied to data from human preadipocyte differentiation. In parallel, data on gene expression, genome-wide ChIP-seq profiles for peroxisome proliferator-activated receptor (PPAR) , CCAAT/enhancer binding protein (CEBP) α, liver X receptor (LXR) and H3K4me3 and microRNA target identification for miR-27a, miR-29a and miR-222 were collected. Disease-relevant key nodes, including mitochondrial glycerol-3-phosphate acyltransferase (GPAM), were exposed from metabolic pathways predicted to change activity by focusing on association with multiple regulators. In both cell types, our analysis reveals the convergence of microRNAs and TFs within the branched chain amino acid (BCAA) metabolic pathway, possibly providing an explanation for its downregulation in obese and diabetic conditions.

Description: In this paper we consider the three-dimensional wave equation in unbounded domains with Dirichlet boundary conditions. We start from a retarded single-layer potential ansatz for the solution of these equations which leads to the retarded potential integral equation on the bounded surface of the scatterer. We formulate an algorithm for the space-time Galerkin discretization with smooth and compactly supported temporal basis functions, which were introduced in Sauter & Veit (2013, Numer. Math. , 145–176). For the debugging of an implementation and for systematic parameter tests it is essential to have at hand some explicit representations and some analytic properties of the exact solutions for some special cases. We will derive such explicit representations for the case where the scatterer is the unit ball. The obtained formulas are easy to implement and we will present some numerical experiments for these cases to illustrate the convergence behaviour of the proposed method.

Description: In plants, the voltage-dependent anion-selective channel (VDAC) is a major component of a pathway involved in transfer RNA (tRNA) translocation through the mitochondrial outer membrane. However, the way in which VDAC proteins interact with tRNAs is still unknown. Potato mitochondria contain two major mitochondrial VDAC proteins, VDAC34 and VDAC36. These two proteins, composed of a N-terminal α-helix and of 19 β-strands forming a β-barrel structure, share 75% sequence identity. Here, using both northwestern and gel shift experiments, we report that these two proteins interact differentially with nucleic acids. VDAC34 binds more efficiently with tRNAs or other nucleic acids than VDAC36. To further identify specific features and critical amino acids required for tRNA binding, 21 VDAC34 mutants were constructed and analyzed by northwestern. This allowed us to show that the β-barrel structure of VDAC34 and the first 50 amino acids that contain the α-helix are essential for RNA binding. Altogether the work shows that during evolution, plant mitochondrial VDAC proteins have diverged so as to interact differentially with nucleic acids, and this may reflect their involvement in various specialized biological functions.

Description: Phosphorylated creatine (Cr) serves as an energy buffer for ATP replenishment in organs with highly fluctuating energy demand. The central role of Cr in the brain and muscle is emphasized by severe neurometabolic disorders caused by Cr deficiency. Common symptoms of inborn errors of creatine synthesis or distribution include mental retardation and muscular weakness. Human mutations in l -arginine:glycine amidinotransferase (AGAT), the first enzyme of Cr synthesis, lead to severely reduced Cr and guanidinoacetate (GuA) levels. Here, we report the generation and metabolic characterization of AGAT-deficient mice that are devoid of Cr and its precursor GuA. AGAT-deficient mice exhibited decreased fat deposition, attenuated gluconeogenesis, reduced cholesterol levels and enhanced glucose tolerance. Furthermore, Cr deficiency completely protected from the development of metabolic syndrome caused by diet-induced obesity. Biochemical analyses revealed the chronic Cr-dependent activation of AMP-activated protein kinase (AMPK), which stimulates catabolic pathways in metabolically relevant tissues such as the brain, skeletal muscle, adipose tissue and liver, suggesting a mechanism underlying the metabolic phenotype. In summary, our results show marked metabolic effects of Cr deficiency via the chronic activation of AMPK in a first animal model of AGAT deficiency. In addition to insights into metabolic changes in Cr deficiency syndromes, our genetic model reveals a novel mechanism as a potential treatment option for obesity and type 2 diabetes mellitus.

Description: In the mammalian mitochondrial translation apparatus, the proteins and their partner RNAs are coded by two genomes. The proteins are nuclear-encoded and resemble their homologs, whereas the RNAs coming from the rapidly evolving mitochondrial genome have lost critical structural information. This raises the question of molecular adaptation of these proteins to their peculiar partner RNAs. The crystal structure of the homodimeric bacterial-type human mitochondrial aspartyl-tRNA synthetase (DRS) confirmed a 3D architecture close to that of Escherichia coli DRS. However, the mitochondrial enzyme distinguishes by an enlarged catalytic groove, a more electropositive surface potential and an alternate interaction network at the subunits interface. It also presented a thermal stability reduced by as much as 12°C. Isothermal titration calorimetry analyses revealed that the affinity of the mitochondrial enzyme for cognate and non-cognate tRNAs is one order of magnitude higher, but with different enthalpy and entropy contributions. They further indicated that both enzymes bind an adenylate analog by a cooperative allosteric mechanism with different thermodynamic contributions. The larger flexibility of the mitochondrial synthetase with respect to the bacterial enzyme, in combination with a preserved architecture, may represent an evolutionary process, allowing nuclear-encoded proteins to cooperate with degenerated organelle RNAs.

Description: Genome-scale metabolic network reconstructions provide a basis for the investigation of the metabolic properties of an organism. There are reconstructions available for multiple organisms, from prokaryotes to higher organisms and methods for the analysis of a reconstruction. One example is the use of flux balance analysis to improve the yields of a target chemical, which has been applied successfully. However, comparison of results between existing reconstructions and models presents a challenge because of the heterogeneity of the available reconstructions, for example, of standards for presenting gene-protein-reaction associations, nomenclature of metabolites and reactions or selection of protonation states. The lack of comparability for gene identifiers or model-specific reactions without annotated evidence often leads to the creation of a new model from scratch, as data cannot be properly matched otherwise. In this contribution, we propose to improve the predictive power of metabolic models by switching from gene-protein-reaction associations to transcript-isoform-reaction associations, thus taking advantage of the improvement of precision in gene expression measurements. To achieve this precision, we discuss available databases that can be used to retrieve this type of information and point at issues that can arise from their neglect. Further, we stress issues that arise from non-standardized building pipelines, like inconsistencies in protonation states. In addition, problems arising from the use of non-specific cofactors, e.g. artificial futile cycles, are discussed, and finally efforts of the metabolic modelling community to unify model reconstructions are highlighted.