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The satellite era brings new challenges in the development and the implementation of potential field models. Major aspects are, therefore, the exploitation of existing space- and ground-based gravity and magnetic data for the long-term. Moreover, a continuous and near real-time global monitoring of the Earth system, allows for a consistent integration and assimilation of these data into complex models of the Earth’s gravity and magnetic fields, which have to consider the constantly increasing amount of available data. In this paper we propose how to speed up the computation of the normal equation in potential filed modeling by using local multi-polar approximations of the modeling functions. The basic idea is to take advantage of the rather smooth behavior of the internal fields at the satellite altitude and to replace the full available gravity or magnetic data by a collection of local moments. We also investigate what are the optimal values for the free parameters of our method. Results from numerical experiments with spherical harmonic models based on both scalar gravity potential and magnetic vector data are presented and discussed. The new developed method clearly shows that very large datasets can be used in potential field modeling in a fast and more economic manner.
Quantifying uncertainty, variability and likelihood for ordinary differential equation models
(2010)
Background
In many applications, ordinary differential equation (ODE) models are subject to uncertainty or variability in initial conditions and parameters. Both, uncertainty and variability can be quantified in terms of a probability density function on the state and parameter space.
Results
The partial differential equation that describes the evolution of this probability density function has a form that is particularly amenable to application of the well-known method of characteristics. The value of the density at some point in time is directly accessible by the solution of the original ODE extended by a single extra dimension (for the value of the density). This leads to simple methods for studying uncertainty, variability and likelihood, with significant advantages over more traditional Monte Carlo and related approaches especially when studying regions with low probability.
Conclusions
While such approaches based on the method of characteristics are common practice in other disciplines, their advantages for the study of biological systems have so far remained unrecognized. Several examples illustrate performance and accuracy of the approach and its limitations.
Background: Cysteine is a component in organic compounds including glutathione that have been implicated in the adaptation of plants to stresses. O-acetylserine (thiol) lyase (OAS-TL) catalyses the final step of cysteine biosynthesis. OAS-TL enzyme isoforms are localised in the cytoplasm, the plastids and mitochondria but the contribution of individual OAS-TL isoforms to plant sulphur metabolism has not yet been fully clarified.
Results: The seedling lethal phenotype of the Arabidopsis onset of leaf death3-1 (old3-1) mutant is due to a point mutation in the OAS-A1 gene, encoding the cytosolic OAS-TL. The mutation causes a single amino acid substitution from Gly(162) to Glu(162), abolishing old3-1 OAS-TL activity in vitro. The old3-1 mutation segregates as a monogenic semidominant trait when backcrossed to its wild type accession Landsberg erecta (Ler-0) and the Di-2 accession. Consistent with its semi-dominant behaviour, wild type Ler-0 plants transformed with the mutated old3-1 gene, displayed the early leaf death phenotype. However, the old3-1 mutation segregates in an 11: 4: 1 (wild type: semi-dominant: mutant) ratio when backcrossed to the Colombia-0 and Wassilewskija accessions. Thus, the early leaf death phenotype depends on two semi-dominant loci. The second locus that determines the old3-1 early leaf death phenotype is referred to as odd-ler (for old3 determinant in the Ler accession) and is located on chromosome 3. The early leaf death phenotype is temperature dependent and is associated with increased expression of defence-response and oxidative-stress marker genes. Independent of the presence of the odd-ler gene, OAS-A1 is involved in maintaining sulphur and thiol levels and is required for resistance against cadmium stress.
Conclusions: The cytosolic OAS-TL is involved in maintaining organic sulphur levels. The old3-1 mutation causes genome-dependent and independent phenotypes and uncovers a novel function for the mutated OAS-TL in cell death regulation.
Und der Zukunft abgewandt
(2010)
Seit dem Ende der DDR, das den Zusammenbruch des Ostblocks und damit die Beendigung des »Kalten Kriegs« einleitete, wird verstärkt versucht, das Wesen dieses Staates zu definieren und damit seine Folgen auf wirtschaftlicher, sozialer, psychologischer und bildungspolitischer Ebene zu verstehen und einzuordnen. Alexandra Budke analysiert in diesem Band das Schulfach Geographie, das neben der Staatsbürgerkunde und der Geschichte ein zentrales Fach war und in dem die in den Lehrplänen definierte »staatsbürgerliche, weltanschauliche oder ideologische Erziehung« auf der Grundlage des Marxismus-Leninismus stattfinden sollte. Sie klärt, inwiefern Geographieunterricht in der DDR genutzt wurde, um geopolitische Interessen des Staates zu kommunizieren und zu verbreiten. Damit lässt sich durch die detaillierte Analyse des Fachunterrichts auch die Frage beantworten, ob SchülerInnen im Unterricht politisch manipuliert wurden und welche Handlungsmöglichkeiten die zentralen Akteure des Unterrichts, die LehrerInnen und die SchülerInnen, im Rahmen der durch die Bildungspolitik gesetzten curricularen Vorgaben wahrgenommen haben.
Live cell flattening
(2010)
Eukaryotic cell flattening is valuable for improving microscopic observations, ranging from bright field (BF) to total internal reflection fluorescence (TIRF) microscopy. Fundamental processes, such as mitosis and in vivo actin polymerization, have been investigated using these techniques. Here, we review the well known agar overlayer protocol and the oil overlay method. In addition, we present more elaborate microfluidics-based techniques that provide us with a greater level of control. We demonstrate these techniques on the social amoebae Dictyostelium discoideum, comparing the advantages and disadvantages of each method.
Background: For heterogeneous tissues, such as blood, measurements of gene expression are confounded by relative proportions of cell types involved. Conclusions have to rely on estimation of gene expression signals for homogeneous cell populations, e.g. by applying micro-dissection, fluorescence activated cell sorting, or in-silico deconfounding. We studied feasibility and validity of a non-negative matrix decomposition algorithm using experimental gene expression data for blood and sorted cells from the same donor samples. Our objective was to optimize the algorithm regarding detection of differentially expressed genes and to enable its use for classification in the difficult scenario of reversely regulated genes. This would be of importance for the identification of candidate biomarkers in heterogeneous tissues.
Results: Experimental data and simulation studies involving noise parameters estimated from these data revealed that for valid detection of differential gene expression, quantile normalization and use of non-log data are optimal. We demonstrate the feasibility of predicting proportions of constituting cell types from gene expression data of single samples, as a prerequisite for a deconfounding-based classification approach. Classification cross-validation errors with and without using deconfounding results are reported as well as sample-size dependencies. Implementation of the algorithm, simulation and analysis scripts are available.
Conclusions: The deconfounding algorithm without decorrelation using quantile normalization on non-log data is proposed for biomarkers that are difficult to detect, and for cases where confounding by varying proportions of cell types is the suspected reason. In this case, a deconfounding ranking approach can be used as a powerful alternative to, or complement of, other statistical learning approaches to define candidate biomarkers for molecular diagnosis and prediction in biomedicine, in realistically noisy conditions and with moderate sample sizes.
Multi-color fluorescence imaging experiments of wave forming Dictyostelium cells have revealed that actin waves separate two domains of the cell cortex that differ in their actin structure and phosphoinositide composition. We propose a bistable model of actin dynamics to account for these experimental observation. The model is based on the simplifying assumption that the actin cytoskeleton is composed of two distinct network types, a dendritic and a bundled network. The two structurally different states that were observed in experiments correspond to the stable fixed points in the bistable regime of this model. Each fixed point is dominated by one of the two network types. The experimentally observed actin waves can be considered as trigger waves that propagate transitions between the two stable fixed points.
The Takab complex is composed of a variety of metamorphic rocks including amphibolites, metapelites, mafic granulites, migmatites and meta-ultramafics, which are intruded by the granitoid. The granitoid magmatic activity occurred in relation to the subduction of the Neo-Tethys oceanic crust beneath the Iranian crust during Tertiary times. The granitoids are mainly granodiorite, quartz monzodiorite, monzonite and quartz diorite. Chemically, the magmatic rocks are characterized by ASI < 1.04, AI < 0.87 and high contents of CaO (up to ∼ 14.5 wt %), which are consistent with the I-type magmatic series. Low FeO t /(FeO t +MgO) values (< 0.75) as well as low Nb, Y and K 2 O contents of the investigated rocks resemble the calc-alkaline series. Low SiO 2 , K 2 O/Na 2 O and Al 2 O 3 accompanied by high CaO and FeO contents indicate melting of metabasites as an appropriate source for the intrusions. Negative Ti and Nb anomalies verify a metaluminous crustal origin for the protoliths of the investigated igneous rocks. These are comparable with compositions of the associated mafic migmatites, in the Takab metamorphic complex, which originated from the partial melting of amphibolites. Therefore, crustal melting and a collision-related origin for the Takab calc-alkaline intrusions are proposed here on the basis of mineralogy and geochemical characteristics. The P–T evolution during magmatic crystallization and subsolidus cooling stages is determined by the study of mineral chemistry of the granodiorite and the quartz diorite. Magmatic crystallization pressure and temperature for the quartz-diorite and the granodiorite are estimated to be P ∼ 7.8 ± 2.5 kbar, T ∼ 760 ± 75 ◦C and P ∼ 5 ± 1 kbar, T ∼ 700 ◦C, respectively. Subsolidus conditions are consistent with temperatures of ∼ 620 ◦C and ∼ 600 ◦C, and pressures of ∼ 5 kbar and ∼ 3.5 kbar for the quartz-diorite and the granodiorite, respectively.
We present an approach that provides automatic or semi-automatic support for evolution and change management in heterogeneous legacy landscapes where (1) legacy heterogeneous, possibly distributed platforms are integrated in a service oriented fashion, (2) the coordination of functionality is provided at the service level, through orchestration, (3) compliance and correctness are provided through policies and business rules, (4) evolution and correctness-by-design are supported by the eXtreme Model Driven Development paradigm (XMDD) offered by the jABC (Margaria and Steffen in Annu. Rev. Commun. 57, 2004)—the model-driven service oriented development platform we use here for integration, design, evolution, and governance. The artifacts are here semantically enriched, so that automatic synthesis plugins can field the vision of Enterprise Physics: knowledge driven business process development for the end user.
We demonstrate this vision along a concrete case study that became over the past three years a benchmark for Semantic Web Service discovery and mediation. We enhance the Mediation Scenario of the Semantic Web Service Challenge along the 2 central evolution paradigms that occur in practice: (a) Platform migration: platform substitution of a legacy system by an ERP system and (b) Backend extension: extension of the legacy Customer Relationship Management (CRM) and Order Management System (OMS) backends via an additional ERP layer.
Background: Protein phosphorylation is an important post-translational modification influencing many aspects of dynamic cellular behavior. Site-specific phosphorylation of amino acid residues serine, threonine, and tyrosine can have profound effects on protein structure, activity, stability, and interaction with other biomolecules. Phosphorylation sites can be affected in diverse ways in members of any species, one such way is through single nucleotide polymorphisms (SNPs). The availability of large numbers of experimentally identified phosphorylation sites, and of natural variation datasets in Arabidopsis thaliana prompted us to analyze the effect of non-synonymous SNPs (nsSNPs) onto phosphorylation sites.
Results: From the analyses of 7,178 experimentally identified phosphorylation sites we found that: (i) Proteins with multiple phosphorylation sites occur more often than expected by chance. (ii) Phosphorylation hotspots show a preference to be located outside conserved domains. (iii) nsSNPs affected experimental phosphorylation sites as much as the corresponding non-phosphorylated amino acid residues. (iv) Losses of experimental phosphorylation sites by nsSNPs were identified in 86 A. thaliana proteins, among them receptor proteins were overrepresented.
These results were confirmed by similar analyses of predicted phosphorylation sites in A. thaliana. In addition, predicted threonine phosphorylation sites showed a significant enrichment of nsSNPs towards asparagines and a significant depletion of the synonymous substitution. Proteins in which predicted phosphorylation sites were affected by nsSNPs (loss and gain), were determined to be mainly receptor proteins, stress response proteins and proteins involved in nucleotide and protein binding. Proteins involved in metabolism, catalytic activity and biosynthesis were less affected.
Conclusions: We analyzed more than 7,100 experimentally identified phosphorylation sites in almost 4,300 protein-coding loci in silico, thus constituting the largest phosphoproteomics dataset for A. thaliana available to date. Our findings suggest a relatively high variability in the presence or absence of phosphorylation sites between different natural accessions in receptor and other proteins involved in signal transduction. Elucidating the effect of phosphorylation sites affected by nsSNPs on adaptive responses represents an exciting research goal for the future.
We show that the residue density of the logarithm of a generalized Laplacian on a closed manifold definesan invariant polynomial-valued differential form. We express it in terms of a finite sum of residues ofclassical pseudodifferential symbols. In the case of the square of a Dirac operator, these formulas providea pedestrian proof of the Atiyah–Singer formula for a pure Dirac operator in four dimensions and for atwisted Dirac operator on a flat space of any dimension. These correspond to special cases of a moregeneral formula by Scott and Zagier. In our approach, which is of perturbative nature, we use either aCampbell–Hausdorff formula derived by Okikiolu or a noncommutative Taylor-type formula.
It has been suggested that coronal mass ejections (CMEs) remove the magnetic he-licity of their coronal source region from the Sun. Such removal is often regarded to be necessary due to the hemispheric sign preference of the helicity, which inhibits a simple annihilation by reconnection between volumes of opposite chirality. Here we monitor the relative magnetic he-licity contained in the coronal volume of a simulated flux rope CME, as well as the upward flux of relative helicity through horizontal planes in the simulation box. The unstable and erupting flux rope carries away only a minor part of the initial relative helicity; the major part remains in the volume. This is a consequence of the requirement that the current through an expanding loop must decrease if the magnetic energy of the configuration is to decrease as the loop rises, to provide the kinetic energy of the CME.
Two recent magnetic field models, GRIMM and xCHAOS, describe core field accelerations with similar behavior up to Spherical Harmonic (SH) degree 5, but which differ significantly for higher degrees. These discrepancies, due to different approaches in smoothing rapid time variations of the core field, have strong implications for the interpretation of the secular variation. Furthermore, the amount of smoothing applied to the highest SH degrees is essentially the modeler’s choice. We therefore investigate new ways of regularizing core magnetic field models. Here we propose to constrain field models to be consistent with the frozen flux induction equation by co-estimating a core magnetic field model and a flow model at the top of the outer core. The flow model is required to have smooth spatial and temporal behavior. The implementation of such constraints and their effects on a magnetic field model built from one year of CHAMP satellite and observatory data, are presented. In particular, it is shown that the chosen constraints are efficient and can be used to build reliable core magnetic field secular variation and acceleration model components.
Background
Micrometer resolution placement and immobilization of probe molecules is an important step in the preparation of biochips and a wide range of lab-on-chip systems. Most known methods for such a deposition of several different substances are costly and only suitable for a limited number of probes. In this article we present a flexible procedure for simultaneous spatially controlled immobilization of functional biomolecules by molecular ink lithography.
Results
For the bottom-up fabrication of surface bound nanostructures a universal method is presented that allows the immobilization of different types of biomolecules with micrometer resolution. A supporting surface is biotinylated and streptavidin molecules are deposited with an AFM (atomic force microscope) tip at distinct positions. Subsequent incubation with a biotinylated molecule species leads to binding only at these positions. After washing streptavidin is deposited a second time with the same AFM tip and then a second biotinylated molecule species is coupled by incubation. This procedure can be repeated several times. Here we show how to immobilize different types of biomolecules in an arbitrary arrangement whereas most common methods can deposit only one type of molecules. The presented method works on transparent as well as on opaque substrates. The spatial resolution is better than 400 nm and is limited only by the AFM's positional accuracy after repeated z-cycles since all steps are performed in situ without moving the supporting surface. The principle is demonstrated by hybridization to different immobilized DNA oligomers and was validated by fluorescence microscopy.
Conclusions
The immobilization of different types of biomolecules in high-density microarrays is a challenging task for biotechnology. The method presented here not only allows for the deposition of DNA at submicrometer resolution but also for proteins and other molecules of biological relevance that can be coupled to biotin.
Fusarium spp. infection of cereal grain is a common problem, which leads to a dramatic loss of grain quality. The aim of the present study was to investigate the effect of Fusarium infection on the wheat storage protein gluten and its fractions, the gliadins and glutenins, in an in vitro model system. Gluten proteins were digested by F. graminearum proteases for 2, 4, 8 and 24 h, separated by Osborne fractionation and characterised by chromatographic (RP-HPLC) and electrophoretic analysis (SDS-Page). Gluten digestion by F. graminearum proteases showed in comparison with gliadins a preference for the glutenins whereas the HMW subfraction was at most affected. In comparison with a untreated control, the HMW subfraction was degraded of about 97% after 4 h incubation with Fusarium proteases. Separate digestion of gliadin and glutenin underlined the preference for HMW-GS. Analogue to the observed change in the gluten composition, the yield of the proteins extracted changed. A higher amount of glutenin fragments was found in the gliadin extraction solution after digestion and could mask a gliadin destruction at the same time. This observation can contribute to explain the frequently reported reduced glutenin amount parallel to an increase in gliadin quantity after Fusarium infection in grains.
Many organisms have developed defences to avoid predation by species at higher trophic levels. The capability of primary producers to defend themselves against herbivores affects their own survival, can modulate the strength of trophic cascades and changes rates of competitive exclusion in aquatic communities. Algal species are highly flexible in their morphology, growth form, biochemical composition and production of toxic and deterrent compounds. Several of these variable traits in phytoplankton have been interpreted as defence mechanisms against grazing. Zooplankton feed with differing success on various phytoplankton species, depending primarily on size, shape, cell wall structure and the production of toxins and deterrents. Chemical cues associated with (i) mechanical damage, (ii) herbivore presence and (iii) grazing are the main factors triggering induced defences in both marine and freshwater phytoplankton, but most studies have failed to disentangle the exact mechanism(s) governing defence induction in any particular species. Induced defences in phytoplankton include changes in morphology (e.g. the formation of spines, colonies and thicker cell walls), biochemistry (such as production of toxins, repellents) and in life history characteristics (formation of cysts, reduced recruitment rate). Our categorization of inducible defences in terms of the responsible induction mechanism provides guidance for future work, as hardly any of the available studies on marine or freshwater plankton have performed all the treatments that are required to pinpoint the actual cue(s) for induction. We discuss the ecology of inducible defences in marine and freshwater phytoplankton with a special focus on the mechanisms of induction, the types of defences, their costs and benefits, and their consequences at the community level.
Due to their optical and electro-conductive attributes, carbazole derivatives are interesting materials for a large range of biosensor applications. In this study, we present the synthesis routes and fluorescence evaluation of newly designed carbazole fluorosensors that, by modification with uracil, have a special affinity for antiretroviral drugs via either Watson–Crick or Hoogsteen base pairing. To an N-octylcarbazole-uracil compound, four different groups were attached, namely thiophene, furane, ethylenedioxythiophene, and another uracil; yielding four different derivatives. Photophysical properties of these newly obtained derivatives are described, as are their interactions with the reverse transcriptase inhibitors such as abacavir, zidovudine, lamivudine and didanosine. The influence of each analyte on biosensor fluorescence was assessed on the basis of the Stern–Volmer equation and represented by Stern–Volmer constants. Consequently we have demonstrated that these structures based on carbazole, with a uracil group, may be successfully incorporated into alternative carbazole derivatives to form biosensors for the molecular recognition of antiretroviral drugs.
Background
More than in other domains the heterogeneous services world in bioinformatics demands for a methodology to classify and relate resources in a both human and machine accessible manner. The Semantic Web, which is meant to address exactly this challenge, is currently one of the most ambitious projects in computer science. Collective efforts within the community have already led to a basis of standards for semantic service descriptions and meta-information. In combination with process synthesis and planning methods, such knowledge about types and services can facilitate the automatic composition of workflows for particular research questions.
Results
In this study we apply the synthesis methodology that is available in the Bio-jETI workflow management framework for the semantics-based composition of EMBOSS services. EMBOSS (European Molecular Biology Open Software Suite) is a collection of 350 tools (March 2010) for various sequence analysis tasks, and thus a rich source of services and types that imply comprehensive domain models for planning and synthesis approaches. We use and compare two different setups of our EMBOSS synthesis domain: 1) a manually defined domain setup where an intuitive, high-level, semantically meaningful nomenclature is applied to describe the input/output behavior of the single EMBOSS tools and their classifications, and 2) a domain setup where this information has been automatically derived from the EMBOSS Ajax Command Definition (ACD) files and the EMBRACE Data and Methods ontology (EDAM). Our experiments demonstrate that these domain models in combination with our synthesis methodology greatly simplify working with the large, heterogeneous, and hence manually intractable EMBOSS collection. However, they also show that with the information that can be derived from the (current) ACD files and EDAM ontology alone, some essential connections between services can not be recognized.
Conclusions
Our results show that adequate domain modeling requires to incorporate as much domain knowledge as possible, far beyond the mere technical aspects of the different types and services. Finding or defining semantically appropriate service and type descriptions is a difficult task, but the bioinformatics community appears to be on the right track towards a Life Science Semantic Web, which will eventually allow automatic service composition methods to unfold their full potential.
Background
Riociguat is the first of a new class of drugs, the soluble guanylate cyclase (sGC) stimulators. Riociguat has a dual mode of action: it sensitizes sGC to the body’s own NO and can also increase sGC activity in the absence of NO. The NO-sGC-pathway is impaired in many cardiovascular diseases such as heart failure, pulmonary hypertension and diabetic nephropathy (DN). DN leads to high cardiovascular morbidity and mortality. There is still a high unmet medical need. The urinary albumin excretion rate is a predictive biomarker for these clinical events. Therefore, we investigated the effect of riociguat, alone and in combination with the angiotensin II receptor antagonist (ARB) telmisartan on the progression of DN in diabetic eNOS knock out mice, a new model closely resembling human pathology.
Methods
Seventy-six male eNOS knockout C57BL/6J mice were divided into 4 groups after receiving intraperitoneal high-dose streptozotocin: telmisartan (1 mg/kg), riociguat (3 mg/kg), riociguat+telmisartan (3 and 1 mg/kg), and vehicle. Fourteen mice were used as non-diabetic controls. After 12 weeks, urine and blood were obtained and blood pressure measured. Glucose concentrations were highly increased and similar in all diabetic groups.
Results
Riociguat, alone (105.2 ± 2.5 mmHg; mean±SEM; n = 14) and in combination with telmisartan (105.0 ± 3.2 mmHg; n = 12), significantly reduced blood pressure versus diabetic controls (117.1 ± 2.2 mmHg; n = 14; p = 0.002 and p = 0.004, respectively), whereas telmisartan alone (111.2 ± 2.6 mmHg) showed a modest blood pressure lowering trend (p = 0.071; n = 14). The effects of single treatment with either riociguat (97.1 ± 15.7 µg/d; n = 13) or telmisartan (97.8 ± 26.4 µg/d; n = 14) did not significantly lower albumin excretion on its own (p = 0.067 and p = 0.101, respectively). However, the combined treatment led to significantly lower urinary albumin excretion (47.3 ± 9.6 µg/d; n = 12) compared to diabetic controls (170.8 ± 34.2 µg/d; n = 13; p = 0.004), and reached levels similar to non-diabetic controls (31.4 ± 10.1 µg/d, n = 12).
Conclusion
Riociguat significantly reduced urinary albumin excretion in diabetic eNOS knock out mice that were refractory to treatment with ARB’s alone. Patients with diabetic nephropathy refractory to treatment with ARB’s have the worst prognosis among all patients with diabetic nephropathy. Our data indicate that additional stimulation of sGC on top of standard treatment with ARB`s may offer a new therapeutic approach for patients with diabetic nephropathy resistant to ARB treatment.