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Background
High blood glucose and diabetes are amongst the conditions causing the greatest losses in years of healthy life worldwide. Therefore, numerous studies aim to identify reliable risk markers for development of impaired glucose metabolism and type 2 diabetes. However, the molecular basis of impaired glucose metabolism is so far insufficiently understood. The development of so called 'omics' approaches in the recent years promises to identify molecular markers and to further understand the molecular basis of impaired glucose metabolism and type 2 diabetes. Although univariate statistical approaches are often applied, we demonstrate here that the application of multivariate statistical approaches is highly recommended to fully capture the complexity of data gained using high-throughput methods.
Methods
We took blood plasma samples from 172 subjects who participated in the prospective Metabolic Syndrome Berlin Potsdam follow-up study (MESY-BEPO Follow-up). We analysed these samples using Gas Chromatography coupled with Mass Spectrometry (GC-MS), and measured 286 metabolites. Furthermore, fasting glucose levels were measured using standard methods at baseline, and after an average of six years. We did correlation analysis and built linear regression models as well as Random Forest regression models to identify metabolites that predict the development of fasting glucose in our cohort.
Results
We found a metabolic pattern consisting of nine metabolites that predicted fasting glucose development with an accuracy of 0.47 in tenfold cross-validation using Random Forest regression. We also showed that adding established risk markers did not improve the model accuracy. However, external validation is eventually desirable. Although not all metabolites belonging to the final pattern are identified yet, the pattern directs attention to amino acid metabolism, energy metabolism and redox homeostasis.
Conclusions
We demonstrate that metabolites identified using a high-throughput method (GC-MS) perform well in predicting the development of fasting plasma glucose over several years. Notably, not single, but a complex pattern of metabolites propels the prediction and therefore reflects the complexity of the underlying molecular mechanisms. This result could only be captured by application of multivariate statistical approaches. Therefore, we highly recommend the usage of statistical methods that seize the complexity of the information given by high-throughput methods.
All's well that ends well
(2012)
The transition from cell proliferation to cell expansion is critical for determining leaf size. Andriankaja et al. (2012) demonstrate that in leaves of dicotyledonous plants, a basal proliferation zone is maintained for several days before abruptly disappearing, and that chloroplast differentiation is required to trigger the onset of cell expansion.
ASP modulo CSP
(2012)
We present the hybrid ASP solver clingcon, combining the simple modeling language and the high performance Boolean solving capacities of Answer Set Programming (ASP) with techniques for using non-Boolean constraints from the area of Constraint Programming (CP). The new clingcon system features an extended syntax supporting global constraints and optimize statements for constraint variables. The major technical innovation improves the interaction between ASP and CP solver through elaborated learning techniques based on irreducible inconsistent sets. A broad empirical evaluation shows that these techniques yield a performance improvement of an order of magnitude.
The clumping of massive star winds is an established paradigm, which is confirmed by multiple lines of evidence and is supported by stellar wind theory. We use the results from time-dependent hydrodynamical models of the instability in the line-driven wind of a massive supergiant star to derive the time-dependent accretion rate on to a compact object in the Bondi-Hoyle-Lyttleton approximation. The strong density and velocity fluctuations in the wind result in strong variability of the synthetic X-ray light curves. Photoionization of inhomogeneous winds is different from the photoinization of smooth winds. The degree of ionization is affected by the wind clumping. The wind clumping must also be taken into account when comparing the observed and model spectra of the photoionized stellar wind.
The size of plant organs, such as leaves and flowers, is determined by an interaction of genotype and environmental influences. Organ growth occurs through the two successive processes of cell proliferation followed by cell expansion. A number of genes influencing either or both of these processes and thus contributing to the control of final organ size have been identified in the last decade. Although the overall picture of the genetic regulation of organ size remains fragmentary, two transcription factor/microRNA-based genetic pathways are emerging in the control of cell proliferation. However, despite this progress, fundamental questions remain unanswered, such as the problem of how the size of a growing organ could be monitored to determine the appropriate time for terminating growth. While genetic analysis will undoubtedly continue to advance our knowledge about size control in plants, a deeper understanding of this and other basic questions will require including advanced live-imaging and mathematical modeling, as impressively demonstrated by some recent examples. This should ultimately allow the comparison of the mechanisms underlying size control in plants and in animals to extract common principles and lineage-specific solutions.
Much of our knowledge about the solar dynamo is based on sunspot observations. It is thus desirable to extend the set of positional and morphological data of sunspots into the past. Gustav Spörer observed in Germany from Anklam (1861–1873) and Potsdam (1874–1894). He left detailed prints of sunspot groups, which we digitized and processed to mitigate artifacts left in the print by the passage of time. After careful geometrical correction, the sunspot data are now available as synoptic charts for almost 450 solar rotation periods. Individual sunspot positions can thus be precisely determined and spot areas can be accurately measured using morphological image processing techniques. These methods also allow us to determine tilt angles of active regions (Joy’s law) and to assess the complexity of an active region.
The project of public-reason liberalism faces a basic problem: publicly justified principles are typically too abstract and vague to be directly applied to practical political disputes, whereas applicable specifications of these principles are not uniquely publicly justified. One solution could be a legislative procedure that selects one member from the eligible set of inconclusively justified proposals. Yet if liberal principles are too vague to select sufficiently specific legislative proposals, can they, nevertheless, select specific legislative procedures? Based on the work of Gerald Gaus, this article argues that the only candidate for a conclusively justified decision procedure is a majoritarian or otherwise ‘neutral’ democracy. If the justification of democracy requires an equality baseline in the design of political regimes and if justifications for departure from this baseline are subject to reasonable disagreement, a majoritarian design is justified by default. Gaus’s own preference for super-majoritarian procedures is based on disputable specifications of justified liberal principles. These procedures can only be defended as a sectarian preference if the equality baseline is rejected, but then it is not clear how the set of justifiable political regimes can be restricted to full democracies.
Dynamic regulatory on/off minimization for biological systems under internal temporal perturbations
(2012)
Background: Flux balance analysis (FBA) together with its extension, dynamic FBA, have proven instrumental for analyzing the robustness and dynamics of metabolic networks by employing only the stoichiometry of the included reactions coupled with adequately chosen objective function. In addition, under the assumption of minimization of metabolic adjustment, dynamic FBA has recently been employed to analyze the transition between metabolic states.
Results: Here, we propose a suite of novel methods for analyzing the dynamics of (internally perturbed) metabolic networks and for quantifying their robustness with limited knowledge of kinetic parameters. Following the biochemically meaningful premise that metabolite concentrations exhibit smooth temporal changes, the proposed methods rely on minimizing the significant fluctuations of metabolic profiles to predict the time-resolved metabolic state, characterized by both fluxes and concentrations. By conducting a comparative analysis with a kinetic model of the Calvin-Benson cycle and a model of plant carbohydrate metabolism, we demonstrate that the principle of regulatory on/off minimization coupled with dynamic FBA can accurately predict the changes in metabolic states.
Conclusions: Our methods outperform the existing dynamic FBA-based modeling alternatives, and could help in revealing the mechanisms for maintaining robustness of dynamic processes in metabolic networks over time.
Early acquisition of a second language influences the development of language abilities and cognitive functions. In the present study, we used functional Magnetic Resonance Imaging (fMRI) to investigate the impact of early bilingualism on the organization of the cortical language network during sentence production. Two groups of adult multilinguals, proficient in three languages, were tested on a narrative task; early multilinguals acquired the second language before the age of three years, late multilinguals after the age of nine. All participants learned a third language after nine years of age. Comparison of the two groups revealed substantial differences in language-related brain activity for early as well as late acquired languages. Most importantly, early multilinguals preferentially activated a fronto-striatal network in the left hemisphere, whereas the left posterior superior temporal gyrus (pSTG) was activated to a lesser degree than in late multilinguals. The same brain regions were highlighted in previous studies when a non-target language had to be controlled. Hence the engagement of language control in adult early multilinguals appears to be influenced by the specific learning and acquisition conditions during early childhood. Remarkably, our results reveal that the functional control of early and subsequently later acquired languages is similarly affected, suggesting that language experience has a pervasive influence into adulthood. As such, our findings extend the current understanding of control functions in multilinguals.
F2C2
(2012)
Background: Flux coupling analysis (FCA) has become a useful tool in the constraint-based analysis of genome-scale metabolic networks. FCA allows detecting dependencies between reaction fluxes of metabolic networks at steady-state. On the one hand, this can help in the curation of reconstructed metabolic networks by verifying whether the coupling between reactions is in agreement with the experimental findings. On the other hand, FCA can aid in defining intervention strategies to knock out target reactions.
Results: We present a new method F2C2 for FCA, which is orders of magnitude faster than previous approaches. As a consequence, FCA of genome-scale metabolic networks can now be performed in a routine manner.
Conclusions: We propose F2C2 as a fast tool for the computation of flux coupling in genome-scale metabolic networks. F2C2 is freely available for non-commercial use at https://sourceforge.net/projects/f2c2/files/.
During reading, saccadic eye movements are generated to shift words into the center of the visual field for lexical processing. Recently, Krugel and Engbert (Vision Research 50:1532-1539, 2010) demonstrated that within-word fixation positions are largely shifted to the left after skipped words. However, explanations of the origin of this effect cannot be drawn from normal reading data alone. Here we show that the large effect of skipped words on the distribution of within-word fixation positions is primarily based on rather subtle differences in the low-level visual information acquired before saccades. Using arrangements of "x" letter strings, we reproduced the effect of skipped character strings in a highly controlled single-saccade task. Our results demonstrate that the effect of skipped words in reading is the signature of a general visuomotor phenomenon. Moreover, our findings extend beyond the scope of the widely accepted range-error model, which posits that within-word fixation positions in reading depend solely on the distances of target words. We expect that our results will provide critical boundary conditions for the development of visuomotor models of saccade planning during reading.
Flux-P
(2012)
Quantitative knowledge of intracellular fluxes in metabolic networks is invaluable for inferring metabolic system behavior and the design principles of biological systems. However, intracellular reaction rates can not often be calculated directly but have to be estimated; for instance, via 13C-based metabolic flux analysis, a model-based interpretation of stable carbon isotope patterns in intermediates of metabolism. Existing software such as FiatFlux, OpenFLUX or 13CFLUX supports experts in this complex analysis, but requires several steps that have to be carried out manually, hence restricting the use of this software for data interpretation to a rather small number of experiments. In this paper, we present Flux-P as an approach to automate and standardize 13C-based metabolic flux analysis, using the Bio-jETI workflow framework. Exemplarily based on the FiatFlux software, it demonstrates how services can be created that carry out the different analysis steps autonomously and how these can subsequently be assembled into software workflows that perform automated, high-throughput intracellular flux analysis of high quality and reproducibility. Besides significant acceleration and standardization of the data analysis, the agile workflow-based realization supports flexible changes of the analysis workflows on the user level, making it easy to perform custom analyses.
The distinctness of, and overlap between, pea genotypes held in several Pisum germplasm collections has been used to determine their relatedness and to test previous ideas about the genetic diversity of Pisum. Our characterisation of genetic diversity among 4,538 Pisum accessions held in 7 European Genebanks has identified sources of novel genetic variation, and both reinforces and refines previous interpretations of the overall structure of genetic diversity in Pisum. Molecular marker analysis was based upon the presence/absence of polymorphism of retrotransposon insertions scored by a high-throughput microarray and SSAP approaches. We conclude that the diversity of Pisum constitutes a broad continuum, with graded differentiation into sub-populations which display various degrees of distinctness. The most distinct genetic groups correspond to the named taxa while the cultivars and landraces of Pisum sativum can be divided into two broad types, one of which is strongly enriched for modern cultivars. The addition of germplasm sets from six European Genebanks, chosen to represent high diversity, to a single collection previously studied with these markers resulted in modest additions to the overall diversity observed, suggesting that the great majority of the total genetic diversity collected for the Pisum genus has now been described. Two interesting sources of novel genetic variation have been identified. Finally, we have proposed reference sets of core accessions with a range of sample sizes to represent Pisum diversity for the future study and exploitation by researchers and breeders.
Much previous experimental research on morphological processing has focused on surface and meaning-level properties of morphologically complex words, without paying much attention to the morphological differences between inflectional and derivational processes. Realization-based theories of morphology, for example, assume specific morpholexical representations for derived words that distinguish them from the products of inflectional or paradigmatic processes. The present study reports results from a series of masked priming experiments investigating the processing of inflectional and derivational phenomena in native (L1) and non-native (L2) speakers in a non-Indo-European language, Turkish. We specifically compared regular (Aorist) verb inflection with deadjectival nominalization, both of which are highly frequent, productive and transparent in Turkish. The experiments demonstrated different priming patterns for inflection and derivation, specifically within the L2 group. Implications of these findings are discussed both for accounts of L2 morphological processing and for the controversial linguistic distinction between inflection and derivation.
Although all bilinguals encounter cross-language interference (CLI), some bilinguals are more susceptible to interference than others. Here, we report on language performance of late bilinguals (Russian/German) on two bilingual tasks (interview, verbal fluency), their language use and switching habits. The only between-group difference was CLI: one group consistently produced significantly more errors of CLI on both tasks than the other (thereby replicating our findings from a bilingual picture naming task). This striking group difference in language control ability can only be explained by differences in cognitive control, not in language proficiency or language mode.
Background: Detection of immunogenic proteins remains an important task for life sciences as it nourishes the understanding of pathogenicity, illuminates new potential vaccine candidates and broadens the spectrum of biomarkers applicable in diagnostic tools. Traditionally, immunoscreenings of expression libraries via polyclonal sera on nitrocellulose membranes or screenings of whole proteome lysates in 2-D gel electrophoresis are performed. However, these methods feature some rather inconvenient disadvantages. Screening of expression libraries to expose novel antigens from bacteria often lead to an abundance of false positive signals owing to the high cross reactivity of polyclonal antibodies towards the proteins of the expression host. A method is presented that overcomes many disadvantages of the old procedures.
Results: Four proteins that have previously been described as immunogenic have successfully been assessed immunogenic abilities with our method. One protein with no known immunogenic behaviour before suggested potential immunogenicity. We incorporated a fusion tag prior to our genes of interest and attached the expressed fusion proteins covalently on microarrays. This enhances the specific binding of the proteins compared to nitrocellulose. Thus, it helps to reduce the number of false positives significantly. It enables us to screen for immunogenic proteins in a shorter time, with more samples and statistical reliability. We validated our method by employing several known genes from Campylobacter jejuni NCTC 11168.
Conclusions: The method presented offers a new approach for screening of bacterial expression libraries to illuminate novel proteins with immunogenic features. It could provide a powerful and attractive alternative to existing methods and help to detect and identify vaccine candidates, biomarkers and potential virulence-associated factors with immunogenic behaviour furthering the knowledge of virulence and pathogenicity of studied bacteria.
Mineral chemistry and thermobarometry of the staurolite-chloritoid schists from Poshtuk, NW Iran
(2012)
The Poshtuk metapelitic rocks in northwestern Iran underwent two main phases of regional and contact metamorphism. Microstructures, textural features and field relations indicate that these rocks underwent a polymetamorphic history. The dominant metamorphic assemblage of the metapelites is garnet, staurolite, chloritoid, chlorite, muscovite and quartz, which grew mainly syntectonically during the later contact metamorphic event. Peak metamorphic conditions of this event took place at 580 ◦ C and ∼ 3–4 kbar, indicating that this event occurred under high-temperature and low-pressure conditions (HT/LP metamorphism), which reflects the high heat flow in this part of the crust. This event is mainly controlled by advective heat input through magmatic intrusions into all levels of the crust. These extensive Eocene metamorphic and magmatic activities can be associated with the early Alpine Orogeny, which resulted in this area from the convergence between the Arabian and Eurasian plates, and the Cenozoic closure of the Tethys oceanic tract(s).
We present the new multi-threaded version of the state-of-the-art answer set solver clasp. We detail its component and communication architecture and illustrate how they support the principal functionalities of clasp. Also, we provide some insights into the data representation used for different constraint types handled by clasp. All this is accompanied by an extensive experimental analysis of the major features related to multi-threading in clasp.
In older research literature, the prose epics emerging from the court of Elisabeth of Lorraine and Nassau-Saarbrücken have repeatedly been accused of lacking structure and literariness. By contrast, this article shows that narrative principles of seriality generate the complex structure of the voluminous ›Loher und Maller‹: literary strategies of repetition and variation organize the text on different levels. Recurring narrative structures, thematic constellations and motivations as well as lexical stereotypes are part of this comprehensive principle of seriality. Not triviality and insufficiency, but structural and narrative complexity and lexical accumulation of significance characterize ›Loher und Maller‹.
We present 3D zero-beta ideal MHD simulations of the solar flare/CME event that occurred in Active Region 11060 on 2010 April 8. The initial magnetic configurations of the two simulations are stable nonlinear force-free field and unstable magnetic field models constructed by Su et al. (2011) using the flux rope insertion method. The MHD simulations confirm that the stable model relaxes to a stable equilibrium, while the unstable model erupts as a CME. Comparisons between observations and MHD simulations of the CME are also presented.