Challenges in horizontal model integration

BACKGROUND: Systems Biology has motivated dynamic models of important intracellular processes at the pathway level, for example, in signal transduction and cell cycle control. To answer important biomedical questions, however, one has to go beyond the study of isolated pathways towards the joint study of interacting signaling pathways or the joint study of signal transduction and cell cycle control. Thereby the reuse of established models is preferable, as it will generally reduce the modeling effort and increase the acceptance of the combined model in the field. RESULTS: Obtaining a combined model can be challenging, especially if the submodels are large and/or come from different working groups (as is generally the case, when models stored in established repositories are used). To support this task, we describe a semi-automatic workflow based on established software tools. In particular, two frequent challenges are described: identification of the overlap and subsequent (re)parameterization of the integrated model. CONCLUSIONS: The reparameterization step is crucial, if the goal is to obtain a model that can reproduce the data explained by the individual models. For demonstration purposes we apply our workflow to integrate two signaling pathways (EGF and NGF) from the BioModels Database. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12918-016-0266-3) contains supplementary material, which is available to authorized users

The Process-Interaction-Model: a common representation of rule-based and logical models allows studying signal transduction on different levels of detail

BACKGROUND: Signaling systems typically involve large, structured molecules each consisting of a large number of subunits called molecule domains. In modeling such systems these domains can be considered as the main players. In order to handle the resulting combinatorial complexity, rule-based modeling has been established as the tool of choice. In contrast to the detailed quantitative rule-based modeling, qualitative modeling approaches like logical modeling rely solely on the network structure and are particularly useful for analyzing structural and functional properties of signaling systems. RESULTS: We introduce the Process-Interaction-Model (PIM) concept. It defines a common representation (or basis) of rule-based models and site-specific logical models, and, furthermore, includes methods to derive models of both types from a given PIM. A PIM is based on directed graphs with nodes representing processes like post-translational modifications or binding processes and edges representing the interactions among processes. The applicability of the concept has been demonstrated by applying it to a model describing EGF insulin crosstalk. A prototypic implementation of the PIM concept has been integrated in the modeling software ProMoT. CONCLUSIONS: The PIM concept provides a common basis for two modeling formalisms tailored to the study of signaling systems: a quantitative (rule-based) and a qualitative (logical) modeling formalism. Every PIM is a compact specification of a rule-based model and facilitates the systematic set-up of a rule-based model, while at the same time facilitating the automatic generation of a site-specific logical model. Consequently, modifications can be made on the underlying basis and then be propagated into the different model specifications – ensuring consistency of all models, regardless of the modeling formalism. This facilitates the analysis of a system on different levels of detail as it guarantees the application of established simulation and analysis methods to consistent descriptions (rule-based and logical) of a particular signaling system

High-pressure spin shifts in the pseudogap regime of superconducting YBa2Cu4O8 as revealed by 17O NMR

A new NMR anvil cell design is used for measuring the influence of high pressure on the electronic properties of the high-temperature superconductor YBa$_2$Cu$_4$O$_8$ above the superconducting transition temperature $T_{\rm c}$. It is found that pressure increases the spin shift at all temperatures in such a way that the pseudo-gap feature has almost disappeared at 63 kbar. This change of the temperature dependent spin susceptibility can be explained by a pressure induced proportional decrease (factor of two) of a temperature dependent component, and an increase (factor of 9) of a temperature independent component, contrary to the effects of increasing doping. The results demonstrate that one can use anvil cell NMR to investigate the tuning of the electronic properties of correlated electronic materials with pressure.Comment: 4 pages, 4 figures, accepted for publication in Phys. Rev.

Quantum Cosmology of Kantowski-Sachs like Models

The Wheeler-DeWitt equation for a class of Kantowski-Sachs like models is completely solved. The generalized models include the Kantowski-Sachs model with cosmological constant and pressureless dust. Likewise contained is a joined model which consists of a Kantowski-Sachs cylinder inserted between two FRW half--spheres. The (second order) WKB approximation is exact for the wave functions of the complete set and this facilitates the product structure of the wave function for the joined model. In spite of the product structure the wave function can not be interpreted as admitting no correlations between the different regions. This problem is due to the joining procedure and may therefore be present for all joined models. Finally, the {s}ymmetric {i}nitial {c}ondition (SIC) for the wave function is analyzed and compared with the ``no bouindary'' condition. The consequences of the different boundary conditions for the arrow of time are briefly mentioned.Comment: 21 pages, uses LaTeX2e, epsf.sty and float.sty, three figures (50 kb); changes: one figure added, new interpretation of quantizing procedure for the joined model and many minor change

Quantum creation of an Inhomogeneous universe

In this paper we study a class of inhomogeneous cosmological models which is a modified version of what is usually called the Lema\^itre-Tolman model. We assume that we have a space with 2-dimensional locally homogeneous spacelike surfaces. In addition we assume they are compact. Classically we investigate both homogeneous and inhomogeneous spacetimes which this model describe. For instance one is a quotient of the AdS$_4$ space which resembles the BTZ black hole in AdS$_3$. Due to the complexity of the model we indicate a simpler model which can be quantized easily. This model still has the feature that it is in general inhomogeneous. How this model could describe a spontaneous creation of a universe through a tunneling event is emphasized.Comment: 21 pages, 5 ps figures, REVTeX, new subsection include

Transcriptomes of Electrophysiologically Recorded Dbx1-derived Respiratory Neurons of the preBötzinger Complex in Neonatal Mice

Breathing depends on interneurons in the preBötzinger complex (preBötC) derived from Dbx1-expressing precursors. Here we investigate whether rhythm- and pattern-generating functions reside in discrete classes of Dbx1 preBötC neurons. In a slice model of breathing with ~ 5 s cycle period, putatively rhythmogenic Type-1 Dbx1 preBötC neurons activate 100–300 ms prior to Type-2 neurons, putatively specialized for output pattern, and 300–500 ms prior to the inspiratory motor output. We sequenced Type-1 and Type-2 transcriptomes and identified differential expression of 123 genes including ionotropic receptors (Gria3, Gabra1) that may explain their preinspiratory activation profiles and Ca2+ signaling (Cracr2a, Sgk1) involved in inspiratory and sigh bursts. Surprisingly, neuropeptide receptors that influence breathing (e.g., µ-opioid and bombesin-like peptide receptors) were only sparsely expressed, which suggests that cognate peptides and opioid drugs exert their profound effects on a small fraction of the preBötC core. These data in the public domain help explain the neural origins of breathing

The QCD phase diagram at nonzero quark density

We determine the phase diagram of QCD on the \mu-T plane for small to moderate chemical potentials. Two transition lines are defined with two quantities, the chiral condensate and the strange quark number susceptibility. The calculations are carried out on N_t =6,8 and 10 lattices generated with a Symanzik improved gauge and stout-link improved 2+1 flavor staggered fermion action using physical quark masses. After carrying out the continuum extrapolation we find that both quantities result in a similar curvature of the transition line. Furthermore, our results indicate that in leading order the width of the transition region remains essentially the same as the chemical potential is increased.Comment: 12 pages, 6 figure

Probing the unusual anion mobility of LiBH_4 confined in highly ordered nanoporous carbon frameworks via solid state NMR and quasielastic neutron scattering

Particle size and particle–framework interactions have profound effects on the kinetics, reaction pathways, and even thermodynamics of complex hydrides incorporated in frameworks possessing nanoscale features. Tuning these properties may hold the key to the utilization of complex hydrides in practical applications for hydrogen storage. Using carefully synthesized, highly-ordered, nanoporous carbons (NPCs), we have previously shown quantitative differences in the kinetics and reaction pathways of LiBH_4 when incorporated into the frameworks. In this paper, we probe the anion mobility of LiBH_4 confined in NPC frameworks by a combination of solid state NMR and quasielastic neutron scattering (QENS) and present some new insights into the nanoconfinement effect. NMR and QENS spectra of LiBH_4 confined in a 4 nm pore NPC suggest that the BH_4− anions nearer the LiBH_4–carbon pore interface exhibit much more rapid translational and reorientational motions compared to those in the LiBH_4 interior. Moreover, an overly broadened BH_4− torsional vibration band reveals a disorder-induced array of BH_4− rotational potentials. XRD results are consistent with a lack of LiBH_4 long-range order in the pores. Consistent with differential scanning calorimetry measurements, neither NMR nor QENS detects a clear solid–solid phase transition as observed in the bulk, indicating that borohydride–framework interactions and/or nanosize effects have large roles in confined LiBH_4