10,254 research outputs found
Universally Sloppy Parameter Sensitivities in Systems Biology
Quantitative computational models play an increasingly important role in
modern biology. Such models typically involve many free parameters, and
assigning their values is often a substantial obstacle to model development.
Directly measuring \emph{in vivo} biochemical parameters is difficult, and
collectively fitting them to other data often yields large parameter
uncertainties. Nevertheless, in earlier work we showed in a
growth-factor-signaling model that collective fitting could yield
well-constrained predictions, even when it left individual parameters very
poorly constrained. We also showed that the model had a `sloppy' spectrum of
parameter sensitivities, with eigenvalues roughly evenly distributed over many
decades. Here we use a collection of models from the literature to test whether
such sloppy spectra are common in systems biology. Strikingly, we find that
every model we examine has a sloppy spectrum of sensitivities. We also test
several consequences of this sloppiness for building predictive models. In
particular, sloppiness suggests that collective fits to even large amounts of
ideal time-series data will often leave many parameters poorly constrained.
Tests over our model collection are consistent with this suggestion. This
difficulty with collective fits may seem to argue for direct parameter
measurements, but sloppiness also implies that such measurements must be
formidably precise and complete to usefully constrain many model predictions.
We confirm this implication in our signaling model. Our results suggest that
sloppy sensitivity spectra are universal in systems biology models. The
prevalence of sloppiness highlights the power of collective fits and suggests
that modelers should focus on predictions rather than on parameters.Comment: Submitted to PLoS Computational Biology. Supplementary Information
available in "Other Formats" bundle. Discussion slightly revised to add
historical contex
Systems biology in animal sciences
Systems biology is a rapidly expanding field of research and is applied in a number of biological disciplines. In animal sciences, omics approaches are increasingly used, yielding vast amounts of data, but systems biology approaches to extract understanding from these data of biological processes and animal traits are not yet frequently used. This paper aims to explain what systems biology is and which areas of animal sciences could benefit from systems biology approaches. Systems biology aims to understand whole biological systems working as a unit, rather than investigating their individual components. Therefore, systems biology can be considered a holistic approach, as opposed to reductionism. The recently developed ‘omics’ technologies enable biological sciences to characterize the molecular components of life with ever increasing speed, yielding vast amounts of data. However, biological functions do not follow from the simple addition of the properties of system components, but rather arise from the dynamic interactions of these components. Systems biology combines statistics, bioinformatics and mathematical modeling to integrate and analyze large amounts of data in order to extract a better understanding of the biology from these huge data sets and to predict the behavior of biological systems. A ‘system’ approach and mathematical modeling in biological sciences are not new in itself, as they were used in biochemistry, physiology and genetics long before the name systems biology was coined. However, the present combination of mass biological data and of computational and modeling tools is unprecedented and truly represents a major paradigm shift in biology. Significant advances have been made using systems biology approaches, especially in the field of bacterial and eukaryotic cells and in human medicine. Similarly, progress is being made with ‘system approaches’ in animal sciences, providing exciting opportunities to predict and modulate animal traits
Forward Flux Sampling for rare event simulations
Rare events are ubiquitous in many different fields, yet they are notoriously
difficult to simulate because few, if any, events are observed in a conventiona
l simulation run. Over the past several decades, specialised simulation methods
have been developed to overcome this problem. We review one recently-developed
class of such methods, known as Forward Flux Sampling. Forward Flux Sampling
uses a series of interfaces between the initial and final states to calculate
rate constants and generate transition paths, for rare events in equilibrium or
nonequilibrium systems with stochastic dynamics. This review draws together a
number of recent advances, summarizes several applications of the method and
highlights challenges that remain to be overcome.Comment: minor typos in the manuscript. J.Phys.:Condensed Matter (accepted for
publication
Functional Classification of Skeletal Muscle Networks. I. Normal Physiology
Extensive measurements of the parts list of human skeletal muscle through transcriptomics and other phenotypic assays offer the opportunity to reconstruct detailed functional models. Through integration of vast amounts of data present in databases and extant knowledge of muscle function combined with robust analyses that include a clustering approach, we present both a protein parts list and network models for skeletal muscle function. The model comprises the four key functional family networks that coexist within a functional space; namely, excitation-activation family (forward pathways that transmit a motoneuronal command signal into the spatial volume of the cell and then use Ca2+ fluxes to bind Ca2+ to troponin C sites on F-actin filaments, plus transmembrane pumps that maintain transmission capacity); mechanical transmission family (a sophisticated three-dimensional mechanical apparatus that bidirectionally couples the millions of actin-myosin nanomotors with external axial tensile forces at insertion sites); metabolic and bioenergetics family (pathways that supply energy for the skeletal muscle function under widely varying demands and provide for other cellular processes); and signaling-production family (which represents various sensing, signal transduction, and nuclear infrastructure that controls the turn over and structural integrity and regulates the maintenance, regeneration, and remodeling of the muscle). Within each family, we identify subfamilies that function as a unit through analysis of large-scale transcription profiles of muscle and other tissues. This comprehensive network model provides a framework for exploring functional mechanisms of the skeletal muscle in normal and pathophysiology, as well as for quantitative modeling
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High-resolution and high-accuracy topographic and transcriptional maps of the nucleosome barrier.
Nucleosomes represent mechanical and energetic barriers that RNA Polymerase II (Pol II) must overcome during transcription. A high-resolution description of the barrier topography, its modulation by epigenetic modifications, and their effects on Pol II nucleosome crossing dynamics, is still missing. Here, we obtain topographic and transcriptional (Pol II residence time) maps of canonical, H2A.Z, and monoubiquitinated H2B (uH2B) nucleosomes at near base-pair resolution and accuracy. Pol II crossing dynamics are complex, displaying pauses at specific loci, backtracking, and nucleosome hopping between wrapped states. While H2A.Z widens the barrier, uH2B heightens it, and both modifications greatly lengthen Pol II crossing time. Using the dwell times of Pol II at each nucleosomal position we extract the energetics of the barrier. The orthogonal barrier modifications of H2A.Z and uH2B, and their effects on Pol II dynamics rationalize their observed enrichment in +1 nucleosomes and suggest a mechanism for selective control of gene expression
The Informational Model of Consciousness: Mechanisms of Embodiment/Disembodiment of Information
It was shown recently that information is the central concept which it is to be considered to understand consciousness
and its properties. Arguing that consciousness is a consequence of the operational activity of the informational
system of the human body, it was shown that this system is composed by seven informational components, reflected
in consciousness by corresponding cognitive centers. It was argued also that consciousness can be connected to the
environment not only by the common senses, but also by a special connection pole to the bipolar properties of the
universe, allowing to explain the associated phenomena of the near-death experiences and other special phenomena.
Starting from the characteristics of this model, defined as the Informational Model of Consciousness and to complete
the info-communication panorama, in this paper it is analyzed the info-connectivity of the informational system with
the body itself. The brain areas where the activity of each informational component are identified, and a definition of
consciousness in terms of information is proposed. As the electrical connectivity by means of the nervous system was
already proved, allowing the application of the analysis and developing tools of the information science, a particular
attention is paid to the non-electrical mechanisms implied in the internal communication.
For this, it is shown that the key mechanisms consists in embodiment/disembodiment processes of information during
the inter and intra communication of the cells. This process can be modeled also by means of, and in correlation with specific
concepts of the science and technology of information, referred to network communication structures, and is represented
by epigenetic mechanisms, allowing the acquired trait transmission to the offspring generation. From the perspective of the
informational model of consciousness, the human organism appears therefore as a dynamic reactive informational system,
actuating in correlation with matter for adaptation, by embodiment/disembodiment processes of information
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