3,792 research outputs found
A stochastic and dynamical view of pluripotency in mouse embryonic stem cells
Pluripotent embryonic stem cells are of paramount importance for biomedical
research thanks to their innate ability for self-renewal and differentiation
into all major cell lines. The fateful decision to exit or remain in the
pluripotent state is regulated by complex genetic regulatory network. Latest
advances in transcriptomics have made it possible to infer basic topologies of
pluripotency governing networks. The inferred network topologies, however, only
encode boolean information while remaining silent about the roles of dynamics
and molecular noise in gene expression. These features are widely considered
essential for functional decision making. Herein we developed a framework for
extending the boolean level networks into models accounting for individual
genetic switches and promoter architecture which allows mechanistic
interrogation of the roles of molecular noise, external signaling, and network
topology. We demonstrate the pluripotent state of the network to be a broad
attractor which is robust to variations of gene expression. Dynamics of exiting
the pluripotent state, on the other hand, is significantly influenced by the
molecular noise originating from genetic switching events which makes cells
more responsive to extracellular signals. Lastly we show that steady state
probability landscape can be significantly remodeled by global gene switching
rates alone which can be taken as a proxy for how global epigenetic
modifications exert control over stability of pluripotent states.Comment: 11 pages, 7 figure
Universality and predictability in molecular quantitative genetics
Molecular traits, such as gene expression levels or protein binding
affinities, are increasingly accessible to quantitative measurement by modern
high-throughput techniques. Such traits measure molecular functions and, from
an evolutionary point of view, are important as targets of natural selection.
We review recent developments in evolutionary theory and experiments that are
expected to become building blocks of a quantitative genetics of molecular
traits. We focus on universal evolutionary characteristics: these are largely
independent of a trait's genetic basis, which is often at least partially
unknown. We show that universal measurements can be used to infer selection on
a quantitative trait, which determines its evolutionary mode of conservation or
adaptation. Furthermore, universality is closely linked to predictability of
trait evolution across lineages. We argue that universal trait statistics
extends over a range of cellular scales and opens new avenues of quantitative
evolutionary systems biology
Stochastic Physics, Complex Systems and Biology
In complex systems, the interplay between nonlinear and stochastic dynamics,
e.g., J. Monod's necessity and chance, gives rise to an evolutionary process in
Darwinian sense, in terms of discrete jumps among attractors, with punctuated
equilibrium, spontaneous random "mutations" and "adaptations". On an
evlutionary time scale it produces sustainable diversity among individuals in a
homogeneous population rather than convergence as usually predicted by a
deterministic dynamics. The emergent discrete states in such a system, i.e.,
attractors, have natural robustness against both internal and external
perturbations. Phenotypic states of a biological cell, a mesoscopic nonlinear
stochastic open biochemical system, could be understood through such a
perspective.Comment: 10 page
On the role of synaptic stochasticity in training low-precision neural networks
Stochasticity and limited precision of synaptic weights in neural network
models are key aspects of both biological and hardware modeling of learning
processes. Here we show that a neural network model with stochastic binary
weights naturally gives prominence to exponentially rare dense regions of
solutions with a number of desirable properties such as robustness and good
generalization performance, while typical solutions are isolated and hard to
find. Binary solutions of the standard perceptron problem are obtained from a
simple gradient descent procedure on a set of real values parametrizing a
probability distribution over the binary synapses. Both analytical and
numerical results are presented. An algorithmic extension aimed at training
discrete deep neural networks is also investigated.Comment: 7 pages + 14 pages of supplementary materia
Synthetic biology—putting engineering into biology
Synthetic biology is interpreted as the engineering-driven building of increasingly complex biological entities for novel applications. Encouraged by progress in the design of artificial gene networks, de novo DNA synthesis and protein engineering, we review the case for this emerging discipline. Key aspects of an engineering approach are purpose-orientation, deep insight into the underlying scientific principles, a hierarchy of abstraction including suitable interfaces between and within the levels of the hierarchy, standardization and the separation of design and fabrication. Synthetic biology investigates possibilities to implement these requirements into the process of engineering biological systems. This is illustrated on the DNA level by the implementation of engineering-inspired artificial operations such as toggle switching, oscillating or production of spatial patterns. On the protein level, the functionally self-contained domain structure of a number of proteins suggests possibilities for essentially Lego-like recombination which can be exploited for reprogramming DNA binding domain specificities or signaling pathways. Alternatively, computational design emerges to rationally reprogram enzyme function. Finally, the increasing facility of de novo DNA synthesis—synthetic biology’s system fabrication process—supplies the possibility to implement novel designs for ever more complex systems. Some of these elements have merged to realize the first tangible synthetic biology applications in the area of manufacturing of pharmaceutical compounds.
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