arXiv subjects

Anne Shiu

Publications and source records attributed to Anne Shiu.

At least 37 records · Page 2Linked to original sources

arXiv2020

Neural Codes With Three Maximal Codewords: Convexity and Minimal Embedding Dimension

Neural codes, represented as collections of binary strings called codewords, are used to encode neural activity. A code is called convex if its codewords are represented as an arrangement of convex open sets in Euclidean space. Previous work has focused on addressing the question: how can we tell when a neural code is convex? Giusti and Itskov identified a local obstruction and proved that convex neural codes have no local obstructions. The converse is true for codes on up to four neurons, but false in general. Nevertheless, we prove this converse holds for codes with up to three maximal codewords, and moreover the minimal embedding dimension of such codes is at most two.

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arXiv2020

Mixed volume of small reaction networks

An important invariant of a chemical reaction network is its maximum number of positive steady states. This number, however, is in general difficult to compute. Nonetheless, there is an upper bound on this number -- namely, a network's mixed volume -- that is easy to compute. Moreover, recent work has shown that, for certain biological signaling networks, the mixed volume does not greatly exceed the maximum number of positive steady states. Continuing this line of research, we further investigate this overcount and also compute the mixed volumes of small networks, those with only a few species or reactions.

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arXiv2020

Identifiability of Linear Compartmental Models: The Effect of Moving Inputs, Outputs, and Leaks

A mathematical model is identifiable if its parameters can be recovered from data. Here we investigate, for linear compartmental models, whether (local, generic) identifiability is preserved when parts of the model -- specifically, inputs, outputs, leaks, and edges -- are moved, added, or deleted. Our results are as follows. First, for certain catenary, cycle, and mammillary models, moving or deleting the leak preserves identifiability. Next, for cycle models with up to one leak, moving inputs or outputs preserves identifiability. Thus, every cycle model with up to one leak (and at least one input and at least one output) is identifiable. Next, we give conditions under which adding leaks renders a cycle model unidentifiable. Finally, for certain cycle models with no leaks, adding specific edges again preserves identifiability. Our proofs, which are algebraic and combinatorial in nature, rely on results on elementary symmetric polynomials and the theory of input-output equations for linear compartmental models.

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arXiv2019

Neural Codes and the Factor Complex

We introduce the factor complex of a neural code, and show how intervals and maximal codewords are captured by the combinatorics of factor complexes. We use these results to obtain algebraic and combinatorial characterizations of max-intersection-complete codes, as well as a new combinatorial characterization of intersection-complete codes.

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arXiv2019

Joining and decomposing reaction networks

In systems and synthetic biology, much research has focused on the behavior and design of single pathways, while, more recently, experimental efforts have focused on how cross-talk (coupling two or more pathways) or inhibiting molecular function (isolating one part of the pathway) affects systems-level behavior. However, the theory for tackling these larger systems in general has lagged behind. Here, we analyze how joining networks (e.g., cross-talk) or decomposing networks (e.g., inhibition or knock-outs) affects three properties that reaction networks may possess---identifiability (recoverability of parameter values from data), steady-state invariants (relationships among species concentrations at steady state, used in model selection), and multistationarity (capacity for multiple steady states, which correspond to multiple cell decisions). Specifically, we prove results that clarify, for a network obtained by joining two smaller networks, how properties of the smaller networks can be inferred from or can imply similar properties of the original network. Our proofs use techniques from computational algebraic geometry, including elimination theory and differential algebra.

math.DS↗

arXiv2019

Linear compartmental models: input-output equations and operations that preserve identifiability

This work focuses on the question of how identifiability of a mathematical model, that is, whether parameters can be recovered from data, is related to identifiability of its submodels. We look specifically at linear compartmental models and investigate when identifiability is preserved after adding or removing model components. In particular, we examine whether identifiability is preserved when an input, output, edge, or leak is added or deleted. Our approach, via differential algebra, is to analyze specific input-output equations of a model and the Jacobian of the associated coefficient map. We clarify a prior determinantal formula for these equations, and then use it to prove that, under some hypotheses, a model's input-output equations can be understood in terms of certain submodels we call "output-reachable". Our proofs use algebraic and combinatorial techniques.

math.AG↗

arXiv2019

Oscillations and bistability in a model of ERK regulation

This work concerns the question of how two important dynamical properties, oscillations and bistability, emerge in an important biological signaling network. Specifically, we consider a model for dual-site phosphorylation and dephosphorylation of extracellular signal-regulated kinase (ERK). We prove that oscillations persist even as the model is greatly simplified (reactions are made irreversible and intermediates are removed). Bistability, however, is much less robust -- this property is lost when intermediates are removed or even when all reactions are made irreversible. Moreover, bistability is characterized by the presence of two reversible, catalytic reactions: as other reactions are made irreversible, bistability persists as long as one or both of the specified reactions is preserved. Finally, we investigate the maximum number of steady states, aided by a network's "mixed volume" (a concept from convex geometry). Taken together, our results shed light on the question of how oscillations and bistability emerge from a limiting network of the ERK network -- namely, the fully processive dual-site network -- which is known to be globally stable and therefore lack both oscillations and bistability. Our proofs are enabled by a Hopf bifurcation criterion due to Yang, analyses of Newton polytopes arising from Hurwitz determinants, and recent characterizations of multistationarity for networks having a steady-state parametrization.

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arXiv2019

Multistationarity in Structured Reaction Networks

Many dynamical systems arising in biology and other areas exhibit multistationarity (two or more positive steady states with the same conserved quantities). Although deciding multistationarity for a polynomial dynamical system is an effective question in real algebraic geometry, it is in general difficult to determine whether a given network can give rise to a multistationary system, and if so, to identify witnesses to multistationarity, that is, specific parameter values for which the system exhibits multiple steady states. Here we investigate both problems. First, we build on work of Conradi, Feliu, Mincheva, and Wiuf, who showed that for certain reaction networks whose steady states admit a positive parametrization, multistationarity is characterized by whether a certain "critical function" changes sign. Here, we allow for more general parametrizations, which make it much easier to determine the existence of a sign change. This is particularly simple when the steady-state equations are linearly equivalent to binomials; we give necessary conditions for this to happen, which hold for many networks studied in the literature. We also give a sufficient condition for multistationarity of networks whose steady-state equations can be replaced by equivalent triangular-form equations. Finally, we present methods for finding witnesses to multistationarity, which we show work well for certain structured reaction networks, including those common to biological signaling pathways. Our work relies on results from degree theory, on the existence of explicit rational parametrizations of the steady states, and on the specialization of Groebner bases.

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arXiv2019

Emergence of oscillations in a mixed-mechanism phosphorylation system

This work investigates the emergence of oscillations in one of the simplest cellular signaling networks exhibiting oscillations, namely, the dual-site phosphorylation and dephosphorylation network (futile cycle), in which the mechanism for phosphorylation is processive while the one for dephosphorylation is distributive (or vice-versa). The fact that this network yields oscillations was shown recently by Suwanmajo and Krishnan. Our results, which significantly extend their analyses, are as follows. First, in the three-dimensional space of total amounts, the border between systems with a stable versus unstable steady state is a surface defined by the vanishing of a single Hurwitz determinant. Second, this surface consists generically of simple Hopf bifurcations. Next, simulations suggest that when the steady state is unstable, oscillations are the norm. Finally, the emergence of oscillations via a Hopf bifurcation is enabled by the catalytic and association constants of the distributive part of the mechanism: if these rate constants satisfy two inequalities, then the system generically admits a Hopf bifurcation. Our proofs are enabled by the Routh-Hurwitz criterion, a Hopf-bifurcation criterion due to Yang, and a monomial parametrization of steady states.

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arXiv2018

Revisiting a synthetic intracellular regulatory network that exhibits oscillations

In 2000, Elowitz and Leibler introduced the repressilator--a synthetic gene circuit with three genes that cyclically repress transcription of the next gene--as well as a corresponding mathematical model. Experimental data and model simulations exhibited oscillations in the protein concentrations across generations. In 2006, Müller \textit{et al.}\ generalized the model to an arbitrary number of genes and analyzed the resulting dynamics. Their new model arose from five key assumptions, two of which are restrictive given current biological knowledge. Accordingly, we propose a new repressilator system that allows for general functions to model transcription, degradation, and translation. We prove that, with an odd number of genes, the new model has a unique steady state and the system converges to this steady state or to a periodic orbit. We also give a necessary and sufficient condition for stability of steady states when the number of genes is even and conjecture a condition for stability for an odd number. Finally, we derive a new rate function describing transcription that arises under more reasonable biological assumptions than the widely used single-step binding assumption. With this new transcription-rate function, we compare the model's amplitude and period with that of a model with the conventional transcription-rate function. Taken together, our results enhance our understanding of genetic regulation by repression.

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arXiv2018

Neural codes, decidability, and a new local obstruction to convexity

Given an intersection pattern of arbitrary sets in Euclidean space, is there an arrangement of convex open sets in Euclidean space that exhibits the same intersections? This question is combinatorial and topological in nature, but is motivated by neuroscience. Specifically, we are interested in a type of neuron called a place cell, which fires precisely when an organism is in a certain region, usually convex, called a place field. The earlier question, therefore, can be rephrased as follows: Which neural codes, that is, patterns of neural activity, can arise from a collection of convex open sets? To address this question, Giusti and Itskov proved that convex neural codes have no "local obstructions," which are defined via the topology of a code's simplicial complex. Codes without local obstructions are called locally good, because the obstruction precludes the code from encoding the intersections of open sets that form a good cover. In other words, every good-cover code is locally good. Here we prove the converse: Every locally good code is a good-cover code. We also prove that the good-cover decision problem is undecidable. Finally, we reveal a stronger type of local obstruction that prevents a code from being convex, and prove that the corresponding decision problem is NP-hard. Our proofs use combinatorial and topological methods.

math.CO↗

arXiv2018

Algebraic signatures of convex and non-convex codes

A convex code is a binary code generated by the pattern of intersections of a collection of open convex sets in some Euclidean space. Convex codes are relevant to neuroscience as they arise from the activity of neurons that have convex receptive fields. In this paper, we use algebraic methods to determine if a code is convex. Specifically, we use the neural ideal of a code, which is a generalization of the Stanley-Reisner ideal. Using the neural ideal together with its standard generating set, the canonical form, we provide algebraic signatures of certain families of codes that are non-convex. We connect these signatures to the precise conditions on the arrangement of sets that prevent the codes from being convex. Finally, we also provide algebraic signatures for some families of codes that are convex, including the class of intersection-complete codes. These results allow us to detect convexity and non-convexity in a variety of situations, and point to some interesting open questions.

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arXiv2018

Nondegenerate multistationarity in small reaction networks

Much attention has been focused in recent years on the following algebraic problem arising from applications: which chemical reaction networks, when taken with mass-action kinetics, admit multiple positive steady states? The interest behind this question is in steady states that are stable. As a step toward this difficult question, here we address the question of multiple nondegenerate positive steady states. Mathematically, this asks whether certain families of parametrized, real, sparse polynomial systems ever admit multiple positive real roots that are simple. Our main results settle this problem for certain types of small networks, and our techniques point the way forward for larger networks.

math.DS↗

arXiv2018

Gröbner Bases of Neural Ideals

The brain processes information about the environment via neural codes. The neural ideal was introduced recently as an algebraic object that can be used to better understand the combinatorial structure of neural codes. Every neural ideal has a particular generating set, called the canonical form, that directly encodes a minimal description of the receptive field structure intrinsic to the neural code. On the other hand, for a given monomial order, any polynomial ideal is also generated by its unique (reduced) Gröbner basis with respect to that monomial order. How are these two types of generating sets -- canonical forms and Gröbner bases -- related? Our main result states that if the canonical form of a neural ideal is a Gröbner basis, then it is the universal Gröbner basis (that is, the union of all reduced Gröbner bases). Furthermore, we prove that this situation -- when the canonical form is a Gröbner basis -- occurs precisely when the universal Gröbner basis contains only pseudo-monomials (certain generalizations of monomials). Our results motivate two questions: (1)~When is the canonical form a Gröbner basis? (2)~When the universal Gröbner basis of a neural ideal is {\em not} a canonical form, what can the non-pseudo-monomial elements in the basis tell us about the receptive fields of the code? We give partial answers to both questions. Along the way, we develop a representation of pseudo-monomials as hypercubes in a Boolean lattice.

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arXiv2017

Dynamics of post-translational modification systems: recent progress and future directions

Post-translational modification (PTM) of proteins plays a key role in signal transduction, and hence significant effort has gone toward understanding how PTM networks process information. This involves, on the theory side, analyzing the dynamical systems arising from such networks. Which networks are, for instance, bistable? Which networks admit sustained oscillations? Which parameter values enable such behaviors? In this Perspective, we highlight recent progress in this area and point out some important future directions. Along the way, we summarize several techniques for analyzing general networks, such as eliminating variables to obtain steady-state parametrizations, and harnessing results on how incorporating intermediates affects dynamics.

q-bio.MN↗

arXiv2017

An All-Encompassing Global Convergence Result for Processive Multisite Phosphorylation Systems

Phosphorylation, the enzyme-mediated addition of a phosphate group to a molecule, is a ubiquitous chemical mechanism in biology. Multisite phosphorylation, the addition of phosphate groups to multiple sites of a single molecule, may be distributive or processive. Distributive systems can be bistable, while processive systems were recently shown to be globally stable. However, this global convergence result was proven only for a specific mechanism of processive phosphorylation/dephosphorylation (namely, all catalytic reactions are reversible). Accordingly, we generalize this result to allow for processive phosphorylation networks in which each reaction may be irreversible, and also to account for possible product inhibition. We accomplish this by defining an all-encompassing processive network that encapsulates all of these schemes, and then appealing to recent results of Marcondes de Freitas, Wiuf, and Feliu that assert global convergence by way of monontone systems theory and network/graph reductions (which correspond to removal of intermediate complexes). Our results form a case study into the question of when global convergence is preserved when reactions and/or intermediate complexes are added to or removed from a network.

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arXiv2016

What makes a neural code convex?

Neural codes allow the brain to represent, process, and store information about the world. Combinatorial codes, comprised of binary patterns of neural activity, encode information via the collective behavior of populations of neurons. A code is called convex if its codewords correspond to regions defined by an arrangement of convex open sets in Euclidean space. Convex codes have been observed experimentally in many brain areas, including sensory cortices and the hippocampus, where neurons exhibit convex receptive fields. What makes a neural code convex? That is, how can we tell from the intrinsic structure of a code if there exists a corresponding arrangement of convex open sets? In this work, we provide a complete characterization of local obstructions to convexity. This motivates us to define max intersection-complete codes, a family guaranteed to have no local obstructions. We then show how our characterization enables one to use free resolutions of Stanley-Reisner ideals in order to detect violations of convexity. Taken together, these results provide a significant advance in understanding the intrinsic combinatorial properties of convex codes.

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arXiv2016

Obstructions to convexity in neural codes

How does the brain encode spatial structure? One way is through hippocampal neurons called place cells, which become associated to convex regions of space known as their receptive fields: each place cell fires at a high rate precisely when the animal is in the receptive field. The firing patterns of multiple place cells form what is known as a convex neural code. How can we tell when a neural code is convex? To address this question, Giusti and Itskov identified a local obstruction, defined via the topology of a code's simplicial complex, and proved that convex neural codes have no local obstructions. Curto et al. proved the converse for all neural codes on at most four neurons. Via a counterexample on five neurons, we show that this converse is false in general. Additionally, we classify all codes on five neurons with no local obstructions. This classification is enabled by our enumeration of connected simplicial complexes on 5 vertices up to isomorphism. Finally, we examine how local obstructions are related to maximal codewords (maximal sets of neurons that co-fire). Curto et al. proved that a code has no local obstructions if and only if it contains certain "mandatory" intersections of maximal codewords. We give a new criterion for an intersection of maximal codewords to be non-mandatory, and prove that it classifies all such non-mandatory codewords for codes on up to 5 neurons.

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