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Philip Greulich

Publications and source records attributed to Philip Greulich.

17 recordsLinked to original sources

Oncomorphic neural agent populations for resource-limited sequential learning

Distributed artificial intelligence (AI) often operates under sequential task exposure, uneven compute, and decentralized coordination. Here, we present a cancer-inspired, or oncomorphic, multi-agent framework in which simulated neural agents can replicate, mutate their neural network architecture, migrate across task environments, undergo ecological turnover, and recruit learning/ecological resources from a finite shared reserve. We evaluate the framework in controlled synthetic nonlinear classification environments in which each agent trains only on its local task, allowing population ecology rather than centralized optimization to determine which neural network architectures persist. For various initial conditions, we find that stronger selection increased the endpoint local accuracy of surviving agent populations. Architecture mutation played a state-dependent role: diverse initial populations performed best at low mutation, whereas clonal large-architecture populations benefited from mutation-generated variation. Selection also increased end-of-run multi-task competence, measured by evaluating surviving agents on all environments without additional training. Recruitment and elevated baseline replication reshaped demographic support while prediction quality remained within a narrow band, consistent with redistribution of finite learning resources. Time-resolved entropy and dominance analyses revealed concentration toward successful architectures, while finite training cycles kept agents in a non-asymptotic learning regime. These results provide proof-of-concept mechanistic evidence that oncomorphic population dynamics may offer a route to decentralized adaptation in engineering applications under bounded local resources.

cs.NE

Cooperative SIR dynamics as a model for spontaneous blood clot initiation

Blood clotting is an important physiological process to suppress bleeding upon injury, but when it occurs inadvertently, it can cause thrombosis, which can lead to life threatening conditions. Hence, understanding the microscopic mechanistic factors for inadvertent, spontaneous blood clotting, in absence of a vessel breach, can help in predicting and adverting such conditions. Here, we present a minimal model -- reminiscent of the SIR model -- for the initiating stage of spontaneous blood clotting, the collective activation of blood platelets. This model predicts that in the presence of very small initial activation signals, macroscopic activation of the platelet population requires a sufficient degree of heterogeneity of platelet sensitivity. To propagate the activation signal and achieve collective activation of the bulk platelet population, it requires the presence of, possibly only few, hyper-sensitive platelets, but also a sufficient proportion of platelets with intermediate, yet higher-than-average sensitivity. A comparison with experimental results demonstrates a qualitative agreement for high platelet signalling activity.

q-bio.QM

Homeostatic regulation of renewing tissue cell populations via crowding control

To maintain renewing epithelial tissues in a healthy, homeostatic state, (stem) cell divisions and differentiation need to be tightly regulated. Mechanisms of homeostatic control often rely on crowding control: cells are able to sense the cell density in their environment (via various molecular and mechanosensing pathways) and respond by adjusting division, differentiation, and cell state transitions appropriately. Here we determine, via a mathematically rigorous framework, which general conditions for the crowding feedback regulation (i) must be minimally met, and (ii) are sufficient, to allow the maintenance of homeostasis in renewing tissues. We show that those conditions naturally allow for a degree of robustness toward disruption of regulation. Furthermore, intrinsic to this feedback regulation is that stem cell identity is established collectively by the cell population, not by individual cells, which implies the possibility of `quasi-dedifferentiation', in which cells committed to differentiation may reacquire stem cell properties upon depletion of the stem cell pool. These findings can guide future experimental campaigns to identify specific crowding feedback mechanisms.

q-bio.TO

Stability and steady state of complex cooperative systems: a diakoptic approach

Cooperative dynamics are common in ecology and population dynamics. However, their commonly high degree of complexity with a large number of coupled degrees of freedom renders them difficult to analyse. Here we present a graph-theoretical criterion, via a diakoptic approach (`divide-and-conquer') to determine a cooperative system's stability by decomposing the system's dependence graph into its strongly connected components (SCCs). In particular, we show that a linear cooperative system is Lyapunov stable if the SCCs of the associated dependence graph all have non-positive dominant eigenvalues, and if no SCCs which have dominant eigenvalue zero are connected by a path.

math.DS

Totally asymmetric exclusion process with site-wise dynamic disorder

We propose an extension of the totally asymmetric simple exclusion process (TASEP) in which particles hopping along a lattice can be blocked by obstacles that dynamically attach/detach from lattice sites. The model can be thought as TASEP with site-wise dynamic disorder. We consider two versions of defect dynamics: (i) defects can bind to any site, irrespective of particle occupation, (ii) defects only bind to sites which are not occupied by particles (particle-obstacle exclusion). In case (i) there is a symmetric, parabolic-like relationship between the current and particle density, as in the standard TASEP. Case (ii) leads to a skewed relationship for slow defect dynamics. We also show that the presence of defects induces particle clustering, despite the translation invariance of the system. For open boundaries the same three phases as for the standard TASEP are observed, albeit the position of phase boundaries is affected by the presence of obstacles. We develop a simple mean-field theory that captures the model's quantitative behaviour for periodic and open boundary conditions and yields good estimates for the current-density relationship, mean cluster sizes and phase boundaries. Lastly, we discuss an application of the model to the biological process of gene transcription.

cond-mat.stat-mech

Extreme value statistics of mutation accumulation in renewing cell populations

The emergence of a predominant phenotype within a cell population is often triggered by a rare accumulation of DNA mutations in a single cell. For example, tumors may be initiated by a single cell in which multiple mutations cooperate to bypass a cell's defense mechanisms. The risk of such an event is thus determined by the extremal accumulation of mutations across tissue cells. To address this risk, we study the statistics of the maximum mutation numbers in a generic, but tested, model of a renewing cell population. By drawing an analogy between the genealogy of a cell population and the theory of branching random walks, we obtain analytical estimates for the probability of exceeding a threshold number of mutations and determine how the statistical distribution of maximum mutation numbers scales with age and cell population size.

q-bio.TO

Predicting the dynamics of bacterial growth inhibition by ribosome-targeting antibiotics

Understanding how antibiotics inhibit bacteria can help to reduce antibiotic use and hence avoid antimicrobial resistance - yet few theoretical models exist for bacterial growth inhibition by a clinically relevant antibiotic treatment regimen. In particular, in the clinic, antibiotic treatment is time dependent. Here, we use a recently-developed model to obtain predictions for the dynamical response of a bacterial cell to a time-dependent dose of ribosome-targeting antibiotic. Our results depend strongly on whether the antibiotic shows reversible transport and/or low-affinity ribosome binding ("low-affinity antibiotic") or, in contrast, irreversible transport and/or high affinity ribosome binding ("high-affinity antibiotic"). For low-affinity antibiotics, our model predicts that growth inhibition depends on the duration of the antibiotic pulse, with a transient period of very fast growth following removal of the antibiotic. For high-affinity antibiotics, growth inhibition depends on peak dosage rather than dose duration, and the model predicts a pronounced post-antibiotic effect, due to hysteresis, in which growth can be suppressed for long times after the antibiotic dose has ended. These predictions are experimentally testable and may be of clinical significance.

q-bio.CB

Growth-dependent bacterial susceptibility to ribosome-targeting antibiotics

Bacterial growth environment strongly influences the efficacy of antibiotic treatment, with slow growth often being associated with decreased susceptibility. Yet in many cases the connection between antibiotic susceptibility and pathogen physiology remains unclear. We show that for ribosome-targeting antibiotics acting on Escherichia coli, a complex interplay exists between physiology and antibiotic action; for some antibiotics within this class faster growth indeed increases susceptibility, but for other antibiotics the opposite is true. Remarkably, these observations can be explained by a simple mathematical model that combines drug transport and binding with physiological constraints. Our model reveals that growth-dependent susceptibility is controlled by a single parameter characterizing the `reversibility' of antibiotic transport and binding. This parameter provides a spectrum-classification of antibiotic growth-dependent efficacy that appears to correspond at its extremes to existing binary classification schemes. In these limits the model predicts universal, parameter-free limiting forms for growth inhibition curves. The model also leads to non-trivial predictions for the drug susceptibility of a translation-mutant strain of E. coli, which we verify experimentally. Drug action and bacterial metabolism are mechanistically complex; nevertheless this study illustrates how coarse-grained models can be used to integrate pathogen physiology into drug design and treatment strategies.

q-bio.CB

Mutational pathway determines whether drug gradients accelerate evolution of drug-resistant cells

Drug gradients are believed to play an important role in the evolution of bacteria resistant to antibiotics and tumors resistant to anti-cancer drugs. We use a statistical physics model to study the evolution of a population of malignant cells exposed to drug gradients, where drug resistance emerges via a mutational pathway involving multiple mutations. We show that a non-uniform drug distribution has the potential to accelerate the emergence of resistance when the mutational pathway involves a long sequence of mutants with increasing resistance, but if the pathway is short or crosses a fitness valley, the evolution of resistance may actually be slowed down by drug gradients. These predictions can be verified experimentally, and may help to improve strategies for combatting the emergence of resistance.

q-bio.PE

Mixed population of competing TASEPs with a shared reservoir of particles

We introduce a mean-field theoretical framework to describe multiple totally asymmetric simple exclusion processes (TASEPs) with different lattice lengths, entry and exit rates, competing for a finite reservoir of particles. We present relations for the partitioning of particles between the reservoir and the lattices: these relations allow us to show that competition for particles can have non-trivial effects on the phase behavior of individual lattices. For a system with non-identical lattices, we find that when a subset of lattices undergoes a phase transition from low to high density, the entire set of lattice currents becomes independent of total particle number. We generalize our approach to systems with a continuous distribution of lattice parameters, for which we demonstrate that measurements of the current carried by a single lattice type can be used to extract the entire distribution of lattice parameters. Our approach applies to populations of TASEPs with any distribution of lattice parameters, and could easily be extended beyond the mean-field case.

cond-mat.stat-mech

Boundary-induced orientation of dynamic filament networks and vesicle agglomerations

We find a statistical mechanism that can adjust orientations of intracellular filaments to cell geometry in absence of organizing centers. The effect is based on random and isotropic filament (de-)polymerization dynamics and is independent of filament interactions and explicit regulation. It can be understood by an analogy to electrostatics and appears to be induced by the confining boundaries; for periodic boundary conditions no orientational bias emerges. Including active transport of particles, the model reproduces experimental observations of vesicle accumulations in transected axons.

physics.bio-ph

Active transport and cluster formation on 2D networks

We introduce a model for active transport on inhomogeneous networks embedded in a diffusive environment and investigate the formation of particle clusters. In the presence of a hard-core interaction, cluster sizes exhibit an algebraically decaying distribution in a large parameter regime, indicating the existence of clusters on all scales. The results are compared with a diffusion limited aggregation model and active transport on a regular network. For both models we observe aggregation of particles to clusters which are characterized by a finite size-scale if the relevant time-scales and particle densities are considered.

physics.bio-ph

Disordered driven lattice gases with boundary reservoirs and Langmuir kinetics

The asymmetric simple exclusion process with additional Langmuir kinetics, i.e. attachment and detachment in the bulk, is a paradigmatic model for intracellular transport. Here we study this model in the presence of randomly distributed inhomogeneities ('defects'). Using Monte Carlo simulations, we find a multitude of coexisting high- and low-density domains. The results are generic for one-dimensional driven diffusive systems with short-range interactions and can be understood in terms of a local extremal principle for the current profile. This principle is used to determine current profiles and phase diagrams as well as statistical properties of ensembles of defect samples.

cond-mat.stat-mech

Intra-cellular traffic: bio-molecular motors on filamentary tracks

Molecular motors are macromolecular complexes which use some form of input energy to perform mechanical work. The filamentary tracks, on which these motors move, are made of either proteins (e.g., microtubules) or nucleic acids (DNA or RNA). Often, many such motors move simultaneously on the same track and their collective properties have superficial similarities with vehicular traffic on highways. The models we have developed provide ``unified'' description: in the low-density limit, a model captures the transport properties of a single motor while, at higher densities the same model accounts for the collective spatio-temporal organization of interacting motors. By drawing analogy with vehicular traffic, we have introduced novel quantities for characterizing the nature of the spatio-temporal organization of molecular motors on their tracks. We show how the traffic-like intracellular collective phenomena depend on the mechano-chemistry of the corresponding individual motors.

physics.bio-ph

Single-Bottleneck Approximation for Driven Lattice Gases with Disorder and Open Boundary Conditions

We investigate the effects of disorder on driven lattice gases with open boundaries using the totally asymmetric simple exclusion process as a paradigmatic example. Disorder is realized by randomly distributed defect sites with reduced hopping rate. In contrast to equilibrium, even macroscopic quantities in disordered non-equilibrium systems depend sensitively on the defect sample. We study the current as function of the entry and exit rates and the realization of disorder and find that it is, in leading order, determined by the longest stretch of consecutive defect sites (single-bottleneck approximation, SBA). Using results from extreme value statistics the SBA allows to study ensembles with fixed defect density which gives accurate results, e.g. for the expectation value of the current. Corrections to SBA come from effective interactions of bottlenecks close to the longest one. Defects close to the boundaries can be described by effective boundary rates and lead to shifts of the phase transitions. Finally it is shown that the SBA also works for more complex models. As an example we discuss a model with internal states that has been proposed to describe transport of the kinesin KIF1A.

cond-mat.stat-mech

Phase diagram and edge effects in the ASEP with bottlenecks

We investigate the totally asymmetric simple exclusion process (TASEP) in the presence of a bottleneck, i.e. a sequence of consecutive defect sites with reduced hopping rate. The influence of such a bottleneck on the phase diagram is studied by computer simulations and a novel analytical approach. We find a clear dependence of the current and the properties of the phase diagram not only on the length of the bottleneck, but also on its position. For bottlenecks near the boundaries, this motivates the concept of effective boundary rates. Furthermore the inclusion of a second, smaller bottleneck far from the first one has no influence on the transport capacity. These results will form the basis of an effective description of the disordered TASEP and are relevant for the modelling of protein synthesis or intracellular transport systems where the motion of molecular motors is hindered by immobile blocking molecules.

nlin.CG

Intra-cellular transport by single-headed kinesin KIF1A: effects of single-motor mechano-chemistry and steric interactions

In eukaryotic cells, many motor proteins can move simultaneously on a single microtubule track. This leads to interesting collective phenomena like jamming. Recently we reported ({\it Phys. Rev. Lett. {\bf 95}, 118101 (2005)}) a lattice-gas model which describes traffic of unconventional (single-headed) kinesins KIF1A. Here we generalize this model, introducing a novel interaction parameter $c$, to account for an interesting mechano-chemical process which has not been considered in any earlier model. We have been able to extract all the parameters of the model, except $c$, from experimentally measured quantities. In contrast to earlier models of intra-cellular molecular motor traffic, our model assigns distinct ``chemical'' (or, conformational) states to each kinesin to account for the hydrolysis of ATP, the chemical fuel of the motor. Our model makes experimentally testable theoretical predictions. We determine the phase diagram of the model in planes spanned by experimentally controllable parameters, namely, the concentrations of kinesins and ATP. Furthermore, the phase-separated regime is studied in some detail using analytical methods and simulations to determine e.g. the position of shocks. Comparison of our theoretical predictions with experimental results is expected to elucidate the nature of the mechano-chemical process captured by the parameter $c$.

physics.bio-ph