arXiv subjects

Andrew D. Rutenberg

Publications and source records attributed to Andrew D. Rutenberg.

At least 19 recordsLinked to original sources

arXiv2024

Systems-level health of patients living with end-stage kidney disease using standard lab values

We present a systems-level analysis of end-stage kidney disease (ESKD) with a dynamical network analysis of 14 commonly measured blood-based biomarkers in patients undergoing regular haemodialysis. Utilizing a validated pipeline for declining homeostatic systems, our approach learns a dynamical model together with an invertible transformation that simplifies the behaviour of observed biomarkers into natural variables. Within the natural variables, we identified two distinct dynamical behaviours: (i) stochastic accumulation, the random accumulation of abnormal values, and (ii) mallostasis, a deterministic drift towards worse health. These behaviours are identified by persistent fluctuations indicating weak stability, or a gradual shift in homeostatic set point, respectively. Both lead to worsening natural variable values, making the natural variables salient survival predictors with preferred directions of increasing risk. When this worsening is transformed back into observable biomarkers, it generates a coherent spectrum of worsening medical signs characteristic of a medical syndrome. Specifically, we found that small modules of natural variables corresponded to two existing syndromes commonly afflicting ESKD patients: protein-energy wasting and sepsis. We also identified new prospective syndromes. Our findings suggest that natural variables are robust, systems-level biomarkers, capturing the complex, holistic changes in health associated with ESKD.

q-bio.QM↗

arXiv2024

Dynamical network stability analysis of multiple biological ages provides a framework for understanding the aging process

Widespread interest in non-destructive biomarkers of aging has led to a curse of plenty: a multitude of biological ages that each proffers a 'true' health-adjusted age of an individual. While each measure provides salient information on the aging process, they are each univariate, in contrast to the "hallmark" and "pillar" theories of aging which are explicitly multidimensional, multicausal and multiscale. Fortunately, multiple biological ages can be systematically combined into a multidimensional network representation. The interaction network between these biological ages permits analysis of the multidimensional effects of aging, as well as quantification of causal influences during both natural aging and, potentially, after anti-aging intervention. The behaviour of the system as a whole can then be explored using dynamical network stability analysis which identifies new, efficient biomarkers that quantify long term resilience scores on the timescale between measurements (years). We demonstrate this approach using a set of 8 biological ages from the longitudinal Swedish Adoption/Twin Study of Aging (SATSA). After extracting an interaction network between these biological ages, we observed that physiological age, a proxy for cardiometabolic health, serves as a central node in the network, implicating it as a key vulnerability for slow, age-related decline. We furthermore show that while the system as a whole is stable, there is a weakly stable direction along which recovery is slow - on the timescale of a human lifespan. This slow direction provides an aging biomarker which correlates strongly with chronological age and predicts longitudinal decline in health - suggesting that it estimates an important driver of age-related changes.

q-bio.QM↗

arXiv2023

Anisotropic swelling due to hydration constrains anisotropic elasticity in biomaterial fibers

Naturally occurring protein fibers often undergo anisotropic swelling when hydrated. Within a tendon, a hydrated collagen fibril's radius expands by 40% but its length only increases by 5%. The same effect, with a similar relative magnitude, is observed for single hair shafts. Fiber hydration is known to affect elastic properties. Here we show that anisotropic swelling constrains the anisotropic linear elastic properties of fibers. First we show, using data from disparate previously reported studies, that anisotropic swelling can be described as an approximately linear function of water content. Then, under the observation that the elastic energy of swelling can be minimized by the anisotropic shape, we relate swelling anisotropy to elastic anisotropy -- assuming radial (transverse) symmetry within a cylindrical geometry. We find an upper bound for the commonly measured axial Poisson ratio $\nu_{zx}<1/2$. This is significantly below recently estimated values for collagen fibrils extracted from tissue-level measurements, but is consistent with both single hair shaft and single collagen fibril mechanical and hydration studies. Using $\nu_{zx}$, we can then constrain the product $\gamma \equiv (1-\nu_{xy}) E_z/E_x$ -- where $\nu_{xy}$ is the seldom measured transverse Poisson ratio and $E_z/E_x$ is the ratio of axial to radial Young's moduli.

cond-mat.soft↗

arXiv2023

Network dynamical stability analysis reveals key "mallostatic" natural variables that erode homeostasis and drive age-related decline of health

Using longitudinal study data, we dynamically model how aging affects homeostasis in both mice and humans. We operationalize homeostasis as a multivariate mean-reverting stochastic process. We hypothesize that biomarkers have stable equilibrium values, but that deviations from equilibrium of each biomarker affects other biomarkers through an interaction network - this precludes univariate analysis. We therefore looked for age-related changes to homeostasis using dynamic network stability analysis, which transforms observed biomarker data into independent "natural" variables and determines their associated recovery rates. Most natural variables remained near equilibrium and were essentially constant in time. A small number of natural variables were unable to equilibrate due to a gradual drift with age in their homeostatic equilibrium, i.e. allostasis. This drift caused them to accumulate over the lifespan course and makes them natural aging variables. Their rate of accumulation was correlated with risk of adverse outcomes: death or dementia onset. We call this tendency for aging organisms to drift towards an equilibrium position of ever-worsening health "mallostasis". We demonstrate that the effects of mallostasis on observed biomarkers are spread out through the interaction network. This could provide a redundancy mechanism to preserve functioning until multi-system dysfunction emerges at advanced ages.

q-bio.OT↗

arXiv2023

Torsion and Bistability of Double-Twist Elastomers

We investigate the elastic properties of anisotropic elastomers with a double-twist director field, which is a model for collagen fibrils or blue phases. We observe a significant Poynting-like effect, coupling torsion (fibril twist) and extension. For freely-rotating boundary conditions, we identify a structural bistability at very small extensional strains which undergoes a saddle-node bifurcation at a critical strain -- at approximately 1% strain for a parameterization appropriate for collagen fibrils. With clamped boundary conditions appropriate for many experimental setups, the bifurcation is not present. We expect significant helical shape effects when fixed torsion does not equal the equilibrium torsion of freely-rotating boundary conditions, due to residual torques.

cond-mat.soft↗

arXiv2023

Modelling disease impact: lifespan reduction is greatest for young adults in an exogenous damage model of disease

We model the effects of disease and other exogenous damage during human aging. Even when the exogenous damage is repaired at the end of acute disease, propagated secondary damage remains. We consider both short-term mortality effects due to (acute) exogenous damage and long-term mortality effects due to propagated damage within the context of a generic network model (GNM) of individual aging that simulates a U.S. population. Across a wide range of disease durations and severities we find that while excess short-term mortality is highest for the oldest individuals, the long-term years of life lost are highest for the youngest individuals. These appear to be universal effects of human disease. We support this conclusion with a phenomenological model coupling damage and mortality. Our results are consistent with previous lifetime mortality studies of atom bomb survivors and post-recovery health studies of COVID-19. We suggest that short-term health impact studies could complement lifetime mortality studies to better characterize the lifetime impacts of disease on both individuals and populations.

q-bio.PE↗

arXiv2021

D-band strain underestimates fibril strain for twisted collagen fibrils at low strains

Collagen fibrils are the main structural component of load-bearing tissues such as tendons, ligaments, skin, the cornea of the eye, and the heart. The D-band of collagen fibrils is an axial periodic density modulation that can be easily characterized by tissue-level X-ray scattering. During mechanical testing, D-band strain is often used as a proxy for fibril strain. However, this approach ignores the coupling between strain and molecular tilt. We examine the validity of this approximation using an elastomeric collagen fibril model that includes both the D-band and a molecular tilt field. In the low strain regime, we show that the D-band strain substantially underestimates fibril strain for strongly twisted collagen fibrils -- such as fibrils from skin or corneal tissue.

physics.bio-ph↗

arXiv2021

Chiral phase-coexistence in compressed double-twist elastomers

We adapt the theory of anisotropic rubber elasticity to model cross-linked double-twist liquid crystal cylinders such as exhibited in biological systems. In mechanical extension we recover strain-straightening, but with an exact expression in the small twist-angle limit. In compression, we observe coexistence between high and low twist phases. Coexistence begins at small compressive strains and is robustly observed for any anisotropic cross-links and for general double-twist functions -- but disappears at large twist angles. Within the coexistence region, significant compression of double-twist cylinders is allowed at constant stress. Our results are qualitatively consistent with previous observations of swollen or compressed collagen fibrils, indicating that this phenomenon may be readily accessible experimentally.

physics.bio-ph↗

arXiv2020

Non-equilibrium Growth and Twist of Cross-Linked Collagen Fibrils

The lysyl oxidase (LOX) enzyme that catalyses cross-link formation during the assembly of collagen fibrils in vivo is too large to diffuse within assembled fibrils, and so is incompatible with a fully equilibrium mechanism for fibril formation. We propose that enzymatic cross-links are formed at the fibril surface during the growth of collagen fibrils; as a consequence no significant reorientation of previously cross-linked collagen molecules occurs inside collagen fibrils during fibril growth in vivo. By imposing local equilibrium only at the fibril surface, we develop a coarse-grained quantitative model of in vivo fibril structure that incorporates a double-twist orientation of collagen molecules and a periodic D-band density modulation along the fibril axis. Radial growth is controlled by the density of available collagen molecules around the fibril. In contrast with earlier equilibrium models of fibril structure, we find that all fibrils can exhibit a core-shell structure that is controlled only by the fibril radius. At small radii a core is developed with a linear double-twist structure as a function of radius. Within the core the double-twist structure is largely independent of the D-band. Within the shell at larger radii, the structure approaches a constant twist configuration that is strongly coupled with the D-band. We suggest a stable radius control mechanism that corneal fibrils can exploit near the edge of the linear core regime; while larger tendon fibrils can use a cruder version of growth control that does not select a preferred radius.

physics.bio-ph↗

arXiv2020

Phase-field collagen fibrils: Coupling chirality and density modulations

To describe the interaction between longitudinal density modulations along collagen fibrils (the D-band) with the radial twist-field of molecular orientation (double-twist), we couple phase-field-crystal (PFC) with liquid-crystalline free-energies to obtain a hybrid model of equilibrium collagen fibril structure. We numerically compute the resulting axial and radial structure. We find two distinct fibrillar phases, `L' and `C', with a coexistence line that ends in an Ising-like critical point. We propose that coexistence between these phases can explain the bimodal distribution of fibril radii that has been widely reported within tendon tissues. Tensile strain applied to our model fibrils straightens the average fibrillar twist and flattens the D-band modulation. Our PFC approach should apply directly to other longitudinally-modulated chiral filaments, such as fibrin and intermediate filaments.

cond-mat.soft↗

arXiv2018

Probing the network structure of health deficits in human aging

We confront a network model of human aging and mortality in which nodes represent health attributes that interact within a scale-free network topology, with observational data that uses both clinical and laboratory (pre-clinical) health deficits as network nodes. We find that individual health attributes exhibit a wide range of mutual information with mortality and that, with a re- construction of their relative connectivity, higher-ranked nodes are more informative. Surprisingly, we find a broad and overlapping range of mutual information of laboratory measures as compared with clinical measures. We confirm similar behavior between most-connected and least-connected model nodes, controlled by the nearest-neighbor connectivity. Furthermore, in both model and observational data, we find that the least-connected (laboratory) nodes damage earlier than the most-connected (clinical) deficits. A mean-field theory of our network model captures and explains this phenomenon, which results from the connectivity of nodes and of their connected neighbors. We find that other network topologies, including random, small-world, and assortative scale-free net- works, exhibit qualitatively different behavior. Our disassortative scale-free network model behaves consistently with our expanded phenomenology observed in human aging, and so is a useful tool to explore mechanisms of and to develop new predictive measures for human aging and mortality.

q-bio.PE↗

arXiv2018

Anomalously slow transport in single-file diffusion with slow binding kinetics

We computationally study the effects of binding kinetics to the channel wall, leading to transient immobility, on the diffusive transport of particles within narrow channels, that exhibit single-file diffusion (SFD). We find that slow binding kinetics leads to an anomalously slow diffusive transport. Remarkably, the scaled diffusivity $\hat{D}$ characterizing transport exhibits scaling collapse with respect to the occupation fraction $p$ of sites along the channel. We present a simple "cage-physics" picture that captures the characteristic occupation fraction $p_{scale}$ and the asymptotic $1/p^2$ behavior for $p/p_{scale} \gtrsim 1$. We confirm that subdiffusive behavior of tracer particles is controlled by the same $\hat{D}$ as particle transport.

cond-mat.stat-mech↗

arXiv2018

Polymorphism of stable collagen fibrils

Collagen fibrils are versatile self-assembled structures that provide mechanical integrity within mammalian tissues. The radius of collagen fibrils vary widely depending on experimental conditions \textit{in vitro} or anatomical location \textit{in vivo}. Here we explore the variety of thermodynamically stable fibril configurations that are available. We use a liquid crystal model of radial collagen fibril structure with a double-twist director field. Using a numerical relaxation method we show that two dimensionless parameters, the ratio of saddle-splay to twist elastic constants $ k_{24}/K_{22}$ and the ratio of surface tension to chiral strength $\hatγ \equiv γ/(K_{22}q)$, largely specify both the scaled fibril radius and the associated surface twist of equilibrium fibrils. We find that collagen fibrils are the stable phase with respect to the cholesteric phase only when the reduced surface tension is small, $\hatγ \lesssim 0.2$. Within this stable regime, collagen fibrils can access a wide range of radii and associated surface twists. Remarkably, we find a maximal equilibrium surface twist of $0.33$ rad ($19^{\text{o}}$). Our results are compatible with corneal collagen fibrils, and we show how the large surface twist is needed to explain the narrow distribution of corneal fibril radii. Conversely, we show how small surface twist is required for the thermodynamic stability of tendon fibrils in the face of considerable polydispersity of radius.

cond-mat.soft↗

arXiv2017

Photobleaching of randomly-rotating fluorescently-decorated particles

Randomly rotating particles that have been isotropically labeled with rigidly linked fluorophores will undergo non-isotropic (patchy) photobleaching under illumination due to the dipole coupling of fluorophores with light. For a rotational diffusion rate $D$ of the particle and a photobleaching timescale $τ$ of the fluorophores, the dynamics of this process are characterized by the dimensionless combination $D τ$. We find significant interparticle fluctuations at intermediate $D τ$. These fluctuations vanish at both large and small $D τ$, or at small or large elapsed times $t$. Associated with these fluctuations between particles, we also observe transient non-monotonicities of the brightness of individual particles. These non-monotonicities can be as much 20\% of the original brightness. We show that these novel photobleach-fluctuations dominate over variability of single-fluorophore orientation when there are at least $10^3$ fluorophores on individual particles.

physics.chem-ph↗

arXiv2017

Unifying ageing and frailty through complex dynamical networks

To explore the mechanistic relationships between ageing, frailty and mortality, we developed a computational model in which possible health attributes are represented by the nodes of a complex network. Each node can be either damaged (i.e. a deficit) or undamaged. Damage of connected nodes facilitates further local damage. Our model recovers the known patterns of frailty and mortality without any programmed ageing. It helps us to understand how the observed maximum of the frailty index (FI) might arise, and allows us to start to understand how health deficits accumulate. Large model populations allow us to exploit new analytic tools, including information theory. This will allow us to systematically characterize the effects of sudden changes in the health trajectories of individuals and serve as a way to evaluate large clinical and population databases.

q-bio.PE↗

arXiv2016

A dynamical network model for age-related health deficits and mortality

How long people live depends on their health, and how it changes with age. Individual health can be tracked by the accumulation of age-related health deficits. The fraction of age-related deficits is a simple quantitative measure of human aging. This quantitative frailty index (F) is as good as chronological age in predicting mortality. In this paper, we use a dynamical network model of deficits to explore the effects of interactions between deficits, deficit damage and repair processes, and the connection between the F and mortality. With our model, we qualitatively reproduce Gompertz's law of increasing human mortality with age, the broadening of the F distribution with age, the characteristic non-linear increase of the F with age, and the increased mortality of high-frailty individuals. No explicit time-dependence in damage or repair rates is needed in our model. Instead, implicit time-dependence arises through deficit interactions -- so that the average deficit damage rates increases, and deficit repair rates decreases, with age . We use a simple mortality criterion, where mortality occurs when the most connected node is damaged.

q-bio.QM↗

arXiv2014

Protein translocation without specific quality control in a computational model of the Tat system

The twin-arginine translocation (Tat) system transports folded proteins of various sizes across both bacterial and plant thylakoid membranes. The membrane-associated TatA protein is an essential component of the Tat translocon, and a broad distribution of different sized TatA-clusters is observed in bacterial membranes. We assume that the size dynamics of TatA clusters are affected by substrate binding, unbinding, and translocation to associated TatBC clusters, where clusters with bound translocation substrates favour growth and those without associated substrates favour shrinkage. With a stochastic model of substrate binding and cluster dynamics, we numerically determine the TatA cluster size distribution. We include a proportion of targeted but non-translocatable (NT) substrates, with the simplifying hypothesis that the substrate translocatability does not directly affect cluster dynamical rate constants or substrate binding or unbinding rates. This amounts to a translocation model without specific quality control. Nevertheless, NT substrates will remain associated with TatA clusters until unbound and so will affect cluster sizes and translocation rates. We find that the number of larger TatA clusters depends on the NT fraction $f$. The translocation rate can be optimized by tuning the rate of spontaneous substrate unbinding, $Γ_U$. We present an analytically solvable three-state model of substrate translocation without cluster size dynamics that follows our computed translocation rates, and that is consistent with {\em in vitro} Tat-translocation data in the presence of NT substrates.

q-bio.SC↗

arXiv2013

Circumferential gap propagation in an anisotropic elastic bacterial sacculus

We have modelled stress concentration around small gaps in anisotropic elastic sheets, corresponding to the peptidoglycan sacculus of bacterial cells, under loading corresponding to the effects of turgor pressure in rod-shaped bacteria. We find that under normal conditions the stress concentration is insufficient to mechanically rupture bacteria, even for gaps up to a micron in length. We then explored the effects of stress-dependent smart-autolysins, as hypothesised by Arthur L Koch [Advances in Microbial Physiology 24, 301 (1983); Research in Microbiology 141, 529 (1990)]. We show that the measured anisotropic elasticity of the PG sacculus can lead to stable circumferential propagation of small gaps in the sacculus. This is consistent with the recent observation of circumferential propagation of PG-associated MreB patches in rod-shaped bacteria. We also find a bistable regime of both circumferential and axial gap propagation, which agrees with behavior reported in cytoskeletal mutants of B. subtilis. We conclude that the elastic anisotropies of a bacterial sacculus, as characterised experimentally, may be relevant for maintaining rod-shaped bacterial growth.

physics.bio-ph↗