Biology subjects

Marom, S.

Publications and source records attributed to Marom, S..

7 recordsLinked to original sources

bioRxiv2026

Bounded Multiplicative Dynamics Govern Axonal Conduction Slowdown

Conduction velocity slows along axons, yet the terminal-to-initial ratio{rho} = vend/vstart is branch-length invariant and right-skewed. A bounded multiplicative framework is introduced, in which local geometric and kinetic factors compound proportionally, but only within a finite distal domain set by termination conditions that saturate the effective multiplicative depth. The model accounts for the observed stability of the slowdown distribution across lengths and yields discriminating experimental signatures that distinguish between structural load and kinetic reserve depletion.

neuroscience↗

bioRxiv2025

Invariance and proportional scaling in axonal conduction

Conduction velocity along axons reflects geometric and biophysical influences whose joint statistical organization remains largely uncharacterized. Using high-resolution time-of-arrival measurements along hundreds of identified axonal branches in vitro, we quantified how propagation speed changes along trajectories. The ratio between terminal and initial velocities,{rho} = vend/vstart, follows a right-skewed distribution whose shape remains invariant across branch lengths, positions within neurons, and hierarchical aggregation levels. Local conduction profiles reveal a predominantly progressive deceleration along branches. These observations indicate a simple and robust statistical organization of slowdown, suggesting that proportional modulation of propagation speed is a consistent feature of axonal signaling in structurally variable substrates.

biophysics↗

bioRxiv2025

Aberrant inheritance of extrachromosomal DNA amplifications promotes cancer evolution

Gene amplification in the form of extrachromosomal DNA (ecDNA) is a frequent driver in multiple cancer types. As ecDNA lack centromeres, their mitotic segregation does not follow traditional inheritance principles. However, the mechanisms that govern ecDNA fate following mitosis remain unclear. We found that ecDNA undergo numerical and structural optimization under increased selective pressure, with mitotic chromosomal tethering, or detachment, dictating ecDNA fate. When tethered, ecDNA aggregates promote uneven distribution into the newly formed daughter cells, thereby driving inter-cellular numerical heterogeneity and rapid increase of amplification under selective pressure. Mitotically detached ecDNA frequently encapsulate within micronuclei of variable size and content that appear to be highly fragile. Strikingly, ecDNA enclosed in very small micronuclei, which we term nanonuclei, are being actively degraded through autophagy. Together with ongoing structural rearrangements, nanonuclear ecDNA degradation promotes their structural evolution, which facilitates cancer cell adaptation. Our work highlights ecDNA aggregation, micronucleation, and degradation, as pivotal events in directing cancer genome evolution trajectories.

cancer biology↗

bioRxiv2025

Dynamics of Excitability in Axonal Trees

We report that axons of cortical neurons, structurally intricate excitable media, maintain remarkably high fidelity in transmitting somatic spike timing, even during complex spontaneous network activity that includes extremely short (2-3 msec) inter-spike intervals. This robustness underscores their function as reliable conducting devices under physiological conditions. It is nevertheless well established that under artificially imposed, high-rate pulsing stimuli, axonal conduction can fail, with vulnerability depending on distance and branching. In line with this, we demonstrate that conduction failures can also occur at frequencies as low as 10 Hz, provided that stimulation is sustained for several seconds. Under these conditions, propagation delays increase and failures accumulate, particularly in distal branches, whereas effects are negligible at 1-4 Hz. Simulations incorporating cumulative sodium channel inactivation at vulnerable sites reproduce these dynamics. Our findings refine the view of axons as active, heterogeneous structures: they are exceptionally reliable across most physiological regimes, yet exhibit limits under prolonged or extreme stimulation, a regime rarely encountered in vivo but critical for understanding axonal excitability. Significance StatementAxons are widely regarded as reliable conduits of action potentials from the neuron cell body to downstream targets. We confirm this reliability during spontaneous network activity, even when spikes occur in complex patterns with very short interspike intervals. Prior studies have shown that conduction can fail under rapid, high-frequency trains of artificial stimuli. Here we extend this principle by showing that sustained stimulation at 10 Hz--a frequency within physiological ranges--can also induce propagation delays and failures, particularly in distal and higher-order axonal branches. Simulations incorporating cumulative sodium channel inactivation reproduce these effects. Thus, axons should be understood as highly reliable under natural conditions, yet context-dependent, with excitability shaped by the history of sustained activity.

neuroscience↗

bioRxiv2022

Sodium channel slow inactivation normalizes firing in axons with uneven conductance distributions

The Na+ channels that are important for action potentials show rapid inactivation, a state in which they do not conduct, although the membrane potential remains depolarized1,2. Rapid inactivation is a determinant of millisecond scale phenomena, such as spike shape and refractory period. Na+ channels also inactivate orders of magnitude more slowly, and therefore have impacts on excitability over much longer time scales than those of a single spike or a single inter-spike interval3-9. Here, we focus on the contribution of slow inactivation to the resilience of axonal excitability10,11 when ion channels are unevenly distributed across the axonal membrane. We study models in which the voltage-gated Na+ and K+ channels are unevenly distributed along axons with different variances, capturing the heterogeneity that biological axons display12. In the absence of slow inactivation many conductance distributions result in spontaneous tonic activity. Faithful axonal propagation is achieved with the introduction of Na+ channel slow inactivation. This "normalization" effect depends on relations between the kinetics of slow inactivation and the firing frequency. Consequently, neurons with characteristically different firing frequencies will need to implement different sets of channel properties to achieve resilience. The results of this study demonstrate the importance of the intrinsic biophysical properties of ion channels in normalizing axonal function. HighlightsO_LIVariation in ion channel density in axons may compromise axonal spike propagation. C_LIO_LISlow inactivation of Na+ channels modulates their availability. C_LIO_LINa+ channel slow inactivation increases the reliability of spike propagation. C_LIO_LINormalization by slow inactivation can compensate for uneven channel distributions. C_LI

neuroscience↗

bioRxiv2022

Identifying Regulation with Adversarial Surrogate

Homeostasis, the ability to maintain a relatively constant internal environment in the face of perturbations, is a hallmark of biological systems. It is believed that this constancy is achieved through multiple internal regulation and control processes. Given observations of a system, or even a detailed model of one, it is both valuable and extremely challenging to extract the control objectives of the homeostatic mechanisms. In this work, we develop a robust data-driven method to identify these objectives, namely to understand: "what does the system care about?". We propose an algorithm, Identifying Regulation with Adversarial Surrogates (IRAS), that receives an array of temporal measurements of the system, and outputs a candidate for the control objective, expressed as a combination of observed variables. IRAS is an iterative algorithm consisting of two competing players. The first player, realized by an artificial deep neural network, aims to minimize a measure of invariance we refer to as the coefficient of regulation. The second player aims to render the task of the first player more difficult by forcing it to extract information about the temporal structure of the data, which is absent from similar surrogate data. We test the algorithm on two synthetic and one natural data set, demonstrating excellent empirical results. Interestingly, our approach can also be used to extract conserved quantities, e.g., energy and momentum, in purely physical systems, as we demonstrate empirically.

bioengineering↗

bioRxiv2019

Dynamic clamp constructed phase diagram of the Hodgkin-Huxley action potential model

Excitability - a threshold governed transient in transmembrane voltage - is a fundamental physiological process that controls the function of the heart, endocrine, muscles and neuronal tissues. The 1950s Hodgkin and Huxley explicit formulation provides a mathematical framework for understanding excitability, as the consequence of the properties of voltage-gated sodium and potassium channels. The Hodgkin-Huxley model is more sensitive to parametric variations of protein densities and kinetics than biological systems whose excitability is apparently more robust. It is generally assumed that the models sensitivity reflects missing functional relations between its parameters or other components present in biological systems. Here we experimentally construct excitable membranes using the dynamic clamp and voltage-gated potassium ionic channels (Kv1.3) expressed in Xenopus oocytes. We take advantage of a theoretically derived phase diagram, where the phenomenon of excitability is reduced to two dimensions defined as combinations of the Hodgkin-Huxley model parameters. This biological-computational hybrid enabled us to explore functional relations in the parameter space, experimentally validate the phase diagram of the Hodgkin-Huxley model, and demonstrate activity-dependence and hysteretic dynamics due to the impacts of slow inactivation kinetics. The experimental results presented here provide new in-sights into the gap between technology-guided high-dimensional descriptions, and a lower, physiological dimensionality, within which biological function is embedded.

neuroscience↗