Biology subjects

Politi, A.

Publications and source records attributed to Politi, A..

13 recordsLinked to original sources

bioRxiv2025

Selective silencing of antibiotic-tethered ribosomes as a resistance mechanism against aminoglycosides

Antibiotic resistance is a growing threat, underscoring the need to understand the underlying mechanisms. Aminoglycosides kill bacteria by disrupting translation fidelity, leading to the synthesis of aberrant proteins. Surprisingly, mutations in fusA, a gene encoding translation elongation factor G (EF-G), frequently confer resistance, even though EF-G neither participates in mRNA decoding nor blocks aminoglycoside binding. Here, we show that EF-G resistance variants selectively slow ribosome movement along mRNA when aminoglycosides are bound. This delay increases the chance that the drug dissociates before misreading occurs. Over several elongation cycles, this selective silencing of drug-bound ribosomes prevents error cluster formation, preserving proteome and membrane integrity. As a result, fusA mutations confer resistance early in treatment by preventing self-promoted aminoglycoside uptake. Translation on drug-free ribosomes remains sufficiently rapid to sustain near-normal bacterial growth. This previously unrecognized resistance mechanism-- selective silencing of corrupted targets--reveals a novel antibiotic resistance strategy with potential therapeutic implications.

molecular biology↗

bioRxiv2024

Chaotic synchronization in adaptive networks of pulse-coupled oscillators

Ensembles of phase-oscillators are known to exhibit a variety of collective regimes. Here, we show that a simple mean-field model involving two heterogenous populations of pulse-coupled oscillators, exhibits, in the strong-coupling limit, a robust irregular macroscopic dynamics. The resulting, strongly synchronized, regime is sustained by a homeostatic mechanism induced by the shape of the phase-response curve combined with adaptive coupling strength, included to account for energy dissipated by the pulse emission. The proposed setup mimicks a neural network composed of excitatory and inhibitory neurons.

neuroscience↗

bioRxiv2024

Plk1 inhibition delays mitotic entry revealing prophase-specific changes to the phosphoproteome

Polo-like kinase 1 (plk1) is a conserved regulator of cell division. During prophase, plk1 phosphorylates direct substrates and is involved in activation of the cyclin-dependent kinase 1 (cdk1). However, the exact functions of plk1 in prophase remain incompletely understood. By testing several cell lines and small-molecule inhibitors, we confirm that plk1 inhibition causes a delay in mitotic entry. We show that cells are delayed in a prophase-like state displaying progressively condensing chromosomes, increased microtubule dynamics, reorganization of the actin cortex, while the nuclear envelope remains intact. We show that during this prolonged prophase cdk1 activity increases gradually over several hours with individual cells stochastically reaching the entry threshold, explaining the highly variable timing of mitotic entry. We then use phosphoproteomics to characterize this prolonged prophase state revealing for the first time phosphosites specific to prophase including several regulators of chromatin organization and the cytoskeleton. Together, we show that plk1 functions as a catalyst of prophase to prometaphase transition, and by using plk1 inhibition as a tool, we identify early changes in the phosphoproteome as the cell prepares for division.

cell biology↗

bioRxiv2023

A robust balancing mechanism for spiking neural networks

Dynamical balance of excitation and inhibition is usually invoked to explain the irregular low firing activity observed in the cortex. We propose a robust nonlinear balancing mechanism for a random network of spiking neurons, in absence of strong external currents. The mechanism exploits the plasticity of excitatory-excitatory synapses induced by short-term depression. A simple self-consistent analysis accompanied by direct simulations shows the emergence and stability of a balanced asynchronous state in the thermodynamic limit. This regime is essentially fluctuation driven and characterized by highly irregular spiking dynamics of all neurons.

neuroscience↗

bioRxiv2021

Coherent oscillations in balanced neural networks driven by endogenous fluctuations

We present a detailed analysis of the dynamical regimes observed in a balanced network of identical Quadratic Integrate-and-Fire (QIF) neurons with a sparse connectivity for homogeneous and heterogeneous in-degree distribution. Depending on the parameter values, either an asynchronous regime or periodic oscillations spontaneously emerge. Numerical simulations are compared with a mean field model based on a self-consistent Fokker-Planck equation (FPE). The FPE reproduces quite well the asynchronous dynamics in the homogeneous case by either assuming a Poissonian or renewal distribution for the incoming spike trains. An exact self consistent solution for the mean firing rate obtained in the limit of infinite in-degree allows identifying balanced regimes that can be either mean- or fluctuation-driven. A low-dimensional reduction of the FPE in terms of circular cumulants is also considered. Two cumulants suffice to reproduce the transition scenario observed in the network. The emergence of periodic collective oscillations is well captured both in the homogeneous and heterogeneous set-ups by the mean field models upon tuning either the connectivity, or the input DC current. In the heterogeneous situation we analyze also the role of structural heterogeneity.

neuroscience↗

bioRxiv2021

Co-localization of different Neurotransmitter Transporters on the same Synaptic Vesicle is Bona-fide yet Sparse

Vesicular transporters (VTs) define the type of neurotransmitter that synaptic vesicles (SVs) store and release. While certain neurons in mammalian brain release multiple transmitters, the prevalence, physiology of such pluralism and if the release occurs from same or distinct vesicle pools is not clear. Using quantitative single vesicle imaging, we show that a small population of neuronal SVs indeed contain different VTs to accomplish corelease. Surprisingly, this population is highly diverse (27 types), expressing distinct dual transporters suggesting corelease of various combinations of neurotransmitters. Using glutamatergic vesicles as an example, we demonstrate that transporter colocalization not only determine the transmitter type but also influences the SV content and synaptic quantal size. Thus, presence of diverse transporters on the same vesicle is bona-fide and, depending on the VT types, this may act as one mechanism to regulate neurotransmitter type, content and release in space and time.

neuroscience↗

bioRxiv2021

The effect of pulse width on the dynamics of pulse-coupled oscillators

The idealisation of neuronal pulses as{delta} -spikes is a convenient approach in neuroscience but can sometimes lead to erroneous conclusions. We investigate the effect of a finite pulse-width on the dynamics of balanced neuronal networks. In particular, we study two populations of identical excitatory and inhibitory neurons in a random network of phase oscillators coupled through exponential pulses with different widths. We consider three coupling functions, inspired by leaky integrate-and-fire neurons with delay and type-I phase-response curves. By exploring the role of the pulse-widths for different coupling strengths we find a robust collective irregular dynamics, which collapses onto a fully synchronous regime if the inhibitory pulses are sufficiently wider than the excitatory ones. The transition to synchrony is accompanied by hysteretic phenomena (i.e. the co-existence of collective irregular and synchronous dynamics). Our numerical results are supported by a detailed scaling and stability analysis of the fully synchronous solution. A conjectured first-order phase transition emerging for{delta} -spikes is smoothed out for finite-width pulses.

neuroscience↗

bioRxiv2020

Stability of synchronous states in sparse neuronal networks

The stability of synchronous states is analysed in the context of two populations of inhibitory and excitatory neurons, characterized by different pulse-widths. The problem is reduced to that of determining the eigenvalues of a suitable class of sparse random matrices, randomness being a consequence of the network structure. A detailed analysis, which includes also the study of finite-amplitude perturbations, is performed in the limit of narrow pulses, finding that the stability depends crucially on the relative pulse-width. This has implications for the overall property of the asynchronous (balanced) regime.

neuroscience↗

bioRxiv2019

Quantitative and qualitative analysis of asynchronous neural activity

The activity of a sparse network of leaky integrate-and-fire neurons is carefully revisited with reference to a regime of a bona-fide asynchronous dynamics. The study is preceded by a finite-size scaling analysis, carried out to identify a setup where collective synchronization is negligible. The comparison between quenched and annealed networks reveals the emergence of substantial differences when the coupling strength is increased, via a scenario somehow reminiscent of a phase transition. For sufficiently strong synaptic coupling, quenched networks exhibit a highly bursting neural activity, well reproduced by a self-consistent approach, based on the assumption that the input synaptic current is the superposition of independent renewal processes. The distribution of interspike intervals turns out to be relatively long-tailed; a crucial feature required for the self-sustainment of the bursting activity in a regime where neurons operate on average (much) below threshold. A semi-quantitative analogy with Ornstein-Uhlenbeck processes helps validating this interpretation. Finally, an alternative explanation in terms of Poisson processes is offered under the additional assumption of mutual correlations among excitatory and inhibitory spikes.

neuroscience↗

bioRxiv2018

Ubiquity of collective irregular dynamics in balanced networks of spiking neurons

We revisit the dynamics of a prototypical model of balanced activity in networks of spiking neurons. A detailed investigation of the thermodynamic limit for fixed density of connections (massive coupling) shows that, when inhibition prevails, the asymptotic regime is not asynchronous but rather characterized by a self-sustained irregular, macroscopic (collective) dynamics. So long as the connectivity is massive, this regime is found in many different setups: leaky as well as quadratic integrate-and-fire neurons; large and small coupling strength; weak and strong external currents.

neuroscience↗

bioRxiv2018

Collective irregular dynamics in balanced networks of leaky integrate-and-fire neurons

We extensively explore networks of weakly unbalanced, leaky integrate-and-fire (LIF) neurons for different coupling strength, connectivity, and by varying the degree of refractoriness, as well as the delay in the spike transmission. We find that the neural network does not only exhibit a microscopic (single-neuron) stochastic-like evolution, but also a collective irregular dynamics (CID). Our analysis is based on the computation of a suitable order parameter, typically used to characterize synchronization phenomena and on a detailed scaling analysis (i.e. simulations of different network sizes). As a result, we can conclude that CID is a true thermodynamic phase, intrinsically different from the standard asynchronous regime.

neuroscience↗

bioRxiv2017

Real-time chromatin dynamics at the single gene levelduring transcription activation

Genome dynamics relate to regulation of gene expression, the most fundamental process in biology. Yet we still do not know whether the very process of transcription drives spatial organization and chromatin conformation at specific gene loci. To address this issue, we have optimized the ANCHOR/ParB DNA labeling system for real-time imaging and quantitative analysis of the dynamics of a single-copy transgene in human cells. Transcription of the transgene under the control of the endogenous Cyclin D1 promoter was induced by addition of 17{beta}-estradiol. Motion of the ANCHOR3-tagged DNA locus was recorded in the same cell prior to and during appearance of nascent mRNA visualized using the MS2 system. We found that transcription initiation resulted in rapid confinement of the mRNA-producing gene. The confinement was maintained even upon inhibition of pol2 elongation. It did not occur when recruitment of pol2 or transcription initiation was blocked by anti-estrogens or Triptolide. These results suggest that preinitiation complex formation and concomitant reorganization of the chromatin domain constrains freedom of movement of an induced genes promoter within minutes. Confined diffusion reflects assembly of functional protein hubs and DNA processing during the rate-limiting steps of transcription.

cell biology↗

bioRxiv2016

Mechanism of Nuclear Movements in a Multinucleated Cell

Multinucleated cells are important in many organisms but the mechanisms governing the movements of nuclei sharing a common cytoplasm are not understood. In the hyphae of the plant pathogenic fungus Ashbya gossypii, nuclei move back and forth, occasionally bypassing each other, and, preventing the formation of nuclear clusters, this is essential for genetic stability. These movements depend on cytoplasmic microtubules emanating from the nuclei, that are pulled by dynein motors anchored at the cortex. Using 3D stochastic simulations with parameters constrained by the literature, we predict the cortical anchors density from the characteristics of nuclear movements. Altogether, the model accounts for the complex nuclear movements seen in vivo, using a minimal set of experimentally determined ingredients. Interestingly, these ingredients power the oscillations of the anaphase spindle in budding yeast, but in A. gossypii this system is not restricted to a specific nuclear cycle stage, possibly as a result of adaptation to hyphal growth and multinuclearity.

cell biology↗