Biomedical subjects

Simona Cocco

Publications and source records attributed to Simona Cocco.

7 recordsLinked to original sources

PubMed2025

Repeats mimic pathogen-associated patterns across a vast evolutionary landscape.

An emerging hallmark of many human diseases is transcription of typically silenced repetitive DNA containing pathogen-associated molecular patterns (PAMPs). These PAMPs engage the innate immune system via pattern recognition receptors (PRRs)-a phenomenon known as viral mimicry. We propose a statistical physics framework to quantify viral mimicry by measuring "selective forces" that enrich PAMPs compared to a genome-wide reference distribution. We validate our predictions by identifying repeats that bind different PRRs and show potential viral mimics in different repeat families across eukaryotic genomes, suggesting shared mechanisms drive emergence and retention. We propose two non-exclusive evolutionary hypotheses. The first "repeat-centric" hypothesis posits PAMPs are integral to the repeat life cycle and are therefore enriched as they mediate repeat expansion. The second "organism-centric" hypothesis proposes viral mimicry functions as a cell-intrinsic feedback mechanism for sensing and reacting to transcriptional dysregulation, which provides a selective pressure to maintain PAMPs in genomes.

Humans↗

PubMed2005

Protein-mediated DNA loops: effects of protein bridge size and kinks.

This paper focuses on the probability that a portion of DNA closes on itself through thermal fluctuations. We investigate the dependence of this probability upon the size of a protein bridge and/or the presence of a kink at half DNA length. The DNA is modeled by the wormlike chain model, and the probability of loop formation is calculated in two ways: exact numerical evaluation of the constrained path integral and the extension of the Shimada and Yamakawa saddle point approximation. For example, we find that the looping free energy of a 100-base-pairs DNA decreases from 24 kBT to 13 kBT when the loop is closed by a protein of r=10 length. It further decreases 5 kBT to when the loop has a kink of 120 degrees at half-length.

Binding Sites↗

PubMed2005

Dynamics of excitatory synaptic components in sustained firing at low rates.

Sustained firing is necessary for the persistent activity associated with working memory. The relative contributions of the reverberation of excitation and of the temporal dynamics of the excitatory postsynaptic potential (EPSP) to the maintenance of activity are difficult to evaluate in classical preparations. We used simplified models of synchronous excitatory networks, hippocampal autapses and pairs, to study the synaptic mechanisms underlying firing at low rates. Calcium imaging and cell attached recordings showed that these neurons spontaneously fired bursts of action potentials that lasted for seconds over a wide range of frequencies. In 2-wk-old cells, the median firing frequency was low (11 +/- 8.8 Hz), whereas in 3- to 4-wk-old cells, it decreased to a very low value (2 +/- 1.3 Hz). In both cases, we have shown that the slowest synaptic component supported firing. In 2-wk-old autapses, antagonists of N-methyl-d-aspartate receptors (NMDARs) induced rare isolated spikes showing that the NMDA component of the EPSP was essential for bursts at low frequency. In 3- to 4-wk-old neurons, the very low frequency firing was maintained without the NMDAR activation. However EGTA-AM or alpha-methyl-4-carboxyphenylglycine (MCPG) removed the very slow depolarizing component of the EPSP and prevented the sustained firing at very low rate. A metabotropic glutamate receptor (mGluR)-activated calcium sensitive conductance is therefore responsible for a very slow synaptic component associated with firing at very low rate. In addition, our observations suggested that the asynchronous release of glutamate might participate also in the recurring bursting.

Action Potentials↗

PubMed2004

Overstretching and force-driven strand separation of double-helix DNA.

We analyze whether the "overstretched," or "S" form of double-stranded DNA consists of essentially separated, or essentially interacting, polynucleotide strands. Comparison of force-extension data for S-DNA and single-stranded DNA shows S-DNA to be distinct from both double helix and single-stranded forms. We use a simple thermodynamical model for tension-melted double-stranded DNA, which indicates that the overstretching transition near 65 piconewtons cannot be explained in terms of conversion of double helix to noninteracting polynucleotide strands. However, the single-strand-like response observed in some experiments can be explained in terms of "unpeeling" of large regions of one strand, starting from nicks on the original double helix. We show that S-DNA becomes unstable to unpeeling at large forces, and that at low ionic strength, or for weakly base-paired sequences, unpeeling can preempt formation of S-DNA. We also analyze the kinetics of unpeeling including the effect of sequence-generated free energy inhomogeneity. We find that strongly base-paired regions generate large barriers that stabilize DNA against unpeeling. For long genomic sequences, these barriers to unpeeling cannot be kinetically crossed until force exceeds approximately 150 piconewtons.

Base Pairing↗

PubMed2002

Unzipping dynamics of long DNAs.

The two strands of the DNA double helix can be "unzipped" by the application of approximately 15 pN force. We analyze the dynamics of unzipping and rezipping for the case where the molecule ends are separated and reapproached at constant velocity. For unzipping of 50-kilobase DNAs at less than about 1000 bases per second, thermal-equilibrium-based theory applies. However, for higher unzipping velocities, rotational viscous drag creates a buildup of elastic torque to levels above k(B)T in the double-stranded DNA region, causing the unzipping force to be well above or well below the equilibrium unzipping force during, respectively, unzipping and rezipping, in accord with recent experimental results of Thomen et al. [Phys. Rev. Lett. 88, 248102 (2002)]. Our analysis includes the effect of sequence on unzipping and rezipping, and the transient delay in buildup of the unzipping force due to the approach to the steady state.

Biophysical Phenomena↗

PubMed2002

Exponentially hard problems are sometimes polynomial, a large deviation analysis of search algorithms for the random satisfiability problem, and its application to stop-and-restart resolutions.

A large deviation analysis of the solving complexity of random 3-satisfiability instances slightly below threshold is presented. While finding a solution for such instances demands an exponential effort with high probability, we show that an exponentially small fraction of resolutions require a computation scaling linearly in the size of the instance only. This exponentially small probability of easy resolutions is analytically calculated, and the corresponding exponent is shown to be smaller (in absolute value) than the growth exponent of the typical resolution time. Our study therefore gives some theoretical basis to heuristic stop-and-restart solving procedures, and suggests a natural cutoff (the size of the instance) for the restart.

Journal Article↗

PubMed2002

Force and kinetic barriers to initiation of DNA unzipping.

A semimicroscopic model of the binding of the two nucleotide strands in a double-stranded DNA is used to describe the effects of applied tension on strand unpairing. We show that the model describes strand separation by elevated temperature, applied torque, and applied force. In particular, we show how the interactions responsible for stabilizing the double helix against thermal denaturation determine the approximately 12 pN force threshold for DNA strand separation. The larger rigidity of the strands when formed into double-stranded DNA, relative to that of isolated strands, gives rise to a potential barrier to unzipping. We show that this barrier results in a approximately 250 pN force barrier opposing the beginning of strand separation. The thermal-fluctuation-assisted "tunnelling" through the barrier is then analyzed using instanton calculations. The resulting kinetics of unzipping initiation is shown to be consistent with solution-phase strand dissociation experiments, and can explain results of two recent unzipping experiments done using atomic-force microscopy.

Base Pairing↗