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Red Blood Cells (RBCs) are the simplest cell types with complex dynamical and viscoelastic phenomenology. While the mechanical rigidity and the flickering noise of RBCs have been extensively investigated, an accurate determination of the constitutive equations of the relaxational kinetics is lacking. Here we measure the force relaxation of RBCs under different types of tensional and compressive extension-jump protocols by attaching an optically trapped bead to the RBC membrane. Relaxational kinetics follows linear response from 60pN (tensional) to -20pN (compressive) applied forces, exhibiting a triple-exponential function with three well-separated timescales over four decades (0.01-100s). While the fast timescale ($\tau_F\sim 0.02(1)s$) corresponds to the relaxation of the membrane, the intermediate and slow timescales ($\tau_I=4(1)s$; $\tau_S=70(8)s$) likely arise from the cortex dynamics and the cytosol viscosity. Relaxation is highly heterogeneous across the RBC population, yet the three relaxation times are correlated, showing dynamical scaling. Finally, we find that glucose depletion and laser illumination of RBCs lead to faster triple-exponential kinetics and RBC rigidification. Viscoelastic phenotyping is a promising dynamical biomarker applicable to other cell types and active systems., Comment: Main text (10 pages, 7 figures, 2 tables) and Supplementary (8 pages, 8 figures, 2 tables and 2 movies). paper submitted to Biophysical Journal

Entropy production is the hallmark of nonequilibrium physics, quantifying irreversibility, dissipation, and the efficiency of energy transduction processes. Despite many efforts, its measurement at the nanoscale remains challenging. We introduce a variance sum rule for displacement and force variances that permits us to measure the entropy production rate $\sigma$ in nonequilibrium steady states. We first illustrate it for directly measurable forces, such as an active Brownian particle in an optical trap. We then apply the variance sum rule to flickering experiments in human red blood cells. We find that $\sigma$ is spatially heterogeneous with a finite correlation length and its average value agrees with calorimetry measurements. The VSR paves the way to derive $\sigma$ using force spectroscopy and time-resolved imaging in living and active matter., Comment: 5 pages and 4 figures. It also contains Supp. Info. with 6 additional figures and 4 tables

Single-molecule force spectroscopy has opened a new field of research in molecular biophysics and biochemistry. Pulling experiments on individual proteins permit us to monitor conformational transitions with high temporal resolution and measure their free energy landscape. The force-extension curves of single proteins often present large hysteresis, with unfolding forces that are higher than refolding ones. Therefore, the high energy of the transition state (TS) in these molecules precludes kinetic rates measurements in equilibrium hopping experiments. In irreversible pulling experiments, force-dependent kinetic rates measurements show a systematic discrepancy between the sum of the folding and unfolding TS distances derived by the kinetic Bell-Evans model and the full molecular extension predicted by elastic models. Here, we show that this discrepancy originates from the force-induced movement of TS. Specifically, we investigate the highly kinetically stable protein barnase, using pulling experiments and the Bell-Evans model to characterize the position of its kinetic barrier. Experimental results show that while the TS stays at a roughly constant distance relative to the native state, it shifts with force relative to the unfolded state. Interestingly, a conversion of the protein extension into amino acid units shows that the TS position follows the Leffler-Hammond postulate: the higher the force, the lower the number of unzipped amino acids relative to the native state. The results are compared with the quasi-reversible unfolding-folding of a short DNA hairpin., Comment: 8 pages, 4 figures

The accurate knowledge of the elastic properties of single-stranded DNA (ssDNA) is key to characterize the thermodynamics of molecular reactions that are studied by force spectroscopy methods where DNA is mechanically unfolded. Examples range from DNA hybridization, DNA ligand binding, DNA unwinding by helicases, etc. To date, ssDNA elasticity has been studied with different methods in molecules of varying sequence and contour length. A dispersion of results has been reported and the value of the persistence length has been found to be larger for shorter ssDNA molecules. We carried out pulling experiments with optical tweezers to characterize the elastic response of ssDNA over three orders of magnitude in length (60-14 k bases). By fitting the force-extension curves (FECs) to the Worm-Like Chain model we confirmed the above trend:the persistence length nearly doubles for the shortest molecule (60 b) with respect to the longest one (14 kb). We demonstrate that the observed trend is due to the different force regimes fitted for long and short molecules, which translates into two distinct elastic regimes at low and high forces. We interpret this behavior in terms of a force-induced sugar pucker conformational transition (C3'-endo to C2'-endo) upon pulling ssDNA.

The folding of biological macromolecules is a fundamental process of which we lack a full comprehension. Mostly studied in proteins and RNA, single-stranded DNA (ssDNA) also folds, at physiological salt conditions, by forming non-specific secondary structures that are difficult to characterize with biophysical techniques. Here we present a helix-coil model for secondary structure formation, where ssDNA bases are organized in two different types of domains (compact and free). The model contains two parameters: the energy gain per base in a compact domain, $\epsilon$, and the cooperativity related to the interfacial energy between different domains, $\gamma$. We tested the ability of the model to quantify the formation of secondary structure in ssDNA molecules mechanically stretched with optical tweezers. The model reproduces the experimental force-extension curves in ssDNA of different molecular lengths and varying sodium and magnesium concentrations. Salt-correction effects for the energy of compact domains and the interfacial energy are found to be compatible with those of DNA hybridization. The model also predicts the folding free energy and the average size of domains at zero force, finding good agreement with secondary structure predictions by Mfold. We envision the model could be further extended to investigate native folding in RNA and proteins., Comment: Published in PRX

A fluctuation relation is derived to extract the order parameter function $q(x)$ in weakly ergodic systems. The relation is based on measuring and classifying entropy production fluctuations according to the value of the overlap $q$ between configurations. For a fixed value of $q$, entropy production fluctuations are Gaussian distributed allowing us to derive the quasi-FDT so characteristic of aging systems. The theory is validated by extracting the $q(x)$ in various types of glassy models. It might be generally applicable to other nonequilibrium systems and experimental small systems., Comment: 4 pages, 4 figures

A fluctuation relation for aging systems is introduced, and verified by extensive numerical simulations. It is based on the hypothesis of partial equilibration over phase space regions in a scenario of entropy-driven relaxation. The relation provides a simple alternative method, amenable of experimental implementation, to measure replica symmetry breaking parameters in aging systems. The connection with the effective temperatures obtained from the fluctuation-dissipation theorem is discussed., Comment: 5 pages, 3 figures, Phys Rev Lett (in press)

Stochastic resonance (SR) is a well known phenomenon in dynamical systems. It consists of the amplification and optimization of the response of a system assisted by stochastic noise. Here we carry out the first experimental study of SR in single DNA hairpins which exhibit cooperatively folding/unfolding transitions under the action of an applied oscillating mechanical force with optical tweezers. By varying the frequency of the force oscillation, we investigated the folding/unfolding kinetics of DNA hairpins in a periodically driven bistable free-energy potential. We measured several SR quantifiers under varied conditions of the experimental setup such as trap stiffness and length of the molecular handles used for single-molecule manipulation. We find that the signal-to-noise ratio (SNR) of the spectral density of measured fluctuations in molecular extension of the DNA hairpins is a good quantifier of the SR. The frequency dependence of the SNR exhibits a peak at a frequency value given by the resonance matching condition. Finally, we carried out experiments in short hairpins that show how SR might be useful to enhance the detection of conformational molecular transitions of low SNR., Comment: 11 pages, 7 figures, supplementary material (http://prx.aps.org/epaps/PRX/v2/i3/e031012/prx-supp.pdf)

RNA duplex stability depends strongly on ionic conditions, and inside cells RNAs are exposed to both monovalent and multivalent ions. Despite recent advances, we do not have general methods to quantitatively account for the effects of monovalent and multivalent ions on RNA stability, and the thermodynamic parameters for secondary structure prediction have only been derived at 1M [Na$^+$]. Here, by mechanically unfolding and folding a 20 bp RNA hairpin using optical tweezers, we study the RNA thermodynamics and kinetics at different monovalent and mixed monovalent/Mg$^{2+}$ salt conditions. We measure the unfolding and folding rupture forces and apply Kramers theory to extract accurate information about the hairpin free energy landscape under tension at a wide range of ionic conditions. We obtain non-specific corrections for the free energy of formation of the RNA hairpin and measure how the distance of the transition state to the folded state changes with force and ionic strength. We experimentally validate the Tightly Bound Ion model and obtain values for the persistence length of ssRNA. Finally, we test the approximate rule by which the non-specific binding affinity of divalent cations at a given concentration is equivalent to that of monovalent cations taken at 100 fold that concentration for small molecular constructs., Comment: main paper (32 pages, 11 figures, 1 table) + supplementary information (15 pages)

We investigate unfolding/folding force kinetics in DNA hairpins exhibiting two and three states with newly designed short dsDNA handles (29 bp) using optical tweezers. We show how the higher stiffness of the molecular setup moderately enhances the signal-to-noise ratio (SNR) in hopping experiments as compared to conventional long handles constructs (approximately 700 bp). The shorter construct results in a signal of higher SNR and slower folding/unfolding kinetics, thereby facilitating the detection of otherwise fast structural transitions. A novel analysis of the elastic properties of the molecular setup, based on high-bandwidth measurements of force fluctuations along the folded branch, reveals that the highest SNR that can be achieved with short handles is potentially limited by the marked reduction of the effective persistence length and stretch modulus of the short linker complex., Comment: Main paper: 20 pages and 6 figures. Supplementary Material: 25 pages

Accurate knowledge of the thermodynamic properties of nucleic acids is crucial to predicting their structure and stability. To date most measurements of base-pair free energies in DNA are obtained in thermal denaturation experiments, which depend on several assumptions. Here we report measurements of the DNA base-pair free energies based on a simplified system, the mechanical unzipping of single DNA molecules. By combining experimental data with a physical model and an optimization algorithm for analysis, we measure the 10 unique nearest-neighbor base-pair free energies with 0.1 kcal mol-1 precision over two orders of magnitude of monovalent salt concentration. We find an improved set of standard energy values compared with Unified Oligonucleotide energies and a unique set of 10 base-pair-specific salt-correction values. The latter are found to be strongest for AA/TT and weakest for CC/GG. Our new energy values and salt corrections improve predictions of DNA unzipping forces and are fully compatible with melting temperatures for oligos. The method should make it possible to obtain free energies, enthalpies and entropies in conditions not accessible by bulk methodologies., Comment: Main text: 27 pages, 4 figures, 2 tables. Supporting Information: 51 pages, 19 figures, 4 tables

We unzip DNA molecules using optical tweezers and determine the sizes of the cooperatively unzipping and zipping regions separating consecutive metastable intermediates along the unzipping pathway. Sizes are found to be distributed following a power law, ranging from one base pair up to more than a hundred base pairs. We find that a large fraction of unzipping regions smaller than 10 bp are seldom detected because of the high compliance of the released single stranded DNA. We show how the compliance of a single nucleotide sets a limit value around 0.1 N/m for the stiffness of any local force probe aiming to discriminate one base pair at a time in DNA unzipping experiments., Comment: Main text: 4 pages, 3 figures. Supplementary Information: 18 pages, 15 figures

We analyze fluctuation-dissipation relations in the Backgammon model: a system that displays glassy behavior at zero temperature due to the existence of entropy barriers. We study local and global fluctuation relations for the different observables in the model. For the case of a global perturbation we find a unique negative fluctuation-dissipation ratio that is independent of the observable and which diverges linearly with the waiting time. This result suggests that a negative effective temperature can be observed in glassy systems even in the absence of thermally activated processes., Comment: 32 pages, 10 figures. Accepted in PRE

RNA folding is a kinetic process governed by the competition of a large number of structures stabilized by the transient formation of base pairs that may induce complex folding pathways and the formation of misfolded structures. Despite of its importance in modern biophysics, the current understanding of RNA folding kinetics is limited by the complex interplay between the weak base-pair interactions that stabilize the native structure and the disordering effect of thermal forces. The possibility of mechanically pulling individual molecules offers a new perspective to understand the folding of nucleic acids. Here we investigate the folding and misfolding mechanism in RNA secondary structures pulled by mechanical forces. We introduce a model based on the identification of the minimal set of structures that reproduce the patterns of force-extension curves obtained in single molecule experiments. The model requires only two fitting parameters: the attempt frequency at the level of individual base pairs and a parameter associated to a free energy correction that accounts for the configurational entropy of an exponentially large number of neglected secondary structures. We apply the model to interpret results recently obtained in pulling experiments in the three-helix junction S15 RNA molecule (RNAS15). We show that RNAS15 undergoes force-induced misfolding where force favors the formation of a stable non-native hairpin. The model reproduces the pattern of unfolding and refolding force-extension curves, the distribution of breakage forces and the misfolding probability obtained in the experiments., Comment: 28 pages, 11 figures

Experimental variables of optical tweezers instrumentation that affect RNA folding/unfolding kinetics were investigated. A model RNA hairpin, P5ab, was attached to two micron-sized beads through hybrid RNA/DNA handles; one bead was trapped by dual-beam lasers and the other was held by a micropipette. Several experimental variables were changed while measuring the unfolding/refolding kinetics, including handle lengths, trap stiffness, and modes of force applied to the molecule. In constant-force mode where the tension applied to the RNA was maintained through feedback control, the measured rate coefficients varied within 40% when the handle lengths were changed by 10 fold (1.1 to 10.2 Kbp); they increased by two- to three-fold when the trap stiffness was lowered to one third (from 0.1 to 0.035 pN/nm). In the passive mode, without feedback control and where the force applied to the RNA varied in response to the end-to-end distance change of the tether, the RNA hopped between a high-force folded-state and a low-force unfolded-state. In this mode, the rates increased up to two-fold with longer handles or softer traps. Overall, the measured rates remained with the same order-of-magnitude over the wide range of conditions studied. In the companion paper (1), we analyze how the measured kinetics parameters differ from the intrinsic molecular rates of the RNA, and thus how to obtain the molecular rates., Comment: PDF file, 30 pages, 7 figures

By exerting mechanical force it is possible to unfold/refold RNA molecules one at a time. In a small range of forces, an RNA molecule can hop between the folded and the unfolded state with force-dependent kinetic rates. Here, we introduce a mesoscopic model to analyze the hopping kinetics of RNA hairpins in an optical tweezers setup. The model includes different elements of the experimental setup (beads, handles and RNA sequence) and limitations of the instrument (time lag of the force-feedback mechanism and finite bandwidth of data acquisition). We investigated the influence of the instrument on the measured hopping rates. Results from the model are in good agreement with the experiments reported in the companion article (1). The comparison between theory and experiments allowed us to infer the values of the intrinsic molecular rates of the RNA hairpin alone and to search for the optimal experimental conditions to do the measurements. We conclude that long handles and soft laser traps represent the best conditions to extract rate estimates that are closest to the intrinsic molecular rates. The methodology and rationale presented here can be applied to other experimental setups and other molecules., Comment: PDF file, 32 pages including 9 figures plus supplementary material

In this paper I am presenting an overview on several topics related to nonequilibrium fluctuations in small systems. I start with a general discussion about fluctuation theorems and applications to physical examples extracted from physics and biology: a bead in an optical trap and single molecule force experiments. Next I present a general discussion on path thermodynamics and consider distributions of work/heat fluctuations as large deviation functions. Then I address the topic of glassy dynamics from the perspective of nonequilibrium fluctuations due to small cooperatively rearranging regions. Finally, I conclude with a brief digression on future perspectives., Comment: Invited contribution to "Advances in Chemical Physics" to appear in Vol. 137, Ed. Wiley & Sons, 81 pages + 19 PS figures

I review single-molecule experiments (SME) in biological physics. Recent technological developments have provided the tools to design and build scientific instruments of high enough sensitivity and precision to manipulate and visualize individual molecules and measure microscopic forces. Using SME it is possible to: manipulate molecules one at a time and measure distributions describing molecular properties; characterize the kinetics of biomolecular reactions and; detect molecular intermediates. SME provide the additional information about thermodynamics and kinetics of biomolecular processes. This complements information obtained in traditional bulk assays. In SME it is also possible to measure small energies and detect large Brownian deviations in biomolecular reactions, thereby offering new methods and systems to scrutinize the basic foundations of statistical mechanics. This review is written at a very introductory level emphasizing the importance of SME to scientists interested in knowing the common playground of ideas and the interdisciplinary topics accessible by these techniques. The review discusses SME from an experimental perspective, first exposing the most common experimental methodologies and later presenting various molecular systems where such techniques have been applied. I briefly discuss experimental techniques such as atomic-force microscopy (AFM), laser optical tweezers (LOT), magnetic tweezers (MT), biomembrane force probe (BFP) and single-molecule fluorescence (SMF). I then present several applications of SME to the study of nucleic acids (DNA, RNA and DNA condensation), proteins (protein-protein interactions, protein folding and molecular motors). Finally, I discuss applications of SME to the study of the nonequilibrium thermodynamics of small systems and the experimental verification of fluctuation theorems. I conclude with a discussion of open questions and future perspectives., Comment: Latex, 60 pages, 12 figures, Topical Review for J. Phys. C (Cond. Matt)

We apply Kramers theory to investigate the dissociation of multiple bonds under mechanical force and interpret experimental results for the unfolding/refolding force distributions of an RNA hairpin pulled at different loading rates using laser tweezers. We identify two different kinetic regimes depending on the range of forces explored during the unfolding and refolding process. The present approach extends the range of validity of the two-states approximation by providing a theoretical framework to reconstruct free-energy landscapes and identify force-induced structural changes in molecular transition states using single molecule pulling experiments. The method should be applicable to RNA hairpins with multiple kinetic barriers., Comment: Latex file, 4 pages+3 figures

When mixed together, DNA and polyaminoamide (PAMAM) dendrimers form fibers that condense into a compact structure. We use optical tweezers to pull condensed fibers and investigate the decondensation transition by measuring force-extension curves (FECs). A characteristic plateau force (around 10 pN) and hysteresis between the pulling and relaxation cycles are observed for different dendrimer sizes, indicating the existence of a first-order transition between two phases (condensed and extended) of the fiber. The fact that we can reproduce the same FECs in the absence of additional dendrimers in the buffer medium indicates that dendrimers remain irreversibly bound to the DNA backbone. Upon salt variation FECs change noticeably confirming that electrostatic forces drive the condensation transition. Finally, we propose a simple model for the decondensing transition that qualitatively reproduces the FECs and which is confirmed by AFM images., Comment: Latex version, 4 pages+3 color figures

The description of nonequilibrium processes in nano-sized objects, where the typical energies involved are a few times, is increasingly becoming central to disciplines as diverse as condensed-matter physics, materials science, and biophysics. Major recent developments towards a unified treatment of arbitrarily large fluctuations in small systems are described by fluctuation theorems that relate the probabilities of a system absorbing from or releasing to the bath a given amount of energy in a nonequilibrium process. Here we experimentally verify the Crooks Fluctuation Theorem (CFT) under weak and strong nonequilibrium conditions by using optical tweezers to measure the irreversible mechanical work during the unfolding and refolding of a small RNA hairpin and an RNA three-helix junction. We also show that the CFT provides a powerful way to obtain folding free energies in biomolecules by determining the crossing between the unfolding and refolding irreversible work distributions. The method makes it possible to obtain folding free energies in nonequilibrium processes that dissipate up to of the average total work exerted, thereby paving the way for reconstructing free energy landscapes along reaction coordinates in nonequilibrium single-molecule experiments., Comment: PDF file, 19 pages. Supplementary information available online at www.nature.com

The interactions of tiny objects with their environment are dominated by thermal fluctuations. Guided by theory and assisted by micromanipulation tools, scientists have begun to study such interactions in detail., Comment: PDF file, 13 pages. Long version of the paper published in Physics Today

Biomolecules carry out very specialized tasks inside the cell where energies involved are few tens of k_BT, small enough for thermal fluctuations to be relevant in many biomolecular processes. In this paper I discuss a few concepts and present some experimental results that show how the study of fluctuation theorems applied to biomolecules contributes to our understanding of the nonequilibrium thermal behavior of small systems., Comment: Proceedings of the 22nd Statphys Conference 2004 (Bangalore,India). Invited contribution

We introduce an exactly solvable model for glassy dynamics with many relaxational modes, each one characterized by a different relaxational time-scale. Analytical solution of the aging dynamics at low temperatures shows that a nonequilibrium or effective temperature can be associated to each time-scale or mode. The spectrum of effective temperatures shows two regions that are separated by an age dependent boundary threshold. Region I is characterized by partially equilibrated modes that relax faster than the modes at the threshold boundary. Thermal fluctuations and time-correlations for modes in region I show that those modes are in mutual thermal equilibrium at a unique age-dependent effective temperature $\Theta (s)$. In contrast, modes with relaxational timescales longer than that of modes at the threshold (region II) show diffusive properties and do not share the common temperature $\Theta (s)$. The shift of the threshold toward lower energy modes as the system ages, and the progressive shrinking of region II, determines how the full spectrum of modes equilibrates. As is usually done in experiments, we have defined a frequency-dependent effective temperature and we have found that all modes in region I are mutually equilibrated at the temperature $\Theta (s)$ independently of the probing frequency. The present model aims to explain transport anomalies observed in supercooled liquids in terms of a collection of structurally disordered and cooperative rearranging mesoscopic regions., Comment: 26 pages, 11 figures

We investigate nonequilibrium temperatures in a two-state system driven to a nonequilibrium steady state by the action of an oscillatory field. The nonequilibrium temperature is determined by coupling a small cavity or probe to the nonequilibrium system and studying the fluctuating noise in the cavity, as has been proposed in the context of glassy systems. We show the presence of resonant effects in the nonequilibrium temperature and discuss the existence of a constitutive steady-state equation in such nonequilibrium conditions. We propose this simple model as an excellent system to carry out experimental measurements of nonequilibrium temperatures. This may help to better understand the physical meaning of this elusive concept., Comment: 8 pages, 2 figures. Contribution to the special issue 'D. Chandler Festschrift'

We calculate analytically the fluctuation-dissipation ratio (FDR) for Ising ferromagnets quenched to criticality, both for the long-range model and its short-range analogue in the limit of large dimension. Our exact solution shows that, for both models, $X^\infty=1/2$ if the system is unmagnetized while $X^\infty=4/5$ if the initial magnetization is non-zero. This indicates that two different classes of critical coarsening dynamics need to be distinguished depending on the initial conditions, each with its own nontrivial FDR. We also analyze the dependence of the FDR on whether local and global observables are used. These results clarify how a proper local FDR (and the corresponding effective temperature) should be defined in long-range models in order to avoid spurious inconsistencies and maintain the expected correspondence between local and global results; global observables turn out to be far more robust tools for detecting non-equilibrium FDRs., Comment: 14 pages, revtex4, published version. Changes from v1: added discussion of refs [16,36,37], other observables and local correlation/response in short-range model

In this paper we introduce the generalized oscillator model (GOM) as a family of exactly solvable models useful to investigate theoretical aspects related to the statistical description of the aging state. GOMs are defined by a potential function V(x) and characterized by a zero-temperature relaxation determined by entropy barriers and partial equilibration. Analytic expressions for the effective temperature can be derived using a fluctuation theorem valid in the aging regime without the need to solve the dynamical equations for correlations and responses. Two classes of models are investigated in detail: the homogeneous potential model with V(x)=(k/2p)x^{2p} (p being a positive integer) and the wedge potential model (V(x)=k|x|) where V(x) has a singularity at the ground state coordinate x=0. For the latter, we present some numerical simulations that reinforce the validity of the main analytical results. GOMs offer a conceptual framework to develop a statistical description of the spontaneous relaxation process that has been recently proposed to be at the root of the intermittency phenomenon observed in glasses and colloids., Comment: Latex file, 21 pages, Contribution to the special issue 'Hans C. Andersen Festschrift'

Two-state models provide phenomenological descriptions of many different systems, ranging from physics to chemistry and biology. We investigate work fluctuations in an ensemble of two-state systems driven out of equilibrium under the action of an external perturbation. We calculate the probability density P(W) that a work equal to W is exerted upon the system along a given non-equilibrium trajectory and introduce a trajectory thermodynamics formalism to quantify work fluctuations in the large-size limit. We then define a trajectory entropy S(W) that counts the number of non-equilibrium trajectories P(W)=exp(S(W)/kT) with work equal to W. A trajectory free-energy F(W) can also be defined, which has a minimum at a value of the work that has to be efficiently sampled to quantitatively test the Jarzynski equality. Within this formalism a Lagrange multiplier is also introduced, the inverse of which plays the role of a trajectory temperature. Our solution for P(W) exactly satisfies the fluctuation theorem by Crooks and allows us to investigate heat-fluctuations for a protocol that is invariant under time reversal. The heat distribution is then characterized by a Gaussian component (describing small and frequent heat exchange events) and exponential tails (describing the statistics of large deviations and rare events). For the latter, the width of the exponential tails is related to the aforementioned trajectory temperature. Finite-size effects to the large-N theory and the recovery of work distributions for finite N are also discussed. Finally, we pay particular attention to the case of magnetic nanoparticle systems under the action of a magnetic field H where work and heat fluctuations are predicted to be observable in ramping experiments in micro-SQUIDs., Comment: 28 pages, 14 figures (Latex)

In this report I discuss fluctuation theorems and transient violations of the second law of thermodynamics in small systems. Special emphasis is placed on free-energy recovery methods in the framework of non-equilibrium single-molecule pulling experiments. The treatment is done from a unified theoretical-experimental perspective and emphasizes how these experiments contribute to our understanding of the thermodynamic behavior of small systems, Comment: 35 pages, 16 figures (Latex). Talk given at the Poincare seminar

Recent numerical simulations of a disordered system (Preprint arXiv:condmat/0307554) have shown the existence of two different relaxational processes (called stimulated and spontaneous) characterizing the relaxation observed in structural glasses. The existence of these two processes has been claimed to be at the roots of the intermittency phenomenon observed in recent experiments. Here we consider a generic system put in contact with a bath at temperature T and characterized by an adiabatic slow relaxation (i.e. by a negligible net heat flow from the system to the bath) in the aging state. We focus on a simplified scenario (termed as partial equilibration) characterized by the fact that $=0 (where only the spontaneous process is observable) and whose microscopic stochastic dynamics is ergodic when constrained to the constant energy surface. Three different effective temperatures can be defined: a) from the fluctuation-dissipation theorem (FDT), b) from a fluctuation theorem describing the statistical distribution of heat exchange events between system and bath and c) from a set of observable-dependent microcanonical relations in the aging state. In a partial equilibration scenario we show how all three temperatures coincide reinforcing the idea that a statistical (rather than thermometric) definition of a non-equilibrium temperature is physically meaningful in aging systems. These results are explicitly checked in a simple model system, Comment: 16 pages, 3 figures (Latex)

We consider heat exchange processes between non-equilibrium aging systems (in their activated regime) and the thermal bath in contact. We discuss a scenario where two different heat exchange processes concur in the overall heat dissipation: a stimulated fast process determined by the temperature of the bath and a spontaneous intermittent process determined by the fact that the system has been prepared in a non-equilibrium state. The latter is described by a probability distribution function (PDF) that has an exponential tail of width given by a parameter $\lambda$, and satisfies a fluctuation theorem (FT) governed by that parameter. The value of $\lambda$ is proportional to the so-called effective temperature, thereby providing a practical way to experimentally measure it by analyzing the PDF of intermittent events., Comment: Latex file, 8 pages + 5 postscript figures

We have computed the time-dependent susceptibility for the finite-size mean-field Random Orthogonal model (ROM). We find that for temperatures above the mode-coupling temperature the imaginary part of the susceptibility $\chi''(\nu)$ obeys the scaling forms proposed for glass-forming liquids. Furthermore, as the temperature is lowered the peak frequency of $\chi''$ decreases following a Vogel-Fulcher law with a critical temperature remarkably close to the known critical temperature $T_c$ where the configurational entropy vanishes., Comment: 7 pages, 4 figures, epl LaTeX package

We investigate violations of the fluctuation-dissipation theorem in two classes of trap models by studying the influence of the perturbing field on the transition rates. We show that for perturbed rates depending upon the value of the observable at the arrival trap, a limiting value of the fluctuation-dissipation ratio does exist. However, the mechanism behind the emergence of this value is different in both classes of models. In particular, for an entropically governed dynamics (where the perturbing field shifts the relative population of traps according to the value of the observable) perturbed rates are argued to take a form that guarantees the existence of a limiting value for the effective temperature, utterly related to the exponential character of the distribution of trap energies. Fluctuation-dissipation (FD) plots reproduce some of the patterns found in a broad class of glassy systems, reinforcing the idea that structural glasses self-generate a dynamical measure that is captured by phenomenological trap models., Comment: 15 pages, 4 figures (Latex) Misprints corrected and additional comments included in Section 4. Contribution to a special issue of J. Phys. A "Statistical Physics of Disordered Systems"

This review reports on the research done during the past years on violations of the fluctuation-dissipation theorem (FDT) in glassy systems. It is focused on the existence of a quasi-fluctuation-dissipation theorem (QFDT) in glassy systems and the currently supporting knowledge gained from numerical simulation studies. It covers a broad range of non-stationary aging and stationary driven systems such as structural-glasses, spin-glasses, coarsening systems, ferromagnetic models at criticality, trap models, models with entropy barriers, kinetically constrained models, sheared systems and granular media. The review is divided into four main parts: 1) An introductory section explaining basic notions related to the existence of the FDT in equilibrium and its possible extension to the glassy regime (QFDT), 2) A description of the basic analytical tools and results derived in the framework of some exactly solvable models, 3) A detailed report of the current evidence in favour of the QFDT and 4) A brief digression on the experimental evidence in its favour. This review is intended for inexpert readers who want to learn about the basic notions and concepts related to the existence of the QFDT as well as for the more expert readers who may be interested in more specific results., Comment: 120 pages, 37 figures. Topical review paper . Several typos and misprints corrected, new references included and others updated. to be published in J. Phys. A (Math. Gen.)

We investigate the work dissipated during the irreversible unfolding of single molecules by mechanical force, using the simplest model necessary to represent experimental data. The model consists of two levels (folded and unfolded states) separated by an intermediate barrier. We compute the probability distribution for the dissipated work and give analytical expressions for the average and variance of the distribution. To first order, the amount of dissipated work is directly proportional to the rate of application of force (the loading rate), and to the relaxation time of the molecule. The model yields estimates for parameters that characterize the unfolding kinetics under force in agreement with those obtained in recent experimental results (Liphardt, J., et al. (2002) {\em Science}, {\bf 296} 1832-1835). We obtain a general equation for the minimum number of repeated experiments needed to obtain an equilibrium free energy, to within $k_BT$, from non-equilibrium experiments using the Jarzynski formula. The number of irreversible experiments grows exponentially with the ratio of the average dissipated work, $\bar{\Wdis}$, to $k_BT$.}, Comment: PDF file, 5 pages

In this paper we consider an exactly solvable model which displays glassy behavior at zero temperature due to entropic barriers. The new ingredient of the model is the existence of different energy scales or modes associated to different relaxational time-scales. Low-temperature relaxation takes place by partial equilibration of successive lower energy modes. An adiabatic scaling solution, defined in terms of a threshold energy scale $\eps^*$, is proposed. For such a solution, modes with energy $\eps\gg\eps^*$ are equilibrated at the bath temperature, modes with $\eps\ll\eps^*$ remain out of equilibrium and relaxation occurs in the neighborhood of the threshold $\eps\sim \eps^*$. The model is presented as a toy example to investigate conditions related to the existence of an effective temperature in glassy systems and its possible dependence on the energy sector probed by the corresponding observable., Comment: 24 pages, 11 figures

The mean field theory of a spin glass with a specific form of nearest and next nearest neighbor interactions is investigated. Depending on the sign of the interaction matrix chosen we either find the continuous replica symmetry breaking seen in the Sherrington-Kirkpartick model or a one step solution similar to that found in structural glasses. Our results are confirmed by numerical simulations and the link between the type of spin-glass behavior and the density of eigenvalues of the interaction matrix is discussed., Comment: 15 pages, 9 figures, Latex file

We give a short introduction to the inherent structure approach, with particular emphasis on the Stillinger and Weber decomposition, of glassy systems. We present some of the results obtained in the framework of spin-glass models and Lennard-Jones glasses. We discuss how to generalize the standard Stillinger and Weber approach by including the entropy of inherent structures. Finally we discuss why this approach is probably insufficient to describe the behavior of some kinetically constrained models., Comment: 16 pages, 8 figures, Contribution to the ESF SPHINX meeting `Glassy behaviour of kinetically constrained models' (Barcelona, March 22-25, 2001)

We study three kinetic models with constraint, namely the Symmetrically Constrained Ising Chain, the Asymmetrically Constrained Ising Chain, and the Backgammon Model. All these models show glassy behavior and coarsening. We apply to them the Stillinger and Weber decomposition, and find that they share the same configurational entropy, despite of their different nonequilibrium dynamics. We conclude therefore that the Stillinger and Weber decomposition is not relevant for this type of models., Comment: 14 pages, 12 figures

In a previous paper (cond-mat/0106554) we showed the existence of two new zero-temperature exponents (\lambda and \theta') in two dimensional Gaussian spin glasses. Here we introduce a novel low-temperature expansion for spin glasses expressed in terms of the gap probability distributions for successive energy levels. After presenting the numerical evidence in favor of a random-energy levels scenario, we analyze the main consequences on the low-temperature equilibrium behavior. We find that the specific heat is anomalous at low-temperatures c ~ T**\alpha with \alpha=-d/\theta' which turns out to be linear for the case \theta'=-d., Comment: 6 pages, 3 figures. v2 : substantially revised version

A detailed investigation of lowest excitations in two-dimensional Gaussian spin glasses is presented. We show the existence of a new zero-temperature exponent lambda describing the relative number of finite-volume excitations with respect to large-scale ones. This exponent yields the standard thermal exponent of droplet theory theta through the relation, theta=d(lambda-1). Our work provides a new way to measure the thermal exponent theta without any assumption about the procedure to generate typical low-lying excitations. We find clear evidence that theta < theta_{DW} where theta_{DW} is the thermal exponent obtained in domain-wall theory showing that MacMillan excitations are not typical., Comment: 4 pages, 3 figures, (v2) revised version, (v3) corrected typos

We propose a scenario for the glass transition based on the cooperative nature of nucleation processes and entropic effects. The main point is the relation between the off-equilibrium energy dissipation and nucleation processes in off-equilibrium supercooled liquids which leads to a natural definition of the complexity. From the absence of coarsening growth we can derive an entropy based fluctuation formula which relates the free energy dissipation rate in the glass with the nucleation rate of the largest cooperative regions. As by-product we obtain a new phenomenological relation between the largest relaxation time in the supercooled liquid phase and an effective temperature. This differs from the Adam-Gibbs relation in that predicts no divergence of the primary relaxation time at the Kauzmann temperature and the existence of a crossover from fragile to strong behavior., Comment: 8th International Workshop on Disordered Systems, Andalo (Trento), Italy, 12-15 March 2001

We propose a new method to compute the configurational entropy of glassy systems as a function of the free energy of valleys at a given temperature, in the framework of the Stillinger and Weber approach. In this method, which we call free-energy inherent structures (FEIS) approach, valleys are represented by inherent structures that are statistically grouped according to their free-energy rather than the energy as is commonly done in the standard procedure. The FEIS method provides a further step toward a description of the relaxational behavior of glassy systems in terms of a free energy measure. It can be used to determine the character of the glass transition as well as the mode coupling and the Kauzmann temperatures. We illustrate the usefulness of the method by applying it to simple models of glasses and spin glasses., Comment: 14 pages, 3 figures, LaTeX2e with EJP class. EPJ B (in press)

We present a detailed study of the scaling behavior of correlations functions and AC susceptibility relaxations in the aging regime in three dimensional spin glasses. The agreement between simulations and experiments is excellent confirming the validity of the full aging scenario with logarithmic corrections which manifests as weak sub-aging effects., Comment: 6 pages, 6 figures. Previously appeared as a part of cond-mat/0005541