We consider the mutual interactions, via cytokine exchanges, among helper lymphocytes, B lymphocytes and killer lymphocytes, and we model them as a unique system by means of a tripartite network. Each part includes all the different clones of the same lymphatic subpopulation, whose couplings to the others are either excitatory or inhibitory (mirroring elicitation and suppression by cytokine). First of all, we show that this system can be mapped into an associative neural network, where helper cells directly interact with each other and are able to secrete cytokines according to "strategies" learn by the system and profitable to cope with possible antigenic stimulation; the ability of such a retrieval corresponds to a healthy reaction of the immune system. We then investigate the possible conditions for the failure of a correct retrieval and distinguish between the following outcomes: massive lymphocyte expansion/suppression (e.g. lymphoproliferative syndromes), subpopulation unbalance (e.g. HIV, EBV infections) and ageing (thought of as noise growth); the correlation of such states to autoimmune diseases is also highlighted. Lastly, we discuss how self-regulatory effects within each effector branch (i.e. B and killer lymphocytes) can be modeled in terms of a stochastic process, ultimately providing a consistent bridge between the tripartite-network approach introduced here and the immune networks developed in the last decades.

How does immigrant integration in a country change with immigration density? Guided by a statistical mechanics perspective we propose a novel approach to this problem. The analysis focuses on classical integration quantifiers such as the percentage of jobs (temporary and permanent) given to immigrants, mixed marriages, and newborns with parents of mixed origin. We find that the average values of different quantifiers may exhibit either linear or non-linear growth on immigrant density and we suggest that social action, a concept identified by Max Weber, causes the observed non-linearity. Using the statistical mechanics notion of interaction to quantitatively emulate social action, a unified mathematical model for integration is proposed and it is shown to explain both growth behaviors observed. The linear theory instead, ignoring the possibility of interaction effects would underestimate the quantifiers up to 30% when immigrant densities are low, and overestimate them as much when densities are high. The capacity to quantitatively isolate different types of integration mechanisms makes our framework a suitable tool in the quest for more efficient integration policies.

We study the phase diagram of a minority game where three classes of agents are present. Two types of agents play a risk-loving game that we model by the standard Snowdrift Game. The behaviour of the third type of agents is coded by indifference with respect to the game at all: their dynamics is designed to account for risk-aversion as an innovative behavioral gambit. From this point of view, the choice of this solitary strategy is enhanced when innovation starts, while is depressed when it becomes the majority option. This implies that the payoff matrix of the game becomes dependent on the global awareness of the agents measured by the relevance of the population of the indifferent players. The resulting dynamics is nontrivial with different kinds of phase transition depending on a few model parameters. The phase diagram is studied on regular as well as complex networks.

Self-directed lymphocytes may evade clonal deletion at ontogenesis but still remain harmless due to a mechanism called clonal anergy. For B-lymphocytes, two major explanations for anergy developed over the last decades: according to Varela theory, anergy stems from a proper orchestration of the whole B-repertoire, such that self-reactive clones, due to intensive feed-back from other clones, display strong inertia when mounting a response. Conversely, according to the model of cognate response, self-reacting cells are not stimulated by helper lymphocytes and the absence of such signaling yields anergy. Through statistical mechanics we show that helpers do not prompt activation of a sub-group of B-cells: remarkably, the latter are just those broadly interacting in the idiotypic network. Hence Varela theory can finally be reabsorbed into the prevailing framework of the cognate response model. Further, we show how the B-repertoire architecture may emerge, where highly connected clones are self-directed as a natural consequence of ontogenetic learning.

In this manuscript we apply stochastic modeling to investigate the risk of reactivation of latent mycobacterial infections in patients undergoing treatment with tumor necrosis factor inhibitors. First, we review the perspective proposed by one of the authors in a previous work and which consists in predicting the occurrence of reactivation of latent tuberculosis infection or newly acquired tuberculosis during treatment; this is based on variational procedures on a simple set of parameters (e.g. rate of reactivation of a latent infection). Then, we develop a full analytical study of this approach through a Markov chain analysis and we find an exact solution for the temporal evolution of the number of cases of tuberculosis infection (re)activation. The analytical solution is compared with Monte Carlo simulations and with experimental data, showing overall excellent agreement. The generality of this theoretical framework allows to investigate also the case of non-tuberculous mycobacteria infections; in particular, we show that reactivation in that context plays a minor role. This may suggest that, while the screening for tuberculous is necessary prior to initiating biologics, when considering non-tuberculous mycobacteria only a watchful monitoring during the treatment is recommended. The framework outlined in this paper is quite general and could be extremely promising in further researches on drug-related adverse events.

Scope of the present work is to infer the migratory ability of leukocytes by stochastic processes in order to distinguish the spontaneous organization of immune cells against an insult (namely cancer). For this purpose, spleen cells from immunodeficient mice, selectively lacking the transcription factor IRF-8 (IRF-8 knockout; IRF-8 KO), or from immunocompetent animals (wild-type; WT), were allowed to interact, alternatively, with murine B16.F10 melanoma cells in an ad hoc microfluidic environment developed on a LabOnChip technology. In this setting, only WT spleen cells were able to establish physical interactions with melanoma cells. Conversely, IRF-8 KO immune cells exhibited poor dynamical reactivity towards the neoplastic cells. In the present study, we collected data on the motility of these two types of spleen cells and built a complete set of observables that recapitulate the biological complexity of the system in these experiments. With remarkable accuracy, we concluded that the IRF-8 KO cells performed pure uncorrelated random walks, while WT splenocytes were able to make singular drifted random walks that collapsed on a straight ballistic motion for the system as a whole, hence giving rise to a highly coordinate response. These results may provide a useful system to quantitatively analyse the real time cell-cell interactions and to foresee the behavior of immune cells with tumor cells at the tissue level.

Chronic fatigue syndrome is a protracted illness condition (lasting even years) appearing with strong flu symptoms and systemic defiances by the immune system. Here, by means of statistical mechanics techniques, we study the most widely accepted picture for its genesis, namely a persistent acute mononucleosis infection, and we show how such infection may drive the immune system towards an out-of-equilibrium metastable state displaying chronic activation of both humoral and cellular responses (a state of full inflammation without a direct 'causes-effect' reason). By exploiting a bridge with a neural scenario, we mirror killer lymphocytes T(K) and B cells to neurons and helper lymphocytes [Formula: see text] and [Formula: see text] to synapses, hence showing that the immune system may experience the Pavlov conditional reflex phenomenon: if the exposition to a stimulus (Epstein-Barr virus antigens) lasts for too long, strong internal correlations among B,T(K) and T(H) may develop ultimately resulting in a persistent activation even though the stimulus itself is removed. These outcomes are corroborated by several experimental findings.

In this work we aim to highlight a close analogy between cooperative behaviors in chemical kinetics and cybernetics; this is realized by using a common language for their description, that is mean-field statistical mechanics. First, we perform a one-to-one mapping between paradigmatic behaviors in chemical kinetics (i.e., non-cooperative, cooperative, ultra-sensitive, anti-cooperative) and in mean-field statistical mechanics (i.e., paramagnetic, high and low temperature ferromagnetic, anti-ferromagnetic). Interestingly, the statistical mechanics approach allows a unified, broad theory for all scenarios and, in particular, Michaelis-Menten, Hill and Adair equations are consistently recovered. This framework is then tested against experimental biological data with an overall excellent agreement. One step forward, we consistently read the whole mapping from a cybernetic perspective, highlighting deep structural analogies between the above-mentioned kinetics and fundamental bricks in electronics (i.e. operational amplifiers, flashes, flip-flops), so to build a clear bridge linking biochemical kinetics and cybernetics.

Statistical mechanics provides an effective framework to investigate information processing in biochemical reactions. Within such framework far-reaching analogies are established among (anti-) cooperative collective behaviors in chemical kinetics, (anti-)ferromagnetic spin models in statistical mechanics and operational amplifiers/flip-flops in cybernetics. The underlying modeling - based on spin systems - has been proved to be accurate for a wide class of systems matching classical (e.g. Michaelis-Menten, Hill, Adair) scenarios in the infinite-size approximation. However, the current research in biochemical information processing has been focusing on systems involving a relatively small number of units, where this approximation is no longer valid. Here we show that the whole statistical mechanical description of reaction kinetics can be re-formulated via a mechanical analogy - based on completely integrable hydrodynamic-type systems of PDEs - which provides explicit finite-size solutions, matching recently investigated phenomena (e.g. noise-induced cooperativity, stochastic bi-stability, quorum sensing). The resulting picture, successfully tested against a broad spectrum of data, constitutes a neat rationale for a numerically effective and theoretically consistent description of collective behaviors in biochemical reactions.

In this work we apply techniques and modus operandi typical of Statistical Mechanics to a large dataset about key social quantifiers and compare the resulting behaviors of five European nations, namely France, Germany, Italy, Spain and Switzerland. The social quantifiers considered are i. the evolution of the number of autochthonous marriages (i.e., between two natives) within a given territorial district and ii. the evolution of the number of mixed marriages (i.e., between a native and an immigrant) within a given territorial district. Our investigations are twofold. From a theoretical perspective, we develop novel techniques, complementary to classical methods (e.g., historical series and logistic regression), in order to detect possible collective features underlying the empirical behaviors; from an experimental perspective, we evidence a clear outline for the evolution of the social quantifiers considered. The comparison between experimental results and theoretical predictions is excellent and allows speculating that France, Italy and Spain display a certain degree of internal heterogeneity, that is not found in Germany and Switzerland; such heterogeneity, quite mild in France and in Spain, is not negligible in Italy and highlights quantitative differences in the habits of Northern and Southern regions. These findings may suggest the persistence of two culturally distinct communities, long-term lasting heritages of different and well-established customs. Also, we find qualitative differences between the evolution of autochthonous and of mixed marriages: for the former imitation in decisional mechanisms seems to play a key role (and this results in a square root relation between the number of autochthonous marriages versus the percentage of possible couples inside that country), while for the latter the emerging behavior can be recovered (in most cases) with elementary models with no interactions, suggesting weak imitation patterns between natives and migrants (and this translates in a linear growth for the number of mixed marriages versus the percentage of possible mixed couples in the country). However, the case of mixed marriages displays a more complex phenomenology, where further details (e.g., the provenance and the status of migrants, linguistic barriers, etc.) should also be accounted for.

We adapt belief-propagation techniques to study the equilibrium behavior of a bipartite spin glass, with interactions between two sets of N and P=αN spins each having an arbitrary degree, i.e., number of interaction partners in the opposite set. An equivalent view is then of a system of N neurons storing P diluted patterns via Hebbian learning, in the high storage regime. Our method allows analysis of parallel pattern processing on a broad class of graphs, including those with pattern asymmetry and heterogeneous dilution; previous replica approaches assumed homogeneity. We show that in a large part of the parameter space of noise, dilution, and storage load, delimited by a critical surface, the network behaves as an extensive parallel processor, retrieving all P patterns in parallel without falling into spurious states due to pattern cross talk, as would be typical of the structural glassiness built into the network. Parallel extensive retrieval is more robust for homogeneous degree distributions, and is not disrupted by asymmetric pattern distributions. For scale-free pattern degree distributions, Hebbian learning induces modularity in the neural network; thus, our Letter gives the first theoretical description for extensive information processing on modular and scale-free networks.

In this work we study a Hebbian neural network, where neurons are arranged according to a hierarchical architecture such that their couplings scale with their reciprocal distance. As a full statistical mechanics solution is not yet available, after a streamlined introduction to the state of the art via that route, the problem is consistently approached through signal-to-noise technique and extensive numerical simulations. Focusing on the low-storage regime, where the amount of stored patterns grows at most logarithmical with the system size, we prove that these non-mean-field Hopfield-like networks display a richer phase diagram than their classical counterparts. In particular, these networks are able to perform serial processing (i.e. retrieve one pattern at a time through a complete rearrangement of the whole ensemble of neurons) as well as parallel processing (i.e. retrieve several patterns simultaneously, delegating the management of different patterns to diverse communities that build network). The tune between the two regimes is given by the rate of the coupling decay and by the level of noise affecting the system. The price to pay for those remarkable capabilities lies in a network's capacity smaller than the mean field counterpart, thus yielding a new budget principle: the wider the multitasking capabilities, the lower the network load and vice versa. This may have important implications in our understanding of biological complexity.

We introduce a bipartite, diluted and frustrated, network as a sparse restricted Boltzmann machine and we show its thermodynamical equivalence to an associative working memory able to retrieve several patterns in parallel without falling into spurious states typical of classical neural networks. We focus on systems processing in parallel a finite (up to logarithmic growth in the volume) amount of patterns, mirroring the low-level storage of standard Amit-Gutfreund-Sompolinsky theory. Results obtained through statistical mechanics, the signal-to-noise technique, and Monte Carlo simulations are overall in perfect agreement and carry interesting biological insights. Indeed, these associative networks pave new perspectives in the understanding of multitasking features expressed by complex systems, e.g., neural and immune networks.

We consider the multitasking associative network in the low-storage limit and we study its phase diagram with respect to the noise level T and the degree d of dilution in pattern entries. We find that the system is characterized by a rich variety of stable states, including pure states, parallel retrieval states, hierarchically organized states and symmetric mixtures (remarkably, both even and odd), whose complexity increases as the number of patterns P grows. The analysis is performed both analytically and numerically: Exploiting techniques based on partial differential equations, we are able to get the self-consistencies for the order parameters. Such self-consistency equations are then solved and the solutions are further checked through stability theory to catalog their organizations into the phase diagram, which is outlined at the end. This is a further step towards the understanding of spontaneous parallel processing in associative networks.

Recent experimental breakthroughs have finally allowed to implement in-vitro reaction kinetics (the so called enzyme based logic) which code for two-inputs logic gates and mimic the stochastic AND (and NAND) as well as the stochastic OR (and NOR). This accomplishment, together with the already-known single-input gates (performing as YES and NOT), provides a logic base and paves the way to the development of powerful biotechnological devices. However, as biochemical systems are always affected by the presence of noise (e.g. thermal), standard logic is not the correct theoretical reference framework, rather we show that statistical mechanics can work for this scope: here we formulate a complete statistical mechanical description of the Monod-Wyman-Changeaux allosteric model for both single and double ligand systems, with the purpose of exploring their practical capabilities to express noisy logical operators and/or perform stochastic logical operations. Mixing statistical mechanics with logics, and testing quantitatively the resulting findings on the available biochemical data, we successfully revise the concept of cooperativity (and anti-cooperativity) for allosteric systems, with particular emphasis on its computational capabilities, the related ranges and scaling of the involved parameters and its differences with classical cooperativity (and anti-cooperativity).

A specific type of neural networks, the Restricted Boltzmann Machines (RBM), are implemented for classification and feature detection in machine learning. They are characterized by separate layers of visible and hidden units, which are able to learn efficiently a generative model of the observed data. We study a "hybrid" version of RBMs, in which hidden units are analog and visible units are binary, and we show that thermodynamics of visible units are equivalent to those of a Hopfield network, in which the N visible units are the neurons and the P hidden units are the learned patterns. We apply the method of stochastic stability to derive the thermodynamics of the model, by considering a formal extension of this technique to the case of multiple sets of stored patterns, which may act as a benchmark for the study of correlated sets. Our results imply that simulating the dynamics of a Hopfield network, requiring the update of N neurons and the storage of N(N-1)/2 synapses, can be accomplished by a hybrid Boltzmann Machine, requiring the update of N+P neurons but the storage of only NP synapses. In addition, the well known glass transition of the Hopfield network has a counterpart in the Boltzmann Machine: it corresponds to an optimum criterion for selecting the relative sizes of the hidden and visible layers, resolving the trade-off between flexibility and generality of the model. The low storage phase of the Hopfield model corresponds to few hidden units and hence a overly constrained RBM, while the spin-glass phase (too many hidden units) corresponds to unconstrained RBM prone to overfitting of the observed data.

We introduce a class of weighted graphs whose properties are meant to mimic the topological features of idiotypic networks, namely, the interaction networks involving the B core of the immune system. Each node is endowed with a bit string representing the idiotypic specificity of the corresponding B cell, and the proper distance between any couple of bit strings provides the coupling strength between the two nodes. We show that a biased distribution of the entries in bit strings can yield fringes in the (weighted) degree distribution, small-world features, and scaling laws, in agreement with experimental findings. We also investigate the role of aging, thought of as a progressive increase in the degree of bias in bit strings, and we show that it can possibly induce mild percolation phenomena, which are investigated too.

In this work, we adopt a statistical-mechanics approach to investigate basic, systemic features exhibited by adaptive immune systems. The lymphocyte network made by B cells and T cells is modeled by a bipartite spin glass, where, following biological prescriptions, links connecting B cells and T cells are sparse. Interestingly, the dilution performed on links is shown to make the system able to orchestrate parallel strategies to fight several pathogens at the same time; this multitasking capability constitutes a remarkable, key property of immune systems as multiple antigens are always present within the host. We also define the stochastic process ruling the temporal evolution of lymphocyte activity and show its relaxation toward an equilibrium measure allowing statistical-mechanics investigations. Analytical results are compared with Monte Carlo simulations and signal-to-noise outcomes showing overall excellent agreement. Finally, within our model, a rationale for the experimentally well-evidenced correlation between lymphocytosis and autoimmunity is achieved; this sheds further light on the systemic features exhibited by immune networks.

In this work, we first revise some extensions of the standard Hopfield model in the low storage limit, namely the correlated attractor case and the multitasking case recently introduced by the authors. The former case is based on a modification of the Hebbian prescription, which induces a coupling between consecutive patterns and this effect is tuned by a parameter a. In the latter case, dilution is introduced in pattern entries, in such a way that a fraction d of them is blank. Then, we merge these two extensions to obtain a system able to retrieve several patterns in parallel and the quality of retrieval, encoded by the set of Mattis magnetizations m(μ), is reminiscent of the correlation among patterns. By tuning the parameters d and a, qualitatively different outputs emerge, ranging from highly hierarchical to symmetric. The investigations are accomplished by means of both numerical simulations and statistical mechanics analysis, properly adapting a novel technique originally developed for spin glasses, i.e. the Hamilton-Jacobi interpolation, with excellent agreement. Finally, we show the thermodynamical equivalence of this associative network with a (restricted) Boltzmann machine and study its stochastic dynamics to obtain even a dynamical picture, perfectly consistent with the static scenario earlier discussed.

We consider statistical-mechanics models for spin systems built on hierarchical structures, which provide a simple example of non-mean-field framework. We show that the coupling decay with spin distance can give rise to peculiar features and phase diagrams much richer than their mean-field counterpart. In particular, we consider the Dyson model, mimicking ferromagnetism in lattices, and we prove the existence of a number of metastabilities, beyond the ordered state, which become stable in the thermodynamic limit. Such a feature is retained when the hierarchical structure is coupled with the Hebb rule for learning, hence mimicking the modular architecture of neurons, and gives rise to an associative network able to perform single pattern retrieval as well as multiple-pattern retrieval, depending crucially on the external stimuli and on the rate of interaction decay with distance; however, those emergent multitasking features reduce the network capacity with respect to the mean-field counterpart. The analysis is accomplished through statistical mechanics, Markov chain theory, signal-to-noise ratio technique, and numerical simulations in full consistency. Our results shed light on the biological complexity shown by real networks, and suggest future directions for understanding more realistic models.

Hierarchical networks are attracting a renewal interest for modeling the organization of a number of biological systems and for tackling the complexity of statistical mechanical models beyond mean-field limitations. Here we consider the Dyson hierarchical construction for ferromagnets, neural networks, and spin glasses, recently analyzed from a statistical-mechanics perspective, and we focus on the topological properties of the underlying structures. In particular, we find that such structures are weighted graphs that exhibit a high degree of clustering and of modularity, with a small spectral gap; the robustness of such features with respect to the presence of thermal noise is also studied. These outcomes are then discussed and related to the statistical-mechanics scenario in full consistency. Last, we look at these weighted graphs as Markov chains and we show that in the limit of infinite size, the emergence of ergodicity breakdown for the stochastic process mirrors the emergence of metastabilities in the corresponding statistical mechanical analysis.