Inverse modeling of time-delayed interactions via the dynamic-entropy formalism.

Although instantaneous interactions are unphysical, a large variety of maximum entropy statistical inference methods match the model-inferred and the empirically measured equal-time correlation functions. Focusing on collective motion of active units, this constraint is reasonable when the interaction timescale is much faster than that of the interacting units, as in starling flocks, yet it fails in a number of counterexamples, as in leukocyte coordination (where signaling proteins diffuse among two cells). Here, we relax this assumption and develop a path integral approach to maximum-entropy framework, which includes delay in signaling. Our method is able to infer the strength of couplings and fields, but also the time required by the couplings to completely transfer information among the units. We demonstrate the validity of our approach providing excellent results on synthetic datasets of non-Markovian trajectories generated by the Heisenberg-Kuramoto and Vicsek models equipped with delayed interactions. As a proof of concept, we also apply the method to experiments on dendritic migration, where matching equal-time correlations results in a significant information loss.

Hebbian dreaming for small datasets.

The dreaming Hopfield model constitutes a generalization of the Hebbian paradigm for neural networks, that is able to perform on-line learning when "awake" and also to account for off-line "sleeping" mechanisms. The latter have been shown to enhance storing in such a way that, in the long sleep-time limit, this model can reach the maximal storage capacity achievable by networks equipped with symmetric pairwise interactions. In this paper, we inspect the minimal amount of information that must be supplied to such a network to guarantee a successful generalization, and we test it both on random synthetic and on standard structured datasets (i.e., MNIST, Fashion-MNIST and Olivetti). By comparing these minimal thresholds of information with those required by the standard (i.e., always "awake") Hopfield model, we prove that the present network can save up to ∼90% of the dataset size, yet preserving the same performance of the standard counterpart. This suggests that sleep may play a pivotal role in explaining the gap between the large volumes of data required to train artificial neural networks and the relatively small volumes needed by their biological counterparts. Further, we prove that the model Cost function (typically used in statistical mechanics) admits a representation in terms of a standard Loss function (typically used in machine learning) and this allows us to analyze its emergent computational skills both theoretically and computationally: a quantitative picture of its capabilities as a function of its control parameters is achieved and consistency between the two approaches is highlighted. The resulting network is an associative memory for pattern recognition tasks that learns from examples on-line, generalizes correctly (in suitable regions of its control parameters) and optimizes its storage capacity by off-line sleeping: such a reduction of the training cost can be inspiring toward sustainable AI and in situations where data are relatively sparse.

Quantifying heterogeneity to drug response in cancer-stroma kinetics.

A crucial challenge in medicine is choosing which drug (or combination) will be the most advantageous for a particular patient. Usually, drug response rates differ substantially, and the reasons for this response unpredictability remain ambiguous. Consequently, it is central to classify features that contribute to the observed drug response variability. Pancreatic cancer is one of the deadliest cancers with limited therapeutic achievements due to the massive presence of stroma that generates an environment that enables tumor growth, metastasis, and drug resistance. To understand the cancer-stroma cross talk within the tumor microenvironment and to develop personalized adjuvant therapies, there is a necessity for effective approaches that offer measurable data to monitor the effect of drugs at the single-cell level. Here, we develop a computational approach, based on cell imaging, that quantifies the cellular cross talk between pancreatic tumor cells (L3.6pl or AsPC1) and pancreatic stellate cells (PSCs), coordinating their kinetics in presence of the chemotherapeutic agent gemcitabine. We report significant heterogeneity in the organization of cellular interactions in response to the drug. For L3.6pl cells, gemcitabine sensibly decreases stroma-stroma interactions but increases stroma-cancer interactions, overall enhancing motility and crowding. In the AsPC1 case, gemcitabine promotes the interactions among tumor cells, but it does not affect stroma-cancer interplay, possibly suggesting a milder effect of the drug on cell dynamics.

Probing Single-Cell Fermentation Fluxes and Exchange Networks via pH-Sensing Hybrid Nanofibers.

The homeostatic control of their environment is an essential task of living cells. It has been hypothesized that, when microenvironmental pH inhomogeneities are induced by high cellular metabolic activity, diffusing protons act as signaling molecules, driving the establishment of exchange networks sustained by the cell-to-cell shuttling of overflow products such as lactate. Despite their fundamental role, the extent and dynamics of such networks is largely unknown due to the lack of methods in single-cell flux analysis. In this study, we provide direct experimental characterization of such exchange networks. We devise a method to quantify single-cell fermentation fluxes over time by integrating high-resolution pH microenvironment sensing via ratiometric nanofibers with constraint-based inverse modeling. We apply our method to cell cultures with mixed populations of cancer cells and fibroblasts. We find that the proton trafficking underlying bulk acidification is strongly heterogeneous, with maximal single-cell fluxes exceeding typical values by up to 3 orders of magnitude. In addition, a crossover in time from a networked phase sustained by densely connected "hubs" (corresponding to cells with high activity) to a sparse phase dominated by isolated dipolar motifs (i.e., by pairwise cell-to-cell exchanges) is uncovered, which parallels the time course of bulk acidification. Our method addresses issues ranging from the homeostatic function of proton exchange to the metabolic coupling of cells with different energetic demands, allowing for real-time noninvasive single-cell metabolic flux analysis.

Outperforming RBM Feature-Extraction Capabilities by "Dreaming" Mechanism.

Inspired by a formal equivalence between the Hopfield model and restricted Boltzmann machines (RBMs), we design a Boltzmann machine, referred to as the dreaming Boltzmann machine (DBM), which achieves better performances than the standard one. The novelty in our model lies in a precise prescription for intralayer connections among hidden neurons whose strengths depend on features correlations. We analyze learning and retrieving capabilities in DBMs, both theoretically and numerically, and compare them to the RBM reference. We find that, in a supervised scenario, the former significantly outperforms the latter. Furthermore, in the unsupervised case, the DBM achieves better performances both in features extraction and representation learning, especially when the network is properly pretrained. Finally, we compare both models in simple classification tasks and find that the DBM again outperforms the RBM reference.

Fully Automated Computational Approach for Precisely Measuring Organelle Acidification with Optical pH Sensors.

pH balance and regulation within organelles are fundamental to cell homeostasis and proliferation. The ability to track pH in cells becomes significantly important to understand these processes in detail. Fluorescent sensors based on micro- and nanoparticles have been applied to measure intracellular pH; however, an accurate methodology to precisely monitor acidification kinetics of organelles in living cells has not been established, limiting the scope of this class of sensors. Here, silica-based fluorescent microparticles were utilized to probe the pH of intracellular organelles in MDA-MB-231 and MCF-7 breast cancer cells. In addition to the robust, ratiometric, trackable, and bioinert pH sensors, we developed a novel dimensionality reduction algorithm to automatically track and screen massive internalization events of pH sensors. We found that the mean acidification time is comparable among the two cell lines (ΔTMCF-7 = 16.3 min; ΔTMDA-MB-231 = 19.5 min); however, MCF-7 cells showed a much broader heterogeneity in comparison to MDA-MB-231 cells. The use of pH sensors and ratiometric imaging of living cells in combination with a novel computational approach allow analysis of thousands of events in a computationally inexpensive and faster way than the standard routes. The reported methodology can potentially be used to monitor pH as well as several other parameters associated with endocytosis.

The emergence of a concept in shallow neural networks.

We consider restricted Boltzmann machine (RBMs) trained over an unstructured dataset made of blurred copies of definite but unavailable "archetypes" and we show that there exists a critical sample size beyond which the RBM can learn archetypes, namely the machine can successfully play as a generative model or as a classifier, according to the operational routine. In general, assessing a critical sample size (possibly in relation to the quality of the dataset) is still an open problem in machine learning. Here, restricting to the random theory, where shallow networks suffice and the "grandmother-cell" scenario is correct, we leverage the formal equivalence between RBMs and Hopfield networks, to obtain a phase diagram for both the neural architectures which highlights regions, in the space of the control parameters (i.e., number of archetypes, number of neurons, size and quality of the training set), where learning can be accomplished. Our investigations are led by analytical methods based on the statistical-mechanics of disordered systems and results are further corroborated by extensive Monte Carlo simulations.

Analysis of temporal correlation in heart rate variability through maximum entropy principle in a minimal pairwise glassy model.

In this work we apply statistical mechanics tools to infer cardiac pathologies over a sample of M patients whose heart rate variability has been recorded via 24 h Holter device and that are divided in different classes according to their clinical status (providing a repository of labelled data). Considering the set of inter-beat interval sequences [Formula: see text], with [Formula: see text], we estimate their probability distribution [Formula: see text] exploiting the maximum entropy principle. By setting constraints on the first and on the second moment we obtain an effective pairwise [Formula: see text] model, whose parameters are shown to depend on the clinical status of the patient. In order to check this framework, we generate synthetic data from our model and we show that their distribution is in excellent agreement with the one obtained from experimental data. Further, our model can be related to a one-dimensional spin-glass with quenched long-range couplings decaying with the spin-spin distance as a power-law. This allows us to speculate that the 1/f noise typical of heart-rate variability may stem from the interplay between the parasympathetic and orthosympathetic systems.

Generalized Guerra's interpolation schemes for dense associative neural networks.

In this work we develop analytical techniques to investigate a broad class of associative neural networks set in the high-storage regime. These techniques translate the original statistical-mechanical problem into an analytical-mechanical one which implies solving a set of partial differential equations, rather than tackling the canonical probabilistic route. We test the method on the classical Hopfield model - where the cost function includes only two-body interactions (i.e., quadratic terms) - and on the "relativistic" Hopfield model - where the (expansion of the) cost function includes p-body (i.e., of degree p) contributions. Under the replica symmetric assumption, we paint the phase diagrams of these models by obtaining the explicit expression of their free energy as a function of the model parameters (i.e., noise level and memory storage). Further, since for non-pairwise models ergodicity breaking is non necessarily a critical phenomenon, we develop a fluctuation analysis and find that criticality is preserved in the relativistic model.

Neural Networks with a Redundant Representation: Detecting the Undetectable.

We consider a three-layer Sejnowski machine and show that features learnt via contrastive divergence have a dual representation as patterns in a dense associative memory of order P=4. The latter is known to be able to Hebbian store an amount of patterns scaling as N^{P-1}, where N denotes the number of constituting binary neurons interacting P wisely. We also prove that, by keeping the dense associative network far from the saturation regime (namely, allowing for a number of patterns scaling only linearly with N, while P>2) such a system is able to perform pattern recognition far below the standard signal-to-noise threshold. In particular, a network with P=4 is able to retrieve information whose intensity is O(1) even in the presence of a noise O(sqrt[N]) in the large N limit. This striking skill stems from a redundancy representation of patterns-which is afforded given the (relatively) low-load information storage-and it contributes to explain the impressive abilities in pattern recognition exhibited by new-generation neural networks. The whole theory is developed rigorously, at the replica symmetric level of approximation, and corroborated by signal-to-noise analysis and Monte Carlo simulations.