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Autonomous Retrieval for Continuous Learning in Associative Memory Networks

The brains faculty to assimilate and retain information, continually updating its memory while limiting the loss of valuable past knowledge, remains largely a mystery. We address this challenge related to continuous learning in the context of associative memory networks, where the sequential storage of correlated patterns typically requires non-local learning rules or external memory systems. Our work demonstrates how incorporating biologically-inspired inhibitory plasticity enables networks to autonomously explore their attractor landscape. The algorithm presented here allows for the autonomous retrieval of stored patterns, enabling the progressive incorporation of correlated memories. This mechanism is reminiscent of memory consolidation during sleep-like states in biological systems. The resulting framework provides insights into how neural circuits might maintain memories through purely local interactions, and takes a step forward towards a more biologically plausible mechanism for continuous learning. Author summaryCatastrophic forgetting - when acquiring new knowledge seriously degrades previously learned information - remains a fundamental challenge in machine learning, affecting systems from simple associative networks to complex language models. One widely studied approach to mitigate forgetting is memory rehearsal, in which prior stored information are periodically replayed, an idea supported by neurophysiological evidence of memory consolidation during sleep. In this work, we show that networks with plastic inhibitory connections can spontaneously recall stored memories without external guidance. This built-in retrieval mechanism allows for the incorporation of new memories while preserving older ones, opening a path toward a biologically inspired solution to the problem of catastrophic forgetting.

neuroscience↗

Control mechanisms for stochastic biochemical systems via computation of reachable sets

Controlling the behaviour of cells by rationally guiding molecular processes is an overarching aim of much of synthetic biology. Molecular processes, however, are notoriously noisy and frequently non-linear. We present an approach to studying the impact of control measures on motifs of molecular interactions, that addresses the problems faced in biological systems: stochasticity, parameter uncertainty, and non-linearity. We show that our reachability analysis formalism can describe the potential behaviour of biological (naturally evolved as well as engineered) systems, and provides a set of bounds on their dynamics at the level of population statistics: for example, we can obtain the possible ranges of means and variances of mRNA and protein expression levels, even in the presence of uncertainty about model parameters.

Systems Biology↗

Information-theoretic analysis of a model of CAR-4-1BB-mediated NFκB activation

Systems biology utilizes computational approaches to examine an array of biological processes, such as cell signaling, metabolomics and pharmacology. This includes mathematical modeling of CAR T cells, a modality of cancer therapy by which genetically engineered immune cells recognize and combat a cancerous target. While successful against hematologic malignancies, CAR T cells have shown limited success against other cancer types. Thus, more research is needed to understand their mechanisms of action and leverage their full potential. In our work, we set out to apply information theory on a mathematical model of cell signaling of CAR-mediated activation following antigen encounter. First, we estimated channel capacity for CAR-4-1BB-mediated NF{kappa}B signal transduction. Next, we evaluated the pathways ability to distinguish contrasting "low" and "high" antigen concentration levels, depending on the amount of intrinsic noise. Finally, we assessed the fidelity by which NF{kappa}B activation reflects the encountered antigen concentration, depending on the prevalence of antigen-positive targets in tumor population. We found that in most scenarios, fold change in the nuclear concentration of NF{kappa}B carries a higher channel capacity for the pathway than NF{kappa}Bs absolute response. Additionally, we found that most errors in transducing the antigen signal through the pathway skew towards underestimating the concentration of encountered antigen. Finally, we found that disabling IKK{beta} deactivation could increase signaling fidelity against targets with antigen-negative cells. Our information-theoretic analysis of signal transduction can provide novel perspectives on biological signaling, as well as enable a more informed path to cell engineering.

systems biology↗

Reverse-Engineering Biological Networks From Large Data Sets

Much of contemporary systems biology owes its success to the abstraction of a network, the idea that diverse kinds of molecular, cellular, and organismal species and interactions can be modeled as relational nodes and edges in a graph of dependencies. Since the advent of high-throughput data acquisition technologies in fields such as genomics, metabolomics, and neuroscience, the automated inference and reconstruction of such interaction networks directly from large sets of activation data, commonly known as reverse-engineering, has become a routine procedure. Whereas early attempts at network reverse-engineering focused predominantly on producing maps of system architectures with minimal predictive modeling, reconstructions now play instrumental roles in answering questions about the statistics and dynamics of the underlying systems they represent. Many of these predictions have clinical relevance, suggesting novel paradigms for drug discovery and disease treatment. While other reviews focus predominantly on the details and effectiveness of individual network inference algorithms, here we examine the emerging field as a whole. We first summarize several key application areas in which inferred networks have made successful predictions. We then outline the two major classes of reverse-engineering methodologies, emphasizing that the type of prediction that one aims to make dictates the algorithms one should employ. We conclude by discussing whether recent breakthroughs justify the computational costs of large-scale reverse-engineering sufficiently to admit it as a mainstay in the quantitative analysis of living systems.

bioinformatics↗

A general temperature dependence for biological nitrogen fixation across systems and levels of organization

Biological nitrogen fixation (BNF) provides half of global new nitrogen annually and plays an important role in biodiversity patterns and global biological carbon uptake processes. BNF rates accelerate with warming, with known implications for ecological functioning, yet the strength of this temperature sensitivity and its context dependence are not well understood. Here we synthesized 70 controlled experimental tests of the acute temperature dependence of nitrogen fixation rates and found that BNF rates accelerate with temperature in a consistent way across levels of biological organization from enzyme to community, mirroring scaling of metabolic temperature dependence across levels of organization for respiration, photosynthesis and methane production. This BNF temperature dependence is also remarkably consistent across biological systems. This analysis shows multiple lines of evidence for general, scalable effects of temperature on nitrogen fixation rates, in line with previous suggestions of a strong enzyme-level constraint. This widespread pattern may be important for understanding effects of warming on coupled carbon-nitrogen systems with ongoing global change.

ecology↗

SLIMP: Supervised learning of metabolite-protein interactions from co-fractionation mass spectrometry data

Metabolite-protein interactions affect and shape diverse cellular processes. Yet, despite advances, approaches for identifying metabolite-protein interactions at a genome-wide scale are lacking. Here we present an approach termed SLIMP that predicts metabolite-protein interactions using supervised machine learning on features engineered from metabolic and proteomic profiles from a co-fractionation mass spectrometry-based technique. By applying SLIMP with gold standards, assembled from public databases, along with metabolic and proteomic data sets from multiple conditions and growth stages we predicted over 9,000 and 20,000 metabolite-protein interactions for Saccharomyces cerevisiae and Arabidopsis thaliana, respectively. Extensive comparative analyses corroborated the quality of the predictions from SLIMP with respect to widely-used performance measures (e.g. F1-score exceeding 0.8). SLIMP predicted novel targets of 2, 3 cyclic nucleotides and dipeptides, which we analysed comparatively between the two organisms. Finally, predicted interactions for the dipeptide Tyr-Asp in Arabidopsis and the dipeptide Ser-Leu in yeast were independently validated, opening the possibility for future applications of supervised machine learning approaches in this area of systems biology.

systems biology↗

MIDOE: Maximally-informed Design of Experiment to infer experimentally inaccessible transcription factors dynamics

1The TGF-{beta}/Smad signaling pathway regulates growth, development, and homeostasis of tissues across the animal kingdom. The pathway is activated when transforming growth factor -{beta} (TGF-{beta}) binds to its cognate transmembrane receptors to activate Smad2 by phosphorylation. The activated phosphor-Smad2 (PSmad2) undergoes a series of biochemical interactions with transcriptional activator Smad4 to form several oligomers, including the transcription factor (PSmad2)2/Smad4, which regulates target gene expression. Quantitative live cell imaging and mathematical modeling have been used to estimate the dynamics of (PSmad2)2/Smad4. However, due to the emergent nature of Smad2-Smad4 interactions, deconvolving the dynamics of the (PSmad2)2/Smad4 is challenging. We show that the Smad model is sloppy, has large parameter uncertainties (O[~]1015), and the eigenvalues of the Fisher Information Matrix span over several decades. As such, well-fit parameter sets generate highly under-constrained predictions. To overcome this, we employ Profile Log-Likelihood to guide maximally informed design of experiments (MIDOE) and infer the dynamics of (PSmad2)2/Smad4. We generate these experiments computationally and validate that MIDOE can optimally constrain model predictions. We demonstrate that such careful analysis would not only improve the predictive power of models in systems biology but also reduce the time and expense of performing non-optimal experiments.

systems biology↗

A novel yeast hybrid modeling framework integrating Boolean and enzyme-constrained networks enables exploration of the interplay between signaling and metabolism

The interplay between nutrient-induced signaling and metabolism plays an important role in maintaining homeostasis and its malfunction has been implicated in many different human diseases such as obesity, type 2 diabetes, cancer and neurological disorders. Therefore, unravelling the role of nutrients as signaling molecules and metabolites as well as their interconnectivity may provide a deeper understanding of how these conditions occur. Both signalling and metabolism have been extensively studied using various systems biology approaches. However, they are mainly studied individually and in addition current models lack both the complexity of the dynamics and the effects of the crosstalk in the signaling system. To gain a better understanding of the interconnectivity between nutrient signaling and metabolism, we developed a hybrid model, combining Boolean model, describing the signalling layer and the enzyme constraint model accounting for metabolism using a regulatory network as a link. The model was capable of reproducing the regulatory effects that are associated with the Crabtree effect and glucose repression. We show that using this methodology one can investigat intrinsically different systems, such as signaling and metabolism, in the same model and gain insight into how the interplay between them can have non-trivial effects by showing a connection between Snf1 signaling and chronological lifespan by the regulation of NDE and NDI usage in respiring conditions. In addition, the model showed that during fermentation, enzyme utilization is the more important factor governing the protein allocation, while in low glucose conditions robustness and control is prioritized. Author summaryElucidating the complex relationship between nutrient-induced signaling and metabolism represents a key in understanding the onset of many different human diseases like obesity, type 3 diabetes, cancer and many neurological disorders. In this work we proposed a hybrid modeling approach, combining Boolean representation of singaling pathways, like Snf11, TORC1 and PKA with the enzyme constrained model of metabolism linking them via the regulatory network. This allowed us to improve individual model predictions and elucidate how single components in the dynamic signaling layer affect the steady-state metabolism. The model has been tested under respiration and fermentation, reveling novel connections and further reproducing the regulatory effects that are associated with the Crabtree effect and glucose repression. Finally, we show a connection between Snf1 signaling and chronological lifespan by the regulation of NDE and NDI usage in respiring conditions.

systems biology↗

Robust Ultrasensitive Transcriptional Switch in Noisy Cellular Environments

Ultrasensitive transcriptional switches enable sharp transitions between on and off states of transcription and are essential for cells to respond to environmental cues precisely. However, conventional switches, relying on direct repressor-DNA binding, are extremely sensitive to noise. Here, we discovered an alternative design combining three indirect transcriptional repression mechanisms, sequestration, blocking, and displacement, to generate a noise-resilient ultrasensitive switch. Although sequestration alone can generate an ultrasensitive switch, it remains sensitive to noise because the unintended transcriptional state induced by noise can persist for long periods. However, by jointly utilizing blocking and displacement, these noise-induced transitions can be rapidly restored to the original transcriptional state. Because this transcriptional switch is effective in noisy cellular contexts, it goes beyond previous synthetic transcriptional switches utilizing direct repression mechanisms, making it particularly valuable for robust synthetic system design. Our findings also provide insights into the evolution of robust ultrasensitive switches in real cells. Specifically, the concurrent use of seemingly redundant indirect repression mechanisms in diverse biological systems appears to be a strategy to achieve noise-resilience of ultrasensitive switches. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=175 SRC="FIGDIR/small/553401v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@e6f1e6org.highwire.dtl.DTLVardef@1369deorg.highwire.dtl.DTLVardef@8b9f19org.highwire.dtl.DTLVardef@7a2fec_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

Harnessing secretory pathway differences between HEK293 and CHO to rescue production of difficult to express proteins

Biologics represent the fastest growing group of therapeutics, but many advanced recombinant protein moieties remain difficult to produce. Here, we identify bottlenecks limiting expression of recombinant human proteins through a systems biology analysis of the transcriptomes of CHO and HEK293 during recombinant overexpression. Surprisingly, one third of the challenging human proteins displayed improved secretion upon host cell swapping from CHO to HEK293. While most components of the secretory machinery showed comparable expression levels in both expression hosts, genes with significant expression variation were identified. Among these, ATF4, SRP9, JUN, PDIA3 and HSPA8 were validated as productivity boosters in CHO. Further, more heavily glycosylated products benefitted more from the elevated activities of the N- and O-glycosyltransferases found in HEK293. Collectively, our results demonstrate the utilization of HEK293 for expression rescue of human proteins and suggest a methodology for identification of secretory pathway components improving recombinant protein yield in HEK293 and CHO.

systems biology↗

Robust parameter estimation and identifiability analysis with Hybrid Neural Ordinary Differential Equations in Computational Biology

Parameter estimation is one of the central problems in computational modeling of biological systems. Typically, scientists must fully specify the mathematical structure of the model, often expressed as a system of ordinary differential equations, to estimate the parameters. This process poses significant challenges due to the necessity for a detailed understanding of the underlying biological mechanisms. In this paper, we present an approach for estimating model parameters and assessing their identifiability in situations where only partial knowledge of the system structure is available. The partially known model is extended into a system of Hybrid Neural Ordinary Differential Equations, which captures the unknown portions of the system using neural networks. Integrating neural networks into the model structure introduces two primary challenges for parameter estimation: the need to globally explore the search space while employing gradient-based optimization, and the assessment of parameter identifiability, which may be hindered by the expressive nature of neural networks. To overcome the first issue, we treat biological parameters as hyperparameters in the extended model, exploring the parameter search space during hyperparameter tuning. The second issue is then addressed by an a posteriori analysis of parameter identifiability, computed by introducing a variant of a well-established approach for mechanistic models. These two components are integrated into an end-to-end pipeline that is thoroughly described in the paper. We assess the effectiveness of the proposed workflow on test cases derived from three different benchmark models. These test cases have been designed to mimic real-world conditions, including the presence of noise in the training data and various levels of data availability for the system variables. Author summaryParameter estimation is a central challenge in modeling biological systems. Typically, scientists calibrate the parameters by aligning model predictions with measured data once the model structure is defined. Our paper introduces a workflow that leverages the integration between mechanistic modeling and machine learning to estimate model parameters when the model structure is not fully known. We focus mainly on analyzing the identifiability of the model parameters, which measures how confident we can be in the parameter estimates given the available experimental data and partial mechanistic understanding of the system. We assessed the effectiveness of our approach in various in silico scenarios. Our workflow represents a first step to adapting traditional methods used in fully mechanistic models to the scenario of hybrid modeling.

systems biology↗

Reverse enGENEering of regulatory networks from Big Data: a guide for a biologist

Omics technologies enable unbiased investigation of biological systems through massively parallel sequence acquisition or molecular measurements, bringing the life sciences into the era of Big Data. A central challenge posed by such omics datasets is how to transform this data into biological knowledge. For example, how to use this data to answer questions such as: which functional pathways are involved in cell differentiation? Which genes should we target to stop cancer? Network analysis is a powerful and general approach to solve this problem consisting of two fundamental stages, network reconstruction and network interrogation. Herein, we provide an overview of network analysis including a step by step guide on how to perform and use this approach to investigate a biological question. In this guide, we also include the software packages that we and others employ for each of the steps of a network analysis workflow.

Systems Biology↗

Beyond Pairwise Connections in Complex Systems: Insights into the Human Multiscale Psychotic Brain

Complex biological systems, like the brain, exhibit intricate multiway and multiscale interactions that drive emergent behaviors. In psychiatry, neural processes extend beyond pairwise connectivity, involving higher-order interactions critical for understanding mental disorders. Conventional brain network studies focus on pairwise links, offering insights into basic connectivity but failing to capture the complexity of neural dysfunction in psychiatric conditions. This study aims to bridge this gap by applying a matrix-based entropy functional to estimate total correlation, a mathematical framework that incorporates multivariate information measures extending beyond pairwise interactions. We apply this framework to fMRI-ICA-derived multiscale brain networks, enabling the investigation of interactions beyond pairwise relationships in the human multiscale brain. Additionally, this approach holds promise for psychiatric studies, providing a new lens through which to explore beyond pairwise brain network interactions. By examining both triple interactions and the latent factors underlying the triadic relationships among intrinsic brain connectivity networks through tensor decomposition, our study presents a novel approach to understanding higher-order brain dynamics. This framework not only enhances our understanding of complex brain functions but also offers new opportunities for investigating pathophysiology, potentially informing more targeted diagnostic and therapeutic strategies. Moreover, the methodology of analyzing multiway interactions beyond pairwise connections can be applied to any signal analysis. In this study, we specifically explore its application to neural signals, demonstrating its power in uncovering complex multiway interaction patterns of brain activity, which provide a window to explore connectivity beyond pairwise interactions in the multiscale functionality of the brain.

neuroscience↗

A Framework for Collective Behavior in Plant Inspired Growth-Driven Systems, Based on Kinematics of Allotropism

A variety of biological systems are not motile, but sessile in nature, relying on growth as the main driver of their movement. Groups of such growing organisms can form complex structures, such as the functional architecture of growing axons, or the adaptive structure of plant root systems. These processes are not yet understood, however the decentralized growth dynamics bear similarities to the collective behavior observed in groups of motile organisms, such as flocks of birds or schools of fish. Equivalent growth mechanisms make these systems amenable to a theoretical framework inspired by tropic responses of plants, where growth is considered implicitly as the driver of the observed bending towards a stimulus. We introduce two new concepts related to plant tropisms: point tropism, the response of a plant to a nearby point signal source, and allotropism, the growth-driven response of plant organs to neighboring plants. We first analytically and numerically investigate the 2D dynamics of single organs responding to point signals fixed in space. Building on this we study pairs of organs interacting via allotropism, i.e.each organ senses signals emitted at the tip of their neighbor and responds accordingly. In the case of local sensing we find a rich phase space. We describe the different phases, as well as the sharp transitions between them. We also find that the form of the phase space depends on initial conditions. This work sets the stage towards a theoretical framework for the investigation and understanding of systems of interacting growth-driven individuals.

biophysics↗

The PNt-Methodology: a top-down network modelling approach to estimate dose-and time-dependent cell responses to complex multifactorial environments

BackgroundNetwork models are convenient to represent in a mechanistic way the complexity of cell biological activity. Dynamic simulations of such networks might require approximations of equation parameters through reverse engineering, numerous and costly experimental research, and/or have limited capacity to explore cell responses to chronic, dose-dependent stimulus exposure. Here we present a mechanistic methodology allowing the simulation of interrelated cell responses of multicellular systems to multifactorial stimuli with dose-and time dependent network links. Methodsa mathematical framework to approach systems biology research questions is presented, the Parallel Networks (PN)-Methodology. It consists of a novel concept, where multicellular systems are described as many relatively small feed-forward networks acting in parallel. Each parallel network is calculated through a specifically designed ordinary differential equation (ODE). Through a unique approach to feed the ODE with interrelated parameters, a system of decoupled, analytically resolvable ODE was obtained. ResultsApplied to intervertebral disc multicellular systems, virtual environments of multifactorial stimuli and multiple cell responses simulating daily moving activities, and to microgravity could successfully be created. ConclusionsThe PN-Methodology stands for a one-of-a-kind mathematical methodology to approximate dynamics of complex multicellular systems over long periods of time at low computational costs.

systems biology↗

Blue light sensor-guided opto-modulation for enhanced production of valuable metabolites in microalgae

Light sensing proteins, photoreceptor, coordinate with photosynthetic machinery, influencing both photosynthetic efficiency and several metabolic outcomes. This work deals with bottleneck issue of astaxanthin production from Chlamydomonas reinhardtii. We report a non-genetic, illumination-based strategy for biomanufacturing of astaxanthin under optimised blue light illumination in C. reinhardtii. Notably, first time ever, we identified and report astaxanthin synthesis-associated BGC in C. reinhardtii using plantiSMASH analysis. We discover experimental evidences for phototropin-modulated biosynthetic gene clusters (BGC)-mediated metabolite production in C. reinhardtii. We established that the prolonged exposure to fine-tuned blue light illumination substantially enhances the biomanufacturing of astaxanthin (1.6 times compared to red light) and pigments via the phototropin. It suggests that fine-tuned illumination conditions modulate molecular components in specific metabolite production. We are providing biochemical, genetic, transcriptomic, quantitative proteomics and systems biology evidences for opto-biomanufacturing of bioactive from green lineage via modulation of phototropin network with artificial illumination (without any genetic modification). By integrating data-driven analytics and systems biology-based computational pipeline, we elucidate the functional crosstalk between biosynthetic gene clusters with the phototropin and carotenoid metabolism synthesis pathway in the green lineage (terrestrial alga and higher plants). Thus, highlighting a new opto-biotechnology approach in metabolite production from various phototrophic organisms. These results establish a new avenue for opto-biomanufacturing strategies to generate bioactive molecules from microorganisms and other green lineages simply by illumination. Highlights O_LIOpto-biomanufacturing of astaxanthin in C. reinhardtii is achieved simply by illumination. C_LIO_LIBiosynthetic gene clusters of metabolite production are also controlled by light. C_LIO_LIPhotoreceptor-based opto-biomanufacturing of valuable bioactives is established. C_LIO_LIOpto-biomanufacturing opens avenues for bioactive production in various organisms. C_LI

biochemistry↗

Robust latent-variable interpretation of in vivo regression models by nested resampling

Simple multilinear methods, such as partial least squares regression (PLSR), are effective at interrelating dynamic, multivariate datasets of cell-molecular biology through high-dimensional arrays. However, data collected in vivo are more difficult, because animal-to-animal variability is often high, and each time-point measured is usually a terminal endpoint for that animal. Observations are further complicated by the nesting of cells within tissues or tissue sections, which themselves are nested within animals. Here, we introduce principled resampling strategies that preserve the tissue-animal hierarchy of individual replicates and compute the uncertainty of multidimensional decompositions applied to global averages. Using molecular-phenotypic data from the mouse aorta and colon, we find that interpretation of decomposed latent variables (LVs) changes when PLSR models are resampled. Lagging LVs, which statistically improve global-average models, are unstable in resampled iterations that preserve nesting relationships, arguing that these LVs should not be mined for biological insight. Interestingly, resampling is less discriminatory for multidimensional regressions of in vitro data, suggesting it is unnecessary when replicate-to-replicate variance is low. Our work illustrates the challenges and opportunities in translating systems-biology approaches from cultured cells to living organisms. Nested resampling adds a straightforward quality-control step aiding the interpretability of in vivo regression models.

systems biology↗

A Comparison of Weighted Stochastic Simulation Methods

1Rare events are of particular interest in biology because rare biochemical events may be catastrophic to a biological system. To estimate the probability of rare events, several weighted stochastic simulation methods have been developed. Unfortunately, the robustness of these methods is questionable. Here, an analysis of weighted stochastic simulation methods is presented. The methods considered here fail to accomplish the task of rare event simulation, in general, suggesting that new methods are necessary to adequately study rare biological events.

systems biology↗