Identifying key driver genes governing biological processes such as development and disease progression remains a challenge. While existing methods can reconstruct cellular trajectories or infer static gene regulatory networks (GRNs), they often fail to quantify time-resolved regulatory effects within specific temporal windows. Here, we present Time-varying Network Driver Estimation (TNDE), a computational framework quantifying dynamic gene driver effects from single-cell snapshot data under a linear Markov assumption. TNDE leverages a shared graph attention encoder to preserve the local topological structure of the data. Furthermore, by incorporating partial optimal transport, TNDE accounts for unmatched cells arising from proliferation or apoptosis, thereby enabling trajectory alignment in non-equilibrium processes. Benchmarking on simulated datasets demonstrates that TNDE outperforms existing baseline methods across diverse complex regulatory scenarios. Applied to mouse erythropoiesis data, TNDE identifies stage-specific driver genes, the functional relevance of which is corroborated by biological validation. TNDE offers an effective quantitative tool for dissecting dynamic regulatory mechanisms underlying complex biological processes.

The escalating demand for personalized AI chatbot interactions, capable of dynamically adapting to user emotional states and real-time requests, has highlighted critical limitations in current development paradigms. Existing methodologies, which rely on baseline programming, custom personalities, and manual response adjustments, often prove difficult to maintain and are susceptible to errors such as hallucinations, erratic outputs, and software bugs. This paper hypothesizes that a framework rooted in human psychological principles, specifically therapeutic modalities, can provide a more robust and sustainable solution than purely technical interventions. Drawing an analogy to the simulated neural networks of AI mirroring the human brain, we propose the application of Dialectical Behavior Therapy (DBT) principles to regulate chatbot responses to diverse user inputs. This research investigates the impact of a DBT-based framework on AI chatbot performance, aiming to ascertain its efficacy in yielding more reliable, safe, and accurate responses, while mitigating the occurrence of hallucinations, erratic behaviors, and other systemic issues.

The notion of homeostasis typically conceptualises biological and artificial systems as maintaining stability by resisting deviations caused by environmental and social perturbations. In contrast, (social) allostasis proposes that these systems can proactively leverage these very perturbations to reconfigure their regulatory parameters in anticipation of environmental demands, aligning with von Foerster's ``order through noise'' principle. This paper formulates a computational model of allostatic and social allostatic regulation that employs biophysiologically inspired signal transducers, analogous to hormones like cortisol and oxytocin, to encode information from both the environment and social interactions, which mediate this dynamic reconfiguration. The models are tested in a small society of ``animats'' across several dynamic environments, using an agent-based model. The results show that allostatic and social allostatic regulation enable agents to leverage environmental and social ``noise'' for adaptive reconfiguration, leading to improved viability compared to purely reactive homeostatic agents. This work offers a novel computational perspective on the principles of social allostasis and their potential for designing more robust, bio-inspired, adaptive systems

Bioprocess mechanistic modeling is essential for advancing intelligent digital twin representation of biomanufacturing, yet challenges persist due to complex intracellular regulation, stochastic system behavior, and limited experimental data. This paper introduces a symbolic and statistical learning framework to identify key regulatory mechanisms and quantify model uncertainty. Bioprocess dynamics is formulated with stochastic differential equations characterizing intrinsic process variability, with a predefined set of candidate regulatory mechanisms constructed from biological knowledge. A Bayesian learning approach is developed, which is based on a joint learning of kinetic parameters and regulatory structure through a formulation of the mixture model. To enhance computational efficiency, a Metropolis-adjusted Langevin algorithm with adjoint sensitivity analysis is developed for posterior exploration. Compared to state-of-the-art Bayesian inference approaches, the proposed framework achieves improved sample efficiency and robust model selection. An empirical study demonstrates its ability to recover missing regulatory mechanisms and improve model fidelity under data-limited conditions.

Natural groups of animals, such as swarms of social insects, exhibit astonishing degrees of task specialization, useful to address complex tasks and to survive. This is supported by phenotypic plasticity: individuals sharing the same genotype that is expressed differently for different classes of individuals, each specializing in one task. In this work, we evolve a swarm of simulated robots with phenotypic plasticity to study the emergence of specialized collective behavior during an emergent perception task. Phenotypic plasticity is realized in the form of heterogeneity of behavior by dividing the genotype into two components, with one different neural network controller associated to each component. The whole genotype, expressing the behavior of the whole group through the two components, is subject to evolution with a single fitness function. We analyse the obtained behaviors and use the insights provided by these results to design an online regulatory mechanism. Our experiments show three main findings: 1) The sub-groups evolve distinct emergent behaviors. 2) The effectiveness of the whole swarm depends on the interaction between the two sub-groups, leading to a more robust performance than with singular sub-group behavior. 3) The online regulatory mechanism enhances overall performance and scalability.

Epigenomic profiling has enabled large-scale identification of regulatory elements, yet we still lack a systematic mapping from any sequence or variant to regulatory activities. We address this challenge with Sei, a framework for integrating human genetics data with sequence information to discover the regulatory basis of traits and diseases. Sei learns a vocabulary of regulatory activities, called sequence classes, using a deep learning model that predicts 21,907 chromatin profiles across >1,300 cell lines and tissues. Sequence classes provide a global classification and quantification of sequence and variant effects based on diverse regulatory activities, such as cell type-specific enhancer functions. These predictions are supported by tissue-specific expression, expression quantitative trait loci and evolutionary constraint data. Furthermore, sequence classes enable characterization of the tissue-specific, regulatory architecture of complex traits and generate mechanistic hypotheses for individual regulatory pathogenic mutations. We provide Sei as a resource to elucidate the regulatory basis of human health and disease. Sei is a new framework for integrating human genetics data with a sequence-based mapping of predicted regulatory activities to elucidate mechanisms contributing to complex traits and diseases.

Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful experimental approach to study cellular heterogeneity. One of the challenges in scRNA-seq data analysis is integrating different types of biological data to consistently recognize discrete biological functions and regulatory mechanisms of cells, such as transcription factor activities and gene regulatory networks in distinct cell populations. We have developed an approach to infer transcription factor activities from scRNA-seq data that leverages existing biological data on transcription factor binding sites. We show that the inferred transcription factor activities for key cell types identify regulatory transcription factors that are known to mechanistically control cell function and cell fate. The BITFAM approach not only identifies biologically meaningful transcription factor activities, but also provides valuable insights into underlying transcription factor regulatory mechanisms.

Unlike most cells in the rest of our body, the DNA (the genome) in each of our brain cells is not the same: it varies from cell to cell, caused by somatic changes. This could explain many mysteries--from the cause of Alzheimer's disease and autism to how our personality develops. But much remains unknown, including when these changes arise, their size and locations, and whether they are random or regulated. DNA technologies used to study these "copy number variations" (CNVs) in single brain cells have been limited to longer DNA sequences--those above one million base pairs. Now, scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have developed new single-cell analysis approaches wedded to machine learning, allowing the detection of CNVs smaller than one million base pairs.

Unlike most cells in the rest of our body, the DNA in each of our brain cells is not the same: it varies from cell to cell, caused by somatic changes. This could explain many mysteries--from the cause of Alzheimer's disease and autism to how our personality develops. But much remains unknown, including when these changes arise, their size and locations and whether they are random or regulated. DNA technologies used to study these "copy number variations" (CNVs) in single brain cells have been limited to longer DNA sequences--those above one million base pairs. Now, scientists at Sanford Burnham Prebys Medical Discovery Institute have developed new single-cell analysis approaches wedded to machine learning, allowing the detection of CNVs smaller than one million base pairs.