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Maria Rodriguez Martinez

Publications and source records attributed to Maria Rodriguez Martinez.

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AI Developments for T and B Cell Receptor Modeling and Therapeutic Design

Artificial intelligence (AI) is accelerating progress in modeling T and B cell receptors by enabling predictive and generative frameworks grounded in sequence data and immune context. This chapter surveys recent advances in the use of protein language models, machine learning, and multimodal integration for immune receptor modeling. We highlight emerging strategies to leverage single-cell and repertoire-scale datasets, and optimize immune receptor candidates for therapeutic design. These developments point toward a new generation of data-efficient, generalizable, and clinically relevant models that better capture the diversity and complexity of adaptive immunity.

q-bio.BM

Aligned Diffusion Schrödinger Bridges

Diffusion Schrödinger bridges (DSB) have recently emerged as a powerful framework for recovering stochastic dynamics via their marginal observations at different time points. Despite numerous successful applications, existing algorithms for solving DSBs have so far failed to utilize the structure of aligned data, which naturally arises in many biological phenomena. In this paper, we propose a novel algorithmic framework that, for the first time, solves DSBs while respecting the data alignment. Our approach hinges on a combination of two decades-old ideas: The classical Schrödinger bridge theory and Doob's $h$-transform. Compared to prior methods, our approach leads to a simpler training procedure with lower variance, which we further augment with principled regularization schemes. This ultimately leads to sizeable improvements across experiments on synthetic and real data, including the tasks of predicting conformational changes in proteins and temporal evolution of cellular differentiation processes.

cs.LG

DockGame: Cooperative Games for Multimeric Rigid Protein Docking

Protein interactions and assembly formation are fundamental to most biological processes. Predicting the assembly structure from constituent proteins -- referred to as the protein docking task -- is thus a crucial step in protein design applications. Most traditional and deep learning methods for docking have focused mainly on binary docking, following either a search-based, regression-based, or generative modeling paradigm. In this paper, we focus on the less-studied multimeric (i.e., two or more proteins) docking problem. We introduce DockGame, a novel game-theoretic framework for docking -- we view protein docking as a cooperative game between proteins, where the final assembly structure(s) constitute stable equilibria w.r.t. the underlying game potential. Since we do not have access to the true potential, we consider two approaches - i) learning a surrogate game potential guided by physics-based energy functions and computing equilibria by simultaneous gradient updates, and ii) sampling from the Gibbs distribution of the true potential by learning a diffusion generative model over the action spaces (rotations and translations) of all proteins. Empirically, on the Docking Benchmark 5.5 (DB5.5) dataset, DockGame has much faster runtimes than traditional docking methods, can generate multiple plausible assembly structures, and achieves comparable performance to existing binary docking baselines, despite solving the harder task of coordinating multiple protein chains.

cs.LG

Adaptive Conformal Regression with Jackknife+ Rescaled Scores

Conformal regression provides prediction intervals with global coverage guarantees, but often fails to capture local error distributions, leading to non-homogeneous coverage. We address this with a new adaptive method based on rescaling conformal scores with an estimate of local score distribution, inspired by the Jackknife+ method, which enables the use of calibration data in conformal scores without breaking calibration-test exchangeability. Our approach ensures formal global coverage guarantees and is supported by new theoretical results on local coverage, including an a posteriori bound on any calibration score. The strength of our approach lies in achieving local coverage without sacrificing calibration set size, improving the applicability of conformal prediction intervals in various settings. As a result, our method provides prediction intervals that outperform previous methods, particularly in the low-data regime, making it especially relevant for real-world applications such as healthcare and biomedical domains where uncertainty needs to be quantified accurately despite low sample data.

cs.LG

Practical and scalable simulations of non-Markovian stochastic processes and temporal networks with individual node properties

Discrete stochastic processes are prevalent in natural systems, with applications in physics, biochemistry, epidemiology, sociology, and finance. While analytic solutions often cannot be derived, existing simulation frameworks can generate stochastic trajectories compatible with the dynamical laws underlying the random phenomena. Still, most simulation algorithms assume the system dynamics are memoryless (Markovian assumption), under which assumption, future occurrences only depend on the system's present state. This enables efficient and exact simulation via the Gillespie algorithm. However, many real-world systems are inherently non-Markovian and exhibit memory effects. Such systems are difficult to study analytically, and current numerical methods are often computationally expensive or limited by strong simplifying assumptions that conflict with empirical data. To address these limitations, we introduce the Rejection-based Gillespie algorithm for non-Markovian Reactions (REGIR), a general and scalable framework for simulating non-Markovian stochastic systems with arbitrary inter-event time distributions. REGIR provides user-defined accuracy while preserving the same asymptotic computational complexity as the classical Gillespie algorithm. We derive a lower bound on REGIR's approximation accuracy and demonstrate its capabilities across three representative classes of non-Markovian systems: (1) reaction channels with delays, (2) stochastic processes driven by individual reactant properties, and (3) temporal networks governed by node activity. In all cases, REGIR accurately captures memory-dependent dynamics and outperforms existing approaches in terms of flexibility and efficiency.

q-bio.QM

It's FLAN time! Summing feature-wise latent representations for interpretability

Interpretability has become a necessary feature for machine learning models deployed in critical scenarios, e.g. legal system, healthcare. In these situations, algorithmic decisions may have (potentially negative) long-lasting effects on the end-user affected by the decision. In many cases, the representational power of deep learning models is not needed, therefore simple and interpretable models (e.g. linear models) should be preferred. However, in high-dimensional and/or complex domains (e.g. computer vision), the universal approximation capabilities of neural networks are required. Inspired by linear models and the Kolmogorov-Arnold representation theorem, we propose a novel class of structurally-constrained neural networks, which we call FLANs (Feature-wise Latent Additive Networks). Crucially, FLANs process each input feature separately, computing for each of them a representation in a common latent space. These feature-wise latent representations are then simply summed, and the aggregated representation is used for prediction. These constraints (which are at the core of the interpretability of linear models) allow a user to estimate the effect of each individual feature independently from the others, enhancing interpretability. In a set of experiments across different domains, we show how without compromising excessively the test performance, the structural constraints proposed in FLANs indeed facilitates the interpretability of deep learning models. We quantitatively compare FLANs interpretability to post-hoc methods using recently introduced metrics, discussing the advantages of natively interpretable models over a post-hoc analysis.

cs.LG

Pre-training Protein Language Models with Label-Agnostic Binding Pairs Enhances Performance in Downstream Tasks

Less than 1% of protein sequences are structurally and functionally annotated. Natural Language Processing (NLP) community has recently embraced self-supervised learning as a powerful approach to learn representations from unlabeled text, in large part due to the attention-based context-aware Transformer models. In this work we present a modification to the RoBERTa model by inputting during pre-training a mixture of binding and non-binding protein sequences (from STRING database). However, the sequence pairs have no label to indicate their binding status, as the model relies solely on Masked Language Modeling (MLM) objective during pre-training. After fine-tuning, such approach surpasses models trained on single protein sequences for protein-protein binding prediction, TCR-epitope binding prediction, cellular-localization and remote homology classification tasks. We suggest that the Transformer's attention mechanism contributes to protein binding site discovery. Furthermore, we compress protein sequences by 64% with the Byte Pair Encoding (BPE) vocabulary consisting of 10K subwords, each around 3-4 amino acids long. Finally, to expand the model input space to even larger proteins and multi-protein assemblies, we pre-train Longformer models that support 2,048 tokens. Further work in token-level classification for secondary structure prediction is needed. Code available at: https://github.com/PaccMann/paccmann_proteomics

q-bio.BM

Network-based Biased Tree Ensembles (NetBiTE) for Drug Sensitivity Prediction and Drug Sensitivity Biomarker Identification in Cancer

We present the Network-based Biased Tree Ensembles (NetBiTE) method for drug sensitivity prediction and drug sensitivity biomarker identification in cancer using a combination of prior knowledge and gene expression data. Our devised method consists of a biased tree ensemble that is built according to a probabilistic bias weight distribution. The bias weight distribution is obtained from the assignment of high weights to the drug targets and propagating the assigned weights over a protein-protein interaction network such as STRING. The propagation of weights, defines neighborhoods of influence around the drug targets and as such simulates the spread of perturbations within the cell, following drug administration. Using a synthetic dataset, we showcase how application of biased tree ensembles (BiTE) results in significant accuracy gains at a much lower computational cost compared to the unbiased random forests (RF) algorithm. We then apply NetBiTE to the Genomics of Drug Sensitivity in Cancer (GDSC) dataset and demonstrate that NetBiTE outperforms RF in predicting IC50 drug sensitivity, only for drugs that target membrane receptor pathways (MRPs): RTK, EGFR and IGFR signaling pathways. We propose based on the NetBiTE results, that for drugs that inhibit MRPs, the expression of target genes prior to drug administration is a biomarker for IC50 drug sensitivity following drug administration. We further verify and reinforce this proposition through control studies on, PI3K/MTOR signaling pathway inhibitors, a drug category that does not target MRPs, and through assignment of dummy targets to MRP inhibiting drugs and investigating the variation in NetBiTE accuracy.

q-bio.QM

Observational Consequences of a Landscape: Epilogue

In this follow-up to our paper from 2005, we briefly discuss the implications of the apparent detection of B modes in the Cosmic Microwave Background for the issues raised in that paper. We argue that under the assumptions of eternal inflation, there is now stronger support for the detectability of a Coleman-De Luccia bubble nucleation event in our past. In particular, the odds that the spatial curvature of the universe is large enough to be detectable by near future experiments are increased.

astro-ph.CO

Constraining Lorentz violations with Gamma Ray Bursts

Gamma ray bursts are excellent candidates to constrain physical models which break Lorentz symmetry. We consider deformed dispersion relations which break the boost invariance and lead to an energy-dependent speed of light. In these models, simultaneously emitted photons from cosmological sources reach Earth with a spectral time delay that depends on the symmetry breaking scale. We estimate the possible bounds which can be obtained by comparing the spectral time delays with the time resolution of available telescopes. We discuss the best strategy to reach the strongest bounds. We compute the probability of detecting bursts that improve the current bounds. The results are encouraging. Depending on the model, it is possible to build a detector that within several years will improve the present limits of 0.015 m_pl.

astro-ph

GRB 051221A and Tests of Lorentz Symmetry

Various approaches to quantum gravity suggest the possibility of violation of Lorentz symmetry at very high energies. In these cases we expect a modification at low energies of the dispersion relation of photons that contains extra powers of the momentum suppressed by a high energy scale. These terms break boost invariance and can be tested even at relatively low energies. We use the light curves of the very bright short Gamma-Ray Burst GRB 051221A and compare the arrival times of photons at different energies with the expected time delay due to a modified dispersion relation. As no time delay was observed, we set a lower bound of 0.0066 E_{pl} \sim 0.66 10^{17} GeV on the scale of Lorentz invariance violation.

astro-ph

Observational Consequences of a Landscape

In this paper we consider the implications of the "landscape" paradigm for the large scale properties of the universe. The most direct implication of a rich landscape is that our local universe was born in a tunnelling event from a neighboring vacuum. This would imply that we live in an open FRW universe with negative spatial curvature. We argue that the "overshoot" problem, which in other settings would make it difficult to achieve slow roll inflation, actually favors such a cosmology. We consider anthropic bounds on the value of the curvature and on the parameters of inflation. When supplemented by statistical arguments these bounds suggest that the number of inflationary efolds is not very much larger than the observed lower bound. Although not statistically favored, the likelihood that the number of efolds is close to the bound set by observations is not negligible. The possible signatures of such a low number of efolds are briefly described.

hep-th