Metabolic

In order to understand complex systems such as the human metabolome or human brain, different sensing technologies are used, generating complex data. These datasets are often multiway, i.e., with more than two axes of variation such as a subjects by metabolites by time array. While tensor factorizations have successfully revealed interpretable patterns from such complex data, they have so far been mainly data-driven. On the other hand, there is more to data -- there are computational models (of these systems), which are rich sources of prior information. In this paper, we introduce a knowledge-guided approach that brings together data and computational models by jointly analyzing real data and simulated data (generated using a computational model) using coupled tensor factorizations with linear coupling. Our experiments on real metabolomics measurements demonstrate that guiding the analysis of such noisy data with simulated data improves the pattern discovery performance while also revealing potential discrepancies between data and computational models.

Overlapping peaks and sample-dependent chemical shift variability prevent reliable metabolite recovery from complex biological spectra. This problem is critical in one-dimensional proton (1D 1H) NMR which has become the standard method providing fast acquisition and information-rich spectra in metabolomics and foodomics. This study demonstrates how chemical shifts can be utilised as a strength in 1D 1H NMR, when suitably modeled through the proposed Bayesian Shift-Invariant Non-negative Matrix Factorization (BSI-NMF) procedure. We find that BSI-NMF accurately recovers the underlying chemical signals in 1D 1H NMR spectra missed by existing analyses approaches across simulations, laboratory created datasets, and a large urine dataset obtained from 2439 people across Europe. Our study highlights how shifts in the chemical signatures - until now perceived as a nuisance - can in fact when suitably modelled be instrumental for unique recovery of metabolites. This creates an opportunity to experimentally induce chemical shifts changes to facilitate unique recovery of spectra.

Metabolomics knowledge is distributed across heterogeneous resources and remains difficult to translate into predictive representations. We developed MetaboLLM, a metabolomics-specialized large language model adapted through continual pretraining, supervised fine-tuning, and structured retrieval, together with MetaboLLM-GIN, which converts generated biochemical descriptions into metabolite graphs for patient-level prediction using a graph isomorphism network. Across four backbone families, MetaboLLM outperformed corresponding base and medically adapted models on metabolomics knowledge, relational, and description tasks, and transferred to an external public benchmark. MetaboLLM-GIN achieved the highest AUC for stress hyperglycemia prediction after coronary artery bypass grafting (0.8616) and postmenopausal hormone-regimen classification (0.8123), outperforming conventional models, alternative graph constructions, and graphs generated from unadapted or non-retrieval LLM configurations. Model interpretation further produced biologically meaningful findings in both applications. These results show that domain-specialized language models can organize heterogeneous biochemical knowledge into predictive and interpretable metabolite graph representations.

Learning-based controllers can deliver exoskeleton assistance after training entirely in physics-based simulation, yet few controllers that address human-device co-adaptation have been validated on real users by whole-body metabolic measurement, the standard benchmark for assistive walking. Co-adaptation is challenging: as the device alters joint dynamics, the wearer reorganizes neuromuscular coordination, producing a non-stationary learning problem. Staged Multi-Agent Training (SMAT), a four-stage curriculum that progressively trains a musculoskeletal human actor and a bilateral hip exoskeleton actor, was introduced and shown to reduce simulated hip-muscle activation and provide positive assistance on hardware. This article provides the first physiological validation of SMAT. The policy was deployed on a hip exoskeleton and tested with eight healthy adults, with metabolic cost measured by indirect calorimetry across no-exoskeleton, passive, and active conditions. Active assistance lowered net metabolic rate by 19.7% relative to the passive device (p < 0.001). Biomechanical analysis confirmed predominantly positive hip mechanical power across all subjects (positive-power ratio 0.98), and the policy generalized across walking speeds and terrains. Together, these results show that a single simulation-trained SMAT policy, deployed without subject-specific retraining, delivers a significant metabolic benefit on real users while remaining robust beyond the conditions it was trained on.

Plant biosynthetic gene clusters (BGCs) encode specialized-metabolite pathways, yet curated plant BGC labels remain scarce, hindering supervised discovery at genome scale. Existing plant BGC mining tools are largely signature- and rule-driven and do not fully leverage recent advances in contextual representation learning for modeling long-range domain context and controlling false positives under strong domain shift. We seek an AI-assisted workflow that narrows experimental search space by transferring supervision from well-annotated microbial BGCs to plant genomes. We present PlantBGC, representing genomes as ordered Pfam-domain sequences and learning BGC-likeness with an encoder-only Transformer trained on MIBiG microbial BGCs and adapted to plants via label-free masked language modeling. On microbial benchmarks, PlantBGC achieves token-level AUC = 0.988 (10-fold CV) and 0.979 (leave-class-out). On plants, adaptation improves known-BGC recovery on n = 34 curated loci under strict 100% coverage, increasing recovery from 29.4% to 67.6% and indicating more complete boundaries. GO/KEGG-derived weak supervision reduces proxy primary-like ratio by 48.40% (GO) and 45.20% (KEGG), with consistent per-species reductions (paired Wilcoxon p = 1.53e-5). Compared to plantiSMASH, PlantBGC yields more compact loci on matched regions (median length ratio = 0.278; 93.8% of pairs are shorter).

Computational AMP discovery is often evaluated through AMP/non-AMP recognition, yet follow-up decisions depend on assay-derived evidence such as target-species potency, hemolysis, toxicity, and selectivity. Existing AMP and peptide benchmarks cover binary recognition, multilabel annotation, assay regression, or broader peptide-model comparison, but they do not jointly place AMP recognition, species-conditioned potency, spectrum, safety-facing proxy endpoints, and cross-endpoint behavior within one sequence-homology-controlled protocol. To address this problem, we introduce AMPBench-MT, a provenance-preserving benchmark that standardizes canonical peptide records and organizes them into binary recognition, species-conditioned pMIC regression, and endpoint-specific potency and safety-facing readouts. Across 161 endpoint-specific model evaluations, high binary performance does not reliably indicate assay-endpoint behavior. Frozen protein-language-model embeddings form the leading pMIC error cluster, while graph and classical regressors remain close. Spectrum labels further reveal that PR-oriented metrics can be misleading under scarce observed negatives, whereas low-toxicity, HC50 hemolysis, and selectivity expose smaller but more assay-facing signals. AMPBench-MT shows that AMP evaluation should move beyond recognition leaderboards toward endpoint-aware evidence auditing. Our proposed benchmark is available at https://huggingface.co/datasets/ZihengZhou06/AMPBench-MT.

Predicting the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of small molecules remains a major challenge in drug discovery. Here, we present MEGA-CL, a foundation graph neural network framework for universal molecular ADMET prediction. MEGA-CL integrates self-supervised contrastive learning with a multi-head external attention mechanism and an enhanced message-passing architecture, enabling simultaneous modeling of local chemical substructures and global inter-graph relationships while mitigating over-smoothing effects commonly observed in deep graph networks. Across 13 benchmark datasets and 21 downstream ADMET tasks, MEGA-CL consistently outperforms state-of-the-art baseline models. In particular, the framework demonstrates robust performance on challenging regression tasks, including clearance (CL) and steady-state volume of distribution (VDss), while maintaining strong generalization ability in independent external validation. Clinically relevant predictive accuracy was achieved, with more than 75% of predictions falling within a 3-fold error range. In an external evaluation on 18 novel compounds derived from recently approved FDA drugs, over 50% of human liver microsome clearance (HLMC) predictions were within a 2-fold error range. To further assess its practical applicability, MEGA-CL was prospectively evaluated on three preclinical drug candidates using in vitro hepatic microsomal metabolism assays and CYP450 inhibition assays guided by model predictions. The predicted HLMC values for all candidates were within 2.5-fold of the experimentally measured values, and 73.3% of CYP450 inhibition endpoints (11/15) were correctly classified. These results demonstrate the potential of MEGA-CL as a generalizable framework for accelerating in silico ADMET evaluation and early-stage drug candidate optimization.

Deep learning models can effectively use Rapid Evaporative Ionization Mass Spectrometry (REIMS) data for surgical margin assessment. However, their clinical adoption remains challenging due to limited generalization to operating room conditions. This difficulty arises because models are typically trained on labeled spectra collected from resected tissue samples, while they must operate on noisy, unlabeled data acquired directly during surgery. In addition, the black-box nature of deep learning models makes it difficult to understand and systematically improve their behavior. Concept-based learning offers a promising way to address these challenges by mapping raw measurements to human-understandable concepts. However, supervised concept-based approaches rely on concept annotations, which are difficult to obtain in complex mass spectrometry workflows. We propose Agent-Guided Concept Discovery, a framework that learns meaningful concepts directly from data without requiring predefined concept labels. During training, a reasoning agent refines semantic descriptions of the learned concepts and adaptively adjusts their weight based on diagnostic relevance. These concepts are further grounded using a biochemical knowledge graph to ensure consistency with known metabolic relationships. Across Skin and Breast Cancer datasets, our model improves balanced accuracy and sensitivity over the baseline. In a representative intraoperative case, it shows fewer false positives, indicating better generalization to surgical conditions.

Background: Untargeted LC-MS metabolomics requires a long chain of preprocessing decisions, each with several equally defensible options. Analysts typically commit to one pipeline and report the resulting feature shortlist. How strongly that shortlist depends on choices that were never varied stays invisible. Results: We adapt multiverse analysis to untargeted metabolomics feature selection. We present an auditable, configuration-driven pipeline that (i) applies a ten-stage quality-control filter cascade in which every feature's fate is logged, and (ii) runs the downstream analysis as a multiverse over four contrasting preprocessing philosophies, each combined with four feature-ranking methods under bootstrap stability selection and label-permutation testing. Only features recurring across paths enter a tiered consensus. On a demonstration dataset of five breast-cancer cell lines (30,370 detected features), the four single pipelines individually returned shortlists of 4-20 features whose pairwise agreement was as low as Jaccard = 0.05. The multiverse consensus retained 15 features (>=2/4 paths), of which one recurred across all four, although two paths (sharing normalization and drift-correction methods) dominate the consensus. A pipeline-wide label-permutation test found no false discoveries in 50 null permutations. Conclusions: Reporting only preprocessing-robust features, with a complete kept/dropped audit trail, converts hidden analytical degrees of freedom into an explicit, inspectable output. We discuss scope and limitations, including single-batch design and the need for independent validation.

Designing microbial strains that produce high-value chemicals at commercially viable titers remains a central challenge in metabolic engineering. Existing computational approaches either rely on stoichiometric constraint-based models that cannot learn from experimental data, or apply tabular machine learning to hand-crafted features that discard the relational structure of biological knowledge. We present Canopy, a heterogeneous graph foundation model that integrates ten public and proprietary data sources into a unified knowledge graph (KG) of 6.9M nodes across 13 types and 34 edge types, covering genes, proteins, metabolites, reactions, pathways, strains, and fermentation experiments. Node features are encoded through domain-specific foundation models (ESM-2 for protein sequences, MoLFormer for chemical SMILES, and PubMedBERT for biomedical text), yielding a multi-modal representation within a single graph. We pretrain a Heterogeneous Graph Transformer (HGT) augmented with SignNet positional encodings, Jumping Knowledge aggregation, and virtual nodes using four self-supervised objectives (link prediction, masked node modelling, distance prediction, and contrastive experiment clustering), balanced via learned homoscedastic uncertainty weighting. On the downstream task of fermentation titer prediction, frozen Canopy embeddings achieve $R^{2} = 0.41$ with a lightweight probe, outperforming tabular baselines (best $R^{2} = 0.24$) and homogeneous GNN variants.

Whole-body fluorodeoxyglucose positron emission tomography combined with computed tomography is widely used in cancer care, but manual lesion delineation is slow, subjective, and difficult to scale. We present GLOW-FDG, an open-source artificial intelligence model for whole-body cancer lesion segmentation in fluorodeoxyglucose positron emission tomography and computed tomography. The model was trained on 1,563 scans spanning multiple cancer types and evaluated on 185 external scans from independent institutions. Across breast cancer, nonmetastatic and oligometastatic lung cancer, head and neck cancer, and metastatic melanoma, GLOW-FDG consistently outperformed publicly available benchmark models in lesion detection, while reducing false positives and maintaining strong segmentation accuracy. Quantification of total tumor burden and total lesion glycolysis was robust across cohorts, and performance approached the variability observed between expert radiation oncologists. These results support GLOW-FDG as a generalizable tool for automated cancer segmentation and quantitative imaging biomarker extraction in whole-body imaging.

This paper studies the Metabolic Multi-Agent Optimizer (MMAO) at the framework level rather than at the implementation or benchmark level. The central question is whether the metabolic resource loop of private energy, communal budget, role drift, and lifecycle turnover has a framework-level interpretation beyond narrative metaphor. We introduce a generic MMAO state model that abstracts away domain-specific move operators while retaining the resource bookkeeping that defines the framework. Under mild bounded-gain and bounded-spending assumptions, we establish boundedness and nonnegativity properties for private energy, communal budget, role state, and active population size. We then characterize three endogenous behavioral regimes of the loop: contraction under sustained resource deficit, reinvestment under surplus communal accumulation, and search redistribution under heterogeneous marginal returns across agents or subgroups. The analysis is intentionally conservative. It does not claim global convergence of the full adaptive system, universal superiority over specialist optimizers, or a complete stationary characterization of the resulting process. Instead, it identifies which internal regulation properties are generic consequences of the loop and which remain implementation specific. A compact mechanism-validation package on representative continuous and discrete MMAO realizations provides supporting empirical evidence for this reading, but is not intended to replace a full benchmark study. The resulting contribution is therefore a bounded, regenerative, resource-regulated interpretation of MMAO, rather than a complete proof of all adaptive behaviors of the full algorithm family.

This paper studies whether the Metabolic Multi-Agent Optimizer (MMAO) can act as a credible outer-loop optimizer for classification model selection. We propose MMAO-Cls, a mixed-space realization in which each agent jointly encodes a binary feature mask and classifier hyperparameters, while private energy, communal budget, role drift, and lifecycle turnover are mapped to the accuracy-complexity tradeoff of wrapper learning. The implementation is strengthened by deriving feature-budget adaptation from feature-information priors and by regularizing validation reward with both subset compactness and train-validation overfitting gap. We evaluate MMAO-Cls on seven standard tabular benchmarks with three seeds each and compare it against RandomSearch, GA-lite, PSO-lite, and an endogenous no-sharing ablation. On the aggregate validation objective, MMAO-Cls ranks second ($0.9433$) behind GA-lite ($0.9446$). On held-out test performance, it reaches mean score $0.8882$, improving over RandomSearch ($0.8808$) and GA-lite ($0.8857$), remaining close to PSO-lite ($0.8874$) and the no-sharing ablation ($0.8900$), while using the most compact mean held-out feature subset among all compared methods (feature ratio $0.4881$). Pairwise tests show that these margins are not yet statistically significant. The resulting claim is therefore conservative: MMAO-Cls supports classification applicability and compact mixed-space search more clearly than it isolates communal sharing as a decisive standalone advantage.

This paper studies whether the Metabolic Multi-Agent Optimizer (MMAO) can be credibly derived into a dynamic-optimization method without replacing its core metabolic control loop by external adaptation modules. The proposed MMAO-Dyn maps private energy, communal budget, role drift, success feedback, and lifecycle turnover to a nonstationary setting in which environmental changes repeatedly invalidate previously useful local structure. We evaluate MMAO-Dyn on an 18-scenario synthetic dynamic continuous benchmark matrix covering shifted sphere, shifted Ackley, and shifted Rastrigin landscapes at $10D$, $20D$, and $30D$, with two change severities and 12 seeds per scenario. The comparison layer includes a generic MMAO variant without dynamic derivation, dynamic random search, dynamic PSO-lite, dynamic DE-lite, and three endogenous ablations. Across the full 216-run matrix, MMAO-Dyn attains mean offline error $28.07$, improving over Generic-MMAO ($29.36$), Dynamic-PSO-lite ($34.65$), Dynamic-DE-lite ($67.09$), and Dynamic-RandomSearch ($111.37$). The gains are clearest in aggregate robustness on sphere and Rastrigin families and in 10-step post-change recovery relative to the generic backbone, whereas the seed-aligned comparison with Dynamic-PSO-lite remains unfavorable in win-loss count and the \texttt{NoMemoryRefresh} ablation stays very close to the full method. We therefore position MMAO-Dyn as a credible family-expansion result for MMAO: the metabolic loop can generate meaningful dynamic behavior, but the strongest current value lies in recovery-oriented resource redistribution rather than in universal dominance or in a fully optimized submechanism design.

This paper evaluates the Metabolic Multi-Agent Optimizer (MMAO) under a stricter empirical protocol rather than reintroducing the framework itself. The study asks whether MMAO's closed-loop resource-allocation principle remains credible under broader, more standard, and more explicitly budget-controlled continuous and discrete benchmarks. The main completed matrix covers eight CEC2017 functions at 10D and 30D with 20 seeds each, and five TSPLIB instances with 20 seeds each, together with stronger reproducible baselines including PSO-lite, ES-lite, and an iterated-greedy 2-opt route baseline. We further add trajectory-level diagnostics for communal budget, success rate, role evolution, and population turnover, plus an auxiliary OR-Library multiple-knapsack slice to extend the discrete evidence beyond routing. Under this protocol, MMAO clearly outperforms the external baseline set on the continuous side and on the TSPLIB side, while the ablation variants remain much closer to the full method than the external baselines are. We therefore position MMAO as a benchmark-backed cross-domain adaptive framework whose most clearly validated value is endogenous resource redistribution under evidence pressure, while also noting that the strongest remaining gap is not basic workability but sharper mechanism isolation and broader competition-grade comparison.

This paper presents the Metabolic Multi-Agent Optimizer (MMAO) as an adaptive metaheuristic built around endogenous resource circulation. The central premise is that search intensity, exploration--exploitation balance, and lifecycle turnover should be induced by a shared metabolic controller rather than by separately attached schedules. We formulate MMAO through bounded private energy, a communal budget, normalized reward, continuous role adaptation, and resource-financed branching and pruning. The method is then instantiated in both continuous and discrete domains and evaluated on a matched small-scale suite including Sphere, Rastrigin, a synthetic Euclidean TSP, and two TSPLIB instances. The results show a consistent pattern: the same metabolic loop remains workable across domains, the discrete realization remains relatively stable under a compact design, and continuous refinement quality is the main cost of keeping the method lean. Taken together, these findings position MMAO as a coherent framework for adaptive heuristic design rather than a loose collection of operators.

Positron Emission Tomography (PET) reveals brain metabolism and is clinically central to neurodegenerative disease assessment, yet existing 3D brain foundation models treat PET as generic volumetric data, missing the structured regional metabolic information that distinguishes it from structural neuroimaging. To address these limitations, we propose ReMAP-PET, a framework that moves beyond visual encoding by supervising a partially-tuned MedicalNet 3D ResNet-50 with brain regional standardized uptake value ratio (SUVR) profiles through joint regression and contrastive objectives, enabling the encoder to learn the metabolic semantics underlying PET modality. On 1015 paired PET--SUVR samples, ReMAP-PET achieves 0.070 SUVR MAE and 77.8% PET SUVR Recall@1, substantially outperforming five frozen pretrained baselines. We further connect the metabolic embedding to clinical language via contrastive alignment with frozen BioClinicalBERT and demonstrate end-to-end PET-to-report generation through SUVR-constrained verbalization. Linear probing on diagnostic classification and cognitive regression tasks confirms that the embeddings retain clinically relevant information without task-specific fine-tuning. Our results show that grounding PET encoders in regional metabolic semantics -- rather than treating PET as generic volumetric data -- yields representations that are structured, interpretable, and language-compatible, pointing to a new direction for metabolic-aware PET understanding.

Traditional meta-heuristics often rely on fixed population sizes, manually chosen search scales, and externally attached parameter-control modules. This paper presents the \textit{Metabolic Multi-Agent Optimizer} (MMAO), a cross-domain optimization framework in which adaptation is derived endogenously from a private-public metabolic resource loop. Each agent carries internal energy, a continuous role state, motion or structural memory, and local search history, while the population shares a communal resource pool. Fitness improvements are converted into normalized metabolic gains through a robust progress scale and a recent success statistic; the same closed loop then regulates sensing intensity, search amplitude, role drift, branching, pruning, respawning, and elite reinvestment. In the continuous setting, MMAO uses energy-regulated symmetric zero-order probing and role-interpolated motion. In the discrete setting, the same control law is instantiated through structural sensing, local route improvement, guided perturbation, and energy-weighted edge reuse. The paper combines an implementation-faithful formulation with a reproducible experimental study on a CEC2017 subset (10D/30D, 20 seeds) and five TSPLIB instances (100 discrete runs in total). The current evidence supports MMAO primarily as a parameter-light, self-calibrating optimization framework whose main validated originality lies in metabolically endogenous resource allocation across heterogeneous search behaviors, rather than as a universally superior optimizer.

Graph neural networks (GNNs) applied to drug-drug interaction (DDI) prediction rely exclusively on molecular structure encoded as SMILES-derived graphs. Prior work in this series demonstrated that model performance is bounded by the structural information content of training labels -- an Information Ceiling -- that architectural refinements alone cannot overcome. The present study investigates whether pharmacogenomic prior knowledge from the PharmGKB database partially closes this ceiling by providing metabolic pathway context that is independent of, and complementary to, molecular structure. Cytochrome P450 (CYP) enzyme substrate, inhibitor, and inducer annotations for four clinically relevant isoforms (CYP2D6, CYP3A4, CYP2C19, CYP2C9) are extracted and incorporated as a 12-dimensional feature vector concatenated to the molecular embedding prior to interaction prediction. Experiments are conducted under both pair-level and drug-level data splits to quantify generalization to unseen drugs. Results indicate that knowledge graph (KG) augmentation substantially improves DDI type classification under pair-level split conditions (F1-macro: 0.532 vs. 0.241 baseline), while binary interaction detection and drug-level generalization remain bounded by the Information Ceiling (AUC inflation: 0.224 vs. 0.250 baseline). Mechanistic validation on strictly held-out compounds confirms that augmentation preferentially improves CYP2C9-mediated interaction prediction, with probabilities increasing from 0.033-0.117 (baseline) to 0.560-0.586 (KG-augmented). An extension to single-molecule toxicity prediction on the Tox21 benchmark confirms that the effect is contingent on pharmacogenomic annotation coverage. These findings motivate the multimodal framework proposed for the subsequent study in this series.

Untargeted liquid chromatography-high-resolution mass spectrometry (LC-HRMS) detects thousands of molecular features per sample, yet only 2-20% receive confident structural annotations. A root cause of this "dark metabolome" is that tandem MS/MS acquisition is reactive: instruments select precursors only after ions appear, blind to what elutes next. We reframe chromatographic elution as an autoregressive sequence prediction task. Because reversed-phase elution order is governed by hydrophobicity, successive features form a physically constrained sequence, like tokens in language. We discretize the mass-to-charge (m/z) axis into 110 bins and train long short-term memory (LSTM) and Transformer models to predict the next eluting m/z bin from five annotation-free per-token features: m/z bin, mass defect, retention-time gap, polarity, and intensity rank. Trained on 15,242 features from four clinical lipidomics cohorts (342 plasma samples; SCIEX TripleTOF 6600+, Waters CSH C18), the LSTM reaches 98.4% top-1 accuracy (99.99% top-5; mean absolute error 3.6 Da) and the Transformer 98.0%. Ablation shows autoregressive context accounts for 55.5 percentage points while no single feature contributes more than 0.2 pp: the sequential pattern, not molecular properties, drives prediction. Models transfer across instruments sharing the method (r=0.999 on an independent Agilent 6530 dataset) but fail under a different column chemistry (5.1% top-1) or polarity mode (2.6%), confirming method- and mode-specificity. Fine-tuning on as few as two to five quality-control injections recovers held-out accuracy from 2.6% to nearly 50%, so cross-condition deployment needs minimal calibration. These results establish that elution sequences are highly predictable and lay the groundwork for predictive MS/MS acquisition to improve annotation coverage in untargeted metabolomics.

Accurately identifying metabolites i.e. small molecules from mass spectrometry data remains a core challenge in metabolomics, with broad applications in drug discovery, environmental analysis, and clinical research. We address the Molecule Retrieval task, which consists in recovering the chemical structure of a metabolite from its MS/MS spectrum given a set of candidate molecules. While the recent release of benchmark datasets such as MassSpecGym and Spectraverse has considerably accelerated the development of novel machine learning approaches, the complexity of data preprocessing pipelines and the lack of unified implementations make methods and results difficult to reproduce and compare. We make three contributions. First, we propose a unified framework encompassing recent approaches based on representation alignment and contrastive learning. Second, we introduce MSAlign, inspired by multimodal alignment in vision-language models, which learns a shared representation space by aligning two frozen foundation models (DreaMS for mass spectra and ChemBERTa for molecules) through lightweight MLP projections trained with a candidate-based contrastive objective. MSAlign is simple to implement, fast to train and consistently outperforms existing approaches across all benchmarks. Third, we investigate a long-standing evaluation problem: data splitting strategies in molecule retrieval implicitly trade off data leakage against domain shift. We formalize this tension by introducing a quantitative measure of distribution shift, and use it to evaluate splitting strategies in existing benchmarks. All datasets, splits, candidate sets, and a unified implementation of MSAlign and baselines are publicly released to support reproducible research.

Biologically-inspired AI agent frameworks claim reliability benefits through structural guarantees adapted from gene regulatory networks, immune systems, and metabolic control. These claims are rarely tested empirically against simpler alternatives. We present three deep benchmarks: metabolic priority gating, autoinducer-based quorum sensing, and Bayesian stagnation detection, each comparing a biologically-grounded implementation against a naive non-biological alternative and an ablated control, across 1,000 trials per seed and 10 seeds (10M+ data points total).

Optimization over the Stiefel manifold $\mathrm{St}(p,d)$, the set of $p \times d$ column-orthonormal matrices, is fundamental in statistics, machine learning, and scientific computing, yet remains challenging in the presence of non-convex, non-smooth, or black-box objectives. Existing methods largely rely on either convex relaxations or gradient-based Riemannian optimization, limiting applicability in derivative-free and highly multimodal settings. We propose \textsc{BOOOM} (Black-box Optimization Over Orthonormal Manifolds), a general-purpose framework for loss-function-agnostic optimization on $\mathrm{St}(p,d)$. The key idea is a global Givens rotation-based parametrization that maps the manifold to an unconstrained Euclidean angle space while preserving feasibility exactly. Building on this representation, BOOOM employs a structured, parallelizable, derivative-free search based on Recursive Modified Pattern Search, enabling systematic exploration through plane-wise rotations without requiring gradient information and facilitating escape from poor local optima. We establish a unified theoretical framework showing equivalence between angle-space and manifold optimization, transfer of stationarity, and global convergence in probability under mild conditions. Empirical results across diverse problems, including heterogeneous quadratic optimization, low-rank and sparse matrix decomposition, independent component analysis, and orthogonal joint diagonalization, among other widely studied settings, demonstrate strong performance relative to state-of-the-art methods, particularly in non-smooth and highly multimodal regimes. We further illustrate its practical utility through a novel supervised PCA formulation applied to metabolomics data in colorectal cancer.

Tandem mass spectrometry (MS/MS) is central to small molecule identification, but current deep learning systems for spectrum prediction still remain difficult to evaluate and deploy in practice. While novel architectures constantly claim state-of-the-art performance, inconsistent metadata conditioning and entangled preprocessing pipelines hinder fair architectural comparisons. Besides, existing evaluations are often restricted to curated datasets, failing to capture the heterogeneity and cross-domain shifts of real-world metabolomics. Furthermore, current benchmarks lack difficulty-aware diagnostics and leave blind to how models behave under specific compute or data constraints. To address this, we present FlexMS, a modular public-data benchmark framework that standardizes MS/MS prediction across public resources while keeping molecular encoders, metadata conditioning, predictor heads, and downstream retrieval under one protocol. FlexMS establishes a fair evaluation playground which significantly lowers the barrier for integrating new predictive tools. Rather than solely optimizing for average scores, FlexMS augments aggregate accuracy with difficulty-aware diagnostics, providing actionable guidance on model selection across different compute constraints, data scales, and downstream retrieval objectives. Ultimately, FlexMS provides the community with a reproducible standard to identify which algorithmic conclusions are stable and which operating points are most viable in practice.

A fundamental challenge in microbial ecology is determining whether bacteria compete or cooperate in different environmental conditions. With recent advances in genome-scale metabolic models, we are now capable of simulating interactions between thousands of pairs of bacteria in thousands of different environmental settings at a scale infeasible experimentally. These approaches can generate tremendous amounts of data that can be exploited by state-of-the-art machine learning algorithms to uncover the mechanisms driving interactions. Here, we present Friend or Foe, a compendium of 64 tabular environmental datasets, consisting of more than 26M shared environments for more than 10K pairs of bacteria sampled from two of the largest collections of metabolic models. The Friend or Foe datasets are curated for a wide range of machine learning tasks -- supervised, unsupervised, and generative -- to address specific questions underlying bacterial interactions. We benchmarked a selection of the most recent models for each of these tasks and our results indicate that machine learning can be successful in this application to microbial ecology. Going beyond, analyses of the Friend or Foe compendium can shed light on the predictability of bacterial interactions and highlight novel research directions into how bacteria infer and navigate their relationships.

Magnetic resonance spectroscopy (MRS) is a non-invasive technique to measure the metabolic composition of tissues, offering valuable insights into neurological disorders, tumor detection, and other metabolic dysfunctions. However, accurate metabolite quantification is hindered by challenges such as spectral overlap, low signal-to-noise ratio, and various artifacts. Traditional methods like linear-combination modeling are susceptible to ambiguities and commonly only provide a theoretical lower bound on estimation accuracy in the form of the Cramér-Rao bound. This work introduces a Bayesian inference framework using Sylvester normalizing flows (SNFs) to approximate posterior distributions over metabolite concentrations, enhancing quantification reliability. A physics-based decoder incorporates prior knowledge of MRS signal formation, ensuring realistic distribution representations. We validate the method on simulated 7T proton MRS data, demonstrating accurate metabolite quantification, well-calibrated uncertainties, and insights into parameter correlations and multi-modal distributions.