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01.
arXiv (CS.AI) 2026-06-18

Something from Nothing: Data Augmentation for Robust Severity Level Estimation of Dysarthric Speech

arXiv:2603.15988v3 Announce Type: replace-cross Abstract: Dysarthric speech quality assessment (DSQA) is critical for clinical diagnostics and inclusive speech technologies. However, subjective evaluation is costly and difficult to scale, and the scarcity of labeled data limits robust objective modeling. To address this, we propose a three-stage framework that leverages unlabeled dysarthric speech and large-scale typical speech datasets to scale training. A teacher model first generates pseudo-labels for unlabeled samples, followed by weakly supervised pretraining using a label-aware contrastive learning strategy that exposes the model to diverse speakers and acoustic conditions. The pretrained model is then fine-tuned for the downstream DSQA task. Experiments on five unseen datasets spanning multiple etiologies and languages demonstrate the robustness of our approach. Our Whisper-based baseline significantly outperforms SOTA DSQA predictors such as SpICE, and the full framework achieves an average SRCC of 0.761 across unseen test datasets.

02.
arXiv (quant-ph) 2026-06-15

Physics-Informed Variational Quantum Classifier for Phase Detection in Strongly Correlated Matter

arXiv:2606.14489v1 Announce Type: new Abstract: The characterisation of quantum phases in strongly correlated systems is a crucial milestone for the deployment of quantum sensors. In this work, we present a Physics-Informed Variational Quantum Classifier (VQC) designed to detect the topological phase transition between the Fermi polaron quasiparticle and the molecular bound state. Unlike conventional Machine Learning approaches, our quantum architecture is constructed via the Trotterised time-evolution of an effective Hamiltonian, ensuring that the learnable parameters correspond to interpretable physical quantities. We show that the VQC efficiently discovers the optimal interferometric protocol, specifically the evolution time and effective bath interactions required to maximise the visibility of Ramsey fringes, thereby clearly distinguishing the Bose-Einstein Condensate (BEC) and Bardeen-Cooper-Schrieffer (BCS) regimes. Furthermore, we report the validation of this classifier on the QRed superconducting quantum processor (BSC-CNS). Despite the intrinsic hardware noise and decoherence, the VQC preserves the relative ordering of the topological phases. We demonstrate that the physics-informed architecture achieves a linear gate complexity $\mathcal{O}(N)$, bypassing the exponential memory wall of classical simulation and ensuring scalability to many-body regimes.

03.
arXiv (CS.CL) 2026-06-16

AuAu: A Benchmark for Auditing Authoritarian Alignment in Large Language Models

The worldwide surge of authoritarianism, combined with the increasing central role in users' everyday lives, raises the question of to what extent specific models exhibit or promote authoritarian attitudes and characteristics. We introduce AuAu, a comprehensive benchmark that aims to assess the risk of LLMs generating responses with authoritarian tendencies. This benchmark combines three evaluation approaches: (i) psychometric questions from an extensive pool of 15 human validated instruments; (ii) contextual behavior vignettes probing intended actions in concrete situations; and (iii) responses to realistic user prompts. Unlike prior work, AuAu evaluates not only a general closeness towards authoritarianism but also the established sub-concepts Authoritarian Aggression, Authoritarian Submission, and Conventionalism. Evaluating 17 models from China, the EU, Russia, and the USA, we find that all tested models exhibit substantial authoritarian response rates under the psychometric evaluation, though rates drop significantly in increasingly more realistic downstream task. We further find that an authoritarian system prompt easily manipulates 15 out of 17 models to promote increased authoritarianism. Our results underscore the need for continued, systematic auditing of LLM-based AI systems to detect and ultimately mitigate undesired authoritarian tendencies in generated output. Our code and data are available at: https://github.com/andreaseinwiller/AuAu

04.
arXiv (quant-ph) 2026-06-11

Linear Combination of Hamiltonian Simulation with Commutator Scaling

arXiv:2606.11475v1 Announce Type: new Abstract: The Linear Combination of Hamiltonian Simulation (LCHS) framework simulates dissipative linear dynamics by representing time evolution as an integral over unitary operators, which is discretized by quadrature and implemented via Hamiltonian simulation. While existing analyses achieve near-optimal scaling in time and precision using norm-based quantities of the dissipative generator, we show that implementing the Hamiltonian simulation steps with Multi-Product Formulas (MPFs) yields commutator-sensitive error and complexity bounds. We demonstrate that the quadrature rule affects not only discretization error but also commutator structure and query complexity. This dependence is quantified through post-quadrature analysis for abstract MPF error profiles and for general time-independent and local Hamiltonians using known commutator-sensitive MPF error estimates. We compare uniform trapezoidal and free-scale sinh–sinh quadrature, showing improved quadrature-cardinality scaling for the latter, and illustrate the framework with applications to fractional diffusion, advection–diffusion, and open quantum systems.

05.
arXiv (CS.CL) 2026-06-19

Light-weight Pronunciation Assessment via Discrete Speech Token Surprisal

Training automated pronunciation assessment often relies on labeled learner errors or non-native corpora that are costly to collect. We propose a lightweight framework trained only on native speech resources, operating unsupervised or lightly calibrated with a small set of scored utterances. At inference, learner speech is discretized with an SSL encoder and a K-means codebook. A token language model trained on native sequences computes surprisal where higher surprisal indicates phonotactic deviation. We add a transcript-guided Text2DUnit–DTW module that predicts native token sequences from reference text and aligns them to acoustic tokens to derive error-sensitive features. Surprisal and alignment features are fused via simple regression. On SpeechOcean762, PCC improves from 0.60 to 0.66 with transcript guidance, near supervised baselines. Cross-dataset evaluation on L2-ARCTIC shows consistent gains.

06.
arXiv (CS.LG) 2026-06-18

Measurement noise limits the advantage of nonlinear models over linear models in biomedical prediction

arXiv:2606.18420v1 Announce Type: new Abstract: On biomedical tabular data, flexible models such as deep networks, gradient-boosted trees, and kernel methods are repeatedly matched or beaten by linear and logistic regression given the same features. The usual reaction is to treat this as a model-side shortfall, to be fixed with more data, a better architecture, or tuning, on the assumption that the nonlinear structure is there and the model has failed to capture it. We argue that these fixes cannot help when the binding limit is the measurement rather than the model, as it frequently is in biomedicine. Additive noise blurs the population-optimal predictor, and because blurring removes a function's fine, rapidly varying detail before its broad shape, it erases nonlinear structure faster than linear structure. A degree-$k$ interaction is attenuated by the $k$-th power of feature reliability, while the linear part is attenuated only once. At the reliabilities typical of biomedical measurement, the nonlinear advantage can vanish even when the underlying biology is strongly nonlinear, and what the noise removes cannot be recovered by a larger cohort or a more flexible model, only by better measurement. The nonlinearity is hidden, not absent, and a tie between linear and flexible models is not by itself a verdict on the biology. These pieces are classical, drawn from measurement-error statistics, psychometrics, and Gaussian analysis, and we assemble them into an exact excess-risk identity. Measurement reliability is one of three conditions, alongside sample size and feature representation, that must align for a flexible model to help, and together they leave only a narrow window that most biomedical tasks fall outside. Across 140 UK Biobank tasks, the gap between flexible and linear models, where it exists, carries the predicted noise signature, and the three conditions can be separated by intervention but not by a benchmark alone.

07.
arXiv (quant-ph) 2026-06-19

Vine Codes: Low-Overhead Quantum LDPC Codes on a Planar Square Grid

arXiv:2606.20263v1 Announce Type: new Abstract: The surface code is a promising route towards large-scale quantum computing, requiring only nearest-neighbour gates amenable to superconducting hardware. However, surface codes incur large qubit overheads. Novel quantum low-density parity check (qLDPC) codes promise to reduce overheads but require long-range connections that are difficult to achieve on superconducting platforms. Here, we introduce "Vine Codes" - qLDPC codes that are implementable on a planar square grid through nearest-neighbour, two-qubit gates native to superconducting platforms (iSWAP and CZ). Our approach generalises "Directional Codes" recently introduced by Gehér et. al. (2025) which are constrained to a torus. In contrast, vine codes have open boundary conditions constructed with the aid of routing qubits. We perform extensive numeric searches and find promising candidate vine codes, e.g. [[121,4,6]], [[221,6,7]], and [[234,9,6]] codes. We verify the circuit distances and show that data and measure qubits required can be reduced by up to ~28% relative to the surface code at a circuit distance of 7. Even including routing qubits, vine codes require fewer total qubits than the surface code (e.g. ~18% reduction at circuit distance 10) and benefits are expected to increase at higher distances. We perform circuit-level noise simulations to demonstrate that under a realistic noise model and at a near-term noise rate of $10^{-3}$, vine codes can perform better than the surface code while using fewer qubits. We give an exhaustive list of all unique vine codes up to stabiliser-weight 9. We additionally introduce "Flip-Vine Codes" which possess single-qubit transversal Clifford gates useful for fault-tolerant logic and magic state cultivation. We furthermore construct examples of generalised open boundaries for vine codes that go beyond the familiar X/Z boundaries of the surface and tile codes.

08.
Nature (Science) 2026-06-10

Whole-genome duplication shaped cell-type evolution in the vertebrate brain

Authors:

The complex brains of vertebrates have more cell types than those of their closest relatives. Whole-genome duplications (WGDs) occurred during early vertebrate evolution1, but it is unclear whether the duplicated genes (ohnologues) facilitated cell-type evolution. Here using brain single-cell transcriptomes from five chordates—human2, mouse3, lizard4, lamprey5 and amphioxus—we report that many cell-type families with conserved core transcription factors in vertebrates do not show one-to-one homology with amphioxus. Moreover, ohnologues, particularly those from the first WGD, were more important than small-scale duplication paralogues for vertebrate cell-type evolution. To explore whether ohnologues are mechanistically important for this process, we predicted ancestral cell-type states and compared them to amphioxus and experimentally investigated macroglia. The findings indicate that ohnologues had a role in early vertebrate cell-type diversification. Moreover, by examining paralogue expression across cell types and species, we show that expression changes were mainly driven by dosage selection and subfunctionalization. We also link ohnologues to cellular diversity at different anatomical and cell-type scales. Our findings demonstrate the importance of WGDs for the evolution of early vertebrate brain complexity and highlight that the resultant ohnologues continued to capacitate cell-type evolution long after they were formed. Analyses of brain single-cell transcriptomes from human, mouse, lizard, lamprey and amphioxus reveal that duplicated genes (ohnologues) played a pivotal part in early vertebrate cell-type diversification.

09.
arXiv (CS.CL) 2026-06-11

Self-Prompting Small Language Models for Privacy-Sensitive Clinical Information Extraction

Clinical named entity recognition from dental progress notes is challenging because documentation is highly unstructured, domain-specific, and often privacy-sensitive. We developed a locally deployable framework that enables small language models to self-generate, verify, refine, and evaluate entity-specific prompts for extracting multiple clinical entities from dental notes. Using 1,200 annotated notes, we evaluated candidate open-weight models with multi-prompt ensemble inference and further adapted selected models using QLoRA-based supervised fine-tuning and direct preference optimization. Model performance varied substantially, highlighting the need for task-specific evaluation rather than reliance on generic benchmarks. Qwen2.5-14B-Instruct achieved the strongest baseline performance. After DPO, Qwen2.5-14B-Instruct and Llama-3.1-8B-Instruct achieved micro/macro F1 scores of 0.864/0.837 and 0.806/0.797, respectively. These findings suggest that automated prompt optimization combined with lightweight preference-based post-training can support scalable clinical information extraction using locally deployed small language models.

10.
arXiv (CS.AI) 2026-06-16

Trust-Region Diffusion Policies for Massively Parallel On-Policy RL

arXiv:2606.15260v1 Announce Type: cross Abstract: Reinforcement learning with massively parallel simulations has become a standard framework for developing robust, deployable policies; however, most existing approaches still rely on simple Gaussian policy parameterizations. Diffusion models provide a more expressive policy class and have shown strong performance on challenging control problems, yet most diffusion-based RL methods are designed for offline or off-policy training. In this work, we ask whether diffusion policies can be trained effectively in the massively parallel, on-policy regime. To this end, we introduce Trust-region Diffusion Policies (TruDi), which enables diffusion policies for on-policy RL with massively parallel simulations. This setting is particularly challenging because the data distribution changes quickly across updates, making stable training with complex policies difficult. TruDi addresses this by integrating a trust-region optimization rule to enforce a KL-divergence constraint over the entire diffusion trajectory. Empirically, we evaluate TruDi on a diverse set of 4 massively parallel RL benchmarks comprising a total of 73 tasks. Across these tasks, TruDi consistently outperforms or is on-par with strong baselines on standard tasks and achieves clear gains on more challenging humanoid control tasks, establishing a strong new baseline for massively parallel on-policy RL.

11.
arXiv (CS.LG) 2026-06-19

BLISS: A Lightweight Bilevel Influence Scoring Method for Data Selection in Language Model Pretraining

arXiv:2510.06048v5 Announce Type: replace Abstract: Effective data selection is essential for pretraining large language models (LLMs), enhancing efficiency and improving generalization to downstream tasks. However, existing approaches often require leveraging external pretrained models, making it difficult to disentangle the effects of data selection from those of the external pretrained models. In addition, they often overlook the long-term impact of selected data if the model is trained to convergence, primarily due to the prohibitive cost of full-scale LLM pretraining. In this paper, we introduce BLISS (BileveL Influence Scoring method for data Selection): a lightweight data selection method that operates entirely from scratch, without relying on any external pretrained oracle models, while explicitly accounting for the long-term impact of selected data. BLISS leverages a small proxy model as a surrogate for the LLM and employs a score model to estimate the long-term influence of training samples if the proxy model is trained to convergence. We formulate data selection as a bilevel optimization problem, where the upper-level objective optimizes the score model to assign importance weights to training samples, ensuring that minimizing the lower-level objective (i.e., training the proxy model over the weighted training loss until convergence) leads to best validation performance. Once optimized, the trained score model predicts influence scores for the dataset, enabling efficient selection of high-quality samples for LLM pretraining. We validate BLISS by pretraining 410M/1B/2.8B Pythia and LLaMA-0.5B models on selected subsets of the C4 dataset. Notably, under the 1B model setting, BLISS achieves $1.7\times$ speedup in reaching the same performance as the state-of-the-art method, demonstrating superior performance across multiple downstream tasks.

12.
arXiv (CS.LG) 2026-06-16

A Validated LBM Dataset and Pipeline for Surrogate Modeling of Turbulent 3D Obstructed Channel Flows

arXiv:2606.16765v1 Announce Type: new Abstract: Evaluating neural operators for 3D turbulent flow requires validated datasets with physical benchmarks. We present a reproducible pipeline generating training data for 3D channel flows around generated geometries at Re=1,000-10,000. Our lattice Boltzmann solver with cumulant collision operators is rigorously verified against experimental measurements (Strouhal number, drag coefficients, turbulent fluctuations) with comprehensive grid convergence studies at resolution 1024x512x512. Building upon an established framework, this validated pipeline enables standardized surrogate model comparison. We outline planned systematic evaluation of Fourier Neural Operator and U-Net variants on forecasting, super-resolution, and error correction tasks, using physics-informed metrics to assess turbulent energy cascade representation. Future work will compare computational efficiency between numerical solvers and neural surrogates, exploring practical application. We seek community feedback on our validation approach, planned benchmark methodology, and evaluation priorities for neural operators in turbulent flows.

13.
arXiv (CS.CV) 2026-06-11

Detecting AI-Generated Content on Social Media with Multi-modal Language Models

Generative AI has enabled the creation of photorealistic images and videos that are increasingly disseminated on social media, often used for spam, misinformation, manipulation, and fraud. Existing AI-generated content (AIGC) detection methods face challenges including poor generalization to new generation models, reliance on single modalities, and lack of interpretable explanations. We present our pipeline that mitigates these issues by continuously curating diverse multi-modal social media data and training a compact vision-language model for detection and explanation. Our model achieves state-of-the-art detection performance on public benchmarks and demonstrates robust detection and explanation capabilities on internal social media datasets across multiple platforms. We deployed our model for post recommendation on social media platforms and observed positive downstream impacts on user engagement, demonstrating that it is feasible to perform effective AIGC detection in dynamic, real-world social media environments.

14.
arXiv (CS.CV) 2026-06-11

Anatomically Conditioned Recurrent Refinement for Topology-Aware Circle of Willis Segmentation

Segmenting the Circle of Willis (CoW) from Magnetic Resonance Angiography (MRA) is challenging due to complex topology and thin vascular structures that are prone to fragmentation. Standard Convolutional Neural Networks (CNNs) often fail to capture these topological constraints, resulting in "broken vessel" artifacts. To address this, we propose the Anatomically Conditioned Recurrent Refinement U-Net (AC2RUNet). Our architecture decouples segmentation into two streams: a Static Stream that extracts invariant anatomical features and a lightweight Dynamic Stream that iteratively refines topological errors over time. We further introduce a dynamic curriculum learning strategy that transitions from high-recall geometric supervision to topology-aware constraints. Validated on the TopCoW dataset, AC2RUNet substantially reduces Hausdorff Distance (4.72 mm vs 9.17 mm) and Betti number errors (0.19 vs 0.40), improving topological connectivity over the nnU-Net baseline while maintaining comparable volumetric Dice.

15.
arXiv (CS.LG) 2026-06-18

MetaboNet-Bench: A Multi-modal Benchmark for Glucose Forecasting in Type 1 Diabetes

arXiv:2606.18640v1 Announce Type: new Abstract: Glucose forecasting algorithms are an important aspect of glycemic control management in type 1 diabetes. So far, the research community has developed numerous algorithms and models for forecasting. However, it is well-recognized that the lack of standardized model performance evaluation benchmarks makes fair comparison difficult and hinders further innovation, and thus benchmark standardization is in urgent need. Furthermore, many published glucose forecasting algorithms are limited to CGM data alone, ignoring other multimodal signals such as insulin dosing and carbohydrate intake. Here, we introduce MetaboNet-Bench, a benchmark for multimodal glucose forecasting for patients with type 1 diabetes that provides an extensible open-source evaluation framework for comparison of glucose forecasting algorithms that leverage glucose, insulin, and carbohydrate data. We then demonstrate its utility by benchmarking several recently published glucose forecasting models and a custom multimodal time-series model, representing different model architectures. The results show that the benefit of adding data modalities is conditioned on the complexity of the model and that incorporating more clinical metrics helps identify meaningful gaps to fill for future research.

16.
bioRxiv (Bioinfo) 2026-06-13

MoE-Bind: Guiding De Novo Protein Binder Generation with Sparse Experts

Authors:

De novo protein binder design has been dominated by structure-based pipelines that require known three-dimensional target conformations and consume substantial compute and generation time per design, limiting their throughput and accessibility for routine large-scale binder exploration. Sequence-only generative models promise a faster and lighter alternative, yet existing systems remain uniformly dense and frequently reintroduce structural computation at inference, undermining the core advantages they were intended to deliver. Across the broader language modelling community, transformers have meanwhile transitioned from fully dense designs to sparse Mixture-of-Experts architectures that decouple capacity from per-token compute, a shift that has yet to reach sequence-only protein binder generation. We present MoE-Bind, an autoregressive protein binder generator that, for the first time in this domain, combines Multi-head Latent Attention with a sparse Mixture-of-Experts feed-forward network and is evaluated under two independent structure predictors, Boltz-2 and AlphaFold2-Multimer. Despite activating less than half the per-token parameters of compute-matched dense baselines, MoE-Bind matches or exceeds them on full-length receptor-conditioned binder generation on a leakage-free Docking Benchmark 5.0 evaluation, transfers without peptide-specific training to short-peptide design, and reduces training and inference compute by a large margin. Routing analysis on generated binders reveals interpretable expert specialization at both the individual amino acid and biochemical group level, a structured expert-token alignment not previously reported for natural-language MoE models. These results show that sparse architectural design, rather than scale, can deliver fast, structure-free, and interpretable protein binder generation.

17.
arXiv (CS.LG) 2026-06-12

LongSpike: Fractional Order Spiking State Space Models for Efficient Long Sequence Learning

arXiv:2606.12895v1 Announce Type: new Abstract: Spiking Neural Networks (SNNs) are well-regarded for their biological plausibility and energy efficiency in processing sequential data. However, dominant SNN architectures typically rely on first-order Ordinary Differential Equations (ODEs) to govern neuronal state transitions. This first-order assumption imposes a "memoryless" bottleneck, limiting the model's capacity to capture the complex, long-range dependencies inherent in long-sequence tasks. In this work, we propose LongSpike, a novel SNN framework that integrates fractional-order State-Space Modeling, or f-SSM, from control theory into the spiking domain. By extending traditional integer-order SSMs to the fractional-calculus regime, LongSpike enables the hierarchical integration of neuronal dynamics with long-memory kernels. To mitigate the computational overhead and parallelization challenges typically associated with fractional operators, we leverage a state-space formulation that supports efficient, parallel training. Empirical evaluations on challenging benchmarks, including Long Range Arena (LRA), large-scale WikiText-103, and Speech Commands, demonstrate that LongSpike outperforms state-of-the-art SNNs in accuracy while preserving sparse synaptic computation. The code is available at https://github.com/xinruihe389-commits/LongSpike.

18.
Science (Express) 2026-06-11

Laser phase plate improves structure determination of small proteins by cryo-EM | Science

Authors: Unknown Author

Phase plates can in principle overcome the poor image contrast in electron cryo–microscopy (cryo-EM) and the resulting limits on the structural reconstruction of small proteins. However, previous designs have been unstable and compromised the high-resolution signal. They have thus been unable to surpass results achieved by standard cryo-EM. Here, we show that the laser phase plate (LPP), installed in a custom, modern Titan Krios microscope, enhances the resolution in single-particle reconstruction of small proteins by improving specimen-motion correction, recovery of information from the early frames, as well as particle visualization, 3D classification, and alignment. These advances use standard defocus ranges and reconstruction procedures, but open the door to LPP-tailored protocols offering further improvements by leveraging the LPP demonstrated here.

19.
arXiv (CS.CL) 2026-06-12

Rigel: Reverse-Engineering the Metal 4.1 Tensor Compute Path on the Apple M4 Max GPU

Apple's Metal 4.1 exposes a tensor compute path: the Metal Performance Primitives (MPP) matmul2d operation over cooperative_tensor fragments, whose interface is documented but whose hardware behavior is deliberately hidden. The specification states which data-type rows are supported, never whether they are hardware-accelerated, where the operation physically executes, what its accumulator width is, or how it partitions matrix fragments across threads. We present Rigel, an empirical characterization of this path on a single Apple M4 Max (a pre-neural-accelerator generation). Using a checksum-gated, provenance-tracked microbenchmark harness, Rigel recovers eleven facts the v4.1 specification hides or contradicts. The headline finding: the Metal 4.1 fp8 (E4M3) matmul2d is emulated, not accelerated: it sustains 0.94x the throughput of fp16 despite reading half the operand bytes, so on M4 it is a memory-footprint feature, not a performance feature. We further show, via a three-signal triangulation (throughput ceiling, comparison against simdgroup_matrix, and per-rail power attribution), that matmul2d executes entirely on the GPU shader cores with no dedicated matrix datapath and no evidence of Apple Neural Engine routing; that it accumulates in >=fp32; and we reconstruct the opaque 8x8 cooperative_tensor fragment layout Apple documents nowhere. Acting on the characterization, a hand-fused GEMM + bias + GELU kernel beats the decomposed path by +6.5-12.9% in the cache-resident regime. All findings are reproducible from committed MIT-licensed code and per-cell CSVs.

20.
arXiv (CS.AI) 2026-06-15

StreamMemBench: Streaming Evaluation of Agent Memory for Future-Oriented Assistance

arXiv:2606.14571v1 Announce Type: new Abstract: A central role of personal-agent memory is to turn stored information and prior interactions into future-oriented assistance. In daily use, useful cues come from what the agent observes and how the user interacts with the agent, and the agent must carry them forward from the current request to similar future tasks. Existing memory benchmarks usually test dialogue recall or task improvement in isolation, leaving the trajectory from streaming observations to later assistance largely untested. We introduce StreamMemBench, a streaming benchmark that constructs a two-step task sequence around each evidence anchor from EgoLife egocentric streams. The initial task tests evidence use, while the follow-up task tests whether feedback and interaction experience are reused. Four metrics diagnose evidence recall, initial evidence use, feedback incorporation, and follow-up reuse. Experiments with eight memory systems across two backbones show that current systems often fail to use observed evidence or turn feedback into reliable follow-up behavior, even when evidence is stored or feedback is incorporated locally. StreamMemBench is publicly available at https://github.com/landian60/StreamMemBench.

21.
arXiv (CS.CL) 2026-06-11

ProHiFlo: Hierarchical Flow Matching with Functional Guidance for De Novo Protein Generation

De novo protein generation has transformative potential in therapeutic design, enzyme engineering, and synthetic biology. While diffusion-based and flow matching approaches have achieved progress, they typically operate at single resolution and lack mechanisms for incorporating functional constraints. We introduce ProHiFlo, a hierarchical flow matching framework with three innovations: (1) coarse-to-fine generation that models backbone geometry before refining to all-atom coordinates, reducing computational cost while maintaining accuracy; (2) functional guidance leveraging pretrained predictors to steer generation toward desired properties without retraining; (3) adaptive SE(3)-equivariant architecture for efficient multi-scale processing. Experiments on unconditional generation, motif scaffolding, and functional design demonstrate state-ofthe-art performance while requiring 4 fewer sampling steps. On enzyme active site scaffolding, ProHiFlo achieves 58.9% success rate compared to 41.2% for RFDiffusion.

22.
arXiv (CS.AI) 2026-06-11

SPEA2$^+$: Improved Density Estimation in SPEA2 with Provable Runtime Guarantees

arXiv:2606.12382v1 Announce Type: cross Abstract: The Strength Pareto Evolutionary Algorithm 2 (SPEA2) is a popular and prominent evolutionary algorithm for solving multi-objective optimisation problems. Despite its popularity, theoretical analyses of SPEA2 have only appeared recently. Moreover, these analyses focus exclusively on how SPEA2 handles non-dominated solutions and disregard the algorithmic components responsible for handling dominated solutions. We conduct a first runtime analysis of SPEA2 for which these components are analysed. We prove that, unlike other prominent algorithms, including NSGA-II, NSGA-III and SMS-EMOA under the same setting of constant population size and duplicate elimination, SPEA2 is unable to cover the Pareto front of the OneTrapZeroTrap benchmark efficiently. Our results indicate that using k-th nearest-neighbour distance in the fitness assignment provides an insufficient signal to maintain diversity among dominated individuals. To address this issue, we propose an improved variant, SPEA2$^+$, that considers all pairwise distances. The new algorithm achieves the same performance guarantees as the other prominent algorithms on OneTrapZeroTrap, while matching the performance of the original SPEA2 on simpler problems. Experimental results complement our theoretical findings.

23.
bioRxiv (Bioinfo) 2026-06-17

DNA-binding specificity recognition from predicted homologous protein-DNA structures

Predicting protein DNA-binding specificity is essential for understanding gene regulation and disease mechanisms. Existing deep learning methods typically infer specificity from a single protein-DNA complex structure, which limits their ability to capture the diverse geometric patterns underlying protein-DNA recognition. Homologous protein-DNA interfaces provide complementary structural evidence and richer geometric features related to interatomic interactions. To address the limited diversity and coverage of experimentally determined complexes, we constructed a large-scale library of predicted homologous protein-DNA complex structures. Building on this resource, we propose HomoDSP, a template-retrieval-based framework for accurate DNA-binding specificity prediction. Benchmark evaluations and validation on newly released JASPAR 2026 samples indicate that HomoDSP outperforms existing methods in both accuracy and generalization, with particularly substantial gains on high-error samples. Moreover, this performance is largely retained when AlphaFold3-predicted complex structures are used as input. Template- and residue-level interpretability analyses suggest that HomoDSP improves prediction by focusing on DNA-affinity residues across multiple homologous templates. Finally, universal Protein Binding Microarrays evaluations on AI-designed DNA-binding proteins show that HomoDSP rescues a baseline failure mode in which the baseline method produces incorrect predictions because of training-set bias. Together, these results support the use of homologous template interfaces as informative structural priors for decoding protein DNA-binding specificity.

24.
bioRxiv (Bioinfo) 2026-06-21

Machine learning evaluation of gene expression-based ALS subtypes across brain and blood tissues

The clinical and molecular heterogeneity observed in amyotrophic lateral sclerosis (ALS) presents a challenge for diagnosis, prognosis, and treatment. RNA sequencing of post-mortem brain samples from ALS patients has identified several subtypes with distinct molecular signatures. We sought to evaluate these subtypes across diverse tissues and datasets and assess the feasibility of supervised machine learning models for sample classification. Unsupervised clustering and pathway analysis were performed to confirm the presence of ALS subtypes in motor cortex samples. Three machine learning strategies were then used to create models based on post-mortem motor cortex expression data of 112 people with ALS from the London Neurodegenerative Diseases Brain Bank. These models were subsequently improved through feature selection and evaluated in independent cohorts from motor cortex (n = 257, NYGC ALS Consortium) and blood (n = 96, Macquarie University Neurodegenerative Disease Biobank) samples. Multi-class linear discriminant analysis (LDA) models were then used for subtype classification. Clustering of ALS post-mortem motor cortex samples confirmed the presence of three subtypes: neuroinflammation (ALS-Neu), extracellular matrix organisation and muscle contraction (ALS-OxA), and synaptic and neuropeptide signalling (ALS-SNs). Among all machine learning strategies, random forests produced the most accurate and stable models for binary classification (~93% accuracy across the three subtypes). After feature selection, random forest models were able to classify samples from an independent post-mortem motor cortex cohort in their respective subtypes (AUC of ~0.98 across the three subtypes). When these models were evaluated in blood using LDA, we found consistent clustering patterns, with samples aligning in the same subtype regions of the post-mortem motor cortex samples, with ALS-SNs being the subtype in which samples were classified with the highest confidence (LDA class probability ~86%). Moreover, classification for this subtype improved when blood samples were collected closer to death. Our findings support the presence of three gene expression-based ALS subtypes in motor cortex samples and the utility of machine learning strategies for subtype classification. We also observed that the subtypes identified in the brain partially match those in the blood, with samples from the late stages of the disease more likely to be correctly predicted into the ALS-SNs cluster. This suggests a longitudinal effect in subtype identification that requires further investigation.

25.
arXiv (CS.CV) 2026-06-11

Active Sampling for Ultra-Low-Bit-Rate Video Compression via Conditional Controlled Diffusion

Diffusion models provide a powerful generative prior for perceptual reconstruction at ultra-low bitrates, but effective video compression requires controlling the generative process using highly compact conditioning signals. In this work, we present ActDiff-VC, a diffusion-based video compression framework for the ultra-low-bitrate regime. Our method partitions videos into variable-length segments, transmits keyframes only when needed, and summarizes temporal dynamics using a compact set of tracked point trajectories. Conditioned on these sparse signals, a conditional diffusion decoder synthesizes the remaining frames, enabling perceptually realistic reconstruction under severe rate constraints. To support this design, we introduce two mechanisms: content-adaptive keyframe selection and budget-aware sparse trajectory selection, which together enable compact yet effective conditioning for generative reconstruction. Experiments on the UVG and MCL-JCV benchmarks show that ActDiff-VC achieves up to 64.6\% bitrate reduction at matched NIQE, improves KID by up to 64.6\% and FID by up to 37.7\% at comparable bitrates against strong learned codecs, and delivers favorable perceptual rate–distortion trade-offs relative to learned and diffusion-based baselines in the ultra-low-bitrate regime.