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01.
arXiv (CS.CV) 2026-06-17

Attention Sinks in Diffusion Transformers: A Causal Analysis

Attention sinks – tokens that receive disproportionate attention mass – are assumed to be functionally important in autoregressive language models, but their role in diffusion transformers remains unclear. We present a causal analysis in text-to-image diffusion, dynamically identifying dominant attention recipients per timestep and suppressing them via paired, training-free interventions on the score and value paths. Across 553 GenEval prompts on Stable Diffusion~3 (with SDXL corroboration), removing these sinks does not degrade text-image alignment (CLIP-T) or preference proxies (ImageReward, HPS-v2) at $k{=}1$; only under stronger interventions ($k\!\geq\!10$) does HPS-v2 exhibit a metric-dependent boundary, while CLIP-T remains robust throughout. The perceptual shifts induced by suppression are nonetheless sink-specific – $\sim\!6\times$ larger than equal-budget random masking – revealing an empirical dissociation between trajectory-level perturbation and semantic alignment in diffusion transformers. \footnote{Code available at https://github.com/wfz666/ICML26-attention-sink.}

02.
arXiv (CS.AI) 2026-06-24

Assessing Distribution Shift in Human Activity Recognition for Domain Generalization

arXiv:2606.24781v1 Announce Type: new Abstract: While the field of Human Activity Recognition (HAR) continues to draw interest from researchers and advance in important ways, some key challenges remain. One of the most difficult aspects of building HAR models that show good performance in real-world settings is dealing with data diversity from device and sensor heterogeneity, and contextual changes that are intrinsic to real-world applications. While data diversity in HAR has been well-acknowledged in the literature, there remains a gap in understanding the effect of various types of distribution shifts on HAR models and the domain generalization problem that arises. Towards that end, this paper systematically evaluates 4 different types of distribution shifts, including variations in device type, sensor placement, sampling rate, and user behavior. Quantifying their effects, we illustrate that diversity shifts predominantly define all types of shifts, indicating the existence of unique features that are not shared across different domains. We then introduce a uniform HAR-based distribution shift benchmarks and conduct a comprehensive evaluation of up to 28 domain generalization methods. Our analysis exposes the limitations of current domain generalization algorithms in achieving model generalizability, marginally outperforming the empirical risk minimization baseline. This work represents the first systematic exploration of domain generalization and adaptation concerning specific distribution shifts in sensor-based HAR, offering an open-source benchmark platform and datasets to spur further research.

03.
bioRxiv (Bioinfo) 2026-06-15

Inferring Cell Fate Trajectories in Time-Resolved Metabolic RNA Labeling data

Single-cell RNA sequencing provides high-resolution snapshots of cellular states but lacks direct information about transcriptional dynamics. Metabolic RNA labeling addresses this limitation by distinguishing newly synthesized RNA, offering insight into the direction of cell state changes, and providing valuable information when attempting to recover the underlying continuous dynamics from static snapshots of cell distributions. However, existing trajectory inference methods do not fully exploit this additional signal. Here, we propose FLOWSATATE, a framework for single-cell trajectory inference that leverages time-resolved RNA labeling within an Optimal Transport setting. We model cell dynamics as a gradient flow in an inferred potential landscape parameterized by a neural network, integrating both total and labeled RNA across time points. The learned potential enables identification of key genes and transcription factors driving cell fate decisions and supports prediction of future cellular states. We benchmark our approach on its ability to generalize unseen data and recover coherent trajectories. We also apply it to study colorectal cancer response to demethylation treatment as well as neuronal differentiation of embryonic stem cells.

04.
bioRxiv (Bioinfo) 2026-06-21

ReSeT: a taxonomy-aware reference genome selection tool

Motivation: Reference genome composition determines which taxa a profiling pipeline can detect and distinguish, and becomes of critical importance for high-resolution profiling where taxonomic boundaries begin to blur. Existing selection tools optimize within-taxon representativeness but disregard discrimination across taxa, leaving open whether explicitly accounting for inter-taxon discrimination during selection improves profiling. Results: Here we present ReSeT, a facility-location-based reference genome selection tool that operates on arbitrary pairwise distance matrices, extended with a tunable inter-taxon discrimination term and per-genome selection cost, and solved by local search. We benchmark ReSeT against established selection methods on three viral datasets spanning varying degrees of taxonomic ambiguity. On the high-ambiguity SARS-CoV-2 datasets, appropriately tuned ReSeT selections matched or exceeded the strongest alternatives in terms of profiling accuracy, whereas on the low ambiguity IAV dataset VSEARCH remained dominant. Interestingly, we find that the novel inter-taxon discrimination term contributed weakly, indicating that ReSeT's facility-location formulation and selection cost drives ReSeT's performance. We further propose a novel taxonomic ambiguity index, computable from ReSeT's inputs, that summarizes the taxonomic ambiguity of reference genomes and aligns with where ReSeT improves over existing selection methods. Availability and implementation: ReSeT is implemented in Python ([≥]3.10) and is freely available under the MIT license. The source code is available on GitHub at https://github.com/JaspervB-tud/ReSeT and ReSeT can also be installed directly from the Python Package Index (PyPI) via pip install reset-bio.

05.
arXiv (CS.AI) 2026-06-16

Fusion is not one-size-fits-all: Cross-Modal Representation Alignment for Time-to-Event Modeling

arXiv:2606.15038v1 Announce Type: new Abstract: Accurate time-to-event (TTE) prediction from multimodal clinical data remains challenging due to modality imbalance and distribution shift. We introduce a foundation model-driven framework for cross-modal representation alignment between CT imaging and longitudinal EHR data, designed to generalize across tasks and institutions. CT and EHR modalities are encoded independently using domain-specific foundation models and aligned in a shared latent space through four principled fusion strategies: late fusion, contrastive alignment, cross-attention, and co-attention. We evaluate two clinically distinct TTE tasks: pulmonary embolism (PE) mortality and cardiovascular disease (CVD) outcomes, on large-scale multi-institutional cohorts (PE: N=3,099 train; 1,098 internal; 435 external; CVD: N=2,951 train; 837 internal; 682 external). Fusion consistently improves concordance index by 1.5-5.4% over unimodal baselines when modalities contribute comparably. Overall, contrastive multimodal fusion, particularly with CLMBR representations, provided the most consistent and statistically robust improvements, especially for PE mortality prediction. For MACE, cross-attention (one-hot) achieved the highest internal performance and image-guided co-attention achieved the best external performance. We therefore introduce a generalizable foundation model-based cross-modal alignment framework and provide the first systematic analysis of fusion behavior under modality imbalance in TTE prediction. Our results establish task-aware multimodal alignment as a necessary design principle for robust generalization and scalable clinical deployment.

06.
PLOS Computational Biology 2026-06-22

GrassSV – hybrid method to detect structural variants in high throughput DNA-seq data

by Dominik Witczak, Krzysztof Sychla, Julia Wysocka, Artur Laskowski, Wojciech Frohmberg, Marta Glowacka, Alicja Dzik, Piotr Lukasiak, Jacek Blazewicz, Aleksandra Swiercz Genetic diversity is crucial for populations to adapt and survive in dynamic environments. This diversity arises from genetic mutations, which manifest in the genome as structural variants (SVs). Several types of SVs exist, but not all are equally easy to detect. Current SV detection tools tend to specialize in certain SV types or require the use of multiple tools to obtain a comprehensive variant profile, which increases computational cost and complexity. While some methods excel at identifying breakpoints, they often struggle with accurately classifying variant types, and their precision depends strongly on data quality and sequencing technology. At present, the majority of available genomic data originates from high-quality short reads, which remain the most affordable sequencing technology. In this manuscript, we introduce GrassSV, a novel and computationally efficient method that employs a hybrid pattern-matching approach to detect all major classes of structural variants using short-read sequencing data. GrassSV integrates depth-of-coverage analysis with contig-based pattern recognition to ensure both sensitivity and precision while minimizing false positives and runtime. Its robustness was demonstrated on the human Genome in a Bottle dataset, as well as on synthetic data derived from the yeast genome, where it achieved high accuracy across all SV types at a lower computational cost compared to existing methods. This makes GrassSV a practical alternative to multi-tool pipelines typically required for comprehensive SV detection. GrassSV is available at https://github.com/Domomod/GrassSV under GPL-3.0 license and the benchmark at: https://github.com/Domomod/GrassBenchmark.

07.
arXiv (quant-ph) 2026-06-24

Dimensionality Reduction of QAOA Parameter Space with Kernel PCA for Max-Cut

arXiv:2606.23718v1 Announce Type: new Abstract: The Quantum Approximate Optimization Algorithm (QAOA) is a leading variational algorithm for combinatorial optimization on near term quantum devices. As circuit depth increases, the number of optimization parameters grows, making the search landscape increasingly nonlinear and difficult to optimize. Previous studies have shown that optimal QAOA parameters often lie on a low dimensional manifold that can be approximated using Principal Component Analysis (PCA) at shallow circuit depths. However, the effectiveness of PCA decreases at higher depths because the underlying parameter manifold becomes increasingly nonlinear. In this work, we investigate Kernel Principal Component Analysis (KPCA) with a radial basis function kernel as a nonlinear dimensionality reduction technique for QAOA parameter optimization. The model is trained using 200 graphs from each of 3 graph families, namely Erdos-Renyi, Barabasi-Albert, and Watts-Strogatz, with graph sizes ranging from 7 to 10 nodes. Performance is evaluated on 30 test graphs containing 12 nodes at circuit depths 1, 2, 4, and 8. Experimental results demonstrate that KPCA consistently outperforms PCA at deeper circuit depths across all graph families. At depth 8, KPCA achieves approximation ratios above 0.86, while PCA declines to approximately 0.81 to 0.83. Both methods reduce the number of quantum circuit evaluations by more than 93 percent relative to unrestricted QAOA optimization. These findings suggest that nonlinear kernel methods more effectively capture the structure of the QAOA parameter manifold and provide a practical approach for scaling variational quantum optimization to deeper circuits.

08.
arXiv (quant-ph) 2026-06-16

VQE as Initial State Preparation for QPE on Heisenberg Spin-Glass Hamiltonians

arXiv:2606.15061v1 Announce Type: new Abstract: Quantum Phase Estimation (QPE) is the quantum algorithmic workhorse for computing ground state energies of quantum Hamiltonians with quantum computers. Ground state energy calculation of physical systems is perhaps the most promising use case for quantum computing in terms of scientific and commercial value with a plausible path to outperformance of classical alternatives. This path, however, hinges on the availability of initial states for QPE with significant overlap with the true ground state. Using extensive (classical) numerical computations, we study whether the NISQ-era algorithm VQE (Variational Quantum Eigensolver) could be used to efficiently prepare high-overlap states of disordered fully-connected anisotropic Heisenberg spin glass quantum Hamiltonians with up to $15$ qubits. We find that (i) – consistent with widely held, but rarely numerically illustrated beliefs – VQE is generally unable to efficiently converge to the ground state for our Hamiltonians, which is a well-known issue with VQE due to a variety of factors including vanishing gradients and local minima; (ii) low energy states do not necessarily have large ground-state overlap, but there is typically a correlation between the two measures; (iii) adding more than three layers to the VQE ansatz neither improves overlap nor the energies found; and (iv) the best-found overlap scaling as a function of the Hamiltonian system size is not strongly exponentially decreasing, suggesting potential for VQE to be a heuristic state preparation algorithm for QPE.

09.
medRxiv (Medicine) 2026-06-24

The role of Mediterranean diet adherence, smoking and their interactions in epigenetic age acceleration: A cross-sectional analysis of the Airwave cohort.

Background: Epigenetic clocks are markers of biological aging that may vary in their sensitivity to environmental stressors and lifestyle modifiers. To evaluate the utility of these biomarkers as sensors of the human exposome, we investigated how they respond to two powerful and opposing exposures: smoking, a source of oxidative stress, and the antioxidant-rich Mediterranean diet. Objectives: We assessed the sensitivity of eleven epigenetic clocks to diet and smoking and evaluated whether Mediterranean diet adherence modifies associations between smoking and epigenetic aging. Methods: We analysed 928 participants (mean age 41 years, 59% male) from the Airwave Health Monitoring Study. Linear regression models assessed associations between Mediterranean Diet Score (MDS) and epigenetic age acceleration (EAA), alongside smoking status and blood cotinine. Interaction terms between smoking status and MDS were included to detect dietary attenuation of smoking-related EAA. Models were adjusted for demographic, socioeconomic, lifestyle, and psychological covariates. Results: Higher MDS was associated with lower EAA for GrimAge ({beta} = -0.07 SD; 95% CI: -0.13, -0.01) and Bernabeu ({beta} = -0.08 SD; 95% CI: -0.14, -0.02) after false discovery rate correction. Smoking was strongly associated with increased EAA, particularly for GrimAge, Bernabeu, and DunedinPACE. Among current smokers, effect sizes were greater in those with lower dietary adherence (e.g. GrimAge: 1.79 SD, 95% CI: 1.54, 2.04) compared with those with higher adherence (1.35 SD, 95% CI: 1.01, 1.68; P_interaction < 0.001). Similar attenuation patterns were observed for Bernabeu. Higher intake of fruits, vegetables, and whole grains contributed most to the attenuation of smoking-related EAA. Conclusions: Our findings indicate that certain epigenetic clocks effectively capture the tension between harmful and protective exposures within the exposome. Rather than suggesting that diet neutralises the risks of tobacco, these results demonstrate that specific clocks are sensitive enough to monitor how lifestyle factors modify molecular responses to environmental toxins. This highlights the value of second-generation clocks in quantifying biological resilience.

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

Communication-Efficient Neural Tangent Kernels for Heterogeneous Decentralized Federated Learning

Authors:

arXiv:2512.12737v2 Announce Type: replace Abstract: Decentralized federated learning (DFL) enables collaborative model training without a central server, but converges slowly under statistical heterogeneity. Recent work has shown that neural tangent kernel (NTK) methods achieve faster convergence than gradient-based updates in DFL, while momentum has proven effective for accelerating gradient-based FL. However, applying momentum to NTK updates can destabilize training under heterogeneous data. We propose SPARK, which addresses this instability with a stage-wise annealed soft-label regularizer evaluated on neighborhood-aggregated data, so that momentum can accelerate NTK updates stably. Under high heterogeneity, SPARK converges about 3$\times$ faster than baselines and lowers the total communication to a target accuracy by up to about 70\%, and it attains higher accuracy across heterogeneity levels. We further study random projection as an optional Jacobian-compression strategy for bandwidth-constrained settings. We validate the approach across multiple datasets, network topologies, and heterogeneity levels.

11.
arXiv (math.PR) 2026-06-19

Towards practical PDMP sampling: Metropolis adjustments, locally adaptive step-sizes, and NUTS-based time lengths

arXiv:2503.11479v2 Announce Type: replace-cross Abstract: Piecewise-Deterministic Markov Processes (PDMPs) hold significant promise for sampling from complex probability distributions. However, their practical implementation is hindered by the need to compute model-specific bounds. Conversely, while Hamiltonian Monte Carlo (HMC) offers a generally efficient approach to sampling, its inability to adaptively tune step sizes impedes its performance when sampling complex distributions like funnels. To address these limitations, we introduce three innovative concepts: (a) a Metropolis-adjusted approximation for PDMP simulation that eliminates the need for explicit bounds without compromising the invariant measure, (b) an adaptive step size mechanism compatible with the Metropolis correction, and (c) a No U-Turn Sampler (NUTS)-inspired scheme for dynamically selecting path lengths in PDMPs. These three ideas can be seamlessly integrated into a single, `doubly-adaptive' PDMP sampler with favourable robustness and efficiency properties.

12.
arXiv (CS.CV) 2026-06-15

Prompt2Effect: Training-Free Image-to-Video Model Specialization via LoRA Generation

Personalizing Image-to-Video (I2V) diffusion models with specific visual effects is increasingly demanded for high-end video generation. Current practice requires training a separate Low-Rank Adaptation (LoRA) module for each effect, incurring substantial data curation and iterative optimization costs that hinder interactive control. We present Prompt2Effect, a weight-driven hypernetwork that amortizes per-effect training by directly synthesizing effect-specific LoRA weights in a single forward pass. Unlike prior hypernetworks that regress adapter weights purely from semantics, Prompt2Effect is explicitly conditioned on the frozen base model weights, grounding weight prediction in the structural geometry of each layer. Furthermore, instead of predicting raw LoRA matrices, we introduce an SVD-canonicalized parameterization that resolves factorization ambiguity and stabilizes large-scale weight synthesis. Together, these design principles enable accurate and scalable LoRA prediction for high-dimensional I2V diffusion models. Extensive experiments demonstrate that Prompt2Effect achieves on-par or superior video quality and effect alignment compared to conventional LoRA fine-tuning, while reducing the computational cost from 56 GPU training hours to 3.3 seconds of hypernetwork inference. When used as initialization for subsequent fine-tuning, our predicted weights further improve final performance and accelerate optimization by approximately 10x.

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

On The Effectiveness-Fluency Trade-Off In LLM Conditioning: A Systematic Study

Controlling the output of Large Language Models (LLMs) is a central challenge for their reliable deployment, yet a clear understanding of the involved trade-offs remains elusive. Current approaches to conditioning are often evaluated with a narrow focus on their effectiveness at injecting or removing a target concept, neglecting generation quality. We systematically investigate a range of conditioning methods in both injection and removal scenarios. We find that efficient steering methods frequently achieve conditioning at a steep cost to fluency. Furthermore, we identify a critical yet previously overlooked interaction with the training paradigm: activation steering methods are far less effective on instruction-tuned models than on their base counterparts. Simple prompting and full-fledged supervised fine-tuning, on the other hand, are viable options for concept injection, but are not as good at concept removal. Finally, cheaply computed textual metrics highly correlate to costly LLM-as-judge scores, and provide insights on the behavior of conditioning methods.

14.
arXiv (CS.CV) 2026-06-18

Where Will They Go? Modelling Multimodal Pedestrian Manoeuvres from Ego-centric Videos

Pedestrian trajectory prediction from an ego-centric camera is challenging since it depends on complex interactions with vehicles and scene context, as well as the intention of the pedestrian. By modelling correlation and intent from the historical and future trajectories of the pedestrian, it will usually result in a multimodal (i.e. multiple modes) distribution. Existing stochastic predictors often sample multiple futures from a single unimodal distribution, which can yield sub-optimal 'mixed-mode' trajectories that lie between distinct motion patterns and become implausible in real scenes. In this paper, we propose MMPM, a mode-aware framework that separately models future trajectory distributions into semantically meaningful modes based on the pedestrian's crossing behavior. MMPM consists of two modules: behavior-aware Pedestrian Interaction Module (PIM) that jointly captures pedestrian-vehicle and pedestrian-environment interactions by introducing gaze, head and hand gesture, and a CVAE-based Mode-aware Trajectory Predictor (MTP) module to model the future trajectory distributions on two modes, crossing and non-crossing the road, separately. A query-based decoder further enforces mode consistency during decoding. Experiments on PIE and JAAD datasets show that our method surpasses state-of-the-art baselines. Our proposed MTP is model-agnostic, which can be integrated into existing frameworks such as BiTrap-NP and SGNet-ED to further improve future trajectory prediction performance. We additionally introduce a data-driven validation protocol that matches predictions to spatio-temporally consistent ground-truth trajectories, demonstrating improved frame-wise displacement errors over previous work.

15.
arXiv (CS.CL) 2026-06-11

BaltiVoice: A Speech Corpus and Fine-tuned Whisper ASR System for the Balti Language

Authors:

We present BaltiVoice, a 16.8-hour read-speech corpus for Balti (ISO 639-3: bft), a Tibetic language spoken in Gilgit-Baltistan, Pakistan, with no prior publicly available ASR resources. The corpus contains 10,060 validated utterances in native Nastaliq script, derived from Mozilla Common Voice recordings. Fine-tuning OpenAI Whisper-small yields a Word Error Rate (WER) of 26.74% and a Character Error Rate (CER) of 8.67% on a 538-utterance speaker-disjoint validation set, down from a zero-shot baseline of 159.19% WER and 152.52% CER. A Whisper-base fine-tuned on the same data achieves 44.54% WER and 15.61% CER, confirming that model capacity matters for this low-resource setting. The dataset, fine-tuned model, and a live transcription demo are publicly available on HuggingFace.

16.
arXiv (math.PR) 2026-06-16

Plateau Gaps of Poisson Correctors Encode Metastable Reaction Rates

arXiv:2606.14789v1 Announce Type: cross Abstract: Metastable reaction rates are commonly inferred from transition-state fluxes, mean first-passage times, or fitted kinetic models. We show that they are directly encoded in the plateau gap of an occupation-time Poisson corrector. For a centered basin-occupation observable, the Poisson corrector develops metastable plateaus in the reactant and product basins, and their separation determines the forward and backward transition rates. This construction requires only the generator, stationary measure, and metastable partition, and therefore does not rely on a predefined transition-state surface. In overdamped and underdamped double-well dynamics, the plateau-gap rate recovers the Kramers, Grote-Hynes, and Pollak-Grabert-Hänggi hierarchy. The same corrector-martingale decomposition yields a reactive-noise density, revealing where stochastic forcing contributes to transitions in configuration or phase space. Thus, reaction rates and their fluctuation sources emerge from a single corrector field.

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

Small LLMs for Biomedical Claim Verification: Cost-Effective Fine-Tuning, Structural Dataset Shortcuts, and Cross-Domain Generalization

Authors:

Large Language Models such as GPT-4o and GPT-5 achieve strong zero-shot performance on biomedical claim verification, but cost and opacity limit scalable use. We fine-tune three small LLMs: Phi-3-mini (3.8B), Qwen2.5-3B, and Mistral-7B, via QLoRA on SciFact and HealthVer, providing the first study of QLoRA models against GPT-4o and fine-tuned BioLinkBERT encoders. Mistral-7B QLoRA surpasses both GPT-4o and GPT-5 (up to 12% F1 gain) at a fractional cost using just 1,008 training examples. We conduct extensive in-domain and cross-domain evaluation: models trained on SciFact tested on HealthVer and vice versa, at matched sizes to isolate dataset structure from data quantity. We identify a previously unreported structural artifact in SciFact that inflates in-domain scores, and show through bidirectional out-of-domain evaluation that training on structurally sound data enables robust cross-domain transfer. We plan to release all code and adapter checkpoints.

18.
arXiv (quant-ph) 2026-06-16

Synthesizing Arbitrary Non-Hermitian Hamiltonian with Stochastic Floquet Engineering

arXiv:2606.15664v1 Announce Type: new Abstract: The conventional Floquet engineering scheme synthesizes a given target Hamiltonian with a deterministic temporal periodic driving field. In this work, we introduce the stochastic Floquet engineering scheme that can synthesize an arbitrary non-Hermitian target Hamiltonian using a time-periodic driving field with noisy amplitude. Our method is rooted in the Hermitian dynamics taking noise as a valuable quantum resource with no need for loss or gain in prior. We apply our method to engineer a cavity Hamiltonian with dissipative coupling between Fock states, and to prepare a given quantum state from a generally arbitrary quantum state. The stochastic Floqut engineering also provides a way to generate non-unitary quantum gates, which take advantage in certain tasks compared to unitary quantum computing, without the need for ancillae or state-dependent updating.

19.
arXiv (CS.CL) 2026-06-24

Speculative Pipeline Decoding: Higher-Accruacy and Zero-Bubble Speculation via Pipeline Parallelism

Speculative Decoding (SD) accelerates low-concurrency LLM inference by employing a draft-then-verify paradigm. However, mainstream methods typically rely on multi-token prediction, which introduces escalating prediction difficulty and serial drafting latency. To address these, we propose Speculative Pipeline Decoding (SPD), a groundbreaking framework that unlocks the true potential of pipeline parallelism. By partitioning the target LLM into $n$ pipeline stages, SPD allows LLM to process $n$ tokens within single sequence in parallel to accelerate decoding. To continuous fill the pipeline in single sequence decoding, a speculation module aggregates intermediate features across different pipeline depths to predict the next token, executing strictly in parallel with the target model's pipeline step, to realize bounded difficulty, higher acceptance rates, and zero latency bubbles. Our experiments demonstrate that SPD achieves significantly higher theoretical and wall-clock speedup compared to mainstream baselines at moderate pipeline depth, though more aggressive settings require further improvement. Our code is available at https://github.com/yuyijiong/speculative_pipeline_decoding

20.
Science (Express) 2026-04-16

Protein-templated synthesis of dinucleotide repeat DNA by an antiphage reverse transcriptase | Science

Authors: Unknown Author

Defense-associated reverse transcriptases (DRTs) are widespread bacterial anti-phage systems that use unconventional mechanisms of polynucleotide synthesis. We show that DRT3, which comprises two distinct RTs (Drt3a and Drt3b) and a noncoding RNA (ncRNA), synthesizes alternating poly(GT/AC) double-stranded DNA. Cryo–electron microscopy structures at 2.6 Å resolution reveal a D3-symmetric 6:6:6 complex of Drt3a, Drt3b, and ncRNA. Drt3a produces the poly(GT) strand using a conserved ACACAC template within the ncRNA. Notably, Drt3b synthesizes a complementary, protein-primed poly(AC) strand in the complete absence of a nucleic acid template, using conserved active site residues specific to Drt3b to enforce precise base alternation. These findings expand the functional landscape of nucleic acid polymerases, revealing a protein-templated mechanism for sequence-specific DNA synthesis.

21.
Nature (Science) 2026-06-24

Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover

Authors:

Metabolism of the hepatic low-density lipoprotein receptor (LDLR) is a key determinant of cholesterol homeostasis1,2. The molecular switches that coordinate LDLR trafficking and turnover in response to nutritional cues, including high dietary cholesterol, remain poorly defined3–6. Here we identify a new pathway regulated by Ral GTPases that links extracellular cholesterol signals to the intracellular trafficking machinery controlling LDLR turnover. Chronic dietary cholesterol activates the Ral proteins by increasing RAS activity, routing LDLR to lysosomes for degradation and inhibiting its recycling independently of transcriptional regulation or PCSK9. Constitutive activation of Ral via RalGAPB deletion or overexpression of constitutively active Ral mutants in hepatocytes reduces LDLR levels and impairs cholesterol clearance. Ral engages the endocytic RalBP1–REPS1 complex to promote LDLR internalization and lysosomal routing, where LDLR is degraded by the lysosomal protease cathepsin A (CTSA). Ral activation directs CTSA towards lysosomes for maturation while limiting its secretion, further promoting LDLR degradation in lysosomes. Genetic variants in this pathway significantly associate with altered cholesterol in humans. Pharmacological inhibition of CTSA activity increases hepatic LDLR function and improves cholesterol clearance, offering a potential new therapeutic strategy for hypercholesterolaemia and cardiovascular disease. Chronic dietary cholesterol activates Ral GTPases, which promote LDLR internalization and lysosomal degradation through RalBP1–REPS1 and CTSA, thereby reducing cholesterol clearance, whereas CTSA inhibition restores LDLR function and may offer a therapeutic strategy for cardiovascular disease.

22.
arXiv (quant-ph) 2026-06-15

Real-time pseudo entropy and modular-Hamiltonian correlations

arXiv:2606.14208v1 Announce Type: cross Abstract: Pseudo entropy is a complex-valued generalization of entanglement entropy defined from a reduced transition matrix. We study the pseudo entropy associated with a real-time transition matrix between an initial pure state and its unitary time evolution. For a subsystem $A$, we show that the short-time behavior of real-time pseudo entropy is governed by the correlation between the physical Hamiltonian $H$ and the modular Hamiltonian $K_A=-\log\rho_A$ of the initial reduced state, $ S_A(t,0)=S_A(0)-it \langle K_A(H-\langle H\rangle)\rangle + \mathcal{O}(t^2)$. For Hermitian dynamics, the initial imaginary response is controlled by the symmetrized covariance of $H$ and $K_A$ with an overall minus sign, while the initial real response is governed by their commutator. Thus the imaginary part of real-time pseudo entropy is not merely a branch artifact: it is a time-oriented modular response generated by the correlation between microscopic time evolution and subsystem coarse graining. We clarify the relation of this result to the known first law of pseudo entropy, derive an all-order expression in a Schmidt-diagonal model, recover thermal pseudo entropy as a special case, illustrate the covariance/commutator decomposition in a two-qubit model, and confirm the covariance response in transverse-field Ising-chain quenches, including a finite-size study of a modular susceptibility near the Ising critical region. We discuss how this amplitude-level oriented response can be related to ordinary entropy production, and also give a concrete $\mathcal{PT}$-symmetric toy-model illustration of the non-Hermitian extension.

23.
arXiv (CS.AI) 2026-06-15

Squeeze-Release: Iterative Pruning with Exact Structural Minimization

arXiv:2606.14346v1 Announce Type: cross Abstract: Unstructured pruning produces sparse weight tensors, but the standard implementation keeps tensor shapes unchanged so the deployed model is no smaller than before pruning. We present an exact structural rewrite, which we call minimization, that converts a masked network into a smaller dense network with the same forward function up to floating-point rounding. The Squeeze-Release cycle iterates pruning and minimization with an intermediate release step that re-enables the exact-zero positions inside the compacted tensors as small calibrated noise, turning otherwise wasted capacity back into trainable parameters. Successive cycles use that capacity to find structural redundancy a single pass cannot reach. We additionally introduce CompensatedLayerNorm, a function-preserving replacement for LayerNorm that extends minimization to channel reduction across LayerNorm-equipped residual streams. Squeeze-Release compresses the deployable network to 39x smaller than the unpruned model on a fully-connected model network and 14.8x smaller on modern CNN (ConvNeXt-Tiny), at comparable accuracy. In addition we prove that the rewrite can be extended to transformer architectures.

24.
arXiv (CS.AI) 2026-06-24

World Models in Pieces: Structural Certification for General Agents

arXiv:2606.24842v1 Announce Type: new Abstract: In the big-world regime, agents cannot be universally capable and their ability is inevitably specialized across a world model in pieces. Consequently, standard uniform guarantees fail to distinguish between the understanding of critical bottlenecks and irrelevant failures. We first formalize this limitation by proving that general agents are not universal, rendering standard worst-case analysis uninformative. To overcome this, we introduce structural certification, a transition-local framework that maps bounded goal-conditioned performance to entry-wise guarantees on the agent's internal world model. Our main contribution is constructive. We provide algorithms that filter specific transitions using deep compositional goals and prove that a general agent on these goals has a structural world model with a $\mathcal{O}(1/n) + \mathcal{O}(\delta)$ error bound. Conversely, this bound is tight in the small-$\delta$ regime, whose existence is explicitly guaranteed by our certification. These results enable the certifiable deployment of general agents by localizing the specific transitions where long-horizon planning is reliable.

25.
arXiv (CS.AI) 2026-06-16

Forced Deferral: Manipulating Routing Decisions in Multimodal LLM Cascades

arXiv:2606.15308v1 Announce Type: new Abstract: While multimodal large language models (MLLMs) have shown strong visual reasoning abilities, serving a large model for every query is computationally expensive. MLLM cascades mitigate this cost by first querying a weak but cheaper model and deferring to a strong model when the weak model's output is unconfident. However, since the weak model's confidence directly controls compute allocation, these systems expose a new attack surface: an adversary can manipulate confidence so that their queries are consistently deferred to the strong model. Motivated by this vulnerability, we introduce the Forced Deferral Attack (FDA), an adversarial image attack that lowers the weak model's confidence and causes cascades to route queries to the strong model. FDA learns a universal border trigger by optimizing a temperature-flattened objective. This objective pushes the weak model's token distribution on triggered inputs toward less concentrated targets constructed from its clean responses. Across datasets, model families, and deferral metrics, FDA consistently increases strong-model routing while outperforming image-perturbation and prompt-injection baselines. These results show that MLLM cascades are vulnerable to attacks that manipulate compute allocation, forcing unintended strong-model usage without directly targeting answer correctness.