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

Does the Data Processing Inequality Reflect Practice? On the Utility of Low-Level Tasks

The data processing inequality is an information-theoretic principle stating that the information content of a signal cannot be increased by processing the observations. In particular, it suggests that there is no benefit in enhancing the signal or encoding it before addressing a classification problem. This assertion can be proven to be true for the case of the optimal Bayes classifier. However, in practice, it is common to perform "low-level" tasks before "high-level" downstream tasks despite the overwhelming capabilities of modern deep neural networks. In this paper, we aim to understand when and why low-level processing can be beneficial for classification. We present a comprehensive theoretical study of a binary classification setup, where we consider a classifier that is tightly connected to the optimal Bayes classifier and converges to it as the number of training samples increases. We prove that for any finite number of training samples, there exists a pre-classification processing that improves the classification accuracy. We also explore the effect of class separation, training set size, and class balance on the relative gain from this procedure. We support our theory with an empirical investigation of the theoretical setup. Finally, we conduct an empirical study where we investigate the effect of denoising and encoding on the performance of practical deep classifiers on benchmark datasets. Specifically, we vary the size and class distribution of the training set, and the noise level, and demonstrate trends that are consistent with our theoretical results.

02.
arXiv (quant-ph) 2026-06-12

Approximability limits for bounded-degree max-LINSAT and implications for decoded quantum interferometry

arXiv:2606.13570v1 Announce Type: new Abstract: For general max-k-XORSAT with $k \geq 3$, no polynomial-time algorithm can do substantially better than random guessing on worst-case instances unless $\mathsf{P} = \mathsf{NP}$: approximating beyond the random-assignment value of $1/2$ is $\mathsf{NP}$-hard. The picture changes when each variable appears in at most $D$ constraints. In that bounded-degree setting, polynomial-time algorithms can provably beat the random baseline by an additive amount of order $1/\sqrt{D}$. For Boolean instances, this scaling is known to be optimal: the matching hardness result is due to Trevisan, while the corresponding algorithmic guarantee was established by Barak et al. Whether the same holds over general finite fields, and what it implies for quantum algorithms, has not been established. We make this connection explicit and extend the hardness to max-E$k$-LINSAT$(q,r)$ with bounded degree $D$ and over arbitrary finite fields $\mathbb{F}_q$, proving that it is $\mathsf{NP}$-hard to exceed $r/q + \mathcal{O}_{q,r}(1/\sqrt{D})$. These results provide the complexity-theoretic benchmark for the bounded-degree instances targeted by decoded quantum interferometry (DQI), QAOA, and classical heuristics. Any quantum advantage on bounded-degree instances is therefore confined to the constant prefactor. We further show that in the context of DQI and on $(k,D)$-regular instances, this prefactor is sensitive to the nature of the decoder: DQI with classical decoders faces an information-theoretic $1/\sqrt{D \log D}$ barrier that prevents it from matching the hardness scaling, while DQI with quantum decoders is compatible with the $1/\sqrt{D}$ scaling – identifying quantum decoding as the key ingredient for matching the complexity-theoretic scaling with DQI.

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

On the Adversarial Robustness of Multimodal LLM Judges

Multimodal Large Language Models (MLLMs) are increasingly used as automated judges, e.g., for image quality and safety assessment. However, their adversarial robustness remains largely unexplored, threatening the fairness and reliability of automated judging. To bridge this gap, we introduce RobustMLLMJudge, the first general framework for evaluating the adversarial robustness of general-purpose MLLMs when functioning as judges. It covers diverse attacks against popular judge approaches across quality and safety evaluation scenarios. Using RobustMLLMJudge, we reveal that i) different MLLM judges are highly vulnerable to score-inflating adversarial attacks; and ii) although effective, these attack methods face a critical challenge due to unique constraints in the evaluation protocols of MLLM judges. We further propose MGSIA, namely Manifold-Guided Semantic Induction Attack, a novel method that bypasses these constraints to enable more effective and transferable attacks on MLLM judges. The core idea of MGSIA is to combine affirmative semantic induction with high-score manifold alignment: it maximizes the probability that judges yield affirmative responses (e.g., "Yes") to binary semantic queries, while regularizing adversarial representations toward high-score centers estimated from proxy protocols. Together, these objectives yield transferable score-inflating perturbations. Extensive experiments demonstrate the superiority and generalizability of MGSIA in deceiving advanced MLLM judges under different evaluation scenarios, highlighting the need for robust MLLM judges. Code and data will be made available at https://github.com/mala-lab/RobustMLLMJudge.

04.
arXiv (CS.CL) 2026-06-18

Enhancing Multilingual Reasoning via Steerable Model Merging

Model merging is an effective technique for composing the capabilities of a multilingual model and a reasoning model. It has achieved promising generalization in multilingual reasoning tasks by aligning feature spaces of different models. However, the merged single model often fails to address the conflicts between source models, leading to suboptimal performance. In other words, the one-size-fits-all merging strategy may not align with the characteristics of different inputs which may require prioritizing certain models over others. To this end, we propose a Steerable Model Merging (ST-Merge) framework to modulate the contribution of each source model. To realize this idea, we introduce a gated cross-attention mechanism to weight or filter the two attended source models in an adaptive manner. Extensive experiments demonstrate that ST-Merge consistently outperforms multiple strong baselines on four multilingual reasoning benchmarks across 21 different languages.

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

MixTeX: Data-Efficient LaTeX OCR via Synthetic Pretraining and Limited Fine-Tuning

LaTeX OCR converts scientific document images into editable LaTeX code. Existing systems rely on large paired datasets, which are costly to collect and limited for low-resource languages. This paper presents MIXTEX, a data-efficient system using synthetic pretraining without real LaTeX sources. Unlike Nougat that depends on arXiv datasets, we generate training data by randomly pairing grammatical Wikipedia text with LaTeX formulas, requiring only syntactic correctness. This eliminates dependency on real document collections, enables scalable data generation (120M tokens), and supports low-resource languages. Following synthetic pretraining, adaptation requires only 400 real samples. Evaluation on a 977-sample benchmark with printed and handwritten English and Chinese shows that this two-stage strategy outperforms methods trained on large real datasets while requiring less human effort and computation. Data, code, and models are publicly available.

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

DecNefSimulator: A Modular, Interpretable Framework for Decoded Neurofeedback Simulation Using Generative Models

arXiv:2511.14555v4 Announce Type: replace-cross Abstract: Decoded Neurofeedback (DecNef) is a promising non-invasive approach to brain modulation with wide-ranging applications in neuromedicine and cognitive neuroscience. However, progress in DecNef research remains constrained by subject-dependent learning variability, reliance on indirect measures to quantify progress, and the high cost and time demands of experimentation. We present DecNefSimulator, a modular and interpretable simulation framework that formalizes DecNef as a machine learning problem. Beyond providing a virtual laboratory, DecNefSimulator enables researchers to model, analyze and understand neurofeedback dynamics. Using latent variable generative models as simulated participants, DecNefSimulator allows direct observation of internal cognitive states and systematic evaluation of how different protocol designs and subject characteristics influence learning. We demonstrate how this approach can (i) reproduce empirical phenomena of DecNef learning, (ii) identify conditions under which DecNef feedback fails to induce learning, and (iii) guide the design of more robust and reliable DecNef protocols in silico before human implementation. In summary, DecNefSimulator bridges computational modeling and cognitive neuroscience, offering a principled foundation for methodological innovation, robust protocol design, and ultimately, a deeper understanding of DecNef-based brain modulation.

07.
arXiv (CS.LG) 2026-06-16

Decomposing one-class support vector machine into an ensemble of one-data support vector machines

arXiv:2606.16002v1 Announce Type: new Abstract: One-class classification (OCC) is a classification problem in which the training data contains only one class. The one-class support vector machine (OCSVM) is one of the most competitive OCC algorithms. However, OCSVM has scalability issues with large-scale datasets. This paper proposes the acceleration strategy of OCSVM. The idea is to decompose the dataset into samples and train OCSVM models for single data points. Subsequently, ensemble learning is applied to combine all models to compute the OCSVM model for the dataset. In addition, further acceleration is achieved through a data-reduction strategy with an OCSVM model trained on the average of the training samples. The experiment compared the proposal and traditional OCSVM using the Python package. The proposed strategy is faster than traditional OCSVM, while achieving similar classification results. Moreover, the proposed strategy can create one-to-one correspondence between samples and models. Source code is uploaded at https://github.com/ToshiHayashi/ODSVM

08.
arXiv (CS.CV) 2026-06-11

i1: A Simple and Fully Open Recipe for Strong Text-to-Image Models

Diffusion models have consistently driven progress in text-to-image generation. However, it is challenging to attribute recent progress to specific modeling and data choices: state-of-the-art open-weight models provide limited ablations, and do not disclose their training data and full training details. The research community needs fully open (weights, data, and code) models as a foundation for further research; yet existing fully open models still fall significantly short of leading models in performance. In this project, we conduct a systematic investigation of the modeling and data design choices in text-to-image diffusion training and inference with 300+ controlled experiments totaling 700K+ TPU v6e hours. Our experiments highlight several empirical findings (e.g., equal weighting is a strong default for mixing curated datasets) and simple design decisions (e.g., larger text encoder adapters improve performance with minimal added parameters) for training strong models. Guided by these insights, we train i1, a 3B-parameter text-to-image diffusion model using only publicly available datasets. i1 is competitive with leading models on five representative benchmarks (GenEval, DPG, PRISM, CVTG-2K, and LongText), and outperforms the best existing fully open model by 29.5 absolute percentage points on average. We provide the i1 checkpoints, training and inference code, and the data processing pipeline. Together, our findings and the i1 recipe establish a practical foundation for future open research in text-to-image diffusion models. Our code is available at https://github.com/zlab-princeton/i1.

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

Momentum LMS Theory beyond Stationarity: Stability, Tracking, and Regret

arXiv:2602.11995v2 Announce Type: replace Abstract: In large-scale data processing scenarios, data often arrive in sequential streams generated by complex systems that exhibit drifting distributions and time-varying system parameters. This nonstationarity challenges theoretical analysis, as it violates classical assumptions of i.i.d. (independent and identically distributed) samples, necessitating algorithms capable of real-time updates without expensive retraining. An effective approach should process each sample in a single pass, while maintaining computational and memory complexities independent of the data stream length. Motivated by these challenges, this paper investigates the Momentum Least Mean Squares (MLMS) algorithm as an adaptive identification tool, leveraging its computational simplicity and online processing capabilities. Theoretically, we derive tracking performance and regret bounds for the MLMS in time-varying stochastic linear systems under various practical conditions. Unlike classical LMS, whose stability can be characterized by first-order random vector difference equations, MLMS introduces an additional dynamical state due to momentum, leading to second-order time-varying random vector difference equations whose stability analysis hinges on more complicated products of random matrices, which poses a substantially challenging problem to resolve. Experiments on synthetic and real-world data streams demonstrate that MLMS achieves rapid adaptation and robust tracking, in agreement with our theoretical results especially in nonstationary settings, highlighting its promise for modern streaming and online learning applications.

10.
arXiv (quant-ph) 2026-06-17

Matrix Product States for Modulated Symmetries: SPT, LSM, and Beyond

arXiv:2603.19189v2 Announce Type: replace-cross Abstract: Matrix product states (MPS) provide a powerful framework for characterizing one-dimensional symmetry-protected topological (SPT) phases of matter and for formulating Lieb-Schultz-Mattis (LSM)-type constraints. Here we generalize the MPS formalism to translationally invariant systems with general modulated symmetries. We show that the standard symmetry "push-through" condition for conventional global symmetry must be revised to account for symmetry modulation, and we derive the appropriate generalized condition. Using this generalized push-through structure, we classify one-dimensional SPT phases with modulated symmetries and formulate LSM-type constraints within the same MPS-based framework.

11.
arXiv (CS.AI) 2026-06-16

CAP: Towards PPG Universal Representation Learning with Patient-level Supervision

arXiv:2606.15284v1 Announce Type: cross Abstract: Photoplethysmography (PPG) plays a central role in wearable health monitoring and clinical decision support. Yet existing approaches to universal PPG representation learning largely focus on signal-level objectives and often overlook patient-level health context, which limits generalization to complex clinical tasks and heterogeneous cohorts. To address this gap, we construct a large-scale paired PPG-EHR multimodal dataset by distilling fragmented medical histories and clinical records into cohesive, patient-level electronic health records (EHR). Building on this resource, we propose Clinical Anchored Pretraining for PPG (CAP). During pretraining, CAP performs cross-modal contrastive alignment that anchors PPG representations to patient-level clinical semantics, guiding the encoder beyond waveform fitting toward modeling consistency in a patient's overall physiological state. During downstream adaptation, the pretrained PPG encoder provides clinically grounded representations that strengthen inductive bias and improve robustness and transferability. Experiments demonstrate that CAP consistently outperforms strong baselines on four diverse downstream tasks. CAP achieves a particularly large gain on respiratory rate prediction (up to +87.6% relative improvement over the state-of-the-art baseline) and delivers an average relative +26.7% across all tasks. We further enhance the interpretability of our approach through comprehensive analyses, including ablations and multiple complementary visualizations of the learned representations. The code for our experiments is available at: https://github.com/gody123gody/CAP .

12.
arXiv (CS.AI) 2026-06-18

Deep-Learning-Based Pixelated Microwave Filter Design and Characterization using Electro-Optical Electric-Field Measurements

arXiv:2606.18402v1 Announce Type: cross Abstract: Traditional microwave filter design typically relies on iterative parameter tuning and predefined topologies, which limits design space and increases development time. This study uses a deep learning approach combining convolutional neural networks with genetic algorithms to automate pixelated microwave filter synthesis. To validate the approach experimentally, both S-parameter and spatial electric-field measurements were analyzed. The synthesized low-pass filter demonstrated excellent agreement between simulated and measured performance, achieving a 7 GHz passband with over 20 dB suppression beyond 9.5 GHz. Electro-optical measurements, for the first time, revealed electric field patterns that resemble coupled transmission-lines or stub structures, providing insight into the emergent characteristics of AI-generated designs.

13.
PLOS Computational Biology 2026-06-01

Histology-informed spatial domain identification through multi-view graph convolutional networks

Authors:

by Huihui Zhang, Jiaxing Chang, Zirong Li, Yue Sun, Pinli Hu, Haoxiu Wang, Hang Yang, Yonglin Ren, Xingtan Zhang, Zehua Chen, Kok Wai Wong, Haojing Shao Identifying spatial domains is crucial in spatial transcriptomics, yet effectively integrating gene expression, spatial location, and histology remains challenging. We present STESH, a Spatial Transcriptomics clustering method that combines Expression, Spatial information and Histology. STESH extracts histological features using a convolutional neural network and generates expression, histology, spatial, and collaborative convolution modules for a multi-view graph convolutional network with a decoder and attention mechanism. We evaluated STESH on multiple tissue types and technology platforms. STESH consistently outperformed ten state-of-the-art methods, achieving superior clustering accuracy with the highest scores in adjusted Rand index, normalized mutual information, and Fowlkes-Mallows index.

14.
arXiv (CS.LG) 2026-06-15

Curvature-Informed Potential Energy Surface for Protein-Ligand Binding Affinity Prediction

arXiv:2606.14217v1 Announce Type: new Abstract: Accurate prediction of protein-ligand binding affinity is essential for structure-based drug discovery. Recent geometric deep learning methods have achieved promising performance by representing protein-ligand complexes as three-dimensional graphs. However, most existing approaches mainly rely on static interaction geometry from a single bound conformation, while neglecting molecular flexibility and binding-induced conformational changes. To address this limitation, we propose a curvature-informed potential energy surface (CPES) graph neural network for protein-ligand binding affinity prediction, which incorporates physics-informed curvature representations to model conformational flexibility. CPES first derives curvature spectral descriptors from the Hessian of the potential energy surface evaluated at equilibrium configurations, whose eigenvalues define the local principal curvatures of the potential energy surface. It then uses spectral cross-attention to compare the unbound ligand and protein with the bound complex, thereby capturing binding-induced changes in conformational dynamics. In parallel, hierarchical protein-ligand interaction representations are learned from static structural features through geometry-aware message passing, soft clustering, and bidirectional cross-attention. Finally, CPES fuses the curvature-informed dynamic representations with static interaction representations for affinity regression. Extensive evaluations on multiple benchmark datasets demonstrate that CPES achieves improved predictive performance and offers physical interpretability.

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

AMALIA-VL: A Native European Portuguese Open-Source Vision and Language Model

Large Vision and Language Models (LVLMs) have advanced rapidly, yet European Portuguese (pt-PT) remains systematically underserved by existing open-source multimodal models, which either conflate it with Brazilian Portuguese or severely under-represent it in their training data mixes. We introduce AMALIA-VL, the first open-source instruction-tuned LVLM built natively for pt-PT, pairing a high-resolution vision encoder with dynamic image tiling and a fully open pt-PT-optimized language model via a learned connector. We contribute with a purposefully designed three-stage training process - vision-language alignment, general visual instruction tuning, and preference optimization - together with a pt-PT-centric multimodal data mix combining curated and translated public datasets with novel datasets that address the near-total absence of European Portuguese multimodal resources. Our evaluation shows that AMALIA-VL establishes a strong baseline for open-source pt-PT LVLMs.We will release model weights, training data, and construction pipelines along with machine-translated pt-PT evaluation benchmarks to help democratize pt-PT LVLM development.

16.
arXiv (CS.LG) 2026-06-17

Turning music identification into a neural forward pass

arXiv:2606.17301v1 Announce Type: cross Abstract: Search, a foundational operation in computer science, maps a query to a matching item in a collection. It is typically implemented as a System-2 like, rule-based pipeline in which a key is computed, an index is probed, and candidates are verified. By contrast, human recognition resembles a System-1 like, associative model of identity recovery, in which even partial cues can trigger a recall without explicitly enumerating, ranking, or even accessing discrete candidates. Here, we show that music sound identification, a difficult search problem, can be performed in a single neural feed-forward pass by a generative transformer. Trained on an audio dataset, the model predicts the corresponding track identifier from a short audio excerpt. This approach surpasses state-of-the-art acoustic fingerprinting, with the largest gains for short audio segments (1 second), demonstrating the method is not only viable but advantageous. Moreover, it reduces external storage to 0.33% of the baseline footprint and improves inference latency by 2.3x (p95). Furthermore, the model can reject queries for unseen tracks, supporting open-set operation while reducing misattribution risk. Using music track identification as an example, this work reframes search, bringing it closer in spirit to human associative recognition and away from algorithmic database lookup.

17.
arXiv (math.PR) 2026-06-16

A Machine-Checked Itô Calculus for Brownian Motion

arXiv:2606.15089v1 Announce Type: cross Abstract: We present a machine-checked development of the $L^2$ Itô calculus of Brownian motion on a bounded time interval $[0,T]$, formalized in Lean 4 on top of Mathlib and the BrownianMotion package. The development contains: the construction of the Itô integral as an isometry of Hilbert spaces, from a predictable-rectangle $\pi$-system through the density of simple adapted processes; the Itô integral as a process, proved to be an $L^2$-continuous martingale through a single structural identity (the integral at time $t$ is the conditional-expectation projection of its terminal value onto $\mathcal{F}t$), from which adaptedness, the martingale property, the contraction bound, and both the terminal and the time-indexed Itô isometries follow as corollaries; and Itô's formula for $C^3$ functions with bounded derivatives, including its time-dependent form $df = f_x,dB + (f_t + \tfrac12 f{xx}),dt$, obtained by a discrete-to-continuous argument through weighted quadratic variation and explicit $L^2$ remainder bounds. To our knowledge this includes the first machine-checked proof of Itô's formula, and the first machine-checked construction of the Itô integral as a martingale-valued process, in any proof assistant. We are deliberate about the boundary: the theory is the $L^2$ theory on $[0,T]$ with bounded-derivative integrand classes; localization to the unrestricted $C^2$ formula, integrators beyond Brownian motion, and pathwise statements are out of scope, and we say precisely why and where. The development is roughly 7,200 lines of Lean across 22 modules; every theorem is sorry-free, the axioms of each headline result are pinned to Mathlib's classical defaults by a build-enforced gate, and the whole is reproducible from a pinned toolchain.

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

Generative models for decision-making under distributional shift

arXiv:2604.04342v2 Announce Type: replace Abstract: Many data-driven decision problems are formulated using a nominal distribution estimated from historical data, while performance is ultimately determined by a deployment distribution that may be shifted, context-dependent, partially observed, or stress-induced. This tutorial presents modern generative models, particularly flow- and score-based methods, as mathematical tools for constructing decision-relevant distributions. From an operations research perspective, their primary value lies not in unconstrained sample synthesis but in representing and transforming distributions through transport maps, velocity fields, score fields, and guided stochastic dynamics. We present a unified framework based on pushforward maps, continuity, Fokker-Planck equations, Wasserstein geometry, and optimization in probability space. Within this framework, generative models can be used to learn nominal uncertainty, construct stressed or least-favorable distributions for robustness, and produce conditional or posterior distributions under side information and partial observation. We also highlight representative theoretical guarantees, including forward-reverse convergence for iterative flow models, first-order minimax analysis in transport-map space, and error-transfer bounds for posterior sampling with generative priors. The tutorial provides a principled introduction to using generative models for scenario generation, robust decision-making, uncertainty quantification, and related problems under distributional shift.

19.
arXiv (CS.LG) 2026-06-18

Some Complexity Results for Robustness Verification for Binarized Neural Networks

arXiv:2606.18918v1 Announce Type: new Abstract: This paper studies the computational complexity of verification problems for Binarized Neural Networks (BNNs), where activations (and sometimes weights) are binary. We analyze two problems: satisfiability and robustness under uniform image occlusion. We show that BNN satisfiability is NP-complete via a reduction from Boolean satisfiability problem (SAT), and that uniform occlusion induces a piecewise-constant structure in the network output, enabling a polynomial-time robustness-checking algorithm.

20.
arXiv (CS.AI) 2026-06-17

Handling Feature Heterogeneity with Learnable Graph Patches

arXiv:2606.17667v1 Announce Type: cross Abstract: In recent years, the rapid development of foundation models and graph pre-training technologies has spurred increasing interest in constructing a universal pre-trained graph model or Graph Foundation Model (GFM). However, a significant challenge is that existing models are unable to address feature heterogeneity in graph data without textual information, which hinders the transferability of graph models across different datasets. To bridge this gap, we propose the concept of learnable graph patches, which we regard as the smallest semantic units of any graph data. We decompose the graph into learnable graph patches by unfolding the node features and constructing corresponding patch structures separately. We then design a framework that mines transferable information from graph data across domains. Specifically, after extracting graph patches, we propose a patch encoder to extract knowledge from each unit and a patch aggregator to learn how the units are combined into a whole. Due to its domain-agnostic nature, the model can be applied to downstream data across different domains. Furthermore, we analyze the connection between our method and existing graph models, as well as the transferability of the node embeddings it generates. Empirically, our method not only achieves the capability to use multi-domain graphs for pre-training, but also shows enhanced performance across various downstream datasets and tasks. Moreover, we observe consistent improvement in downstream performance as the volume of pre-training data increases.

21.
arXiv (CS.AI) 2026-06-16

Reward Hacking in Language Model Agents: Revisiting AI Safety Gridworlds

arXiv:2606.15385v1 Announce Type: new Abstract: Reward hacking, where AI systems exploit misspecified objectives to achieve high reward without satisfying intended goals, remains a central challenge in AI safety. Yet most known instances have been discovered post hoc in frontier systems where controlled study is impractical. We adapt the AI Safety Gridworlds framework into a text-based evaluation suite that reformulates classic reinforcement learning safety tasks for language-based agents. Across frontier and mid-scale models, we find that specification gaming emerges zero-shot: models systematically achieve high observed reward while underperforming on hidden safety objectives, and even apparently safe behaviors can reflect misunderstanding rather than principled safety. Reinforcement learning does not correct these failures: direct reward optimization widens the gap between observed and hidden reward, as the model's initial competence causes it to lock into locally rewarding strategies before discovering safer alternatives. This pattern persists across model scales (1.5B–14B) and is not resolved by finer credit assignment, exploration prompts, or entropy regularization. Our results show that reward hacking arises naturally when optimizing proxy objectives with capable language model agents and resists standard mitigations, suggesting that proxy-reward failures in agentic settings may require approaches beyond standard exploration and credit-assignment fixes. To facilitate reproducibility, the code for this work is available at \href{https://github.com/asparius/verl-agent-safety}{our public repository}.

22.
bioRxiv (Bioinfo) 2026-06-22

Drug-Prot: A query system for statistical inference of drug effects and interactions in dynamic proteomic networks

Understanding drug effects and drug-drug interactions is essential for developing combination therapies. We present Drug-Prot, a computational framework that leverages large-scale perturbation proteomics to quantify causal drug effects, drug-drug interactions, and dynamic protein relationships. Using data from 63 single drugs and 59 drug combinations applied to 18 breast cancer cell lines at 6, 24, and 48 hours, Drug-Prot estimates drug effects on protein expression and reconstructs directed temporal protein dependency networks. The publicly available software enables targeted analyses of user-defined protein sets, substantially reducing the multiple-testing burden. Through an interactive web application, users obtain corrected p-values for single-drug and combination effects, directed temporal dependency networks, and downloadable results without requiring access to the underlying proteomic dataset. As a use case, we apply invariance-regularized Random Forests to triple-negative breast cancer cell lines to identify proteins associated with drug response. Querying these proteins in Drug-Prot reveals drug-specific and interaction effects at the protein-network level, illustrating how the framework links candidate causal protein features to actionable drug combinations.

23.
PLOS Computational Biology 2026-06-22

Heterogeneous suppressive effect of <i>Wolbachia</i> incompatible insect technique coupled with sterile insect technique across time and historical <i>Ae. aegypti</i> abundance - using distributional synthetic controls

Authors:

by Yichen Zhai, Chia-Chen Chang, Zhiyong Xi, Cheong Huat Tan, Lee Ching Ng, Jue Tao Lim Background Biological control tools such as Wolbachia incompatible-insect technique, are a promising class of interventions to modify and suppress Aedes aegypti mosquitoes to reduce risk of Aedes-borne diseases. Due to the spatial nature of the intervention, intervention effects can be spatio-temporally heterogeneous. Yet, most evaluations of field-based technologies rely on average treatment effects, which preclude characterization and understanding of treatment effect heterogeneities and the factors influencing it. Methods Here, we developed a causal inference framework using distributional synthetic controls to explicitly account for spatio-temporal trap-level mosquito abundance data to ascertain the entomological efficacy of Wolbachia in suppressing Ae. aegypti abundance. This method is able to construct counterfactual distributions of intervened areas, provide detailed comparisons to actual distributions and quantify treatment effects of the intervention on mosquito abundance over different quantiles. By employing our framework to trap-level mosquito abundance data from 57,990 unique mosquito traps routinely maintained and measured twice a week, and a large-scale field trial of Wolbachia incompatible-insect technique coupled with sterile insect technique (IIT-SIT) in Singapore, we (1) quantified heterogeneous treatment effects for IIT-SIT across the time-since-intervention, over the traps’ historical mosquito abundance, over calendar time, (2) quantified whether elimination of wild-type Aedes aegypti was possible in intervention locations and (3) addressed if suppressive effects in spillover locations adjacent to directly intervened locations were heterogeneous. Results IIT-SIT interventions led to a strong suppressive effect on adult Aedes aegypti abundance. From the onset of intervention in directly treated locations, sector-specific intervention effectiveness (IE) ranged from 24.04% in the earliest treatment period, and reached 86.08% in the latest treatment period. Raw reductions in aegypti abundance were also found to increase over time as sectors were intervened over longer time periods. In spillover sectors, IE was lower in magnitude and more variable, but average IE reached a maximum of 78.08% in 2-years post-treatment. Wolbachia interventions also led to an increase in the percentage of traps recording no mosquitoes from 6.8% at the start of intervention to 33.01% 124-weeks post-intervention. We found that IE was higher in sectors with lower historical mosquito abundance. However, IE converged across sectors with different historical mosquito abundance as intervention time increased. Conclusion This study revealed spatial heterogeneities in suppressing wild-type female Ae. aegypti by IIT-SIT and provided strong evidence that IIT-SIT can drastically suppress wild-type Ae. aegypti populations despite heterogeneous treatment effects over time.

24.
medRxiv (Medicine) 2026-06-10

Epidemiology of Cervical Precancerous Lesions: Prevalence and Predictors from Pap Smear Screening in Hawassa City Hospitals, Sidama Region, Ethiopia. Institutional-Based Cross-sectional Study

Background: Cervical cancer is the fourth most common cancer in women worldwide and remains a major public health challenge. In Ethiopia, it is the second leading cause of cancer deaths, with around 8,000 new cases and 6,000 deaths each year. Region?specific data on the prevalence and predictors of precancerous lesions remain scarce, yet such information is vital for guiding targeted reproductive health strategies. This study therefore examined the prevalence and predictors of cervical precancerous lesions among women aged 21-60 years undergoing Pap smear screening in public hospitals in Hawassa City, Sidama Region. Methods: An institution-based cross-sectional study was conducted among 241 women attending Pap smear screening at public hospitals in Hawassa City from March to August 2025. Sociodemographic and clinical data were collected via interviews and medical records. Lesions were classified based on the standardized international framework for reporting cervical cytology results from Pap smears per the Bethesda system. Multivariable logistic regression identified predictors p

25.
bioRxiv (Bioinfo) 2026-06-22

From hotspot dependence to distributed robustness in resistance-aware lead optimization

Drug resistance remains a recurrent failure mode in targeted anticancer and antiviral therapy, and resistance evidence often enters only after compound selection. ResistAgent is an evidence-constrained framework that converts mutational liabilities into design-time objectives through site- and combo-aware resistance mapping, deterministic mechanism diagnosis and robust counter-design. In EGFR-Erlotinib and HIV-RT-Rilpivirine, the framework separated residue-level liabilities from observed HIV combination liabilities and linked prioritized mutations to anchor loss, pocket rearrangement, electrostatic shifts and contact redistribution. Same-budget paired searches showed that robust objectives changed lower-tail mutant-panel behavior and interaction-dependence profiles while prioritizing robustness over average-affinity behavior. Under predefined liability panels, selected robust-best trajectories shifted support away from mutable hotspot contacts toward more distributed interaction networks. Supplementary physical summaries and ranking-first benchmarks support the scope of this resistance-aware design strategy while preserving clear boundaries for prospective validation.