Academic Intelligence · Curated Daily

探索全球前沿学术脉络

AcademicHub 汇聚顶级期刊与预印本平台的实时文献。定制您的专属科研雷达,利用大语言模型自动生成交叉领域文献分析简报。

01.
arXiv (CS.LG) 2026-06-25

Adaptive Cumulative Mass Calibration with Conformal Prediction

arXiv:2505.15437v3 Announce Type: replace-cross Abstract: Reliable probability estimates by classifiers are essential in high-risk applications. In practice, however, predicted probabilities are often miscalibrated, and many existing post-hoc calibration methods typically lack guarantees that a specific notion of calibration is achieved after the correction procedure is applied. We introduce a set-based perspective on calibration through the notion of cumulative mass calibration and the corresponding error measures. We propose a new calibration procedure based on conformal prediction that forms cumulative probabilities with guaranteed marginal coverage. We introduce an adaptive temperature scaling algorithm, with the temperature tuned for each input to satisfy the conformal coverage constraint. As we show, this procedure can be efficiently implemented. Across image classification tasks, particularly in settings with many classes, our method improves newly introduced calibration error measures (CMCE and $\alpha$-CMCE) and standard metrics (such as ECE, cw-ECE, MCE) over the existing baselines.

02.
PLOS Medicine 2026-05-11

Connected or chained by social media? Child and adolescent mental health in a digital era

作者:

by Silja Kosola Social media has evolved from connection to compulsion, disproportionately harming children and adolescents. Addictive designs together with developmental vulnerability fuel mental health risks and highlight the urgent need for stricter age limits and stronger protections. In this Perspective, Silja Kosola outlines how social media disproportionately harms child and adolescent mental health, and argues that while recent policy changes aimed at protecting youth from social media are welcome, stricter age limits and greater accountability of social media companies are needed.

03.
arXiv (math.PR) 2026-06-15

Ergodicity for stochastic 2D Boussinesq equations with a highly degenerate pure jump Levy noise

arXiv:2503.18045v2 Announce Type: replace Abstract: This study aims to analyze the ergodicity for stochastic 2D Boussinesq equations and explore the impact of a highly degenerate pure jump L\'{e}vy noise acting only in the temperature equation, where this noise could appear on only a few Fourier modes. By leveraging the equi-continuity of the semigroup established through Malliavin calculus and an analysis of stochastic calculus, together with the weak irreducibility of the solution process, we prove the existence and uniqueness of the invariant measure. Moreover, we overcome the main challenge of establishing time asymptotic smoothing properties of the Markovian dynamics corresponding to this system by conducting spectral analysis of the Malliavin covariance matrix.

04.
medRxiv (Medicine) 2026-06-22

Between Patterns and Predictions: Interpretable Latent EEG Representations for Clinical Insights

Electroencephalography (EEG) captures rich brain dynamics, yet in clinical practice this complexity is often reduced to simplified summaries or categorical labels, limiting its interpretability for decision-making. We tested the hypothesis that a pretrained latent embedding framework, the Universal Map of EEG (UM-EEG), can preserve clinically meaningful structure across heterogeneous datasets and provide a generalizable representation of brain states. We applied UM-EEG, without retraining, to three independent cohorts spanning distinct clinical contexts: long-term EEG recordings from cardiac arrest patients (n = 576), subarachnoid hemorrhage (n = 100), and routine clinical EEG recordings containing physiological and pathological patterns (n = 141). EEG segments were projected into a shared 128-dimensional space anchored by expert-derived reference states, including wakefulness, sleep stages, ictal-interictal continuum activity, and burst suppression. Across datasets, favorable outcome or physiological recordings were consistently located closer to healthy reference states, whereas poor outcome and pathological recordings shifted toward pathological regions of the embedding space. Trajectory-derived geometric and temporal features discriminated outcome in cardiac arrest (ROC-AUC 0.83) and subarachnoid hemorrhage (ROC-AUC 0.76), and distinguished physiological from pathological routine EEGs (ROC-AUC 0.93). In routine EEG, similarity relationships derived from embedding trajectories correlated with those derived from structured clinical reports, indicating that the latent space recapitulates clinically relevant organization. These findings show that a fixed, semantically structured EEG embedding generalizes across etiologies and recording settings, enabling prognostic stratification and contextual interpretation while preserving the relational structure of brain states.

05.
arXiv (quant-ph) 2026-06-24

When does dissipation help neural surrogates learn open quantum dynamics?

arXiv:2606.23894v1 Announce Type: new Abstract: Dissipation is usually viewed as an obstacle to predicting quantum dynamics, yet it can also contract trajectories toward steady states and thereby suppress accumulated prediction errors, leaving it unclear whether dissipation ultimately helps or hinders the learnability of open quantum dynamics. We investigate this question using Neural Ordinary Differential Equation (NODE) surrogates for open Heisenberg XYZ spin chains. Closed-system learnability deteriorates rapidly with system size, culminating in a static-prediction collapse at four qubits; dissipation reverses this trend, creating a broad high-fidelity regime at intermediate system sizes, while at four qubits a fidelity-aware objective recovers learnable rollout structure that is absent under closed-system training. Comparison against static and steady-state baselines reveals that dissipation improves performance through two fundamentally different mechanisms: at weak-to-moderate dissipation the surrogate captures nontrivial transient dynamics and substantially outperforms trivial predictors, whereas at stronger damping high fidelity increasingly reflects trajectory simplification toward the steady state rather than improved learned dynamics. These results show that dissipation can enhance the learnability of open quantum dynamics, but that fidelity alone is insufficient to distinguish genuine dynamical learning from steady-state trivialization: dissipative contraction and trajectory simplification are distinct effects that peak in different regimes and should be disentangled when evaluating learned quantum-dynamical surrogates.

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

Enhanced Evolutionary Multi-Objective Deep Reinforcement Learning for Reliable and Efficient Wireless Rechargeable Sensor Networks

arXiv:2510.21127v2 Announce Type: replace-cross Abstract: Despite rapid advancements in sensor networks, conventional battery-powered sensor networks suffer from limited operational lifespans and frequent maintenance requirements that severely constrain their deployment in remote and inaccessible environments. As such, wireless rechargeable sensor networks (WRSNs) with mobile charging capabilities offer a promising solution to extend network lifetime. However, WRSNs face critical challenges from the inherent trade-off between maximizing the node survival rates and maximizing charging energy efficiency under dynamic operational conditions. In this paper, we investigate a typical scenario where mobile chargers move and charge the sensor, thereby maintaining the network connectivity while minimizing the energy waste. Specifically, we formulate a multi-objective optimization problem that simultaneously maximizes the network node survival rate and mobile charger energy usage efficiency across multiple time slots, which presents NP-hard computational complexity with long-term temporal dependencies that make traditional optimization approaches ineffective. To address these challenges, we propose an enhanced evolutionary multi-objective deep reinforcement learning algorithm, which integrates a long short-term memory (LSTM)-based policy network for temporal pattern recognition, a multilayer perceptron-based prospective increment model for future state prediction, and a time-varying Pareto policy evaluation method for dynamic preference adaptation. Extensive simulation results demonstrate that the proposed algorithm significantly outperforms existing approaches in balancing node survival rate and energy efficiency while generating diverse Pareto-optimal solutions. Moreover, the LSTM-enhanced policy network converges 25% faster than conventional networks, with the time-varying evaluation method effectively adapting to dynamic conditions.

07.
arXiv (CS.LG) 2026-06-11

PianoKontext: Expressive Performance Rendering from Deadpan Context

arXiv:2606.12282v1 Announce Type: cross Abstract: Expressive performance rendering (EPR) aims to generate realistic performances constrained on sequences of notes. However, flow matching audio editing models manipulate only synchronized music samples of the same duration, limiting their understanding of expressive timing. We introduce PianoKontext, a flow matching rendering model for classical piano music that generates variable-length performances in the latent space of a pretrained Music2Latent model. We synthesize MIDI scores into deadpan audio and employ Dynamic Time Warping (DTW) in the latent space to construct paired data for training. The aligned embeddings are concatenated in DiT blocks, allowing for a simple and effective learning of the dependencies between the score and performances. Audio samples are available at our demo page: https://realfolkcode.github.io/pianokontext_demo/.

08.
arXiv (CS.AI) 2026-06-17

Mental Health AI Safety Claims Must Preserve Temporal Evidence

arXiv:2605.08827v2 Announce Type: replace Abstract: The safety of mental health AI is often judged at the wrong temporal scale. Current evaluations typically score isolated responses, endpoint outcomes, or aggregate dialogue quality, while clinically consequential failures may arise from the order and accumulation of interactions themselves, including delayed escalation, repeated reinforcement, dependency formation, failed repair, and gradual deterioration across turns. This paper argues that this mismatch is not merely a limitation of evaluation coverage but a source of invalid safety conclusions. We introduce Temporal Safety Non-Identifiability, a formal account of why safety properties that depend on sequence, timing, accumulation, or recovery cannot be certified by protocols that discard those features. From this formalization, we develop SCOPE (Safety Claims Over Preserved Evidence) as a general principle for aligning safety claims with the evidence an evaluation actually retains, and instantiate it as SCOPE-MH, a mental-health instantiation of this reporting standard. We operationalize SCOPE-MH through a proof-of-concept on the AnnoMI dataset of expert-annotated motivational interviewing conversations, which reveals mechanisms of failure that per-turn behavior scoring does not represent. We propose SCOPE-MH as a diagnostic complement to existing evaluation infrastructure and argue that evaluation preserving temporal evidence is necessary, not optional, for safety-critical mental health AI deployment.

09.
arXiv (CS.AI) 2026-06-16

Learning aligned EEG representations with subject-specific encoders

arXiv:2606.16462v1 Announce Type: cross Abstract: Cross-subject EEG decoding promises more training data, but it also exposes neural networks to strong inter-subject distribution shifts. We study whether task supervision and architecture alone can learn subject-aligned representations. We replace a shared EEG encoder with subject-specific encoders followed by a common classifier, and compare this hybrid model with standard EEGNet, AttentionBaseNet, and CTNet baselines with Euclidean Alignment (EA) on four motor-imagery datasets. EA improves shared encoders by recentering subject covariances, but the hybrid encoder largely internalises this role: validation-loss curves and latent-distance analyses change little when EA is removed. Subject-specific heads increase class distinctiveness and place each subject close to its own latent manifold, improving most subjects while leaving a method-sensitive subset. These results support subject-specific encoders as a learned alignment mechanism for EEG decoding and identify head selection for unseen subjects as the remaining bottleneck.

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

DeepRoot: A KG-Coordinated Multi-Agent System for Therapeutic Reasoning over Historical Medical Texts

arXiv:2606.15931v1 Announce Type: cross Abstract: Historical medical archives and traditional medicines hold immense potential for drug discovery and remain a primary source for current drug development. However, pre-ontological prose and idiosyncratic taxonomies prevent the standardization and medical modernization of the data for use in current biomedical pipelines. Furthermore, no existing LLM agent system, whether tool-calling, retrieval-augmented, or agentic deep-research, can convert such text into verifiable drug-discovery leads at scale. We close this gap with DeepRoot, a multi-agent LLM system that jointly builds and utilizes a verified knowledge graph, showing that grounding and reasoning – often conflated – are separable axes the system can compose for therapeutic reasoning. Applied to the Shen Nong Ben Cao Jing, DeepRoot recovers $10$ of $21$ held-out compound-disease treatment pairs at R@$20$ ($47.6\%$ vs $4.8\%$ for a raw corpus LLM and $\sim\!2.4\%$ random) and dominates an LLM-as-judge audit for reasoning quality over baseline LLMs and LLMs with direct tool-call access to the same APIs DeepRoot itself queries. Tool-using LLMs hallucinate evidence on $87\%$ of claims, versus 7-10% for DeepRoot. Graph-only inference hallucinates $0\%$ but ranks lowest on reasoning coherence; DeepRoot KG+LLM is the only condition to win on both axes, pointing toward a route for systematic mining and repurposing of historical medical knowledge.

11.
arXiv (CS.CV) 2026-06-12

OmniDirector: General Multi-Shot Camera Cloning without Cross-Paired Data

Cloning camera motion from reference videos is an important task in video generation, as videos provide intuitive and precise control. Existing methods either directly use parametric representations that fail to handle multi-shot generation or synthesize cross-paired data, which suffer from data scarcity, resulting in poor performance in complicated camera motion cloning. To address these issues, we introduce a general camera motion representation that encodes cameras as grid motion videos. This camera grid represents the camera parameters visually and supports the integration of diverse trajectories for multi-shot video generation. Building upon this, we propose OmniDirector, a unified framework trained on a million-scale camera grid-video pairs that coordinates characters, actions, and cameras to provide director-level control for multimodal diffusion transformers. Furthermore, we design a novel hierarchical prompt expansion agent that harmoniously integrates different control signals by systematically describing camera motion and visual content through understanding signal relationships. Extensive experiments demonstrate the superior performance and outstanding controllability of our framework. Project page: https://ymlinfeng.github.io/OmniDirector.github.io/

12.
arXiv (math.PR) 2026-06-17

Convergence Analysis of the Random Bisection Method

arXiv:2603.20483v2 Announce Type: replace-cross Abstract: We propose a generalized version of the bisection method where the cutting point between the two subintervals is chosen at random following an arbitrary distribution. We compute expected convergence rates with respect to any arbitrary a priori distribution for the position of the root in the initial interval and proved that it depends only on the the expectation $\mathbb{E}[c(1-c)]$ of the cut $c$. We also provide a generalization of the method for $K$ random cuts and study its convergence properties. Most probabilistic derivations are kept fairly simple for the ease of understanding of a larger audience. Our theoretical results are then validated numerically using statistical simulation.

13.
arXiv (CS.LG) 2026-06-24

Accelerated Stochastic Min-Max Optimization Based on Bias-corrected Momentum

arXiv:2406.13041v3 Announce Type: replace Abstract: Lower-bound analyses for nonconvex strongly-concave minimax optimization problems have shown that stochastic first-order algorithms require at least $\mathcal{O}(\varepsilon^{-4})$ sample complexity to find an $\varepsilon$-stationary point. Some works indicate that this complexity can be improved to $\mathcal{O}(\varepsilon^{-3})$ when the stochastic loss gradient is Lipschitz continuous. The question of achieving enhanced convergence rates under distinct conditions, remains open. In this work, we address this question for optimization problems that are nonconvex in the minimization variable and strongly concave or Polyak-Lojasiewicz (PL) in the maximization variable. We introduce novel bias-corrected momentum algorithms utilizing efficient Hessian-vector products. We establish convergence conditions and demonstrate a lower iteration complexity of $\mathcal{O}(\varepsilon^{-3})$ for the proposed algorithms. The effectiveness of the proposed method is validated through applications to robust logistic regression and robust adaptive cruise control.

15.
arXiv (CS.CV) 2026-06-24

FlowDec: Temporal Conditional Flow Decorruptor for Robust Continuous Vision-Language Navigation

Vision-and-Language Navigation in Continuous Environments (VLN-CE) requires agents to follow natural-language instructions in unseen scenes. While Large Models (LMs) have advanced VLN-CE, their performance remains severely degraded by real-world visual corruptions, a critical yet underexplored domain constraint. We introduce Temporal Conditional Flow Decorruptor (FlowDec), a novel image restoration framework tailored for LM-based VLN-CE. FlowDec integrates a hybrid temporal conditioning strategy to align the generative flow path with historical context and employs action-centroid guided filtering to dynamically assess and integrate outputs. Extensive experiments demonstrate that FlowDec outperforms state-of-the-art decorruption methods in both navigation accuracy and generation latency. Our approach establishes a robust, efficient paradigm for resilient embodied navigation in unpredictable real-world conditions.

16.
arXiv (quant-ph) 2026-06-24

Quantum Adaptive Self-Attention for Quantum Transformer Models

arXiv:2504.05336v4 Announce Type: replace Abstract: A recurring weakness in quantum machine learning (QML) is that reported ``quantum advantages'' are seldom tested against a capacity-matched classical control, leaving it unclear whether a gain comes from the quantum substrate or from the architectural change that accompanies it. Our primary contribution is methodological: a protocol for attributing such gains honestly – a capacity-matched classical bottleneck of identical parameter budget, transparent reporting of where quantum does not help, and validation on real quantum hardware – which we develop and apply through a concrete case study. That case study is Quantum Adaptive Self-Attention (QASA), a hybrid Transformer that replaces the value projection of a single encoder layer with a 36-parameter parameterized quantum circuit (PQC), keeping all other layers classical. Across nine synthetic benchmarks and the real-world ETTh1 dataset, QASA improves on a full-capacity classical Transformer for chaotic and trend-dominated signals. To ask whether this is a genuinely quantum effect, we introduce a control rarely applied in quantum machine learning – a capacity-matched classical bottleneck with the same parameter budget – and find that it matches the PQC on the error metrics. The gain is therefore attributable to the low-rank value-projection bottleneck (an architectural parsimony principle), not to quantumness; adding further quantum layers only degrades performance and trainability. We accordingly position the quantum layer not as a source of accuracy advantage but as a competitive instantiation of this principle: its low-rank compression onto the signal's intrinsic dimensionality is matched by a classical bottleneck, so the gain is architectural rather than quantum.

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

S-GBT: Smooth Growth Bound Tensor for Certified Robustness Against Word Substitution Attacks in NLP

Despite recent progress in Natural Language Processing (NLP), models remain vulnerable to word substitution attacks. Most existing defenses focus on first order sensitivity and measure how much the output changes when the input is slightly perturbed. However, they ignore how this sensitivity evolves, which is described by curvature. When gradients vary sharply, models can still fail. This paper introduces the Smooth Growth Bound Tensor (S-GBT), a second order method that bounds the Hessian element-wise, for which we provide formal theoretical proofs on the resulting robustness bounds. A regularization term is added during training to minimize these bounds. This yields tighter certified robustness against word substitution attacks. The change in the output under word substitution is bounded by both a linear term and a quadratic term. S-GBT is derived for two architectures: Long Short-Term Memory (LSTM) and Convolutional Neural Networks (CNN). The method is integrated directly into the training objective. Its effectiveness is evaluated on multiple benchmark datasets. The results show that combining first and second order regularization improves certified robust accuracy by up to 23.4% compared to prior methods, while clean accuracy remains competitive. These findings indicate that controlling both the gradient and its variation is a promising direction for building more robust models.

18.
arXiv (quant-ph) 2026-06-19

A Finite-Volume Scheme for the Continuum Extrapolation of Lattice Step-Scaling in (2+1)D Hamiltonian U(1) Gauge Theory

arXiv:2606.20029v1 Announce Type: cross Abstract: We propose a finite-volume scheme to perform controlled continuum extrapolations of the lattice step-scaling function, a key ingredient for determining the running coupling in a Hamiltonian lattice gauge theory in small volumes. As a testbed, we employ a dual Hamiltonian formulation of pure U(1) gauge theory in (2+1) dimensions and an operator basis that remains efficient toward weak coupling. We describe the implementation of static external charges on the spatial lattice and study, using matrix product states, the resulting confining string, from which we extract the static potential and a force-based renormalized coupling. Using the proposed finite-volume scheme, we demonstrate a stable continuum limit of the step-scaling function on the lattice sizes accessible to present Hamiltonian simulations. The method is readily extendable to other gauge groups and dimensions, providing a pathway toward Hamiltonian step-scaling studies in other theories.

19.
medRxiv (Medicine) 2026-06-17

Wearable-Grade Lead Reduction Disproportionately Degrades ECG AI Performance in Elderly Patients: Evidence from PTB-XL and MIT-BIH

Consumer wearable devices increasingly use single-lead electrocardiograms (ECGs) for cardiac monitoring, but these signals contain substantially less spatial information than the clinical 12-lead standard. Whether this reduction dispro- portionately affects older adults, who often present with more complex cardiac conditions, remains poorly understood. In this study, we evaluated the impact of lead reduction on AI-ECG diagnostic performance across age groups. A 1D resid- ual neural network was trained on 21,091 PTB-XL ECG recordings spanning five diagnostic superclasses and assessed using 12-, 6-, 2-, and 1-lead configurations. Under the full 12-lead setting, model accuracy declined from 84.5% in patients younger than 40 years to 66.2% in patients aged 75 years or older. Progressive lead reduction further widened this gap. Under the 1-lead configuration, accuracy decreased by 14.1 percentage points in the 75+ group but by only 0.4 percent- age points in the

20.
arXiv (quant-ph) 2026-06-15

Dissipation-induced superradiance in matter coupled to a self-interacting cavity

arXiv:2606.14526v1 Announce Type: new Abstract: Light-matter interactions are often modeled via the Dicke model, namely, by two-level systems coupled to a cavity mode. Alas, the threshold for superradiance is often experimentally inaccessible or hindered by light's diamagnetic term. Here, within the Dicke setting, we consider self-interacting light in a cavity, modeled by a photonic Kerr nonlinearity. We show that negative Kerr nonlinearity gives rise to a low-threshold superradiant phase with spin inversion. While unstable in a closed system, cavity dissipation stabilizes this lit phase, opening avenues for lasing and bath-engineered phases.

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

Unstable Features, Reproducible Subspaces: Understanding Seed Dependence in Sparse Autoencoders

Sparse autoencoders (SAEs) are widely used to interpret neural network representations, but their utility depends on whether the learned features are reproducible across training runs. We study this question through feature stability: for each SAE feature, we estimate the probability that a similar feature reappears in an independently trained SAE. This yields a scalable per-feature signal that separates stable from unstable features. In a large-scale study across seeds, models, layers, dictionary sizes, and SAE variants, we find a pronounced functional asymmetry: stable features carry most of the reconstruction- and prediction-relevant signal, while unstable features have weak marginal impact and are dominated by low-frequency surface-form triggers in both activation statistics and automatic explanations. Geometrically, unstable features are individually non-reproducible but concentrate in reproducible lower-rank subspaces, suggesting that seed dependence often reflects basis ambiguity within a shared region of activation space rather than pure noise. A controlled synthetic model makes this mechanism explicit, showing that low-rank ground-truth features can be recovered at the subspace level while remaining non-identifiable as individual SAE latents across seeds. Finally, by pooling unique cross-seed features, we construct more stable SAEs while preserving explained variance in this setting. Together, these results show that unstable features are not merely failed or noisy latents: they have weak individual functional impact, but reflect reproducible low-dimensional structure that standard SAEs resolve differently across seeds.

22.
arXiv (CS.LG) 2026-06-18

Detecting Hidden ML Training With Zero-Overhead Telemetry

arXiv:2606.19262v1 Announce Type: new Abstract: Hardware-enabled monitoring of GPU workloads underpins many proposals for AI compute governance, but if developers can defeat monitoring mechanisms, such schemes are unworkable. We evaluate the adversarial robustness of GPU workload classification using only zero-overhead, privacy-preserving NVML telemetry: content-agnostic signals that observe physical effects of computation without accessing model weights, training data, or hyperparameters. Across 5 rounds of monitor-evader iteration, we evaluate 20 evasion strategy families on 9 GPU models spanning 4 architecture generations. We develop a classifier that achieves 98.2% binary accuracy at identifying training workloads across the whole corpus, and 43-87% accuracy against the most challenging unexpected workloads even when they are adversarially disguised.

23.
arXiv (CS.CV) 2026-06-11

Reason, Then Re-reason: Cross-view Revisiting Improves Spatial Reasoning

Spatial reasoning from egocentric videos is inherently challenging because the observable evidence is constrained by the camera trajectory. Existing methods rely on single-turn inference, forcing models to resolve geometric ambiguity through semantic priors rather than verifiable evidence. We argue that spatial reasoning should be revisitable: conclusions formed under limited evidence should remain open to revision when complementary viewpoints become available. Building on this insight, we propose Reason, then Re-reason (ReRe), a training-free, inference-time framework with two phases: in the Reason Phase, an MLLM forms a spatial hypothesis from the original video; in the Re-reason Phase, it verifies or revises the hypothesis by observing a synthesized novel-view video. To enable effective cross-view revisiting, we design a Geometry-to-Video pipeline that renders strategically complementary novel views from predicted 3D geometry. These views feature an elevated, oblique perspective with scene-spanning coverage, while preserving the MLLM's native video interface without architectural modifications. Extensive evaluations on VSI-Bench and STI-Bench demonstrate that ReRe substantially boosts open-source MLLMs to rival proprietary state-of-the-art performance. Project page: https://zhenjiemao.github.io/ReRe/

24.
bioRxiv (Bioinfo) 2026-06-15

Multi-platform reassessment of human mitochondrial DNA methylation reveals signals consistent with technical artifacts

The existence and functional relevance of mitochondrial DNA methylation remain controversial. Here, we systematically profiled cytosine methylation and hydroxymethylation across human brain and blood tissues spanning healthy and malignant states using orthogonal sequencing approaches that avoid chemical conversion during library preparation. While nuclear DNA exhibited canonical methylation patterns, mitochondrial DNA consistently showed negligible signal, indistinguishable from background technical noise. By mapping cytosine-guanine sites between mitochondrial DNA and nuclear-embedded mitochondrial sequences, we demonstrate the potential of these nuclear counterparts to confound not only cytosine methylation but also hydroxymethylation measurements, corroborating and extending prior findings implicating nuclear contamination as a potential source of apparent mitochondrial epigenetic signals. Additional technical factors that inflate apparent mtDNA methylation signals were identified, including sequence context biases, flow cell chemistries, and coverage-dependent discrepancies between the heavy and light strands. Collectively, these results provide convergent evidence against the presence of biologically meaningful cytosine methylation or hydroxymethylation in mitochondrial DNA. These findings caution against interpreting apparent mtDNA methylation signals in human adult tissues as meaningful without rigorous orthogonal validation and comprehensive consideration of technical and analytical confounding factors.

25.
bioRxiv (Bioinfo) 2026-06-24

A comprehensive analysis of calreticulin mutants reveals distinct biophysicochemical proprieties with a potential for refined targeted therapies

Calreticulin mutations in myeloproliferative neoplasms result in the replacement of the C-terminus acidic sequence with a positively charged tail that causes pathological activation of the thrombopoietin. The two canonical variants are Type-1 and Type-2. The remaining are mainly classified as Type-1 or Type-2 like based on the wild type sequence retained. Here, we performed in silico biophysicochemical analyses of 76 CALR exon 9 frameshift variants by their sequence and predicted biophysical properties, complemented by structural modeling of the mutant homodimers. Beyond confirming the Type-1 versus Type-2 distinction, we found that the Type 1-like variants form a continuum of charge architecture along which two reproducible subgroups can be identified, rather than sharply separated classes. This work refines the conventional mechanism-based classification into a charge-resolved framework and provides testable hypotheses linking novel-tail chemistry to receptor activation in CALR-mutant neoplasms and paves the way for improved targeted therapies based on individual mutants characteristics