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01.
arXiv (quant-ph) 2026-06-11

Robust Mixed-State Cluster States and Spurious Topological Entanglement Negativity

arXiv:2504.16165v2 Announce Type: replace Abstract: We investigate 1D and 2D cluster states under local decoherence to assess the robustness of their mixed-state subsystem symmetry-protected topological (SSPT) order. By exactly computing fidelity correlators via dimensional reduction of effective statistical mechanics models, we pinpoint the critical error rate for strong-to-weak spontaneous breaking of strong subsystem symmetry. Without resorting to the replica trick, we demonstrate that mixed-state SSPT order remains remarkably robust up to the maximal decoherence rate when noise respects strong subsystem symmetry. Furthermore, we propose that the mixed-state SSPT order can be detected by a constant correction to the area-law scaling of entanglement negativity, termed spurious topological entanglement negativity. This also highlights that topological entanglement negativity, a widely used diagnostic for mixed-state topological order, is generally not invariant under finite-depth quantum channels.

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

Legal Reasoning Is Not Lawyering: Rethinking Legal Benchmarks for Pro Se Access to Justice

arXiv:2606.23716v1 Announce Type: cross Abstract: Legal AI benchmark research frequently invokes the assumption that large language models can improve access to justice, including for people who cannot access lawyers in order to understand and exercise their legal rights. We argue that current benchmarks are not equipped to support this assumption because they evaluate legal reasoning over inputs that have already been preprocessed by legal experts, which measures the upper bound of model performance. Access to justice depends on a lower bound: how models perform when inputs come from pro se litigants, whose prompts may contain noisy narratives, buried facts, omissions, folk-legal assumptions, and surface-level errors. These degradations are comparable to conditions under which LLMs are known to degrade in the general machine learning literature, including long-context sensitivity, underspecification, hallucination, and typographical perturbations. We connect evidence from pro se literature with this body of machine learning research and present a small perturbation experiment on LEXam, a legal benchmark, to illustrate the gap between these two bounds. If model development continues to focus on benchmarks that measure only the upper bound, this gap may remain hidden or even widen. We conclude by calling for legal benchmarks that directly measure robustness under pro se-like inputs so that access-to-justice claims about legal AI can become empirically testable.

03.
Science (Express) 2026-06-11

Chemically induced skin tumors arise from long-lived stem cells of the upper hair follicle | Science

Authors: Unknown Author

The identification of the cancer cell of origin is a fundamental question in cancer biology. We used fluorescent lineage tracing of independent mouse skin stem cell populations, single cell transcriptomics, and Duplex sequencing, to identify the origin of chemically induced skin tumors. Tumors arose predominantly from Lgr6+ and / or Lrig1+ stem cells of the upper hair follicle, but only very rarely from the Lgr5 + and Krt19 + hair follicle bulge. Lgr6 + stem cells initiated by dimethylbenzanthracene responded to tumor promoter treatment resulting in clonal expansion of initiated cells carrying the canonical Hras Q61L mutation. Spontaneous mutations in Kras also clonally expanded, but did not generate tumors unless the Hras gene was deleted, thus revealing a competitive interaction between Hras and Kras pathways that influences clonal selection.

04.
arXiv (CS.CL) 2026-06-11

Beyond representational alignment with brain-guided language models for robust reasoning

The correspondence between large language models (LLMs) and the neural mechanisms underlying human higher-order cognition remains insufficiently characterized. Given that language and reasoning in the human brain appear dissociable, an open question is whether LLMs align with neural signals from reasoning-related regions and whether such signals can improve them. Here, focusing on deductive reasoning, we show that LLM internal representations are not only partially aligned with task-fMRI activity but can also be directly enhanced by these signals. Using a neural-predictivity metric, we find that LLMs explain a substantial fraction of the explainable variance in reasoning-related regions at the aggregate level, whereas predictivity within specific reasoning types is lower, indicating both alignment and divergence. Building on this, we propose a brain-guided framework: we steer model representations along directions induced by the joint structure of model and brain representations, applying intervention at inference and fine-tuning during training. We demonstrate that task-evoked brain signals can directly enhance LLM reasoning, yielding gains orthogonal to language-only supervision across 10 LLMs (1.5B-72B), with transfer across reasoning types and up to 13\% absolute accuracy gain. Our results advance LLM-brain correspondences from correlation to guidance, establishing a brain-signal-driven pathway toward more robust and cognitively aligned AI.

05.
arXiv (CS.AI) 2026-06-24

Cycle-Consistent Neural Explanation of Formal Verification Certificates

arXiv:2606.24414v1 Announce Type: new Abstract: Formal verification produces machine-checkable certificates that attest to the satisfaction or violation of temporal properties, yet these certificates remain opaque to non-specialist stakeholders. We propose a cycle-consistent neural architecture that generates faithful natural language explanations of verification certificates. A forward network NN1 maps certificates to explanations, and an inverse network NN2 reconstructs certificates from explanations; a symbolic verifier closes the loop, providing a differentiable faithfulness proxy. A pointer-generator mechanism ensures lexical grounding by copying state names directly from the certificate. We evaluate on 420 test certificates spanning six verification methods (bounded proof, k-induction, inductive invariant, lasso, reachability, witness pair) in both YES and NO verdict variants, drawn from a financial compliance domain with 207 named states. Our trained architecture, combined with a hybrid inference-time routing strategy, achieves 90.0% cycle-verified soundness, surpassing a multi- LLM few-shot baseline (76.1% for the best of 16 LLM combinations across four frontier models) by 13.9 percentage points. The neural model wins on 10 of 12 verdict/kind categories, with three categories reaching 100% soundness. The architecture offers 860x faster inference (185 ms vs. 160 s per certificate for the full multi-LLM baseline), offline operation, deterministic outputs, and zero per-inference cost. These results demonstrate that trained specialization outperforms general-purpose LLM prompting for structured certificate explanation, while eliminating the deployment constraints of cloud-based inference.

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

Amortizing Maximum Inner Product Search with Learned Support Functions

arXiv:2603.08001v2 Announce Type: replace Abstract: Maximum inner product search (MIPS) is a crucial subroutine in machine learning, requiring the identification of a vector taken within a database (the keys) that best aligns with a given query. We propose amortized MIPS: a regression-based approach that trains neural networks to directly predict MIPS solutions, amortizing the cost of repeatedly solving MIPS for queries drawn from a known distribution over a fixed key database. Our key insight is that the MIPS value function is the support function of the set of keys, a well-studied convex function whose gradient yields the optimal key. This motivates two complementary amortized models: SupportNet, an input-convex neural network trained to regress the support function, and KeyNet, a vector-valued network that directly regresses the optimal key. SupportNet can serve as a cluster router, steering queries toward relevant database partitions, while KeyNet can be used as a drop-in replacement for the original query, fed directly to off-the-shelf indexing pipelines. Our experiments on the BEIR benchmark show that, for document embeddings, learned \SupportNet{}s and \KeyNet{}s significantly improve IVF match rates when accounting for compute effort, whether measured in FLOPs, number of probes, or wall-clock time. Our code is available at: https://github.com/apple/ml-amips.

07.
arXiv (math.PR) 2026-06-19

Theory of uncertain probability: can we derive the probability density function of uncertain random experiments with continuously changing conditions?

Authors:

arXiv:2606.20169v1 Announce Type: new Abstract: This paper aims to explore the formation mechanism of probability distribution in situations where the differences among random experiments are distinguishable, and these differences continue to evolve along with the dynamic changes in conditions and their mechanisms of action. To this end, we are motivated to devise a new theoretical system – theory of uncertain probability (TUP) with Kolmogorov's system and nonlinear theories as special cases. TUP develops a novel model that integrates probability and uncertainty as well as the known and unknown to more accurately depict numerous typical random phenomena under more realistic assumptions, and thus provides appropriate tools for greater variety of real needs. It also allows for pioneering interpretation of the causal mechanisms underlying many important distributional characteristics and incorporation of pathwise property to distribution model.

08.
bioRxiv (Bioinfo) 2026-06-22

PanRes: A database of latent and acquired antimicrobial resistance allowing 3D-based protein homology search

Antimicrobial resistance databases are central to genomic surveillance, but resistance determinants remain distributed across resources with different scopes, structures, and annotations. We developed PanRes, a curated resistance database of 11,717 genes integrating acquired and latent determinants of antibiotic, biocide, and metal resistance within a unified ontology. We predicted representative protein structures and clustered them by structural similarity, grouping proteins into 598 structurally conserved clusters coherent despite sequence divergence. Their structure-guided alignments were used to build Hidden Markov Models (HMMs) for remote homology search. In wastewater metagenomes from seven European cities, PanRes 3D-based HMMs expanded detection beyond high-confidence BLAST, with 35.2% of retained hits identified only by the HMMs and generally showing greater divergence from known proteins. For beta-lactamases, several proteins retained beta-lactamase-like folds and catalytic geometry despite weak sequence similarity. PanRes is available through an interactive web platform (https://panres.rambio.dk/), a structure-informed resource for exploring the whole resistome.

09.
arXiv (CS.AI) 2026-06-18

A Clinician-Centered Pipeline for Annotation and Evaluation in Ultrasound AI Studies

arXiv:2606.19174v1 Announce Type: cross Abstract: Clinician-centered evaluation is critical for validating medical AI systems, especially in ultrasound imaging where quantitative metrics do not always capture clinical usability. Existing medical image platforms primarily focus on dataset labeling. They lack integrated support for blinded model comparison and reproducible evaluation workflows. We present a clinician-centered pipeline for remote annotation and evaluation in ultrasound AI studies. The proposed pipeline uses a centralized server and lightweight browser interfaces to enable clinicians to perform annotation, blinded ranking, and review without local dataset downloads. The pipeline also supports multi-rater participation, centralized result aggregation, and automated statistical analysis. We validate the pipeline in a fetal ultrasound segmentation study with six raters spanning expert, generalist, and non-expert experience levels. The system automatically generated Spearman correlation, Kendall's $\tau$, and top-1 selection statistics. Results indicated moderate to strong agreement across experts and other groups. The blinded evaluation results showed a tendency for later active learning models to be preferred. These outcomes suggest that the pipeline can support clinician-centered annotation and reproducible human-\ac{AI} evaluation studies in ultrasound imaging. The proposed pipeline is available on \href{https://github.com/13204942/SonoRate}{GitHub}.

10.
arXiv (CS.CL) 2026-06-19

LedgerAgent: Structured State for Policy-Adherent Tool-Calling Agents

Policy-adherent tool-calling agents in customer-service domains must maintain task states across turns while calling tools and obeying domain policies. Task states consist of relevant facts, identifiers, constraints, and conditions observed through user interaction and tool calls. In standard agents, task states are not represented separately. Observations, tool returns, and policy instructions are placed in the prompt, leaving agents to reconstruct the relevant states from the prompt each time they decide what to do next. This design makes state management implicit, creating two common failure modes. An agent may retrieve the right facts but later ground its decision in stale, missing, or incorrect information; and a syntactically valid tool call may still violate a domain policy that depends on the current task state. We introduce \textsc{LedgerAgent}, an inference-time method for tool-calling agents that maintains observed task states in a separate ledger and renders the states into the prompt. The ledger is also used to check state-dependent policy constraints before environment-changing tool calls are executed, blocking policy violations. Across four customer-service domains and a mixed panel of open- and closed-weight models, \textsc{LedgerAgent} improves average pass\textasciicircum{}k over a standard prompt-based tool-calling approach, with the largest gains under stricter multi-trial consistency metrics.

11.
arXiv (quant-ph) 2026-06-19

Optimal multi-spectral squeezing via deterministic 2D-phase optimization

arXiv:2606.20192v1 Announce Type: new Abstract: Optimization routines are ubiquitous in quantum information technologies and essential to reach the resource levels required by quantum protocols. Specifically, multi-spectral squeezing for use in such protocols requires that losses be kept minimal at every stage, including coherent detection, which is performed by interfering the signal with a classical local-oscillator beam. This in turn requires control over all optical degrees of freedom of the beam in order to optimize the detection. The most general framework for this optimization relies on agnostic, off-the-shelf machine-learning techniques. Here we take the opposite approach: by focusing on a physical description of the specific optical process, we develop a deterministic sequential algorithm that provably reaches the global maximum of the visibility in a pixel basis and scales linearly with the number of pixels, thereby offering an efficient and theoretically grounded alternative to black-box optimization. In our waveguide-based setup, the optimized mask increases the visibility from 76% to 84%, corresponding to a 20% gain in mode-matching efficiency. Multi-spectral squeezing measurements confirm that this improvement translates directly into quantum readout: for the most squeezed spectral mode, the squeezing increases from $-2.08$ dB to $-2.64$ dB, consistent with the inferred efficiency gain. These results establish deterministic spatial phase shaping as an effective, interpretable route to enhanced multimode squeezing in waveguide platforms.

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

ECA: Efficient Continual Alignment for Open-Ended Image-to-Text Generation

Incremental Learning (IL) for Open-ended Image-to-Text Generation (OpenITG) enables models to continuously generate accurate, contextually relevant text for new images while preserving previously acquired knowledge. Unlike prior studies, this paper addresses a more practical scenario in which the predominant category of visual data shifts over time as environments evolve. In this context, we introduce a new notion of continual alignment, which incrementally adapts the alignment module within pre-trained VLMs to preserve high-quality cross-modal representations. Based on this idea, we propose Efficient Continual Alignment (ECA), a novel exemplar-free IL approach for OpenITG. The key challenge is enabling the model to acquire new, task-specific features while minimizing interference with the established alignment without accessing raw data from previous tasks. To address this, ECA employs three core mechanisms: a Mixture of Query (MoQ) module that adapts task-specific query tokens, a Fisher Dynamic Expansion (FeDEx) that dynamically expands model structure based on a Fisher Information Matrix (FIM)-based metric, and an embedding dictionary with Dictionary Replay (DR) to retain past knowledge. To evaluate ECA's performance, we construct four new IL OpenITG benchmarks that better reflect real-world scenarios. Experimental results demonstrate that ECA significantly mitigates catastrophic forgetting and improves IL performance compared to baseline methods. Code and benchmarks are available at https://github.com/Snowball0823/ECA.

13.
arXiv (CS.CV) 2026-06-16

HanDyVQA: A Video QA Benchmark for Fine-Grained Hand-Object Interaction Dynamics

Hand-object interaction (HOI) inherently involves dynamics where human manipulations produce distinct spatio-temporal effects on objects. However, existing semantic HOI benchmarks focused either on manipulation or on the resulting effects at a coarse level, lacking fine-grained spatio-temporal reasoning to capture the underlying dynamics in HOI. We introduce HanDyVQA, a fine-grained video question-answering benchmark that comprehensively covers both the manipulation and effect aspects of HOI. HanDyVQA comprises six complementary question types (Action, Process, Objects, Location, State Change, and Object Parts), totalling 11.1K multiple-choice QA pairs. Collected QA pairs recognizing manipulation styles, hand/object motions, and part-level state changes. HanDyVQA also includes 10.3K segmentation masks for Objects and Object Parts questions, enabling the evaluation of object/part-level reasoning in video object segmentation. We evaluated recent video foundation models on our benchmark and found that even the best-performing model, Gemini-2.5-Pro, reached only 73% average accuracy, which is far from human performance (97%). Further analysis shows the remaining challenges in spatial relationship, motion, and part-level geometric understanding. We also found that integrating explicit HOI-related cues into visual features improves performance, offering insights for developing future models with a deeper understanding of HOI dynamics.

14.
arXiv (math.PR) 2026-06-16

Balanced affine Motzkin paths: Pearson geometry and global endpoint asymptotics

arXiv:2601.17634v2 Announce Type: replace Abstract: We study endpoint distributions of balanced affine weighted Motzkin paths. In the balanced case, the generating-function equation has Pearson-type characteristic geometry. We show that this geometry controls the terminal-height law globally: the characteristic escape time determines the limiting cumulant generating function, the large-deviation rate function, and the ray-scale asymptotics. Thus the usual Gaussian window is only the local quadratic approximation to a global Pearson-driven profile. For finite sizes, we prove a uniform Daniels saddlepoint approximation in the one-dominant-singularity regimes and identify the exceptional antipodal case requiring a lattice/interference correction.

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

From Benchmarks to Skills: Low-Rank Factors for LLM Evaluation

Current evaluations of large language models (LLMs) rely heavily on a growing collection of benchmarks and on aggregate benchmark scores, yet it remains unclear what this comparison actually captures, and what these scores reveal about models' underlying capabilities. Here, we propose a new paradigm for LLM evaluation, by asking whether benchmark performance reflects many independent abilities, or rather relies on a small number of shared dimensions. To answer this, we apply Factor Analysis (FA) to a massive performance matrix of LLMs versus benchmarks \((60\times44)\) revealing an intrinsically low-rank structure of that matrix. That is, a small number of latent factors captures most of the structure in the full task space. This low-rank geometry reveals substantial redundancy across existing tasks and explains why many benchmarks appear to be measuring overlapping abilities. We further show that these latent factors correspond to coherent, skill-like, dimensions of LLM behavior. Leveraging this latent skill-space, we deliver three practical tools for LLM evaluation and downstream users: (i)~identifying redundant tasks, (ii)~profiling new models using a small subset of tasks, and (iii)~selecting models aligned with desired skill profiles. Our method provides a solid alternative to the de-facto standard of a single aggregate score, and establishes an interpretable and practical framework for understanding and benchmarking LLM core capabilities.

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

Right Regions, Wrong Labels: Semantic Label Flips in Segmentation under Correlation Shift

The robustness of machine learning models can be compromised by spurious correlations between non-causal features in the input data and target labels. A common way to test for such correlations is to train on data where the label is strongly tied to some non-causal cue, then evaluate on examples where that tie no longer holds. This idea is well established for classification tasks, but for semantic segmentation the specific failure modes are not well understood. We show that a model may achieve reasonable overlap while assigning the wrong semantic label, swapping one plausible foreground class for another, even when object boundaries are largely correct. We focus on this semantic label-flip behaviour and quantify it with a simple diagnostic (Flip) that counts how often ground truth foreground pixels are assigned the wrong foreground identity while remaining predicted as foreground. In a setting where category and scene are correlated during training, increasing the correlation consistently widens the gap between common and rare test conditions and increases these within-object label swaps on counterfactual groups. Overall, our results motivate assessing segmentation robustness under distribution shift beyond overlap by decomposing foreground errors into correct pixels, flipped-identity pixels, and missed-to-background pixels. We also propose an entropy-based, ground truth label-free `flip-risk' score, which is computed from foreground identity uncertainty, and show that it can flag flip-prone cases at inference time. Code is available at https://github.com/acharaakshit/label-flips.

17.
arXiv (CS.CV) 2026-06-19

Current World Models Lack a Persistent State Core

World models are increasingly regarded as a decisive step toward artificial general intelligence, yet modeling the physical world demands more than rendering convincing frames on demand: it requires an internal world state that keeps evolving over time, decoupled from observation, so that objects endure and events run to their conclusions whether or not a camera is watching, much as the moon holds to its orbit when no one is looking. This requirement is a blind spot of existing benchmarks, which reward surface properties such as fidelity, motion, and camera controllability while never asking whether a generated world keeps evolving once it is unobserved. We introduce WRBench, the first systematic diagnostic benchmark that treats camera motion as an intervention on observability and resolves evaluation into a human-calibrated chain that asks whether the camera executes the requested interaction, whether the scene stays continuous and identifiable while in view, and whether a returning target remains consistent with the event that was set in motion. Across 9{,}600 videos from 23 models spanning four control paradigms, one finding proves stubborn: current systems maintain the observed world as a tracking shot, resuming a returning target in the state at which it was abandoned rather than advancing the event while it went unseen. Because this failure recurs across control paradigms, model families, and increments of scale, robust world-state evolution does not follow from cleaner imagery, tighter control, richer geometric priors, or sheer parameter count We therefore argue that the stability of the physical state kernel and the consistency of worldlines under viewpoint intervention should become first-class objectives of world-model design, so that a world model captures how the world will unfold rather than how the next frame appears.

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

AfriSUD: A Dependency Treebank Collection for Evaluating Models on African Languages

Despite their linguistic diversity and global significance, African languages remain underrepresented in research and resources to support NLP. We aim to bridge this gap by introducing AfriSUD, the first large-scale collection of syntactically annotated treebanks for nine diverse African languages spanning major language families and regions across Sub-Saharan Africa. Using the Surface-Syntactic Universal Dependencies (SUD) framework, our community-led effort provides high-quality, native-speaker verified data that capture typological key features such as agglutination and tone. We evaluate a range of models on AfriSUD for part-of-speech tagging and dependency parsing including non-transformer baselines, multilingual pretrained encoders, and LLMs. Our results reveal a significant syntax gap, where models still show clear limitations across the nine languages, suggesting that existing architectures may not fully capture the structural diversity of African-language syntax.

19.
arXiv (quant-ph) 2026-06-12

Quantum-Driven Neuromorphic Computing for Million-Qubit-Scale Workloads

arXiv:2606.12968v1 Announce Type: new Abstract: We introduce Apollo, a 10000 node p-qubit neuromorphic processor fabricated in 16 nm mixed signal CMOS and operating fully at room temperature with a typical analog core power envelope of about 0.5 W. Its fundamental element, the p-qubit, is a bistable stochastic unit whose continuous time state fluctuations are driven by integrated quantum entropy units that inject true quantum derived randomness. This enables ultrafast stochastic transitions at low energy while preserving a classical state representation. Apollo combines these p-qubits with a high degree Hyperion 256 interconnect topology, allowing efficient embedding of dense Ising and QUBO problems with substantially reduced minor embedding overhead compared with sparse annealing platforms. We show that, through the Suzuki Trotter correspondence, the equilibrium statistics and annealing dynamics of the p-qubit network reproduce key properties of transverse field quantum annealing without cryogenic cooling, long lived coherence, or microwave control. Beyond device level validation, Apollo is evaluated on a three dimensional spin glass benchmark previously used to study quantum advantage in superconducting annealers. Across 300 disorder realizations, Apollo reaches substantially lower ground state energies than reported cryogenic quantum annealing hardware, while remaining distinct from classical simulated annealing and simulated quantum annealing. A 350 nm release candidate device experimentally validates the core p-qubit dynamics, thermodynamic sampling correctness, and continuous time annealing behavior. These results establish Apollo as a room temperature, industrially scalable platform for quantum driven energy based optimization, probabilistic inference, generative modeling, and hybrid classical quantum workflows.

20.
arXiv (CS.CV) 2026-06-16

Selective Synergistic Learning for Video Object-Centric Learning

Typical video object-centric learning (VOCL) approaches employ slot-based frameworks that rely on reconstruction-driven encoder-decoder architectures, where learning is mediated by two spatial maps: attention maps from the encoder and object maps from the decoder. As these two distinct maps exhibit different properties, a recent dense alignment strategy attempted to reconcile this discrepancy by enforcing agreement across all spatio-temporal patches via contrastive learning. However, this indiscriminate alignment inadvertently propagates the inherent weaknesses of each module, such as noisy encoder predictions and blurred decoder boundaries. Moreover, computing dense similarities across all pairs incurs a computational cost quadratic in the total number of spatio-temporal patches, severely limiting scalability. Motivated by this, we propose Selective Synergistic Learning (SSync). Instead of exhaustive patch-to-patch alignment, SSync prevents error propagation by selectively distilling only the most reliable cues: leveraging the encoder strictly for boundary refinement and the decoder for interior denoising. This is realized via a pseudo-labeling with linear complexity, eliminating the need for quadratic spatial comparisons. Also, to prevent the reinforcement of architectural biases like slot redundancy, we introduce a transitive pseudo-label merging that consolidates overlapping slots based on spatio-temporal activation consistency. Extensive studies demonstrate that SSync improves decomposition quality and serves as a versatile, plug-and-play module while also exhibiting exceptional robustness to slot configurations. Code is available at github.com/wjun0830/SSync.

21.
arXiv (CS.AI) 2026-06-17

A T-API-Compliant ReAct Agentic Loop for Optical Networks: Generic vs. Domain-Specific Tool Abstractions

arXiv:2606.18000v1 Announce Type: cross Abstract: Optical networks need intent-driven, closed-loop agentic management, a key enabler for higher autonomy levels. We present the first T-API-compliant reasoning and act (ReAct) loop. We show that domain-specific composite tools achieve 90% oracle-validated correctness with threefold token savings compared to generic tools.

22.
bioRxiv (Bioinfo) 2026-06-11

DeePEn - A Depth sensitive benchmark for Protein Engineering

Recent progress in modeling techniques and high-throughput screening has significantly enhanced the accessibility of protein engineering. Nevertheless, further progress gets hindered by the lack of robust benchmarks that capture the practical challenges for real-world protein engineering. Here, we introduced DeePEn, a Depth-sensitive benchmark for Protein Engineering that quantifies a models generalization capabilities when predicting protein fitness at increasing mutational distance from the wildtype or training data. We defined distance as the number of simultaneous point mutations, i.e., single amino acid variants (SAVs), moving from wild-type to mutant (edit distance in computer science jargon). Specifically selecting four deep mutational scanning (DMS) datasets with sufficient multi-mutation data points from ProteinGym, we assessed recent predictive models, including general and biophysics-informed protein Language Models (pLMs), and a non-transformer neural network. Our results highlight how the performance of all models deteriorates with increasing mutational distance and that no single metric sufficiently captures the diverse requirements of protein engineering. To overcome these shortcomings, DeePEn provides a readily available resource for multi-metric benchmarking that focuses on the prediction of distant variants.

23.
medRxiv (Medicine) 2026-06-19

Reassessing Instrument Strength in Two-Sample Mendelian Randomization Analysis

Mendelian randomization (MR) analysis is widely used to estimate causal relationships between risk factors and outcomes of interest. Two-sample MR approaches have gained increasing attention in genetic epidemiology due to the growing availability of Genome-Wide Association Study (GWAS) summary statistics from public databases. A critical step in two-sample MR is the selection of genetic variants as instrumental variables (IVs). Although genome-wide significant variants are typically preferred, the inclusion of variants with weaker association p-values is considered, as they may potentially improve power through an increased instrument number of instruments, while they may introduce weak instrument bias and attenuate effect estimates towards the null. Our simulation results show that even modest levels of pleiotropy substantially increase the variability of causal effect estimates, while the inclusion of weak IVs does not substantially affect the direction and variability of causal effect estimates in most cases. In real data analyses, we used two released versions of FinnGen GWAS summary statistics with different sample sizes as exposure GWASs to assess the influence of weak IVs. Here, the inclusion of IVs with higher exposure-association p-values resulted in weakened estimated effect sizes, particularly when the exposure GWAS sample size was small. These findings suggest that incorporating weak IVs is reasonable when the exposure GWAS sample size is large, but it poses a risk of falsely concluding null associations when the exposure GWAS sample size is small.

24.
Nature (Science) 2026-06-10

Mitochondria tethered to the nucleus secure its energy supply

Direct interactions between the cell’s powerhouses and nuclear pores might channel energy straight into the nucleus, fuelling cell division and differentiation. Direct interactions between the cell’s powerhouses and nuclear pores might channel energy straight into the nucleus, fuelling cell division and differentiation.

25.
arXiv (CS.AI) 2026-06-24

MOCHA: Multi-modal Objects-aware Cross-arcHitecture Alignment

arXiv:2509.14001v5 Announce Type: replace-cross Abstract: Personalized object detection aims to adapt a general-purpose detector to recognize user-specific instances from only a few examples. Lightweight models often struggle in this setting due to their weak semantic priors, while large vision-language models (VLMs) offer strong object-level understanding but are too computationally demanding for real-time or on-device applications. We introduce MOCHA (Multi-modal Objects-aware Cross-arcHitecture Alignment), a distillation framework that transfers multimodal region-level knowledge from a frozen VLM teacher into a lightweight vision-only detector. MOCHA extracts fused visual and textual teacher's embeddings and uses them to guide student training through a dual-objective loss that enforces accurate local alignment and global relational consistency across regions. This process enables efficient transfer of semantics without the need for teacher modifications or textual input at inference. MOCHA consistently outperforms prior baselines across four personalized detection benchmarks under strict few-shot regimes, yielding a +10.1 average improvement, with minimal inference cost.