The Haber–Bosch fertilizer production process should be taught through a social-ecological lens
Letter to the Editor
Academic Intelligence · Curated Daily
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Letter to the Editor
arXiv:2606.13912v1 Announce Type: cross Abstract: Neural-network quantum states (NQS) are a leading variational tool for quantum many-body physics, yet their optimization is fragile whenever the ground state carries a non-trivial sign or complex phase structure, a situation generic to gauge fields, broken time-reversal symmetry, and fermionic statistics. We trace this fragility to the stochastic estimator of the phase gradient rather than to network expressiveness. The phase sector of the Monte Carlo energy gradient is a noisy score-function estimator; differentiating the local energy instead yields a direct estimator that is unbiased for the same phase force, has far lower variance, and requires only a separated amplitude–phase ansatz. Demonstrated on a 100-site flux ladder, a small network trained this way reaches $0.89\%$ median error, where tuned standard baselines plateau at $1.8\%$ and wider or deeper standard-gradient networks degrade from $8.4\%$ to $24.6\%$. The advantage carries over to chiral XXX chains: the direct estimator again converges to a markedly lower error than the standard one, across $\alpha$ and size; it grows with flux and vanishes in zero-flux controls. An adaptive-mixture of the two estimators is provably never worse in variance than the better endpoint at the optimal mixing coefficient, with seed-resolved diagnostics tracing much of the gain to eliminating failed runs. Estimator design thus emerges as a first-class lever for complex-valued neural quantum states.
Ordered bottlenecks aim to provide utility at flexible budgets by assigning coarse information to early tokens and task-relevant detail to later ones. Prior work, including tail dropping (TD), typically enforces ordering by means of a masking-based ordering pressure (MBOP): Late tokens are masked more frequently than early tokens and are therefore encouraged to store less essential fine details. We introduce predictive residual inference for ordered representations (PRIOR), a framework designed to address inherent weaknesses of MBOP. MBOP is prone to weak late-token utility because it lacks an explicit refinement objective and uses gradient exposure as a proxy for importance. Furthermore, representations may become particularly brittle in optimization-sensitive settings, such as when using discrete or quantized token representations. PRIOR replaces activation-rate control with log2-scaled levels and level-wise predictors. These predictors separate already explained from unexplained information, focusing each level on residual error. We compare PRIOR against MBOP-TD and independent tail-biased dropout (MBOP-ITD) in contrastive learning and image reconstruction tasks. Unlike the baselines, PRIOR learns well-ordered representations across experiments: low budgets provide coarse descriptors, while high budgets add refinements. Simultaneously, full-budget performance with PRIOR is higher in all but one experimental setting, where performance remains comparable. MBOP baselines are severely limited in discrete and quantized settings, while PRIOR approaches the performance of continuous counterparts. Taken together, these findings establish PRIOR as an effective framework for ordered representation learning.
Advanced surgical robotics has made robot-assisted endoscopic submucosal dissection (ESD) a promising approach for the en-bloc resection of large lesions, with the potential to reduce recurrence and improve long-term outcomes. However, the technical complexity and risk of complications in ESD demand stable and precise visual guidance to maintain an accurate dissection corridor and a safe tissue margin. Dense confidence fields provide an effective representation for this purpose by describing both the preferred dissection region and its spatial transition to surrounding tissue. However, reliable confidence field estimation remains challenging in dynamic endoscopic scenes due to smoke, specular highlights, tissue deformation, weak texture, and the thin geometric structure of the target region. To address these challenges, we formulate dissection guidance as a geometry-aware confidence field estimation problem and propose GeoCFNet, a geometry-aware confidence field network built on a pretrained DINOv3 backbone. GeoCFNet integrates a Token-Differentiated Fusion module to aggregate class-token context with dense patch representations, a SegFormer decoder for confidence regression, and Geometry-Aware Spatial Regularization (GASR) to preserve spatial coherence and local geometric transitions. Experimental results show that GeoCFNet achieves RMSE 0.0480, PSNR 27.1995, SSIM 0.3397, and CC 0.2466, indicating accurate and geometrically stable confidence field estimation for robot-assisted ESD guidance.
arXiv:2606.16461v1 Announce Type: new Abstract: Running large language models locally is often impractical, pushing inference on sensitive text to third-party providers. Split inference partially mitigates this by keeping tokens on the client and sending only hidden representations, but these representations can still be recovered via nearest-neighbor search against the public embedding table. We propose an orthogonal obfuscation procedure in which the client multiplies embeddings by a secret orthogonal matrix before transmission. To enable correct inference under arbitrary rotations, we introduce ConjFormer, a transformer variant that is exactly $\mathrm{O}(d)$-equivariant via a lightweight normalization change (scalar RMSNorm) together with blockwise orthogonal conjugation of all linear weights. As a result, the server performs the full forward pass entirely in the rotated basis and never observes unrotated hidden states. Experiments on GPT-2 and Llama 3.2 1B models fine-tuned on PubMed show that orthogonal obfuscation eliminates direct cosine nearest-neighbor inversion and reduces token recovery from over 35% top-10 to at most 1.3%, while increasing perplexity by only 0.4% after fine-tuning. These results indicate that enforcing symmetry at the architectural level can provide a practical defense for privacy-preserving LLM inference without noise injection or heavy cryptographic machinery.
arXiv:2606.19627v1 Announce Type: cross Abstract: The digital commerce landscape is shifting from static, search-driven catalogs to dynamic, immersive video feeds. This transition introduces an ``extreme cold-start'' problem: unlike traditional items, new short-form videos lack the dense interaction history required for collaborative filtering. Furthermore, immersive feeds introduce strong position and duration biases that distort standard engagement signals. In this paper, we demonstrate the Video Candidate Generation (VCG) system, a scalable multimodal retrieval engine designed to solve these challenges in a large-scale e-commerce environment. By leveraging a domain-adapted vision-language model (based on CLIP), we map users and videos into a shared semantic space, enabling zero-shot retrieval based on visual content rather than behavioral history. We detail the system's architecture and present a rigorous evaluation comparing generative (LLM) vs. discriminative (CLIP) embeddings. Our results show that while generative models excel at attribute prediction, they suffer from embedding space collapse in retrieval tasks. Online A/B testing demonstrates that VCG effectively mitigates engagement biases, yielding a 50\% uplift in deep video completion. To showcase the system's capabilities, we present an interactive demonstration featuring three bi-directional retrieval scenarios: Product-to-Video, Video-to-Product, and Zero-Shot Semantic Search.
Single-cell RNA sequencing integration methods that rely solely on transcriptomic data often struggle to preserve fine-grained distinctions between closely related cell subtypes. As a result, cell populations that are separable in the raw data may become over-mixed after integration, reducing biological resolution and interpretability. Incorporating marker gene information can potentially address these issues; however, the variability and complexity of available marker sets limit their effective application. To address this, we introduce scCRAFT+, a semi-supervised integration model that innovatively incorporates marker gene information through Virtual Adversarial Training (VAT). By jointly optimizing marker-derived supervision and transcriptome-wide representations, VAT enforces local prediction smoothness among transcriptionally similar cells, improving robustness to noisy marker annotations while enhancing both integration quality and cell type auto-annotation. This targeted approach significantly enhances annotation accuracy and robustness, particularly when faced with incomplete or incorrect marker gene sets. Benchmarking shows that scCRAFT+ achieves consistently stronger performance than current unsupervised and supervised integration approaches, resulting in improved integration quality and biologically meaningful sub-cell type auto-annotations.
Vision-language-action (VLA) policies typically inherit their vision encoder from upstream VLM releases, but it is unclear whether an encoder choice validated on a small VLA transfers to a larger backbone. We introduce a frozen-backbone grafting diagnostic: the vision tower of a released VLA is replaced by a candidate encoder under a fixed protocol (adaptive average pooling, LayerNorm, and a single trainable linear projector), with the language model and action expert frozen. Across four encoders, two LIBERO suites, two backbones (SmolVLA-450M and $\pi_{0.5}$-3.3B), and two-to-three seeds per cell (40 main grafting runs plus native, LoRA, pooling, and zero-/shuffled-image controls, all scored by offline action MSE), the small-backbone winner does not reliably select the large-backbone top tier: SigLIP is best on SmolVLA across both suites, while on $\pi_{0.5}$ DINOv2-small leads the spatial suite and the object suite is a seed-sensitive near-tie band; three of the four backbone-suite comparisons (and 11 of 12 seed-level cells) support backbone-dependent rankings. The grafting wrapper is itself non-neutral with opposite sign across backbones (+45-56% MSE on the SmolVLA native tower, -50-52% on $\pi_{0.5}$), so all conclusions are conditional on the fixed grafting protocol. We position frozen grafting as a cheap target-backbone diagnostic to run before committing to an encoder at scale, not as a closed-loop deployment claim.
Accurate pediatric brain tumor segmentation remains challenging due to limited annotated data, heterogeneous imaging phenotypes, diffuse tumor boundaries, and class imbalance across tumor subregions. Here, we present a two-stage deep learning framework for improving multi-modal pediatric brain MRI segmentation and clinical interpretation. First, we evaluate 3D Res U-Net and Swin-UNETR baselines on BraTS-PEDs MRI scans, using four co-registered modalities to predict tumor core, whole tumor, and enhancing tumor regions. Second, we introduce diffusion-based refinement models conditioned on coarse Swin-UNETR predictions, including a 3D DDPM refiner and MedSegDiff. Conditioning substantially improves diffusion stability and performance, particularly for enhancing tumor boundary segmentation. Conditioned MedSegDiff achieves the strongest boundary agreement with the lowest HD95. Finally, predicted tumor volumes and representative segmentation overlays are integrated with a multimodal language model to generate structured radiology-style reports. Together, our results suggest that coarse-to-refined diffusion segmentation can improve pediatric tumor boundary delineation and support end-to-end interpretable AI-assisted neuro-oncology workflows.
The plasma proteome is a valuable resource for assessment of the physiological state of the donor. Containing hundreds of different proteins of variable concentrations, it displays substantial inter-donor differences in individual protein levels, making each plasma proteome highly donor-specific. Less is known about intra-donor variability in the plasma proteome over time, although such variations may even be more indicative of a changing physiological state. Here we assessed data obtained from the TIMES cohort, comprising 51 apparently healthy participants monitored monthly over 12 months, focusing especially on temporal variations in blood protein levels. Most strikingly, we observed that several women in this cohort revealed strongly correlated temporal variations in their plasma proteome, including most notably PZP, SHBG, FETUB, AGT, SERPINA6, SERPINA7, CP, APOL1 and KNG1, with levels sometimes fluctuating by more than 20-fold. In contrast, such variations were absent in men. Some of the fluctuating proteins have been known to be hormone-regulated (e.g., PZP, SHBG), but for others this was not yet fully clear. Through the tight co-variation observed for these proteins in the plasma proteome of women, we can conclude that all these proteins are similarly hormone regulated. The findings reported here not only corroborate previous studies showing estrogen-dependent regulation of several plasma proteins, but also extend this category to include also CP, APOL1, and KNG1. As these latter have been often proposed as candidate biomarkers, they should be validated in sex-balanced cohorts and interpreted with caution, especially in large-scale plasma proteomics studies wherein often only one or a few sampling time points are measured per donor.
by Christos A. Ouzounis
Realistic visual simulation of food manipulation requires accurate material parameters, yet these are difficult to measure directly and vary across the heterogeneous regions of a single food item. We address the inverse problem of estimating material parameters from a target description of fracture behavior in a non-differentiable continuum damage mechanics simulator. Using orange peeling as a test case, we train a neural surrogate on 2,000 forward simulations and compare Covariance Matrix Adaptation Evolution Strategy (CMA-ES, a gradient-free evolutionary optimizer) with Proximal Policy Optimization (PPO, a reinforcement learning algorithm) across the original 9-dimensional parameter space and two learned 4-dimensional latent representations. Since different oranges have different material properties, a practical inverse system must handle arbitrary targets without retraining. We train a goal-conditioned PPO policy that learns a general inverse mapping: given any target description of peeling behavior, the policy produces a material parameter estimate in a single forward pass (8 surrogate evaluations, approximately 10ms). Operating in a normalizing flow latent space with a shared surrogate evaluator, the goal-conditioned policy achieves 0.642 actual recovery when validated through the simulator, outperforming the original parameter space by 23%. A warm-start extension that initializes CMA-ES refinement from the policy's output further improves recovery to 0.828 with 540 evaluations. These findings provide a practical framework for inverse food physics and lay groundwork for vision-driven material identification from video observations of food manipulation.
Compressing large language models reduces memory use and inference cost, but it can also create failures that standard benchmarks miss. A pruned model may still perform well on multiple-choice evaluations, yet fail to answer the same question in open generation. We ask what pruning changes: does it erase the correct answer, or does it make the answer harder to produce as the top output? We study this question with multilingual question answering, tracking the same questions before and after pruning. We find a benchmark illusion. Under high-sparsity pruning, especially Wanda, models often fail in greedy open generation while still selecting the correct answer under multiple-choice scoring. In these recognition-only errors, the answer is usually not gone, but demoted: it often reappears with beam search, sampling, or one in-context example. Overall, multiple-choice benchmarks can overstate the usability of compressed LLMs, creating an evaluation blind spot. Compressed models should be tested on what they can produce, not only on what they can recognize.
Longitudinal monitoring of circulating tumor DNA (ctDNA) has emerged as a promising framework for characterizing treatment response dynamics in cancer. Scalable tumor-naive approaches for quantifying ctDNA often involve whole-genome sequencing (WGS) or DNA methylation profiling, but their comparative performance and capacity for complementary integration remain poorly understood. Here we systematically benchmarked tumor-naive WGS- and methylation-based ctDNA quantification methods using plasma from 150 patients with colorectal, lung and breast cancer. Using paired high-depth WGS and EM-seq data, we generated 40,000 in silico samples and evaluated detection accuracy, limits of detection (LoD) and quantification (LoQ) across cancer types and sequencing depths (0.1x-30x). We further assessed single- and multimodal method combinations, identifying conditions under which integrated approaches enhance analytical performance for detection and quantification relative to single modalities. This benchmark delineates key performance trade-offs and provides a practical framework to support method development and guide future research applications in ctDNA-based biomarker studies.
Recent progress in foundation models has shifted toward agentic behavior involving multi-step reasoning and tool use. However, open-source efforts largely focus on text-dominant settings, leaving long-horizon multimodal tasks underexplored. This gap is evident in video tasks requiring sustained temporal understanding and iterative interaction. We present InternVideo3, a framework enhancing these capabilities via Multimodal Contextual Reasoning (MCR). MCR treats understanding as a closed-loop process over a shared, evolving context containing observations, instructions, reasoning, tool actions, and memory. This frames long-video understanding as evidence accumulation and verification. To ensure efficiency, we introduce Multimodal Multi-head Latent Attention (M^2LA), a token-preserving reparameterization compressing KV-cache states while retaining the full token stream. Our staged training includes continued pretraining, short-to-long supervised fine-tuning, rule-based reinforcement learning, and on-policy distillation. Experiments show InternVideo3 achieves strong performance on benchmarks like Video-MME, MLVU, and EgoSchema. We further instantiate the model as a video agent with retrieval tools, demonstrating robust evidence-grounded behavior. Our results suggest that efficient context handling and closed-loop reasoning are vital for adapting open multimodal models toward long-horizon visually grounded agency.
Training computer-use agents (CUAs) – models that interact with graphical desktops through screenshots and keyboard/mouse actions – requires large-scale, diverse trajectory data collected in full desktop environments. The largest public resource, AgentNet (22.5K human trajectories), leads to negative transfer when used for supervised fine-tuning (SFT): continuing training UI-TARS 7B on AgentNet causes OSWorld success rate to fall from 26.3% to 8-10%. We present ProCUA-SFT, a dataset of 3.1M step-level SFT samples distilled from 93K synthetic trajectories across 2,484 application combinations. The dataset is produced by a fully automated pipeline that (i) synthesizes grounded tasks on live desktops seeded with real-world content – 912 spreadsheets from SpreadsheetBench, approximately 10K permissively-licensed presentations from Zenodo10K, and multi-application OSWorld configs – and (ii) verifies each task's feasibility through binary precondition checking before rollout. A single VLM (Kimi-K2.5) serves as goal generator, precondition judge, and trajectory executor, eliminating planner-actor capability gaps. Each trajectory is expanded into step-prefix samples that exactly reproduce the context layout seen at inference time. Fine-tuning UI-TARS 7B on ProCUA-SFT for one epoch yields 45.0% on OSWorld – an 18.7 percentage-point improvement over the base model and over 35% above AgentNet-trained counterparts. A subset of ProCUA was incorporated into the training data for the Nemotron 3 Nano Omni model, contributing to its computer-use capabilities.
arXiv:2606.25650v1 Announce Type: new Abstract: Absorbing boundaries are often treated as scalar sinks. Here we show that a spin-coupled absorbing boundary for a Pauli particle acts instead as a spin–momentum impedance. Its tangential boundary symbol has two branches, $i\kappa\pm|\boldsymbol{\xi}|$, coupling normal absorption to in-plane momentum. In a harmonic guide, the transverse ground state samples $|\boldsymbol{\xi}|\sim \ell_\perp^{-1}\sim\sqrt{\omega}$; narrowing the guide therefore strengthens a local evanescent boundary response without introducing a bulk potential barrier. Solving the detector-present spinor absorbing-boundary evolution, we identify boundary-induced filtering: the prompt detector flux is suppressed, the fixed-window detected fraction is reduced, and a delayed oscillatory sector appears. Over that window the restricted mean detection time is fitted by $A+B\sqrt{\omega}$, with setup-dependent coefficients. The robust result is a spin–momentum filtering mechanism with boundary scale $|\boldsymbol{\xi}|\sim\sqrt{\omega}$, not a universal arrival-time law.
arXiv:2606.18288v1 Announce Type: cross Abstract: This volume develops a knowledge theory of capital for economies in which productive capacity increasingly resides in software, data, models, routines, expertise, platforms, organizations, commons, and public epistemic infrastructure. Beginning from Adam Smith's theory of labour, stock, specialization, and market extent, it asks what changes when knowledge becomes stock-like, mobile across forms, scalable, governable, recombinable, and imperfectly visible in accounting. The book introduces knowledge-bearing stock as the central object and analyses how it is generated, converted into governable form, deployed, improved through feedback, enclosed or shared, measured, impaired, and used as input to future production. It distinguishes embodied, disembodied, institutionalized, commons, and public knowledge forms and develops concepts such as first conversion, cognitive enclosure, feedback capture, dark capital, and expected knowledge loss. The argument is conditional and testable: modern wealth depends not only on capital accumulation, but on how productive knowledge is governed.
arXiv:2602.22179v2 Announce Type: replace Abstract: In many applications, it is important to identify subpopulations that survive longer or shorter than the rest of the population. In medicine, for example, it allows determining which patients benefit from treatment, and in predictive maintenance, which components are more likely to fail. Existing methods for discovering subgroups with exceptional survival characteristics rely on restrictive assumptions about the survival model (e.g. proportional hazards), require pre-discretized features, and, as they compare average statistics, tend to overlook individual heterogeneity. In this paper, we propose Sysurv, a non-parametric, fully differentiable method that discovers human-readable rules selecting subgroups with exceptional survival characteristics. Empirical evaluation on a wide range of datasets and settings, including a case study on cancer data, shows that Sysurv reveals insightful and actionable survival subgroups, outperforming the state of the art.
arXiv:2606.15646v1 Announce Type: new Abstract: Large Language Models (LLMs) have transformed natural language processing, but their lack of interpretable reasoning and tendency to hallucinate pose significant challenges for legal applications. While LLMs show promise for legal text analysis and generation, they struggle with accurate citation attribution and precedent verification. For example, in legal contexts, a single incorrect precedent can jeopardize a case. Current approaches to improve LLM reliability in legal domains suffer from two key limitations: inadequate integration of structured legal knowledge during training or fine-tuning, and insufficient verification mechanisms for generated legal content. To address these challenges, we propose the TRISM (Trustworthy, Reliable, Interpretable, Safe Models) framework, which integrates NeuroSymbolic AI principles with LLMs to leverage both neural learning capabilities and symbolic reasoning over structured legal knowledge. The TRISM approach addresses the above limitations while maintaining interpretable decision pathways. Our framework formalizes the extraction of symbolic knowledge from legal textual documents and incorporates Retrieval-Augmented Generation (RAG) as a core component for grounding LLM outputs in verified legal sources. In this position paper, we make the following contributions: (1) An analysis of the limitations of AI in law; (2) Introduce RASOR RAG which creates foundations for neurosymbolic RAG by generating explicit interpretable rationales that could be formalized into symbolic representations; (3) A formalized methodology for creating symbolic legal knowledge bases that support both interpretable reasoning and output verification in LLMs; and (4) The TRISM framework for integrating symbolic legal knowledge with LLMs.
arXiv:2606.19179v1 Announce Type: cross Abstract: Stochastic momentum methods such as heavy ball (HB), Nesterov momentum, and variants of Accelerated SGD (ASGD) [Kidambi et al., 2018] are widely used in modern training, but their stochastic benefits depend on two distinct quantities: serial runtime, the number of iterations needed to reach a target accuracy, and compute efficiency (CE), the inverse total gradient-query or FLOP cost. Larger batches reduce serial runtime without hurting CE only when the contraction gap grows linearly with batch size. We study stochastic HB and ASGD for consistent linear regression with Gaussian covariates and prove finite-dimensional, discrete-time lower bounds on their batch-size tradeoffs. Our first result shows that HB does not improve the CE frontier over SGD for arbitrary spectra; rather, it preserves SGD-level CE over a larger batch-size window, allowing larger batches to reduce serial runtime until HB reaches its deterministic accelerated scale. This window can be a factor $\sqrt{\kappa}$ larger than the SGD critical batch size. For ASGD, the picture is more spectrum-dependent: for rapidly decaying power-law spectra, ASGD improves small-batch CE over HB/SGD, but as batch size grows it trades this CE advantage for improved serial runtime. Synthetic linear-regression experiments verify these qualitative regimes, including near-overlap of ASGD and HB for slowly decaying spectra and the predicted CE–serial tradeoff for rapidly decaying spectra.
Long input sequences are central to document understanding and multi-step reasoning in Large Language Models, yet the quadratic cost of attention makes inference both memory-intensive and slow. Context distillation mitigates this by compressing contextual information into model parameters, and recent work such as Doc-to-LoRA amortizes context distillation into a single forward pass that generates one LoRA adapter per document. However, producing a single monolithic adapter for all queries leads to irrelevant-query interference, limited compositional recall, and poor scalability to long-document reasoning. To address these challenges, we propose Doc-to-Atom (Doc2Atom), a compositional parametric memory framework that decomposes each document into semantically typed knowledge atoms. Each atom is compiled into an independent micro-LoRA adapter and a provenance retrieval key. At inference time, a lightweight query router selects and assembles only the relevant atoms into a query-specific adapter, which is then injected into a frozen base model. The entire system is trained end-to-end through a multi-objective distillation framework. Experiments on six diverse QA benchmarks demonstrate that Doc2Atom outperforms Doc-to-LoRA baselines while reducing the memory cost of document internalization.
We ask whether the geographic origin of Tang-dynasty poets leaves a detectable linguistic trace in their work. Aggregating every poem attributed to each author in the Complete Tang Poems (Quan Tang Shi) and linking poets to their administrative circuit of origin via the China Biographical Database (CBDB), we build a poet-level corpus of 357 poets across the ten Tang circuits and frame origin prediction as multi-class classification. Using character $n$-gram TF-IDF together with interpretable domain features (imagery, season, and allusion), classical and neural models predict a poet's broad region (South vs.\ North) at $0.69$ accuracy, well above the $0.53$ majority baseline, and finer circuit-level origin above chance. Beyond classification, three findings emerge. (i) Linguistic distance between circuits grows with geographic distance (Mantel $r=0.40$, $p\approx0.09$ over nine circuits), evidence of a distance-decay effect in poetic language. (ii) The signal interacts with time: South/North separability is at chance in the High Tang and strongest in the Late Tang, consistent with court-driven homogenization at the empire's height followed by regional divergence. (iii) The model's confident errors are historically meaningful – in the Early Tang, every misclassification is a southern poet read as northern, reflecting the prestige of the northern court idiom. We further show that, when given the whole corpus through a hierarchical frozen-encoder representation, a classical-Chinese transformer (GuwenBERT) only matches – not beats – simple TF-IDF, and that combining them adds nothing, indicating that character $n$-grams already capture the regional signal. Our results position interpretable machine learning as a hypothesis generator for literary history.
T cell receptor (TCR)-based immunotherapy holds immense potential for treating cancers and infectious diseases, where highly antigen-specific TCR recognition is crucial for adaptive immunity against tumors and pathogens. Engineering or de novo generation of the complementarity-determining region 3 (CDR3) loops of TCRs using artificial intelligence offers a powerful alternative to designing reactive TCRs rather than laborious experimental screening. However, current in silico approaches are constrained by weak conditional guidance, limited flexibility, and a lack of rigorous functional validation. To address these limitations, we introduce TCRDiff, a generative diffusion framework for designing antigen-specific TCRs conditioned on peptide-MHC (pMHC) targets and germline-encoded variable genes. By leveraging pre-trained knowledge from massive T-cell repertoires and TCR-pMHC recognition data, TCRDiff generates CDR3{beta} sequences with state-of-the-art fidelity to native binding TCRs through a denoising diffusion process. Furthermore, incorporating the interface geometry features generated TCR-pMHC complexes with superior structural plausibility. As a proof of concept, we deployed TCRDiff in a systematic pipeline to design candidate TCRs for immunotherapy. In vitro activation assays validated that TCRDiff-generated TCRs specifically recognize the MAGE-A3 epitope with minimized off-target cross-reactivity. Together, TCRDiff establishes a powerful, validated computational paradigm to accelerate the development of TCR-based immunotherapies.
Introduction: Aphasia is an acquired language disorder with a significant negative functional impact. Much of the research on aphasia has focused on word-level language comprehension and production. Further evaluation of discourse-level tasks, both at behavioral and neural levels, will allow for an ecologically valid understanding of the functional implications of language impairment in this population. Method: This study evaluated bilateral frontal, temporal, and parietal cortical activity during computer-based narrative production in 14 young neurotypical individuals, 17 individuals with post-stroke aphasia, and 15 age-matched neurotypical participants using functional near-infrared spectroscopy (fNIRS). Oxygenated hemoglobin (HbO) was measured during narrative production following short video clips and compared to HbO during counting aloud. In addition, behavioral measures quantifying in-task performance were correlated with averaged HbO values. Results: Young neurotypical individuals showed greater cortical activity in bilateral language regions for narrative production compared to counting aloud. In contrast, people with aphasia showed positive condition-related effects in the right frontal ROI and the age-matched group showed positive condition-related effects in the left frontal and right precentral ROIs. Each group showed different patterns in relationships between cortical activity and discourse performance measures. Conclusion: Overall, young participants showing more consistent condition-related effects for narrative discourse production than individuals with aphasia and age-matched controls. This study shows the potential for fNIRS to evaluate cortical activity for ecologically valid language tasks in individuals with post-stroke aphasia.