探索全球前沿学术脉络

An AI-Powered Trisomy 21 Research Assistant

Down syndrome, caused by trisomy 21, increases the risk of diverse co-occurring conditions. With more than 34,000 related publications indexed in PubMed as of early 2026, keeping pace with this expanding literature is challenging. While general-purpose large language models are widely used for information retrieval, they often rely on broad training data rather than specific evidence. Retrieval-augmented generation (RAG) improves rigor and reliability of responses by linking model outputs to source texts. In research, source texts are peer-reviewed articles. Standard implementations treat all manuscript sections equally, allowing background text to rank as highly as experimental results. To focus model outputs on experimentally supported responses, we developed the T21 Research Assistant, a section-aware RAG system that prioritizes Results sections to ground responses in primary experimental evidence. The system draws exclusively from 1,789 open-access Down syndrome publications from PubMed Central, including 327 NIH INCLUDE-funded studies, and uses a multistage pipeline for query validation, retrieval, reranking, synthesis, and citation verification. Built on NVIDIA Nemotron models, it generates structured, cited responses. Evaluation using expert-curated questions demonstrated strong performance, achieving a BERTScore F1 of 0.712 and recall of 0.758, comparable to or exceeding leading proprietary and open-source models. T21 Research Assistant is available at: https://bioinformatics.cuanschutz.edu/t21-res-assi/

Avidity of anti-pertussis toxin antibodies is associated with symptomatic Bordetella pertussis infection in a novel controlled human infection model

Background The association between functional antibody responses following Bordetella pertussis infection and symptomatic disease remains unclear. We characterized the maturation of anti-pertussis toxin (PT) IgG avidity after human challenge with B. pertussis and determined its association with symptomatic infection. Methods Healthy adults were intranasally inoculated with live B. pertussis organisms in a controlled human infection model and monitored for development of pertussis symptoms (NCT05136599). Serum samples were collected one day before inoculation and at 14, 28, 56, 180, and 365 days post challenge. Anti PT IgG avidity was tested using a titration of ammonium isothiocyanate (the bond breaking agent) to quantify a wide range of antibody avidities from low to very-high. Associations between covariates and avidity were examined using linear regression models, and high dimensional analyses were used to integrate all data. Findings Anti PT IgG avidity increased in both symptomatic (n=20) and asymptomatic (n=10) participants after the challenge, reached maximum levels at day 56, and then declined through day 365. Symptomatic participants developed significantly higher levels of high- and very high-avidity anti-PT antibodies at 28, 56, 180, and 365 days post-challenge compared with those who remained asymptomatic. In multivariate analyses, symptomatic infection was associated with higher levels of high and very high avidity anti-PT IgG at day180 and365 after challenge. Distinct avidity profiles in symptomatic vs asymptomatic participants emerged at day28 onwards, with the former group having higher levels of antibodies with higher avidities. However, levels of medium-high, high and very high avidity antibodies in symptomatic participants were lower at day 365 after challenge compared to their peak levels. Interpretation Anti-PT IgG avidity was associated with symptomatic B. pertussis infection and thus may serve as a surrogate of clinical disease outcome. These results highlight that antibody avidity provides an additional functional assay besides antibody quantitation to dissect immune responses to pertussis. Further investigation of anti PT IgG avidity should be pursued in natural pertussis outbreaks to determine whether it might be used to differentiate symptomatic from asymptomatic infections for epidemiologic purposes.

Early-life Urban Environment, Nutrition, and Pubertal Timing in Southern Europe: An Exposome Analysis

Background: Urban environmental and lifestyle factors during early life may influence pubertal timing, but the combined effects of multiple environmental exposures within an exposome analytical framework remain poorly understood. Objective: To examine the association between early-life urban environmental exposures and pubertal timing, and to explore whether these exposures interact with early-life nutritional factors, namely breastfeeding duration and childhood diet quality. Methods: Data from two European population-based birth cohorts were analysed: Generation XXI (G21, Portugal; n=5263; 51.5% girls) and INfancia y Medio Ambiente (INMA, Spain; n=1019; 50.1% girls). Urban environmental exposures including indicators of air pollution, traffic, built environment, and natural spaces were estimated at 4 early-life stages at both cohorts: pregnancy (INMA only), birth, 1 year, and 4-5 years of age. Pubertal development timing was assessed using Tanner staging and/or the Pubertal Development Scale (PDS), and age at menarche was self-reported. Exposome-Wide Association Study (ExWAS) models and unsupervised clustering followed by ordinal logistic regression models were used to examine single- and multi-exposure associations, respectively. Regression models were fitted adjusting for relevant child characteristics, maternal factors, and household socioeconomic conditions, and corrected for multiple testing. Results: Individuals living in more unfavourable urban environments characterised by higher building density, air pollution, and lower access to natural spaces showed earlier pubertal timing according to multiple outcomes, across multiple early-life exposure periods, and in both cohorts. In the G21 cohort, these environmental profiles were associated with earlier age at menarche, particularly for exposures at 1-1.5 and 4-5 years (e.g., 1-1.5y: {beta}=-0.172, FDR-adjusted p-value=0.041), while in the INMA cohort, boys exposed to more unfavourable environmental profiles showed more advanced pubertal development, also particularly for exposures at 1-1.5 and 4-5 years of age (e.g., 1-1.5y; {beta}=0.572, FDR-adjusted p-value=0.008). Among environmental domains, air pollution and traffic were the factors most consistently associated with pubertal timing. Regarding early-life nutritional factors, longer duration of exclusive breastfeeding was associated with a lower Tanner stage among girls in G21. No significant interactions between breastfeeding duration and environmental exposure clusters were observed. Conclusion: Early-life urban environmental exposures, particularly air pollution and traffic, may influence pubertal timing. Exclusive breastfeeding may have a protective role against earlier pubertal development. These findings highlight the importance of improving urban environmental conditions and promoting breastfeeding to support healthy developmental trajectories.

Actionable Interpretability Must Be Defined in Terms of Symmetries

arXiv:2601.12913v4 Announce Type: replace Abstract: This paper argues that interpretability research in Artificial Intelligence (AI) is fundamentally ill-posed as existing definitions of interpretability fail to describe how interpretability can be formally tested or designed for. We posit that actionable definitions of interpretability must be formulated in terms of *symmetries* that inform model design and lead to testable conditions. Under a probabilistic view, we hypothesise that four symmetries (inference equivariance, information invariance, concept-closure invariance, and structural invariance) suffice to (i) formalise interpretable models as a subclass of probabilistic models, (ii) yield a unified formulation of interpretable inference (e.g., alignment, interventions, and counterfactuals) as a form of Bayesian inversion, and (iii) provide a formal framework to verify compliance with safety standards and regulations.

The Standard Interpretable Model: A general theory of interpretable machine learning to deductively design interpretable methods using Lagrangian mechanics

arXiv:2606.12289v1 Announce Type: cross Abstract: As Artificial Intelligence models grow in complexity, interpretability has become an indispensable tool for understanding, debugging, and controlling their computations. However, interpretability lacks general theories to deductively design interpretable methods. This gap between theories and methods results in a fragmented literature and inconsistent evaluation protocols. To fill this gap, we introduce the Standard Interpretable Model (SIM), a general theory grounded in Lagrangian mechanics that enables the deductive design of interpretable methods. Specifically, the SIM summarises, in a set of premises, what interpretability is for a target user. From these premises, the SIM systematically derives interpretability symmetries and corresponding constraints, which shape the landscape of a Lagrangian whose minima correspond to optimal interpretable models. To reach the minima, one can either update the parameter values of an opaque model to make it more interpretable or compile constraints into an interpretable architecture. We empirically show that the SIM identifies and solves limitations of existing methods (including traditional, concept-based, and mechanistic interpretability), highlights underexplored research directions, and informs the design of core programming interfaces. Beyond being a research method, the deductive nature of the SIM offers pedagogical grounding for interpretability curricula and may shift the scientific community's perspective of a discipline that has long been fragmented.