Allen, J. W. | Search bioRxiv

bioRxiv2026

Time-Varying Directed Interactions in Functional Brain Networks: Modeling and Validation

Brain function depends on time-resolved directional organization: influence is continuously redistributed across regions, shaping who drives whom, when, and for how long. Yet dynamic neuroimaging has largely emphasized undirected fluctuations in functional connectivity, limiting biological interpretation of asymmetric interactions. Here we show that directed influence can be resolved into two biologically distinct signatures: strength, reflecting the efficacy of influence, and duration, reflecting its temporal extent. To test this principle, we developed sliding-window prediction correlation (SWpC), a framework for estimating these signatures in fMRI and related signals. Across simultaneous rat local field potential (LFP)-fMRI and human motor-task fMRI, strength more closely tracks neural-BOLD coupling and task-evoked reconfiguration, whereas duration captures temporally extended BOLD patterns more susceptible to hemodynamic timing. In post-concussion vestibular dysfunction, altered strength-duration profiles define reproducible vestibular-multisensory states and improve patient-control discrimination. Together, these findings support a general principle of dynamic brain organization spanning neurophysiology, behavior, and disease.

bioengineering↗

bioRxiv2025

Perturbational single-cell profiling of patient tumors defines lineage- and context-specific programs of innate immune resistance

AbstractDespite promise in preclinical models, most immuno-oncology drug candidates fail in clinical trials. These failures reflect limitations in our ability to directly model the response of human tumor and immune cells to immunotherapies. To address this gap and test the effect of innate immune agonists, we developed PERCEPT, an approach that uses ex vivo perturbational single-cell RNA sequencing to compare the response of immunomodulatory treatments with unstimulated controls directly in patient samples. Using PERCEPT, we tested cytokines and innate immune agonists in melanoma and Merkel cell carcinoma (MCC) and identified the dsRNA mimetic, RIG-I agonist, Stem Loop RNA (SLR) 14 as a powerful inducer of anti-viral states and enhancer of T cell activation. We compared transcriptional responder and non-responder patient samples and identified midkine (MDK), a multifunctional cytokine, as a potent repressor of IFN signaling in both tumor and immune cells. MDK expression dampened MHC-I presentation in human tumor cells and reduced activation of antigen-presenting cells, disrupting tumor immunity at multiple levels. In contrast to prior studies, we identified MDK as specifically enriched in neuroendocrine cancers such as MCC and small cell lung cancer compared with melanoma, suggesting the importance of lineage- and context-specific targeting. Our results demonstrate the utility of high-dimensional controlled perturbation of patient samples to identify mechanisms of innate immune response and resistance and demonstrate an actionable path towards clinical development of MDK-inhibiting therapies including FDA-approved ALK inhibitors in neuroendocrine cancers.

cancer biology↗