Roy Chowdhury, S. | Search bioRxiv

bioRxiv2026

Answering clinicians' questions over trial evidence tables with verifiable, feedback-driven language models

Systematic reviews condense clinical trials into evidence tables, yet clinicians can interrogate these tables only through database queries, and many questions concern attributes that the table does not record, such as a drug's target class or a harmonised endpoint. Here we introduce FD-SCoPE, a language-model framework that answers both kinds of question, exposes the query, the selected trials and the derivation rule behind every answer, and learns from expert corrections. On an oncology evidence table of 159 immune checkpoint inhibitor trial records, FD-SCoPE completed all 140 clinician-style tasks (alternatives, 90.7--97.9%). For questions needing derived attributes it retrieved 99.3% of relevant trial records at a positive predictive value of 89.8% and outperformed four alternative approaches (derived-value F1 77.7% versus 64.8--73.4%). Corrections on 299 questions, simulated from reference answers, raised F1 on 1,201 unseen questions from 77.9% to 84.9%. Language models coupled with executable queries, verified programs and expert feedback can give clinicians auditable access to trial evidence.

bioengineering↗

bioRxiv2024

Lipid bilayers determine the allostery but not intrinsic affinity of cAMP binding to pacemaker channels

Cyclic adenosine monophosphate (cAMP), a second messenger, binds to hyperpolarization and cyclic nucleotide-gated (HCN) ion channels and regulates the automaticity of pacemaking activity. While cellular studies suggest that cAMP binding to HCN channels exhibits unusual cooperativity, recent findings using purified detergent-solubilized channels indicate independent binding to each subunit. This discrepancy raises the question of whether the lipid environment or endogenous cellular cofactors influence cAMP-dependent gating. To address this, we reconstituted purified human HCN channels in nanodiscs and resolved cAMP binding energetics at single-molecule resolution using nanophotonic waveguides. Our measurements reveal that, in contrast to detergent-solubilized channels, cAMP binds cooperatively to HCN channels reconstituted in a variety of lipid nanodiscs. Remarkably, the presence of lipid bilayer promotes ligand-binding allostery but not intrinsic binding affinity. To explore the molecular basis of bilayer-induced allostery, we determine the cryo-EM structure of HCN1 in soy polar lipid nanodiscs at a nominal resolution of 3.77 [A] resolution. Although the overall architecture is conserved, the average interfacial distance between the transmembrane domain and C-terminal domain of neighboring subunits are shorter in lipid nanodiscs. These findings indicate that the lipid bilayer regulates the function of pacemaker ion channels by enhancing inter-subunit interactions and underscore the fundamental role of membranes in amplifying the gating sensitivity of ion channels by promoting long-range cooperative interactions. Significance StatementLipid membranes are essential for the structure and function of membrane proteins, including ion channels. Lipid mimetics, such as non-ionic detergents, are widely used as surrogates for the membrane environment in structural and biophysical studies. Here, we demonstrate that while the overall structure of the pacemaker ion channel remains similar, lipid membranes--unlike detergents--promote cooperative ligand-binding transitions by modifying interactions at intersubunit interfaces. These findings provide new insights into the mechanism of ion channel regulation by lipid membranes.

biophysics↗