Biology subjects

Xuan, F.

Publications and source records attributed to Xuan, F..

3 recordsLinked to original sources

bioRxiv2026

Achieving near single-molecule sensitivity in separation-free protein detection using engineered kinetic proofreading

Unlike nucleic acids, proteins cannot be directly amplified. Ultrasensitive detection must therefore couple efficient analyte-to-signal conversion with strong suppression of target-independent background. Consistently detecting ~100 molecules (below which Poisson sampling noise alone causes CV to exceed 10%) across protein targets in a format as scalable and accessible as PCR remains unsolved. Separation-based ultrasensitive immunoassays require target binding stable enough to survive stringent washing and are therefore constrained by wash-induced signal loss and, more fundamentally, the relative scarcity of exceptionally tight binders. Performance consequently varies across targets; detection limits below 1,000 molecules remain rare. Conventional separation-free proximity assays avoid washing but incur background from random probe collisions, with reported detection limits frequently exceeding 100,000 molecules. Here we introduce Successive Proximity Extension Amplification Reaction (SPEAR), a separation-free architecture in which autonomous engineered DNA nanodevices emulate biological kinetic proofreading. Two successive irreversible proximity-extension steps compound discrimination between analyte-dependent and background reactions, suppressing spurious signals while preserving efficient analyte-to-signal conversion. This design reduces reliance on high-affinity binders and enables sub-fM detection from 1 uL samples through simple 3-step mixing followed by standard qPCR readout. Across 11 biomarkers tested, SPEAR consistently achieved sub-100-molecule detection limits. Where compared, it outperformed ultrasensitive separation-based platforms, analytically and clinically, including for low-abundance Alzheimer's disease biomarkers. SPEAR also precisely quantified SARS-CoV-2 neutralizing antibody titers from finger-prick dried blood spots, concordant with the cell-based reference assay on venous blood. It detected a distinct mixed phosphorylation state of Tau, and targeting this state resolved previously observed capillary-venous discordance and improved amyloid-status discrimination. These results establish engineered autonomous successive molecular discrimination as a practical strategy for near-single-molecule protein detection, extending the sensitivity, scalability and accessibility of PCR-based testing to non-amplifiable analytes.

bioengineering↗

bioRxiv2025

Navigating uncertainty: reward location variability induces reorganization of hippocampal spatial representations

Navigating uncertainty is crucial for survival, with the location and availability of reward varying in different and unsignalled ways. Hippocampal place cell populations over-represent salient locations in an animals environment, including those associated with rewards; however, how the spatial uncertainties impact the cognitive map is unclear. We report a virtual spatial navigation task designed to test the impact of different levels and types of uncertainty about reward on place cell populations. When the reward location changed on a trial-by-trial basis, inducing expected uncertainty, a greater proportion of place cells followed along, and the reward and the track end became anchors of a warped spatial metric. When the reward location then unexpectedly moved, the fraction of reward place cells that followed was greater when starting from a state of expected, compared to low, uncertainty. Overall, we show that different forms of potentially interacting uncertainty generate remapping in parallel, task-relevant, reference frames.

neuroscience↗

bioRxiv2023

Lateral entorhinal cortex subpopulations represent experiential epochs surrounding reward

During goal-directed navigation, "what" information, which describes the experiences occurring in periods surrounding a reward, can be combined with spatial "where" information to guide behavior and form episodic memories1,2. This integrative process is thought to occur in the hippocampus3, which receives spatial information from the medial entorhinal cortex (MEC)4; however, the source of the "what" information and how it is represented is largely unknown. Here, by establishing a novel imaging method, we show that the lateral entorhinal cortex (LEC) of mice represents key experiential epochs during a reward-based navigation task. We discover a population of neurons that signals goal approach and a separate population of neurons that signals goal departure. A third population of neurons signals reward consumption. When reward location is moved, these populations immediately shift their respective representations of each experiential epoch relative to reward, while optogenetic inhibition of LEC disrupts learning of the new reward location. Together, these results indicate the LEC provides a stable code of experiential epochs surrounding and including reward consumption, providing reward-centric information to contextualize the spatial information carried by the MEC. Such parallel representations are well-suited for generating episodic memories of rewarding experiences and guiding flexible and efficient goal-directed navigation5-7.

neuroscience↗