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Wu, S.

Publications and source records attributed to Wu, S..

At least 55 records · Page 3Linked to original sources

MedMisBench: Measuring Epistemic Resilience of LLMs Under Misleading Medical Context

Large language models (LLMs) now reach expert-level scores on medical licensing exams, encouraging the assumption that high scores imply safe medical judgment while patients increasingly use them for health advice. We show this assumption is fragile: when misleading context is injected into questions that LLMs originally answer correctly, they abandon the correct answer. We call the ability to maintain correct judgment under adversarial context epistemic resilience, and introduce MedMisBench to measure it. MedMisBench contains 10,932 medical question items and 48,889 misleading context-option pairs spanning medical reasoning, agentic capability, and patient-journey evaluation. Across 11 model configurations, mean accuracy falls from 71.1% on original questions to 38.0% under focused misleading context, with 51.5% attack success. The most damaging injections are formal, rule-like fabrications: authority-framed falsehoods reach 69.5% attack success and exception-poisoning claims reach 64.1%. A 14-member clinical panel from 7 countries identified serious potential harm in 38.2% of reviewed cases. MedMisBench exposes a structural blind spot in LLM evaluation in medical settings: existing benchmarks measure what models know, but not whether they preserve correct medical judgment under misleading context.1

bioengineering↗

cGAS bends unpaired DNA to form an unconventional structure that hyperactivates the innate immune response

cGAS is a pattern-recognition receptor for dsDNA and forms 2cGAS:2DNA dimers followed by oligomerization into phase-separated condensates when fully-complementary DNA is studied. However, many DNAs are not fully complementary. We report that DNA with unpaired regions such as those found during transcription, recombination or replication (designated as bubble-DNA, Bu-DNA) causes cGAS hyper-activation. Hyperactivation is observed by Bu-DNA embedded in linear DNA, circular DNA, plasmid DNA and mitochondria DNA. Bu-DNA binds significantly more tightly to the cGAS catalytic domain than paired-DNA but suppresses condensation. Cryo-EM and single-molecule FRET reveal that cGAS forms 2cGAS:1DNA complexes by bending Bu-DNA into a V-shape using the unpaired region as a hinge, limiting its oligomeric state. This uncovers a novel mode of cGAS activation attributed to pattern diversity within pattern ligands.

immunology↗

An ASXL3-thyroid hormone axis in parvalbumin interneurons controls autism-like behaviors

Pathogenic variants in ASXL3 underlie autism spectrum disorder (ASD), but how they perturb neural circuits and whether defects are reversible remain unclear. Here we show that Asxl3 haploinsufficiency in mice reduces cortical thickness and upper-layer projection neurons while increasing parvalbumin (PV) interneuron density and producing ASD-like behavioral abnormalities. Mechanistically, Asxl3 loss derepresses the thyroid hormone (TH)-inactivating enzyme DIO3 via altered histone H2A monoubiquitination, depleting brain TH. Conditional deletion of the TH receptor Thra in inhibitory neuron progenitors phenocopies the PV interneuron expansion, linking impaired TH signaling to PV circuit remodeling. Neonatal, but not adolescent, TH supplementation restores PV interneuron numbers and rescues behavior in Asxl3+/- mice, defining a critical early window for intervention. An intein-based AAV system that reconstitutes full-length ASXL3 normalizes cortical architecture and behavior in Asxl3+/- mice and drives efficient ASXL3 expression in non-human primate brain, establishing an ASXL3-TH-PV interneuron axis as a targetable pathway in ASD.

neuroscience↗

Mirror-Image L-DNA Nanocubes for Stable and Targeted Multimodal Drug Delivery

Nucleic acid nanostructures provide programmable architectures for molecular delivery but remain limited by rapid nuclease degradation, poor in vivo persistence and inefficient intracellular cargo release. Here we report a mirror-image L-DNA nanocube as a biologically persistent and modular therapeutic delivery platform. The nanocube self-assembles from synthetic L-DNA oligonucleotides into a structurally defined architecture that exhibits substantially enhanced resistance to enzymatic degradation and prolonged stability under physiological conditions compared with the corresponding D-DNA nanostructure. Surface functionalization with folic acid enables selective tumour targeting in vitro and in vivo. The L-DNA nanocube supports the delivery of chemically distinct therapeutic cargos, including doxorubicin, a bortezomib prodrug and MCL1-targeting small interfering RNA (siRNA). In tumour-bearing mice, L-DNA nanocube-mediated delivery improves therapeutic efficacy while reducing systemic toxicity relative to free drug and D-DNA nanocube controls. For siRNA delivery, we engineer a pH-responsive release mechanism that promotes endosomal escape and cytosolic cargo localization, as visualized by cryo-electron tomography, resulting in efficient gene silencing. Together, these results establish mirror-image nucleic acid nanostructures as a class of biologically functional nanomaterials for programmable intracellular therapeutic delivery.

biochemistry↗

Protein-DNA mesh assembly drives dsDNA-specific and duplex length-dependent activation of cGAS

Cyclic G/AMP synthase (cGAS) forms condensates on dysregulated double-stranded (ds) DNA to trigger inflammatory responses. Currently, how it specifically recognizes dsDNA and why activation depends on duplex length remain poorly understood. Using cryo-electron microscopy, biochemical assays, and single-molecule methods, we show that full-length cGAS assembles a protein*dsDNA mesh by reiteratively propagating dimers-of-dimers, driving an associative phase transition. Previously uncharacterized N- and C-terminal interactions, together with inter-dimer junction-loops, track the B-form groove and bend dsDNA to build an extensive mesh network spanning multiple duplexes. These interactions are critical for cross-stabilizing active cGAS, revealing why higher-order assembly on long duplexes maximizes signaling activity. Remarkably, cGAS can build the protein*dsDNA mesh on a single contiguous duplex by entangling its oligomerization platform, resulting in a mechanically resilient and kinetically stable signaling platform. Together, our findings establish higher-order mesh assembly of cGAS as the foundation for dsDNA selectivity, duplex-length-dependent activation, and condensate formation.

biophysics↗

Specialized outputs and behavioral contributions of Purkinje cell subtypes

Purkinje cells (PCs), the sole outputs of the cerebellar cortex, transform granule cell firing patterns into appropriate outputs to drive learning and behavior. Two major PC classes (typically defined by Aldoc expression) can be further subdivided into nine molecularly distinct PC subtypes, suggesting that each subtype might be specialized for distinct categories of cerebellar processing. This has been difficult to test due to limited tools to target PC subtypes. We therefore developed intersectional tools to target PC subtypes, specifically Kcng4+ PCs (primarily Aldoc-) and Gpr176+ PCs (Aldoc1). We mapped their distributions within the cerebellar cortex and quantitatively characterized their outputs onto different types of cerebellar nuclei (CbN) neurons. Although projections by PC subtypes defined by Kcng4 and Gpr176 are regionally segregated within the CbN, each PC subtype synapses onto many types of CbN neurons, and individual CbN neurons often receive convergent inputs from multiple PC subtypes. We also selectively silenced PC subtype outputs and found that silencing Kcng4+ PC outputs impaired motor behaviors while sparing emotional and social behaviors, whereas silencing Gpr176+ PC outputs selectively increased exploratory behavior and reduced anxiety without affecting motor and social behaviors. These findings demonstrate that molecularly defined PC subtypes differentially regulate specific behaviors and establish a versatile framework for uncovering how cerebellar circuits are specialized to control diverse behaviors.

neuroscience↗

Visuospatial coding by theta oscillations in human hippocampus

The hippocampus has been proposed to support visual processing and perception, challenging longstanding accounts that emphasize navigation or declarative memory. A key prediction of visual-processing accounts is that the hippocampus should exhibit similar visuospatial coding properties to those of higher-order visual neocortical areas, such as sensitivity to the size of visual stimuli and contralateral visual field biases. We tested for these properties using intracranial EEG to measure hippocampal neural activity during a retinotopic mapping task. The hippocampus exhibited characteristic slow ([~]2 Hz) and fast ([~]8 Hz) theta oscillations throughout the task. Fast theta was responsive to the presence but not the amount of visual stimulation. In contrast, slow theta did not generally respond to stimulus presence but scaled with the size of the visual stimulus, consistent with larger receptive fields. Slow theta also showed a contralateral bias, an effect that was specific to the right hippocampus. None of these effects were attributable to microsaccades or performance of the concurrent vigilance task. These findings provide electrophysiological evidence for visual field coding by human hippocampus, supporting accounts of hippocampal function that emphasize its role atop the visual hierarchy. Visual processing of this kind may combine with self-motion, memory, and other signals to support the broader spatial and mnemonic functions with which hippocampal theta oscillations have long been associated.

neuroscience↗

Loss of Flotillin-2 enhances trastuzumab emtansine internalization and cytotoxicity by relieving negative regulation of HER2 internalization in HER2-amplified cancers

While Trastuzumab emtansine (T-DM1) and other HER2-targeting antibody-drug conjugates (ADCs) are used to treat cancer patients with HER2-amplified tumors, there is a need to improve the efficacy through the understanding of their mechanism of uptake into cells. Flotillin-2 (FLOT2) regulates the internalization of epidermal growth factor receptor (EGFR), leading us to investigate FLOT2 effects on HER2 internalization. Higher FLOT2 expression in nine HER2 amplified cell lines correlated with a higher T-DM1 IC50 in vitro, and breast cancer patients with high FLOT2 expression had worse survival when receiving either T-DXd (16.2 months (m) vs 18.3 m, p=0.04) or T-DM1 (38.0 m vs 41.3 m, p=0.1) in real-world Caris Life Sciences data. FLOT2 interacts with HER2 and positively regulates HER2 activation and downstream signaling, while FLOT2 knockdown reduces the viability of HER2 amplified cancer cells. FLOT2 knockdown results in increased HER2 internalization upon binding of T-DM1, mediated by ubiquitination by the Cbl ubiquitin ligases. We investigated the effects of various small molecules and discovered that zoledronic acid binds to FLOT2 and disrupts the HER2/FLOT2 interaction, which enhances T-DM1 internalization and cytotoxicity. In conclusion, FLOT2 regulates the internalization and cytotoxicity of T-DM1 mediated by Cbl-dependent ubiquitination of HER2. Zoledronic acid disrupts the HER2/FLOT2 interaction, therefore increasing the internalization and cytotoxicity of T-DM1, providing proof of principle that a small molecule inhibitor of the HER2/FLOT2 interaction can enhance the activity of the HER2-targeting ADC.

cancer biology↗

Immune Biomarkers of Islet Transplant Rejection Revealed by Synthetic Immunological Niche

Islet transplantation can restore glycemic control in type 1 diabetes, yet the heterogeneity of patient immune responses and transplant outcomes motivates the need for technologies to monitor the graft. Since transplanted islets are not readily accessible for biopsy due to their diffuse engraftment within the liver, clinical monitoring relies on measurements such as islet mass, blood glucose, and C-peptide levels, which are lagging indicators that change only after substantial graft injury. Here, we developed a minimally invasive synthetic immunological niche (IN) that captures graft-associated immune responses through serial subcutaneous biopsy. We evaluated the IN across murine syngeneic, allogeneic, and autoimmune islet transplant models, including CD40/CD154 costimulatory blockade with anti-CD40L. In syngeneic versus allogeneic recipients, IN identified immune populations and transcriptomic signatures that mirrored the graft and distinguished healthy from rejecting grafts. In anti-CD40L treated allografts, IN revealed innate macrophage- and dendritic cell-associated programs linked to graft acceptance versus rejection, whereas IN from untreated allografts showed stronger adaptive immune signatures. Longitudinal IN profiling further detected progressive inflammatory activation in accepted allografts, indicating persistent subclinical risk. Finally, in an autoimmune allograft model treated with anti-CD40L plus rapamycin, IN identified a 13-gene signature that separated early from late rejection trajectories and distinguished autoimmune-from alloimmune-associated rejection programs. Overall, these findings establish IN as a surrogate tissue for minimally invasive monitoring of islet graft and early detection of rejection-associated immune dysregulation. One Sentence SummaryAn engineered immunological niche captures distinct immune signatures of allo- and auto-mediated islet transplant rejection

bioengineering↗

Structural Basis of Ligand-Specific Orthosteric-Allosteric Coupling and Sensory Tuning in the Human Bitter Taste Receptor TAS2R14

The bitter taste receptor TAS2R14 recognizes hundreds of structurally diverse ligands, yet the mechanisms governing its broad promiscuity, graded agonist efficacy, and multi-site regulation remain unclear. Here, we report cryo-EM structures of TAS2R14-Gi1 complexes bound to 3,5-diiodosalicylic acid (DA), flufenamic acid (FA) and aristolochic acid (AA) at resolutions of 2.44 [A], 2.39 [A], and 2.69 [A], with a clear efficacy hierarchy of AA > FA > DA. Transmembrane helix 6 (TM6) acts as a core regulatory hub, with agonist binding triggering 12 [A] lever-like TM6 rearrangements to reshape receptor interfaces and modulate G-protein coupling strength. We also identify cholesterol hemisuccinate (CHS) as a new TAS2R14 orthosteric agonist, selectively potentiating DA-mediated signaling potency by [~]5-fold via allosteric-orthosteric coupling without affecting FA or AA. Our findings show TM6 dynamics unify TAS2R14s key functional features, advancing insights into bitter receptor activation and sterol regulation.

molecular biology↗

An interaction between HP1 and the Chromosomal Passenger Complex Initiates Acentrosomal Spindle Assembly in Drosophila oocytes

Chromosome segregation fidelity during meiosis is critical for genome integrity, with aneuploidy causing infertility, miscarriages, and congenital anomalies. In the oocytes of many species, spindle assembly occurs in the absence of centrosomes that normally function as microtubule-organizing centers at the poles. Such acentrosomal spindles are believed to pose significant challenges for accurate chromosome segregation compared to centrosomal organized spindles. Previous work in Drosophila has shown that the chromosomal passenger complex (CPC) is required for acentrosomal spindle assembly. We found that heterochromatin protein-1 (HP1) plays a critical role in regulating CPC localization and spindle assembly. Furthermore, HP1 moves to the microtubules, where it has roles in building a functional spindle and interacts with the CPC to regulate chromosome biorientation. These results indicate that spindle assembly is mediated by multiple interactions between the CPC, HP1, and the chromosomes, and provide insights into the mechanisms that restricts spindle assembly to the chromosomes in Drosophila oocytes.

cell biology↗

From Representation to Action: A Unified Laplacian Framework for Spatial Representation and Path Planning

Navigation in complex environments relies on internal spatial representations that guide action. While the brain employs a diverse repertoire of spatial tuning cells--including grid, place, and head-direction cells--a normative theory linking these static neural codes to the dynamic process of navigation remains elusive. In this work, we propose a Unified Laplacian Framework derived from first principles of representational smoothness and efficiency. We first demonstrate that diverse spatial codes emerge naturally as spectral decompositions of the Laplace operator. Crucially, bridging the gap from representation to action, we derive a biologically plausible navigation policy based on the Greens function potential. We show that this potential encodes the environments intrinsic geometry to enable simple, trap-free gradient ascent, achieving improved sample efficiency and generalization in goal-reaching tasks. Furthermore, we demonstrate that these spectral representations can be learned directly from high-dimensional visual inputs, confirming their plausibility in realistic environments. Our results suggest that the "cognitive map" can be viewed as a spectral embedding of the Laplacian, providing a rigorous foundation for spatial cognition in both biological and artificial agents.

neuroscience↗

Coordinated immune architecture underlies durable survival in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterised by profound immune dysfunction and limited response to immunotherapy. Although tertiary lymphoid structures (TLSs) are associated with improved outcomes, most studies focus on their presence or density, providing limited insight into how their organisation contributes to tumour control. Here, we analyse a unique cohort of treatment-naive PDAC patients enriched for exceptionally rare long-term survivors (LTS, n = 23; >5-year survival) alongside more common short-term survivors (STS, n = 24), enabling direct interrogation of mechanisms underlying durable tumour control. We develop a multi-scale spatial framework integrating multiplex imaging, computational modelling, and transcriptomics to quantify TLS architecture. By modelling TLSs as higher-order immune assemblies, we define their structural states, spatial organisation, assembly rules and tissue context-dependency within the tumour microenvironment. We show that long-term survival is associated with organised, spatially integrated TLSs exhibiting coordinated B and T cell zoning, whereas short-term survival is characterised by disorganised, Treg-enriched, and spatially isolated TLSs, despite similar immune cell abundance. These architectural differences align with transcriptional programmes: LTS tumours display coordinated lymphoid and NF-{kappa}B-driven chemokine signalling, while STS tumours exhibit inflammation uncoupled from immune organisation. Together, these findings demonstrate that durable anti-tumour immunity in PDAC is defined by coordinated transcriptional, cellular, and spatial organisation, rather than immune presence alone. This study provides a blueprint for structure-informed strategies to reprogram the tumour microenvironment and improve outcomes in PDAC. Statement of significanceIntegrating multiplex imaging, computational modelling and transcriptomics in treatment-naive PDAC enriched for exceptional survivors shows that durable tumour control is associated with organised TLS architecture rather than immune abundance alone, providing a framework for immune-architecture-based biomarkers and therapeutic reprogramming.

cancer biology↗

ICON: An isoform-aware hierarchical random forest model for cell type classification

Single-cell RNA sequencing (scRNA-seq) has transformed our ability to resolve cellular heterogeneity across complex biological systems. However, conventional short-read scRNA-seq is inherently limited in its inability to capture full-length transcripts. Isoform profiles, arising from alternative splicing, provide a deeper layer of resolution, enabling finer discrimination of cellular subtypes and dynamic states, particularly in heterogenous tissues. Long-read RNA sequencing technologies enable accurate transcript-level profiling and more comprehensive characterisation of isoform diversity. Despite these advances, existing cell type annotation methods remain largely tailored to gene-level data, thereby limiting fidelity and leaving isoform-level information an untapped reservoir of biological insight. Here, we present a hierarchical random forest (HRF) framework, ICON, for isoform-aware cell classification in scRNA-seq data. By jointly modelling gene- and isoform-level expression the framework captures both abundance and useage patterns, enabling classification beyond gene-level resolution. A two-stage strategy first assigns cell identities using highly variable gene and isoform features, followed by targeted reclassification of ambiguous cells based on relative isoform and gene usage, thereby resolving conflicts that arise from transcriptional heterogeneity. Importantly, ICON provides interpretable outputs by identifying key genes and isoforms that drive cell type discrimination, linking classification to underlying regulatory mechanisms. Benchmarking on long-read scRNA-seq datasets demonstrates consistent improvements over conventional gene-based approaches. With increasing adoption of long-read sequencing, our framework provides a robust, interpretable foundation for isoform-aware cell type annotation, improving resolution and insight.

bioinformatics↗

A new species of Rana from Anhui, China (Anura, Ranidae)

The diversity of the brown frog genus Rana may be underestimated as the high similarity of morphological characters. A new species belonging to the genus Rana is delineated based on eight specimens obtained from the Tianma National Nature Reserve, Jinzhai County, Luan City, Anhui Province, China. The phylogenetic analysis based on three mitochondrial genes (12S, ND2, and Cyt b) and one nuclear gene (BDNF) showed that the new species formed an independent clade closely related to R. culainensis and received strong support. In addition, morphological differentiation confirmed the phylogenetic results, and both supported the validity of a new species (Rana tianmaensis sp. nov.) in the R. japonica species group. The discovery of this new species enhances peoples understanding of the biodiversity of Rana and can provide important foundational data for scientific decision-making on protected area construction, ecological conservation, and species diversity. With the inclusion of newly described species in this study, the distribution of Rana genus in China now includes 31 recognized species.

zoology↗

An auxiliary protein tunes reductase activity in alkaloid biosynthesis

Monoterpene indole alkaloids encompass a diverse class of plant natural products. Many of these valuable compounds, including the anticancer medicines vinblastine and vincristine (Catharanthus roseus) and the antiaddiction treatment ibogaine (Tabernanthe iboga) utilize a common biosynthetic intermediate, 19E-geissoschizine, which is produced by the medium-chain dehydrogenase/reductase geissoschizine synthase (GS). Herein we report the discovery of a non-catalytic auxiliary protein (facilitator of geissoschizine synthase, FoGS) that improves formation of 19E-geissoschizine by acting in combination with GS. The discovery of a FoGS orthologue that works with GS to produce 19Z-geissoschizine shows how this protein also controls the stereochemistry of the product. We demonstrate that FoGS and GS interact to form a stable heterodimer, and show through mutagenesis that FoGS likely modulates the structure of the GS active site. Microscopy studies suggest that FoGS also changes the subcellular localization of GS. The discovery of FoGS will enable efforts to heterologously reconstitute commercially important geissoschizine-derived monoterpene indole alkaloids, and moreover, highlights how metabolic pathways utilize proteins that are not essential for production of the products, but nevertheless enhance the efficiency and specificity of the catalytic biosynthetic pathway components.

biochemistry↗

Identification of a neural circuit that enables safe, long-term torpor in mice

Torpor, a state of regulated hypothermia and hypometabolism, is a critical survival strategy in certain mammals. Previous studies established the primacy of neuron control in initiating acute torpor. However, whether neuromodulation can safely sustain torpor over the long term, and the specific governing pathways, remain unanswered challenges limiting its translational potential. Here we identify a distinct preoptic neuronal population expressing General control nonderepressible 2 ( G neurons) in mice that is essential and sufficient for torpor induction. Strikingly, sustained and selective activation of G neurons induces a stable, weeks-long torpid state (G neuron-driven long-term torpor, GLT), from which animals arouse without obvious behavioral deficits or tissue pathology. In contrast, long-term torpor driven by pan-neuronal activation of the same brain region (PLT) causes multiple post-recovery damages, underscoring the unique safety profile of selective pathway of G neurons. In a mouse cancer model, GLT directly suppressed tumor proliferation and markedly sensitized tumors to chemotherapy, achieving profound therapeutic outcomes. Together, we delineate a distinct neuronal population safely enabling prolonged torpor. This establishes a specific paradigm for inducing a stable and sustained hypometabolic state, providing a transformative platform for fundamental physiological research and pioneering clinical strategies against chronic pathologies such as cancer.

neuroscience↗

Spatial-neighbour encoding enables fast RNA 3D structure search

Experimental and predicted RNA three-dimensional structures are expanding rapidly, but RNA structure search still lacks a compact residue-level representation that supports database-scale comparison. Using family-held-out ablations across the currently available experimental RNA structure collection, we found that spatial-neighbour features are markedly more informative for family-level discrimination than conventional backbone and base descriptors. Building on this result, we developed RiboSeek, a search framework based on a 20-letter geometric alphabet (RS-20), an 80-letter structure-and-base composite alphabet (RS-80). Across family-level classification and retrieval benchmarks, RS-80 delivered the strongest overall performance, whereas RS-20 most closely tracked US-align TM-score, indicating better preservation of geometric similarity. RiboSeek searches the full experimental RNA structure database in 204 ms per query and can be applied to predicted RNA structure libraries to prioritize candidate structural relationships for downstream analysis.

bioinformatics↗