Biology subjects

Qi, T.

Publications and source records attributed to Qi, T..

At least 19 recordsLinked to original sources

bioRxiv2026

Bio-CM{superscript 2}: Distributed computational optics for cortex-widecellular imaging

Understanding distributed biological systems, particularly neural circuits, requires simultaneous cellular-resolution imaging across millimeter-scale fields of view (FOV). Existing miniature microscopes remain fundamentally constrained by trade-offs among FOV, spatial resolution, and optical complexity, limiting their ability to bridge cellular microscopy with cortex-scale imaging. Here we introduce distributed computational optics, a framework that distributes image formation across coordinated optical modules and computationally integrates their measurements into a unified image. We realize this framework in Bio-CM2, a computational miniature mesoscope that partitions the imaging field across four optical modules while converging their measurements onto a common image sensor. This architecture overcomes the aberration-scaling limitations of conventional miniature optics while avoiding the hardware complexity of multi-camera systems and the contrast degradation associated with optical multiplexing. Bio-CM2 achieves a 7.5 x 10 mm2 FOV while enabling cellular-resolution in vivo imaging at video rates. We demonstrate its utility through two complementary imaging modalities in head-fixed mice: cortex-wide functional vascular imaging, enabling simultaneous quantification of pial arteriole vasomotion and mesoscale hemodynamic functional connectivity, and cellular-resolution calcium imaging, resolving the activity of over 3,000 neurons together with mesoscale neuronal functional connectivity. We further demonstrate the versatility of the platform through cellular-resolution imaging of entire coronal mouse brain sections, population-scale imaging of freely behaving Caenorhabditis elegans, and odor-evoked calcium imaging of the main olfactory bulb in head-fixed mice, highlighting its broad applicability across diverse biological systems and imaging modalities. By overcoming the conventional trade-off between FOV and spatial resolution in a compact miniature platform, Bio-CM2 establishes distributed computational optics as a scalable framework for multiscale biological imaging.

bioengineering↗

bioRxiv2026

Learning Shapes the Energy Cost of Neural Tasks

The stark difference in energy use between AI systems and biological brains highlights both the remarkable efficiency of the brain and our limited understanding of the energetics underlying neural computation. Although efficiency is widely cited as a principle of neural design, direct measurement of the energy cost of specific neural tasks within their corresponding circuits has remained limited. Here, by simultaneously measuring intracellular glucose and calcium dynamics in the same behaving mice in vivo, we use neuronal glucose consumption to define circuit-level energy costs associated with learning-based behavioral tasks. We found that the post-learning fuel cost per task was significantly lower than pre-learning levels across multiple hippocampus- and cortex-dependent learning models, with or without changes in bulk calcium dynamics. This change in fuel cost was not mediated by extracellular glucose transport but instead reflected a reduction in intracellular glucose consumption and depended on canonical plasticity mechanisms, including NMDAR signaling and protein synthesis. Together, these findings suggest that attenuation of task-specific energy cost may represent a general bioenergetic trajectory of learning and plasticity. This "energy minimization" hypothesis provides insight into how the biological brain achieves efficiency and offers an orthogonal, complementary perspective to neural activity-centered frameworks.

neuroscience↗

bioRxiv2026

Systematic benchmarking of multi-modal approaches for tumor-naive ctDNA detection and quantification

Longitudinal monitoring of circulating tumor DNA (ctDNA) has emerged as a promising framework for characterizing treatment response dynamics in cancer. Scalable tumor-naive approaches for quantifying ctDNA often involve whole-genome sequencing (WGS) or DNA methylation profiling, but their comparative performance and capacity for complementary integration remain poorly understood. Here we systematically benchmarked tumor-naive WGS- and methylation-based ctDNA quantification methods using plasma from 150 patients with colorectal, lung and breast cancer. Using paired high-depth WGS and EM-seq data, we generated 40,000 in silico samples and evaluated detection accuracy, limits of detection (LoD) and quantification (LoQ) across cancer types and sequencing depths (0.1x-30x). We further assessed single- and multimodal method combinations, identifying conditions under which integrated approaches enhance analytical performance for detection and quantification relative to single modalities. This benchmark delineates key performance trade-offs and provides a practical framework to support method development and guide future research applications in ctDNA-based biomarker studies.

bioinformatics↗

bioRxiv2026

A Decade of Deep Learning-based Biomedical Image Segmentation

Biomedical image segmentation is a fundamental problem in computational biomedicine that aims to precisely delineate anatomical and biological structures, tissue types, or pathological regions in biomedical images. Accurate segmentation is essential for interpretation, decision-making, and quantitative analysis across a wide range of biological and medical applications. Over the past decade, the field has undergone a profound paradigm shift, evolving from task-specific specialist models to universal foundation models. This review provides an in-depth analysis of the evolution, tracing how the limitations of local discriminative learning drove the transition toward transformer-based global modeling, and large-scale generative pre-training. To help navigate the diverse landscape of interaction paradigms, we introduce the first systematic taxonomy of promptable biomedical image segmentation, categorizing existing methods into six distinct types, enabling users to intuitively select appropriate prompting strategies based on visual demonstrations and quickly pinpoint relevant literature (Prompt Type Visualization). Beyond model architectures, we discuss parallel advancements in dataset development, evaluation protocols, and application-specific adaptations across radiology, pathology, and biology. Integrating these powerful foundation models with rigorous domain-specific adaptation has great potential to improve patient outcomes and healthcare efficiency. Finally, we highlight key challenges in trustworthiness and clinical integration that must be overcome to realize the potential of the next generation of biological and medical generalists.

bioengineering↗

bioRxiv2026

Top-down regulation of ingestive behavior fragmentation

AbstractIn natural environments, animals rarely feed continuously to satiation; instead, feeding occurs in brief bouts separated by pauses. This fragmentation is thought to balance internal drives with external demands, yet its underlying neural mechanisms remain unclear. By combining bidirectional neural activity mapping and behavioral phenotyping, we identify a projection from the dorsal subiculum (dSub) of the hippocampus to the mammillary body (MB) as a key regulator of this fragmentation. Activity along the dSub-MB pathway tracks and gates the duration of individual feeding bouts, independent of homeostatic state. A simple bistable attractor model captures both dSub-MB neural dynamics and associated behaviors across optogenetic and behavioral perturbations. Together, these findings identify a top-down circuit mechanism that implements action selection in a naturalistic setting.

neuroscience↗

bioRxiv2026

Elimination of intramuscular immunoglobulin accumulation alleviates Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disorder due to loss of dystrophin, a cytoskeletal protein critical for muscle integrity and functionality. Despite recent therapeutic advances, there remains a significant unmet need for more effective and accessible therapeutics. Here, we discovered an early accumulation of immunoglobulin G (IgG) in the sarcolemma, which exacerbates tissue inflammation and disease progression. The IgG accumulation primarily resulted from ectopic localization of Fc{gamma}R1, a high-affinity IgG Fc receptor, on dystrophin-deficient myofibers. In two independent murine models, eliminating IgG accumulation via B cell depletion provided sustained benefit to alleviate DMD progression. Our findings uncover a novel disease accelerator in DMD and demonstrate the potential to target this mechanism as therapeutics for broader population of patients with DMD.

immunology↗

bioRxiv2025

Intratumoral microbiota-derived S1P sensitizes the combination therapy of Capecitabine and Nivolumab

Clinical responses of colorectal cancer (CRC) treatments vary considerably due to the heterogeneity of tumor micro-environment (TME), where intratumoral microbiota may reshape the unique inflammation imprints. However, its complex mechanistic underpinnings remain incompletely elucidated. Herein we sought to delineate the critical role of intratumoral microbiota in potentiating combination therapeutics against CRC. By comparing germ-free (GF) and specific pathogen-free (SPF) mouse models of 33 potential CRC treatments, we screened out the combination regimen of Capecitabine-Nivolumab significantly augmented by intratumoral microbiota in tumor regression and survival prolongation. The enrichment of Bacteroides fragilis induced by Capecitabine-Nivolumab was concomitant with elevated microbial sphingosine-1-phosphate (S1P), which further upregulated tumoral PD-L1 expression by enhancing histone deacetylation at the CD274 locus. Activation of microbial sphingosine kinase 2 (SphK2) ultimately led to an expansion of effector memory CD8+ T cells and reduction of exhausted T cell subsets within TME. To conclude, these findings advance our understanding of the intricate interplay among intratumoral microbiota, sphingolipid metabolites and immunochemotherapeutics. It highlights microbial sphingolipids as potential predictive biomarkers for strategies of targeting intratumoral microbiota in CRC management.

microbiology↗

bioRxiv2025

Deep Volumetric Localization Super-Resolution Microscopy

Super-resolution microscopy, particularly localization-based methods, necessitates careful balancing of optical complexity, computational demands, and user accessibility. Conventional strategies typically adopt either deterministic or learning-based approaches, overlooking opportunities to leverage their syn-ergistic strengths. In this work, we introduce deep volumetric localization microscopy (VLM), a super-resolution methodology that integrates instrumental and algorithmic advancements for high-fidelity 3D single-molecule imaging. VLM employs a wavefront-optimized light-field configuration to capture single-molecule data, while a cascaded neural network reconstructs 3D volumes and extracts molecular coordinates at a 10 nm and 25 nm localization precision in the lateral and axial dimensions, respectively, across an imaging depth exceeding 5 {micro}m. Unlike existing methods, VLM is trained exclusively with system-aware intrinsic point-spread functions, bypassing dependencies on external imaging modalities or sample-specific data training. We validate VLM across diverse biological specimens, demonstrating hardware simplicity, data efficiency, and minimal phototoxicity. We anticipate VLM will overcome current limitations in fluorescence microscopy, empowering broader advancements in biomedical research.

bioengineering↗

bioRxiv2025

Highly heterozygous Citrus changshan-huyou Y. B. Chang originated from ancient hybridization between mandarin and pummelo and displayed distinct tissue-specific allelic imbalance

The genus Citrus is characterized by a reticulate evolutionary history with frequent hybridization, making it an intriguing subject for genome evolution investigation. Citrus changshan Y. B. Chang (Huyou) is a unique landrace first discovered in Zhejiang Province, China with premium fruit quality. The evolutionary origin of Huyou has puzzled local botanists and growers. Here, we sequenced a 120-years-old "ancestral tree" of Huyou using PacBio long read and Hi-C sequencing and assembled 2 high-quality haplotype-resolved genomes HY1 and HY2. Huyou displayed a genome heterozygosity level at 3.07%, among the highest in published citrus genomes. Using a k-mer-based tracing approach, we explicitly resolved that HY1 genome contained 87.8% mandarin, 7.3% pummelo, 0.2% citron origin, whereas HY2 had 85.0% pummelo, 2.9% mandarin, 0.3% citron, implying a hybridization event between mandarin and pummelo. Phylogeny dating showed that HY1 (2.0 Mya) and HY2 (2.18 Mya) had diverged earlier than the split of Citrus clementina and Citrus reticulata, and the split of Citrus grandis and Citrus maxima, respectively. We observed clear chromosomal recombination on chr8 and chr9 in HY1, which may have occurred after the ancestral hybridization. Further transcriptome analyses in 6 tissues revealed a strong allelic dominance of HY2 over HY1 in root tissue and moderately in stem, leaf, flower, and fruits. KEGG enrichment analyses revealed that genes related to antioxidants biosynthesis and lipid metabolisms were most significantly affected by allelic imbalance. This first report of allelic imbalance in citrus species support Huyou as an interesting model to investigate genome evolution following distant hybridization.

evolutionary biology↗

bioRxiv2025

Single-Cell Genomics Elucidates Molecular Variations and Regulatory Mechanisms in Circulating Immune Cells

The human peripheral blood displays diverse molecular characteristics across populations, understanding the drivers and underlying mechanisms of which remains challenging. Here, we introduce the Chinese Immune Multi-Omics Atlas (CIMA), elucidating sex-, age-, and genetic-related molecular variations by analyzing multi-omics data from 428 adults with over 10 million immune cells. CIMA generated an enhancer-driven gene regulatory network, identifying 237 high-quality regulons and revealing cell type-specific regulatory mechanisms. Additionally, 11,521 lead cis-expression quantitative trait loci (eQTLs) and 46,339 chromatin accessibility QTLs (caQTLs) were identified at cell type level. CIMA also uncovered pleiotropic associations among immune-related disease risk loci, eQTLs, and caQTLs in a cell type-specific manner. Lastly, a novel cell language model, CIMA-CLM, was developed to predict chromatin accessibility and noncoding variant effects using chromatin sequences and gene expressions. This work represents a population-scale multi-omics resource of human immune cells, providing a valuable reference for future investigation of immune-related diseases.

immunology↗

bioRxiv2024

Functional fingerprinting for the developing brain using deep metric learning: an ABCD study

Brain fingerprinting is a promising approach for characterizing the uniqueness of individual brain functioning using functional magnetic resonance imaging (fMRI) data. Here, we propose a novel deep learning framework, the metric-BoIT, for brain fingerprinting and demonstrate its effectiveness in capturing individual variability among early adolescents undergoing dramatic brain changes. Utilizing resting-state fMRI data from the Adolescent Brain Cognitive Development (ABCD) dataset, we identified brain functional fingerprints that achieved remarkable individual identification accuracy, reaching 97.6% within a single session and maintaining 86.6% accuracy over a four-year developmental period. Annotation analysis revealed that higher-order association regions, particularly those within the default-mode network, contributed most significantly to these distinctive brain fingerprints (t = 5.618, p < 0.001). Moreover, these brain fingerprints were relevant to cognitive functions, as evidenced by significant correlations with fluid intelligence (F = 1.282, p = 0.027) and crystallized intelligence (F = 1.405, p < 0.001). The extracted brain fingerprints were additionally associated with genetics, showing that individuals with strong genomic relationships exhibited more similar brain fingerprint patterns (t = -12.330, p < 0.001). Together, our study not only presents an innovative approach to brain functional fingerprinting but also provides valuable insights into the individual variability underlying adolescent neurodevelopment.

neuroscience↗

bioRxiv2024

Switch of TIR signaling by a Ca2+ sensor activates ADR1 recognition of pRib-AMP-EDS1-PAD4 for stomatal immunity

Plants swiftly close stomata upon detecting pathogen entry, a crucial defense termed stomatal immunity. The process is initiated by cell-surface pattern recognition receptors (PRRs) that perceive pathogen-associated molecular patterns (PAMPs) and evoke a series of early cellular responses including calcium ions (Ca2+) influx, and is conducted by the intracellular nucleotide-binding leucine-rich-repeat receptors (NLRs) ADR1s within an EDS1-PAD4-ADR1 module. However, the underlying mechanisms linking PRR signaling to the NLRs ADR1s remain unclear. Here, we show that the Nicotiana benthamiana Toll/interleukin-1 receptor (TIR)-only protein Stomatal TIR1 (STIR1) produces the immune molecule pRib-AMP, induces formation of EDS1-PAD4-ADR1 complexes, and mediates stomatal immunity. The Inhibitor of Stomatal Immunity C2-domain protein 1 (ISIC1) interacts with and constrains STIR1 function at basal condition, whereas upon pathogen infection, ISIC1 senses Ca2+ signals and de-represses STIR1 signaling. Cryo-electron microscopy structure of pathogen infection-elicited Arabidopsis AtEDS1-AtPAD4-AtADR1-L2 complex reveals the pRib-AMP binding to AtEDS1-AtPAD4 receptor and the AtADR1-L2 recognition of pRib-AMP-AtPAD4-AtEDS1 for stomatal immunity. Collectively, this study uncovers a repression/de-repression mechanism linking PRR signaling to NLRs by a Ca2+ sensor/TIR-only node, and elucidates an NLR recognition mechanism of the pRib-AMP-EDS1-PAD4 complex in governing innate immunity. SynopsisAt basal condition, the Ca2+ sensor ISIC1 interacts with and inhibits the TIR-only protein STIR1; upon pathogen infection, ISIC1 perceives Ca2+ signal and releases STIR1 to produce pRib-AMP; the EDS1-PAD4 receptor binds pRib-AMP and is recognized by the NLR ADR1-L2, thereby activating stomatal immunity.

plant biology↗

bioRxiv2023

Anatomical and behavioral correlates of auditory perception in developmental dyslexia

Developmental dyslexia is typically associated with difficulties in basic auditory processing and in manipulating speech sounds. However, the neuroanatomical correlates of auditory difficulties in developmental dyslexia (DD) and their contribution to individual clinical phenotypes are still unknown. Recent intracranial electrocorticography findings associated processing of sound amplitude rises and speech sounds with posterior and middle superior temporal gyrus (STG), respectively. We hypothesize that regional STG anatomy will relate to specific auditory abilities in DD, and that auditory processing abilities will relate to behavioral difficulties with speech and reading. One hundred and ten children (78 DD, 32 typically developing, age 7-15 years) completed amplitude rise time and speech in noise discrimination tasks. They also underwent a battery of cognitive tests. Anatomical MRI scans were used to identify regions in which local cortical gyrification complexity correlated with auditory behavior. Behaviorally, amplitude rise time but not speech in noise performance was impaired in DD. Neurally, amplitude rise time and speech in noise performance correlated with gyrification in posterior and middle STG, respectively. Furthermore, amplitude rise time significantly contributed to reading impairments in DD, while speech in noise only explained variance in phonological awareness. Finally, amplitude rise time and speech in noise performance were not correlated, and each task was correlated with distinct neuropsychological measures, emphasizing their unique contributions to DD. Overall, we provide a direct link between the neurodevelopment of the left STG and individual variability in auditory processing abilities in neurotypical and dyslexic populations.

neuroscience↗

bioRxiv2023

Xiphoid nucleus of the midline thalamus controls cold-induced food seeking

Maintaining body temperature is calorically expensive for endothermic animals. Mammals eat more in the cold to compensate for energy expenditure, but the neural mechanism underlying this coupling is not well understood. Through behavioral and metabolic analyses, we found that mice dynamically switch between energy conservation and food-seeking states in the cold, the latter of which is primarily driven by energy expenditure rather than the sensation of cold. To identify the neural mechanisms underlying cold-induced food seeking, we use whole-brain cFos mapping and found that the xiphoid (Xi), a small nucleus in the midline thalamus, was selectively activated by prolonged cold associated with elevated energy expenditure but not with acute cold exposure. In vivo calcium imaging showed that Xi activity correlates with food-seeking episodes in cold conditions. Using activity-dependent viral strategies, we found that optogenetic and chemogenetic stimulation of cold-activated Xi neurons recapitulated cold-induced feeding, whereas their inhibition suppressed it. Mechanistically, Xi encodes a context-dependent valence switch promoting food-seeking behaviors in cold but not warm conditions. Furthermore, these behaviors are mediated by a Xi to nucleus accumbens projection. Our results establish Xi as a key region for controlling cold-induced feeding, an important mechanism for maintaining energy homeostasis in endothermic animals.

neuroscience↗

bioRxiv2023

Phosphorylation of pyruvate dehydrogenase marks the inhibition of in vivo neuronal activity

For decades, the expression of immediate early genes (IEGs) such as c-fos has been the most widely used molecular marker representing neuronal activation. However, to date, there is no equivalent surrogate available for the decrease of neuronal activity (i.e., inhibition). Here, we developed an optogenetic-based biochemical screen in which population neural activities can be controlled by light with single action potential precision, followed by unbiased phosphoproteomic profiling. We identified that the phosphorylation of pyruvate dehydrogenase (pPDH) inversely correlated with the intensity of action potential firing in primary neurons. In in vivo mouse models, monoclonal antibody-based pPDH immunostaining detected neuronal inhibition across the brain induced by a wide range of factors including general anesthesia, sensory experiences, and natural behaviors. Thus, as an in vivo marker for neuronal inhibition, pPDH can be used together with IEGs or other cell-type markers to profile and identify bi-directional neural dynamics induced by experiences or behaviors.

neuroscience↗

bioRxiv2023

Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor.

Patient symptom relief is often heavily influenced by the residence time of the inhibitor-target complex. For the human muscarinic receptor 3 (hMR3), tiotropium is a long-acting bronchodylator used in conditions such as asthma or chronic obstructive pulmonary disease (COPD). The mechanistic insights of this inhibitor remain unclear, specifically, elucidation of the main factors determining the unbinding rates could help develop the next generation of antimuscarinic agents. Using our novel unbinding algorithm, we were able to investigate ligand dissociation from hMR3. The unbinding paths of tiotropium and two of its analogues, N-methylscopolamin and homatropine methylbromide show a consistent qualitative mechanism and allowed us to identify the structural bottleneck of the process. Furthermore, our machine learning-based analysis identified key roles of the ECL2/TM5 junction involved at the transition state. Additionally, our results point at relevant changes at the intracellular end of the TM6 helix leading to the ICL3 kinase domain, highlighting the closest residue L482. This residue is located right between two main protein binding sites involved in signal transduction for hMR3s activation and regulation. We also highlight key pharmacophores of tiotropium that play determining roles in the unbinding kinetics and could aid towards drug design and lead optimization. Description O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/522558v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@2598b2org.highwire.dtl.DTLVardef@4bf425org.highwire.dtl.DTLVardef@89dfa8org.highwire.dtl.DTLVardef@1ba9f48_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical abstract of the work, showing the unbinding for ligands 1 (tiotropium, TTP), 2 (N-methylscopolamin, NMS) and 3 (homatropine methylbromide, CPD2). Using TTPs downhill simulations from its unbinding transition state, different protein-ligand and proteinprotein interactions were analyzed with MLTSA to find relevant CVs driving the different outcomes.

biophysics↗

bioRxiv2022

Immunological Synapse Dynamics Induced by Bispecific T-cell Engagers Predict Clinical Pharmacodynamics and Tumor Evolution across Anatomical Sites

Effector T cells form immunological synapses (IS) with recognized target cells to elicit cytolytic effects. Facilitating IS formation is the principal pharmacological action of most T cell-based cancer immunotherapies. However, the dynamics of IS formation at the cell population level, the primary driver of the pharmacodynamics of many cancer immunotherapies, remains poorly defined. With classic immunotherapy CD3/CD19 bispecific T cell engager (BiTE) as a model system, we integrate experimental and theoretical approaches to investigate the population dynamics of IS formation and their relevance to clinical pharmacodynamics and treatment resistance. Our models produce experimentally consistent predictions when defining IS formation as a series of spatiotemporally coordinated events driven by molecular and cellular interactions. The models predict tumor-killing pharmacodynamics in patients and reveal trajectories of tumor evolution across anatomical sites under BiTE immunotherapy. Our model highlight the bone marrow may serve as a sanctuary site permitting tumor evolution and antigen escape. The models also suggest the optimal dosing regimens as a function of tumor growth and patient T cell abundance that confer adequate tumor control with minimal disease evolution. This work has implications for developing more effective T cell-based cancer immunotherapies.

pharmacology and toxicology↗

bioRxiv2022

Closely related type II-C Cas9 orthologs recognize diverse PAMs

Autosomal dominant diseases can be treated by allele-specific disruption of mutant alleles. If the missense mutation generates a novel protospacer-adjacent motif (PAM), CRISPR-Cas9 can distinguish mutant alleles from wild-type alleles by a PAM-specific approach. Therefore, it is crucial to develop a CRISPR toolbox capable of recognizing multiple PAMs. Here, by using a GFP-activation assay, we tested the activities of 29 type II-C orthologs closely related to Nme1Cas9, 25 of which are active in human cells. These orthologs recognize diverse PAMs with variable length and nucleotide preference, including purine-rich, pyrimidine-rich, and mixed purine and pyrimidine PAMs. We characterized in depth the activity and specificity of Nsp2Cas9. We also generated a chimeric Cas9 nuclease that recognizes a simple N4C PAM, representing the most relaxed PAM preference for compact Cas9s to date. These Cas9 nucleases significantly enhance our ability to perform allele-specific genome editing.

genetics↗