Biology subjects

Qiu, L.

Publications and source records attributed to Qiu, L..

At least 19 recordsLinked to original sources

bioRxiv2026

Bayesian in situ point spread function modeling enables high-fidelity three-dimensional nanoscopy in deep tissue

Three-dimensional single-molecule localization microscopy enables nanometer-resolution mapping of biomolecular organization in native cellular environments, but extending this capability to deep tissue requires in situ point spread function (PSF) modeling to account for specimen-induced optical distortions. Existing in situ approaches rely on a deterministic mapping between each single-molecule detection and the underlying PSF model. In deep tissue, however, specimen-induced aberrations, optical scattering and elevated background degrade the information content of single-molecule observations, posing a fundamental barrier to reliable PSF estimation. Here we introduce Bayesian in situ PSF modeling (BIM), a computational framework that explicitly models uncertainty in emitter axial position and propagates it through PSF reconstruction. By using an uncertainty-aware posterior fusion strategy, BIM retrieves accurate specimen-matched PSF models directly from raw blinking data under native imaging conditions. We demonstrate BIM by resolving hollow mitochondrial membranes, amyloid-{beta} fibrils, dendrites and spines with high fidelity. When combined with adaptive optics, BIM improves high-fidelity 3D reconstruction in deep tissue at depths exceeding one hundred micrometers.

biophysics↗

bioRxiv2026

The cleaved C-terminal domain of GmERS1-1 modulates cell cycle via GmACR1

Ethylene signaling orchestrates plant development and stress adaptation, yet how post-translational modifications of its receptors coordinate growth regulation remains unresolved. Here, we uncover a proteolytic processing mechanism of the soybean ethylene receptor GmERS1-1 that directly gates cell cycle progression. The GmERS1-1 mutants exhibit elevated yield under field conditions, whereas overexpression suppresses growth and hypersensitizes plants to ethylene. Ethylene triggers nuclear translocation of C-terminal domain (GmERS1-1-CEND), which is indispensable for receptor function. Mechanistically, GmERS1-1-CEND scaffolds a trimeric complex with GmACR1 and GmCDK7, enforcing G2/M phase arrest, thereby decoupling cell division from canonical ethylene transcriptional responses. Strikingly, ethylene-induced cell cycle blockade during apple fruit maturation mirrors this pathway, suggesting deep conservation across angiosperms. Our work defines a receptor processing-dependent signaling axis that directly interlinks phytohormone perception with cell cycle control, proposing tunable targets (e.g., GmERS1-1 cleavage efficiency) for engineering crop architecture and productivity.

plant biology↗

bioRxiv2026

Breathlessness catastrophising after COVID-19 involves both interoceptive and visceromotor connectivity

Persistent breathlessness is common after COVID-19, yet its severity typically correlates weakly with objective clinical measures. This discordance is often attributed to perceptual inference amplified by anxiety. Because breathing involves a closed perception-action loop, breathlessness may also reflect alterations in interoceptive and visceromotor pathways. We acquired 7-tesla resting-state functional MRI in 53 post-COVID patients with varying breathlessness and estimated functional connectivity across 18 pre-defined interoceptive and visceromotor regions. Linear regression identified two connections associated with breathlessness catastrophising: reduced dorsal periaqueductal grey-posterior insula (dPAG-PoI1) and increased basolateral amygdala-dorsal anterior cingulate (BLA-dACC) connectivity. The dPAG-PoI1 association was stronger in patients who had required mechanical ventilation, whereas the BLA-dACC association was attenuated at higher generalised anxiety. These findings are consistent with two potentially separable contributions to symptom burden: weakened interoceptive signalling between brainstem and sensory cortex, and heightened visceromotor influence of threat processing on autonomic control, rather than anxiety-driven misperception alone.

neuroscience↗

bioRxiv2026

AutoScreen: AI Co-Scientist System for Target Discovery in Functional Genomics

Target discovery in functional genomics remains largely manual and time-consuming, lacking systematic tools for efficient and reproducible gene-level hypothesis generation. We introduce AutoScreen, an AI co-scientist system supporting target discovery through both Pre-screen Design, which constructs perturbation libraries de novo from free-text research descriptions, and Post-screen Analysis, which re-ranks experimental screen hits by integrating statistical scores with biological context. AutoScreen leverages the complementary strengths of multiple specialist agents that perform deep research into multi-modal evidence, information restructuring, parallel searches across >26 biomedical databases, evidence synthesis, and target review to provide transparent, explainable gene prioritization with pipeline provenance. Across 320 genome-scale CRISPR screens as expert-curated benchmarks, AutoScreen achieved a ~19% increase in validated-hit recovery among its top 100 predictions, relative to the strongest agent baseline, and required a 1.2-fold smaller library to recover the same number of hits at the top-500 reference point. AutoScreen reached mean average precision more than two orders-of-magnitude above random baseline. Further, we validated AutoScreen in cancer immune-evasion case studies focusing on natural killer (NK) and T-cell therapeutics. AutoScreen recovered NK-resistance genes that were initially lower-ranked in a leukemia screen, moving MUC1, PDPN, and LRRC15 from raw ranks of 118, 81, 1384 to 5, 44, 659, respectively. In follow-up tumor killing assay with primary human NK cells, individual perturbation validated all three hits successfully. Next, in prospective benchmarking across two cytotoxic T-cell-killing screens, AutoScreen recovered 77.1% of ground-truth hits called by the consensus of two gold-standard analysis pipelines (FDR<0.1), achieving 8% improvement over the strongest general-purpose LLM agent baseline. Finally, we re-analyzed >500 public datasets to construct the AutoScreen Resource Hub, a growing knowledge base of pre-computed, annotated reports for CRISPR screens, RNA-seq differential expression, and gene-level UK Biobank genome-wide association studies. This agentic AI approach enables real-time genomics benchmark construction that are continuously updated, expanded, for evaluating frontier AI co-scientists. Overall, AutoScreen enables AI-powered target discovery to be more auditable, scalable, extensible, and reproducible.

bioengineering↗

bioRxiv2026

The south Congo Basin was critical to Bantu settlement of south central Africa

South central Africa, between the Congo Basin, the Great Lakes, and southern Africa, has long served as a corridor for human movement. Yet, it remains unclear whether there is genetic continuity between pre-Iron Age foragers and later Bantu-associated populations and whether the settlement of this region reflects multiple Bantu-associated migrations rather than the simpler serial founder model suggested by existing genomic data. To do so, we generated genome-wide ancient DNA from 71 Iron Age and historical individuals from present-day Zambia and Malawi, and analyzed these genomes alongside published data from present-day Africans. One late Iron Age individual (16th-17th century) from Kalala Island in the Kafue River, Zambia, carries 40% non Bantu related ancestry that closely matches local Later Stone Age foragers. Admixture for this individual is estimated to be 850 years ago, several centuries earlier than reported for present day BaTwa from the same region. Focusing on the Bantu-related ancestry, haplotype-based analyses identify two main clusters among Iron Age, historical, and present-day south central Bantu groups associated with different Bantu-related migrations. These results reveal a layered history in which at least two Bantu expansions radiated from the southern Congo Basin, with south central Africa acting both as a crossroads of these movements and as a staging area for the subsequent southward expansion toward southern Africa.

evolutionary biology↗

bioRxiv2026

Ancient DNA reveals matrilineal organisation and recurrent unions between dominant matrilines in Iron Age Britain

Kinship practices underpin all traditional societies, forming the basis for socially sanctioned reproductive unions, residence patterns and the inheritance of rights and property1,2. Although the relationship between biological relatedness and kinship is not always straightforward, ancient DNA studies are increasingly used to examine the extent to which biological relatedness underpinned social constructs of kinship in prehistoric societies3-6. Here, we report the analysis of genome-wide data for 534 individuals from the Arras Culture of Middle Iron Age northeast England (including 390 from Wetwang Slack, 100 from Pocklington, and 29 from Melton), finding evidence for communities with kinship systems structured along matrilineal lines. At Wetwang Slack, we reconstruct a 13-generation pedigree comprising 195 individuals structured around female-line connections: matrilineal transmissions greatly outnumbered patrilineal ones and male reproductive partners were largely absent from the cemetery, plausibly because they were buried in their own natal communities. Furthermore, the three main sites with robust sample sizes were characterised by non-overlapping dominant mitochondrial haplogroups, implying a maternal clan-based structure. Reproductive unions at Wetwang Slack suggest a recurrent alliance between two dominant maternal descent groups, with members of each group never reproducing with members of their own maternal lineage. Meanwhile, three individuals from lavishly furnished chariot burials at Wetwang Slack were close maternal relatives belonging to a lineage with consecutive generations of close kin unions, a pattern largely absent among other individuals at the site. These results indicate highly distinctive social practices among an elite group embedded in the wider kinship network of the Arras community.

genetics↗

bioRxiv2026

Hidden genetic diversity in 320 nearly-complete East Asian genome assemblies

East Asian populations, representing over 20% of the global population, remain critically underrepresented in human genomic studies, limiting our understanding of population-stratified genetic variation and its implications for health and disease. Here we present the first phase of the Asian Pan-Genome project (APG), comprising 320 nearly complete, fully phased haploid genome assemblies from 160 East Asian individuals. These assemblies achieve unprecedented quality, with an average contig N50 of 144.3 megabase pairs and an average quality value of 64.5. Leveraging these superior assemblies, we reveal previously uncharacterized diversity in human repeatome, including population-stratified patterns in centromere satellites and rDNA arrays. Compared to existing global human genome assemblies, the newly generated genomes supplement 152 million base pairs of novel sequences, 355 gene gains, 18,300 structural variation loci and 26 large euchromatic inversions missing from current human pangenomes. We perform population stratification analyses of structural variations, and further resolve the structural haplotypes of complex genomic regions such as Major Histocompatibility Complex and Survival Motor Neuron loci across global pangenomes, exemplifying tandem-duplicate and inversion-rich complex locus architectures in the human genome, respectively. This resource provides a critical foundation for human genetic studies, especially for East Asian populations, promoting more accurate variant discovery, reducing bias, and ultimately advancing the equity and efficacy of genomic medicine.

genomics↗

bioRxiv2026

Decoding the oxytocinergic and behavioral signatures of milk ejection

Oxytocin-mediated milk ejection (ME) is pivotal to effective breastfeeding and productive health, yet behaviorally decoding and revealing neural mechanisms of ME remains challenging. Here, we combined in vivo calcium imaging and intramammary pressure recording to uncover the temporal connections between episodic activity of oxytocin neurons and ME in conscious lactating rats. Leveraging the association and behavioral responses in dam and pup, we developed a supervised machine learning framework (ME Decoder) to enable automated analyses of ME. Inspired by its interpretable features, we defined the activity-coupled dam-pup interactions (ADPI), manifested by high kyphosis of the dam followed by pup treading and stretch, as the behavioral signatures of ME. By ME Decoder and ADPI analyses, we detected reduced ME but unaffected activity of oxytocinergic neurons after systemic blockade of oxytocin receptor. Our study uncovers the oxytocinergic and behavioral signatures of ME and provides a generalizable approach for further investigation.

neuroscience↗

bioRxiv2026

The lung tissue environment in Mycobacterium tuberculosis infection determines local monocyte differentiation

Infection by Mycobacterium tuberculosis (Mtb) is characterized by pathogen persistence in lung cells derived from blood monocytes. Since monocyte-derived lung subsets differ in their ability to restrict the growth of intracellular Mtb in mice, understanding the ontogeny of these subsets can inform development of host-directed therapies. Circulating monocytes are proposed to be heterogeneous, arising from distinct bone marrow or spleen progenitors that direct local differentiation. However, the role of the Mtb-infected lung environment in this process has not been addressed. We found that infected and uninfected mice had similar bone marrow monopoiesis, resulting in equivalent monocyte differentiation within the infected lung. While pulmonary Mtb infection also induced splenic monopoiesis, we found no impact on lung monocyte differentiation in splenectomized mice. However, when wildtype monocytes were transferred into Mtb-infected Sp140-/- recipients, in which excess Type I interferons and neutrophils alter the lung environment, we observed that donor-derived lung subsets resembled recipient-derived cells. In the lungs of Mtb-infected mice, we identified monocyte-derived lung subsets with unique gene expression, associated with specific spatial distributions and cell neighborhoods. These findings suggest that the local lung environment has a larger influence on the phenotypic diversity of monocyte-derived lung cells than does the peripheral environment.

immunology↗

bioRxiv2026

Bamsnap-LRS: an automated batch visualization tool for long-read sequencing alignments

SummaryLong-read sequencing (LRS) has become essential for genome assembly, structural variations (SVs) detection, haplotype phasing and transcript isoform characterization. However, these applications often require manual inspection of read alignment for validation. Existing visualization tools are either interactive genome browsers that are difficult to scale to large datasets or batch-oriented tools that are not optimized for the unique alignment patterns of long-read data. We developed Bamsnap-LRS, an automated command-line tool for high-throughput LRS alignment visualization. It supports long-read-specific features, phased SNP inspection, and publication-ready batch figure generation within a unified framework for genomic, transcriptomic, and haplotype-aware analyses. Availability and ImplementationAll codes and examples are freely available at https://github.com/comery/Bamsnap-LRS. ContactChentao Yang (yangchentao@genomics.cn) and Yang Zhou (zhouyang@genomics.cn). Supplementary informationSupplementary Table 1 and Supplementary Figures 1-8 are available at xxx online.

bioinformatics↗

bioRxiv2026

Buried in two places: Lineages from elite Maya tombs also found in distant caves

Classic Maya societies (250-900 CE) carved out urban centers in the rainforest reaching population heights and political complexity previously unknown in the Mesoamerican tropics. Kinship was a central feature of the social fabric, and rulership was legitimized through claims of direct descent from mythical ancestors. Mortuary practices kept the dead close to the living, and ancestor veneration sometimes produced complex deposits of disarticulated remains that are difficult to identify and whose biological relationships to one another cannot be understood without genetic data. We screened 487 human tooth and bone samples and successfully generated genome-wide data for 430 of them. Of these, 341 samples representing 107 distinct individuals were recovered from both elite and non-elite tombs in a Classic period kingdom (250-900) CE in the rugged Maya Mountains of Belize. Remarkably, 24 of these individuals have skeletal elements in both an elite tomb and in a ritual tooth cache in a distant cave located 26.5km away on the other side of the Maya Mountains. These results indicate that elite lineages created ancestors from their deceased relatives in geographically expansive ways and highlights the importance of caves in the belief system of Classic Maya elites.

genetics↗

bioRxiv2026

Mite-induced migratory skin-like CD103+ ILC2s establish lung residency and impact immunity

Tissue-resident immune cells are critical for lung homeostasis and protection against inflammation. Here, we describe a novel population of migratory inflammatory CD103+ skin ILC2s (skILC2s) that accumulate in the lung vasculature following transient infestation with ubiquitous Demodex mites, hair follicle commensals that drive local skILC2 proliferation and entry into blood. With time, ex-skILC2s become tissue resident in the lung, occupy previously described immune cell adventitial niches and respond earlier to lung perturbations than endogenous lung ST2+ ILC2s to alter the trajectories of a subsequent immune response. Thus, like transiting ex-gut ILC2s described after small intestinal infection by helminths and protists, ex-skILC2s migrate post-birth in response to pathobionts to change the inflammatory milieu of the lung, revealing a common paradigm by which internal mucosal responses become shaped by ILC2s from barrier epithelia colonized post-birth. HighlightsO_LIDemodex mites infestation drives local expansion of CD103+ skin ILC2s that egress and enter the circulation C_LIO_LIMigratory CD103+ skin-like ILC2s infiltrate into lung, adapt to the local environment and establish long-term residency C_LIO_LIPrior Demodex mite exposure re-organizes the lung ILC2 landscape C_LIO_LIThe distinct cytokine and receptor repertoire of ex-skILC2 alters lung immunity C_LI

immunology↗

bioRxiv2026

Selective Elimination of TP53 Mutant Cells by Transcript-Activated Chromatin Shredding

Genetic mutations that drive cancer often occur in tumor suppressor proteins, including the p53 transcription factor which is altered in [~]40-50% of cases1,2. However, current therapies fail to target most such mutations because the mutant proteins typically lack defined drug-binding pockets, and restoring the endogenous function has proven challenging. Here, we programmed CRISPR-Cas12a2, an RNA-guided nuclease with trans-nucleolytic cleavage activities3,4, to selectively kill cancer cells by targeting cancer-specific transcripts. This approach eliminates cells by inducing trans chromatin cleavage, triggering DNA damage and cell death. Unlike existing methods, RNA-guided Cas12a2 senses cellular RNA signatures to shred chromatin, enabling precise targeting of undruggable mutations. Transcript-activated chromatin shredding provides an innovative paradigm to develop precision disease treatments for undruggable targets.

cell biology↗

bioRxiv2026

Structure-guided discovery and engineering of miniature CRISPR-Cas12m for epigenome editing

CRISPR-based epigenome editing represents a programmable strategy to precisely modulate gene expression, holding immense promise for therapeutic applications. However, the large size of the dCas proteins substantially impedes the delivery via adeno-associated virus (AAV) vectors. Here, through iterative bioinformatics analysis, structure-guided predictions, and functional assays, we identified and characterized PmCas12m, a novel miniature subtype V-M CRISPR-Cas12m. PmCas12m exhibited flexible 5-YTN-3 PAM-dependent recognition and robust double-stranded DNA binding properties, while lacking DNA cleavage activity, thus positioning it as an ideal tool for epigenome editing. Cryogenic electron microscopy (cryo-EM) structures of PmCas12m unveiled its unique molecular mechanism of DNA binding facilitating interference. Guided by these structural insights, we employed deep mutational scanning (DMS) and protein engineering to develop xCas12m, a hypercompact variant with highly potent and specific epigenome editing capabilities in human cells. We further constructed the xCas12m-CRISPRoff platform in a single AAV vector, which achieved durable epigenetic silencing and effective inhibition of hepatitis B virus (HBV) infection in a mouse model. Collectively, these findings establish xCas12m as a versatile epigenome editing platform with transformative potential for treating diseases, paving the way for clinical translation of epigenetic therapies.

bioengineering↗

bioRxiv2026

Subsistence transition preceded population turnover in the eastern Colombian Andes

Northwest South America was a pivotal region for human dispersals and cultural exchange during the Holocene. The Altiplano Cundiboyacense, a high-altitude plateau in the Eastern Cordillera of the Northern Andes of Colombia, preserves one of the most continuous archaeological sequences in the Americas, spanning from late Pleistocene hunter-gatherer groups to final late Holocene Muisca chiefdoms. Increasing the regional ancient DNA sample size 11-fold, we report genome-wide data from 209 individuals who lived over a period of more than 7000 years. This includes hunter-gatherers from the early-middle (10,000-7000 BP) and middle (7000-4000 BP) Holocene, initial late Holocene people (4000-2500 BP) who have the first isotopic evidence of C-enriched diets (attributed to maize), and populations associated with increasing sedentism and food production in the Herrera (2200-1300 BP) and Muisca (1200-500 BP) Periods. Previous work identified a major population turnover distinguishing earlier groups from Herrera-Muisca Period populations, but the absence of individuals dating 6000-2000 BP in that study left unresolved whether this ancestry shift was gradual or abrupt and whether it accompanied the earliest isotopic evidence of dietary input from maize or coincided with the later emergence of Herrera culture. We show that individuals predating the Herrera Period form a lineage that persisted for over five millennia, with population structure driven by drift in small groups and no detectable external gene flow. Two individuals who lived [~]2800 years ago - one directly dated to 983-835 calBCE - exhibit genetic profiles entirely consistent with hunter-gatherer ancestry yet have isotopic values consistent with the incorporation of maize into their diets, indicating subsistence change without population replacement. The emergence of Herrera culture [~]2200 BP coincided with a sharp genetic break, reflecting the migration of people carrying ancestry diverged by up to ten millennia into the Sabana de Bogota and displacing previously established peoples. By co-analyzing ancient data with modern Native Americans, we show these later populations derived from a mixture [~]4000 years ago of groups related to Chibchan language speakers of lower Central America and ones related to present-day people at the Amazonian-Andean interface who may have lived along the Chibchan expansion route. In the Herrera and Muisca Periods, genetic substructure distinguishes people from the southern and northern Altiplano, consistent with the cultural differentiation of these regions in the archaeological record. IN BRIEFAncient DNA data from the eastern Colombian Andes reveal five millennia of population continuity during which C plants were incorporated into subsistence systems without population replacement, followed later by a major ancestry turnover involving a population with ancestry admixed between that found in Chibchan-related groups and at the Amazonian-Andean interface.

genetics↗

bioRxiv2026

Contributions of error correction and the spindle assembly checkpoint to mitotic timing and fidelity

Chromosome segregation is a tightly-regulated process that normally occurs with high fidelity. Errors in chromosome segregation are associated with aging, cancer, and infertility. Initially erroneously attached chromosomes are corrected over the course of mitosis, with the spindle assembly checkpoint preventing entry into anaphase until this error correction is complete. Despite extensive work on the molecular basis of error correction and the spindle assembly checkpoint, it is still unclear how disruption of these processes contribute to chromosome segregation errors. Here, we develop and experimentally test a coarse-grained model of error correction in the presence of a faulty spindle assembly checkpoint. We use the resulting model to disentangle the impact of various small molecule and genetic perturbations on both error correction and the spindle assembly checkpoint, and to compare chromosomally stable hTERT-RPE-1 cells and chromosomally unstable U2-OS cells. We find that the probability of error-free chromosome segregation is determined by the ratio of the checkpoint failure rate to the error correction rate, and validate a simple heuristic for understanding the source of chromosome segregation errors: perturbations which cause errors by disrupting the spindle assembly checkpoint decrease anaphase times, while those that disrupt error correction increase anaphase times. Taken together, this work provides a quantitative framework for understanding how error correction and the spindle assembly checkpoint contribute to mitotic timing and fidelity.

biophysics↗

bioRxiv2026

Intestinal intraepithelial lymphocyte migration and tissue homeostasis are dictated by Gα13

Intestinal intraepithelial lymphocytes (IEL), including conventional CD8{beta} T resident memory (Trm) cells and unconventional CD8 T cells, promote tissue integrity. Here, we studied the G-protein coupled receptor signals regulating IEL positioning, homeostasis, and function. Deficiency in heterotrimeric G-protein subunit G13 or its effector Arhgef1 caused an intestine-specific loss of all types of CD8+ TCR{beta} and TCR{gamma}{delta} IEL. G13-deficient IEL exhibited restricted intraepithelial movement and impaired maturation. Induction of intestinal CD8{beta}+ Trm upon infection was intact in the absence of G13-signaling, but the cells had poor access to the villous niche and defective survival that could be rescued by increasing TGF{beta}+ or interleukin (IL)15. In vivo CRISPR/Cas9 screening identified GPR132 as a G13-coupled receptor that regulates CD8{beta}+ IEL homeostasis and migration to lysophosphatidylcholine. Mice bearing G13-deficient T cells suffered more severe colitis and increased colorectal tumor growth. The selective requirement for G13-signaling for IEL positioning and survival in the villous niche has implications for therapeutic intervention.

immunology↗

bioRxiv2026

DeepSRFusion: a point cloud deep learning framework for super-resolution particle fusion

Deciphering the spatial organization of macromolecular complexes in their native context is central to structural biology. Particle fusion in single-molecule localization microscopy offers a unique capability for high-resolution structural reconstruction in situ. However, existing methods face significant challenges from large rotational perturbations and sparse labeling, resulting in compromised accuracy and substantial computational cost. We present DeepSRFusion, a self-supervised pretraining framework for three-dimensional super-resolution particle fusion. By representing single-molecule point clouds as Gaussian Mixture Models, DeepSRFusion integrates data-driven feature learning with physical imaging constraints. A two-stage optimization strategy with dynamic template updating enhances robustness, and a novel Clustering Error metric quantifies fusion quality. Nanometer-scale validation on both simulated and experimental datasets demonstrates high reconstruction fidelity and structural consistency with cryo-electron microscopy and AlphaFold3. DeepSRFusion remains effective under challenging imaging conditions, including large 3D rotations, sparse labeling, high localization uncertainty, and limited particle numbers, while achieving over 100-fold speedups compared to current methods. It resolves fine structural features with a measured spatial resolution of 1.60 {+/-} 0.10 nm, sufficient to distinguish ~10 nm spaced protein pairs and visualize tilted internal substructures within macromolecular assemblies. DeepSRFusion provides a powerful tool for high-precision structural analysis in native cellular environments.

biophysics↗