Biology subjects

Zhang, B.

Publications and source records attributed to Zhang, B..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

DLL3 expression predicts response and long-term outcome in small cell lung cancer patients treated with tarlatamab

Background: Small cell lung cancer (SCLC) is an aggressive, high-grade neuroendocrine carcinoma (hgNEC) with poor prognosis. Tarlatamab, a DLL3-targeting T cell engager was approved in 2024 for relapsed SCLC, with almost doubled overall survival benefit compared to chemotherapy. However, over half of patients do not respond to tarlatamab and others develop resistance within months. With multiple DLL3-targeting therapies in clinical trials, there are currently no validated predictive biomarkers to identify patients most likely to benefit from tarlatamab. In this study, we evaluate baseline DLL3 IHC level in patients as a predictive biomarker to tarlatamab clinical outcome. Methods: We assembled a cohort of 138 patients within IRB-approved MD Anderson GEMINI database (PA13-0589) with DLL3 expression by CLIA-validated immunohistochemistry (IHC), and those treated with tarlatamab from 7/1/2024 to 3/30/2026. Only those with DLL3 IHC results and treated with tarlatamab were included in this predictive biomarker study. All DLL3 levels were reported as percentage cells with cytoplasmic or surface DLL3 expression, including 24 with additional intensity score and H-score calculation. demographic, clinical, and outcome data were collected. Systemic and intracranial response data were assessed by RECIST and mRANO BM criteria respectively. Longitudinal liquid biopsies were taken from a subset of patients for circulating tumor DNA (ctDNA) and (Cytometry by Time-of-Flight) CyTOF analyses. Results: In the predictive biomarker cohort of 54 patients with SCLC treated with tarlatamab, Median DLL3% level in tarlatamab treated cohort was 75%. Median follow-up time was 9.9 months, median time on tarlatamab treatment (ToT) was 5.8 months. At the data cut-off, 61% (33 out of 54) patients were alive. Kaplan-Meier curve stratified by DLL3 % of <=75% vs. >75 showed significant longer ToT and a trend toward longer median OS (mOS). In DLL3>75% compared to DLL3 <=75%: mToT was 10.1 months vs. 2.9 months (p=0.036), mOS: not reached vs. 9.5 months (p= 0.066). Among 41 patients who completed one cycle of tarlatamab treatment and were eligible for systemic (extra-cranial) response per RECIST criteria; we observed partial response (PR) in 51% (21) patients, stable disease (SD) in 22% (9) patients; and progressive disease (PD) in 27% (11) patients. The median DLL3 % in those with PR vs. PD were 80% vs. 40% (p=0.006); median DLL3% comparing PR and SD were 80% vs. 60% (p=0.051). Among 35 patients evaluable for intracranial response, best objective response prior to any brain radiation were 5 (14%) CR,11(31%) PR, 8 (23%) SD and 11 (31%) PD. 9 received brain radiation (8 SRS, 1 WBRT) during tarlatamab to achieve better intracranial control while systemic control is maintained. DLL3% does not appear to be correlated with intracranial response. Longitudinal ctDNA and CyTOF analyses showed persistent ctDNA positivity, as well as increasing NEUROD1 subtype cells in circulating tumor cells in post-tarlatamab progression samples. We additionally profiled DLL3 expression by IHC in 138 patients with SCLC and found heterogenous DLL3 expression, with Median DLL3% of 70% across different biopsy sites. Conclusions: Our data suggests DLL3 expression in patients with SCLC is heterogeneous and not ubiquitous, with median DLL3 IHC of 70%. DLL3 IHC predicts objective response and long-term outcome with tarlatamab. In addition, dynamic monitoring of ctDNA level and CTCs by CyTOF are suggestive of development of tarlatamab resistance, however further studies with larger cohort of paired longitudinal samples are needed to validate the novel blood-based biomarkers. To our knowledge, this study is the first to validate DLL3 IHC as a predictive biomarker for tarlatamab in SCLC, which leads the way for optimizing treatment selection and combinatorial therapies for the subset of patients less likely to respond to tarlatamab.

cancer biology↗

bioRxiv2026

The rhomboid-like pseudoprotease TMEM115 defines a two-factor mechanism for Rab6A effector recruitment

Protein trafficking and organelle identity depends on precise localisation of membrane proteins, anchored by small GTPases that bind to specific cellular compartments. Here we show that the rhomboid-like pseudoprotease TMEM115 defines an unexpected two-factor system with Rab6A to target the golgin TMF1. In the absence of TMEM115, TMF1 is delocalised from the rim of the Golgi apparatus; instead, it is retained in Golgi-targeting vesicles. TMEM115, TMF1, and Rab6A assemble into a ternary complex which, in striking contrast to canonical rhomboid-like mechanisms, is independent of transmembrane domain interactions. Disruption of the TMEM115-Rab6A-TMF1 complex affects the efficiency of trafficking of proteins from the Golgi; moreover, human disease-associated mutations target the interfaces of this ternary complex, thereby delocalising TMF1 from the Golgi. Finally, loss of TMEM115 in Drosophila causes abnormal Golgi morphology, and mouse knockouts undergo perinatal death. We propose that two-factor effector recruitment defines a mechanism for precise Rab GTPase-mediated membrane targeting.

cell biology↗

bioRxiv2026

A Multi-Omics Study of Cognitive Resilience to Alzheimer's Disease

Alzheimers disease (AD) is the most severe form of dementia. While significant efforts have been made to identify AD risk factors and develop therapeutics, much less attention has been given to neurobiological factors and molecular signatures associated with cognitive resilience. Substantial evidence suggests that modifiable factors, such as physical and mental activity, may contribute to cognitive reserve and resilience. To this end, we developed a resilient cohort of paired genetics, transcriptomics and proteomics data from the prefrontal cortex of 282 cognitively normal older adults. We conducted extensive preprocessing and rigorous quality control (QC), including QC on sequence metrics and sample matching across multiomics. This cohort can be leveraged for identification of molecular signatures of cognitive resilience to AD and is freely shared with the research community.

genomics↗

bioRxiv2026

Multi-kingdom microbial diversity and interaction landscapes in mosquitoes revealed by 5,163 individual meta-transcriptomes

Mosquitoes are pathogen vectors embedded within diverse microbial ecosystems. However, the nature and interactions among their multi-kingdom microbiome remain poorly understood. We conducted a nationwide single-mosquito meta-transcriptomic survey of 5,163 mosquitoes representing 100 species across China, integrating viral discovery with marker-gene profiling of bacteria, archaea, fungi, and other eukaryotic microbes. From this, we identified 1,606 microbial species-level taxa, including extensive novel diversity, and revealed pronounced host species-specific organization of mosquito-associated communities. We detected 34 pathogens or potential pathogens of human or animal relevance, whose prevalence, abundance, host range, and geographic distribution defined distinct epidemiological patterns. Network analysis uncovered pervasive cross-kingdom microbial associations, including candidate antiviral relationships involving Wolbachia and other microbial taxa. Our study establishes a detailed view of the full-spectrum microbiome and provides a resource and conceptual framework for studying vector competence, pathogen emergence, and microbiome-informed mosquito-borne disease control.

microbiology↗

bioRxiv2026

Multi-omic characterization of axolotl perilymph-cerebrospinal fluid reveals shifts in composition during limb regeneration

The axolotl salamander can fully regenerate amputated limbs, yet the systemic consequences underlying this process remain largely understudied. Cerebrospinal fluid is an emerging signaling medium capable of communicating with both the central and peripheral nervous systems, but its composition and potential role in salamander limb regeneration have not yet been examined using modern multi-omics techniques. Here, we developed a protocol for extracting mixed perilymph-cerebrospinal fluid (P-CSF) from axolotl and provided the first proteomic and metabolomic characterization of this biological fluid. We identified 2,626 unique proteins and 173 high-confidence metabolites and quantified them across four time points of early limb regeneration. We demonstrated that limb amputation drives progressive shifts in P-CSF proteins, including an elevation of sarcomeric muscle proteins, regeneration-associated factors, and protease/extracellular matrix proteins. We observed shifts in metabolites involved in oxidative stress, polyunsaturated fatty acid oxidation, and histamine metabolism. Injury-comparison experiments revealed that the observed proteomic changes as a result of limb amputation are different than crush injury, denervation, or tail amputation. This study proposes axolotl P-CSF as a reservoir for limb amputation-associated systemic signaling and as a potential conduit of signals involved in limb regeneration.

systems biology↗

bioRxiv2026

Normalizing LZ+ MYPT1 Expression Prevents the Development of HFpEF

Background: Heart failure (HF) is classified by ejection fraction: reduced EF (<40%) is HFrEF and preserved EF (>50%) is HFpEF. Unlike HFrEF, no therapeutic agent improves mortality in HFpEF. The molecular mechanism that produces HFpEF is not completely understood, but the cascade of pathology that produces HFpEF is thought to begin with changes in vascular reactivity, including a decrease in NO mediated vasodilatation, which coupled with subsequent changes in contractility, energetics and coronary blood flow produce HFpEF. If abnormal vascular reactivity is the initial step in the pathological cascade that produces HFpEF, restoring and/or improving vascular reactivity could represent a novel treatment strategy. Vascular reactivity is primarily regulated by myosin light chain phosphatase, which has catalytic, myosin targeting (MYPT1) and 20kDa subunits. Alternative mRNA splicing of exon24 (E24) of the MYPT1 transcript produces MYPT1 isoforms that differ by the presence or absence of a COOH-terminal leucine zipper (LZ+/LZ-); E24 exclusion produces an NO responsive LZ+ MYPT1, while E24 inclusion produces an NO unresponsive LZ- MYPT. Methods: We used the mouse two-hit model of HFpEF (high fat diet and L-NAME) and treated mice with an antisense octo-guanidine targeting the 5' splice site of E24 (ASO-E24) to increase the expression of the NO responsive, LZ+ MYPT1 isoform in vascular smooth muscle. Invasive and noninvasive hemodynamics were used to determine LV function. Results: Compared to mice with HFpEF, ASO-E24 treatment maintains LZ+ MYPT1 expression (4.7{+/-}0.7au v 1.0{+/-}0.4au v 2.0{+/-}0.4au, control v HFpEF v ASO-E24 Rx, p<0.05), improves diastolic function; LVEDP (10{+/-}1mmHg v 20{+/-}4mmHg v 14{+/-}3mmHg, p<0.05), dP/dtmin (-8000{+/-}300mmHg/s v 6000{+/-}500mmHg/s v 8500{+/-}700mmHg/s, p<0.05), both early (E; 0.60{+/-}0.05m/s v 0.42{+/-}0.06m/s v 0.64{+/-}0.06m/s, p<0.05) and late diastolic filling (A; 0.38{+/-}0.03m/s v 0.24{+/-}0.02m/s v 0.47{+/-}0.04m/s, p<0.050 and also prevents the increase in lung weight (167{+/-}5g v 175{+/-}7g v 166{+/-}5g, p<0.05). Further, mice treated with ASO-E24 maintained normal relaxation to 8Br-cGMP (65{+/-}5% v 44{+/-}9% v 72{+/-}9%, p=0.05). Conclusion: These data demonstrate that maintaining normal LZ+ MYPT1 expression and vascular reactivity prevent the development of HFpEF. These results are consistent with the hypothesis that abnormal vascular reactivity is the initial and primary step in the pathological cascade that produces HFpEF and ASO-E24, which is designed to preserve normal LZ+ MYPT1 expression and vascular reactivity, could represent a novel and effective treatment strategy for HFpEF.

physiology↗

bioRxiv2026

Lifecourse sex-specific molecular response to early-life exposures of toxic substances

Toxicants in the environment can significantly impact physiology. Environmental chemical exposures during early developmental stages disturb normal embryonic development and programming, and dramatically impact long-term health as individuals age. Female and male animals show distinct phenotypes when responding to a given chemical exposure. Here, through the TaRGET II (Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription) consortium, we systematically explored sex-specific transcriptomic and epigenomic alterations in response to various toxicants, including arsenic (As), lead (Pb), tributyltin (TBT), bisphenol A (BPA), di(2-ethylhexyl) phthalate (DEHP), dioxin (TCDD), and fine particulate matter (PM2.5), across three time points in mice exposed two weeks prior to conception through gestation and lactation. After being exposed to toxicants during the embryonic and early postnatal developmental stages, 1,025 omics datasets were generated from the liver and analyzed across three mouse life stages. We discovered a significant sex-biased molecular response to distinct exposures in the liver at both the transcriptomic and epigenetic levels, showing dynamic changes across mouse development and aging. The perturbed pathways and transcription factors in response to different chemical exposures in both sexes were further evaluated to measure the sex-specific impact of each toxic exposure in the liver. Overall, this study presents the most detailed investigation of sex-specific molecular signatures under the influence of developmental exposures to toxic substances.

genomics↗

bioRxiv2026

Within-Subject Optogenetic Model Reveals Spatiotemporal Cortical Reorganization in Artificial Vision

Visual prostheses can elicit simple percepts such as letter forms through dynamically patterned stimulation, yet naturalistic dynamic vision remains out of reach despite hardware fully capable of high-resolution temporal control. This persistent gap suggests the bottleneck lies in how artificial input is represented by the cortex itself. A fundamental question remains unresolved: when artificial vision bypasses natural retinal encoding, what is lost in cortical representation? We address this question in this paper using a retinal optogenetic mouse model that isolates the consequence of bypassing retinal encoding while preserving downstream pathways. Using within-subject V1 cortex electrophysiology and CNN-based decoding under identical dynamic stimuli, we reveal dissociable, dimension-specific gaps. Temporally, artificial vision bypassed the frequency-dependent compression imposed by natural vision, extending stimulus-locked entrainment bandwidth. Spatially, direction-selective representations underwent systematic remapping, with disrupted phase organization and reduced encoding regularity. These findings show that bypassing natural retinal encoding reorganizes cortical representation along dissociable spatiotemporal dimensions, establishing a within-subject framework that renders such structural divergences easy to locate and quantifiable.

bioengineering↗

bioRxiv2026

GlycoMeSH: linking glycan structures to biomedical context for systematic enrichment analysis

Glycan identification has advanced, but glycan structures remain difficult to translate into reproducible biomedical context because reusable glycan-level annotations are sparse. We present GlycoMeSH, a resource that links glycans to Medical Subject Headings (MeSH) through an inference model, a traceable association database and a glycan-set enrichment workflow. GlycoMeSH-BERT recovered ~60% of literature-derived associations at recall@30 and expanded open-vocabulary MeSH coverage beyond closed-label baselines, without higher per-prediction accuracy. At matched candidate counts, its predictions showed motif-level semantic agreement comparable to those baselines, independently of the training labels. GlycoMeSH-DB contains 789,627 associations between 26,954 glycans and 20,302 MeSH terms. GlycoMeSH-EA returned enriched MeSH terms for glycan sets from glycomics and glycoproteomics datasets. Each association represents a biomedical context rather than a validated mechanism, and retains its source PMID or prediction score for audit. GlycoMeSH supplies the missing, evidence-traceable annotation layer that makes glycan sets directly analyzable by enrichment across glycoscience datasets.

bioinformatics↗

bioRxiv2026

The HES1-SOD1 Antagonism Shapes Senescence Heterogeneity and Impacts Metastatic Relapse of Circulating Tumor Cells

Circulating tumor cells (CTCs) encounter multiple challenges within the blood microenvironment, including oxidative stress, flow shear forces, and immune surveillance, often leading to anoikis. Recently, a transitional state of CTC senescence has been identified, contributing to metastatic inefficiency. However, the molecular mechanisms linking senescent CTCs to disease relapse remain to be defined. By integrating a genetic model of cortactin knockdown-induced CTC senescence with single-cell multi-omic analyses, we revealed two distinct senescent CTC subpopulations marked by HES1 expression levels. These HES1low and HES1high subpopulations exhibited differential evolutionary trajectory dynamics and unique molecular and metabolic signatures, which were significantly correlated with adverse clinical outcome across several patient cohorts. HES1low senescent CTCs displayed enhanced mitochondrial fitness, oxidative phosphorylation, and ROS-detoxifying capabilities, resulting in more efficient tumor regrowth with a pro-inflammatory and thrombotic phenotype when compared to the HES1high group. Mechanistically, HES1 directly bound to the Sod1 promoter and repressed its expression, leading to redox imbalance and mitochondrial dysfunction that were linked to weakened tumor regrowth capacity. Both senescent CTC subpopulations were broadly resistant to cytotoxic and targeted therapies, yet they showed elevated dependency on anti-apoptosis programs that make them susceptible to dual blockade by SOD1 inhibitor and the anti-senolytic drug ABT737 in vivo. Finally, in a prospective cohort of on-treatment melanoma patients, HES1 senescent CTCs were highly enriched in patients with progressive disease. Thus, the HES1-SOD1 antagonism shapes CTC senescence heterogeneity and contributes to differential tumor relapse, which can be therapeutically explored for eliminating residual metastatic disease.

cancer biology↗

bioRxiv2026

Ablation and Seed-driven Restoration of an Alpha-Satellite Devoid Human Centromere Reveals Size Homeostasis Mechanisms

Human centromeres are epigenetically defined chromatin domains marked by nucleosomes containing the histone H3 variant CENP-A, which recruit the constitutive centromere-associated network (CCAN) to assemble functional kinetochores. Maintaining centromere function, including chromatin domain size and the ability to assemble the kinetochore, is essential for proper mitotic division across eukaryotes. In humans however, mechanistic studies of centromere establishment, maintenance, and size regulation have been hindered by the highly repetitive nature of canonical alphoid centromeres. Here, we develop a genetically tractable human neocentromere system which is devoid of repetitive DNA sequences. Using targeted genetic manipulation of a monoallelic naturally occurring neocentromere, we show that partial loss of centromeric chromatin triggers restoration of the residual CENP-A domain through seed-driven, sequence-independent expansion into adjacent naive chromatin. In contrast, creation of new domain boundaries without loss of centromeric chromatin mass results only in local boundary remodeling, without substantial domain expansion. These findings indicate that centromere formation proceeds through two mechanistically distinct steps, beginning with acquisition of a CENP-A seed and followed by regulated domain expansion to generate a mature centromere. More broadly, our results support a model in which centromeres transition between a maintenance state that preserves domain size and a restoration state that rebuilds centromeric chromatin following perturbation. Together, this study establishes a genetically tractable platform for dissecting the mechanisms governing human centromere formation, chromatin domain dynamics, and size homeostasis.

cell biology↗

bioRxiv2026

Germline BRCA1 Mutation Deregulates Irradiation-Induced Cell Cycle Checkpoints in Human Mammary Luminal Progenitors

Mammary ductal tree comprises two epithelial lineages, basal and luminal, which harbour stem and progenitor cell subsets essential to breast physiology and are cancer-initiating precursors. Dysregulated cellular stress response is an early event in tumorigenesis, yet lineage-rooted study of primary breast epithelium pertinent to familial mutation carriers is limited. Here, we establish a lineage-resolved monolayer culture system that enables propagation of primary human mammary epithelial populations while preserving lineage identity across passages. We identify intrinsically distinct cell cycle response of luminal progenitors and basal cells to irradiation stress where the former engages both G1/S and G2/M checkpoints to achieve cell cycle arrest and the latter relies on the G2/M checkpoint. These lineage distinctions are diminished in germline BRCA1 mutation carriers with an attenuated G1/S checkpoint in luminal progenitors. Paired transcriptomic-proteomic profiling of acute irradiation response uncovers BRCA1+/- luminal progenitor population with sustained AKT-mTOR signaling and compromised cell cycle arrest marking an early deviation in the stress response of these purported cells-of-origin of aggressive breast cancers known to arise in BRCA1 germline mutation carriers. Our study provides a functional framework for determining critical events in the expansion of genomically altered mammary epithelial cells in the high-risk breast to enable future preventive interventions.

cell biology↗

bioRxiv2026

Valency-Limited Molecular Dynamics Simulations of Stickers-and-Spacers Polymers Reveal a Tradeoff Between Condensation and Organization

Biomolecular condensates formed by intrinsically disordered proteins (IDPs) are often described using stickers-and-spacers models, in which specific sticker motifs form reversible crosslinks and spacer regions modulate phase behavior. Recent theory predicts that heterogeneous nonspecific spacer interactions can promote condensation but may also disrupt sticker-mediated organization. Here, we develop an off-lattice coarse-grained stickers-and-spacers polymer model for continuous molecular dynamics simulations and implement it in the GPU-accelerated OpenABC package. The model uses a directional sticker-sticker interaction to encode limited valency through interaction geometry, producing effectively one-to-one sticker binding without explicit bond assignment. Simulations of one-component systems show that sticker affinity and multivalency promote porous, network-like condensates, while nonspecific spacer interactions can also drive phase separation but produce more compact, spacer-dominated dense phases. When both interaction types are present, strong spacer heterogeneity reduces sticker conversion, suppresses sticker mobility, and disrupts the sticker-mediated network. In two-component systems, specific sticker interactions buffer client recruitment into host condensates, while nonspecific spacer interactions produce reservoir-dependent uptake. These results support a tradeoff in which spacer heterogeneity promotes condensation at the cost of condensate organization and compositional robustness, providing a physical rationale for the suppression of promiscuous spacer interactions in low-complexity IDP regions.

biophysics↗

bioRxiv2026

Resolving Immune Lineage and Cell-State Heterogeneity in Human PBMCs via Mass Spectrometry-Based Single-Cell Proteomics

Single-cell proteomics (SCP) currently lacks validated benchmarking standards, and cell annotation often relies on transcriptomic proxies. Unsupervised clustering offers a proxy-free alternative, but its success depends on biological signal outweighing technical variation. In homogeneous samples this is achievable, but in heterogeneous populations, where closely related cell types differ only subtly, technical variation can dominate the clustering and obscure the biology needed for annotation. To address this, we developed an integrated experimental and computational pipeline for protein-level cell annotation and applied it to human PBMCs as an immune-cell test case. We isolated T cells, B cells, monocytes, and NK cells by negative-selection sorting to build a high-fidelity reference. In parallel, unsorted PBMCs from the same donor were processed on a cellenONE and acquired using label-free DIA on an Orbitrap Astral Zoom. Using the labeled reference dataset, we systematically benchmarked normalization, imputation, and clustering methods to assess their effect on cell-type separation. Unsupervised analysis resolved functional subpopulations within each lineage, and a probabilistic SCP classifier trained on these annotations identified the corresponding cell types and states in the unsorted PBMC fraction, validating the pipeline on unenriched, heterogeneous samples. Together, this work delivers an analytically benchmarked SCP workflow that resolves immune lineage and cell-state heterogeneity in human PBMCs and provides a classifier-ready, protein-level reference for immune-cell assignment.

bioinformatics↗

bioRxiv2026

Deep learning enables cross-species annotation and attribution of ageing states in haematopoietic stem and immune cells

Mouse single-cell ageing studies provide experimentally controlled age contrasts, but using mouse-labelled data to annotate human ageing states is limited by species, donor and assay effects in sparse transcriptomic and chromatin profiles. We developed a cross-species annotation workflow that treats mouse-to-human prediction as a target-validated domain-adaptation problem. The workflow uses orthologue-aligned features, a residual encoder, an age classifier and a species discriminator trained with two-phase adversarial optimisation, and couples prediction with stability-based gene attribution. In haematopoietic stem cells (HSCs), the model achieved held-out human AUROCs of 0.933 in scRNA-seq and 0.953 in scATAC-seq. In an independent CD8+ T-cell scRNA-seq setting, the held-out human AUROC was 0.941. Ablation analyses indicated that residual connections, ELU activation and two-phase training improved predictive performance and attribution stability. Consensus attributions from DeepLIFT, Integrated Gradients and saliency recovered conserved ageing-associated genes with greater cross-species overlap than differential expression alone. In a COVID-19 convalescent cohort, severe disease in younger adults was associated with a higher fraction of CD8+ cells classified as old-like by the pretrained model. These results support a reproducible framework for testing, interpreting and releasing cross-species single-cell ageing models, while highlighting the need for target-domain validation when mouse labels are transferred to human data.

bioinformatics↗

bioRxiv2026

ER Stress-Response Signaling Regulates Chamber-Specific Growth between Right and Left Ventricles during Postnatal Development.

BackgroundDifferential growth between the left (LV) and right ventricles (RV) is a cornerstone of normal heart morphogenesis after birth, leading to the relatively larger and dominant LV over RV in the adult heart regarding size and function. Yet, little is known about the factors that regulate this chamber-specific growth. MethodsWe used both loss-and gain-of-function mouse models, achieved through genetic or pharmacological manipulation of IRE1 or Xbp1 in cardiomyocytes. We also used primary cultured neonatal cardiomyocytes to explore the roles of IRE1, spliced Xbp1 (sXbp1: activated form), and newly identified sXbp1 downstream targets. In addition, we generated heart-specific mosaic mutant mouse models using CRISPR/Cas9/AAV9-based somatic mutagenesis to elucidate the roles of sXbp1 downstream targets in cardiomyocytes. ResultsPharmacological inactivation of IRE1 and genetic depletion of Xbp1 resulted in a smaller LV size, due to decreased cardiomyocyte proliferation and hypertrophic growth, as well as increased cardiomyocyte death. These effects were not observed in the RV. Cardiomyocyte-specific induction of IRE1 or sXbp1 led to increased ventricular size in both ventricles, through enhanced cardiomyocyte proliferation and hypertrophic growth in both LV and RV, and reduced apoptosis in the RV. We identified two ER resident transmembrane proteins, Vimp and Rpn2, as direct binding partners of sXbp1 in targeted gene regulation at the chromatin level. CRISPR/Cas9/AAV9-based somatic mutagenesis mouse models for Vimp and Rpn2 revealed that both genes regulate cardiomyocyte proliferation, hypertrophic growth, and death. We also observed accumulated misfolded proteins in these two mutant hearts. Conclusions We demonstrate that the IRE1-Xbp1-Vimp/Rpn2 axis regulates differential ventricular size between LV and RV during postnatal development by orchestrating cardiomyocyte proliferation, hypertrophic growth, and death through regulating protein homeostasis. Clinical PerspectiveO_ST_ABSWhat Is NewC_ST_ABSO_LIIRE1-Xbp1 axis is dominantly activated in the LV cardiomyocyte during the postnatal period in mouse heart. C_LIO_LIIRE1-Xbp1 mediated ER stress signaling increases cardiomyocyte proliferation and hypertrophic growth and decreases apoptosis in the postnatal period. C_LIO_LIActivated Xbp1 directly regulates LV-specific cardiomyocyte protein homeostasis via interaction with ER membrane targeted Vimp and Rpn2. C_LI What Are the Clinical Implications?O_LIDifferential heart growth patterns between the LV and RV are critical for normal morphogenesis and function of each ventricle. C_LIO_LIControl of protein homeostasis by modulating ER stress signaling could be a potential therapeutic approach for single-chamber heart diseases. C_LI

developmental biology↗

bioRxiv2026

Organism-scale annotation with Pan-human Azimuth

Single-cell atlases now span many human tissues, but inconsistent annotations across studies limit their utility as a unified reference. We introduce Pan-human Azimuth, a supervised neural network that maps human cells from diverse tissues and datasets onto a single hierarchical organism-scale typology. Developed through NIH HuBMAP, the model is trained on a uniquely curated corpus designed to maximize diversity across tissues and technologies while enforcing uniform, interpretable annotations and stringent quality control. The use of a single organism-wide reference enables us to map tens of millions of cells in the Tabula Sapiens and scBaseCamp repositories, perform cross-tissue comparisons across thousands of samples, and identify striking tissue specialization among fibroblast states. Pan-human Azimuth naturally extends to annotating spatial transcriptomic data, recovering canonical kidney cortical structures and distinguishing glomerular states consistent with expert pathology. We release Pan-human Azimuth alongside cloud, R, and Python interfaces to facilitate standardized organism-wide single-cell analysis.

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↗