Biology subjects

Zhao, H.

Publications and source records attributed to Zhao, H..

At least 145 records · Page 8Linked to original sources

bioRxiv2025

Optimized large-scale longitudinal biorepository of gastroesophageal adenocarcinoma patient-derived organoids: High-fidelity models for personalized treatment to overcome resistance.

A major limitation in studying gastroesophageal adenocarcinoma (GEA) has been the lack of reliable models that represent the diseases complexity. We present lessons learned from a comprehensive large-scale biobanking effort combining traditional sample collection with several in vitro models including 3-dimensional patient-derived organoids (PDOs), 2-dimensional cancer-associated fibroblasts (CAFs), tumor-infiltrating lymphocytes (TILs) and/or in vivo xenografts. This initiative started in 2018, integrating multiple advanced ex-vivo models such as PDOs, patient-derived xenografts (PDXs) and organoids (PDXOs). This unique resource now includes tumor avatars from over 380 consented patients, making it the largest living GEA biobank in the world. We achieved > 90% success rate in creating per-patient models, including 227 tumor-derived and 203 neighboring normal PDOs. These organoids accurately mirror key features of the original tumors, such as their histology (e.g. microsatellite instability), mutations, and drug response, across treatment points. Notably, PDOs can predict individual patient responses to chemotherapy within five weeks, underscoring their clinical relevance. Furthermore, high-throughput drug screening on PDO subsets generates personalized chemosensitivity profiles for 22 drugs. Through a process of continued refinement of culture techniques and tumor sampling approach, our large-scale comprehensive collection of GEA avatars represents a unique and valuable preclinical experimental resource for precision oncology. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC="FIGDIR/small/663874v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@f8a032org.highwire.dtl.DTLVardef@dd6fa3org.highwire.dtl.DTLVardef@1cc558corg.highwire.dtl.DTLVardef@492a5_HPS_FORMAT_FIGEXP M_FIG Schematic depiction of GEA live-banking workflow C_FIG

cancer biology↗

bioRxiv2025

PARP1 promotes replication-independent DNA double-strand break formation after acute DNA-methylation damage

Poly-ADP-Ribose Polymerase 1 (PARP1) is a potent regulator of DNA damage response signaling through the recruitment of DNA damage repair proteins to damage sites, and its catalytic function of converting Nicotinamide adenine dinucleotide (NAD+) into poly-ADP-ribose (PAR) which covalently modifies hundreds of protein substrates in a process known as PARylation. However, PARP1s role in the recognition, processing, and intracellular signaling downstream of DNA damage in cells remains incompletely understood, especially in a replication-independent context. Here, we show that cells exposed to high doses of the methylating agent Methyl Methanesulfonate (MMS) generate DNA double-strand breaks (DSBs) in a base excision repair (BER)-dependent and DNA replication-independent manner. The capacity of cells to generate DSBs after MMS exposure relies heavily on intracellular NAD+ availability and PARP1s catalytic production of PAR. In our experimental system, we show that acute MMS exposure causes NAD+ exhaustion in a PARP1-dependent manner, which results in a temporal-dependent loss of downstream PARP1 activity. This functional loss of PARP1 signaling in later timepoints leads to the loss of BER-dependent single-strand break (SSB)-to-DSB conversion, as well as silencing of ATR-Chk1 signaling in both cycling and non-cycling cells, demonstrating a novel PARP1-dependent regulatory mechanism for both ATR-Chk1 signaling and BER-associated processes following methylation challenge. Additionally, we provide experimental evidence supporting the role of PARP1 and NAD+ in promoting the exonuclease-mediated SSB-to-DSB conversion. These findings support a previously uncharacterized mechanism of PARP1-mediated replication-independent DSB generation and provide insight into checkpoint signaling by integrating DDR with PARP1s consumption of NAD+ and production of PAR.

molecular biology↗

bioRxiv2025

Influence of the broadly neutralizing antibody VRC01 on HIV breakthrough virus populations in antibody-mediated prevention trials

In the HIV antibody mediated prevention (AMP) trials, the broadly neutralizing antibody VRC01 demonstrated protective efficacy against new diagnoses with susceptible HIV strains. To understand how VRC01 shaped breakthrough infections, we performed deep sequencing on 172 participants in the placebo and treatment arms, generating 63,444 gag-{Delta}pol (2.5 kb) and 53,088 rev-env-{Delta}nef (3 kb) sequences. Sequences were classified into transmitted founder lineages (TFLs), and infections with multiple distinct lineages were determined. Multilineage infections were detected in [~]38% of participants in both the African (HVTN 703/HPTN 081) and Americas/Europe (HVTN 704/HPTN 085) cohorts, regardless of placebo or treatment group, or cohort. The high levels of multilineage infections could be attributed to minor lineages (<5% abundance) identified in 20% of participants. Infection with VRC01 discordant viruses (IC80s >3-fold different) was observed in 40% of multilineage infections, with a trend toward greater intra-host neutralization differences with increasing VRC01 dose (Jonckheere-Terpstra test, p=0.072). In six VRC01 treated participants who acquired both sensitive (IC80<1{micro}g/ml) and resistant viruses (IC80>3{micro}g/ml), the sensitive lineages declined over time. Recombination was pervasive, observed in 63% of multilineage infections at the time of HIV diagnosis. In one treated participant infected with VRC01 discordant lineages, recombinant viruses preferentially inherited the resistance mutation (binomial p=0.004). In conclusion, our in-depth analysis of breakthrough viruses in the AMP trials revealed a high frequency of multilineage infections, including infections with viruses with different VRC01 sensitivities. This analysis also highlights the role of recombination in shaping intra-host viral evolution and facilitating escape from VRC01. SignificanceThis work advances our understanding of the diversity of initial viral infection and evolution and in vivo activity of broadly neutralizing antibodies (bNAbs). Deep sequencing revealed [~]38% of HIV acquisitions with multiple transmitted founder lineages, higher than previous studies. These occurrences were similar in the placebo and VRC01 groups. Viral recombination among post-acquisition variants was common under antibody selection and appeared to favor resistant sequences in the treatment group. These data suggest as with single antiviral therapy, passive and active immunization of bNAbs should be directed at multiple antigen targets of HIV-1.

molecular biology↗

bioRxiv2025

Circulating tumor cell heterogeneity and MMP9 expression in clinical correlation with breast cancer

ObjectivesThis study aimed to investigate the association between the heterogeneity of circulating tumor cell (CTC) subtypes and the expression patterns of matrix metalloproteinase 9 (MMP9) with clinicopathological parameters in breast cancer patients. The distribution of CTC subtypes, MMP9 expression levels, and their influence on tumor progression. MethodsA total of 303 breast cancer patients were enrolled in this study. The association between CTCs subtypes in peripheral blood, MMP9 expression and clinical or pathological data of patients were analyzed. ResultsThe number of mesenchymal CTCs increased significantly with the number of lymph node metastases (P < 0.05), and high MMP9 expression was positively correlated with lymph node involvement (P < 0.05). The proportion of intermediate to high MMP9 expression was significantly higher in mixed CTCs compared to epithelial and mesenchymal CTCs (P < 0.05). High MMP9 expression in tumor tissues was associated with increased CTCs production and induction of epithelial-mesenchymal transition (EMT) (P < 0.05), as well as an elevated number of MMP9-positive CTCs (P < 0.05). ConclusionsThese findings suggest that MMP9 is positively associated with CTCs production and EMT process, and MMP9 may contribute to tumor metastasis by promoting CTC shedding and EMT by degrading the extracellular matrix. We recommend compliance with the Mesh guidelines: https://www.ncbi.nlm.nih.gov/mesh/

cancer biology↗

bioRxiv2025

Almost Free Enhancement of Multi-Population PRS: From Data-Fission to Pseudo-GWAS Subsampling

Many multi-population polygenic risk score (PRS) methods have been proposed to improve prediction accuracy in underrepresented populations; however, no single method outperforms other methods across all data scenarios. Although integrating PRS results across multiple methods and populations may lead to more accurate predictions, this approach may be limited by the availability of individual-level tuning data to calculate combination weights. In this manuscript, we introduce MIXPRS, a robust PRS integration framework based on data fission principles, to effectively combine multiple multi-population PRS methods using only genome-wide association study (GWAS) summary statistics from multiple populations. Specifically, MIXPRS employs SNP pruning to mitigate linkage disequilibrium (LD) mismatch between the training GWAS summary statistics and LD reference panels, and utilizes non-negative least squares regression to robustly estimate PRS combination weights. Extensive simulations and real-data analyses involving 22 continuous traits and four binary traits across five populations from the UK Biobank and All of Us datasets demonstrate that MIXPRS consistently outperforms the existing methods in prediction accuracy. Because MIXPRS relies solely on GWAS summary statistics, it enjoys broad accessibility, robustness, and generalizability for underrepresented populations.

genetics↗

bioRxiv2025

rAAV-miniBEND: A targeted vector for brain endothelial cell gene delivery and cerebrovascular malformation modeling

Defects in brain endothelial cells (brainECs) can cause severe cerebrovascular malformations, including arteriovenous malformation (AVM) and cerebral cavernous malformation (CCM). The lack of appropriate tools for cerebrovascular disease modeling and local genetic manipulation of the brain vasculature hinders research on cerebrovascular malformations. Here we develop a recombinant adeno-associated virus (rAAV) tool miniBEND (rAAV-based mini-system for brain endothelial cells, rAAV-miniBEND), which combines a minimal promoter and an optimized cis-acting element (cis-element) isolated from the mouse gene Tek. This system achieves gene expression specifically in mouse and rat brainECs. Using rAAV-miniBEND, we achieve high-efficiency and high-specificity gene expression in brainECs through intracranial injection at various developmental stages and through intravenous administration at all postnatal stages in mice. Furthermore, we use rAAV-miniBEND to model sporadic CCMs mediated by MAP3K3I441M and AVMs mediated by BrafV600E. We demonstrate that somatic expression of BrafV600E in brainECs induces an AVM phenotype, and that brainEC proliferation are important for AVM development. Thus, our rAAV-miniBEND system provides a valuable and widely applicable tool for cerebrovascular disease modeling and local or global brainEC gene delivery.

neuroscience↗

bioRxiv2025

Condensate-driven chromatin organization via elastocapillary interactions

Biomolecular condensates are ubiquitous structures found throughout eukaryotic cells, with nuclear condensates playing a key role in the mesoscale organization and functionality of the genome1,2. Protein- and RNA-rich liquid-like condensates form through phase separation on and around chromatin, driving diverse condensate morphologies with varying sphericity and intra-condensate chromatin density3,4. However, a unifying set of physical principles underlying these varied interactions and their implications for chromatin organization remains elusive. Here, we develop and experimentally validate a mesoscopic model that bridges the physics of phase separation and chromatin mechanics. Specifically, by integrating computational modeling with experiments using two canonical condensate proteins, the heterochromatin protein HP1, and the euchromatin protein BRD4, we demonstrate that wetting properties and chromatin stiffness shape condensate morphology, while condensates remodel chromatin mechanics and organization. This two-way interplay is governed by elastocapillarity--the deformation of chromatin by condensate interfacial tension -- and resolves discrepancies in nuclear condensate behavior, with emergent behaviors that deviate from the simplest liquid-liquid phase separation (LLPS) models5-8. Our findings underscore that nuclear condensates and chromatin cannot be studied in isolation, as they are fundamentally interdependent, impacted by biomolecularly-defined wetting properties, with implications for genome organization, transcriptional regulation, and epigenetic control in diverse phenotypes, including cancer2,9,10. Beyond the nucleus, the methodologies we present offer a generalizable platform for exploring multiphase, multicomponent soft matter systems across a broad range of biological and synthetic contexts11.

biophysics↗

bioRxiv2025

Mitochondrial calcium influx-driven bioenergetics in the dopaminergic system selectively enable drug reward

Drugs of abuse hijack the brains reward system, driving pathological dopamine surges that underlie compulsive behavior and addiction. However, directly targeting dopamine signaling for treatment risks disrupting natural reward processes. Here, we identify a bioenergetic mechanism that selectively promotes addiction-related dopamine release and behaviors. Opioids and methamphetamine, but not natural rewards, induce mitochondrial calcium (Ca2+) influx via the mitochondrial calcium uniporter (MCU) in dopaminergic terminals of the nucleus accumbens. Optogenetic stimulation reveals that this mitochondrial Ca2+ influx occurs exclusively during high-intensity dopaminergic neuronal activation. This Ca2+ influx drives rapid ATP production, compensating for energy deficits caused by neuronal hyperactivity and enabling sustained dopamine release. Genetic deletion or pharmacological inhibition of MCU in dopaminergic neurons selectively reduces drug-induced dopamine release and prevents addictive behaviors while sparing natural reward processing in mice. These findings uncover a distinct mitochondrial bioenergetic mechanism underlying drug reward and propose MCU as a promising therapeutic target for addiction treatment.

neuroscience↗

bioRxiv2025

Glis3 is a modifier of cyst progression in autosomal dominant polycystic kidney disease

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is caused by mutations affecting polycystin-1 (PC1) or -2 (PC2). The existence of a cilia-dependent cyst activation (CDCA) pathway has been identified by demonstrating that structurally intact primary cilia are crucial for cyst growth following loss of polycystins. We previously used translating ribosome affinity purification (TRAP) RNA-Seq on pre- cystic mouse kidneys to determine the translatome that meet the criteria for CDCA and identified Glis2 as an early effector of polycystin signaling. Here, we investigate the potential role of Glis3 in ADPKD, which, while not transcriptionally altered, encodes a cilia-localized transcription factor belonging to the same family of genes as Glis2. MethodsWe used live cell confocal imaging to study the subcellular localization of Glis3 in the presence or absence of Pkd1. We used Glis3 conditional knockout mice to investigate the genetic interaction between Glis3 and Pkd1. Changes in gene expression and chromatin accessibility were assessed by RNA-Seq and ATAC-Seq on an allelic series of Glis3 and Pkd1 kidney selective inactivation models at 7-weeks age to evaluate the function of Glis3. ResultsThe ciliary localization of Glis3 is not affected by Pkd1 mutation status. Kidney selective Glis3 by itself does not affect kidney structure or function, but dual inactivation of Glis3 and Pkd1 significantly worsen polycystic kidney disease. Integration of transcriptomic profiling and chromatin accessibility assays suggested that kidney tubule specific Glis3 inactivation results in dysregulated fatty acid metabolism and circadian. ConclusionsGlis3 is a primary cilium localized transcription factor that genetically interacts with Pkd1 and modifies kidney epithelial cell metabolism and circadian function.

genetics↗

bioRxiv2025

DeepPGDB: A Novel Paradigm for AI-Guided Interactive Plant Genomic Database

DeepPGDB (https://www.deeppgdb.chat) is the first AI-driven plant genomics database designed to lower technical barriers in multi-omics research by enabling natural language-based data access and analysis. Integrating over 50 high-quality plant genomes, DeepPGDB combines fine-tuned large language models (LLMs) with prompt engineering to interpret user queries, generate standardized bioinformatics commands, and retrieve or visualize genomic data. Key functionalities include sequence retrieval, BLAST alignment, gene localization, expression profiling, and population genetics analysis, all presented via an intuitive conversational interface. A summarization module further enhances biological reasoning, inferring insights such as haplotype differentiation or protein properties. Benchmarking revealed that Deepseek-r1:14b optimized for short pre-prompts delivers high accuracy and speed. By bridging computational and biological expertise, DeepPGDB democratizes genomic research, fostering interdisciplinary collaboration and accelerating discoveries in agriculture and biotechnology.

bioinformatics↗

bioRxiv2025

AURKA inhibition amplifies DNA replication stress to foster WEE1 kinase dependency and synergistic antitumor effects with WEE1 inhibition in cancers

Highly elevated expression of the oncogene Aurora kinase A (AURKA) occurs in numerous human cancers harboring defective p53, nominating AURKA as a potential vulnerability in TP53-mutated cancer. However, clinical trials have indicated modest monotherapy activity of AURKA inhibitors. Here, we demonstrate that AURKA inhibition promotes phosphorylation of Replication Protein A (RPA), resulting in stalled DNA replication fork progression and eliciting a replication stress response in multiple TP53-mutated models, creating a druggable dependence on the mitotic checkpoint kinase WEE1. Combined inhibition of AURKA and WEE1 synergistically enhanced replication stress, tumor-specific apoptotic cell death, and mitotic catastrophe, and lead to marked tumor regression in cell line- and patient-derived xenograft models of TP53-mutated cancer. Our findings define enhanced DNA replication stress as underlying the strong synergy between AURKA and WEE1 inhibitors and offer preclinical confirmation of efficacy, indicating high potential for clinical translation of this synthetic lethal strategy for TP53-mutated carcinomas. Statement of significanceWe demonstrate that a small molecule AURKA inhibitor amplifies DNA replication stress in TP53-mutated carcinomas. This amplification of DNA replication stress can be leveraged this for synthetic lethal therapy in a combination with WEE1 inhibition that enhances antitumor effects in in vitro, in xenografts and in patient-derived xenograft models, advancing a promising novel combination therapy.

cancer biology↗

bioRxiv2025

Site-Specific Immune and Stromal Architecture Drive Resistance to Trastuzumab Deruxtecan in HER2+ Metastatic Breast Cancer

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that has demonstrated remarkable efficacy in HER2+ and HER2-low metastatic breast cancer (mBC). Yet, 40-50% of patients fail to respond, and mechanisms underlying resistance, particularly those involving the immune microenvironment, remain poorly understood. To address this gap, we conducted spatial proteomic profiling of metastatic lesions from 25 HER2+ mBC patients treated with T-DXd, using the Bruker GeoMX Digital Spatial Profiler (DSP) platform. Regions of interest (ROIs) were segmented by CD45 expression to distinguish immune-rich versus immune-poor compartments, and spatial marker expression was compared between responders (R) and non-responders (NR). Spearman correlation analysis was used to assess spatial coordination among HER2, fibronectin, and immune markers. Non-responders exhibited greater HER2 heterogeneity, lower CD45+ immune infiltration, and consistent upregulation of fibronectin and granzyme B. In both bone and brain metastases, NR tissues showed strong correlations between fibronectin and T cell markers, indicating spatial immune exclusion. In contrast, NR lymph node metastases displayed negative correlations between fibronectin and immune markers and uncoordinated B-T cell clustering, suggesting an alternative resistance mechanism rooted in immune disorganization rather than exclusion. Collectively, these results implicate HER2 heterogeneity, fibrotic immune exclusion, and immune suppression as key drivers of T-DXd resistance across metastatic sites. By integrating spatial proteomics with clinical outcomes, this study provides novel insights into the spatial immune landscape of ADC resistance and identifies actionable biomarkers for patient stratification and combination therapy design, laying a critical foundation for developing biomarker-guided therapies and personalized treatment strategies to overcome ADC resistance in metastatic breast cancer. Translational SignificanceT-DXd represents a major advance in antibody-drug conjugate (ADC) therapies to address HER2 heterogeneity in tumors through bystander killing. However, treatment options following resistance to T-DXd remain limited, leaving a critical unmet need. As new ADCs continue to emerge, resistance will likely remain a persistent challenge across tumor types. This work extends beyond T-DXd resistance--it provides a framework to address resistance mechanisms common to other ADCs. By investigating immune-mediated mechanisms of ADC resistance, this research identifies therapeutic targets that can be leveraged to develop new treatment strategies. By integrating spatial biology with clinical data, this study offers unprecedented insights into immune-tumor interactions within the resistant tumor microenvironment. This approach deepens mechanistic understanding and enables personalized treatment strategies guided by spatially resolved biomarkers. This novel combination of spatial mechanistic research with clinical data represents advancement toward overcoming ADC resistance and improving outcomes for patients with few therapeutic options.

cancer biology↗

bioRxiv2025

Analgesic actions of Intrathecal NaV 1.7 antisense in rats: loss of antagonist channel binding, message depletion, and neuraxial distribution of oligonucleotide

BackgroundGenome targeting strategies to address NaV 1.7 mediated signaling in nociceptive afferents produce highly selective and persistent analgesic outcomes. Here, we analyze the concentration-dependent effects of the reduction of primary afferent NaV 1.7 channel expression by intrathecal delivery of an antisense oligonucleotide on pain behaviors and the covariance of Scn9a knock-down on NaV 1.7 message expression and channel binding. MethodsMale Sprague-Dawley rats were implanted with lumbar intrathecal catheters and dosed with different NaV 1.7 ASO concentrations (100 to 3000 g;10 L). Pain behavior assays were conducted 0-28 days after ASO injections. Brain, spinal cords (SC) and dorsal root ganglia (DRGs) were collected. Quantification of ASO knock-down was assessed through RT-qPCR. NaV 1.7 expression was assessed by binding of NaV 1.7 fluorescent labeled antagonist (ATTO488PTx-II). Distribution studies were performed using anti-ASO antibody staining in brain, SCs and DRGs. ResultsNaV 1.7 message was detected in nerve, DRG and SC. Intrathecal ASO induced a concentration dependent gradient of knock down in DRGs (lumbar to cervical) of Scn9a mRNA and ATTO488PTx-II binding in small DRG neurons, and in spinal parenchyma, and a suppression of pain behaviors initiated by mechanical compression, inflammation and following intraplantar NaV1.7 agonist (OD1) or formalin. At 1000 {micro}g, there was a 47% reduction in phase 2 flinching, a 60% reduction in DRG mRNA and a 36% reduction in ATTO488PTx-II DRG binding in comparison with mismatch controls. Although marked changes were seen at the sensory ganglia level and spinal dorsal horn, no changes in NaV 1.7 binding or mRNA were detected in sciatic nerves. Reduction in DRG message displayed a rostrocaudal gradient that corresponded with ASO distribution. ConclusionsThe study presents how NaV 1.7 ASOs reduce primary afferent channel binding through an effective knock-down on Scn9a mRNA, and channel binding leading to a covariate reduction in pain behavior.

neuroscience↗

bioRxiv2025

Combining structural modeling and deep learning to calculate the E. coli protein interactome and functional networks

We report on the integration of three methods that are computationally efficient enough to predict, on a proteome-wide scale, whether two proteins are likely to form a binary complex. The methods include PrePPI, which uses three-dimensional structure information as a basis for predictions, Topsy-Turvy which analyzes sequences using a protein language model, and ZEPPI which uses evolutionary information to evaluate protein-protein interfaces. We demonstrate how these methods can be integrated and validate the performance of the integrated method and its separate components at predicting E. coli protein-protein interactions through testing on the HINT high-quality literature-curated database of binary interactions. The integrated method identifies more high-confidence (FPR [≤] 0.001) interactions ([~]20K) than any of the component methods. The AF3Complex algorithm was used to predict the structures of 400 protein-protein interactions, and 78% of the integrated method predictions resulted in models deemed accurate by the AF3Complex evaluation score. Notably, essentially all AF3Complex models have at least partially overlapping interfaces with PrePPI models of the complexes. Finally, we clustered the high-confidence E. coli interactome and obtained 385 subnetworks which have high functional coherence defined by enrichment of Gene Ontology Biological Process terms, thus, illustrating that our methods which contain no explicit functional information provide biologically meaningful protein interactions. Biological insights derived from the subnetworks, including the annotation of proteins of unknown function, are discussed in detail. Overall, independent validations support the accuracy of the comprehensive E. coli interactome we have presented.

systems biology↗

bioRxiv2025

Specific Pathogen Free Ten Gene-Edited Pig Donor for Xenotransplantation

Xenotransplantation has entered the clinical phase to fulfill the global organ shortage. However, recent clinical studies revealed that the xenograft from current gene-edited (GE) pigs still poses the risk of immune rejection, and biosafety concerns. In this study, we successfully constructed a large batch of 10- (GTKO/CMAHKO/ {beta}4GalNT2KO/hCD46/hCD55/hCD59/hTBM/hEPCR/hCD39/hCD47) GE cloned (GEC) donor pigs by utilizing gene editing and somatic cell cloning technology, and successfully obtained F1 generation. Phenotypic characterization of 10-GEC pigs showed the deletion of three xenoantigens along with expression of seven human transgenes in various tissues. Digital droplet polymerase chain reaction, and whole genome sequencing indicated 2 copies of hCD46/hCD55/hCD59/hTBM/hCD39 and 1 copy of hEPCR/hCD47 in pig genome without significant off-target and damage to the porcine own functional genes. The validation results showed that 10-GEC pigs effectively inhibited the attacks of human antibodies, complement, and macrophages on porcine endothelial cells and alleviated the coagulation abnormalities between pigs and humans. 10-GEC pigs were negative for all zoonotic pathogens (48) including cytomegalovirus, except streptococcal infections. Kidney, heart, and liver xenografts from these 10-GE pigs were transplanted to non-human primates (NHP), which started working normally without hyperacute rejection. Among them, the heart and liver transplant recipient died without resuscitation due to unexpected interruption of oxygen supply, while the 2 kidney transplant recipients survived for 23 and 16 days, respectively. Pathological analysis showed that 10-GE pig kidney xenografts showed mesenchymal congestion, and fibrosis, cellular hyperplasia, with minor antibody and complement deposition, and significantly reduced the infiltration of CD68+ macrophage. In summary, we successfully produced a group of specific pathogen free GEC donor pigs that effectively mitigated immune rejection upon multi-organ transplantation to NHP.

immunology↗

bioRxiv2025

Cross-species analysis of experimental PH at single cell resolution reveals prominent contributions Ednrb+ EC and Dhcr24+ macrophage populations

BackgroundAnimal models are used widely to study pulmonary hypertension (PH). The cell populations that respond to disease-inducing stimuli in these models and their relationship to human disease remain incompletely defined. Materials and methodThis study analyzed the relationship between several rodent models of PH and human disease at single-cell resolution. scRNA-seq was performed on lungs from mice exposed to hypoxia or Sugen/hypoxia, rats exposed to monocrotaline, and controls. A cross-species single-cell dataset was integrated with human lung cell atlas (HLCA) and single-cell dataset from idiopathic pulmonary arterial hypertension (IPAH) to identify overlapping cell subsets between experimental and human disease and species. ResultsHigh levels of overlap were found between species and models of PH, HLCA, and IPAH datasets. Cell subsets perturbed in rat and mouse PH were similar to those found in human disease, with macrophages and endothelial cells being most affected. A novel Dhcr24high macrophage subset harboring both tissue-remodeling and pro- inflammatory features was consistently increased across models. Several functionally diverse endothelial subtypes were found, including novel Ednrb+ and Nox2+ subpopulations, reflecting enhanced apoptosis, dysregulated angiogenesis and proliferation, and reactive oxygen species-mediated stress. These macrophage and endothelial subtypes expressed numerous PH drug target genes, and exhibited potential disease-specific intercellular interactions involving Angptl4, Cxcl12, and Sema3 signaling. Disease-associated changes in these populations were confirmed by immunofluorescence in lung tissues from animals and patients. ConclusionsWe established a comprehensive cross-species single-cell atlas of mainstream rodent PH models, highlighting several novel macrophage and endothelial subtypes and signaling motifs potentially contributing to human disease.

bioinformatics↗

bioRxiv2025

Plastic-elastomer heterostructure for robust flexible brain-computer interfaces

Electronics for neural signal recording must be robust across multiple and deep brain regions while preserving tissue-level flexibility to ensure stable tracking over months or years. However, existing electronics cannot simultaneously achieve robustness and tissue-level flexibility, limiting their potential for customizable and scalable neuroscience research and clinical applications. Here, we introduce FlexiSoft, an electronic platform based on a plastic-elastomer heterostructure that uniquely integrates mechanical robustness and tissue-level flexibility. Compared to conventional flexible electronics of similar thickness, the FlexiSoft platform demonstrates an order-of- magnitude improvement in both mechanical robustness (critical energy release rate) and flexibility (flexural rigidity). Leveraging these mechanical advantages, we developed FlexiSoft probe for robust implantation, demonstrated by its ability to withstand repeated insertion and removal, as well as to reach centimeter-scale depths comparable to those in the human brain. The platform enables long-term recording from the same neurons across the hippocampus (HPC) and primary motor cortex (M1) during a months-long motor learning task, thereby revealing long-term dynamic changes in neuronal firing patterns. Additionally, FlexiSofts unique robustness and flexibility enable curved implantation routes, opening new directions of customizable implantation pathways. In summary, we present FlexiSoft as a novel, robust, and tissue-level flexible heterostructure electronics platform that advances flexible brain-computer interfaces (BCIs) with strong translational potential for neuroscience and clinical applications.

bioengineering↗

bioRxiv2025

Joint Modeling of Effect Sizes for Two Correlated Traits: Characterizing Trait Properties to Enhance Polygenic Risk Prediction

Recent years have witnessed a surge in the development of innovative polygenic score (PGS) methods, driving their extensive application in disease prevention, monitoring, and treatment. However, the accuracy of genetic risk prediction remains moderate for most traits. Currently, most PGSs were built based on the summary statistics from the target trait, while many traits exhibit varied degrees of shared genetic architecture or pleiotropy. Appropriate leveraging of pleiotropy from correlated traits can potentially improve the performance of PGS of the target trait. In this study, we present PleioSDPR, a novel method that jointly models the genetic effects of complex traits to characterize conditions under which considering pleiotropy enhances polygenic risk prediction. PleioSDPR models the joint distribution of effect sizes across traits, allowing SNPs to be null for both traits, causal for only one trait, or causal for both traits, while accommodating region-specific genetic correlations and unequal heritability between traits. Through extensive simulations and real trait applications, we demonstrate that PleioSDPR improves prediction performance compared with several univariant and multivariate PGS methods, especially when there is no validation dataset. For example, by incorporating information from schizophrenia or leg fat-free mass, PleioSDPR effectively improves the prediction accuracy of bipolar disease (14.2% accuracy gain) and hip circumstance (20.65% accuracy gain), respectively. Moreover, our findings demonstrate that traits exhibiting high genetic correlations and heritability, and low overlapping sample sizes contribute more to the improvement of prediction accuracy of the target trait. Overall, our study highlights the potential of PleioSDPR to enhance the accuracy of genetic risk prediction by leveraging pleiotropy and considering a broader spectrum of traits and diseases. These findings contribute to the understanding of polygenic risk prediction and underscore the importance of incorporating pleiotropic information for improved utilization in disease prevention and treatment strategies.

genetics↗