Biology subjects

Wei, J.

Publications and source records attributed to Wei, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Beyond Acoustic Cues: Olfactory-Mediated Avoidance of Bats by Crickets

The evolutionary arms race between insectivorous bats and their insect prey is a classic paradigm of acoustic predation and evasion, with insects having evolved sophisticated auditory countermeasures. Both bats and insects also rely heavily on olfaction for key behaviors, such as social communication. Moreover, predator-derived odors are well-established as risk cues in many other predator-prey systems. However, whether olfaction plays a role in the bat-insect arms race remains unknown. Here, we unveil a previously unknown olfactory dimension to this interaction. We demonstrated that the body odor of the insectivorous bat Scotophilus kuhlii triggered robust avoidance and electrophysiological antennal responses in a common cricket prey, Loxoblemmus equestris. We identified limonene as a behaviorally active volatile in bat odor that elicited electrophysiological responses in cricket antennae and was sufficient to elicit avoidance in crickets. Field experiments confirmed that limonene exposure reduced cricket calling activity, demonstrating the ecological relevance of this cue. Our findings establish that insects can detect and initiate avoidance of phylogenetically distant vertebrate predators via olfaction, a process that could be mediated by the elemental perception of individual odor compounds. This work broadens the sensory framework of a classic predator-prey system, and highlights olfactory eavesdropping as a functional strategy in phylogenetically distant predator-prey systems.

ecology↗

bioRxiv2026

Reversible peptide self-assembly enables sustained drug delivery with tuneable pharmacokinetics

Therapeutic peptides combine high target specificity with potent biological activity.1 However, treatment success is often limited by rapid clearance and the need for frequent injections.2, 3 This challenge is particularly acute for therapeutic peptides used in obesity, where clinical benefit must be balanced against dose-dependent adverse effects. In nature, these constraints are overcome by storing hormones as reversible fibrils,4 but pharmacokinetic control is essential for widespread adoption of bio-inspired self-assembled depots for therapeutic peptides. Here, we show that tuneable pharmacokinetics can be achieved and modelled by mapping the fundamental chemical parameters of reversibly self-assembly in vitro. We demonstrate this approach for the amylin analogue pramlintide. Amylin analogues are under development for the next generation of diabetes and obesity treatments, with improved mechanism of action e.g. preserving lean body mass.5-8 Pramlintide is an approved drug with a well-established safety profile, however, it has a comparable half-life to native amylin.8-12 In a pilot study, we achieve in vitro-in vivo correlation, increasing the half-life of pramlintide 20-82-fold in rats, while controlling burst release. These findings demonstrate that the optimisation of pharmacokinetics can be decoupled from peptide engineering, establishing a generalisable framework for generating long-acting peptide formulations by emulating native storage mechanisms.

biophysics↗

bioRxiv2026

STING-STAT3-SOX18 Axis Drives EndMT and Epigenetic Reprogramming in SAVI Lung Fibrosis

A high prevalence of early-onset interstitial lung disease, including pulmonary fibrosis, in pediatric patients with Stimulator of interferon genes (STING)-Associated Vasculopathy with onset in infancy (SAVI) suggests a critical role for the cGAS-STING pathway in the pathogenesis of pulmonary fibrosis. We identified an endothelial-to-mesenchymal transition (EndMT) signature in lesional lung biopsies from SAVI patients, marked by a loss of endothelial and acquisition of mesenchymal markers. Consistently, induced pluripotent stem cell-derived endothelial cells (iECs) from SAVI patients harboring gain-of-function STING1 mutations spontaneously undergo EndMT, a process rescued in isogenic-correction. In endothelial cells, STING activation induces IRF3-independent STAT3 phosphorylation, initiating a SLUG-dependent mesenchymal transcriptional program while repressing SOX18 and an epigenetically-regulated endothelial maintenance network. Our studies define a non-canonical cGAS-STING-STAT3 signaling axis that couples a mesenchymal transcriptional program with epigenetic silencing of an endothelial maintenance program, promoting TGF{beta}-independent STING-mediated EndMT and endothelial dysfunction, and suggesting STING as a therapeutic target for inflammatory pulmonary fibrosis.

cell biology↗

bioRxiv2026

Subdiffusive random growth of bacteria

While the regulation of bacterial cell size is widely studied across generations, the stochastic nature of cell volume growth remains elusive within a cell cycle. Here, we investigate the fluctuations of cell volume growth and report a subdiffusive random growth. Specifically, the mean square displacement of the logarithmic volume scales as {Delta}t with an anomalous exponent {approx} 0.27. This low exponent implies strong negative temporal correlations in growth rate noise on timescales of minutes, which are significantly faster than those of gene expression dynamics. We attribute this phenomenon to the physical mechanics of the cell wall. By modeling the cell wall as a complex viscoelastic material with power-law-distributed relaxation times, we successfully recapitulate the observed subdiffusive behavior. Our results suggest that it is the heterogeneous cell-wall viscoelasticity, rather than biological regulatory programs, that governs the short-timescale fluctuations of bacterial growth.

biophysics↗

bioRxiv2026

Co-evolution of Oncogenic KRAS Signaling and LILRBhigh Macrophages Drives Pancreatic Cancer Recurrence

Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after surgical resection, indicating that residual disease is sustained by coordinated tumor-microenvironment interactions. To define the biological basis of recurrence, we leverage large-scale clinical data from 2,710 patients, deeply characterized multi-omics profiling (whole-exome, bulk RNA, and single-nucleus sequencing) of 36 matched primary and locally recurrent PDACs, an in-house multiplex spatial imaging cohort of 190 patients, and extensive public datasets. Recurrent tumors were characterized by increased KRAS mutant allele dosage and reinforced KRAS signaling, accompanied by expansion of basal-like malignant cell states. In parallel, we identified an immunosuppressive macrophage population marked by high LILRB expression that spatially co-localized with KRAS-activated tumor cells. Functional studies showed that LILRB4+ macrophages enhanced tumor cell plasticity and progression, whereas inhibition of macrophage LILRB4 suppressed these phenotypes. Notably, a first-in-class human anti-LILRB4 antibody reduced macrophage-driven tumor traits, and dual targeting of KRAS signaling and LILRB4 achieved superior tumor control in macrophage-containing mouse models. These findings reveal a co-evolved tumor-immune niche underlying PDAC recurrence and nominate the KRAS-LILRB4 axis as a therapeutic vulnerability.

cancer biology↗

bioRxiv2026

Erythropoietin Mediates Glycerophospholipid Remodeling During Human Early Erythropoiesis

The unique biconcave morphology and deformability of mature red blood cells (RBCs) require a specific membrane lipid composition. Disruption of this special lipid profile is seen in multiple types of anemia and bone marrow (BM) failure diseases, yet molecular mechanisms regulating lipid metabolism during normal erythroid differentiation remain poorly defined. Here, we identify a previously undescribed role for erythropoietin (Epo) in contributing to the appropriate lipid composition of differentiating human erythroid cells. Using single-cell transcriptomic profiling of ex vivo cultures of human BM-derived hematopoietic stem and progenitor cells cultured with or without Epo, we delineated transcriptional dynamics across differentiation stages, identifying the Epo-dependent transition of burst-forming unit erythroid (BFU-E) to colony-forming unit erythroid (CFU-E) progenitors. Comparative analysis revealed the activation of canonical erythroid programs involving heme biosynthesis, globin expression, and iron regulation, and additionally, uncovered a transient upregulation of lipid metabolic pathways during the BFU-E to CFU-E transition. Complementary untargeted lipidomics demonstrated Epo-dependent alterations in specific glycerophospholipid (GPL) species, consistent with differential expression of GPL biosynthesis genes in the single cell dataset. Intracellular flow cytometry further confirmed the requirement of Epo for maintaining enzymes critical for phosphatidylcholine and phosphatidylethanolamine synthesis in erythroid cells. Together, these multiomic findings reveal a new role for Epo in modulating lipid metabolism during early erythropoiesis and provide mechanistic insight into how membrane lipid composition is dynamically regulated to support normal red cell development.

cell biology↗

bioRxiv2026

Noncanonical loops regulated by EMF1 and cohesin-associated factors shape the distinct 3D genome architecture in plants

In mammals, cohesin-mediated chromatin loop extrusion is blocked at boundaries, where CTCF, WAPL, and PDS5s co-bind and regulate cohesin, establishing an impermeable barrier with no exceptions. In contrast, our study revealed that in Arabidopsis, some noncanonical contacts have emerged between the boundary flanking regions, which suggest that cohesin is not absolutely blocked but enables sliding beyond boundaries. We identified these interactions as noncanonical loops and clarified their regulatory proteins. Firstly, the plant-specific boundary binding protein EMF1 is essential for noncanonical loops formation. Surprisingly, although both Arabidopsis WAPLs and PDS5s inhibit loop extension as mammals, PDS5s do not co-bind and cooperate with WAPLs at boundaries. Instead, PDS5s bind to boundary-flanking regions enriched with H3K4me1 through their Tudor domains, restricting further extension of noncanonical loops. Consequently, pds5a/b/c mutants lose noncanonical loops, resulting in emergence of larger canonical loops but anchored on boundaries and co-upregulation of anchored gene pairs. Collectively, our findings reveal that the plant-specific noncanonical loop, regulated by plant-specific EMF1 and PDS5 proteins, is the fundamental structure of the distinctive chromatin organization of plants, which provides novel mechanistic insights into eukaryotic chromatin architecture regulation.

plant biology↗

bioRxiv2026

Identification and Characterization of Metastasis-initiating cells

Metastasis, the primary cause of cancer-related mortality, is a dynamic and complex process driven by a subset of cells known as metastasis-initiating cells (MICs). Accurate identification of MICs is therefore critical for metastasis diagnosis and therapeutic decision-making. However, current approaches rely either on mouse tracing experiments, which are difficult to translate to human systems, or on indirect strategies such as stemness, trajectory, pathway, and biomarker analyses that often yield inconsistent results. To address these limitations, we propose scMIC, a computational framework designed to explicitly and reliably identify MICs from single-cell data (available at https://github.com/swu13/scMIC). scMIC integrates an embedding-based representation, unbalanced optimal transport, and a top-k selection strategy to robustly capture metastasis-initiating potential. The framework was validated and applied across multiple cancer types, species, and multi-omics datasets. Our results demonstrate the reliability of scMIC for MIC identification, its potential clinical utility in metastasis prognosis, and its effectiveness in discovering metastasis-related gene programs and molecular biomarkers. Elucidating the mechanisms of metastasis initiation not only advances our understanding of metastatic progression but also enables the development of therapeutic strategies that target the more aggressive MIC population rather than non-MICs, thereby avoiding unintended increases in metastatic risk. Collectively, scMIC provides a powerful tool for cancer metastasis research and drug discovery.

bioinformatics↗

bioRxiv2026

m6A-dependent microRNA binding to chromatin-associated RNA for transcriptional activation

For decades, microRNAs (miRNAs) have been canonically viewed as post-transcriptional repressors. We discovered extensive binding of microRNAs to chromatin-associated RNAs (caRNAs) and uncovered an N6-methyladenosine (m6A)-dependent transcriptional activation mechanism of microRNAs. We show that m6A-binding proteins FXR1/2 anchor AGO1/2 at m6A-marked caRNAs, where AAGUGC-seed microRNAs function as guide RNAs to direct AGO positioning. This dual anchoring stabilizes the AGO-microRNA/FXR-m6A complex at specific loci, which in turn recruits the ATP-dependent chromatin remodeler SMARCA4 (BRG1) to promote local chromatin opening and TET1 for DNA demethylation, respectively. Together, these coordinated activities establish a transcriptionally permissive chromatin environment, enhancing accessibility and transcription across hundreds of genes in diverse cell types. Beyond the AAGUGC-seed family, additional microRNAs and siRNAs also enhance transcription, suggesting that caRNA binding and transcriptional activation may represent a broader property of small RNAs.

molecular biology↗

bioRxiv2026

The endoderm cell trajectory of urochordate Styela clava reveals the dual developmental origin and evolution of digestive tract

The digestive system exhibits extensive diversity in developmental mechanisms and morphology across metazoans, yet the evolutionary origins underlying its organ differentiation remain unclear. Here, single-cell RNA sequencing was employed to investigate endodermal cell lineage specification during metamorphosis in the urochordate Styela clava, a newly established model for chordate evolution. By profiling 26,099 cells across five stages, we identified 21 major cell clusters and reconstructed the endodermal differentiation trajectories. Our analysis reveals two larval endodermal progenitor populations with distinct differentiation potentials. Pseudotime and RNA velocity analyses indicate that these progenitors give rise to stomach and intestinal lineages, respectively. Cross-species comparisons reveal putative homologous relationships between ascidian endodermal lineages and mouse definitive and visceral endodermal lineages, suggesting dual origins of digestive tract in chordates. We also identified conserved TGF-{beta} and FGF regulatory programs in digestive organ patterning and highlight earlier fate restriction of stomach and intestinal progenitors in ascidians compared to vertebrates. These findings provide insights into how chordate digestive organs evolved from ancestral endodermal patterning programs.

evolutionary biology↗

bioRxiv2026

Small brown planthopper infestation enhances it reproduction and insecticide tolerance by manipulating glucose distribution and levels in rice

The evolutionary arms race between plants and insects involves not only direct defense and counter-defense but also sophisticated resource manipulation. However, how herbivorous insects respond to host nutritional signals to modulate their fitness traits remains unclear. This study investigates how the small brown planthopper (SBPH, Laodelphax striatellus) manipulates host plant carbohydrate allocation, and to elucidate the molecular mechanisms by which the acquired glucose enhances SBPH fecundity and insecticide tolerance. Using molecular, pharmacological, and biochemical approaches, we found that SBPH infestation induced systemic carbohydrate reallocation in rice, elevating whole-plant glucose levels by promoting aerial accumulation while depleting root reserves. Host-derived glucose enhanced SBPH fecundity by activating the target of rapamycin (TOR) pathway, upregulating juvenile hormone (JH) signaling, and increasing vitellogenin production. For imidacloprid tolerance, glucose boosted glutathione S-transferase (GST) activity via two synergistic mechanisms: by upregulating glutamate cysteine ligase (GCL) to increase glutathione synthesis, and transcriptionally via the glucose-TOR-JH axis to induce LsGSTe1 (SBPH epsilon class GST) and LsGSTo1 (SBPH omega class GST) expression. Our findings establish host-derived glucose as a central signaling molecule that SBPH utilizes to modulate conserved pathways for simultaneous optimization of reproduction and insecticide resistance. This reveals a multifaceted nutrient-responsive mechanism in insect pests and identifies the glucose-TOR-JH axis as critical molecular targets for developing nutrient-based pest control strategies, such as disrupting insect nutrient-sensing pathways or modulating host carbohydrate metabolism. HighlightsO_LISBPH infestation elevates whole-plant glucose levels by promoting aerial accumulation while suppressing root abundance. C_LIO_LISBPH-induced glucose in the rice aerial tissues boosts reproduction of SBPH via TOR-JH-Vg pathway. C_LIO_LISBPH-induced glucose in the rice aerial tissues enhances imidacloprid tolerance of SBPH through GCL-GSH-GST and TOR-JH-GST axis. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/701313v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@39e084org.highwire.dtl.DTLVardef@1c310cborg.highwire.dtl.DTLVardef@1838575org.highwire.dtl.DTLVardef@1aedebe_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2026

Genomic and pan-genomic insight into longan domestication and improvement

Longan (Dimocarpus longan) is a tropical tree in Sapindaceae family with economic importance known for its nutritous fruits. Genetic improvement of longan requires knowledge of reliable molecular markers and functional genes associated with key traits. However, it is largely impeded by lacking a complete genome and pangenome reference encompassing the broad genetic diversity in diverse longan germplasms. Here, we present a telomere-to-telomere (T2T) gap-free genome of longan cultivar Shixia and a graph-based pangenome constructed using newly assembled chromosome-level genomes of 101 accessions. We completely assemble the longan centromere regions primarily composed of Gypsy-CRM retrotransposons. The pan-genome analysis reveals 58,978 non-redundant structural variants (SVs) that exhibit signs of genomic selective sweep during longan domestication and breeding. Additionally, haplotype-resolved genome analysis suggests allele-specific gene expression associated with SV-driven changes in 3D genome architecture. Importantly, the graph-based pan-genome empowers population-scale SV genotyping and genomewide association with various longan traits. SV-GWAS revealed 12 QTLs significantly linked with longan maturity period. Among them, a 758bp insertion is located downstream of the DlDAZ gene encoding a C2H2 zinc-finger transcription factor, and DIDAZ-transgenic tomatoes showed delayed maturity. Together, our T2T genome and pan-genome provide valuable resources to facilitate longan genetic research and precise improvement.

genomics↗

bioRxiv2025

GenoME: a MoE-based generative model for individualized, multimodal prediction and perturbation of genomic profiles

The non-coding genome operates through a complex, multiscale regulatory system where regulated gene expressions are closely associated with cell-type-specific histone modifications, transcription factor binding and 3D conformation. Developing computational models that can integrate these patterns to predict and interpret the regulatory system remains challenging. Here, we present GenoME, a Mixture of Experts (MoE)-based generative model that uses DNA sequence and cell-type-specific ATAC-seq signals to predict a unified genomic profile encompassing epigenomics, transcriptomics, and chromatin architecture at base-pair to kilobase resolutions. GenoME enables multiscale predictions for held-out genomic regions and, critically, generalizes to predict the full regulatory landscape of unseen or individualized cell types from a single ATAC-seq input. We equip GenoME with an in silico perturbation framework that accurately forecasts the multimodal consequences of genetic perturbations and identifies functional enhancer-promoter connections, outperforming specialized models like Activity-by-Contact. These predictions can also be used to decipher the transcription factor grammar of cell-type-specific enhancers. GenoME thus provides a versatile, all-in-one platform for generative modeling, cross-cell-type generalization, and causal mechanistic investigation of the multiscale regulatory genome.

bioinformatics↗

bioRxiv2025

Two Small Proteins Enable N2O Reduction in Acidic Environments

Denitrifying bacteria are major contributors to nitrous oxide (N2O) emissions, which rise with global soil acidification, likely because low pH impairs maturation of the periplasmic enzyme N2O reductase (NosZ) in most bacteria. While some bacteria can reduce N2O under acidic conditions, the underlying mechanism remain unclear. Here, we isolated bacteria from acidic soils and identified strains that efficiently reduce N2O at low pH. They carry two novel proteins, NosP and NosQ, along with NosZ clade I. Functional analyses of deletion mutants demonstrated that NosP and NosQ are essential for the maturation of NosZ at low pH, but are not required at circumneutral pH. Cryo-EM analysis indicates that NosPQ forms a protective complex with NosZ, safeguarding its maturation under acidic conditions. Metagenomic analysis shows that nosPQ genes are widely distributed across diverse bacterial taxa and soil types. Our findings reveal a key molecular adaptation mechanism for N2O reduction in acidic environments and provide valuable insights for developing efficient N2O mitigation strategies.

biochemistry↗

bioRxiv2025

Perturbational single-cell profiling of patient tumors defines lineage- and context-specific programs of innate immune resistance

AbstractDespite promise in preclinical models, most immuno-oncology drug candidates fail in clinical trials. These failures reflect limitations in our ability to directly model the response of human tumor and immune cells to immunotherapies. To address this gap and test the effect of innate immune agonists, we developed PERCEPT, an approach that uses ex vivo perturbational single-cell RNA sequencing to compare the response of immunomodulatory treatments with unstimulated controls directly in patient samples. Using PERCEPT, we tested cytokines and innate immune agonists in melanoma and Merkel cell carcinoma (MCC) and identified the dsRNA mimetic, RIG-I agonist, Stem Loop RNA (SLR) 14 as a powerful inducer of anti-viral states and enhancer of T cell activation. We compared transcriptional responder and non-responder patient samples and identified midkine (MDK), a multifunctional cytokine, as a potent repressor of IFN signaling in both tumor and immune cells. MDK expression dampened MHC-I presentation in human tumor cells and reduced activation of antigen-presenting cells, disrupting tumor immunity at multiple levels. In contrast to prior studies, we identified MDK as specifically enriched in neuroendocrine cancers such as MCC and small cell lung cancer compared with melanoma, suggesting the importance of lineage- and context-specific targeting. Our results demonstrate the utility of high-dimensional controlled perturbation of patient samples to identify mechanisms of innate immune response and resistance and demonstrate an actionable path towards clinical development of MDK-inhibiting therapies including FDA-approved ALK inhibitors in neuroendocrine cancers.

cancer biology↗

bioRxiv2025

Identification of the protein precursor for thyroid hormone synthesis in the basal chordate ascidian Styela clava

Thyroid hormones (THs) play crucial roles in development, growth, and metabolism across the animal kingdom1,2. Although the mechanism of TH synthesis in vertebrates has been well described, it remains elusive in invertebrates due to the lack of identified orthologs of the thyroglobulin (TG), the protein precursor for TH synthesis3,4. Here, we identified a functional TG protein encompassing multiple TG type 1 (Tg1)-domains, encoded by the ScTg-like gene in proto-vertebrate ascidian Styela clava based on the immunoprecipitation-mass spectrometry combined with phylogenetic and expression pattern analyses. In vitro iodination experiments demonstrated that ScTG-like has the capacity to provide hormonogenic sites for TH synthesis. Furthermore, in vivo gene knockdown of ScTg-like revealed that the larval metamorphosis was significantly inhibited as a consequence of diminished TH levels, indicating that ScTg-like is responsible for the production of endogenous TH. Additionally, an invaginated follicle-like structure was first discovered at the central anterior of the larval trunk where both ScTG-like protein and THs were deposited, suggesting that this structure serves as the location for THs synthesis and storage, functionally similar to vertebrate thyroid follicles. Moreover, we analyzed the structural features of ScTG-like protein and detected the similarly organized Tg1-containing proteins in multiple bilaterian phyla, suggesting that endogenous TH synthesis may be an ancestral, possibly synapomorphic, trait of bilaterians. Our study is the first to identify the TH protein precursor outside vertebrates by providing the direct evidence of endogenous de novo TH synthesis, which offers insights into the evolution of TG protein and the emergence of a major vertebrate endocrine system.

evolutionary biology↗

bioRxiv2025

Integration of single-cell transcriptome and genetic profiles reveals critical cell types and genes in inflammatory bowel disease

The progression of inflammatory bowel disease (IBD), grouped into Crohns disease (CD) and ulcerative colitis (UC), involves multiple cell types and genes, but the identification of critical cell types and genes that contribute to intestinal inflammation remains challenging. By integrating human intestinal single-cell transcriptomic data from approximately 200 donors, we revealed the stromal cell-derived network in CD, enrichments of immune cells such as Th1 in CD, atypical B cells and Tfh in UC, AXL+SIGLEC6+ DCs and IgG+ Plasma B cells in both, and the association between SPP1+ Macrophages, FAP+ Fibroblasts and anti-TNF treatment resistance. We also investigated the gene expression characterization of enteric neurons. Additionally, by linking cell-type-specific transcriptional alterations with genetic profiles of disease risk and intestinal gene expression, we proposed B cells and cycling epithelial cells as critical cell types, and identified epithelial genes, such as GPX4, as associated with CD pathology. In summary, our study comprehensively characterized the single-cell landscape of human intestines in IBD and provided insights into cell types and genes highly involved in genetically determined CD pathology, thereby informing CD prediction, diagnosis, and the development of new therapeutic targets.

immunology↗

bioRxiv2025

Generation of cloned sheep lacking galactose-α1,3-galactose and Nglycolylneuraminic acid antigens

Livestock have long been regarded as a potential source of donor organs to alleviate the global organ shortage for transplantation. Sheep have a similar physiology and anatomy to humans, providing the standard model for demonstrating biocompatibility and performance of biological heart valves to obtain regulatory approval for their use in transplantation. Like most mammals, sheep cells contain two well-characterized carbohydrate epitopes, galactose-1,3-galactose (-Gal) and N-glycolylneuraminic acid (Neu5Gc), which are absent in humans. Formation of these xenoantigens is catalysed by two enzymes, namely (1,3) galactosyltransferase (GGTA1) and CMP-Neu5Gc hydroxylase (CMAH), respectively. Towards generating new sheep models, we used Cas9-mediated genome editing in both male and female ovine fetal fibroblasts to knockout (KO) both alleles of CMAH and GGTA1. Selected double KO (DKO) fibroblast strains were used for somatic cell transfer cloning to produce blastocysts that were transferred into gestational surrogate ewes. Following transfer of 128 male and 40 female cloned blastocysts, 6 male and 8 female lambs were born, however, none of the males survived. Molecular analyses of cells from the five surviving ewes confirmed their compound heterozygous state, resulting in a functional DKO phenotype and subsequent immune rejection of embryonic tissues during natural breeding with wild-type rams. This new DKO sheep model better mimics the human immune status, offering greater physiological relevance for preclinical testing of biological heart valves, alleviation of red meat allergy syndrome due to the presence of dietary xenoantigens, and an alternative source of donor organs that may be culturally more widely accepted than pigs.

cell biology↗