Biology subjects

Guo, S.

Publications and source records attributed to Guo, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Time-resolved cryo-EM reveals conformational trajectory of allosteric activation in isocitrate lyase

Isocitrate lyase 2 (ICL2) from Mycobacterium tuberculosis undergoes dramatic conformational rearrangements upon binding to the allosteric effector acetyl-CoA. Time-resolved cryo-EM captured conformational states along the ICL2 activation trajectory, revealing how acetyl-CoA binding at the allosteric sites leads to asymmetric, half-of-site activity at the catalytic centres. These findings support a conformational selection model of allostery, whereby acetyl-CoA binding shifts the pre-existing equilibrium towards an active state of the enzyme.

biochemistry↗

bioRxiv2026

Tau-induced mitochondrial reverse electron transport drives neurodegeneration

Hyperphosphorylation and aggregation of the microtubule-associated protein tau are recognized as pathological hallmarks of tauopathies; however, the biological activity of tau that drives its pathophysiological effects remains poorly understood1-6. Mitochondrial dysfunction is a common feature of tauopathies7,8. Despite this, the mechanistic link between tau abnormalities and mitochondrial dysfunction, as well as its relationship to taus physiological function, remains unclear. Here, we demonstrate that tau regulates mitochondrial reverse electron transport (RET), which produces excess ROS, reduces the NAD+/NADH ratio, and is activated by aging or stress. In flies, mice, and human induced pluripotent stem cells (hiPSC)-derived neurons, tau depletion eliminates stress-induced RET and confers significant stress resistance. Mechanistically, tau enters mitochondria and directly interacts with the mitochondrial complex I (C-I) subunit NDUFS3, enhancing RET activation in a phosphorylation-dependent manner that correlates with tau pathogenicity. Elevated RET further drives tau hyperphosphorylation, establishing a self-perpetuating pathological loop. Blocking tau entry into mitochondria or disrupting tau/NDUFS3 interaction reduces tau-induced RET. Genetic or pharmacological inhibition of RET protects against tau-induced neurodegeneration across species. RET regulation represents a previously unrecognized normal function of tau that becomes pathological in disease, providing a therapeutic target for conditions characterized by tau abnormalities and mitochondrial dysfunction.

neuroscience↗

bioRxiv2026

Astrocyte-neuron mitochondrial transfer via mitoEVs supports neuronal energy metabolism and is impaired in early Alzheimer's disease

BackgroundMitochondrial dysfunction is an early and central feature of Alzheimers disease (AD). In particular, intercellular mitochondrial transfer has emerged as a mechanism of neuronal support in brain injury and neurodegeneration. However, pathways governing astrocyte-to-neuron transfer and its role in AD pathogenesis remain unknown. MethodsUsing the AppNL-G-F knock-in AD model, we combined high-resolution 4D live-cell imaging with quantitative fluorescence-based reporters to assess synaptic function and mitochondrial network dynamics in neurons and astrocytes. Direct and extracellular vesicle (EV)-restricted neuron-astrocyte co-culture systems were used to investigate bidirectional mitochondrial transfer. We performed the first in-depth structural, proteomic, and functional characterization of astrocyte-derived mitochondrial extracellular vesicles (mitoEVs) using cryo-electron microscopy, quantitative mass spectrometry, and bioenergetic analyses to define their cargo composition and metabolic effects. ResultsWe identified cell-type-specific mitochondrial remodeling in early AD, with compartmentalized synaptic energy deficits in neurons and hyperdynamic, less interconnected, yet metabolically preserved networks in astrocytes, preceding global bioenergetic decline. Bidirectional mitochondrial transfer between astrocytes and neurons, also at axonal terminals, was mediated by specialized mitoEVs but significantly reduced in the AppNL-G-Fmodel. Comprehensive proteomic and functional profiling revealed that WT astrocyte-derived mitoEVs are enriched in inner membrane and matrix proteins, supporting oxidative phosphorylation, lipid and amino acid metabolism, and redox homeostasis. In contrast, AppNL-G-F mitoEVs are selectively depleted of respiratory and fatty acid oxidation components and exhibit impaired respiration with reduced Complex IV activity. Functionally, WT mitoEVs promote mobilization of abnormal accumulation of lipid droplets in AppNL-G-Fneurons, restore fatty acid oxidation, and increase neuronal bioenergetics, including at the synapses. In contrast, disease-derived mitoEVs fail to engage these pathways. ConclusionsTogether, these findings identify mitoEV-mediated mitochondrial transfer as a glia-to-neuron metabolic pathway compromised in early AD and reveal a coordinated role for oxidative phosphorylation and fatty acid oxidation in supporting synaptic energy homeostasis.

neuroscience↗

bioRxiv2026

Neurocognitive deficits in controlling aversive memory among insomnia disorders

BackgroundInsomnia disorder is a common sleep disturbance characterized by adverse daytime cognitive and emotional impairments, such as repetitive negative thinking and increased psychological distress. Memory control, a key self-regulatory ability to control or inhibit unwanted thoughts and memories, plays an essential role in supporting cognitive functions and emotional well-being. Here, we delineate the neurocognitive mechanisms underlying memory control among individuals with insomnia. Methods41 participants meeting DSM-5 criteria for insomnia disorder and 40 healthy sleepers completed an emotional Think/No-Think task, during which participants either retrieved (Think) or suppressed the retrieval (No-Think) of aversive memories in response to memory cues while electroencephalograms were recorded. ResultsLinear mixed model analyses with age and depression scores as covariates showed that participants with insomnia exhibited impaired memory control abilities, as evidenced by reduced suppression-induced forgetting in memory recall when compared to healthy sleepers. Electrophysiologically, healthy sleepers showed enhanced right prefrontal theta power in retrieval suppression than in retrieval, indicating elevated needs of inhibitory control during memory control. In sharp contrast, this difference was absent among those with insomnia. Notably, the greater the severity of insomnia symptoms, the smaller the retrieval vs. retrieval suppression theta power differences across participants, linking inefficient top-down control of unwanted memories with low sleep qualities. ConclusionIndividuals with insomnia showed impaired memory control of aversive memories and aberrant electrophysiological activities during retrieval suppression. Future research shall investigate the causal relationship between memory control abilities and insomnia symptoms.

neuroscience↗

bioRxiv2026

Sex-specific Genetic Regulatory Effects in Chickens

Sexual dimorphism is a defining vertebrate feature, yet its sex-specific molecular architecture remains poorly understood. Here we established a sex-balanced, uniformly reared chicken cohort to map this landscape, integrating individual whole-genome sequencing with 7,969 bulk and 779,380 single nucleus transcriptomes across 32 tissues from 280 birds. We identified 495,098 independent expression quantitative trait loci for 20,194 genes, including 10,937 loci modulated by cell-type composition. Notably, 340 genes were regulated by 449 loci in a sex-dependent manner, significantly enrichment in endocrine tissues like adipose and the adrenal gland. Furthermore, we fine-mapped 1,219 structural variants, demonstrating their unique roles to tissue- and sex-specific expression beyond SNPs. Ultimately, we showed the utility of these regulatory effects in elucidating the molecular basis of metabolism and complex traits in both chickens and humans. This comprehensive atlas of regulatory effects provides profound insights into the genomic and molecular basis of sexual dimorphism in vertebrates.

genomics↗

bioRxiv2026

Transplanting ANXA1- CD8+ Naive T cells Delay Aging Through Senolysis

Immunosenescence is a hallmark of aging, yet strategies using defined immune subsets to counteract it are largely unexplored. We performed paired scRNA/TCR-seq on CD45 cells from human bone marrow (15 donors, 3-91 years). T cells were the most altered lineage, with CD8 naive T cell contraction and functional impairment. We identified an expanding ANXA1 CD8 naive subset with senescence signatures and impaired function. ANXA1-deficient CD8 T cells exhibited increased resting stemness and enhanced activation/cytotoxicity upon stimulation. ANXA1- cells showed senolytic activity in vitro and reduced senescence burden in vivo. Monthly transfer of syngeneic ANXA1- CD8 naive T cells into aged mice extended median lifespan by >30 weeks, improving cardiac function, bone density, motor coordination, and marrow immune microenvironment. Our study identifies ANXA1 as critical in CD8 naive T cell aging and establishes ANXA1- cell transfer as a strategy to counter immunosenescence and promote healthy aging.

immunology↗

bioRxiv2026

Event2Flow: Scalable imaging of peripheral and cerebral hemodynamics with event-based vision sensors

Accurate blood flow mapping over mesoscale fields of view is essential for understanding physiological and pathological processes, yet conventional optical methods often rely on bulky high-speed cameras that generate massive datasets with excessive computation burden. Here, we introduce Event2Flow, a compact and data-efficient framework leveraging event-based vision sensors, which asynchronously capture brightness changes with sub-millisecond latency and minimal data redundancy. Event2Flow supports multiple contrast mechanisms for flow measurement, including speckle fluctuation and particle tracking. By correlating the event count with flow velocity through simulations and experiments, we first demonstrate its application in laser speckle imaging for noninvasive mapping of mouse ear vasculature and ethanol-induced hemodynamic changes. When integrated with widefield fluorescence localization microscopy and point spread function engineering, Event2Flow further enables kilohertz-rate particle tracking for rapid 3D velocity quantification in transcranial brain imaging and snapshot flow direction estimations using event polarity. Overall, Event2Flow offers a scalable alternative to conventional high-speed imaging systems for vascular and neuroimaging applications.

neuroscience↗

bioRxiv2026

Transforming macromolecular structures into simulations of self-assembly

Macromolecular self-assembly is a fundamental process in living and engineered systems, producing molecular machines like the ribosome or highly symmetric viral capsids. Thanks to sources like the Protein Data Bank (PDB) and AlphaFold3, the final target complexes are often known, but these static structures do not provide information on the self-assembly process directly. Computational models provide critical tools to study these essential pathways of self-assembly, but substantial coarse-graining of assembly subunits is necessary to achieve computational tractability of these relatively slow processes while retaining multi-valency. While rule-based or local interactions overcome the often-prohibitive enumeration of all possible assembly intermediates, they must ensure global structural constraints are met. We here demonstrate ioNERDSS, a user-friendly Python package that transforms 3D atomic structures into coarse-grained models for immediate simulation with the stochastic reaction-diffusion NERDSS software, converting static structures into time-resolved assembly trajectories. NERDSS uses rule-based interactions to simulate multi-component self-assembly at the minutes timescales and without limits to complex size or growth pathways. With ioNERDSS, each protein chain is defined by a rigid subunit with discrete interfaces and explicit orientational constraints that enforce a structured assembly. Repeated subunits (such as in viral capsids) are regularized to preserve the target topology across distinct stochastic assembly pathways, supporting assembly of structures with thousands of subunits. We initialize pairwise binding affinities using open-source machine-learned prediction tools, and our default coarse-grained (CG) models are all constrained by thermodynamic reversibility to reach an equilibrium steady-state. The binding rates and subunit abundances necessary to perform simulations are initialized at default values but represent the key variables (along with affinities) that cells and thus users would tune to control productive assembly. Benchmarking on over 40,000 PDB structures shows that the majority of CG models stochastically assemble into target structures. The ioNERDSS Python library links directly to open-source tools for visualization and analysis to facilitate fast and user-friendly structure validation and analysis of output for thermodynamic, kinetic, and nonequilibrium drivers of macromolecular self-assembly.

biophysics↗

bioRxiv2025

Fast Loading and Transformation of Large-Volume Bioimaging Data Consistently Approaching the I/O Peak Speed

High-resolution large-volume biological imaging techniques are now widely used in biological research, but inefficiencies in data processing and visualization persist due to bottlenecks in loading/saving pipelines and limitations of conventional pyramid formats. To address these issues, we have decoupled data loading process into reading from disk and in-memory decompression, while data saving has been separated into in-memory compression and writing to disk. This approach allows us to dedicate more CPU cores to decompression and compression tasks, optimizing resource allocation and maximizing disk I/O throughput. As a result, both loading and saving processes operate near the disks peak data transfer capacity. Further, we integrated a video stream-inspired format into the pyramid structure, allowing direct access to regions of interest (ROIs) without loading extraneous data into RAM, reducing memory overhead. Compared to the latest methods, our approach improves pyramid data transformation efficiency by at least 6x and dramatically accelerates downstream tasks like visualization and deep learning inference. TeaserNovel bioimaging data processing pipeline achieves near-peak I/O throughput via decoupled architecture and video-formatting.

bioinformatics↗

bioRxiv2025

Scalable Human Cellular Models of Parkinson Disease Reveal A Druggable Link Between the Angiotensin Receptor 1 and Alpha-Synuclein Pathology

BackgroundParkinsons disease (PD) involves progressive loss of midbrain dopaminergic (mDA) neurons in the substantia nigra. No disease-modifying treatments exist, only symptomatic relief. Our lab reported an unbiased screen in larval zebrafish identifying renin-angiotensin-aldosterone system (RAAS) inhibitors, including clinically used AGTR1 inhibitors for hypertension, as potent neuroprotective agents. This study aims to investigate the effects of AGTR1 inhibition on human mDA neuron survival using inducible neurodegenerative 2D and 3D models for human mDA neuron degeneration. MethodsWe report a scalable high-content platform, using CRISPR-engineered human induced pluripotent stem cell (hiPSC)-derived mDA neurons expressing a tyrosine hydroxylase (TH) fluorescent reporter, allowing to track mDA neuron survival live "in a dish". We developed chemically inducible neurodegenerative 2D and 3D models for human mDA neuron degeneration, allowing to recapitulate PD pathology in human cells in vitro. ResultsOur model establishes scalable human cellular models of PD well-suited for therapeutic discovery. Using 2D and 3D mono and co-cultures, this study demonstrates that inhibition of AGTR1, via chemical or genetic means, protects against chemically induced mDA neuron degeneration. Transcriptomic analyses show AGTR1 inhibition lowers synuclein transcription, by reducing SNCA and SNCB gene expression. In 3D neuron-glia assembloids, AGTR1 inhibition protects against the accumulation of phosphorylated form of -synuclein (p129-Syn), key PD pathological marker. ConclusionsWe highlight AGTR1 as a key regulator of -synuclein transcription and aggregation in human mDA neurons, and AGTR1 inhibition as pro-survival in human iPSC-derived models. These findings position inhibition of AGTR1 as a promising therapeutic strategy for PD neuroprotection.

neuroscience↗

bioRxiv2025

In situ Architecture of the Tad Pilus Machine in Caulobacter crescentus

The Tight adherence (Tad) pilus is a broadly distributed and evolutionarily distinct subclass of type IV pili that mediates cell adhesion, biofilm formation, predation, and surface sensing in many bacteria, including Caulobacter crescentus, Myxococcus xanthus, Vibrio vulnificus, and Bifidobacterium breve. Tad pili undergo cycles of extension and retraction powered by a cell-envelope-embedded nanomachine. Despite their biological importance, the architecture and assembly mechanism of the Tad pilus system have remained poorly understood. Although cryo-electron tomography (cryo-ET) has elucidated the in situ structures of other type IV pilus systems, no intact Tad machine structure has previously been reported. Here, we use cryo-ET and subtomogram averaging to resolve the near-native architecture of the C. crescentus Tad pilus within the bacterial cell envelope. 3D classification further reveals multiple assembly intermediates, and integrative modelling incorporating AlphaFold3 predictions help define the spatial arrangement of all core components. The resulting structural framework gives insight into the stepwise assembly process of the C. crescentus Tad pilus machine. Altogether, our results provide an in situ architectural model of the Tad pilus machine, establishing a foundation for understanding homologous systems across a broad range of bacteria. ImportanceInvestigating the Tad pilus nanomachine in a genetically tractable, non-pathogenic organism like Caulobacter crescentus provides a powerful model for elucidating the architecture and functional dynamics of this widespread system. Insights gained from studying the Tad machinery can improve our understanding of related Tad pilus systems in pathogenic bacteria such as Aggregatibacter actinomycetemcomitans, where Tad pili are a key determinant of biofilm formation and chronic infection. Additionally, the remarkable functional diversity of Tad systems, ranging from surface sensing in C. crescentus to bacterial predation in M. xanthus, highlights their broad biological relevance. By revealing the in situ structure and assembly mechanism of the Tad pilus biosynthetic machinery, this study advances our understanding of a major class of bacterial nanomachines and may thus provide structural insights that could inform the development of new therapeutic strategies targeting pilus-mediated virulence.

microbiology↗

bioRxiv2025

Repeat associated non-AUG translation as a common mechanism for the polyGln ataxias

Determining if repeat associated non-AUG (RAN) proteins contribute to the CAG polyGln-encoding spinocerebellar ataxias (CAG-SCAs) is critical for understanding mechanisms and developing therapies for these diseases. Immunohistochemistry using antibodies against polySer and polyLeu repeats and locus specific C-terminal regions show sense polySer (AGC frame) and antisense polyLeu (CUG frame) RAN proteins accumulate in affected grey and white-matter brain regions, throughout the cerebellum and pons, in SCA1, SCA2, SCA3, SCA6, and SCA7 autopsy brains. Cerebellar white matter regions with prominent polySer and polyLeu but minimal polyGln aggregates show demyelination, white matter loss, and activated microglia. In SCA3 mice, RAN proteins accumulate in an age-dependent manner. In neural cells, polySer and polyLeu RAN proteins are toxic and cause autophagic dysfunction. In cells, the FDA-approved drug metformin decreases RAN protein levels and reduces toxicity. Taken together, these data identify sense and antisense RAN proteins as a common molecular mechanism shared by the CAG-SCAs.

neuroscience↗

bioRxiv2025

Feasibility of a parent-delivered attention and working memory intervention for early school-aged children born preterm

Preterm birth is a common neurodevelopmental condition that can have lasting impacts on cognition, including attention and working memory. Interventions that strengthen these skills in early childhood could support school readiness. Dino Island is a tablet-based intervention that combines process-specific practice of attention and working memory skills with a compensatory component that teaches metacognitive skills to scaffold learning. In this pilot study, we evaluated the feasibility of parent-delivered Dino Island in young children born preterm (N=10), alongside a control group who played educational games (N=12). Both groups were instructed to play 2-3 times per week for approximately 20 minutes over a 12-week period. Attention and working memory on untrained tasks were assessed before and after completing the intervention. Parents provided fidelity data through tracking sheets and participated in exit interviews to offer feedback and identify barriers and facilitators. We found that the Dino Island program was successfully delivered by parents with high fidelity. Attrition was higher in the Dino Island group, likely reflecting the challenges of delivering cognitive remediation in home settings. Comparison of attention and working memory scores on untrained tasks pre- and post-showed practice effects but no specific benefit of Dino Island. However, parent reports suggested behavioral improvements specific to the Dino Island group, noting far-transfer effects where children applied metacognitive strategies in other contexts. Overall, this work shows feasibility and tolerability of Dino Island in young children born preterm. Future research should examine its potential impact on school readiness and longer-term academic outcomes in this population.

neuroscience↗

bioRxiv2025

Bioinformatic process for the identification and characterization of bacterial repeat-in-toxin adhesins

Gram-negative bacteria attach to host surfaces using ligand-binding domains (LBDs) at the distal tips of fibrillar RTX adhesins. Blocking the initial binding interaction(s) can potentially prevent colonization and subsequent biofilm formation and infection. To this end, adhesins must be identified, and it is also essential to determine the dominant adhesin type for those species that have more than one. RTX adhesins are frequently the largest proteins within each species (ranging from 1500 to 15,000 aa) and are often misannotated as incomplete/pseudogene products because their highly repetitive nature confounds genome assemblies from short-read technologies. Our bioinformatic process collates predicted proteins from long-read assemblies, which are then clustered based on the similarity of their C-terminal regions where the LBDs are typically located. RTX adhesins are identified by their length and domain structure and are modelled using AlphaFold3. An exhaustive search of multiple strains from seven species revealed a total of 35 different RTX adhesins that map to 16 different loci, with differing arrangements of LBDs that include putative carbohydrate-binding modules and von Willebrand Factor A-like domains. Notably, similar adhesins are sometimes found in multiple species, either by descent or through DNA uptake, and three species have an RTX adhesin of uncertain function because it lacks an obvious LBD. ImportanceMany bacteria initiate infection by reaching out with large, complex proteins called adhesins to attach themselves to a host cell. The DNA sequences of adhesins are difficult to read, due to their length and repetitiveness. This study leverages recent technological advances like "long-read sequencing" and structural modelling to identify and characterize the adhesins in seven species of harmful bacteria: Acinetobacter baumannii, Aeromonas hydrophila, Aeromonas salmonicida, Bordetella parapertussis, Legionella pneumophila, Vibrio parahaemolyticus, and Vibrio vulnificus. We identified thirty-five unique versions of adhesins and demonstrated their mix-and-match architecture. This research provides a foundation for strategies to block bacteria from binding surfaces, offering a vital alternative treatment as antibiotic resistance continues to rise.

biochemistry↗

bioRxiv2025

Shugoshin holds the potential to inhibit APC/C and thereby prevents separase activation

Accurate chromosome segregation during mitosis and meiosis depends on shugoshin protein which localizes at the centromere of chromosomes. Sgo1, a meiosis-specific shugoshin in fission yeast, collaborates with the PP2A phosphatase enzyme to remove phosphate groups from Rec8 cohesin, thereby preventing its cleavage by separase during meiosis. Here we show that ectopic expression of Sgo1 causes chromosome segregation errors during mitosis, especially in cut1-206 separase mutant cells, but that the D-box mutant Sgo1 has no effect in cut1-206 cells. Our molecular genetic analyses suggest that the D-box of Sgo1 directly binds Slp1/CDC20 and inhibits APC/C-dependent separase activation, thereby preventing cleavage of Rad21 cohesin. In contrast, during meiosis, the Sgo1 D-box mutant makes the cut1-206 mutant more difficult to cleave Rec8 cohesin. This is because the D-box mutation increases the amount of Sgo1 protein during meiosis, thereby enhancing its canonical protective ability against Rec8 cohesin. Thus, our studies using a separase mutant have revealed that Sgo1 has multiple faces to protect coheisn.

cell biology↗

bioRxiv2025

Molecular architecture of OXGR1 reveals evolutionary conserved mechanisms for metabolite surveillance

The ability of cells to sense and respond to metabolic signals is fundamental to life, yet the molecular mechanisms underlying metabolite surveillance remain incompletely understood. Here, we elucidate the structural basis of metabolite recognition by OXGR1, a GPCR that monitors key intermediates in the tricarboxylic acid cycle (TCA). Using cryo-electron microscopy, we determined four cryo-EM structures of OXGR1 bound to -ketoglutarate (AKG), itaconate (ITA), and structural related succinate (SUC) and maleate (MA). These structures reveal a positively charged binding pocket and an extensive hydrogen-bond network critical for OXGR1 recognizing dicarboxylic acids. In addition, we identify a distinct arrangement of hydrophobic residues that modulates ligand potency and selectivity. Mutational analysis and molecular dynamics simulations further demonstrate that non-canonical micro-switch motifs, including FRY and NLxxY, are essential for ligand recognition and receptor activation. Comparative structural and evolutionary analyses indicate that these mechanisms are conserved across species, underscoring the critical role of OXGR1 in maintaining metabolic homeostasis. Together, our findings provide a mechanistic framework for metabolite sensing via OXGR1 and suggest potential strategies for therapeutic modulation of metabolic and inflammatory diseases.

molecular biology↗

bioRxiv2025

Peptide-based ligand antagonists block a Vibrio cholerae adhesin

Vibrio cholerae, the causative agent of cholera, uses surface proteins such as the repeats-in-toxin (RTX) adhesin FrhA to colonize hosts and initiate infection. Blocking bacterial adhesion represents a promising therapeutic strategy to treat infections without promoting drug resistance. FrhA contains a peptide-binding domain (PBD) that is key for hemagglutination, human epithelial cell binding, and V. cholerae biofilm formation. Previous studies identified a lead pentapeptide ligand with the sequence Ala-Gly-Tyr-Thr-Asp (AGYTD) that blocks V. cholerae colonization of the mouse small intestine at high micromolar concentrations. A structure-guided approach has now identified a minimal D-amino acid-containing tripeptide motif with higher affinity for the FrhA-PBD and predicted metabolic stability. Our results contribute to the development of anti-adhesion strategies to combat infections.

microbiology↗

bioRxiv2025

ALK1-BMPRII agonism by clustering bispecific antibodies treats hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is characterized by arteriovenous malformations (AVMs) and severe bleeding caused by loss-of-function mutations in the ALK1 receptor pathway. We developed clustering agonist bispecific antibodies (BsAbs) targeting ALK1 and its activating partner, the Ser/Thr receptor kinase BMPRII. These BsAbs induced ALK1-BMPRII proximity association, stimulated the downstream Smad1/5/8 signaling cascade, and treated HHT pathologies in various mouse models. BsAb treatment reduced AVM burden by up to 95% in HHT mice, preventing anemia, cardiomegaly, and premature death. The BsAbs also enhanced Smad1/5/8 signaling in endothelial cells derived from HHT patients with ALK1 mutations and prevented retinal AVMs in a newly developed knock-in mouse carrying an HHT-causing ALK1 mutation. These findings establish ALK1-BMPRII agonism as a promising therapeutic strategy for HHT.

cell biology↗