Biology subjects

Yu, A.

Publications and source records attributed to Yu, A..

At least 19 recordsLinked to original sources

bioRxiv2026

C19 trityl and silyl andrographolide analogs exhibit in vitro anticancer activity in murine cancer models

Andrographolide, a labdane diterpenoid isolated from A. paniculata has been investigated for activity in a broad panel of biological contexts, including its anti-inflammatory, antiviral, and anticancer properties. Previously, A-ring analogs of andrographolide bearing silyl and trityl ethers at C19 have demonstrated improved in vitro anticancer activity in human cancer cell lines, with putative activity through the Wnt1/{beta}-catenin signaling axis. In order to investigate the activity of this series of C19 andrographolide analogs, alongside a cyclic A-ring acetonide analog, as anticancer agents in murine cancer cell models, we evaluated antiproliferative activity of these compounds in B16F10 melanoma, CT26 colorectal adenocarcinoma, Neuro2a neuroblastoma, and 4T1 mammary ductal carcinoma cell lines, and found that most compounds exhibited potent micromolar level anticancer activity. Among these, all trityl ethers exhibited nearly indistinguishable IC50 values of 4-20 M, and generally exhibited greater potency compared to C19 silyl ether analogs. This anticancer activity was further validated through apoptosis flow cytometry, wherein we concluded that our compounds induced apoptosis to a greater extent than the parent compound, andrographolide. Further, we examine the role of modulation of canonical Wnt1/{beta}-catenin signaling in a series of co-delivery assays with CHIR-99021, a selective GSK-3{beta} kinase inhibitor, and MSAB, a selective {beta}-catenin degrader. Finally, we demonstrate that a selection of silyl ether analogs of andrographolide elicit cell cycle arrest by flow cytometry in a manner that is decoupled to in vitro potency trends. Altogether, we report the first in vitro evaluation of trityl and silyl ether analogs of andrographolide within murine adherent cancer cells.

cancer biology↗

bioRxiv2026

DeepD enables efficient genome modeling and controllable long-context sequence generation across domains of life

Genome foundation models hold great potential for advancing biological research, but modeling diverse complex genomes and generating controllable genome-scale sequences remain challenging. We present DeepD, a phylogeny-informed sparse mixture-of-experts model operating at single-nucleotide resolution over a 1-million-token context while reducing active computation. Pretrained on unselected whole-genome sequences across all domains of life, DeepD learns genic and intergenic sequence features and supports broad sequence-to-function prediction across species. DeepD performs well in human protein fitness and disease variants effect prediction, such as BRCA1 and BRCA2, with particular strength in regulatory regions, such as promoter and transcription-factor binding sites. Expert routing captures exon-intron boundaries, transposable elements, and distal cis-regulatory elements. DeepD also generates experimentally validated core promoters with specified transcriptional strengths. Finally, the Context-Anchor-Body strategy enables generation of complete yeast chromosome sequences and megabase-scale Arabidopsis segments, preserving gene structure and order while introducing variations within natural ranges. Together, DeepD is an efficient genome foundation model that unifies accurate sequence-to-function prediction with controllable genome-scale generation, advancing predictive and generative design of complex genomes.

bioinformatics↗

bioRxiv2026

One-carbon metabolism sustains effector T cell function through cell-surface glycosylation

Folate is a driver of one-carbon metabolism that is essential in T cells. The cellular consequences of its deprivation in CD8+ T cells and impact on anti-tumor function are unknown. Single cell RNA-seq analysis of primary central nervous system lymphoma (PCNSL) patients' tumor samples revealed exhaustion in T cells with high folate metabolism gene expression signature. Functional genomics, metabolite profiling, and glycomics identified disrupted cell surface glycosylation as a major consequence of folate deprivation in CD8+ T cells. Mechanistically, folate deprivation reduced nucleotide sugar levels, perturbed glycosylation, and triggered the apoptotic unfolded protein response. Overexpressing folate transporters in adoptively transferred CD8+ T cells increased intratumoral T cell numbers and reduced exhaustion. Therefore, our data draw a mechanistic line between one-carbon metabolism, cell-surface glycosylation, and anti-tumor T cell function, and support a hypothesis that increased folate uptake can enhance CD8+ T cell function including ex vivo and in vivo CAR-T cells.

cell biology↗

bioRxiv2026

Characterizing Individual and Population-Level Heterogeneity in Infant BMI Trajectories Using Flexible and Functional Modeling Approaches

Infant body mass index (BMI) follows a rapid and nonlinear trajectory, yet substantial inter-individual variation complicates accurate characterization of growth dynamics. Here we systematically compared individual- and group-based approaches for modeling longitudinal BMI trajectories in 2,114 healthy infants. Among linear spline, natural cubic spline and fractional polynomial mixed-effects models and SITAR, natural cubic splines provided the best fit while preserving individual variation in trajectory shape. Across all models, males reached their BMI peak earlier than females. To characterize population-level heterogeneity, we further compared latent class mixed models with functional principal component analysis (FPCA) followed by Gaussian mixture clustering. Whereas latent class modeling produced numerous small classes, FPCA identified three interpretable trajectory groups in both sexes, including a rare subgroup characterized by higher BMI and delayed or unestimable peak timing. Maternal gestational diabetes was associated with earlier BMI peak timing in females and was enriched in the rare female trajectory subgroup. Together, these results support combining flexible mixed-effects modeling with functional trajectory analysis to characterize both individual growth dynamics and population-level heterogeneity during infancy.

developmental biology↗

bioRxiv2026

DROSOPHILA PRICKLE MUTANTS DISPLAY COMORBID NEUROLOGICAL PHENOTYPES AND PROVIDE A GENETIC LINK BETWEEN EPILEPSY AND AUTISM SPECTRUM DISORDER

Epilepsy affects approximately 30% of individuals with autism spectrum disorder (ASD). Consistent with these observations, while PRICKLE mutations are primarily linked with epilepsy, there is an enrichment of pathogenic DNA sequence variants in PRICKLE genes carried by individuals with ASD. Nonetheless, a connection between PRICKLE function and ASD warrants further investigation. Here, we show that a seizure-prone Drosophila prickle mutant (prickle-spiny-legs, or pksple) exhibits learning and memory deficits, increased pain sensitivity, both communication and social interaction difficulties, and restrictive repetitive grooming behaviors, all of which are strongly correlated with ASD, while a non-seizure prone prickle mutant (prickle-prickle, or pkpk) does not, thereby providing a direct genetic connection between epilepsy and ASD through prickle. Comparing headed versus headless pksple mutants, we also show that the excessive grooming requires higher level cognitive processing from the brain. Finally, both pksple and pkpk mutants exhibit circadian rhythm defects, another feature correlated with ASD, as well as distinct yet overlapping neurological anomalies in processes that include innate immune response, oxidative stress response, neuronal cell death, neurodegeneration, motor dysfunction and reduced lifespan, likely reflecting the unique isoform expression patterns observed in the developing CNS. Collectively, this study highlights the broadscale effects of PRICKLE mutations that extend beyond the primary clinical features of epilepsy to include several of the core features of ASD.

neuroscience↗

bioRxiv2026

The overlooked role of muscle regeneration failure in post-implantation complications: a thorough investigation into mechanisms of recurrent urethral stricture

Bioresorbable collagen membranes rarely achieve complete organ regeneration, often necessitating secondary operations. In this study, urethral defects were modeled in 60 Chinchilla rabbits; 30 were reconstructed using collagen membrane patches. Histological, immunohistochemical and in situ PCR analyses were performed at multiple time points up to 270 days post-implantation to assess inflammatory (TGF-{beta}1, Wnt2, iNOS) and regenerative (collagen I/III, -SMA, E-cadherin) markers. A biopsy from a patient with recurrent urethral stricture was analyzed using the same methodology. At three months after implantation, the mucosal layer had recovered, however, the underlying muscle layer remained incompletely regenerated. The muscle bundles were surrounded by -SMA-positive myofibroblast-rich connective tissue with upregulated profibrotic markers. Comparable patterns of impaired muscle regeneration and high TGF-{beta}1 expression were found in the human specimen. Our findings suggest that while muscle layer regeneration is essential for structural restoration, it may also trigger a sustained profibrotic cascade.

bioengineering↗

bioRxiv2026

Inhibition of RNA splicing is a novel therapeutic strategy for disruption of nuclear replicating viruses

RNA splicing is a fundamental feature of eukaryotic gene expression that is co-opted by many nuclear-replicating viruses to produce viral transcripts. Recent clinical development of spliceosome-targeting therapeutics has demonstrated that splicing can be safely modulated in vivo, raising the possibility that viral dependence on host RNA processing may represent an exploitable antiviral vulnerability. Here, we show that pharmacologic inhibition of cellular RNA splicing preferentially suppresses the expression of spliced viral transcripts and profoundly impairs replication of multiple splicing-dependent viruses. In human adenovirus, low-dose inhibition of the spliceosome using mechanistically distinct chemical inhibitors, or genetic depletion of SF3B1, disrupted splicing of complex late viral transcripts while largely sparing simple early transcripts. This resulted in impaired viral DNA replication, reduced late protein accumulation, and multi-log decreases in infectious progeny production. Splicing inhibitors similarly impaired RNA splicing and viral replication of DNA virus Herpes Simplex virus 1 and RNA virus influenza A, which both rely on host-dependent RNA processing strategies. In contrast, cytoplasmic RNA viruses lacking spliceosome dependence were unaffected, supporting an on-target mechanism. Together, these findings identify viral RNA processing complexity as a determinant of antiviral sensitivity and establish host spliceosome dependence as a shared and targetable vulnerability across diverse viral families.

microbiology↗

bioRxiv2026

Distinct thresholds condition sense PTGS initiation and amplification.

It has long been known that Pro35S-driven sense transgenes have a high propensity to undergo post-transcriptional gene silencing (S-PTGS). However, what exactly conditions S-PTGS initiation and amplification to make it systemic remains unknown. Through genetic screens, we show that antagonistic chromatin-related mutations enhancing and reducing transgene expression, result in enhanced and reduced S-PTGS amplification capacities, respectively, without affecting the initiation rate. Analysis of a large set of independent transgenic plants confirm a direct relationship between transgene expression and its capacity to amplify S-PTGS. Combining an inducible or a tissue-specifically expressed GUS transgene with a Pro35S:GUS transgene locus prone to amplify S-PTGS but unable to spontaneously initiate it induces systemic S-PTGS, indicating that transient and/or local passing of a discrete threshold is sufficient to initiate S-PTGS. Together, these results call for the existence of distinct thresholds related to transiently produced aberrant RNA and permanently produced target mRNA levels, which condition S-PTGS initiation and amplification, respectively. We show that this model also applies to endogenous genes for which RNA Quality Control (RQC) acts as a first layer of protection against S-PTGS, and DCL2s obscuration by DCL4 as a second layer, allowing RQC to dysfunction locally without translating into the drama of systemic S-PTGS.

plant biology↗

bioRxiv2026

Apelin inhibits cyst growth and improves kidney function in mice with polycystic kidney disease

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder marked by numerous renal cysts that impair kidney function, with about half of affected individuals progressing to kidney failure by midlife. Patients exhibit reduced circulating apelin, a ligand of the apelin receptor, known to regulate cardiovascular function including hypertension. We tested whether diminished apelin signaling contributes to cystogenesis and if exogenous apelin receptor activation can improve disease outcomes. MethodsPlasma samples from age- and sex-matched healthy controls and ADPKD participants were analyzed for circulating apelin peptides. To assess direct cystic effects, primary ADPKD renal epithelial cells were grown as 3D collagen-embedded cysts and treated with apelin agonists. Male and female Pkd1RC/RC; Pkd2+/- (PKD) mice were treated for 27 days with apelin agonists, vehicle, or the standard of care drug, Mozavaptan. Kidney and heart weight ratios, BUN, renal cAMP, and kidney transcriptional profiles were evaluated. ResultsCirculating apelin peptides were significantly reduced in ADPKD patients despite normal kidney function (eGFR, BUN, and creatinine). In vitro, both apelin and the small molecule apelin receptor agonist Azelaprag inhibited cyst growth. Apelin and Mozavaptan reduced kidney weight, cystic index, blood urea nitrogen and renal cAMP in PKD mice, whereas Azelaprag did not. Apelin downregulated expression of genes associated with cyst progression, including Lcn2 (Ngal), Postn, and Havcr1 (Kim-1). Mozavaptan, but not apelin, induced diuresis and reduced urinary concentration. ConclusionApelin receptor activation by exogenous apelin inhibited cAMP synthesis and cyst growth and improved kidney function in an orthologous mouse model of ADPKD. We propose that the apelin receptor may be a potential therapeutic target in ADPKD.

pharmacology and toxicology↗

bioRxiv2026

IL-1β and TNF drive endothelial dysfunction and coagulopathy in acute COVID-19.

Vascular dysfunction and coagulopathy are hallmarks of severe COVID-19. How SARS-CoV-2 infection drives endothelial dysfunction, despite the virus not infecting or replicating in endothelial cells, remains controversial. Here, we used an in vitro co-culture model of the human pulmonary epithelial-endothelial cell barrier to investigate which inflammatory mediators drive endothelial dysfunction during SARS-CoV-2 infection. SARS-CoV-2 infection of primary human bronchial epithelial cells increased adjacent endothelial cell expression of the leukocyte adhesion marker ICAM-1, disrupted endothelial VE-cadherin junctions, promoted endothelial cell death, and promoted platelet adherence to gaps in the endothelial monolayers. Dexamethasone treatment rescued these dysregulated endothelial phenotypes in infected co-cultures, confirming that inflammatory signalling was the primary driver of SARS-CoV-2-induced endothelial dysfunction. Specifically, epithelial-derived TNF and IL-1{beta} promoted endothelial dysfunction, as inhibition of TNF or IL-1R signalling blocked SARS-CoV-2-induced endothelial dysfunction in co-cultures. SARS-CoV-2-infected wild-type mice, but not TNF, IL-1{beta}, or TNF/IL-1{beta}- deficient mice, displayed increased endothelial ICAM-1 expression, while an anti-IL-1{beta} monoclonal antibody prevented SARS-CoV-2-induced ICAM-1 expression and fibrin deposition in aged K18-ACE2 mice. Our data indicate that TNF and IL-1{beta} are the specific cytokines that drive multiple aspects of endothelial dysfunction during acute SARS-CoV-2 infection, and that inhibiting their signalling pathways may provide therapeutic benefit in preventing vascular complications of COVID-19.

cell biology↗

bioRxiv2026

Tau-induced ribosomal collisions impair memory through the activation of the integrated stress response

The formation of new long-term memories is reliant upon the spatial and temporal regulation of mRNA translation. Translational control has been demonstrated to be disrupted in neurodegenerative diseases, which exhibit impairments in both homeostatic translation and memory formation, such as Alzheimers disease (AD) and frontotemporal dementia (FTD). However, the precise mechanisms by which this dysregulation occurs, as well as the pathogenic consequences of this dysregulation have yet to be described. Here we establish that FTD-associated tau mutations impair protein synthesis prior to the onset of memory impairments by slowing ribosomal elongation speed, causing ribosomes to collide upon mRNAs. We reveal that this tau-induced ribosomal collision ultimately impairs memory-associated translation through activation of the integrated stress response (ISR) via GCN2. Pharmacological prevention of this ISR activation not only rescues memory formation in the PS19 mouse model of FTD, but also attenuates neuronal death, decreases tau phosphorylation and accumulation, and improves survival. Collectively, our data elucidates a novel mechanism by which mRNA translation is impaired early in neurodegeneration, identifies several pathological phenotypes which are traceable to impairments in mRNA translation, and highlights the therapeutic potential of rescuing these translational impairments.

neuroscience↗

bioRxiv2025

NAPRT expression and epigenetic regulation in pediatric rhabdomyosarcoma as a potential biomarker for NAMPT inhibition

PurposeNew treatments are needed to improve survival in children with rhabdomyosarcoma (RMS). NAD biosynthesis, regulated by the enzymes NAPRT and NAMPT, represents a metabolic vulnerability due to high NAD turnover in cancers. Although NAMPT inhibitors (NAMPTi) show preclinical promise, clinical translation has been limited by toxicity and the lack of predictive biomarkers. Here, we evaluated NAPRT expression in RMS and its potential as an actionable biomarker to guide NAMPTi therapy. Experimental DesignNAPRT promoter methylation, transcript levels, and protein expression were assessed in RMS cells, PDXs, and primary tumors (n=109) from the Childrens Oncology Group. In vitro sensitivity to NAMPTi was tested in molecularly diverse and isogenic RMS cell lines, examining the role of NAPRT expression in mediating cytotoxicity and the ability of nicotinic acid (NA) to rescue viability. In vivo efficacy was assessed using NAPRT-isogenic orthotopic xenograft models. ResultsNAPRT promoter hypermethylation was found in a subset of RMS models and patient samples. Immunohistochemistry showed loss of NAPRT protein in 30-40% of tumors, defined as <1% tumor cell staining. Methylation modestly correlated with protein expression. NAPRT-silenced cells were highly sensitive to NAMPTi, driven by NAD depletion and not reversible with NA. In vivo, NAMPTi induced significant tumor regression, which was not abrogated with NA administration in NAPRT-silenced models. ConclusionsNAPRT loss occurs in a subset of RMS, offering a potential strategy to expand the therapeutic window of NAMPTi. Further research is needed to understand NAPRT regulation and optimize biomarker assay strategies for use in future clinical trials.

cancer biology↗

bioRxiv2025

Oncogenic mutations disrupt lineage differentiation via epigenetic perturbations

Understanding lineage differentiation is an ongoing challenge in the field of stem cell research. We acquired eight gain-of-function (GOF) oncogenic mutations associated with DNA methylation alteration from the TCGA datasets. After introducing each oncogene into wild-type stem cells separately, we found that the mutant stem cells are difficult to reprogram to iPSCs and terminally differentiate to induced neuronal cells, and retain proliferation capacity in the process of differentiation. This findings suggests that oncogenic mutations impair the lineage differentiation. After analyzing the resulting DNA methylation profiles, we identified many novel lineage differentiation genes in mutant cells showing DNA methylation alteration compared with wild-type cells, which is consistent with their methylation states in low-grade gliomas (LGGs) compared with control brain. Collectively, our results indicate that oncogenic mutations in stem cells are associated with DNA methylation changes for genes related to multipotency maintenance, differentiation resistance, and tumorigenesis, therefore, displaying impairment in lineage commitment.

cell biology↗

bioRxiv2025

Mapping the spatiotemporal dynamics of de novo protein synthesis during long-term memory formation

The formation of new associative long-term memory (LTM) following Pavlovian conditioning is dependent upon multiple, temporally distinct windows of mRNA translation. Current methods lack the temporal specificity to robustly characterize the dynamics of protein synthesis throughout the rodent brain following conditioning. Here we resolve these technological limitations and demonstrate that in awake mice, the retro-orbital (RO) injection of azidohomoalanine (AHA) enables the labelling and subsequent visualization of the brain de novo proteome, with labelling periods as short as 30 minutes. Combining this advancement in de novo proteomic labelling with tissue clearing, we identified brain region, cell-type, and neuronal sub-population specific changes in de novo protein synthesis in mice following an auditory threat conditioning paradigm. This approach also allowed us to track the changes in de novo protein synthesis over time, revealing that conditioning-induced changes in mRNA translation exhibit remarkable temporal specificity in brain regions such as the somatosensory cortex. Taken together, our findings highlight how this novel labelling technique can be used to map the highly intricate temporal and spatial dynamics of mRNA translation after behavioral conditioning.

neuroscience↗

bioRxiv2025

Highly sensitive chemiluminescence imaging of misfolded proteins in neurodegenerative models

Visualizing misfolded proteins would greatly facilitate early diagnosis, etiology elucidation, and therapy monitoring of neurodegeneration. Although several probes have been reported, simple and versatile detection in vivo is still challenging. We demonstrated that both generic and precise detection of misfolded proteins could be achieved with a chemiluminescence probe, ADLumin-1. For the generic aspect, ADLumin-1 was highly sensitive to various misfolded proteins, showing up to 127.73-fold higher signal-to-noise ratio than Thioflavin T. ADLumin-1 could also non-invasively visualize misfolded proteins in mouse models of Parkinsons disease, Alzheimers disease and amyotrophic lateral sclerosis. Furthermore, ADLumin-1 displayed precise detection value for -synuclein by combining with PMCA in vitro and bioorthogonal ChRET imaging technology in vivo. ADLumin-1 can selectively detect -synuclein in CSF at the femtomolar level and enables in situ monitoring of misfolded -synuclein in vivo. Combining generality and precision, our findings could be widely applied in preclinical and clinical studies of neurodegenerative diseases. TeaserA highly sensitive chemiluminescence probe enables both generic and precise detection of various misfolded proteins

biochemistry↗

bioRxiv2025

Targeting the Protein-Protein Interaction Between the CDC37 Co-Chaperone and Client Kinases by an Allosteric RAF Dimer Breaker

Braftide, originally designed as a potent allosteric RAF kinase dimer disruptor, was intended to inhibit RAF dimerization by targeting the conserved RAF dimer interface. Intriguingly, Braftide has also been observed to trigger proteasome-mediated protein degradation with an unclear mechanism of action. This study elucidates the mechanism underlying Braftides dual functionality and assesses its potential as a chemical probe to target kinase-chaperone interaction. CDC37, a selectivity co-chaperone in the HSP90 chaperone machinery, plays a crucial role in facilitating the recognition of client kinase. The RAF dimer interface overlaps with the CDC37-kinase client recognition motif, known as the C helix-{beta}4 loop. Using co-immunoprecipitation and NanoBiT assays, we confirmed Braftides ability to selectively disrupt the CDC37-client kinase interaction while sparing HSP90. Through deuterium exchange mass spectrometry, molecular dynamic simulations, and in vitro crosslinking analyses, we mapped Braftides binding region within the BRAF kinase domain, as well as the CDC37 region implicated in the association of CDC37-client kinase complex. Consequently, this disruption destabilizes RAF kinase clients, resulting in proteasomal degradation, reduced cellular proliferation, and increased apoptosis in cancer cell lines. Furthermore, Braftide exhibits synergy with HSP90 inhibitors, jointly destabilizing both the CDC37-RAF complex and HSP90. Our work demonstrates the feasibility of disrupting the CDC37-client kinase interaction as an innovative therapeutic strategy and identifies the C helix-{beta}4 loop as a novel allosteric site with significant potential for the development of next-generation therapeutics.

biochemistry↗

bioRxiv2024

Humans are resource-rational predictors in a sequence learning task

Organisms can solve complex tasks despite having limited cognitive resources when those resources are used optimally. Doing so optimally makes an organism "resource-rational". In this paper, we show for the first time that humans are resource-rational at prediction. In a novel sequence learning experiment, participants predict data generated from hidden Markov models (HMMs) and receive online feedback via clicker training. We compute the predictive rateaccuracy (PRA) curve for each HMM to solve for the highest accuracy achievable for a given cognitive capacity, or "rate", quantified as the mutual information between participants predictions and the underlying causal state of the sequence being predicted. We found that the majority of participants achieve near-optimal prediction with various cognitive capacities, despite performing well below the maximum predictive accuracy on the task overall. We also show that this information-theoretic approach to measuring cognitive capacity can be grounded in the established psychological science concept of working memory: participants who extracted higher quantities of mutual information in the sequence learning task showed significantly higher working memory in a complex digit span test. This research provides new avenues for assessing smart behavior in difficult prediction tasks, provides a new methodology for assessing resource-rationality, and provides evidence that humans are resource-rational predictors.

animal behavior and cognition↗

bioRxiv2024

Integrated Transcriptome and Metabolome Analyses Reveal the Mechanism Regulating Bulbil Initiation and Development in Cystopteris chinensis

Cystopteris chinensis is an endangered fern endemic to China, which only has a small wild population due to its poor reproductive ability. However, we recently found that it can produce bulbils on its pinnule to generate new plants but the molecular mechanism underlying this unique phenomenon remained unknown. In this study, we have identified four distinct stages in the initiation and development of bulbils based on morphological and anatomical observation. We performed transcriptome and metabolome analyses on the collected samples at each stage. Through KEGG enrichment analysis, it was found that the phytohormone signal transduction, starch and sucrose metabolism, phenylpropanoid biosynthesis, and flavonoid biosynthesis pathways play a significant role in regulating bulbil initiation and development. Specifically, the involvement of three phytohormones and sugar substances was identified in the process of bulbil initiation. Our study provides the first detailed observation of the bulbils in C. chinensis and explains their initiation and development at the molecular level. However, more in-depth studies are needed to discover the functions of key genes controlling the formation of bulbils to conserve the endangered C. chinensis population.

plant biology↗