Biology subjects

Du, Y.

Publications and source records attributed to Du, Y..

At least 109 records · Page 6Linked to original sources

bioRxiv2025

MLL1 complex is a critical regulator of fetal hemoglobin repression

Increasing fetal-type hemoglobin (HbF) expression in adult erythroid cells holds promise in the treatment of sickle cell disease (SCD) and {beta}-thalassemia. We have identified MLL1 complex as a critical regulator of fetal and embryonic hemoglobin repression. Knockdowns of MEN1 and KMT2A, encoding essential components of the complex, caused a significant downregulation of BCL11A expression and a substantial increase in {gamma}- and {varepsilon}-globin mRNA levels in HUDEP-2 cells. Significant binding of MEN1 and KMT2A were readily detected at the promoter and a critical enhancer of BCL11A in HUDEP-2 cells, suggesting that BCL11A is a direct transcriptional target of MLL1 complex. Consistent with these results, MEN1 or KMT2A knockdown in normal human CD34+ hematopoietic stem and progenitor cells (HSPCs) induced to undergo erythroid differentiation also significantly decreased their BCL11A expression and increased their {gamma}- and {varepsilon}-globin expression and the production of F cells in the culture. Treatment of these cells with MENIN inhibitors yielded similar results and promoted erythroid differentiation with minimal effects on their growth. These findings underscore a critical role of MLL1 complex in regulating fetal and embryonic hemoglobin expression and suggest that MENIN inhibitors could offer a promising therapeutic approach for sickle cell disease and {beta}-thalassemia.

developmental biology↗

bioRxiv2025

A rapid arousal brake on hunger neurons and its release in narcolepsy

The brain must constantly integrate internal needs with external cues, requiring it to evaluate potential rewards and prioritize urgent environmental demands. How arousal systems control hunger to achieve this is a fundamental question. We targeted the functional connection from arousal hypocretin/orexin neurons (HONs) to hunger (AGRP) neurons and discovered that it operates through a local GABAergic relay, revealing a circuit for rapid, arousal-driven hunger suppression. We found this suppression deployed in several critical functions. In appetitive evaluation, it controls food value perception by suppressing AGRP based on a foods predicted caloric worth. In adaptive vigilance, it creates an opportunity to prioritize other needs, such as responding to novel, arousing stimuli. During spontaneous pupil dilations, it creates hunger-free windows for optimal assessment of the environment. These findings reveal a fundamental inhibitory circuit that allows pupil-linked arousal to dynamically gate hunger on a moment-to-moment basis, providing a new framework for how the brain balances competing internal and external demands.

neuroscience↗

bioRxiv2025

Retinol Binding Protein 4 reactivates latent HIV-1 via the JAK/STAT5 and JNK pathways

Reactivation of the latent viral reservoirs is crucial for a cure of HIV/AIDS. However, current latency reversing agents are inefficient and the endogenous factors that have the potential to reactivate HIV in vivo remain poorly understood. To identify natural activators of latent HIV-1, we screened a comprehensive peptide/protein library derived from human hemofiltrate, representing the entire blood peptidome, using J-Lat cell lines harboring transcriptionally silent HIV-1 GFP reporter viruses. Fractions potently reactivating HIV-1 from latency contained human Retinol Binding Protein 4 (RBP4), the carrier of retinol (vitamin A). We found that retinol-bound holo-RBP4 but not retinol-free apo-RBP4 strongly reactivates HIV-1 in a variety of latently infected T cell lines. Functional analysis revealed that this reactivation depends on the JAK/STAT5 and JNK pathways but does not require retinoic acid production. High levels of RBP4 were detected in plasma from both healthy individuals and people living with HIV-1. Physiological concentrations of RBP4 induced significant viral reactivation in latently infected cells from individuals on long-term antiretroviral therapy with undetectable viral loads. As a potent natural HIV-1 latency-reversing agent, RBP4 offers a novel approach to activating the latent reservoirs and bringing us closer to a cure.

immunology↗

bioRxiv2025

Eye blinks synchronize with musical beats during music listening

Auditory-motor synchronization, the alignment of body movements with rhythmic patterns in music, is a universal human behavior, yet its full scope remains incompletely understood. Through four experiments with 123 young non-musicians, integrating eye-tracking, neurophysiological recordings, white matter structural imaging, and behavioral analysis, we reveal a previously unrecognized form of synchronization: spontaneous eye blinks synchronize with musical beats. Blinks robustly synchronized with beats across a range of tempi and independently of melodic cues. EEG recordings revealed a dynamic correspondence between blink timing and neural beat tracking. Individual differences in blink synchronization were linked to white matter microstructure variation in the left arcuate fasciculus, a key sensorimotor pathway. Additionally, the strength of blink synchronization reflected the modulation of dynamic auditory attention. These findings establish blink synchronization as a novel behavioral paradigm, expanding the auditory-motor synchronization repertoire and highlighting the intricate interplay between music rhythms and oculomotor activity. This discovery underscores a cross-modal active sensing mechanism, offering new insights into embodied music perception, rhythm processing, and their potential clinical applications.

neuroscience↗

bioRxiv2025

KYLO-0603, a novel liver-targeting, thyroid hormone recep-tor-β agonist for the treatment of MASH

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. Kylo-0603 is a novel agonist for the thyroid hormone receptor {beta} (THR-{beta}) that has been developed by merging the structures of three acetylgalactosamine (GalNAc)-modified ASPGR ligands with a triiodothyronine (T3) analog. This unique design allows for both THR-{beta} activation and targeted delivery to hepatocytes, significantly reducing the risk of adversed effects related to increased systemic thyroid hormone-like effects. Additionally, it effectively lowers serum cholesterol by as much as 69.2% and low-density lipoprotein cholesterol (LDL-C) levels by up to 88.2% in the MASH mouse model. Meanwhile, Kylo-0603 was shown to reduce steatosis by up to 1.3 points (P < 0.001), inflammation by 1.8 points (P < 0.0001), and ballooning by 0.8 points (P < 0.01). The non-alcoholic steatohepatitis (NASH) activity score (NAS) decreased by up to 3.7 points (P < 0.0001), and the fibrosis score dropped by 0.6 points (P < 0.05). These findings suggest that Kylo-0603 is effective in enhancing liver tissue NASH status and inhibiting fibrosis progression. In summary, Kylo-0603, as a highly both tissue and target selective and low-toxicity THR-{beta} agonist, shows significant promise for treating MASH and is likely to emerge as a new therapeutic option for patients with this condition.

biochemistry↗

bioRxiv2025

Information Shielding Through Neural Deactivation: A Fundamental Mechanism of Human Information Processing

Information processing is a core issue in cognitive neuroscience. The brain can either accept or shield information. However, information shielding has traditionally been regarded as a byproduct of other cognitive processes that prepare brain areas for activation, with the accompanying brain deactivation seen as merely supportive. Here, we offer an alternative perspective, demonstrating that people can directly perform information shielding without engaging other cognitive processes. Using information shielding as a novel investigative lens, we provide direct evidence that deactivation serves as a primary mechanism in its own right. We found that information shielding was characterized by a deactivation-dominant neural dynamic, with initial executive control region activation giving way to increased sensory region deactivation, especially after a 3-second boundary. Neural decoding results further confirmed this deactivation trend. This deactivation pattern was consistent across both auditory and visual modalities. Furthermore, non-invasive brain stimulation demonstrated a causal relationship between the deactivation pattern and information shielding, and we found that this deactivation mechanism extended to general unnecessary information processing, regardless of whether the necessity was determined objectively or subjectively. This challenges the conventional emphasis on activation as the primary mode of information processing and opens new fundamental avenues for understanding inhibitory cognitive processes.

neuroscience↗

bioRxiv2025

Inhibition of cytosolic translation mitigates mitochondrial dysfunction in C. elegans

The mitochondrial unfolded protein response (UPRmt), which promotes mitochondrial proteostasis and biogenesis is regulated by the transcription factor ATFS-1. In C. elegans, impaired atfs-1 expression perturbs mitochondrial function and slows development. Here, via an RNAi suppressor screen, we found that inhibition of the nuclear hormone receptor NHR-180 increases mitochondrial function and the rate of development in atfs-1(null) worms. NHR-180 is activated during mitochondrial dysfunction and induces transcription of genes required for protein synthesis on cytosolic and mitochondrial ribosomes. Importantly, the NHR-180 ligand binding domain interacts with AMP, which results in increased protein synthesis potentially to promote mitochondrial biogenesis and recovery from transient mitochondrial perturbations. However, NHR-180 exacerbates the mitochondrial dysfunction caused by mutations in genes required for oxidative phosphorylation. Consistent with these findings, we found that inhibition of the S6 kinase homolog RSKS-1 also increased mitochondrial function in atfs-1(null) worms. Importantly, treatment with an S6 kinase inhibitor also increased respiration and mtDNA content in mammalian ATF5-knockout cells and OXPHOS-deficient models, suggesting that translation regulation is a conserved, targetable approach for restoring mitochondrial function in disease.

developmental biology↗

bioRxiv2025

Extreme high-diversity barcoded HIV library enables single cell multi-omics analysis of viral expression and fate determination

HIV-1 persists as a global health challenge due to its ability to establish latent reservoirs that evade eradication by antiretroviral therapy (ART). This study introduces a high-diversity barcoded HIV-1 library combined with a novel peptide barcode system to enable single-cell multi-dimensional analysis of viral integration, transcription, splicing, and translation of distinct viral mRNA isoform. Our method revealed over 80 distinct HIV-1 splicing isoforms and uncovered significant temporal variation in mRNA diversity, driven by integration site and chromatin context. By linking HIV-1 5UTR with peptide barcoding, we quantified the translation efficiency of alternative 5' UTRs and demonstrated correlations with abundance of each viral mRNA isoform. Additionally, we showed that latency reversal agents, such as SAHA and Bryostatin, selectively reactivate proviruses depending on their genomic and chromatin context and leads to distinct viral RNA splicing program. This platform revealed the diversity of HIV-infected cells at levels of transcripts as well as at proteins, and subsequently the fate determination. The detailed understanding of the stochastic diversity and dynamic nature of HIV-1 latency, inform the development of targeted therapies to eliminate latent reservoirs.

microbiology↗

bioRxiv2024

Development of a novel peripherally acting alpha2A-adrenergic receptor antagonist for anti-diabetic

Yohimbine, a potent alpha2A-adrenergic receptor (2AAR) antagonist, was found therapeutic potential for type 2 diabetes through improving insulin release. However, the adverse side effects mediated by its actions in the brain hampered its use. Here, based on molecular docking analysis and structural modification, we have developed a novel peripherally acting yohimbine derivative (CDS479-2). CryoEM data found that yohimbine and CDS479-2 have similar interactions with the structure of 2AAR. Importantly, CDS479-2 shows similar 2AAR antagonist activity as yohimbine, but with very limited access to the brain, and thus avoiding the unwanted central effects such as hypertension and anxiety. Acute administration of CDS479-2 by injection or gavage lowered blood glucose levels and improved glucose tolerance in the high-fat diet-induced obesity (DIO) mice, an animal model for human type 2 diabetes. Remarkably, DIO mice received 2 weeks of daily administration of CDS479-2, but not yohimbine, exhibited sustained normoglycaemia, and increased density of the insulin-producing beta cells, in which important proliferation genes were found upregulated. Moreover, the overall protein expression levels of their pancreas were more similar to that of the healthy chow-fed mice. Thus, CDS479-2 may indicate a new direction for type 2 diabetes treatment. Importantly, the strategy we employed in this study will inspire the optimization for drugs that with both peripheral and central targets. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/628818v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1d3d7corg.highwire.dtl.DTLVardef@1afbad3org.highwire.dtl.DTLVardef@12a1aborg.highwire.dtl.DTLVardef@1341a02_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Evidence for white matter intrinsic connectivity networks at rest and during a task: a large-scale study and templates

Understanding white matter (WM) functional connectivity is crucial for unraveling brain function and dysfunction. In this study, we present a novel WM intrinsic connectivity network (ICN) template derived from over 100,000 fMRI scans, identifying 97 robust WM ICNs using spatially constrained independent component analysis (scICA). This WM template, combined with a previously identified gray matter (GM) ICN template from the same dataset, was applied to analyze a resting-state fMRI (rs-fMRI) dataset from the Bipolar-Schizophrenia Network on Intermediate Phenotypes 2 (BSNIP2; 590 subjects) and a task-based fMRI dataset from the MIND Clinical Imaging Consortium (MCIC; 75 subjects). Our analysis highlights distinct spatial maps for WM and GM ICNs, with WM ICNs showing higher frequency profiles. Modular structure within WM ICNs and interactions between WM and GM modules were identified. Task-based fMRI revealed event-related BOLD signals in WM ICNs, particularly within the corticospinal tract, lateralized to finger movement. Notable differences in static functional network connectivity (sFNC) matrices were observed between controls (HC) and schizophrenia (SZ) subjects in both WM and GM networks. This open-source WM NeuroMark template and automated pipeline offer a powerful tool for advancing WM connectivity research across diverse datasets.

neuroscience↗

bioRxiv2024

Spatially-resolved molecular sex differences at single cell resolution in the adult human hypothalamus

The hypothalamus contains multiple regions, including the ventromedial hypothalamus (VMH) and arcuate (ARC), which are responsible for sex-differentiated functions such as endocrine signaling, metabolism, and reproductive behaviors. While molecular, anatomic, and sex-differentiated features of rodent hypothalamus are well-established, much less is known about these regions in humans. Here we provide a spatially-resolved single cell atlas of sex-differentially expressed (sex-DE) genes in human VMH and ARC. We identify neuronal populations governing hypothalamus-specific functions, define their spatial distributions, and show increased retinoid pathway gene expression compared to rodents. Within VMH and ARC, we find correlated autosomal expression differences localized to ESR1/TAC3-expressing and CRHR2-expressing neurons, and extensive sex-DE of genes linked to sex-biased disorders including autism, depression, and schizophrenia. Our molecular mapping of disease associations to hypothalamic cell types with established roles in sex-divergent physiology and behavior provides insights into mechanistic bases of sex bias in neurodevelopmental and neuropsychiatric disorders.

genomics↗

bioRxiv2024

Soybean Cyst Nematode-Resistant Protein AATRhg1 Affects Amino Acid Homeostasis and Betalain Accumulation

Amino acid transporters play crucial roles in plant nitrogen metabolism but also defense responses. AATRhg1, an apparent amino acid transporter encoded by Glyma.18g022400 (Rhg1-GmAAT) at the soybean Rhg1 locus, contributes to resistance to soybean cyst nematode (SCN), although the in planta function of AATRhg1 remains elusive. In this study we discovered that overexpression of Rhg1-GmAAT in soybean roots enhances the betalain pigment synthesis driven by a RUBY transgene cassette, potentially through its transporter activity affecting tyrosine level and amino acid homeostasis. Silencing Rhg1-GmAAT also moderately increased betalain accumulation while co-overexpression of Rhg1-GmAAT and GmRBOHG (encoding an AATRhg1-interacting NADPH oxidase) blocked the betalain phenotype, indicating a complex role of AATRhg1 in regulating cellular metabolism. Soybean AATRhg1 did not show a betalain accumulation phenotype when co-overexpressed with RUBY in Nicotiana benthamiana leaves, suggesting that soybean AATRhg1 functions differently in N. benthamiana. In soybean, the expression of AATRhg1 proteins mutated at conserved residues D122A or Y268L mitigated or enhanced the betalain phenotypes, respectively, suggesting that these residues are important for AATRhg1 function. This study advances our understanding of AATRhg1 while presenting a novel strategy for enhancing betalain biosynthesis by modulating transport and homeostasis of amino acids.

plant biology↗

bioRxiv2024

Feature similarity: a sensitive method to capture the functional interaction of brain regions and networks to support flexible behavior

The brain is a dynamic system where complex behaviours emerge from interactions across distributed regions. Accurately linking brain function to cognition requires tools that are sensitive to these dynamics. We introduce a novel technique, Feature Similarity (FS), which represents a conceptual advancement in measuring brain region interactions by integrating multiple features across various measures, moving beyond traditional methods that focus on a single measure. Our results show that FS can capture functional brain organisation: regions within the same functional network have greater FS compared to those in different networks, and FS also identifies the principal gradient that spans from unimodal to transmodal cortices. FS demonstrated greater sensitivity to task modulation than traditional functional connectivity (FC) and 46 out of 49 statistical measures of pairwise interactions (SPIs). Specifically, FS reveals interaction patterns missed by FC and most SPIs, such as a double dissociation in Dorsal Attention Network: greater interaction with Visual network during working memory tasks and greater interaction with default mode network during long-term memory tasks. These findings position FS as a powerful tool for capturing task-specific brain network dynamics and advancing our understanding of cognitive flexibility. Using FS to reanalyse existing fMRI data could resolve inconsistencies, lead to novel insights, and prompt revisions of existing theories or the development of new theoretical frameworks.

neuroscience↗

bioRxiv2024

Reversal of vein of Galen aneurysmal malformation by stimulation of flow-mediated vessel fusion

Congenital vascular malformations arise from defective homeostatic development of the vascular tree1. The aneurysmal malformation of the Vein of Galen (VGAM) is the most frequent neurovascular malformation in neonates, with limited therapeutic options and poor outcomes in the most severe cases2. This congenital disease is consecutive to germline genetic mutation of RASA1 or EPHB43,4, but little is known about the mechanisms leading to its development. We generated mutant rasa1a and ephb4a deficiency models in zebrafish reproducing the genetic and structural characteristics of the VGAM in the dorsal longitudinal vein of the cerebral vasculature. We link the development of the malformation to a failure of the fusion of precursor blood vessels into a draining vessel for the choroidal type malformations and to a failure to constrict for the mural type malformations. The fusion process is driven by blood flow, sensed and integrated by endothelial cells. RASA1 deficiency destabilizes the homeostatic response to blood flow and contributes to impaired flow-mediated activation of MAPK and PI3K signaling. We targeted these defective mechanotransduction mechanisms pharmacologically in both rasa1a and ephb4a mutant models, successfully reestablishing the fusion and constriction processes in preexisting malformations. This work identifies molecular actors of the flow-mediated blood vessel fusion mechanism, a specific angiogenetic program, and provides ground for treating VGAM and other vascular remodeling disorders.

developmental biology↗

bioRxiv2024

Separate timescales for spatial and anatomical information processing during action observation

Observing different body stimuli can influence the speed and accuracy of our responses. Prior work indicates this effect is influenced by factors such as spatial congruence and perspective. We hypothesized that the influence of these factors would vary depending on the amount of time that participants had to process visual stimuli. Experiment 1 was a reaction time task (n=29) with stimuli varying in spatial congruence (congruent, incongruent, neutral), perspective (first- or third-person) and stimulus type (body or control). Experiment 2 (n=50) used the same stimuli in a "Forced Response" paradigm, which controlled the time participants had to prepare a response. This allowed us to assess responses as a function of preparation time. Experiment 1 showed effects of spatial congruence, with longer reaction times and more errors for spatially incongruent stimuli. This effect was greater for body stimuli. Experiment 2 showed that spatial information was processed faster than anatomical information, inducing incorrect responses at short preparation times for spatially incongruent body stimuli. There was little-to-no corresponding effect for control stimuli. Both experiments also showed weak-to-no effects of perspective, which appear to have been driven by spatial congruence. Our results indicate that spatial information is processed faster than anatomical information during observation of body stimuli. These data are consistent with the dual visual streams hypothesis, whereby spatial information would be processed rapidly via the dorsal stream, while anatomical processing would occur later via the ventral stream. These data also indicate differences in processing between body and control stimuli. Public significance statementsThis study provides novel insight into the time-course of information processing, showing that spatial information is processed faster than anatomical information for body stimuli. The results also challenge the established view that visual perspective is critical to process body stimuli, demonstrating that this may instead result from lower-level effects of spatial congruence.

neuroscience↗

bioRxiv2024

Mechanistic Insights into the Stimulation of the Histone H3K9 Methyltransferase Clr4 by Proximal H3K14 Ubiquitination

H3K9 methylation is an evolutionarily conserved hallmark of heterochromatin and plays crucial roles in chromosome segregation, genome stability, and gene expression regulation. Clr4 is the sole histone methyltransferase responsible for catalyzing H3K9 methylation in Schizosaccharomyces pombe. Clr4 K455/K472 automethylation and histone H3K14 ubiquitination (H3K14Ub) are vital activators of the catalytic activity of Clr4, ensuring appropriate heterochromatin deposition and preventing deleterious gene silencing. While the mechanism by which automethylation activates Clr4 was recently elucidated, the mechanism of the significantly pronounced stimulatory effect of H3K14Ub on Clr4 remains unclear. Here we determined the crystal structures of Clr4 bound to ubiquitinated and unmodified H3 peptides at resolutions of 2.60 [A] and 2.39 [A], respectively. Our structures reveal a synergistic mechanism underlying the stronger stimulatory effect by H3K14Ub compared to automethylation: site-specific ubiquitination constrained by the H3K14 linkage increases substrate affinity through multivalent interactions between ubiquitin and Clr4. Additionally, H3K14Ub facilitates the allosteric transition of Clr4 from an inactive apo conformation to a hyperactive "catalyzing state", accompanied by conformational changes in the C-SET-insertion (SI) region, complete release of the autoregulatory loop (ARL), and retraction of the {beta}9/10 loop. Finally, we propose a structural model for the Clr4 catalytic-regulatory cycle, depicting varying levels of conformational regulation mediated by automethylation and ubiquitination. This work provides structural insights into the interplay between different histone modifications and their collective impact on epigenetic regulation.

molecular biology↗

bioRxiv2024

Listening to music modulates visual perception of paintings during binocular rivalry

Music, as a hierarchically organized art form, profoundly influences perception and mood through its rich information and intense emotion. While previous research has demonstrated that music can shape visual perception, its influences on visual awareness in aesthetic scenes remain largely unclear. In a series of five experiments involving 138 participants, we used the binocular rivalry paradigm to investigate how sad or lively Chinese folk music influences the perception of traditional Chinese paintings with varying aesthetic emotion (bleak vs. vivid). Paintings were presented in upright or inverted orientations or replaced by patches. Results revealed that sad music significantly increased both the average dominance duration and the predominance score of bleak paintings. Conversely, lively music with a faster tempo accelerated the switch rate of both paintings and patches. These effects were interdependent, exclusively for meaningful (upright) paintings, and correlated with individual sensitivity to musical reward. Our findings support the hierarchical predictive coding model of binocular rivalry, demonstrating that musical aesthetic emotion exerts top-down modulation, while musical tempo provides bottom-up entrainment, jointly shaping visual awareness of paintings.

systems biology↗

bioRxiv2024

High-coverage, massively parallel sequencing of single-cell genomes with CAP-seq

Microbial communities are extraordinarily diverse and play crucial roles in health and disease, yet current methods lack the resolution and scalability needed to dissect their genomic and ecological complexity at the single-cell level. Here, we present CAP-seq, a high-throughput single-microbe genomics platform that combines hydrogel-based semi-permeable encapsulation with minimal microfluidics to recover thousands of single-amplified genomes (SAGs) with long reads and high completeness at low sequencing depth. We benchmarked CAP-seq using defined microbial communities, demonstrating strain-level resolution, accurate detection of rare taxa, and genome recovery exceeding 50% at [~]10x coverage. Applying CAP-seq to pediatric Clostridioides difficile infection microbiomes, we generated a high-resolution single-cell atlas comprising tens of thousands of SAGs across hundreds of species. Host-resolved profiling of the cryptic plasmid pBI143 revealed previously hidden low-abundance host associations, six new plasmid versions, and their coexistence within individuals, indicating complex plasmid evolution in situ. Longitudinal analysis during fecal microbiota transplantation and vancomycin treatment uncovered dynamic remodeling of microbial hosts, antimicrobial resistance genes, and plasmids at single-cell resolution. CAP-seq enables scalable, high-performance single-cell genomics and provides a practical, widely accessible platform for microbiome analysis, paving the way for large-scale exploration of microbial dark matter and host-microbe interactions across diverse ecosystems.

genomics↗