Biology subjects

Song, H.

Publications and source records attributed to Song, H..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

Geometry of neural dynamics along the cortical attractor landscape reflects changes in attention

The brain is a complex dynamical system whose activity reflects changes in internal states, such as attention. While prior work has shown that large-scale brain activity reflects attention, the mechanism governing this association in a time-varying and task-dependent manner remains unknown. Here, we tested a hypothesis that the geometry of neural dynamics on the attractor landscape, or the movement along the "hills and valleys", reflects changes in attentional states over time and variations across controlled and naturalistic contexts. We fit a parametric dynamical systems model to fMRI data collected during rest, task performance, and naturalistic movie-watching. The model decomposes neural dynamics into components that are intrinsic versus extrinsically driven by stimuli. Model parameters were biologically meaningful, reflecting both cognitive states and individual differences. Model simulations revealed a set of attractors that mirrored functional brain networks, spanning the canonical gradient from sensorimotor to default mode network regions. The speed and direction of neural trajectories toward these attractors systematically varied across attentional states in a context-dependent manner. When participants were paying attention to effortful tasks, neural dynamics converged directly toward a task-relevant attractor, suggesting that it occupied a steeper region of the attractor landscape. In contrast, when participants were engaged in sitcom episodes, neural dynamics were in a flattened region of the landscape, directed away from the attractors. These findings demonstrate that while the positions of the attractors are largely determined by the cortical organization, the geometry of neural dynamics on the attractor landscape changes systematically across attentional states and situational contexts.

neuroscience↗

bioRxiv2025

Tumor necrosis factor receptor 2 inhibits HIV-1 infection by blocking the binding of gp120 to CD4

The HIV-1 envelope glycoprotein gp120 binds to CD4 molecule and then undergoes conformational changes to interact with the co-receptors CCR5 or CXCR4, resulting in cellular entrance. However, certain types of cells, such as macrophages and CD4+Foxp3+ regulatory T cells (Tregs), have shown to resist HIV-1 infection despite co-expressing CD4 and co-receptors. In this study, we found that TNF receptor type II (TNFR2) directly bound to gp120, with the binding site on gp120 in close proximity to that of CD4. Intriguingly, exogenous TNFR2 had the capacity to inhibit the binding of gp120 to CD4 T cells. Furthermore, the infection of CD4+CCR5+ cells by pseudoviruses containing the HIV-1 envelope was inhibited by TNFR2 protein. In contrast, TNFR1, similar in structure to TNFR2 and sharing the same ligand, failed to inhibit the infection of CD4+ T cells by HIV-1 pseudoviruses. This property of TNFR2 may be harnessed in the prevention or treatment of HIV-1 infection and thus warrant future investigation. SUMMARYThis study reveals that TNFR2 directly binds to HIV-1 gp120, inhibiting its interaction with CD4 and reducing HIV-1 infection in CD4+ T cells. The findings highlight TNFR2s potential role in protecting cells and offer insights for HIV-1 prevention or therapy.

immunology↗

bioRxiv2025

Interwoven DNA-MOF crystals for multi-millennial data storage

DNA has emerged as a promising medium for high-density and energy-efficient data storage, providing a promising solution to capacity constraints and energy demands resulting from the exponential growth of data. Long-term stable storage of DNA data in ambient conditions is a critical requirement for its practical application. Whereas strategies have been proposed to protect DNA from environmental degradation, they are often at the expense of data storage density. Here, we propose a strategy via interweaving metal-organic framework (MOF) and DNA to synthesize DNA-MOF crystal (DNA-MOF), a high-density and long-lifespan DNA-based information material. The uniform distribution of DNA molecules within the crystalline frameworks enables a high loading capacity of up to 30 wt%, corresponding to a theoretical information density of 106.6 exabytes/g. The crystal structure of MOF-DNA demonstrates efficient resistance to environmental damage such as heat, ultraviolet radiation, DNase, etc., achieving an estimated archival half-life over 24,000 years at 9.4 {degrees}C. The interwoven DNA-MOF crystals establish a material foundation for the reliable operation of DNA storage systems in open-field deployment and provide a new pathway toward sustainable long-term management of massive data.

biochemistry↗

bioRxiv2025

Population-specific brain charts reveal Chinese-Western differences in neurodevelopmental trajectories

Human brain charts provide unprecedented opportunities for decoding neurodevelopmental milestones and establishing clinical benchmarks for precision brain medicine 1-7. However, current lifespan brain charts are primarily derived from European and North American cohorts, with Asian populations severely underrepresented. Here, we present the first population-specific brain charts for China, developed through the Chinese Lifespan Brain Mapping Consortium (Phase I) using neuroimaging data from 43,037 participants (aged 0-100 years) across 384 sites nationwide. We establish the lifespan normative trajectories for 296 structural brain phenotypes, encompassing global, subcortical, and cortical measures. Cross-population comparisons with Western brain charts (based on data from 56,339 participants aged 0-100 years) reveal distinct neurodevelopmental patterns in the Chinese population, including prolonged cortical and subcortical maturation, accelerated cerebellar growth, and earlier development of sensorimotor regions relative to paralimbic regions. Crucially, these Chinese-specific charts outperform Western-derived models in predicting healthy brain phenotypes and detecting pathological deviations in Chinese clinical cohorts. These findings highlight the urgent need for diverse, population-representative brain charts to advance equitable precision neuroscience and improve clinical validity across populations.

neuroscience↗

bioRxiv2025

Single oocyte full-length isoform sequencing unveils the impact of transposable elements on RNA diversity and stability during oocyte maturation

The oocyte-specific isoforms play crucial roles in oocyte maturation, while current understanding of the oocyte transcriptome is mainly focused on gene level. Here, we utilized single cell full-length isoform sequencing based on third generation sequencing to detect entire transcripts in human and mouse oocytes. Isoform diversity during oocyte maturation was systematically profiled, including 6,736 and 4,902 putative novel human and mouse transcripts, respectively. More than half of novel isoforms were categorized as the novel-not-in-catalog (NNC) and may serve specific functions in oocytes, including novel isoforms of ARHGAP18, colocalized with microtubules and targeted knockdown disrupting oocyte maturation. Moreover, over 25% of NNC isoforms were derived from transposable elements (TEs), and their incorporation within transcripts could enhance isoform stability during oocyte maturation. Altogether, our findings represent a valuable resource showcasing the complexity and diversity of RNA isoforms in oocytes, as well as TE co-option for novel isoform generation and isoform stability enhancement.

developmental biology↗

bioRxiv2025

DNA Methylation Dynamics of Dose-dependent Acute Exercise, Training Adaptation, and Detraining

Exercise and diet are direct physical contributors to human health, wellness, resilience, and performance1-5. Endurance and resistance training are known to improve healthspan through various biological processes such as mitochondrial function6-8, telomere maintenance9, and inflammaging10. Although several training prescriptions have been defined with specific merits 1,10-20, the long-term effects of these in terms of their molecular alterations have not yet been well explored. In this study, we focus on two combined endurance and resistance training programs: (1) traditional moderate-intensity continuous endurance and resistance exercise (TRAD) and (2) a variation of high-intensity interval training (HIIT) we refer to as high intensity tactical training (HITT), to assess the dynamics of DNA methylation (DNAm) in blood and muscle derived from males (N=23) and females (N=31), over a 12-week period of training followed by a 4-week period of detraining, sampled at pre-exercise and acute time points, totaling 528 samples. Due to its rapid responsiveness to stimuli and its stability, DNAm has been known to facilitate regulatory cascades that significantly affect various physiological processes and pathways. We find that several thousand differentially methylated regions (DMRs) associated with acute exercise in blood, many of which are shared across males and females. This trend is reversed when comparing the baseline (pre-exercise) time points or post-exercise timepoints at the untrained state with those at the post-conditioned state. Here, muscle shows majority of DNAm changes, with most of those being unique. We also find several hundred "memory" DMRs in muscle that maintain the gain or loss of methylation after four weeks of inactivity. Comparing phenotypic measurements, we find specific DMRs that correlate significantly with mitochondrial function and myofiber switching. Using machine learning, we select a subset of DMRs that are most characteristic of training modalities, sex and timepoint. Most of the DMRs are enriched in pathways associated with immune function, cell differentiation, and exercise adaptation. These findings reveal mechanisms by which exercise- and training-induced epigenetic changes alter immune surveillance, mitochondrial function, and inflammatory response, and underscore the relevance of epigenetic plasticity to health monitoring and wellness.

genomics↗

bioRxiv2025

A biGWAS strategy reveals the genetic architecture of the interaction between wheat and Blumeria graminis f. sp. tritici

BackgroundWheat powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt) is one of the most significant diseases affecting global wheat production. Breeding for disease resistance (R) genes against Bgt often follows a boom-bust cycles, where cultivars with effective resistance are widely deployed on an expanding area until virulence emerges in the avirulence (Avr) pathogen population. While extensive effort has been devoted to identifying and cloning R genes, Avr genes remain relatively understudied, limiting our understanding of R-Avr interactions. That said, understanding R-Avr interactions is crucial for developing durable resistance strategies. ResultsWe conducted whole genome sequencing on 245 Bgt isolates collected from major wheat-growing regions in China, identifying 120 genetically unique isolates. Each of these unique isolates was inoculated and phenotyped on a diverse panel of wheat germplasm. Through Genome-Wide Association Analysis (GWAS) in both Bgt and wheat, we identified 65 Avr loci and 251 R loci overlapping with nine and eight cloned Avr or R genes, respectively. On average, each isolate carries eight Avr alleles, ranging from one to 17. Little geographical preference for Avr alleles or their combinations was observed, suggesting that disease resistance breeding against this pathogen should be coordinated at the national level. The level of resistance level is positively correlated with the number of R alleles carried by a wheat line, and the average frequency of an R allele is 2% among the wheat panel, indicating the potential for accumulating R alleles in breeding programs. We mapped 212 R-Avr interactions based on joint GWAS using both plant and pathogen genomes and cross-species epistasis, where a network of interactions was formed between wheat and Bgt. These interactions indicate that pyramiding five major R loci has the potential to confer resistance to half of the Avr loci. As a proof of concept, we successfully verified two previously described R-Avr pairs using tobacco experiments. Furthermore, we provided molecular validation evidence for three new Avr genes, including Bgt-50651, BgtE-5826 and BgtE-20009, and two new R-Avr interactions. Among them, Bgt-50651 interacts with Pm1a, Pm2a, and another unidentified R gene located near the Pm6/Pm52 interval. ConclusionOur study provides a framework for understanding the genetic interaction between plants and pathogens. The discovery of novel R/Avr loci and their complex interaction network underscores the need to integrate crop and pathogen genetic background, particularly the R/Avr allele composition, into breeding program design. These findings have significant implications for developing durable resistance strategies in wheat alongside offering valuable insights into the broader dynamics of plant-pathogen interactions.

genomics↗

bioRxiv2025

Cerebellin-2 positive (Cbln2+) Neurons in the Parafascicular Thalamic Nucleus Regulate Self-Grooming Behavior

Self-grooming represents a stereotyped repetitive behavior which is commonly observed in various neuropsychiatric disorders. Deep brain stimulation (DBS) targeting the centromedian / parafascicular complex (CM/PF) has been shown to alleviate obsessive-compulsive disorder/behavior (OCD/OCB) symptoms in human. However, little is known about the neural circuits of the PF that are involved in the regulation of self-grooming behavior in rodents. Here, we report that cerebellin-2 positive (Cbln2+) neurons in PF bidirectionally encode self-grooming. Chemogenetic activation of Cbln2+ PF neurons significantly reduces both physiological and pathological self-grooming, and chemogenetic inhibition of Cbln2+ PF neurons increases physiological self-grooming. Moreover, activating synaptic excitatory inputs to Cbln2+ PF neurons inhibits self-grooming, while synaptic inhibitory inputs enhance it. Cbln2+ PF neurons independently transmit neural signals to the dorsal and ventral striatum. Activation of PF-dorsal striatum and PF-ventral striatum pathways both inhibit self-grooming behavior. Most excitingly, we alleviate excessive grooming in OCD mice by the activation of PF neurons using non-invasive ultrasound stimulation. Together, these data reveal that Cbln2+ PF neurons are integral components of a brain network involved in self-grooming behavior and highly promising targets in the non-invasive therapy of OCD.

neuroscience↗

bioRxiv2025

A fatigue-resistant myoneural actuator for implantable biohybrid systems

Implantable biohybrid systems with computer-controlled actuation offer the capacity to modulate biological forces, but require biocompatible, self-sustaining, and scalable actuators. Repurposing biological muscles can fulfill this need. However, muscle fatigue limits the fundamental capabilities of muscle-actuated systems. Here we present a fatigue-resistant myoneural actuator (MNA) with engineered recruitment biophysics in a rodent model. The MNA is based on manipulating native axonal composition through sensory reinnervation. This regenerative approach redirects volitional control to computer control via nerve stimulation while maintaining self-sustainability. Compared to native muscles without the myoneural manipulation, fatigue resistance is augmented by 260%. Furthermore, we demonstrate closed-loop control with reversible neural isolation of the actuator, preventing unintended neural signaling to the central nervous system during operation. To illustrate the potential of the MNA technology, we present a biohybrid neuroprosthetic interface and a biohybrid organ system capable of modulating neural afferents and organ mechanics, respectively. Our framework demonstrates augmented biological muscle actuation while maintaining inherent tissue properties, bridging the technological gap for implantable biohybrid systems.

bioengineering↗

bioRxiv2025

Proteomic Analysis of PTEN-Deficient Cells Reveals Src-Mediated Upregulation of EphA2 and Therapeutic Potential of Dual Inhibition

Loss of the tumor suppressor PTEN is frequently observed in various cancers and promotes tumorigenesis by activating the PI3K-AKT pathway. However, the effectiveness of therapies targeting this pathway is limited by complex signaling crosstalk and compensatory mechanisms. Here, we employed quantitative proteomic and phosphoproteomic analyses using MCF10A PTEN knockout models to comprehensively map the signaling alterations induced by PTEN loss. Our analyses revealed that PTEN deficiency not only activates canonical PI3K-AKT signaling but also induces widespread changes in cytoskeleton organization, cell cycle regulation, and central carbon metabolism. PTEN loss also substantially elevates the activity of a variety of tyrosine kinases, including Src kinase and EphA2, a receptor tyrosine kinase (RTK) implicated in cancer progression. Mechanistic studies demonstrated that Src activation, rather than the canonical AKT signaling pathway, drives the upregulation of the receptor tyrosine kinase EphA2. The activation of the noncanonical tyrosine kinase signaling renders AKT inhibition alone insufficient in PTEN-deficient cancers. Importantly, combined treatment with the FDA-approved AKT inhibitor capivasertib and the Src inhibitor dasatinib synergistically induced apoptosis and suppressed the tumor cell growth in various PTEN-deficient cell lines as well as in three-dimensional cultures of endometrial cancer patient-derived xenograft models. Our study reveals that PTEN loss drives oncogenic signaling via dual activation of PI3K-AKT and tyrosine kinase pathways. Specifically, Src-mediated upregulation of EphA2 in PTEN-deficient cells highlights a therapeutic vulnerability that can be exploited by combined AKT and Src inhibition. This approach addresses the resistance associated with AKT inhibition alone and enhances therapeutic efficacy in PTEN-deficient cancers, supporting its potential application in targeted combination therapies.

cancer biology↗

bioRxiv2025

Cortical reinstatement of causally related events sparks narrative insights by updating neural representation patterns

We make sense of everyday events by reasoning about their underlying causes. When we connect causal links between events separated in time, we often experience a sudden feeling of "aha!", or a moment of insight. What cognitive and neural processes underlie these moments of understanding? We hypothesized that narrative insight accompanies retrieving causally related past events in memory and updating the current event representation. To test this, we designed an fMRI study in which participants watched a TV episode that was cut into multiple events and presented in temporally scrambled orders. Participants pressed an "aha" button whenever they understood something new and verbally explained why they pressed in those moments at the end of each run. Supporting our prediction, more than 40% of insights included the retrieval of past events that were causally related to the current event. Neural patterns representing causally related past events were reinstated in cortical areas. This neural reinstatement drove sudden shifts in cortical representation patterns [~]2 s prior to aha button presses, reflecting an update in situational representation at moments of insight. Moreover, distributed areas in the brain represented causally related events with similar neural patterns, beyond their shared semantic or perceptual features. Together, the study suggests that we comprehend events by reinstating causally related past events via shared neural patterns, followed by updating neural patterns at moments of insight.

neuroscience↗

bioRxiv2025

Comparative molecular landscapes of immature neurons in the mammalian dentate gyrus across species reveal special features in humans

Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity, learning and memory, but their evolutionary changes across species and specialized features in humans remain poorly understood. Here we performed machine learning-augmented analysis of published single-cell RNA-sequencing datasets and identified macaque imGCs with transcriptome-wide immature neuronal characteristics. Our cross-species comparisons among humans, monkeys, pigs, and mice showed few shared (such as DPYSL5), but mostly species-specific gene expression in imGCs that converged onto common biological processes regulating neuronal development. We further identified human-specific transcriptomic features of imGCs and demonstrated functional roles of human imGC-enriched expression of a family of proton-transporting vacuolar-type ATPase subtypes in development of imGCs derived from human pluripotent stem cells. Our study reveals divergent gene expression patterns but convergent biological processes in the molecular characteristics of imGCs across species, highlighting the importance of conducting independent molecular and functional analyses for adult neurogenesis in different species.

neuroscience↗

bioRxiv2025

Distinct memory CD4 subset tropism of two CCR5-tropic HIV-1 in a rapid progressor

CCR5 tropic HIV-1 mainly infect memory CD4+ T cells. Memory CD4+ T cells are heterogenous which comprise central memory (CM), transitional memory (TM) and effector memory (EM) subsets based on cell differentiation stages. Previous studies demonstrate that low viral burden in the CM subset correlates with long-term non-progressive HIV-1 infection (1, 2) and is a hallmark of non-pathogenetic SIV infection (3, 4). These findings indicate the importance of CD4 subset tropism of HIV/SIV in determining disease progression. However, an important, yet unanswered question is whether CCR5 HIV-1 variants have different memory CD4 subset preferences. Here, we demonstrate clear compartmentalization of two CCR5 HIV-1 in different memory CD4 subsets in vivo.

microbiology↗

bioRxiv2025

Neural circuits between nodose ganglion and pulmonary neuroendocrine cells regulate lung inflammatory responses

The lungs are organs exposed to the external environment, and the air we inhale contains various pathogens, such as endotoxins. The vagus nerve, which innervates the lungs, may play a role in detecting pathogens that invade the lungs. Through transcriptome analysis, tissue clearance imaging, electrical excitability recording, and gene- and cell-specific knockout experiments, we found that vagus nerve endings innervate pulmonary neuroendocrine cells (PNECs). These nerve endings sense bacterial endotoxins via pain receptors (TRPA1) rather than toll-like receptors (TLR4), eliciting electrical excitation and enhancing the production of neuropeptides (CGRP) in the nodose ganglia. In turn, CGRP released by sensory neurons from the nodose ganglia promotes both neuropeptide production and the proliferation of PNECs, thereby amplifying endotoxin-induced lung inflammatory responses. This reveals that the neural circuits between the nodose ganglion and PNECs play a critical role in regulating lung inflammatory responses.

neuroscience↗

bioRxiv2024

Identification of molecular and functional subtypes using chronic pancreatitis patient-derived organoid models

Chronic pancreatitis (CP) affects [~]3 million people worldwide, yet altering the course of disease is challenging. We developed a patient-derived organoid (PDO) platform to investigate the molecular pathogenesis of this disease and identify therapeutic strategies. We generated 36 PDOs from patients with idiopathic, hereditary, and alcohol-related CP with high genetic concordance. PDOs retained inflammation-associated transcriptional and proteomic features. Transcriptomic profiling revealed three molecular subtypes of CP independent of etiology. We discovered widespread dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) in half of the CP PDOs, including those with wildtype CFTR. Clinically available CFTR modulators stabilized mutant or wildtype CFTR, restored CFTR function, and decreased mitogenic and inflammatory signaling. This work provides the first comprehensive PDO platform for modeling CP. We demonstrate the utility of this platform for precision therapeutic investigations. Our findings reveal CFTR modulators as a broadly applicable and effective therapeutic strategy.

cell biology↗

bioRxiv2024

CIWARS: a web server for waterborne antibiotic resistance surveillance using longitudinal metagenomic data

The rise of antibiotic resistance (AR) is a major global health crisis, exacerbated by the overuse and misuse of antibiotics, leading to the rapid spread of antibiotic resistance genes (ARGs) in bacterial pathogens. This phenomenon poses significant threats to human and animal health, food security, and economic stability. Water bodies, particularly wastewater treatment plants (WWTPs), serve as critical reservoirs for ARGs, creating environments that favor the proliferation of resistant bacteria. Wastewater-based surveillance (WBS) has emerged as a cost-effective strategy for monitoring AR at the population level, providing real-time data to guide public health and policy decisions. Despite advancements in WBS, there are no comprehensive online analytical platforms for continuous environmental AR surveillance. This paper introduces CIWARS, a web server designed for AR analyses of longitudinal metagenomic data. CIWARS offers comprehensive ARG profiling, taxonomic annotation, and anomalous AR risk points detection. We demonstrate its capabilities through an interactive temporal data visualization, showcasing its potential for enhancing AR risk monitoring and guiding effective mitigation strategies. CIWARS is broadly applicable to longitudinal metagenomic data generated from any environment and aims to support global efforts in addressing the AR crisis by providing cyberinfrastructure for continuous AR surveillance. The web server is freely available at https://ciwars.cs.vt.edu/.

bioinformatics↗

bioRxiv2024

Mutations of schizophrenia risk gene SETD1A dysregulate synaptic function in human neurons

Schizophrenia (SCZ) is a complex neuropsychiatric disorder associated with both common risk variants of small effect sizes and rare risk variants of high penetrance. Rare protein truncating variants (PTVs) in SETD1A (SET Domain Containing 1A) show a strong association with SCZ; however, it remains largely unclear how rare PTVs in SETD1A contribute to the pathophysiology of SCZ. To understand the impact of SETD1A rare PTVs in human neurons, we CRISPR/Cas9-engineered five isogenic pairs of human induced pluripotent stem cells (iPSCs), with a recurrent heterozygous patient-specific PTV mutation c.4582-2delAG in two donor lines and a heterozygous frameshift mutation c.4596_4597insG (p. Leu1533fs) in three donor lines. These two mutations are predicted to cause a premature stop codon in exon 16 of SETD1A, leading to the loss of the conserved SET domain that is critical for its histone methyltransferase activity. We found that these presumably loss-of-function (LoF) mutations caused the SETD1A mRNAs to be degraded by nonsense-mediated decay (NMD), accompanied by a reduction of full-length SETD1A protein level in iPSCs. We then characterized the morphological, electrophysiological, and transcriptomic impacts of the SETD1A+/- LoF mutations in iPSC-derived human excitatory neurons induced by NGN2. We found that the SETD1A+/- exon-16 LoF mutations altered dendrite complexity, dysregulated synaptic transmission, and synaptic plasticity, likely by dysregulating genes involved in synaptic function. These results provide mechanistic insights into how SETD1A+/-exon-16 patient-specific LoF mutations affect neuron phenotypes that may be relevant to the pathophysiology of SCZ.

neuroscience↗

bioRxiv2024

Wheat stripe rust resistance gene Yr9, derived from rye, is a CC-NBS-LRR gene in a highly conserved NLR cluster

Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is a significant threat to global wheat production. Genetic resistance plays a crucial role in controlling this disease. Among wheat breeding innovations, the wheat-rye 1BL.1RS translocations are notable for introducing alien genetic diversity, partly due to the presence of the stripe rust resistance gene Yr9 on 1RS. To clone Yr9, we first identified four Pst-susceptible mutants from Lumai 15, which carries the 1BL.1RS translocation and Yr9. Using these mutants, we performed Sequencing Trait-Associated Mutations (STAM). A single candidate gene, YrChr1B, was identified within the Yr9 locus and later confirmed as Yr9 through genetic complementation and gene editing. The Yr9 gene encodes a coiled-coil nucleotide-binding site leucine-rich repeat (CC-NBS-LRR or NLR) protein and is part of a 14-member NLR gene cluster. This cluster is conserved among Triticeae species and is an ortholog of the barley Mla locus. Cloning Yr9 expands the genetic resources available for molecular wheat breeding aimed at durable and broad-spectrum disease resistance.

plant biology↗