Biology subjects

Ruan, S.

Publications and source records attributed to Ruan, S..

10 recordsLinked to original sources

bioRxiv2026

Basal ganglia output dynamically controls skilled forelimb kinematics in real time

The substantia nigra pars reticulata (SNr), the principal output nucleus of the basal ganglia, is traditionally viewed as a binary gate that permits actions through disinhibition. However, this framework fails to explain the fluid, high-dimensional control required for skilled behavior. Using high-resolution 3D kinematic tracking and automated behavioral classification, we show that SNr population activity paradoxically increases during skilled forelimb reaching and scales with motif-specific kinematics. Systematic optogenetic and chemogenetic perturbations reveal that the SNr bidirectionally controls movement vigor and online kinematics. Remarkably, a transient 12.5 ms pause is sufficient to abort a motor program, while a 12.5 ms burst enhances velocity and reshapes trajectories without altering sequence identity. Calcium imaging at single-neuron resolution further confirms that endogenous SNr dynamics represent real-time 3D kinematics. These findings demonstrate that SNr output does not merely gate movement initiation but continuously regulates the stability and kinematic evolution of skilled actions, expanding the functional framework of basal ganglia output from binary selection to the real-time dynamical control of motor execution. HighlightsO_LISNr activity paradoxically increases and scales with motor motif kinematics C_LIO_LIBidirectional SNr control of action vigor for skilled forelimb reaching C_LIO_LIBrief SNr pauses or bursts reshape online motor execution C_LIO_LIThe SNr acts as a continuous controller for real-time motor execution C_LI

neuroscience↗

bioRxiv2026

TRPV4 Inhibition by a Natural Product Mediates Analgesia

The transient receptor potential vanilloid 4 (TRPV4) channel, a polymodal calcium-permeable cation channel, is activated by diverse stimuli, including hyposmolarity, moderate heat, mechanical stress, and acidic pH. TRPV4 plays a critical role in the onset and progression of pain and is implicated in multiple pathological conditions, positioning it as an attractive therapeutic target. However, the development of TRPV4-targeted therapeutics has been hindered by limited mechanistic understanding of its inhibition. Here, the natural product (R)-1-(3-ethylphenyl)ethane-1,2-diol (AH001) is identified as a potent, subtype-selective TRPV4 inhibitor. A potential gating mechanism of TRPV4 inhibition is proposed through a combination of structural analyses and site-directed mutagenesis. Electrophysiological studies and cryo-electron microscopy (cryo-EM) further reveal that AH001s glucuronide metabolite, AHP, retains robust TRPV4 inhibitory activity, providing a critical structural basis for rational optimization of AH001 as a lead compound. Notably, AH001 demonstrated significant efficacy in reducing neuronal hyperexcitability in dorsal root ganglia (DRGs) and produced pronounced analgesic effects across multiple pain models, highlighting its therapeutic potential in pain relief. This study offers critical structural and mechanistic insights into TRPV4 inhibition and lays the groundwork for the structure-based design of TRPV4-targeted therapeutics.

biochemistry↗

bioRxiv2025

Striatal Pathways for Action Counting and Steering

The basal ganglia (BG) are critical for coordinating voluntary movements, yet their precise contribution remains a subject of debate. Using a novel operant counting task, we trained mice to perform a specific number of lever presses to obtain a reward, enabling quantification of continuous kinematics, discrete actions, and action sequences. Optogenetic manipulations of direct pathway (dSPN) and indirect pathway (iSPN) striatal projection neurons exert bidirectional and dissociable influences on both movement steering and action count progression: activation of dSPNs extends press sequences as if resetting an internal accumulator, whereas activation of iSPNs prematurely terminates them, mimicking completion of the count. In vivo calcium imaging reveals distinct yet intermixed populations of dSPNs and iSPNs representing either lever approach or count progression, with ramping activity patterns consistent with accumulation and discharge dynamics. Importantly, the difference between dSPN and iSPN population activity scales with proximity to both spatial and count-based goals, unifying discrete and continuous control within a push-pull model. These findings establish the BG as a central circuit for integrating kinematic and sequential representations to monitor and steer progress toward behavioral goals.

neuroscience↗

bioRxiv2025

Metabolite-based genome-wide association studies enable the dissection of the genetic bases of bioactive compounds in Chickpea seeds

Chickpea, is the second most consumed food legume, and significantly contributes to the human diet. Chickpea seeds are rich in a wide range of metabolites including bioactive specialized metabolites influencing nutritional qualities and human health. However, the genetic basis underlying the metabolite-based nutrient quality in chickpea remains poorly understood. Here we dissected the genetic architecture of seed metabolic diversity and explored how domestication shaped the chickpea metabolome. Through UPLC-MS we quantify over 3400 metabolic features in 509 chickpea seeds accessions from three independent multi-location field trials. The metabolite genome-wide association study (mGWAS) detected around 130,000 leading SNPs corresponding to 1890 metabolites across different environments. We further found and functionally validated a gene cluster of three CabHLH transcription factors that regulate soyasaponin biosynthesis in chickpea seeds. Our results reveal new insights on the effects of domestication process on chickpea metabolome. and provide valuable resources for the genetic improvement of the bioactive compounds in chickpea seeds.

plant biology↗

bioRxiv2025

Inhibiting RhoA Activation via GDP-state Stabilization to Relieve Heart Failure

High rates of heart failure (HF) morbidity and mortality have made targeting myocardial remodeling--particularly hypertrophy and fibrosis--a key therapeutic focus. RhoA, which regulates cytoskeletal reorganization and cell migration, plays a role in this process. However, RhoA has long been considered "undruggable", due to its strong binding to its endogenous substrates, GDP/GTP, and the lack of well-defined pockets for drug targeting. Here, we discovered a cryptic pocket proximate to GDP within RhoA and identified a natural product, AH001, binds here and interacts with GDP, stabilizing RhoAs interaction with its endogenous inhibitor, RhoGDI. AH001 reduced the downstream MRTFA nuclear translocation and downregulated fibrosis/hypertrophy proteins. Consequently, AH001 mitigated myocardial remodeling in multiple HF animal models, and in the 3D myocardial tissue model. Our findings highlight the therapeutic potential of inhibiting RhoA activation in myocardial remodeling, ultimately targeting HF, and offer a promising avenue for developing reversible inhibitors against undruggable GTPases.

pharmacology and toxicology↗

bioRxiv2025

Systematic evaluation of blood contamination in nanoparticle-based plasma proteomics

Circulating blood proteomics enables minimally invasive biomarker discovery. Nanoparticle (NP)-based circulating plasma proteomics studies have reported varying number of proteins, ranging from ca 2000 to 7000 but its not clear whether higher protein number is more informative. Here, we first develop OmniProt - a silica-NP workflow for plasma proteomics which is optimized through systematic evaluation of NP types and protein corona formation parameters. Next, we present an Astral spectral library for 10,109 protein groups expressed in human plasma. Using Astral with a throughput of 60 sample-per-day, OmniProt identifies ca 3000 to 6000 protein groups from human plasma. Notably, we found that platelet/erythrocyte/coagulation-related contamination artificially elevates protein identifications and compromises quantification accuracy for circulating plasma proteins in NP-enriched samples. Through controlled contamination experiments, we identified and validated protein biomarkers for contaminations of platelet, erythrocyte, and coagulation, respectively, in NP-based plasma proteomics experiments. We further developed an open-access software Baize for accessing plasma proteomics contamination. Finally, we validated our OmniProt workflow and Baize software in a clinical cohort of 193 patients with CT-indistinct benign nodules or early lung cancers. On average, we identified ca 4400 protein groups for each plasma sample without significant contamination. Five samples were flagged out as contaminated. In conclusion, this study reveals that contamination of plasma samples significantly alters the protein identification and quantification in NP-based plasma proteomics experiments, and presents an open-access software Baize to evaluate plasma proteome contamination.

biochemistry↗

bioRxiv2024

A2A-positive neurons in the nucleus accumbens core regulate effort exertion

Previous work has implicated the nucleus accumbens (NAc) in the regulation of effort, defined as the amount of work an animal is willing to perform for a given reward, but little is known about the specific contributions of neuronal populations within the NAc to effort regulation. In this study, we examined the contributions of direct pathway and indirect pathway neurons in the NAc core using an operant effort regulation task, in which the effort requirement is the number of lever presses needed for earning a food reward. Using optogenetics, we manipulated the activity of direct pathway spiny projection neurons (dSPNs, D1+) and indirect pathway SPNs (iSPNs, A2A+). Activating dSPNs reduced lever pressing regardless of the effort requirement, as it elicited gnawing, a competing consummatory behavior. On the other hand, activating iSPNs in the NAc core (but not in the shell) reduced lever pressing in an effort-dependent manner: stimulation-inducted reduction in performance was greater at higher press-to-reward ratio requirements. In contrast, optogenetically inhibiting NAc core iSPN output resulted in increased levels of effort exertion. Our results show that the indirect pathway output from the NAc core can bidirectionally regulate effort exertion.

neuroscience↗

bioRxiv2024

GABAergic neurons from the ventral tegmental area represent and regulate force vectors

The ventral tegmental area (VTA), a midbrain region associated with motivated behaviors, consists predominantly of dopaminergic (DA) neurons and GABAergic (GABA) neurons. Previous work has suggested that VTA GABA neurons provide a reward prediction, which is used in computing a reward prediction error. In this study, using in vivo electrophysiology and continuous quantification of force exertion in head-fixed mice, we discovered distinct populations of VTA GABA neurons that exhibited precise force tuning independently of learning, reward prediction, and outcome valence. Their activity usually preceded force exertion, and selective optogenetic manipulations of these neurons systematically modulated force exertion without influencing reward prediction. Together, these findings show that VTA GABA neurons continuously regulate force vectors during motivated behavior.

neuroscience↗

bioRxiv2023

A telomere-to-telomere genome assembly of Zhonghuang 13, a widely-grown soybean variety from the original center of Glycine max

Soybean (Glycine max) stands as a globally significant agricultural crop, and the comprehensive assembly of its genome is of paramount importance for unraveling its biological characteristics and evolutionary history. Nevertheless, previous soybean genome assemblies have harbored gaps and incompleteness, which have constrained in-depth investigations into soybean. Here, we present the first Telomere-to-Telomere (T2T) assembly of the Chinese soybean cultivar "Zhonghuang 13" (ZH13) genome, termed ZH13-T2T, utilizing PacBio Hifi and ONT ultralong reads. We employed a multi-assembler approach, integrating Hifiasm, NextDenovo, and Canu, to minimize biases and enhance assembly accuracy. The assembly spans 1,015,024,879 bp, effectively resolving all 393 gaps that previously plagued the reference genome. Our annotation efforts identified 50,564 high-confidence protein-coding genes, 707 of which are novel. ZH13-T2T revealed longer chromosomes, 421 not-aligned regions (NARs), 112 structure variations (SVs), and a substantial expansion of repetitive element compared to earlier assemblies. Specifically, we identified 25.67 Mb of tandem repeats, an enrichment of 5S and 48S rDNAs, and characterized their genotypic diversity. In summary, we deliver the first complete Chinese soybean cultivar T2T genome. The comprehensive annotation, along with precise centromere and telomere characterization, as well as insights into structural variations, further enhance our understanding of soybean genetics and evolution.

plant biology↗

bioRxiv2020

Population Bottlenecks and Intra-host Evolution during Human-to-Human Transmission of SARS-CoV-2Population Bottlenecks and Intra-host Evolution during Human-to-Human Transmission of SARS-CoV-2

The emergence of the novel human coronavirus, SARS-CoV-2, causes a global COVID-19 (coronavirus disease 2019) pandemic. Here, we have characterized and compared viral populations of SARS-CoV-2 among COVID-19 patients within and across households. Our work showed an active viral replication activity in the human respiratory tract and the co-existence of genetically distinct viruses within the same host. The inter-host comparison among viral populations further revealed a narrow transmission bottleneck between patients from the same households, suggesting a dominated role of stochastic dynamics in both inter-host and intra-host evolutions. Author summaryIn this study, we compared SARS-CoV-2 populations of 13 Chinese COVID-19 patients. Those viral populations contained a considerable proportion of viral sub-genomic messenger RNAs (sgmRNA), reflecting an active viral replication activity in the respiratory tract tissues. The comparison of 66 identified intra-host variants further showed a low viral genetic distance between intra-household patients and a narrow transmission bottleneck size. Despite the co-existence of genetically distinct viruses within the same host, most intra-host minor variants were not shared between transmission pairs, suggesting a dominated role of stochastic dynamics in both inter-host and intra-host evolutions. Furthermore, the narrow bottleneck and active viral activity in the respiratory tract show that the passage of a small number of virions can cause infection. Our data have therefore delivered a key genomic resource for the SARS-CoV-2 transmission research and enhanced our understanding of the evolutionary dynamics of SARS-CoV-2.

genetics↗