Biology subjects

Yuan, P.

Publications and source records attributed to Yuan, P..

At least 19 recordsLinked to original sources

bioRxiv2026

Extracts of Bacillus proteolyticus strain OSUB18 exhibit cytostatic activity

Although therapeutic advancements have dramatically improved outcomes for cancer patients in recent decades, advanced cancer remains a significant challenge. There is still an urgent need for new and more effective strategies that minimize toxicity and improve survival outcomes in cancer patients. Natural products from microorganisms are a rich and promising source of bioactive compounds with substantial therapeutic potential in cancer treatment. Recently, B. proteolyticus strain OSUB18, isolated from switchgrass, has been demonstrated to promote plant growth and regulate reactive oxygen species (ROS) production. Here, we investigated the anticancer potential of this plant-associated microbe and demonstrated that its crude extracts exhibited broad-spectrum cytostatic activity across diverse solid tumor cell lines. Importantly, OSUB18 extracts displayed limited cytotoxicity toward normal human mammary epithelial cells and mouse fibroblasts. This potentially selective cytostatic activity was retained within a water soluble, heat-labile, and protease-resistant fraction. The extracts primarily suppressed cell proliferation, accompanied by increased lipid peroxidation, with preliminary evidence suggesting the potential involvement of ferroptosis. These findings suggest that the bioactive component may be a selective cytostatic agent with multifaceted mechanisms of action.

cancer biology↗

bioRxiv2026

LTBP isoforms differentially encode TGF-β spatial localization and activation

TGF-{beta} signals through a conserved pathway yet produces diverse outcomes, pointing to regulatory mechanisms upstream of receptor engagement. A family of four latent TGF-{beta} binding proteins (LTBPs) tether pro-TGF-{beta}s and control their localization and activation, but how distinct LTBPs contribute to this regulation is unclear. Here we combine cryo-electron microscopy with functional assays to dissect LTBP-pro-TGF-{beta} interactions. We resolve the LTBP-1/pro-TGF-{beta}1 and LTBP-3/pro-TGF-{beta}3 complex structures, revealing a conserved yet plastic hydrophobic binding interface, and systematically map key residues across all four LTBP and three pro-TGF-{beta} subtypes that determine binding specificity and affinity. Unexpectedly, LTBP-2, previously thought incapable of TGF-{beta} binding, engages pro-TGF-{beta}1 through a covalent linkage via its 16th EGF-like domain, providing a mechanistic link between LTBP-2 function and TGF-{beta} signaling. Beyond tethering, LTBP-3 shifts pro-TGF-{beta}3 from spontaneous activation toward integrin dependence, establishing LTPBs as dynamic modulators that dictate not only where but also how TGF-{beta} is unleashed. Collectively, these findings establish that LTBPs are not redundant ECM scaffolds but a family of functionally distinct regulators that differentially encode TGF-{beta} spatial localization and activation, with implications for isoform-selective therapeutic strategies.

biochemistry↗

bioRxiv2026

A geometric and dynamical theory of latent computations in biological neural networks

Many neural recordings have revealed low-dimensional sets of behaviorally relevant variables encoded within large-scale neural activity patterns. However, dimensionality reduction analyses alone cannot yield causal explanations for how networks stably implement computations that are resilient to the substantial variability of single neuron dynamics. Further, existing methods for dimensionality reduction often rely on simplifying assumptions about network structure that limit their applicability and explanatory power. To provide a theoretical framework describing the dynamics of low-dimensional computation in high-dimensional neural networks, here we introduce the concept of latent processing units (LPUs), which are architecture-agnostic computational elements operating within biological neural circuitry. Six theorems governing coding and computation by LPUs collectively provide explanations for a range of common biological findings: low-dimensional sets of coding variables can generate high-dimensional neural dynamics; many neurons have activity patterns that represent behaviorally relevant variables but exert little influence on downstream circuits; linear readouts of neural population activity commonly permit near-optimal decoding; the drift of neural representations is often substantial even while network computations remain intact. Overall, our treatment of LPUs, as enacted in network dynamics, unifies the geometric and dynamical views of neural computation under a joint framework and provides systems neuroscience with a causal account of how the brain executes reliable computations.

neuroscience↗

bioRxiv2026

Low-dimensional Neural Codes Suppress Neuronal Noise and Extend the Working Memory Duration

Neurons are noisy computational substrates, yet large neural populations achieve reliable computation. What determines the maximal duration that a noisy population can sustain working memory? We study this question with recurrent networks subject to stochastic noise and present three theoretical results. First, networks suppress independent neuronal noise when activity lies on a low-dimensional latent manifold. Second, this structure induces correlated noise across neurons, limiting the downstream information that can be extracted. Third, these effects yield an analytical bound on working memory duration that scales linearly with network size. We test these predictions using large-scale neocortical recordings, and provide a behavioral signature in mice consistent with the theory. Overall, noise suppression constitutes a key functional benefit of low-dimensional neural coding, with which large populations sustain reliable working memory over extended timescales.

neuroscience↗

bioRxiv2026

Microglial pruning of extinction-ensemble synapses preserves fear memory

Fear extinction suppresses learned fear without erasing the original memory, yet how competing fear and extinction ensembles are selectively updated remains unknown. Here, we show that microglia preserve fear memory by selectively editing extinction-ensemble synapses during retrieval. In medial prefrontal cortex, microglial processes, but not somata, expand, ramify, and tighten their engagement with extinction-ensemble dendrites and spines, where they preferentially engulf excitatory postsynaptic material and bias spine remodeling toward elimination. This selectivity is instructed by local find-me, eat-me, and dont-eat-me cues: purinergic signaling recruits microglial processes, phosphatidylserine exposure licenses engulfment of extinction-ensemble synapses, and CD47-SIRP protects fear ensembles from removal. Weakening microglial recruitment or engulfment, or removing this protection, accelerates extinction without impairing fear acquisition. These findings identify microglial processes as active gatekeepers of ensemble competition and reveal a neuroimmune mechanism that preserves fear memory by limiting extinction. In BriefDuring memory updating, microglial processes selectively engage extinction-ensemble synapses rather than globally pruning active circuits. Local recruitment, engulfment, and protection cues determine this choice, allowing microglia to preserve fear memory by limiting extinction. HighlightsO_LIExtinction retrieval selectively recruits microglial processes to extinction ensembles. C_LIO_LIMicroglia preferentially engulf excitatory postsynaptic material from extinction ensembles. C_LIO_LILocal "find-me," "eat-me," and "dont-eat-me" cues determine synapse selection. C_LIO_LIDisrupting microglial pruning facilitates extinction without impairing fear learning. C_LI

neuroscience↗

bioRxiv2025

Modeling structural variations sequencing information to address missing heritability and enhance risk prediction

Missing heritability remains a significant challenge in genome-wide studies focused on single nucleotide polymorphisms (SNPs) when analyzing the genetic basis of complex traits. Structural variations (SVs), which span broader genomic regions and often exert larger functional impacts than SNPs, hold promise for capturing this heritability. Although graph-based pangenomes have advanced SV detection and association analysis, traditional SNP-centric frameworks typically overlook detailed SV sequence information, treating overlapping SVs as independent variants and leading to reduced statistical power. To overcome this limitation, we developed SVrefiner, an algorithm that aligns overlapping SVs and partitions them into non-overlapping refined SVs (rSVs) based on sequence congruence. By generating precise genotype matrices, SVrefiner enables more accurate association studies. When applied to human, tomato, and pig genomes, SVrefiner delineated 48,712 rSVs from 77,696 human SVs, 6,607 rSVs from 51,561 tomato SVs, and 5,237 rSVs from 142,784 pig SVs. Incorporating rSVs alongside SNPs, indels, and unrefined SVs enhanced heritability estimates by up to 24.47%. Further, refined analysis revealed that gene expression traits are often influenced by specific SV subregions rather than entire SVs. Notably, integration of rSVs in human datasets increased total eQTLs by 71.56%, with cis- and trans-eQTLs rising by 21.3% and 94.4%, respectively. Mean risk prediction accuracy across over 16,000 traits improved by as much as 16.8%. These findings deepen the understanding of complex trait heritability and demonstrate the utility of rSVs for genetic improvement and disease risk assessment.

genetics↗

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

Fos labels a distinct excitatory neuron ensemble for memory retrieval

Experience-triggered expression of Fos has been extensively used as a marker representing memory engram. It is generally assumed that Fos-positive neurons are preferentially excited by the experience, yet this has not been directly examined. In this study, we tracked neuron activity and Fos expression in somatosensory cortex and dentate gyrus of hippocampus in mice, during electric shock-induced fear memory formation and retrieval. Contrary to the prevailing view, we found that calcium features fail to predict Fos for individual cells. Fos-positive neurons show no specific activation to stimuli during memory encoding, but their activities become stimuli-selective during retrieval. Surprisingly, inhibiting neurons that will express Fos during encoding does not affect the induction of memory-guided behavior upon their activation. Network simulation and voltage imaging further showed that connectivity to interneurons, not stimulus responsiveness, is a major factor determining Fos expression. Our results indicate that Fos labels excitatory neurons specific for memory retrieval.

neuroscience↗

bioRxiv2025

Key residue Unlocks Dual PIP2-Dependent and Independent Gating in G Protein-Gated Inwardly Rectifying Potassium Channels

G protein-gated inwardly rectifying potassium (GIRK) channels mediate membrane hyperpolarization in response to G protein-coupled receptor activation and are critical for regulating neuronal excitability. The membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) is essential for regulating a large family of ion channels, and disruptions in PIP2 interactions contribute to some neurological diseases. Structural analyses have identified key residues in PIP2-mediated gating of the GIRK2 channel. Notably, Arginine-92 (R92), a highly conserved basic residue at the membrane interface in GIRK2, interacts with PIP2 as well as cholesteryl hemisuccinate (CHS), a potentiator of GIRK2. Here, we used a combination of electrophysiological assays, fluorescent K+ flux measurements, cryo-electron microscopy, and molecular dynamics simulations, and find that mutations at R92 (Y, F, and Q) not only alter PIP2 sensitivity but can also reveal a novel gating mechanism that is independent of PIP2. These findings indicate that R92 plays a crucial role in modulating GIRK2 channel gating, offering new insights into developing potential therapeutic targets for treating neurological disorders linked to GIRK channel dysfunction.

biophysics↗

bioRxiv2024

Inhibition of Notch Signaling Attenuates Epileptic Discharges in the Adolescent Rat Brain after Status Epilepticus Induction

BackgroundNotch signaling plays a critical role in neuroregeneration after injuries such as those caused by status epilepticus (SE). ObjectiveTo explore the effects of Notch signaling on epileptogenesis and the underlying mechanisms in adolescent rat brains in the acute phase after SE induction. MethodsN-[N-(3,5-difluorophenacetyl)- L-alanyl)]-S-phenylglycine t-butyl ester (DAPT), which indirectly inhibits Notch, was injected into rats during the acute phase after SE induction to inhibit Notch signaling. Electroencephalogram (EEG) was used to observe spontaneous recurrent seizures. Differences in the synaptic structures of the hippocampus were observed by transmission electron microscopy. Nissl staining and Timm staining were used to observe the loss of hippocampal neurons and sprouting of mossy fibers, respectively, in the hippocampus at 28 days after SE. ResultsEEG illustrated that DAPT treatment reduced the severity of epileptic discharges after SE induction. Transmission electron microscopy revealed reductions in the presynaptic membrane active band length and postsynaptic membrane dense matter thickness in the CA1 region of the hippocampus. Meanwhile, Nissl staining demonstrated that DAPT treatment reduced the loss of hippocampal neuronal cell degeneration, and the hippocampal structure was repaired to a certain extent. Meanwhile, Timm staining illustrated that DAPT treatment did not affect mossy fiber sprouting (MFS) after SE induction. ConclusionInhibiting Notch signaling reduced EEG epileptic activity, attenuated synaptic damage, and partially restored the hippocampal neuronal structure. However, it did not alter MFS after SE induction.

neuroscience↗

bioRxiv2024

The mechanism and consequences of amyloid-β modulating thiamine pyrophosphokinase-1 expression in microglia

Ample studies attribute cognitive decline in Alzheimers disease to amyloid-{beta} deposition 1-6. However, brain amyloid-{beta} accumulation that saturates years before the manifestation of clinical symptoms is dissociated with cognitive decline of the disease 7. It is unknown how these two processes are mechanistically linked. In this and our accompanied study, we report that thiamine pyrophosphokinase-1 (TPK) deficiency plays essential roles in both processes via distinct mechanisms. Here we describe that diminished microglia Tpk controls the propagation of amyloid-{beta} plaques. In APP/PS1 transgenic mice, microglia showed elevated Tpk expression at 2-month-old, but reduction in a plaque-centric manner at 8-month-old. Interestingly, lipopolysaccharide, but not amyloid-{beta}, induceed Tpk reduction in cultured microglia. Tpk reduction led to microglia dysfunction, showing volatile motility but reduced phagocytosis and weak response to focal tissue injury, with accumulation of intracellular lipid droplets and abnormal mitochrondria. In Alzheimers disease mice, microglia-specific knockout of Tpk caused diminished plaque coverage, exacerbated plaque burden and synaptic loss. However, increased plaques were not accompanied by the development of neurofibrillary tangles or brain atrophy, in contrast to the phenotype described in our accompanied paper with neuronal Tpk deletion. In conclusion, plaque-induced inflammation reduces Tpk in microglia, selectively exacerbating the spread of amyloid pathology.

neuroscience↗

bioRxiv2024

Stable sequential dynamics in prefrontal cortex represents subjective estimation of time

Time estimation is an essential prerequisite underlying various cognitive functions. Previous studies identified "sequential firing" and "activity ramps" as the primary neuron activity patterns in the medial frontal cortex (mPFC) that could convey information regarding time. However, the relationship between these patterns and the timing behavior has not been fully understood. In this study, we utilized in vivo calcium imaging of mPFC in rats performing a timing task. We observed cells that showed selective activation at trial start, end, or during the timing interval. By aligning long-term time-lapse datasets, we discovered that sequential patterns of time coding were stable over weeks, while cells coding for trial start or end showed constant dynamism. Furthermore, with a novel behavior design that allowed the animal to determine individual trial interval, we were able to demonstrate that real-time adjustment in the sequence procession speed closely tracked the trial-to-trial interval variations. And errors in the rats timing behavior can be primarily attributed to the premature ending of the time sequence. Together, our data suggest that sequential activity maybe a stable neural substrate thatrepresentstime under physiological conditions.Furthermore, our results imply the existence of a unique cell type in the mPFC that participates in the time-related sequences. Future characterization of this cell type could provide important insights in the neural mechanism of timing and related cognitive functions.

neuroscience↗

bioRxiv2024

ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism

Fatty acid {beta}-oxidation (FAO) is a central catabolic pathway with broad implications for organismal health. However, various fatty acids are largely incompatible with standard FAO machinery until they are modified by other enzymes. Included among these are the 4-hydroxy acids (4-HAs)--fatty acids hydroxylated at the 4 ({gamma}) position--which can be provided from dietary intake, lipid peroxidation, and certain drugs of abuse. Here, we reveal that two atypical and poorly characterized acyl-CoA dehydrogenases (ACADs), ACAD10 and ACAD11, drive 4-HA catabolism in mice. Unlike other ACADs, ACAD10 and ACAD11 feature kinase domains N-terminal to their ACAD domains that phosphorylate the 4-OH position as a requisite step in the conversion of 4-hydroxyacyl-CoAs into 2-enoyl-CoAs--conventional FAO intermediates. Our ACAD11 cryo-EM structure and molecular modeling reveal a unique binding pocket capable of accommodating this phosphorylated intermediate. We further show that ACAD10 is mitochondrial and necessary for catabolizing shorter-chain 4-HAs, whereas ACAD11 is peroxisomal and enables longer-chain 4-HA catabolism. Mice lacking ACAD11 accumulate 4-HAs in their plasma while comparable 3- and 5-hydroxy acids remain unchanged. Collectively, this work defines ACAD10 and ACAD11 as the primary gatekeepers of mammalian 4-HA catabolism and sets the stage for broader investigations into the ramifications of aberrant 4-HA metabolism in human health and disease.

biochemistry↗

bioRxiv2023

Multi-omics analysis reveals signatures of selection and loci associated with complex traits in pigs

Selection signatures that contribute to phenotypic diversity, especially morphogenesis in pigs, remain to be further elucidated. To reveal the regulatory role of genetic variations in phenotypic differences between Eastern and Western pig breeds, we performed a systematic analysis based on seven high-quality de novo assembled genomes, 1,081 resequencing data representing 78 domestic breeds, 162 methylomes, and 162 transcriptomes of skeletal muscle from Tongcheng (Eastern) and Landrace (Western) pigs at 27 developmental stages. Selective sweep uncovers different genetic architectures behind divergent selection directions for the Eastern and Western breeds. Notably, two loci showed functional alterations by almost fixed missense mutations. By integrating time-course transcriptome and methylome, we revealed differences in developmental timing during myogenesis between Eastern and Western breeds. Genetic variants under artificial selection have critical regulatory effects on progression patterns of heterochronic genes like GHSR and BDH1, by the interaction of local DNA methylation status, particularly during embryonic development. Altogether, our work not only provides valuable resources for understanding pig complex traits, but also contributes to human biomedical research.

genomics↗

bioRxiv2023

GametesOmics: A Comprehensive Multi-Omics Database for Exploring the Gametogenesis in Humans and Mice

Gametogenesis plays an important role in the reproduction and evolution of species. The transcriptomic and epigenetic alterations in this process can influence the reproductive capacity, fertilization, and embryonic development. The rapidly increasing single-cell studies have provided valuable multi-omics resources. However, data from different layers and sequencing platforms have not been uniformed and integrated, which greatly limits their use for exploring the molecular mechanisms that underlie oogenesis and spermatogenesis. Here, we developed GametesOmics, a comprehensive database that integrated the data of gene expression, DNA methylation, and chromatin accessibility during oogenesis and spermatogenesis in humans and mice. GametesOmics provides a user-friendly website and various tools, including Search and Advanced Search for querying the expression and epigenetic modification of each gene; Analysis Tools with Differentially Expressed Gene (DEG) analysis for identifying DEGs, Correlation analysis for demonstrating the genetic and epigenetic changes, Visualization for displaying single-cell cluster and screening marker genes as well as master transcription factors (TFs), and MethylView for studying the genomic distribution of epigenetic modifications. GametesOmics also provides Genome Browser and Orthologs for tracking and comparing gene expression, DNA methylations, as well as chromatin accessibilities between humans and mice. GametesOmics offers a comprehensive resource for biologists and clinicians to decipher the cell fate transition in germ cell development, and can be accessed at http://gametesomics.cn/.

bioinformatics↗

bioRxiv2023

Genomic insights into post-domestication expansion and selection of body size in ponies

Horses domestication revolutionized human civilization by changing transportation, farming, and warfare patterns. Despite extensive studies on modern domestic horse origins, the intricate demographic history and genetic signatures of pony size demand further exploration. Here, we present a high-quality genome of the Chinese Debao pony and extensively analyzed 385 individuals from 49 horse breeds. We reveal the conservation of ancient components in East Asian horses and close relationships between Asian horses and specific European pony lineages. Genetic analysis uncovers Asian paternal origin for European pony breeds, and these pony-sized horses share a close genetic affinity due to the presence of a potential ancestral ghost pony population. Additionally, we identify promising cis-regulatory elements influencing horse withers height by regulating genes like RFLNA and FOXO1. Overall, our study provides insightful perspectives into the development history and genetic determinants underlying body size in ponies and offers broader implications for horse population management and improvement. TeaserDecoding pony genetics: exploring origins and size determinants sheds light on their historical and biological impacts.

genomics↗

bioRxiv2023

Structural Basis for Hyperpolarization-dependent Opening of the Human HCN1 Channel

Hyperpolarization and cyclic-nucleotide (HCN) activated ion channels play a critical role in generating self-propagating action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike most voltage-gated ion channels, the HCN channels activate upon membrane hyperpolarization, but the structural mechanisms underlying this gating behavior remain unclear. Here, we present cryo-electron microscopy structures of human HCN1 in Closed, Intermediate, and Open states. Our structures reveal that the inward motion of two gating charges past the charge transfer center (CTC) and concomitant tilting of the S5 helix drives the opening of the central pore. In the intermediate state structure, a single gating charge is positioned below the CTC and the pore appears closed, whereas in the open state structure, both charges move past CTC and the pore is fully open. Remarkably, the downward motion of the voltage sensor is accompanied by progressive unwinding of the inner end of S4 and S5 helices disrupting the tight gating interface that stabilizes the Closed state structure. This "melting" transition at the intracellular gating interface leads to a concerted iris-like displacement of S5 and S6 helices, resulting in pore opening. These findings reveal key structural features that are likely to underlie reversed voltage-dependence of HCN channels.

biochemistry↗

bioRxiv2023

Structure and function of the human mitochondrial MRS2 channel

The human Mitochondrial RNA Splicing 2 protein (MRS2) has been implicated in Mg2+ transport across mitochondrial inner membranes, thus playing an important role in Mg2+ homeostasis critical for mitochondrial integrity and function. However, the molecular mechanisms underlying its fundamental channel properties such as ion selectivity and regulation remain unclear. Here, we present structural and functional investigation of MRS2. Cryo-electron microscopy structures in various ionic conditions reveal a pentameric channel architecture and the molecular basis of ion permeation and potential regulation mechanisms. Electrophysiological analyses demonstrate that MRS2 is a Ca2+-regulated, non-selective channel permeable to Mg2+, Ca2+, Na+ and K+, which contrasts with its prokaryotic ortholog, CorA, operating as a Mg2+-gated Mg2+ channel. Moreover, a conserved arginine ring within the pore of MRS2 functions to restrict cation movements, likely preventing the channel from collapsing the proton motive force that drives mitochondrial ATP synthesis. Together, our results provide a molecular framework for further understanding MRS2 in mitochondrial function and disease.

biophysics↗