Biology subjects

chen, x.

Publications and source records attributed to chen, x..

11 recordsLinked to original sources

bioRxiv2026

NMDA receptor-dependent presynaptic homeostatic plasticity?

Excitatory glutamatergic synapses in the brain are remarkably plastic. Two forms of plasticity have received the most attention: long-term potentiation (LTP) and synaptic homeostasis. While LTP requires the activation of NMDA receptors, synaptic homeostasis does not. However, both phenomena are mediated by the recruitment of postsynaptic AMPA receptors to the synapses. Recently a new form of plasticity has been described referred to as presynaptic homeostatic plasticity (PHP) (Chipman et al., 2022; Chipman et al., 2025). Pharmacological inhibition of AMPA synaptic responses in CA1 hippocampal pyramidal cells initiates a rapid homeostatic response that results in the recovery of the AMPA responses to normal values in the continued presence of the inhibitor. Accompanying this recovery is a doubling of the NMDA response which is interpreted as an increase in the release of glutamate. This is provocative since it is the first report claiming that a reduction in AMPA responses triggers an enhancement in NMDA responses. Using three different protocols to monitor synaptic responses we fail to observe any recovery of synaptic responses in the presence of an AMPA inhibitor. Furthermore, there was no enhancement in NMDA responses. Thus, we find no evidence for the presence of PHP at CA1 hippocampal synapses.

neuroscience↗

bioRxiv2025

Ginkgolic acid attenuates e chinococcus granulosus infection-induced hepatic fibrosis by inhibiting Smad4 SUMOylation

BackgroundThe SUMOylation modification is closely linked to the progression of fibrotic diseases, yet its role in hepatic fibrosis associated with cystic echinococcosis (CE) remains unclear. This study aimed to investigate the function of SUMOylation in CE-related hepatic fibrosis and evaluate the anti-fibrotic effects and mechanisms of ginkgolic acid (GA) via regulation of the SUMOylation pathway. MethodologyPeri-lesional (PL) and adjacent normal (AN) liver tissues from CE patients were collected to examine histopathology and SUMO pathway proteins. A CE-infected mouse model was established and treated with GA to assess cyst burden, serum TGF-{beta}1 levels, hepatic fibrosis markers, and SUMO-related proteins. In vitro, macrophages and hepatic stellate cells (HSCs, LX-2 line) were stimulated with Echinococcus granulosus cyst fluid (EgCF) or TGF-{beta}1 to evaluate GAs effects on macrophage polarization (CD206/CD86), HSC activation (-SMA/PCNA), Smad4 SUMOylation, and nuclear translocation. Macrophage-HSC crosstalk was investigated via conditioned medium co-culture assays. ResultFibrosis was exacerbated in peri-lesional liver tissues of CE patients, accompanied by SUMO pathway activation. GA significantly alleviated hepatic fibrosis in CE mice and reversed SUMO pathway dysregulation. Mechanistically, GA inhibited EgCF-induced pro-fibrotic M2 macrophage polarization and blocked Smad4 SUMOylation and nuclear translocation by modulating SUMOylation. Furthermore, GA directly suppressed HSC activation and bidirectionally disrupted the pro-fibrotic crosstalk between macrophages and HSCs under EgCF stimulation, ultimately alleviating fibrosis. ConclusionThis study reveals the critical role of SUMOylation modification in CE-associated hepatic fibrosis and elucidates a novel anti-fibrotic mechanism whereby GA targets the SUMOylation-Smad4 axis to regulate the immune microenvironment. Author summaryThis study demonstrates aberrant activation of the SUMOylation pathway during hepatic fibrosis progression in cystic echinococcosis (CE), characterized by upregulated SUMO1/Ubc9 expression and downregulated SENP1 in peri-cystic liver tissue. Ginkgolic acid (GA) intervention significantly attenuated CE-associated liver fibrosis in mice, evidenced by reduced cyst volume, decreased TGF-{beta}1 levels, and suppressed expression of fibrotic markers (-SMA/COL1A1). GA concurrently reversed dysregulated SUMO pathway protein expression. Mechanistically, GA upregulates the deSUMOylating enzyme SENP1, thereby inhibiting Echinococcus granulosus cyst fluid (EgCF)-induced SUMOylation and nuclear translocation of Smad4. This blockade impedes macrophage polarization toward the pro-fibrotic M2 phenotype (CD206{downarrow}) and suppresses hepatic stellate cell (HSC) activation (-SMA/PCNA{downarrow}). Furthermore, GA disrupts the pro-fibrotic bidirectional crosstalk between HSCs and macrophages. Collectively, these findings indicate that GA ameliorates CE-induced hepatic fibrosis by targeting the SUMO-Smad4 axis to modulate the immune microenvironment, providing a novel therapeutic strategy.

molecular biology↗

bioRxiv2025

The Role of Microglia and Complement C5/C5a in the Pathogenesis of Rhegmatogenous Retinal Detachment with Choroidal Detachment

BackgroundRhegmatogenous retinal detachment with choroidal detachment (RRDCD) is an uncommon and sight-threatening disorder marked by fast development and significant inflammation. This study aimed to identify cellular and molecular signatures distinguishing RRDCD from typical rhegmatogenous retinal detachment (RRD) and to investigate the roles of microglia and the complement C5/C5a pathway in disease pathogenesis. MethodsSingle-cell RNA sequencing (scRNA-seq) was employed to analyze vitreous samples from patients with RRD and RRDCD, indicating its involvement in blood-retina barrier impairment. ResultsOur findings revealed a distinct cellular landscape in RRDCD, characterized by enhanced connectivity between microglia and dendritic cells, alongside a significant upregulation of the complement C5-C5AR1 interaction. In vitro experiments indicated that treatment with complement C5 promoted microglial proliferation and activation, induced apoptosis in RF/6A endothelial cells, and disrupted tight junctions in ARPE-19 epithelial cells, suggesting a role in blood-retina barrier dysfunction. ConclusionThe findings substantiate the inflammatory hypothesis regarding the pathogenesis of RRDCD, emphasizing the critical functions of microglia and the complement C5/C5a pathway in intensifying retinal inflammation and undermining vascular integrity.

bioinformatics↗

bioRxiv2025

Protenix - Advancing Structure Prediction Through a Comprehensive AlphaFold3 Reproduction

In this technical report, we present Protenix, a comprehensive reproduction of AlphaFold3 (AF3), aimed at advancing the field of biomolecular structure prediction. Protenix tackles the challenges of predicting complex interactions involving proteins, ligands, and nucleic acids, while enhancing accessibility and reproducibility. Across diverse benchmarks, including PoseBusters V2, low-homology PDB sets, and CASP15 RNA, Protenix achieves state-of-the-art performance in protein-ligand, protein-protein, and protein-nucleic acid predictions. We also address limitations, such as potential memorization effects, and outline future directions for improvement. By open-sourcing Protenix, we aim to democratize advanced structure prediction tools and accelerate interdisciplinary research in computational biology and drug discovery.

bioinformatics↗

bioRxiv2024

Identification and genomic characterization of a novel bisegmented coronavirus in the lesser panda

Coronaviruses (CoVs) are enveloped positive-sense single-stranded RNA viruses and are renowned for their capacity to infect a diverse range of animals, including humans. In this study, we report the identification and characterization of a novel bisegmented coronavirus, designated LpCoV, from a dead lesser panda, which exhibited severe clinical manifestations and lesions in multiple organs. The LpCoV represents the first documented coronavirus with a unique bisegmented genome while maintaining the typical coronavirus morphology. One genomic segment encodes the ORF1ab polyprotein, while the other segment encodes the spike and nucleocapsid proteins, notably lacking the envelope (E) and membrane (M) genes. The pairwise patristic distances of the five concatenated domains in the replicase region (3CLpro, NiRAN, RdRP, ZBD, and HEL1) between LpCoV and -{delta} coronaviruses range from 1.19 to 1.70. Based on the classification criteria established by the International Committee on Taxonomy of Viruses (ICTV), LpCoV is proposed to constitute a new genus within the Coronaviridae family. An epidemiological investigation identified five LpCoV-like viruses in lesser pandas from two different provinces (Sichuan and Jiangsu) indicating the long-term circulation and expansion of bisegmented coronaviruses in wildlife. These findings highlight the imperative for comprehensive viral surveillance in wildlife, which is essential for understanding and mitigating the risk of animal diseases and zoonotic spillover.

microbiology↗

bioRxiv2024

AI-assisted In-silico Trial for the Optimization of Osmotherapy following Ischaemic Stroke

Over the past few decades, osmotherapy has commonly been employed to reduce intracranial pressure in post-stroke oedema. However, evaluating the effectiveness of osmotherapy has been challenging due to the difficulties in clinical intracranial pressure measurement. As a result, there are no established guidelines regarding the selection of administration protocol parameters. Considering that the infusion of osmotic agents can also give rise to various side effects, the effectiveness of osmotherapy has remained a subject of debate. In previous studies, we proposed the first mathematical model for the investigation of osmotherapy and validated the model with clinical intracranial pressure data. The physiological parameters vary among patients and such variations can result in the failure of osmotherapy. Here, we propose an AI-assisted in-silico trial for further investigation of the optimisation of administration protocols. The proposed deep neural network predicts intracranial pressure evolution over osmotherapy episodes. The effects of the parameters and the choice of dose of osmotic agents are investigated using the model. In addition, clinical stratifications of patients are related to a brain model for the first time for the optimisation of treatment of different patient groups. This provides an alternative approach to tackle clinical challenges with in-silico trials supported by both mathematical/physical laws and patient-specific biomedical information.

bioengineering↗

bioRxiv2022

Deeply conserved super-enhancers maintain stem cell pluripotency in placental mammals

Despite pluripotent stem cells sharing key transcription factors, their maintenance involves distinct genetic inputs. Emerging evidence suggests that super-enhancers (SEs) can function as master regulatory hubs to control cell identity and pluripotency in humans and mice. However, whether pluripotency-associated SEs share a deep evolutionary origin in mammals remains elusive. Here, we performed comprehensive comparative epigenomic and transcription factor binding analyses among pigs, humans, and mice to identify pluripotency-associated SEs. Like typical enhancers, SEs displayed rapid evolution in mammals. We showed that BRD4 is an essential and conserved activator for mammalian pluripotency-associated SEs. Comparative motif enrichment analysis revealed 30 shared transcription factor binding motifs among the three species. The majority of the transcriptional factors that bind to identified motifs are known regulators associated with pluripotency. Further, we discovered three pluripotency-associated SEs (SE-SOX2, SE-PIM1, and SE-FGFR1) which displayed deep conservation in placental mammals and are sufficient to drive reporter gene expression in a pluripotency-dependent manner. Disruption of these conserved SEs through the CRISPR/Cas9 approach severely impaired the proliferative potential and the ability to form undifferentiated colonies. Our study provides insights into the understanding of conserved regulatory mechanisms underlying the maintenance of pluripotency as well as species-specific modulation of the pluripotency-associated regulatory networks in mammals. Significance statementSuper-enhancers (SEs) hold stronger power than regular enhancers to direct gene expression in the regulation of stem cell pluripotency. To dissect how pluripotency-associated SEs have evolved in mammals, we performed a systematic comparison of SEs among pigs, humans, and mice. Our analysis allowed the identification of three pluripotency-associated SEs (SE-SOX2, SE-PIM1, and SE-FGFR1) that are highly conserved in Placentalia (accounting for 94% of mammals) as well as many species-specific SEs. All three SEs were sufficient to direct pluripotency-dependent gene expression and disruption of each conserved SE caused the loss of stem cell pluripotency. Our work highlights a small number of highly conserved SEs essential for the maintenance of pluripotency.

cell biology↗

bioRxiv2021

Cryo-EM structure of the human TACAN channel in a closed state

TACAN is an ion channel involved in sensing mechanical pain. It has recently been shown to represent a novel and evolutionarily conserved class of mechanosensitive channels. Here, we present the cryoelectron microscopic structure of human TACAN (hTACAN). hTACAN forms a dimer in which each protomer consists of a transmembrane globular domain (TMD) that is formed of six helices and an intracellular domain (ICD) that is formed of two helices. Molecular dynamic simulations suggest that a putative ion conduction pathway is located inside each protomer. Single point mutation of the key residue Met207 significantly increased the surface tension activated currents. Moreover, cholesterols were identified at the flank of each subunit. Our data show the molecular assembly of hTACAN and suggest that the wild type hTACAN is in a closed state, providing a basis for further understanding the activation mechanism of the hTACAN channel.

biochemistry↗

bioRxiv2021

Evidence for the Presence of Hyphae and Fruiting Body Calcium Oxalate Crystallites in Schizophyllum commune

Biomineralization is a phenomenon in which organisms form crystals. Studies have shown that many fungi have the ability to biomineralize, it can exhibit calcium oxalate crystals on their hyphae and fruiting body. Schizophyllum commune is a common saprophytic fungus distributed all over the world, but there is little research on its biomineralization. In this paper, S. commune fruiting body from three different provinces of China were collected, and isolation for hyphal cultured to obtain several samples. Utilizing light microscope, FE-SEM, and EDAX, the existence of crystals on the fruiting body and mycelium of each strain was found, and their morphological characteristics and ion content were analyzed. It was ultimately established that biomineralization occurs on S. commune.

biochemistry↗

bioRxiv2020

Histone demethylase complexes KDM3A and KDM3B cooperate with OCT4/SOX2 to construct pluripotency gene regulatory network

The pluripotency gene regulatory network of porcine-induced pluripotent stem cells (piPSCs), especially in epigenetics, remains elusive. To determine this biological function of epigenetics, we cultured piPSCs in different culture conditions. We found that activation of pluripotent gene- and pluripotency-related pathways requires the erasure of H3K9 methylation modification which was further influenced by mouse embryonic fibroblast (MEF) served feeder. By dissecting the dynamic change of H3K9 methylation during loss of pluripotency, we demonstrated that the H3K9 demethylases KDM3A and KDM3B regulated global H3K9me2/me3 level and that their co-depletion led to the collapse of the pluripotency gene regulatory network. Immunoprecipitation-mass spectrometry (IP-MS) provided evidence that KDM3A and KDM3B formed a complex to perform H3K9 demethylation. The genome-wide regulation analysis revealed that OCT4 (O) and SOX2 (S), the core pluripotency transcriptional activators, maintained the pluripotent state of piPSCs depending on the H3K9 hypomethylation. Further investigation revealed that O/S cooperating with histone demethylase complex containing KDM3A and KDM3B promoted pluripotency genes expression to maintain the pluripotent state of piPSCs. Together, these data offer a unique insight into the epigenetic pluripotency network of piPSCs. SummaryErasure of H3K9 methylation in porcine pluripotent stem cells depends on the complex of transcription factors OCT4/SOX2 and histone demethylase KDM3A/KDM3B.

cell biology↗

bioRxiv2018

A novel nonsense mutation c.424G>T (p. G142X) in the first exon of XLas leading to osteopetrosis

GNAS is one of the most complex gene loci in the human genome and encodes multiple gene products. XLas, the extra-large isoform of alpha-subunit of the stimulatory guanine nucleotide-binding protein (Gas), is paternally inherited. Although XLas can mimic the action of Gas, its significance remains largely unknown in humans. Here we report a patient presented with increased bone mass, hypophosphatemia, and elevated parathyroid hormone levels. His serum calcium was in the lower limit of normal range. DEXA scan revealed progressive increase in the bone density of this patient. Whole exome sequencing of this subject found a novel nonsense mutation c.424G>T (p. G142X) in the first exon of XLas, which was inherited from his father and transmitted to his daughter. This mutation was predicted to exclusively influence the expression of XLas, while may have no significant effects on other gene products of this locus. SaOS2 cells transfected with mutant XLas failed to generate cAMP under parathyroid hormone stimulation, indicating skeletal resistance to this hormone. This subject showed higher circulating SOST, DKK1 and OPG levels, while lower RANKL levels and RANKL/OPG ratio, leading to reduced bone resorption. It is speculated that this patient may belong to a very rare type of pseudohypoparathyroidism with selective skeletal resistance but normal renal tubular response to parathyroid hormone. Our findings indicate that XLas plays a critical role in bone metabolism and GNAS locus should be considered as a candidate gene for high bone mass.\n\nAuthor summaryGNAS has been regarded as one of the most complex gene loci and encodes multiple transcripts, including Gs, XLs, NESP55 and A/B transcripts. These isoforms share the same 2-13 exons with alternative first exons. Previously reported mutations often disrupt multiple protein-coding transcripts in addition to that encoding Gs, making it difficult to distinguish the contributions of each transcript to disease phenotypes. Here we first report a novel nonsense mutation c.424G>T (p. G142X) in the first exon of XLas in a subject presenting with high bone mass, unclosed cranial suture, and persistent hypophosphatemia, and elevated parathyroid hormone (PTH) levels. This is the first report of a mutation located in the first exon of XLas in humans, which was predicted to exclusively influence the expression of XLas, while may have no significant effects on other gene products of this locus. SaOS2 cells transfected with mutant XLas failed to generate cAMP under PTH stimulation, indicating skeletal resistance to this hormone. Our study suggests that XLas has an important physiological role in humans, and is involved in skeletal PTH/cAMP pathway. Our findings also indicate GNAS locus should be considered as a candidate gene for high bone mass.\n\nFundingThe National Natural Science Foundation of China.\n\nDeclaration of InterestsThe authors declare no competing interests.

genetics↗