Biology subjects

Gui, X.

Publications and source records attributed to Gui, X..

13 recordsLinked to original sources

bioRxiv2026

The Extremely Brilliant Brain: An Isotropic Microscale Human Brain Dataset

We present an isotropic 7.72 {micro}m/voxel post-mortem human brain dataset acquired using Hierarchical Phase-Contrast Tomography (HiP-CT) at the ESRF Extremely Brilliant Source, beamline BM18. This fills a critical gap between whole-brain MRI at 100 {micro}m resolution and serial-section histological reconstructions at 20 {micro}m or finer. HiP-CT contrast, derived from X-ray phase shifts, enables rich 3D visualisation of complex neuroanatomy including white-matter bundles, microvasculature, and sub-nuclei. We provide open-source workflows for online data exploration, subvolume download, segmentation, and reintegration of analyses into the full dataset. We demonstrate the potential of this resource by tracing vasculature over long distances, segmenting nuclei, and extracting whitematter orientations with 3D structure-tensor analysis. High-resolution human brain datasets are transformative for quantitative neuroanatomy, circuit mapping, and validation of clinical imaging; this openly available resource is a critical step for global access to next-generation multiscale brain imaging.

neuroscience↗

bioRxiv2026

An interactive 3D atlas of gene expression in the mouse brain

The Allen Mouse Brain Atlas provides gene expression data for over 20,000 genes and has been extensively used in neuroscience. However, its constrained by a resolution of 200 {micro}m3. We improved this to 25 {micro}m3 for 4,083 genes by re-registering 401,660 sections to atlas space. From this, we produced an atlas with regions defined by shared molecular signatures and built an interactive online platform allowing exploration of gene expression patterns.

neuroscience↗

bioRxiv2025

Viscoelasticity and interface properties of multi-component condensates govern protein sequestration and suppression of amyloid formation

Stress granules (SGs) are multi-component biomolecular condensates widely implicated as sites of protein aggregation by virtue of the high concentrations of amyloidogenic RNA-binding proteins they contain. This model, in which SGs are viewed as crucibles for amyloid formation, has not been rigorously tested. Here, we employed twelve multi-component protein-nucleic acid condensate systems as SG-mimics with diverse physicochemical features. Utilizing three fibril-forming proteins, hnRNPA1, Tau, and FUS, which are concentrated more than 50-fold in condensates, we report that multi-component biomolecular condensates robustly suppress, rather than promote, amyloid formation. Multiscale experimental analyses, including quantitative kinetic measurements, rheology, and microscopy, combined with computational modelling, reveal that condensates serve as sinks for soluble protein, and fibrils form in the dilute phase, although interfaces can promote nucleation. Three key physicochemical properties of condensates govern suppression of fibril formation: First, condensate-mediated sequestration lowers the concentration of fibril-forming proteins in the dilute phase. Second, condensate viscoelasticity constrains efflux-driven fibril growth in the dilute phase. And third, dilution of fibril-forming proteins at condensate interfaces mitigates fibril nucleation. The sink potential of SG-mimics is recapitulated in G3BP1-RNA condensates and SGs reconstituted in mammalian cell lysate, suggesting that SGs may have evolved to suppress stress-induced protein aggregation.

biophysics↗

bioRxiv2025

The equilibrium between two quaternary assembly states determines the activity of SPOP and its cancer mutants

Proteostasis is critical for preventing oncogenesis. Both activating and inactivating mutations in the ubiquitin ligase subunit SPOP result in oncogenesis in different tissues. SPOP assembles into filaments that are multivalent for substrates, and substrates have multiple weak motifs for SPOP that are not activated via post-translational modifications. It is thus unclear how regulation is achieved. Here, we show that SPOP filaments circularize into rings that dimerize into up to 2.5 MDa-large, auto-inhibited double donuts. The equilibrium between double donuts and linear filaments determines SPOP activity. Activating and deactivating cancer mutations shift the equilibrium towards the filament or the double donut, respectively, and this influences substrate turnover and subcellular localization. This regulatory mechanism requires long filaments that can circularize into rings, likely explaining the presence of multiple weak SPOP-binding motifs in substrates. Activating and deactivating mutations combine to give rise to intermediate activities, suggesting new levers for cancer therapies. Highlights- SPOP assemblies exist in an equilibrium between circular double donuts and linear filaments. - Double donuts occlude access to the substrate binding site and are inactive. - Mutations in different cancers shift the equilibrium towards active or inactive states. - Regulation through these structural transitions requires large filamentous assemblies.

biophysics↗

bioRxiv2025

Siibra: A software tool suite for realizing a Multilevel Human Brain Atlas from complex data resources

Computational technology opens new possibilities towards understanding the complexity of the human brain, but it requires integrating measurements from different modalities and scales in anatomical context and exposing them in interoperable, actionable form. Especially with growing big data resources, accessing information from different scales and modalities coherently for visual exploration, reproducible analysis and application development remains challenging. We present siibra, a tool suite that connects diverse data from cloud resources to reference atlases and coordinate spaces. It supports different use cases by making contents accessible through a web viewer, Python library and HTTP API. Using siibra we implemented a Multilevel Human Brain Atlas linking macro-anatomical concepts and their inter-subject variability with measurements of the microstructural composition and intrinsic variance of brain regions, building on cytoarchitecture as a reference and supporting MRI-based and microscopic templates. The atlas is integrated with the EBRAINS research infrastructure. All software and content are openly accessible.

bioinformatics↗

bioRxiv2024

Cardiolipin-mimic lipid nanoparticles without antibody modification delivered senolytic in-vivo CAR-T therapy for inflamm-aging

mRNA-based in vivo CAR T cell engineering offers advantages over ex vivo therapies, including streamlined manufacturing and transient expression. However, current delivery requires antibody-modified vehicles with manufacturing challenges. In this study, inspired by cardiolipin, we identified a cardiolipin-like di-phosphoramide lipid that improved T cell transfection without targeting ligands, both in vivo and in vitro. The T cell-favored tropism is likely due to the lipids packing, shape, and rigidity. Encapsulating circular RNA further prolonged mRNA expression in the spleen and T cells. Using PL40 lipid nanoparticles, we delivered mRNA encoding a CAR targeting the senolytic and inflammatory antigen urokinase-type plasminogen activator receptor (uPAR), alleviating uPAR-related liver fibrosis and rheumatoid arthritis (RA). Single cell sequencing in humans confirmed uPARs relevance to senescence and inflammation in RA. To further enhance clinical translation, we screened and humanized scFvs against uPAR, establishing PL40 mRNA encoding a circular human uPAR CAR, with potential for treating aging-inflamed disorders. One Sentence SummaryWeve developed a unique class of Cardiolipin-mimic lipids that facilitate mRNA delivery to T cells in vivo without the need for antibody modification, enhancing the treatment of liver fibrosis and rheumatoid arthritis through circular CAR uPAR RNA and propelling the clinical application of humanized CAR against human uPAR.

bioengineering↗

bioRxiv2024

Genetic variation in the species Arabidopsis thaliana reveals the existence of natural heat resilience factors for meiosis

Heat interferes with multiple meiotic processes leading to genome instability and sterility in flowering plants, including many crops. Despite its importance for food security, the mechanisms underlying heat tolerance of meiosis are poorly understood. In this study, we analyzed different meiotic processes in the Arabidopsis (Arabidopsis thaliana) accessions Columbia (Col) and Landsberg erecta (Ler), their F1 hybrids and F2 offspring under heat stress (37{degrees}C). At 37{degrees}C, Col exhibits significantly reduced formation of double-stand breaks (DSBs) and completely abolished homolog pairing, synapsis and crossover (CO) formation. Strikingly, Ler and Ler/Col hybrids are much less affected than Col. Interestingly, only 10% [~] 20% of F2 offspring exhibit the same heat tolerance of meiotic recombination as parents, indicating that heat resilience in Ler is controlled by the interplay of several loci. Moreover, F2 offspring show defective chromosome condensation in interkinesis, and untimely sister-chromatid segregation and/or chromosome fragmentation, the levels of which exceed those in either inbreds and/or hybrids thus implying a transgressive effect on heat tolerance of meiosis. Furthermore, correlation and cytogenetic analysis suggest that homolog pairing and/or synapsis have an impact on heat tolerance of chromosome morphology and stability during post-recombination stages under heat stress. Taken together, this study reveals the existence of natural heat resilience factors for meiosis in Arabidopsis, which have the great potential to be exploited in breeding programs. Author summaryEnvironmental temperature alterations affect meiotic recombination and/or chromosome segregation thus perturbing genetic makeup and genome stability in plants. We have previously reported that CO formation is fully abolished in Arabidopsis thaliana accession Col under heat stress (36{degrees}C-38{degrees}C) due to reduced DSB formation and impaired homolog pairing. Here, we show that in Arabidopsis thaliana accession Ler under the same high temperature conditions, both DSB and CO formation occur normally, and homolog pairing is mildly impacted, which indicate a striking difference in heat tolerance of meiotic recombination from Col. Remarkably, Col/Ler hybrids display the same heat tolerance as Ler, however, only 10% [~] 20% of F2 offspring behave the same as parents. Moreover, we found higher levels of defects in chromosome morphology and integrity, and sister-chromatid segregation in F2 population than those in both inbreds and hybrids, which suggest a transgressive effect influencing heat tolerance of meiosis. Our findings reveal that heat resilience in Arabidopsis is controlled by the interplay of multiple genomic loci, holding a great potential to be exploited in crop breeding.

plant biology↗

bioRxiv2023

Decoded EEG Neurofeedback-Guided Cognitive Reappraisal Training for Emotion Regulation

Neurofeedback is an innovative self-training that adjusts and enhances brain function. One of the more studied application scenarios with neurofeedback training is emotion regulation. Compared with regional brain activity-informed neurofeedback techniques, neurofeedback protocols using the decoded brain states as feedback signals could make the setting of regulation targets more specific and objective. In the present study, we constructed an EEG neurofeedback-guided cognitive reappraisal training protocol for emotion regulation. Forty-two healthy participants (20 females; 22.4{+/-}2.2 years old) were recruited and were randomly assigned to either the neurofeedback group or the control group. During the training process, we calculate the real-time self-regulation performance on the evoked emotion based on the decoded emotional states and fed it back to the subjects as the feedback signal. According to our results, real-time feedback of the regulation effect helps subjects improve emotion regulation performance for emotional stimuli with low positive valence. Further analysis of selected EEG features for emotion classification revealed the neural correlates with neurofeedback training. This newly proposed neurofeedback training protocol is a promising treatment for emotion-related mental disorders, with the potential to be a low-cost and high-portability brain-based, non-invasive, neural modulation technique.

neuroscience↗

bioRxiv2022

ATM-Mediated Double-Strand Break Repair Is Required for Meiotic Genome Stability at High Temperature

In eukaryotes, the conserved kinase Ataxia Telangiectasia Mutated (ATM) negatively regulates DNA double-strand break (DSB) formation and plays a central role in DSB repair. Here, by using cytogenetic approaches, we demonstrate that ATM also plays an essential role in protecting meiotic chromosome integrity in Arabidopsis thaliana at extreme high temperature. We determined the chromosome localization patterns of DSB formation proteins SPO11-1 and DFO during prophase I, both of which were disturbed by heat stress. Evaluation of the number of RAD51, DMC1, SPO11-1 and DFO protein foci in meiocytes of Arabidopsis atm mutant clarifies that ATM does not mediate the heat-induced reduction in DSB formation. Interestingly, meiotic spread analysis showed that chromosome fragmentation level was significantly increased in atm but was lowered in the mre11 and mre11 atm mutants under high temperature, indicating that ATM-dependent meiotic chromosome integrity at high temperature relies on the functional MRE1-RAD50-NBS1 (MRN) complex. Moreover, contrary to the rad51 and mnd1 mutants, which exhibited enhanced meiotic chromosome integrity under heat stress, the rad51 atm and mnd1 atm mutants retained high levels of chromosome fragmentation at extreme high temperature. Furthermore, heat stress reduced chromosome fragmentation level in the syn1 and syn1 atm mutants. Collectively, these data suggest that ATM-mediated DSB repair is required for meiotic genome stability in plants at extreme high temperature, which possibly acts in a RAD51-independent manner and relies on functional chromosome axis.

plant biology↗

bioRxiv2021

Chitinase 3-like-1 Contributes to Acetaminophen-induced Liver Injury by Promoting Hepatic Platelet Recruitment

Hepatic platelet accumulation contributes to acetaminophen (APAP)-induced liver injury (AILI). However, little is known about the molecular pathways involved in platelet recruitment to the liver and whether targeting such pathways could attenuate AILI. The present study unveiled a critical role of chitinase 3-like-1 (Chi3l1) in hepatic platelet recruitment during AILI. Increased Chi3l1 and platelets in the liver were observed in patients and mice overdosed with APAP. Compared to wild-type (WT) mice, Chi3l1-/- mice developed attenuated AILI with markedly reduced hepatic platelet accumulation. Mechanistic studies revealed that Chi3l1 signaled through CD44 on macrophages to induce podoplanin expression, which mediated platelet recruitment through C-type lectin-like receptor 2. Moreover, APAP treatment of CD44-/- mice resulted in much lower numbers of hepatic platelets and liver injury than WT mice, a phenotype similar to that in Chi3l1-/- mice. Recombinant Chi3l1 could restore hepatic platelet accumulation and AILI in Chi3l1-/- mice, but not in CD44-/- mice. Importantly, we generated anti-Chi3l1 monoclonal antibodies and demonstrated that they could effectively inhibit hepatic platelet accumulation and AILI. Overall, we uncovered the Chi3l1/CD44 axis as a critical pathway mediating APAP-induced hepatic platelet recruitment and tissue injury. We demonstrated the feasibility and potential of targeting Chi3l1 to treat AILI.

pharmacology and toxicology↗

bioRxiv2020

An antibody-dependent enhancement (ADE) activity eliminated neutralizing antibody with potent prophylactic and therapeutic efficacy against SARS-CoV-2 in rhesus monkeys

Efficacious interventions are urgently needed for the treatment of COVID-19. Here, we report a monoclonal antibody (mAb), MW05, showing high SARS-CoV-2 neutralizing activity by disrupting the interaction of receptor binding domain (RBD) with angiotensin-converting enzyme 2 (ACE2) receptor. Crosslinking of Fc with Fc{gamma}RIIB mediates antibody-dependent enhancement (ADE) activity by MW05. This activity was eliminated by introducing the LALA mutation to the Fc region (MW05/LALA). Most importantly, potent prophylactic and therapeutic effects against SARS-CoV-2 were observed in rhesus monkeys. A single dose of MW05/LALA completely blocked the infection of SARS-CoV-2 in a study of its prophylactic effect and totally cleared SARS-CoV-2 in three days in a treatment setting. These results pave the way for the development of MW05/LALA as an effective strategy for combating COVID-19.

microbiology↗

bioRxiv2020

The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure

Human heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) serves as a key regulating protein in RNA metabolism. Malfunction of hnRNPA1 in nucleo-cytoplasmic transport or dynamic phase separation leads to abnormal amyloid aggregation and neurodegeneration. The low complexity (LC) domain of hnRNPA1 drives both dynamic phase separation and amyloid aggregation. Here, we use cryo-electron microscopy to determine the amyloid fibril structure formed by hnRNPA1 LC domain. Remarkably, the structure reveals that the nuclear localization sequence of hnRNPA1 (termed PY-NLS), which is initially known to mediate the nucleo-cytoplamic transport of hnRNPA1 through binding with karyopherin-{beta}2 (Kap{beta}2), represents the major component of the fibril core. The residues that contribute to the binding of PY-NLS with Kap{beta}2 also exert key molecular interactions to stabilize the fibril structure. Notably, hnRNPA1 mutations found in familial amyotrophic lateral sclerosis (ALS) and multisystem proteinopathoy (MSP) are all involved in the fibril core and contribute to fibril stability. Our work illuminate structural understandings on the pathological amyloid aggregation of hnRNPA1 and the amyloid disaggregase activity of Kap{beta}2, and highlights the multiple roles of PY-NLS in hnRNPA1 homeostasis.

biophysics↗

bioRxiv2020

Glial type specific regulation of CNS angiogenesis by HIFα-activated different signaling pathways

The mechanisms by which oligodendroglia modulate CNS angiogenesis remain elusive. Previous in vitro data suggest that oligodendroglia regulate CNS endothelial cell proliferation and blood vessel formation through hypoxia inducible factor alpha (HIF)-activated Wnt (but not VEGF) signaling. Using in vivo genetic models, we show that HIF in oligodendroglia is necessary and sufficient for angiogenesis independent of CNS regions. At the molecular level, HIF stabilization in oligodendroglia does not perturb Wnt signaling but remarkably activates VEGF. At the functional level, genetically blocking oligodendroglia-derived VEGF but not Wnt significantly decreases oligodendroglial HIF-regulated CNS angiogenesis. Interestingly, blocking astroglia-derived Wnt signaling reduces astroglial HIF-regulated CNS angiogenesis. Together, our in vivo data clearly demonstrate that oligodendroglial HIF regulates CNS angiogenesis through Wnt-independent and VEGF-dependent signaling. Our findings represent an alternative mechanistic understanding of CNS angiogenesis by postnatal glial cells and unveil a glial cell type-dependent HIF-Wnt axis in regulating CNS vessel formation.

neuroscience↗