Biology subjects

Xu, Y.

Publications and source records attributed to Xu, Y..

At least 433 records · Page 24Linked to original sources

bioRxiv2024

Embryo spatial 3D genomics

The 3D architecture of the genome is crucial for controlling gene expression and organ development. Here, we introduce a spatial 3D genomics approach for assessing chromatin conformation in-situ in tissue sections, by integrating microfluidic deterministic barcoding and SPRITE procedures. This method was applied to mouse embryo sections, revealing a hierarchical model of chromatin interactions within and between compartments in various organs. The intra-compartment interactions vary among organs to orchestrate gene expressions, while the inter-compartment interactions remain identical in the most organs. Beyond this, the liver exhibits overwhelmingly packed chromatin with enhanced adjacent-compartment interactions, possibly related to its physiology. These findings highlight the importance of tissue-spatial information in understanding embryonic chromatin organization. The approach presents a powerful tool for investigating these processes in tissues with high heterogeneity. One Sentence SummaryA spatial 3D genomics approach was developed that accesses hierarchical chromatin conformation in-situ in tissue sections.

genetics↗

bioRxiv2024

Spatial domains identification in spatial transcriptomics by domain knowledge-aware and subspace-enhanced graph contrastive learning

Spatial transcriptomics (ST) technologies have emerged as an effective tool to identify the spatial architecture of the tissue, facilitating a comprehensive understanding of organ function and tissue microenvironment. Spatial domain identification is the first and most critical step in ST data analysis, which requires thoughtful utilization of tissue microenvironment and morphological priors. To this end, we propose a graph contrastive learning framework, GRAS4T, which combines contrastive learning and subspace module to accurately distinguish different spatial domains by capturing tissue microenvironment through self-expressiveness of spots within the same domain. To uncover the pertinent features for spatial domain identification, GRAS4T employs a graph augmentation based on histological images prior, preserving information crucial for the clustering task. Experimental results on 8 ST datasets from 5 different platforms show that GRAS4T outperforms five state-of-the-art competing methods in spatial domain identification. Significantly, GRAS4T excels at separating distinct tissue structures and unveiling more detailed spatial domains. GRAS4T combines the advantages of subspace analysis and graph representation learning with extensibility, making it an ideal framework for ST domain identification.

bioinformatics↗

bioRxiv2024

Covalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Non-structural Proteins Inhibitors

The global coronavirus disease 2019 (COVID-19) pandemic persists, with the ongoing mutation of the virus. Consequently, the development of inhibitors with diverse binding modes and mechanisms of action, along with the elucidation of novel binding sites is of paramount importance. The 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro) are two validated cysteine proteases that cleave the viral polyprotein and are essential for viral replication. In this study, we utilized covalent DNA-Encoded libraries (CoDELs) workflow to identify two series of triazine-based covalent inhibitors targeting 3CLpro and PLpro. Molecular docking facilitated the identification of optimization pathways, further refined through medicinal chemistry efforts, leading to the development of the non-peptide 3CLpro inhibitor LU9, which exhibited an IC50 value of 0.34 M, and crystal structure of LU10 revealed a unique binding mode within the active site. Additionally, the X-ray cocrystal structure of SARS-CoV-2 PLpro with XD5 uncovered a previously unexplored binding site, adjacent to the catalytic pocket, providing an opportunity for further development of PLpro inhibitors. Overall, these novel compounds serve as valuable chemical probes for target validation and represent promising drug candidates for the continued development of SARS-CoV-2 antivirals.

biochemistry↗

bioRxiv2024

Singular Odorant Receptor Expression Orchestrated by Promoter Activation Specificity in Apis Mellifera Olfactory Sensory Neurons

Honeybee, positioned as an outgroup of flies and mosquitos, have exhibited intriguing duplications and expansions of OR genes in genomic studies. However, little is known about how the OR genes are expressed and regulated in honeybee olfactory sensory neurons (OSNs). In this study, we utilized a single-cell multi-omics approach to profile the transcriptome and chromatin accessibility in Apis mellifera antennal nuclei, aiming to elucidate OR gene expression and its underlying regulatory mechanisms. Our systematical analysis unveiled a similar singular expression pattern of ligand-specific receptors in Apis mellifera OSNs, parallel with those observed in Drosophila melanogaster. Mechanistically, we discovered that promoter activation of OR genes orchestrates receptor expression patterns. For instance, although multiple adjacent OR genes are co-expressed with a single active promoter through polycistronic transcription, only the first OR gene could produce functional receptor protein, as supported by transcriptome quantification in OSNs. Additionally, we found that co-expression of receptor proteins might occur only when co-expressed OR genes possess multiple accessible promoters. This scenario is less common than expected, considering the number and evolutionary age of OR genes in Apis mellifera, suggesting a selection favoring the specialization of rapidly expanded OR genes in Apis mellifera. Overall, our study provides significant insights into the insect olfaction system and the regulatory mechanisms of OR genes expression.

neuroscience↗

bioRxiv2024

mTOR dysregulation induces IL6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare disease which causes lung cysts and respiratory failure. TSC2 deficient LAM cells with dysregulated mTOR signalling form nodules with fibroblasts causing lung injury. We examined if mTOR dysregulation could induce senescence and impair responses to lung injury. Senescence markers p21 and p16 were increased in LAM lungs and co-localised with alveolar type 2 cells. The SenMayo senescence gene panel was upregulated in LAM alveolar type 2 cells with senescence supressed by mTOR inhibition in patients. LAM cell / fibroblast spheroid cultures induced senescence markers in alveolar type 2 cell organoids, altered their growth and delayed epithelial scratch wound repair. Upstream regulator analysis predicted alveolar type 2 cell IL6 receptor activation. IL6 was produced by LAM cells, induced p16 and p21 in alveolar type 2 cells, inhibited epithelial wound resolution and was overexpressed in LAM patient serum where it was related to lung function. Wound repair in the presence of TSC2 null LAM cell / fibroblast spheroids was enhanced by the IL6 receptor antagonist Tocilizumab. Our findings show TSC2 loss induces senescence and IL6 production which are associated with impaired lung repair. Targeting IL6 signalling in parallel with mTOR inhibition, may reduce lung damage in LAM.

cell biology↗

bioRxiv2024

Proteomic Dynamics and Heat Stress Response in Arabidopsis Seedlings

Global warming poses a grave threat to plant survival, adversely affecting growth and agricultural productivity. To develop thermotolerant crops, a profound comprehension of plant responses to heat stress at the molecular level is imperative. Leveraging a novel fusion of 15N-stable isotope labeling and the ProteinTurnover algorithm, we meticulously investigated proteome dynamics in Arabidopsis thaliana seedlings subjected to moderate heat stress (30{degrees}C). This innovative approach facilitated a comprehensive analysis of proteomic changes across diverse cellular fractions. Our study unveiled significant turnover rate alterations in 571 proteins, with a median increase of 1.4-fold, indicative of accelerated protein dynamics under heat stress. Notably, root soluble proteins exhibited more subdued changes, suggesting tissue-specific adaptations. Moreover, we observed noteworthy turnover variations in proteins associated with redox signaling, stress response, and metabolism, underscoring the complexity of the response network. Conversely, proteins involved in carbohydrate metabolism and mitochondrial ATP synthesis displayed minimal turnover changes, signifying their stability. This exhaustive examination sheds light on the proteomic adjustments of Arabidopsis seedlings to moderate heat stress, elucidating the delicate balance between proteome stability and adaptability. These findings significantly augment our understanding of plant thermal resilience and offer crucial insights for the development of crops endowed with enhanced thermotolerance.

biochemistry↗

bioRxiv2024

5-HT Neurons Integrate GABA and Dopamine Inputs to Regulate Meal Initiation

Obesity is a growing global health epidemic with limited effective therapeutics. Serotonin (5-HT) is one major neurotransmitter which remains an excellent target for new weight-loss therapies, but there remains a gap in knowledge on the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using a closed-loop optogenetic feeding paradigm, we showed that the 5-HTDRN{lozenge}arcuate nucleus (ARH) circuit plays an important role in regulating meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response to GABAergic inputs can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the instrumental role of dopaminergic inputs via dopamine receptor D2 in 5-HTDRN neurons in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, which allows for the initiation of a meal.

neuroscience↗

bioRxiv2024

Disruption of WSB2-mediated NOXA Degradation Induces Synthetic Lethality to Anti-apoptotic BCL-2 Family Protein Inhibitors

Anti-apoptotic BCL-2 family proteins are frequently overexpressed in various cancers, playing a pivotal role in cancer initiation and progression, as well as intrinsic or acquired resistance to therapy. Although inhibitors targeting BCL-2, such as Venetoclax, have shown efficacy in hematological malignancies, their therapeutic potential in solid tumors remains limited. Identifying novel molecular targets to overcome resistance to these inhibitors is of significant clinical importance. Here, we provide evidence of a strong synthetic lethality between WSB2, a previously underexplored substrate-binding receptor of the Cullin 5-RBX2-Elongin B/C (CRL5) E3 ubiquitin ligase complex, and anti-apoptotic BCL-2 family proteins. Mechanistically, WSB assembles a CRL5 E3 ubiquitin ligase complex that facilitates the ubiquitination and subsequent proteasomal degradation of NOXA, a pro-apoptotic BCL-2 family protein. Loss of WSB2 leads to a substantial accumulation of NOXA in both cultured cell lines and knockout mouse tissues. While WSB2 deficiency alone does not significantly impact spontaneous apoptosis, it sensitizes cells to apoptosis when anti-apoptotic BCL-2 family proteins are either genetically depleted or pharmacologically inhibited. Moreover, WSB2 is overexpressed in several human cancer types. These findings identify WSB2 as a critical regulator of mitochondrial apoptosis and reveal the dysregulation of the WSB2-NOXA axis as a key factor contributing to apoptosis resistance in cancer cells. Targeting both WSB2 and anti-apoptotic BCL-2 family proteins holds promising therapeutic potential for overcoming resistance in human cancers.

cell biology↗

bioRxiv2024

Neutrophils secrete exosome-associated DNA to resolve sterile acute inflammation

Acute inflammation, characterized by a rapid influx of neutrophils, is a protective response that can lead to chronic inflammatory diseases when left unresolved. Secretion of LTB4-containing exosomes is required for effective neutrophil infiltration during inflammation. In this study, we show that neutrophils release nuclear DNA in a non-lytic, rapid, and repetitive manner, via a mechanism distinct from suicidal NET release and cell death. The packaging of nuclear DNA occurs in the lumen of nuclear envelope (NE)-derived multivesicular bodies (MVBs) that harbor the LTB4 synthesizing machinery and is mediated by the lamin B receptor (LBR) and chromatin decondensation. Disruption of secreted exosome-associated DNA (SEAD) in a model of sterile inflammation in mouse skin amplifies and prolongs the presence of neutrophils, impeding the onset of resolution. Together, these findings advance our understanding of neutrophil functions during inflammation and the physiological significance of NETs, with implications for novel treatments for inflammatory disorders.

immunology↗

bioRxiv2024

Humoral immunogenicity comparison of XBB and JN.1 in human infections

The continuous evolution of SARS-CoV-2, particularly the emergence of the BA.2.86/JN.1 lineage replacing XBB lineages, necessitates re-evaluation of current vaccine compositions. Here, we provide a comprehensive analysis of the humoral immune response to XBB and JN.1 human exposures, emphasizing the need for JN.1-lineage-based boosters. We demonstrate the antigenic distinctiveness of XBB and JN.1 lineages in SARS-CoV-2-naive individuals but not in those with prior vaccinations or infections, and JN.1 infection elicits superior plasma neutralization titers against its subvariants. We highlight the strong immune evasion and receptor binding capability of KP.3, supporting its foreseeable prevalence. Extensive analysis of the BCR repertoire, isolating [~]2000 RBD-specific monoclonal antibodies (mAbs) with their targeting epitopes characterized by deep mutational scanning (DMS), underscores the systematic superiority of JN.1-elicited memory B cells (MBCs). Notably, Class 1 IGHV3-53/3-66-derived neutralizing antibodies (NAbs) contribute majorly within wildtype (WT)-reactive NAbs against JN.1. However, KP.2 and KP.3 evade a substantial subset of them, even those induced by JN.1, advocating for booster updates to KP.3 for optimized enrichment. JN.1-induced Omicron-specific antibodies also demonstrate high potency across all Omicron lineages. Escape hotspots of these NAbs have mainly been mutated in Omicron RBD, resulting in higher immune barrier to escape, considering the probable recovery of previously escaped NAbs. Additionally, the prevalence of broadly reactive IGHV3-53/3-66- encoding antibodies and MBCs, and their capability of competing with all Omicron-specific NAbs suggests their inhibitory role on the de novo activation of Omicron-specific naive B cells, potentially explaining the heavy immune imprinting in mRNA-vaccinated individuals. These findings delineate the evolving antibody response to Omicron antigenic shift from XBB to JN.1, and highlight the importance of developing JN.1 lineage, especially KP.3-based vaccine boosters, to enhance humoral immunity against current and future SARS-CoV-2 variants.

immunology↗

bioRxiv2024

Discovery and Synthesis of GS-7682, a Novel Prodrug of a 4'-CN-4-Aza-7,9-Dideazaadenosine C-Nucleoside with Broad-Spectrum Potency Against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys.

Acute respiratory viral infections (ARVI), such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 (1) a novel phosphoramidate prodrug of a 4'-CN-4-aza-7,9-dideazaadenosine C-nucleoside GS-646089 (2) with broad antiviral activity against RSV EC50 = 3-46 nM, human metapneumovirus (hMPV) EC50 = 210 {+/-} 50 nM, human rhinovirus (RV) EC50 = 54-61 nM, and enterovirus (EV) EC50 = 83-90 nM. Prodrug optimization for cellular potency and lung cell metabolism identified the 5-methyl((S)-hydroxy(phenoxy)phosphoryl)-L-alaninate in combination with 2,3-diisobutyrate promoieties as optimal for high intracellular triphosphate formation in vitro and in vivo. 1 demonstrated significant reductions of viral loads in the lower respiratory tract of RSV-infected African green monkeys when administered once daily via intratracheal nebulized aerosol. Together these finding support additional evaluation of 1 and its analogs as a potential therapeutic for pneumo- and picornaviruses.

biochemistry↗

bioRxiv2024

Phosphate starvation stops bacteria digesting algal fucan that sequesters carbon

Algae provide a solar powered pathway to capture and sequester carbon by injecting stable fucan made from carbon dioxide into the ocean 1-4. Stability of the pathway is at odds with the presence of marine bacteria with genes of enzymes that can digest fucan and release the carbon dioxide 5. Biochemical explanations for stable fucan remain hypothetical 6. We assembled a biological carbon cycle model and found phosphate limitation enhanced fucan synthesis by algae, stopped digestion by bacteria and thereby stabilized the fucan carbon sequestration pathway. Marine microalgae Glossomastix sp. PLY432 increased synthesis of fucan, a part of its extracellular matrix, under nutrient-growth limiting conditions. Rate and extent of fucan digestion by a marine, isolated bacterium of the Akkermansiaceae family decreased with decreasing phosphate concentration. Phosphate starvation restricted bacterial growth rate, biomass yield and in turn increased the amount of stable fucan. Phosphate is universally required for growth but rare relative to glycan carbon in photosynthesis-derived ecosystems. The fact that phosphate is required for replication, transcription and translation explains why bacteria can digest gigatons of laminarin with a few enzymes, but not fucan during nutrient limited algal blooms. We conclude phosphate starvation constrains the ability of bacteria to digest fucan, which evolves to maintain stability around algal cells and consequentially also to keep carbon dioxide in the ocean.

microbiology↗

bioRxiv2024

Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration

Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, and the molecular mechanisms underlying neurodegeneration are unknown. We found that OPTN C-terminus truncation (OPTN{Delta}C) causes late-onset neurodegeneration of retinal ganglion cells (RGCs), optic nerve (ON), and spinal cord motor neurons, preceded by a striking decrease of axonal mitochondria. Surprisingly, we discover that OPTN directly interacts with both microtubules and the mitochondrial transport complex TRAK1/KIF5B, stabilizing them for proper anterograde axonal mitochondrial transport, in a C- terminus dependent manner. Encouragingly, overexpressing OPTN/TRAK1/KIF5B reverses not only OPTN truncation-induced, but also ocular hypertension-induced neurodegeneration, and promotes striking ON regeneration. Therefore, in addition to generating new animal models for NTG and ALS, our results establish OPTN as a novel facilitator of the microtubule-dependent mitochondrial transport necessary for adequate axonal mitochondria delivery, and its loss as the likely molecular mechanism of neurodegeneration.

neuroscience↗

bioRxiv2024

The subcommissural organ regulates brain development via secreted peptides

The subcommissural organ (SCO) is a gland located at the entrance of the aqueduct of Sylvius in the brain. It exists in species as distantly related as amphioxus and humans, but its function is largely unknown. To explore its function, we compared transcriptomes of SCO and non-SCO brain regions and found three genes, Sspo, Car3, and Spdef, that are highly expressed in the SCO. Mouse strains expressing Cre recombinase from endogenous promoter/enhancer elements of these genes were used to genetically ablate SCO cells during embryonic development, resulting in severe hydrocephalus and defects in neuronal migration and development of neuronal axons and dendrites. Unbiased peptidomic analysis revealed enrichment of three SCO-derived peptides, namely thymosin beta 4, thymosin beta 10, and NP24, and their reintroduction into SCO-ablated brain ventricles substantially rescued developmental defects. Together, these data identify a critical role for the SCO in brain development.

neuroscience↗

bioRxiv2024

Electroencephalographic Biomarkers of Relaxation: A Systematic Review and Meta-analysis

The human electroencephalogram (EEG) is composed of synchronous oscillations within characteristic frequency bands, including 8-13 Hz alpha oscillations that often appear during relaxation. Relaxation is critical for physical and mental health, but the extent to which various EEG components reflect relaxation remains uncertain. This systematic review and meta-analysis investigated associations between EEG components and concurrently measured reference indices of relaxation in healthy adults. A comprehensive database search and screening using preset criteria identified 38 studies involving 1,120 participants published between January 1940 and January 2022 for qualitative synthesis. These studies used various reference relaxation measures such as electrocardiographic indices related to parasympathetic nervous system activity and introspective indices obtained through questionnaires. Risks of bias were evaluated following the risk of bias assessment tool for nonrandomized studies. A meta-analysis of 23 studies using a random-effects model revealed positive correlations between relaxation index and the power of alpha oscillations at central channels (Fishers z-transformed correlation coefficient and [95% confidence interval]: 0.23 [0.10-0.36]) and frontal channels (0.16 [0.02-0.31]). The correlation was significantly higher for the central channel compared with other channels. No significant correlations were detected between relaxation indices and other EEG frequencies or channels. The causal relationships between relaxation and alpha power at central and frontal channels warrant further study.

neuroscience↗

bioRxiv2024

Proteome analysis provides insights into sex differences in Holothuria Scabra

Sex-determining mechanism is still ambiguous for sea cucumber Holothuria scabra which only manifests gonochorism in gonad. In this study, proteomic analysis was employed to delineate sex-related proteins and genes in gonads of H. scabra, subsequently validated through Quantitative real-time polymerase chain reaction (qRT-PCR). A total of 5,313 proteins were identified via proteome sequencing. Among these, 817 proteins exhibited expression in both the ovary and testis, with 445 proteins displaying up-regulation and 372 proteins showing down-regulation. Furthermore, 136 and 69 proteins were identified as ovary-specific and testis-specific Differentially Abundant Proteins (DAPs), respectively. For the validation of 75 DAP coding genes, 9 genes were considered to be reliable. Notably, 25 ovary-bias proteins enriched in ribosome pathway strongly indicated the crucial role of ribosome in ovary. And 5S/18S rRNA ratio in H. Scabra may have potencial to establish a nondestructive method to distinguish sexes unambiguously. This study serves to furnish novel evidence pertaining to sex differences in H. scabra.

molecular biology↗

bioRxiv2024

BET inhibition induces GDH1-dependent glutamine metabolic remodeling and vulnerability in liver cancer

Bromodomain and extra-terminal domain (BET) proteins, which function partly through MYC, are critical epigenetic readers and emerging therapeutic targets in cancer. Whether and how BET inhibition simultaneously induces metabolic remodeling remains unclear. Here we find that even transient BET inhibition by JQ-1 and other pan-BET inhibitors blunts liver cancer cell proliferation and tumor growth. BET inhibition decreases glycolytic gene expression but enhances mitochondrial glucose and glutamine oxidative metabolism revealed by metabolomics and isotope labeling analysis. Specifically, BET inhibition downregulates miR-30a to upregulate glutamate dehydrogenase 1 (GDH1) independent of MYC, which produces -ketoglutarate for mitochondrial oxidative phosphorylation (OXPHOS). Targeting GDH1 or OXPHOS is synthetic lethal to BET inhibiton, and combined BET and OXPHOS inhibition therapeutically prevents liver tumor growth in vitro and in vivo. Together, we uncover an important epigenetic-metabolic crosstalk whereby BET inhibition induces MYC- independent and GDH1-dependendent glutamine metabolic remodeling that can be exploited for innovative combination therapy of liver cancer.

cancer biology↗

bioRxiv2024

Integrative spatial omics reveals distinct tumor-promoting multicellular niches and immunosuppressive mechanisms in African American and European American patients with TNBC

Racial disparities in the clinical outcomes of triple-negative breast cancer (TNBC) have been well-documented, but the underlying biological mechanisms remain poorly understood. To investigate these disparities, we employed a multi-omic approach integrating imaging mass cytometry and spatial transcriptomics to characterize the tumor microenvironment (TME) in self-identified Black American (BA) and White American (WA) TNBC patients. Our analysis revealed that the TME in BA patients is marked by a network of endothelial cells, macrophages, and mesenchymal-like cells, which correlates with reduced patient survival. In contrast, the WA TNBC microenvironment is enriched in T-cells and neutrophils, indicative of T-cell exhaustion and suppressed immune responses. Ligand-receptor and pathway analyses further demonstrated that BA TNBC tumors exhibit a relatively "immune-cold" profile, while WA TNBC tumors display features of an "inflamed" TME, suggesting the evolution of a unique immunosuppressive mechanism. These findings provide insight into racially distinct tumor-promoting and immunosuppressive microenvironments, which may contribute to the observed differences in clinical outcomes among BA and WA TNBC patients. Statement of SignificanceThis study identifies distinct tumor microenvironment (TME) profiles in Black and White American TNBC patients, providing new insights into the biological mechanisms driving outcome disparities. Our findings highlight the role of the tumor-endothelial-macrophage niche in these disparities, offering a potential therapeutic target for race-inclusive strategies aimed at improving clinical outcomes. By revealing racial differences in treatment response profiles, this work underscores the necessity for tailored therapies in TNBC. These insights lay the groundwork for the development of inclusive, precision-driven treatment approaches that may help mitigate racial disparities and enhance patient outcomes.

cancer biology↗