Biology subjects

Liu, Y.

Publications and source records attributed to Liu, Y..

At least 955 records · Page 53Linked to original sources

bioRxiv2024

Phased genome assemblies and pangenome graphs of human populations of Japan and Saudi Arabia

The selection of a reference sequence in genome analysis is critical, as it serves as the foundation for all downstream analyses. Recently, the pangenome graph has been proposed as a data model that incorporates haplotypes from multiple individuals. Here we present JaSaPaGe, a pangenome graph reference for Saudi Arabian and Japanese populations, both of which have been significantly underrepresented in previous genomic studies. We constructed JaSaPaGe from high-quality phased diploid assemblies which were made utilizing PacBio high-fidelity long reads, Nanopore long reads, and Hi-C short reads of 9 Saudi and 10 Japanese individuals. Quality evaluation of the pangenome graph by variant calling showed that our pangenome outperformed earlier linear reference genomes (GRCh38 and T2T-CHM13) and showed comparable performance to the pangenome graph provided by the Human Pangenome Reference Consortium (HPRC), with more variants found in Japanese and Saudi samples using their population-specific pangenomes. This pangenome reference will serve as a valuable resource for both the research and clinical communities in Japan and Saudi Arabia.

genomics↗

bioRxiv2024

Identification of SENP7 and UTF1/VENTX as new loci influencing clusteredprotocadherin methylation across blood and brain using a genome-wide associationstudy

The epigenetic regulation of clustered protocadherin (cPCDH) genes is tightly linked to their function as specific cell surface barcodes for neural self-nonself discrimination. Differential cPCDH DNA methylation in both blood and brain has been implicated in diverse human traits and diseases ranging from BMI, aging, cancer and brain disorders. However, the unique regulation of cPCDH methylation remains poorly understood. Therefore, we performed a genome-wide association study to evaluate the association of >7 million genetic variants with DNA methylation at 607 cPCDH CpGs measured in whole blood of 3777 individuals and validated findings in prefrontal cortex samples obtained from 523 brain donors. We observed concordant cPCDH methylation patterns in blood and prefrontal cortex, which switched between hypo-, intermediate and hypermethylation over short distances with the former overlapping with the promoter regions of each cPCDH member. Through methylation quantitative trait locus (meQTL) analysis in trans, we first confirmed the broad effect of the candidate gene SMCHD1 on cPCDH methylation in blood which validated in prefrontal cortex. Through a genome-wide analysis, we next identified the SENP7 and UTF1/VENTX loci to have widespread, subcluster-specific effects on cPCDH methylation in blood which was validated in prefrontal cortex. While SENP7 can indirectly affect DNA methylation through the deSUMOylation of the chromatin repressor KAP1, UTF1 and VENTX are two genes involved in embryonic development not previously implicated in epigenetic regulation. Our findings shed new light on the processes involved in cPCDH methylation that may underlie associations with disease.

genetics↗

bioRxiv2024

The Porphyromonas gingivalis lipid A 1-phosphatase LpxE has unique features and requires a functional type IX secretion system for its activity

Porphyromonas gingivalis is a Gram-negative bacterium that plays a central role in the development of periodontal disease. It uses a type IX secretion system (T9SS) to export a range of virulence factors to the bacterial surface where they are attached to A-LPS, one of the two forms of lipopolysaccharide (LPS) produced in P. gingivalis, and then packaged into outer membrane vesicles (OMVs). We previously showed that 1-P dephosphorylation of the lipid A component of LPS is regulated by the T9SS outer membrane protein (OMP) PorV, and this is linked to membrane destabilisation and OMV blebbing/formation. In this study we aimed to extend this and investigate the role of other T9SS OMPs in OMV biogenesis. We examined gingipain activity, gingipain secretion, A-LPS production, OMV morphology, and lipid A structure in P. gingivalis W50 and T9SS OMP mutant strains, and our results support an essential role for these proteins in type IX secretion. In addition, we produced a lipid A 1-phosphatase ({Delta}lpxE) mutant and show that all T9SS OMPs are required for LpxE activity and correct vesicle formation. LpxE has a unique C-terminal extension, and we propose that a cargo protein exported by the T9SS can directly/indirectly interact with this and regulate LpxE activity. This study provides insight into a new mechanism that links type IX cargo sorting with OMV blebbing, which may also be present in other Bacteroidota that colonise the gut and oral cavity.

microbiology↗

bioRxiv2024

Diversity and productivity of a natural grassland decline with the number of global change factors

Grasslands are highly diverse ecosystems providing important ecosystem services, but they currently face a variety of anthropogenic stressors simultaneously. Quantifying grassland responses to global change factors (GCFs) is crucial for developing effective strategies to mitigate the negative impacts of global change on grassland communities and to promote their resilience in the face of future environmental challenges. We conducted a field experiment in the Songnen grassland, northeastern China, to test the combined effects of 0, 1, 2, 4, 6, and 8 GCFs, including fungicide, herbicide, insecticide, antibiotic stress, heavy metal pollution, light pollution, microplastic pollution, nitrogen deposition, tillage disturbance, and increased precipitation. We found that within one year, the increasing number of GCFs negatively impacts on both the productivity and diversity of grassland communities. In comparison to exposure to a single GCF, exposure to 8 GCFs led to a reduction in productivity and species richness by 42.8% and 42.9%, respectively. Furthermore, these negative effects seem to be linked to the reduction of dominant species and the concurrent increase in neonative species. The results of hierarchical diversity-interaction modeling suggested that the adverse impacts of an increasing number of GCFs on community productivity and diversity are attributable to both the specific identities of GCFs involved and their unique pairwise interactions. The results suggest that grasslands may quickly loose stability and degrade more rapidly in response to multiple co-occurring GCFs. Greater efforts should be made to conserve the functions and services of grassland ecosystems by reducing the impacts of human activities.

ecology↗

bioRxiv2024

Covalent inhibitors of the RAS binding domain of PI3Ka impair tumor growth driven by RAS and HER2

Genetic disruption of the RAS binding domain (RBD) of PI 3-kinase (PI3K) prevents the growth of mutant RAS driven tumors in mice and does not impact PI3Ks role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3K lipid kinase activity such as alpelisib. Here we report compounds that bind covalently to cysteine 242 in the RBD of PI3K p110 and block the ability of RAS to activate PI3K activity. These inhibitors have a profound impact on the growth of RAS mutant and also HER2 over-expressing tumors, particularly when combined with other inhibitors of the RAS/MAPK pathway, without causing hyperglycemia.

cancer biology↗

bioRxiv2024

Cortical connectivity, local dynamics and stability correlates of global conscious states

Consciousness emerges from complex neural processes, yet its precise neurobiological correlates remain uncertain. Here a space-time-resolved inference-based framework is applied to estimate the neurophysiological variables of a wholecortex model and analyze the neural mechanism correlates of global consciousness by way of a correlation analysis between behavioural and neural variable time-series. Using magnetoencephalography (MEG) data from 15 participants under Xenon-induced anesthesia, interconnected neural mass models (NMMs) were developed and time-evolving regional neurophysiological variables and inter-regional connectivity strengths were inferred from the data. Analyses revealed significant correlations between consciousness levels and inter-regional connectivity, particularly in posterior parietal, occipital, and prefrontal regions. Moreover, results support a parietal, rather than frontal, network backbone to facilitate global consciousness. Regional-level analyses further identified correlates of consciousness within the posterior parietal and occipital regions. Lastly, reductions in consciousness were linked to stabilized cortical dynamics, reflected by changes in the eigenmodes of the system. This framework provides a novel, inference-based approach to investigating consciousness, offering a time-resolved perspective on neural mechanism correlates during altered states.

neuroscience↗

bioRxiv2024

Bottom-up design of calcium channels from defined selectivity filter geometry

Native ion channels play key roles in biological systems, and engineered versions are widely used as chemogenetic tools and in sensing devices1,2. Protein design has been harnessed to generate pore-containing transmembrane proteins, but the capability to design ion selectivity based on the interactions between ions and selectivity filter residues, a crucial feature of native ion channels3, has been constrained by the lack of methods to place the metal-coordinating residues with atomic-level precision. Here we describe a bottom-up RFdiffusion-based approach to construct Ca2+ channels from defined selectivity filter residue geometries, and use this approach to design symmetric oligomeric channels with Ca2+ selectivity filters having different coordination numbers and different geometries at the entrance of a wide pore buttressed by multiple transmembrane helices. The designed channel proteins assemble into homogenous pore-containing particles, and for both tetrameric and hexameric ion-coordinating configurations, patch-clamp experiments show that the designed channels have higher conductances for Ca2+ than for Na+ and other divalent ions (Sr2+ and Mg2+). Cryo-electron microscopy indicates that the design method has high accuracy: the structure of the hexameric Ca2+ channel is nearly identical to the design model. Our bottom-up design approach now enables the testing of hypotheses relating filter geometry to ion selectivity by direct construction, and provides a roadmap for creating selective ion channels for a wide range of applications.

biochemistry↗

bioRxiv2024

Base-modified nucleotides mediate immune signaling in bacteria

Signaling from pathogen sensing to effector activation is a fundamental principle of cellular immunity. While cyclic (oligo)nucleotides have emerged as key signaling molecules, the existence of other messengers remains largely unexplored. Here, we reveal a bacterial anti-phage system that mediates immune signaling through nucleobase modification. Immunity is triggered by phage nucleotide kinases, which, combined with the system-encoded adenosine deaminase, produce deoxyinosine 5-triphosphate (dITP) as immune messengers. The dITP signal activates downstream effector to mediate cellular NAD+ depletion, resulting in population-level defense through the death of infected cells. To counteract immune signaling, phages deploy specialized enzymes that deplete cellular dAMP, the precursor of dITP messengers. Our findings uncover a nucleobase modification-based anti-phage signaling pathway, establishing noncanonical nucleotides as a new type of immune messengers in bacteria.

microbiology↗

bioRxiv2024

CD24-Fc resolves inflammation and rescues CD8 T cells with polyfunctionality during HIV-1 infection under cART

The persistence of HIV-1 reservoirs during combination anti-retroviral therapy (cART) leads to chronic immune activation and systemic inflammation in people with HIV (PWH), associating with a suboptimal immune reconstitution as well as an increased risk of non-AIDS events. This highlights the needs to develop novel therapy for HIV-1 related diseases in PWH. In this study, we assessed the therapeutic effect of CD24-Fc, a fusion protein with anti-inflammatory properties that interacts with danger-associated molecular patterns (DAMPs) and siglec-10, in chronic HIV-1 infection model using humanized mice undergoing suppressive cART. Our findings show that CD24-Fc treatment significantly reduced inflammation and immune hyperactivation in vivo when combined with cART. CD24-Fc mediated resolution of inflammation was associated with improved recovery of CD4 T cells, reduced immune activation, restored central memory T cells and reversal of immune cell exhaustion phenotype. Notably, CD24-Fc treatment rescued CXCR5+ CD8 central memory T cell (TCM) which correlated with increased polyfunctionality in HIV-specific T cells in humanized mice and in cultured peripheral blood mononuclear cells (PBMCs) from PWH. This restoration of CXCR5+ memory CD8 T cells was associated with HIV replication inhibition, delayed viral rebound and reduced HIV-1 pathogenesis upon cART cessation. This study suggests that CD24-Fc treatment could represent a promising new therapeutic strategy for managing chronic systemic inflammation and associated diseases in PWH. Author summaryCombination antiretroviral therapy (cART) cannot block viral gene expression from activated HIV proviral DNA in reservoir cells, contributing to chronic immune activation and inflammation associated diseases in people with HIV (PWH). The therapeutic treatment of anti-inflammatory fusion protein CD24-Fc in humanized mice during suppressive cART (i) resolves inflammation and chronic HIV-1 immune pathogenesis during suppressive cART, (ii) rescues CXCR5-expressing CD8 memory T cells and enhances antiviral response in humanized mice and PWH PBMCs, (iii) delays virus rebound and reduces viral pathogenesis after cART cessation. Thus, CD24-Fc could provide a novel therapeutic strategy for treating chronic systemic inflammation and associated diseases in PWH.

immunology↗

bioRxiv2024

Functional fingerprinting for the developing brain using deep metric learning: an ABCD study

Brain fingerprinting is a promising approach for characterizing the uniqueness of individual brain functioning using functional magnetic resonance imaging (fMRI) data. Here, we propose a novel deep learning framework, the metric-BoIT, for brain fingerprinting and demonstrate its effectiveness in capturing individual variability among early adolescents undergoing dramatic brain changes. Utilizing resting-state fMRI data from the Adolescent Brain Cognitive Development (ABCD) dataset, we identified brain functional fingerprints that achieved remarkable individual identification accuracy, reaching 97.6% within a single session and maintaining 86.6% accuracy over a four-year developmental period. Annotation analysis revealed that higher-order association regions, particularly those within the default-mode network, contributed most significantly to these distinctive brain fingerprints (t = 5.618, p < 0.001). Moreover, these brain fingerprints were relevant to cognitive functions, as evidenced by significant correlations with fluid intelligence (F = 1.282, p = 0.027) and crystallized intelligence (F = 1.405, p < 0.001). The extracted brain fingerprints were additionally associated with genetics, showing that individuals with strong genomic relationships exhibited more similar brain fingerprint patterns (t = -12.330, p < 0.001). Together, our study not only presents an innovative approach to brain functional fingerprinting but also provides valuable insights into the individual variability underlying adolescent neurodevelopment.

neuroscience↗

bioRxiv2024

In vitro biofilm formation only partially predicts beneficial Pseudomonas fluorescens protection against rhizosphere pathogens

Plant roots form associations with both beneficial and pathogenic soil microorganisms. While members of the rhizosphere microbiome can protect against pathogens, the mechanisms are poorly understood. We hypothesized that the ability to form a robust biofilm on the root surface is necessary for the exclusion of pathogens; however, it is not known if the same biofilm formation components required in vitro are necessary in vivo. Pseudomonas fluorescens WCS365 is a beneficial strain that is phylogenetically closely related to an opportunistic pathogen P. fluorescens N2C3 and confers robust protection against P. fluorescens N2C3 in the rhizosphere. We used this plant-mutualist-pathogen model to screen collections of P. fluorescens WCS365 increased attachment mutants (iam) and surface attachment defective (sad) transposon insertion mutants that form increased or decreased levels of biofilm on an abiotic surface, respectively. We found that while the P. fluorescens WCS365 mutants had altered biofilm formation in vitro, only a subset of these mutants, including those involved in large adhesion protein (Lap) biosynthesis, flagellin biosynthesis and O-antigen biosynthesis, lost protection against P. fluorescens N2C3. We found that the inability of P. fluorescens WCS365 mutants to grow in planta, and the inability to suppress pathogen growth, both partially contributed to loss of plant protection. We did not find a correlation between the extent of biofilm formed in vitro and pathogen protection in planta indicating that biofilm formation on abiotic surfaces may not fully predict pathogen exclusion in planta. Collectively, our work provides insights into mechanisms of biofilm formation and host colonization that shape the outcomes of host-microbe-pathogen interactions.

microbiology↗

bioRxiv2024

Neighborhood Deprivation, Genetic Predisposition, and Life Satisfaction: Evidence from the German Twin Family Panel

Both genes and the neighborhood are important for life satisfaction; however, there is little research on gene-environment interactions (GxE) that examines how the effect of genetic endowments varies as a function of the environmental context with life satisfaction as the outcome. This study investigated how neighborhood deprivation moderates the effects of genetic predisposition on life satisfaction. Using data from the German Twin Family Panel (TwinLife), we identified 760 dizygotic (DZ) twins and employed twin fixed-effect models to assess the GxE effects on life satisfaction. The findings reveal that the polygenic score (PGS) for subjective well-being is positively associated with life satisfaction. The effect of PGS for subjective well-being on life satisfaction is strongest for individuals living in moderately deprived areas, while it is weaker for those living in highly deprived and less deprived areas. Thus, there are signs of compensation in less deprived areas and, particularly, diathesis-stress/triggering in highly deprived areas.

genetics↗

bioRxiv2024

EnzymeCAGE: A Geometric Foundation Model for Enzyme Retrieval with Evolutionary Insights

Enzyme catalysis is fundamental to life, driving the chemical transformations that sustain biological processes and support industrial applications. However, unraveling the intertwined relationships between enzymes and their catalytic reactions remains a significant challenge. Here, we present EnzymeCAGE, a catalytic-specific geometric foundation model trained on approximately 1 million structure-informed enzyme-reaction pairs, spanning over 2,000 species and encompassing an extensive diversity of genomic and metabolic information. EnzymeCAGE features a geometry-aware multi-modal architecture coupled with an evolutionary information integration module, enabling it to effectively model the nuanced relationships between enzyme structure, catalytic function, and reaction specificity. EnzymeCAGE supports both experimental and predicted enzyme structures and is applicable across diverse enzyme families, accommodating a broad range of metabolites and reaction types. Extensive evaluations demonstrate EnzymeCAGEs state-of-the-art performance in enzyme function prediction, reaction de-orphaning, catalytic site identification, and biosynthetic pathway reconstruction. These results highlight its potential as a transformative foundation model for understanding enzyme catalysis and accelerating the discovery of novel biocatalysts.

synthetic biology↗

bioRxiv2024

H2B.W2, a Spermatocytes-specific Histone Variant, disrupts nucleosome stability and reduces chromatin compaction

Spermatogenesis is a highly regulated process that requires precise chromatin remodeling, which includes the incorporation of testis-specific histone variants. While several of these variants have been characterized, the role of H2B.W2, a member of the H2BW family, remains largely unclear. Here, we showed that H2B.W2 expression occurs mainly in spermatocytes, slightly later than its paralog H2B.W1. Cryo-electron microscopy (cryo-EM) analysis of H2B.W2-containing nucleosomes reveals a more relaxed conformation compared to canonical nucleosomes caused by weakened interactions between the outer DNA turn and the histone core. We pinpointed the N-terminal tail and 2 helix of H2B.W2, specifically residues D85 and Q101, as critical for nucleosome destabilization. Furthermore, we identify G73 within the L1 loop as a key residue involved in disrupting higher-order chromatin structure. Our findings suggest that H2B.W2-mediated nucleosome and chromatin destabilization may play a role in regulating gene expression during spermatogenesis, with potential implications for sperm development and function.

biochemistry↗

bioRxiv2024

Effect of OASL on OXA-induced immunogenic cell death in gastric cancer via cGAS-STING pathway

This study investigates the role of 2-5 oligoadenylate synthetase-like (OASL) in Oxaliplatin (OXA)-induced immunogenic cell death (ICD) in Gastric cancer (GC) cells through the cGAS-STING signaling pathway. Knockdown of OASL enhanced ICD expression, while overexpression had the opposite effect. RNA sequencing of OASL-knockdown and control GC cells treated with OXA revealed significant enrichment of the second messenger signaling pathway (cGAMP). cGAMP could directly activate STING as a second messenger, and cGAS was a key synthetic enzyme upstream of cGAMP. Next, the role of OASL in OXA-induced ICD in GC cells was validated through the cGAS-STING signaling pathway. The Co-IP and immunofluorescence results confirmed that the OASL and cGAS proteins can bind directly. Further research validated these findings in vivo. Results show that OASL regulates OXA-induced ICD in GC cells via the cGAS-STING pathway, impacting chemosensitivity. The findings suggest new targets and strategies for improving GC therapy by modulating OASL expression to enhance OXA sensitivity through immunogenic mechanisms.

cancer biology↗

bioRxiv2024

Structural and antigenic characterization of novel and diverse Henipavirus glycoproteins

Henipaviruses, a genus within the Paramyxoviridae family, include the highly virulent Nipah and Hendra viruses that cause reoccurring outbreaks of deadly disease. Recent discoveries of several new Paramyxoviridae species, including the zoonotic Langya virus, have revealed much higher antigenic diversity than currently characterized and prompted the reorganization of these viruses into the Henipavirus and Parahenipavirus genera. Here, to explore the limits of structural and antigenic variation in both genera, collectively referred to here as HNVs, we constructed an expanded, antigenically diverse panel of HNV fusion and attachment glycoproteins from 56 unique HNV strains that better reflects global HNV diversity. We expressed and purified the fusion protein ectodomains and the attachment protein head domains and studied their biochemical, biophysical and structural properties. We performed immunization experiments in mice leading to the elicitation of antibodies reactive to multiple HNV fusion proteins. Cryo-electron microscopy structures of diverse fusion proteins elucidated molecular determinants of differential pre-fusion state metastability and higher order contacts. A crystal structure of the Gamak virus attachment head domain revealed an additional domain appended to the conserved 6-bladed, {beta}-propeller fold. Taken together, these studies expand the known structural and antigenic limits of the HNVs, reveal new cross-reactive epitopes within both genera and provide foundational data for the development of broadly reactive countermeasures.

biochemistry↗

bioRxiv2024

Self-organizing human heart assembloids with autologous and developmentally relevant cardiac neural crest-derived tissues

Neural crest cells (NCCs) are a multipotent embryonic cell population of ectodermal origin that extensively migrate during early development and contribute to the formation of multiple tissues. Cardiac NCCs play a critical role in heart development by orchestrating outflow tract septation, valve formation, aortic arch artery patterning, parasympathetic innervation, and maturation of the cardiac conduction system. Abnormal migration, proliferation, or differentiation of cardiac NCCs can lead to severe congenital cardiovascular malformations. However, the complexity and timing of early embryonic heart development pose significant challenges to studying the molecular mechanisms underlying NCC-related cardiac pathologies. Here, we present a sophisticated functional model of human heart assembloids derived from induced pluripotent stem cells, which, for the first time, recapitulates cardiac NCC integration into the human embryonic heart in vitro. NCCs successfully integrated at developmentally relevant stages into heart organoids, and followed developmental trajectories known to occur in the human heart. They demonstrated extensive migration, differentiated into cholinergic neurons capable of generating nerve impulses, and formed mature glial cells. Additionally, they contributed to the mesenchymal populations of the developing outflow tract. Through transcriptomic analysis, we revealed that NCCs acquire molecular features of their cardiac derivatives as heart assembloids develop. NCC-derived parasympathetic neurons formed functional connections with cardiomyocytes, promoting the maturation of the cardiac conduction system. Leveraging this models cellular complexity and functional maturity, we uncovered that early exposure of NCCs to antidepressants harms the development of NCC derivatives in the context of the developing heart. The commonly prescribed antidepressant Paroxetine disrupted the expression of a critical early neuronal transcription factor, resulting in impaired parasympathetic innervation and functional deficits in cardiac tissue. This advanced heart assembloid model holds great promise for high-throughput drug screening and unraveling the molecular mechanisms underlying NCC-related cardiac formation and congenital heart defects. IN BRIEFHuman neural crest heart assembloids resembling the major directions of neural crest differentiation in the human embryonic heart, including parasympathetic innervation and the mesenchymal component of the outflow tract, provide a human-relevant embryonic platform for studying congenital heart defects and drug safety.

bioengineering↗

bioRxiv2024

Revealing long-range heterogeneous organization of nucleoproteins with N6-methyladenine footprinting

A major challenge in epigenetics is uncovering the dynamic distribution of nucleosomes and other DNA-binding proteins, which plays a crucial role in regulating cellular functions. Established approaches such as ATAC-seq, ChIP-seq, and CUT&RUN provide valuable insights but are limited by the ensemble nature of their data, masking the cellular and molecular heterogeneity that is often functionally significant. Recently, long-read sequencing technologies, particularly Single Molecule, Real-Time (SMRT/PacBio) sequencing, have introduced transformative capabilities, such as N6-methyladenine (6mA) footprinting. This technique enables the detection of joint binding events and long-range chromatin organization on individual DNA molecules spanning multiple kilobases. Despite the potential of 6mA footprinting, existing analytical tools for 6mA detection in SMRT sequencing data suffer from significant limitations in both performance and applicability, especially with the latest sequencing platform. To address these gaps, we developed a novel 6mA-calling pipeline based on polymerase kinetics analysis. Our approach significantly outperforms current tools in terms of accuracy and computational efficiency, setting a new benchmark for 6mA detection. Utilizing our optimized experimental and computational framework, we extensively mapped nucleosome positioning and transcription factor occupancy at the single-molecule level, revealing critical features of the transcription-associated epigenetic landscape. Additionally, our work established high-resolution, long-range binding events in mitochondrial DNA, revealing simultaneous loading of two sets of replication machinery onto the displacement loop (D-loop). Our study highlights the potential of 6mA footprinting in capturing the coordinate binding of nucleoproteins and unraveling heterogeneous epigenetic states with unprecedented resolution.

bioinformatics↗