Biology subjects

Wu, F.

Publications and source records attributed to Wu, F..

At least 127 records · Page 7Linked to original sources

bioRxiv2023

Somatic mutation but not aneuploidy differentiates lung cancer in never-smokers and smokers.

Lung cancer in never-smokers disproportionately affects older women. To understand the mutational landscape of this cohort, we performed detailed genome characterization of 73 lung adenocarcinomas from participants of the Womens Health Initiative (WHI). We find enrichment of EGFR mutations in never-/light-smokers and KRAS mutations in heavy smokers as expected, but we also show that the specific variants of these genes differ by smoking status, with important therapeutic implications. Mutational signature analysis revealed signatures of clock, APOBEC, and DNA repair deficiency in never-/light-smokers; however, the mutational load of these signatures did not differ significantly from those found in smokers. Last, tumors from both smokers and never-/light-smokers shared copy number subtypes, with no significant differences in aneuploidy. Thus, the genomic landscape of lung cancer in never-/light-smokers and smokers is predominantly differentiated by somatic mutations and not copy number alterations.

genomics↗

bioRxiv2023

When Geometric Deep Learning Meets Pretrained Protein Language Models

Geometric deep learning has recently achieved great success in non-Euclidean domains, and learning on 3D structures of large biomolecules is emerging as a distinct research area. However, its efficacy is largely constrained due to the limited quantity of structural data. Meanwhile, protein language models trained on substantial 1D sequences have shown burgeoning capabilities with scale in a broad range of applications. Nevertheless, no preceding studies consider combining these different protein modalities to promote the representation power of geometric neural networks. To address this gap, we make the foremost step to integrate the knowledge learned by well-trained protein language models into several state-of-the-art geometric networks. Experiments are evaluated on a variety of protein representation learning benchmarks, including protein-protein interface prediction, model quality assessment, protein-protein rigid-body docking, and binding affinity prediction, leading to an overall improvement of 20% over baselines and the new state-of-the-art performance. Strong evidence indicates that the incorporation of protein language models knowledge enhances geometric networks capacity by a significant margin and can be generalized to complex tasks.

bioinformatics↗

bioRxiv2022

Lipoprotein sorting to the cell surface via a crosstalk between the Lpt and Lol pathways during outer membrane biogenesis

Lipopolysaccharide (LPS) and lipoprotein, two essential components of the outer membrane (OM) in Gram-negative bacteria, play critical roles in bacterial physiology and pathogenicity. LPS translocation to the OM is mediated by LptDE, yet how lipoproteins sort to the cell surface remains elusive. Here we report the identification of an inventory of lipoproteins that are transported to the cell surface via LptDE. Notably, we determined crystal structures of LptDE from Pseudomonas aeruginosa and its complex with an endogenous Escherichia coli lipoprotein YifL. The paLptDE-YifL structure demonstrates that YifL translocates to the OM via LptDE, in a manner similar to LPS transport. The {beta}-barrel domain serves as a passage for the proteinaceous moiety while its acyl chains are transported outside. Our finding has been corroborated by results from native mass spectrometry, immunofluorescence, and photocrosslinking assays, revealing a unique mechanism through which lipoproteins are translocated across the OM in an ATP- and LPS-dependent manner. Moreover, our study expands the scope of current knowledge of lipoprotein sorting by disclosing a crosstalk between the Lpt and Lol pathways.

microbiology↗

bioRxiv2022

Fortuitous Somatic Mutations during Antibody Evolution Endow Broad Neutralization against SARS-CoV-2 Omicron Variants

Striking antibody evasion by emerging circulating SARS-CoV-2 variants drives the identification of broadly neutralizing antibodies (bNAbs). However, how a bNAb acquires increased neutralization breadth during antibody evolution is still elusive. Here, we identified a clonally-related antibody family from a convalescent individual. One of the members, XG005, exhibited potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members showed significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface revealed how crucial somatic mutations endowed XG005 with greater neutralization potency and breadth. A single administration of XG005 with extended half-life, reduced antibody-dependent enhancement (ADE) effect, and increased antibody product quality, exhibited a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provided a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency.

immunology↗

bioRxiv2022

A Deep Learning Approach for Histology-Based Nuclei Segmentation and Tumor Microenvironment Characterization

Microscopic examination of pathology slides is essential to disease diagnosis and biomedical research; however, traditional manual examination of tissue slides is laborious and subjective. Tumor whole-slide image (WSI) scanning is becoming part of routine clinical procedure and produces massive data that capture tumor histological details at high resolution. Furthermore, the rapid development of deep learning algorithms has significantly increased the efficiency and accuracy of pathology image analysis. In light of this progress, digital pathology is fast becoming a powerful tool to assist pathologists. Studying tumor tissue and its surrounding microenvironment provides critical insight into tumor initiation, progression, metastasis, and potential therapeutic targets. Nuclei segmentation and classification are critical to pathology image analysis, especially in characterizing and quantifying the tumor microenvironment (TME). Computational algorithms have been developed for nuclei segmentation and TME quantification within image patches; however, existing algorithms are computationally intensive and time-consuming for WSI analysis. In this study, we present Histology-based Detection using Yolo (HD-Yolo), a new method that significantly accelerates nuclei segmentation and TME quantification. We demonstrate that HD-Yolo outperforms existing methods for WSI analysis in nuclei detection and classification accuracy, as well as computation time.

pathology↗

bioRxiv2022

SapBase (Sapinaceae Genomic DataBase): a central portal for functional and comparative genomics of Sapindaceae species

Sapindaceae is a family of flowering plants, also known as the soapberry family, comprising 141 genera and about 1900 species (Pedro et al., 2010). Most of them are distributed in tropical and subtropical regions, including trees, shrubs, also woody or herbaceous vines. Some are dioecious, while others are monoecious. Many Sapindaceae species possess great economic value; some furnish delicious fruits, like lychee (Litchi chinensis), longan (Dimocarpus longan), rambutan (Nephelium lappaceum); and ackee (Blighia sapida) - the national fruit of Jamaica; some produce abundance secondary metabolites, like saponin from soapberry (Sapindus mukorossi), and seed oil from yellowhorn (Xanthoceras sorbifolium); some yield valuable timber including maple (Acer spp.) and buckeye (Aesculus glabra); and some are of great herbal medicinal value, like balloon-vine (Cardiospermum halicacabum). In the last decade, with the rocketing of next generation sequencing (NGS) and genomic technologies, the full genome sequences of several Sapindaceae plants have been resolved (Lin et al., 2017; Liang et al., 2019; Yang et al., 2019; Zhang et al., 2021; Hu et al., 2022; Xue et al., 2022). Among them, our recent publication of the lychee genome attracted broad attention (Edger, 2022; Hu et al., 2022; Lyu, 2022). Now the post-genome era arrives for Sapindaceae, however, there is no public genomic database available for any Sapindaceae species, let alone an integrative database for the whole Sapindaceae family. A unified data platform is in urgent need to collect, manage and share relevant data resources. Therefore, we integrated our home-brew NGS data with all publicly available data for seven Sapindaceae plants and constructed the Sapinaceae Genomic DataBase, named SapBase (www.sapindaceae.com), in order to provide genomic resources and an online powerful analytic platform for scientific research on Sapinaceae species and comparative studies with other plants.

genomics↗

bioRxiv2022

Physiological adaptation of sulfate reducing bacteria in syntrophic partnership with anaerobic methanotrophic archaea

Sulfate-coupled anaerobic oxidation of methane (AOM) is performed by multicellular consortia of anaerobic methanotrophic archaea (ANME) in obligate syntrophic partnership with sulfate-reducing bacteria (SRB). Diverse ANME and SRB clades co-associate but the physiological basis for their adaptation and diversification is not well understood. In this work, we explore the metabolic adaptation of four syntrophic SRB clades (HotSeep-1, Seep-SRB2, Seep-SRB1a and Seep-SRB1g) from a phylogenomics perspective, tracing the evolution of conserved proteins in the syntrophic SRB clades, and comparing the genomes of syntrophic SRB to their nearest evolutionary neighbors in the phylum Desulfobacterota. We note several examples of gain, loss or biochemical adaptation of proteins within pathways involved in extracellular electron transfer, electron transport chain, nutrient sharing, biofilm formation and cell adhesion. We demonstrate that the metabolic adaptations in each of these syntrophic clades are unique, suggesting that they have independently evolved, converging to a syntrophic partnership with ANME. Within the clades we also investigated the specialization of different syntrophic SRB species to partnerships with different ANME clades, using metagenomic sequences obtained from ANME and SRB partners in individual consortia after fluorescent-sorting of cell aggregates from anaerobic sediments. In one instance of metabolic adaptation to different partnerships, we show that Seep-SRB1a partners of ANME-2c appear to lack nutritional auxotrophies, while the related Seep-SRB1a partners of a different methanotrophic archaeal lineage, ANME-2a, are missing the cobalamin synthesis pathway, suggesting that the Seep-SRB1a partners of ANME-2a may have a nutritional dependence on its partner. Together, our paired genomic analysis of AOM consortia highlights the specific adaptation and diversification of syntrophic SRB clades linked to their associated ANME lineages.

microbiology↗

bioRxiv2022

Coupling of perinuclear actin cap and nuclear mechanics regulates flow-induced YAP spatiotemporal nucleocytoplasmic transport

Mechanical forces, including flow shear stress, regulate fundamental cellular process by modulating the nucleocytoplasmic transport of transcription factors, such as Yes-associated Protein (YAP). However, the mechanical mechanism how flow induces the nucleocytoplasmic transport remains largely unclear. Here we found that unidirectional flow applied to endothelial cells induces biphasic YAP nucleocytoplasmic transport with initial nuclear import, followed by nuclear export as perinuclear actin cap forms and nuclear stiffening in a dose and timing-dependent manner. In contrast, pathological oscillatory flow induces slight actin cap formation and nuclear softening, sustaining YAP nuclear localization. To explain the disparately spatiotemporal distribution of YAP, we developed a three-dimensional mechanochemical model considering coupling processes of flow sensing, cytoskeleton organization, nucleus mechanotransduction, and YAP spatiotemporal transport. We discovered that actin cap formation and nuclear stiffness alteration under flow synergically regulate nuclear deformation, hence governing YAP transport. Furthermore, we expanded our single cell model to a collective vertex framework and found that actin cap irregularities in individual cells under flow shear stress potentially induce topological defects and spatially heterogeneous YAP distribution in cellular monolayers. Our work unveils the unified mechanism of flow-induced nucleocytoplasmic transport, offering a universal linkage between transcriptional regulation and mechanical stimulation.

bioengineering↗

bioRxiv2022

tFold-Ab: Fast and Accurate Antibody Structure Prediction without Sequence Homologs

Accurate prediction of antibody structures is critical in analyzing the function of antibodies, thus enabling the rational design of antibodies. However, existing antibody structure prediction methods often only formulate backbone atoms and rely on additional tools for side-chain conformation prediction. In this work, we propose a fully end-to-end architecture for simultaneous prediction of backbone and side-chain conformations, namely tFold-Ab. Pre-trained language models are adopted for fast structure prediction by avoiding the time-consuming search for sequence homologs. The model firstly predicts monomer structures of each chain, and then refines them into heavy-light chain complex structure prediction, which enables multi-level supervision for model training. Evaluation results verify the effectiveness of tFold-Ab for both antibody and nanobody structure prediction. In addition, we provide a public web service for antibody structure prediction at https://drug.ai.tencent.com/en.

bioinformatics↗

bioRxiv2022

Manipulating Oxalate Decarboxylase Provides the Basis of Antilithic Therapy by Acting on the Gut Microbiota

A high concentration of oxalate is associated with an increased risk of kidney calcium oxalate (CaOx) stones, and the degradation of exogenous oxalate mainly depends on oxalate-degrading enzymes from the intestinal microbiome. We found that Zinc Gluconate supplement to patients with CaOx kidney stones could significantly improve the abundance of oxalate metabolizing bacteria in human body through clinical experiments on the premise of simultaneous antibiotic treatment and the imbalance of Lactobacillus and OxDC was involved in CaOx kidney stones through clinical sample analysis. Then, we identified that Zn2+ could be used as an external factor to improve the activity of OxDC and protect Lactobacillus, achieved the preventive effect on rats with stones aggravated by antibiotics. Finally, by analyzing the three-dimensional structure of OxDC and some in vitro experiments, we propose a hypothesis Zn2+ increases the metabolism of oxalate in humans through its positive effects on Lactobacillus and OxDC to reduce CaOx kidney stone symptoms in rats. IMPORTANCEUrinary stone disease is one of the most common urological disorders, and 70%-80% of urinary stones are calcium oxalate (CaOx) stones. We found the structural basis and metabolic mechanism by which oxalate decarboxylase metabolizes oxalate were elucidated, and Zn2+ was illustrated to have therapeutic effects on CaOx stones by improving the tolerance of Lactobacillus to antibiotics. According to that, proper Zn2+ levels in the diet, the consumption of more probiotic food and avoidance of the antibiotic overuse might be desirable measures for the prevention and treatment of kidney stones. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/512337v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@d3df85org.highwire.dtl.DTLVardef@1f7b3f5org.highwire.dtl.DTLVardef@147d861org.highwire.dtl.DTLVardef@1cf046e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

Increased public health threat of avian-origin H3N2 influenza virus during evolution in dogs

Influenza A viruses in animal reservoirs repeatedly cross species barrier to infect humans. Once an animal-borne virus with novel antigenicity acquired the efficient human to human transmissibility, it will become epidemic in the population. Dogs are the closest animal companions to humans and canine respiratory tract expresses both SA2,3-(avian type) and 2,6-Gal (human type) receptors. However, the role of dogs in the ecology of influenza viruses is unclear. H3N2 avian influenza viruses transmitted to dogs around 2006 and have formed stable lineages. The long-term epidemic of avian-origin H3N2 virus in canine offers the best models to investigate the effect of dogs on the evolution of influenza viruses. Here, we carried out a systematic and comparative identification of the biological characteristics of H3N2 canine influenza viruses (CIVs) isolated in the worldwide over 10 years. We found that during the adaptation of H3N2 CIVs to dogs, H3N2 CIVs became to recognize the human-like SA2,6-Gal receptor, gradually increased HA acid stability and replication ability in human airway epithelial cells, and acquired a 100% transmission rate via respiratory droplet in ferret model, which were essential hallmarks of being adapted to humans. We also identified that the frequency of substitutions related to human adaptation has gradually increased in H3N2 CIVs, and determined four cumulative molecular changes responsible for the increased airborne transmission ability in ferrets. Our results suggested that canine may serve as an intermediate for the adaptation of avian influenza virus to human. Continuous surveillance coordinated with risk assessment for CIVs is necessary.

microbiology↗

bioRxiv2022

Evolutionary Diversification of Methanotrophic Ca. Methanophagales (ANME-1) and Their Expansive Virome

Candidatus Methanophagales (ANME-1) is a major order-level clade of archaea responsible for methane removal in deep-sea sediments through the anaerobic oxidation of methane. Yet the extent of their diversity and factors which drive their dynamics and evolution remain poorly understood. Here, by sampling hydrothermal rocks and sediments, we expand their phylogenetic diversity and characterize a new deep-branching, thermophilic ANME-1 family, Candidatus Methanospirareceae (ANME-1c). They are phylogenetically closest to the short-chain-alkane oxidizers Candidatus Syntrophoarchaeales and Candidatus Alkanophagales, and encode ancestral features including a methyl coenzyme M reductase chaperone McrD and a hydrogenase complex. Global phylogeny and near-complete genomes clarified that the debated hydrogen metabolism within ANME-1 is an ancient trait that was vertically inherited but differentially lost during lineage diversification. Our expanded genomic and metagenomic sampling allowed the discovery of viruses constituting 3 new orders and 16 new families that so far are exclusive to ANME-1 hosts. These viruses represent 4 major archaeal virus assemblages, characterized by tailless icosahedral, head-tailed, rod-shaped, and spindle-shaped virions, but display unique structural and replicative signatures. Exemplified by the analyses of thymidylate synthases that unveiled a virus-mediated ancestral process of host gene displacement, this expansive ANME-1 virome carries a large gene repertoire that can influence their hosts across different timescales. Our study thus puts forth an emerging evolutionary continuum between anaerobic methane and short-chain-alkane oxidizers and opens doors for exploring the impacts of viruses on the dynamics and evolution of the anaerobic methane-driven ecosystems.

microbiology↗

bioRxiv2022

Proteomic Dynamics of Breast Cancers Identifies Potential Therapeutic Protein Targets

Treatment and relevant targets for breast cancer (BC) remain limited, especially for triple-negative BC (TNBC). We quantified the proteomes of 76 human BC cell lines using data independent acquisition (DIA) based proteomics, identifying 6091 proteins. We then established a 24-protein panel distinguishing TNBC from other BC types. Integrating prior multi-omics datasets with the present proteomic results to predict the sensitivity of 90 drugs, we found that proteomics data improved drug sensitivity predictions. The sensitivity of the 90 drugs was mainly associated with cell cytoskeleton, signal transduction and mitochondrial function. We next profiled the proteome changes of nine cell lines (five TNBC cell lines, four non-TNBC cell lines) perturbated by EGFR/AKT/mTOR inhibitors. In the TNBC cell lines, metabolism pathways were dysregulated after EGFR/mTOR inhibitors treatment, while RNA modification and cell cycle pathways were dysregulated after AKT inhibitor treatment. Our study presents a systematic multi-omics and in-depth analysis of the proteome of BC cells. This work aims to aid in prioritization of potential therapeutic targets for TNBC as well as to provide insight into adaptive drug resistance in TNBC.

systems biology↗

bioRxiv2022

A Comparison of Dimension Reduction Methods for Cytometry by Time-of-Flight Data

While experimental and informatic techniques around single cell sequencing (scRNA-seq) are advanced, research around mass cytometry (CyTOF) data analysis has severely lagged behind. CyTOF data are dramatically different from scRNA-seq data in many aspects. This calls for the evaluation and development of computational methods specific for CyTOF data. Dimension reduction (DR) is one of the critical steps of single cell data analysis. Here, we benchmark the performances of 21 DR methods on 110 real and 425 synthetic CyTOF samples. We find that less well-known methods like SAUCIE, SQuaD-MDS, and scvis are the overall best performers. In particular, SAUCIE and scvis are well balanced, SQuaD-MDS excels at structure preservation, whereas UMAP has great downstream analysis performance. We also find that t- SNE (along with SQuad-MDS/t-SNE Hybrid) possesses the best local structure preservation. Nevertheless, there is a high level of complementarity between these tools, so the choice of method should depend on the underlying data structure and the analytical needs.

bioinformatics↗

bioRxiv2022

ASD modelling in organoids reveals imbalance of excitatory cortical neuron subtypes during early neurogenesis

There is no clear genetic etiology or convergent pathophysiology for autism spectrum disorders (ASD). Using cortical organoids and single-cell transcriptomics, we modeled alterations in the formation of the forebrain between sons with idiopathic ASD and their unaffected fathers in thirteen families. Alterations in the transcriptome suggest that ASD pathogenesis in macrocephalic and normocephalic probands involves an opposite disruption of the balance between the excitatory neurons of the dorsal cortical plate and other lineages such as the early-generated neurons from the putative preplate. The imbalance stemmed from a divergent expression of transcription factors driving cell fate during early cortical development. While we did not find probands genomic variants explaining the observed transcriptomic alterations, a significant overlap between altered transcripts and reported ASD risk genes affected by rare variants suggests a degree of gene convergence between rare forms of ASD and developmental transcriptome in idiopathic ASD.

neuroscience↗

bioRxiv2022

The shifting epigenetic landscape and roles of key transcription factors during early retinal cell differentiation

How the diverse neural cell types emerge from multipotent neural progenitor cells during central nervous system development remains poorly understood. Recent scRNA-seq studies have delineated the developmental trajectories of individual neural cell types in many neural systems including the neural retina. Further understanding of the formation of neural cell diversity requires knowledge about how the epigenetic landscape shifts along individual cell lineages and how key transcription factors regulate these changes. In this study, we dissect the changes in the epigenetic landscape during early retinal cell differentiation by scATAC-seq and identify globally the enhancers, enriched motifs, and potential interacting transcription factors underlying the cell state/type specific gene expression in individual lineages. Using CUT&Tag, we further identify the enhancers bound directly by four key transcription factors, Otx2, Atoh7, Pou4f2, and Isl1, and uncover their roles in shaping the epigenetic landscape and controlling gene expression in a sequential and combinatorial fashion along individual retinal cell lineages such as retinal ganglion cells (RGCs). Our results reveal a general paradigm in which transcription factors collaborate and compete to regulate the emergence of distinct retinal cell types such as RGCs from multipotent retinal progenitor cells (RPCs).

developmental biology↗

bioRxiv2022

Rapid quantification of polyhydroxyalkanoates accumulated in living cells based on green fluorescence protein labeled phasin: The qPHA method

Polyhydroxyalkanoates (PHA), are microbial polyesters with possibility to replace non-biodegradable petro-plastics. No rapid in situ PHA quantitation method has been available for the past 40 years to replace the traditional method which is complicated, time and labor consuming. Quantification of PHA in living cells were finally developed from fluorescence intensities generated from green fluorescence protein (GFP) fused with the Halomonas bluephagenesis phasin proteins attached on the PHA granules. Phasins PhaP1 and PhaP2 were used to fuse with GFP which reflects PHA accumulation with an R-square over 0.9, respectively. Also, a standard correlation was established to calculate PHA contents based on the fluorescence and cell density recorded via a microplate reader with R-square over 0.95 when grown on various substrates, respectively. The PhaP2-GFP containing H. bluephagenesis was applied successfully to quantify PHA synthesis in a 7.5 L fermenter with high precision. The method is named qPHA.

bioengineering↗

bioRxiv2022

Fuzzy Supertertiary Interactions within PSD-95 Enable Ligand Binding

The scaffold protein PSD-95 links postsynaptic receptors to sites of presynaptic neurotransmitter release. Flexible linkers between folded domains in PSD-95 enable a dynamic supertertiary structure. Interdomain interactions within the PSG supramodule, formed by PDZ3, SH3 and GuK domains, regulate PSD-95 activity. Here we combined Discrete Molecular Dynamics and single molecule FRET to characterize the PSG supramodule, with time resolution spanning picoseconds to seconds. We used a FRET network to measure distances in full-length PSD-95 and model the conformational ensemble. We found that PDZ3 samples two conformational basins, which we confirmed with disulfide mapping. To understand effects on activity, we measured binding of the synaptic adhesion protein neuroligin. We found that PSD-95 bound neuroligin well at physiological pH while truncated PDZ3 bound poorly. Our hybrid structural models reveal how the supertertiary context of PDZ3 enables recognition of this critical synaptic ligand.

biophysics↗