Biology subjects

Si, Y.

Publications and source records attributed to Si, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Metabolic Divergence Between Healthy and Conditional Presenilin-1/2 knockout Dementia Model Mice under Chronic Nicotine exposure

Nicotine, a primary bioactive compound in tobacco, influences a wide range of metabolic pathways, with potential implications for neurodegenerative diseases such as Alzheimers disease (AD). This study investigates the metabolic effects of chronic nicotine administration in presenilin-1/2 double knockout (DKO) mice and wild-type (WT) control mice. Eight-month-old DKO and WT mice underwent a three-month oral nicotine administration which did not significantly affect body weight or spontaneous locomotor activity in either DKO or WT mice, as measured by weekly body weight measurement and open field test. The metabolomic analyses were performed using untargeted LC-MS and GC-MS techniques. The results revealed distinct metabolic profiles between DKO and WT mice under nicotine exposure. In DKO mice, nicotine exacerbated deficits in purine and nicotinamide metabolism, further highlighting dysregulation in energy homeostasis. Key findings include reduced adenosine and elevated dopamine levels in DKO serum, alongside increased cotinine concentrations, suggesting altered nicotine metabolism. WT mice showed significant changes in energy and lipid metabolism pathways, though with less pronounced alterations compared to DKO mice. Enrichment analyses identified significant pathway disruptions, particularly in choline metabolism, amino acid metabolism, and central carbon metabolism, with genotype-dependent responses to nicotine. This study highlights the intrinsic metabolic alterations in DKO mice, such as disruptions in purine and nicotinamide metabolism, which contribute to their neurodegenerative pathology and unique responses to nicotine. By revealing the differential metabolic impacts of nicotine on healthy and neurodegenerative states, the findings provide valuable insights into its dual therapeutic and pathological roles. These results may guide future research into the metabolic underpinnings of neurodegeneration and the potential for nicotine as a targeted therapeutic intervention.

neuroscience↗

bioRxiv2024

Lack of Ameliorative Effect of Chronic Oral Nicotine on Olfactory Dysfunction in Young Adult Presenilin-1/2 Double Knockout Mice of a Dementia Model

Olfactory dysfunction is a prevalent and early feature of neurodegenerative diseases including Alzheimers disease while the features and underlying mechanisms remain inadequately understood. This investigation aimed to elucidate the olfactory function characteristics of presenilin-1/2 double knockout (DKO) mice, an established mouse model of dementia. Through a series of behavioral tests on DKO and wildtype (WT) mice at 2 and 6 months of age, we assessed their abilities in odor detection, discrimination, and olfactory memory. The findings revealed a substantial deficit in odor detection in 2-month-old DKO mice compared to WT mice, with a noteworthy age-related deterioration observed from 2 to 6 months. Although DKO mice exhibited normal odor discrimination and olfactory memory capabilities at 2 months, these functions declined with age, falling significantly lower levels than observed in WT mice by the age of 6 months. Subsequently, 2-month-old DKO and WT mice underwent a 4-month chronic nicotine treatment through drinking water. This intervention failed to ameliorate olfactory dysfunctions in DKO mice and exhibited no significant impact on WT mice, despite a discernible trend of a potential negative effect. In summary, this behavioral study elucidates that Presenilin-1/2 double knockout impairs odor detection in young adult mice and accelerates declines of olfactory discrimination and memory. The chronic administration of nicotine did not effectively mitigate olfactory function deficiencies in young adult DKO mice, and the results also highlight age as an important contributing factor.

animal behavior and cognition↗

bioRxiv2024

The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity

Amyotrophic lateral sclerosis (ALS) is an age-related and fatal neurodegenerative disease characterized by progressive muscle weakness. There is marked heterogeneity in clinical presentation, progression, and pathophysiology with only modest treatments to slow disease progression. Molecular markers that provide insight into this heterogeneity are crucial for clinical management and identification of new therapeutic targets. In a prior muscle miRNA sequencing investigation, we identified altered FGF pathways in ALS muscle, leading us to investigate FGF21. We analyzed human ALS muscle biopsy samples and found a large increase in FGF21 expression with localization to atrophic myofibers and surrounding endomysium. A concomitant increase in FGF21 was detected in ALS spinal cords which correlated with muscle levels. FGF21 was increased in the SOD1G93A mouse beginning in presymptomatic stages. In parallel, there was dysregulation of the co-receptor, {beta}-Klotho. Plasma FGF21 levels were increased and high levels correlated with slower disease progression, prolonged survival, and increased body mass index. In NSC-34 motor neurons and C2C12 muscle cells expressing SOD1G93A or exposed to oxidative stress, ectopic FGF21 mitigated loss of cell viability. In summary, FGF21 is a novel biomarker in ALS that correlates with slower disease progression and exerts trophic effects under conditions of cellular stress.

neuroscience↗

bioRxiv2024

The m6A reader IGF2BP3 promotes gastric cancer progression via increasing the expression of FBXO32 protein

N6-methyladenosine (m6A) represents the most prevalent chemical modification on eukaryotic mRNA, with an accumulating body of literature indicating its pivotal significance in the pathogenesis of human cancers. Nevertheless, the precise molecular interplay between the m6A reader protein IGF2BP3 and gastric cancer remains to be thoroughly delineated. Our study uncovered that the expression of IGF2BP3 in gastric cancer tissues is markedly elevated in comparison to adjacent normal tissues, and this upregulation is tightly correlated with the incidence of lymph node metastasis, more advanced TNM stages, and deeper invasion depth of tumor in patients. In vitro experiments demonstrated that IGF2BP3 potentiates the proliferative, migratory, and invasive capacities of gastric cancer cells, while concurrently inhibiting apoptosis and augmenting the intracellular levels of aerobic glycolysis. In vivo experiments revealed that IGF2BP3 contributes to the growth of gastric cancer. Mechanistically, IGF2BP3 can increase the expression of FBXO32 protein by recognizing and binding to the m6A binding site on FBXO32 mRNA and further activate the downstream cGMP-PKG signaling pathway, thereby modulating various biological functions of gastric cancer cells and ultimately promoting the progression of gastric cancer. In summary, our findings suggest that IGF2BP3 upregulates the expression of FBXO32 protein in an m6A dependent manner and subsequently activates the cGMP-PKG signaling pathway, ultimately leading to the onset and progression of gastric cancer. Consequently, the targeting of the IGF2BP3/FBXO32/cGMP-PKG axis emerges as a promising therapeutic modality for the treatment of gastric cancer.

cancer biology↗

bioRxiv2024

The long-chain fatty acid-CoA ligase FadD1 monitors Pseudomonas aeruginosa quorum sensing as a receptor of cis-2-decenoic acid

Diffusible signal factor (DSF)-family quorum sensing (QS) signals are widely utilized by many bacterial pathogens to modulate various biological functions and virulence. Previous studies showed that cis-2-decenoic acid (cis-DA) is involved in modulation of biofilm dispersion in Pseudomonas aeruginosa, but its signaling mechanism remains vague. Here, we report that cis-DA regulates the physiology and virulence of P. aeruginosa through the long-chain fatty acid-CoA ligase FadD1. Cis-DA specifically binds to FadD1 with high affinity and enhances the binding of FadD1 to the promoter DNA region of lasR. Further analysis showed that the FadD1 is a response regulator of cis-DA with a DNA-binding leucine zipper motif to control the transcription of various target genes. Moreover, FadD1 exhibited catalytic activity on cis-2-dodecenoic acid (BDSF) of Burkholderia cenocepacia and enhanced the competitiveness of P. aeruginosa. Together, our work presents a new DSF-type QS signaling system, which is highlighted by its receptor and response regulator evolved from a canonical enzyme of fatty acid metabolism. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/598097v2_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@66b8aaorg.highwire.dtl.DTLVardef@1e5b9b9org.highwire.dtl.DTLVardef@1043525org.highwire.dtl.DTLVardef@13d3ed1_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsThe long-chain fatty acid-CoA ligase FadD1 acts as a global transcriptional regulator in P. aeruginosa. FadD1 is a receptor of QS signal cis-DA and functions at the top of the QS hierarchy in P. aeruginosa. The homolog of FadD1 in P. fluorescens could bind to the target gene promoter by responding to cis-DA. In briefPseudomonas aeruginosa is a human pathogen with antibiotic resistance and a wide range of dynamic defenses makes it an extremely challenging organism to treat in modern-day medicine. It employs cis-2-decenoic acid (cis-DA) quorum sensing to regulate the physiology and pathogenesis. Song et al. demonstrate that the long-chain fatty acid-CoA ligase FadD1 controls the important biological functions and virulence in P. aeruginosa as a novel response regulator of cis-DA signal.

microbiology↗

bioRxiv2024

Late-Stage Skeletal Muscle Transcriptome in Duchenne muscular dystrophy shows a BMP4-Induced Molecular Signature

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disease due to loss-of-function mutations in the DYSTROPHIN gene. DMD-related skeletal muscle wasting is typified by an aberrant immune response involving upregulation of TGF{beta} family of cytokines. We previously demonstrated that bone morphogenetic protein 4 (BMP4) is increased in DMD and BMP4 stimulation induces a 20-fold upregulation of Smad8 transcription. However, the role of BMP4 in severely affected DMD skeletal muscle is unknown. We hypothesized that transcriptomic signatures in severely affected human DMD skeletal muscle are driven by BMP4 signaling. Transcriptomes from skeletal muscle biopsies of late-stage DMD vs. non-DMD controls and C2C12 muscle cells with or without BMP4 stimulation were generated by RNA-Seq and analyzed for single transcript differential expression as well as by Ingenuity Pathway Analysis and weighted gene co-expression network analyses. A total of 2,328 and 5,291 transcripts in the human muscle and C2C12 muscle cells, respectively, were differentially expressed. We identified an overlapping molecular signature of 1,027 genes dysregulated in DMD muscle that were induced in BMP4-stimulated C2C12 muscle cells. Highly upregulated DMD transcripts that overlapped with BMP4-stimulated C2C12 muscle cells included ADAMTS3, HCAR2, SERPING1, SMAD8, and UNC13C. The DMD transcriptome was characterized by dysregulation of pathways involving immune function, extracellular matrix remodeling, and metabolic/mitochondrial function. In summary, we define a late-stage DMD skeletal muscle transcriptome that substantially overlaps with the BMP4-induced molecular signature in C2C12 muscle cells. This supports BMP4 as a disease-driving regulator of transcriptomic changes in late-stage DMD skeletal muscle and expands our understanding of the evolution of dystrophic signaling pathways and their associated gene networks that could be explored for therapeutic development.

bioinformatics↗

bioRxiv2024

Seq-Scope Protocol: Repurposing Illumina Sequencing Flow Cells for High-Resolution Spatial Transcriptomics

Spatial transcriptomics (ST) technologies represent a significant advance in gene expression studies, aiming to profile the entire transcriptome from a single histological slide. These techniques are designed to overcome the constraints faced by traditional methods such as immunostaining and RNA in situ hybridization, which are capable of analyzing only a few target genes simultaneously. However, the application of ST in histopathological analysis is also limited by several factors, including low resolution, a limited range of genes, scalability issues, high cost, and the need for sophisticated equipment and complex methodologies. Seq-Scope--a recently developed novel technology--repurposes the Illumina sequencing platform for high-resolution, high-content spatial transcriptome analysis, thereby overcoming these limitations. Here we provide a detailed step-by-step protocol to implement Seq-Scope with an Illumina NovaSeq 6000 sequencing flow cell that allows for the profiling of multiple tissue sections in an area of 7 mm x 7 mm or larger. In addition to detailing how to prepare a frozen tissue section for both histological imaging and sequencing library preparation, we provide comprehensive instructions and a streamlined computational pipeline to integrate histological and transcriptomic data for high-resolution spatial analysis. This includes the use of conventional software tools for single cell and spatial analysis, as well as our recently developed segmentation-free method for analyzing spatial data at submicrometer resolution. Given its adaptability across various biological tissues, Seq-Scope establishes itself as an invaluable tool for researchers in molecular biology and histology. KEY POINTSO_LIThe protocol outlines a method for repurposing an Illumina NovaSeq 6000 flow cell as a spatial transcriptomics array, enabling the generation of high-resolution spatial datasets. C_LIO_LIThe protocol introduces a streamlined data analysis pipeline that produces a spatial digital gene expression matrix suitable for various single-cell and spatial transcriptome analysis methods. C_LIO_LIThe protocol allows for the capture of histology images from the same tissue section subjected to spatial transcriptomics analysis and allows users to precisely align the transcriptome dataset with the histological image using fiducial marks engraved on the flow cell surface. C_LIO_LILeveraging commonly available Illumina equipment, the protocol offers researchers ultra-high submicrometer resolution in spatial transcriptomics analysis with a comprehensive pipeline, rapid turnaround, cost efficiency, and versatility. C_LI

genomics↗

bioRxiv2024

An Innovative Mitochondrial-targeted Gene Therapy for Cancer Treatment

Targeting cancer cell mitochondria holds great therapeutic promise, yet current strategies to specifically and effectively destroy cancer mitochondria in vivo are limited. Here, we introduce mLumiOpto, an innovative mitochondrial-targeted luminoptogenetics gene therapy designed to directly disrupt the inner mitochondrial membrane (IMM) potential and induce cancer cell death. We synthesize a blue light-gated channelrhodopsin (CoChR) in the IMM and co-express a blue bioluminescence-emitting Nanoluciferase (NLuc) in the cytosol of the same cells. The mLumiOpto genes are selectively delivered to cancer cells in vivo by using adeno-associated virus (AAV) carrying a cancer-specific promoter or cancer-targeted monoclonal antibody-tagged exosome-associated AAV. Induction with NLuc luciferin elicits robust endogenous bioluminescence, which activates mitochondrial CoChR, triggering cancer cell IMM permeability disruption, mitochondrial damage, and subsequent cell death. Importantly, mLumiOpto demonstrates remarkable efficacy in reducing tumor burden and killing tumor cells in glioblastoma or triple-negative breast cancer xenografted mouse models. These findings establish mLumiOpto as a novel and promising therapeutic strategy by targeting cancer cell mitochondria in vivo.

cancer biology↗

bioRxiv2024

High-Resolution Spatial Transcriptomic Atlas of Mouse Soleus Muscle: Unveiling Single Cell and Subcellular Heterogeneity in Health and Denervation

Skeletal muscle exhibits pronounced cellular and subcellular heterogeneity, but comprehensive spatial mapping has been constrained by cell/nuclei dissociation-based methods that lose tissue architecture and by spatial platforms with insufficient resolution or limited transcriptome coverage. Here we present a high-resolution spatial transcriptomic atlas of mouse soleus muscle in longitudinal sections with unbiased whole-transcriptome coverage, enabling myofiber-resolved transcriptomes while preserving subcellular expression domains across the length of fibers. Combining histology-guided myofiber segmentation with unbiased grid-based mapping, we recover canonical fiber types and reveal widespread hybrid myofiber states in situ, including type IIb-associated signatures that are rare in soleus muscle and evident only when intramyofiber heterogeneity is assessed. At subcellular scale, we delineate the neuromuscular junction (NMJ) as a multi-compartment niche comprising postsynaptic myonuclei and spatially distinct peri-synaptic and myelinating Schwann cell-associated regions, each with characteristic gene programs. Applying this framework to denervation (3 and 7 days) identifies robust fiber-type-specific stress responses, coordinated remodeling of macrophage and fibroblast transcriptomes, and marked intramyofiber heterogeneity, including spatially nonuniform activation of damage-response genes along individual myofibers, with distinct transcriptional domains proximal and distal to the NMJ and associated degenerative histological features. Together, this atlas provides a high-resolution reference for muscle biology and clarifies how denervation reshapes myofiber, synaptic, and stromal-immune programs across cells and within cells in intact tissue.

physiology↗

bioRxiv2023

INHBA/Activin A promotes tumor growth and induces resistance to anti-PD-L1 therapy by suppressing IFN-γ signaling

Inhibin beta A (INHBA) and its homodimer activin A have pleiotropic effects on modulation of immune responses and tumor progression, respectively, but it remains uncertain whether tumors may release activin A to regulate anti-tumor immunity. As evidenced by our RNA-Seq and in vitro results, the interferon-{gamma} (IFN-{gamma}) signaling pathway was significantly down-regulated by tumor intrinsic activin A. Tumor INHBA deficiency led to lower expression of PD-L1 induced by IFN-{gamma}, resulting in poor responsiveness to anti-PD-L1 therapy. On the other hand, decreased secretion of IFN-{gamma}-stimulated chemokines, including C-X-C motif chemokine 9 (CXCL9) and 10 (CXCL10), impaired the infiltration of effector T cells into the tumor microenvironment. Furthermore, the activin A-specific antibody garetosmab improved anti-tumor immunity and its combination with the anti-PD-L1 antibody atezolizumab showed a superior therapeutic effect to monotherapy. Our findings reveal that INHBA/activin A is involved in anti-tumor immunity by inhibiting the IFN-{gamma} signaling pathway and considered to be a potential target to overcome anti-PD-L1 resistance in clinical cancer treatment.

immunology↗

bioRxiv2023

FICTURE: Scalable segmentation-free analysis of sub-micron resolution spatial transcriptomics

Spatial transcriptomics (ST) technologies have advanced to enable transcriptome-wide gene expression analysis at submicron resolution over large areas. Analysis of high-resolution ST data relies heavily on image-based cell segmentation or gridding, which often fails in complex tissues due to diversity and irregularity of cell size and shape. Existing segmentation-free analysis methods scale only to small regions and a small number of genes, limiting their utility in high-throughput studies. Here we present FICTURE, a segmentation-free spatial factorization method that can handle transcriptome-wide data labeled with billions of submicron resolution spatial coordinates. FICTURE is orders of magnitude more efficient than existing methods and it is compatible with both sequencing- and imaging-based ST data. FICTURE reveals the microscopic ST architecture for challenging tissues, such as vascular, fibrotic, muscular, and lipid-laden areas in real data where previous methods failed. FICTUREs cross-platform generality, scalability, and precision make it a powerful tool for exploring high-resolution ST.

bioinformatics↗

bioRxiv2023

Reference-free multiplexed single-cell sequencing identifies genetic modifiers of the human immune response

Multiplexed single-cell sequencing (mux-seq) using single-nucleotide polymorphisms (SNPs) has emerged as an efficient approach to perform expression quantitative trait loci (eQTL) studies that map interactions between genetic variants and cell types, cell states, or experimental perturbations. Here we introduce the clue framework, a novel approach to encode mux-seq experiments that eliminates the need for reference genotypes and experimental barcoding. The clue framework is made possible by the development of freemuxlet, an algorithm that clusters cells based on SNPs called from single-cell RNA-seq or ATAC-seq data. To demonstrate the feasibility of clue, we profiled the surface protein and RNA abundances of peripheral blood mononuclear cells from 64 individuals, stimulated with 5 distinct extracellular stimuli -- all within a single day. Our analysis of the demultiplexed data identified rare immune cell types and cell type-specific responses to interferon and toll-like receptor stimulation. Furthermore, by integrating genotyping data, we mapped response eQTLs specific to certain cell types. These findings showcase the potential and scalability of the clue framework for reference-free multiplexed single-cell sequencing studies.

genomics↗

bioRxiv2023

Migratory herbivorous waterfowl couple the seed wave and the green wave during spring migration

East Asian herbivorous waterfowl intensively use farmland in spring, next to their natural habitat. Accordingly, they might have expanded their migration strategy from merely tracking the green wave of newly emerging vegetation to also incorporating the availability of post-harvest agricultural seeds (here dubbed the seed wave). However, if and how waterfowl use multiple food resources to time their seasonal migration is still unknown. We test this migration strategy using 167 spring migration tracks of five East Asian herbivorous waterfowl species and mixed-effect resource selection function models. We find all study species arrive at their core stopover sites in the Northeast China Plain after agricultural seeds become available, extend their stay after spring vegetation emerges, and arrive at breeding sites around the emergence of vegetation. Moreover, the cue used in exploiting the availability of both food resources varies in different regions and among species. At the core stopover sites, larger-bodied species use the seed wave and smaller-bodied ones adopt the green wave. At the breeding sites, the former follow the green wave, and the latter track the snow-free time. Our findings suggest that waterfowl track multiple resource waves to finetune their migration, highlighting new opportunities for conservation.

ecology↗

bioRxiv2023

Inferring CpG methylation signatures accumulated along human history from genetic variation catalogs

Understanding the DNA methylation patterns in the human genome is a key step to decipher gene regulatory mechanisms and model mutation rate heterogeneity in the human genome. We analyzed existing whole genome bisulfite sequencing (WGBS) data across tissues and large genetic variation catalogs and observed that 93.2% CpGs hyper-methylated in sperm are polymorphic. Moreover, methylation status of CpGs is spatially correlated, as 94% of CpG pairs within 1kb share the same methylation status. Leveraging only these properties, we infer germline CpG methylation in the human population using a new method, Methylation Hidden Markov Model (MHMM), and the polymorphism data from TOPMed. Our inference is orthogonal to WGBS-based experimental results; still we observed 90% concordance with human sperm WGBS while overcoming several challenges in that data: We inferred methylation status for [~] 721, 000 CpG sites that were missing from WGBS due to low coverage, and show that 42.2% of CpGs with allele frequency > 5% are hyper-methylated in the population but could not be captured in WGBS due to sample genetic variation. Our results provide a unique resource for CpG methylation levels in germline cells complementary to the existing WGBS-based measures, and can thus be leveraged to enhance analysis such as annotating regulatory and inactivated genomic regions in the germline.

genetics↗

bioRxiv2023

A novel triptolide analog downregulates NF-κB and induces mitochondrial apoptosis pathways in human pancreatic cancer

BackgroundPancreatic cancer is the seventh leading cause of cancer-related death worldwide, and despite advancements in disease management, the 5-year survival rates stands at only 9%. Triptolides have potent anti-tumor activity against different types of cancers, including pancreatic cancer, however poor solubility and toxicity limit their translation into clinical use. MethodsWe synthesized a novel pro-drug of triptolide, (E)-19-[(1-benzoyloxy-1-phenyl)-methylidene]-Triptolide (CK21), and formulated into an emulsion for in vitro and in vivo testing in rats and mice, and using human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids. A time-course transcriptomic profiling of tumor organoids treated with CK21 in vitro was conducted to define its mechanism of action, as well as transcriptomic profiling at a single time point post-CK21 administration in vivo. FindingsIntravenous administration of emulsified CK21 resulted in the stable release of triptolide, and potent anti-proliferative effects on human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids in vitro, and with minimal toxicity in vivo. Time course transcriptomic profiling of tumor organoids treated with CK21 in vitro revealed <10 differentially expressed genes (DEGs) at 3 h and [~]8,000 DEGs at 12 h. Overall inhibition of general RNA transcription was observed, and Ingenuity pathway analysis together with functional cellular assays confirmed inhibition of the NF-{kappa}B pathway, increased oxidative phosphorylation and mitochondrial dysfunction, leading ultimately to increased reactive oxygen species (ROS) production, reduced B-cell-lymphoma protein 2 (BCL2) expression, and mitochondrial-mediated tumor cell apoptosis. InterpretationCK21 is a novel pro-drug of triptolide that exerts potent anti-proliferative effects on human pancreatic tumors by inhibiting the NF-{kappa}B pathway, leading ultimately to mitochondrial-mediated tumor cell apoptosis. FundingThe study of the anti-tumor efficacy of CK21 supported in part by a research grant from Cinkate Pharmaceutical Corp; the funders had no role in the study design, interpretation or decision to publish. Patient-derived pancreatic tumor organoids were a generous gift from the Organoid and Primary Culture Research Core at University of Chicago.

pharmacology and toxicology↗

bioRxiv2023

Protein language model embedded geometric graphs power inter-protein contact prediction

Accurate prediction of contacting residue pairs between interacting proteins is very useful for structural characterization of protein-protein interactions (PPIs). Although significant improvement has been made in inter-protein contact prediction recently, there is still large room for improving the prediction accuracy. Here we present a new deep learning method referred to as PLMGraph-Inter for inter-protein contact prediction. Specifically, we employ rotationally and translationally invariant geometric graphs obtained from structures of interacting proteins to integrate multiple protein language models, which are successively transformed by graph encoders formed by geometric vector perceptrons and residual networks formed by dimensional hybrid residual blocks to predict inter-protein contacts. Extensive evaluation on multiple test sets illustrates that PLMGraph-Inter outperforms five top inter-protein contact prediction methods, including DeepHomo, GLINTER, CDPred, DeepHomo2 and DRN-1D2D_Inter by large margins. In addition, we also show that the prediction of PLMGraph-Inter can complement the result of AlphaFold-Multimer. Finally, we show leveraging the contacts predicted by PLMGraph-Inter as constraints for protein-protein docking can dramatically improve its performance for protein complex structure prediction.

bioinformatics↗

bioRxiv2022

Improved inter-protein contact prediction using dimensional hybrid residual networks and protein language models

The knowledge of contacting residue pairs between interacting proteins is very useful for structural characterization of protein-protein interactions (PPIs). However, accurately identifying the tens of contacting ones from hundreds of thousands of inter-protein residue pairs is extremely challenging, and performances of the state-of-the-art inter-protein contact prediction methods are still quite limited. In this study, we developed a deep learning method for inter-protein contact prediction, referred to as DRN-1D2D_Inter. Specifically, we employed pretrained protein language models to generate structural information enriched input features to residual networks formed by dimensional hybrid residual blocks to perform inter-protein contact prediction. Extensively benchmarked DRN-1D2D_Inter on multiple datasets including both heteromeric PPIs and homomeric PPIs, we show DRN-1D2D_Inter consistently and significantly outperformed two state-of-the-art inter-protein contact prediction methods including GLINTER and DeepHomo, although both the latter two methods leveraged native structures of interacting proteins in the prediction, and DRN-1D2D_Inter made the prediction purely from sequences.

bioinformatics↗

bioRxiv2022

Strong and consistent associations of waterbird community composition with HPAI H5 occurrence in European wild birds

Since 2014, highly pathogenic avian influenza (HPAI) H5 viruses of clade 2.3.4.4 have been dominating the outbreaks across Europe, causing massive deaths among poultry and wild birds. However, the factors shaping its broad-scale outbreak patterns remain unclear. With extensive waterbird survey datasets of about 7,000 sites across Europe, we here demonstrated that H5N8 occurrence in wild birds in the 2016/17 and 2020/21 epidemics as well as H5N1 occurrence in 2005/06 epidemic were strongly associated with very similar waterbird community attributes, pointing to the possibility of similar interspecific transmission processes between different epidemics. A simple extrapolation of the model constructed from the 2016/17 epidemic can well predict the H5N8 pattern in wild birds in 2020/21 epidemic. We also found a dilution effect of phylogenetic diversity that was always negatively correlated with H5 occurrence in wild birds. In contrast, H5N8 occurrence in poultry was subject to different risk factors between the two epidemics. In general, waterbird community composition play a much more important role in determining the spatial pattern of H5N8 in wild birds than in poultry. Our work contributes to reveal the factors driving H5N8 patterns, and highlights the value of waterbird community factors in future HPAI surveillance and prediction.

ecology↗