Biology subjects

Liu, H.

Publications and source records attributed to Liu, H..

At least 451 records · Page 25Linked to original sources

bioRxiv2024

The long noncoding RNA lnc-FANCI-2 restricts RAS signaling and phosphorylation of Akt and Erk in HPV16-infected cervical cancer cells

We recently discovered the expression of a long noncoding RNA, lnc-FANCI-2, coinciding with cervical lesion progression from CIN1, CIN2-3 to cervical cancer. Viral E7 of high-risk HPVs and host transcription factor YY1 are two major factors promoting lnc-FANCI-2 expression. To explore possible roles of lnc-FANCI-2 in HPV-induced cervical carcinogenesis, we ablated the expression of lnc-FANCI-2 in the HPV16-positive cervical cancer cell line, CaSki. Knock-out (KO) single cell clones expressed HPV16 oncogenes normally but displayed altered cell morphology and proliferation when compared with the parental cells. Proteomic profiling of cytosolic and secreted proteins from the parental and KO cells showed that lnc-FANCI-2 regulates expression of a subset of cell soluble receptors responsible for cell signaling, epithelial mesenchymal transition, and IFN responses. RNA-seq analyses revealed that, relative to the parental cells, lnc-FANCI-2 KO cells exhibited significantly increased RAS signaling but decreased IFN pathways. In the KO cells, phosphorylated Akt and Erk1/2, two important RAS pathway effectors, were increased more than 3-fold, accompanied by increase of IGFBP3, MCAM, VIM, and CCND2 (cyclin D2) and decrease of RAC3 expression. High levels of lnc-FANCI-2 and lower levels of MCAM in cervical cancer patients are associated with improved survival. We found that lnc-FANCI-2 interacts specifically with 32 host proteins, including H13, HNRH1, K1H1, MAP4K4, and RNPS1, and knockdown of MAP4K4 in CaSki cells led to an increase of phosphorylation of Erk1/2 and somewhat Akt. In summary, a key function of lnc-FANCI-2 is to intrinsically regulate RAS signaling to impact cervical lesion progression and affect cervical cancer prognosis. SignificanceExpression of lnc-FANCI-2 is related to cervical lesion progression. Knock-out (KO) or knock-down (KD) of lnc-FANCI-2 expression in HPV16-positive cervical cancer cells CaSki significantly increases RAS signaling, phosphorylation of Akt and Erk1/2, and the epithelial mesenchymal transition factors. lnc-FANCI-2 KO also regulates the expression of a subset of cell soluble receptor proteins IGFBP3 and MCAM. A high level of lnc-FANCI-2 and lower level of MCAM in cervical cancer patients are associated with improved survival. lnc-FANCI-2 in CaSki cells interacts specifically with 32 host proteins, including MAP4K4. KD of MAP4K4 expression in CaSki cells led to an increase in phosphorylation of Erk1/2 and Akt. Thus, one lnc-FANCI-2 function is to intrinsically regulate RAS signaling to impact cervical lesion progression.

cancer biology↗

bioRxiv2024

IL-1beta-induced epithelial cell and fibroblast transdifferentiation fuels neutrophil recruitment in chronic rhinosinusitis with nasal polyps

Neutrophilic inflammation contributes to multiple chronic inflammatory airway diseases, including asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), and is associated with an unfavorable prognosis. Here, using single-cell RNA sequencing (scRNA-seq) to profile human nasal mucosa obtained from the inferior turbinates, middle turbinates, and nasal polyps of CRSwNP patients, we identified two IL-1 signaling-induced cell subsets--LY6D+ club cells and IDO1+ fibroblasts--that promote neutrophil recruitment by respectively releasing S100A8/A9 and CXCL1/2/3/5/6/8 into inflammatory regions. IL-1{beta}, a pro-inflammatory cytokine involved in IL-1 signaling, induces the transdifferentiation of LY6D+ club cells and IDO1+ fibroblasts from primary epithelial cells and fibroblasts, respectively. In an LPS-induced neutrophilic CRSwNP mouse model, blocking IL-1{beta} activity with a receptor antagonist significantly reduced the numbers of LY6D+ club cells and IDO1+ fibroblasts and mitigated nasal inflammation. This study reveals the roles of two cell subsets in neutrophil recruitment and demonstrates an IL-1-based intervention for mitigating neutrophilic inflammation in CRSwNP.

immunology↗

bioRxiv2024

Charting the Spatial Transcriptome of the Human Cerebral Cortex at Single-Cell Resolution

In our pursuit of creating a comprehensive human cortical atlas to understand human intelligence, we examined the single-nuclei transcriptomes of 307,738 cells alongside spatial transcriptomics data from 46,948 VISIUM spots and 1,355,582 Stereo cells. Atlases reveal distinct expression patterns and spatial arrangements of cortical neural cell types. Glutamatergic neurons exhibit precise laminar patterns, often mirroring expression patterns in adjacent cortical regions. Overlaying our atlas with functional networks delineated substantial correlations between neural cell types and cortical region function. Notably, regions involved in processing sensory information (pain) display a pronounced accumulation of extratelencephalic neurons. Additionally, our atlas enabled precise localization of the thicker layer 4 of the visual cortex and an in-depth study of the stabilize the subplate structure, known as layer 6b, revealed specific marker genes and cellular compositions. Collectively, our research sheds light on the cellular foundations of the intricate and intelligent regions within the human cortex.

neuroscience↗

bioRxiv2024

Loss of NAT10 disrupts enhancer organization via p300 mislocalization and suppresses transcription of genes necessary for metastasis progression.

Acetylation of protein and RNA represent a critical event for development and cancer progression. NAT10 is the only known RNA acetylase that catalyzes the N4-actylcytidine (ac4C) modification of RNAs. Here, we show that the loss of NAT10 significantly decreases lung metastasis in allograft and genetically engineered mouse models of breast cancer. NAT10 interacts with a mechanosensitive, metastasis susceptibility protein complex at the nuclear pore. In addition to its canonical role in RNA acetylation, we find that NAT10 interacts with p300 at gene enhancers. NAT10 loss is associated with p300 mislocalization into heterochromatin regions. NAT10 depletion disrupts enhancer organization, leading to alteration of gene transcription necessary for metastatic progression, including reduced myeloid cell-recruiting chemokines that results in a less metastasis-prone tumor microenvironment. Our study uncovers a distinct role of NAT10 in enhancer organization of metastatic tumor cells and suggests its involvement in the tumor-immune crosstalk dictating metastatic outcomes.

cancer biology↗

bioRxiv2024

Comparative transcriptome analysis provides insights into the resistance regulation mechanism and inhibitory effect of fungicide phenamacril in Fusarium asiaticum

Fusarium asiaticum is a destructive phytopathogenic fungus that causes Fusarium head blight of wheat (FHB), leading to serious yield and economic losses to cereal crops worldwide. Our previous studies indicated that target-site mutations (K216R/E, S217P/L, or E420K/G/D) of Type I myosin FaMyo5 conferred high resistance to phenamacril. Here, we first constructed a sensitive strain H1S and point mutation resistant strains HA, HC and H1R. Then we conducted comparative transcriptome analysis of these strains in F. asiaticum after 1 g{middle dot}mL-1 and 10 g{middle dot}mL-1 phenamacril treatment. Results indicated that 2135 genes were differentially expressed (DEGs) among the sensitive and resistant strains. Among them, the DEGs encoding ammonium transporter MEP1/MEP2, nitrate reductase, copper amine oxidase 1, 4-aminobutyrate aminotransferase, amino-acid permease inda1, succinate-semialdehyde dehydrogenase, 2, 3-dihydroxybenzoic acid decarboxylase, etc., were significantly up-regulated in all the phenamacril-resistant strains. Compared to the control group, a total of 1778 and 2097 DEGs were identified in these strains after 1 g{middle dot}mL-1 and 10 g{middle dot}mL-1 phenamacril treatment, respectively. These DEGs involved in 4-aminobutyrate aminotransferase, chitin synthase 1, multiprotein-bridging factor 1, transcriptional regulatory protein pro-1, amino-acid permease inda1, ATP-dependent RNA helicase DED, acetyl-coenzyme A synthetase, sarcoplasmic/endoplasmic reticulum calcium ATPase 2, etc., showed significantly down-regulated expression in phenamacril-sensitive strain but not in resistant strains after phenamacril treatment. In addition, cyanide hydratase, mating-type protein MAT-1, putative purine nucleoside permease, plasma membrane protein yro2, etc., showed significantly co-down-regulated expression in all the strains after phenamacril treatment. Taken together, This study provide deep insights into the resistance regulation mechanism and inhibitory effect of fungicide phenamacril and these new annotated proteins or enzymes are worth for the discovery of new fungicide targets. Author summaryFungicide phenamacril resistance occur in F. asiaticum and the resistance regulation mechanis are systematic and complex. Here, we conducted comparative transcriptome analysis of a sensitive strain H1S and point mutation resistant strains HA, HC and H1R in F. asiaticum after 1 g{middle dot}mL-1 and 10 g{middle dot}mL-1 phenamacril treatment. Among these annotated proteins or enzymes, amino-acid permease inda1, 1, 4-aminobutyrate aminotransferase, chitin synthase 1, multiprotein-bridging factor 1, ATP-dependent RNA helicase DED, acetyl-coenzyme A synthetase, sarcoplasmic/endoplasmic reticulum calcium ATPase 2, cyanide hydratase, mating-type protein MAT-1, putative purine nucleoside permease, plasma membrane protein yro2, etc., were involved in the resistance regulation mechanism and inhibitory effect of fungicide phenamacril. Our paper provides a reference basis for the study of drug resistance in other microorganisms. In addition, the relevant proteins or enzymes annotated in our study also have reference value for the discovery of new fungicide targets.

pathology↗

bioRxiv2024

LRG1 promotes atherosclerosis by activating macrophages

BackgroundAtherosclerosis is a chronic inflammatory disease of the arterial wall characterized by the accumulation of cholesterol-rich lipoproteins in macrophages. Leucine-rich alpha-2 glycoprotein 1 (LRG1) is a circulating protein associated with inflammation, however, its role in atherosclerosis remains unclear. This study identified its role in macrophage pro-inflammatory differentiation and revealed the relationship between LRG1 and atherosclerosis. MethodWe evaluated the impact of LRG1 on atherosclerosis progression by analyzing atherosclerotic tissue and serum samples from patients with coronary artery disease (CAD) and healthy individuals and analyzed its role in such a process using two types of mice models: Apoe knock-out mice (Apoe-/-) and Apoe and Lrg1 double knock-out mice (Apoe-/-/Lrg1-/-). These mice were fed with a high-fat diet for 16 to 32 weeks to simulate conditions exacerbating atherosclerosis. To examine the effects of inhibiting LRG1 on atherogenesis, we administered intraperitoneal injections of LRG1 neutralizing antibody (50g/kg) weekly to Apoe-/- mice for 8 weeks. We conducted in vitro assays using bone marrow-derived macrophages isolated from wild-type mice and analyzed transcriptional signatures using RNA sequencing. Additionally, we utilized small molecular inhibitors to validate the signaling pathway through which LRG1 promotes macrophage-driven inflammation. ResultsLRG1 levels were found to be elevated in patients with atherosclerosis and correlated with higher levels of a plasma pro-inflammatory biomarker high-sensitive C-reactive protein (hsCRP), and several macrophage-related pro-inflammatory markers including CD68, VE-Cadherin and VCAM-1. In a high fat diet induced Apoe-/- mouse atherosclerosis model, the deletion of LRG1 gene significantly delayed atherogenesis progression and reduced levels of macrophage-related pro-inflammatory cytokines. Addition of purified LRG1 to cultured macrophages stimulated those macrophages to pro-inflammatory M1-like polarization regulated by the activation of ERK and JNK pathways. An anti-LRG1 neutralizing antibody effectively blocked LRG1-induced macrophage M1-like polarization in vitro and conferred therapeutic benefits to animals with ApoE deficiency-induced atherosclerosis. ConclusionLRG1 plays an important pro-inflammatory role in atherosclerosis by influencing macrophage polarization towards a pro-inflammatory state. The inhibition of LRG1 with neutralizing antibodies may offer a potential therapeutic strategy for patients with atherosclerosis by mitigating the pro-inflammatory response and delaying disease progression, offering a novel therapy in atherosclerosis management. Translational PerspectiveAtherosclerosis, a persistent inflammatory condition affecting the arterial wall, serves as the underlying pathophysiological basis for acute ischemic cardiovascular events. The involvement of macrophages is crucial in the advancement of atherosclerosis. In this investigation, heightened levels of plasma LRG1 were observed in individuals with coronary artery disease. Moreover, this study presents initial evidence highlighting LRG1 as a pivotal activator of macrophages, instigating a pro-inflammatory M1 polarization during atherogenesis through the activation of ERK1/2 and JNK pathways. The use of an anti-LRG1 neutralizing antibody demonstrated a delay in atherosclerosis progression in an animal model, suggesting a potential therapeutic target for atherosclerosis treatment. Suppression of LRG1 production could impede atherosclerosis advancement and enhance plaque stability. Utilizing neutralizing antibodies against LRG1 emerges as a promising therapeutic approach for treating atherosclerosis.

pathology↗

bioRxiv2024

scMeFormer: a transformer-based deep learning model for imputing DNA methylation states in single cells enhances the detection of epigenetic alterations in schizophrenia

DNA methylation (DNAm), a crucial epigenetic mark, plays a key role in gene regulation, mammalian development, and various human diseases. Single-cell technologies enable the profiling of DNAm states at cytosines within the DNA sequence of individual cells, but they often suffer from limited coverage of CpG sites. In this study, we introduce scMeFormer, a transformer-based deep learning model designed to impute DNAm states for each CpG site in single cells. Through comprehensive evaluations, we demonstrate the superior performance of scMeFormer compared to alternative models across four single-nucleus DNAm datasets generated by distinct technologies. Remarkably, scMeFormer exhibits high-fidelity imputation, even when dealing with significantly reduced coverage, as low as 10% of the original CpG sites. Furthermore, we applied scMeFormer to a single-nucleus DNAm dataset generated from the prefrontal cortex of four schizophrenia patients and four neurotypical controls. This enabled the identification of thousands of differentially methylated regions associated with schizophrenia that would have remained undetectable without imputation and added granularity to our understanding of epigenetic alterations in schizophrenia within specific cell types. Our study highlights the power of deep learning in imputing DNAm states in single cells, and we expect scMeFormer to be a valuable tool for single-cell DNAm studies.

genomics↗

bioRxiv2024

A Comprehensive Evaluation of Large Language Models in Mining Gene Interactions and Pathway Knowledge

BackgroundUnderstanding complex biological pathways, including gene-gene interactions and gene regulatory networks, is critical for exploring disease mechanisms and drug development. Manual literature curation of biological pathways is useful but cannot keep up with the exponential growth of the literature. Large-scale language models (LLMs), notable for their vast parameter sizes and comprehensive training on extensive text corpora, have great potential in automated text mining of biological pathways. MethodThis study assesses the effectiveness of 21 LLMs, including both API-based models and open-source models. The evaluation focused on two key aspects: gene regulatory relations (specifically, activation, inhibition, and phosphorylation) and KEGG pathway component recognition. The performance of these models was analyzed using statistical metrics such as precision, recall, F1 scores, and the Jaccard similarity index. ResultsOur results indicated a significant disparity in model performance. Among the API-based models, ChatGPT-4 and Claude-Pro showed superior performance, with an F1 score of 0.4448 and 0.4386 for the gene regulatory relation prediction, and a Jaccard similarity index of 0.2778 and 0.2657 for the KEGG pathway prediction, respectively. Open-source models lagged their API-based counterparts, where Falcon-180b-chat and llama1-7b led with the highest performance in gene regulatory relations (F1 of 0.2787 and 0.1923, respectively) and KEGG pathway recognition (Jaccard similarity index of 0.2237 and 0. 2207, respectively). ConclusionLLMs are valuable in biomedical research, especially in gene network analysis and pathway mapping. However, their effectiveness varies, necessitating careful model selection. This work also provided a case study and insight into using LLMs as knowledge graphs.

bioinformatics↗

bioRxiv2024

Retinoic acid generates a beneficial microenvironment for liver progenitor cell activation in acute liver failure

ObjectiveWhen massive necrosis occurs in acute liver failure (ALF), rapid expansion of hepatic stem cells called liver progenitor cells (LPC) in a process called ductular reaction (DR) is required for survival. The exact underlying mechanisms of this process are not known to date. In ALF, high levels of retinoic acid (RA), a molecule known for its pleiotropic roles in embryonic development, are secreted by activated hepatic stellate cells (HSCs). We hypothesized that RA plays a key role during DR in ALF. MethodsRNA-Seq was performed to identify molecular signaling pathways affected by all-trans retinoid acid (atRA) treatment in HepaRG LPC cells. Functional assays for RA were performed in HepaRG cells with atRA treatment as well as co-culture with LX-2 cells in vitro, and liver tissue of patients suffering from ALF in vivo. ResultsUnder ALF conditions, activated HSCs secreted RA, inducing RAR nuclear translocation in LPCs. RNA-seq data and investigations in HepaRG cells revealed that atRA treatment activated the WNT-{beta}-Catenin pathway, enhanced stemness genes (SOX9, AFP, et.al), promoted energy storage, and elevated the expression of ATP-binding cassette (ABC) transporters depending on RAR nuclear translocation. Further, atRA treatment-induced pathways were confirmed in a co-culture system of HepaRG with LX-2 cells. Patients with ALF who displayed RAR nuclear translocation in LPC had significantly better MELD scores than those without. ConclusionIn ALF, RA secreted by activated hepatic stellate cells promotes LPC activation, a prerequisite for subsequent LPC-mediated liver regeneration.

cell biology↗

bioRxiv2024

Exploring social modulation: Microglia as a key mediator of individual immune response, plasticity and pathology in App-NL-G-F mouse model of Alzheimer's disease

This study explores the influence of lifestyle on Alzheimers disease (AD) progression using App-NL-G-F mice in a complex enrichment system. Mice exhibited social deficits before plaque pathology or memory impairment, revealing a crucial link between lifestyle, behavior, and neuroinflammation. Plasma analysis indicates early inflammation and apoptosis-related changes, setting the stage for identifying markers predicting plaque manifestation. Beyond pathology, social behavior is linked to adult neurogenesis and microglia coverage, forming a dynamic connection with microglia activation. Further, sc-RNA sequencing unveiled a decrease in interferon-responsive microglia and alteration in antigen processing with enrichment. These findings underscore the beneficial impact of social housing on microglia and interconnected factors, pointing to microglia as a critical mediator of the behavior-pathology-plasticity interplay in AD. The study enhances our understanding of AD complexity and offers insights into potential therapeutic strategies, emphasizing the multifaceted nature of AD progression and the role of lifestyle in shaping its course.

neuroscience↗

bioRxiv2024

Tmc7 deficiency causes acrosome biogenesis defects and male infertility in mice

Transmembrane channel-like (TMC) proteins are a highly conserved ion channel family consisting of eight members (TMC1-TMC8) in mammals. TMC1/2 are components of the mechanotransduction channel in hair cells, and mutations of TMC1/2 cause deafness in humans and mice. However, the physiological roles of other TMC proteins remain largely unknown. Here, we show that Tmc7 is specifically expressed in the testis and that it is required for acrosome biogenesis during spermatogenesis. Tmc7-/- mice exhibited abnormal sperm head, disorganized mitochondrial sheaths, and reduced number of elongating spermatids, similar to human oligo-astheno-teratozoospermia. We further demonstrate that TMC7 is colocalized with GM130 at the cis-Golgi region in round spermatids. TMC7 deficiency leads to aberrant Golgi morphology and impaired fusion of Golgi-derived vesicles to the developing acrosome. Moreover, upon loss of TMC7 intracellular ion homeostasis is impaired and ROS levels are increased, which in turn causes Golgi and endoplasmic reticulum (ER) stress. Taken together, these results suggest that TMC7 is required to maintain pH and ion homeostasis, which is needed for acrosome biogenesis. Our findings unveil a novel role for TMC7 in acrosome biogenesis during spermiogenesis.

developmental biology↗

bioRxiv2024

Structure of hepatitis B/D antiviral drug Bulevirtide bound to its receptor protein NTCP

Cellular entry of the hepatitis B and D viruses (HBV/HDV) require binding of the viral surface polypeptide preS1 to the hepatobiliary transporter NTCP. This interaction can be blocked by bulevirtide (BLV, formerly Myrcludex B), a preS1 derivative and approved drug for treating HDV infection. To elucidate the basis of this inhibitory function, we determined a cryo-EM structure of BLV-bound human NTCP. BLV forms two domains, a plug lodged in the bile salt transport tunnel of NTCP and a string that covers the receptors extracellular surface. The N-terminally attached myristoyl group of BLV interacts with the lipid-exposed surface of NTCP. Our structure reveals how BLV inhibits bile salt transport, rationalizes NTCP mutations that decrease the risk of HBV/HDV infection, and provides a basis for understanding the host specificity of HBV/HDV. Our results provide opportunities for structure-guided development of inhibitors that target HBV/HDV docking to NTCP.

biochemistry↗

bioRxiv2024

Stimulation of NCAM1-14.3.3.ζδ-derived Peptide Interaction Fuels Angiogenesis and Osteogenesis in Ageing

The skeletal structure and bone marrow endothelium collectively form a critical functional unit essential for bone development, health, and aging. At the core of osteogenesis and bone formation lies the dynamic process of angiogenesis. In this study, we reveal a potent new endogenous anabolic NCAM1-14.3.3.{zeta}{delta}-derived-Peptide interaction, which stimulates bone angiogenesis and osteogenesis during homeostasis, aging, and age-related bone diseases. Employing high-resolution imaging and inducible cell-specific mouse genetics, our results elucidate the pivotal role of the NCAM1-14.3.3.{zeta}{delta}-derived-Peptide interaction in driving the expansion of Clec14a+ angiogenic endothelial cells. Notably, Clec14a+ endothelial cells express key osteogenic factors. The NCAM1-14.3.3.{zeta}{delta}-derived-Peptide interaction in osteoblasts drives osteoblast differentiation, ultimately contributing to the genesis of new bone. Moreover, the NCAM1-14.3.3.{zeta}{delta}-derived-Peptide interaction leads to a reduction in bone resorption. In age-associated vascular and bone loss diseases, stimulating the NCAM1-14.3.3.{zeta}{delta}-derived-Peptide interaction not only promotes angiogenesis but also reverses bone loss. Consequently, harnessing the endogenous anabolic potential of the NCAM1-14.3.3.{zeta}{delta}-derived-Peptide interaction emerges as a promising therapeutic modality for managing age-related bone diseases.

cell biology↗

bioRxiv2024

Target-aware Molecule Generation for Drug Design Using a Chemical Language Model

Generative drug design facilitates the creation of compounds effective against pathogenic target proteins. This opens up the potential to discover novel compounds within the vast chemical space and fosters the development of innovative therapeutic strategies. However, the practicality of generated molecules is often limited, as many designs focus on a narrow set of drug-related properties, failing to improve the success rate of subsequent drug discovery process. To overcome these challenges, we develop TamGen, a method that employs a GPT-like chemical language model and enables target-aware molecule generation and compound refinement. We demonstrate that the compounds generated by TamGen have improved molecular quality and viability. Additionally, we have integrated TamGen into a drug discovery pipeline and identified 7 compounds showing compelling inhibitory activity against the Tuberculosis ClpP protease, with the most effective compound exhibiting a half maximal inhibitory concentration (IC50) of 1.9 M. Our findings underscore the practical potential and real-world applicability of generative drug design approaches, paving the way for future advancements in the field.

biochemistry↗

bioRxiv2024

Reprogramming of 3D genome structure underlying HSPC development in zebrafish

Development of hematopoietic stem and progenitor cells (HSPC) is a multi-staged complex process that conserved between zebrafish and mammals; however, the mechanism underlying HSPC development is not fully understood. Chromatin conformation plays important roles in transcriptional regulation and cell fate decision, its dynamic and role in HSPC development is poorly investigated. Here, we performed chromatin structure and multi-omics dissection across different stages of HSPC developmental trajectory in zebrafish. Chromatin organization of zebrafish HSPC resemble mammalian cells with similar hierarchical structure and characteristics. We revealed the multi-scale reorganization of 3D genome and its influence on transcriptional regulation and transition of cell function during HSPC development. Nascent HSPC is featured by loose conformation with obscure structure at all layers. Notably, PU.1 was identified as a potential factor mediating formation of promoter-involved loops and regulating gene expression as well as HSPC function. Our results provided a global view of chromatin structure dynamics associated with development of zebrafish HSPC and discovered key transcription factor involved in HSPC chromatin interactions, which will provide new insights into the epigenetic regulatory mechanisms underlying vertebrate HSPC fate decision.

genomics↗

bioRxiv2024

TEMINET: A Co-Informative and Trustworthy Multi-Omics Integration Network for Diagnostic Prediction

Advancing the domain of biomedical investigation, integrated multi-omics data have shown exceptional performance in elucidating complex human diseases. However, as the variety of omics information expands, precisely perceiving the informativeness of intra- and inter-omics becomes challenging due to the intricate interrelations, thus posing significant obstacles in multi-omics data integration. To address this, we introduce a novel multi-omics integration approach, referred to as TEMINET. This approach enhances diagnostic prediction by leveraging an intra-omics co-informative representation method and a trustworthy learning strategy used to address inter-omics fusion. Considering the multifactorial nature of complex diseases, TEMINET utilizes intra-omics features to construct disease-specific networks, then applies graph attention networks and a multi-level framework to capture more collective informativeness than pairwise relations. To perceive the contribution of co-informative representations within intra-omics, we design a trustworthy learning strategy to identify the reliability of each omics in integration. To integrate inter-omics information, a combined beliefs fusion approach is deployed to harmonize the trustworthy representations of different omics types effectively. Our experiments across four different diseases using mRNA, methylation, and miRNA data demonstrate that TEMINET achieves advanced performance and robustness in classification tasks.

bioinformatics↗

bioRxiv2024

Determination and characterization of papillomaviurs and parvovirus causing mass mortality of Chinese tongue sole (Cynoglossus semilaevis) in China

Chinese tongue sole (Cynoglossus semilaevis) is one of the representative species in flatfish aquaculture in China. In recent years, massive mortality of farmed Chinese tongue soles occurred in Tianjin, China. The causative pathogens were determined as Cynoglossus semilaevis papillomavirus (CsPaV) and parvovirus (CsPV) by electron microscopy, virus isolation, experimental challenge, histopathological analysis, genome sequencing, fluorescence In situ hybridization (FISH) and epidemiology investigation. Electron microscopy showed large numbers of spherical non-enveloped virus particles presenting in liver, kidney, spleen, gill and heart of the diseased fish. The viruses were isolated and propagated in flounder gill cells (FG) and induced a typical cytopathic effect (CPE). The cumulative mortality reached 100% at 8 dpi by intraperitoneal injection. The complete genome of CsPaV and CsPV was 5939 bp and 3663 bp in size respectively, and both viral genomes shared no nucleotide sequence similarity with other viruses. The CsPaV contained seven predicated protein coding regions (E1, E2, L2, L1a, L1b, sORF1 and sORF2) and CsPV contained three predicated protein coding regions (NS1, VP and ORF3). Phylogenetic analysis basing on L1 and NS1 protein sequences revealed that CsPaV and CsPV are novel members belonging to new genus in Papillomaviridae and Parvoviridae family. FISH results showed positive signals in spleen and kidney tissues from CsPaV and CsPV infected fish and the two viruses could co-infected one cell. Epidemiological investigation showed that the two viruses cocurrented in 82.9% sampled fish and they were proved to be the pathogenic agents of the emerging disease in farmed Chinese tongue soles in China. This study represents the first report of co-infection of papillomavirus and parvovirus in farmed fish and provides a basis for further studies on prevention and treatment of the emerging viral disease, and also represents clues to elucidate the the mechanisms of viruses co-infection and evolution of viruses. Author summaryChinese tongue sole is a valuable fish kept in marincultures. Outbreak of an emerging disease caused massive mortality and resulted in significant economic loss. The pathogenic agent remains unknown. In this study, we identified papillomavirus (CsPaV) and parvovirus (CsPV) from the diseased fish simultaneously, and they are proved to be novel members belonging to new genus in Papillomaviridae and Parvoviridae family. It was shown that the emerging disease was caused by co-infection with the two viruses. Viral co-infections are widespread in nature, however, studies and available data on viral co-infections in fish aquaculture are limited. Our findings represent new clues to elucidate the mechanisms of viruses co-infection and evolution of viruses, and moreover, the present study provide a solution for the control of emerging viral diseases in Chinese tongue sole.

microbiology↗

bioRxiv2024

Control of ciliary transcriptional programs during spermatogenesis by antagonistic transcription factors

Existence of cilia in the last eukaryotic common ancestor (LECA) raises a fundamental question in biology: how the transcriptional regulation of ciliogenesis has evolved? One conceptual answer to this question is by an ancient transcription factor regulating ciliary gene expression in both unicellular and multicellular organisms, but examples of such transcription factors in eukaryotes are lacking. Previously, we showed that an ancient transcription factor XAP5 is required for flagellar assembly in Chlamydomonas. Here, we show that XAP5 and XAP5L are two conserved pairs of antagonistic transcription regulators that control ciliary transcriptional programs during spermatogenesis. Male mice lacking either XAP5 or XAP5L display infertility, as a result of meiotic prophase arrest and sperm flagella malformation, respectively. Mechanistically, XAP5 positively regulates the ciliary gene expression by activating the key regulators including FOXJ1 and RFX families during the early stage of spermatogenesis. In contrast, XAP5L negatively regulates the expression of ciliary genes via repressing these ciliary transcription factors during the spermiogenesis stage. Our results provide new insights into the mechanisms by which temporal and spatial transcription regulators are coordinated to control ciliary transcriptional programs during spermatogenesis.

cell biology↗