Biology subjects

Ge, X.

Publications and source records attributed to Ge, X..

At least 91 records · Page 5Linked to original sources

bioRxiv2022

Predator-prey interactions in a warming world: the critical role of cold tolerance

Thermal tolerance mismatch within predator-prey systems may have pro-found effects on species population abundances and geographical distributions. To examine the generalized responses of a predator-prey system to climate change, we construct a biologically detailed stage-structured population dynamic model of interactions between ladybird beetles and aphids. We explore the models dynamics across the entire feasible parameter space of mean temperature and seasonality. Within this space, we explore different scenarios of predator and prey thermal tolerance mismatch to gain insight into how these thermal sensitivities affect the interacting species responses to climatic change. Our results indicate a predators cold tolerance has a larger effect on prey abundance than its heat tolerance. Mismatches between the predators and preys thermal tolerances also affect the species response to climate change. We identify three common patterns of species abundance across the feasible parameter space that relate to the type of thermal tolerance mismatches. Our study highlights the importance of understanding the complex interplay between climate change and species interactions.

ecology↗

bioRxiv2022

Molecular basis of broad neutralization against SARS-CoV-2 variants including Omicron by a human antibody

Omicron, a newly emerging SARS-CoV-2 variant, carried a large number of mutations in the spike protein leading to an unprecedented evasion from many neutralizing antibodies (nAbs). Here, we performed a head-to-head comparison of Omicron with other existing highly evasive variants in terms of their reduced sensitivities to antibodies, and found that Omicron variant is significantly more evasive than Beta and Mu variants. Of note, some key mutations occur in the conserved epitopes identified previously, especially in the binding sites of Class 4 nAbs, contributing to the increased Ab evasion. We also reported a broadly nAb (bnAb), VacW-209, which effectively neutralized all tested SARS-CoV-2 variants and even SARS-CoV. Finally, we determined six cryo-electron microscopy structures of VacW-209 complexed with the spike ectodomains of wild-type, Delta, Mu, C.1.2, Omicron, and SARS-CoV, and revealed the molecular basis of the broadly neutralizing activities of VacW-209 against SARS-CoV-2 variants. Overall, Omicron has once again raised the alarm over virus variation with significantly compromised neutralization. BnAbs targeting more conserved epitopes among variants will continue to play a key role in pandemic control and prevention. One sentence summaryStructural and functional analyses reveal that a human antibody named VacW-209 confers broad neutralization against SARS-CoV-2 variants including Omicron by recognizing a highly conserved epitope.

immunology↗

bioRxiv2021

Subfamily-specific differential contribution of individual monomers and the tether sequence to mouse L1 promoter activity

BackgroundThe internal promoter in L1 5UTR is critical for autonomous L1 transcription and initiating retrotransposition. Unlike the human genome, which features one contemporarily active subfamily, four subfamilies (A_I, Gf_I and Tf_I/II) have been amplifying in the mouse genome in the last one million years. Moreover, mouse L1 5UTRs are organized into tandem repeats called monomers, which are separated from ORF1 by a tether domain. In this study, we aim to compare promoter activities across young mouse L1 subfamilies and investigate the contribution of individual monomers and the tether sequence. ResultsWe observed an inverse relationship between subfamily age and the average number of monomers among evolutionarily young mouse L1 subfamilies. The youngest subgroup (A_I and Tf_I/II) on average carry 3-4 monomers in the 5UTR. Using a single-vector dual-luciferase reporter assay, we compared promoter activities across six L1 subfamilies (A_I/II, Gf_I and Tf_I/II/III) and established their antisense promoter activities in a mouse embryonic fibroblast cell line. Using consensus promoter sequences for three subfamilies (A_I, Gf_I and Tf_I), we dissected the differential roles of individual monomers and the tether domain in L1 promoter activity. We validated that, across multiple subfamilies, the second monomer consistently enhances the overall promoter activity. For individual promoter components, monomer 2 is consistently more active than the corresponding monomer 1 and/or the tether for each subfamily. Importantly, we revealed intricate interactions between monomer 2, monomer 1 and tether domains in a subfamily-specific manner. Furthermore, using three-monomer 5UTRs, we established a complex nonlinear relationship between the length of the outmost monomer and the overall promoter activity. ConclusionsThe laboratory mouse is an important mammalian model system for human diseases as well as L1 biology. Our study extends previous findings and represents an important step toward a better understanding of the molecular mechanism controlling mouse L1 transcription as well as L1s impact on development and disease.

genomics↗

bioRxiv2021

Potent antibody immunity to SARS-CoV-2 variants elicited by a third dose of inactivated vaccine

SARS-CoV-2 variants are still prevalent worldwide and continue to pose a challenge to the effectiveness of current vaccines. It remains unknown whether a third dose of inactivated vaccine elicits immune potential against SARS-CoV-2 variants. Here, we showed a significant decline in plasma neutralization against SARS-CoV-2 at seven months after a second dose of the inactivated vaccine in a large-scale cohort. However, we also found that a third vaccination with an inactivated vaccine largely increased plasma neutralization against variants including Beta, Delta, and Lambda. More importantly, the high-affinity anti-RBD memory B cells were also generated by the third vaccination, suggesting a more potent and longer protection. These findings highlighted the importance and effectiveness of a third dose of inactivated vaccine in conferring higher protection against the emerging variants in populations.

immunology↗

bioRxiv2021

An atlas of human viruses provides new insights into diversity and tissue tropism of human viruses

Viruses continue to threaten human health. Yet, the complete viral species carried by humans and their infection characteristics have not been fully revealed. This study curated an atlas of human viruses from public databases and literatures, and built the Human Virus Database (HVD) available at http://computationalbiology.cn/humanVirusBase/#/. The HVD contains 1,131 virus species of 54 viral families which were more than twice the number of the human-infecting virus species reported in previous studies. These viruses were identified in human samples including 68 human tissues, the excreta and body fluid. The viral diversity in humans was age-dependent with a peak in the infant and a valley in the teenager. The tissue range of viruses was found to be associated with several factors including the viral group (DNA, RNA or reverse-transcribing viruses), enveloped or not, viral genome length and GC content, viral receptors and the virus-interacting proteins. Finally, the tissue range of DNA viruses was predicted using a random-forest algorithm with a medium performance. Overall, the study not only provides a valuable resource for further studies of human viruses, but also deepens our understanding towards the diversity and tissue tropism of human viruses.

microbiology↗

bioRxiv2021

Lateralized phenotypic differences in females in the intrahippocampal kainic acid mouse model of temporal lobe epilepsy

Clinical evidence indicates that patients with temporal lobe epilepsy (TLE) often show differential outcomes of comorbid conditions in relation to the lateralization of the seizure focus. A particularly strong relationship exists between the side of seizure focus and the propensity for distinct reproductive endocrine comorbidities in women with TLE. Therefore, here we evaluated whether targeting of left or right dorsal hippocampus for intrahippocampal kainic acid (IHKA) injection, a model of TLE, produces different outcomes in hippocampal granule cell dispersion, body weight gain, and multiple measures of reproductive endocrine dysfunction in female mice. One, two, and four months after IHKA or saline injection, in vivo measurements of estrous cycles and weight were followed by ex vivo examination of hippocampal dentate granule cell dispersion, circulating ovarian hormone and corticosterone levels, ovarian morphology, and pituitary gene expression. IHKA mice with right-targeted injection (IHKA-R) showed greater granule cell dispersion and pituitary Fshb expression compared to mice with left-targeted injection (IHKA-L). By contrast, pituitary expression of Lhb and Gnrhr were higher in IHKA-L mice compared to IHKA-R, but these values were not different from respective saline-injected controls. IHKA-L mice also showed an increased rate of weight gain compared to IHKA-R mice. Increases in estrous cycle length, however, were similar in both IHKA-L and IHKA-R mice. These findings indicate that although major reproductive endocrine dysfunction phenotypes present similarly after targeting left or right dorsal hippocampus for IHKA injection, distinct underlying mechanisms based on lateralization of epileptogenic insult may contribute to produce similar emergent reproductive endocrine outcomes. HighlightsO_LIGreater granule cell dispersion with right-sided IHKA injection C_LIO_LIChanges in pituitary gene expression vary with side of injection C_LIO_LIIncreased weight gain after left-sided injection C_LIO_LISimilar estrous cycle disruption after injection of left or right hippocampus C_LI

neuroscience↗

bioRxiv2021

APIR: a universal FDR-control framework for boosting peptide identification power by aggregating multiple proteomics database search algorithms

Advances in mass spectrometry (MS) have enabled high-throughput analysis of proteomes in biological systems. The state-of-the-art MS data analysis relies on database search algorithms to quantify proteins by identifying peptide-spectrum matches (PSMs), which convert mass spectra to peptide sequences. Different database search algorithms use distinct search strategies and thus may identify unique PSMs. However, no existing approaches can aggregate all user-specified database search algorithms with a guaranteed increase in the number of identified peptides and control on the false discovery rate (FDR). To fill in this gap, we propose a statistical framework, Aggregation of Peptide Identification Results (APIR), that is universally compatible with all database search algorithms. Notably, under an FDR threshold, APIR is guaranteed to identify at least as many, if not more, peptides as individual database search algorithms do. Evaluation of APIR on a complex proteomics standard shows that APIR outpowers individual database search algorithms and empirically controls the FDR. Real data studies show that APIR can identify disease-related proteins and post-translational modifications missed by some individual database search algorithms. The APIR framework is easily extendable to aggregating discoveries made by multiple algorithms in other high-throughput biomedical data analysis, e.g., differential gene expression analysis on RNA sequencing data. The APIR R package is available at https://github.com/yiling0210/APIR.

bioinformatics↗

bioRxiv2021

A large-sample crisis? Exaggerated false positives by popular differential expression methods

We report a surprising phenomenon about identifying differentially expressed genes (DEGs) from population-level RNA-seq data: two popular bioinformatics methods, DESeq2 and edgeR, have unexpectedly high false discovery rates (FDRs). Via permutation analysis on an immunotherapy RNA-seq dataset, we observed that DESeq2 and edgeR identified even more DEGs after samples condition labels were randomly permuted. Motivated by this, we evaluated six DEG identification methods (DESeq2, edgeR, limma-voom, NOISeq, dearseq, and the Wilcoxon rank-sum test) on population-level RNA-seq datasets. We found that the FDR control was often failed by the three popular parametric methods--DESeq2, edgeR, and limma-voom-- and the new non-parametric method dearseq. In particular, the actual FDRs of DESeq2 and edgeR sometimes exceeded 20% when the target FDR threshold was only 5%. Although NOISeq, a non-parametric method used by GTEx, controlled the FDR better than the other four methods did, its power was much lower than that of the Wilcoxon rank-sum test, a classic nonparametric test that consistently controlled the FDR and achieved good power in our evaluation. Based on these results, for population-level RNA-seq studies, we recommend the Wilcoxon rank-sum test.

bioinformatics↗

bioRxiv2021

Prediction of coronavirus 3C-like protease cleavage sites using machine-learning algorithms

The coronavirus 3C-like (3CL) protease is a Cysteine protease. It plays an important role in viral infection and immune escape by not only cleaving the viral polyprotein ORF1ab at 11 sites, but also cleaving the host proteins. However, there is still a lack of effective tools for determining the cleavage sites of the 3CL protease. This study systematically investigated the diversity of the cleavage sites of the coronavirus 3CL protease on the viral polyprotein, and found that the cleavage motif were highly conserved for viruses in the genera of Alphacoronavirus, Betacoronavirus and Gammacoronavirus. Strong residue preferences were observed at the neighboring positions of the cleavage sites. A random forest (RF) model was built to predict the cleavage sites of the coronavirus 3CL protease based on the representation of residues at cleavage site and neighboring positions by amino acid indexes, and the model achieved an AUC of 0.96 in cross-validations. The RF model was further tested on an independent test dataset composed of cleavage sites on host proteins, and achieved an AUC of 0.88 and a prediction precision of 0.80 when considering the accessibility of the cleavage site. Then, 1,079 human proteins were predicted to be cleaved by the 3CL protease by the RF model. These proteins were enriched in pathways related to neurodegenerative diseases and pathogen infection. Finally, a user-friendly online server named 3CLP was built to predict the cleavage sites of the coronavirus 3CL protease based on the RF model. Overall, the study not only provides an effective tool for identifying the cleavage sites of the 3CL protease, but also provides insights into the molecular mechanism underlying the pathogenicity of coronaviruses.

bioinformatics↗

bioRxiv2021

SRS-FISH: High-Throughput Platform Linking Microbiome Function to Identity at the Single Cell Level

One of the biggest challenges in microbiome research in environmental and medical samples is to better understand functional properties of microbial community members at a single cell level. Single cell isotope probing has become a key tool for this purpose, but the currently applied detection methods for measuring isotope incorporation into single cells do not allow high-throughput analyses. Here, we report on the development of an imaging-based approach termed stimulated Raman scattering - two-photon fluorescence in situ hybridization (SRS-FISH) for high-throughput structure-function analyses of microbial communities with single cell resolution. SRS-FISH has an imaging speed of 10 to 100 milliseconds per cell, which is two to three orders of magnitude faster than spontaneous Raman-FISH. Using this technique, we delineated metabolic responses of thirty thousand individual cells to various mucosal sugars in the human gut microbiome via incorporation of deuterium from heavy water as an activity marker. Application of SRS-FISH to investigate the utilization of host-derived nutrients by two major human gut microbiome taxa revealed that response to mucosal sugars tends to be dominated by Bacteroidales, with an unexpected finding that Clostridia can outperform Bacteroidales at foraging fucose.

microbiology↗

bioRxiv2021

Mouse Antibodies with Activity Against the SARS-CoV-2 D614G and B.1.351 Variants

With the rapid spread of SARS-CoV-2 variants, including those that are resistant to antibodies authorized for emergency use, it is apparent that new antibodies may be needed to effectively protect patients against more severe disease. Differences between the murine and human antibody repertoires may allow for the isolation of murine monoclonal antibodies that recognize a different or broader range of SARS-CoV-2 variants than the human antibodies that have been characterized so far. We describe mouse antibodies B13 and O24 that demonstrate neutralizing potency against SARS-CoV-2 Wuhan (D614G) and B.1.351 variants. Such murine antibodies may have advantages in protecting against severe symptoms when individuals are exposed to new SARS-CoV-2 variants.

molecular biology↗

bioRxiv2021

Clinical Strains of Pseudomonas aeruginosa secret LasB protease to induce hemorrhagic diffused alveolar damage and acute lung injury in mice

BackgroundAcute lung injury and acute respiratory distress syndrome are most often caused by bacterial pneumonia, characterized by severe dyspnea and high mortality. Knowledge about the lung injury effects of current clinical bacteria strains is lacking. The aim of this study was to investigate the ability of representative pathogenic bacteria isolated from patients to cause ALI/ARDS in mice and identify the virulent factors. Method7 major bacteria species were isolated from clinical sputum and instilled in to mice airway unilaterally. Histology study was used to judge the lung injury effect. Virulence genes were examined by PCR. Sequence type of P. aeruginosa strains were identified by MLST. LC-MS/MS was used to identify the suspicious protein bands. LasB was purified through DEAE-cellulose column and its toxicity was tested both in vitro and in vivo. ResultsStaphylococcus aureus, Streptococcus pneumoniae, Streptococcus agalactiae, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli were randomly separated and tested 3 times. Among them, gram-negative bacteria are more potential than gram-positive bacteria to cause acute lung injury. However, P. aeruginosa is the only pathogen which induced diffused alveolar damage, hemorrhage and hyaline membrane in the lung of mice. The lung injury effect is associated to the excreted matrix metalloproteinase LasB of P. aeruginosa. Purified LasB recapitulated hemorrhagic acute lung injury identical to P. aeruginosa infection in vivo. We found this was due to the powerful degradation effect of LasB on both lung extracellular matrix and key proteins in coagulation cascade without inducing cellular apoptosis. ConclusionP. aeruginosa strains are most capable to induce ALI/ARDS among major clinical pathogenic bacteria, this ability is specifically attributed to their LasB production.

microbiology↗

bioRxiv2020

VarSAn: Associating pathways with a set of genomic variants using network analysis

There is a pressing need today to mechanistically interpret sets of genomic variants associated with diseases. Here we present a tool called VarSAn that uses a network analysis algorithm to identify pathways relevant to a given set of variants. VarSAn analyzes a configurable network whose nodes represent variants, genes and pathways, using a Random Walk with Restarts algorithm to rank pathways for relevance to the given variants, and reports p-values for pathway relevance. It treats non-coding and coding variants differently, properly accounts for the number of pathways impacted by each variant and identifies relevant pathways even if many variants do not directly impact genes of the pathway. We use VarSAn to identify pathways relevant to variants related to cancer and several other diseases, as well as drug response variation. We find VarSAns pathway ranking to be complementary to the standard approach of enrichment tests on genes related to the query set. We adopt a novel benchmarking strategy to quantify its advantage over this baseline approach. Finally, we use VarSAn to discover key pathways, including the VEGFA-VEGFR2 pathway, related to de novo variants in patients of Hypoplastic Left Heart Syndrome, a rare and severe congenital heart defect.

bioinformatics↗

bioRxiv2020

Hippocampal Asymmetry of Regional Development and Structural Covariance in Preterm Neonates

Premature birth is associated with high prevalence of neurodevelopmental impairments in surviving infants. The hippocampus is known to be critical for learning and memory, the putative role of hippocampus dysfunction remains poorly understood in preterm neonates. Particularly, hemispherical asymmetry of the hippocampus has been well-noted, either structurally or functionally. How the preterm birth impairs the hippocampal development, and to what extent the hippocampus was impaired by preterm birth asymmetrical has not been well studied. In this study, we compared regional and local hippocampal development in term born neonates (n=361) and prematurely born infants at term-born equivalent age on MRI studies (n = 53) using T2 MRI images collected from the Developing Human Connectome Project (dHCP); We compared 1) volumetric growth; 2) shape development in the hippocampal hemispheres using Laplace-Beltrami eigen-projection and boundary deformation between the two groups; and 3) structural covariance between hippocampal vertices and the cortical thickness in cerebral cortex regions. We demonstrated that premature infants have smaller volume for the right hippocampi, while no difference was observed for the left hippocampi. Lower thickness was observed in the hippocampal head in both hemispheres for preterm neonates compared to full-term peers, while an accelerated hippocampal thickness growth rate was found in left hippocampus only. Structural covariance analysis demonstrated that in premature infants, the structural covariance between hippocampi and limbic lobe were severely impaired compared to healthy term neonates only in left hemisphere. These data suggest that the development of the hippocampus during the third trimester may be altered following early extrauterine exposure, with high degree of asymmetry. These findings suggested that the hippocampus shows high degree of vulnerability, particularly asymmetrical vulnerability or plasticity, in preterm neonates at the term-born equivalent age compared to full-term healthy controls.

neuroscience↗

bioRxiv2020

Clipper: p-value-free FDR control on high-throughput data from two conditions

High-throughput biological data analysis commonly involves identifying features such as genes, genomic regions, and proteins, whose values differ between two conditions, from numerous features measured simultaneously. The most widely-used criterion to ensure the analysis reliability is the false discovery rate (FDR), which is primarily controlled based on p-values. However, obtaining valid p-values relies on either reasonable assumptions of data distribution or large numbers of replicates under both conditions. Clipper is a general statistical framework for FDR control without relying on p-values or specific data distributions. Clipper outperforms existing methods for a broad range of applications in high-throughput data analysis.

bioinformatics↗

bioRxiv2020

Structural basis for bivalent binding and inhibition of SARS-CoV-2 infection by human potent neutralizing antibodies

Neutralizing monoclonal antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent promising candidates for clinical intervention against coronavirus virus diseases 2019 (COVID-19). We isolated a large number of nAbs from SARS-CoV-2 infected individuals capable of disrupting proper interaction between the receptor binding domain (RBD) of the viral spike (S) protein and the receptor angiotensin converting enzyme 2 (ACE2). In order to understand the mechanism of these nAbs on neutralizing SARS-CoV-2 virus infections, we have performed cryo-EM analysis and here report cryo-EM structures of the ten most potent nAbs in their native full-length IgG or Fab forms bound to the trimeric S protein of SARS-CoV-2. The bivalent binding of the full-length IgG is found to associate with more RBD in the "up" conformation than the monovalent binding of Fab, perhaps contributing to the enhanced neutralizing activity of IgG and triggering more shedding of the S1 subunit from the S protein. Comparison of large number of nAbs identified common and unique structural features associated with their potent neutralizing activities. This work provides structural basis for further understanding the mechanism of nAbs, especially through revealing the bivalent binding and their correlation with more potent neutralization and the shedding of S1 subunit.

microbiology↗

bioRxiv2020

MicroED structure of the human adenosine receptor determined from a single nanocrystal in LCP

G Protein-Coupled Receptors (GPCRs), or 7-transmembrane receptors, are a superfamily of membrane proteins that are critically important to physiological processes in the human body. Determining high-resolution structures of GPCRs without signaling partners bound requires crystallization in lipidic cubic phase (LCP). GPCR crystals grown in LCP are often too small for traditional X-ray crystallography. These microcrystals are ideal for investigation by microcrystal electron diffraction (MicroED), but the gel-like nature of LCP makes traditional approaches to MicroED sample preparation insurmountable. Here we show that the structure of a human A2A adenosine receptor can be determined by MicroED after converting the LCP into the sponge phase followed by cryoFIB milling. We determined the structure of the A2A receptor to 2.8 [A] resolution and resolved an antagonist in its orthosteric ligand-binding site as well as 4 cholesterol molecules bound to the receptor. This study lays the groundwork for future GPCR structural studies using single microcrystals that would otherwise be impossible by other crystallographic methods. One sentence summaryFIB milled LCP-GPCR structure determined by MicroED

biophysics↗

bioRxiv2020

The ESCRT protein CHMP5 restrains skeletal progenitor cell senescence by preserving endo-lysosomal-mitochondrial network

The dysfunction of the cellular endolysosomal pathway, such as in lysosomal storage diseases, can cause severe musculoskeletal disorders. However, how endolysosomal dysfunction causes musculoskeletal abnormalities remains poorly understood, limiting therapeutic options. Here, we report that CHMP5, a member of the endosomal sorting complex required for transport (ESCRT)-III protein family, is essential to maintain the endolysosomal pathway and regulate bone formation in osteogenic lineage cells. Genetic ablation of Chmp5 in mouse osteogenic cells increases bone formation in vivo and in vitro. Mechanistically, Chmp5 deletion causes endolysosomal dysfunction by decreasing the VPS4A protein, and CHMP5 overexpression is sufficient to increase the VPS4A protein. Subsequently, endolysosomal dysfunction disturbs mitochondrial functions and increases mitochondrial ROS, ultimately resulting in skeletal cell senescence. Senescent skeletal cells cause abnormal bone formation by combining cell-autonomous and paracrine actions. Importantly, the elimination of senescent cells using senolytic drugs can alleviate musculoskeletal abnormalities in Chmp5 conditional knockout mice. Therefore, our results show that cell senescence represents an underpinning mechanism and a therapeutic target for musculoskeletal disorders caused by the aberrant endolysosomal pathway, such as in lysosomal storage diseases. These results also uncover the function and mechanism of CHMP5 in the regulation of cell senescence by affecting the endolysosomal-mitochondrial pathway.

cell biology↗