Biology subjects

Ge, X.

Publications and source records attributed to Ge, X..

106 records · Page 6Linked to original sources

bioRxiv2020

DORGE: Discovery of Oncogenes and Tumor SuppressoR Genes Using Genetic and Epigenetic Features

Comprehensive data-driven discovery of cancer driver genes, including tumor suppressor genes (TSGs) and oncogenes (OGs), is imperative for cancer prevention, diagnosis, and treatment. Although epigenetic alterations are important contributors to tumor initiation and progression, most known driver genes were identified based on genetic alterations alone, and it remains unclear to what the extent epigenetic features would facilitate the identification and characterization of cancer driver genes. Here we developed a prediction algorithm DORGE (Discovery of Oncogenes and tumor suppressoR genes using Genetic and Epigenetic features), which integrates the most comprehensive collection of tumor genetic and epigenetic data to identify TSGs and OGs, particularly those with rare mutations. DORGE identified histone modifications as strong predictors for TSGs, and it found missense mutations, super enhancer percentages, and methylation differences between cancer and normal samples as strong predictors for OGs. We extensively validated novel cancer driver genes predicted by DORGE using independent functional genomics data. We also found that the dual-functional genes, which are both TSGs and OGs predicted by DORGE, are enriched at hubs in protein-protein interaction and drug-gene networks. Overall, our study has deepened the understanding of epigenetic mechanisms in tumorigenesis and revealed a previously undetected repertoire of cancer driver genes.

bioinformatics↗

bioRxiv2020

DreamAI: algorithm for the imputation of proteomics data

Deep proteomics profiling using labeled LC-MS/MS experiments has been proven to be powerful to study complex diseases. However, due to the dynamic nature of the discovery mass spectrometry, the generated data contain a substantial fraction of missing values. This poses great challenges for data analyses, as many tools, especially those for high dimensional data, cannot deal with missing values directly. To address this problem, the NCI-CPTAC Proteogenomics DREAM Challenge was carried out to develop effective imputation algorithms for labeled LC-MS/MS proteomics data through crowd learning. The final resulting algorithm, DreamAI, is based on an ensemble of six different imputation methods. The imputation accuracy of DreamAI, as measured by Pearson correlation, is about 15%-50% greater than existing tools among less abundant proteins, which are more vulnerable to be missed in proteomics data sets. This new tool notably enhances data analysis capabilities in proteomics research.

bioinformatics↗

bioRxiv2020

Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome

Mutations in the Hedgehog (Hh) signaling are implicated in birth defects and cancers, including medulloblastoma, one of the most malignant pediatric brain tumors. Current Hh inhibitors face the challenge of drug resistance and tumor relapse, urging new insights in the Hh pathway regulation. Our previous study revealed how PDE4D controls global levels of cAMP in the cytoplasm to positively regulate Hh signaling; in the present study we found that a specific isoform PDE4D3 is tethered to the centrosome by myomegalin, a centrosome/Golgi associated protein. Myomegalin loss dislocates PDE4D3 from the centrosome, leading to local PKA over-activation and inhibition of the Hh signaling, leaving other PKA-related pathways unaffected. Myomegalin loss suppresses the proliferation of granule neuron precursors, and blocks the growth of medulloblastoma in mouse model. Our findings specify a new regulatory mechanism of the Hh pathway, and highlight an exciting therapeutic avenue for Hh-related cancers with reduced side effects.

cell biology↗

bioRxiv2020

Rapid development of an inactivated vaccine for SARS-CoV-2

The COVID-19 pandemic caused by SARS-CoV-2 has brought about an unprecedented crisis, taking a heavy toll on human health, lives as well as the global economy. There are no SARS-CoV-2-specific treatments or vaccines available due to the novelty of this virus. Hence, rapid development of effective vaccines against SARS-CoV-2 is urgently needed. Here we developed a pilot-scale production of a purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc), which induced SARS-CoV-2-specific neutralizing antibodies in mice, rats and non-human primates. These antibodies potently neutralized 10 representative SARS-CoV-2 strains, indicative of a possible broader neutralizing ability against SARS-CoV-2 strains circulating worldwide. Immunization with two different doses (3g or 6 g per dose) provided partial or complete protection in macaques against SARS-CoV-2 challenge, respectively, without any antibody-dependent enhancement of infection. Systematic evaluation of PiCoVacc via monitoring clinical signs, hematological and biochemical index, and histophathological analysis in macaques suggests that it is safe. These data support the rapid clinical development of SARS-CoV-2 vaccines for humans. One Sentence SummaryA purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc) confers complete protection in non-human primates against SARS-CoV-2 strains circulating worldwide by eliciting potent humoral responses devoid of immunopathology

microbiology↗

bioRxiv2020

In-field bioreactors demonstrate dynamic shifts in microbial communities in response to geochemical perturbations.

Subsurface microbial communities mediate the transformation and fate of redox sensitive materials including organic matter, metals and radionuclides. Few studies have explored how changing geochemical conditions influence the composition of groundwater microbial communities over time. We temporally monitored alterations in abiotic forces on microbial community structure using 1L in-field bioreactors receiving background and contaminated groundwater at the Oak Ridge Reservation, TN. Planktonic and biofilm microbial communities were initialized with background water for 4 days to establish communities in triplicate control reactors and triplicate test reactors and then fed filtered water for 14 days. On day 18, three reactors were switched to receive filtered groundwater from a contaminated well, enriched in total dissolved solids relative to the background site, particularly chloride, nitrate, uranium, and sulfate. Biological and geochemical data were collected throughout the experiment, including planktonic and biofilm DNA for 16S rRNA amplicon sequencing, cell counts, total protein, anions, cations, trace metals, organic acids, bicarbonate, pH, Eh, DO, and conductivity. We observed significant shifts in both planktonic and biofilm microbial communities receiving contaminated water. This included a loss of rare taxa, especially amongst members of the Bacteroidetes, Acidobacteria, Chloroflexi, and Betaproteobacteria, but enrichment in the Fe- and nitrate-reducing Ferribacterium and parasitic Bdellovibrio. These shifted communities were more similar to the contaminated well community, suggesting that geochemical forces substantially influence microbial community diversity and structure. These influences can only be captured through such comprehensive temporal studies, which also enable more robust and accurate predictive models to be developed.

microbiology↗

bioRxiv2020

Potent human neutralizing antibodies elicited by SARS-CoV-2 infection

The pandemic caused by emerging coronavirus SARS-CoV-2 presents a serious global public health emergency in urgent need of prophylactic and therapeutic interventions. SARS-CoV-2 cellular entry depends on binding between the viral Spike protein receptor-binding domain (RBD) and the angiotensin converting enzyme 2 (ACE2) target cell receptor. Here, we report on the isolation and characterization of 206 RBD-specific monoclonal antibodies (mAbs) derived from single B cells of eight SARS-CoV-2 infected individuals. These mAbs come from diverse families of antibody heavy and light chains without apparent enrichment for particular families in the repertoire. In samples from one patient selected for further analyses, we found coexistence of germline and germline divergent clones. Both clone types demonstrated impressive binding and neutralizing activity against pseudovirus and live SARS-CoV-2. However, the antibody neutralizing potency is determined by competition with ACE2 receptor for RBD binding. Surprisingly, none of the SARS-CoV-2 antibodies nor the infected plasma cross-reacted with RBDs from either SARS-CoV or MERS-CoV although substantial plasma cross-reactivity to the trimeric Spike proteins from SARS-CoV and MERS-CoV was found. These results suggest that antibody response to RBDs is viral species-specific while that cross-recognition target regions outside the RBD. The specificity and neutralizing characteristics of this plasma cross-reactivity requires further investigation. Nevertheless, the diverse and potent neutralizing antibodies identified here are promising candidates for prophylactic and therapeutic SARS-CoV-2 interventions.

immunology↗

bioRxiv2019

Protein adlayer thickness on colloidal nanoparticle determined by Rayleigh-Gans-Debye approximation

Reference materials (RM)-assisted Rayleigh-Gans-Debye approximation (rm-RGDA) has been developed and used to in situ determine the size and thickness of the adlayer on the particles in solution. The particle size determined by rm-RGDA is quite close to that measured by electron microscopy but significantly smaller than that measured by DLS. The BSA adlayer absorbed on PS50, PS100 and SiO2 NPs is 3.3, 0.9 and 1.2 nm, respectively, and close to those observed by SEM, which is 4.6, 1.3 and 3.8 nm, respectively. The FTIR analysis results show that the BSA absorbed on larger particles or hydroxyl-abundant surface, e.g. PS100 and SiO2 NPs can lose its secondary structure, e.g. -helix, to a great extent and that absorbed on a more curve surface, e.g. smaller PS50 particles can largely preserve its secondary structure as its free state. The measurement results show the curvature of the NPs is closely related to the structure change of the adsorbed protein. This method provide a facile and new approach to measure the size and its adlayer change of the hybrid and core-shell structured nanoparticles in a wide range of wavelength. SIGNIFICANCEQuantitative study on the adsorption of the protein on colloidal nanoparticles is an important approach to understand the biophysical effect, compared with other ex situ methods such as TEM and SEM, where the specimen are undergone pre-processing and no longer the original state in measurement. It is, therefore, a big challenge. In order to cope with this challenge, UV-vis based RGDA has been developed and applied to in situ measure the size of the dispersed colloidal nanoparticles and their protein adlayer thickness, where the protein adlayer thickness on the colloidal nanoparticles can be easily determined. We believe this method provide a facile and sensitive way to in situ measure the dimension change of hybrid colloidal nanoparticles.

biophysics↗

bioRxiv2019

Integrated characterization of subsurface media from locations up- and down-gradient of a uranium-contaminated aquifer

The processing of sediment to accurately characterize the spatially-resolved depth profiles of geophysical and geochemical properties along with signatures of microbial density and activity remains a challenge especially in complex contaminated environments. To provide site assessment for a larger study, we processed cores from two sediment boreholes from background and contaminated core sediments and surrounding groundwater from the ENIGMA Field Research Site at the United States Department of Energy (DOE) Oak Ridge Reservation (ORR). We compared fresh core sediments by depth to capture the changes in sediment structure, sediment minerals, biomass, and pore water geochemistry in terms of major and trace elements including contaminants, cations, anions, and organic acids. Soil porewater samples were matched to groundwater level, flow rate, and preferential flows and compared to homogenized groundwater-only samples from neighboring monitoring wells. This environmental systems approach provided detailed site-specific biogeochemical information from the various properties of subsurface media to reveal the influences of solid, liquid, and gas phases. Groundwater analysis of nearby wells only revealed high sulfate and nitrate concentrations while the same analysis using sediment pore water samples with depth was able to suggest areas high in sulfate- and nitrate- reducing bacteria based on their decreased concentration and production of reduced by-products that could not be seen in the groundwater samples. Positive correlations among porewater content, total organic carbon, trace metals and clay minerals revealed a more complicated relationship among contaminant, sediment texture, groundwater table, and biomass. This suggested that groundwater predominantly flowed through preferential paths with high flux and little mixing with water in the interstices of sediment particles, which could impact microbial activity. The abundant clay minerals with high surface area and high water-holding capacity of micro-pores of the fine clay rich layer suggest suppression of nutrient supply to microbes from the surface. The fluctuating capillary interface had high concentrations of Fe and Mn-oxides combined with trace elements including U, Th, Sr, Ba, Cu, and Co. This suggests the mobility of highly toxic elements, sediment structure, and biogeochemical factors are all linked together to impact microbial communities, emphasizing that solid interfaces play an important role in determining the abundance of bacteria in the sediments.

systems biology↗

bioRxiv2019

PI3K/AKT inhibition in tumor propagating cells of DLBCL reverses R-CHOP resistance by destabilizing SOX2

Drug resistance is a major obstacle for the success of conventional anticancer therapy, and the development of drug resistance is at least partly attributed to tumor propagating cells (TPCs). Up to one-third of diffuse large B cell lymphoma (DLBCL) patients eventually develop resistance to R-CHOP regimen. We found that the TPC proportion was remarkably increased in resistant germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL subtypes. Elevated SOX2 was the determinant for resistance development, and SOX2 was phosphorylated by activated PI3K/AKT1 signaling, thus preventing ubiquitin-mediated SOX2 degradation. Furthermore, multiple factors, including BCR, integrins, chemokines and FGFR1/2 signaling, regulated PI3K/AKT1 activation. CDK6 in the GCB subtype and FGFR1/2 in the ABC subtype were SOX2 targets in the PI3K/AKT1 pathway. Chemical inhibition of PI3K/AKT1 in both subtypes, CDK6 in the GCB subtype, and FGFR1/2 in the ABC subtype significantly enhanced the susceptibility of resistant cells to CHO treatment. More importantly, PI3K and FGFR1/2 inhibitors but not a CDK6 inhibitor effectively suppressed the tumor growth of R-CHO-resistant DLBCL cells, most likely by converting TPCs to chemo-sensitive differentiated cells. Therefore, this pro-differentiation therapy against TPCs warrants further study in clinical trials for the treatment of resistant DLBCL.

cancer biology↗

bioRxiv2019

Selective translation by alternative bacterial ribosomes

Alternative ribosome subunit proteins are prevalent in the genomes of diverse bacterial species but their functional significance is controversial. Attempts to study microbial ribosomal heterogeneity have mostly relied on comparing wild-type strains with mutants in which subunits have been deleted, but this approach does not allow direct comparison of alternate ribosome isoforms isolated from identical cellular contexts. Here, by simultaneously purifying canonical and alternative RpsR ribosomes from Mycobacterium smegmatis, we show that alternative ribosomes have distinct translational features compared with their canonical counterparts. Both alternative and canonical ribosomes actively take part in gene translation, although they translate a subset of genes with differential efficiency as measured by ribosome profiling. We also show that alternative ribosomes have a relative defect in initiation complex formation. Our work convincingly confirms the distinct and non-redundant contribution of alternative bacterial ribosomes for adaptation to hostile environments.\n\nSignificance StatementMany organisms, including most bacteria code for multiple paralogues of some ribosomal protein subunits. The relative contribution of these alternative subunits to ribosome function and gene translation is unknown and controversial. Furthermore, many studies on alternative ribosomes have been confounded by isolation of alternative and canonical ribosomes from different strains and/ or different growth conditions, potentially confounding results. Here, we show unequivocally that one form of alternative ribosome from Mycobacterium smegmatis actively engages in gene translation, but its translational profile from an identical cellular context is subtly different from canonical ribosomes. Given the prevalence of alternative ribosomal genes in diverse organisms, our study suggests that alternative ribosomes may represent a further layer of regulation of gene translation.

microbiology↗

bioRxiv2019

EpiAlign: an alignment-based bioinformatic tool for comparing chromatin state sequences

The availability of genome-wide epigenomic datasets enables in-depth studies of epigenetic modifications and their relationships with chromatin structures and gene expression. Various alignment tools have been developed to align nucleotide or protein sequences in order to identify structurally similar regions. However, there are currently no alignment methods specifically designed for comparing multi-track epigenomic signals and detecting common patterns that may explain functional or evolutionary similarities. We propose a new local alignment algorithm, EpiAlign, designed to compare chromatin state sequences learned from multi-track epigenomic signals and to identify locally aligned chromatin regions. EpiAlign is a dynamic programming algorithm that novelly incorporates varying lengths and frequencies of chromatin states. We demonstrate the effcacy of EpiAlign through extensive simulations and studies on the real data from the NIH Roadmap Epigenomics project. EpiAlign is able to extract recurrent chromatin state patterns along a single epigenome, and many of these patterns carry cell-type-specific characteristics. EpiAlign can also detect common chromatin state patterns across multiple epigenomes, and it will serve as a useful tool to group and distinguish epigenomic samples based on genome-wide or local chromatin state patterns.

bioinformatics↗

bioRxiv2019

Unbinding Kinetics and Multiple Pathways of p38 MAPK Inhibitors

Rational Drug Discovery still faces a major hurdle for the prediction of drug efficacy in vivo solely based on its binding affinity for the target in vitro. The traditional perspective has clearly proven to be inadequate as it lacks the consideration of essential aspects such as pharmacokinetics and binding kinetics in determining drug efficacy as well as toxicity. Residence time, the average lifetime of drug-target complex, has undoubtedly gained broader recognition as a better predictor for lead optimization. Long residence time can lead to sustained pharmacological effect and may also mitigate off-target toxicity. To showcase the importance of drug-target binding kinetics and unravel the underlining mechanism for variation of residence time, unbinding kinetics of two distinct type II inhibitors of p38 MAP kinase were for the first time investigated and compared by molecular dynamics and metadynamics simulation approaches. Free energy landscape of key motions associated with unbinding process was constructed for inhibitors with different unbinding rates. Multiple unbinding pathways and rebinding were revealed during the drug-target dissociation process of faster unbinder Lig3 and slower unbinder Lig8 respectively, suggesting a novel mechanism of unbinding kinetics. The comparative studies imply the hydrophobic and Hydrogen-bonding interaction in the R1 group of ligands is crucial for the slow unbinding. Such kind of computational approaches could also be applied to predict unbinding pathways and kinetics of many other drugs, and facilitate the design of efficient kinase inhibitors.

pharmacology and toxicology↗

bioRxiv2018

Spanning spatiotemporal scales with simultaneous mesoscopic Ca2+ imaging and functional MRI

Neuroscience encompasses the investigation of brain function across multiple spatiotemporal scales. Yet, most research is confined to Ca2+ one spatiotemporal milieu limiting the integration of knowledge across scales. Here we describe an imaging and analytic approach that spans spatiotemporal scales by combining simultaneous wide field mesoscopic 1-photon Ca2+ imaging and functional magnetic resonance imaging (fMRI) at 11.7T. Given the confined space within the magnet, that metal is prohibited, and the unique/conflicting needs of each methodology, these techniques have never before been combined. In addition to describing the new hardware and software, we present evoked and spontaneous activity measurements made in lightly anesthetized animals. We have three findings: (1) for both evoked and spontaneous activity the magnitude of the Ca2+ and fMRI signals show correspondence, (2) connectivity matrices derived from Ca2+ and fMRI measurements are stable throughout an imaging session, and (3) there is correspondence between Ca2+ and fMRI spontaneous activity patterns.

neuroscience↗

bioRxiv2018

Bifunctional enzyme SpoT is involved in biofilm formation of Helicobacter pylori with multidrug resistance by upregulating efflux pump Hp1174 (gluP)

The drug resistance of Helicobacter pylori (H. pylori) is gradually becoming a serious problem. Biofilm formation is an important factor that leads to multidrug resistance in bacteria. The ability of H. pylori to form biofilms on the gastric mucosa has been known. However, there are few studies on the regulation mechanisms of H. pylori biofilm formation and multidrug resistance. Guanosine 3-diphosphate 5-triphosphate and guanosine 3,5-bispyrophosphate [(p)ppGpp] are global regulatory factors and are synthesized in H. pylori by the bifunctional enzyme SpoT. It has been reported that (p)ppGpp is involved in the biofilm formation and multidrug resistance of various bacteria. In this study, we found that SpoT also plays an important role in H. pylori biofilm formation and multidrug resistance. Therefore, it is necessary to carry out some further studies regarding its regulatory mechanism. Considering that efflux pumps are of great importance in the biofilm formation and multidrug resistance of bacteria, we tried to find if efflux pumps controlled by SpoT participate in these activities. Then, we found that Hp1174 (glucose/galactose transporter, gluP), an efflux pump of the MFS family, is highly expressed in biofilm-forming and multi-drug resistance (MDR) H. pylori and is upregulated by SpoT. Through further research, we determined that gluP involved in H. pylori biofilm formation and multidrug resistance. Furthermore, the average expression level of gluP in clinical MDR strains was considerably higher than that in clinical drug-sensitive strains. Taken together, our results revealed a novel molecular mechanism of H. pylori tolerance to multidrug.

microbiology↗

bioRxiv2018

Membrane proteins with high N-glycosylation, high expression, and multiple interaction partners were preferred by mammalian viruses as receptors

Receptor mediated entry is the first step for viral infection. However, the relationship between viruses and receptors is still obscure. Here, by manually curating a high-quality database of 268 pairs of mammalian virus-host receptor interaction, which included 128 unique viral species or sub-species and 119 virus receptors, we found the viral receptors were structurally and functionally diverse, yet they had several common features when compared to other cell membrane proteins: more protein domains, higher level of N-glycosylation, higher ratio of self-interaction and more interaction partners, and higher expression in most tissues of the host. Additionally, the receptors used by the same virus tended to co-evolve. Further correlation analysis between viral receptors and the tissue and host specificity of the virus shows that the virus receptor similarity was a significant predictor for mammalian virus cross-species. This work could deepen our understanding towards the viral receptor selection and help evaluate the risk of viral zoonotic diseases.

microbiology↗

bioRxiv2017

Very low depth whole genome sequencing in complex trait association studies

MotivationVery low depth sequencing has been proposed as a cost-effective approach to capture low-frequency and rare variation in complex trait association studies. However, a full characterisation of the genotype quality and association power for very low depth sequencing designs is still lacking.\n\nResultsWe perform cohort-wide whole genome sequencing (WGS) at low depth in 1,239 individuals (990 at 1x depth and 249 at 4x depth) from an isolated population, and establish a robust pipeline for calling and imputing very low depth WGS genotypes from standard bioinformatics tools. Using genotyping chip, whole-exome sequencing (WES, 75x depth) and high-depth (22x) WGS data in the same samples, we examine in detail the sensitivity of this approach, and show that imputed 1x WGS recapitulates 95.2% of variants found by imputed GWAS with an average minor allele concordance of 97% for common and low-frequency variants. In our study, 1x further allowed the discovery of 140,844 true low-frequency variants with 73% genotype concordance when compared to high-depth WGS data. Finally, using association results for 57 quantitative traits, we show that very low depth WGS is an efficient alternative to imputed GWAS chip designs, allowing the discovery of up to twice as many true association signals than the classical imputed GWAS design.\n\nSupplementary DataSupplementary Data are appended to this manuscript.

genetics↗