Biology subjects

Yuan, Q.

Publications and source records attributed to Yuan, Q..

88 records · Page 5Linked to original sources

bioRxiv2020

Sterilizing immunity against SARS-CoV-2 in hamsters conferred by a novel recombinant subunit vaccine

A safe and effective SARS-CoV-2 vaccine is essential to avert the on-going COVID-19 pandemic. Here, we developed a subunit vaccine, which is comprised of CHO-expressed spike ectodomain protein (StriFK) and nitrogen bisphosphonates-modified zinc-aluminum hybrid adjuvant (FH002C). This vaccine candidate rapidly elicited the robust humoral response, Th1/Th2 balanced helper CD4 T cell and CD8 T cell immune response in animal models. In mice, hamsters, and non-human primates, 2-shot and 3-shot immunization of StriFK-FH002C generated 28- to 38-fold and 47- to 269-fold higher neutralizing antibody titers than the human COVID-19 convalescent plasmas, respectively. More importantly, the StriFK-FH002C immunization conferred sterilizing immunity to prevent SARS-CoV-2 infection and transmission, which also protected animals from virus-induced weight loss, COVID-19-like symptoms, and pneumonia in hamsters. Vaccine-induced neutralizing and cell-based receptor-blocking antibody titers correlated well with protective efficacy in hamsters, suggesting vaccine-elicited protection is immune-associated. The StriFK-FH002C provided a promising SARS-CoV-2 vaccine candidate for further clinical evaluation.

microbiology↗

bioRxiv2020

Duple extinguishment of COVID-19: single compound synergized inhibition of SARS-CoV-2 replication and direct suppression of inflammatory cytokines in vitro/vivo

We firstly disclose single compound yields better therapeutic outcome than Remdesivir in COVID-19 hamster treatments as it is armed with direct inhibition viral replication and intrinsic suppression inflammatory cytokines expression. Crystal data reveals that Au (I), released from Au22Glutathione18 (GA), covalently binds thiolate of Cys145 of SARS-CoV-2 Mpro. GA directly decreases SARS-CoV-2 viral replication (EC50: ~0.24 M) and intrinsically down-regulates NF{kappa}B pathway therefore significantly inhibiting expression of inflammatory cytokines in cells. The lung viral load and inflammatory cytokines in GA-treated COVID-19 transgenic mice are found to be significantly lower than that of control mice. When COVID-19 golden hamsters are treated by GA, the lung inflammatory cytokines levels are significantly lower than that of Remdesivir while their lung viral load are decreased to same level. The pathological results show that GA treatment significantly reduce lung inflammatory injuries when compared to that of Remdesivir-treated COVID-19 golden hamsters. One Sentence SummaryWe found that gold cluster molecule directly inhibits SARS-CoV-2 replication and intrinsically suppresses inflammatory cytokines expression in COVID-19 transgenic mouse and golden hamster model, gold cluster providing a better lung injury protection than Remdesivir in COVID-19 golden hamsters via intranasally dropping administration.

microbiology↗

bioRxiv2020

Virus-free and live-cell visualizing SARS-CoV-2 cell entry for studies of neutralizing antibodies and compound inhibitors

The ongoing COVID-19 pandemic, caused by SARS-CoV-2 infection, has resulted in hundreds of thousands of deaths. Cellular entry of SARS-CoV-2, which is mediated by the viral spike protein and host ACE2 receptor, is an essential target for the development of vaccines, therapeutic antibodies, and drugs. Using a mammalian cell expression system, we generated a recombinant fluorescent protein (Gamillus)-fused SARS-CoV-2 spike trimer (STG) to probe the viral entry process. In ACE2-expressing cells, we found that the STG probe has excellent performance in the live-cell visualization of receptor binding, cellular uptake, and intracellular trafficking of SARS-CoV-2 under virus-free conditions. The new system allows quantitative analyses of the inhibition potentials and detailed influence of COVID-19-convalescent human plasmas, neutralizing antibodies and compounds, providing a versatile tool for high-throughput screening and phenotypic characterization of SARS-CoV-2 entry inhibitors. This approach may also be adapted to develop a viral entry visualization system for other viruses.

microbiology↗

bioRxiv2020

Several FDA-approved drugs effectively inhibit SARS-CoV-2 infection in vitro

To identify drugs that are potentially used for the treatment of COVID-19, the potency of 1403 FDA-approved drugs were evaluated using a robust pseudovirus assay and the candidates were further confirmed by authentic SARS-CoV-2 assay. Four compounds, Clomiphene (citrate), Vortioxetine, Vortioxetine (hydrobromide) and Asenapine (hydrochloride), showed potent inhibitory effects in both pseudovirus and authentic virus assay. The combination of Clomiphene (citrate), Vortioxetine and Asenapine (hydrochloride) is much more potent than used alone, with IC50 of 0.34 M.

microbiology↗

bioRxiv2020

BAP31 regulated polarization of macrophages through C/EBP β in cutaneous wound healing

The functions carried out by macrophages are essential in the processes of repairing skin injury. However, the mechanism of the M2 macrophage and its role in cutaneous wound healing remain elusive. B cell receptor associated protein 31 (BAP31) plays an important role in the immune system, and its function in connection with macrophages has yet to be determined. The present study demonstrates that the process of cutaneous wound healing slowed down in bone marrow-specific BAP31 knock down Lyz2-cre-BAP31flox/flox mice. In addition, further studies show that various kinds of macrophage M2 polarization related factors were regulated by BAP31. Among these molecules C/EBP {beta} was significantly affected. However, IL-4 but not IFN-{gamma}, is able to recover the expression levels of C/EBP {beta} and its downstream transcript factors induced by BAP31. Then, we demonstrated that BAP31 regulated macrophage M2 polarization by negative regulation of IL-4R and positive influence on Egr-2 to affect C/EBP {beta}. Our findings reveal a novel mechanism of BAP31 in regulating M2 macrophage, and provide novel targets for the prevention and treatment of chronic wounds.

molecular biology↗

bioRxiv2020

Locus coeruleus patterns differentially modulate learning and valence in rat via the ventral tegmental area and basolateral amygdala respectively

The locus coeruleus (LC), the main source of forebrain norepinephrine, produces phasic and tonic firing patterns that are theorized to have distinct functional consequences. However, how different firing modes affect learning and valence coding of sensory information are unknown. Here bilateral optogenetic activation of rat LC neurons using 10-Hz phasic trains of either 300 msec or 10 sec accelerates acquisition of a food-rewarded similar odor discrimination, but not a dissimilar odor discrimination, consistent with LC-supported enhanced pattern separation and plasticity. Similar odor discrimination learning is impaired by noradrenergic blockade in the piriform cortex (PC). However, here 10-Hz LC phasic light-mediated learning facilitation is prevented by a dopaminergic antagonist in the PC, or by ventral tegmental area (VTA) silencing with lidocaine, suggesting an LC-VTA-PC dopamine circuitry mediates 10-Hz phasic learning facilitation. Tonic stimulation at 10 Hz did not alter odor discrimination acquisition, and was less effective in activating VTA DA neurons. For valence encoding, tonic stimulation at 25 Hz induced freezing, anxiety and conditioned odor aversion, while 10-Hz phasic stimulation produced an odor preference consistent with positive valence. Noradrenergic blockade in the basolateral amygdala (BLA) prevented conditioned odor preference and aversion induced by 10-Hz phasic and 25-Hz tonic light respectively. CTB retro-labeling showed relatively larger engagement of nucleus accumbens projecting neurons over central amygdala projecting neurons in the BLA with 10-Hz LC phasic activation, compared to 25-Hz tonic. These outcomes argue that LC pauses, as well as LC firing frequencies, differentially influence both target networks and behaviour.

neuroscience↗

bioRxiv2020

Robust neutralization assay based on SARS-CoV-2 S-bearing vesicular stomatitis virus (VSV) pseudovirus and ACE2-overexpressed BHK21 cells

The global pandemic of Coronavirus disease 2019 (COVID-19) is a disaster for human society. A convenient and reliable in vitro neutralization assay is very important for the development of neutralizing antibodies, vaccines and other inhibitors. In this study, G protein-deficient vesicular stomatitis virus (VSVdG) bearing full-length and truncated spike (S) protein of SARS-CoV-2 were evaluated. The virus packaging efficiency of VSV-SARS-CoV-2-Sdel18 (S with C-terminal 18 amino acid truncation) is much higher than VSV-SARS-CoV-2-S. A neutralization assay for antibody screening and serum neutralizing titer quantification was established based on VSV-SARS-CoV-2-Sdel18 pseudovirus and human angiotensin-converting enzyme 2 (ACE2) overexpressed BHK21 cell (BHK21-hACE2). The experimental results can be obtained by automatically counting EGFP positive cell number at 12 hours after infection, making the assay convenient and high-throughput. The serum neutralizing titer of COVID-19 convalescent patients measured by VSV-SARS-CoV-2-Sdel18 pseudovirus assay has a good correlation with live SARS-CoV-2 assay. Seven neutralizing monoclonal antibodies targeting receptor binding domain (RBD) of SARS-CoV-2-S were obtained. This efficient and reliable pseudovirus assay model could facilitate the development of new drugs and vaccines.

microbiology↗

bioRxiv2020

ERG orchestrates chromatin interactions to drive prostate cell fate reprogramming

While cancer is commonly perceived as a disease of dedifferentiation, the hallmark of early stage prostate cancer is paradoxically the loss of more plastic basal cells and the abnormal proliferation of more differentiated secretory luminal cells. However, the mechanism of prostate cancer pro-luminal differentiation is largely unknown. Through integrating analysis of the transcription factors (TFs) from 806 human prostate cancers, we have identified that ERG highly correlated with prostate cancer luminal subtyping. ERG overexpression in luminal epithelial cells inhibits its normal plasticity to transdifferentiate into basal lineage and ERG supersedes PTEN-loss which favors basal differentiation. ERG knock-out disrupted prostate cell luminal differentiation, whereas AR knock-out had no such effects. Trp63 is a known master regulator of prostate basal lineage. Through analysis of 3D chromatin architecture, we found that ERG binds and inhibits the enhancer activity and chromatin looping of a Trp63 distal enhancer, thereby silencing its gene expression. Specific deletion of the distal ERG binding site resulted in the loss of ERG-mediated inhibition of basal differentiation. Thus, ERG orchestrates chromatin interactions and regulates prostate cell lineage toward pro-luminal program, as its fundamental role on lineage differentiation in prostate cancer initiation.

cancer biology↗

bioRxiv2020

Derived ecological niches of indoor microbes are crucial for asthma symptoms in university dormitories

Increasing evidences from home environment indicate that microbiome community is associated with asthma. However, indoor microbiome composition can be highly diverse and dynamic, and thus current studies fail to produce consistent association. Chinese university dormitories are special high-density dwellings with a standard built environment and personal characteristics for occupants, which can be used to disentangle the complex interactions between microbes, environmental characteristics and asthma. Settled air dust and floor dust was collected from 87 dormitory rooms in Shanxi University. Bacterial community was characterized by 16S rRNA amplicon sequencing. Students (n = 357) were surveyed for asthma symptoms. Asthma symptoms were not associated with the overall bacterial richness, but associated with different phylogenetic classes. Taxa richness and abundance in Clostridia and Bacteroidia were positively associated with asthma (p < 0.05), and these taxa were mainly derived from human gut. Taxa richness (p < 0.1) and abundance (p < 0.05) in Alphaproteobacteria and Actinobacteria were protectively associated with asthma, and these taxa were mainly derived from outdoor environment. Building age, floor and curtain cleaning frequency shaped the overall bacterial community of air dust (p < 0.05). Frequent curtain cleaning increased the relative abundance of 10 protective genera (p < 0.05), and old buildings had mix effects to protective genera (p < 0.05). Our data shows that taxa from different phylogenetic classes and ecological niches have different health effects, indicating the importance of incorporating evolutionary and ecological concepts in revealing general patterns in the microbiome asthma association analysis.

microbiology↗

bioRxiv2020

Mining the Selective Remodeling of DNA Methylation in Promoter Regions to Identify Robust Gene-Level Associations with Phenotype

Epigenetics is an essential biological frontier linking genetics to the environment, where DNA methylation is one of the most studied epigenetic events. In recent years, through the epigenome-wide association study (EWAS), researchers have identified thousands of phenotype-related methylation sites. However, the overlap between identified phenotype-related DNA methylation sites are often quite small, and it might clue to methylation remodeling has a certain degree of randomness within the genome. Thus, the identification of robust gene-phenotype associations is crucial for interpreting pathogenesis. How to integrate the methylation values of different sites on the same gene and to mining the DNA methylation at the gene level remains a challenge. A recent study found that the DNA methylation difference of the gene body and promoter region has a strong correlation with gene expression. In this study, we proposed a Statistical difference of DNA Methylation between Promoter and Other Body Region (SIMPO) algorithm to extract DNA methylation values at the gene level. First, by choosing to smoke as an environmental exposure factor, our method led to significant improvements in gene overlaps (from 5% to 17%) between different datasets. In addition, the biological significance of these genes ([~]23%) are significantly better than those identified by traditional probe-based methods ([~]18%, P-value = 5.18e-03). Then, we selected two disease content (e.g., insulin resistance and Parkinsons disease) to show that the biological efficiency of disease-related gene identification increased from 15.43% to 44.44% (P-value = 1.20e-28). Thus, our results declare that mining the selective remodeling of DNA methylation in promoter regions can identify robust gene-level associations with phenotype, and the characteristic remodeling of a given genes promoter region can reflect the essence of disease.

bioinformatics↗

bioRxiv2019

Distinct microbiome composition of floor and air dust distort richness estimation in university dormitories

The number of culture-independent indoor microbiome study has increased remarkably in recent years, but microbial composition among different sampling strategies remains poorly characterized and their impact to downstream microbiome analysis is also not clear. In this study, we reported a case study of microbial composition of floor and air dust in 87 dormitory rooms of Shanxi University, China. Floor and air dust were collected by vacuum cleaner and petri-dish, respectively, and the bacterial composition was characterized by 16S rRNA sequencing. The composition of floor and air dust differed significantly (R2 = 0.65, p < 0.001, Adonis), and Pseudomonas dominated in floor dust (75.1%) but was less common in air dust (1.9%). The top genera in air dust, including Ralstonia (15.6%), Pelomonas (11.3%), Anoxybacillus (9.3%) and Ochrobactrum (6.2%), all accounted for < 1% abundance in floor dust. The dominant Pseudomonas in floor dust swamped low frequency organisms, leading to significant lower number of operational taxonomic units (OTUs) compared with air dust in the same sequencing depth. The different microbial composition of floor and air dust can lead to differences in downstream bioinformatics analyses. We searched the dormitory microbiome against ~200,000 samples deposited in Microbiome Search Engine (MSE), and found that the compositions of floor dust samples were similar to samples from building environment and human nasopharynx, whereas the compositions of the air dust samples were similar to mosquito tissues. ImportanceIncreasing number of indoor microbiome studies has been conducted in recent years, but the impact of sampling strategy is far from clear. In this study, we reported that the floor and air sampling can lead to drastic variation in microbial composition and downstream analyses in university dormitories, including microbial diversity estimation and compositional similarity search. Thus, the bioinformatics analysis results need to be interpreted with caution in microbiome studies, and it may be necessary to collected samples from different sampling strategies to comprehensively characterize the microbial composition and exposure to human occupants in an indoor environment.

microbiology↗

bioRxiv2019

Continental-scale microbiome study reveals different environmental characteristics determining microbial richness and composition/quantity in hotel rooms

Culture-independent microbiome surveys have been conducted in homes, hospitals, schools, kindergartens and vehicles for public transport, revealing diverse microbial distributions in built environments. However, microbiome surveys have not been conducted in hotel environments; thus, the composition and associated environmental factors are not clear. We presented the first continental-scale microbiome study of hotel rooms (n = 68) spanning large geographic regions. Bacterial and fungal communities were described by amplicon sequencing of the 16S rRNA gene and internal transcribed spacer (ITS) region and quantitative PCR. Similar numbers of bacterial (4,344) and fungal (4,555) operational taxonomic units were identified, but fungal taxa showed a local distribution compared with bacterial taxa. Aerobic, ubiquitous bacteria dominated the hotel microbiome with high compositional similarity to previous samples from building and human nasopharynx environments. The abundance of Aspergillus was negatively correlated with latitude and accounted for [~]80% of the total fungal load in seven low-latitude hotels. We calculated the association between hotel microbial dynamics and 16 indoor and outdoor environmental characteristics. Fungal {beta}-diversity and quantity showed concordant variation and were associated with the same environmental characteristics, including latitude, quality of the interior, proximity to the sea and visible mold, while -diversity decreased with heavy traffic (95% CI: -127.05 to -0.25) and wall-to-wall carpet (95% CI: -47.60 to -3.82). Bacterial {beta}-diversity was associated with latitude, quality of the interior and floor type, while -diversity decreased with recent decoration (95% CI -179.00 to -44.55) and mechanical ventilation (95% CI: -136.71 to -5.12). ImportanceThis is the first microbiome study to characterize microbial composition and associated environmental characteristics. In this study, we found concordant variation between microbial {beta}-diversity and absolute quantity and discordant variation between {beta}-diversity/quantity and -diversity. Our study can be used to promote hotel hygiene standards and provide resource information for future microbiome and exposure studies associated with health effects in hotel rooms.

microbiology↗

bioRxiv2019

Temporal regulation of nicotinic acetylcholine receptor subunits supports central cholinergic synapse development

Construction and maturation of the postsynaptic apparatus are crucial for synapse and dendrite development. The fundamental mechanisms underlying these processes are most often studied in glutamatergic central synapses in vertebrates. Whether the same principles apply to excitatory cholinergic synapses in the insect central nervous system (CNS) is not known. To address this question, we investigated Drosophila ventral lateral neurons (LNvs) and identified nAchR1 (D1) and nAchR6 (D6) as the main functional nicotinic acetylcholine receptor (nAchR) subunits in these cells. With morphological and calcium imaging studies, we demonstrated their distinct roles in supporting dendrite morphogenesis and synaptic transmission. Furthermore, our analyses revealed a transcriptional upregulation of D1 and downregulation of D6 during larval development, indicating a close association between the temporal regulation of nAchR subunits and synapse maturation. Together, our findings show transcriptional regulation of nAchR composition is a core element of developmental and activity-dependent regulation of central cholinergic synapses.

neuroscience↗

bioRxiv2019

Integrated Low-Energy and Low Carbon Shortcut Nitrogen removal with Biological Phosphorus Removal for Sustainable Mainstream Wastewater Treatment

While enhanced biological phosphorus removal (EBPR) is widely utilized for phosphorus (P) removal from wastewater, understanding of efficient process alternatives that allow combined biological P removal and shortcut nitrogen (N) removal, such as nitritation-denitritation, is limited. Here, we demonstrate efficient and reliable combined total N, P, and chemical oxygen demand removal (70%, 83%, and 81%, respectively) in a sequencing batch reactor (SBR) treating real mainstream wastewater (primary effluent) at 20{degrees}C. Anaerobic - aerobic cycling (with intermittent oxic/anoxic periods during aeration) was used to achieve consistent removal rates, nitrite oxidizing organism (NOO) suppression, and high effluent quality. Importantly, high resolution process monitoring coupled to ex situ batch activity assays demonstrated that robust biological P removal was coupled to energy and carbon efficient nitritation-denitritation, not simultaneous nitrification-denitrification, for the last >400 days of 531 total days of operation. Nitrous oxide emissions of 2.2% relative to the influent TKN (or 5.2% relative to total inorganic nitrogen removal) were similar to those measured in other shortcut N bioprocesses. No exogenous chemicals were needed to achieve consistent process stability and high removal rates in the face of frequent wet weather flows and highly variable influent concentrations. Process modeling reproduced the performance observed in the SBR and confirmed that nitrite drawdown via denitritation contributed to suppression of NOO activity.

bioengineering↗

bioRxiv2019

Are Sources of EEG and MEG rhythmic activity the same? An analysis based on BC-VARETA

In the resting state (closed or open eyes) the electroencephalogram (EEG) and the magnetoencephalogram (MEG) exhibit rhythmic brain activity is typically the 10 Hz alpha rhythm. It has a topographic frequency spectral distribution that is, quite similar for both modalities--something not surprising since both EEG and MEG are generated by the same basic oscillations in thalamocortical circuitry. However, different physical aspects underpin the two types of signals. Does this difference lead to a different distribution of reconstructed sources for EEG and MEG rhythms? This question is important for the transferal of results from one modality to the other but has surprisingly received scant attention till now. We address this issue by comparing eyes open EEG source spectra recorded from 70 subjects from the Cuban Human Brain Mapping project with the MEG of 70 subjects from the Human Connectome Project. Source spectra for each voxel and frequencies between 0-50Hz with 100 frequency points were obtained via a novel sparse-covariance inverse method (BC-VARETA) based on individualized BEM head models with subject-specific regularization parameters (noise to signal ratio). We performed a univariate permutation-based rank test among sources of both modalities and found out no differences. To carry out an unbiased comparison we computed sources from eLORETA and LCMV, performed the same permutation-based comparison, and found the same results we got with BC-VARETA.

neuroscience↗

bioRxiv2019

Temporal control of inhibition via muscarinic acetylcholine receptor signaling generates ON and OFF selectivity in a simple visual circuit

ON and OFF selectivity in visual processing is encoded by parallel pathways that respond to either increments or decrements of light. Despite lacking anatomical features to support split channels, Drosophila larvae effectively perform visually-guided behaviors. To understand principles guiding visual computation in this simple circuit, we focus on the physiological properties and behavioral relevance of larval visual interneurons and elucidate their functions in visual processing. We find that the ON vs. OFF discrimination in the larval visual circuit emerges through light-elicited cholinergic signaling that depolarizes the cholinergic interneuron (cha-lOLP) and hyperpolarizes the glutamatergic interneuron (glu-lOLP). Genetic studies further indicate that muscarinic acetylcholine receptor (mAchR)/Go signaling in glu-lOLP separates the ON and OFF signals through temporal delays, the disruption of which strongly impacts both physiological responses of downstream projection neurons and dark-induced pausing behavior. Together, our studies identify cellular and molecular substrates for OFF detection in the larval visual circuit and suggests temporal control of inhibition functions as an effective strategy in generating ON and OFF selectivity without anatomical segregation.

neuroscience↗