Biology subjects

Ye, F.

Publications and source records attributed to Ye, F..

At least 73 records · Page 4Linked to original sources

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

Imaging transmembrane dynamics of biomolecules at live cell plasma membranes using quenchers in extracellular environment

It is a big challenge to measure position changes of biomolecules in the direction normal to the plasma membranes of living cells. We developed a one donor-multiple quenchers F[o]rster resonance energy transfer method by using non-fluorescent quenchers in the extracellular environment. It senses subnanometer position changes of a fluorophore-labeled biomolecule in the plasma membrane. The method was validated by monitoring flip-flops of individual lipid molecules incorporated in plasma membranes. We studies membrane perforation by a host defense peptide from the extracellular side and found that the pore-forming peptide is dynamic, switching among different insertion depths. The method is especially useful in studying interactions of membrane proteins with the inner surfaces of plasma membranes. Our method will find wide applications in systematic analysis of fundamental cellular processes at plasma membranes.

biophysics↗

bioRxiv2020

Comparative transcriptome analysis reveals the intensive early-stage responses of host cells to SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a widespread outbreak of highly pathogenic COVID-19. It is therefore important and timely to characterize interactions between the virus and host cell at the molecular level to understand its disease pathogenesis. To gain insights, we performed high-throughput sequencing that generated time-series data simultaneously for bioinformatics analysis of virus genomes and host transcriptomes implicated in SARS-CoV-2 infection. Our analysis results showed that the rapid growth of the virus was accompanied by an early intensive response of host genes. We also systematically compared the molecular footprints of the host cells in response to SARS-CoV-2, SARS-CoV and MERS-CoV. Upon infection, SARS-CoV-2 induced hundreds of up-regulated host genes hallmarked by a significant cytokine production followed by virus-specific host antiviral responses. While the cytokine and antiviral responses triggered by SARS-CoV and MERS-CoV were only observed during the late stage of infection, the host antiviral responses during the SARS-CoV-2 infection were gradually enhanced lagging behind the production of cytokine. The early rapid host responses were potentially attributed to the high efficiency of SARS-CoV-2 entry into host cells, underscored by evidence of a remarkably up-regulated gene expression of TPRMSS2 soon after infection. Taken together, our findings provide novel molecular insights into the mechanisms underlying the infectivity and pathogenicity of SARS-CoV-2.

microbiology↗

bioRxiv2020

Determining the Depth Limit of Bioluminescent Sources in Scattering Media

Bioluminescence has several potential advantages compared to fluorescence microscopy for in vivo biological imaging. Because bioluminescence does not require excitation light, imaging can be performed for extended periods of time without phototoxicity or photobleaching, and optical systems can be smaller, simpler, and lighter. Eliminating the need for excitation light may also affect how deeply one can image in scattering biological tissue, but the imaging depth limits for bioluminescence have yet to be reported. Here, we perform a theoretical study of the depth limits of bioluminescence microscopy and find that cellular resolution imaging should be possible at a depth of 5-10 mean free paths (MFPs). This limit is deeper than the depth limit for confocal microscopy and slightly lower than the imaging limit expected for two-photon microscopy under similar conditions. We also validate our predictions experimentally using tissue phantoms. Overall we show that with advancements in the brightness of bioluminescent indicators, it should be possible to achieve deep, long-term imaging in biological tissue with cellular resolution.

bioengineering↗

bioRxiv2020

Scutellaria baicalensis extract and baicalein inhibit replication of SARS-CoV-2 and its 3C-like protease in vitro

COVID-19 has become a global pandemic that threatens millions of people worldwide. There is an urgent call for developing effective drugs against the virus (SARS-CoV-2) causing this disease. The main protease of SARS-CoV-2, 3C-like protease (3CLpro), is highly conserved across coronaviruses and is essential for the maturation process of viral polyprotein. Scutellariae radix (Huangqin in Chinese), the root of Scutellaria baicalensis has been widely used in traditional Chinese medicine to treat viral infection related symptoms. The extracts of S. baicalensis have exhibited broad spectrum antiviral activities. We studied the anti-SARS-CoV-2 activity of S. baicalensis and its ingredient compounds. We found that the ethanol extract of S. baicalensis inhibits SARS-CoV-2 3CLpro activity in vitro and the replication of SARS-CoV-2 in Vero cells with an EC50 of 0.74 g/ml. Among the major components of S. baicalensis, baicalein strongly inhibits SARS-CoV-2 3CLpro activity with an IC50 of 0.39 M. We further identified four baicalein analogue compounds from other herbs that inhibit SARS-CoV-2 3CLpro activity at microM concentration. Our study demonstrates that the extract of S. baicalensis has effective anti-SARS-CoV-2 activity and baicalein and analogue compounds are strong SARS-CoV-2 3CLpro inhibitors.

pharmacology and toxicology↗

bioRxiv2020

CovProfile: profiling the viral genome and gene expressions of SARS-COV2

The SARS-CoV-2 virus has infected more than one million people worldwide to date. Knowing its genome and gene expressions is essential to understand the virus mechanism. Here, we propose a computational tool CovProfile to detect the viral genomic variations as well as viral gene expressions from the sequences obtained from Nanopore devices. We applied CovProfile to 11 samples, each from a terminally ill patient, and discovered that all the patients are infected by multiple viral strains, which might affect the reliability of phylogenetic analysis. Moreover, the expression of viral genes ORF1ab gene, S gene, M gene, and N gene are high among most of the samples. While performing the tests, we noticed a consistent abundance of transcript segments of MUC5B, presumably from the host, across all the samples.

bioinformatics↗

bioRxiv2020

Orthogonal genome-wide screenings in bat cells identify MTHFD1 as a target of broad antiviral therapy

Bats are responsible for the zoonotic transmission of several major viral diseases including the 2003 SARS outbreak and the ongoing COVID-19 pandemic. While bat genomic sequencing studies have revealed characteristic adaptations of the innate immune system, functional genomic studies are urgently needed to provide a foundation for the molecular dissection of the tolerance of viral infections in bats. Here we report the establishment and screening of genome-wide RNAi library and CRISPR library for the model megabat, Pteropus Alecto. We used the complementary RNAi and CRISPR libraries to interrogate Pteropus Alecto cells for infection with two different viruses, mumps virus and Influenza A virus, respectively. Screening results converged on the endocytosis pathway and the protein secretory pathway as required for both viral infections. Additionally, we revealed a general dependence of the C-1-tetrahydrofolate synthase gene, MTHFD1, for viral replication in bat cells as well as in human cells. MTHFD1 inhibitor carolacton potently blocked replication of several RNA viruses including SARS-CoV-2. Our studies provide a resource for systematic inquiry into the genetic underpinnings of bat biology and a potential target for developing broad spectrum antiviral therapy.

microbiology↗

bioRxiv2020

Evaluation of biodiversity in estuaries using environmental DNA metabarcoding

Biodiversity is an important parameter for the evaluation of the extant environmental conditions. Here, we used environmental DNA (eDNA) metabarcoding to investigate fish biodiversity in five different estuaries in Japan. Water samples for eDNA were collected from river mouths and adjacent coastal areas of two estuaries with high degrees of development (the Tama and Miya Rivers) and three estuaries with relatively low degrees of development (the Aka, Takatsu, and Sendai Rivers). A total of 182 fish species across 67 families were detected. Among them, 11 species occurred in all the rivers studied. Rare fishes including endangered species were successfully detected in rich natural rivers. Biodiversity was the highest in the Sendai River and lowest in the Tama River, reflecting the degree of human development along each river. Even though nutrient concentration was low in both the Aka and Sendai Rivers, the latter exhibited greater diversity, including many tropical or subtropical species, owing to its more southern location. Species composition detected by eDNA varied among rivers, reflecting the distribution and migration of fishes. Our results are in accordance with the ecology of each fish species and environmental conditions of each river, suggesting the potential of eDNA for non-invasive assessment of aquatic biodiversity.

ecology↗

bioRxiv2020

Mutations, Recombination and Insertion in the Evolution of 2019-nCoV

BackgroundThe 2019 novel coronavirus (2019-nCoV or SARS-CoV-2) has spread more rapidly than any other betacoronavirus including SARS-CoV and MERS-CoV. However, the mechanisms responsible for infection and molecular evolution of this virus remained unclear. MethodsWe collected and analyzed 120 genomic sequences of 2019-nCoV including 11 novel genomes from patients in China. Through comprehensive analysis of the available genome sequences of 2019-nCoV strains, we have tracked multiple inheritable SNPs and determined the evolution of 2019-nCoV relative to other coronaviruses. ResultsSystematic analysis of 120 genomic sequences of 2019-nCoV revealed co-circulation of two genetic subgroups with distinct SNPs markers, which can be used to trace the 2019-nCoV spreading pathways to different regions and countries. Although 2019-nCoV, human and bat SARS-CoV share high homologous in overall genome structures, they evolved into two distinct groups with different receptor entry specificities through potential recombination in the receptor binding regions. In addition, 2019-nCoV has a unique four amino acid insertion between S1 and S2 domains of the spike protein, which created a potential furin or TMPRSS2 cleavage site. ConclusionsOur studies provided comprehensive insights into the evolution and spread of the 2019-nCoV. Our results provided evidence suggesting that 2019-nCoV may increase its infectivity through the receptor binding domain recombination and a cleavage site insertion. One Sentence SummaryNovel 2019-nCoV sequences revealed the evolution and specificity of betacoronavirus with possible mechanisms of enhanced infectivity.

microbiology↗

bioRxiv2020

The Pathogenicity of 2019 Novel Coronavirus in hACE2 Transgenic Mice

Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) caused the Corona Virus Disease 2019 (COVID-19) cases in China has become a public health emergency of international concern (PHEIC). Based on angiotensin converting enzyme 2 (ACE2) as cell entry receptor of SARS-CoV, we used the hACE2 transgenic mice infected with SARS-CoV-2 to study the pathogenicity of the virus. Weight loss and virus replication in lung were observed in hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia with infiltration of significant lymphocytes and monocytes in alveolar interstitium, and accumulation of macrophages in alveolar cavities. Viral antigens were observed in the bronchial epithelial cells, alveolar macrophages and alveolar epithelia. The phenomenon was not found in wild type mice with SARS-CoV-2 infection. The pathogenicity of SARS-CoV-2 in hACE2 mice was clarified and the Kochs postulates were fulfilled as well, and the mouse model may facilitate the development of therapeutics and vaccines against SARS-CoV-2.

microbiology↗

bioRxiv2019

Structural basis of transcription inhibition by the DNA mimic protein Ocr of bacteriophage T7

Bacteriophage T7 infects Escherichia coli and evades the host defence system. The Ocr protein of T7 was shown to exist as a dimer mimicking DNA and to bind to host restriction enzymes, thus preventing the degradation of the viral genome by the host. Here we report that Ocr can also inhibit host transcription by directly binding to bacterial RNA polymerase (RNAP) and competing with the recruitment of RNAP by sigma factors. Using cryo electron microscopy, we determined the structures of Ocr bound to RNAP. The structures show that an Ocr dimer binds to RNAP in the cleft, where key regions of sigma bind and where DNA resides during transcription synthesis, thus providing a structural basis for the transcription inhibition. Our results reveal the versatility of Ocr in interfering with host systems and suggest possible strategies that could be exploited in adopting DNA mimicry as a basis for forming novel antibiotics.\n\nImpact statementDNA mimicry Ocr protein, a well-studied T7 phage protein that inhibits host restriction enzymes, can also inhibit host transcription through competing with sigma factors in binding to RNA polymerase.

biophysics↗

bioRxiv2019

Kaposi sarcoma-associated herpesvirus infection in HIV patients: potential role of HIV-associated extracellular vesicles

Kaposi sarcoma-associated herpesvirus (KSHV) is the causal agent for Kaposi sarcoma (KS), the most common malignancy in people living with HIV/AIDS. The oral cavity is a major route for KSHV infection and transmission. However, how KSHV breaches the oral epithelial barrier for spreading to the body is not clear. Here we show that extracellular vesicles (EVs) purified from saliva of HIV-positive individuals and secreted by HIV-1-infected T cells promote KSHV infectivity in both monolayer and 3-dimensional models of immortalized and primary human oral epithelial cells, establishing the latency of the virus. The HIV trans-activation response (TAR) element RNA in HIV-associated EVs contributes to the infectivity of KSHV through the epidermal growth factor receptor (EGFR). Cetuximab, a monoclonal neutralizing antibody to EGFR, blocks HIV-associated EV-enhanced KSHV infection. Our findings reveal that saliva containing HIV-associated EVs is a risk factor for enhancement of KSHV infection and that inhibition of EGFR serves as a novel strategy for controlling KSHV infection and transmission in the oral cavity.\n\nAuthor summaryKaposi sarcoma-associated herpesvirus (KSHV) is a causal agent for Kaposi sarcoma (KS), the most common malignancy in HIV/AIDS patients. Oral transmission through saliva is considered the most common route for spreading of the virus among HIV/AIDS patients. However, the role of HIV-specific components in co-transfection of KSHV is unclear. We demonstrate that extracellular vesicles (EV) purified from saliva of HIV patients and secreted by HIV-infected T cells promote KSHV infectivity in immortalized and primary oral epithelial cells. HIV-associated EVs promote KSHV infection depends on the HIV trans-activation element (TAR) RNA and EGFR of oral epithelial cells, both can be targeted for reducing KSHV infection. These results reveal that HIV-EVs is a risk factor for KSHV co-infection in the HIV-infected population.

microbiology↗

bioRxiv2019

Detection of EGFR deletion using unique RepSeq technology

We are reporting a novel sequencing technology, RepSeq (Repetitive Sequence), that has high sensitivity, specificity and quick turn-around time. This new sequencing technology is developed by modifying traditional Sanger sequencing technology in several aspects. The first, a homopolymer tail is added to the PCR primer(s), which makes interpreting electropherograms a lot easier than that in traditional Sanger sequencing. The second, an indicator nucleotide is added at the 5end of the homopolymer tail. In the presence of a deletion, the position of the indicator nucleotide in relation to the wild type confirms the deletion. At the same time, the indicator of the wild type serves as the internal control. Furthermore, the specific design of the PCR and/or sequencing primers will specifically enrich/select mutant alleles, which increases sensitivity and specificity significantly. Based on serial dilution studies, the analytical lower limit of detection was 1.47 copies. A total of 89 samples were tested for EGFR exon 19 deletion, of which 21 were normal blood samples and 68 were samples previously tested by either pyrosequencing or TruSeq Next Generation Sequencing Cancer Panel. There was 100 % concordance among all the samples tested. RepSeq technology has overcome the shortcomings of Sanger sequencing and offers an easy-to-use novel sequencing method for personalized precision medicine.

genomics↗

bioRxiv2018

The role of BMP6 in the proliferation and differentiation of chicken cartilage cells

Previous studies have indicated that bone morphogenetic protein (BMP) 6 plays an important role in skeletal system development and progression. However, the mechanism underlying the effects of BMP6 in cartilage cell proliferation and differentiation remains unknown. In this study, cartilage cells were isolated from shanks of chicken embryos and treated with different concentrations of GH. Cell proliferation and differentiation potential was assessed using real-time polymerase chain reaction (RT-PCR) and CCK-8 assays in vitro. The results showed that at 48 h, the Collagen II and BMP6 expression levels in 50 ng/l GH-treated cartilage cells were significantly higher than in groups treated with 100 ng/l or 200 ng/l GH. We further observed that knockdown of BMP6 in cartilage cells led to significantly decreased expression levels of Collagen II and Collagen X. Moreover, the suppression of BMP6 expression by a specific siRNA vector led to significantly decreased expression levels of IGF1R, JAK, PKC, PTH, IHH and PTHrP. Taken together, our data suggest that BMP6 may play a critical role in chicken cartilage cell proliferation and differentiation through the regulation of IGF1, JAK2, PKC, PTH, and Ihh-PTHrP signaling pathways.

cell biology↗

bioRxiv2017

An open resource for nonhuman primate imaging

Non-human primate neuroimaging is a rapidly growing area of research that promises to transform and scale translational and cross-species comparative neuroscience.\n\nUnfortunately, the technological and methodological advances of the past two decades have outpaced the accrual of data, which is particularly challenging given the relatively few centers that have the necessary facilities and capabilities. The PRIMate Data Exchange (PRIME-DE) addresses this challenge by aggregating independently acquired non-human primate magnetic resonance imaging (MRI) datasets and openly sharing them via the International Neuroimaging Data-sharing Initiative (INDI). Here, we present the rationale, design and procedures for the PRIME-DE consortium, as well as the initial release, consisting of 13 independent data collections aggregated across 11 sites (total = 98 macaque monkeys). We also outline the unique pitfalls and challenges that should be considered in the analysis of the non-human primate MRI datasets, including providing automated quality assessment of the contributed datasets.

neuroscience↗

bioRxiv2017

Brain Modularity Mediates the Relation of Cognitive Performance to Task Complexity

Recent work in cognitive neuroscience has focused on analyzing the brain as a network, rather than as a collection of independent regions. Prior studies taking this approach have found that individual differences in the degree of modularity of the brain network relate to performance on cognitive tasks. However, inconsistent results concerning the direction of this relationship have been obtained, with some tasks showing better performance as modularity increases and other tasks showing worse performance. A recent theoretical model (Chen & Deem, 2015) suggests that these inconsistencies may be explained on the grounds that high-modularity networks favor performance on simple tasks whereas low-modularity networks favor performance on more complex tasks. The current study tests these predictions by relating modularity from resting-state fMRI to performance on a set of simple and complex behavioral tasks. Complex and simple tasks were defined on the basis of whether they did or did not draw on executive attention. Consistent with predictions, we found a negative correlation between individuals modularity and their performance on a composite measure combining scores from the complex tasks but a positive correlation with performance on a composite measure combining scores from the simple tasks. These results and theory presented here provide a framework for linking measures of whole brain organization from network neuroscience to cognitive processing.

neuroscience↗

bioRxiv2017

Static and dynamic measures of human brain connectivity predict complementary aspects of human cognitive performance

In cognitive network neuroscience, the connectivity and community structure of the brain network is related to cognition. Much of this research has focused on two measures of connectivity - modularity and flexibility - which frequently have been examined in isolation. By using resting state fMRI data from 52 young adults, we investigate the relationship between modularity, flexibility and performance on cognitive tasks. We show that flexibility and modularity are highly negatively correlated. However, we also demonstrate that flexibility and modularity make unique contributions to explain task performance, with modularity predicting performance for simple tasks and flexibility predicting performance on complex tasks that require cognitive control and executive functioning. The theory and results presented here allow for stronger links between measures of brain network connectivity and cognitive processes.

neuroscience↗

bioRxiv2017

Modularity of the metabolic gene network as a prognostic biomarker for hepatocellular carcinoma

Abnormal metabolism is an emerging hallmark of cancer. Cancer cells utilize both aerobic glycolysis and oxidative phosphorylation (OXPHOS) for energy production and biomass synthesis. Understanding the metabolic reprogramming in cancer can help design therapies to target metabolism and thereby to improve prognosis. We have previously argued that more malignant tumors are usually characterized by a more modular expression pattern of cancer-associated genes. In this work, we analyzed the expression patterns of metabolism genes in terms of modularity for 371 hepatocellular carcinoma (HCC) samples from the Cancer Genome Atlas (TCGA). We found that higher modularity significantly correlated with glycolytic phenotype, later tumor stages, higher metastatic potential, and cancer recurrence, all of which contributed to poorer prognosis. Among patients with recurred tumor, we found the correlation of higher modularity with worse prognosis during early to mid-progression. Furthermore, we developed metrics to calculate individual modularity, which was shown to be predictive of cancer recurrence and patients survival and therefore may serve as a prognostic biomarker. Our overall conclusion is that more aggressive HCC tumors, as judged by decreased host survival probability, had more modular expression patterns of metabolic genes. These results may be used to identify cancer driver genes and for drug design.

cancer biology↗