Biology subjects

Yuan, S.

Publications and source records attributed to Yuan, S..

136 records · Page 8Linked to original sources

bioRxiv2020

A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals

The emergence of novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19). To date, more than 2.1 million confirmed cases and 139,500 deaths have been reported worldwide, and there are currently no medical countermeasures available to prevent or treat the disease. As the development of a vaccine could require at least 12-18 months, and the typical timeline from hit finding to drug registration of an antiviral is >10 years, repositioning of known drugs can significantly accelerate the development and deployment of therapies for COVID-19. To identify therapeutics that can be repurposed as SARS-CoV-2 antivirals, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules. Here, we report the identification of 30 known drugs that inhibit viral replication. Of these, six were characterized for cellular dose-activity relationships, and showed effective concentrations likely to be commensurate with therapeutic doses in patients. These include the PIKfyve kinase inhibitor Apilimod, cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334, and the CCR1 antagonist MLN-3897. Since many of these molecules have advanced into the clinic, the known pharmacological and human safety profiles of these compounds will accelerate their preclinical and clinical evaluation for COVID-19 treatment.

microbiology↗

bioRxiv2020

Mitofusin2 cooperates with Nuage-associated proteins and involves mRNA translational machinery in controlling mRNA fates during spermatogenesis

Mitochondria play a critical role in spermatogenesis and regulated by several mitochondrial fusion proteins. Its interaction with other organelles forms several unique structures, including mitochondria-associated ER membrane (MAM) and a specific type of Nuage close to mitochondria. However, the importance of mitochondria functions and mitochondrial fusion proteins in its associated-structure formation and mRNA translation during spermatogenesis remain unclear. Here, we show that Mitofusin 2 (MFN2), a mitochondrial fusion GTPase protein, cooperates with Nuage-associated proteins, including MIWI, DDX4, TDRKH and GASZ and involves translational machinery to control the fates of gamete-specific mRNAs in spermatogenesis. Conditional mutation of Mfn2 in postnatal germ cells results in male sterility due to germ cell developmental defects characterized by disruption of mitochondrial morphology, abnormal MAMs structure, aberrant mRNA translational processes, and anomalous splicing events. Moreover, MFN2 interacts with MFN1, another mitochondrial fusion protein with high-sequence similar to MFN2, in testes to facilitate spermatogenesis. Mutation of Mfn1 and Mfn2 simultaneously in testes causes very severe infertile phenotypes. Importantly, we further show that MFN2 is enriched in polysome fractions in testes and interacts with MSY2, a germ cell-specific DNA/RNA-binding protein, and eukaryotic elongation factor 1 alpha (eEF1A) to control gamete-specific mRNA translational delay during spermatogenesis. Collectively, our findings demonstrate that MFN2 works with Nuage-associated proteins and involves translational secession to regulate gamete-specific mRNA fates. Our data reveal a novel molecular link among Mitofusins, Nuage-associated proteins, and mRNA translational processes in controlling male germ cell development.

developmental biology↗

bioRxiv2020

Inhibitory effect of the TSG-6 on the BMP-4/Smad signaling pathway and odonto/osteogenic differentiation of dental pulp stem cells

This study aimed to observe the molecular mechanism underlying the effect of tumor necrosis factor-inducible protein 6 (TSG-6) on the bone morphogenetic protein-4 (BMP-4)/drosophila mothers against decapentaplegic protein(Smad) signaling pathway and mineralization of dental pulp stem cells (DPSCs) in inflammatory environment. Normal and TSG-6 gene-modified DPSCs were cultured in a mineralization-inducing fluid containing 0 and 50 ng/mL TNF- separately. The real-time polymerase chain reaction was used to measure the expression of TSG-6 and odonto/osteogenic differentiation makers at the mRNA level. Western blot analysis and cellular immunofluorescence were used to observe the odonto/osteogenic differentiation of DPSCs and the variation of BMP-4/Smad signaling pathway at the protein level. Moreover, normal and modified DPSCs combined with hydrogel were used for subcutaneous implantation in nude mice. The expression of odonto/osteogenic markers and BMP-4/Smad-related proteins was lower in Ad-TSG-6 DPSCs than in normal DPSCs after mineralization induction, and was higher in TSG-6-RNAi DPSCs than in normal DPSCs after culturing with mineralization-inducing fluid containing 50 ng/mL TNF-. The subcutaneous transplantation of normal and modified DPSCs combined with hydrogel in nude mice demonstrated that normal DPSCs were formed in the tissue containing collagen. The tissue formed by Ad-TSG-6 DPSCs was highly variable, and the cells were very dense. The expression of odonto/osteogenic markers of Ad-TSG-6 DPSCs were lower in Ad-TSG-6 DPSCs than in normal DPSCs. We can know that TNF- regulates the expression of TSG-6, thereby inhibiting the BMP-4/Smad signaling pathway and the odonto/osteogenic differentiation ability of DPSCs.

cell biology↗

bioRxiv2020

Single cell RNA-seq analysis reveals compartment-specific heterogeneity and plasticity of microglia

Microglia are heterogeneous and ubiquitous CNS-resident macrophages that maintain homeostasis of neural tissues and protect them from pathogen attacks. Yet, their differentiation in different compartments remains elusive. We performed single cell RNA-seq (scRNA-seq) analysis to compare the transcriptomes of microglia in adult mouse (C57/Bl) brains and spinal cords to identify microglial subtypes in these CNS compartments. Cortical microglia from 2-month mice consisted of a predominant population of the homeostatic subtype (HOM-M) and a small population (4%) of the inflammatory subtype (IFLAM-M), while spinal microglia consisted of 55% HOM-M and 45% IFLAM-M subtype. Comparison of cortical and spinal microglia at 2, 4 and 8 months revealed consistently a higher composition of the IFLAM-M subtype in the spinal cord. At 8-month, cortical microglia differentiated a small new subtype with interferon response phenotypes (INF-M), while spinal microglia polarized toward a proinflammatory phenotype, as indicated by the increase of microglia expressing IL-1{beta}. To further characterize the differential plasticity of cortical and spinal microglial heterogeneity, we determined the microglial transcriptomes from HIV-1 gp 120 transgenic (Tg) mice, a model of HIV-associated neurological disorders. Compared with wild-type (Wt) cortical microglia, the gp120Tg cortical microglia had three new subtypes, with signatures of interferon I response (INF-M), cell proliferation (PLF-M), and myelination or demyelination (MYE-M) respectively; while INF-M and PLF-M subtypes presented at all ages, the MYE-M only at 4-month. In contrast, only the INF-M subtype was observed in the spinal microglia from 2- and 4-month gp120tg mice. Bioinformatic analysis of regulated molecular pathways of individual microglial subtypes indicated that gp120 more severely impaired the biological function of microglia in cortices than in the spinal cord. The results collectively reveal differential heterogeneity and plasticity of cortical and spinal microglia, and suggest functional differentiation of microglia in different CNS compartments.

neuroscience↗

bioRxiv2020

Ecological stoichiometric characteristics of Carbon (C), Nitrogen (N) and Phosphorus (P) in leaf, root, stem, and soil in four wetland plants communities in Shengjin Lake, China,

Ecological stoichiometric should be incorporated into management and nutrient impacted ecosystems dynamic to understand the status of ecosystems and ecological interaction. The present study focused on ecological stoichiometric characteristics of different macrophyte plants soil, leave, stem and root after the removal of seine fishing since 2000 from Shengjin Lake. For C, N and P analysis from leaves, stems, roots and soil to explore their stoichiometric ratio and deriving environmental forces here four dominant plant communities (Zizania caduciflora, Vallisineria natans, Trapa quadrispinosa and Carex schmidtii) were collected. C, N, P and C: N: P ratio in leafs, stems, roots and soil among the plant communities vary and the studied plant communities had significant effect on the measured variables. There was high C: N in C.schmidtii soil (7.08{+/-}1.504) but not vary significantly (P >0.05), and N: P ratio measured high in V. natans (13.7{+/-}4.05) and C: P in T.quadrispinosa soil (81.14{+/-}43.88) and showed significant variation (P<0.05) respectively. High leaf C: N and N: P ratio was measured in C. schmidtii and V. natans respectively. Nevertheless, high leaf C: P ratio was measured in Z.caduciflora. From the three studied organs leafs C: N, N: P ratio showed high values compared to root and stems. The correlation analysis result showed that, at 0-10cm depth ranges SOC correlated negatively with stem total phosphorus (STP), and RTN (P<0.05) but positively strongly with LTP and LTN (P<0.01) respectively. Soil total nitrogen at 0-10cm strongly positively correlated with LTP (P<0.01) and positively with RN: P and LTC (P<0.05). Soil basic properties such as SMC.BD and pH positively correlated with soil ecological stoichiometric characteristics. Redundancy analysis (RDA) result showed pH and available phosphorus were the potential determinant of soil stoichiometry.

ecology↗

bioRxiv2020

Study of the Influence of Preprint in bioRχiv for Peer Review and Acceptance Time of PLOS ONE

This study examines the relation between acceptance times in preprint publishing and journal publishing. Specifically, we investigated the association between a papers posting time to bioR{chi}iv, a preprints server, and journal articles peer-review and acceptance time for PLOS ONE. So far, of the total papers published in 1,626 academic journals, the average publication rate of those posted in bioR{chi}iv is 40.67%. Meanwhile, PLOS ONE was the journal that published more papers. Analysis of peer-review and acceptance time of papers published in journals via preprints showed the time these papers are posted in relation to these intervals. The median of the peer-review and acceptance time of the journal submission date that was later than the date of first posting to bioR{chi}iv was 110.00 days, and in the reverse case, it was 139.50 days. Posting to the preprint server before journal submission shows a better order than vice versa. This study provides us a good understanding of the peer-review process. It also gives us good insights into optimizing this process, which would then facilitate paper publication and knowledge dissemination.

scientific communication and education↗

bioRxiv2019

The histone modification reader ZCWPW1 links histone methylation to repair of PRDM9-induced meiotic double stand breaks

The histone modification writer PRDM9 has been shown to deposit H3K4me3 and H3K36me3 at future double-strand break (DSB) sites during the very early stages of meiosis, but the reader of these marks remains unclear. Here, we demonstrate that ZCWPW1 is an H3K4me3 reader that is required for DSB repair and synapsis in mouse testes. We generated H3K4me3 reader-dead ZCWPW1 mutant mice and found that their spermatocytes were arrested at the pachytene-like stage, which phenocopies the Zcwpw1 knock-out mice. Based on various ChIP-seq and immunofluorescence analyses using several mutants, we found that ZCWPW1s occupancy on chromatin is strongly promoted by the histone-modification activity of PRDM9. ZCWPW1 localizes to DMC1-labelled hotspots in a largely PRDM9-dependent manner, where it facilitates completion of synapsis by mediating the DSB repair process. In sum, our study demonstrates the function of ZCWPW1 that acts as part of the selection system for epigenetics-based recombination hotspots in mammals.

developmental biology↗

bioRxiv2019

Applying Machine Learning to Investigate Long Term Insect-Plant Interactions Preserved on Digitized Herbarium Specimens

Premise of the studyDespite the economic importance of insect damage to plants, long-term data documenting changes in insect damage ( herbivory) and diversity are limited. Millions of pressed plant specimens are now available online for collecting big data on plant-insect interactions during the Anthropocene.\n\nMethodsWe initiated development of machine learning methods to automate extraction of herbivory data from herbarium specimens. We trained an insect damage detector and a damage type classifier on two distantly related plant species. We experimented with 1) classifying six types of herbivory and two control categories of undamaged leaf, and 2) detecting two of these damage categories for which several hundred annotations were available.\n\nResultsClassification models identified the correct type of herbivory 81.5% of the time. The damage classifier was accurate for categories with at least one hundred test samples. We show anecdotally that the detector works well when asked to detect two types of damage.\n\nDiscussionThe classifier and detector together are a promising first step for the automation of herbivory data collection. We describe ongoing efforts to increase the accuracy of these models to allow other researchers to extract similar data and apply them to address a variety of biological hypotheses.

ecology↗

bioRxiv2018

A novel qacA allele results in an elevated chlorhexidine gluconate minimum inhibitory concentration in cutaneous Staphylococcus epidermidis isolates

Chlorhexidine gluconate (CHG) is a topical antiseptic widely used in healthcare settings. In Staphylococcus spp., the pump QacA effluxes CHG, while the closely related QacB cannot due to a single amino acid substitution. We characterized 1,050 cutaneous Staphylococcus isolates obtained from 173 pediatric oncology patients enrolled in a multicenter CHG bathing trial. CHG susceptibility testing revealed 63 (6%) of these isolates had elevated CHG MICs ([≥] 4 g/mL). Screening of all 1,050 isolates for qacA/B by restriction fragment length polymorphism (RFLP) yielded 56 isolates with a novel qacA/B RFLP pattern, qacAB273. The CHG MIC was significantly higher for qacAB273-positive isolates (MIC50: 4 g/mL, [range: 0.5 - 4 g/mL]) compared to other qac groups: qacA-positive (n=559, 1 g/mL, [0.5 - 4 g/mL]), qacB-positive (n=17, 1 g/mL, [0.25 - 2 g/mL]), and qacA/B-negative (n=418, 1 g/mL, [0.125 - 2 g/mL], p=0.001). The qacAB273-positive isolates also displayed a high proportion of methicillin resistance (96.4%) compared to other qac groups (24.9 - 61.7%, p=0.001). Whole genome sequencing revealed that qacAB273-positive isolates encoded a variant of QacA with 2 amino acid substitutions. This new allele, named qacA4, was carried on the novel plasmid pAQZ1. The qacA4-carrying isolates belonged to the highly resistant S. epidermidis clone ST2 and were collected from multiple centers across the United States and Canada. Curing an isolate of qacA4 resulted in a four-fold decrease in the CHG MIC, confirming the role of qacA4 in the elevated CHG MIC. Our results highlight the importance of further studying qacA4 and its functional role in clinical staphylococci.\n\nImportanceStaphylococcus epidermidis is an important cause of infections in patients with implanted devices. Bathing with chlorhexidine gluconate (CHG), a topical antiseptic, has been shown to reduce rates of device-associated infections, especially those caused by S. epidermidis. In S. epidermidis, reduced susceptibility to CHG is associated with carriage of the qacA gene. As part of a multicenter CHG bathing trial, we obtained cutaneous Staphylococcus isolates from pediatric oncology patients across the United States and Canada. We identified a group of isolates capable of surviving in higher concentrations of CHG and determined a novel allele of qacA, termed qacA4 and carried on the novel plasmid pAQZ1, was responsible for the isolates survival in higher CHG concentrations. The qacA4-carrying S. epidermidis isolates belonged to the highly resistant and virulent ST2 clonal type. Our results highlight the need to understand the global distribution of novel qacA alleles, including qacA4, and their mechanistic effect on efflux.

microbiology↗

bioRxiv2017

Divergent In vitro MIC Characteristics and underlying isogenic mutations in host-specialized Pseudomonas aeruginosa

Clinical isolates of Pseudomonas aeruginosa (Pa) from patients with cystic fibrosis (CF) are known to differ from those associated with infections of non-CF hosts in colony morphology, drug susceptibility patterns, and genomic hypermutability. Although Pa isolates from CF have long been recognized for their overall higher resistance rate calculated generally by reduced \"percent susceptible\", this study takes the approach to compare and contrast Etest MIC distributions between two distinct cohorts of clinical strains (n=224 from 56 CF patients and n=130 from 68 non-CF patients respectively) isolated in 2013. Logarithmic transformed MIC (logMIC) values of 11 antimicrobial agents were compared between the two groups. CF isolates tended to produce heterogeneous and widely dispersed MICs compared to non-CF isolates. By applying a test for equality of variances, we were able to confirm that the MICs generated from CF isolates against 9 out of the 11 agents were significantly more dispersed than those from non-CF (p<0.02-<0.001). Quantile-quantiles plots indicated little agreement between the two cohorts of isolates. Based on whole genome sequencing of 19 representative CF Pa isolates, divergent gain- or loss-of-function mutations in efflux and porin genes and their regulators between isogenic or intra-clonal associates were evident. Not one, not a few, but the net effect all adaptive mutational changes in the genomes of CF Pa, both shared and unshared between isogenic strains, are responsible for the divergent heteroresistance patterns. Moreover, the isogenic variations are suggestive of a bacterial syntrophic lifestyle when \"lockedo inside a host focal airway environment over prolonged periods.\n\nSignificance statementBacterial heteroresistance is associated with niche specialized organisms interacting with host species for prolonged period of time, medically characterized by \"chronic focal infections\". A prime example is found in Pseudomonas aeruginosa isogenic/non-homogeneous isolates from patient airways with cystic fibrosis. The development of pseudomonal polarizing MICs in vitro to many actively used antimicrobial agents among isogenic isolates and \"Eagle-type\" heteroresistance patterns are common and characteristic. Widespread isogenic gene lesions were evident for defects in drug transporters, DNA mismatch repair, and many other structural or cellular functions--a result of pseudomonal symbiotic response to host selection. Co-isolation of extremely susceptible and resistant isogenic Pa strains suggests intra-airway evolution of a multicellular syntrophic bacterial lifestyle, which has laboratory interpretation and clinical treatment implications.

microbiology↗